JP2017506244A - Treatment method using nolvogine and related compounds - Google Patents

Abstract

The present invention relates to norivogaine, norivogaine derivatives, or pharmaceutically acceptable salts and / or solvents thereof at dosages that provide therapeutic serum concentrations for the treatment of the diseases or disorders described herein in a patient. For the use of Japanese products.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is based on US Provisional Application No. 61 / 941,387, filed February 18, 2014, US Provisional Application No. 61 / 945,746, filed February 27, 2014, 2014 US Provisional Application No. 61 / 941,390 filed on May 18, 2014, US Provisional Application No. 62 / 035,335 filed on August 8, 2014, US Provisional Application No. 61/952 filed on March 13, 2014 No. 731, U.S. provisional application 61 / 952,727 filed March 13, 2014, U.S. provisional application 62 / 005,851 filed May 30, 2014, filed March 13, 2014 US provisional application 61 / 952,733, US provisional application 62 / 005,847 filed May 30, 2014, US provisional application 61 / 952,738, filed March 13, 2014, 2014 May 30, U.S. Provisional Application No. 62 / 005,855, U.S. Provisional Application No. 61 / 952,741 filed March 13, 2014, U.S. Provisional Application No. 62 / 005,841 filed May 30, 2014 US Provisional Application No. 61 / 952,744 filed on March 13, 2014, US Provisional Application No. 62 / 005,858 filed on May 30, 2014, US Provisional Application filed on June 3, 2014 No. 62 / 007,346, U.S. Provisional Application No. 62 / 024,388, filed June 14, 2014, and U.S. Provisional Application No. 62 / 033,538, filed Aug. 5, 2014, and 2014. U.S. Application No. 14 / 195,822, filed on March 3, U.S. Application No. 14 / 292,632, filed on Mar. 30, 2014, and U.S. Application No. 14/485, filed on Sep. 12, 2014. 514, Rabbi claims priority to PCT Application No. PCT / US14 / 19692, filed Feb. 28, 2014, these are respectively, in its entirety, is incorporated herein by reference.

  The present invention is directed to the use of norivogaine, norivogaine derivatives, or pharmaceutically acceptable salts and / or solvates thereof at dosages that provide therapeutic serum concentrations for the treatment of diseases or disorders in patients. To do.

Norivogaine is sometimes referred to as 12-hydroxyibogine. U.S. Pat. No. 2,813,873 provides an incorrect structural formula for ibogaine, despite being "12-O-demethylribogaine" and claims to be nolibogaine doing. Norevogaine can be represented by the following formula:

  Norivogaine and its pharmaceutically acceptable salts are useful as non-addictive alkaloids (US Pat. No. 6,348,456) and as potent analgesics (US Pat. No. 7,220,737) useful in drug-dependent therapy. No.), has recently attracted a lot of attention. Such treatment generally requires administration of norivogaine at high doses, typically 0.1 mg to 100 mg per kg body weight.

  Noibogaine is a metabolite of ibogaine found in humans, dogs, rats, and monkeys. Although the prior art suggests that high doses of ibogaine are useful as a treatment for addiction, the use of ibogaine is associated with hallucinations and other negative side effects. In the United States, Ibogaine is classified as a Schedule I controlled substance. It has been suggested that in norbogaine, the activity towards reducing addictive substance cravings and drug-dependent treatment in humans is increased and sustained over time compared to ibogaine. US Pat. No. 6,348,456 discloses highly purified norivogaine, and for the treatment of addiction, noriobogaine should be given at a dosage of about 0.01 to about 100 mg / kg body weight per day However, human data showing effective doses for treating drug addiction were not provided. This patent document is incorporated herein by reference in its entirety.

  Therapeutic medication of norivogaine for long-term treatment in humans has not been addressed so far, and has not been addressed in particular with respect to effective dosing protocols and safety concerns. Indeed, prior to the present invention, it was uncertain whether norbogaine could be administered at a dose that is both therapeutic and safe for the patient.

Addiction Nicotine addiction generally relates to smoking, but other forms of nicotine addiction are also common (eg, chewing tobacco). Smoking and other forms of nicotine pose a significant threat to global health. In the United States alone, annual deaths from smoking (including environmental exposure, or “passive smoking”) exceed 440,000. The total annual cost of smoking-related illnesses in the United States is $ 96 billion in health care costs and $ 97 billion in lost productivity. In addition, smoking significantly increases the risk of many diseases, such as coronary artery disease, stroke, lung cancer and other cancers, and chronic obstructive pulmonary disease. In the United States, 46 million people are estimated to be smokers, which is 20.6% of the US population.

  Every year, over 40% of existing smokers try to stop smoking. Various approved therapies (Varenicline, Bupropion, Nicotine Patch / Gum, Nicotine Nasal Spray / Inhaler, Hypnosis, Biofeedback) have long been used clinically to treat nicotine addiction. Current treatments for smoking cessation tend to focus on behavioral treatments such as counseling, hypnosis, and / or pharmaceutical treatments. Smoking cessation is difficult and may require several trials, and the success rate is between 4% and 25%, depending on the technique used. Users often relapse due to stress, weight gain, and withdrawal symptoms. In addition, nicotine replacement therapies (eg, nicotine patch, nicotine gum, nicotine nasal spray, or nicotine inhaler) do not directly treat nicotine addiction, and throughout the treatment period patients will become addictive to nicotine. Still have.

  A remission nicotine addict may exhibit psychological symptoms of nicotine addiction after a long period of time has elapsed after the physical symptoms of nicotine addiction have disappeared. Many former smokers relapse due to incentives such as stress or environmental triggers. For example, if the former smoker continues to drink, the recurrence rate is approximately 50%.

  Given the tremendous harm that smoking and other forms of nicotine cause to the human body, the high costs to the health care system, the addictive nature of nicotine use, and the difficulty of stopping even when receiving conventional treatment, nicotine There remains an urgent need for effective methods for the treatment of addiction. There is still an urgent need for effective methods for relapse prevention of nicotine addiction in remission nicotine addicts.

  Alcohol dependence (sometimes referred to as alcohol abuse, alcohol addiction, or alcoholism) is also a major public health problem throughout the world. As many as 14,000,000 people worldwide have the problem of alcohol abuse, but only a few of them have been treated. Alcohol abuse can cause damage to almost every organ in the body, including the brain. Long-term alcohol abuse is known to cause or contribute to a number of diseases, including cirrhosis, pancreatitis, epilepsy, dementia, heart disease, peptic ulcers, central nervous system and / or peripheral nerves Damage to the system, cancer, polyneuropathy, nutritional disorders, and death.

  When trying to stop alcohol use, alcohol dependent patients generally develop withdrawal symptoms that are prominent and potentially fatal, complicating the treatment of alcohol dependence. Acute withdrawal persists for 1-3 weeks after cessation of alcohol consumption. Acute withdrawal symptoms include anxiety, seizures, tremor delirium, hallucinations, tremors, and heart failure. After acute withdrawal, it can persist with symptoms such as anxiety, depression, sleep disturbances, fatigue, and daily tension, and can be significantly prolonged.

  Treatment towards alcohol dependence generally includes detoxification, followed by individual treatment and / or mass treatment. Detoxification can include treatment with an agent (such as benzodiazepine) that reduces withdrawal symptoms. However, drugs such as benzodiazepines have a number of negative side effects including adverse psychological effects and physical dependence. Benzodiazepines are also known to increase alcohol craving in alcoholics and are therefore not suitable for long-term treatment of alcohol dependence / addiction. Alcohol dependent patients have a high recurrence rate.

  Alcohol intake has been shown to stimulate the release of endogenous opioids in both human and laboratory animal brains. The action of alcohol on the opioid system is thought to be central to drug-induced rewards and alcohol use recurrence, and alcohol sensitivity.

  Due to the severity and duration of withdrawal symptoms, alcohol dependent patients have a high recurrence rate. There is a great need for effective and non-addictive treatments for acute withdrawal symptoms and post-acute withdrawal symptoms, as well as methods for preventing recurrence of alcohol use by detoxified patients.

  Alcohol intake has been shown to stimulate the release of endogenous opioids in both human and laboratory animal brains. The action of alcohol on the opioid system is thought to be central to drug-induced rewards and alcohol use recurrence, and alcohol sensitivity.

  Substance addiction is a serious public health problem throughout the world. In the United States, as many as 23.5 million people have drug or alcohol abuse problems, but only a few of them are being treated.

When trying to stop drug use, drug addiction patients generally have significant withdrawal symptoms, complicating the treatment of drug addiction. Acute withdrawal from drug dependence is characterized by dramatic and traumatic symptoms, which include sweating, intense heartbeat, palpitation, muscle tension, chest suffering, dyspnea, tremor, nausea and vomiting. Diarrhea, major seizures, heart attacks, stroke, hallucinations, and tremor delirium (DT). Withdrawal symptoms can also include severe craving for drugs, fatigue, lack of joy, anxiety, irritability, drowsiness, suicidal ideation, and in some cases agitation or extreme suspicion or delusional disorder. Once the acute withdrawal symptoms subside, the acute post withdrawal syndrome can last for months or years. Acute post-withdrawal syndrome includes physical, emotional, and psychological symptoms such as fatigue, depression, lack of motivation, and increased pain sensitivity. Acute withdrawal symptoms and post-acute withdrawal symptoms are a major reason why drug addict patients use the drug again after treatment, even when the patient has been out of the drug for a significant amount of time.

  Treatments have been developed that attempt to ameliorate acute withdrawal symptoms and post-acute withdrawal symptoms, but such treatments do not work for all types of drugs. Furthermore, treatment of withdrawal may require the use of other addictive substances such as morphine, buprenorphine, or methadone. Due to the severity and duration of withdrawal symptoms, addiction patients have a high relapse rate. There is a great need for effective and non-addictive treatments for acute withdrawal symptoms and post-acute withdrawal symptoms.

  Although the prior art suggests that high doses of ibogaine are useful as a treatment for addiction, the use of ibogaine is associated with hallucinations and other negative side effects. In the United States, Ibogaine is classified as a Schedule I controlled substance.

Pain and migraine Pain is broadly defined as an unpleasant sensory experience associated with actual or potential tissue damage, or is described in terms of such damage. When peripheral nerve endings, called nociceptors, are stimulated and subsequently signaled through sensory neurons in the spinal cord, sensory pain is interpreted. The signal is then transmitted to the brain, at which point the individual recognizes the pain.

  There are a number of pain categories and classifications, which can be grouped into four categories, for example, by source and associated nociceptors. That is, (1) skin pain, (2) somatic pain, (3) visceral pain, and (4) neuropathic pain. Other pain categories include acute pain and chronic pain. Acute pain is defined as pain that is short-term or has an easily identifiable cause. Acute pain refers to current tissue damage or disease and can be “fast” and “sharp” followed by pain. Acute pain concentrates in one area before spreading somewhat. Acute pain is generally better achieved by drugs (eg, morphine).

  Chronic pain can be medically defined as pain that persists for 6 months or longer. This stationary or intermittent pain often loses its purpose over time because it does not help prevent injury to the body. Chronic pain is often more difficult to treat compared to acute pain. Treatment of any chronic pain typically requires professional supervision. In addition, stronger drugs are usually used for a long time in an attempt to control pain. This can lead to drug addiction. For example, opioids are used for some time to control chronic pain in some instances. Drug resistance, drug addiction, and even psychological addiction can occur.

  Tens of millions of people are affected by debilitating chronic pain each year, costing hundreds of millions of dollars in terms of drugs, physical treatment, and loss of production. Numerous treatments have been developed to ameliorate pain in various categories. The success rate of current methods for the treatment of chronic pain is limited and in some cases can lead to drug addiction.

  Migraine (also referred to as “headache”) is a neurological disorder whose symptoms include moderate to severe headache and are sensitive to nausea, vomiting, sensory influx (light, sound, And / or odor), fatigue, irritability, and / or precursors. Migraine can last for a long time, usually lasting 4 to 72 hours. Approximately 15% of the human population is affected by migraine, and up to 2.2% of the population has chronic migraine. Migraine-related costs in the United States (eg, patient management, productivity loss, etc.) are estimated to be up to $ 17 billion per year.

  Migraine is generally managed by avoidance of triggers, control of symptoms, and prevention of pharmacological drug use. Acupuncture, shiatsu, massage, and relaxation may also be used. In more severe cases, and particularly when other treatments are not successful, biofeedback, nerve stimulator, or migraine surgery may be performed. Given the prevalence of migraine and the difficulty of treatment and / or prevention, there remains an urgent need for effective methods for the treatment and prevention of migraine and its symptoms.

Depression, anxiety, psychiatric disorders, and related disorders According to the CDC, it is estimated that approximately 1 in 10 adults in the United States suffer from depression. Severe depression is associated with a high proportion of other diseases, including obesity, heart disease, and stroke.

  Similarly, anxiety related disorders are prevalent in the United States. Anxiety related disorders include obsessive-compulsive disorder, panic disorder, social anxiety disorder, and generalized anxiety disorder.

  Approximately 8% of Americans are affected by PTSD at some point in their lives. More prominently, up to 30% of those who spend time in the war zone, including veterans, develop PTSD. PTSD is increasingly recognized as a major problem for US troops returning from Iraq and Afghanistan, as well as those engaged in previous wars, and PTSD is a potential contributor to the high suicide rate of veterans. It is.

Impulsive control disorders are a class of mental disorders that involve temptation, urge, or lack of resistance to urges (impulsivity), and such urges are potentially damaging to patients and / or others It is harmful. The American Psychiatric Association's DSM-5 (March 2013) includes impulsive control disorders “characterized by problems in emotional and behavioral self-control”. These include borderline personality disorder, behavioral disorder, antisocial personality disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, mood disorder, pathological gambling, arsonism, intermittent explosive disorder, theft Symptoms, sexual compulsive behavior, sexual perversion, Internet addiction, hair loss, pathological skin irritation, and impulse buying. Impulsive control disorders can be associated with anxiety disorders and / or OCD.

  Violence and anger are associated with a number of mental disorders, particularly when unbalanced with the consequences of stimulation and / or morbid anger. These include rebellious challenge disorder, attention deficit / hyperactivity disorder, and behavioral disorder (in children and adolescents), mental disorder, bipolar disorder, antisocial personality disorder, borderline personality disorder, delusional personality disorder , And self-love personality disorders, adaptation disorders with behavioral disorders, and intermittent explosive disorders. Pathological anger and violence account for a significant portion of violent crime, including many prominent crimes involving multiple victims. In the US prison system, individuals who are highly prone to excitement account for a large percentage.

Food intake In the United States, over 2/3 adults are overweight, about half of which are obese. The US weight loss market is estimated to be over $ 60 billion, and lean drugs alone account for about $ 1 billion. However, many of the slimming drugs contain ingredients that are most suspected of effectiveness and highest risk. Obesity greatly increases an individual's risk for various diseases, including coronary heart disease, hypertension, stroke, type 2 diabetes, abnormal levels of blood fat, metabolic syndrome, cancer, Osteoarthritis, sleep apnea, reproductive problems, and gallstones.

Opioid analgesic tolerance Addictive opioid analgesics such as morphine are well known and exceptionally powerful analgesics. Such opioids function as mu receptor agonists. Upon administration, opioids initiate a cascade of biological events including increased expression of serotonin and dopamine. As is well known, the continued use of many such opioids (especially at high doses) poses a significant risk of addiction / addiction. Indeed, pre-existing addiction to such opioids is a significant problem that limits the therapeutic use of addictive opioids as analgesics. For example, the use of morphine as an analgesic is common among end-stage patients who suffer from severe pain where addiction is no longer a concern.

  Drug resistance to opioid analgesics is common and can be psychological and / or physiological. Patients who develop resistance to opioid analgesics are not necessarily addictive or misuse analgesics. Drug resistance occurs when the patient's response to the drug decreases and the dose needs to be increased to produce the same desired effect. There are several potential pathways for how resistance develops, including receptor desensitization, receptor phosphorylation, receptor internalization or downregulation, and inhibition. There is an upward control of the route.

  In drug resistance, it is necessary to increase the dose of the analgesic in order to continuously give the action of the analgesic. However, high doses of opioids can have serious complications and side effects, including physical dependence, addiction, respiratory depression, nausea, sedation, euphoria or discomfort, gastrointestinal motility Reduction, and pruritus.

  Noibogaine is a metabolite of ibogaine found in humans, dogs, rats, and monkeys. Therapeutic dosing of norbogaine for the treatment of drug addiction and other illnesses in humans has not been addressed so far, particularly with regard to effective dosing protocols and safety concerns. Indeed, prior to the present invention, it was uncertain whether norbogaine could be administered at a dose that is both therapeutic and safe for the patient.

Depression Noibogaine is a well-known member of the ibogaine family of alkaloids, sometimes referred to as 12-hydroxyibogaine. U.S. Pat. No. 2,813,873 provides an incorrect structural formula for ibogaine, despite being “12-O-demethylibogaine”, and claims to be nolibogaine. The structure of nolibogaine has now been thoroughly investigated and has been shown to be a combination of the characteristics of tryptamine, tetrahydrohavaine, and indolazepine. Norevogaine can be represented by the following formula:

  Depressive disorders include major depressive disorders and mood modulation disorders (American Psychiatric Association, 1994a, American Psychiatric Association, 1994b). A major depressive disorder is characterized by the occurrence of one or more major depressive episodes without mania or hypomania episodes. Major depressive episodes are defined as being depressed or unpleasant, usually disturbing daily functioning (at least daily for at least 2 weeks) and prominent and relatively persistent. It may include at least 4 of the symptoms. Changes in appetite, sleep changes, psychomotor agitation or slow psychomotor development, loss of interest in daily activities or decreased sexual urges, increased fatigue, guilt or worthlessness, slowed thinking or reduced concentration, and Suicide attempt or suicidal ideation. Dysthymia disorders involve a type of depression that is less severe than what is called a major depressive episode, but is not associated with a high stage and lasts much longer compared to major depressive disorders. ing.

Post-traumatic stress disorder (PTSD) is a risk of actual death or death or serious as defined by DSM-III-R / IV (American Psychiatric Association, 1987, American Psychiatric Association, 1994a). Requires injury, or exposure to traumatic events involving threats to self or others' physical integrity, and responses involving intense fear, helplessness, or warfare. Although PTSD is classified as an anxiety disorder, PTSD is unique compared to other anxiety disorders because exposure to traumatic events is a requirement.

  Symptoms resulting from exposure to traumatic events include events that are in the form of intrusive thoughts, flashbacks, or dreams, and severe psychological distress and relapse of physiological responsiveness when exposed to the trigger of the event And avoiding situations reminiscent of traumatic events, inability to recall details of events, and / or reduced interest in meaningful activities, separation from others, limited emotional range, or manifested as a sense of shortening the future General responsive paralysis and autonomic wakefulness symptoms, including hyperalgesia, exaggerated startle response, sleep disturbance, poor concentration, and irritability or anger. In the diagnosis of PTSD, symptoms are present for at least one month, and these symptoms are in clinically meaningful distress, or social, occupational, or other important areas of function. It is necessary to cause dysfunction.

  Given the prevalence and effects of depression and PTSD, treatment is needed to address these issues. Prior to the description of the embodiments herein, the therapeutic dosing of norivogaine and its derivatives for the treatment of depression and / or PTSD in humans with an acceptable QT interval extension has previously been described. It has not been addressed and has not been addressed in particular with regard to effective dosing protocols and safety concerns.

  While norbogaine has been disclosed for the treatment of substance addiction, the fact that the range in the prior art is exceptionally broad (0.01-1000 mg / kg body weight) is its use in humans. Is complicated. Furthermore, human clinical trials have shown that low dose dosing of norvocain has minimal impact on withdrawal symptoms in addicted patients. Thus, it has now become clear that the widespread previously disclosed is insufficient at the lower end of this range for human treatment.

  In addition, the use of norivogaine prolongs the QT interval of the patient being treated in a dose-dependent manner, thereby making high dose dosing of norivogaine unacceptable. QT interval prolongation is a sign of potential polymorphic ventricular tachycardia, a severe arrhythmia that can lead to death.

  The present invention is directed to treating a patient with opioid addiction in a narrow dose range of about 1 mg / kg body weight to about 4 mg / kg body weight of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof. Based in part on the surprising discovery that it provides reduced treatment of withdrawal symptoms and / or increased time to resume opioid use. Preferably, in opioid addicts and opioid-like drug addicts, the dose range that provides both treatment results and an acceptable QT interval extension of less than about 50 milliseconds is about 1.3 mg per kg body weight to about 4 mg or less, more preferably from about 1.3 mg / kg body weight to about 3 mg / kg body weight, or any subrange or subvalue within the above range. Opioid-like drugs, including cocaine, ketamine, and methamphetamine, are not opioids, but act through opioid receptors and therefore addiction to such drugs can also be treated with nolibogaine.

  In some embodiments, the unit dose that provides both treatment results and an acceptable QT interval extension of less than about 50 milliseconds in opioid and opioid-like drug adders is about 60 mg to about 150 mg. In some embodiments, the unit dose that provides both treatment results and an acceptable QT interval extension of less than about 50 milliseconds in opioid and opioid-like drug adders is about 120 mg. In some embodiments, the unit dose that provides both treatment results and an acceptable QT interval extension of less than about 50 milliseconds in opioid and opioid-like drug adders is about 2 mg / kg body weight.

  In some embodiments, the patient is administered an initial dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof, followed by one or more additional doses. The In one embodiment, the initial dose is about 50 mg to about 120 mg. In one embodiment, the one or more additional doses are less than the initial dose. In one embodiment, the one or more additional doses are from about 5 mg to about 50 mg. In one embodiment, such a dosing regimen provides an average serum concentration of norivogaine that is about 50 ng / mL to about 180 ng / mL. In one embodiment, the one or more additional doses maintain an average serum concentration from about 50 ng / mL to about 180 ng / mL over a period of time. In one embodiment, one or more additional doses are administered periodically.

  In a preferred embodiment, the narrow therapeutic doses of norivogaine, norivogaine derivatives, or pharmaceutically acceptable salts or solvates do not unexpectedly extend the QT interval to unacceptable levels in human addicted patients. . In clinical situations involving cardiac monitoring, a therapeutic dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof will be administered to an opioid or opioid-like drug addiction patient. is expected. In some embodiments, patients will be pre-screened for assessment of resistance towards QT interval prolongation, for example, any existing patient that will be ineligible for treatment with norbogaine. It is determined whether you have any heart disease.

  Some embodiments of the present invention provide for opioids at low doses of norivogaine, norivogaine derivatives, or even pharmaceutically acceptable salts and / or solvates thereof, for example, at therapeutic doses of approximately 80% or less. It is further based on the discovery that it may be useful for preventing recurrence of opioid (or opioid-like drug) use in opioid-addicted patients treated for remission of use. That is, low doses of norivogaine can prevent recurrence of opioid use in patients who are no longer physically addictive to opioids. Without being bound by theory, patients who are no longer physically addictive to opioids or opioid-like drugs require less norbogaine to prevent recurrence, because opioids or opioid-like drugs This is because it does not compete with norivogaine for receptor binding and / or when the patient stops taking the drug, desensitization of one or more receptors in the brain by the opioid or opioid-like drug It is thought that this is to return to. This low maintenance dose of norbogaine results in QT interval prolongation that does not require clinical cardiac monitoring.

  In some embodiments, the maintenance dose of nolibogaine is about 5 mg to about 100 mg. In some embodiments, the maintenance dose of norbogaine is about 1.5 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 1 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.9 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.8 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.7 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.6 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.5 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.4 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.3 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.2 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.1 mg / kg body weight.

  In some embodiments, the therapeutic dose of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof administered to a patient has a serum concentration of about 1000 to about 6000 ng * hr / mL. Enough to give. In some embodiments, the therapeutic dose of norivogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof administered to a patient has a maximum serum concentration (Cmax) of less than about 250 ng / mL. Enough to give. In preferred embodiments, the therapeutic dose provides a Cmax of about 100 ng / mL to about 200 ng / mL.

  In some embodiments, the therapeutic dose of norivogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate administered to the patient is between about 50 ng / mL and about 180 ng / mL, or between It is sufficient to give an average serum concentration of any subrange or subvalue present. In preferred embodiments, the dose of norivogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate administered to the patient provides an average serum concentration of about 80 ng / mL to about 100 ng / ml. .

  In some embodiments, the patient administers a high (therapeutic) dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof for a period of time to ameliorate the most prominent withdrawal symptoms. And then administered a low (maintenance) dose to prevent recurrence of opioid or opioid-like drug use. In some embodiments, the patient is administered a therapeutic dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof for a period of time to ameliorate the most prominent withdrawal symptoms. A decreasing (gradually) amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered over a period of time until a maintenance dose is reached. In some embodiments, a high initial therapeutic dose is administered followed by a low therapeutic dose. In some embodiments, the norbogaine dose is gradually reduced over a period of high to low therapeutic dose

  In some embodiments, a dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof that provides an average serum concentration of about 50 ng / mL to about 180 ng / mL is administered as a single dose. Is done. In some embodiments, a dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof that provides an average serum concentration of about 50 ng / mL to about 180 ng / mL is administered as multiple doses. Is done. In one embodiment, the total dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from about 1 mg / kg to about 3 mg / kg. In another preferred embodiment, the total dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from about 1 mg / kg to about 2.5 mg / kg.

  In some embodiments, the serum concentration is sufficient to suppress or ameliorate the abuse while maintaining a QT interval of less than about 500 milliseconds (ms) during the treatment. In a preferred embodiment, the serum concentration is sufficient to suppress or ameliorate the abuse while maintaining the QT interval below about 450 ms during the treatment.

  In some embodiments, the therapeutic dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof provides a QT interval extension of less than about 80 ms. In one embodiment, the maintenance dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof provides a QT interval extension of less than about 50 ms. In some embodiments, a maintenance or therapeutic dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof provides a QT interval extension of less than about 30 ms. In a preferred embodiment, the maintenance dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof provides a QT interval extension of less than about 20 ms. In one embodiment, the QT prolongation is equivalent to or less than that observed in patients receiving methadone treatment. In a preferred embodiment, a patient is tested to determine the QT interval prior to treatment with norivogaine, and if the clinician determines that QT prolongation would be an unacceptable risk, the noriobogaine treatment Will be contraindicated.

  In another embodiment, norivogaine or a pharmaceutically acceptable salt thereof is administered.

Abuse of Opioids or Opioid-Like Drugs In one aspect, this document provides a method of treating abuse in a human patient addicted to opioids or opioid-like drugs, the method comprising: Including administration to a patient of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that the therapeutic dose provides an average serum concentration of about 50 ng / mL to about 180 ng / mL. The concentration is sufficient to suppress or ameliorate the abuse while maintaining the QT interval below about 500 ms during the treatment.

In one embodiment, norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method comprises:
a) administration of an initial dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of about 50 ng / mL to about 180 ng / mL The administration;
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose has a mean serum concentration over a period of time. The administration maintaining a medium concentration from about 50 ng / mL to about 180 ng / mL;
including.

  In another embodiment, the initial dose is about 75 mg to about 120 mg. In another embodiment, the at least one additional dose is from about 5 mg to about 25 mg. In another embodiment, at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and the additional dose is administered from about 6 hours to about 24 hours after the previous dose. In another embodiment, the method further includes selection of addicted patients that are prescreened for assessment of tolerance towards QT interval extension. In another embodiment, the maximum serum concentration is from about 40 ng / mL to about 250 ng / mL. In another embodiment, the serum concentration of nolubogaine is about 1000 ng * hour / mL to about 5800 ng * hour / mL.

  In another aspect, the specification provides a method of treating abuse in a human patient addicted to opioids or opioid-like drugs, the method comprising an average of about 50 ng / mL to about 180 ng / mL Including administration to a patient of a dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof that provides a serum concentration, wherein the concentration is about a 20 ms QT interval extension during the treatment. Sufficient to suppress or ameliorate the abuse while maintaining below.

  In one embodiment, the norbogaine, norivogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses.

In another embodiment, the method comprises:
a) administration of an initial dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of about 50 ng / mL to about 180 ng / mL The administration;
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose has a mean serum concentration over a period of time. The administration maintaining a medium concentration from about 50 ng / mL to about 180 ng / mL;
including.

  In another embodiment, the initial dose is about 75 mg to about 120 mg. In another embodiment, the at least one additional dose is from about 5 mg to about 25 mg. In another embodiment, at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose. In another embodiment, at least two additional doses are administered. In another embodiment, at least two additional doses are administered, and the additional dose is administered from about 6 hours to about 24 hours after the previous dose.

  In another aspect, the specification provides a method of attenuating such symptoms in a human patient that is susceptible to withdrawal symptoms due to an opioid or opioid-like drug addiction, the method comprising about 50 ng / mL to about 50 ng / mL. Administration to a patient of a dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof that gives an average serum concentration of 180 ng / mL, said concentration during the treatment Sufficient to attenuate the symptom while maintaining the interval below about 500 ms.

In one embodiment, the withdrawal symptoms are due to acute withdrawal. In another embodiment, nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method comprises:
a) administration of an initial dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of about 50 ng / mL to about 180 ng / mL The administration;
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose has a mean serum concentration over a period of time. The administration maintaining a medium concentration from about 50 ng / mL to about 180 ng / mL;
including.

  In another embodiment, the initial dose is about 75 mg to about 120 mg. In another embodiment, the at least one additional dose is from about 5 mg to about 25 mg. In another embodiment, at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and the additional dose is administered from about 6 hours to about 24 hours after the previous dose.

  In another aspect, the specification provides a method for preventing recurrence of abuse in a patient previously treated to ameliorate the abuse of an opioid or opioid-like drug, the method comprising a maintenance dose of norivogaine, Including regular administration to the patient of a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, the patient is no longer abused the opioid or opioid-like drug and the dosage is Less than about 70% of the dose, and the QT interval extension is about 30 ms or less.

  In one embodiment, the total dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from about 5 mg to about 100 mg per day.

Nicotine The present invention is based in part on the discovery that direct blood flow delivery of norivogaine at very low doses reduces the desire for smoking. Such dosing is well below that previously described. The direct blood flow delivery of nolubogaine enhances the amount of nolibogaine delivered to the brain. This is because the norbogaine so administered does not first pass through the liver before reaching the brain, unlike when taken orally. Direct blood flow delivery of nolibogaine includes sublingual delivery, pulmonary delivery, and intranasal delivery, which is absorbed directly into the bloodstream and then enters the brain. The rapid delivery of norivogaine to the brain quickly causes a marked decrease in craving for smoking, which is typically less than 5 minutes after administration.

  Nolibogain is thought to bind to several receptors in the brain, including nicotinic acetylcholine receptor (nAChR) and opioid receptors (eg, μ-opioid receptors). Without being bound by theory, it is believed that nAChR has a higher binding affinity towards nolubogaine compared to other receptors in the brain. This makes it possible to treat nicotine addiction and / or nicotine craving using a much lower dose of norivogaine than is currently used for the treatment of other diseases such as opioid withdrawal. Furthermore, remission nicotine addicts may not show physical symptoms of addiction, but rather may have psychological cravings towards tobacco or other forms of nicotine, or in certain situations such Expect cravings. Thus, while not being bound by theory, the amount of norbogaine required for the treatment or prevention of nicotine craving in such situations is less than would be required in patients who are currently addictive to nicotine. Expected to be less.

  In one aspect, the invention relates to a method of treating nicotine addiction or a method of preventing recurrence of nicotine use, the method comprising administering a therapeutic amount of norivogaine. As used herein, unless otherwise indicated, nolibogaine includes nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt thereof.

  In one aspect, the invention relates to the treatment of nicotine addiction in a patient in need, the treatment comprising administering to the patient a therapeutically effective amount of norivogaine by direct blood flow delivery. In one aspect, the therapeutically effective amount of norivogaine or derivative is less than about 50 ng to 10 μg / kg body weight. In some embodiments, the therapeutically effective amount of nolibogaine or noribogaine derivative is administered once a day, twice a day, or three or more times a day.

  In another aspect, the present invention provides a method of treating nicotine addiction in a patient in need thereof, wherein the method comprises a therapeutically effective amount of norivogaine, or a norivogaine derivative, or a pharmaceutically acceptable salt thereof. The norbogaine, or derivative, or pharmaceutically acceptable salt thereof, is administered by sublingual delivery, intranasal delivery, or pulmonary delivery.

  In one aspect, the present invention relates to a method for preventing recurrence of nicotine use, the method comprising administering a prophylactic amount of norivogaine for the suppression of behavioral craving for nicotine. As used herein, unless otherwise indicated, nolibogaine includes nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt thereof.

  In one aspect, the invention relates to preventing recurrence of nicotine use in a patient in need, wherein the prevention comprises administering to the patient a prophylactically effective amount of norivogaine by direct blood flow delivery. In one aspect, the prophylactically effective amount of norivogaine is less than about 50 ng to 10 μg / kg body weight. In some embodiments, the prophylactically effective amount of norivogaine or norivogaine derivative is administered once a day, twice a day, or three or more times a day. In some embodiments, a prophylactically effective amount is administered when a patient expects to feel a craving for nicotine or a craving for nicotine.

  In another aspect, the present invention provides a method for preventing the recurrence of nicotine use in a patient in need thereof, wherein the method comprises a prophylactically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof. The norbogaine, derivative, or salt thereof is administered by sublingual delivery, intranasal delivery, or intrapulmonary delivery.

  In one aspect, the present specification provides a method of treating nicotine addiction in a patient in need thereof, wherein the method comprises a therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof. The therapeutically effective amount, including administration to a patient, is less than about 50 ng to 10 μg / kg body weight per day.

  In one embodiment, the therapeutically effective amount is about 50 ng to about 1 μg / kg body weight per day. In another embodiment, norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt thereof is administered by sublingual delivery, intranasal delivery, or pulmonary delivery. In another embodiment, the therapeutically effective amount is administered once a day. In another embodiment, the therapeutically effective amount is administered more than once per day.

  In one aspect, the present description provides a method for preventing nicotine craving in a patient in need thereof, wherein the method comprises a prophylactically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof. Including a dose to a patient, the prophylactically effective amount is less than about 50 ng to 10 μg / kg body weight per day.

  In one embodiment, the patient is no longer physically addictive to nicotine. In another embodiment, the therapeutically effective amount is from about 50 ng / kg to about 1 μg / kg body weight per day. In another embodiment, nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt thereof is administered by sublingual delivery, intranasal delivery, or pulmonary delivery. In another embodiment, nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt thereof is administered as needed according to the subject's determination. In another embodiment, nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt thereof is administered before nicotine craving occurs. In another embodiment, nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt thereof is administered after nicotine craving has occurred.

Alcohol dependence Nolibogaine has been disclosed towards alcohol dependence therapy, while the fact that the range in the prior art is exceptionally broad (0.01-1000 mg / kg body weight) in humans The use is complicated. Furthermore, human clinical trials have shown that low dose dosing of norvocain has minimal impact on withdrawal symptoms in addicted patients. Thus, it is now clear that the previously disclosed wide range is insufficient for human therapy at the lower end of this range.

The present invention is directed to patients with alcohol dependence who are treated with norivogaine, norivogaine derivatives, or pharmaceutically acceptable salts and / or solvates thereof in a narrow dosage range of greater than about 1 mg / kg body weight to about 8 mg / kg body weight. Based in part on the surprising discovery that it gives a reduced treatment of withdrawal symptoms. Preferably, in addicts, the dose range that provides both treatment results and an acceptable QT interval extension of less than 50 milliseconds is from about 1.3 mg / kg body weight to about 4 mg / kg body weight or less. Is about 1.3 mg / kg body weight to about 3 mg / kg body weight or any subrange or subvalue within the above range.

  In a preferred embodiment, the narrow therapeutic doses of norivogaine, norivogaine derivatives, or pharmaceutically acceptable salts and / or solvates do not extend the QT interval to unacceptable levels in human patients. In clinical situations involving cardiac monitoring, it is expected that therapeutic doses of norivogaine, norivogaine derivatives, or pharmaceutically acceptable salts and / or solvates thereof will be administered to alcohol dependent patients. In some embodiments, patients will be pre-screened for assessment of resistance towards QT interval prolongation, for example, any existing patient that will be ineligible for treatment with norbogaine. It is determined whether you have any other heart disease or other indication. In one embodiment, patients exhibiting a QT interval extension of less than about 20 ms after treatment with one or more therapeutic doses of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof. Will not require further clinical monitoring.

  Some embodiments of the present invention may reduce alcohol dependence, for example, at low doses of norivogaine, norivogaine derivatives, or pharmaceutically acceptable salts and / or solvates thereof, eg, a therapeutic dose of approximately 80% or less. It is further based on the discovery that it can be effective in preventing the recurrence of alcohol use in addicted patients treated to remission. That is, a low dose of norbogaine can prevent a recurrence of alcohol use in patients who are no longer physically dependent on alcohol. Without being bound by theory, patients who are no longer physically dependent on alcohol need less norbogaine to at least partially prevent recurrence, which means that once a patient is detoxified from alcohol, It is thought that the changes to the brain made by alcohol dependence are at least partially reversed. This low maintenance dose of norbogaine results in QT interval prolongation that does not require clinical cardiac monitoring.

  In some embodiments, the therapeutic dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof administered to a patient averages about 50 ng / mL to about 850 ng / mL. Sufficient to give a serum concentration, or any subrange or subvalue present in between. In preferred embodiments, the dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof administered to a patient has an average serum concentration of about 50 ng / mL to about 400 ng / mL. give.

  In some embodiments, a high (therapeutic) dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof is given to a patient for a period of time to ameliorate the most prominent withdrawal symptoms. Followed by a low (maintenance) dose to prevent recurrence of alcohol use. In some embodiments, in order to ameliorate the most prominent withdrawal symptoms, a therapeutic dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof may be administered to the patient for a period of time. Is administered, and thereafter a decreasing (decreasing) amount of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is administered over a period of time until a maintenance dose is reached. In some embodiments, a high initial therapeutic dose is administered followed by a low therapeutic dose. In some embodiments, the norbogaine dose is gradually reduced over a period of high to low therapeutic dose

  In some embodiments, a dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof that provides an average serum concentration of about 50 ng / mL to about 850 ng / mL is a single dose. As administered. In some embodiments, a dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof that provides an average serum concentration of about 50 ng / mL to about 850 ng / mL is administered in multiple doses. As administered. In some embodiments, the total dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is greater than about 1 mg / kg to about 8 mg / kg. In a preferred embodiment, the total dose of norivogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is greater than about 1 mg / kg to about 4 mg / kg. In another preferred embodiment, the total dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is greater than about 1 mg / kg to 3 mg / kg.

  In some embodiments, the serum concentration of norivogaine is sufficient to suppress or ameliorate the abuse while maintaining the QT interval below 500 milliseconds (ms) during the treatment. In some embodiments, the therapeutic dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof provides a QT interval extension of less than 80 ms. In one embodiment, a maintenance dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof provides a QT interval extension of less than 50 ms. In some embodiments, a maintenance or therapeutic dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof provides a QT interval extension of less than 30 ms. In a preferred embodiment, a maintenance dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof provides a QT interval extension of less than 20 ms. In a preferred embodiment, a patient is tested to determine the QT interval prior to treatment with norivogaine, and if the clinician determines that QT prolongation would be an unacceptable risk, the noriobogaine treatment Will be contraindicated.

  In one aspect, the present specification provides a method for the treatment thereof in a human patient suffering from alcohol dependence, the method comprising a dose of norbogaine that provides an average serum concentration of about 50 ng / mL to about 500 ng / mL, Administration of a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof to a patient, wherein the concentration ameliorates the dependence while maintaining a QT interval of less than about 500 ms during the treatment. Enough to let you.

  In one embodiment, norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the total dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 1.3 mg / kg to about 4 mg / kg per day. In another embodiment, the total dose of norivogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 1.5 mg / kg to about 3 mg / kg per day. In another embodiment, the total dose of norivogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 2 mg / kg to about 4 mg / kg per day. In another embodiment, the total dose of norivogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 2 mg / kg to about 3 mg / kg per day. In another embodiment, the total dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 2 mg / kg per day. In another embodiment, the dosage of norivogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof provides an average serum concentration of about 50 ng / mL to about 200 ng / mL. In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms. In another embodiment, the method further includes selection of addicted patients that are prescreened for assessment of tolerance towards QT interval extension. In another embodiment, the screening step includes confirmation that the norbogaine treatment will not result in a QT interval greater than about 500 ms. In another embodiment, the screening step includes confirmation that the norbogaine treatment will not result in a QT interval greater than about 470 ms. In another embodiment, the screening step includes confirmation that the norbogaine treatment will not result in a QT interval greater than about 450 ms.

  In another aspect, the specification provides a method of attenuating such symptoms in a human patient that is susceptible to withdrawal symptoms due to alcohol dependence, the method comprising an average of about 50 ng / mL to about 400 ng / mL Including administration to a patient of a dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof that provides a serum concentration, wherein the concentration includes a QT interval of about 500 ms during the treatment. Sufficient to attenuate the symptoms while maintaining below.

  In one embodiment, the withdrawal symptoms are due to acute withdrawal. In another embodiment, norivogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the total dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 1.3 mg / kg to about 4 mg / kg per day. In another embodiment, the total dose of norivogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 1.5 mg / kg to about 3 mg / kg per day. In another embodiment, the total dose of norivogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 2 mg / kg to about 4 mg / kg per day. In another embodiment, the total dose of norivogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 2 mg / kg to about 3 mg / kg per day. In another embodiment, the total dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 2 mg / kg per day. In another embodiment, the QT interval is less than about 470 ms. In another embodiment, the QT interval is less than about 450 ms.

  In one aspect, the present specification provides a method for preventing the recurrence of abuse in a patient being treated to ameliorate alcohol abuse, wherein the method comprises a maintenance dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable Including periodic administration to the patient of possible salts and / or solvates thereof, the patient is no longer physically dependent on alcohol.

  In one embodiment, the maintenance dose is less than about 70% of the therapeutic dose and the QT interval extension is about 30 ms or less. In another embodiment, the dosage is less than about 70% of the therapeutic dose, and further, the QT interval extension is about 20 ms or less. In another embodiment, norbogaine, or a pharmaceutically acceptable salt and / or solvate thereof is administered.

While the drug addiction norbogaine has been disclosed for the treatment of substance addiction, the fact that the range in the prior art is exceptionally broad (0.01-1000 mg / kg body weight) Complicating its use in Furthermore, human clinical trials have shown that low dose dosing of norvocain has minimal impact on withdrawal symptoms in addicted patients. Thus, it is now clear that the previously disclosed wide range is insufficient for human therapy at the lower end of this range.

  The present invention relates to the treatment of withdrawal symptoms in addicted patients when treatment with a narrow dose range of 1 mg / kg body weight to 4 mg / kg body weight of norivogaine, norivogaine derivatives, or pharmaceutically acceptable salts and / or solvates thereof. Based in part on the surprising discovery of reducing treatment and / or reducing time to relapse of drug use. Preferably, in addicts, the dose range that provides both treatment results and an acceptable QT interval extension of less than 50 milliseconds is 1.3 mg / kg body weight to 4 mg / kg body weight or less, more preferably 1.3 mg per kg to 3 mg or less per kg body weight, or any subrange or subvalue within the above range.

  In some embodiments, the dose that provides both treatment outcome and an acceptable QT interval extension of less than 50 milliseconds in a drug addict is about 120 mg. In some embodiments, in a drug addict, the dose that provides both treatment results and an acceptable QT interval extension of less than 50 milliseconds is about 2 mg / kg body weight.

  In some embodiments, an initial dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered to a patient, followed by one or more additional doses. . In one embodiment, the initial dose is 75 mg to 120 mg. In one embodiment, the one or more additional doses are less than the initial dose. In one embodiment, the one or more additional doses are from 5 mg to 50 mg. In one embodiment, such a dosing regimen provides a mean serum concentration of norbogaine between 50 ng / mL and 180 ng / mL. In one embodiment, the one or more additional doses maintain an average serum concentration between 50 ng / mL and 180 ng / mL over a period of time. In one embodiment, one or more additional doses are administered periodically.

In some embodiments, the narrow therapeutic doses of norivogaine, norivogaine derivatives, or pharmaceutically acceptable salts and / or solvates described above are unexpectedly unacceptable for QT intervals in human addicted patients. Do not extend to level. In clinical situations involving cardiac monitoring, it is expected that therapeutic doses of norivogaine, norivogaine derivatives, or pharmaceutically acceptable salts and / or solvates thereof will be administered to drug addicted patients. In some embodiments, patients will be pre-screened for assessment of resistance towards QT interval prolongation, for example, any existing patient that will be ineligible for treatment with norbogaine. It is determined whether you have any heart disease.

Some embodiments of the present invention provide for substance abuse, for example, low doses of norivogaine, norivogaine derivatives, or even pharmaceutically acceptable salts and / or solvates thereof, such as a therapeutic dose of approximately 80% or less. It is further based on the discovery that it can be effective in preventing the recurrence of drug use in addicted patients treated to ameliorate. That is, a low dose of norbogaine can prevent recurrence of use of the substance in patients who are no longer physically addictive to the addictive substance. Without being bound by theory, patients who are no longer physically addictive to drugs require less norbogaine to prevent recurrence, which means that drugs are directed toward receptor binding. This is because it does not compete with norivogaine and / or because when a patient stops taking a drug, desensitization of one or more receptors in the brain by the drug is reversed. This low maintenance dose of norbogaine results in QT interval prolongation that does not require clinical cardiac monitoring.

  In some embodiments, the maintenance dose of norbogaine is between 5 mg and 100 mg. In some embodiments, the maintenance dose of norbogaine is about 1.5 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 1 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.9 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.8 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.7 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.6 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.5 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.4 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.3 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.2 mg / kg body weight. In some embodiments, the maintenance dose of norbogaine is about 0.1 mg / kg body weight.

  In some embodiments, the therapeutic dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof administered to a patient is in an average serum of 50 ng / mL to 400 ng / mL. It is sufficient to give the concentration, or any subrange or subvalue present in between. In a preferred embodiment, the dose of norivogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof administered to a patient provides an average serum concentration of 50 ng / mL to 180 ng / mL. .

  In some embodiments, a high (therapeutic) dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof is given to a patient for a period of time to ameliorate the most prominent withdrawal symptoms. Followed by a low (maintenance) dose to prevent recurrence of drug use. In some embodiments, in order to ameliorate the most prominent withdrawal symptoms, a therapeutic dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof may be administered to the patient for a period of time. Is administered, and thereafter a decreasing (decreasing) amount of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is administered over a period of time until a maintenance dose is reached. In some embodiments, a high initial therapeutic dose is administered followed by a low therapeutic dose. In some embodiments, the norbogaine dose is gradually reduced over a period of high to low therapeutic dose.

In some embodiments, a dose of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof that provides an average serum concentration of 50 ng / mL to 180 ng / mL is administered as a single dose. Is done. In some embodiments, a dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof that provides an average serum concentration of 50 ng / mL to 180 ng / mL is administered as multiple doses. Is done. In one embodiment, the total dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is 1 mg / kg to 3 mg / kg. In another embodiment, the total dose of norivogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is 1 mg / kg to 2.5 mg / kg.

  In some embodiments, the serum concentration is sufficient to suppress or ameliorate the abuse while maintaining the QT interval below 500 milliseconds (ms) during the treatment. In some embodiments, the therapeutic dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof provides a QT interval extension of less than 80 ms. In one embodiment, a maintenance dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof provides a QT interval extension of less than 50 ms. In some embodiments, a maintenance or therapeutic dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof provides a QT interval extension of less than 30 ms. In one embodiment, a maintenance dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof provides a QT interval extension of less than 20 ms. In one embodiment, the QT prolongation is equivalent to or less than that observed in patients receiving methadone treatment. In a preferred embodiment, a patient is tested to determine the QT interval prior to treatment with norivogaine, and if the clinician determines that QT prolongation would be an unacceptable risk, the noriobogaine treatment Will be contraindicated.

  In another aspect, the present specification provides a method for its treatment in a human patient addictive to substance abuse, wherein the method comprises a dosage of providing an average serum concentration of 50 ng / mL to 180 ng / mL. Including administration to a patient of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the concentration is maintained while maintaining a QT interval of less than about 500 ms during the treatment. Enough to suppress or ameliorate.

In one embodiment, norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method comprises:
a) administration of an initial dose of nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / mL to 180 ng / mL When,
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose has a mean serum concentration over a period of time. The administration maintaining a medium concentration between 50 ng / mL and 180 ng / mL;
including.

  In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is 5 mg-25 mg. In another embodiment, at least one additional dose is administered between 6 and 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and the additional dose is administered between 6 and 24 hours after the previous dose. In another embodiment, the method further includes selection of addicted patients that are prescreened for assessment of tolerance towards QT interval extension.

  In another aspect, the present specification provides a method for its treatment in a human patient addictive to substance abuse, wherein the method comprises a dosage of providing an average serum concentration of 50 ng / mL to 180 ng / mL. Including administration to a patient of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the concentration is maintained while maintaining a QT interval extension of less than about 20 ms during the treatment. Sufficient to suppress or ameliorate abuse.

In one embodiment, norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method comprises:
a) administration of an initial dose of nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / mL to 180 ng / mL When,
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose has a mean serum concentration over a period of time. The administration maintaining a medium concentration between 50 ng / mL and 180 ng / mL;
including.

  In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is 5 mg-25 mg. In another embodiment, at least one additional dose is administered between 6 and 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and the additional dose is administered between 6 and 24 hours after the previous dose.

