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WO2008118141A2 - Utilisation de composés de modulation des cannabinoïdes en association avec d'autres composés thérapeutiques comme traitement d'appoint - Google Patents

Utilisation de composés de modulation des cannabinoïdes en association avec d'autres composés thérapeutiques comme traitement d'appoint Download PDF

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Publication number
WO2008118141A2
WO2008118141A2 PCT/US2007/022464 US2007022464W WO2008118141A2 WO 2008118141 A2 WO2008118141 A2 WO 2008118141A2 US 2007022464 W US2007022464 W US 2007022464W WO 2008118141 A2 WO2008118141 A2 WO 2008118141A2
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compound
group
formula
antipsychotic
disease
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PCT/US2007/022464
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English (en)
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WO2008118141A3 (fr
Inventor
Ethan S. Burstein
Luis R. Gardell
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Acadia Pharmaceuticals Inc.
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Publication of WO2008118141A2 publication Critical patent/WO2008118141A2/fr
Publication of WO2008118141A3 publication Critical patent/WO2008118141A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system

Definitions

  • This invention relates to the fields of organic chemistry, pharmaceutical chemistry, biochemistry, molecular biology and medicine.
  • compositions that contain a compound that modulate the activity of a cannabinoid receptor in conjunction with another therapeutic compound and uses of compounds that modulate the activity of a cannabinoid receptor in conjunction with another therapeutic compound to treat various conditions (e.g., side effects).
  • the cannabinoids which are bioactive lipids, naturally found in the cannabis sativa (marijuana) plant, have been used recreational Iy and therapeutically for at least 5000 years. In addition to their well-documented effects on mood, cannabinoids (often in the form of marijuana) have been prescribed to treat nausea, pain, migraine, epilepsy, glaucoma, hypertension, cachexia and pain associated with childbirth.
  • Two cannabinoid receptors, CBl and CB2 have been identified. Both are members of the G protein-coupled receptor superfamily, and are negatively coupled through Gi protein. The CB2 receptor has 44% sequence similarity to the CBl receptor.
  • the CBl receptor unlike the CB2 receptor, is highly expressed in the central nervous system, mostly presynaptically. Indeed, the CBl receptor is present in the brain at higher levels than many other GPCRs. It is found in the cortex, cerebellum, hippocampus, and basal ganglia (reviewed in Brievogel and Childres, 1998). In addition, the CBl receptor has also been detected in sperm, the prostate gland, and other peripheral tissues (including structures of the eye). The CB2 receptor is present in the cells of the immune system (spleen, thymus), testis, and lung.
  • An embodiment described herein relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • compositions that can include a first compound and a second compound, wherein the first compound is a compound used to treat Parkinsons's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another embodiment relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Yet still another embodiment described herein relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II), wherein the first compound is present in an amount less than the amount needed to elicit the same therapeutic effect compared to when the first compound is administered alone.
  • An embodiment described herein relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II), wherein the first compound is present in an amount less than the amount needed to elicit the same therapeutic effect compared to when the first compound is administered alone.
  • Another embodiment described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to reduce an adverse side effect associated with an antipsychotic in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another embodiment described herein relate to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or treat a negative symptom of schizophrenia in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Yet still another embodiment described herein relate to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to reduce an adverse side effect associated with a compound used to treat Parkinson's disease in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • An embodiment relates described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or inhibit a loss of cognition or improves cognition in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Another embodiment described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or inhibit weight gain in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another embodiment described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to shorten or prevent the need for a drug holiday in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • An embodiment described hereien relates to a method of ameliorating or inhibiting an adverse effect associated with an antipsychotic that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Another embodiment described herein relates to a method of inhibiting or preventing weight gain associated with the use of a therapeutic compound that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another embodiment described herein relates to a method of suppressing the appetite of a subject that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Yet still another embodiment described herein releates to a method of ameliorating or inhibiting a negative symptom of schizophrenia that can inlcude administering to a subject in need thereof a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • An embodiment described herein relates to a method of ameliorating or inhibiting a loss of cognition or improving cognition that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • hererin relates to a method of ameliorating or inhibiting an adverse effect associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another described herein relates to a method of ameliorating or inhibiting a propensity for gambling associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Yet still another embodiment described herein relates to a method of ameliorating or inhibiting dyskinesia associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • An embodiment described herein relate to a method of ameliorating or inhibiting psychosis associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Another embodiment described herein relates to a method for shortening or preventing a need for a drug holiday that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • An embodiment described hererin relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat an adverse effect associated with the administration of an antipsychotic in a subject taking the antipsychotic that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or treats at least one adverse effect associated with the administration of the antipsychotic, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Another embodiment described hererin relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat an adverse effect associated with the administration of a compound used to treat Parkinson's disease in a subject taking the compound used to treat Parkinson's disease that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or treats at least one adverse effect associated with the administration of the compound used to treat Parkinson's disease, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat a negative symptom of schizophrenia in a subject taking an antipsychotic that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or inhibits at least one negative symptom of schizophrenia, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Yet still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit a loss of cognition or improve cognition in a subject taking a therapeutic compound that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the therapeutic compound ameliorates or inhibits a loss of cognition or improves cognition, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • An embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit a propensity for gambling in a subject taking a compound used to treat Parkinson's disease comprising informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits the propensity for gambling, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit dyskinesia associated with a compound used to treat Parkinson's disease in a subject that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits dyskinesia, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit psychosis associated with a compound used to treat Parkinson's disease in a subject that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits psychosis, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Yet still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to shorten or prevent a need for a drug holiday that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with a compound used to treat Parkinson's disease shortens or prevents the need for a drug holiday, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • An embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to inhibit or prevent weight gain that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with an antipsychotic or a compound used to treat Parkinson's disease inhibits or prevents weight gain, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Another embodiment described herein relates to a method for lowering the amount of an antipsychotic needed to elicit the same therapeutic effect compared to when the first is administered alone that can include administering to a subject a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another embodiment described herein relates to a method for lowering the amount of a compound used to treat Parkinson's disease needed to elicit the same therapeutic effect compared to when the first compound is administered alone that can include administering to a subject a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Some embodiment described herein relate to a method of manufacturing a pharmaceutical composition, said method that can include the steps of: obtaining a first compound comprising an antipsychotic or a compound used to treat Parkinson's disease; obtaining a second compound selected from a compound of Formula (I) and a compound of Formula (II); and packaging together the first compound and the second compound.
  • the first compound and the second compound can be merged together, thereby forming a combined dosage form.
  • the compound of Formula (I) can be selected from any of the compounds disclosed herein, including the claims. In some embodiments described herein, the compound of Formula (II) can be selected from any of the compounds disclosed herein, including the claims.
  • antipsychotics compounds used to treat Parkinson's disease, therapeutic compounds, adverse side effects associated with antipschotics and/or compounds used to treat Parkinson's disease, and negative symptoms of schizophrenia are described herein.
  • Figure IA is a graph showing the percent response of the CB 1 receptor as the concentration of l l-Cyclohexyl-dibenzo[b,fj [1,4]thiazepine-8-carboxylic acid piperidin-1-ylamide (Compound I) increases.
  • Figure IB is a graph showing the percent response of the CB2 receptor as the concentration of Compound I increase.
  • Figure 2 is a bar graph showing the food intake in fasted rats 1 and 2 hours after being administered either 1, 3, or 10 mg/kg doses of Compound I. * Indicates p ⁇ 0.05 as compared to the vehicle-treated controls. ** Indicates p ⁇ 0.01 as compared to the vehicle-treated controls.
  • Figure 3 is bar graph showing the time course food intake in fasted rats after being administered 1 mg/kg of Compound I. * Indicates p ⁇ 0.05 as compared to the vehicle-treated controls. ** Indicates p ⁇ 0.01 as compared to the vehicle-treated controls.
  • Figure 4 is a bar graph showing cumulative food consumption at several points in time after the rats had been dosed with 10 mg/kg of Compound I. * Indicates p ⁇ 0.05 as compared to the vehicle-treated controls.
  • Figure 5 A is a line graph showing the attenuation of CBl agonist- mediated effects after administration of CP 55,940 (0.3 and 1.0 mg/kg).
  • Figure 5B is a line graph showing the attenuation of CB 1 agonist-mediated effects after administration of Compound I alone or in combination with CP55,940.
  • Figure 6 is a bar graph showing the body temperature of the rats at several points in time after the rats had been dosed with various doses of CP 55,950 or CP55,950 and Compound I.
  • Figure 7 is a bar graph showing the concentration of Compound I in the plasma and brain at several points in time.
  • Figures 8A and 8B are bar graphs showing the concentration of compound, N-(butyl)-l l-(4-chlorophenyl)-dibenzo[b,f,][1,4]thiazepine-8-carboxamide (Compound II) in tissue and brain at several points in time.
  • Figures 8C and 8D are line graphs showing the concentration of Compound II in the plasma and brain at several points in time.
  • Figure 9B is a line graph showing the effects of Compound II (1 and 3 mg/kg/day) on food intake and water intake.
  • Figure 9C line graph showing the effects of Compound II (10 mg/kg/day) on body weight.
  • Figure 9D is a line graph showing the effects of Compound II (10 mg/kg/day) on food intake and water intake.
  • Figures 1OA and 1OC are bar graphs showing the exploration ratio at 1 and 2 hours after the mice had been dosed with the vehicle, CP 55,940 (0.3 mg/kg, ip), or SR 141716A (1 mg/kg, ip).
  • Figures 1OB and 1OD are bar graphs showing the discrimination index at 1 and 2 hours after the mice had been dosed with the vehicle, CP 55,940 (0.3 mg/kg, ip), or SR 141716A (1 mg/kg, ip).
  • Figure 1 IA is a bar graph showing the exploration ratio 2 hours after the mice had been dosed with Compound II (3 mg/kg, ip).
  • Figure HB is a bar graph showing the discrimination index 2 hours after the mice had been dosed with Compound II (3 mg/kg, ip).
  • Figure 12 is a bar graph showing percentage of novel recognition of a familiar object 2 hours after the mice had been dosed with 1, 3, or 10 mg/kg of Compound II.
  • Figure 13 is a line graph showing the working memory errors of the mice after being dosed with the vehicle, tacrine (0.3 mg/kg), or Compound II (3 mg/kg).
  • Figure 14 is a line graph showing the contralateral rotations over time of the mice after being dosed with apomorphine (0.05, 0.16, and 0.5 mg/kg).
  • Figure 15 is a line graph showing the contralateral rotations over time of the mice after being dosed with apomorphine (0.05 mg/kg), Compound II (3.0 mg/kg), or apomorphine (0.05 mg/kg) and Compound II (3.0 mg/kg).
  • Figure 16 is a line graph showing the contralateral rotations over time of the mice after being dosed with apomorphine (0.16 mg/kg), Compound II (3.0 mg/kg), or apomorphine (0.16 mg/kg) and Compound II (3.0 mg/kg).
  • Cognitive function is markedly impaired in most patients with schizophrenia.
  • second generation drugs such as olanzapine treat the psychosis caused by schizophrenia, they do not have the ability to improve all cognitive functions impaired by the disease.
  • Typical antipsychotics like haloperidol not only are unable to improve cognitive functions affected by schizophrenia but have actually been shown to impair cognitive performance.