  In another aspect, the present specification provides a method of attenuating such symptoms in a human patient that is susceptible to withdrawal symptoms due to drug addiction, the method comprising in an average serum of 50 ng / mL to 180 ng / mL Including administration to a patient of a dose-providing dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the concentration reduces the QT interval to less than about 500 ms during the treatment. Sufficient to attenuate the symptoms while maintaining.

In another embodiment, the withdrawal symptoms are due to acute withdrawal. In another embodiment, norivogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method comprises:
a) administration of an initial dose of nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / mL to 180 ng / mL When,
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose has a mean serum concentration over a period of time. The administration maintaining a medium concentration between 50 ng / mL and 180 ng / mL;
including.

  In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is 5 mg-25 mg. In another embodiment, at least one additional dose is administered between 6 and 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and the additional dose is administered between 6 and 24 hours after the previous dose.

  In another aspect, the present specification provides a method for preventing the recurrence of abuse in a patient being treated to ameliorate drug abuse, the method comprising a maintenance dose of norivogaine, a norivogaine derivative, or pharmaceutically Including periodic administration to the patient of an acceptable salt and / or solvate thereof, the patient no longer abused the drug and the dosage is less than about 70% of the therapeutic dose; Further, the QT interval extension is about 30 ms or less.

  In another embodiment, the total dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt or solvate thereof is 50 mg to 100 mg per day.

Pain In some embodiments, the present invention is a surprising discovery that treatment with ibogaine in a narrow dosage range of greater than about 0.1 mg / kg body weight to about 8 mg / kg body weight provides therapeutic relief of pain. based on. Preferably, in humans, the dose range that provides both treatment results and an acceptable QT interval extension of less than 50 milliseconds is from about 0.1 mg / kg body weight to about 3 mg / kg body weight or less, more preferably , About 0.7 mg per kg body weight to about 2 mg or less per kg body weight, or any subrange or subvalue within the above range.

  In some embodiments, the narrow therapeutic dose of ibogaine does not extend the QT interval to unacceptable levels in human patients. In some embodiments, the patient is administered a therapeutic dose of ibogaine in a clinical situation involving cardiac monitoring. In some embodiments, the patient will be pre-screened for assessment of resistance towards QT interval prolongation, for example, any pre-existing patient who will be ineligible for treatment with ibogaine. It is determined whether you have any heart disease. In one embodiment, patients exhibiting QT interval extension of less than about 20 ms after treatment with one or more therapeutic doses of ibogaine will not require further clinical monitoring. In one embodiment, the patient is not monitored after ibogaine administration.

  In some embodiments, the therapeutic dose of ibogaine administered to a patient provides an average serum concentration of about 50 ng / mL to about 850 ng / mL, or any subrange or subvalue present therebetween. Enough. In a preferred embodiment, the dose of ibogaine administered to the patient provides an average serum concentration of about 50 ng / mL to about 400 ng / mL.

  In some embodiments, the dose of ibogaine that provides an average serum concentration of about 50 ng / mL to about 850 ng / mL is administered as a single dose. In some embodiments, the dose of ibogaine that provides an average serum concentration of about 50 ng / mL to about 850 ng / mL is administered as multiple doses. In some embodiments, the total amount of ibogaine is about 0.1 mg / kg to about 8 mg / kg. In one embodiment, the total amount of ibogaine is about 0.1 mg / kg to about 3 mg / kg. In another embodiment, the total amount of ibogaine is about 0.7 mg / kg to 1.5 mg / kg.

  In one aspect, the present specification provides a method of treating pain in a patient, the method comprising administering a dose of norivogaine, a norivogaine derivative, or pharmaceutically that provides an average serum concentration of 50 ng / mL to 180 ng / mL. Administration of an acceptable salt and / or solvate thereof to a patient, the concentration being sufficient to reduce and / or inhibit the pain while maintaining a QT interval of less than about 500 ms during the treatment It is.

In one embodiment, norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof is administered as a single dose or multiple doses. In one embodiment, the method comprises:
a) administration of an initial dose of nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / mL to 180 ng / mL When,
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose has a mean serum concentration over a period of time. The administration maintaining a medium concentration between 50 ng / mL and 180 ng / mL;
including.

  In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is 5 mg-25 mg. In another embodiment, at least one additional dose is administered between 6 and 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and the additional dose is administered between 6 and 24 hours after the previous dose. In another embodiment, the method further includes selection of addicted patients that are prescreened for assessment of tolerance towards extending the QT interval. In another embodiment, the total dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt or solvate thereof is 70 mg to 150 mg per day.

  In another aspect, the present specification provides a method of treating pain in a patient, the method comprising administering a dosage of norivogaine, a norivogaine derivative, or pharmaceutically that provides an average serum concentration of 50 ng / mL to 180 ng / mL. Administration of an acceptable salt and / or solvate thereof to a patient, wherein the concentration is to reduce and / or inhibit the pain while maintaining a QT interval extension of less than about 20 ms during the treatment. It is enough.

In one embodiment, norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method comprises:
a) administration of an initial dose of nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / mL to 180 ng / mL When,
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose has a mean serum concentration over a period of time. The administration maintaining a medium concentration between 50 ng / mL and 180 ng / mL;
including.

  In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is 5 mg-25 mg. In another embodiment, at least one additional dose is administered between 6 and 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and the additional dose is administered between 6 and 24 hours after the previous dose.

  In another aspect, the present specification provides a method of alleviating such symptoms in a human patient susceptible to pain symptoms, the method providing a dosage that provides an average serum concentration of 50 ng / mL to 180 ng / mL. Administration of to the patient, wherein the concentration is maintained while maintaining a QT interval of less than about 500 ms during the treatment. Sufficient to attenuate symptoms.

In another embodiment, the pain symptom is due to chronic pain. In another embodiment, norivogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method comprises:
a) administration of an initial dose of nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / mL to 180 ng / mL When,
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose has a mean serum concentration over a period of time. The administration maintaining a medium concentration between 50 ng / mL and 180 ng / mL;
including.

  In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is 5 mg-25 mg. In another embodiment, at least one additional dose is administered between 6 and 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and the additional dose is administered between 6 and 24 hours after the previous dose.

Migraine The present invention relates to treatment with a narrow dosage range of about 1 mg / kg body weight to about 4 mg / kg body weight of norivogaine, norivogaine derivatives, or pharmaceutically acceptable salts and / or solvates thereof. Based in part on the surprising discovery of providing therapeutic relief. Preferably, the dose provides both a therapeutic outcome and an acceptable QT interval extension of less than about 50 milliseconds (ms) in humans.

  The present invention is based in part on the discovery that nolubogaine reduces the frequency, severity, and / or length of headache, and specifically, migraine. The present invention is further based on the discovery that direct blood flow delivery of norivogaine at a very low dose can treat and / or prevent migraine. The direct blood flow delivery of norivogaine enhances the amount of norivogaine delivered to the brain, which is different from that administered so that, when taken orally, the first This is because it does not pass through the liver. Direct blood flow delivery of nolvogane includes sublingual delivery, buccal delivery, pulmonary delivery, and intranasal delivery, which is absorbed directly into the bloodstream for delivery to the brain. . Rapid delivery of norbogaine to the brain can cause a significant reduction in migraine symptoms, which is typically less than 15 minutes after administration.

  Migraine can include four phases, but in all cases not all phases occur. Phase 1 is a prodromal phase where patients develop irritability, mood changes, depression or euphoria, fatigue, food craving, muscle stiffness, constipation or diarrhea, and susceptibility to odor and / or noise . The second period is a precursor period and is characterized by visual, sensory, or motor effects. Only a small population of migraine includes aura. The third period is the pain period. Pain is nausea, vomiting, sensitivity to sensory influx, fatigue, irritability, rotational dizziness, deafness, confusion, foggy, nasal congestion, diarrhea, frequent urination, facial pallor Often accompanied by sweating. The final phase is a late symptom phase and may include a tingling sensation at the migraine site, thought disorder, fatigue, headache, mood changes, gastrointestinal symptoms, and weakness.

  The cause of migraine is unknown, but migraine can be caused by triggers, including hormonal changes, stress, hunger, fatigue, specific odors, food, poor air quality, and the like. Migraine can also be affected by genetic factors.

  In one aspect, the invention relates to a method for the treatment or prevention of migraine and / or symptoms thereof, the method comprising administration of a therapeutic amount of norivogaine. As used herein, unless otherwise indicated, nolibogaine includes nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt thereof. In one embodiment, in addition to nolubogaine, a therapeutic amount of an agent known in the treatment of migraine is co-administered to the patient. In preferred embodiments, the co-treatment dose does not result in a QT interval extension of more than 50 ms. In one embodiment, both compounds are administered simultaneously. In one embodiment, the compound is administered at different times (eg, sequentially).

  In one aspect, the invention relates to the treatment of migraine and / or symptoms thereof in a patient in need thereof, the treatment comprising administering to the patient a therapeutically effective amount of norivogaine or derivative by direct blood flow delivery. including. In one aspect, the therapeutically effective amount of norivogaine or derivative is about 50 ng to about 10 μg / kg body weight. In some embodiments, the therapeutically effective amount of nolibogaine or noribogaine derivative is administered once a day, twice a day, or three or more times a day. In one embodiment, agents known for the treatment and / or prevention of migraine are also administered.

  In another aspect, the present invention provides a method of treating migraine and / or symptoms thereof in a patient in need thereof, wherein the method comprises a therapeutic amount of norivogaine or a norivogaine derivative or a pharmaceutically acceptable salt thereof. The norbogaine or derivative or a pharmaceutically acceptable salt thereof is administered by sublingual delivery, intranasal delivery, buccal delivery, or pulmonary delivery.

  The present invention relates to a method for preventing migraine and / or symptoms thereof, the method comprising administration of a prophylactic amount of norivogaine to prevent or ameliorate migraine and / or symptoms thereof. As used herein, unless otherwise indicated, nolibogaine includes nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt thereof. In one embodiment, agents known for the treatment and / or prevention of migraine are also administered.

  In one aspect, the invention relates to the prevention of migraine and / or symptoms thereof in a patient in need thereof, the prevention comprising administering to the patient a prophylactically effective amount of norivogaine by direct blood flow delivery. . In one aspect, the prophylactically effective amount of norivogaine is from about 1 mg / kg to about 2 mg / kg body weight. In one aspect, the prophylactically effective amount of norivogaine is about 50 ng to about 10 μg / kg body weight. In some embodiments, the prophylactically effective amount of norivogaine or norivogaine derivative is administered once a day, twice a day, or three or more times a day. In some embodiments, the prophylactically effective amount is administered periodically (eg, daily). In some embodiments, a prophylactically effective amount is administered before, simultaneously with, or immediately after a potential trigger for migraine. In some embodiments, a prophylactically effective amount is administered when the patient feels the onset of at least one migraine symptom. In one embodiment, an agent known for the treatment and / or prevention of migraine is administered.

  In another aspect, the present invention provides a method for the prevention of migraine and / or symptoms thereof in a patient in need thereof, the method comprising a prophylactically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable Administration of the salt or solvate thereof to a patient, wherein the norbogaine, derivative, or salt thereof is administered by sublingual delivery, intranasal delivery, buccal delivery, or intrapulmonary delivery.

  As will be apparent to those of skill in the art upon reading this disclosure, the present invention, in one aspect, provides a method for treating or preventing migraine and / or symptoms thereof in a subject, said method being therapeutically effective. Administration to a patient in need thereof of any amount of norivogaine, a norivogaine derivative, a nolibogaine prodrug, or a pharmaceutically acceptable salt thereof. In one embodiment, the method further comprises administration of at least one agent known in the treatment or prevention of migraine and / or symptoms thereof.

  In one aspect, the present invention provides a composition for the treatment and / or prevention of migraine, wherein the composition comprises a therapeutic or prophylactic amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof. Salt or solvate, at least one drug known in the treatment and / or prevention of migraine, and optionally, a pharmaceutically acceptable additive.

  In another aspect, the present specification provides a method of treating migraine and / or symptoms thereof in a patient in need thereof, wherein the method comprises a therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable Including administration to the patient of possible salts thereof.

  In one embodiment, the therapeutically effective amount is about 50 ng to about 10 μg / kg body weight per day. In another embodiment, the therapeutically effective amount is from about 1 mg / kg to about 4 mg / kg body weight per day. In another embodiment, norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt thereof is administered by sublingual delivery, buccal delivery, intranasal delivery, or intrapulmonary delivery. In another embodiment, the therapeutically effective amount is administered once a day. In another embodiment, the therapeutically effective amount is administered more than once per day.

  In another aspect, the present description provides a method for preventing migraine and / or symptoms thereof in a patient in need thereof, wherein the method comprises a prophylactically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable Including administration to the patient of possible salts thereof.

  In one embodiment, a prophylactically effective amount is about 50 ng to about 10 μg / kg body weight per day. In another embodiment, the prophylactically effective amount is less than about 90% of the therapeutically effective amount. In another embodiment, nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt thereof is administered by sublingual delivery, intranasal delivery, buccal delivery, or intrapulmonary delivery. In another embodiment, nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt thereof is administered as needed according to the subject's determination. In another embodiment, the patient's QT interval extension does not exceed about 30 ms. In another embodiment, the method further comprises administration of at least one agent known in the treatment and / or prevention of migraine and / or symptoms thereof. In another embodiment, the at least one agent is selected from the group consisting of an analgesic, triptan, ergotamine, and dexamethasone.

Reducing resistance to opioid analgesics. set to target. In such a method, effective analgesia in the patient is achieved while resensitizing the patient to an addictive opioid analgesic. As used herein, “patient resensitization the patient” refers to a reduction, reduction, attenuation, and / or reversal of resistance to an analgesic. In one aspect, a resensitized patient obtains a therapeutic effect with a lower dose of opioid analgesic compared to before resensitization. In one aspect, a resensitized patient obtains an improved therapeutic effect with the same dose of opioid analgesic compared to before resensitization.

  In one embodiment, norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof is administered concurrently with an opioid analgesic. In one embodiment, the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is administered after administration of the analgesic, for example, 1, 2, 3, Administered at 4, 8, 10, 12, 24 hours, or later. In one embodiment, a single dose of norbogaine is administered. In one embodiment, two or more doses of norbogaine are administered. In one embodiment, the opioid analgesic is interrupted for a period of time while nolibogaine is administered. In one embodiment, the non-opioid analgesic is administered while the opioid analgesic is interrupted. In one embodiment, norbogaine acts as an analgesic. In one embodiment, the opioid analgesic is interrupted during nolibogaine treatment.

  In some embodiments, the unit dose that provides both treatment results in opioid resistant individuals and an acceptable QT interval extension of less than 50 milliseconds is about 120 mg. In some embodiments, the unit dose that provides both treatment results in opioid resistant individuals and an acceptable QT interval extension of less than 50 milliseconds is 2 mg / kg body weight.

  In one aspect, the specification provides a method of modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesia, the method providing an average serum concentration of 50 ng / mL to 180 ng / mL Including simultaneous discontinuation or co-administration of an amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof with the opioid analgesic treatment, wherein the concentration is measured over a QT interval during the treatment. Sufficient to resensitize the patient to the opioid as an analgesic while maintaining below about 500 ms.

In one embodiment, norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method further comprises discontinuing the dose of analgesic. In another embodiment, the method further comprises the co-administration of nolubogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof with an analgesic. In another embodiment, during the co-administration, the opioid analgesic dose is reduced. In another embodiment, the method comprises:
a) administration of an initial dose of nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / mL to 180 ng / mL When,
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose has a mean serum concentration over a period of time. The administration maintaining a medium concentration between 50 ng / mL and 180 ng / mL;
including.

In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is 5 mg-25 mg. In another embodiment, at least one additional dose is administered between 6 and 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and the additional dose is administered between 6 and 24 hours after the previous dose. In another embodiment, the method further includes selection of addicted patients that are prescreened for assessment of tolerance towards extending the QT interval.

  In one aspect, the specification provides a method of modulating tolerance to an opioid analgesic in a patient undergoing opioid analgesia, the method providing an average serum concentration of 50 ng / mL to 180 ng / mL Including simultaneous discontinuation or co-administration of an amount of norivogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof with the opioid analgesic treatment, the concentration extending the QT interval during the treatment Is sufficient to resensitize the patient to opioids as analgesics while maintaining <10 ms below.

In one embodiment, norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof is administered as a single dose or multiple doses. In another embodiment, the method further comprises discontinuing the dose of analgesic. In another embodiment, the method further comprises the co-administration of nolubogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof with an analgesic. In another embodiment, during the co-administration, the opioid analgesic dose is reduced. In another embodiment, the method comprises:
a) administration of an initial dose of nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / mL to 180 ng / mL When,
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose has a mean serum concentration over a period of time. The administration maintaining a medium concentration between 50 ng / mL and 180 ng / mL;
Further included.

  In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is 5 mg-25 mg. In another embodiment, at least one additional dose is administered between 6 and 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and the additional dose is administered between 6 and 24 hours after the previous dose. In another embodiment, the method further includes selection of addicted patients that are prescreened for assessment of tolerance towards extending the QT interval.

  In another embodiment, the opioid analgesic is from fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, buprenorphine, codeine, thebaine, buprenorphine, methadone, meperidine, tramadol, tapentadol, levorphanol, sufentanil, pentazocine, and oxymorphone. Selected from the group consisting of In another embodiment, the opioid analgesic is morphine.

Depression Norbogaine has certain properties that make it a very attractive candidate for the treatment of depression and / or post-traumatic stress disorder (PTSD). These properties include the interaction of nolibogain with various receptors in the brain, including nicotinic acetylcholine receptor (nAChR) and opioid receptors (eg, μ-opioid receptors). Can be mentioned. In addition, norbogaine increases brain secretion levels by blocking synaptic reuptake via the SERT transporter. Accordingly, the present invention relates to a method for treating depression and / or PTSD, or a symptom thereof, the method comprising administering to a patient nolubogaine, a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof. including.

  Direct blood flow delivery of norivogaine at very low doses can reduce the symptoms of depression and / or PTSD. Such dosing is well below that previously described. The direct blood flow delivery of nolibogaine enhances the amount of nolibogaine delivered to the brain, because nolibogaine does not pass through the liver as it does when taken orally. Direct blood flow delivery of nolibogaine includes sublingual delivery, pulmonary delivery, and intranasal delivery, which is absorbed directly into the bloodstream and then enters the brain. Rapid delivery of norivogaine to the brain is, for example, less than 15 minutes and can cause a significant reduction in the symptoms of depression and / or PTSD.

  In one aspect, the present invention relates to the treatment of depression and / or PTSD in a patient in need thereof, wherein the treatment comprises a therapeutically effective amount of norivogaine, a norivogaine derivative, solvate, or pharmaceutically acceptable. Administration of such salts and / or solvates thereof to a patient. In one embodiment, the present invention treats depression. In another embodiment, the present invention treats PTSD. In preferred embodiments, the patient is not addictive to cocaine or opiates. Conventional anxiety disorders different from PTSD do not fall within the scope of the present invention.

  In some embodiments, the therapeutic dose of norivogaine administered to the patient, or a pharmaceutically acceptable salt and / or solvate thereof, is between 50 ng / mL and 180 ng / mL, or any present therebetween Is sufficient to give an average serum concentration of a subrange or value. In one embodiment, the dose of norivogaine administered to the patient, or a pharmaceutically acceptable salt and / or solvate thereof, provides an average serum concentration of 50 ng / mL to 150 ng / mL. In one embodiment, the dose of norivogaine administered to the patient, or a pharmaceutically acceptable salt and / or solvate thereof, provides an average serum concentration of 80 ng / mL to 100 ng / mL.

  In some embodiments, the serum concentration is sufficient to suppress or ameliorate symptoms of depression and / or PTSD while maintaining a QT interval of less than 500 milliseconds (ms) during the treatment. is there. In some embodiments, a dose of norbogaine, or a pharmaceutically acceptable salt and / or solvate thereof, provides a QT interval extension of less than 50 ms. In some embodiments, the dose of norbogaine, or a pharmaceutically acceptable salt and / or solvate thereof, provides a QT interval extension of less than 30 ms. In a preferred embodiment, a dose of norbogaine, or a pharmaceutically acceptable salt and / or solvate thereof, provides a QT interval extension of less than 20 ms. In a preferred embodiment, if a patient is tested to determine the QT interval prior to treatment with norivogaine and the clinician determines that QT prolongation will be an unacceptable risk, Would be contraindicated.

  In another aspect, the present invention provides a method of treating depression and / or PTSD in a patient in need, comprising administering to the patient norivogaine or a norivogaine derivative in a sustained release manner, wherein The result is about 6 hours, about 12 hours, about 18 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, or a period that exists between any two of these durations, The concentration of the norbogaine derivative, pharmaceutically acceptable salt and / or solvate thereof is maintained in a therapeutically effective amount.

  In another aspect, the present specification provides a method of treating depression and / or post-traumatic stress disorder in a patient in need thereof, wherein the method comprises a therapeutically effective amount of norivogaine, a norivogaine derivative, or Including administration to a patient of a pharmaceutically acceptable salt and / or solvate thereof, wherein the patient is not addictive to cocaine or an opiate, and the therapeutically effective amount is In the meantime, an effective average norbogaine serum level of about 50 ng / mL to about 180 ng / mL is provided while maintaining the QT interval below about 500 ms.

  In another aspect, the present specification provides a method of treating depression and / or post-traumatic stress disorder in a patient in need thereof, wherein the method comprises a therapeutically effective amount of norivogaine, a norivogaine derivative, or Including administration to a patient of a pharmaceutically acceptable salt and / or solvate thereof, wherein the patient is not addictive to cocaine or an opiate, and the therapeutically effective amount is Meanwhile, effective average norbogaine serum levels of about 50 ng / mL to about 180 ng / mL are provided while maintaining QT interval extension below about 20 ms.

  In one embodiment, the norbogaine, norivogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered as a single dose or multiple doses.

In another embodiment, the method comprises:
a) administration of an initial dose of nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / mL to 180 ng / mL When,
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose has a mean serum concentration over a period of time. The administration maintaining a medium concentration between 50 ng / mL and 180 ng / mL;
including.

In another embodiment, the initial dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is 5 mg-25 mg. In another embodiment, at least one additional dose is administered between 6 and 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and the additional dose is administered between 6 and 24 hours after the previous dose. In another embodiment, the method further includes selection of addicted patients that are prescreened for assessment of tolerance towards extending the QT interval. In another embodiment, depression is treated. In another embodiment, post-traumatic stress disorder is treated.

Anxiety Noibogaine has certain properties that make it very attractive for treating anxiety disorders, impulse control disorders, anger / violence-related disorders, or regulating food intake It is a candidate. These properties include the interaction of nolibogain with various receptors in the brain, including nicotinic acetylcholine receptor (nAChR) and opioid receptors (eg, μ-opioid receptors). Can be mentioned. In addition, norbogaine increases brain secretion levels by blocking synaptic reuptake via the SERT transporter. Accordingly, the present invention relates to a method for the treatment of anxiety disorders, impulse control disorders, anger / violence related disorders, or symptoms thereof, or regulation of food intake, said methods comprising noriobogaine, noriobogaine derivatives, or pharmaceutically acceptable Administration of such salts and / or solvates thereof to a patient.

  Direct blood flow delivery of norivogaine at very low doses may reduce symptoms of anxiety disorders, impulsive control disorders, anger / violence related disorders, or may provide control of food intake. Such dosing is well below that previously described. The direct blood flow delivery of nolibogaine enhances the amount of nolibogaine delivered to the brain, because nolibogaine does not pass through the liver as it does when taken orally. Direct blood flow delivery of nolibogaine includes sublingual delivery, pulmonary delivery, and intranasal delivery, which is absorbed directly into the bloodstream and then enters the brain. Rapid delivery of norbogaine to the brain is, for example, less than about 15 minutes and can cause a significant reduction in symptoms of anxiety disorders, impulse control disorders, anger / violence related disorders, or food cravings.

  In one aspect, the invention relates to treating anxiety disorders, impulse control disorders, anger / violence related disorders, or regulating food intake in a patient in need, wherein the treatment or regulation is a therapeutically effective amount. This includes administration to a patient of norivogaine, a norivogaine derivative, a solvate, or a pharmaceutically acceptable salt and / or solvate thereof. In one embodiment, the present invention treats anxiety disorders. In one embodiment, the present invention treats OCD. In one embodiment, the present invention treats generalized anxiety disorder. In one embodiment, the present invention treats social anxiety disorder. In one embodiment, the present invention treats a panic disorder. In another embodiment, the present invention treats impulse control disorders. In another embodiment, the present invention treats pathological anger and / or violence. In another embodiment, the present invention treats anger / violence related disorders. In another embodiment, the present invention reduces morbid anger in a patient. In another embodiment, the present invention reduces violent outbreaks in patients. In another embodiment, the present invention regulates food intake. In one embodiment, food intake is reduced. In one embodiment, food craving is reduced. In preferred embodiments, the patient is not addictive to cocaine or opiates.

  In some embodiments, the therapeutic dose of norivogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate administered to the patient is between about 50 ng / mL and about 180 ng / mL, or between It is sufficient to give an average serum concentration of any subrange or subvalue present. In a preferred embodiment, the dose of norbogaine administered to the patient, or a pharmaceutically acceptable salt and / or solvate thereof, provides an average serum concentration of about 50 ng / mL to about 110 ng / mL. In one embodiment, the dose of norivogaine administered to the patient, or a pharmaceutically acceptable salt and / or solvate thereof, provides an average serum concentration of about 50 ng / mL to about 100 ng / mL. . In one embodiment, the dose of norivogaine administered to the patient, or a pharmaceutically acceptable salt and / or solvate thereof, provides an average serum concentration of less than about 50 ng / mL.

  In some embodiments, the serum concentration suppresses symptoms of anxiety disorders, impulse control disorders, anger / violence related disorders, while maintaining a QT interval of less than about 500 milliseconds (ms) during the treatment. Or enough to remit, or enough to regulate food intake. In some embodiments, the dose of norbogaine, or a pharmaceutically acceptable salt and / or solvate thereof, maintains a QT interval of less than about 450 ms. In some embodiments, the dose of norbogaine, or a pharmaceutically acceptable salt and / or solvate thereof, maintains a QT interval of less than about 420 ms.

  In some embodiments, a dose of norbogaine, or a pharmaceutically acceptable salt and / or solvate thereof, provides a QT interval extension of less than about 50 ms. In some embodiments, a dose of norbogaine, or a pharmaceutically acceptable salt and / or solvate thereof, provides a QT interval extension of less than about 30 ms. In a preferred embodiment, a dose of norbogaine, or a pharmaceutically acceptable salt and / or solvate thereof, provides a QT interval extension of less than about 20 ms. In a preferred embodiment, a patient is tested to determine the QT interval prior to treatment with norivogaine, and if the clinician determines that QT prolongation would be an unacceptable risk, the noriobogaine treatment Will be contraindicated.

  In another embodiment, the present invention provides a method for treating anxiety disorders, impulse control disorders, anger / violence related disorders, or methods for regulating food intake in a patient in need thereof, the method comprising a sustained release mode Administration of norivogaine or a norbogaine derivative to a patient, resulting in about 6 hours, about 12 hours, about 18 hours, about 24 hours, about 36 hours, about 48 hours, about 72 hours, about 96 hours, or For a period that exists between any two of these durations, the concentration of norivogaine, a norivogaine derivative, pharmaceutically acceptable salts and / or solvates thereof is maintained in a therapeutically effective amount.

  In one aspect, the present specification provides a method of treating an anxiety related disorder in a patient in need thereof, wherein the method comprises a therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof. And / or solvate administration to the patient, the patient is not addictive to cocaine or opiates, and the therapeutically effective amount is less than about 500 ms QT interval during the treatment Effective average norbogaine serum levels of about 50 ng / mL to about 180 ng / mL.

  In one embodiment, the anxiety related disorder is selected from the group consisting of generalized anxiety disorder, panic disorder, obsessive compulsive disorder, and social anxiety disorder.

  In one aspect, the present specification provides a method of treating impulsive control disorders in a patient in need thereof, wherein the method comprises a therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof. And / or the solvate is administered to the patient, the patient is not addictive to cocaine or opiates, and the therapeutically effective amount is the therapeutically effective amount of the therapeutic In the meantime, an effective average norbogaine serum level of about 50 ng / mL to about 180 ng / mL is provided while maintaining the QT interval below about 500 ms.

  In one embodiment, the impulsive control disorder is borderline personality disorder, conduct disorder, antisocial personality disorder, attention deficit hyperactivity disorder, attention deficit disorder, schizophrenia, mood disorder, morbid gaming, arson, Selected from the group consisting of intermittent explosive disorder, theft, sexual compulsive behavior, sexual perversion, internet addiction, hair loss, pathologic skin irritation, and impulse buying.

  In one aspect, the present description provides a method for regulating food intake and / or a method for diminishing food craving in a patient in need thereof, wherein the method comprises a therapeutically effective amount of norivogaine, a norivogaine derivative, or Including administration to a patient of a pharmaceutically acceptable salt and / or solvate thereof, wherein the patient is not addictive to cocaine or an opiate, and the therapeutically effective amount is An effective amount provides an effective average norbogaine serum level of about 50 ng / mL to about 180 ng / mL while maintaining a QT interval of less than about 500 ms during the treatment.

  In one aspect, the present specification provides a method of treating an anger-related disorder in a patient in need thereof, wherein the method comprises a therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof. And / or administration of a solvate to the patient, and wherein the therapeutically effective amount is from about 50 ng / mL to about 180 ng / mL while maintaining a QT interval of less than about 500 ms during the treatment. Provides effective mean norbogaine serum levels.

In one embodiment, the method comprises:
a) administration of an initial dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of about 50 ng / mL to about 180 ng / mL The administration;
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose has a mean serum concentration over a period of time. The administration maintaining a medium concentration from about 50 ng / mL to about 180 ng / mL;
including.

  In another embodiment, the initial dose is about 75 mg to about 120 mg. In another embodiment, the at least one additional dose is from about 5 mg to about 25 mg. In another embodiment, at least one additional dose is administered from about 6 hours to about 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and the additional dose is administered from about 6 hours to about 24 hours after the previous dose. In another embodiment, the QT interval is less than about 450 ms. In another embodiment, the method further comprises selecting a patient that is prescreened for assessment of tolerance towards QT interval extension. In another embodiment, norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof is administered by sublingual delivery, buccal delivery, intranasal delivery, or intrapulmonary delivery.

  Nolubogain induces side effects in some patients. The method requires pre-selection of opioid addicted patients to determine patient tolerance towards a therapeutic dose of norbogaine.

  Nolubogaine is administered to ameliorate acute withdrawal symptoms and acute withdrawal symptoms. Specifically, in a first trial of nolvogane treatment in a methadone addicted patient, a single 120 mg dose of nolibogaine generally gives a meaningful therapeutic response, whereas a single 60 mg dose of nolibogaine is generally It is shown that it does not give a therapeutic response. Furthermore, a single 90 mg dose of norivogaine is somewhat therapeutic, but partial therapeutic for commercial purposes.

  Unexpectedly, it was discovered that Nolubogaine behaves in a linear pattern with respect to QT interval extension. For example, doubling the norbogaine dose will result in an approximately double QT interval extension in the patient. Thus, QT interval and QT interval extension data obtained from sub-therapeutic doses of nolubogain less than 120 mg, such as about 90 mg, are used as a predictor of patient tolerance towards therapeutic norbogaine treatment at the 120 mg therapeutic dose. can do. This is possible because the QT interval and QT interval extension data obtained from a partial therapeutic dose of norivogaine that is less than 120 mg without exposing the patient to side effects at therapeutic doses, which can be life threatening, 120 mg To be able to extrapolate accurately towards the dose of norbogaine.

  As first described above, opioid addiction patients treated with 120 mg of norbogaine have a significantly longer time to resumption of opioid replacement therapy compared to patients treated with 60 mg. Patients receiving 120 mg of norbogaine also show variable QT interval prolongation with an average prolongation of approximately 38 milliseconds (ms). Some patients exhibit QT interval extension greater than 50 ms, or QT intervals greater than 500 ms. Patients whose QT interval exceeds 500 ms or whose QT interval is extended beyond 50 ms are at high risk of ventricular tachyarrhythmia and may die.

  A pre-screening method is provided for predicting which patients are eligible for norbogaine treatment, which, when treated with nolibogaine, has an unacceptable QT interval extension or a QT interval of greater than 500 milliseconds. Based on the patient shown. The method for predicting either an unacceptable QT interval extension of greater than 50 milliseconds, or a QT interval of greater than 500 milliseconds may be performed prior to initiating treatment with a therapeutic dose (120 mg) of norbogaine. To screen out such patients, it can be used as a means of using a partial therapeutic dose (less than 120 mg) of norbogaine.

Patient Prescreening As will be apparent to those of skill in the art upon reading this disclosure, the present invention provides an opioid addicted patient, or herein, for determining a patient's tolerance to a therapeutic dose of norbogaine. Provide a pre-screening method for another patient in need of treatment or prevention.

In one aspect, an opioid addicted patient, or a treatment provided herein for determining a patient's tolerance to a therapeutic dose of norbogaine, or a pharmaceutically acceptable salt and / or solvate thereof. Alternatively, another method of screening for patients in need of prevention is provided,
Measuring the patient's pre-dose QT interval;
Administering to a patient a partial therapeutic dose of norivogaine or a pharmaceutically acceptable salt thereof;
Measuring the patient's post-administration QT interval;
including.

In some embodiments, the method includes one or more of:
Determining a difference between a pre-dose QT interval and a post-dose QT interval to determine a first extension;
An estimate of a second extension based on the first extension, wherein the second extension is an estimated QT interval extension expected to be observed in the patient upon administration of a therapeutic dose of norbogaine; ,
Determining the patient's tolerance to the therapeutic dose of norbogaine;
If the therapeutic dose of norivogaine is to be administered to the patient, or if the second extension is estimated to be less than about 50 ms, if the second extension is estimated to be less than about 50 ms, the therapeutic dose is administered. Administration or interruption,
Further included.

In one embodiment, a method for screening patients with opioid addiction for determining a patient's tolerance to a therapeutic dose of norbogaine or a pharmaceutically acceptable salt and / or solvate thereof is provided, the method comprising: ,
Measuring the patient's pre-dose QT interval;
Administering to a patient a partial therapeutic dose of norivogaine or a pharmaceutically acceptable salt thereof;
Measuring the patient's post-administration QT interval;
Determining a difference between a pre-dose QT interval and a post-dose QT interval to determine a first extension;
An estimate of a second extension based on the first extension, wherein the second extension is an estimated QT interval extension expected to be observed in the patient upon administration of a therapeutic dose of norbogaine; ,
Determining the patient's tolerance to the therapeutic dose of norbogaine;
If the therapeutic dose of norivogaine is to be administered to the patient, or if the second extension is estimated to be less than about 50 ms, if the second extension is estimated to be less than about 50 ms, the therapeutic dose is administered. Administration or interruption,
including.

  In one embodiment, a therapeutic dose is administered if the second extension is estimated to be less than about 40 ms. In one embodiment, a therapeutic dose is administered if the second extension is estimated to be less than about 30 ms. In one embodiment, a therapeutic dose is administered if the second extension is estimated to be less than about 20 ms. In one embodiment, a therapeutic dose is administered if the second extension is estimated to be less than about 10 ms.

  In one embodiment, the therapeutic dose provides an average serum concentration of 50 ng / mL to 180 ng / mL, which provides the patient with a QT interval extension that is below an acceptable limit, eg, about 50 ms, while opioid addiction Enough to suppress or ameliorate.

  In a preferred embodiment, the therapeutic dose is about 120 mg nolubogaine. In another embodiment, the therapeutic dose is 70-120 mg nolubogaine. In another embodiment, the therapeutic dose is 100-150 mg nolubogaine. In another embodiment, the therapeutic dose is noribogaine greater than 150 mg. In one embodiment, the therapeutic dose is 1 mg / kg body weight to 4 mg / kg body weight.

  In one embodiment, the therapeutic dose is administered in one or more doses, such as one, two, three, four, five, or more doses over one or more days. Is done.

  In one embodiment, the partial therapeutic dose is in one or more doses, such as one, two, three, four, five, or more doses over one or more days. Be administered.

  In one embodiment, the partial therapeutic dose of norivogaine is, for example, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, 30% of a therapeutically effective dose (eg, 120 mg) of norivogaine. May be less than, less than 20%, or less than 10%, or any subrange or subvalue present therebetween.

  In one embodiment, the partial therapeutic dose of norivogaine is, for example, 110 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 40 mg, 30 mg, 20 mg, 10 mg, 5 mg, 2 mg, 1 mg norbogaine, or between Can be any subrange or subvalue present.

  In one embodiment, if the second extension is estimated to be greater than the acceptable limit of the QT interval extension, the patient is administered a partial therapeutic dose of norbogaine.

  In one embodiment, if the second extension is estimated to be greater than the acceptable limit of QT interval extension, then the patient is administered a therapeutic dose of norivogaine in multiple doses. For example, if the therapeutic dose is 120 mg per day, 60 mg may be given every 12 hours. Without being bound by theory, multiple administrations are believed to reduce the maximum serum concentration of norivogaine that occurs in the patient, thereby reducing QT interval prolongation.

  In one embodiment, if the second extension is estimated to be greater than the acceptable limit of QT interval extension, the patient is administered an initial dose of norbogaine followed by one or more additional doses. Is done. In one embodiment, the initial dose is 75 mg to 120 mg. In one embodiment, the one or more additional doses are less than the initial dose. In one embodiment, the one or more additional doses are from 5 mg to 50 mg. In one embodiment, such a dosing regimen provides a mean serum concentration of norbogaine between 50 ng / mL and 180 ng / mL. In one embodiment, such a dosing regimen provides a mean serum concentration of norbogaine from 80 ng / mL to 100 ng / mL. In one embodiment, the one or more additional doses maintain an average serum concentration between 50 ng / mL and 180 ng / mL over a period of time. In one embodiment, the one or more additional doses maintain an average serum concentration between 80 ng / mL and 100 ng / mL over a period of time. In one embodiment, one or more additional doses are administered periodically, such as every 4 hours, every 6 hours, every 8 hours, every 12 hours, or every 24 hours.

  In one embodiment, the tolerance limit QT interval extension is 50 ms. In one embodiment, the tolerance limit QT interval extension is 40 ms. In one embodiment, the tolerance limit QT interval extension is 30 ms. In one embodiment, the tolerance limit QT interval extension is 20 ms. In one embodiment, the acceptable limit QT interval extension is 10 ms.

  In one embodiment, the therapeutic amount of norivogaine is sufficient to give an average serum concentration of norivogaine of 50 ng / mL to 180 ng / mL, or 60 ng / mL to 180 ng / mL. In one embodiment, the therapeutic amount of norivogaine is sufficient to provide an average serum concentration of norivogaine of 50 ng / mL to 150 ng / mL, or 60 ng / mL to 150 ng / mL. In one embodiment, the therapeutic amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from 50 ng / mL to 100 ng / mL, or from 60 ng / mL to 100 ng / mL. In one embodiment, the therapeutic amount of norivogaine is sufficient to provide an average serum concentration of noriobogain between 80 ng / mL and 100 ng / mL. A range includes both end values as well as any subranges between them.

In one aspect, a method for screening patients with opioid addiction for determining a patient's tolerance to a therapeutic dose of norbogaine or a pharmaceutically acceptable salt and / or solvate thereof is provided, the method comprising:
Measuring the patient's pre-dose QT interval;
Administering to a patient a partial therapeutic dose of norivogaine or a pharmaceutically acceptable salt thereof;
Measuring the patient's post-administration QT interval;
including.

In one embodiment, the method comprises one or more of:
Determining a difference between a pre-dose QT interval and a post-dose QT interval to determine a first extension;
An estimate of a second extension based on the first extension, wherein the second extension is an estimated QT interval extension expected to be observed in the patient upon administration of a therapeutic dose of norbogaine; ,
Determining the patient's tolerance to the therapeutic dose of norbogaine;
If the therapeutic dose of norivogaine is to be administered to the patient, or if the second extension is estimated to be less than about 50 ms, if the second extension is estimated to be less than about 50 ms, the therapeutic dose is administered. Administration or interruption,
Further included.

  In another embodiment, the therapeutic dose provides an average serum concentration of 50 ng / mL to 180 ng / mL, which suppresses or ameliorates opioid addiction while providing the patient with a QT interval extension of less than about 50 ms. Enough.

In another embodiment, the method comprises:
a) administration of an initial dose of nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / mL to 180 ng / mL When,
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose has a mean serum concentration over a period of time. The administration maintaining a medium concentration between 50 ng / mL and 180 ng / mL;
Further included.

  In another embodiment, the therapeutic dose is administered in one or more doses. In another embodiment, the partial therapeutic dose is administered in one or more doses. In another embodiment, the partial therapeutic dose is 80% or less of the therapeutic dose. In another embodiment, the partial therapeutic dose is 70% or less of the therapeutic dose. In another embodiment, the partial therapeutic dose is from 60 mg to 100 mg. In another embodiment, the partial therapeutic dose is about 90 mg.

Sustained treatment In one aspect, the present invention provides therapeutic serum concentrations in a patient for whom treatment with a narrow dosage range of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is treated. Based on the surprising discovery of giving.

In some aspects, the invention provides in a patient that is treatable with nolubogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, while maintaining an acceptable QT interval extension in the patient. A method of treating a disease state, the method comprising:
a) Administration of an initial unit dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof to the patient, wherein the unit dose is between 50 ng / mL and 180 ng / mL of the therapeutic mean serum The administration wherein the serum concentration provides a minimal QT interval extension,
b) maintenance of the serum concentration by periodic administration of at least one additional dose of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that the at least one dose Additional doses maintain the average serum concentration between 50 ng / mL and 180 ng / mL during treatment, and the one or more additional doses are continued as needed for treatment of the condition. Maintenance and
including.

  In one embodiment, the therapeutic serum concentration is between 50 ng / mL and 180 ng / mL. In a preferred embodiment, the therapeutic serum concentration is between 80 ng / mL and 100 ng / mL. In one embodiment, the dose range provides both treatment results and an acceptable QT interval extension of less than 50 milliseconds in the patient. In one embodiment, an initial unit dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered. In one embodiment, the initial unit dose provides a therapeutic serum concentration with minimal QT interval extension. In one embodiment, the QT interval extension is 20 ms or less.

  In some embodiments, the patient is administered the initial dose unit of luibogaine, nolubogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, followed by one or more additional doses. . In one embodiment, the initial unit dose is 50 mg to 120 mg. In one embodiment, the one or more additional doses are less than the initial dose. In one embodiment, the one or more additional doses are from 5 mg to 50 mg. In one embodiment, such a dosing regimen provides a therapeutic average serum concentration of roivogaine between 50 ng / mL and 180 ng / mL. In one embodiment, the one or more additional doses maintain a therapeutic mean serum concentration between 50 ng / mL and 180 ng / mL over a period of time. In one embodiment, one or more additional doses are administered periodically. In one embodiment, at least one additional dose is administered from about 6 hours to about 24 hours after administration of the initial unit dose. In one embodiment, at least one additional dose is administered from about 6 hours to about 24 hours after administration of the previous dose. In one embodiment, one or more doses are administered as a controlled release formulation.

  In one embodiment, the narrow therapeutic doses of norivogaine, norbogaine derivatives, or pharmaceutically acceptable salts or solvates described above do not unexpectedly extend the QT interval to unacceptable levels in human patients. . In some embodiments, patients will be pre-screened for assessment of resistance towards QT interval prolongation, for example, any existing patient that will be ineligible for treatment with norbogaine. It is determined whether you have any heart disease. In some embodiments, the patient undergoes cardiac monitoring for some period of treatment. In a preferred embodiment, no cardiac monitoring is required. In one embodiment, if the patient is tested to determine the QT interval prior to treatment with norivogaine and the clinician determines that QT prolongation would be an unacceptable risk, Treatment will be contraindicated.

In one aspect, the present specification provides in a patient that is treatable with nolubogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, while maintaining an acceptable QT interval extension in the patient. A method of treating a disease state, the method comprising:
a) administration of the initial unit dose of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof to the patient, wherein the unit dose is in a therapeutic mean serum of 50 ng / mL to 180 ng / mL Administering the concentration, wherein the serum concentration provides an acceptable QT interval in the patient;
b) maintenance of the serum concentration by periodic administration of at least one additional dose of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that the at least one dose Maintaining the additional dose to maintain the therapeutic mean serum concentration between 50 ng / mL and 180 ng / mL during treatment;
Including
The one or more additional doses are continued as needed for treatment of the condition, and the length of the acceptable QT interval is 500 ms or less.

  In one embodiment, the QT interval extension is less than 50 ms. In another embodiment, the QT interval extension is less than 20 ms. In another embodiment, the initial unit dose is greater than any of at least one dose. In another embodiment, the initial unit dose and at least one additional dose are combined into a single controlled release formulation. In another embodiment, the initial unit dose is administered as a divided unit dose, the divided unit dose is administered continuously until the unit dose level is achieved, and the total divided unit dose provides the initial unit dose Along with that, a therapeutic mean serum concentration is further given. In another embodiment, the initial unit dose is 75 mg to 120 mg. In another embodiment, the initial unit dose is between 5 mg and 25 mg at least one additional dose. In another embodiment, at least one additional dose is administered between 6 and 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and the additional dose is administered between 6 and 24 hours after the previous dose. In another embodiment, the method further includes screening addicted patients that are prescreened for assessment of tolerance towards QT interval extension.

In another aspect, the present specification provides in a patient that is treatable with nolibogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, while maintaining an acceptable QT interval extension in the patient. A method of treating a disease state, the method comprising:
a) administration of the initial unit dose of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof to the patient, wherein the unit dose is in a therapeutic mean serum of 50 ng / mL to 180 ng / mL Providing the concentration, wherein the serum concentration provides an acceptable QT interval extension in the patient;
b) maintenance of the serum concentration by periodic administration of at least one additional dose of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that the at least one dose Maintaining the additional dose to maintain the therapeutic mean serum concentration between 50 ng / mL and 180 ng / mL during treatment;
Including
The one or more additional doses are continued as needed for treatment of the condition, and the acceptable QT interval extension is 50 ms or less.

  In one embodiment, the QT interval extension is less than 20 ms. In another embodiment, the initial unit dose is greater than any of the at least one additional dose. In another embodiment, the initial unit dose and at least one additional dose are incorporated into a single controlled release formulation. In another embodiment, the initial unit dose is administered as a divided unit dose, which is administered continuously until the unit dose level is achieved, and the total divided unit dose is the initial unit dose. As well as giving further treatment mean serum concentrations. In another embodiment, the initial unit dose is 75 mg to 120 mg. In another embodiment, the at least one additional dose is 5 mg-25 mg. In another embodiment, at least one additional dose is administered between 6 and 24 hours after the initial dose. In another embodiment, at least two additional doses are administered, and the additional dose is administered between 6 and 24 hours after the previous dose. In another embodiment, the method further includes selection of addicted patients that are prescreened for assessment of tolerance towards QT interval extension.

  In another embodiment, norbogaine, or a pharmaceutically acceptable salt and / or solvate thereof is administered.

Formulations In another aspect, the specification provides a pharmaceutically acceptable formulation comprising a unit dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein Is sufficient to give a serum concentration of about 50 ng / mL to about 180 ng / mL. In one embodiment, a unit dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered in one or more doses. In another embodiment, the unit dose of norivogaine, norivogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from about 20 mg to about 120 mg.

Shown is the average norbogaine concentration-time profile in healthy patients after a single oral dose at doses of 3, 10, 30, or 60 mg. The inset shows individual concentration-time profiles from 0 to 12 hours after the 10 mg dose. FIG. 5 shows mean plasma norbogaine glucuronide concentration-time profiles in healthy patients after a single oral 30 mg dose or 60 mg dose. FIG. 6 shows the mean norivogaine concentration-time profile in opioid-addicted patients after administration of a single oral 60 mg (diamond), 120 mg (square), or 180 mg (triangle) dose of norivogaine. Time to resumption of opioid replacement therapy (OST) for each patient who received placebo (circle) or a single oral dose of noribogaine (60 mg square, 120 mg triangular, 180 mg inverted) Is shown. The middle horizontal line shows the average value. Error bars indicate standard deviation. The final COWS score before restarting OST shows the result of nolvogine treatment. The box contains values indicating 25% -75% quartiles. Diamonds indicate median values, and crossbars indicate average values. The whisker indicates a value within one standard deviation of the central quartile. There was no outlier. It shows the mean change in the total COWS score over the first 6 hours after dosing with norivogaine (60 mg is square, 120 mg is triangle, 180 mg is diamond) or placebo (circle). Data is given against a baseline COWS score. FIG. 6 shows the mean area under the curve (AUC) over the first 6 hours after administration of nolubogaine or placebo, based on the COWS score data given in FIG. 6A. A negative change in score indicates that withdrawal symptoms have subsided over time. It shows the mean change in the total OOWS score over the first 6 hours after dosing with nolubogaine (60 mg is square, 120 mg is triangular, 180 mg is diamond) or placebo (circle). Data is given against a baseline OOWS score. FIG. 7 shows the average area under the curve (AUC) over the first 6 hours after administration of nolubogaine or placebo, based on the OOWS score data given in FIG. 7A. A negative change in score indicates that withdrawal symptoms have subsided over time. It shows the mean change in total SOWS score over the first 6 hours after dosing with nolubogaine (60 mg is square, 120 mg is triangle, 180 mg is diamond) or placebo (circle). Data is given against a baseline SOWS score. FIG. 8 shows the average area under the curve (AUC) over the first 6 hours after administration of norbogaine or placebo, based on the SOWS score data given in FIG. 8A. A negative change in score indicates that withdrawal symptoms have subsided over time. It shows the mean change in the QT interval (ΔQTcl) of each cohort (60 mg is square, 120 mg is triangular, 180 mg is shown by diamonds) or placebo (circle) over the first 24 hours after administration. The correlation between the serum norbogaine concentration over time of each patient and ΔQTcl is shown. The line formula is given. It shows the action of norivogaine and varenicline in nicotine-dependent rats. The data shows the mean value + standard error of the mean value (SEM). #P <0.10, *** P <0.001 is due to comparison with vehicle or saline treatment. FIG. 5 shows the effects of nolvogane and varenicline on the pause rate of lever press during nicotine self-administration. Data show mean + SEM. Figure 9 shows the effect of nolibogaine on general motor activity of zebrafish during nicotine withdrawal. The behavioral endpoints examined included latency to the upper half of the tank (panel A), transition to the upper half of the tank (panel B), transition to the upper half of the tank per minute (panel C), upper half of the tank Time (panel D), time in the upper half of the tank per minute (panel E), average penetration duration (panel F), and average penetration duration per minute (panel G). Figure 9 shows the effect of nolibogaine on general motor activity of zebrafish during nicotine withdrawal. The behavioral evaluation items examined included travel distance (panel A), speed (panel B), rotation angle (panel C), number of rotation events (panel D), body direction change / orientation (panel E), movement Change in motion direction per distance / meander total (panel F and panel G) is included. It shows the effect of nolibogaine on tonic seizure frequency (panel A) and duration of tonic seizures (panel B and panel C). It shows the effect of the norbogaine treatment on motion mobility. Immobility (black squares) was used to indicate the frequency of episodes with a degree of motion unrelated to spatial transposition (immobility duration). Mobility (intermediate gray square) indicates global locomotor activity. High mobility (light gray squares) indicates swimming accelerated seizures (> 60% of individual average). Representative trajectories (from top to bottom) of control, chronic nicotine, repeated nicotine withdrawal (WD), and WD + 1 mg / L of norbogaine treatment are shown in Ethobion XT8 in a 5 minute new tank test (NTT). .5 Recorded by software. FIG. 4 shows the effect of nolvogine treatment (1, 5, and 10 mg / L doses) on the general locomotor activity of zebrafish. The behavioral endpoints examined included latency to the upper half of the tank (panel A), transition to the upper half of the tank (panel B), transition to the upper half of the tank per minute (panel C), upper half of the tank Time (panel D), time in the upper half of the tank per minute (panel E), average penetration duration (panel F), and average penetration duration per minute (panel G). FIG. 4 shows the effect of nolvogine treatment (1, 5, and 10 mg / L doses) on the general locomotor activity of zebrafish. The behavioral evaluation items examined included travel distance (panel A), speed (panel B), rotation angle (panel C), number of rotation events (panel D), body direction change / orientation (panel E), movement Change in motion direction per distance / meander total (panel F and panel G) is included. FIG. 5 shows the effect of nolvogane (1, 5, and 10 mg / L dose) on tonic seizure frequency (panel A) and duration of tonic seizures (panel B). FIG. 4 shows the effect of nolvogane treatment on motion mobility including rate of events per animal (panel A) and duration (panel B). “Migration” (high frequency “HF” or low frequency “LF”) was used to indicate the frequency of episodes with a degree of motion unrelated to spatial transposition (immobility duration). Mobility (HF or LF) indicates the episode frequency of moderate locomotor activity. High mobility (HF and LF) indicates rate-accelerated seizures (> 60% of individual average). The trajectories of control (upper row) and norivogaine treated fish (1, 5, and 10 mg / L from top to bottom) are shown, and Ethovision XT8.5 in a new 5 minute tank test (NTT). 5 Recorded by software.

DETAILED DESCRIPTION It will be understood that the present invention is not limited to the specific embodiments described and, therefore, can vary. Since the scope of the present invention is to be limited only by the appended claims, the terminology used herein is for the purpose of describing particular embodiments only and is not limited. It will be understood that there is no intention.

  Although the detailed description of the invention has been divided into various sections, this is for the convenience of the reader only, and the disclosure described in any section may be described in another section. May be combined. Unless defined otherwise herein, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

  In this specification and the appended claims, it should be noted that the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. . Thus, for example, reference to “a compound” includes a plurality of compounds.

I. Definitions Unless defined otherwise herein, all technical and scientific terms have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein, the following terms have the following meanings:

  When the term “about” is used before a numerical notation including ranges such as temperature, time, amount, concentration, and the like, (+) or (−) 20%, 10%, Approximate values that can vary by 5%, 1%, or any subrange or subvalue present therebetween. Preferably, the term “about” as used in reference to a dose means that the dose can vary by +/− 20%. For example, “about 2 mg / kg of norevogaine” indicates that the patient can be administered a dose of 1.6 mg / kg to 2.4 mg / kg of norbogaine. In another example, about 120 mg of norbogaine per unit dose indicates that the unit dose can range from 96 mg to 144 mg.

  “Administration” refers to the introduction of a drug, such as nolubogaine, to a patient. Typically, an effective amount is administered, and the amount can be determined by the treating physician or the like. Any route of administration can be used, including oral, topical, subcutaneous, intraperitoneal, intraarterial, inhalation, intravaginal, rectal, nasal, cerebrospinal fluid, or infusion into the body compartment. Agents such as norbogaine may be administered by direct blood flow delivery, for example, subcutaneous administration, buccal administration, intranasal administration, or intrapulmonary administration.

  When the related terms and related phrases “administration” and “administration of” are used in connection with a compound or pharmaceutical composition (and grammatical equivalents), by a healthcare professional Both refer to direct administration, which can be by administration to the patient or by self-administration by the patient, and / or indirect administration, which can be a drug prescription act. For example, a physician instructing a patient about self-administration of the drug and / or providing the patient with a prescription for the drug is administering the drug to the patient.

  “Periodic administration” or “periodic administration” refers to multiple treatments that occur on a daily, weekly, or monthly basis. Periodic administration may also refer to administration of a drug such as noriobogain once, twice, three times or more times per day. Administration may be via a transdermal patch, gum, troche, sublingual tablet, intranasal administration, pulmonary administration, oral administration, or other administration.

  “Comprising” or “comprises” is intended to mean that the compositions and methods include the recited elements, but not exclude others. “Consisting essentially of” when used to define compositions and methods will mean excluding other elements that have any essential significance to the combination for the stated purposes. . Thus, a composition consisting essentially of the elements defined herein will not exclude other materials or steps that do not materially affect the basic and novel characteristics of the claimed invention. “Consisting of” will mean the exclusion of other component elements and substantial method steps in excess of trace amounts. Embodiments defined by each of these transition terms are within the scope of this invention.

As used herein, the term “alkyl” refers to 1 to 12 carbon atoms, 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 3 carbon atoms. Refers to a monovalent saturated aliphatic hydrocarbyl group having the formula: This term include, by way of example, methyl _(CH 3 -), ethyl _{(CH 3 CH 2 -),} n- propyl _{(CH 3 CH 2 CH 2 -} ), isopropyl _{((CH 3) 2 CH -} ), n- butyl _{(CH 3 CH 2 CH 2 CH} 2 -), isobutyl _{((CH 3) 2 CHCH 2} -), sec- butyl _{((CH 3) (CH 3} CH 2) CH -), t- butyl ((CH ₃ ) ₃ C -), n- pentyl _{(CH 3 CH 2 CH 2 CH} 2 CH 2 -), and neopentyl _{((CH 3) 3 CCH 2} -) include hydrocarbyl groups straight and branched chains such as. The term “C _x alkyl” refers to an alkyl group having x carbon atoms, where x is an integer, for example, C ₃ refers to an alkyl group having 3 carbon atoms.

  “Alkenyl” has 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and has at least 1, preferably 1 to 2 vinyl (> C═C <) unsaturated sites. Refers to a straight or branched hydrocarbyl group. Such groups are exemplified by, for example, vinyl, allyl, and but-3-en-1-yl. The term includes cis and trans isomers or mixtures of these isomers.

“Alkynyl” has 2 to 6 carbon atoms, preferably 2 to 3 carbon atoms, and has at least 1, preferably 1 to 2, acetylene (—C≡C—) unsaturated sites. A linear or branched monovalent hydrocarbyl group. Examples of such alkynyl groups include acetylenyl (—C≡CH) and propargyl (—CH ₂ C≡CH).

“Substituted alkyl” refers to alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, amino Sulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyl Oxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, Low alkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroary From the group consisting of ruthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃ H, substituted sulfonyl, sulfonyloxy, thioacyl, thioacyl, alkylthio, and substituted alkylthio Refers to an alkyl group having 1 to 5 substituents, preferably 1 to 3 substituents, or more preferably 1 to 2 substituents, wherein the substituents are as defined herein. Fixed It is justified.

“Substituted alkenyl” is alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, amino Sulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyl Oxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, Chloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroary From the group consisting of ruthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃ H, substituted sulfonyl, sulfonyloxy, thioacyl, thioacyl, alkylthio, and substituted alkylthio Refers to an alkenyl group having 1 to 3 substituents, preferably 1 to 2 substituents, wherein the substituents are as defined herein, provided that The condition is that neither the xyl or thiol substitution binds to a vinyl (unsaturated) carbon atom.

“Substituted alkynyl” is alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, amino Sulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyl Oxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, Chloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroary From the group consisting of ruthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO ₃ H, substituted sulfonyl, sulfonyloxy, thioacyl, thioacyl, alkylthio, and substituted alkylthio Refers to an alkynyl group having 1 to 3 substituents, preferably 1 to 2 substituents, wherein the substituents are as defined herein, provided that It is a condition that neither xyl substitution nor thiol substitution is bonded to the acetylene carbon atom.

  “Alkoxy” refers to the group —O-alkyl, where alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, and n-pentoxy.

  “Substituted alkoxy” refers to the group —O- (substituted alkyl), where substituted alkyl is as defined herein.

“Acyl” refers to HC (O) — group, alkyl-C (O) — group, substituted alkyl-C (O) — group, alkenyl-C (O) — group, substituted alkenyl-C (O) —. Group, alkynyl-C (O)-group, substituted alkynyl-C (O)-group, cycloalkyl-C (O)-group, substituted cycloalkyl-C (O)-group, cycloalkenyl-C (O)- Group, substituted cycloalkenyl-C (O)-group, aryl-C (O)-group, substituted aryl-C (O)-group, heteroaryl-C (O)-group, substituted heteroaryl-C (O) -Group, heterocyclic-C (O)-group, and substituted heterocyclic-C (O)-group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, Substituted cycloalkyl, cycloalkenyl, substituted cycloal Cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Acyl includes CH ₃ C (O) — groups that are “acetyl”.

“Acylamino” means —NR ³⁸ C (O) alkyl group, —NR ³⁸ C (O) -substituted alkyl group, —NR ³⁸ C (O) cycloalkyl group, —NR ³⁸ C (O) -substituted cycloalkyl group, — NR ³⁸ C (O) cycloalkenyl group, —NR ³⁸ C (O) substituted cycloalkenyl group, —NR ³⁸ C (O) alkenyl group, —NR ³⁸ C (O) substituted alkenyl group, —NR ³⁸ C (O) ^{alkynyl, -NR} 38 C (O) substituted alkynyl ^{group, -NR} 38 C (O) aryl ^{groups, -NR} 38 C (O) substituted ^{aryl, -NR} 38 C (O) heteroaryl, ^{-NR 38} C (O) refers to a substituted heteroaryl group, —NR ³⁸ C (O) heterocyclic group, and —NR ³⁸ C (O) substituted heterocyclic group, wherein R ³⁸ is hydrogen or alkyl, where so Alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic Is as defined herein.

  “Acyloxy” means an alkyl-C (O) O— group, a substituted alkyl-C (O) O— group, an alkenyl-C (O) O— group, a substituted alkenyl-C (O) O— group, an alkynyl-C (O) O— group, substituted alkynyl-C (O) O— group, aryl-C (O) O— group, substituted aryl-C (O) O— group, cycloalkyl-C (O) O— group, Substituted cycloalkyl-C (O) O— group, cycloalkenyl-C (O) O— group, substituted cycloalkenyl-C (O) O— group, heteroaryl-C (O) O— group, substituted heteroaryl- C (O) O— group, heterocyclic-C (O) O— group, and substituted heterocyclic-C (O) O— group, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl Substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl Le, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Amino” refers to the group —NH ₂ .

“Substituted amino” refers to the group —NR ³⁹ R ⁴⁰ , where R ³⁹ and R ⁴⁰ are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SO ₂ - alkyl, -SO ₂ - substituted alkyl, -SO ₂ - alkenyl, -SO ₂ - substituted alkenyl, -SO ₂ - cycloalkyl, -SO ₂ - substituted cycloalkyl, -SO ₂ - cycloalkenyl, -SO ₂ - substituted cycloalkenyl, -SO ₂ - aryl, -SO ₂ - substituted aryl, -SO ₂ - heteroaryl, -SO ₂ - substituted heteroaryl, -SO ₂ - heteroaryl Independently selected from the group consisting of cyclic, and —SO ₂ -substituted heterocyclic, wherein R ³⁹ and R ⁴⁰ are optionally attached together with the nitrogen attached to them; Forms a heterocyclic or substituted heterocyclic group, provided that R ³⁹ and R ⁴⁰ are not both hydrogen, where alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, Substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. . When R ³⁹ is hydrogen and R ⁴⁰ is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R ³⁹ and R ⁴⁰ are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R ³⁹ or R ⁴⁰ is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R ³⁹ nor R ⁴⁰ is hydrogen.

“Aminocarbonyl” refers to the group —C (O) NR ⁴¹ R ⁴² where R ⁴¹ and R ⁴² are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl. , Cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, wherein R ⁴¹ and R ⁴² are Optionally attached and together with the nitrogen attached thereto, forms a heterocyclic or substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl , Cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, Aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Aminothiocarbonyl” refers to the group —C (S) NR ⁴¹ R ⁴² where R ⁴¹ and R ⁴² are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted Independently selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, wherein R ⁴¹ and R ⁴² are Optionally combined and taken together with the nitrogen attached to them to form a heterocyclic or substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted Alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkene R, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Aminocarbonylamino” refers to the group —NR ³⁸ C (O) NR ⁴¹ R ⁴² where R ³⁸ is hydrogen or alkyl and R ⁴¹ and R ⁴² are hydrogen, alkyl, substituted alkyl, alkenyl. Independently from the group consisting of, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic Wherein R ⁴¹ and R ⁴² are optionally joined together with the nitrogen attached to them to form a heterocyclic or substituted heterocyclic group, wherein alkyl , Substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycl Bloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Aminothiocarbonylamino” refers to the group —NR ³⁸ C (S) NR ⁴¹ R ⁴² , where R ³⁸ is hydrogen or alkyl, and R ⁴¹ and R ⁴² are hydrogen, alkyl, substituted alkyl, Independently from the group consisting of alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic Wherein R ⁴¹ and R ⁴² are optionally joined together with the nitrogen attached to them to form a heterocyclic or substituted heterocyclic group, wherein Alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted Cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Aminocarbonyloxy” refers to the group —O—C (O) NR ⁴¹ R ⁴² where R ⁴¹ and R ⁴² are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl , Substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, wherein R ⁴¹ and R ^{41 42} is optionally attached and together with the nitrogen attached to them forms a heterocyclic or substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl Substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloa Lucenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Aminosulfonyl” refers to the group —SO ₂ NR ⁴¹ R ⁴² where R ⁴¹ and R ⁴² are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cyclo Independently selected from the group consisting of alkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, wherein R ⁴¹ and R ⁴² are optional Together with the nitrogen attached to them to form a heterocyclic or substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cyclo Alkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, Reel, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Aminosulfonyloxy” refers to the group —O—SO ₂ NR ⁴¹ R ⁴² where R ⁴¹ and R ⁴² are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted Independently selected from the group consisting of aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, wherein R ⁴¹ and R ⁴² are Optionally combined and taken together with the nitrogen attached to them to form a heterocyclic or substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted Alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloa Kenyir, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Aminosulfonylamino” refers to the group —NR ³⁸ —SO ₂ NR ⁴¹ R ⁴² , where R ³⁸ is hydrogen or alkyl, and R ⁴¹ and R ⁴² are hydrogen, alkyl, substituted alkyl, alkenyl, Independently selected from the group consisting of substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic Wherein R ⁴¹ and R ⁴² are optionally joined together with the nitrogen attached to them to form a heterocyclic or substituted heterocyclic group, wherein alkyl, Substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted Roarukiru, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“Amidino” refers to the group —C (═NR ⁴³ ) NR ⁴¹ R ⁴² , where R ⁴¹ , R ⁴² , and R ⁴³ are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl. , Aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, wherein R ⁴¹ And R ⁴² are optionally joined together with the nitrogen attached to them to form a heterocyclic or substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl , Alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycline Alkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

  “Aryl” or “aryl” is a monovalent aromatic of 6 to 14 carbon atoms having a single ring (eg, phenyl) or multiple condensed rings (eg, naphthyl or anthryl). The fused ring may be aromatic or non-aromatic (for example, 2-benzoxazolinone, 2H-1,4-benzoxazine-3 (4H ) -On-7-yl and the like) provided that the point of attachment is an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

“Substituted aryl” means alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothio Carbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester) amino, (carboxyl Ester) oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cyclo Alkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy , substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 _H, substituted sulfonyl, sulfonyloxy, 1 to 5 substituents selected from the group consisting of thioacyl, thiol, alkylthio, and substituted alkylthio, preferably 1 to 3 substituents, or more preferred Alternatively, it refers to an aryl group substituted with 1 to 2 substituents, where the substituents are those defined herein.

  “Aryloxy” refers to the group —O-aryl, where aryl is as defined herein, and examples include phenoxy and naphthoxy.

  “Substituted aryloxy” refers to the group —O- (substituted aryl), where substituted aryl is as defined herein.

  “Arylthio” refers to the group —S-aryl, where aryl is as defined herein.

  “Substituted arylthio” refers to the group —S- (substituted aryl), where substituted aryl is as defined herein.

  “Carbonyl” refers to a divalent —C (O) — group that is equivalent to —C (═O) —.

  “Carboxy” or “carboxyl” refers to —COOH or salts thereof.

  “Carboxyl ester” or “carboxy ester” means —C (O) O-alkyl group, —C (O) O-substituted alkyl group, —C (O) O-alkenyl group, —C (O) O-substituted. Alkenyl group, -C (O) O-alkynyl group, -C (O) O-substituted alkynyl group, -C (O) O-aryl group, -C (O) O-substituted aryl group, -C (O) O-cycloalkyl group, -C (O) O-substituted cycloalkyl group, -C (O) O-cycloalkenyl group, -C (O) O-substituted cycloalkenyl group, -C (O) O-heteroaryl Group, -C (O) O-substituted heteroaryl group, -C (O) O-heterocyclic group, and -C (O) O-substituted heterocyclic group, wherein alkyl, substituted alkyl, Alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkenyl , Substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

“(Carboxyl ester) amino” means —NR ³⁸ —C (O) O-alkyl group, —NR ³⁸ —C (O) O-substituted alkyl group, —NR ³⁸ —C (O) O-alkenyl group, — NR ³⁸ —C (O) O-substituted alkenyl group, —NR ³⁸ —C (O) O-alkynyl group, —NR ³⁸ —C (O) O-substituted alkynyl group, —NR ³⁸ —C (O) O— An aryl group, —NR ³⁸ —C (O) O-substituted aryl group, —NR ³⁸ —C (O) O-cycloalkyl group, —NR ³⁸ —C (O) O-substituted cycloalkyl group, —NR ³⁸ — C (O) O-cycloalkenyl group, —NR ³⁸ —C (O) O-substituted cycloalkenyl group, —NR ³⁸ —C (O) O-heteroaryl group, —NR ³⁸ —C (O) O-substituted heteroaryl ^group, -NR 38 -C (O) O- het Refers to cyclic groups, and ^-NR 38 -C (O) O- substituted heterocyclic group, ^{wherein R 38} is alkyl or hydrogen, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl , Substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. is there.

  “(Carboxyl ester) oxy” means —O—C (O) O-alkyl group, substituted —O—C (O) O-alkyl group, —O—C (O) O-alkenyl group, —O—C. (O) O-substituted alkenyl group, —O—C (O) O-alkynyl group, —O—C (O) O-substituted alkynyl group, —O—C (O) O-aryl group, —O—C (O) O-substituted aryl group, —O—C (O) O-cycloalkyl group, —O—C (O) O-substituted cycloalkyl group, —O—C (O) O-cycloalkenyl group, — O—C (O) O-substituted cycloalkenyl group, —O—C (O) O-heteroaryl group, —O—C (O) O-substituted heteroaryl group, —O—C (O) O-hetero. Refers to cyclic groups and —O—C (O) O— group substituted heterocyclic groups, where alkyl, substituted alkyl, alkenyl, substituted alkyl Nyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are defined herein. That's right.

  “Cyano” refers to the group —CN.

  “Cycloalkyl” refers to cyclic alkyl groups of 3 to 10 carbon atoms having single or multiple cyclic rings, including fused ring systems, bridged ring systems, and spiro ring systems. The ring or rings can be aryl, heteroaryl, or heterocyclic, provided that the point of attachment is through a carbocyclic ring that is non-aromatic and is a non-heterocyclic ring. Is a condition. Examples of suitable cycloalkyl groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. Other examples of cycloalkyl groups include bicyclic [2,2,2] octanyl (bicycle [2,2,2,] octanyl), norbornyl, and spiro [4.5] dec-8-yl ( spiro [4.5] dec-8-yl) and the like.

  “Cycloalkenyl” has one or more cyclic rings and at least one> C═C <ring unsaturation, preferably 1 to 2> C═C <3- Refers to a non-aromatic cyclic alkyl group of 10 carbon atoms.

“Substituted cycloalkyl” and “substituted cycloalkenyl” are oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl , Aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, Carboxyl ester, (carboxyl ester) amino, (carboxyl ester) oxy, cyano, cycloalkyl, substituted cycloalkyl, cycl Alkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, hetero Aryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 1 to 5 substituents selected from ₃ H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, and Preferably refers to a cycloalkyl or cycloalkenyl group having 1 to 3 substituents, where the substituents are as defined herein.

  “Cycloalkyloxy” refers to —O-cycloalkyl.

  “Substituted cycloalkyloxy” refers to —O- (substituted cycloalkyl).

  “Cycloalkylthio” refers to —S-cycloalkyl.

  “Substituted cycloalkylthio” refers to —S- (substituted cycloalkyl).

  “Cycloalkenyloxy” refers to —O-cycloalkenyl.

  “Substituted cycloalkenyloxy” refers to —O- (substituted cycloalkenyl).

  “Cycloalkenylthio” refers to —S-cycloalkenyl.

  “Substituted cycloalkenylthio” refers to —S- (substituted cycloalkenyl).

“Guanidino” refers to the group —NHC (═NH) NH ₂ .

“Substituted guanidino” refers to —NR ⁴⁴ C (═NR ⁴⁴ ) N (R ⁴⁴ ) ₂ , wherein each R ⁴⁴ is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, hetero Two R ⁴⁴ groups independently selected from the group consisting of cyclic and substituted heterocyclic and bonded to a common guanidino nitrogen atom are optionally bonded together with the nitrogen bonded to them. To form a heterocyclic group or a substituted heterocyclic group, provided that at least one R ⁴⁴ is not hydrogen, where the substituent is as defined herein. It is as it is done.

  “Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo, preferably fluoro or chloro.

  “Haloalkyl” refers to an alkyl group substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkyl and halo are as defined herein. .

  “Haloalkoxy” refers to an alkoxy group substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkoxy and halo are as defined herein. is there.

  “Haloalkylthio” refers to an alkylthio group substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkylthio and halo are as defined herein. is there.

  “Hydroxy” or “hydroxyl” refers to the group —OH.

  “Heteroaryl” refers to an aromatic group of 1 to 4 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of ring oxygen, ring nitrogen, and ring sulfur. Such heteroaryl groups can have a single ring (eg, pyridyl, pyridinyl, or furyl) or multiple condensed rings (eg, indolizinyl or benzothienyl), where the fused ring is aromatic Or may be non-aromatic and / or may contain heteroatoms provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and / or sulfur ring atoms of the heteroaryl group are optionally oxidized to provide an N-oxide (N → O) moiety, a sulfinyl moiety, and / or a sulfonyl moiety. Preferred heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.

  “Substituted heteroaryl” refers to 1 to 5 substituents, preferably 1 to 3 substituents, or more preferably selected from the group consisting of the same groups as the substituents defined for substituted aryl , Refers to a heteroaryl group substituted with 1-2 substituents.

  “Heteroaryloxy” refers to —O-heteroaryl.

  “Substituted heteroaryloxy” refers to the group —O- (substituted heteroaryl).

  “Heteroarylthio” refers to the group —S-heteroaryl.

  “Substituted heteroarylthio” refers to the group —S- (substituted heteroaryl).

  “Heterocycle” or “heterocyclic” or “heterocycloalkyl” or “heterocyclyl” is a group that is saturated or partially saturated but not aromatic, A group having 1 to 4 heteroatoms selected from the group consisting of carbon atoms and nitrogen, sulfur, or oxygen. A heterocycle includes a single ring or multiple condensed rings including fused ring systems, bridged ring systems, and spiro ring systems. In a fused ring system, one or more rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through a non-aromatic heterocyclic ring. In one embodiment, the nitrogen and / or sulfur atoms of the heterocyclic group are optionally oxidized to give an N-oxide moiety, a sulfinyl moiety, and / or a sulfonyl moiety.

  "Substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" is 1 to 5 substituents identical to those defined for substituted cycloalkyl, or preferably 1 to 3 substituents A heterocyclyl group substituted with a group.

  “Heterocyclyloxy” refers to the group —O-heterocyclyl.

  “Substituted heterocyclyloxy” refers to the group —O- (substituted heterocyclyl).

  “Heterocyclylthio” refers to the group —S-heterocyclyl.

  “Substituted heterocyclylthio” refers to the group —S- (substituted heterocyclyl).

  Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolidine, isoquinoline, Quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline Phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo [b] thio E down, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1- dioxothiomorpholinyl, piperidinyl, pyrrolidine, and include tetrahydrofuranyl.

“Nitro” refers to the —NO ₂ radical.

“Oxo” refers to an (═O) atom or a (—O ⁻ ) atom.

  “Spiro ring system” refers to a bicyclic ring system having a single ring carbon atom common to both rings.

“Sulfonyl” refers to the divalent group —S (O) ₂ —.

“Substituted sulfonyl” refers to —SO ₂ -alkyl group, —SO ₂ -substituted alkyl group, —SO ₂ -alkenyl group, —SO ₂ -substituted alkenyl group, —SO ₂ -cycloalkyl group, —SO ₂ -substituted cyclo alkyl group, -SO ₂ - cycloalkenyl group, -SO ₂ - substituted cycloalkenyl group, -SO ₂ - aryl, -SO ₂ - substituted aryl group, -SO ₂ - heteroaryl, -SO ₂ - substituted heteroaryl group, -SO 2 _- heterocyclic group, -SO 2 _- refers to substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl, substituted cycloalkyl, cycloalkenyl , Substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic And substituted heterocycles are as defined herein. The substituted sulfonyl, methyl -SO ₂ -, phenyl -SO ₂ -, and 4-methylphenyl -SO ₂ - include groups such. The term “alkylsulfonyl” refers to —SO ₂ -alkyl. The term “haloalkylsulfonyl” refers to —SO ₂ -haloalkyl, where haloalkyl is as defined herein. The term “(substituted sulfonyl) amino” refers to —NH (substituted sulfonyl) and the term “(substituted sulfonyl) aminocarbonyl” refers to —C (O) NH (substituted sulfonyl), wherein the substituted sulfonyl Is as defined herein.

“Sulfonyloxy” includes —OSO ₂ -alkyl group, —OSO ₂ -substituted alkyl group, —OSO ₂ -alkenyl group, —OSO ₂ -substituted alkenyl group, —OSO ₂ -cycloalkyl group, —OSO ₂ -substituted cyclo alkyl group, -OSO ₂ - cycloalkenyl group, -OSO ₂ - substituted cycloalkenyl group, -OSO ₂ - aryl, -OSO ₂ - substituted aryl, -OSO ₂ - heteroaryl, -OSO ₂ - substituted heteroaryl Group, —OSO ₂ -heterocyclic group, —OSO ₂ -substituted heterocyclic group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl Substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, The substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

  “Thioacyl” refers to HC (S) — group, alkyl-C (S) — group, substituted alkyl-C (S) — group, alkenyl-C (S) — group, substituted alkenyl-C (S) —. Group, alkynyl-C (S)-group, substituted alkynyl-C (S)-group, cycloalkynyl-C (S)-group, substituted cycloalkynyl-C (S)-group, cycloalkenyl-C (S)- Group, substituted cycloalkenyl-C (S)-group, aryl-C (S)-group, substituted aryl-C (S)-group, heteroaryl-C (S)-group, substituted heteroaryl-C (S) -Group, heterocyclic-C (S) -group, and substituted heterocyclic-C (S) -group, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, Substituted cycloalkyl, cycloalkenyl, substituted Roarukeniru, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

  “Thiol” refers to the group —SH.

  “Thiocarbonyl” refers to a divalent —C (S) — group and is equivalent to —C (═S) —.

  “Thion” refers to the (═S) atom.

  “Alkylthio” refers to the group —S-alkyl, where alkyl is as defined herein.

  “Substituted alkylthio” refers to the group —S- (substituted alkyl), where substituted alkyl is as defined herein.

  As used herein, “compound” or “compound” is meant to include stereoisomers and tautomers of the indicated formula.

  “Stereoisomer” or “stereoisomer” refers to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.

  “Tautomers” refers to alternating forms of compounds with different proton positions, such as enol-keto tautomers and imine-enamine tautomers, or pyrazoles, imidazoles, benzimidazoles, Refers to tautomeric forms of heteroaryl groups containing ring atoms attached to both the -NH- moiety of the ring and the = N- moiety of the ring, such as triazole and tetrazole.

  As used herein, the term “phosphate ester” refers to any one of monobogaine monophosphate, diphosphate, or triphosphate, wherein the monophosphate moiety, diphosphate, The phosphate ester or triphosphate ester moiety is attached to the 12-hydroxy group and / or the indole nitrogen of norivogaine.

  As used herein, the term “phosphate ester” refers to any one of monobogaine monophosphate, diphosphate, or triphosphate, wherein the monophosphate moiety, diphosphate, The phosphate ester or triphosphate ester moiety is attached to the 12-hydroxy group and / or the indole nitrogen of norivogaine.

As used herein, the term “monophosphate” refers to the group —P (O) (OH) ₂ .

As used herein, the term “diphosphate” refers to the group —P (O) (OH) —OP (O) (OH) ₂ .

As used herein, the term “triphosphate” refers to the group —P (O) (OH) — (OP (O) (OH)) ₂ OH.

As used herein, the term “ester” refers to an ester of monophosphate, such that the term refers to an ester of a monophosphate group, an ester of a diphosphate group, or an ester of a triphosphate group. -P (O) (OR ⁴⁵ ) ₂ means that each R ⁴⁵ is independently hydrogen, C ₁ -C ₁₂ alkyl, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₄ aryl, 1 to 10 carbon atoms and 1 to 4 optionally oxidized heteroatoms heteroaryl selected from the group consisting of oxygen, nitrogen, and sulfur, and the like, provided that at least 1 The condition is that each R ⁴⁵ is not hydrogen. Similarly, exemplary esters of diphosphate or triphosphate are of formula —P (O) (OR ⁴⁵ ) —OP (O) (OR ⁴⁵ ) ₂ and formula —P (O) (OR ⁴⁵ ) — (OP (O) (OR ⁴⁵ )) ₂ OR ⁴⁵ , where R ⁴⁵ is as defined above.

As used herein, the term “hydrolyzable group” refers to a group that can be hydrolyzed to release a free hydroxy group under hydrolysis conditions. Examples of hydrolyzable groups include, but are not limited to, those defined for R above. Preferred hydrolyzable groups include carboxyl esters, phosphoric acid, and phosphate esters. Hydrolysis may occur by chemical reaction conditions such as base hydrolysis or acid hydrolysis, or may occur in vivo by a biological process such as that catalyzed by phosphate hydrolase. Non-limiting examples of hydrolyzable groups include ester-based linkers (—C (O) O— or —OC (O) —) linked groups, amide-based linkers (—C (O) NR ⁴⁶ — or ^-NR 46 C (O) -) linked group or phosphoric acid ^{linker, (-P (O) (oR} 46) -O -, - O-P (S) (oR 46) -O-, ^{-O-P (S) (SR} 46) -O -, - S-P (O) (OR 46) -O -, - O-P (O) (OR 46) -S -, - S-P ( ^{O) (OR 46) -S -} , - O-P (S) (OR 46) -S -, - S-P (S) (OR 46) -O -, - O-P (O) (R 46 ) -O-, -OP (S) (R ⁴⁶ ) -O-, -SP (O) (R ⁴⁶ ) -O-, -SP (S) (R ⁴⁶ ) -O-, ^{-S-P (O) (R} 46) S-, or linked group are exemplified by ^{-O-P (S) (R} 46) -S-), ^{wherein, R 46} may be hydrogen or alkyl.

  As described above, the substituent of the present invention does not include a polymer obtained by an infinite chain of substituents. At most, the maximum number of times any substituent can be substituted is five.

ならびにノルイボガイン誘導体または医薬的に許容可能なその塩及び医薬的に許容可能なその溶媒和物を指す。本明細書で「ノルイボガイン」について記載される場合、もう１つの多形のノルイボガインを利用することができると共に、それを企図すると理解されるべきである。いくつかの実施形態では、ノルイボガインは、ノルイボガイングルクロニドである。 “Norbogaine” means the compound,

And norbogaine derivatives or pharmaceutically acceptable salts and pharmaceutically acceptable solvates thereof. As described herein for “Norivogaine”, it should be understood that another polymorphic Norivogaine can be utilized and is contemplated. In some embodiments, the nolubogaine is nolubogaine glucuronide.

天然起源のイボガインは、西アフリカの低木であるＴａｂｅｒｎａｎｔｈ ｉｂｏｇａから単離される。脱メチル化は、室温で、三臭化ホウ素／ジクロロメタンとの反応を実施した後、従来の精製を行うなどの従来手法によって達成してよい。例えば、Ｈｕｆｆｍａｎ，ｅｔ ａｌ．，Ｊ．Ｏｒｇ．Ｃｈｅｍ．５０：１４６０（１９８５）を参照のこと。当該文献は、その全体が、参照によって本明細書に組み込まれる。ノルイボガインは、例えば、米国特許公開第２０１３／０１６５６４７号、第２０１３／０３０３７５６号、及び第２０１２／０２５３０３７号、ＰＣＴ特許公開第ＷＯ２０１３／０４０４７１号（ノルイボガイン多形の調製に関する説明を含む）、ならびに米国特許出願第１３／５９３，４５４号において説明されるように合成することができ、これらはそれぞれ、その全体が、参照によって本明細書に組み込まれる。 Nolibogaine can be prepared by demethylating naturally occurring ibogaine,

Naturally occurring ibogaine is isolated from Tabernanth ibaga, a West African shrub. Demethylation may be accomplished by conventional techniques such as performing a reaction with boron tribromide / dichloromethane at room temperature followed by conventional purification. See, for example, Huffman, et al. , J .; Org. Chem. 50: 1460 (1985). This document is incorporated herein by reference in its entirety. Nolubogaine is, for example, U.S. Patent Publication Nos. 2013/0165647, 2013/0303756, and 2012/0253037, PCT Patent Publication No. WO2013 / 040471 (including a description of the preparation of a norbogaine polymorph), and U.S. Patents. They can be synthesized as described in application 13 / 593,454, each of which is hereby incorporated by reference in its entirety.

  “Norivogaine derivative” refers to, but is not limited to, an ester or O-carbamate of norivogaine, or a pharmaceutically acceptable salt and / or solvate thereof. Also included within the present invention are derivatives of nolibogaine that serve as prodrug forms of nolibogaine. Prodrugs are pharmacological substances that are administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolized in vivo to the active metabolite. Norivogaine derivatives include, but are not limited to, U.S. Patent Nos. 6,348,456 and 8,362,007, and U.S. Patent Application No. 13 / 165,626, and U.S. Patent Application Publication No. US2013 / 0131046. US2013 / 0165647, US2013 / 0165425, and US2013 / 0165414, all of which are incorporated herein by reference. Non-limiting examples of norbogaine derivatives encompassed by the present invention are given in more detail in the “Compositions” section below.

  In some embodiments, the methods of the present disclosure involve administration of a prodrug of norivogaine that provides a desired maximum serum concentration and an effective average norbogaine serum level. A prodrug of nolubogaine refers to a compound that is metabolized in vivo to nolibogaine. In some embodiments, by cleavage of a prodrug entity that is readily cleavable by a cleavable linking arm or that binds to norivogaine, such that cleavage of norivogaine is generated in vivo. The prodrug is selected to be either easily cleavable. In one preferred embodiment, in the brain, either by facilitating passage through the blood brain barrier or by targeting brain receptors other than μ and / or κ receptors. Prodrug moieties are selected to facilitate binding to the μ receptor and / or the kappa receptor. Examples of prodrugs of norbogaine are provided in US Patent Application No. 13 / 165,626, the entire contents of which are hereby incorporated by reference.

  The present invention is not limited to any particular chemical form of norivogaine or a norbogaine derivative, and the drug is free base, solvate, or pharmaceutically acceptable acid addition when given to a patient. Any salt may be used. In the latter case, the hydrochloride salt is generally preferred, but other salts derived from organic or inorganic acids may also be used. Examples of such acids include, but are not limited to, those described below under “Pharmaceutically acceptable salts” and the like.

  “Pharmaceutically acceptable composition” refers to a composition suitable for administration to a mammal, preferably a human. Such compositions include various additives, diluents, and carriers, and other such inert agents well known to those skilled in the art.

  “Pharmaceutically acceptable salt” refers to a pharmaceutically acceptable salt of a compound, including pharmaceutically acceptable partial salts, which include various organic counterions well known in the art. And is derived from inorganic counter ions. Examples of the counter ions include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid, Examples include lactic acid, succinic acid, citric acid, malic acid, maleic acid, aconitic acid, salicylic acid, phthalic acid, embonic acid, enanthic acid, oxalic acid, and the like, when the molecule contains an acidic function. None, but includes sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like.

  A “pharmaceutically acceptable solvate” or “hydrate” of a compound of the invention is a solvate complex or water that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. Means a complex of, but is not limited to, a complex of a compound of the invention with one or more solvent molecules or water molecules, or a compound of the invention with 1 to about 100, or 1 to about 10 or 1 to about 2, 3, or 4 solvent molecules or complexes with water molecules.

As used herein, the term “solvate” is taken to mean a solid form of a compound that crystallizes with one or more solvent molecules entrapped therein. A few examples of solvents that can be used to make solvates such as pharmaceutically acceptable solvates include, but are not limited to, water, methanol, ethanol, isopropanol, butanol, common C ₁ -C ₆ alcohols (optionally substituted), tetrahydrofuran, acetone, ethylene glycol, propylene glycol, acetic acid, formic acid, water, and solvent mixtures thereof. Other such biocompatible solvents that can be useful in the preparation of pharmaceutically acceptable solvates are well known in the art and are applicable to the present invention. In addition, various organic and inorganic acids, and organic and inorganic bases can be added or even used alone as a solvent to make the desired solvate. Such acids and bases are well known in the art. When the solvent is water, the solvate can be referred to as a hydrate. Furthermore, by placing in the atmosphere or crystallizing, the compounds of the present invention can absorb moisture and can contain one or more water molecules in the crystals formed, thus hydrating. It becomes a thing. Even when such a hydrate is formed, it is included in the term “solvate”. Solvate is also meant to include compositions wherein another compound or complex co-crystallizes with the compound of interest. As used herein, the term “solvate” refers to a complex with a solvent in which norivogaine reacts or a complex with a solvent from which norivogaine precipitates or crystallizes. For example, a complex with water is known as a “hydrate”. Norevogaine solvates are within the scope of the present invention. Those skilled in the art of organic chemistry will appreciate that many organic compounds can exist in one or more crystalline forms. For example, the crystalline form can vary based on the solvate used. Accordingly, all crystalline forms of norivogaine or pharmaceutically acceptable solvates thereof are within the scope of the invention.

  A “therapeutically effective amount” or “therapeutic amount” refers to the amount of a drug or agent that would exert the intended therapeutic effect when administered to a patient suffering from a pathological condition, where the intended therapeutic effect is For example, reduction, remission, alleviation, or disappearance of one or more disease states in a patient. The therapeutically effective amount is the patient and the condition being treated, the weight and age of the subject, the severity of the condition, the salt, solvate or derivative of the active drug moiety selected, the particular composition or additive selected Will vary depending on the subsequent dosing regimen, timing of administration, mode of administration, and the like, all of which can be readily determined by one skilled in the art. A complete therapeutic effect need not occur by administration of a single dose, but may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered by one or more administrations. For example, but not limited to, a therapeutically effective amount of nolibogain associated with opioid dependent or opioid-like drug dependent treatment is at least about 2 hours above control (placebo), at least about 5 hours above control, and Preferably, it refers to an amount of nolubogaine that attenuates dependence and / or acute withdrawal symptoms for at least about 10 hours over control. For example, but not limited to, a therapeutically effective amount of a drug, such as norivogain, associated with nicotine-dependent therapy attenuates dependence and / or has a statistically little risk of recurrence of nicotine use, or Refers to an amount of a drug that is not present. For example, but not limited to, a therapeutically effective amount of norivogaine associated with alcohol-dependent treatment is at least 2 hours above control (placebo), at least 5 hours above control, and preferably above control Refers to an amount of norbogaine that attenuates dependence and / or acute withdrawal symptoms for at least 10 hours. For example, but not limited to, a therapeutically effective amount of norivogain associated with drug-dependent treatment is at least 2 hours above control (placebo), at least 5 hours above control, and preferably above control Refers to an amount of norbogaine that attenuates dependence and / or acute withdrawal symptoms for at least 10 hours. For example, without limitation, a therapeutically effective amount of nolibogain associated with modulation of opioid analgesic resistance refers to an amount of nolibogaine that resensitizes the patient to opioid analgesic treatment.

  A therapeutically effective amount of the compound may be more or less depending on the route of administration used. For example, when direct blood administration (eg, sublingual delivery, pulmonary delivery, and intranasal delivery) is used, a low dose of the compound may be administered. In one aspect, the therapeutically effective amount of norivogaine or derivative is about 50 ng to less than 100 μg / kg body weight. When other routes of administration are used, higher doses of the compound are administered. In one embodiment, the therapeutically effective amount of the compound is greater than about 1 mg / kg to about 8 mg / kg body weight per day.

  A “therapeutic level” of a drug is sufficient for the treatment of a disease or disorder, or a symptom of a disease or disorder, or for the treatment, prevention, or attenuation of a disease or disorder, or symptom of a disease or disorder An amount of norivogaine, a norivogaine derivative, or a pharmaceutical salt or solvate thereof that is sufficient but not so high as to cause any significant risk to the patient. The drug treatment level can be determined by a test that measures the actual concentration of the compound in the blood of the patient. This concentration is referred to as “serum concentration”. When described for serum concentration of nolibogaine, the term nolibogain will be understood to encompass any form of nolibogaine, including derivatives thereof.

  A “sub-therapeutic level” of norivogaine or a pharmaceutically salt and / or solvate thereof is below the therapeutic level described above. For example, a partial therapeutic level of norivogaine is, for example, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, 20% of a therapeutically effective amount (eg, 120 mg) It may be less than, or less than 10%, or any partial value or range that exists in between. A partial therapeutic level of norivogaine is less than a therapeutically effective amount, consistent with a “maintenance dose” of norivogaine, an amount that provides some attenuation and / or prevention of acute post withdrawal syndrome in the patient. Also good. The maintenance dose of the compound is expected to be less than the therapeutically effective amount, which should be high in patients who are no longer physically addictive to opioids or opioid-like drugs. This is because there is not.

  As used herein, a “prophylactically effective amount” of a drug is typically an amount that is less than a therapeutically effective amount, and attenuates and / or prevents a disease or disorder, or a symptom of a disease or disorder, in a patient. Is the amount to give. For example, a prophylactically effective amount of a compound is expected to be less than a therapeutically effective amount, which no longer has a disease or disorder, or a symptom of the disease or disorder (eg, for nicotine no longer This is because in patients who are not physically addictive, the suppression level need not be high. For example, a prophylactically effective amount is preferably less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20% of the therapeutically effective amount, Or less than 10%. However, for example, when a patient who is physically addicted to nicotine due to diminished craving during periods when nicotine use is not possible, the prophylactically effective amount is therapeutically effective. The same amount. In different diseases or disorders, or symptoms of different diseases or disorders, the therapeutically effective amount may vary.

  As used herein, a “maintenance amount” of a drug or agent is typically less than a therapeutically effective amount that provides attenuation and / or prevention of a syndrome disease or disorder, or symptom of a disease or disorder, in a patient. Amount. A maintenance amount of the compound is expected to be less than a therapeutically effective amount, which means that in patients who are no longer physically showing the disease or disorder or symptoms of the disease or disorder, the level of suppression should be high. This is because there is not. For example, the maintenance dose is preferably less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, or 10% of the therapeutically effective amount. It can be any partial value or subrange that is less than or in between.

  “Treatment”, “treating”, and “treat” are detrimental of a disease, disorder, or condition and / or its symptoms to a disease, disorder, or condition, or It is defined as an action with a drug such as nolubogaine to reduce or ameliorate any other undesirable effects. As used herein, “treatment” includes treatment of a human patient, (a) a reduction in the risk of developing a condition in a patient who has been determined to be susceptible to a condition but has not yet been diagnosed as having a condition, (B) impeding the onset of the pathological condition and / or (C) reducing the pathological condition, eg, inducing the regression of the pathological condition and / or the regression of the symptoms of one or more pathological conditions. “Treating” or “treating of” a condition or patient refers to the steps taken to obtain an advantageous or desired result, including clinical results such as a reduction in symptoms. The beneficial or desired clinical results for the purposes of the present invention include, but are not limited to, nicotine addiction treatment, treatment, prevention, and / or attenuation of craving for nicotine and prevention of recurrence of nicotine use And so on. This includes a reduction or elimination of smoking in the patient and / or a reduction or elimination of symptoms of withdrawal, craving, and the like. Advantageous or desired clinical results for some purposes of the present invention include, but are not limited to, treatment of substance addiction, treatment, prevention, and / or attenuation of acute withdrawal symptoms, and long-term (acute After) treatment, prevention and / or attenuation of withdrawal symptoms and prevention of recurrence of substance use. Advantageous or desired clinical results for the purpose of certain aspects of the invention include, but are not limited to, pain relief in all pain categories and classifications and treatment of acute and / or chronic pain, Reduction, and / or prevention; treatment, reduction, and / or prevention of skin pain, somatic pain, and / or neuropathic pain; and prevention of recurrence of long-term pain.

  As used herein, the term “patient” refers to mammals and includes human and non-human mammals.

  As used herein, the term “opiate” refers to a naturally occurring alkaloid found in poppies. These include codeine, morphine, oripavine, pseudomorphine, and thebaine. These include opium, poppy, poppy, and extracts and concentrates thereof.

  As used herein, the term “opioid” refers to a synthetic or semi-synthetic opioid having a naturally occurring opiate and psychoactive action. Non-limiting examples include acetyl-alpha-methylfentanyl, acetylmethadol, alfentanil, allylprozin, alphaacetylmethadol, alphamethadol, alpha-methylfentanyl, alpha-methylthiofentanyl, alphaprozine, anilidine, benzylmorphine, Benzethidine, betaacetylmethadol, beta-hydroxyfentanyl, beta-hydroxy-3-methylfentanyl, betameprodine, betaacetylmethadol, beta-hydroxyfentanyl, beta-hydroxy-3-methylfentanyl, betameprozin , Betamethadol, betaprozine, vegitramide, buprenorphine, butorphanol, carfentanil, cloni Zen, Codeine, Desomorphine, Dextromoramide, Dextropropoxyphene, Dezocine, Diampromide, Dimorphine, Diethylthianbutene, Dihydrocodeine, Dihydroethorphine, Dihydromorphine, Dimenoxadol, Dimefeptanol, Dimethylthiambutene, Dioxafetil Butyrate, diphenoxylate, diphenoxin, dipipanone, eptazocine, etoheptadine, ethyl methyl thianbutene, ethyl morphine, etnitazene, etorphine, ethoxeridine, fentanyl, fretidine, heroin, hydrocodone, hydromorphone, hydroxypetidin, isomethadone, ketobemidon, levobyl acetyl Methador, Levomethorphan, Levorphanol, Levophenacylmorphane, Levo Lamide, lofentanil, loperamide, opium tincture (laudanum), meperidine, meptazinol, metazosin, methadone, 3-methylfentanyl, 3-methylthiofentanyl, methopone, morphine, morpheridine, MPPP (1-methyl-4-phenyl-4-propiyl) Onoxypiperidine), myrophine, narcein, nicomorphine, norasimesadole, norlevorphanol, normesadone, nalolphine, nalbuphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretane, para-fluorofentanyl , Paregoric, PEPAP (1-(-2-phenethyl) -4-phenyl-4-acetoxypiperidine), pentazocine , Phenadoxone, phenampramide, phenomorphan, phenazocine, phenoperidine, pimidine, pyritramide, propeptazine, promedol, propperidine, propyrame, propoxyphene, racemoramide, racemetorphane, racentanyl, fensmoltanre Tapentadol, thebaine, thiophentanyl, thyridine, tramadol, trimeperidine, mixtures of any of the foregoing, salts of any of the foregoing, derivatives of any of the foregoing, and the like. The term opioid also includes opioid intermediates, which include 4-cyano-2-dimethylamino-4,4-diphenylbutane, 2-methyl-3-morpholino-1,1-diphenylpropane- Examples include carboxylic acid, 4-cyano-1-methyl-4-phenylpiperidine, ethyl-4-phenylpiperidine-4-carboxylate, and 1-methyl-4-phenylpiperidine-4-carboxylic acid. In the United States, many of the opioids are Schedule I or Schedule II drugs. Specific preferred examples of opioids include, but are not limited to, buprenorphine, codeine, heroin, hydrocodone, oxycodone, morphine, thebaine, and derivatives thereof that would be well known to those skilled in the art.