  • antiarrhythmic agents disopyramide, , quinidine, and tocainide
  • antibiotics such as cephalexin, cephalothin, metronidazole, ciprofloxacin, and ofloxacin
  • anticholinergic agents such as benztropine, homatropine, scopolamine, and trihexyphenidyl
  • antidepressants such as amitriptyline, imipramine, desipramine, and fluoxetine
  • anticonvulsants like phenyltoin, valproic acid, and carbamazepine
  • antiemetics including promethazine, hyroxyzine, metocloporamide, and prochloroperazine
  • antihypertensive agents like propranolol, metoprolol, atenolol, verapamil, methyldopa, prazosin, and nifedipine
  • antineoplastic agents like chloramb
  • Blockade of dopamine receptors is the key mechanistic feature of antipsychotic medications believed to mediate many of their therapeutic benefits, but it is also responsible for many of the debilitating side effects associated with these drugs, particularly the movement disorder, extrapyramidal side effects (EPS) and hyperprolactinemia EPS consists of involuntary movements that occur due to blockade of dopamine receptors in the nigrostriatal pathway of the basal ganglia. Antipsychotic medications also cause hyperprolactinemia, a condition marked by unusually high levels of the hormone prolactin in non-pregnant individuals that can lead to loss of sexual function and infertility.
  • EPS extrapyramidal side effects
  • hyperprolactinemia a condition marked by unusually high levels of the hormone prolactin in non-pregnant individuals that can lead to loss of sexual function and infertility.
  • Parkinson's occurs when there is a loss of cells in a part of the brain that produces dopamine.
  • the conventional medical response is to raise dopamine levels in the brain by using L-dopa, a drug that binds to cells that have the D3 receptor.
  • L-dopa initially reduces the tremor, slow movement, and muscular rigidity associated with Parkinson's, but in most patients, a jerky and writhing side effect called dyskinesia sets in after a number of years, possibly as a result of the cells' excess exposure to dopamine.
  • Dyskinesia is resistant to treatment and is often treated by having patients reducing or stopping treatment with the prescribed Parkinson's drug (often referred to as taking a "drug holiday").
  • Current Parkinson's agents are also limited by desensitization effects which limit their effectiveness for chronic use, also necessitating frequent "drug holidays.”
  • a reduction in the dosage of Parkinson's drugs needed to maintain efficacy would increase the length of time they could be used, and reduce the need for or extent of "drug holidays.”
  • dopamine agonist therapy for example pramipexone
  • pathological gambling This may relate to disproportionate stimulation of dopamine D3 receptors.
  • a reduction of domapine levels in the mesocorticolimbic system would be expected to suppress such drug-induced behaviors.
  • Weight gain is among side effects listed in official information sheets for many medications including selective serotonin reuptake inhibitors such as citalopram (Celexa®), fluoxetine (Prozac®), fluvoxamine (Luvox®), paroxetine (Paxil®), and sertraline (Zoloft®); tricyclic antidepressants such as amitriptyline (Elavil®), amoxapine (Asendin®), clomipramine (Anafranil®), desipramine (Norepramine®, Pertofrane®), doxepin (Adapin®, Sinequan®), imipramine (Janimine®, Tofranil®), nortriptyline (Aventyl®, Pamelor®), protriptyline (Vivactil®), and trimipramine (Rhotramine®, Surmontil®); monoamine oxidase inhibitors such as isocarboxazid (Marplan®), phenelzine (N
  • Pronounced weight gain, and associated deterioration of serum lipid, and metabolic profiles is associated with chronic use of certain antipsychotics, particularly olanzapine.
  • Second-generation antipsychotics such as risperidone, clozapine, olanzapine, and quetiapine were shown to directly induce insulin resistance and alter lipogenesis and lipolysis in favor of progressive lipid accumulation and adipocyte enlargement.
  • the medical and psychological consequences of drug-induced obesity are often so intolerable that patients may discontinue treatment even if it is effective. Therefore, there is an unmet need in the art to provide pharmaceutical compositions that can ameliorate the weight-gain induced by certain drugs.
  • the CBl receptor is believed to be responsible for the appetite stimulating properties and habituation associated with cannabinoid use.
  • the CBl receptor antagonist, SR 141716 (rimonabant, Acomplia; Sanofi-Aventis) has shown efficacy in late-stage clinical trials for obesity and nicotine dependence, with no psychotropic effects. The compound has been shown to reduce both food intake and adipose tissue (by a mechanism independent of food intake).
  • Use of SR 141716 in animal models suggests additional use of CBl receptor antagonists and inverse agonists for the treatment of alcohol addiction, opiate addiction, cocaine addiction, anxiety, and septic shock.
  • mice null for the CBl gene also display impaired cocaine self- administration, and less severe withdrawal from morphine addiction compared to wild- type mice.
  • CB 1 knockout mice also display increased bone mineral density, and both CBl knockout mice and mice treated with CB antagonists are resistant to bone loss in a model for osteoporosis.
  • Other animal models indicate a use for CBl receptor antagonists and inverse agonists for the prevention of premature spontaneous abortion.
  • Cannabinoid signaling is hyperactive in animal models of several diseases suggesting that cannabinoids either have a protective role (e.g., CB l agonists may be therapeutic) or are involved in the pathology of these diseases (e.g., CBl antagonists or inverse agonists may be therapeutic). These include Parkinson's disease, Alzheimer's disease, multiple sclerosis, epilepsy, and intestinal disorders. In addition, the levels of endogenous cannabinoids and CBl receptors are elevated in the liver and blood of patients with cirrhosis of the liver. Moreover, cannabinoid levels have been shown to be elevated in the cerebrospinal fluid of a patient with stroke, as well as in the brains of depressed suicide victims.
  • Endogenous cannabinoids have also been shown to be higher in the cerebrospinal fluid of drug-naive paranoid schizophrenics compared to normal patients; interestingly, schizophrenic patients treated with atypical but not typical antipsychotics also exhibit higher CSF levels of anandamide. Additionally, the CB l gene is located in a chromosomal region that has been linked to schizophrenia. Moreover, high levels of the endogenous cannabinoid, anandamide, are correlated with premature abortion and failure of in vitro fertilization. Finally, activation of CB receptors by an anandamide analogue has been shown to reduce sperm fertilizing capacity by 50%.
  • CBl receptors by agonists or partial agonists may also be used to treat a number of disorders.
  • THC tetrahydrocannabinol; active cannabinoid in Cannabis sativa
  • cannabinoids have been shown to improve mobility and alleviate pain in patients with multiple sclerosis.
  • Other promising results for cannabinoids have been shown in clinical trials for Tourette's syndrome, Parkinson's disease, glaucoma, and pain.
  • cannabinoids have been shown to inhibit cancer growth, angiogenesis, and metastasis in animal models.
  • any "R" group(s) such as, without limitation, R 1 , R 1a and R 1 b , represent substituents that can be attached to the indicated atom.
  • R groups include but are not limited to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroalicyclyl.
  • An R group may be substituted or unsubstituted.
  • R groups are covalently bonded to the same atom or to adjacent atoms, then they may be “taken together” as defined herein to form a cycloalkyl, aryl, heteroaryl or heteroalicyclyl group.
  • R 3 and R b of an NR 3 R b group are indicated to be “taken together”, it means that they are covalently bonded to one another at their terminal atoms to form a ring that includes the nitrogen:
  • IC 50 refers to an amount, concentration, or dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as modulation of GPCR, including cannabinoid receptor, activity an assay that measures such response.
  • the assay may be an R-S AT ® assay as described herein but is not limited to an RSAT assay.
  • EC 5 o refers to an amount, concentration or dosage of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound, in an assay that measures such response such as but not limited to R-SAT ® assay described herein.
  • substituent is a group that may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N
  • C m to C n in which "m” and “n” are integers refers to the number of carbon atoms in an alkyl, alkenyl or alkynyl group or the number of carbon atoms in the ring of a cycloalkyl or cycloalkenyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl or ring of the cycloalkenyl can contain from “m” to "n", inclusive, carbon atoms.
  • a "C 1 to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CHb) 3 C-. If no "m” and "n” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group, the broadest range described in these definitions is to be assumed.
  • alkyl refers to a straight or branched hydrocarbon chain fully saturated (no double or triple bonds) hydrocarbon group.
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., "1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 5 carbon atoms.
  • the alkyl group of the compounds may be designated as "C 1 -C 4 alkyl” or similar designations.
  • “C 1 -C 4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like.
  • the alkyl group may be substituted or unsubstituted.
  • the substituent group(s) is(are) one or more group(s) individually and independently selected from alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
  • An alkenyl group of * this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution unless otherwise indicated.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
  • An alkynyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution unless otherwise indicated.
  • aryl refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system that has a fully delocalized pi-electron system throughout all the rings.
  • aryl groups include, but are not limited to, benzene, naphthalene and azulene.
  • An aryl group of this invention may be substituted or unsubstituted.
  • substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, iso
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system throughout all the rings), one or two or more fused rings that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • heteroaryl rings include, but are not limited to, furan, thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine.
  • a heteroaryl group of this invention may be substituted or unsubstituted.
  • substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, iso
  • an "aralkyl” is an aryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, substituted benzyl, 2- phenylethyl, 3-phenylpropyl, and naphtylalkyl.
  • a “heteroaralkyl” is heteroaryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylmethyl, 3- thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl, and their substituted as well as benzo-fused analogs.
  • Lower alkylene groups are straight-chained tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (- CH 2 CH 2 CH 2 -), and butylene (-(CH2V) groups. A lower alkylene group may be substituted or unsubstituted.
  • arylalkylidene refers to an alkylidene group in which either R' and R" is an aryl group. An alkylidene group may be substituted or unsubstituted.
  • alkoxy refers to the formula -OR wherein R is an alkyl is defined as above, e.g. methoxy, ethoxy, n-propoxy, 1-methylethoxy (isoproppxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amoxy, tert-amoxy and the like.
  • An alkoxy may be substituted or unsubstituted.
  • alkylthio refers to the formula -SR wherein R is an alkyl is defined as above, e.g. methylmercapto, ethylmercapto, n-propylmercapto, 1- methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec- butylmercapto, tert-butylmercapto, and the like.
  • An alkylthio may be substituted or unsubstituted.
  • aryloxy and arylthio refers to RO- and RS-, in which R is an aryl, such as but not limited to phenyl. Both an aryloxy and arylthio may be substituted or unsubstituted.
  • acyl refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted. An acyl may be substituted or unsubstituted.
  • cycloalkyl refers to a completely saturated (no double bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. Cycloalkyl groups of this invention may range from C 3 to C 10 , in other embodiments it may range from C 3 to C 6 . A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, the substituent(s) may be an alkyl or selected from those indicated above with regard to substitution of an alkyl group unless otherwise indicated.
  • cycloalkenyl refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there is more than one, they cannot form a fully delocalized pi-electron system in the ring (otherwise the group would be "aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro-connected fashion.
  • a cycloalkenyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwise indicated.
  • cycloalkynyl refers to a cycloalkyl group that contains one or more triple bonds in the ring. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion.
  • a cycloalkynyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwise indicated.
  • heteroalicyclic or “heteroalicyclyl” refers to a stable 3- to 18 membered ring which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, oxygen and sulfur.
  • the "heteroalicyclic” or “heteroalicyclyl” may be monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be joined together in a fused, bridged or spiro-connected fashion; and the nitrogen, carbon and sulfur atoms in the "heteroalicyclic” or “heteroalicyclyl” may be optionally oxidized; the nitrogen may be optionally quaternized; and the rings may also contain one or more double bonds provided that they do not form a fully delocalized pi-electron system throughout all the rings.
  • Heteroalicyclyl groups of this invention may be unsubstituted or substituted.
  • the substituent(s) may be one or more groups independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, iso
  • heteroalicyclic or “heteroalicyclyl” include but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, morpholinyl, oxiranyl, piperidinyl N-Oxide, piperidinyl, piperazinyl, pyrrolidinyl, 4-piperidonyl, pyrazolidinyl, 2-oxopyrrolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone unless the substituent groups are otherwise indicated.
  • a "(heteroalicyclyl)alkyl” is a heterocyclic or a heterocyclyl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heterocyclic or a heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited 4-methyltetrahydro-2H-pyran, substituted 4-methyltetrahydro-2H-pyran, 4-ethylpiperidine, 4-propylpiperidine, 4- methyltetrahydro-2H-thiopyran, and 4-methyl-1,3-thiazinane.
  • a "(cycloalkyl)alkyl” is a cycloalkyl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and cycloalkyl of a (cycloalkyl)alkyl may be substituted or unsubstituted.
  • Examples include but are not limited cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like.
  • a "(cycloalkenyl)alkyl” is a cycloalkenyl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and cycloalkenyl of a (cycloalkenyl)alkyl may be substituted or unsubstituted.
  • a "(cycloalkynyl)alkyl” is a cycloalkynyl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and cycloalkynyl of a (cycloalkynyl)alkyl may be substituted or unsubstituted.
  • halo or “halogen” refers to F (fluoro), Cl (chloro), Br (bromo) or I (iodo).
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and l-chloro-2- fluoromethyl, 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.
  • haloalkoxy refers to RO-group in which R is a haloalkyl group.
  • groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and l-chloro-2-fluoromethoxy, 2- fluoroisobutyoxy.
  • a haloalkoxy may be substituted or unsubstituted.
  • An "O-carboxy” group refers to a "RC(O)O-" group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein.
  • R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein.
  • An O- carboxy may be substituted or unsubstituted.
  • a "C-carboxy” group refers to a "-C(O)R” group in which R can be the same as defined with respect to O-carboxy.
  • a C-carboxy may be substituted or unsubstituted.
  • a "trihalomethanesulfonyl” group refers to an "X 3 CSO 2 -" group wherein X is a halogen.
  • a "cyano” group refers to a "-CN” group.
  • a "thiocyanato" group refers to a "-CNS” group.
  • An "isothiocyanato" group refers to an " -NCS” group.
  • a “sulfinyl” group refers to an "-S(O)-R” group in which R can be the same as defined with respect to O-carboxy.
  • a sulfinyl may be substituted or unsubstituted.
  • a “sulfonyl” group refers to an “SO 2 R” group in which R can be the same as defined with respect to O-carboxy.
  • a sulfonyl may be' substituted or unsubstituted.
  • S-sulfonamido refers to a "-SO 2 NR A R B " group in which R A and R B can be the same as R defined with respect to O-carboxy.
  • An S-sulfonamido may be substituted or unsubstituted.
  • An "N-sulfonamido” group refers to a "RSO 2 N(R A )-” group in which R and R A can be the same as R defined with respect to O-carboxy.
  • a sulfonyl may be substituted or unsubstituted.
  • a "trihalomethanesulfonamido" group refers to an "X 3 CSO 2 N(R)-" group with X as halogen and R can be the same as defined with respect to O-carboxy.
  • a trihalomethanesulfonamido may be substituted or unsubstituted.
  • An O-carbamyl may be substituted or unsubstituted.
  • An N-carbamyl may be substituted or unsubstituted.
  • An O-thiocarbamyl may be substituted or unsubstituted.
  • An N-thiocarbamyl may be substituted or unsubstituted.
  • a C-amido may be substituted or unsubstituted.
  • An N-amido may be substituted or unsubstituted.
  • An ester may be substituted or unsubstituted.
  • a lower aminoalkyl refers to an amino group connected via a lower alkylene group.
  • a lower aminoalkyl may be substituted or unsubstituted.
  • a lower alkoxyalkyl refers to an alkoxy group connected via a lower alkylene group.
  • a lower alkoxyalkyl may be substituted or unsubstituted.
  • Any unsubstituted or monosubstituted amine group on a compound herein can be converted to an amide, any hydroxyl group can be converted to an ester and any carboxyl group can be converted to either an amide or ester using techniques well- known to those skilled in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999).
  • substituents there may be one or more substituents present.
  • haloalkyl may include one or more of the same or different halogens.
  • C 1 -C 3 alkoxyphenyl may include one or more of the same or different alkoxygroups containing one, two or three atoms.
  • each center may independently be of R-configuration or S-configuration or a mixture thereof.
  • the compounds provided herein may be enatiomerically pure or be stereoisomeric mixtures.
  • each double bond may independently be E or Z a mixture thereof.
  • all tautomeric forms are also intended to be included.
  • salts refers to a salt of a compound that does not abrogate the biological activity and properties of the compound.
  • Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base.
  • Base-formed salts include, without limitation, ammonium salt (NH 4 + ); alkali metal, such as, without limitation, sodium or potassium, salts; alkaline earth, such as, without limitation, calcium or magnesium, salts; salts of organic bases such as, without limitation, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine; and salts with the amino group of amino acids such as, without limitation, arginine and lysine.
  • NH 4 + ammonium salt
  • alkali metal such as, without limitation, sodium or potassium
  • alkaline earth such as, without limitation, calcium or magnesium
  • salts of organic bases such as, without limitation, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine
  • Useful acid-based salts include, without limitation, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, methanesulfonates, ethanesulfonates, p-toluenesulfonates and salicylates.
  • solvates and hydrates are complexes of a compound with one or more solvent of water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
  • a "prodrug” refers to a compound that may not be pharmaceutically active but that is converted into an active drug upon in vivo administration.
  • the prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • Prodrugs are often useful because they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have better solubility than the active parent drug in pharmaceutical compositions.
  • prodrug a compound disclosed herein, which is administered as an ester (the "prodrug") to facilitate absorption through a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to a carboxylic acid (the active entity) once inside the cell where water-solubility is beneficial.
  • a further example of a. prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized in vivo to release the active parent compound.
  • the term “complement” refers to a oligonucleotide or polynucleotide that hybridizes by base-pairing, adenine to tyrosine and guanine to cytosine, to another oligonucleotide.
  • to "modulate" the activity of CBl means either to activate it, i.e., to increase its cellular function over the base level measured in the particular environment in which it is found, or deactivate it, i.e., decrease its cellular function to less than the measured base level in the environment in which it is found and/or render it unable to perform its cellular function at all, even in the presence of a natural binding partner.
  • a natural binding partner is an endogenous molecule that is an agonist for the receptor.
  • to "detect" changes in the activity of CBl or of a CBl sub-type refers to the process of analyzing the result of an experiment using whatever analytical techniques are best suited to the particular situation. In some cases simple visual observation may suffice, in other cases the use of a microscope, visual or UV light analyzer or specific protein assays may be required. The proper selection of analytical tools and techniques to detect changes in the activity of CB 1 or a CB 1 sub-type are well- known to those skilled in the art.
  • An "agonist” is defined as a compound that increases the basal activity of a receptor (i.e. signal transduction mediated by the receptor).
  • partial agonist refers to a compound that has an affinity for a receptor but, unlike an agonist, when bound to the receptor it elicits only a fractional degree of the pharmacological response normally associated with the receptor even if a large number of receptors are occupied by the compound.
  • An "inverse agonist” is defined as a compound, which reduces, or suppresses the basal activity of a receptor, such that the compound is not technically an antagonist but, rather, is an agonist with negative intrinsic activity.
  • antagonist refers to a compound that binds to a receptor to form a complex that does not give rise to any response, as if the receptor were unoccupied.
  • An antagonist attenuates the action of an agonist on a receptor.
  • An antagonist may bind reversibly or irreversibly, effectively eliminating the activity of the receptor permanently or at least until the antagonist is metabolized or dissociates or is otherwise removed by a physical or biological process.
  • a "subject” refers to an animal that is the object of treatment, observation or experiment.
  • Animal includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
  • “Mammal” includes, without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
  • a "patient” refers to a subject that is being treated in order to attempt to cure, or at least ameliorate the effects of, a particular disease or disorder or to prevent the disease or disorder from occurring in the first place.
  • treating do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment or therapy. Furthermore, treatment may include acts that may worsen the patient's overall feeling of well-being or appearance.
  • a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • a "diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
  • a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
  • an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
  • a “diluent” is a type of excipient.
  • adjunctive therapy refers to the administration of two pharmaceutical compositions to achieve a beneficial therapeutic effect relative to the therapeutic effect obtained by administering either of the pharmaceutical compositions alone.
  • the administration of a cannabinoid antagonist or inverse agonist and another pharmaceutical composition may ameliorate or inhibit an adverse effect associated with an antipsychotic or other medication such as, preventing weight gain associated with the use of an antipsychotic, suppressing the appetite of a subject taking a therapeutic compound, ameliorate or inhibit a negative symptom of schizophrenia in a subject taking an antipsychotic, ameliorate or inhibit a loss of cognition or improve cognition in a subject taking a therapeutic compound, ameliorate or inhibit an adverse effect associated with a compound used to treat Parkinson's disease, ameliorate or inhibit the propensity for gambling associated with a compound used to treat Parkinson's disease, ameliorate or inhibit the dyskinesia associated with a compound used to treat Parkinson's disease, ameliorate or inhibit the psychosis associated with a compound used to
  • Y can be -N(R 2 ) — or -C(R 1 R 2 ) — ; the symbol — represents a single or double bond, where when — is a double bond, R 2 is absent;
  • Z can be O (oxygen) or S (sulfur);
  • R 1 a and R 1 b can be taken together to form an unsubstituted or substituted heteroalicyclyl having 2 to 9 carbon atoms or an unsubstituted or substituted carbocyclyl having 3 to 9 carbon atoms;
  • R 2 can be absent or is selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroalicyclyl, wherein any member of said group can be substituted or unsubstituted except for hydrogen;
  • R 3, R 3a , and R 3b can each independently selected from the group consisting of: hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, and (heteroalicyclyl)alkyl, wherein any member of said group can be substituted or unsubstituted except for hydrogen;
  • A cannot be a substituted or unsubstituted piperazine.
  • H is not selected from -CF 3 , phenyl, -OS(O) 2 -
  • CF 3 methyl, -CN, halogen, and when A is a substituted or unsubstituted heteroalicyclyl containing at least one nitrogen, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or -NR 1 a R 1 b .
  • H cannot be halogen when A is substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, halogen, and substituted or unsubstituted sulfenyl;
  • X is -NR 1 , wherein R 1 is hydrogen; and
  • Y is -N(R 2 ) — , wherein — is a double bond and R 2 is absent.