  As used herein, the term “opioid-like drug” refers to any illegal drug that binds to one or more opioid receptors and causes opioid-like addiction. Acute and long-term withdrawal symptoms from discontinuing use of such drugs can be similar to withdrawal symptoms from discontinuing opioids. Opioid-like drugs include amphetamine, methamphetamine, ketamine, and cocaine.

  As used herein, the term “QT interval” refers to a unit of time between the beginning of a Q wave at the heart's electrical frequency and the end of a T wave. An extension of the QT interval refers to an increase in the QT interval.

As used herein, the terms “addiction”, “abuse” and “dependence” are used interchangeably, no matter how best to stop him / her, opioid or opioid-like drug, nicotine , Refers to the patient's inability to stop using alcohol, addictive substances, or the like. Dependent DSMIV-TR standards are
In 12 months, include the following three or more manifestations of dependence or significant dysfunction or distress.
1. 1. Tolerance or significant increase in the amount of substance to produce euphoria or the desired effect, or significant loss of action with continued use of the same amount of substance 2. Use of specific substances for withdrawal symptoms or avoidance of withdrawal symptoms 3. Use of large amounts of material, or material usage over longer periods of time 4. Sustained desire or failure to reduce or control substance use 5. Concomitant chronic behavior for substance acquisition, substance use, or recovery from its action 6. Decrease or abandon social, professional, or recreational activities due to substance use Substance use that occurs despite the presence of persistent or repetitive physical or psychological problems that may have been caused or exacerbated by the substance

  As used herein, the term “remissioned nicotine addict” refers to any patient who has stopped using nicotine for a period of time. As used herein, remission nicotine addict includes any individual who was previously addictive to any form of nicotine, including but not limited to tobacco, electronic cigarettes, Or inhalers (“steam inhalation”), chewing tobacco, cigars, snuff, xels, hookah, and the like. The period of time since a remission nicotine addict has stopped using nicotine may be short, for example, a day to a few weeks or longer, for example months or years. Preferably, the patient has stopped using nicotine for a sufficiently long time and no longer exhibits the physical symptoms of nicotine addiction. The patient may exhibit psychological symptoms of nicotine addiction. In some embodiments, the patient does not exhibit psychological symptoms of nicotine addiction.

  As used herein, the terms “addictive substance”, “drug”, “addictive drug” and the like refer to drugs and other substances whose use results in addiction to at least a small population of individuals using it. Point to. Addictive substances include, but are not limited to, benzodiazepines (chlordiazepoxide, chlorazepate, diazepam, flurazepam, halazepam, prazepam, lorazepam, lormetazepam, oxazepam, temazepam, clonazepam, flunitrazepam azolam, trametazepam Including climazolam, loprazolam, and midazolam, cannabinoids and synthetic cannabinoids, stimulants (amphetamine, methylphenidate, dexmethylphenidate, dextroamphetamine, mixed amphetamine salt, dextromethamphetamine, dextromethamphetamine Lisde Sanphetamine, modafinil, adrafinil, armodafinil, caffeine, ephedrine, methylenedioxymethamphetamine, methylenedioxypylobalerone, mephedrone, phenylpropanolamine, propylhexadrine, pseudoephedrine, and cartephate, barbi Tool acids (including allobarbital, amobarbital, aprobarbital, alphenal, barbital, bralobarbital, pentobarbital, phenobarbital, and secobarbital), gamma-hydroxybutyric acid (GHB), ketamine, opiate, opioid, Opioid-like drugs, PCP, dextromethorphan (DXM), resell Acid diethylamide (LSD), mescaline, anabolic steroids, and their respective derivatives thereof. Addictive substances may be illegal drugs, prescription drugs that are prone to abuse, or other legal drugs that are prone to abuse.

  Obsessive-compulsive disorder (OCD) is an ego-unnatural, repetitive and persistent idea, thought, impulse, or image (obsession) and / or that individual is excessive or irrational Recognize, repetitive, purposeful, and characterized by intentional behavior (American Psychiatric Association, 1994a). Obsessions or compulsive behaviors cause significant distress, are time consuming, and / or significantly interfere with social or professional functions.

  Panic disorder is characterized by concerns related to recurring unexpected panic attacks and additional attacks, concerns about the effects or consequences of the attacks, and / or significant changes in behavior associated with the attacks (American Psychiatric) Association, 1994a). A panic attack is defined as a period of dispersal of intense fear or discomfort and suddenly develops (or more) four of the following symptoms and peaks within 10 minutes. (1) Palpitation, intense heartbeat or heart rate acceleration, (2) sweating, (3) tremor or tremor, (4) shortness of breath or suffocation, (5) sensation of breathing, (6) Chest pain or chest discomfort, (7) nausea or abdominal distress, (8) dizziness, instability, consciousness or fainting, (9) loss of reality (unrealism) or feeling of being separated (self Dissociation from), (10) fear of losing control, (11) fear of death, (12) sensory abnormalities (numbness or tingling sensation), (13) burning due to chills or heat. Panic disorder may or may not be associated with agoraphobia, or it may be associated with fear that is irrational and almost impossible to go public , You do not have to.

  Social anxiety disorder, also known as social phobia, is a marked and persistent fear of one or more social or stage situations where an individual is exposed to the possibility of surveillance by an unacquainted person or others. Characterized (American Psychiatric Association, 1994a). Exposure to a fearful situation induces anxiety almost constantly, which can approach the intensity of a panic attack. Fearful situations are avoided or endured with intense anxiety and tightness. Avoidance, anxiety expectation, or distress in fearful situations can significantly interfere with an individual's normal habitual, professional, or academic functions, or social activities or relationships, or There is significant pressure on having. Mild stage anxiety or shyness generally does not require psychopharmacological treatment.

Generalized anxiety disorder is characterized by excessive anxiety and anxiety (anxiety expectation) that persists for at least 6 months and the individual feels difficulty controlling (American Psychiatric Association, 1994a). Generalized anxiety disorder must be associated with at least three of the following six symptoms: That is, restlessness or feelings of tension or irritation, fatigue, difficulty concentrating or spontaneous loss, irritability, muscle tension, and sleep disorders. The diagnostic criteria for this disease are described in more detail in DSM-IV and are incorporated herein by reference (American Psychiatric Association, 1994a).

  Impulsive control disorders are a class of psychiatric disorders that involve a temptation, urgency, or lack of resistance to urge (impulsivity), and such urges are potentially harmful to the patient and / or others. The American Psychiatric Association's DSM-5 (March 2013) includes impulsive control disorders “characterized by problems in emotional and behavioral self-control”. These include borderline personality disorder, behavioral disorder, antisocial personality disorder, attention deficit hyperactivity disorder (ADHD), schizophrenia, mood disorder, pathological gambling, arsonism, intermittent explosive disorder, theft Symptoms, sexual compulsive behavior, sexual perversion, Internet addiction, hair loss, pathological skin irritation, and impulse buying. Impulsive control disorders can be associated with anxiety disorders and / or OCD.

  Violence and anger are associated with a number of mental disorders, particularly when they come from stimuli and / or part of the consequences of morbid anger. These include rebellious challenge disorder, attention deficit / hyperactivity disorder and behavior disorder (in children and adolescents), mental disorder, bipolar disorder, antisocial personality disorder, delusional personality disorder, and self-loving personality Disorders, adaptation disorders with behavioral disorders, and intermittent explosive disorders. Pathological anger and violence account for a significant portion of violent crime, including many prominent crimes involving multiple victims. In the US prison system, individuals who are highly prone to excitement account for a large percentage.

  As used herein, the term “pain” refers to all categories and classifications of pain and is summarized below for purposes of illustration. First, skin pain is caused by damage to the skin or surface tissue. Skin nociceptors terminate well under the skin and give well-defined, localized, short duration pain due to the high density of nerve endings. Examples of skin painful injuries include paper cuts, minor burns (eg, first degree burns), and surface lacerations.

  Second, somatic pain arises from ligaments, tendons, bones, blood vessels, and even the nerve itself and is detected by somatic nociceptors. The lack of nociceptors in these areas gives sharp, aching pain with a prolonged duration compared to cutaneous pain and is somewhat less localized. Examples include ankle sprains and fractures.

  Third, visceral pain arises from body organs. Visceral nociceptors are located in body organs and lumens. Similar to somatic pain, the lack of nociceptors in these areas usually gives more pain and prolonged duration of pain compared to somatic pain. Visceral pain can be more difficult to localize. Damage to visceral tissue can indicate “related” pain, and sensation is localized to a region completely independent of the site of injury. Myocardial ischemia (ie, loss of blood flow to a portion of myocardial tissue) is an example of related pain, and sensations can occur in the upper chest as a feeling of tightening, or pain in the left shoulder, arm, or hand Can occur as Another example of related pain is phantom limb pain. Phantom limb pain is a pain sensation from the limb that the individual no longer has or a sensation of pain from the limb that the individual no longer receives physical signals. This phenomenon, also known as afferent block pain, is reported with few exceptions by amputees and limb paralysis patients.

  Fourth, neuropathic pain (eg, “trigeminal neuralgia”) can occur as a result of damage or disease to the nerve tissue itself. Injury or disease can disrupt the ability of sensory nerves to transmit the correct information to the thalamus or cortex. As a result, the brain interprets painful stimuli even though there is no obvious or proven cause of physical pain.

  Other pain categories include acute pain and chronic pain. Acute pain is defined as pain that is short-term or has an easily identifiable cause. Acute pain refers to current damage or disease to the tissue, which can be “fast” and “sharp”, followed by pain. Acute pain concentrates in one area before spreading somewhat. Acute pain is generally better achieved by drugs (eg, morphine).

  Chronic pain can be medically defined as pain that persists for 6 months or longer. This constant or intermittent pain often loses its purpose over time because it does not help prevent injury to the body. Chronic pain is often more difficult to treat compared to acute pain. Treatment of any chronic pain typically requires professional supervision. In addition, stronger drugs are usually used for a long time in an attempt to control pain. This can lead to drug addiction. For example, opioids are used for some time to control chronic pain in some instances. Drug resistance, drug addiction, and even psychological addiction can occur.

  “Nociceptive pain” refers to pain felt by nociceptors, which are nerves that sense and respond to damaged parts of the body. The nociceptors can signal tissue stimulation, imminent injury, or actual damage. When activated, nociceptors transmit pain signals (via peripheral nerves as well as the spinal cord) to the brain. Nociceptive pain is typically well localized, stationary, often aching or pulsatile. A subtype of nociceptive pain includes visceral pain and involves the viscera. Visceral pain is idiopathic and tends to be less localized. Nociceptive pain can be timed and usually recovers from pain as tissue damage heals. However, nociceptive pain associated with arthritis or cancer cannot be timed. Nociceptive pain tends to be successfully treated with opiate analgesics such as, for example, buprenorphine, codeine, hydrocodone, oxycodone, morphine, and the like. Examples of nociceptive pain include, but are not limited to, pain from sprains, fractures, burns, bumps, contusions, inflammatory pain from infections or joint disorders, pain from obstruction, cancer pain, And fascial pain associated with abnormal muscle tone.

  “Neuropathic pain” refers to chronic pain, often resulting from tissue damage. Neuropathic pain is generally caused by injuries or damage to nerve fibers. Neuropathic pain may include a burning or cold feeling, a tingling sensation like a pin or needle stimulus, numbness, and / or pruritus. Neuropathic pain can be continuous and / or sudden. Neuropathic pain is difficult to treat, but opioids include, but are not limited to, methadone, tramadol, tapentadol, oxycodone, methadone, morphine, levorphanol, and the like. Causes of neuropathic pain include but are not limited to alcoholism, amputation, problems with back, lower limbs, and buttocks, chemotherapy, diabetes, facial nerve problems, HIV / AIDS, multiple sclerosis, Include herpes zoster, spinal surgery, trigeminal neuralgia, fibromyalgia, and the like. In some cases, the cause of neuropathic pain may be unknown or unknown.

  “Addictive” refers to a compound that, when administered to a mammal over a period of time, produces a dependence on the compound in the mammal. Dependence can be physiological and / or psychological. The therapeutic effect of addictive compounds on mammals can decrease with prolonged administration of addictive compounds, which is a non-limiting example of physiological dependence. When an addictive compound is administered to a mammal, it can also cause craving for more of the compound in the mammal, which is a non-limiting example of physiological dependence. Examples of addictive compounds include, but are not limited to, addictive opioids and the like.

  “Analgesic” and “analgesic agent” refer to compounds capable of suppressing and / or reducing pain in a mammal. Pain can be suppressed / reduced in mammals by binding opioid analgesics to mu receptors. When analgesia is effected via a mu receptor, the analgesic is referred to as a mu receptor agonist. Certain analgesics are capable of suppressing nociceptive pain and / or neuropathic pain, and examples of such analgesics include morphine, codeine, hydromorphone, oxycodone, hydrocodone, buprenorphine, and the like. It is done.

  As used herein, the term “tolerance” refers to a psychological and / or physiological process in which a patient is accustomed to the high presence of a substance and consequently achieves the same effect. High doses of material are required. Tolerance can occur at different times towards different actions (eg analgesic and side effects) of the same drug. The mechanism of resistance is not fully understood, but it may include receptor down-regulation or desensitization, up-regulation of inhibition pathways, increased metabolism, and / or changes in receptor processes (e.g. Phosphorylation).

  The term “dose” refers to a range of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof that, when given to a patient in need, provides a therapeutic serum level of norivogaine. . The dose is described, for example, in the range of about 20 mg to about 120 mg and can be expressed in either milligrams or mg / kg body weight. The appropriate clinician will select the appropriate dose based on the patient's weight, age, degree of addiction, health, and other relevant factors, all of which are well matched to the skill in the art. It is.

  The term “unit dose” refers to the dose of drug given to a patient, regardless of the patient's weight, to give a therapeutic result. In such instances, unit doses are sold in standard form (eg, 20 mg tablets). A unit dose may be administered as a single dose or as a series of divided doses. In some embodiments, the unit dose provides a standard level of drug to the patient regardless of the patient's weight. Many of the drugs are marketed based on doses that are therapeutic to all patients based on therapeutic concentrations. In such cases, it is not necessary to set a dose based on the weight of the patient.

II. Compositions As will be apparent to those of skill in the art upon reading this disclosure, the present invention provides compositions directed to the treatment or prevention of the diseases or disorders described herein, or symptoms of the diseases or disorders, and The composition comprises nolubogaine, a nolibogaine derivative, a prodrug of norivogaine, a pharmaceutically acceptable salt and / or solvate thereof. The present invention further provides a composition for the treatment, attenuation, or prevention of the symptoms of the diseases or disorders described herein, wherein the composition comprises norivogaine, a norivogaine derivative, a prodrug of norivogaine, a pharmaceutically Including their respective salts and / or solvates that are acceptable.

  In some embodiments, the composition comprises oral delivery, transdermal delivery, intracorporeal delivery, pulmonary delivery, intrarectal delivery, nasal delivery, vaginal delivery, tongue delivery, intravenous delivery, intraarterial delivery, intramuscular delivery. Formulated for intraperitoneal delivery, intradermal delivery, or subcutaneous delivery. In one embodiment, the therapeutically effective amount of the compound is about 1 mg / kg to about 4 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1 mg / kg to about 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1 mg / kg to about 2 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.3 mg / kg to about 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.5 mg / kg to about 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.3 mg / kg to about 4 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.5 mg / kg to about 4 mg / kg body weight per day. A range includes both end values as well as any subranges existing between

  In one embodiment, the therapeutically effective amount of the compound is about 1 mg / kg to about 8 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.3 mg / kg to about 7 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.3 mg / kg to about 6 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.3 mg / kg to about 5 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.3 mg / kg to about 4 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.3 mg / kg to about 2 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.5 mg / kg to about 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 1.7 mg / kg to about 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 2 mg / kg to about 4 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 2 mg / kg to about 3 mg / kg body weight per day.

  In one embodiment, the therapeutically effective amount of compound is about 8 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of compound is about 7 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 6 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of compound is about 5 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of compound is about 4 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of compound is about 3 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of compound is about 2 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of compound is about 1 mg / kg body weight per day.

  In one embodiment, the therapeutically effective amount of compound is about 4 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of compound is about 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 2 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.7 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.5 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of compound is about 1.2 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1 mg / kg body weight per day.

  In one aspect, the present invention provides a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of norivogaine and a pharmaceutically acceptable additive, wherein the therapeutically or prophylactically effective amount of norivogaine comprises: An amount that delivers a total amount of nolubogaine that is less than about 50 ng to 10 μg / kg body weight per day. In some embodiments, the therapeutically or prophylactically effective amount of norivogaine is an amount that delivers a total amount of norivogaine that is about 50 ng to about 5 μg / kg body weight per day. In some embodiments, the therapeutically or prophylactically effective amount of norivogaine is an amount that delivers a total amount of norivogaine that is about 50 ng to about 1 μg per kg body weight per day. In some embodiments, the composition is formulated for administration once per day. In some embodiments, the composition is formulated for administration more than once per day.

  In some embodiments, the composition is formulated for sublingual, intranasal or pulmonary delivery. In one aspect, the present invention provides a pharmaceutical composition comprising a pharmaceutically effective amount of norivogaine and a pharmaceutically acceptable additive, wherein the therapeutically effective amount of norivogaine is per kg body weight per day. The amount that delivers a total amount of norbogaine that is between 50 ng and less than 100 μg. In some embodiments, the therapeutically effective amount of norivogaine is an amount that delivers a total amount of norivogaine that is 50 ng to 50 μg / kg body weight per day. In some embodiments, the therapeutically effective amount of norivogaine is an amount that delivers a total amount of norivogaine that is 50 ng to 10 μg / kg body weight per day. In some embodiments, the therapeutically effective amount of norivogaine is an amount that delivers a total amount of norivogaine that is 50 ng to 1 μg / kg body weight per day. In some embodiments, the composition is formulated for administration once per day. In some embodiments, the composition is formulated for more than one administration per day. A range includes both end values as well as any subranges between them.

  In another embodiment, the therapeutically effective amount of compound is 1.3 mg to 4 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is 1.5-3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is 1.7-3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is 2-4 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is 2 mg / kg to 3 mg / kg body weight per day.

または医薬的に許容可能なその塩及び／もしくは溶媒和物であり、
ここで、Ｒは、水素または１〜１２個の炭素原子の加水分解性エステルなどの加水分解性基である。 Compounds utilized In one embodiment, the norbogaine derivative is represented by Formula I:

Or a pharmaceutically acceptable salt and / or solvate thereof,
Here, R is a hydrolyzable group such as hydrogen or a hydrolyzable ester of 1 to 12 carbon atoms.

ここで、Ｘは、Ｃ_１〜Ｃ_１２基であり、非置換であるか、または置換されている。例えば、Ｘは、メチル、エチル、ｎ−プロピル、ｎ−ブチル、ｎ−ペンチル、ｎ−へキシル、ｎ−ヘプチル、ｎ−オクチル、ｎ−ノニル、ｎ−デシル、ｎ−ウンデシル、もしくはｎ−ドデシルなどの直鎖アルキル基であるか、またはｉ−プロピルもしくはｓｅｃ−ブチルなどの分岐鎖アルキル基であってよい。また、Ｘは、フェニル基またはベンジル基であってよく、これらのいずれも低級アルキル基または低級アルコキシ基で置換されていてよい。一般に低級アルキル基及び／または低級アルコキシ基は、１〜約６個の炭素を有する。例えば、Ｒ基は、アセチル、プロピオニル、またはベンゾイルであってよい。しかしながら、こうした基は、例示にすぎない。 In general, in the above formula, R is hydrogen or a group of the formula

_Here, X is C 1 _{-C 12} group, and is unsubstituted or substituted. For example, X is methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, or n-dodecyl. Or a branched alkyl group such as i-propyl or sec-butyl. X may be a phenyl group or a benzyl group, any of which may be substituted with a lower alkyl group or a lower alkoxy group. Generally lower alkyl groups and / or lower alkoxy groups have from 1 to about 6 carbons. For example, the R group can be acetyl, propionyl, or benzoyl. However, such groups are merely exemplary.

  In general, all X groups are unsubstituted or substituted with a lower alkyl group or a lower alkoxy group, which may be either. For example, the substituted X may be an o-methylbenzyl group, an m-methylbenzyl group, or a p-methylbenzyl group, or an o-methoxybenzyl group, an m-methoxybenzyl group, or a p-methoxybenzyl group.

C ₁ -C ₁₂ groups include C ₁ -C ₁₂ alkyl groups, C ₃ -C ₁₂ cycloalkyl groups, C ₆ -C ₁₂ aryl groups, C ₇ -C ₁₂ arylalkyl groups, where C _x indicates that the group contains x carbon atoms. Lower alkyl _refers to C 1 -C ₄ alkyl, lower alkoxy _refers to C 1 -C ₄ alkoxy.

または、医薬的に許容可能なその塩及び／もしくは溶媒和物であり、
ここで、

Ｒ^１は、ハロ、ＯＲ^２、または１〜５個のＲ^１０で任意選択で置換されたＣ_１〜Ｃ_１２アルキルであり；
Ｒ^２は、水素であるか、またはＣ（Ｏ）Ｒ^ｘ、−Ｃ（Ｏ）ＯＲ^ｘ、及び−Ｃ（Ｏ）Ｎ（Ｒ^ｙ）_２からなる群から選択される加水分解性基であり、ここで、それぞれのＲ^ｘは、１〜５個のＲ^１０で任意選択で置換されたＣ_１〜Ｃ_６アルキルからなる群から選択され、それぞれのＲ^ｙは、水素、１〜５個のＲ^１０で任意選択で置換されたＣ_１〜Ｃ_６アルキル、１〜５個のＲ^１０で任意選択で置換されたＣ_６〜Ｃ_１４アリール、１〜５個のＲ^１０で任意選択で置換されたＣ_３〜Ｃ_１０シクロアルキル、１〜４個のヘテロ原子を有し、１〜５個のＲ^１０で任意選択で置換されたＣ_１〜Ｃ_１０ヘテロアリール、１〜４個のヘテロ原子を有し、１〜５個のＲ^１０で任意選択で置換されたＣ_１〜Ｃ_１０ヘテロ環式からなる群から独立に選択され、ここで、それぞれのＲ^ｙは、Ｒ^ｙに結合している窒素原子と一緒になって、１〜４個のヘテロ原子を有し、１〜５個のＲ^１０で任意選択で置換されたＣ_１〜Ｃ_６ヘテロ環式を形成するか、または１〜４個のヘテロ原子を有し、１〜５個のＲ^１０で任意選択で置換されたＣ_１〜Ｃ_６ヘテロアリールを形成し；
Ｒ^３は、水素、１〜５個のＲ^１０で任意選択で置換されたＣ_１〜Ｃ_１２アルキル、１〜５個のＲ^１０で任意選択で置換されたアリール、−Ｃ（Ｏ）Ｒ^６、−Ｃ（Ｏ）ＮＲ^６Ｒ^６、及び−Ｃ（Ｏ）ＯＲ^６からなる群から選択され；
Ｒ^４は、水素、−（ＣＨ_２）_ｍＯＲ^８、−ＣＲ^７（ＯＨ）Ｒ^８、−（ＣＨ_２）_ｍＣＮ、−（ＣＨ_２）_ｍＣＯＲ^８、−（ＣＨ_２）_ｍＣＯ_２Ｒ^８、−（ＣＨ_２）_ｍＣ（Ｏ）ＮＲ^７Ｒ^８、−（ＣＨ_２）_ｍＣ（Ｏ）ＮＲ^７ＮＲ^８Ｒ^８、−（ＣＨ_２）_ｍＣ（Ｏ）ＮＲ^７ＮＲ^８Ｃ（Ｏ）Ｒ^９、及び−（ＣＨ_２）_ｍＮＲ^７Ｒ^８からなる群から選択され；
ｍは、０、１、または２であり；
Ｌは、結合であるか、またはＣ_１〜Ｃ_１２アルキレンであり；
Ｒ^５は、水素、１〜５個のＲ^１０で置換されたＣ_１〜Ｃ_１２アルキル、１〜５個のＲ^１０で置換されたＣ_１〜Ｃ_１２アルケニル、−Ｘ^１−Ｒ^７、−（Ｘ^１−Ｙ）_ｎ−Ｘ^１−Ｒ^７、−ＳＯ_２ＮＲ^７Ｒ^８、−Ｏ−Ｃ（Ｏ）Ｒ^９、−Ｃ（Ｏ）ＯＲ^８、−Ｃ（Ｏ）ＮＲ^７Ｒ^８、−ＮＲ^７Ｒ^８、−ＮＨＣ（Ｏ）Ｒ^９、及び−ＮＲ^７Ｃ（Ｏ）Ｒ^９からなる群から選択され；
それぞれのＲ^６は、水素、Ｃ_１〜Ｃ_１２アルキル、Ｃ_２〜Ｃ_１２アルケニル、Ｃ_２〜Ｃ_１２アルキニル、Ｃ_６〜Ｃ_１０アリール、１〜４個のヘテロ原子を有するＣ_１〜Ｃ_６ヘテロアリール、及び１〜４個のヘテロ原子を有するＣ_１〜Ｃ_６ヘテロ環からなる群から独立に選択され、ここで、当該アルキル、アルケニル、アルキニル、アリール、ヘテロアリール、及びヘテロ環は、１〜５個のＲ^１０で任意選択で置換され；
Ｘ^１は、Ｏ及びＳからなる群から選択され；
Ｙは、Ｃ_１〜Ｃ_４アルキレンもしくはＣ_６〜Ｃ_１０アリーレンであるか、またはそれらの組み合わせであり；
ｎは、１、２、または３であり；
Ｒ^７及びＲ^８は、水素、１〜５個のＲ^１０で任意選択で置換されたＣ_１〜Ｃ_１２アルキル、１〜４個のヘテロ原子を有し、１〜５個のＲ^１０で任意選択で置換されたＣ_１〜Ｃ_６ヘテロ環、１〜５個のＲ^１０で任意選択で置換されたＣ_３〜Ｃ_１０シクロアルキル、１〜５個のＲ^１０で任意選択で置換されたＣ_６〜Ｃ_１０アリール、及び１〜４個のヘテロ原子を有し、１〜５個のＲ^１０で任意選択で置換されたＣ_１〜Ｃ_６ヘテロアリールからなる群からそれぞれ独立に選択され；
Ｒ^９は、１〜５個のＲ^１０で任意選択で置換されたＣ_１〜Ｃ_１２アルキル、１〜４個のヘテロ原子を有し、１〜５個のＲ^１０で任意選択で置換されたＣ_１〜Ｃ_６ヘテロ環、１〜５個のＲ^１０で任意選択で置換されたＣ_３〜Ｃ_１０シクロアルキル、１〜５個のＲ^１０で任意選択で置換されたＣ_６〜Ｃ_１０アリール、及び１〜４個のヘテロ原子を有し、１〜５個のＲ^１０で任意選択で置換されたＣ_１〜Ｃ_６ヘテロアリールからなる群から選択され；
Ｒ^１０は、Ｃ_１〜Ｃ_４アルキル、フェニル、ハロ、−ＯＲ^１１、−ＣＮ、−ＣＯＲ^１１、−ＣＯ_２Ｒ^１１、−Ｃ（Ｏ）ＮＨＲ^１１、−ＮＲ^１１Ｒ^１１、−Ｃ（Ｏ）ＮＲ^１１Ｒ^１１、−Ｃ（Ｏ）ＮＨＮＨＲ^１１、−Ｃ（Ｏ）ＮＲ^１１ＮＨＲ^１１、−Ｃ（Ｏ）ＮＲ^１１ＮＲ^１１Ｒ^１１、−Ｃ（Ｏ）ＮＨＮＲ^１１Ｃ（Ｏ）Ｒ^１１、−Ｃ（Ｏ）ＮＨＮＨＣ（Ｏ）Ｒ^１１、−ＳＯ_２ＮＲ^１１Ｒ^１１、−Ｃ（Ｏ）ＮＲ^１１ＮＲ^１１Ｃ（Ｏ）Ｒ^１１、及び−Ｃ（Ｏ）ＮＲ^１１ＮＨＣ（Ｏ）Ｒ^１１からなる群から選択され、ならびに
Ｒ^１１は、独立に水素であるか、またはＣ_１〜Ｃ_１２アルキルであるが；
但し：
Ｌが結合であるとき、Ｒ^５は水素ではなく；

In one embodiment, the norbogaine derivative is represented by Formula II

Or a pharmaceutically acceptable salt and / or solvate thereof,
here,

R ¹ is halo, OR ² , or C ₁ -C ₁₂ alkyl optionally substituted with 1 to 5 R ¹⁰ ;
R ² is hydrogen or a hydrolyzable group selected from the group consisting of C (O) R ^x , —C (O) OR ^x , and —C (O) N (R ^y ) ₂ . Wherein each R ^x is selected from the group consisting of C ₁ -C ₆ alkyl optionally substituted with 1-5 R ¹⁰ , wherein each R ^y is hydrogen, 1-5 _C 1 -C ₆ alkyl optionally substituted with R ^10, 1-5 _C 6 optionally substituted with a ^{R 10} _{-C 14} aryl, optionally substituted with 1-5 ^{R 10} C ₃ -C ₁₀ cycloalkyl, having 1 to 4 heteroatoms, optionally substituted with 1 to 5 R ¹⁰ , and C _{1 to} C ₁₀ heteroaryl, 1 to 4 heteroatoms Independent of the group consisting of C ₁ -C ₁₀ heterocyclic optionally having 1 to 5 R ¹⁰ and optionally substituted It is selected, wherein each R ^y are taken together with the nitrogen atom attached to R ^y, having from 1 to 4 heteroatoms, optionally with 1-5 R ¹⁰ or form a substituted _C 1 -C ₆ heterocyclic, or have 1 to 4 heteroatoms, a _C 1 -C ₆ heteroaryl optionally substituted with 1-5 ^{R 10} Forming;
R ³ is hydrogen, 1-5 _C 1 optionally substituted with a ^{R 10} _{-C 12} alkyl, aryl optionally substituted with 1-5 ^{R 10, -C (O) R} 6 , —C (O) NR ⁶ R ⁶ , and —C (O) OR ⁶ ;
R ⁴ is hydrogen, — (CH ₂ ) _m OR ⁸ , —CR ⁷ (OH) R ⁸ , — (CH ₂ ) _m CN, — (CH ₂ ) _m COR ⁸ , — (CH ₂ ) _m CO ₂ R ⁸ , — (CH ₂ ) _m C (O) NR ⁷ R ⁸ , — (CH ₂ ) _m C (O) NR ⁷ NR ⁸ R ⁸ , — (CH ₂ ) _m C (O) NR ⁷ NR ⁸ C ( O) selected from the group consisting of R ⁹ and — (CH ₂ ) _m NR ⁷ R ⁸ ;
m is 0, 1, or 2;
L is a bond or C ₁ -C ₁₂ alkylene;
R ⁵ is hydrogen, 1-5 _C 1 _{-C 12} alkyl substituted with ^{R 10,} _C 1 substituted with 1-5 ^{R 10} _{-C 12} ^alkenyl, -X 1 ^-R 7, - _{^{(X 1 -Y) n -X 1}} -R 7, -SO 2 NR 7 R 8, -O-C (O) R 9, -C (O) OR 8, -C (O) NR 7 R 8, Selected from the group consisting of —NR ⁷ R ⁸ , —NHC (O) R ⁹ , and —NR ⁷ C (O) R ⁹ ;
Each R ⁶ is hydrogen, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ alkynyl, C ₆ -C ₁₀ aryl, C ₁ -C ₆ having 1-4 heteroatoms. Independently selected from the group consisting of heteroaryl and C ₁ -C ₆ heterocycles having ₁ to ₄ heteroatoms, wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are 1 optionally substituted with to five ^{R 10;}
X ¹ is selected from the group consisting of O and S;
Y is C ₁ -C ₄ alkylene or C ₆ -C ₁₀ arylene, or a combination thereof;
n is 1, 2, or 3;
R ⁷ and ^{R 8} are hydrogen, 1-5 _C 1 optionally substituted with a ^{R 10} _{-C 12} alkyl having 1 to 4 heteroatoms, optionally with 1-5 ^{R 10} _C 1 -C ₆ heterocycle substituted with selected, _C is optionally substituted with 1-5 ^{R 10} 3 _{-C 10} cycloalkyl, optionally substituted with 1-5 ^{R 10} C Each independently selected from the group consisting of _{6 to} C ₁₀ aryl and C _{1 to} C ₆ heteroaryl having 1 to 4 heteroatoms and optionally substituted with 1 to 5 R ¹⁰ ;
R ⁹ is 1-5 _C 1 optionally substituted with a ^{R 10} _{-C 12} alkyl having one to four heteroatoms, optionally substituted with 1-5 ^{R 10} C ₁ -C ₆ heterocyclic, 1-5 _C 3 _{-C 10} cycloalkyl optionally substituted with ^{R 10,} 1-5 _C 6 optionally substituted with a ^{R 10} _{-C 10} aryl Selected from the group consisting of C ₁ -C ₆ heteroaryl, having 1 to 4 heteroatoms and optionally substituted with 1 to 5 R ¹⁰ ;
R ¹⁰ is C ₁ -C ₄ alkyl, phenyl, halo, —OR ¹¹ , —CN, —COR ¹¹ , —CO ₂ R ¹¹ , —C (O) NHR ¹¹ , —NR ¹¹ R ¹¹ , —C (O ) NR ¹¹ R ¹¹ , —C (O) NHNHR ¹¹ , —C (O) NR ¹¹ NHR ¹¹ , —C (O) NR ¹¹ NR ¹¹ R ¹¹ , —C (O) NHNR ¹¹ C (O) R ¹¹ , —C (O) NHNHC (O) R ¹¹ , —SO ₂ NR ¹¹ R ¹¹ , —C (O) NR ¹¹ NR ¹¹ C (O) R ¹¹ , and —C (O) NR ¹¹ NHC (O) R ¹¹ And R ¹¹ is independently hydrogen or C ₁ -C ₁₂ alkyl, but is selected from the group consisting of:
However:
When L is a bond, R ⁵ is not hydrogen;

または医薬的に許容可能なその塩及び／もしくは溶媒和物であり、
ここで、

Ｒ^１２は、ハロ、−ＯＨ、−ＳＨ、−ＮＨ_２、−Ｓ（Ｏ）_２Ｎ（Ｒ^１７）_２、−Ｒ^ｚ−Ｌ^１−Ｒ^１８、−Ｒ^ｚ−Ｌ^１−Ｒ^１９、−Ｒ^ｚ−Ｌ^１−Ｒ^２０、または−Ｒ^ｚ−Ｌ^１−ＣＨＲ^１８Ｒ^１９であり、ここで、Ｒ^ｚは、Ｏ、Ｓ、またはＮＲ^１７であり；
Ｌ^１は、アルキレン、アリーレン、−Ｃ（Ｏ）−アルキレン、−Ｃ（Ｏ）−アリーレン、−Ｃ（Ｏ）Ｏ−アリーレン、−Ｃ（Ｏ）Ｏ−アルキレン、−Ｃ（Ｏ）ＮＲ^２０−アルキレン、−Ｃ（Ｏ）ＮＲ^２０−アリーレン、−Ｃ（ＮＲ^２０）ＮＲ^２０−アルキレン、または−Ｃ（ＮＲ^２０）ＮＲ^２０−アリーレンであり、ここで、Ｌ^１は、−Ｏ−Ｌ^１−Ｒ^１８が、−ＯＣ（Ｏ）−アルキレン−Ｒ^１８、−ＯＣ（Ｏ）Ｏ−アリーレン−Ｒ^１８、−ＯＣ（Ｏ）Ｏ−アルキレン−Ｒ^１８、−ＯＣ（Ｏ）−アリーレン−Ｒ^１８、−ＯＣ（Ｏ）ＮＲ^２０−アルキレン−Ｒ^１８、−ＯＣ（Ｏ）ＮＲ^２０−アリーレン−Ｒ^１８、−ＯＣ（ＮＲ^２０）ＮＲ^２０−アルキレン−Ｒ^１８、または−ＯＣ（ＮＲ^２０）ＮＲ^２０−アリーレン−Ｒ^１８となるように構成され、ここで、当該アルキレン及びアリーレンは、１〜２個のＲ^１６で任意選択で置換され；
Ｒ^１３は、水素、−Ｓ（Ｏ）_２ＯＲ^２０、−Ｓ（Ｏ）_２Ｒ^２０、−Ｃ（Ｏ）Ｒ^１５、−Ｃ（Ｏ）ＮＲ^１５Ｒ^１５、−Ｃ（Ｏ）ＯＲ^１５、１〜５個のＲ^１６で任意選択で置換されたＣ_１〜Ｃ_１２アルキル、１〜５個のＲ^１６で任意選択で置換されたＣ_１〜Ｃ_１２アルケニル、または１〜５個のＲ^１６で任意選択で置換されたアリールであり；
Ｒ^１４は、水素、ハロ、−ＯＲ^１７、−ＣＮ、Ｃ_１〜Ｃ_１２アルキル、Ｃ_１〜Ｃ_１２アルコキシ、アリール、またはアリールオキシであり、ここで、当該アルキル、アルコキシ、アリール、及びアリールオキシは、１〜５個のＲ^１６で任意選択で置換され；
それぞれのＲ^１５は、水素、Ｃ_１〜Ｃ_１２アルキル、Ｃ_２〜Ｃ_１２アルケニル、Ｃ_２〜Ｃ_１２アルキニル、アリール、ヘテロアリール、及びヘテロ環からなる群から独立に選択され、ここで、当該アルキル、アルケニル、アルキニル、アリール、ヘテロアリール、及びヘテロ環は、１〜５個のＲ^１６で任意選択で置換され；
Ｒ^１６は、フェニル、ハロ、−ＯＲ^１７、−ＣＮ、−ＣＯＲ^１７、−ＣＯ_２Ｒ^１７、−ＮＲ^１７Ｒ^１７、−ＮＲ^１７Ｃ（Ｏ）Ｒ^１７、−ＮＲ^１７ＳＯ_２Ｒ^１７、−Ｃ（Ｏ）ＮＲ^１７Ｒ^１７、−Ｃ（Ｏ）ＮＲ^１７ＮＲ^１７Ｒ^１７、−ＳＯ_２ＮＲ^１７Ｒ^１７、及び−Ｃ（Ｏ）ＮＲ^１７ＮＲ^１７Ｃ（Ｏ）Ｒ^１７からなる群から選択され；
それぞれのＲ^１７は、独立に、水素であるか、または１〜３個のハロで任意選択で置換されたＣ_１〜Ｃ_１２アルキルであり；
Ｒ^１８は、水素、−Ｃ（Ｏ）Ｒ^２０、−Ｃ（Ｏ）ＯＲ^２０、−Ｃ（Ｏ）Ｎ（Ｒ^２０）_２、または−Ｎ（Ｒ^２０）Ｃ（Ｏ）Ｒ^２０であり；
Ｒ^１９は、水素、−Ｎ（Ｒ^２０）_２、−Ｃ（Ｏ）Ｎ（Ｒ^２０）_２、−Ｃ（ＮＲ^２０）Ｎ（Ｒ^２０）_２、−Ｃ（ＮＳＯ_２Ｒ^２０）Ｎ（Ｒ^２０）_２、−ＮＲ^２０Ｃ（Ｏ）Ｎ（Ｒ^２０）_２、−ＮＲ^２０Ｃ（Ｓ）Ｎ（Ｒ^２０）_２、−ＮＲ^２０Ｃ（ＮＲ^２０）Ｎ（Ｒ^２０）_２、−ＮＲ^２０Ｃ（ＮＳＯ_２Ｒ^２０）Ｎ（Ｒ^２０）_２、またはテトラゾールであり；ならびに
それぞれＲ^２０は、水素、Ｃ_１〜Ｃ_１２アルキル、及びアリールからなる群から独立に選択されるが；
但し：

In one embodiment, the norbogaine derivative is represented by Formula III:

Or a pharmaceutically acceptable salt and / or solvate thereof,
here,

R ¹² is halo, —OH, —SH, —NH ₂ , —S (O) ₂ N (R ¹⁷ ) ₂ , —R ^z —L ¹ —R ¹⁸ , —R ^z —L ¹ —R ¹⁹ , — an R ^z -L ¹ -R ²⁰ or ^{-R z -L 1 -CHR 18 R 19} ,, wherein, ^{R z} is, O, S or ^{NR 17,;}
L ¹ is alkylene, arylene, —C (O) -alkylene, —C (O) -arylene, —C (O) O-arylene, —C (O) O-alkylene, —C (O) NR ²⁰ —. Alkylene, —C (O) NR ²⁰ -arylene, —C (NR ²⁰ ) NR ²⁰ -alkylene, or —C (NR ²⁰ ) NR ²⁰ -arylene, wherein L ¹ is —O—L ¹ —. R ¹⁸ is —OC (O) -alkylene-R ¹⁸ , —OC (O) O-arylene-R ¹⁸ , —OC (O) O-alkylene-R ¹⁸ , —OC (O) -arylene-R ¹⁸ , -OC (O) ^{NR 20} - alkylene ^{-R 18, -OC (O) NR} 20 - arylene ^{-R 18, -OC (NR 20)} NR 20 - alkylene ^{-R 18} or ^{-OC (NR 20) NR 20,} - Arylene -R ¹⁸ where the alkylene and arylene are optionally substituted with 1 to 2 R ¹⁶ ;
R ¹³ is hydrogen, —S (O) ₂ OR ²⁰ , —S (O) ₂ R ²⁰ , —C (O) R ¹⁵ , —C (O) NR ¹⁵ R ¹⁵ , —C (O) OR ¹⁵ , 1-5 _C 1 optionally substituted with ^{R 16} in _{-C 12} alkyl, _C 1 _{-C 12} alkenyl optionally substituted with 1-5 ^{R 16} or 1-5 ^{R 16,} Aryl optionally substituted with
R ¹⁴ is hydrogen, halo, —OR ¹⁷ , —CN, C ₁ -C ₁₂ alkyl, C ₁ -C ₁₂ alkoxy, aryl, or aryloxy, wherein the alkyl, alkoxy, aryl, and aryloxy Is optionally substituted with 1 to 5 R ¹⁶ ;
Each R ¹⁵ is independently selected from the group consisting of hydrogen, C ₁ -C ₁₂ alkyl, C ₂ -C ₁₂ alkenyl, C ₂ -C ₁₂ alkynyl, aryl, heteroaryl, and heterocycle, wherein Alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are optionally substituted with 1-5 R ¹⁶ ;
R ¹⁶ is phenyl, halo, —OR ¹⁷ , —CN, —COR ¹⁷ , —CO ₂ R ¹⁷ , —NR ¹⁷ R ¹⁷ , —NR ¹⁷ C (O) R ¹⁷ , —NR ¹⁷ SO ₂ R ¹⁷ , — Selected from the group consisting of C (O) NR ¹⁷ R ¹⁷ , —C (O) NR ¹⁷ NR ¹⁷ R ¹⁷ , —SO ₂ NR ¹⁷ R ¹⁷ , and —C (O) NR ¹⁷ NR ¹⁷ C (O) R ¹⁷ Is;
Each R ¹⁷ is independently hydrogen or C ₁ -C ₁₂ alkyl optionally substituted with 1 to 3 halo;
R ¹⁸ is hydrogen, —C (O) R ²⁰ , —C (O) OR ²⁰ , —C (O) N (R ²⁰ ) ₂ , or —N (R ²⁰ ) C (O) R ²⁰ ;
R ¹⁹ is hydrogen, —N (R ²⁰ ) ₂ , —C (O) N (R ²⁰ ) ₂ , —C (NR ²⁰ ) N (R ²⁰ ) ₂ , —C (NSO ₂ R ²⁰ ) N (R _{^{20) 2, -NR 20 C (}} O) N (R 20) 2, -NR 20 C (S) N (R 20) 2, -NR 20 C (NR 20) N (R 20) 2, -NR 20 C (NSO ₂ R ²⁰ ) N (R ²⁰ ) ₂ , or tetrazole; and each R ²⁰ is independently selected from the group consisting of hydrogen, C ₁ -C ₁₂ alkyl, and aryl;
However:

または医薬的に許容可能なその塩及び／もしくは溶媒和物であり、
ここで、
Ｒ^２１は、水素、−Ｃ（Ｏ）Ｒ^２３、−Ｃ（Ｏ）ＮＲ^２４Ｒ^２５、及び−Ｃ（Ｏ）ＯＲ^２６からなる群から選択される加水分解性基からなる群から選択され、ここで、Ｒ^２３は、水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、及び置換アルキニルからなる群から選択され、Ｒ^２４及びＲ^２５は、水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヘテロ環式、及び置換ヘテロ環式からなる群から独立に選択され、Ｒ^２６は、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、ヘテロ環式、及び置換ヘテロ環式からなる群から選択されるが、但し、Ｒ^２１は、糖類またはオリゴ糖ではないことが条件であり；
Ｌ^２は、共有結合及び切断可能なリンカー基からなる群から選択され；
Ｒ^２２は、水素、アルキル、置換アルキル、アルケニル、置換アルケニル、アルキニル、置換アルキニル、アリール、置換アリール、シクロアルキル、置換シクロアルキル、ヘテロアリール、置換ヘテロアリール、ヘテロ環式、及び置換ヘテロ環式からなる群から選択されるが、但し、Ｒは、糖類またはオリゴ糖ではないことが条件であり；
但し、Ｌ^２が、共有結合であり、Ｒ^２２が、水素であるとき、Ｒ^２１は、−Ｃ（Ｏ）ＮＲ^２４Ｒ^２５、及び−Ｃ（Ｏ）ＯＲ^２６からなる群から選択されることが条件であり；ならびに
さらに但し、Ｒ^２１は、水素であるか、または−Ｃ（Ｏ）Ｒ^２３であり、Ｌ^２が、共有結合であるとき、Ｒ^２２は、水素ではないことが条件である。 In one embodiment, the norbogaine derivative is represented by Formula IV:

Or a pharmaceutically acceptable salt and / or solvate thereof,
here,
R ²¹ is selected from the group consisting of hydrolyzable groups selected from the group consisting of hydrogen, —C (O) R ²³ , —C (O) NR ²⁴ R ²⁵ , and —C (O) OR ²⁶ ; Wherein R ²³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl, and R ²⁴ and R ²⁵ are hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, Independently selected from the group consisting of alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, wherein R ²⁶ is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl , Substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic And it is selected from the group consisting of substituted heterocyclic, provided that, R ²¹ is an condition not a saccharide or oligosaccharide;
L ² is selected from the group consisting of a covalent bond and a cleavable linker group;
R ²² is from hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic Selected from the group provided that R is not a saccharide or oligosaccharide;
Provided that when L ² is a covalent bond and R ²² is hydrogen, R ²¹ is selected from the group consisting of —C (O) NR ²⁴ R ²⁵ and —C (O) OR ^26. As well as with the proviso that R ²¹ is hydrogen or —C (O) R ²³ and when L ² is a covalent bond, R ²² is not hydrogen. is there.

または医薬的に許容可能なその塩及び／もしくは溶媒和物であり、
ここで、

式Ｖは、対応するジヒドロ化合物を指すことが条件であり；
Ｒ^２７は、水素であるか、またはＳＯ_２ＯＲ^２９であり；
Ｒ^２８は、水素であるか、またはＳＯ_２ＯＲ^２９であり；
Ｒ^２９は、水素であるか、またはＣ_１〜Ｃ_６アルキルであるが；
但し、Ｒ^２７及びＲ^２８の少なくとも１個は、水素ではないことが条件である。 In one embodiment, the norbogaine derivative is represented by Formula V:

Or a pharmaceutically acceptable salt and / or solvate thereof,
here,

Formula V is conditional on referring to the corresponding dihydro compound;
R ²⁷ is hydrogen or SO ₂ OR ²⁹ ;
R ²⁸ is hydrogen or SO ₂ OR ²⁹ ;
R ²⁹ is hydrogen or C ₁ -C ₆ alkyl;
However, it is a condition that at least one of R ²⁷ and R ²⁸ is not hydrogen.