  • Y is -N(R 2 ) — , wherein — is a double bond and R 2 is absent, and X is S then F cannot be -S(O) 2 NR ⁇ a R 1 b , wherein R 1 a and R 1 b are both hydrogen.
  • X can be S;
  • Y can be -N(R 2 ) — wherein the symbol — represents a double bond and R 2 does not exist;
  • X can be S;
  • A can be selected from aryl (e.g., unsubstituted or substituted phenyl) or a heteroaryl (e.g., thiophene and pyridine);
  • X can be S;
  • A can be selected from cycloalkyl (e.g., cyclohexyl), a heteroalicyclyl (e.g., piperidine), or - NR 1 a R 1 b group;
  • X can be S;
  • Y can be -N(R 2 ) — wherein the symbol — represents a double bond and R 2 does not exist;
  • the optionally substituted cycloalkyl, cycloalkenyl, or cycloalkynyl is selected from: and and in some of the embodiments, n can be 1 or 2.
  • X can be S;
  • X can be S;
  • Y can be - N(R 2 ) — wherein the symbol — represents a double bond and R 2 does not exist;
  • A can be selected from aryl (e.g., unsubstituted or substituted phenyl) or a heteroaryl (e.g., thiophene and pyridine);
  • X can be S;
  • Y can be -N(R 2 ) — wherein the symbol — represents a double bond and R 2 does not exist;
  • A can be selected from cycloalkyl (e.g., cyclohexyl), a heteroalicyclyl (e.g., piperidine), or -NR 1 a R 1 b group;
  • X can be S;
  • Y can be -N(R 2 ) — wherein the symbol — represents a double bond and R 2 does not exist; and
  • substituted aryl or aralkyl can be selected from: ,wherein Q can be -N(R 4 )-, oxygen or sulfur; and R 4 can be hydrogen or C 1-4 alkyl, and in some of the embodiments, n can be 1 or 2.
  • X can be S;
  • X can be S;
  • Y can be -N(R 2 ) — wherein the symbol — represents a double bond and R 2 does not exist;
  • A can be selected from aryl (e.g., unsubstituted or substituted phenyl) or a heteroaryl (e.g., thiophene and pyridine);
  • X can be S;
  • Y can be -N(R 2 ) — wherein the symbol — represents a double bond and R 2 does not exist;
  • A can be selected from cycloalkyl (e.g., cyclohexyl), a heteroalicyclyl (e.g., piperidine), or - NR 1 a R 1 b group;
  • X can be S;
  • the optionally substituted heteroalicyclyl or (heteroalicyclyl)alkyl can be selected from:
  • n can be 1 or 2.
  • X can be S;
  • X can be S;
  • Y can be -N(R 2 ) — wherein the symbol — represents a double bond and R 2 does not exist; and
  • A can be selected from aryl (e.g., unsubstituted or substituted phenyl) or a heteroaryl (e.g., thiophene and pyridine);
  • X can be S;
  • A can be selected from cycloalkyl (e.g., cyclohexyl), a heteroalicyclyl (e.g., piperidine), or -NR 1 a R 1 b group;
  • X can be S;
  • Y can be -N(R 2 ) ⁇ wherein the symbol :r ⁇ : represents a double bond and R 2 does not exist;
  • the optionally substituted heteroaralkyl is from the
  • n 1 or 2.
  • the optionally substituted heteroaralkyl can be , wherein Q can be oxygen or sulfur, and in some of the embodiments, n can be 1 or 2.
  • A can be an aryl or a heteroaryl group
  • X can be S
  • H can be -C(-Z)NR 1 a R 1b , wherein R 1 a is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heteroalicyclyl, heteroaralkyl, and (heteroalicyclyl)alkyl.
  • A can be an aryl or a heteroaryl group
  • X can be S
  • A can be an aryl or a heteroaryl group
  • X can be S
  • A can be an aryl or a heteroaryl group
  • X can be S
  • Y can be -N(R 2 ) ⁇ wherein the symbol ⁇ represents a double bond and R 2 does not exist
  • H can be wherein R ⁇ a is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heteroalicyclyl, heteroaralkyl, and (heteroalicyclyl)alkyl
  • R 1 and R ⁇ can be hydrogen.
  • D' can be part of Ar', and is selected from the group consisting of CR' 1 , NR' 2 , S, and O.
  • R' 2 can be absent or is selected from the group consisting of hydrogen; mono-substituted, poly-substituted, or unsubstituted, straight or branched chain variants of the following residues: alkyl, alkenyl, and alkynyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and heteroalicyclyl.
  • R' 3j R' 3a , and R' 3b can be each independently selected from the group consisting of: hydrogen; mono-substituted, poly-substituted, or unsubstituted, straight or branched chain variants of the following residues: alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, and (heteroalicycyl)alkyl; and mono-substituted, poly- substituted or unsubstituted variants of the following residues: cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heteroalicyclyl.
  • Z' can be O or S.
  • B' is not selected from -CF 3 , phenyl, -OS(O) 2 -
  • A' is a substituted or unsubstituted heteroalicyclyl containing at least one nitrogen, cycloalkyl, cycloalkenyl, phenyl, heteroaryl, or -NR 1 a -R 1 b --
  • B' is not halogen when A' is substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl, halogen, or substituted or unsubstituted sulfenyl;
  • X' is -NH; and
  • X' when X' is CR ⁇ a R 1 b ' and A' is phenyl, then B' cannot be NH 2 .
  • X' when both Ar r and Ar 2 - are pyridinyl rings, then X' cannot be NRp in which R 1 ' is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, trihalomethyl and hydroxyalkyl.
  • X' when X' is S or NRp, wherein Rp is hydrogen or alkyl, then A' cannot be a phenyl ring substituted at the O 2 H or C ⁇ 2(alkyl).
  • Rp is hydrogen or alkyl
  • A' when X' is CR 1a R 1 b ' R 1a - and R 1 b - cannot be a cycloalkyl, cycloalkenyl or piperazine rin nnot be taken together to a form a cycloalkyl, cycloalkenyl or piperazine ring.
  • X' can be S; and A' can be selected from a mono-substituted, poly- substituted, or unsubstituted, straight or branched chain variants of the following residues: alkyl, alkenyl and alkynyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, aralkyl and heteroaralkyl.
  • A' can be selected from a mono-substituted, poly-substituted, or unsubstituted, straight or branched alkyl; and mono-substituted, poly-substituted or unsubstituted variants of the following residues: cycloalkyl, aryl, heteroaryl and heteroalicyclyl.
  • A' can be a mono- substituted, poly-substituted, or unsubstituted, straight or branched alkyl; or mono- substituted, poly-substituted or unsubstituted aryl.
  • A' can be a mono- substituted, poly-substituted, or unsubstituted, straight or branched alkyl; or mono- substituted, poly-substituted or unsubstituted aryl;
  • B' can be -S(O) 2 NR 1 a -R 1 b --
  • Z' can be O (oxygen).
  • Rp 1 R 13 1 and R 1 b3 - can be independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl and (heteroalicyclyl)alkyl.
  • Rp and R 13 ' can be independently selected from alkyl, cycloalkyl, heteroaryl, heteroalicyclyl and heteroaralkyl; and Ru, 1 is hydrogen.
  • R 1a and R 1b are as defined above for Formula (I).
  • R 3 and R 4 can be selected from the same group of substituents as R 1a and R 1b as defined above for Formula (I).
  • R 13 , R 1b , and A are as defined above for Formula (I).
  • R 3 and R 4 can be selected from the same group of substituents as R 1 a and R 1 b as defined above for Formula (I).
  • R 1 a , R 1 b ,, and A are as defined above for Formula (I).
  • R 3 and R 4 can be selected from the same group of substituents as R 1 a and R 1 b as defined above for Formula (I).
  • R 1 a , R 1 b> and A are as defined above for Formula (I), and X is a halogen.
  • R 3 and R 4 can be selected from the same group of substituents as R 1 a and R ⁇ as defined above for Formula (I).
  • R 1a , R 1 b , and A are as defined above for Formula (I), and X is a halogen.
  • R 3 and R 4 can be selected from the same group of substituents as R 1 a and R 1 b as defined above for Formula (I).
  • R 1 a , R 1 b , and A are as defined above for Formula (I), and X is a halogen.
  • R 3 and R 4 can be selected from the same group of substituents as R 1a and R 1 b as defined above for Formula (I).
  • R 1 a , R 1 b , and A are as defined above for Formula (I), and X is a halogen.
  • R 3 and R 4 can be selected from the same group of substituents as R 1 a and R 1 b as defined above for Formula (I).
  • R' 1a and A' are as defined above for Formula (II).
  • R' 4) R' 5 , and R ⁇ are appropriate radicals selected to obtain the desired A' group.
  • R' 1 a , R'4, R's, and R' 6 compounds 2a, 5a, 6a, 10a, 16a, 26a, 28a - 31a, 40a, 44a, 46a, 48a, 51a, and 58a can be prepared according to Scheme 1 1.
  • compound 2a can be prepared by using «-butyl amine as H 2 N-R'
  • Suitable heterocyclic 2-mercaptosubstituted carboxylic acids can be prepared as described in Blank et al, J. Med. Chem. 1911 , 20, 572-576; Sen et al, Indian J Chem B Og, 1981, 2OB, 275-278, and Solomon et al, Heterocycles, 1987, 26, 651-674), all of which are incorporated herein by reference in their entirety.
  • R' ⁇ a and A' are as defined above for Formula (II).
  • R' 4 , R's, and R ⁇ are appropriate radicals selected to obtain the desired A' group.
  • R' 1a , R' 4 , R' 5 , and R' 6 compounds 13a-16a, 18a, 36a-42a, 54a, 55a, 57a-60a can be prepared according to Scheme 12.
  • compound 13 can be prepared by using cyclohexyl amine a H 2 N-R' 1a and p-Cl-phenyl zinc iodide as R' 6 ZnX.
  • heterocyclic 2-chloro carboxylic acids include commercially available 2-chloro nicotinic acid, 3-chloro-4-pyridine carboxylic acid, 4-chloronicotinic acid and 3-chloro-2-pyrazine carboxylic acid and those synthesised by methods described in Bredereck et al. Chem. Ber, 1962, 95, 956-963 and Krasovskiy et al, Angew. Chem. Int. Ed., 2006, 45, 2958-2961, both of which are incorporated herein by reference in their entirety.
  • Scheme 13 illustrates one method of obtaining compound 7a.
  • compounds Ia, 3a, 8a, 9a, 1 1a, 19a- 25a, 27a, 32a- 34a, 43a, 45a, 49a, 50a, 52a, 53a, 61a, 62a, 82a-84a can be obtained using a similar method.
  • Suitable iodo-or bromo benzoheterophenones can be obtained commercially, synthesised by the methods described in Reynolds et al., Tetrahedron, 2001, 57, 7765-7770, Liu et al., Org. Lett. 2006, 8, 617-619 or by generation of zinc reagents from dibromo- or diiodo heterocycles followed by reaction with the appropriately substituted benzoyl chloride (Knochel et al., Angew. Chem. 2006). AU of the foregoing references are incorporated herein by reference in their entirety.
  • R' 1a and A' are as defined above for Formula (II).
  • R' 4 , R' 5) and R' 6 are appropriate radicals selected to obtain the desired A' group.
  • R' 1a , R'4, R' 5 , and R' 6 compounds 4a, 12a, 17a, 47a, 56a, 63a, and 84a can be prepared according to Scheme 14 by using the appropriate heterocyclic 2- mercaptosubstituted carboxylic acids followed by the appropriate alkyl or aryl metal halide or amine and the desired amine in the last step.
  • R' ⁇ a and A' are as defined above for Formula (II).
  • R' 4 , R' 5 , and R' 6 are appropriate radicals selected to obtain the desired A' group.
  • R' 1a , R' 4 , R' 5 , and R' 6 compounds 64a, 68a, 72a, 78a, 88a, 92a, and 96a can be prepared by using the appropriate heterocycle, amine, metal reagent/amine and amine. Further relevant synthetic methods can be found in Thompson et al. , J. Org. Chem. 1988, 53, 2052-2055, which is incorporated herein by reference in its entirety.
  • a and A' are as defined above for Formula (II).
  • R' 4 , R' 5 , and R' 6 are appropriate radicals selected to obtain the desired A' group.
  • R' 1a , R'4, R' 5 , and R' 6 compounds 64a-74a, 85a 86a, 88a-91a, 93a- 95a, 97a -101a, and 104a can be prepared by using appropriate pyridines obtained either commercially or synthesized by magnesiation of heterocycles via selective deprotonation as described in Liu et al, Org. Lett.
  • Scheme 17 illustrates one method of obtaining compound 102a.
  • Other pyrazines such as compound 87a can be obtained in a similar fashion following the methods described in PIe et al, J. Org. Chem. 1995, 60, 3781-3786, which is incorporated herein by reference in its entirety.
  • Pyrazines containing an amide side chain instead of sulfonamide side chain can be obtained by reacting the metalated species with a variety of alky 1 isocyanates.
  • Ar' ⁇ , Ar ⁇ , B', and D' are as described above for Formula (II).
  • A' is an aryl or heteroaryl.
  • X is Br, Cl, F, OTf, or OTs.
  • Scheme 18 proceeds by dilithiation of arylthiols or heteroaryl thiols as described in Figuly et al, J Am. Chem. Soc, 1989, ///, 654, Block et al, J. Am. Chem. Soc, 1989, 111, 658, and Smith et al, J. Am. Chem. Soc, 1989, / / /, 665, which are incorporated herein by reference in their entirety.
  • the dilithioketimine intermediate is obtained.
  • This intermediate can be in turn treated with suitable ⁇ -dihaloaryls or o- dihaloheteroaryls to obtain the thiazepine product.
  • ⁇ - deficient o-dihaloazaarenes constitute outstanding substrates for the reactions with ketimines, providing the thiazepine products in high yield simply by adding 1 equiv of a neat ⁇ -deficient o-dihaloazaarene to a reaction mixture containing a premade ketimine.
  • Ar' 2 and D' are as described above for Formula (II).
  • A' is an aryl or heteroaryl.
  • X is Br, Cl, F, OTf, or OTs.
  • Ar' i is a ⁇ -deficient azaaryl.
  • E' is an electrophile including, but not limited to, isocyanates, acid chlorides, nitriles, tosyl cyanide or 1-cyanoimidazole, aldehydes or ketones, halogens or organic halides, carbon dioxide, Weinreb amides, tosyl azide, zinc chloride, tin chloride and trimethyl borate.
  • organometallic intermediates thus generated can be treated with convenient electrophiles to give substituted thiazepines.
  • substitution tactics afford a mixture of two or more regioisomeric products
  • the products can be easily separated from each other by one of the standard methods known in the art.
  • an electrophile can be added to a ⁇ - deficient ⁇ -dihaloazaryl by a similar method as described above.
  • the resulting heteroaryl can be in turn be reacted with a ketimine to produce the desired thiazepine product.
  • Convenient substituents that can be introduced on the azaryl include, but are not limited to, nitrile or ester moieties. Introduction of such electron withdrawing groups on the rings of azaryls improves their reactivity towards ketimines. Also, at a later stage, these groups can be easily converted to other pertinent functional groups.
  • Ar' i, Ar' 2 , B', and D' are as described above for Formula (II).
  • A' is an alkyl, aryl, heteroaryl, or amino.
  • X is Br, Cl, F, OTf, or OTs.
  • Scheme 20 provides alkyl and amino substituted thiazepines by addition of 2 equiv of alkyllithiums, aryllithiums, heteroaryllithiums or 2 equiv of lithium amides to 2- cyanoarene thiols, giving rise to a ketimine, which can be reacted with o-dihaloaryl (or heteroaryl) to produce the desired thiazepine product.
  • the requisite 2-cyanoaryl thiols can be prepared for example by heating a 2-cyanobromoaryl (or heteroaryl) with mercaptoacetic ethyl ester in the presence of potassium /-butoxide and liquid ammonia (Brugelmans et al, Tetrahedron, 1983, 39, 4153, which is incorporated herein by reference in its entirety).
  • Ar' ( , Ar' 2 , B', and D' are as described above for Formula (II).
  • A' is an alkyl, amino, aryl, or heteroaryl.
  • X is I, Br, or Cl.
  • Scheme 21 provides thiazepines by hydrolysis of ketimines followed by reacting the resulting ketoaryl thiol with a suitable o-aminohaloaryl (or heteroaryl). The cyclization to produce the thiazepines can be carried under copper catalysis (Bates et al, Org. Lett., 2002, 4, 2803, Kwong et al, Org.
  • ketones can also be prepared by other methods known in the art, for example by addition of organolithiums to mercaptoaryl(or heteroaryl)carboxylic acids (Bull. Chem. Soc.
  • Ar'i, Ar' 2 , B', and D' are as described above for Formula (II).
  • A' is an alkyl, amino, aryl, or heteroaryl.
  • X is I, Br, or Cl.
  • M is a main group metal.
  • Scheme 22 described the production of thiazepines by reacting a haloketones with an ⁇ -aryl(or heteroaryl) thiol. In particular, such cyclizations can be carried out very efficiently under copper catalysis (Kwong et al, Org. Lett., 2002, 4, 3517, incorporated herein by reference in its entirety) using iodoketones and o-aminoaryl(or heteroaryl) thiols.
  • the requisite iodoketones can be synthesized by one of the methods known in the art, for example by addition of organomagnesium reagents (Reynolds and Hermitage, Tetrahedron, 2001, 57, 7765, incorporated herein by reference in its entirety) to 2-iodo Weinreb amides (Brunette and Lipton, J Org. Chem., 2000, 65, 51 14, incorporated herein by reference in its entirety), by copper catalyzed aromatic Finkelstein reaction (Klapars and Buchwald, J. Am. Chem.
  • o-aminoaryl(or heteroaryl) thiol employed herein for the synthesis of thiazepines can be prepared by one of the methods known in the art, for example by reduction of o-nitroaryl(or heteroaryl) thiols (Foster and Reid, J. Am. Chem. Soc, 1924, 46, 1936, incorporated herein by reference in its entirety), by heating of 2- halonitroaryls(or heteroaryls) with sodium sulphide in water (Jain et al, Chem.
  • chloroketones can be reacted with o- aminoaryl(or heteroaryl) thiols to afford thiazepines. Presence of several strongly electron withdrawing groups (such as nitro or cyano groups) on the aromatic ring of the chloroketones (Jarret and Loudon, J. Chem. Soc, 1957, 3818, Gait and Loudon, J. Chem. Soc, 1959, 885, incorporated herein by reference in its entirety), or a ⁇ -deficient azaromatic chloroketone (Warmhof, Synthesis., 1972, 151, Shalaby, Phosphorus, Sulfur Relat. Elem., 2003, 178, 199, incorporated herein by reference in its entirety), is typically required.
  • strongly electron withdrawing groups such as nitro or cyano groups
  • compositions comprising at one compound of Formula (I) and/or Formula (II) as described above in combination with another therapeutic compound, and a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.
  • An embodiment described herein relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • the antipsychotic can act on a dopamine receptor such as a D2 receptor.
  • the antipsychotic can be selected from olanzapine, risperidone, haloperidol, aripirazole, quetiapine, ziprasidone, raclopride, clozapine, Molindone (Moban®), Thioridazine (Apo-Thioridazine®, Mellaril®, Novo-Ridazine®, PMS-Thioridazine®), Risperidone (Risperdal®), Sertindole (Serlect®) and Ziprasidone (Seldox®).
  • the first compound and second compound can be provided in dosages which reduce an adverse side effect associated with an antipsychotic. In other embodiments, the first compound and second compound can be provided in dosages which ameliorate or treat a negative symptom of schizophrenia.
  • the adverse side effect can be selected from weight gain, metabolic syndrome, an extra- pyramidal side effect, akathisia, dystonia, acute dystonia, Parkinsonism, dykensia, tardive dyskinesia, neuroleptic malignant syndrome, hyperprolactinemia, and catalepsy.
  • the negative symptom can be selected from affective flattening, poverty of speech, absence of volition, apathy, self-neglect, inappropriate emotion, inability to experience pleasure, inattentiveness, inability to show a facial expression, and inability to start or complete a task.
  • a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is a compound used to treat Parkinsons' s disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • the compound used to treat Parkinson' disease can be selected from L-dopa, pramipexole, ropinerole, talipexole, roxindole, bromocriptine, pergolide, quinpirole, and lisuride.
  • the first compound and second compound can be provided in dosages which reduce an adverse side effect associated with a compound used to treat Parkinson's disease.
  • the adverse side effect can be selected from increased propensity for gambling, dyskinesia, and psychosis.
  • the first compound and second compound can be provided in dosages which shortens or prevents the need for a drug holiday.
  • Still another embodiment relates to a pharmaceutical composition that can include a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • the first compound and second compound can be provided in dosages which ameliorates or inhibits a loss of cognition or improves cognition. In some embodiment, the first compound and second compound can . be provided in dosages which ameliorate or inhibits weight gain and/or suppresses the appetite of a subject.
  • the instruction set comprising dosage amounts and dosing schedules for ameliorating or inhibiting weight gain and/or suppressing the appetite of a subject.
  • the therapeutic compound can be selected from an antidepressant, an anticonvulsant, a mood stabilizer, an antipsychotic, an antiarrhythmic agent, an antibiotic, an anticholinergic agent, an antiemetic, an antihypertensive agent, an antineoplastic agent, an anti-Parkinson's agent, an antihistamine, an cardiotonic agent, a corticosteroid, a H 2 receptor antagonist, an immunosuppressive agent, a narcotic analgesic, a muscle relaxant, a non-steroids antiinflammatory agent, a radiocontrast agent, and a sedative.
  • antidepressants include, but are not limited to, Buproprion HCL (Wellbutrin®), Mitrazapine (Remeron®), Nefazadone (Serzone®), Trazadone (Desyrel®), and Venlafaxine (Effexor®), clovoxamine, amitriptyline and imipramine.
  • Additional antidepressants include selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants and monoamine oxidase inhibitors. Examples of selective serotonin reuptake inhibitors include, but are not limited to citalopram, fluoxetine, fluvoxamine, paroxetine, and sertraline.