または医薬的に許容可能なその塩及び／もしくは溶媒和物であり、
ここで、

式ＶＩは、対応する隣接ジヒドロ化合物を指し；
Ｒ^３０は、水素、一リン酸、二リン酸、または三リン酸であり；及び
Ｒ^３１は、水素、一リン酸、二リン酸、または三リン酸であるが；
但し、Ｒ^３０及びＲ^３１は、両方共、水素ではないことが条件であり；
ここで、Ｒ^３０及びＲ^３１の１個または複数個の一リン酸基、二リン酸基、及び三リン酸基は、１個または複数個のＣ_１〜Ｃ_６アルキルエステルで任意選択でエステル化される。 In one embodiment, the norbogaine derivative is represented by Formula VI:

Or a pharmaceutically acceptable salt and / or solvate thereof,
here,

Formula VI refers to the corresponding adjacent dihydro compound;
R ³⁰ is hydrogen, monophosphate, diphosphate, or triphosphate; and R ³¹ is hydrogen, monophosphate, diphosphate, or triphosphate;
Provided that R ³⁰ and R ³¹ are not both hydrogen;
Wherein one or more monophosphate groups, diphosphate groups, and triphosphate groups of R ³⁰ and R ³¹ are optionally esterified with one or more C ₁ -C ₆ alkyl esters. It becomes.

  The norbogaine utilized herein can be replaced by a nolibogaine derivative, or a salt of norivogaine or a norbogaine derivative, or the respective solvate described above.

  In a preferred embodiment, the compound utilized herein is norivogaine or a salt thereof. In a more preferred embodiment, the compound utilized herein is norbogaine.

III. Methods of the Invention As will be apparent to those of skill in the art upon reading the present disclosure, the present invention is a method of treating a disease treatable by administering the norbogaine described herein, comprising: There is provided a method of treatment as described above, comprising administering a dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof.

Nicotine addiction As will be apparent to those of skill in the art upon reading this disclosure, the present invention provides a method of treating a subject's nicotine addiction, wherein the therapeutically effective amount is for said patient in need of such treatment. There is provided a method of treatment as described above, comprising administering a norbogaine, a nolibogaine derivative, a nolibogaine prodrug, or a pharmaceutically acceptable salt thereof. The present invention further provides a method for treating, attenuating or preventing nicotine craving in a subject, wherein the therapeutically or prophylactically effective amount of norivogaine, norivogaine derivative, norivoga for said patient in need thereof. There is provided a method as described above comprising administering an inprodrug, or a pharmaceutically acceptable salt thereof.

  In some embodiments, the present invention provides a method of treating a subject's nicotine addiction, wherein the therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically agent for said patient in need of the method of treatment. There is provided a method of treatment as described above comprising administering an acceptable salt thereof.

  The subject or patient is any patient who uses nicotine in any form, including cigarettes, electronic cigarettes or vaporizers ("steam aspiration"), chewing tobacco, cigars, snuff, pipes, hookahs, etc. It may be. In some embodiments, the patient has nicotine addiction. In some embodiments, the patient is physically addicted to nicotine. In some embodiments, the patient is psychologically addicted to nicotine.

  In some embodiments, the therapeutically effective amount of the compound is less than about 50 ng to 10 μg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 50 ng / kg to about 5 μg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 50 ng / kg to about 1 μg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 50 ng / kg to about 1 μg / kg body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is less than about 500 ng to 10 μg / kg body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is less than about 1 μg to 10 μg / kg body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is about 50 ng, about 100 ng, about 150 ng, about 200 ng, about 250 ng, about 300 ng, about 350 ng, about 400 ng, about 450 ng, per kg body weight per day, About 500 ng, about 550 ng, about 600 ng, about 650 ng, about 700 ng, about 750 ng, about 800 ng, about 850 ng, about 900 ng, about 950 ng, about 1 μg, about 2 μg, about 3 μg, about 3 μg, about 4 μg, about 5 μg, about 6 μg , About 7 μg, about 8 μg, about 9 μg, about 10 μg. The therapeutically effective amount of the compound may be any amount within any of these ranges including endpoints.

  In some embodiments, the therapeutically effective amount of norivogaine, derivative, prodrug, or salt thereof is administered once daily. In some embodiments, the therapeutically effective amount is administered twice per day. In some embodiments, the therapeutically effective amount is administered three or more times per day.

  Where the therapeutically effective amount is administered multiple times per day, a portion of the therapeutically effective amount is administered each time. For example, a 90 kg patient who receives 1 μg of norbogaine per kg of body weight per day will receive 90 μg once a day, 45 μg twice a day, 30 μg three times a day, and so on.

  In some embodiments, the therapeutically effective amount of norivogaine, derivative, prodrug, or salt thereof is needed, for example, when the patient feels craving for nicotine as described herein, or against nicotine. It is given once when predicting feeling craving.

  In some embodiments, nolibogaine or a nolibogaine derivative is administered sublingually, pulmonary or intranasally. These routes of administration are discussed in further detail in the subsection below, entitled “Dosage and Route of Administration”.

Prevention of recurrence of nicotine use In some embodiments, the present invention provides a method for treating, preventing, or attenuating nicotine craving in a subject, wherein the amount is prophylactically effective for the patient in need thereof. A method of the invention, comprising administering a norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method for preventing nicotine addiction recurrence in a subject, wherein said subject in need thereof has a prophylactically effective amount of norivogaine, a norivogaine derivative, or pharmaceutically. There is provided the above method comprising administering an acceptable salt thereof.

  Nonetheless, patients who have not stopped using nicotine cannot use nicotine for extended periods in some situations. For example, most aircraft flights no longer allow smoking, but also ban vaporizers and electronic cigarettes as well. Other places or situations where the use of nicotine is not possible or difficult include movie theaters, other recreational facilities (including theatres, operas, concerts, etc.), and even workplaces, especially all places on the premises Examples include hospitals and schools where smoking is not permitted. In some embodiments, the prophylactically effective amount of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt thereof is before and / or before a period in which the patient is expected not to use nicotine. When administered, norbogaine, a derivative, or a salt prevents, interrupts, or attenuates craving for nicotine. In some embodiments, nicotine craving is attenuated, interrupted, or prevented for at least 2, 3, 4, 5, 6, 7, 8, 10, 15, or 24 hours.

  In some embodiments, the norbogaine is administered as needed by the patient. In some embodiments, norbogaine may be administered before nicotine craving occurs. For example, the patient may take Noribogaine in anticipation of craving, such as before drinking, before a stressful situation occurs, or in the face of inducing another nicotine use. In some embodiments, the patient takes nolibogaine to reduce or eliminate craving after nicotine craving has occurred, for example during craving. In some embodiments, the above dose of norbogaine is taken once before craving occurs and may be taken once more later on the same day if he / she feels or expects more. Low enough.

  In one embodiment, the prophylactically effective amount of the compound is less than about 50 ng to 10 μg / kg body weight per day. In another embodiment, the prophylactically effective amount of the compound is about 50 ng / kg to about 5 μg / kg body weight per day. In another embodiment, the prophylactically effective amount of the compound is about 50 ng / kg to about 1 μg / kg body weight per day. In yet another embodiment, the prophylactically effective amount of the compound is less than about 500 ng to 10 μg / kg body weight per day. In yet another embodiment, the prophylactically effective amount of the compound is less than about 1 μg to 10 μg / kg body weight per day. The prophylactically effective amount of the compound may be any amount within any of these ranges including the endpoints.

  In some embodiments, the prophylactically effective amount of norivogaine, derivative, prodrug, or salt thereof is administered once daily. In some embodiments, the prophylactically effective amount is administered twice per day. In some embodiments, the prophylactically effective amount is administered three or more times per day.

  When the prophylactically effective amount of norivogaine is administered multiple times per day, a portion of the total therapeutically effective amount is administered each time. For example, a 90 kg patient who receives 1 μg of norbogaine per kg of body weight per day will receive 90 μg once a day, 45 μg twice a day, 30 μg three times a day, and so on.

  In some embodiments, nolibogaine or a nolibogaine derivative is administered sublingually, pulmonary or intranasally. These routes of administration are discussed in further detail in the subsection below, entitled “Dosage and Route of Administration”.

Opioid or opioid-like drug addiction In one aspect, the present invention provides an opioid or addictive opioid comprising administration of a therapeutically effective amount of norivogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt or solvate thereof. It relates to the treatment of acute withdrawal from opioid-like drugs.

  In one aspect, the invention provides a method for treating opioid or opioid-like drug abuse in an addicted patient, wherein the abuse is maintained for the patient while maintaining a QT interval of less than about 500 ms during the treatment. A dose of roivogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof that provides an average serum concentration of about 50 ng / mL to about 180 ng / mL, a concentration sufficient to inhibit or ameliorate It is related with the said treatment method including administering a thing.

  In one aspect, the invention relates to a method of attenuating withdrawal symptoms in a human patient that is sensitive to withdrawal symptoms due to opioids or opioid-like drug addiction, wherein A dose of norbogaine, norbogaine derivative, or pharmaceutical that provides an average serum concentration of about 80 ng / mL to about 100 ng / mL, a concentration sufficient to attenuate the above symptoms while maintaining a QT interval of less than 500 ms Or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. The concentration is preferably sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, the withdrawal symptom is an acute withdrawal symptom.

  In one embodiment, the QT interval is not extended beyond about 50 ms. In one embodiment, the QT interval is not extended beyond about 40 ms. In one embodiment, the QT interval is not extended beyond about 30 ms. In one embodiment, the QT interval is not extended beyond about 20 ms. In one embodiment, the QT interval is not extended beyond about 10 ms. In one embodiment, the QT interval extension is equal to or less than that observed for patients treated with methadone.

  In one aspect, the invention relates to a method of attenuating withdrawal symptoms in a human patient that is sensitive to withdrawal symptoms due to opioids or opioid-like drug addiction, wherein Dosage of norbogaine, norivogaine derivative, or pharmaceutical that provides an average serum concentration of about 60 ng / mL to about 180 ng / mL that is sufficient to attenuate the above symptoms while maintaining a QT interval of less than 500 ms Or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. The concentration is preferably sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, the withdrawal symptom is an acute withdrawal symptom.

  In one embodiment, the average serum concentration of norivogaine is about 50 ng / mL to about 180 ng / mL, or about 60 ng / mL about 180 ng / mL. In one embodiment, the average serum concentration of norbogaine is about 50 ng / mL to about 150 ng / mL, or about 60 ng / mL to about 150 ng / mL. In one embodiment, the average serum concentration of norbogaine is from about 50 ng / mL to about 100 ng / mL, or from about 60 ng / mL to about 100 ng / mL. In one embodiment, the average serum concentration of said norbogaine is about 80 ng / mL to about 150 ng / mL. In one embodiment, the average serum concentration of said norbogaine is about 80 ng / mL to about 100 ng / mL. The above ranges include both end values as well as any subranges between them.

  In one embodiment, the dosage of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of about 1000 ng · hr / mL to about 6000 ng · hr / mL. In one embodiment, the dosage of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of about 1200 ng · hr / mL to about 5800 ng · hr / mL. In one embodiment, the dosage of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of about 1200 ng · hr / mL to about 5500 ng · hr / mL. The above ranges include both end values as well as any subranges between them.

  In one embodiment, a dosage of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a maximum serum concentration (Cmax) of less than about 250 ng / mL. In one embodiment, the dosage of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax of about 40 ng / mL to about 250 ng / mL. In a preferred embodiment, a dosage of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax of about 60 ng / mL to about 200 ng / mL. In one embodiment, the dosage of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax of about 100 ng / mL to about 180 ng / mL.

  In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 1 mg / kg to about 4 mg / kg body weight per day. The total dose is a combined dose, for example, norbogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof administered over a period of 24 hours when smaller doses are administered multiple times per day Total amount of solvate. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 1.3 mg / kg to about 4 mg / kg body weight. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 1.3 mg / kg to about 3 mg / kg body weight. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 1.3 mg / kg to about 2 mg / kg body weight. In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 1.5 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 1.7 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 2 mg / kg to about 4 mg / kg body weight. In one embodiment, the dosage or total dosage of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 2 mg / kg to about 3 mg / kg body weight. In one embodiment, the dose or total dose of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 2 mg / kg body weight. The above ranges include both end values as well as any subranges between them.

  In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 4 mg / kg body weight per day. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 3 mg / kg body weight per day. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 2 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 1.9 mg / kg body weight per day. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 1.8 mg / kg body weight per day. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 1.7 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 1.6 mg / kg body weight per day. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 1.5 mg / kg body weight per day. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 1.4 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 1.3 mg / kg body weight per day. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 1.2 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 1.1 mg / kg body weight per day. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 1 mg / kg body weight per day.

  In one embodiment, the dose or total dose of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 70 mg to about 150 mg. In one embodiment, the dosage or total dosage of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 75 mg to about 150 mg. In one embodiment, the dosage or total dosage of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 80 mg to about 140 mg. In one embodiment, the dosage or total dosage of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 90 mg to about 140 mg. In one embodiment, the dosage or total dosage of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 90 mg to about 130 mg. In one embodiment, the dose or total dose of the norbogaine, norivogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 100 mg to about 130 mg. In one embodiment, the dosage or total dosage of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 110 mg to about 130 mg.

  In another embodiment, a unit dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, which is about 120 mg per administration is provided. The term “unit dose” should be understood to mean a dose sufficient to provide a therapeutic result, whether administered all at once or sequentially over a period of time.

  In some embodiments, the patient receives an initial dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, followed by one or more additional doses. receive. In one embodiment, such a dosing regimen provides a mean serum concentration of norivogaine from about 50 ng / mL to about 180 ng / mL. In one embodiment, the one or more additional doses maintain an average serum concentration of about 50 ng / mL to about 180 ng / mL over a period of time.

  In some embodiments, the initial dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is about 60 mg to about 120 mg. In one embodiment, the initial dose is about 75 mg. In one embodiment, the initial dose is about 80 mg. In one embodiment, the initial dose is about 85 mg. In one embodiment, the initial dose is about 90 mg. In one embodiment, the initial dose is about 95 mg. In one embodiment, the initial dose is about 100 mg. In one embodiment, the initial dose is about 105 mg. In one embodiment, the initial dose is about 110 mg. In one embodiment, the initial dose is about 115 mg. In one embodiment, the initial dose is about 120 mg.

  In some embodiments, the one or more additional doses are lower than the initial dose. In one embodiment, the one or more additional doses are between 5 mg and 50 mg. In one embodiment, the one or more additional doses may or may not include the same amount of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the at least one additional dose is about 5 mg. In one embodiment, the at least one additional dose is about 10 mg. In one embodiment, the at least one additional dose is about 15 mg. In one embodiment, the at least one additional dose is about 20 mg. In one embodiment, the at least one additional dose is about 25 mg. In one embodiment, the at least one additional dose is about 30 mg. In one embodiment, the at least one additional dose is about 35 mg. In one embodiment, the at least one additional dose is about 40 mg. In one embodiment, the at least one additional dose is about 45 mg. In one embodiment, the at least one additional dose is about 50 mg.

  In one embodiment, the one or more additional doses are administered periodically. In one embodiment, the one or more additional doses are administered every 4 hours. In one embodiment, the one or more additional doses are administered every 6 hours. In one embodiment, the one or more additional doses are administered every 8 hours. In one embodiment, the one or more additional doses are administered every 10 hours. In one embodiment, the one or more additional doses are administered every 12 hours. In one embodiment, the one or more additional doses are administered every 18 hours. In one embodiment, the one or more additional doses are administered every 24 hours. In one embodiment, the one or more additional doses are administered every 36 hours. In one embodiment, the one or more additional doses are administered every 48 hours.

  In some embodiments, the therapeutic dose of norivogaine, norivogaine derivative, or salt or solvate thereof is a dose that is gradually reduced over a period of time during which the patient experiences, for example, significant acute withdrawal symptoms. Without dependence is treated. Without being bound by theory, it is believed that the gradual reduction allows the full therapeutic effect of norivogaine while making the QT interval extension smaller. The tapering involves the administration of the next lower dose of norivogaine over one or more times. For example, in some embodiments, the first decreasing dose is 50% to 95% of the initial or initial dose. In some embodiments, the second decreasing dose is 40% to 90% of the initial or initial dose. In some embodiments, the third decreasing dose is 30% to 85% of the initial or initial dose. In some embodiments, the fourth decreasing dose is 20% to 80% of the initial or initial dose. In some embodiments, the fifth decreasing dose is 10% to 75% of the initial or initial dose.

  In some embodiments, the first tapering dose is administered after the first dose of norbogaine. In some embodiments, the first decreasing dose is administered after the second, third, or subsequent doses of nolubogaine. The first declining dose can be administered at any time after the previous administration of norbogaine. For example, a first decreasing dose may be administered once, followed by a further decreasing dose, or a first decreasing dose may be administered multiple times, followed by a further decreasing dose (eg, , Second, third, fourth, etc.), and may be administered over one or more doses as well, for example. In some embodiments, the first decreasing dose is administered about 1 hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or more after the previous administration of norbogaine. Is done. Similarly, the second, third, fourth, etc. tapering dose, if administered, is about 1 hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or It can be administered after that time.

  In some embodiments, a single declining dose is administered to reach the desired lower therapeutic dose. In some embodiments, two declining doses are administered to reach the desired lower therapeutic dose. In some embodiments, three decreasing doses are administered to reach the desired lower therapeutic dose. In some embodiments, four or more decreasing doses are administered to reach the desired lower therapeutic dose. Decreasing doses, the number of decreasing doses, etc. can be readily determined by a qualified clinician.

  In some embodiments, the norbogaine, norivogaine derivative, or pharmaceutically acceptable salt or solvate thereof for the patient is once, twice, three times, four times or five times daily. Administered regularly. In some embodiments, the administration is once daily, or once every two days, once every three days, three times a week, twice a week, or once a week. The amount and frequency of administration will depend on, but is not limited to, the route of administration, the dose, the age and weight of the patient, the patient's condition. Suitable dosages and frequencies for the present technology can be readily determined by a qualified clinician.

  Norivogaine, norivogaine derivatives, or pharmaceutically acceptable solvates or salts thereof suitable for administration according to the methods provided herein include, but are not limited to oral delivery, transdermal delivery, sublingual delivery. Suitable for a variety of delivery modes including buccal delivery, intrapulmonary delivery or intranasal delivery. Compositions suitable for the internal route, pulmonary route, rectal route, nasal route, vaginal route, tongue route, intravenous route, intraarterial route, intramuscular route, intraperitoneal route, intradermal route and subcutaneous route may be used. . Possible dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral solutions including suspensions, solutions and emulsions. Sustained release dosage forms may be used. All dosage forms can be formulated using standard methods in the art (see, for example, Remington's Pharmaceutical Sciences, 16th edition, edited by A. Oslo, Easton, Pa. 1980).

  In a preferred embodiment, norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered orally and can be conveniently provided in the form of a tablet, caplet, sublingual, liquid or capsule. In a specific embodiment, the norivogaine is provided as norivogaine HCl, where the dose is recorded as the amount of free base norivogaine. In some embodiments, the norbogaine HCl is provided in a hard gelatin capsule that contains no nobogaine HCl without any additives.

  The patient may suffer from addiction to any opioid or opiate or opioid-like drug. In a preferred embodiment, the opioid or opioid-like drug is selected from the group consisting of heroin, cocaine, opiate, methadone, morphine, codeine, oxycodone, hydrocodone, and methamphetamine. In one embodiment, the opioid or opioid-like drug is heroin. In one embodiment, the opioid or opioid-like drug is methadone. In one embodiment, the opioid or opioid-like drug is morphine.

  In one aspect, the invention provides treatment of an addictive patient after an acute withdrawal from an opioid or opioid-like drug, using a maintenance amount of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, or Regarding attenuation.

  In some embodiments, the present invention provides a method for preventing the recurrence of abuse in an addicted patient who has been treated and ameliorated opioid or opioid-like drug abuse, wherein the patient is administered a maintenance dose of norivogaine. It relates to a method as described above comprising administering periodically.

  In some embodiments, the patient is treated for a long time (eg, 1 year or more) with a maintenance dose of norivogaine, a norbogaine derivative, or a salt or solvate thereof. In some embodiments, the patient is treated for acute withdrawal with the therapeutic dose of norivogaine described above, and then the amount of norivogaine is reduced to a maintenance level after the acute withdrawal symptoms are expected to have subsided. Is done. Acute withdrawal symptoms are generally most prominent during the first 48-72 hours after withdrawal of addictive drugs. However, acute withdrawal may continue for as long as one week.

  In some embodiments, the patient is administered a high (therapeutic) dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof during a period that ameliorates the most prominent withdrawal symptoms. Then, a lower (maintenance) dose is administered to prevent recurrence of opioid or opioid-like drug use. In some embodiments, the patient is administered a therapeutic dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, and then decreased during a period of remission of the most prominent withdrawal symptoms. A gradual (decreasing) amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered over time until the maintenance dose is reached.

  In some embodiments, the maintenance dose of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is 70% of the therapeutic dose. In some embodiments, the maintenance dose is 60% of the therapeutic dose. In some embodiments, the maintenance dose is 50% of the therapeutic dose. In some embodiments, the maintenance dose is 40% of the therapeutic dose. In some embodiments, the maintenance dose is 30% of the therapeutic dose. In some embodiments, the maintenance dose is 20% of the therapeutic dose. In some embodiments, the maintenance dose is 10% of the therapeutic dose.

  In some embodiments, the maintenance average serum level of norivogaine is about 70% of the therapeutic average serum level of norivogaine. In some embodiments, the maintenance average serum level of norivogaine is about 60% of the therapeutic average serum level of norivogaine. In some embodiments, the maintenance average serum level of norivogaine is about 50% of the therapeutic average serum level of norivogaine. In some embodiments, the maintenance average serum level of norivogaine is about 40% of the therapeutic average serum level of norivogaine. In some embodiments, the maintenance average serum level of norivogaine is about 30% of the therapeutic average serum level of norivogaine. In some embodiments, the maintenance average serum level of norivogaine is about 20% of the therapeutic average serum level of norivogaine. In some embodiments, the maintenance average serum level of norivogaine is about 10% of the therapeutic average serum level of norivogaine.

  In some embodiments, the maintenance Cmax of norivogaine is about 70% of the therapeutic Cmax of noriobogain. In some embodiments, the maintenance Cmax of norivogaine is about 60% of the therapeutic Cmax of noriobogain. In some embodiments, the maintenance Cmax for norivogaine is about 50% of the therapeutic Cmax for norivogaine. In some embodiments, the maintenance Cmax of norivogaine is about 40% of the therapeutic Cmax of noriobogain. In some embodiments, the maintenance Cmax of norivogaine is about 30% of the therapeutic Cmax of noriobogain. In some embodiments, the maintenance Cmax of norivogaine is about 20% of the therapeutic Cmax of noriobogain. In some embodiments, the maintenance Cmax of norivogaine is about 10% of the treatment Cmax of noriobogain.

  In some embodiments, the maintenance AUC / 24h of norivogaine is about 70% of the treatment AUC / 24h of noriobogain. In some embodiments, the maintenance AUC / 24h of norivogaine is about 60% of the therapeutic AUC / 24h of noriobogain. In some embodiments, the maintenance AUC / 24h of norivogaine is about 50% of the treatment AUC / 24h of noriobogain. In some embodiments, the maintenance AUC / 24h for norivogaine is about 40% of the treatment AUC / 24h for noriobogain. In some embodiments, the maintenance AUC / 24h of norivogaine is about 30% of the treatment AUC / 24h of noriobogaine. In some embodiments, the maintenance AUC / 24h for norivogaine is about 20% of the treatment AUC / 24h for noriobogaine. In some embodiments, the maintenance AUC / 24h for norivogaine is about 10% of the treatment AUC / 24h for noriobogain.

  In one embodiment, the therapeutic dose is gradually reduced over time until the desired maintenance dose is reached. For example, in some embodiments, the first decreasing dose is 50% to 95% of the therapeutic dose. In some embodiments, the second decreasing dose is 40% to 90% of the therapeutic dose. In some embodiments, the third decreasing dose is 30% to 85% of the therapeutic dose. In some embodiments, the fourth decreasing dose is 20% to 80% of the therapeutic dose. In some embodiments, the fifth decreasing dose is 10% to 75% of the therapeutic dose. In some embodiments, a single declining dose is administered to reach a maintenance dose. In some embodiments, two decreasing doses are administered to reach the maintenance dose. In some embodiments, three decreasing doses are administered to reach a maintenance dose. In some embodiments, four or more decreasing doses are administered to reach a maintenance dose. Decreasing doses, the number of decreasing doses, etc. can be readily determined by a qualified clinician.

  In one embodiment, the QT interval is not extended beyond about 30 ms. In a preferred embodiment, the QT interval is not extended beyond about 20 ms. In one embodiment, the QT interval is not extended beyond about 10 ms.

  In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or salt or solvate thereof is about 10 mg to about 100 mg. In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or salt or solvate thereof is about 20 mg to about 100 mg. In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or salt or solvate thereof is about 30 mg to about 100 mg. In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or salt or solvate thereof is about 40 mg to about 100 mg. In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or salt or solvate thereof is about 50 mg to about 100 mg. In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or salt or solvate thereof is about 60 mg to about 100 mg. In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or salt or solvate thereof is about 60 mg to about 90 mg. In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or salt or solvate thereof is about 60 mg to about 80 mg. In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or salt or solvate thereof is about 60 mg to about 70 mg.

  In some embodiments, the patient is treated with norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof once, twice, three times, four times, or five times daily. It is given regularly. In some embodiments, the administration is once daily, or once every two days, once every three days, three times a week, twice a week, or once a week. The amount and frequency of administration will depend on, but is not limited to, the route of administration, the content of the composition, the age and weight of the patient, the condition of the patient. Suitable dosages and frequencies for the present technology can be readily determined by a qualified clinician.

  Norivogaine, norivogaine derivatives, or pharmaceutically acceptable salts or solvates thereof suitable for administration according to the methods provided herein include, but are not limited to oral delivery, transdermal delivery, sublingual delivery. Suitable for a variety of delivery modes including buccal delivery, intrapulmonary delivery or intranasal delivery. Compositions suitable for the internal route, pulmonary route, rectal route, nasal route, vaginal route, tongue route, intravenous route, intraarterial route, intramuscular route, intraperitoneal route, intradermal route and subcutaneous route may be used. . Possible dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral solutions including suspensions, solutions and emulsions. Sustained release dosage forms may be used. All dosage forms can be formulated using standard methods in the art (see, for example, Remington's Pharmaceutical Sciences, 16th edition, edited by A. Oslo, Easton, Pa. 1980).

  In a preferred embodiment, norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered orally and can be conveniently provided in the form of a tablet, caplet, sublingual, liquid or capsule. In a specific embodiment, the norivogaine is provided as norivogaine HCl, where the dose is recorded as the amount of free base norivogaine. In some embodiments, the norbogaine HCl is provided in a hard gelatin capsule that contains no nobogaine HCl without any additives.

  The patient may suffer from addiction to any opioid or opiate or opioid-like drug. In a preferred embodiment, the opioid or opioid-like drug is selected from the group consisting of heroin, cocaine, opiate, methadone, morphine, codeine, hydrocodone, oxycodone, and methamphetamine. In one embodiment, the opioid or opioid-like drug is heroin. In one embodiment, the opioid or opioid-like drug is methadone. In one embodiment, the opioid or opioid-like drug is morphine.

Alcohol Dependence In one aspect, the present invention relates to alcohol from patients with alcohol dependence comprising the administration of a therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof. It relates to the treatment of acute withdrawal.

  In one aspect, the invention is a method of treating alcohol abuse in an alcoholic patient, wherein the abuse is suppressed for the patient while maintaining a QT interval of less than about 500 ms during the treatment. Or a dose of roivogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof that provides an average serum concentration of about 50 ng / mL to about 850 ng / mL, a concentration sufficient for remission It is related with the said treatment method including administering.

  In one aspect, the invention relates to a method of attenuating withdrawal symptoms in a human patient that is sensitive to withdrawal symptoms due to alcohol dependence, wherein the patient is given a QT of less than about 500 ms during the treatment. A dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable dose that provides an average serum concentration of about 60 ng / mL to about 400 ng / mL, a concentration sufficient to attenuate the above symptoms while maintaining the interval And the salt and / or solvate thereof. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. The concentration is preferably sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, the withdrawal symptom is an acute withdrawal symptom.

  In one aspect, the invention relates to a method of attenuating withdrawal symptoms in a human patient that is sensitive to withdrawal symptoms due to alcohol dependence, wherein the patient is given a QT of less than about 500 ms during the treatment. A dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable dosage that provides an average serum concentration of about 50 ng / mL to about 400 ng / mL, sufficient to attenuate the above symptoms while maintaining the interval And the salt and / or solvate thereof. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. The concentration is preferably sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, the withdrawal symptom is an acute withdrawal symptom.

  In one embodiment, the average serum concentration of norbogaine is about 50 ng / mL to about 800 ng / mL or about 60 ng / mL to about 800 ng / mL. In one embodiment, the average serum concentration of norbogaine is about 50 ng / mL to about 700 ng / mL or about 60 ng / mL to about 700 ng / mL. In one embodiment, the average serum concentration of norbogaine is about 50 ng / mL to about 600 ng / mL or about 60 ng / mL to about 600 ng / mL. In a preferred embodiment, the average serum concentration of norbogaine is from about 50 ng / mL to about 500 ng / mL, or from about 60 ng / mL to about 500 ng / mL. In one embodiment, the average serum concentration of norbogaine is from about 50 ng / mL to about 400 ng / mL, or from about 60 ng / mL to about 400 ng / mL. In one embodiment, the average serum concentration of norbogaine is about 50 ng / mL to about 300 ng / mL, or about 60 ng / mL to about 300 ng / mL. In one embodiment, the average serum concentration of norbogaine is from about 50 ng / mL to about 200 ng / mL, or from about 60 ng / mL to about 200 ng / mL. In one embodiment, the average serum concentration of norbogaine is from about 50 ng / mL to about 100 ng / mL, or from about 60 ng / mL to about 100 ng / mL. The above ranges include both end values as well as any subranges between them.

  In one embodiment, the dosage or total dosage of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is greater than about 1 mg / kg to about 8 mg / kg body weight per day. is there. The total dosage is a combined dosage, for example, norbogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof administered over a 24-hour period when smaller doses are administered multiple times per day and / Or the total amount of solvate. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 1.3 mg / kg to about 7 mg / kg body weight. . In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 1.3 mg / kg to about 6 mg / kg body weight. . In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 1.3 mg / kg to about 5 mg / kg body weight. . In a preferred embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 1.3 mg / kg to about 4 mg / kg body weight. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 1.3 mg / kg to about 3 mg / kg body weight. . In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 1.3 mg / kg to about 2 mg / kg body weight. . In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 1.5 mg / kg to about 3 mg / kg body weight. . In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 1.7 mg / kg to about 3 mg / kg body weight. . In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 2 mg / kg to about 4 mg / kg body weight. In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 2 mg / kg to about 3 mg / kg body weight. In one embodiment, the dose or total dose of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 2 mg / kg body weight. The above ranges include both end values as well as any subranges between them.

  In one embodiment, the dose or the total dose of the norbogaine, norbogaine derivative, or salt and / or solvate thereof is about 8 mg / kg body weight per day. In one embodiment, the dose or total dose of the norbogaine, the norbogaine derivative, or a salt and / or solvate thereof is about 7 mg / kg body weight per day. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or salt and / or solvate thereof is about 6 mg / kg body weight per day. In one embodiment, the dose or the total dose of the norbogaine, norbogaine derivative, or salt and / or solvate thereof is about 5 mg / kg body weight per day. In one embodiment, the dose or the total dose of the norbogaine, the nolibogaine derivative, or a salt and / or solvate thereof is about 4 mg / kg body weight per day. In one embodiment, the dose or the total dose of the norbogaine, norbogaine derivative, or salt and / or solvate thereof is about 3 mg / kg body weight per day. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or salt and / or solvate thereof is about 2 mg / kg body weight per day. In one embodiment, the dosage or total dosage of the norbogaine, the norbogaine derivative, or a salt and / or solvate thereof is about 1.7 mg / kg body weight per day. In one embodiment, the dose or total dose of the norbogaine, the norbogaine derivative, or a salt and / or solvate thereof is about 1.5 mg / kg body weight per day. In one embodiment, the dose or the total dose of the norbogaine, norbogaine derivative, or salt and / or solvate thereof is about 1.3 mg / kg body weight per day. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is about 1 mg / kg body weight per day.

  In one aspect, the present invention provides for an acute withdrawal from alcohol dependence in an addicted patient by administering a maintenance amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof, And / or a method of treating or attenuating symptoms of withdrawal.

  In some aspects, the present invention provides a method for preventing recurrence of alcohol abuse and / or use in an addicted patient who has been treated and ameliorated alcohol abuse, wherein the patient has a maintenance dose of norbogaine, It relates to a method as described above, which comprises the regular administration of a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof.

  In some embodiments, the patient is treated for a long time (eg, 1 month, 3 months, 6 months, 1 year or more) with a maintenance dose of norivogaine, a norivogaine derivative, or a salt and / or solvate thereof. Receive. In some embodiments, the patient is treated for acute withdrawal with the therapeutic dose of norivogaine described above, and then the amount of norivogaine is reduced to a maintenance level after the acute withdrawal symptoms are expected to have subsided. Is done. Acute withdrawal symptoms are generally most pronounced in the first week after cessation of alcohol use. However, acute withdrawal may continue for longer than 6 weeks.

  In some embodiments, the patient receives a high (therapeutic) dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof during a period of remission of the most prominent withdrawal symptoms. Administered, followed by a lower (maintenance) dose to prevent recurrence of drug use. In some embodiments, the patient is administered a therapeutic dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof for a period of remission of the most prominent withdrawal symptoms, and then Decreasing (decreasing) amounts of norivogaine, norivogaine derivatives, or pharmaceutically acceptable salts and / or solvates thereof are administered over time until the maintenance dose is reached.

Drug Dependence In one aspect, the present invention relates to an addictive substance of an addictive patient comprising the administration of a therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof. Relates to the treatment of acute withdrawal.

  In one aspect, the invention provides a method for treating substance abuse in an addicted patient, wherein the abuse is suppressed for the patient while maintaining a QT interval of less than about 500 ms during the treatment. Administer a dose of Luibogaine, a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof that provides an average serum concentration of 50 ng / mL to 180 ng / mL, a concentration sufficient to relieve The above-mentioned treatment method.

  In one aspect, the invention relates to a method of attenuating withdrawal symptoms in a human patient that is susceptible to withdrawal symptoms due to substance addiction, wherein the patient has a QT of less than about 500 ms during the treatment. A dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable one thereof that gives an average serum concentration of 80 ng / mL to 180 ng / mL, a concentration sufficient to attenuate the above symptoms while maintaining the interval The method relates to administering a salt and / or solvate. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. The concentration is preferably sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, the withdrawal symptom is an acute withdrawal symptom.

  In one aspect, the invention relates to a method of attenuating withdrawal symptoms in a human patient that is susceptible to withdrawal symptoms due to substance addiction, wherein the patient has a QT of less than about 500 ms during the treatment. A dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable one thereof that provides an average serum concentration of 50 ng / mL to 180 ng / mL that is sufficient to attenuate the above symptoms while maintaining the interval The method relates to administering a salt and / or solvate. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. The concentration is preferably sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment. In one embodiment, the withdrawal symptom is an acute withdrawal symptom.

  In one embodiment, the average serum concentration of the norbogaine is 50 ng / mL to 180 ng / mL, or 60 ng / mL to 180 ng / mL. In one embodiment, the average serum concentration of the norbogaine is 50 ng / mL to 150 ng / mL, or 60 ng / mL to 150 ng / mL. In one embodiment, the average serum concentration of norbogaine is 50 ng / mL to 100 ng / mL, or 60 ng / mL to 100 ng / mL. In one embodiment, the average serum concentration of said norbogaine is 80 ng / mL to 150 ng / mL. In one embodiment, the average serum concentration of said norbogaine is between 80 ng / mL and 100 ng / mL. The above ranges include both end values as well as any subranges between them.

  The patient may suffer from addiction to any addictive drug or substance. In a preferred embodiment, the drug is benzodiazepine, cannabinoids and synthetic cannabinoids, stimulants, barbiturates, gamma-hydroxybutyric acid (GHB), ketamine, PCP, dextromethorphan (DXM), lysergic acid diethylamide (LSD), Selected from the group consisting of mescaline, anabolic steroids, and their respective derivatives.

  In one aspect, the present invention provides for the use of a maintenance amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof after acute withdrawal from an addictive substance in an addictive patient, and / or Alternatively, it relates to a method for treating or attenuating withdrawal symptoms.

  In some embodiments, the present invention provides a method for preventing relapse of drug abuse in an addicted patient who has been treated and ameliorated drug abuse, wherein a maintenance dose of norivogaine, a norbogaine derivative, Or a method as described above, comprising periodically administering a pharmaceutically acceptable salt and / or solvate thereof.

Pain As will be apparent to those of skill in the art upon reading this disclosure, the present invention provides a method of treating pain in a patient by reducing and / or suppressing the patient's pain, comprising administering to the patient There is provided a method of treatment as described above, comprising administering an amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt / or solvate thereof.

  In one aspect, the present invention relates to a method for treating pain in a patient suffering from pain comprising administration of a therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof. .

  In one aspect, the invention provides a method for treating pain in a patient suffering from pain, wherein the pain is suppressed or maintained for the patient while maintaining a QT interval of less than about 500 ms during the treatment. Administer a dose of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof that provides an average serum concentration of 20 ng / mL to 180 ng / mL, a concentration sufficient to relieve The above method. In some embodiments, the concentration is sufficient to suppress or ameliorate the pain while maintaining a QT interval extension of less than about 20 ms during treatment.

  In one aspect, the present invention is a method for attenuating pain in a human patient that attenuates the symptoms while maintaining a QT interval of less than about 500 ms for the patient during the treatment. Administering a dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof, giving a mean serum concentration of 20 ng / mL to 180 ng / mL, a concentration sufficient for Including the above method. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. The concentration is preferably sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment.

  In one aspect, the present invention provides a method for attenuating pain in a human patient that is sensitive to pain, wherein the patient is maintained at a QT interval of less than about 500 ms during the treatment, while Dosage of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof giving an average serum concentration of 50 ng / mL to 180 ng / mL, a concentration sufficient to attenuate symptoms In connection with the above method. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. The concentration is preferably sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment.

  In one aspect, the present invention provides a method for attenuating pain in a human patient that is sensitive to pain, wherein the patient is maintained at a QT interval of less than about 500 ms during the treatment, while Dosage of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof that provides an average serum concentration of 80 ng / mL to 100 ng / mL, a concentration sufficient to attenuate symptoms In connection with the above method. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. The concentration is preferably sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment.

  In one embodiment, the average serum concentration of the norbogaine is 50 ng / mL to 180 ng / mL, or 20 ng / mL to 180 ng / mL. In one embodiment, the average serum concentration of norbogaine is 50 ng / mL to 150 ng / mL, or 20 ng / mL to 150 ng / mL. In one embodiment, the average serum concentration of norbogaine is 50 ng / mL to 100 ng / mL, or 20 ng / mL to 100 ng / mL. In one embodiment, the average serum concentration of said norbogaine is between 80 ng / mL and 100 ng / mL. In one embodiment, the average serum concentration of said norbogaine is between 80 ng / mL and 100 ng / mL. The above ranges include both end values as well as any subranges between them.

  In one embodiment, the dose or the total dose of the norbogaine, the norivogaine derivative, or a salt and / or solvate thereof is 0.1 mg / kg to 4 mg / kg body weight per day. The total dosage is a combined dosage, for example, norbogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof administered over a 24-hour period when smaller doses are administered multiple times per day and / Or the total amount of solvate. In another embodiment, the therapeutically effective amount of the compound is from 0.1 mg / kg to 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.1 mg / kg to 2 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is 0.1 mg-1.5 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.1 mg / kg to 1 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg / kg to 3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg / kg to 2 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg / kg to 1.5 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is 0.5 mg-1.3 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is 0.5 mg-1.2 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg / kg to 1.1 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.5 mg / kg to 1 mg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from 0.7 mg / kg to 1.5 mg / kg body weight per day. The above ranges include both end values as well as any subranges between them.

  In one embodiment, the therapeutically effective amount of the compound is about 3 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 2 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.5 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.4 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.3 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.2 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1.1 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 1 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.9 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.8 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.7 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.6 mg / kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 0.5 mg / kg body weight per day. A therapeutically effective amount of the compound is about 0.4 mg / kg body weight per day. A therapeutically effective amount of the compound is about 0.3 mg / kg body weight per day. A therapeutically effective amount of the compound is about 0.2 mg / kg body weight per day. A therapeutically effective amount of the compound is about 0.1 mg / kg body weight per day.

  In one embodiment, the dose or total dose of the norbogaine or a salt or solvate thereof is 60 mg to 150 mg. In one embodiment, the dose or total dose of the norbogaine or a salt or solvate thereof is 70 mg to 150 mg. In one embodiment, the dose or total dose of the norbogaine or a salt or solvate thereof is 80 mg to 140 mg. In one embodiment, the dose or total dose of the norbogaine or a salt or solvate thereof is 90 mg to 140 mg. In one embodiment, the dose or total dose of the norbogaine or a salt or solvate thereof is 90 mg to 130 mg. In one embodiment, the dose or total dose of the norbogaine or a salt or solvate thereof is 100 mg to 130 mg. In one embodiment, the dose or total dose of the norbogaine salt or solvate is 110 mg to 130 mg.

  In another embodiment, a unit dose of norivogaine or a salt or solvate thereof is provided that is about 120 mg per administration. The term “unit dose” should be understood to mean a dose sufficient to provide a therapeutic result, whether administered all at once or sequentially over a period of time.

  In one embodiment, the dose or total dose of the norbogaine or a salt or solvate thereof is 10 mg to 100 mg. In one embodiment, the dose or total dose of the norbogaine or a salt or solvate thereof is 50 mg to 100 mg. In one embodiment, the dose or total dose of the norbogaine or a salt or solvate thereof is 60 mg to 100 mg. In one embodiment, the dose or total dose of the norbogaine or a salt or solvate thereof is 60 mg to 90 mg. In one embodiment, the dose or total dose of the norbogaine or a salt or solvate thereof is 60 mg to 80 mg. In one embodiment, the dose or total dose of the norbogaine or a salt or solvate thereof is 60 mg to 70 mg.

Treatment of Migraine In some embodiments, the present invention provides a method of treating a subject's migraine and / or symptoms thereof, wherein the therapeutically effective amount of norivogain for a patient in need thereof. There is provided a method of treatment as described above comprising administering a norbogaine derivative, or a pharmaceutically acceptable salt thereof. In one embodiment, the method further comprises administering at least one agent known to treat or prevent migraine and / or symptoms thereof. In a preferred embodiment, treatment with nolubogaine and / or the agent does not extend the QT interval beyond about 50 ms. Where nolubogaine is discussed throughout this specification, it is understood that such agents may optionally be administered in combination with (eg, before, after, or simultaneously with) norbogaine or a derivative. Should be.

  The subject or patient may be any patient who exhibits migraine and / or symptoms thereof. In a preferred embodiment, the patient is susceptible to recurrent migraines. In one embodiment, the patient has chronic migraine. Chronic migraine is a headache (tensile headache and more than 15 days per month for at least 3 months, with at least 8 days (without aura) migraine (or successful treatment of expected symptoms) per month. (Or migraine).

  In one aspect, the invention provides a method for treating a migraine in a patient and / or a symptom thereof, wherein the migraine is maintained for the patient while maintaining a QT interval of less than about 500 ms during the treatment. And / or a dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvent thereof that provides an average serum concentration of about 50 ng / mL to about 180 ng / mL, which is a concentration sufficient to treat symptoms It relates to the above-mentioned method of treatment, comprising administering a Japanese product.

In some embodiments, the concentration is sufficient to treat the patient while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to treat the patient while maintaining a QT interval of less than about 450 ms during treatment.
In one embodiment, the concentration is sufficient to treat the patient while maintaining a QT interval of less than about 420 ms during treatment.

  In one embodiment, the QT interval is not extended beyond about 50 ms. In one embodiment, the QT interval is not extended beyond about 40 ms. In one embodiment, the QT interval is not extended beyond about 30 ms. In one embodiment, the QT interval is not extended beyond about 20 ms. In one embodiment, the QT interval is not extended beyond about 10 ms.

  In one embodiment, the dosage of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of about 1000 ng · hr / mL to about 6000 ng · hr / mL. In one embodiment, the dosage of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of about 1200 ng · hr / mL to about 5800 ng · hr / mL. In one embodiment, the dosage of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of about 1200 ng · hr / mL to about 5500 ng · hr / mL. The above ranges include both end values as well as any subranges between them.

  In one embodiment, a dosage of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a maximum serum concentration (Cmax) of less than about 250 ng / mL. In one embodiment, the dosage of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax of about 40 ng / mL to about 250 ng / mL. In a preferred embodiment, a dosage of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax of about 60 ng / mL to about 200 ng / mL. In one embodiment, the dosage of the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax of about 100 ng / mL to about 180 ng / mL.

  In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or salt or solvate thereof is about 1 mg / kg to about 4 mg / kg body weight per day. The total dose is a combined dose, for example, norbogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof administered over a period of 24 hours when smaller doses are administered multiple times per day Total amount of solvate. In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or salt or solvate thereof is about 1.3 mg / kg to about 4 mg / kg body weight. In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or salt or solvate thereof is about 1.3 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or salt or solvate thereof is about 1.3 mg / kg to about 2 mg / kg body weight. In one embodiment, the dose or total dose of the norbogaine, norbogaine derivative, or salt or solvate thereof is about 1.5 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or salt or solvate thereof is about 1.7 mg / kg to about 3 mg / kg body weight. In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or salt or solvate thereof is about 2 mg / kg to about 4 mg / kg body weight. In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or salt or solvate thereof is about 2 mg / kg to about 3 mg / kg body weight. In one embodiment, the dose or total dose of the norbogaine, the nolibogaine derivative, or a salt or solvate thereof is about 2 mg / kg body weight. The above ranges include both end values as well as any subranges between them.

  In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or salt or solvate thereof is about 70 mg to about 150 mg. In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or salt or solvate thereof is about 75 mg to about 150 mg. In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or salt or solvate thereof is about 80 mg to about 140 mg. In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or salt or solvate thereof is about 90 mg to about 140 mg. In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or salt or solvate thereof is about 90 mg to about 130 mg. In one embodiment, the dosage or total dosage of the norbogaine, norivogaine derivative, or salt or solvate thereof is about 100 mg to about 130 mg. In one embodiment, the dosage or total dosage of the norbogaine, norbogaine derivative, or salt or solvate thereof is about 110 mg to about 130 mg.

  In some embodiments, the therapeutically effective amount of the compound is about 50 ng to about 10 μg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng / kg to about 5 μg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng / kg to about 1 μg / kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng / kg to about 1 μg / kg body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is from about 500 ng to about 10 μg / kg body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is about 1 μg to about 10 μg per kg body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is about 50 ng / kg body weight / day, about 100 ng, about 150 ng, about 200 ng, about 250 ng, about 300 ng, about 350 ng, about 400 ng, about 450 ng, about 500 ng, about 550 ng, about 600 ng, about 650 ng, about 700 ng, about 750 ng, about 800 ng, about 850 ng, about 900 ng, about 950 ng, about 1 μg, about 2 μg, about 3 μg, about 3 μg, about 4 μg, about 5 μg, about 6 μg, About 7 μg, about 8 μg, about 9 μg, or about 10 μg. The therapeutically effective amount of the compound may be any amount within any of these ranges including endpoints.

  In some embodiments, the therapeutically effective amount of norivogaine, derivative, prodrug, or salt thereof is administered once a day. In some embodiments, the therapeutically effective amount is administered twice a day. In some embodiments, the therapeutically effective amount is administered three or more times per day.

  Where the therapeutically effective amount is administered multiple times per day, a portion of the therapeutically effective amount is administered each time. For example, a 90 kg patient who receives 1 μg of norbogaine per kg of body weight per day will receive 90 μg once a day, 45 μg twice a day, 30 μg three times a day, and so on.

  In some embodiments, the therapeutically effective amount of norivogaine, derivative, prodrug, or salt thereof is needed if, for example, migraine or symptoms thereof occur in the patient, or the patient Administered when a migraine is expected to occur (eg, an attraction was expected or the patient had an attraction, a symptom or prodromal phase occurred).

  In some embodiments, the norbogaine, norivogaine derivative, or pharmaceutically acceptable salt or solvate thereof is given to the patient once, twice, three times, four times or five times daily. It is given regularly. In some embodiments, the administration is once daily, or once every two days, once every three days, three times a week, twice a week, or once a week. The amount and frequency of administration will depend on, but is not limited to, the route of administration, the content of the composition, the age and weight of the patient, the condition of the patient. Suitable dosages and frequencies for the present technology can be readily determined by a qualified clinician.

  In some embodiments, the noribogaine or nolibogaine derivative is administered sublingually, intrapulmonary, buccal, or intranasally. These routes of administration are discussed in further detail in the subsection entitled “Dose and Route of Administration” below.

Prevention of Migraine In some embodiments, the present invention provides a method of preventing or attenuating a subject's migraine and / or symptoms thereof, in a prophylactically effective amount for a patient in need thereof. A method of the invention comprising administering a norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt thereof. In some embodiments, the present invention provides a method for preventing or attenuating migraine and / or symptoms thereof in a subject, wherein a prophylactically effective amount of norivogaine, norivogaine for a patient in need thereof. There is provided a method as described above, comprising administering a derivative, or a pharmaceutically acceptable salt thereof, in combination with an agent known to prevent migraine and / or symptoms thereof. Where nolubogaine is discussed throughout this specification, such agents may optionally be administered in combination with (eg, before, after, simultaneously with, or substantially simultaneously with) norbogaine or a derivative. It should be understood that it is good.

  In some embodiments, the norbogaine is administered as needed by the patient. In some embodiments, the norbogaine may be administered before migraine and / or symptoms thereof occur. For example, the patient may ingest noriobogaine in anticipation of symptoms (eg, after attraction of migraine, at the same time as the attraction, or when the attraction is expected; such as when one or more prodrome occurs) May be. In some embodiments, a prophylactically effective amount of norbogaine may be administered on a regular schedule (eg, daily, every other day, weekly, etc.) to prevent migraine.

  In one embodiment, the prophylactically effective amount of the compound is up to about 90% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 80% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 70% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 60% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 50% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 40% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 30% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 20% of the therapeutic amount. In one embodiment, the prophylactically effective amount of the compound is up to about 10% of the therapeutic amount.

  In one embodiment, the prophylactically effective amount of the compound is less than about 50 ng to 10 μg / kg body weight per day. In another embodiment, the prophylactically effective amount of the compound is about 50 ng / kg to about 5 μg / kg body weight per day. In another embodiment, the prophylactically effective amount of the compound is about 50 ng / kg to about 1 μg / kg body weight per day. In yet another embodiment, the prophylactically effective amount of the compound is less than about 500 ng to 10 μg / kg body weight per day. In yet another embodiment, the prophylactically effective amount of the compound is less than about 1 μg to 10 μg / kg body weight per day. The prophylactically effective amount of the compound may be any amount within any of these ranges including the endpoints.

  In one embodiment, the QT interval is not extended beyond about 30 ms. In a preferred embodiment, the QT interval is not extended beyond about 20 ms. In one embodiment, the QT interval is not extended beyond about 10 ms.

  In some embodiments, the prophylactically effective amount of norivogaine, derivative, prodrug, or salt thereof is administered once daily. In some embodiments, the prophylactically effective amount is administered twice per day. In some embodiments, the prophylactically effective amount is administered three or more times per day.

When the prophylactically effective amount of norivogaine is administered more than once per day,
Each time a portion of the total therapeutically effective amount is administered. For example, a 90 kg patient who receives 1 μg of norbogaine per kg of body weight per day will receive 90 μg once a day, 45 μg twice a day, 30 μg three times a day, and so on.

  In some embodiments, the patient is treated with norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof once, twice, three times, four times, or five times daily. It is given regularly. In some embodiments, the administration is once daily, or once every two days, once every three days, three times a week, twice a week, or once a week. The amount and frequency of administration will depend on, but is not limited to, the route of administration, the content of the composition, the age and weight of the patient, the condition of the patient. Suitable dosages and frequencies for the present technology can be readily determined by a qualified clinician.

  In some embodiments, the noribogaine or nolibogaine derivative is administered orally, sublingually, intrapulmonary, buccal, or intranasally. These routes of administration are discussed in further detail in the subsection entitled “Dose and Route of Administration” below.

  In some embodiments, the maintenance average serum level of nolibogaine is about 10% to about 80% of the therapeutic average serum level of nolibogaine. In some embodiments, the norbogaine maintenance average serum level is about 70% of the norbogaine therapeutic average serum level. In some embodiments, the norbogaine maintenance average serum level is about 60% of the norbogaine therapeutic average serum level. In some embodiments, the maintenance average serum level of nolibogaine is about 50% of the therapeutic average serum level of said norbogaine. In some embodiments, the maintenance average serum level of nolibogaine is about 40% of the therapeutic average serum level of nolibogaine. In some embodiments, the norbogaine maintenance average serum level is about 30% of the norbogaine therapeutic average serum level. In some embodiments, the norbogaine maintenance average serum level is about 20% of the norbogaine therapeutic average serum level. In some embodiments, the maintenance average serum level of nolibogaine is about 10% of the therapeutic average serum level of nolibogaine.

Reducing analgesic tolerance In one aspect of the invention, a patient is being treated with an addictive opioid analgesic to relieve the patient's pain. The pain may be of any type and any origin. In one embodiment, the patient is being treated for acute pain. In one embodiment, the patient is being treated for chronic pain. In one embodiment, the patient is being treated for nociceptive pain. In one embodiment, the patient is being treated for neuropathic pain. In some embodiments, the pain is due to surgery, diabetes, trigeminal neuralgia, fibromyalgia, cancer, central pain syndrome, tissue damage, physical injury, and the like. In some embodiments, the cause of the pain is unknown or unclear.

  In one aspect, the invention relates to a method of modulating resistance to an opioid analgesic in a patient undergoing opioid analgesic therapy, wherein the opioid analgesic is interrupted or less than about 500 ms during the treatment. A dose of norbogaine that provides an average serum concentration of about 50 ng / mL to about 180 ng / mL, sufficient to reduce the patient's sensitivity to the opioid as an analgesic while maintaining a QT interval. , A norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, which is administered simultaneously with the opioid analgesic.

  In one embodiment, the average serum concentration of the norbogaine is 50 ng / mL to 180 ng / mL, or 60 ng / mL to 180 ng / mL. In one embodiment, the average serum concentration of the norbogaine is 50 ng / mL to 150 ng / mL, or 60 ng / mL to 150 ng / mL. In one embodiment, the average serum concentration of norbogaine is 50 ng / mL to 100 ng / mL, or 60 ng / mL to 100 ng / mL. In one embodiment, the average serum concentration of said norbogaine is between 80 ng / mL and 100 ng / mL. The above ranges include both end values as well as any subranges between them.

  In one embodiment, the dose or the total dose of the norbogaine, the norbogaine derivative, or a salt or solvate thereof is 10 mg to 100 mg. In one embodiment, the dose or the total dose of the norbogaine, the norbogaine derivative, or a salt or solvate thereof is 20 mg to 100 mg. In one embodiment, the dose or the total dose of the norbogaine, the norbogaine derivative, or a salt or solvate thereof is 30 mg to 100 mg. In one embodiment, the dose or the total dose of the norbogaine, the norbogaine derivative, or a salt or solvate thereof is 40 mg to 100 mg. In one embodiment, the dose or the total dose of the norbogaine, the norbogaine derivative, or a salt or solvate thereof is 50 mg to 100 mg. In one embodiment, the dose or the total dose of the norbogaine, norbogaine derivative, or a salt or solvate thereof is 60 mg to 100 mg. In one embodiment, the dose or the total dose of the norbogaine, the norbogaine derivative, or a salt or solvate thereof is 60 mg to 90 mg. In one embodiment, the dose or the total dose of the norbogaine, the norbogaine derivative, or a salt or solvate thereof is 60 mg to 80 mg. In one embodiment, the dose or the total dose of the norbogaine, the norbogaine derivative, or a salt or solvate thereof is 60 mg to 70 mg.

  The patient may have received any addictive opioid analgesic for the treatment of pain. In a preferred embodiment, the opioid analgesic is fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, buprenorphine, codeine, heroin, thebaine, buprenorphine, methadone, meperidine, tramadol, tapentadol, levorphanol, sufentanil, pentazocine, oxymorphone, And their respective derivatives.

Depression As will be apparent to those of skill in the art upon reading this disclosure, the present invention provides a method for treating depression and / or PTSD in a patient in need of the method of treatment, wherein the patient is therapeutically treated. There is provided a method of treatment as described above, comprising administering an effective amount of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt / or solvate thereof. In a preferred embodiment, the patient is not cocaine or opiate addict. Examples of the norbogaine derivative include, but are not limited to, the compounds described in the section “Composition of the present invention” above.

  The following descriptions of depressive disorders and PTSD are set forth to facilitate an understanding of the utility of the compounds and compositions of the present invention. The following definitions of depressive disorder and PTSD are those published in American Psychiatric Association, 1994a or American Psychiatric Association, 1987. Additional information regarding these disorders can be found in this reference as well as other references cited later, all of which are hereby incorporated herein by reference.

  In some embodiments, the compounds of the invention may be used in any of the following tests: Hamilton Depression Rating Scale (HDLS), Hamilton Depressive Mood Item, Clinical Global Impression (CGI) / Disease Severity. On the basis, it is contemplated that it will be effective in the treatment of depression in patients diagnosed with depression. The compounds of the present invention are effective in improving specific factors measured in these tests, such as depression factor, sleep disorder factor and anxiety factor, HDRS subfactor score and CGI / disease severity assessment. It is further contemplated that It is also contemplated that the compounds of the invention will be effective in preventing recurrence of major depressive episodes.

  In certain embodiments, the present invention is a method of treating a patient with major depressive disorder, wherein the patient is treated with a therapeutically effective amount of the subject's major depressive disorder. There is provided a method of treatment as described above comprising administering any of the effective compounds utilized herein.

  The invention also includes dysthymic disorder, bipolar type I or type II disorder, schizophrenic emotional disorder, cognitive impairment with depressed mood, personality disorder, insomnia, hypersomnia, narcolepsy, circadian rhythm sleep disorder, nightmare disorder Provide a method for treating patients with night wonder or sleepwalking disorder.

  The compounds utilized herein have been diagnosed with PTSD based on the implementation of one of the following tests: PTSD Clinical Diagnostic Interview Scale Part 2 (CAPS), Patient Assessment Event Impact Scale (IES) It is contemplated that it may be effective in treating patients with PTSD. It is further contemplated that the compounds described in the present invention will be effective in inducing improvement in CAPS, IES, CGI disease severity or CGI general improvement test scores. It is also contemplated that the compounds described in the present invention will be effective in preventing recurrence of PTSD.

  The present invention provides a method for treating post-traumatic stress disorder in a subject, the present specification for treating the subject with post-traumatic stress disorder in a therapeutically effective amount. The method of treatment is provided comprising administering any of the compounds utilized in.

  Another aspect of the present invention is a method for treating depression and / or PTSD in a patient in need of the present method of treatment, wherein the patient is treated with norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof. And / or administering a solvate, wherein the amount of the norbogaine or norivogaine derivative is sufficient to treat depression and / or PTSD in the patient.

  In a preferred embodiment, the present invention provides a method of treating depression and / or post traumatic stress disorder in a patient in need of the method of treatment, wherein the patient has a therapeutically effective amount of norbogaine, Administration of a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the patient is not a cocaine or opiate addiction, and the therapeutically effective amount is 50-800 ng / Provided is the method of treatment as described above, which provides a mean Norivogaine serum level in mL. In some embodiments, the average norbogaine serum level provided by the dosage is less than about 50 ng / mL. In one embodiment, the therapeutically effective amount is from 0.5 mg to 4 mg per kg body weight. In one embodiment, the therapeutically effective amount is from 50 ng to less than 100 μg / kg body weight. In one embodiment, depression is treated. In one embodiment, post-traumatic stress disorder is treated. In one embodiment, the noribogaine, norivogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is administered by sublingual delivery, intranasal delivery, or intrapulmonary delivery.

  In some embodiments, the composition is administered via sublingual delivery, intranasal delivery, or pulmonary delivery. In one aspect, the invention provides for the administration of a pharmaceutical composition comprising a pharmaceutically effective amount of norivogaine and a pharmaceutically acceptable additive, wherein the therapeutically effective amount of said noriobogaine is weight per day. The administration is provided in an amount that delivers a total amount of norbogaine from 50 ng to less than 100 μg per kg. In some embodiments, the therapeutically effective amount of norivogaine is an amount that delivers a total amount of 50 to 50 μg of norivogaine per kg body weight per day. In some embodiments, the therapeutically effective amount of norivogaine is an amount that delivers a total amount of 50 to 10 [mu] g norivogaine per kg body weight per day. In some embodiments, the therapeutically effective amount of nolibogaine is an amount that delivers a total amount of nolibogaine from 50 ng to 1 μg per kg body weight per day. In some embodiments, the composition is administered once per day. In some embodiments, the composition is administered more than once per day. In some embodiments, the composition is administered less than once a day, such as once every two days, once every three days, once every four days, once a week, and so on.

  In some embodiments, the composition comprises oral delivery, transdermal delivery, internal delivery, pulmonary delivery, rectal delivery, nasal delivery, vaginal delivery, tongue delivery, intravenous delivery, intraarterial delivery, intramuscular delivery, intraperitoneal delivery. Administered via internal delivery, intradermal delivery or subcutaneous delivery. In one embodiment, the dose or total dose of the compound is from 0.5 mg to 4 mg per kg body weight per day. The total dose is a combined dose, for example, norbogaine or a pharmaceutically acceptable salt and / or solvate thereof administered over a period of 24 hours when smaller doses are administered multiple times per day. The total amount of things. In one embodiment, the dose or total dose of the compound is from 1 mg / kg to 4 mg / kg body weight per day. In one embodiment, the dose or total dose of the compound is about 1 mg to 3 mg per kg body weight per day. In one embodiment, the dose or total dose of the compound is 1 mg / kg to 2 mg / kg body weight per day. In one embodiment, the dose or total dose of the compound is from 1.5 mg / kg to 3 mg / kg body weight per day. In one embodiment, the dose or total dose of the compound is from 1.7 mg / kg to 3 mg / kg body weight per day. In one embodiment, the dose or total dose of the compound is from 2 mg / kg to 4 mg / kg body weight per day. In one embodiment, the dose or total dose of the compound is 2 mg to 3 mg per kg body weight per day. In one embodiment, the dose or total dose of the compound is about 2 per kg body weight per day.

  In one embodiment, the dose or total dose of the compound is about 4 mg / kg body weight per day. In one embodiment, the dose or total dose of the compound is about 3 mg / kg body weight per day. In one embodiment, the dose or total dose of the compound is about 2 mg / kg body weight per day. In one embodiment, the dose or total dose of the compound is about 1.7 mg / kg body weight per day. In one embodiment, the dose or total dose of the compound is about 1.5 mg / kg body weight per day. In one embodiment, the dose or total dose of the compound is about 1.3 mg / kg body weight per day. In one embodiment, the dose or total dose of the compound is about 1 mg / kg body weight per day. In one embodiment, the dose or total dose of the compound is less than about 1 mg / kg body weight per day.

  In certain preferred embodiments of the present invention, the rooibogain, rouibogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is 50 ng / mL to 180 ng / mL, or 60 ng / mL to 180 ng / mL of roivogaine. Is administered in an amount giving an average serum concentration of In one embodiment, the average serum concentration of the rooibogain is 50 ng / mL to 150 ng / mL, or 60 ng / mL to 150 ng / mL. In one embodiment, the average serum concentration of the rooibogain is 50 ng / mL to 100 ng / mL, or 60 ng / mL to 100 ng / mL. In one embodiment, the average serum concentration of rooiboine is between 80 ng / mL and 100 ng / mL. The above ranges include both end values as well as any subranges between them.

  In some embodiments, the patient periodically administers noriobogaine, noriobogaine derivatives, or salts and / or solvates thereof, such as once, twice, three times, four times, or five times daily. Is done. In some embodiments, the administration is once daily, or once every two days, once every three days, three times a week, twice a week, or once a week. The amount and frequency of administration will depend on, but is not limited to, the route of administration, the content of the composition, the age and weight of the patient, the condition of the patient. Suitable dosages and frequencies for the present technology can be readily determined by a qualified clinician.

  In one aspect, the present invention is a method of attenuating depression and / or PTSD symptoms in a human patient, wherein the patient is maintained with a QT interval of less than about 500 ms during the treatment. Administration of a dose of norivogaine or a pharmaceutically acceptable salt and / or solvate thereof that provides an average serum concentration of 50 ng / mL to 180 ng / mL, a concentration sufficient to attenuate the above symptoms To the above method. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. The concentration is preferably sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment.

  In one embodiment, the QT interval is not extended beyond about 50 ms. In one embodiment, the QT interval is not extended beyond about 40 ms. In one embodiment, the QT interval is not extended beyond about 30 ms. In a preferred embodiment, the QT interval is not extended beyond about 20 ms. In one embodiment, the QT interval is not extended beyond about 10 ms.

  Norivogaine, norivogaine derivatives, or pharmaceutically acceptable salts and / or solvates thereof, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives It can also be used in combination with any vehicle and excipient commonly used in pharmaceutical formulations, such as, glycols. Coloring and flavoring agents can also be added to the formulations, particularly to formulations for oral administration. Solutions can be formulated using water or ethanol, 1,2-propylene glycol, polyglycol, dimethyl sulfoxide, aliphatic alcohols, triglycerides, physiologically compatible organic solvents such as partial esters of glycerin. Examples of parenteral compositions containing norbogaine include sterile isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycol mixed with water, Ringer's solution, and the like. Can be prepared using conventional methods.

Anxiety, etc. As will be apparent to those of skill in the art upon reading this disclosure, the present invention is a method of treating anxiety disorders, impulse control disorders, anger / violence related disorders, or methods of adjusting food intake in patients in need of the method. A method is provided comprising administering to the patient a therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt / solvate thereof. In a preferred embodiment, the patient is not cocaine or opiate addict. Examples of the norbogaine derivative include, but are not limited to, the compounds described in the section “Composition of the present invention” above.

  The following descriptions of anxiety disorders and impulse control disorders are set forth to facilitate an understanding of the utility of the compounds and compositions of the present invention. Violence and / or anger-related disabilities are included in these descriptions. The following definitions of anxiety disorder and impulse control disorder are those published in American Psychiatric Association, 1994a or American Psychiatric Association, 1987. Additional information regarding these disorders can be found in this reference as well as other references cited later, all of which are hereby incorporated herein by reference.

  Anxiety disorders include panic disorder, agoraphobia with or without history of panic disorder, specific phobias, social phobia, obsessive compulsive disorder, post-traumatic stress disorder, acute stress disorder and generalized anxiety disorder To do. It is contemplated that the compounds of the invention will be effective for treating these disorders in patients diagnosed with such disorders.

  The present invention is a method of treating a patient with anxiety, comprising administering to the patient an amount of any of the compounds described herein in an amount effective to treat the subject's anxiety. The above-mentioned treatment method is provided.

  It is contemplated that the compounds described herein will be effective in the treatment of obsessions and obsessive behaviors in patients diagnosed with obsessive-compulsive disorder based on the conduct of appropriate studies, Include, but are not limited to, the Yale Brown Obsession and Obsession Scale (YBOCS) (for adults), the National Occupational Health Institute General OCD Scale (NIMH GOCS), or the CGI / Disease Severity Scale be able to. It is further contemplated that the compounds described herein will be effective in inducing improvements in certain factors measured in these tests, such as a several point decrease in the YBOCS total score. It is also contemplated that the compounds described herein will be effective in preventing the recurrence of obsessive-compulsive disorder.

  The present invention is a method for treating obsessions and obsessive behaviors in patients with obsessive-compulsive disorder, and is effective for treating the patients' obsessions and obsessive behaviors in a therapeutically effective amount. Providing a method as described above, comprising administering any of the compounds utilized herein.

  The compounds described herein may be effective in treating panic disorder in patients diagnosed with panic disorder based on the frequency of panic attacks or using the CGI / disease severity scale Intended. The compounds described herein have reduced panic attacks frequency or disappearance of panic attacks, improved CGI / disease severity scale or CGI / general improvement score 1 (very much improved), 2 (significantly improved) It is further contemplated that it will be effective in inducing improvements in specific factors measured in these assessments, such as 3) (minimum improvement). It is also contemplated that the compounds described herein will be effective in preventing the recurrence of panic disorders.

  The present invention provides a method of treating a subject's panic disorder with or without agoraphobia for treating the subject's panic disorder in a therapeutically effective amount. There is provided a method of the above treatment comprising administering any of the compounds utilized in the literature.

  It is contemplated that the compounds described herein can be effective in the treatment of social anxiety disorder in patients diagnosed with social anxiety disorder based on the conduct of any of the following tests, Witz Social Anxiety Scale (LSAS), CGI / Disease Severity Scale, Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), DSM-IV Axis V Social Social Function Rating Scale Axis II (ICD-10) World Health Organization Disability Assessment, Schedule 2 (DAS-2), Sheehan Disability Scale, Schneider Disability Profile, World Health Organization Quality of Life-100 (WHOQOL-100), hereby reference Other tests described in Bobes, 1998, incorporated by reference. The compounds described herein may have a change from baseline in the Reebowitz Social Anxiety Scale (LSAS), or 1 (very much improved), 2 (significantly improved) or 1 It is further contemplated that it will be effective in inducing improvements measured in these tests, such as 3 (minimum improvement). It is also contemplated that the compounds described herein will be effective in preventing recurrence of social anxiety disorders.

  The present invention is a method of treating a social anxiety disorder in a patient comprising the therapeutically effective amount of a compound utilized herein to treat the subject's social anxiety disorder. There is provided a method of treatment as described above, comprising administering either.

  It is contemplated that the compounds utilized herein can be effective in the treatment of patients diagnosed with generalized anxiety disorder based on the diagnostic criteria described in DSM-IV or DSM-5. Is done. The compounds utilized herein have the following symptoms of this disorder: excessive anxiety and anxiety, difficulty controlling anxiety, restlessness or tension or irritation, fatigue, concentration It is further contemplated that it would be effective in reducing difficulty or self-determination, irritability, muscle tone, or sleep disturbances. It is also contemplated that the compounds described herein will be effective in preventing the recurrence of generalized anxiety disorder.

  The present invention provides a method for treating a generalized anxiety disorder in a subject, wherein the compound is an effective amount of any of the compounds described herein for treating the subject's generalized anxiety disorder. The method of treatment is provided comprising administering

  Impulsive control disorders include pathological gambling (PG), stealing, hair removal (TTM), intermittent explosive disorder (IED), and arson. Impulsive control disorders also include pathological skin scratching (PSP), compulsive sexual behavior (CSB), compulsive purchasing (CB), behavioral disorder, antisocial personality disorder, rebellious challenge disorder, borderline personality disorder, attention Also included are deficit / hyperactivity disorder (including ADHD, attention deficit disorder ADD), schizophrenia, mood disorders, sexual perversion, and Internet addiction. Symptoms of impulse control disorder include taking repeated actions despite adverse consequences, reduced control over the action, urge / urge to take the action, and feeling joy while taking the action. It is done.

  It is contemplated that the compounds utilized herein may be effective in treating impulse control disorders in patients who are at least one impulse control disorder based on the diagnostic criteria described in DSM-IV or DSM-5. The It is further contemplated that the compounds utilized herein will be effective in reducing the symptoms of this disorder, including impulsivity or lack of self-regulation. It is also contemplated that the compounds described herein will be effective in preventing recurrence of impulse control disorders.

  It is contemplated that the compounds utilized herein can be effective in treating the disorder in patients with ADHD or ADD based on the diagnostic criteria described in DSM-IV or DSM-5. It is further contemplated that the compounds utilized herein will be effective in reducing the symptoms of this disorder, including impulsivity or lack of self-regulation. It is also contemplated that the compounds described herein will be effective in preventing ADHD or ADD recurrence.

  It is contemplated that the compounds utilized herein can be effective in treating the disorder in patients with schizophrenia based on the diagnostic criteria described in DSM-IV or DSM-5. Schizophrenia is characterized by delusions, hallucinations, disorganized conversations and behaviors, and other symptoms that cause social or occupational dysfunction. It is further contemplated that the compounds utilized herein will be effective in reducing the symptoms of this disorder. It is also contemplated that the compounds described herein will be effective in preventing relapse of schizophrenia.

  The compounds described herein are based on the fact that patients exhibit symptoms including intentional tissue damage (eg, cuts, burns, poisoning, or self-injury) that are not intended to commit suicide. It is contemplated that it will be effective in treating the disorder in the above patients who have been diagnosed with It is further contemplated that the compounds utilized herein will be effective in inducing improvements in certain of these factors, such as reducing the frequency of self-injury or eliminating self-injury. It is also contemplated that the compounds described herein will be effective in preventing the recurrence of non-suicidal self-injury disorders.

  The present invention is a method for treating a subject's non-suicide self-injury disorder, and is used herein to treat the subject with a therapeutically effective amount of the subject's non-suicide self-injury disorder. There is provided a method of treatment as described above comprising administering any of the compounds described.

  The compounds described herein have been diagnosed with Münchhausen syndrome based on a disease, illness, or trait pretending to be traumatic to receive attention, sympathy, or encouragement to the patient's self. It is contemplated that it will be effective in treating the disorder in some patients. Symptoms include frequent hospitalizations, knowledge of some illnesses, frequent drug therapy (eg, analgesic) requirements, willingness to undergo extensive surgery, few or no in-patients , And exaggerated or fictional stories about many medical problems. It is further contemplated that the compounds described herein will be effective in inducing an improvement in certain of these factors, such as reducing the frequency of one or more symptoms or eliminating the symptoms. It is also contemplated that the compounds described herein will be effective in preventing recurrence of Munchausen syndrome. Munchausen Syndrome also encompasses Münchhausen Syndrome by an agent, where the caregiver exaggerates, builds up or induces the illness of the person he / she is caring for.

  The present invention provides a method of treating a subject Munchausen syndrome, wherein the compound is any of the compounds utilized herein to treat the subject Munchausen syndrome in a therapeutically effective amount. The method of treatment is provided comprising administering

  The compounds described herein are based on severe and repetitive emotional outbreaks that are significantly disproportionate to the stimulus or situation, as well as the constant irritability / anger mood for most of the time. It is contemplated that it will be effective in treating the disorder in patients diagnosed with severe mood regulation. It is further contemplated that the compounds described herein will be effective in inducing improvements in certain of these factors, such as reducing the frequency of emotional exacerbations or disappearing emotional exacerbations and / or improving mood. Is done. It is also contemplated that the compounds described herein will be effective in preventing recurrence of severe mood regulation.

  The present invention is a method of treating severe mood regulation in a subject, and is used herein to treat the subject's severe mood regulation in a therapeutically effective amount of the subject. There is provided a method of treatment as described above comprising administering any of the compounds described.

  It is contemplated that the compounds utilized herein can be effective in reducing the frequency, intensity, and duration of anger and / or violence in individuals who are prone to one or both of anger and / or violence. Although anger and violence disorders other than those associated with other disorders (eg, as described above) are not outlined in DSM-IV or DSM-5, many healthcare professionals are associated with serious malfunctions Recognize that Anger management training and other social psychological treatments are often used to treat these individuals.

  It is contemplated that the compounds utilized herein can be effective in regulating food intake and / or reducing food craving in patients in need of the method. In some embodiments, the patient is overweight. In some embodiments, the patient is obese. In some embodiments, the patient has, for example, coronary heart disease, hypertension, stroke, type 2 diabetes, abnormal levels of blood lipids, metabolic syndrome, cancer, osteoarthritis, sleep apnea, Reproductive problems and / or comorbidities associated with overweight / obesity, such as gallstones.

  In preferred embodiments, the present invention is a method of treating anxiety disorder, impulse control disorder, OCD, and / or anger / violence related disorders in a patient in need of the method, or a method of regulating food intake and / or food craving. Comprising administering to the patient a therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt / solvate thereof, wherein the patient is in a cocaine or opiate addiction In addition, there is further provided the method, wherein the therapeutically effective amount provides an average norbogaine serum level of about 50 to about 180 ng / ml. In some embodiments, the average norbogaine serum level provided by the dosage is less than about 50 ng / mL. In one embodiment, the therapeutically effective amount is from about 1 mg / kg to about 4 mg / kg body weight. In one embodiment, the therapeutically effective amount is about 50 ng to about 100 μg / kg body weight. In one embodiment, an anxiety disorder is treated. In one embodiment, OCD is treated. In one embodiment, impulse control disorders are treated. In one embodiment, an anger-related disorder is treated. In one embodiment, violence related disorders are treated. In one embodiment, anger symptoms are reduced or eliminated. In one embodiment, the excitement is reduced or eliminated. In one embodiment, food intake is adjusted. In one embodiment, food craving is attenuated. In one embodiment, norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt / or solvate thereof is administered by sublingual delivery, intranasal delivery, or pulmonary delivery.

Dosage and Route of Administration In some embodiments, the composition is administered via sublingual delivery, intranasal delivery, or pulmonary delivery. In one aspect, the present invention provides for the administration of a pharmaceutical composition comprising a pharmaceutically effective amount of norivogaine and a pharmaceutically acceptable additive, wherein the therapeutically effective amount of norivogaine is weight per day. The administration is provided in an amount that delivers a total amount of norbogaine from about 50 ng to about 100 μg per kg. In some embodiments, the therapeutically effective amount of norivogaine is an amount that delivers a total amount of norivogaine from about 50 ng to about 50 μg / kg body weight per day. In some embodiments, the therapeutically effective amount of nolibogaine is an amount that delivers a total amount of nolibogaine from about 50 ng to about 10 μg per kg body weight per day. In some embodiments, the therapeutically effective amount of nolibogaine is an amount that delivers a total amount of nolibogaine from about 50 ng to about 1 μg per kg body weight per day. In some embodiments, the composition is administered once per day. In some embodiments, the composition is administered more than once per day. In some embodiments, the composition is administered less than once a day, such as once every two days, once every three days, once every four days, once a week, and so on.

  In some embodiments, the composition comprises oral delivery, buccal delivery, transdermal delivery, internal delivery, pulmonary delivery, rectal delivery, nasal delivery, vaginal delivery, tongue delivery, intravenous delivery, intraarterial delivery, muscle Administered via internal delivery, intraperitoneal delivery, intradermal delivery or subcutaneous delivery.

  In one embodiment, the dose or total dose of the compound is about 1 mg / kg to about 4 mg / kg body weight per day. The total dosage is a combined dosage, for example, norbogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof administered over a 24-hour period when smaller doses are administered multiple times per day and / Or the total amount of solvate.

  In some embodiments, the patient periodically administers noriobogaine, noriobogaine derivatives, or salts and / or solvates thereof, such as once, twice, three times, four times, or five times daily. Is done. In some embodiments, the administration is once daily, or once every two days, once every three days, three times a week, twice a week, or once a week. The amount and frequency of administration will depend on, but is not limited to, the route of administration, the content of the composition, the age and weight of the patient, the condition of the patient. Suitable dosages and frequencies for the present technology can be readily determined by a qualified clinician.

  In another embodiment, a unit dose of norivogaine, a norivogaine derivative, or a salt or solvate thereof is provided that is about 50 mg to about 200 mg per administration. In one embodiment, the unit dose is about 50 to about 120 mg per dose. In one embodiment, the unit dose is about 120 mg per administration. The term “unit dose” should be understood to mean a dose sufficient to provide a therapeutic result, whether administered all at once or sequentially over a period of time.

  In one aspect, the present invention provides a method for attenuating symptoms of anxiety disorder, impulse control disorder, or anger and / or violence related disorders in a human patient, wherein said patient is A dose of norbogaine or a pharmaceutically acceptable dose that provides an average serum concentration of about 50 ng / mL to about 180 ng / mL, sufficient to attenuate the above symptoms while maintaining a QT interval of less than 500 ms And the salt and / or solvate thereof. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. The concentration is preferably sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment.

  In one aspect, the present invention is a method for attenuating food cravings in a human patient, wherein the cravings are attenuated for the patient while maintaining a QT interval of less than about 500 ms during the treatment. Administering a dosage of norivogaine or a pharmaceutically acceptable salt and / or solvate thereof that provides a mean serum concentration of about 50 ng / mL to about 400 ng / mL, a concentration sufficient to To the above method. In some embodiments, the concentration is sufficient to attenuate the craving while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to attenuate the craving while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the craving while maintaining a QT interval of less than about 420 ms during treatment.

  In one embodiment, the QT interval is not extended beyond about 50 ms. In one embodiment, the QT interval is not extended beyond about 40 ms. In one embodiment, the QT interval is not extended beyond about 30 ms. In a preferred embodiment, the QT interval is not extended beyond about 20 ms. In one embodiment, the QT interval is not extended beyond about 10 ms.

  Norivogaine, norivogaine derivatives, or pharmaceutically acceptable salts and / or solvates thereof, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives It can also be used in combination with any vehicle and excipient commonly used in pharmaceutical formulations, such as, glycols. Coloring and flavoring agents can also be added to the formulations, particularly to formulations for oral administration. Solutions can be formulated using water or ethanol, 1,2-propylene glycol, polyglycol, dimethyl sulfoxide, aliphatic alcohols, triglycerides, physiologically compatible organic solvents such as partial esters of glycerin. The parenteral composition containing norivogaine may include aseptic isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycol mixed with water, Ringer's solution, etc. Can be prepared using conventional methods.

Sustained treatment As will be apparent to those of skill in the art upon reading this disclosure, one aspect of the present invention is treatable by a patient's nolubogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof. A method of treating a condition, wherein the patient is administered an initial unit dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, followed by at least one additional dose of norivogaine, Administering a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, such that the initial unit dose provides an average therapeutic serum concentration, and the at least one additional dose reduces the serum concentration. The method of treatment is provided, comprising being maintained.

In one aspect, the invention provides in a patient capable of being treated with norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, while maintaining an acceptable QT interval extension in the patient. Regarding a method for treating a disease state, the method includes:
a) administration of the initial unit dose of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof to the patient, wherein the unit dose is in a therapeutic mean serum of 50 ng / mL to 180 ng / mL Providing the concentration, wherein the serum concentration provides minimal QT interval extension;
b) maintenance of the serum concentration by periodic administration of at least one additional dose of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that the at least one dose Such maintenance that the additional dose maintains an average serum concentration between 50 ng / mL and 180 ng / mL during treatment;
Including
The one or more additional doses are continued as needed for the treatment of the condition.

  In one aspect, during the treatment, the serum concentration provides a maximum QT interval of less than about 500 ms. In some embodiments, during treatment, the serum concentration provides a maximum QT interval of less than about 470 ms. During the treatment, the serum concentration preferably provides a maximum QT interval of less than about 450 ms. In one embodiment, during treatment, the serum concentration provides a maximum QT interval of less than about 420 ms.

  In one embodiment, the QT interval is not extended beyond about 50 ms. In one embodiment, the QT interval is not extended beyond about 40 ms. In one embodiment, the QT interval is not extended beyond about 30 ms. In one embodiment, the QT interval is not extended beyond about 20 ms. In one embodiment, the QT interval is not extended beyond about 10 ms.

  In one embodiment, the average serum concentration of the norbogaine is 50 ng / mL to 180 ng / mL, or 60 ng / mL to 180 ng / mL. In one embodiment, the average serum concentration of the norbogaine is 50 ng / mL to 150 ng / mL, or 60 ng / mL to 150 ng / mL. In one embodiment, the average serum concentration of norbogaine is 50 ng / mL to 100 ng / ml, or 60 ng / mL to 100 ng / mL. In one embodiment, the average serum concentration of said norbogaine is 80 ng / mL to 150 ng / mL. In one embodiment, the average serum concentration of said norbogaine is between 80 ng / mL and 100 ng / mL. In some aspects of the invention, lower serum concentrations may be more therapeutic for a given condition. In one embodiment, the therapeutic serum concentration is between 1 ng / mL and 10 ng / mL. As a non-limiting example, the therapeutic serum concentration for treatment of nicotine addiction is believed to be lower than the therapeutic serum concentration for opioid addiction. The above ranges include both end values as well as any subranges between them.

  In some embodiments, the initial unit dose of the noribogaine, nolibogaine derivative, or salt or solvate thereof is 50 mg to 120 mg. In one embodiment, the initial unit dose is about 50 mg. In one embodiment, the initial unit dose is about 55 mg. In one embodiment, the initial unit dose is about 60 mg. In one embodiment, the initial unit dose is about 65 mg. In one embodiment, the initial unit dose is about 70 mg. In one embodiment, the initial unit dose is about 75 mg. In one embodiment, the initial unit dose is about 80 mg. In one embodiment, the initial unit dose is about 85 mg. In one embodiment, the initial unit dose is about 90 mg. In one embodiment, the initial unit dose is about 95 mg. In one embodiment, the initial unit dose is about 100 mg. In one embodiment, the initial unit dose is about 105 mg. In one embodiment, the initial unit dose is about 110 mg. In one embodiment, the initial unit dose is about 115 mg. In one embodiment, the initial unit dose is about 120 mg.

  In some embodiments, the initial unit dose of nolibogaine, a nolibogaine derivative, or a salt or solvate thereof is administered as a divided dose such that the total dose reaches the unit dose. In some embodiments, the initial unit dose is administered as a divided dose, the divided doses are administered sequentially until the unit dose is reached, the total divided dose provides the initial unit dose, and further in the therapeutic mean serum. Give the concentration. In one embodiment, the total dose provides a therapeutic mean serum concentration of 80 ng / mL to 150 ng / mL. In some embodiments, the divided dose is administered every 15 minutes to 6 hours until the unit dose is reached. In some embodiments, the divided dose reaches the unit dose every 15 minutes, every 30 minutes, every hour, every 2 hours, every 3 hours, every 4 hours, every 5 hours, or every 6 hours. To be administered. The above ranges include both end values as well as any subranges between them.

  In some embodiments, the one or more additional doses are lower than the initial dose. In one embodiment, the one or more additional doses are from 5 mg to 75 mg. In one embodiment, the one or more additional doses may or may not include the same amount of norivogaine, norivogaine derivative, or a salt or solvate thereof. In one embodiment, the at least one additional dose is about 5 mg. In one embodiment, the at least one additional dose is about 10 mg. In one embodiment, the at least one additional dose is about 15 mg. In one embodiment, the at least one additional dose is about 20 mg. In one embodiment, the at least one additional dose is about 25 mg. In one embodiment, the at least one additional dose is about 30 mg. In one embodiment, the at least one additional dose is about 35 mg. In one embodiment, the at least one additional dose is about 40 mg. In one embodiment, the at least one additional dose is about 45 mg. In one embodiment, the at least one additional dose is about 50 mg. In one embodiment, the at least one additional dose is about 55 mg. In one embodiment, the at least one additional dose is about 60 mg. In one embodiment, the at least one additional dose is about 65 mg. In one embodiment, the at least one additional dose is about 70 mg. In one embodiment, the at least one additional dose is about 75 mg. The above ranges include both end values as well as any subranges between them.

  In one embodiment, the one or more additional doses are administered periodically. In one embodiment, the one or more additional doses are administered every 4 to 48 hours. In preferred embodiments, the one or more additional doses are administered every 6 to 24 hours. In one embodiment, the one or more additional doses are administered every 4 hours. The one or more additional doses are administered every 6 hours. The one or more additional doses are administered every 8 hours. The one or more additional doses are administered every 10 hours. The one or more additional doses are administered every 12 hours. The one or more additional doses are administered every 18 hours. The one or more additional doses are administered every 24 hours. The one or more additional doses are administered every 36 hours. The one or more additional doses are administered every 48 hours. The above ranges include both end values as well as any subranges between them.

  In some embodiments, the therapeutic dose of nolibogaine, a nolibogaine derivative, or a salt or solvate thereof is a dose that is gradually reduced over a period of time during which the patient experiences, for example, significant acute withdrawal symptoms. Without being treated, addiction. Without being bound by theory, it is believed that the gradual reduction allows the full therapeutic effect of norivogaine while making the QT interval extension smaller. The tapering involves the administration of the next lower dose of norivogaine over one or more times. For example, in some embodiments, the first decreasing dose is 50% to 95% of the initial or at least one additional dose. In some embodiments, the second decreasing dose is 40% to 90% of the initial or at least one additional dose. In some embodiments, the third decreasing dose is 30% to 85% of the initial or at least one additional dose. In some embodiments, the fourth decreasing dose is 20% to 80% of the initial or at least one additional dose. In some embodiments, the fifth decreasing dose is 10% to 75% of the initial or at least one additional dose.

  In some embodiments, the first tapering dose is administered after the first dose of norbogaine. In some embodiments, the first decreasing dose is administered after the second, third, or subsequent dose of norivogaine. The first declining dose can be administered at any time after the previous administration of norbogaine. For example, a first decreasing dose may be administered once, followed by further decreasing doses, or a first decreasing dose may be administered multiple times, followed by further decreasing doses ( For example, the second, third, fourth, etc. tapering doses) may or may not be administered, and the further tapering dose may be administered, for example, over one or more doses as well. In some embodiments, the first decreasing dose is administered about 1 hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or more after the previous administration of norbogaine. Is done. Similarly, the second, third, fourth, etc., decreasing doses, if administered, are about 1 hour, 6 hours, 12 hours, 18 hours, 24 hours, 36 hours, 48 hours, or It can be administered after that time.

  In some embodiments, the dose is gradually reduced starting 12-96 hours after the initial dose. In some embodiments, the dose is gradually reduced starting 12 hours after the initial dose. In some embodiments, the dose is gradually reduced starting 18 hours after the initial dose. In some embodiments, the dose is gradually reduced starting 24 hours after the initial dose. In some embodiments, the dose is gradually reduced starting 30 hours after the initial dose. In some embodiments, the dose is gradually reduced starting 36 hours after the initial dose. In some embodiments, the dose is gradually reduced starting 42 hours after the initial dose. In some embodiments, the dose is gradually reduced starting 48 hours after the initial dose. In some embodiments, the dose is gradually reduced starting 54 hours after the initial dose. In some embodiments, the dose is gradually reduced starting 60 hours after the initial dose. In some embodiments, the dose is gradually reduced starting 66 hours after the initial dose. In some embodiments, the dose is gradually reduced starting 72 hours after the initial dose. In some embodiments, the dose is gradually reduced starting 78 hours after the initial dose. In some embodiments, the dose is gradually reduced starting 84 hours after the initial dose. In some embodiments, the dose is gradually reduced starting 90 hours after the initial dose. In some embodiments, the dose is gradually reduced starting 96 hours after the initial dose.

  In some embodiments, at least one additional dose is administered 4-24 hours after the initial unit dose. In some embodiments, the additional dose is administered 4-24 hours after the previous dose. In some embodiments, the dose is administered every 4 to 24 hours. In some embodiments, the dose is administered as needed. The dosage and frequency of the administration depend on the administration route, the dosage, the age and weight of the patient, and the condition of the patient, but are not limited thereto. Suitable dosages and frequencies for the present technology can be readily determined by a qualified clinician.

  In some embodiments, the dose is administered at various times. That is, each dose need not be administered at the same interval as the previous dose. In some embodiments, the additional dose is administered more frequently at the start of treatment and less frequently after a period of time. For example and without limitation, withdrawal symptoms are most severe in the first 72 hours after the last dose of addictive drug. Nolubogaine, a norbogaine derivative, or a pharmaceutically acceptable solvate or salt thereof is administered, for example, every 4-12 hours during the first 72 hours, and less frequently thereafter (eg, , 12-24 hours).

  In some embodiments, the norbogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered over an indefinite period of time (eg, spanning the patient's lifetime for months or years). Is done.

  In some embodiments, the patient is treated for a long time (eg, 1 year or more) with a maintenance dose of norivogaine, a norivogaine derivative, or a salt or solvate thereof. In some embodiments, the patient is first treated with the above therapeutic doses of norivogaine for acute symptoms of the condition, and then, for example, after the acute symptoms are expected to have subsided, Is reduced to a maintenance level. This method is particularly suitable for the treatment of drug addiction. This is because acute withdrawal symptoms are generally most noticeable during the first 48-72 hours after withdrawal of an addictive drug. However, acute withdrawal may continue for longer than a week.

Pre-selection and monitoring of patients To ensure that the QT interval is not extended beyond a certain value, pre-selection of patients prior to treatment with nolubogaine and / or nolibogaine, norbogaine derivatives, or pharmaceutically acceptable Patients may need to be monitored during treatment with possible salts and / or solvates thereof. For example, QT intervals greater than about 500 ms may be considered dangerous for an individual patient. High levels of norbogaine treatment may require prior screening and / or monitoring.

  In preferred embodiments, patients receiving a therapeutic dose of norbogaine are monitored in a clinical setting. Monitoring may be necessary to ensure that the QT interval is not extended to an unacceptable extent. “Clinical environment” means an inpatient environment (eg, an inpatient clinic, a hospital, a rehabilitation facility) or an outpatient environment with a high frequency of regular monitoring (eg, outpatient practice administered and monitored daily) Place). As monitoring, QT interval monitoring can be mentioned. A method of monitoring the QT interval is well known in the art, for example by ECG.

  In one embodiment, patients receiving a maintenance dose of norbogaine are not monitored in the clinical environment. In one embodiment, patients receiving a maintenance dose of norbogaine are monitored regularly, eg daily, weekly, monthly, or occasionally.

  In one aspect, the invention provides for the treatment of a disease or disorder or a symptom of a disease or disorder as described herein, wherein said patient undergoes prior screening to assess a patient's resistance to expected QT interval prolongation. With respect to a prevention or attenuation method, the method provides the patient with a concentration sufficient to suppress or ameliorate the abuse or symptoms while maintaining a QT interval of less than about 500 ms during the treatment. Administering a dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof that provides a mean serum concentration of about 50 ng / mL to about 180 ng / mL. In some embodiments, the concentration is sufficient to attenuate the abuse or symptom while maintaining a QT interval of less than about 470 ms during treatment. The concentration is preferably sufficient to attenuate the abuse or symptom while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the abuse or symptom while maintaining a QT interval of less than about 420 ms during treatment.

  In one embodiment, the pre-screening of the patient includes confirming that no Qibo interval greater than about 500 ms will result as a result of nolubogaine treatment. In one embodiment, the pre-screening of the patient includes confirming that no norbogaine treatment will result in a maximum QT interval of greater than about 470 ms. In one embodiment, the pre-screening of the patient comprises confirming that no Noibogaine treatment will result in a maximum QT interval greater than about 450 ms. In one embodiment, the pre-screening of the patient includes confirming that no Qibo interval greater than about 420 ms will result as a result of nolubogaine treatment. In one embodiment, the screening includes measuring a pre-treatment QT interval for the patient.

  Since screening relates to patient pre-screening or pre-selection, the patient can select based on any criteria determined by a skilled clinician. Non-limiting examples of such criteria include QT interval before treatment, preexisting heart disease, risk of heart disease, age, sex, general health status, and the like. The following are examples of selection criteria for disallowing norivogaine treatment or limiting the dose of norivogaine administered to a patient. I.e. high QT interval before treatment (such as the risk that the patient's QT interval exceeds about 500 ms during treatment), congenital long QT syndrome, bradycardia, hypokalemia or hypomagnesemia , Recent acute myocardial infarction, decompensated heart failure, and other medications that increase the QT interval. In some embodiments, the method may include selecting a patient that does not have another such criterion and / or administering / providing norivogaine to the patient.

  In one embodiment, the present invention relates to prior patient screening, wherein said screening is to determine whether the patient is at risk of extending the QT interval beyond a safe level. In one embodiment, nolibogaine is not administered to patients at risk of extending the QT interval beyond a safe level. In one embodiment, nolibogaine is administered at a limited dose to patients at risk of QT interval extension above a safe level.

  In one embodiment, the present invention relates to monitoring a patient who is administered a therapeutic dose of norbogaine. In one embodiment, if the patient has serious side effects, the dose of norivogaine is reduced. In one embodiment, nolibogaine treatment is discontinued if the patient has serious side effects. In one embodiment, the side effect is a QT interval extended beyond a safe level. Determining the safe level of extension is a category of qualified clinician skill.

  In one aspect, the invention provides a method of treating a patient's anxiety disorder, impulse control disorder, or anger / violence related disorder, and / or a method of treating or attenuating those symptoms, wherein the patient is expected Selecting patients exhibiting symptoms of anxiety disorder, impulsive control disorder, or anger / violence related disorders that are subject to prior screening to assess resistance to prolonged QT interval; and A dose that provides an average serum concentration of about 50 ng / mL to about 850 ng / mL, a concentration sufficient to inhibit or ameliorate the disorder or symptom while maintaining a QT interval of less than about 500 ms. Administering a norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof. In some embodiments, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 470 ms during treatment. The concentration is preferably sufficient to attenuate the symptoms while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to attenuate the symptoms while maintaining a QT interval of less than about 420 ms during treatment.

  In one aspect, the present invention provides a method for adjusting a patient's food intake and / or a method for treating or attenuating food craving, in order to assess the patient's tolerance to expected QT interval prolongation. Selecting an overweight or obese patient to receive the screening, and suppressing or ameliorating the disorder or symptom for the patient while maintaining a QT interval of less than about 500 ms during the treatment Administering a dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof that provides an average serum concentration of about 50 ng / mL to about 180 ng / mL, a concentration sufficient for And to the above method.

Component Kit One aspect of the present invention is directed to a kit of components for the treatment of a patient's condition, which can be treated with nolubogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof. The kit comprises a composition comprising nolubogaine, a nolibogaine derivative, or a salt or solvate thereof, and means for administering the composition to a patient in need thereof. Means for administration to the patient include any one of any pharmaceutically acceptable formulations, including, for example, norivogaine, or norivogaine derivatives, or pharmaceutically acceptable salts or solvates thereof, or Combinations (eg, including but not limited to pills, transdermal patches, injection solutions, etc.) and optionally means for administering and / or formulating the formulation (eg, syringe, needle, composition) IV bag, vial containing the above composition, inhaler containing the above composition, etc., but not limited thereto). In one embodiment, the component kit further comprises instructions for dosing and / or administration of the composition.