  • tricyclic antidepressants include, but are not limited to, Amitriptyline (Elavil®), Amoxapine (Asendin®), Clomipramine (Anafranil®), Desipramine (Norepramine®, Pertofrane®), Doxepin (Adapin®, Sinequan®), Imipramine (Janimine®, Tofranil®), Nortriptyline (Aventyl®, Pamelor®), Protriptyline (Vivactil®), Trimipramine (Rhotramine®, and Surmontil®).
  • An exemplary monoamine oxidase inhibitor is a nonselective, irreversible monoamine oxidase inhibitor such as Isocarboxazid (Marplan®), Phenelzine (Nardil®), and/or Tranylcypromine (Parnate®). Additional monoamine oxidase inhibitors include, but are not limited to, Moclobemide (Manerix®) and/or Toloxatone (Humoryl®).
  • Suitable anticonvulsants include, but are not limited to, valproic acid, phenobarbital, Carbamazepine (Tegretol®), Divalproex (Depakote®), Gabapentin (Neurontin®), Lamotrigine (Lamictal®), Topiramate (Topamax®), and phenyltoin.
  • Exemplary mood stabilizers include, but are not limited to, Lithium, Cibalith-S®, Duralith®, Ekalith®, Eskalith CR®, Lithane®, Lithobid®, Lithonate®, and Lithotabs®.
  • Suitable antipsychotics include, but are not limited to, phenothiazines, phenylbutylpiperdines, debenzapines, benzisoxidils, salt of lithiums, butyrophenones, substituted benzamides (sulpiride), and racloprides.
  • phenothiazines include chlorpromazine (Thorazine®), mesoridazine (Serentil®), prochlorperazine (Compazine®), thioridazine (Mellaril), Fluphenazine (Prolixin®), Perpehnazine (Trilafon®), and Trifluoperazine (Stelazine®).
  • Examples of debenzapines include clozapine (Clozaril®), loxapine (Loxitane®), olanzapine (Zyprexa®), and quetiapine (Seroquel®).
  • Examples of benzisoxidils include resperidone (Resperdal®), ziprasidone (Geodon®, Zeldox®)), 9-hydroxy- risperidone.
  • An example of a salt of lithium is lithium carbonate.
  • antipsychotics include, but are not limited to, Aripiprazole (Ability®), Etrafon®, Droperidol (Inapsine®), Thioridazine (Mellaril®), Thiothixene (Navane®), Promethazine (Phenergan®), Metoclopramide (Reglan®), Chlorprothixene (Taractan®), Triavil®, Molindone (Moban®), Sertindole (Serlect®), Droperidol, Amisulpride (Solian®), Melperone, Paliperidone (Invega®), Tetrabenazine, Thioridazine (Apo-Thioridazine®, Mellaril®, Novo-Ridazine®, PMS-Thioridazine®), and thioxanthine (Fluphenthixol).
  • Aripiprazole Ability®
  • Etrafon® Droperido
  • the antipsychotic can be a typical antipsychotic. In other embodiments, the antipsychotic can be an atypical antipsychotic. In an embodiment, theantipsychotic can act on a dopamine receptor such as a D2 receptor Suitable antiarrhythmics include, but are not limited to, disopyramide, quinidine, and tocainide. Exemplary antibiotics include, but are not limited to, cephalexin, cephalothin, metronidazole, ciprofloxacin, and ofloxacin. Examples of suitable anticholinergic agents include, but are not limited to, benztropine, homatropine, scopolamine and trihexyphenidyl. A suitable antiemetic is lithium.
  • antihypertensive agents include, but are not limited to, propranolol, metoprolol, atenolol, verapamil, methyldopa, prazosin, and nifedipine.
  • suitable antineoplastic agents include, but are not limited to, cytosine arabinoside, and interleukin-2.
  • Suitable anti-Parkinson's agents include, but are not limited to, L-dopa, pramipexole, ropinerole, talipexole, roxindole, bromocriptine, pergolide, quinpirole, and lisuride.
  • Exemplary antihistamines include, but are not limited to, phenylpropanolamine, diphenhydramine, chlorpheniramine brompheniramine, and pseudoephedrine.
  • An example of a suitable cardiotonic agent is digoxin.
  • Suitable corticosteroids include, but are not limited to, hydrocortisone and prednisone.
  • Exemplary H 2 receptor antagonists include, but are not limited to, cimetidine and ranitidine.
  • suitable immunosuppressive agents include, but are not limited to, cyclosporine and interferon.
  • Suitable narcotic analgesics include, but are not limited to, codeine, hydrocodone oxycodone, meperidine, and propoxyphene.
  • Exemplary muscle relaxants include, but are not limited to, baclofen, cyclobenzaprine, and methocarbimol.
  • suitable non-steroids anti-inflammatory agents include, but are not limited to, aspirin, ibuprofen, indomethacin, naproxen, and sulindac.
  • Suitable radiocontrast agents include, but are not limited to, metrizamide, iothalamate and iohexol.
  • Exemplary sedatives include, but are not limited to, benzodiazepine, alprazolam, diazepam, lorazepam, phenobarbital, butabarbital, and chloral hydrate.
  • the first compound and the second compound can be in the same container or each can be in separate containers.
  • compositions that can include a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II), wherein the first compound is present in an amount less than the amount needed to elicit the same therapeutic effect compared to when the first compound is administered alone.
  • the antipsychotic can act on a dopamine receptor such as a D2 receptor.
  • a dopamine receptor such as a D2 receptor.
  • Exemplary antipsychotics are described herein.
  • An embodiment described herein relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II), wherein the first compound is present in an amount less than the amount needed to elicit the same therapeutic effect compared to when the first compound is administered alone.
  • suitable compounds used to treat Parkinson' disease are described herein.
  • a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to reduce an adverse side effect associated with an antipsychotic in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the instructions can include instructions for taking the cannabinoid antagonist or inverse agonist in combination with an antipsychotic so as to reduce an adverse side effect associated with the antipsychotic.
  • the adverse side effect can be selected from weight gain, metabolic syndrome, an extra-pyramidal side effect, akathisia, dystonia, acute dystonia, Parkinsonism, dykensia, tardive dyskinesia, neuroleptic malignant syndrome, hyperprolactinemia, and catalepsy.
  • Still another embodiment described herein relate to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or treat a negative symptom of schizophrenia
  • the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the instructions can include instructions for taking the cannabinoid antagonist or inverse agonist in combination with an antipsychotic that causes a negative symptom of schizophrenia so as to ameliorate of treat a negative symptom of schizophrenia.
  • the negative symptom can be selected from affective flattening, poverty of speech, absence of volition, apathy, self-neglect, inappropriate emotion, inability to experience pleasure, inattentiveness, inability to show a facial expression, and inability to start or complete a task.
  • Yet still another embodiment described herein relate to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to reduce an adverse side effect associated with a compound used to treat Parkinson's disease
  • the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the instructions can include instructions for taking the cannabinoid antagonist or inverse agonist in combination with a compound used to treat Parkinson's disease so as to reduce an adverse side effect associated with the compound used to treat Parkinson's disease.
  • the adverse side effect is selected from the group consisting of increased propensity for gambling, dyskinesia, and psychosis.
  • An embodiment relates described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or inhibit a loss of cognition or improves cognition in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the instructions can include instructions for taking the cannabinoid antagonist or inverse agonist in combination with a therapeutic compound ameliorate or inhibit a loss of cognition or improves cognition associated with the therapeutic compound.
  • a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to ameliorate or inhibit weight gain in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the instructions can include instructions for taking the cannabinoid antagonist or inverse agonist in combination with an antipsychotic and/or a compound used to treat Parkinson's disease ameliorate or inhibit weight gain associated with the antipsychotic and/or the compound used to treat Parkinson's disease.
  • Still another embodiment described herein relates to a pharmaceutical composition that can include a cannabinoid antagonist or inverse agonist and instructions for taking the cannabinoid antagonist or inverse agonist so as to shorten or prevent the need for a drug holiday in which the cannabinoid antagonist or inverse agonist can be a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the instructions can include instructions for taking the catinabinoid antagonist or inverse agonist in combination with a compound used to treat Parkinson'sdisease shorten or prevent the need for a drug holiday associated with the compound used to treat Parkinson's disease.
  • Some embodiment described herein relate to a method of manufacturing a pharmaceutical composition, said method that can include the steps of: obtaining a first compound comprising an antipsychotic or a compound used to treat Parkinson's disease; obtaining a second compound selected from a compound of Formula (I) and a compound of Formula (II); and packaging together the first compound and the second compound.
  • the first compound and the second compound can be merged together, thereby forming a combined dosage form.
  • An embodiment described herein relates to a pharmaceutical composition manufactured by the method described in this paragraph.
  • the compound of Formula (I) can be selected from any of the compounds disclosed herein, including the claims. In some embodiments described herein, the compound of Formula (II) can be selected from any of the compounds disclosed herein, including the claims.
  • composition refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, intramuscular, intraocular, intranasal, intravenous, injection, aerosol, parenteral, and topical administration.
  • compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
  • compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990, which is hereby incorporated by reference in its entirety.
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, intraocular injections or as an aerosol inhalant.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
  • compositions for use in accordance with the present disclosure thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., as disclosed in Remington's Pharmaceutical Sciences, cited above. [0227]
  • the agents disclosed herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels', syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination disclosed herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present disclosure are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increase the solubility of the compounds to allow for the preparation of highly, concentrated solutions. [0235] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • An exemplary pharmaceutical carrier for the hydrophobic compounds disclosed herein is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • a common co-solvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • VPD co-solvent system which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80TM; the fraction size of polyethylene glycol may be varied; and other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone.
  • other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art.
  • Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • salts may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acids or base forms.
  • compositions suitable for use in the methods disclosed herein include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the exact formulation, route of administration and dosage for the pharmaceutical compositions disclosed herein can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Chapter 1, which is hereby incorporated by reference in its entirety).
  • the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight, or 1 to 500 mg/kg, or 10 to 500 mg/kg, or 50 to 100 mg/kg of the patient's body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. Where no human dosage is established, a suitable human dosage can be inferred from ED 50 or ID 50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg of each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical compositions disclosed herein or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day.
  • compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day.
  • the total daily dosage by oral administration of each ingredient will typically be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will typically be in the range 0.1 to 400 mg.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound disclosed herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • An embodiment described hereien relates to a method of ameliorating or inhibiting an adverse effect associated with an antipsychotic that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II). Examples of antipsychotics and side effects associated with antipsychotics have been described previously.
  • the antipsychotic can act a dopamine receptor such as a D2 receptor.
  • Another embodiment described herein relates to a method of inhibiting or preventing weight gain associated with the use of a therapeutic compound that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • exemplary therapeutic compounds that can cause weight gain have been described previously.
  • antidepressant that can cause weight gain can be selected from Buproprion HCL (Wellbutrin®), Mitrazapine (Remeron®), Nefazadone (Serzone®), Trazadone (Desyrel®), and Venlafaxine (Effexor®).
  • antidepressant that can cause weight gain can be selected from is selected from a selective serotonin reuptake inhibitor (SSRJ), a tricyclic antidepressant and a monoamine oxidase inhibitor,
  • Still another embodiment described herein relates to a method of suppressing the appetite of a subject that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Yet still another embodiment described herein releates to a method of ameliorating or inhibiting a negative symptom of schizophrenia that can inlcude administering to a subject in need thereof a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II). Examples of negative symptoms of schizophrenia have been described previously.