  In some aspects, the present invention is directed to a kit of components for administration of norivogaine, the kit comprising a plurality of delivery vehicles, each delivery vehicle containing a discrete amount of norivogaine, and each delivery The vehicle is identified by the amount of norbogaine provided therein, and optionally further comprises a medication regimen in a readable medium. In some embodiments, the dosing regimen includes the amount of norbogaine required to obtain each mean serum level. In some embodiments, the component kit allows the attending physician to select a norbogaine dosing regimen based on the patient's gender, patient mass, and the serum level that the clinician wishes to reach. Including medication regimes that enable In some embodiments, the dosing regimen further provides information corresponding to the patient's blood volume based on the patient's weight (ie, mass) and gender. In certain embodiments, the storage medium may include an accompanying brochure or similar written information that accompanies the unit dosage form in the kit. In some embodiments, the storage medium may be an electronic, optical, or other data storage device, such as a non-volatile memory, for example, for storing a digitally encoded machine-readable representation of such information. Can be mentioned.

  As used herein, the term “delivery vehicle” refers to any formulation that can be used to administer norbogaine to a patient. Non-limiting exemplary delivery vehicles include caplets, pills, capsules, tablets, powders, solutions, or any other form capable of administering a drug. The delivery vehicle may be intended for administration by oral, inhalation, injection, or any other means.

  As used herein, the term “readable medium” refers to a representation of data that can be read, for example, by a human or by a machine. Non-limiting examples of human readable forms include brochures, package inserts, or other written forms. Non-limiting examples of machine-readable formats include any mechanism that provides (ie, stores and / or transmits) information in a form readable by a machine (eg, a computer, tablet, and / or smartphone). For example, machine readable media include read only memory (ROM), random access memory (RAM), magnetic disk storage media, optical storage media, and flash memory devices. In one embodiment, the machine readable medium is a CD-ROM. In one embodiment, the machine readable medium is a USB drive. In one embodiment, the machine readable medium is a quick response code (QR code®) or other matrix barcode.

  In some aspects, the machine-readable medium comprises software that contains information about the dosage regimen of the norbogaine unit dosage form and optionally information about other drugs. In some embodiments, the software may be interactive so that the attending physician or other health care professional can enter patient information. In a non-limiting example, a health care professional can enter the weight and gender of a patient to be treated, and the software program presents a recommended dosing regimen based on the entered information. The amount and timing of norbogaine recommended to be delivered will be within the dosage range that results in the serum concentrations presented herein.

  In some embodiments, the component kit comprises a plurality of delivery vehicles in various administration options. For example, the component kit may comprise pills or tablets at multiple doses, such as 120 mg, 90 mg, 60 mg, 30 mg, 20 mg, 10 mg, and / or 5 mg of norbogaine per pill. Each pill is labeled so that medical personnel and / or patients can easily distinguish between different doses. The label can be printed or embossed on the pill, the shape of the pill, the color of the pill, the location of the separate labeled compartment in the kit, and / or the distinguishing features of any other pill Can be based. In some embodiments, it is contemplated that all delivery vehicles in the kit are for a single patient. In some embodiments, the delivery vehicle in the kit is intended for multiple patients.

  One aspect of the present invention is directed to a kit of components for the treatment, prevention, or attenuation of a disease or disorder described herein or a symptom of the disease or disorder, wherein the kit comprises nolubogaine, a norbogaine derivative. Or a unit dosage form of a salt or solvate thereof. The unit dosage form provides the patient with an average serum level of norivogaine from about 50 ng / mL to about 180 ng / mL or from about 60 ng / mL to about 180 ng / mL. The unit dosage form provides the patient with an average serum level of norivogaine from about 50 ng / mL to about 800 ng / mL or from about 60 ng / mL to about 800 ng / mL. In one embodiment, the unit dosage form provides the patient with a mean serum level of nolvogine from about 50 ng / mL to about 400 ng / mL or from about 60 ng / mL to about 400 ng / mL. In one embodiment, the unit dosage form provides the patient with a mean serum level of norbogaine from 80 ng / mL to 100 ng / mL.

  In some embodiments, the unit dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is 20 mg to 120 mg. In one embodiment, the unit dose is 20 mg. In one embodiment, the unit dose is 30 mg. In one embodiment, the unit dose is 40 mg. In one embodiment, the unit dose is 50 mg. In one embodiment, the unit dose is 60 mg. In one embodiment, the unit dose is 70 mg. In one embodiment, the unit dose is 80 mg. In one embodiment, the unit dose is 90 mg. In one embodiment, the unit dose is 100 mg. In one embodiment, the unit dose is 110 mg. In one embodiment, the unit dose is 120 mg.

  In some embodiments, the unit dosage form comprises one or more doses administered periodically, such as once, twice, three times, four times, or five times daily. In some embodiments, the administration is once daily, or once every two days, once every three days, three times a week, twice a week, or once a week. The amount and frequency of administration will depend on criteria including but not limited to route of administration, composition content, patient age and weight, patient condition, patient gender, and severity of addiction. . A unit dosage form that provides the appropriate dosage and frequency for a given patient can be readily determined by a qualified clinician.

  In some embodiments, the initial unit dose and one or more additional doses of norivogaine, norivogaine derivative, or a salt or solvate thereof are once, twice, three times, four times, or five times daily. It is given as a single dose or a plurality of doses administered periodically. In some embodiments, the administration is once daily, or once every two days, once every three days, three times a week, twice a week, or once a week. The amount and frequency of administration will depend on criteria including but not limited to route of administration, composition content, patient age and weight, patient condition, patient gender, and severity of addiction. . A unit dosage form that provides the appropriate dosage and frequency for a given patient can be readily determined by a qualified clinician.

  In one aspect, provided herein is a kit of components comprising two or more batches of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, the two or more batches of Contains a sufficient amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof to maintain a serum concentration of 50 ng / mL to 180 ng / mL when administered to a patient.

  In one embodiment, a single dose is an initial dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof that, when administered to a patient, is sufficient to obtain a therapeutic serum concentration. And at least one additional dose that is sufficient to maintain the therapeutic serum concentration when administered to a patient, wherein the therapeutic serum concentration is between 50 ng / mL and 180 ng / mL. In another embodiment, the initial dose is from 75 mg to 120 mg. In another embodiment, the at least one additional dose is from 5 mg to 25 mg.

  These dosage ranges can be obtained by transdermal, oral, or parenteral administration of norivogaine, norivogaine derivatives, or pharmaceutically acceptable salts or solvates thereof in unit dosage form. Such unit dosage forms can be conveniently provided in the form of transdermal patches, tablets, caplets, solutions, or capsules. In a specific embodiment, the norivogaine is provided as norivogaine HCl, where the dose is recorded as the amount of free base norivogaine. In some embodiments, the norbogaine HCl is provided in a hard gelatin capsule that contains no nobogaine HCl without any additives. In some embodiments, norbogaine is provided in saline for intravenous administration.

Formulations The present invention further comprises unit doses of norivogaine, norivogaine derivatives, or a pharmaceutically acceptable salt or solvate thereof, wherein the amount of said norbogaine is about 50 ng / mL to about 180 ng when administered to a patient. Relates to a pharmaceutically acceptable formulation which is sufficient to give an average serum concentration of / ml. In a preferred embodiment, the amount of norbogaine is sufficient to provide an average serum concentration of about 80 ng / mL to about 100 ng / mL when administered to a patient. In one embodiment, the amount of said norbogaine, norbogaine derivative, or a pharmaceutically acceptable salt thereof is an amount that delivers a total amount of about 50 ng to about 10 μg of norivogaine per kg body weight per day.

  In some embodiments, the unit dose of norivogaine is administered in one or more doses.

  The present invention further includes a unit dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the amount of norivogaine is from about 50 ng / mL to about 180 ng / mg when administered to a patient. It relates to a pharmaceutically acceptable formulation which is sufficient to give and / or maintain an average serum concentration of mL. In a preferred embodiment, the amount of norivogaine is sufficient to provide and / or maintain an average serum concentration of about 80 ng / mL to about 100 ng / mL when administered to a patient.

  In some embodiments, the unit dose of norivogaine is administered in one or more doses.

  In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from 50 ng / mL to 180 ng / mL, or from 60 ng / mL to 180 ng / mL. In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from 50 ng / mL to 150 ng / mL, or from 60 ng / mL to 150 ng / mL. In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 50 ng / mL to about 120 ng / mL, or from about 60 ng / mL to about 120 ng / mL. In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 50 ng / mL to about 100 ng / mL, or from about 60 ng / mL to about 100 ng / mL. In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 50 ng / mL to about 120 ng / mL, or from about 60 ng / mL to about 120 ng / mL. In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 50 ng / mL to about 100 ng / mL, or from about 60 ng / mL to about 100 ng / mL. In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 80 ng / mL to about 100 ng / mL. The above ranges include both end values as well as any subranges between them.

  In some embodiments, the initial unit dose of the noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is about 50 mg to about 120 mg. In one embodiment, the unit dose is about 50 mg. In one embodiment, the unit dose is about 55 mg. In one embodiment, the unit dose is 60 mg. In one embodiment, the unit dose is about 65 mg. In one embodiment, the unit dose is about 70 mg. In one embodiment, the unit dose is about 75 mg. In one embodiment, the unit dose is about 80 mg. In one embodiment, the unit dose is about 85 mg. In one embodiment, the unit dose is about 90 mg. In one embodiment, the unit dose is about 95 mg. In one embodiment, the unit dose is about 100 mg. In one embodiment, the unit dose is about 105 mg. In one embodiment, the unit dose is about 110 mg. In one embodiment, the unit dose is about 115 mg. In one embodiment, the unit dose is about 120 mg.

  In some embodiments, the at least one additional dose of the noribogaine, norbogaine derivative, or pharmaceutically acceptable salt or solvate thereof is 5 mg to 75 mg. In one embodiment, the unit dose is 5 mg. In one embodiment, the unit dose is 10 mg. In one embodiment, the unit dose is 15 mg. In one embodiment, the unit dose is 20 mg. In one embodiment, the unit dose is 25 mg. In one embodiment, the unit dose is 30 mg. In one embodiment, the unit dose is 35 mg. In one embodiment, the unit dose is 40 mg. In one embodiment, the unit dose is 45 mg. In one embodiment, the unit dose is 50 mg. In one embodiment, the unit dose is 55 mg. In one embodiment, the unit dose is 60 mg. In one embodiment, the unit dose is 65 mg. In one embodiment, the unit dose is 70 mg. In one embodiment, the unit dose is 75 mg.

  In some embodiments, the formulation consists of the delivery vehicle described above. In one embodiment, the delivery vehicle comprises 5 mg to 120 mg of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof.

  In some embodiments, the formulation is a controlled release formulation. The term “controlled release formulation” encompasses sustained release and sustained release formulations. Controlled release formulations are well known in the art. Controlled release formulations include additives that allow sustained release, regular release, pulsed release, or delayed release of the drug. Controlled release formulations include embedding drugs in matrices, enteric coatings, microencapsulation, gels and hydrogels, implants, transdermal patches, and any other formulation that allows controlled release of the drug. However, it is not limited to these.

  In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 50 ng / mL to about 180 ng / mL, or from about 60 ng / mL to about 180 ng / mL. In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 50 ng / mL to about 150 ng / mL, or from about 60 ng / mL to about 150 ng / mL. In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 50 ng / mL to about 120 ng / mL, or from about 60 ng / mL to about 120 ng / mL. In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 50 ng / mL to about 100 ng / mL, or from about 60 ng / mL to about 100 ng / mL. In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 80 ng / mL to about 100 ng / mL. The above ranges include both end values as well as any subranges between them.

In some embodiments, the unit dose of nolubogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is about 20 mg to about 120 mg.
In one embodiment, the unit dose is about 20 mg. In one embodiment, the unit dose is about 30 mg. In one embodiment, the unit dose is about 40 mg. In one embodiment, the unit dose is about 50 mg. In one embodiment, the unit dose is about 60 mg. In one embodiment, the unit dose is about 70 mg. In one embodiment, the unit dose is about 80 mg. In one embodiment, the unit dose is about 90 mg. In one embodiment, the unit dose is about 100 mg. In one embodiment, the unit dose is about 110 mg. In one embodiment, the unit dose is about 120 mg.

  The present invention further includes a unit dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the amount of said norbogaine is about 50 ng / mL to about It relates to a pharmaceutically acceptable formulation which is sufficient to give an average serum concentration of 850 ng / mL. In a preferred embodiment, the amount of norbogaine is sufficient to provide an average serum concentration of about 50 ng / mL to about 400 ng / mL when administered to a patient.

  In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 50 ng / mL to about 800 ng / mL or from about 60 ng / mL to about 800 ng / mL. In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 50 ng / mL to about 700 ng / mL or from about 60 ng / mL to about 700 ng / mL. In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 50 ng / mL to about 600 ng / mL or from about 60 ng / mL to about 600 ng / mL. In a preferred embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 50 ng / mL to about 500 ng / mL or from about 60 ng / mL to about 500 ng / mL. In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 50 ng / mL to about 400 ng / mL or from about 60 ng / mL to about 400 ng / mL. In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 50 ng / mL to about 300 ng / mL or from about 60 ng / mL to about 300 ng / mL. In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 50 ng / mL to about 200 ng / mL or from about 60 ng / mL to about 200 ng / mL. In one embodiment, the amount of norivogaine is sufficient to provide an average serum concentration of norivogaine from about 50 ng / mL to about 100 ng / mL or from about 60 ng / mL to about 100 ng / mL. The above ranges include both end values as well as any subranges between them.

  In some embodiments, the formulation is designed for periodic administration, such as once daily, twice, three times, four times, or five times, of norivogaine, a norbogaine derivative, or a salt or solvate thereof. The In some embodiments, the administration is once daily, or once every two days, once every three days, three times a week, twice a week, or once a week. The amount and frequency of administration will depend on, but is not limited to, the route of administration, the content of the composition, the age and weight of the patient, the condition of the patient. Suitable dosages and frequencies for the present technology can be readily determined by a qualified clinician.

  In some embodiments, formulations designed for administration according to the methods provided herein include, but are not limited to, oral delivery, transdermal delivery, sublingual delivery, buccal delivery, intrapulmonary It can be suitable for various delivery modes including delivery or intranasal delivery. Formulations suitable for the internal route, pulmonary route, rectal route, nasal route, vaginal route, tongue route, intravenous route, intraarterial route, intramuscular route, intraperitoneal route, intradermal route and subcutaneous route may be used. Possible dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral solutions including suspensions, solutions and emulsions. Sustained release dosage forms may be used. All dosage forms can be formulated using standard methods in the art (see, for example, Remington's Pharmaceutical Sciences, 16th edition, edited by A. Oslo, Easton, Pa. 1980).

  In a preferred embodiment, the dosage form is designed for oral administration and can be conveniently provided in the form of a tablet, caplet, sublingual, liquid or capsule. In a specific embodiment, the norivogaine is provided as norivogaine HCl, where the dose is recorded as the amount of free base norivogaine. In some embodiments, the norbogaine HCl is provided in a hard gelatin capsule that contains no nobogaine HCl without any additives.

  Nolubogaine or norbogaine derivatives are any vehicles and excipients commonly used in pharmaceutical formulations, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. It can also be used in combination with a form. Coloring and flavoring agents can also be added to the formulations, particularly to formulations for oral administration. Solutions can be formulated using water or ethanol, 1,2-propylene glycol, polyglycol, dimethyl sulfoxide, aliphatic alcohols, triglycerides, physiologically compatible organic solvents such as partial esters of glycerin. The parenteral composition containing norivogaine may include aseptic isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, polyglycol mixed with water, Ringer's solution, etc. Can be prepared using conventional methods.

  The compositions utilized herein can be specifically formulated for aerosol administration to the respiratory tract, including intrapulmonary or intranasal administration. The compound will generally have a small particle size on the order of, for example, less than 5 microns. Such a particle size can be obtained by means known in the art, such as micronization. The active ingredient should be provided in a pressurized pack containing a suitable propellant such as chlorofluorocarbon (CFC) (eg, dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane), carbon dioxide or other suitable gas. Can do. The aerosol is convenient and can also contain a surfactant such as lecithin. The dose of drug can be controlled by a metering valve. Alternatively, the active ingredient can be provided in the form of a dry powder, such as a powder mixture of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidone. In some embodiments, the powder carrier will form a gel in the nasal cavity. The powder composition can be provided, for example, in unit dosage forms in capsules or cartridges, gelatin or blister packs from which the powder can be administered by inhaler.

  The compositions utilized herein can be formulated for sublingual administration, eg, as a sublingual tablet. Sublingual tablets are designed to dissolve very quickly. These tablet formulations contain, in addition to the drug, a limited number of soluble excipients, usually lactose, powdered sucrose, and sometimes dextrose and mannitol.

  Nolubogaine has been found to have a bitter taste for at least some patients. Thus, compositions for oral use (including sublingual, inhalation, and other oral preparations) may be formulated using taste masking techniques. Addition of sugar, flavor, sweetener, or skin; use of lipoproteins, vesicles, and / or liposomes; granulation; microencapsulation; paralysis of miso; multi-component emulsions; viscosity modification; prodrug or salt Many methods for masking the taste of bitter drugs are known in the art, including formation; inclusion or molecular complexes; ion exchange resins; and solid dispersions. Any method of masking the bitter taste of the compounds of the present invention can be used.

  The following examples are intended to further illustrate certain embodiments of the present disclosure and are not intended to limit the scope of the present disclosure.

Example 1 Pharmacokinetics and Pharmacodynamics of Nolubogain in Humans 36 healthy, drug-free, 18-55 year old male volunteers participated in the study and completed it. The trial was a escalating single dose, placebo-controlled, randomized, double-blind, parallel group study. The average (standard deviation) age is 22.0 (3.3) years old, the average (standard deviation) height is 1.82 (0.08) m, and the average (standard deviation) weight is 78.0 (9.2) kg. Met. Twenty-six subjects were Caucasian, 3 Asian, 1 Maori, 1 Pacific Islander, and 5 other races. The protocol for this trial was approved by the Low Southern Regional Ethics Committee (LRS / 12/06/015) and the trial was registered in the Australian New Zealand Clinical Trial Registry (ACTRN12612000821897). All subjects submitted informed consent signed prior to enrollment and were assessed as appropriate for participation based on medical history reviews, physical examinations, safety laboratory tests, vital signs and ECG.

  Within each dose level, 6 participants received noriobogain and 3 received placebo, based on a random code generated by the computer. Dosing begins with the lowest dose of norivogaine, reviews the safety, tolerability, and blinded pharmacokinetics of the completed cohort, and is approved for dose escalation by an independent data safety monitoring committee. The subsequent cohort received the next higher dose. The blinded study drug was administered as a capsule with 240 ml of water after an overnight fast of at least 10 hours. Participants did not receive any food until at least 5 hours after dosing. Participants were restrained at the study site from 12 hours before drug administration to 72 hours after administration, and continued outpatient evaluation until 216 hours after administration.

  For pharmacokinetic assessment, before administration and then after administration 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 2.5, 3, 3.5 At 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 14, 18, 24, 30, 36, 48, 60, 72, 96, 120, 168 and 216 hours Blood was collected. Samples were centrifuged and plasma was stored at −70 ° C. until analysis. For the 30 mg and 60 mg cohorts, a series of samples of urine every 24 hours were taken after study drug administration. Aliquots were frozen at -20 ° C until analysis.

  Using GE Carescape B650, pulse oximetry and capnography continuously from 2 hours before dosing to 6 hours after dosing and then at 12, 24, 48 and 72 hours after dosing Data was collected. Additional oximetry data was collected at 120, 168 and 216 hours. Miosis was evaluated by pupil measurement. Using a Neurooptics PLR-200 pupillometer, dark-adapted pupil diameter was measured before administration and at 2, 4, 6, 12, 24, 48, 72, 96, 120, 168 and 216 hours after dosing. The measurement was repeated three times under standardized light intensity (<5 lux).

In the 3 mg and 10 mg dose groups, plasma norbogaine concentrations were measured using a sensitive LCMSMS method that was validated. Sample preparation consisted of two extractions of a basified plasma sample with tert-butyl methyl ether, drying the sample under a nitrogen stream and acetonitrile containing 0.1% (v / v) formic acid: B . P. Sample reconstitution with water (5:95, v / v) was included. The compounds were separated by a 150 × 2.0 mm Luna 5 μm C18 column and detected by a triple-quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization and multiple reaction monitoring in positive mode. The noribogaine -d ₄ was used as an internal standard. The precursor ion-product ion transition value for norbogaine was m / z 297.6 → 122.3, and for the internal standard norbogaine-d ₄ was m / z 301.1 → 122.2. Analyst® software was used for data acquisition and processing. For calibration and measurement of the unknown concentration of norivogaine, the peak area ratio of norivogaine to norivogaine-d ₄ of the internal standard was used. The lower limit of quantification (LLOQ) was 0.025 ng / ml of norbogaine. The calibration curve was 0.025-25.600 ng / ml of norbogaine. Mobile phase A is acetonitrile containing 0.1% (v / v) formic acid: B.I. P. Water (5:95, v / v) and mobile phase B is acetonitrile containing 0.1% (v / v) formic acid: B.I. P. Water (95: 5, v / v). Total operation time was 6 minutes. Binary feed: Initial concentration is 8% mobile phase B; hold at 8% mobile phase B for 0.5 minutes and rise linearly to 90% mobile phase B over 1.5 minutes; 1 minute 90 % Mobile phase B and then returned to 8% mobile phase B over 0.01 minutes. The system was equilibrated for 3 minutes. Total operation time was 6 minutes. Day and day assay accuracy was <9% and day and day assay accuracy was <9%.

In the 30 mg and 60 mg dose groups, plasma norbogaine concentrations were measured using a sensitive LCMSMS method that was validated. Sample preparation included deproteinization of the plasma sample with acetonitrile and dilution of the sample with 0.1% (v / v) formic acid. The compounds were separated by a 150 × 2.0 mm Lina 5 μm C18 column and detected by a triple-quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization and multiple reaction monitoring in positive mode. The noribogaine -d ₄ was used as an internal standard. The precursor ion-product ion transition value for norbogaine was m / z 297.6 → 122.3, and for the internal standard norbogaine-d ₄ was m / z 301.1 → 122.2. Analyst® software was used for data acquisition and processing. For calibration and measurement of the unknown concentration of norivogaine, the peak area ratio of norivogaine to norivogaine-d ₄ of the internal standard was used. The LLOQ was 0.50 ng / ml nolubogaine. The calibration curve was 0.50-256.00 ng / ml of norbogaine. The mobile phase was the same as method A, and the binary feed was also the same as method A. Day and day assay accuracy was <9% and day and day assay accuracy was <9%.

In the 30 mg and 60 mg dose groups, plasma norbogaine glucuronide concentrations were measured using a sensitive LCMSMS method that was validated. Sample preparation consisted of deproteinization of the plasma sample with acetonitrile, drying the sample under a nitrogen stream and acetonitrile containing 0.1% (v / v) formic acid: P. Sample reconstitution with water (5:95, v / v) was included. The compounds were separated by a 150 × 2.0 mm Lina 5 μm C18 column and detected by a triple-quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization and multiple reaction monitoring in positive mode. The noribogaine -d ₄ was used as an internal standard. The precursor ion-product ion transition value for norivogaine glucuronide was m / z 472.8 → 297.3, and for the internal standard norbogaine-d ₄ was m / z 301.1 → 122.2. . Analyst® software was used for data acquisition and processing. For calibration and determination of the unknown concentration of norbogaine glucuronide, the peak area ratio of norivogain glucuronide to norivogaine-d _{4 as} an internal standard was used. The LLOQ was 0.050 ng / ml nolubogaine glucuronide. The calibration curve was 0.050 to 6.400 ng / ml of norbogaine glucuronide. The mobile phase was the same as Method A. Binary feed: Initial concentration is 6% mobile phase B; hold at 6% mobile phase B for 0.5 minutes and rise linearly to 90% mobile phase B over 2 minutes; 90% for 1 minute It was held in mobile phase B and then returned to 6% mobile phase B over 0.01 minutes. The system was equilibrated for 3.5 minutes. Total operation time was 7 minutes. Day and day assay accuracy was <11% and day and day assay accuracy was <10%.

In the 30 mg and 60 mg dose groups, urinary norbogaine and norivogaine glucuronide concentrations were measured using a highly sensitive LCMSMS method with validated efficacy. Sample preparation included deproteinization of the urine sample with acetonitrile and dilution of the sample with 0.1% (v / v) formic acid. The compounds were separated by a 150 × 2.0 mm Lina 5 μm C18 column and detected by a triple-quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization and multiple reaction monitoring in positive mode. The noribogaine -d ₄ was used as an internal standard. The precursor ion-product ion transition value for norbogaine is m / z 297.6 → 122.3 and for nolibogaine glucuronide is m / z 472.8 → 297.3, the internal standard norbogaine-d. ₄ was m / z 301.1 → 122.2. Analyst® software was used for data acquisition and processing. The measurement of the unknown concentration of the calibration and noribogaine and its glucuronide, was used noribogaine and peak area ratio of nor Iboga queuing glucuronide for noribogaine -d ₄ of the internal standard. The LLOQ of the assay was 20.0 ng / ml for Nolibogaing and 2.0 ng / ml for Nolibogain Glucuronide. The calibration curves were 20.0-5120.0 ng / ml norivogaine and 2.0-512.0 ng / ml norivogaine glucuronide. The mobile phase was as described in Method A, and the binary liquid feed was as described in Method C. Day and day assay accuracy was <13%, and day and day assay accuracy was <12%.

Pharmacokinetic parameters were calculated using a model-independent method using norivogaine and norivogaine glucuronide concentrations exceeding the quantitation limit. Maximum plasma concentration (Cmax) and maximum plasma concentration arrival time (Tmax) were observed values. Plasma concentration data after the distribution phase of the plasma concentration-time plot is expressed by linear regression using the formula ln C = ln Co-t · Kel, where Co is the extrapolated terminal zero-time intercept, and Kel is the terminal Fit to the disappearance rate constant. The half-life (t _1/2 ) was determined using the formula t _1/2 = 0.693 / Kel. The area under the concentration-time curve (AUC) from time zero to the concentration-time point (tf) after the last measured distribution phase was calculated using the trapezoidal rule. The area under the curve from the last concentration-time point (Ctf) to the time infinity after the distribution phase was calculated from AUC _t-∞ = Ctf / Kel. The concentration used for Ctf is the last measured value above the LLOQ at that time. Total AUC _0-∞ was obtained by adding AUC _tf and AUC _t-∞ together. The apparent discharge amount (CL / F) of norbogaine is obtained using the formula CL / F = dose / AUC _0−∞ × 1000, and the volume of the apparent distribution (Vd / F) is calculated using the formula Vd / F = (CL / F) / Kel. Total urinary norbogaine was the sum of both samples.

  For each dose group, summary statistics (mean, standard deviation, and coefficient of variation) were determined for safety laboratory data, ECG and pharmacokinetic parameters and pharmacodynamic variables. Categorical variables were analyzed using counts and percentages. The dose proportionality of AUC and Cmax was evaluated using linear regression. The effect of dose over time on pharmacodynamic parameter values was assessed using a two-factor analysis of variance (ANOVA). Paired comparisons between each dose group and placebo (by Tukey-Kramer correction) were performed at each time point using the least square estimate obtained from ANOVA using SAS Proc Mixed (SAS version 6.0). went.

Results Pharmacokinetics: The average plasma concentration-time plot of norivogaine is shown in FIG. 1, and the average pharmacokinetic parameters are shown in Table 1.

  Nolibogaine was rapidly absorbed and produced a peak concentration 2-3 hours after oral administration. Variations in the concentration-time profile of the individual's distribution phase may indicate the possibility of enterohepatic circulation (see the highlighted individual 4-8 hour profile in the inset of FIG. 1). Both Cmax and AUC increased linearly with dose (Table 1, upper compartment). A mean half-life estimate of 28-50 hours was observed across the dose group for norbogaine. The volume of distribution was extensive (1417-3086 L across dose groups).

  The mean plasma norbogaine glucuronide concentration-time plot for the 30 mg and 60 mg dose groups is shown in FIG. 2, and the average pharmacokinetic parameters are shown in the lower compartment of Table 1. In all subjects, norivogaine glucuronide was detected by 0.75 hours after dosing with norivogaine, resulting in peak concentrations in the same 3-4 hours. An average half-life of 21-23 hours was estimated for plasma norbogaine glucuronide. The ratio of C- and AUC of noribogaine glucuronide to noribogain was 3-4% for both dose groups. Total urinary norbogaine excretion was 1.16 mg and 0.82 mg for the 30 mg and 60 mg dose groups, respectively, which corresponded to 3.9% and 1.4% of the dose administered.

  The mean serum levels of norivogaine free base over time from a single dose of 3 mg of norivogaine free base under fasting conditions were plotted. An average Cmax of 5.2 ng / ml was obtained at 1.9 hours after administration, while an average AUC / 24h of 3.1 ng / ml was obtained.

  The mean serum levels of norivogaine free base over time from a single dose of 10 mg of norivogaine free base under fasting conditions were plotted. An average Cmax of 14.5 ng / ml was obtained 2.9 hours after administration, while an average AUC / 24h of 10.6 ng / ml was obtained.

  The mean serum levels of norivogaine free base over time from a single dose of 30 mg of norivogaine free base under fasting conditions were plotted. An average Cmax of 55.9 ng / ml was obtained at 1.75 hours after administration, while an average AUC / 24h of 29.2 ng / ml was obtained.

  The mean serum levels of norivogaine free base over time from a single dose of 60 mg of norivogaine free base under fasting conditions were plotted. An average Cmax of 116 ng / ml was obtained at 1.75 hours after administration, while an average AUC / 24h of 61 ng / ml was obtained.

  The mean serum levels of subject's nolibogaine free base over time for all four cohorts were plotted. The extrabogaine free base extrapolated dose required to give a Cmax in the range of about 5.2 ng / ml to about 1980 ng / ml and an AUC / 24 h of about 3.1 ng / ml to about 1100 ng / ml was determined.

  Pharmacodynamics: No evidence of miosis was found in subjects who received norbogaine. Over time, no difference in pupil diameter between dose groups was detected. After correcting for baseline differences, comparison of each dose group with placebo with ANOVA showed no statistically significant differences (P> 0.9).

  In the cold pressor test, norbogaine treatment showed no analgesic effect. The analgesic effect was evaluated based on the duration of immersion of the hand in ice water and the visual analog scale (VAS) pain score when the hand was removed from the water bath. For hand soaking duration, after correcting for baseline differences, comparison of ANOVA with placebo in each dose group showed no statistically significant difference (P> 0.9). Similarly, for the VAS pain score, after correcting for baseline differences, comparison of ANOVA to each dose group with placebo showed no statistically significant difference (P = 0.17).

Example 2 Safety and Tolerability of Nolibogaine in Healthy Humans The safety and tolerability of Noribogaine was tested in a group of volunteers from within Example 1. The cold pressor test was carried out in 1 ° C. water according to the method of Mitchell et al. (J Pain 5: 233-237, 2004) before administration and at 6, 24, 48, 72 and 216 hours after administration. Safety assessment includes clinical monitoring, adverse event (AE) recording, safety clinical examination, vital signs, ECG telemetry from -2 hours to 6 hours after dosing, and 12-lead ECG (ECG) up to 216 hours after dosing Was included.

Results A total of 13 adverse events were reported by 7 participants (Table 2). 6 adverse events were reported by 3 participants in the placebo group, 5 adverse events were reported by 2 subjects in the 3 mg dose group, 1 adverse event was 1 in each of the 10 mg and 30 mg dose groups. Reported by 1 subject. The most common adverse events were headache (4 reports) and nasal bleeding (2 reports). All adverse events were mild to moderate in intensity and all resolved before the trial was completed. Vital signs and safety laboratory tests showed no measurable changes. In particular, there were no changes in oximetry or capnography, or changes in respiratory rate. No QTcF value exceeding 500 milliseconds was seen at any time point. In one subject who received 10 mg of norbogaine, there was one increase in QTcF greater than 60 milliseconds at 24 hours post-dose.

Example 3 Safety, Tolerability, and Efficacy of Nolibogaine in Humans with Opioid Addiction This example illustrates that nolibogaine can be administered in therapeutic dosing while maintaining an acceptable QT interval. Is to do. The treatments used will be for opioid-dependent participants in randomized, placebo-controlled, double-blind trials, but these results indicate that a treatment window can be established for norbogaine Yes.

  The efficacy of norbogaine in humans was evaluated in opioid-dependent participants in randomized, placebo-controlled, double-blind trials. The patient was treated with methadone as an opioid replacement therapy, but switched to treatment with morphine prior to administration of norbogaine. This was done to avoid the negative interaction between norivogaine and methadone, which was not observed between norivogaine and morphine. See US application Ser. No. 14 / 214,157 filed Mar. 14, 2014 and No. 14 / 346,655 filed Mar. 21, 2014, which are hereby incorporated by reference in their entirety. Embedded in the book.

Nine (9) subject cohorts were evaluated for tolerability, pharmacokinetics, and efficacy in three cohorts of subjects (in each cohort, 6 were given noribogaine and 3 were given placebo). Cohort 1 received a single dose of 60 mg nolubogaine or placebo. Cohort 2 received a single dose of 120 mg nolubogaine or placebo. Cohort 3 received a single dose of 180 mg nolubogaine or placebo. Treatment was given 2 hours after the last dose of morphine and the time to resumption of morphine (opioid replacement therapy, OST) was measured. A few, no hallucinogenic side effects of norivogaine were observed in all participants. Table 3 shows the reported adverse events for each treatment that are not due to withdrawal from the opioid. Headache was more frequent in the placebo and 60 mg nolibogaine treatment groups, but was attenuated in the 120 mg and 180 mg dose groups.
Table 3 Summary of adverse events that occurred during treatment

  FIG. 3 shows the mean serum norbogaine concentration over time after administration of norivogaine for each cohort (60 mg is diamond, 120 mg is square, or 180 mg is triangle). Further results are detailed in US Provisional Patent Application No. 62 / 023,100, filed July 10, 2014 and entitled “METHODS FOR ACUTE AND LONG-TERM TREATMENT OF DRUG ADDICTION”. Which is incorporated herein by reference in its entirety.

Results The pharmacokinetic results for each cohort are shown in Table 4. The maximum serum concentration (Cmax) of norivogaine increased in a dose-dependent manner. The time to reach Cmax (Tmax) was similar in all three cohorts. The average half-life of serum norbogaine was similar to that observed in healthy patients.

Table 4 Pharmacokinetic results from patients in phase IB trials

  FIG. 4 shows the time to resumption of morphine (OST) for patients treated with placebo (circles), 60 mg of norbogaine (squares), 120 mg of norbogaine (triangles), and 180 mg of norivogaine (inverted triangles). Patients who received 120 mg of a single dose of norbogaine showed an average time to opioid resumption over 20 hours. Patients who received a single dose of 180 mg norbogaine showed an average time to opioid resumption similar to placebo. This indicates that increasing the dose of norivogaine to 180 mg results in a shorter time to restart of OST than that observed in patients receiving 120 mg of norivogaine. Nonetheless, the time to resumption of OST after treatment with 180 mg was longer than for patients who had not received treatment (7 hours, not shown) or who received 60 mg of norbogaine.

  Patients based on clinical opiate withdrawal scale (COWS), subjective opiate withdrawal scale (SOWS), and objective opiate withdrawal scale (OOWS) scoring system over the period from administration of norbogaine (or placebo) to resumption of OST evaluated. These measures are outlined in the Guideline for the Psychosocially Assisted Pharmaceutical Treatment of Opioid Dependence, World Health Organization, Geneva (2009), Appendix 10, which is incorporated by reference in its entirety. The scale measures the intensity of withdrawal symptoms based on clinical, subjective and objective signs.

  FIG. 5 shows the COWS score at the restart of OST for each cohort. The box contains a value representing the quartile between 25% and 75%. Diamond = median, horizontal bar in box = average value, whiskers = value within standard quartile standard deviation. There was no outlier. A highly variable COWS score between cohorts and within each cohort indicates that the patient resumed opiate regardless of withdrawal intensity. This was also reflected in the SOWS and OOWS scores at the time of OST resumption.

  FIG. 6A shows the mean change in total COWS score over the first 6 hours after administration and before resuming OST. FIG. 6B shows the change from baseline in mean AUC (0-6 hours) of the COWS total score. FIG. 7A shows the mean change in total OOWS score over the first 6 hours after administration and before resuming OST. FIG. 7B shows the change in change from baseline in the average AUC (0-6 hours) of the OOWS total score. FIG. 8A shows the mean change in total SOWS score over the first 6 hours after dosing and before resuming OST. FIG. 8B shows the change from baseline in the mean AUC (0-6 hours) of the SOWS total score. These data show that withdrawal symptoms worsen over time after OST cessation, and that patients who received placebo generally have worse withdrawal symptoms over that period. Patients who received 120 mg of norbogaine generally had fewer withdrawal symptoms than other patients, regardless of the scale used. Patients who received placebo generally had more withdrawal symptoms than those who received norbogaine.

  Throughout the trial, patients' QT intervals were evaluated at regular time points. FIG. 9A shows the mean change in QT interval (ΔQTcl, ie QT interval prolongation) over the first 24 hours after administration of norbogaine (or placebo). FIG. 9B shows the estimated correlation between the norbogaine concentration and the change in the QT interval. There is a dose-dependent increase in QT interval prolongation that correlates with the serum concentration of norivogain.

Based on the above data, it is believed that the treatment window for a single bolus administration of norivogaine is limited to a lower end of up to 50 mg and an upper end of less than 180 mg. In particular, the therapeutic serum concentration in vivo appears to be between about 50 ng / mL and about 180 ng / mL.
^** I can now delete this with the latest results, and I think this is included in Example 3 of “Others” above.

Example 4 Multiple doses of norivogaine in humans The efficacy of multiple doses of norivogaine in humans is evaluated in participants with opioid dependence in a randomized, placebo-controlled, double-blind trial. The patient is being treated with methadone as an opioid replacement therapy, but is transferred to treatment with morphine prior to administration of norivogaine.

As shown in Table 5, patients are treated with 80 mg of the initial unit dose of norivogaine followed by 15 mg to 20 mg of norivogaine every 6-12 hours.

The patient is treated with 80 mg of the initial unit dose of norivogaine, which is administered as 40 mg followed by 20 mg divided doses 2 hours and 4 hours after the first dose. As shown in Table 6, the initial unit dose is followed by 15 to 20 mg of norbogaine every 6 to 12 hours.

Example 5 Efficacy of Norbogaine in Modulating Opioid Tolerance in Humans A 59-year-old female patient receiving opioid analgesic therapy for chronic back pain was treated with the opioid at a dose of about 2 mg / kg of noribogaine. Treat with hydrochloride. After the nolubogaine treatment, the amount of opioid required to treat the patient's back pain to the same level as before the nolibogaine treatment is measured.

Example 6 Effect of Nolubogaine on Nicotine Dependence in Sprague-Dawley Rats In this study, 14 young male adult Sprague-Dawley rats (300-325 g) from Harlan were used. The rats were trained in catheterization surgery and nicotine self-administration.

  Upon arrival, the rat was assigned a unique identification number (tail mark). Animals were housed at 2-3 animals per cage in suspended polycarbonate rat cages with wire mesh shelves covered with filter paper and allowed to acclimatize for up to 7 days. Before starting the study, all rats were examined, picked and weighed to ensure that they were properly healthy and compatible. A 12/12 hour light / dark cycle was maintained during the course of the study. The room temperature was 20-23 ° C and the relative humidity was maintained at 30-70%. Water was given freely during the duration of the study. After surgery (in 14 nicotine-trained rats), all rats were bred alone and maintained alone throughout the duration of the study.

Test compound Norivogaine (12.5, 25 and 50 mg / kg, converted to free base dose using a correction factor of 1.12), 35% of the total required volume, 5% including 0.5% Tween 80 Dissolved in dextrose. The suspension was stirred for at least 30 minutes. 1.5% methylcellulose was added to make up 65% of the total volume and the suspension was stirred again for at least 30 minutes. As a result, the 12.5 mg / kg and 25 mg / kg doses were clear solutions and 50 mg / kg was a slightly cloudy suspension.

  A mixture of 5% dextrose (35% of total volume) containing 0.5% Tween 80 and 1.5% methylcellulose solution (65% of total volume) was used as a compound vehicle treatment.

  Vehicle and norbogaine were administered orally 2 hours prior to the study at a dose volume of 5 ml / kg.

  Varenicline (1.7 mg / kg) was dissolved in physiological saline (0.9% NaCl) and administered intraperitoneally 30 minutes before the test. The dose volume of varenicline was 1 ml / kg. The varenicline formulation (1.7 mg / kg) was a clear solution.

Nicotine self-administration test Apparatus: Intravenous drug self-administration and testing was performed in an experimental chamber (Med Associates, Vermont) in a silenced compartment equipped with an exhaust fan. Each chamber was equipped with two response levers located on one wall of the chamber. A stimulating light was placed above each lever, and a room light was placed on top of the opposite wall. An infusion pump attached above each chamber delivered medicinal solution via a Tygon tube connected to a single-channel fluid loop joint, which was mounted on a balance arm above the operant chamber . The output of the fluid swivel was coupled to the external end of the intravenous catheter.

  Diet training and surgery: Prior to intravenous catheter placement, the animals were trained to push the levers to get food. After learning the lever pressing response, the rat was fitted with an intravenous catheter. One week later, the rat was given a Nikontin solution (0.03 mg in 0.1 ml over 0.8 seconds under a fixed ratio 3 (FR3)) by pushing the lever paired with the diet in return for drug delivery in advance. Self-administered. In this study, in order to obtain a stable nicotine infusion (defined as less than 20% variation in the average number of intensifiers acquired and 6 or more infusions over 1 hour training over 3 consecutive days) Four weeks of operant training was required.

  Self-administration procedure: Initially the animals were trained to respond to nicotine (0.03 mg / kg / infusion) under the step of a strengthener that expired at FR3, 20 seconds. After the training was completed and a stable baseline was established, the effects of nolibogaine were evaluated. Animals responded at baseline levels (ie, less than 20% variation in mean number of intensifiers acquired and more than 6 injections in the 1 hour training over the last 3 consecutive days of non-drug testing) Only in some cases was norbogaine or the control compound varenicline (a nicotinic acetylcholine receptor partial agonist) administered. Compound testing was conducted on Wednesday and Friday, assuming that self-administration behavior was at baseline levels on Tuesdays and Thursdays.

Study design and analysis An in-subjects plan in which each rat received all treatment was applied using a Latin square test plan. The six treatments that were blinded to study participants were as follows.
1. Physiological saline Varenicline 1.7mg / kg
3. Vehicle (5% dextrose 35% with 0.5% Tween-80 and 1.5% methylcellulose 65%)
4). Noribogaine 12.5mg / kg
5). Noribogaine 25mg / kg
6). Noribogaine 50mg / kg

  Nicotine infusion data obtained during the test session was analyzed by repeated measures ANOVA, followed by Fisher LSD post hoc comparison, where appropriate. The rate of invalid lever press was also analyzed using repeated measures ANOVA for non-specific behavioral effects. The effect is considered significant when P <0.05. Data are expressed as mean and standard error (sem) to mean. Statistical outliers outside the mean +/− (2 × standard deviation) are removed from the analysis. This criterion excluded outliers from 0 to 2 in different measurements.

Results The effect of nolibogaine and varenicline on nicotine infusion is shown in FIG. 10A. Repeated measures ANOVA found significant treatment main effects [F (5,58) = 29.708, P <0.001]. A post hoc comparison showed that varenicline and nolibogain significantly reduced nicotine infusion at both 25 mg / kg and 50 mg / kg (Ps <0.001). A trend for reduced nicotine infusion was also found at the 12.5 mg / kg dose (P <0.10). Data are mean + s. e. m. Represents.

  The effect of nolibogaine and varenicline on ineffective lever press during nicotine self-administration is shown in FIG. 10B. Repeated measures ANOVA found no significant main treatment effect [F (5,54) = 0.356, P> 0.05]. These results suggest that the effect of the test compound on lever pressing for nicotine infusion was not impaired by nonspecific ineffective lever pressing.

Example 7 Low Dose Noribogaine Effect on Human Smoking Cessation A female habitual smoker absorbed a nanogram amount of noribogaine hydrochloride intranasally. For a few hours, the craving for any smoking ceased and then only returned. The patient was unaware of any nicotine or craving for smoking during that period.

Example 8 Effect of Nolibogaine on Human Alcohol Withdrawal In a randomized, placebo-controlled, double-blind trial, 6 patients received 2 mg / kg of a single dose of norbogaine administered orally. Patients receive a placebo. All patients have alcoholism. Treatment is given at least 2 hours after the last alcohol use. As determined by self-assessment (eg, questionnaires) and clinical observations, patients receiving nolubogaine exhibit fewer and / or less severe alcohol withdrawal symptoms compared to patients receiving placebo.

Example 9 Efficacy of Noribogaine in the Treatment of Substance Addiction The efficacy of Noribogaine is evaluated in participants of substance addiction in randomized, placebo-controlled, double-blind trials. Patients are dosed with 60 mg or 120 mg of compound and the QT interval is measured.

Example 10 Effect of Nolubogaine on the Treatment of Human Pain A 57 year old female patient with chronic back pain is treated with nolibogaine hydrochloride at a dose of about 2 mg / kg. The patient's pain is attenuated as judged by self-assessment and clinical assessment.

Example 11 Effect of Nolibogaine on Human Chronic Migraine A 25 year old female patient with recurrent migraine not due to withdrawal from opioids is treated with nolibogaine hydrochloride at a dose of about 1.5 mg / kg. For several hours, the patient's migraine symptoms are attenuated as judged by self-assessment and clinical assessment.

Example 12 Forced swimming test (FST) using rats
Animals: Male Sprague Dawley rats (Taconic Farms, NY) are used in all experiments. Rats are housed 5 per cage and maintained on a 12:12 hour light-dark cycle. Rats are picked for 1 minute each day for 4 days prior to behavioral testing.

  Drug administration: Animals are randomly assigned, vehicle (2.5% ethanol / 2.5% Tween-80), imipramine (positive control; 60 mg / kg), or before the start of the 5 minute test period A single intraperitoneal administration of the test compound is received. All injections are made using a 1 cc tuberculin syringe (Becton Dickinson, VWR Scientific, Bridgeport, NJ) fitted with a 26 3/8 gauge needle. The volume of injection is 1 ml / kg.

  Experimental design: The procedure used in this study employs a water depth of 31 cm. In this test, the greater water depth prevents the rat from standing on its own by touching the bottom of the cylinder. A swimming session is performed by placing the rat in a separate plexiglass cylinder (45 cm in height and 20 cm in diameter) containing 23-25 ° C. water. The swim test was always performed from 9:00 to 17:00 and included an initial 15 minute conditioning test and a 24 minute later 5 minute test. Drug treatment is given 60 minutes before the 5 minute test period. After every swimming session, the rat is removed from the cylinder, dried with a paper towel, placed in a warmed cage for 15 minutes, and returned to the rat's home cage. All test sessions are recorded on videotape using a color video camera and recorded for later scoring.

  Behavioral score: Rat behavior is assessed by a single individual blinded to treatment conditions at 5 second intervals during a 5 minute study. The actions to score are: Immobility--the rat remains floating in the water without struggling, performing only the movements necessary to keep the head above the water; 2. Climbing--rats are actively moving with their forelimbs in and out of the water, usually towards the wall; Swimming--the rats are not only necessary to keep their heads on the water, but are undergoing aggressive swimming movements, such as moving around in a cylinder; and Diving--the entire body of the rat is sinking.

  Data analysis: Forced swimming test data (immobility, swimming, climbing, diving) are subjected to a post-hoc test performed using randomized one-way ANOVA and Newman-Kylos tests. Data is analyzed using GraphPad Prism (v2.01) (GraphPad Software Inc., San Diego, CA).

Example 13 Forced swimming test (FST) using mice
Animals: DBA / 2 mice (Taconic Farms, NY) are used for all experiments. Animals are housed 5 per cage in a controlled environment under a 12:12 hour light / dark cycle. Animals are picked for 1 minute daily for 4 days prior to the experiment. This procedure involves simulated forced feeding using 1.5 inch feeding tubes.

  Drug administration: Animals were randomly assigned and one hour prior to the swim test, vehicle (5% ethanol / 5% Tween-80), test compound, or imipramine (60 mg / kg) by oral gavage. Accept multiple doses.

  Experimental design: The procedure of the forced swimming test in mice is similar to that described above for rats, with the following changes. The cylinder used for the test is a 1 liter beaker (diameter 10.5 cm and height 15 cm) filled with water of 23 to 25 ° C. to 800 ml (water depth 10 cm). From 13:00 to 17:00, each mouse is subjected to a single 5-minute swimming test. Drug treatment is given 30-60 minutes prior to the 5 minute test period. After every swimming session, the mouse is removed from the cylinder, dried with a paper towel and placed in a warmed cage for 15 minutes. All test sessions are recorded on videotape for later scoring using a Sony color video camera and recorder.

  Behavior scoring: Behavior between 2 and 5 minutes of the test is replayed on a TV monitor and a researcher scores. Record the total time spent in the immobile state (animals that float with minimal movement to remain floating) and in the mobile state (movements beyond what is necessary for swimming and floating).

  Data analysis: Forced swimming test data (immobility, mobility indicating time, seconds) are subjected to a post-hoc test performed using randomized one-way ANOVA and Newman-Coils tests. Data is analyzed using GraphPad Prism (v2.01) (GraphPad Software Inc., San Diego, CA).