  • An embodiment described herein relates to a method of ameliorating or inhibiting a loss of cognition or improving cognition that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a therapeutic compound and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • hererin relates to a method of ameliorating or inhibiting an adverse effect associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Still another described herein relates to a method of ameliorating or inhibiting a propensity for gambling associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • the compound used to treat Parkinson's disease can be L-dopa.
  • Yet still another embodiment described herein relates to a method of ameliorating or inhibiting dyskinesia associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • An embodiment described herein relate to a method of ameliorating or inhibiting psychosis associated with a compound used to treat Parkinson's disease that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Another embodiment described herein relates to a method for shortening or preventing a need for a drug holiday that can include administering to a subject in need thereof a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II). Exemplary compounds used to treat Parkinson's disease are described herein.
  • An embodiment described hererin relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat an adverse effect associated with the administration of an antipsychotic in a subject taking an antipsychotic that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates at least one adverse effect associated with the administration of the antipsychotic, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II). Examples of antipsychotics and side effects associated with antipsychotics have been described previously.
  • the antipsychotic can act a dopamine receptor such as a D2 receptor.
  • the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or treats at least one adverse effect associated with the administration of the antipsychotic.
  • An embodiment described hererin relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat an adverse effect associated with the administration of a compound used to treat Parkinson's disease in a subject taking a compound used to treat Parkinson's disease that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or treats at least one adverse effect associated with the administration of the compound used to treat Parkinson's disease, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates at least one adverse effect associated with the administration of the compound used to treat Parkinson's disease.
  • Still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or treat a negative symptom of schizophrenia in a subject taking an antipsychotic that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or inhibits at least one negative symptom of schizophrenia, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II). Examples of negative symptoms of schizophrenia have been described previously.
  • the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic ameliorates or inhibits at least one negative symptom of schizophrenia.
  • Yet still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit a loss of cognition or improve cognition in a subject taking a therapeutic compound that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the therapeutic compound ameliorates or inhibits a loss of cognition or improves cognition, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • Exemplary therapeutic compounds such as antidepressants, anticonvulsants, mood stabilizers, antipsychotics, antiarrhythmic agents, antibiotics, anticholinergic agents, antiemetics, antihypertensive agents, antineoplastic agents, anti-Parkinson's agents, antihistamines, cardiotonic agents, corticosteroids, H 2 receptor antagonists, immunosuppressive agents, narcotic analgesics, muscle relaxants, non-steroids anti-inflammatory agents, radiocontrast agents, and sedatives are described herein.
  • the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the therapeutic compound ameliorates or inhibits a loss of cognition or improves cognition.
  • An embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit a propensity for gambling in a subject taking a compound used to treat Parkinson's disease comprising informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits the propensity for gambling, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits the propensity for gambling.
  • Another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit dyskinesia associated with a compound used to treat Parkinson's disease in a subject that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits dyskinesia, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits dyskinesia associated with a compound used to treat Parkinson's disease.
  • Still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to ameliorate or inhibit psychosis associated with a compound used to treat Parkinson's disease in a subject that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits psychosis, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the informing of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease ameliorates or inhibits psychosis associated with a compound used to treat Parkinson's disease.
  • Yet still another embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to shorten or prevent a need for a drug holiday that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with a compound used to treat Parkinson's disease shortens or prevents the need for a drug holiday, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the information of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the compound used to treat Parkinson's disease shortens or prevents the need for a drug holiday.
  • An embodiment described herein relates to a method of using a cannabinoid antagonist or inverse agonist to inhibit or prevent weight gain that can include informing the subject that co-administering the cannabinoid antagonist or inverse agonist with an antipsychotic or a compound used to treat Parkinson's disease inhibits or prevents weight gain, wherein the cannabinoid antagonist or inverse agonist is a compound selected from a compound of Formula (I) and a compound of Formula (II).
  • the information of the subject can include providing printed matter that advises that co-administering the cannabinoid antagonist or inverse agonist with the antipsychotic or the compound used to treat Parkinson's disease inhibits or prevents weight gain.
  • the printed matter can be a label.
  • An embodiment described herein relates to a method for lowering the amount of an antipsychotic needed to elicit the same therapeutic effect compared to when the first is administered alone that can include administering to a subject a first compound and a second compound, wherein the first compound is an antipsychotic and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • Another embodiment described herein relates to a method for lowering the amount of a compound used to treat Parkinson's disease needed to elicit the same therapeutic effect compared to when the first compound is administered alone that can include administering to a subject a first compound and a second compound, wherein the first compound is a compound used to treat Parkinson's disease and the second compound is selected from a compound of Formula (I) and a compound of Formula (II).
  • the compound selected from the compound of Formula (I) and the compound of Formula (II) can bind to CB-I receptors in human tissue with a higher pKi compared to N-piperidino-5-(4- chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide.
  • the compound of Formula (I) and/or the compound of Formula (II) can bind to CB-I receptors in human tissue with a pKi > 9.0.
  • the compound selected from the compound of Formula (I) and the compound of Formula (II) can supress food intake more effectively compared to N-piperidino-5-(4-chlorophenyl)-1-(2,4- dichlorophenyl)-4-methylpyrazole-3-carboxamide.
  • the first compound can be administered prior to the second compound. In any of the embodiments, the first compound can be administered subsequent to the second compound. In any of the embodiments, the first compound can be at the same time as the second compound.
  • Procedure 1 The analysis was performed on a combined prep/analytical Waters/Micromass system consisting of a ZMD single quadropole mass spectrometer equipped with electro-spray ionization interface.
  • the HPLC system consisted of a Waters 600 gradient pump with on-line degassing, a 2700 sample manager and a 996 PDA detector.
  • GC method 50 was used. Method 50 starts at 5O°C and has a gradient of 20 °C/min until 250 °C then holds the temperature for 5 minutes.
  • the analysis was performed on an Aglient 6850 series GC system with capillary S/SL inlet and FID with EPC installation.
  • the column was a 30 m X 0.32 mm x 0.25 ⁇ m HP5 column.
  • PaVC (10%, 200 mg) and PtO 2 were added to 4-(2-carboxy- phenylsulfanyl)-3-nitro-benzoic acid (2.9 g, 9.1 mmol) dissolved in 100 ml of MeOH.
  • the reaction flask were repeatedly evacuated and filled with H 2 .
  • a balloon containing H 2 was connected to the flask.
  • the reaction mixture was filtered through a pad of celite, which was then washed carefully with MeOH. Concentration of the filtrate at reduced pressure gave 2.5 g (96% yield, approximately 95% purity) of the titled compound as a white solid.
  • the purity could be increased to 97% by recrystallization from EtOAc/MeOH (2.3g, 88% yield).
  • CDI (4.53 g, 29 mmol, 4 eq) was added to 3-Amino-4-(2-carboxy- phenylsulfanyl)-benzoic acid (2.1 g, 7.3 mmol) dissolved in THF (30 ml). The reaction was stirred for 16h at room temperature. Water (200 ml) was then added to the mixture resulting in, after filtration and drying, l.78g (91%) of the titled compound as a off-white solid.
  • Example 7b Alternative synthesis of 1 1 -Chloro-dibenzo fb,f
  • Example 12 (l l-chloro-dibenzofb.f] [1,41thiazepin-8-yl)- f2,4-dimethyl-phenvD- piperazin-1 -yli-methanone.
  • Example 13 l l-chloro-dibenzo[b,f
  • Example 14 4-[(l l-chloro-dibenzorb,fl f1,41thiazepine-8-carbonyl)-amino]-piperidine-
  • Example 16 f4-(2,4-Dimethyl-phenyl)-piperazin-1-y I]-(I l-pentyl-dibenzo[b,f] [1 ,41thiazepin-8-yl)methanone.
  • Example 17 [4-(2,4-Dimethyl-phenyl)-piperazin-1-yll-(l l-isobutyl-dibenzorb,f
  • Example 18 d l-Cvclohexyl-dibenzo[b,f1 rK41thiazepin-8-ylV f4-(2,4-dimethyl- phenvD-piperazin- 1 -y 11 methanone.
  • Example 19 [l l-(4-chloro-phenylVdibenzorb,f] fL41thiazepin-8-ylY144-(2,4-dimethyl- phenyl)-piperzin- 1 -yl]-methanone.
  • Example 20 l l-Propyl-dibenzofb,f
  • Example 21 l l-Butyl-dibenzo[b,f] [1,41thiazepine-8-carboxylic acid piperidin-1- ylamide.
  • Example 22 l l-Pentyl-dibenzofb,f] ⁇ ,41thiazepine-8-carboxylic acid piperidin-1- ylamide.
  • Example 23 l l-Isobutyl-dibenzo[b,f
  • Example 24 11 -Cyclohexyl-dibenzof b,f
  • Example 25 4-
  • Example 27 4-f(l l-Pentyl-dibenzorb,f) fl ,41thiazepine-8-carbonyD-amino1-piperidine- 1-carboxylic acid ethyl ester.
  • Example 28 4-1Y1 l-Isobutyl-dibenzo[b,f] rU41thiazepine-8-carbonylVaminol- piperidine-1-carboxylic acid ethyl ester.
  • Example 29 4-[(l l-Cyclohexyl-dibenzofb,f) f1,41thiazepine-8-carbonyl)-aminol- piperidine-1-carboxylic acid ethyl ester.
  • Example 30 4-[(l l-(4-chloro-phenyl)-dibenzofb 1 fj [L4]thiazepine-8-carbonyl)-aminol- piperidine-1-carboxylic acid ethyl ester.
  • Example 30b Alternative synthesis of 4-[Yl l-(4-chloro-phenyl)-dibenzofb,f] ⁇ thiazepine-S-carbonyl)-aminol-piperidine-1-carboxylic acid ethyl ester.
  • Example 32 l l-(2-cyanophenyl)-dibenzo[b,f
  • Example 33 l l-(3-bromophenylVdibenzofb,f1 ⁇ ,4]thiazepin-8-carboxylic acid piperidin- 1 -ylamide
  • Example 35 1 l-piperidinyl-dibenzo[b,f] ri,41thiazepin-8-carboxylic acid piperidin-1- ylamide
  • Example 37 1 l-(propylaminyl)-dibenzo[b,f] [1,4]thiazepin-8-carboxylic acid piperidin- 1 -ylamide
  • Example 38 l l-(4-methylpiperazinyl>-dibenzo[b,fl ⁇ ,41thiazepin-8-carboxylic acid piperidin- 1 -ylamide
  • reaction mixture was concentrated in vacuo and purified by column chromatography using EtOAc (0-10%) in heptane as the eluent furnishing 338 mg of 4-(2-Methoxycarbonyl-benzyl)-3-nitro- benzoic acid ethyl ester as a colorless solid (1.13 mmol, 65%).
  • Example 53 1 l-(4-Fluorophenyl)-dibenzo[d,/1f1,4]oxazepine-8-carboxylic acid piperidin- 1 -ylamide
  • Example 54 1 l ⁇ -ChlorophenylVdibenzof ⁇ ./iri ⁇ ioxazepine-S-carboxylic acid piperidin- 1 -ylamide
  • Example 55 1 l-(3-Chlorophenyl)-dibenzo[ ⁇ ,/][L41oxazepine-8-carboxylic acid piperidin- 1 -ylamide
  • Example 61-66 are examples of compounds synthesised from 8-bromo-l l-chloro-dibenzo[6,/][l ,4]thiazepine according to the general procedure for palladium catalysed Negishi couplings and the procedures described by Pandya et al. J. Org. Chem. (2003), 68, 8274-8276 and Sezen and Sames et al., Org. Lett. (2003), 5, 3607-3610, which are both incorporated by reference in their entireties.