Example 14 Single-Dose Toxicity in Rats The purpose of this study was to determine the toxicity and toxicokinetic profile of norivogaine HCl after single oral (gavage) administration in Sprague-Dawley rats. A single dose of 100, 300 and 800 mg / kg (achieved at two doses of 400 mg / kg at intervals of 3 hours ± 30 minutes due to limitation of maximum dose formulation concentration). Five male rats / group were used. All of the 800 mg / kg male rats died about 2-3 hours after the second dose of 400 mg / kg. Decreased activity, vocalization, mastication, breathing / posture change, fluency, irritation, tremor, convulsions and penile erections occurred before death. In 3/5 of the rats given 300 mg / kg, on the day of treatment, there was decreased activity, vocalization, fluency, irritation, loss of limb function and lying on the cage floor, which continued until day 2. . Low dose rats treated with 100 mg / kg did not show any treatment related signs. The maximum non-toxic dose (NOAEL) was determined to be 100 mg / kg.

Example 15 Single dose toxicity in dogs In acute oral toxicity / toxicokinetic studies in dogs, no deaths occurred at doses of 5 mg / kg (n = 2) or 10 mg / kg (n = 2). At the 10 mg / kg dose, seizures and other CNS-related clinical signs, including short contractions, fluency, vocalization, coordination impairment and hypofunction, occur 20 minutes after administration and continue for 3 hours and 40 minutes after administration did. A dose of 5 mg / kg was considered NOAEL. This is because at that dose, only a transient reduction in food consumption occurred in one dog.

Example 16 Single-dose toxicity in cynomolgus monkeys The purpose of this study was to determine the toxicity and toxicokinetic profile of nolibogaine after oral (forced feeding) administration to cynomolgus monkeys. A 7-day withdrawal period was provided after each administration. Dosing was shifted for 45 minutes. On the 15th day of the study, 80 mg / kg was administered to one animal and 160 mg / kg was administered to the other animal. Test articles were administered as shown in Table 7 below.
Table 7. Examination of toxicity and toxicokinetics in cynomolgus monkeys

  Parameters monitored in this study include death, clinical signs and body weight. Blood samples were collected for toxicokinetic evaluation. There were no clinical signs associated with death or treatment for doses up to 160 mg / kg. The maximum tolerated dose (MTD) for a single dose was determined to exceed 160 mg / kg based on the parameters monitored during the study.

Example 17 14-Day Repeated Dose Toxicity and Toxicology in Rats This study is to evaluate the toxicity profile of norivogaine-HCl after 14 days of oral (gavage) administration to rats, according to Table 8 below. Carried out.
Table 8 Examination of toxicity and toxicokinetics in rats

  Male and female Sprague-Dawley rats, 10 / sex / group, were administered 0, 25, 50 or 100 mg / kg of norbogaine HCl by single daily oral gavage for 14 days. In the 0 mg / kg (control) and 100 mg / kg groups, an additional 5 rats / sex / group were maintained during the 28-day recovery period during which no drug was administered. 6 rats / sex / group (3 rats / sex / control) were administered in the same manner, sampled on day 1 and 14 of the study, and analyzed for norivogain-HCl concentration in blood did. Rats were killed, clinical signs, body weight, food consumption, ophthalmic observation (pre-dose, during the second week, and at the end of recovery), hematology, coagulation, clinical chemistry, urinalysis, gross necropsy, organ weight And histopathology (whole tissue panel, plus 5 brain compartments and spinal cord immunocytochemistry by staining for GFAP and calbindin). There were no test-related effects on death (not occurring), clinical signs, fundus examination, hematology, coagulation parameters, clinical chemistry, urinalysis, gross necropsy or histopathology. In the high dose (100 mg / kg) group, food consumption and body weight were slightly decreased (food consumption: -4.7% for males and females; body weight: -5.5% for males, -2. 6%). A slight increase in liver weight in the medium and high dose groups does not correlate with histopathological changes and is considered incidental. No differences related to treatment in the brain were seen in sections stained for GFAP or calbindin.

  The NOAEL dose in this study was interpreted as the maximum dose tested in this study, 100 mg / kg.

Example 18 14-Day Repeated Dose Toxicity and Toxicology in Dogs The purpose of this study is to determine the toxicity profile of noriobogaine HCl given after oral (gavage) administration to dogs for 14 days according to Table 9 below. Was that.
Table 19 Examination of toxicity and toxicokinetics in dogs

  Nolibogaine HCl is administered daily to a group of 4 male and 4 female dogs at a dose of 0, 0.5, 1.0 and 5.0 mg / kg / day by single oral gavage for 14 days did. An additional group of 4 male and 4 female dogs received either vehicle control or 5.0 mg / kg / day for 14 days and held this for another 28 days after dosing stopped, Recovery from potential drug-induced changes was assessed. The study will be conducted under GLP guidelines, and comprehensive analysis of plasma for clinical signs, weight, clinicopathological parameters, ophthalmic examinations, ECG recordings and bioanalytical measurements of drug levels at appropriate intervals during the study. New trials were included. At the end of the dosing phase and at the end of the recovery phase, all dogs were subjected to a post-mortem examination including gross examination of major organs and extensive histological examination of tissues. Additional brain sections were obtained from the cerebrum, cerebellum, brain stem and spinal cord and examined histologically to assess potential effects on brain histopathology. In addition, these sections were examined using an immunohistochemical stain for GFAP for evidence of gliosis and using the stain for calbindin for a more comprehensive examination of cerebellar Purkinje cells. Harmful in any dog from any treatment group during the administration phase or recovery phase, in clinical observations, body weight, clinicopathological parameters, ophthalmic examination, ECG recording, or gross lesions at necropsy No evidence of action was observed. The results of measurement of plasma drug levels on day 1 and day 14 of this study are shown in the following table. The maximum plasma concentration (Cmax) of norivogaine-HCl is reached 0.5 to 0.9 hours after administration, after which the plasma concentration is determined except in the case of group 4 male and female dogs, There was a gradual decrease over a period of up to 24 hours, and for the fourth group of dogs, significant levels of norbogaine were still detected both at day 1 and day 14 at 24 hours after dosing.

表１１ 第１日及び第１４日での雌のイヌにおけるノルイボガインに関する平均の血漿毒物動態パラメータ

The only target tissue identified in this study was the dog lacrimal gland that received 5 mg / kg / day. The lacrimal gland changes were characterized by slight to moderate acinar cell atrophy and degeneration, with slight to moderate brown / yellow pigment deposition and mononuclear cell infiltration. Dogs affected by this dose group had associated mononuclear cell infiltration in the draining mandibular lymph nodes. Despite the appearance of isolated eye abnormalities in several dogs in this high-dose group on ophthalmology, there is no clear association between these eye signs and the development of lacrimal gland changes This suggests that these morphological changes did not lead to dysfunction of the glands sufficient to cause physical changes in the external structure of the eye. There was no clear evidence of local irritation associated with drug treatment in these high dose dogs. Evidence for drug-induced effects was not observed in any other tissue, including extensive sections of the brain assessed using conventional histopathology or immunohistochemistry. A study of animals in the recovery group showed clear evidence of regeneration of this lacrimal gland change. Even after 28 days of drug withdrawal, slight atrophy was still evident in the acinar cells of the gland, but there was no evidence of continuous and ongoing degeneration or cell infiltration. The NOAEL in this study was 1 mg / kg / day based on lacrimal gland changes at 5 mg / kg / day. The results are summarized in Tables 10 and 11.
Table 10 Mean plasma toxicokinetic parameters for nolibogaine in male dogs on day 1 and day 14

Table 11 Mean plasma toxicokinetic parameters for nolvogine in female dogs on day 1 and day 14

Example 19 Effect of Nolibogaine on Human Depression A 55 year old male patient with depression unrelated to the use of any illegal substance is treated with nolibogaine hydrochloride at a dose of about 1 mg / kg / day for a period of 4 weeks. . During the treatment period, the patient's depression changes in symptoms and / or changes in one or more of the following tests: HDRS, Hamilton Depressive Mood Item, and CGI and Disease Severity Scale.

Example 20 Social Interaction Test (SIT)
Animals: two male albinoid Sprague Dawley rats (Taconic Farm, New York) with free access to food and water under a 12-hour light-dark cycle (lights up at 07:00) Breed in.

  Rats are acclimated to the animal housing facility for 5 days and kept alone for 5 days prior to testing. The animals are picked up for 5 minutes per day. On the test day, a pair of rats that are unfamiliar with each other and whose weight is matched (± 5%) are given the same treatment and returned to their home cage. Animals are randomly divided into 5 treatment groups, 5 pairs per group, and given one of the following intraperitoneal treatments. Test compound (1, 2 or 4 mg / kg), vehicle (1 ml / kg) or chlordiazepoxide (5 mg / kg). Dosing is performed 1 hour prior to testing. Rats are then placed for 15 minutes in a white Perspex test box or active area (54 × 37 × 26 cm) with the floor divided into 24 equal squares. An air conditioner is used to generate background noise and maintain the room temperature at about 74 ° F. All sessions using JVC's integrated video camera (model GR-SZ1, Elmwood Park, NJ) with a 30-minute video cassette from either TDK (superlative quality HG) or Sony Record on videotape. All sessions are conducted from 13:00 to 16:30. Active social interaction, defined as hair-brushing behavior, odor-sniffing behavior, biting behavior, boxing behavior, wrestling behavior, follow-up behavior, and coasting behavior on the upper side or lower side, is expressed as a stopwatch (sport line model, No. .226, 1/100 second distinguishable). The number of episodes of standing up behavior (animal standing on hind limbs and raising the body completely), grooming behavior (licking, biting, scratching), and facial cleansing behavior (ie, repeatedly moving the hand over the face), As well, score the number of times to cross the square. Passive social interactions (animals lying beside or on top of each other) are not scored. All behavior is later evaluated by a blinded observer for each pair of treatments. At the end of each test, wipe the box thoroughly with a damp paper towel.

  Data analysis: Social interaction data (interacting time, standing behavior and crossed squares) are subjected to a post-test performed using randomized one-way ANOVA and Student Newman-Kyrks test. The data is subjected to a normality test (Shapiro-Wilk test). Data is analyzed using the GBSTAT program, version 6.5 (Dynamics Microsystems, Inc., Silver Spring, MD, 1997).

Example 21: Effect of nolibogaine on food intake The effect of nolibogaine and varenicline on food intake in food maintenance-responsive rats is shown in FIG. 10A. Repeated measures ANOVA found a significant main treatment effect [F (5,33) = 16.905, P <0.001]. Post hoc comparisons showed that norbogaine (25 mg / kg and 50 mg / kg) significantly reduced food intake compared to vehicle treatment (P <0.05 and P <0. 0, respectively). 001). Norivogaine (12.5 mg / kg) and varenicline (1.7 mg / kg) had no significant effect on this measurement.

  The effect of nolibogaine and varenicline on the response to ineffective liver in food maintenance responsive rats is shown in FIG. 10B. Repeated measures ANOVA found a significant main treatment effect [F (5,31) = 7.583, P <0.001]. As shown in the post hoc comparison, this main effect is due solely to the contribution of high dose norbogaine (50 mg / kg) (P <0.001 compared to treatment with vehicle). This result suggests that high doses of noribogaine (50 mg / kg) may cause some behavioral disorder for frequent lever presses in dietary tests.

  At 12.5 mg / kg, nolibogaine had no effect on food intake. At 25 mg / kg, norbogaine reduced food intake by 10% (P <0.05). At 50 mg / kg, norbogaine reduced food intake by 25% (P <0.001). Overall, the rate of response to ineffective liver was very low during all treatment feeding studies.

Example 22 Single-Dose Toxicity in Rats The purpose of this study was to determine the toxicity and toxicokinetic profile of norivogaine HCl after single oral (gavage) administration in Sprague-Dawley rats. A single dose of 100, 300 and 800 mg / kg (achieved at two doses of 400 mg / kg at intervals of 3 hours ± 30 minutes due to limitation of maximum dose formulation concentration). Five male rats / group were used. All of the 800 mg / kg male rats died about 2-3 hours after the second dose of 400 mg / kg. Decreased activity, vocalization, mastication, breathing / posture change, fluency, irritation, tremor, convulsions and penile erections occurred before death. In 3/5 of the rats given 300 mg / kg, on the day of treatment, there was decreased activity, vocalization, fluency, irritation, loss of limb function and lying on the cage floor, which continued until day 2. . Low dose rats treated with 100 mg / kg did not show any treatment related signs. NOAEL was determined to be 100 mg / kg.

Example 23 Effect of Nolibogaine on Anxiety Disorders in Humans A 45 year old male patient with generalized anxiety disorder unrelated to the use of any illegal substance was treated with norivogaine hydrochloride at a dose of about 1 mg / kg / day for a period of 4 weeks. treat. The patient's generalized anxiety level is reduced by at least one of the following symptoms: restlessness or feeling of tension or irritation, fatigue, difficulty concentrating or self-defeat, nervousness, muscle tension, and sleep disturbance Measure by patient self-report.

Example 24 Effect of Nolibogaine on Zebrafish Nicotine withdrawal shown by anxiety-related endpoints In this study, a total of 60 adult wild-type short fin zebrafish (approximately 50:50 male: female ratio) were used. It was. Fish were reared in groups of 20-30 fish per 40L aquarium. The water tank was filled with filtered water and maintained at 25 ° C. According to the standard of zebrafish breeding, illumination (1000 to 1100 lux) was performed with a fluorescent lamp attached to the top board at a cycle of 12 hours (6:00 on, 18:00 off). All fish used in this study were experimentally naive and were fed Tetramin Tropical Flakes (Tetra USA, Blacksburg, VA) twice daily. After behavioral testing, the animals were euthanized in tricaine (Sigma Aldrich, St. Louis, MO) buffered to 500 mg / L pH = 7.0. Animal experiments in this study strictly adhered to national and institutional guidelines and regulations.

Test Compound A 1 mg / L dose of nolibogaine (DMX1) was selected based on preliminary experiments and literature reports on effective doses of other similar compounds. Preliminary experiments revealed sub-maximal efficacy of norivogaine at 1 mg / L, a dose that did not promote any locomotor activity that was easily confused with the efficacy endpoints of interest in other protocols. A standard 20 minute pretreatment time was chosen based on experience with a wide range of other neuroactive compounds and the results of preliminary experiments. This exposure time was also sufficient to elicit zebrafish physiological (eg, cortisol and c-fos) responses to multiple drugs. Drug exposure in this study was performed by immersing individual zebrafish in a 1 L plastic beaker for 20 minutes prior to testing. In order to ensure that each fish was exposed to a consistent concentration of norbogaine, the solution was changed completely after each exposure. As described above, control fish were exposed to water without the same treatment time norbogaine.

Tests and Procedures Apparatus: A behavioral test was performed between 11:00 and 15:00 using a water tank containing water adjusted to the temperature of the installed room (25 ° C.). This study used a new tank test (NTT) protocol. NTT represents one of the most commonly used neurophenotypic tests for adult zebrafish. To avoid a series of testing or handling effects, each assay was performed once on a separate individual naïve fish at each time. Prior to testing, the fish were individually pre-exposed to either drug-treated water or drug-free water for 20 minutes in a 1 L plastic beaker. During the study, zebrafish behavior was recorded by two skilled observers blinded to treatment, who manually scored different behavioral endpoints (assessment in all experiments). Inter-rater and intra-rater confidence> 0.85), then the generated results were automatically analyzed by Ethovision XT8.5 software (Noldus IT, Wageningen, The Netherlands). The NTT used to assess zebrafish anxiety and locomotor activity is a 1.5L trapezoid filled with a maximum amount of water and divided into two equal virtual horizontal parts by the markings on the outer wall. Water tank (15 cm high x 28 cm upper x 23 cm low x 7 cm wide, Aquatic Habitats, Apopka, FL). Fish were individually pre-exposed to water (water control), chronic nicotine (1 mg / L), repeated withdrawal from chronic nicotine (WD), and norivogaine (1 mg / L) in addition to repeated withdrawal for 20 minutes. Tested for 5 minutes of NTT.

  Behavior analysis: Skilled observers record zebrafish behavior, latency to reach the upper half of the aquarium (seconds), time spent in the upper part (seconds), number of moves up, and stiff seizures The number and duration (seconds) were scored. Stiffness was defined as the absence of any motion except for error and eyes for more than 2 seconds. The test was also recorded on a computer using a USB webcam (2.0 megapixel, Gigaware, UK) and later analyzed by Ethovision XT8.5, travel distance (m), speed (m / sec), and meandering Evaluation items were evaluated. During manual observation, video was recorded in MPEG1 format at a maximum sampling rate of 30 fps for each test by an autofocus 2.0 MP USB webcam placed 25 cm in front of the aquarium and connected to a laptop computer. Video recorded using Ethovision XT8.5 was analyzed. All environments were calibrated for each active area, and the calibration axis was positioned so that the origin (0,0) was set at the center of each tank. Track data for each fish was exported as raw data to individual spreadsheets. The exported results were independently evaluated by two skilled observers blinded to treatment based on consensus to explain the spatial pattern of zebrafish swimming.

  Study design and data analysis: This study is for adult zebrafish individually (15 fish per group), soaked in water, acutely in water controls, chronic nicotine, repeated nicotine withdrawal, and nicotine withdrawal + 1 mg / L of norbogaine Exposure (20 minutes) followed by testing with NTT for 5 minutes, after which the fish were euthanized. Raw data from manual and automatic assessment items were analyzed using GraphPad Prism to produce graphics and descriptive statistics for manual and computer-generated assessment items. A Dagostino Pearson omnibus normality K-square test was performed on the data group. If the control group passed the normality test, the data group was analyzed by Bennett's test or Bonferroni all pairwise comparison test (ANOVA). If the data does not follow a Gaussian distribution or is not suitable for the statistical methods described above, subgrouping and / or ranking is performed, and the data is processed in a differential manner to provide subgroup and / or category Allow comparison. The acceptable value for significance is p <0.05, which is indicated when higher significance is applied. For illustrative purposes, data analyzed by parametric statistics were expressed as mean ± SEM, while non-parametric data was expressed as scattered points or categorized subgroups.

Results The effects of nolibogaine on zebrafish behavior are shown in FIG. 11, panels A-G, and FIG. 12, panels A-G. Zebrafish in the chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups show an increase in latency (in seconds) to the top, while in the withdrawal +1 mg / L noriobogaine (Nic WD-DMX1) group Zebrafish showed a statistically significant decrease. FIG. 11, panel A. Zebrafish in the chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups also show a decrease in the upper transition, while the zebrafish in the withdrawal +1 mg / L noriobogaine (Nic WD-DMX1) group Showed a statistically significant increase. FIG. 11, panel B. Also, the zebrafish in the chronic nicotine (Chr Nic) group and the nicotine withdrawal (Nic WD) group show normal habituation patterns, while the zebrafish in the withdrawal +1 mg / L noribogaine (Nic WD-DMX1) group At 5 minutes, it reached the same value as the control group. FIG. 11, panel C. A statistically significant increase in duration (seconds) spent in the upper part of the aquarium was observed with a withdrawal +1 mg / L of norbogaine (Nic WD) compared to the control, chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups ( Shown by zebrafish in the Nic WD-DMX1) group. FIG. 11, panel D. In addition, zebrafish in the withdrawal +1 mg / L Nolibogaine (Nic WD-DMX1) group spent at the top of the aquarium compared to the control, chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups. There was a statistically significant increase in duration (seconds) and average upper entry duration (seconds). FIG. 11, panels E and F. Fish that were treated with nolubogaine spent an average of more time on each move to the top of the fish, suggesting a possible anxiolytic-like action of norbogaine. The fish treated with norbogaine also showed an increase in mean entry duration to the top compared to the control, chronic nicotine (Chr Nic) and nicotine withdrawal (Nic WD) groups. It was. FIG. 11, panel G.

  The total distance traveled in the aquarium was measured and zebrafish in the nicotine withdrawal group showed an increase in anxiety-like responses that were cured by treatment with norbogaine (FIG. 12, panel A). The average rate of zebrafish was also cured by nolubogaine treatment (FIG. 12, panel B). In any test group, no difference was observed in the absolute change in direction of zebrafish (FIG. 12, panel C). Also, zebrafish treated with norbogaine showed a slight increase in turn / rotation ratio over both the chronic nicotine group and the nicotine withdrawal group (FIG. 12, panel D). On the other hand, there was no change in the relative direction change between any groups or the change in the absolute movement direction per movement distance (FIG. 12, panels E and F). The decrease in the absolute change in direction of travel per mile observed in the nicotine withdrawal group was cured by treatment with norbogaine. (FIG. 12, panel G). These results suggest an anxiolytic-like anti-withdrawal effect of norivogaine treatment.

  Anxiety / fear responses were also tested by recording the frequency of stiff seizures and duration of stiffness. FIG. More stiff seizures and longer stiff durations indicate increased anxiety and / or fear. Norivogaine treatment (Nic WD + Cpd 1 mg / L) restored high frequency seizures due to nicotine withdrawal to near control levels (panel A) and restored stiffness duration (panels B and C).

  We also detected the effect of nolubogaine treatment on mobility. FIG. The indication “immobil” was used to represent the frequency of episodes with some degree of movement (duration duration) independent of spatial transposition. The indication “mobile” represents the overall spontaneous movement. The indication “Hi-mobile” represents seizures of accelerated swimming (over 60% of the individual average). In nicotine withdrawal zebrafish, a significant reduction in immobile, migratory, and high-mobility events was observed, while zebrafish treated with norbogaine showed an increase in the number of high-mobility events. . (FIG. 14, panel A). Also, nicotine withdrawal decreased fish mobility and increased immobility, especially. Chronic nicotine-treated fish showed a moderate increase in mobility and a moderate decrease in duration of immobility, while fish treated with norbogaine showed comparable values with respect to mobility and immobility endpoints. Showed a slight increase in highly mobile movement. (FIG. 14, panel B).

Discussion Analysis of manual NTT endpoints showed that fish treated with norbogaine had a shorter latency to enter the upper part and longer (compared to the more “protected” lower part compared to the control) A statistically significant 1 mg / L nolibogaine anti-anxiety-like effect is shown, as assessed by the time spent in the more abducted upper test compartment (FIG. 11, panels A and D). In fish with nicotine withdrawal, the number of transitions from the upper part to the lower part (entry into the upper part) was different for 1 mg / L of norbogaine, and this dose suggested activation of general exploration behavior (FIG. 11, Panel B). The frequency and duration of tonic seizures was increased in chronic nicotine and especially nicotine withdrawal fish. Nolibogaine at 1 mg / L reversed this effect in nicotine withdrawal fish. (FIG. 13). All fish show normal habituation responses assessed by minute distribution of swimming behavior in all manual parameters, are standard and consistent with other reported NTT studies It was generally confirmed that there were no behavioral exceptions in the tested conditions. Analysis of computer-generated NTT endpoints revealed a consistent pattern of motor activity that was unchanged (evaluated by measuring distance traveled and velocity) at 1 mg / L of norbogaine, but active in the WD group The decline became clear. (FIG. 12, panels A and B). The direction of travel (movement directionality index) and meandering (straightness index) were similar in all groups. (Figure 12, Panels E and F).

  Abnormal movements in this study were automatically measured using the frequency of highly mobile episodes. These endpoints are typically characteristic of a higher anxiety state, but may also be seen when a state characteristic of a change in perception (eg, a hallucinogen) is reached. In this experiment, there was no change regarding treatment of chronic nicotine and nicotine withdrawal. (FIG. 14). A high mobility duration and increased frequency (approximately 2 fold) was observed in nicotine withdrawal fish treated with norbogaine. Nolibogaine does not induce orbiting behavior (even if the turning angle is not changed), which is commonly seen if it is an acutely given antiglutamate agonist. Mobility (mobility frequency) and mobility duration, whose endpoints reflect general locomotor activity and anxiety-related treatments, show significant effects of chronic nicotine, nicotine withdrawal and norivogaine treatment (FIG. 14). Spontaneous movement-inhibiting action of nicotine withdrawal was observed (as seen in both the duration and frequency of mobility assessment items, and assessment items for distance traveled and speed). (FIG. 14). Moderate locomotor activity (in literature) of chronic nicotine was observed. (FIG. 14). 1 mg / L of norbogaine restores mobility (mobility and immobility) duration and frequency to control values in nicotine-treated fish, which rescues the locomotor activity of the nicotine withdrawal state It was suggested that it was possible. (FIG. 14).

CONCLUSION Norivogaine treatment can reverse both the effects of nicotine withdrawal, particularly the anxiety-inducing action and suppression of locomotor activity induced by nicotine withdrawal. In a zebrafish model of repeated nicotine withdrawal, a 1 mg / L dose of acute nolibogain elicited robust anxiolytic-like behavior without any apparent hyperactivity / defunction compared to controls. Chronic nicotine, and in particular repetitive WD, induces anxiety-like and locomotor effects in zebrafish, consistent with literature on zebrafish and rodents. Anxiety-like and locomotor effects of repeated nicotine withdrawal were completely reversed by 1 mg / L dose of norivogaine. Based on these results, the beneficial activity of nolibogaine in other behavioral paradigms associated with nicotine abuse, as well as other drug abuse-related models, can be expected at a potential dose of 1 mg / L.

Example 25 Effects of Nolibogaine in zebrafish represented by anxiety-related endpoints In this study, a total of 60 adult wild-type short fin zebrafish (approximately 50:50 male: female ratio) were used. Fish were reared in groups of 20-30 fish per 40L aquarium. The water tank was filled with filtered water and maintained at 25 ° C. According to the standard of zebrafish breeding, illumination (1000 to 1100 lux) was performed with a fluorescent lamp attached to the top board at a cycle of 12 hours (6:00 on, 18:00 off). All fish used in this study were experimentally naive and were fed Tetramin Tropical Flakes (Tetra USA, Blacksburg, VA) twice daily. After behavioral testing, the animals were euthanized in tricaine (Sigma Aldrich, St. Louis, MO) buffered to 500 mg / L pH = 7.0. Animal experiments in this study strictly adhered to national and institutional guidelines and regulations.

Noriobogain at 1 mg / L, which was a dose that did not promote any locomotor activity that was likely to be confused with the efficacy endpoints of interest in other protocols, according to preliminary experiments conducted at test compounds 1, 5 and 10 mg / L While the sub-maximal efficacy of 5 and 10 mg / L doses were revealed, the selected swimming activity was reduced. Thus, a 1 mg / L dose of norbogaine (DMX1 or Cpd) was selected. A standard 20 minute pretreatment time was chosen based on experience with a wide range of other neuroactive compounds and the results of preliminary experiments. This exposure time was also sufficient to elicit zebrafish physiological (eg, cortisol and c-fos) responses to multiple drugs. In this study, norbogaine exposure was performed by immersing individual zebrafish in a 1 L plastic beaker for 20 minutes before the test. In order to ensure that each fish was exposed to a consistent concentration of norbogaine, the solution was changed completely after each exposure. As described above, control fish were exposed to water without the same treatment time norbogaine.

Tests and Procedures Apparatus: A behavioral test was performed between 11:00 and 15:00 using a water tank containing water adjusted to the temperature of the installed room (25 ° C.). This study used a new tank test (NTT) protocol. NTT represents one of the most commonly used neurophenotypic tests for adult zebrafish. To avoid a series of testing or handling effects, each assay was performed once on a separate individual naïve fish at each time. Prior to testing, the fish were individually pre-exposed to either norbogaine-treated water or water without norbogaine for 20 minutes in a 1 L plastic beaker. During the study, zebrafish behavior was recorded by two skilled observers blinded to treatment, who manually scored different behavioral endpoints (assessment in all experiments). Inter-rater and intra-rater confidence> 0.85), and the resulting results were then automatically analyzed by Ethovision XT8.5 software (Noldus IT, Wageningen, The Netherlands). The NTT used to assess zebrafish anxiety and locomotor activity is a 1.5L trapezoid filled with a maximum amount of water and divided into two equal virtual horizontal parts by the markings on the outer wall. Water tank (15 cm high x 28 cm upper x 23 cm low x 7 cm wide, Aquatic Habitats, Apopka, FL). Fish were individually pre-exposed to water (water control) or norbogaine (1, 5 and 10 mg / L) for 20 minutes and tested with standard 5 minute NTT.

  Behavior analysis: Skilled observers record zebrafish behavior, latency to reach the upper half of the tank (seconds), time spent at the top (seconds), number of transitions to the top, and stiff seizures The number and duration (seconds) were scored. Stiffness was defined as the absence of any motion except for error and eyes for more than 2 seconds. The test was also recorded on a computer using a USB webcam (2.0 megapixel, Gigaware, UK) and later analyzed by Ethovision XT8.5, travel distance (m), speed (m / sec), and meandering Evaluation items were evaluated. During manual observation, video was recorded in MPEG1 format at a maximum sampling rate of 30 fps for each test by an autofocus 2.0 MP USB webcam placed 25 cm in front of the aquarium and connected to a laptop computer. Video recorded using Ethovision XT8.5 was analyzed. All environments were calibrated for each active area, and the calibration axis was positioned so that the origin (0,0) was set at the center of each tank. Track data for each fish was exported as raw data to individual spreadsheets. The exported results were independently evaluated by two skilled observers blinded to treatment based on consensus to explain the spatial pattern of zebrafish swimming.

  Study design and data analysis: This study is for adult zebrafish individually (15 fish per group), acutely in water control and 3 doses of norbogaine (1, 5 and 10 mg / L) by immersion in water. Exposure (20 minutes) followed by testing with NTT for 5 minutes, after which the fish were euthanized. Raw data from manual and automatic assessment items were analyzed using GraphPad Prism to produce graphics and descriptive statistics for manual and computer-generated assessment items. A Dagostino Pearson omnibus normality K-square test was performed on the data group. If the control group passed the normality test, the data group was analyzed by Bennett's test or Bonferroni all pairwise comparison test (ANOVA). If the data does not follow a Gaussian distribution or is not suitable for the statistical methods described above, subgrouping and / or ranking is performed, and the data is processed in a differential manner to provide subgroup and / or category Enabled comparison. The acceptable value for significance is p <0.05, which is indicated when higher significance is applied. For illustrative purposes, data analyzed by parametric statistics was expressed as mean ± SEM, while non-parametric data was expressed as scattered points or categorized subgroups.

Results The effects of nolibogaine on the behavior of zebrafish are shown in FIG. 16, panels AG and FIG. 17, panels AG. The zebrafish in each group (1, 5, and 10 mg / L) that received nolubogaine treatment showed a statistically significant decrease in latency to reach the upper half of the aquarium. FIG. 16, panel A. In contrast, none of the treatment groups changed statistically significantly from the control group in the transition to the upper half of the aquarium (FIG. 16, panels B and C), while zebrafish in each treatment group Showed a statistically significant increase in the duration of time spent in the defined upper part of the aquarium (FIG. 16, panels D and E). The zebrafish treated with Nolibogaine spend an average of more time on each move to the top, with 2-3 fish in the 5 and 10 mg / L treatment groups all at the top of the aquarium. (Figure 16, Panel F). The mean entry duration of zebrafish treated with nolubogaine was longer in the first minute and then decreased to a steady level during the remaining 2-5 minutes (FIG. 16, panel G).

  The total travel distance and speed in the aquarium were measured, and zebrafish in the nolubogaine treatment group showed a moderate but non-significant decrease in travel distance (Figure 17, Panel A) and speed (Figure 17, Panel B). Indicated. In addition, for zebrafish treated with nolubogaine, there was a high trend of decreasing turn angle events (Figure 17, Panel C) and a decrease in turn / rotation ratio, which was significant at the 10 mg / L dose range. (FIG. 17, panel D). When relative changes in body orientation were observed, unchanged behavior was observed between the control and the norbogaine treatment group (Figure 17, Panel E). A statistically significant decrease in overall turnaround rate and pattern (meandering) was observed in the norbogaine treatment groups at 510 mg / L and 10 mg / L (Figure 17, Panel F), but differences in mean values of meandering Was not observed (FIG. 17, panel G).

  Anxiety / fear responses were also tested by recording the stiffness episode and stiffness duration. FIG. More stiff seizures and longer stiff seizure duration indicate increased anxiety / fear. There was no difference in stiff seizure frequency (number of stiff seizures per 5 minutes) or stiff duration (Figure 18, Panels A and B).

  We also detected the effect of nolubogaine treatment on mobility. FIG. The indication “immobil” was used to represent the frequency of episodes with some degree of movement (duration duration) independent of spatial transposition. The indication “mobile” represents the overall spontaneous movement. The indication “Hi-mobile” represents seizures of accelerated swimming (over 60% of the individual average). The subgroup was evident by the classification attributes of high frequency (HF) zebrafish versus low frequency (LF) zebrafish in each cohort (HF / LF threshold 35%). There was no difference in the average value of each subgroup. There was also a loss of dose correlation for high mobility events in HF and loss of dose correlation for immobility events with LF. There was a full redistribution into HF-immobility events and HF-mobility events (Figure 19, Panel A). The subgroups observed in each cohort were defined as moderate (M) duration of locomotor activity versus high (H) duration of locomotor activity, and there was no difference in the mean value of each subcategory group ( FIG. 19, panel B). There seemed to be no impact on the mobility category. H-immobility category by contingency analysis using medium (M) duration (threshold 50 seconds) for high (H) duration for each category (immobility, mobility, high mobility) Increased dose correlation and decreased dose correlation in the M-high mobility category.

DISCUSSION Analysis of manual NTT endpoints resulted in a shorter latency to enter the upper upper part (Figure 16, Panel A) and longer (more "protection", compared to controls, with fish treated with norbogaine Statistically significant 1, 5, and 10 mg / L of norbogaine, as assessed by time spent in the upper test compartment, which is more abolished (in contrast to “lower”) (FIG. 16, panels D and E) Shows an anxiolytic-like action. Also, as researchers noted independently during the experiment, zebrafish that received drug treatment appeared to be easier to capture on the net, which was anxiety in these cohorts. Indirectly supports the reduction (data not shown). In the norbogaine treatment group at 1 mg / L, the number of transitions from top to bottom (upper entry) is not different and there is no movement disorder at this dose (ie, the ability to cross the water layer). (Fig. 16, panels B and C). The top two doses tended to slightly reduce the number of transitions from 10 (control) to about 7 for both doses (FIG. 16, panel B).

  During the study, the frequency and duration of tonic seizures were not affected and remained generally at a low level (Figure 18, Panels A and B). This situation is generally not unique with respect to zebrafish studies by NTT, but reflects the specific behavioral characteristics and baseline profile of the zebrafish cohort used. All fish show normal habituation responses assessed by minute distribution of swimming behavior in all manual parameters, are standard and consistent with other reported NTT studies It was generally confirmed that there were no behavioral exceptions in the tested conditions. Analysis of computer generated NTT endpoints revealed a consistent pattern of invariant motor activity (assessed by measuring distance traveled and velocity) at 1 mg / L of norbogaine (Figure 17, Panel A and B). Nolubogaine slightly decreased (not significant) the total distance traveled at 5 mg / L and 10 mg / L compared to the control group (FIG. 17, panels A and B).

  While the direction of travel (movement direction index) and mean meander (straightness index) were similar in all groups, the significance of norbogaine, which generally reduces total meander, as occurs with anxiolytic and serotonergic compounds The dose-dependent effects may be due to reduced anxiety and / or due to relatively slower and more linear “gentle” swimming at the top of NTT. (FIG. 17, panels EG).

  Abnormal behavior in this study was automatically evaluated by measuring the frequency of highly mobile episodes (FIG. 19, panels A and B). These endpoints are typically characteristic of a higher anxiety state, but may also be seen when a state characteristic of a change in perception (eg, a hallucinogen) is reached. As part of natural zebrafish anxiety-like arousal behavior and / or during certain hallucinogen treatments, fish typically undergo many rotations / turns. Nolibogaine does not induce orbiting behavior (even if the turning angle is not changed), which is commonly seen if it is an acutely given antiglutamate agonist. Conversely, norbogaine induces a statistically significant dose-dependent decrease in the number of turn / rotation ratios, which may be anxiolytic and / or, for example, direct or indirect May suggest stimulation of NMDA function.

  The mobility (mobility frequency) and the duration of mobility, whose endpoints reflect general locomotor activity and anxiety-induced treatment, showed a statistically significant effect of norivogaine treatment (FIG. 19, Panels A and B). Subgroups were observed in these evaluation items, and classification attributes were assigned to the subgroups. A specific redistribution of the high mobility duration swimming category was observed, benefiting the immobile duration category with no change in moderate mobility. Since “mobility” (representing normal swimming) remains unchanged, the effects of nolibogaine do not seem to be related to general locomotor suppression. However, immobility / high mobility redistribution suggests that norbogaine has reduced high-speed accelerated swimming episodes common to anxious fish that are swimming in an unusual “high stress” swimming. This can be consistent with the observed anxiolytic effects. In addition, dose-related disappearance of drug-treated HF (high frequency) high mobility events and LF (low frequency) mobility events due to overall redistribution to HF-immobility and HF-mobility events. Dose-related disappearance was observed (Figure 19, Panel B). The latest variance shows a specific subgroup of fish (about 50% of all individuals), where the high score total count showed a more conservative event count than the other 50% correlated with more frequent immobile events Came out of. At 10 mg / L, fish showed the lowest “high mobility” high duration contingent events (the events are still the highest in the control zebrafish cohort that caused more anxiety). A similar trend was observed for the rotation parameter, particularly for the 10 mg / L group.

CONCLUSION Nolubogaine treatment at 1 mg / L induces robust anxiolytic-like behavior in zebrafish without any apparent hyperactivity / hypofunction or rotational behavior. Under the conditions studied, higher doses of norbogaine did not show any further efficacy on the relevant and sensitive indicators of anxiety levels (upper time, upper latency) This indicates that the norbogaine has a half-efficacy in this domain of less than 1 mg / L. While 5 mg / L and 10 mg / L of norbogaine continue to induce anxiolytic-like effects, these behavioral profiles in vivo show a decrease in the duration of fast swimming and “moderate” / slowly The transition to swimming behavior at the top was added.

Claims (41)

  A method for the treatment of abuse in a human patient addicted to opioids or opioid-like drugs, wherein the therapeutic dose of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, Administration to a patient so that the therapeutic dose provides an average serum concentration of about 50 ng / mL to about 180 ng / mL, and the concentration maintains a QT interval of less than about 500 ms during the treatment. While the method is sufficient to inhibit or ameliorate the abuse. a) administration of an initial dose of norivogaine, a nolibogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of about 50 ng / mL to about 180 ng / mL; Said administration;
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose is said mean for a period of time Said administration maintaining a serum concentration between about 50 ng / mL and about 180 ng / mL;
The method of claim 1 comprising:   The method of claim 1, further comprising selecting addicted patients prescreened for assessment of tolerance towards QT interval extension.   2. The method of claim 1, wherein the maximum serum concentration is from about 40 ng / mL to about 250 ng / mL.   2. The method of claim 1, wherein the serum concentration of nolubogaine is about 1000 ng * hour / mL to about 5800 ng * hour / mL.   A method for the treatment of abuse in a human patient addicted to opioids or opioid-like drugs, wherein the dose of norbogaine, norbogaine derivative provides an average serum concentration of about 50 ng / mL to about 180 ng / mL, or Administration of a pharmaceutically acceptable salt or solvate thereof to the patient, wherein the concentration reduces or ameliorates the abuse while maintaining a QT interval extension of less than about 20 ms during the treatment. Said method being sufficient for.   A method of treatment in a patient in need of treatment for nicotine addiction, comprising administering to said patient a therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof, said therapeutically The method wherein the effective amount is less than about 50 ng to 10 μg / kg body weight per day.   A method of preventing in a patient in need of prevention of nicotine craving, comprising administering to said patient a prophylactically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof, said prophylactic The method wherein the effective amount is less than about 50 ng to 10 μg / kg body weight per day.   9. The method of claim 8, wherein the patient is no longer physically addictive to nicotine.   In a human patient suffering from alcohol dependence, a method of treatment thereof, wherein a dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof, which provides an average serum concentration of about 50 ng / mL to about 500 ng / mL and / or Alternatively, the method comprising administering to the patient a solvate, wherein the concentration is sufficient to ameliorate the dependence while maintaining a QT interval of less than about 500 ms during the treatment.   11. The method of claim 10, wherein the total dose of norivogaine, norbogaine derivative, or pharmaceutically acceptable salt and / or solvate thereof is from about 1.3 mg / kg to about 4 mg / kg per day.   A method for the treatment of abuse in human patients who are addictive to a substance, in dosages that give an average serum concentration of 50 ng / mL to 180 ng / mL, norbogaine derivatives, or pharmaceutically acceptable Administration of the salt and / or solvate to the patient, wherein the concentration is sufficient to inhibit or ameliorate the abuse while maintaining a QT interval of less than about 500 ms during the treatment. Method. a) administration of an initial dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / mL to 180 ng / mL When,
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose is said mean for a period of time Said administration maintaining a serum concentration between 50 ng / mL and 180 ng / mL;
The method of claim 12 comprising:   A method for the treatment of abuse in human patients who are addictive to a substance, in dosages that give an average serum concentration of 50 ng / mL to 180 ng / mL, norbogaine derivatives, or pharmaceutically acceptable Administration of the salt and / or solvate to the patient, wherein the concentration is sufficient to inhibit or ameliorate the abuse while maintaining a QT interval extension of less than about 20 ms during the treatment. Said method. a) administration of an initial dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / mL to 180 ng / mL When,
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose is said mean for a period of time Said administration maintaining a serum concentration between 50 ng / mL and 180 ng / mL;
15. The method of claim 14, comprising:   A method for the treatment of pain in a patient, wherein said dose of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof, giving an average serum concentration of 50 ng / mL to 180 ng / mL. The method comprising administration to a patient, wherein the concentration is sufficient to reduce and / or inhibit the pain while maintaining a QT interval of less than about 500 ms during the treatment. a) administration of an initial dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / mL to 180 ng / mL When,
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose is said mean for a period of time Said administration maintaining a serum concentration between 50 ng / mL and 180 ng / mL;
The method of claim 16 comprising:   A method for the treatment of pain in a patient, wherein said dose of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof, giving an average serum concentration of 50 ng / mL to 180 ng / mL. The method comprising administration to a patient, wherein the concentration is sufficient to reduce and / or inhibit the pain while maintaining QT interval extension less than about 20 ms during the treatment.   A method of treatment in a patient in need of treatment of migraine and / or its symptoms, comprising administering to said patient a therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof. Said method comprising.   20. The method of claim 19, wherein the therapeutically effective amount is from about 50 ng to about 10 [mu] g / kg body weight per day.   A method for the prevention in a patient in need of prevention of migraine and / or its symptoms, comprising administering to said patient a prophylactically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt thereof. Said method comprising.   24. The method of claim 21, wherein the prophylactically effective amount is from about 50 ng to about 10 [mu] g / kg body weight per day. A method of treating a pathological condition in a patient, which is treatable with nolubogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, while maintaining an acceptable QT interval extension in the patient, the method comprising: ,
a) administration of an initial unit dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof to the patient, wherein the unit dose is between 50 ng / mL and 180 ng / mL of the therapeutic mean serum Said administration, wherein said serum concentration provides an acceptable QT interval in said patient;
b) maintenance of the serum concentration by periodic administration of at least one additional dose of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that the at least one dose The maintenance wherein an additional dose maintains the therapeutic mean serum concentration between 50 ng / mL and 180 ng / mL during treatment;
Including
The method wherein the one or more additional doses are continued as needed to treat the condition, and the acceptable QT interval is 500 ms or less.   25. The method of claim 24, wherein the QT interval extension is less than 50 ms or less than 20 ms. A method of treating a pathological condition in a patient, which is treatable with nolubogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, while maintaining an acceptable QT interval extension in the patient, the method comprising: ,
a) administration of an initial unit dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof to the patient, wherein the unit dose is between 50 ng / mL and 180 ng / mL of the therapeutic mean serum Said administration, wherein said serum concentration provides an acceptable QT interval extension in said patient;
b) maintenance of the serum concentration by periodic administration of at least one additional dose of norivogaine, norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that the at least one dose The maintenance wherein an additional dose maintains the therapeutic mean serum concentration between 50 ng / mL and 180 ng / mL during treatment;
Including
The method wherein the one or more additional doses are continued as needed to treat the condition, and the acceptable QT interval extension is 50 ms or less.   26. The method of claim 25, wherein the QT interval extension is less than 20 ms.   A method of modulating resistance to an opioid analgesic in a patient undergoing opioid analgesic treatment, said method comprising an amount of norbogaine, norbogaine derivative, or pharmaceutical that provides an average serum concentration of 50 ng / mL to 180 ng / mL Of a salt and / or solvate acceptable thereof with an opioid analgesic treatment, wherein the concentration maintains a QT interval of less than about 500 ms during the treatment Said method being sufficient to resensitize said patient to said opioid as.   28. The method of claim 27, further comprising discontinuing a dose of analgesic.   28. The method according to claim 27, further comprising co-administration of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof with the analgesic.   A method of modulating resistance to an opioid analgesic in a patient undergoing opioid analgesic treatment, said method comprising an amount of norbogaine, norbogaine derivative, or pharmaceutical that provides an average serum concentration of 50 ng / mL to 180 ng / mL , Including simultaneous interruption or co-administration of an acceptable salt and / or solvate thereof with the opioid analgesic treatment, wherein the concentration maintains an QT interval extension of less than about 20 ms during the treatment. The method, which is sufficient to resensitize the patient to the opioid as an agent.   The opioid analgesic is selected from the group consisting of fentanyl, hydrocodone, hydromorphone, morphine, oxycodone, buprenorphine, codeine, thebaine, buprenorphine, methadone, meperidine, tramadol, tapentadol, levorphanol, sufentanil, pentazocine, and oxymorphone. 31. A method according to any one of claims 27 to 30.   A method of treatment thereof in a patient in need of treatment for depression and / or post-traumatic stress disorder, wherein the therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvent thereof Administration of the Japanese to the patient, the patient is not addictive to cocaine or opiates, and the therapeutically effective amount maintains a QT interval of less than about 500 ms during the treatment. However, the method provides an effective mean norbogaine serum level of about 50 ng / mL to about 180 ng / mL.   A method of treatment thereof in a patient in need of treatment for depression and / or post-traumatic stress disorder, wherein the therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvent thereof Administration of the Japanese to the patient, the patient is not addictive to cocaine or opiate, and the therapeutically effective amount maintains QT interval extension less than about 20 ms during the treatment Wherein the method provides an effective mean norbogaine serum level of about 50 ng / mL to about 180 ng / mL. A method of treatment in a patient in need of treatment of an anxiety-related disorder, comprising administering to said patient a therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof. Wherein the patient is not addictive to cocaine or opiates, and further wherein the therapeutically effective amount is about 50 ng / mL to about 50 ng / mL while maintaining a QT interval of less than about 500 ms during the treatment. Said method giving an effective mean norbogaine serum level of 180 ng / mL. A method of treatment in a patient in need of treatment of impulsive control disorder, comprising administering to said patient a therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof Wherein the patient is not addictive to cocaine or opiates, and further wherein the therapeutically effective amount is about 50 ng / mL to about 50 ng / mL while maintaining a QT interval of less than about 500 ms during the treatment. Said method giving an effective mean norbogaine serum level of 180 ng / mL. A method of regulating and / or attenuating it in a patient in need of regulating food intake and / or diminishing food craving, wherein the therapeutically effective amount of norivogaine, norivogaine derivative, or pharmaceutically acceptable thereof Including administration of a salt and / or solvate to the patient, the patient is not addictive to cocaine or opiates, and further wherein the therapeutically effective amount is about a QT interval during the treatment. The method provides an effective average norbogaine serum level of about 50 ng / mL to about 180 ng / mL while maintaining less than 500 ms. A method of treatment in a patient in need of treatment of an anger-related disorder, comprising administering to the patient a therapeutically effective amount of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof. And wherein the therapeutically effective amount provides an effective mean norbogaine serum level of about 50 ng / mL to about 180 ng / mL while maintaining a QT interval of less than about 500 ms during the treatment. Method. A method for screening a patient for determining tolerance of an opioid addicted patient towards a therapeutic dose of norbogaine, or a pharmaceutically acceptable salt and / or solvate thereof, comprising:
Measuring the pre-dose QT interval of the patient;
Administration of a partial therapeutic dose of norivogaine or a pharmaceutically acceptable salt thereof to said patient;
Measuring the QT interval after administration of said patient;
Including said method. Determining a difference between a pre-dose QT interval and a post-dose QT interval to determine a first extension;
An estimate of a second extension based on the first extension, wherein the second extension is an estimated QT interval extension expected to be observed in the patient upon administration of a therapeutic dose of norbogaine; ,
Determining the patient's tolerance to the therapeutic dose of norbogaine;
A therapeutic dose is administered if administration of the therapeutic dose of norivogaine to the patient or interruption of norivogaine treatment and the second extension is estimated to be less than about 50 ms. Said administration or interruption;
40. The method of claim 38, further comprising one or more of:   The therapeutic dose provides an average serum concentration of 50 ng / mL to 180 ng / mL, and the concentration is sufficient to suppress or ameliorate opioid addiction while providing the patient with a QT interval extension of less than about 50 ms 40. The method of claim 39. a) administration of an initial dose of norivogaine, a norbogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, wherein the initial dose provides an average serum concentration of 50 ng / mL to 180 ng / mL When,
b) administration of at least one additional dose of norivogaine, a norivogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, so that said at least one additional dose is said mean for a period of time Said administration maintaining a serum concentration between 50 ng / mL and 180 ng / mL;
40. The method of claim 39, further comprising:

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