  • Example 62 1 l-(4-Chlorophenyl)-dibenzo[6,/][1,41thiazepine-8-sulfonic acid butylamide
  • Example 63 1 l-(4-Chlorophenyl)-dibenzo[b,f][1,4]thiazepine-8-sulfonic acid piperidin- 1 -ylamide
  • Example 70 2-Fluoro-l l-oxo-10,1 l-dihydro-dibenzo[6,/1[1,4]thiazepine-8-carboxylic acid
  • Example 73 l l-Chloro-2-fluoro-dibenzo[6,/][1,41thiazepme-8-carboxylic acid (3- chlorobenzyl)-amide
  • Example 74 1 l-(4-Chlorophenyl " )-2-fluoro-dibenzo ⁇ ,/i ⁇ ,41thiazepine-8-carboxylic acid (2-phen ⁇ lpropylVamide
  • Example 75 1 l-(3-Chlorophenyl)-2-fluoro-dibenzor ⁇ ,/iri 1 41thiazepine-8-carboxylic acid (2-phenylpropylVamide
  • Example 77 1 l-(3-Chlorophenyl)-2-fluoro-dibenzo[6,/1
  • Example 78 1 l-(4-Chlorophenyl)-2-fluoro-dibenzo[ ⁇ ,/][K4]thiazepine-8-carboxylic acid (3-chlorobenzylVamide
  • Trifluoroacetic acid (90 mL) was added to a solution of 4-tert- butylsulfanyl-3-nitrobenzoic acid ethyl ester (4.65 g; 16.4 mmol) in 20 mL dichloromethane. The mixture was stirred for 3 days at room temperature before evaporation of the solvent. The residue was partitioned between dichloromethane and 1 M aqueous sodium carbonate. After acidification of the aqueous phase using 4M HCl the desired compound was extracted from the aqueous layer with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and evaporated to dryness. The crude compound was used in the next step without purification (1.86 g, 50%).
  • Example 1 1 1 : l l-Chloro-3-chloro-dibenzoF6,/1[L4]thiazepine-8-carboxylic acid butyl amide
  • Example 1 13 N-(4-Fluorobenzyl)-l l-(4-chlorophenyl)-5-oxo-5H-5 ⁇ 4 - dibenzof ⁇ ,/UT,41thiazepine-8-carboxamide
  • Example 1 14 yV-(4-Fluorobenzyl)-l l-(4-chlorophenyl)-5,5-dioxo-5//-5 ⁇ 6 - dibenzof ⁇ ,/irU41thiazepine-8-carboxamide
  • Example 1 15 N-O-Chlorobenzyl)-l l-(4-fluorophenyl)-5-oxo-5H-5X 4 - dibenzo[ ⁇ ,/in,41thiazepine-8-carboxamide
  • Example 1 16 3-Chlorobenzyl)-l l-(4-fluorophenyl)-5,5-dioxo-5//-5 ⁇ 6 - dibenzof6JlfL41thiazepine-8-carboxamide
  • the desired compound was isolated from the crude mixture, which was obtained during the preparation of vV-(3-chlorobenzyl)-l l-(4-fluorophenyl)-5-oxo- 5H-5 ⁇ 4 -dibenzo[ ⁇ ,/][1,4]thiazepine-8-carboxamide. Purification by silica gel column chromatography eluting with a stepwise gradient of 20-50% ethyl acetate in heptane, afforded the desired compound (2.3 mg).
  • Example 117 iV-butyl-1 l-(4-chlorophenvn-5-oxo-5//-5 ⁇ 4 -dibenzor6./i ⁇ ,41thiazepine-8- carboxamide
  • N-Butyl-l l-(4-chlorophenyl)-dibenzo[ ⁇ ,/][1,4]thiazepine-8- carboxamide (86 mg; 0.2 mmol) was dissolved in acetic acid (20 mL) and methanol (15 mL). Hydrogen peroxide (-35% in water; 1 mL) was added. The reaction mixture was stirred at room temperature for 5 hours before it was neutralized by addition of saturated aqueous sodium bicarbonate. The aqueous solution was extracted with DCM (3 x 10 mL) and the combined organic phases were washed with water before drying over sodium sulphate, filtration and evaporation of the solvent in vacuo.
  • Example 118 iV-butyl-l l-(4-chlorophenyl)-5,5-dioxo-5H-5 ⁇ 6 - dibenzofft,fl ⁇ ,41thiazepine-8-carboxamide
  • N-Butyl-l l-(4-chlorophenyl)-dibenzo[6J][1,4]thiazepine-8- carboxamide (70 mg; 0.17 mmol) was dissolved in DCM (10 mL) and 3- chloroperbenzoic acid (225 mg; 1.0 mmol) was added. After 4 hours stirring at room temperature the mixture was diluted with DCM (20 mL) and washed with saturated aqueous sodium hydrogen carbonate (3 x 15 mL). The organic phase was dried over sodium sulphate, filtered and evaporated to dryness. Purification by preparative TLC eluting twice with 50% ethyl acetate in heptane afforded the title compound (7.9 mg; 10 %).
  • Example 119 l l-(l-Oxy-piperidin-1-ylVdibenzor6,/]rK41thiazepine-8-carboxylic acid 3- chlorobenzylamide (A) and 5-oxo-l l-piperidin-1-yl-5H-5 ⁇ 4 -dibenzol ⁇ , ⁇ -ri,41thiazepine- 8-carboxylic acid 3-chlorobenzylamide (B)
  • Example 120 5,5-Dioxo-l l-piperidin-1-yl-5H-5 ⁇ 4 -dibenzo[6,/irU4]thiazepine-8- carboxylic acid 3-chlorobenzylamide
  • Example 121 1 l-Cvclohexyl-5,5-dioxo-5//-5 ⁇ 4 -dibenzo[ ⁇ ,/][1,41thiazepine-8-carboxylic acid 4-fluorobenzylamide
  • Example 123 7V-(4-Fluorobenzyl)-l l-(4-fluorophenyr)-5H-dibenzo[6,e][1,4]diazepine-8- carboxamide
  • Example 125 1 l-(4-FluorophenyiyN-(l-phenylethyl)-5H-dibenzof6,el[l ,4]diazepine-8- carboxamide
  • Example 127 N-(4-Fluorobenzyl)-l l-(4-fluorophenyl)-5-methyl-5H- dibenzor6,eiri,41diazepine-8-carboxamide
  • Example 128 1 [8-Chloro-1 l-(4-fluorophenyl)-dibenzo
  • iV,N-Dimethyl amine 40 mg, 0.33 mmol was added to a solution of 8- chloro-l l-(4-fluorophenyl)-5H-dibenzo[6,e][1,4]diazepine (108 mg, 0.33 mmol) in dry T ⁇ F (2 mL) at room temperature, followed by addition of acetyl chloride (70 ⁇ L, 0.99 mmol). The reaction mixture was shaken overnight at 60°C, allowed to cool to room temperature and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate, filtered and evaporated to dryness.
  • amidoimidoyl chlorides (Examples 147 - 162) were synthesized according to the general procedure for amide formation at 0.5 mmol scale except that the reaction mixture was passed through a pad of acidic alumina oxide and eluted with a mixture of CH 2 Cl 2 and EtOAc. The eluents were concentrated at reduced pressure and the obtained crude products were directly used in the next reactions without further purifications or characterization.
  • Example 150 N-(butyO-l l-(chloro)-dibenzo[b,f
  • Example 151 N-(3-phenylpropyl)- 11 -(chloro " )-dibenzofb,fir 1 ,4]thiazepine-8- carboxamide
  • Example 154 N-(2,4-dichlorobenzyQ-l l-(chloroydibenzofb,f
  • Example 156 N-(2-(3-chlorophenyl)ethyl)-l l-(chloro)-dibenzo
  • Example 160 N-((N-ethyl-N-phenyl)aminoethylVl l-(chloro)- dibenzo[b,f
  • Example 162 N-(4-fluorobenzyl)-l l-(chloro)-dibenzorb, ,fi ⁇ ,41thiazepine-8- carboxamide
  • Example 163 1 l-(piperidinyl)-dibenzofb,f][1,4]thiazepin-8-yl-(piperidin-1-yl)- methanone
  • Example 170 N-(2,4-dichlorobenzyl)-l l-(piperidinyl)-dibenzofb,Fi ⁇ ,41thiazepine-8- carboxamide
  • Example 175 N-(2-phenyl-propyl)-l l-(piperidinyl)-dibenzo[b,f
  • Example 176 N-(Q ⁇ -ethyl-N-phenyl)aminoethyiyi l-(piperidiny ⁇ )- dibenzofb,fU1,4 ⁇ thiazepine-8-carboxam ⁇ de
  • Example 179 1 l-(cvclohexyl)-dibenzo[b,fl[1,4]thiazepin-8-yl-(piperidin-1-yl ' )- methanone
  • Example 190 N-CCN-ethyl-N-phenyHaminoethylVl l-CcyclohexylV dibenzofb,firi,41thiazepine-8-carboxamide
  • Example 191 l l-(cyclohexyl)-dibenzo
  • the arylzinc halide used for Examples 193 - 205 was 3- chlorophenylzinc iodide.
  • Example 193 1 l-(3-chlorophenyl)-dibenzo[b/
  • Example 200 N-(2-(4-chlorophenylkthylyi l-(3-chlorophenvn- dibenzo [b, f] [ 1 ,4] thiazepine -8 -carboxamide
  • Example 201 N-(3-chlorobenzv0-l l-(3-chlorophenylVdibenzo[b,f
  • Example 202 N-(2-phenyl-propyl)-l l-(3-chlorophen ⁇ l)-dibenzo[b,f
  • Example 204 1 l-(3-chlorophenylVdibenzo[b,f
  • Example 205 N-(4-fluorobenzyD-l l-(3-chlorophenyl)-dibenzo[b,f
  • the arylzinc halide used for Examples 206 - 217 was 4- fluorophenylzinc iodide.
  • Example 216 N-(2-phenyl-propyl)-l l-(4-fluorophenyl)-dibenzo[b,f
  • Example 217 N-(flS[-ethyl-N-phenyl)aminoethyl)-l 1 -(4-fluorophenyiy dibenzorb,fi ⁇ ,41thiazepine-8-carboxamide

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Abstract

La présente invention concerne des compositions pharmaceutiques qui contiennent un composé qui module l'activité d'un récepteur cannabinoïde conjointement avec un autre composé thérapeutique et des utilisations des composés qui modulent l'activité d'un récepteur cannabinoïde conjointement avec un autre composé thérapeutique pour traiter diverses affections (par exemple les effets secondaires).
PCT/US2007/022464 2006-10-17 2007-10-17 Utilisation de composés de modulation des cannabinoïdes en association avec d'autres composés thérapeutiques comme traitement d'appoint WO2008118141A2 (fr)

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