HK1160597A - Choline salts of succinic acid for the treatment of depression, anxiety, schizophrenia, sleep disorder, and epilepsy - Google Patents

Description

Choline salts of succinic acid for the treatment of depression, anxiety, schizophrenia, sleep disorders and epilepsy

Technical Field

The present invention relates to pharmaceutical compositions and methods for preventing or treating depression, anxiety, schizophrenia, sleep disorders, and epilepsy. More particularly, the present invention relates to the use of monocholine succinate in pharmaceutical compositions and methods for the treatment of depression, anxiety, schizophrenia, sleep disorders and epilepsy.

Background

Patent RF2228174 discloses the use of the bischoline salt of succinic acid for the treatment of insulin resistance, diabetes, hyperlipidemia and dyslipidemia. Patent RF2281765 discloses the use of the bis-choline salt of succinic acid for the treatment of cerebral ischemia. Patent RF2281766 discloses the use of the bis-choline salt of succinic acid for improving cognitive function.

However, there is no disclosure or disclosure in the art of the use of choline salts of succinic acid for the treatment of depression, anxiety, schizophrenia, sleep disorders, and epilepsy.

It has surprisingly been found that mono-and di-choline salts of succinic acid have therapeutic effects on depression, anxiety, schizophrenia, sleep disorders and epilepsy.

It is an object of the present invention to provide compositions containing choline salts of succinic acid and methods for treating depression, anxiety, schizophrenia, sleep disorders, and epilepsy.

Disclosure of Invention

The present invention provides a method of treating depression, anxiety, schizophrenia, sleep disorders, or epilepsy comprising administering to a mammal in need thereof an effective amount of a monocholine succinate salt of formula (I):

as used herein, the term "depression" refers to a mental disorder, typically characterized by a persistent sad mood and/or a loss of interest in most activities. Examples of depressive disorders that may be preferably treated with an effective amount of a known compound or a pharmaceutically acceptable salt thereof include, but are not limited to: major depressive disorder (also called major depression, unipolar disorder or clinical depression), major depressive episode, atypical depression, depression (mood), melancholic depression, psychogenic depression and postpartum depression.

As used herein, the term "anxiety disorder" refers to an anxiety disorder. Examples of anxiety disorders that may preferably be treated with an effective amount of a known compound or a pharmaceutically acceptable salt thereof include, but are not limited to: panic attacks, agoraphobia, acute stress disorders, specific phobias, panic disorders, psychoactive substance anxiety disorders, organic anxiety disorders, obsessive compulsive disorders, post-traumatic stress disorders, generalized anxiety disorder, and anxiety syndrome NOS.

As used herein, the term "schizophrenia" refers to a psychiatric disorder that includes at least two of the following: delusions, hallucinations, speech disturbances, behavior of severely or catatonic schizophrenic patients, or negative symptoms. The patient can be diagnosed as a schizophrenic patient using the DSM-IV criteria (APA, 1994, handbook of diagnosis and statistics of psychiatric disorders (fourth edition), Washington, D.C.), and the International statistical Classification of ICD-10 of diseases and related health problems of the world health organization.

As used herein, the term "sleep disorder" refers to a disruptive pattern of sleep caused by a number of causes. Examples of sleep disorders that may preferably be treated with an effective amount of a known compound or a pharmaceutically acceptable salt thereof include, but are not limited to: insomnia (e.g., temporary, short-term, and chronic), delayed sleep phase syndrome, hypnotic-dependent sleep disorders, and irritation-dependent sleep disorders; sleep disorders associated with difficulty staying awake, such as sleep apnea, narcolepsy, restless leg syndrome, obstructive sleep apnea, central sleep apnea, essential sleep increase, respiratory muscle weakness; disorders associated with difficulty maintaining regular sleep time, such as sleep state perception errors, shift work sleep disorders, chronic time zone transition syndrome, and irregular sleep-wake symptoms; disorders associated with abnormal behavior such as sleep terror (i.e., parasomnia) and sleepwalking (i.e., sleepwalking); and other disorders such as bruxism, fibromyalgia, and nightmares.

As used herein, the term "epilepsy" refers to a disorder of brain function characterized by frequent unproductive seizures.

As used herein, the term "treatment" refers to the treatment and care of a mammal for the following purposes: (a) preventing the occurrence of a disorder in a subject susceptible to developing the disorder but not yet diagnosed as having the disorder; (b) inhibiting the disorder, i.e. arresting its development; or (c) alleviating the disorder, i.e., allowing the disorder to regress.

As used herein, the term "succinic acid", also known as succinic acid, refers to the molecular formula HOOCCH₂CH₂COOH, CAS number 110-15-6.

As used herein, the term "pharmaceutically acceptable salt" refers to non-toxic plus base salts. The pharmaceutically acceptable salts of the present invention are prepared from succinic acid and pharmaceutically acceptable organic or inorganic bases by reaction according to methods known in the art. Such bases include, but are not limited to: non-toxic alkali and alkaline earth metals, e.g., hydroxides of calcium, lithium, sodium and potassium; ammonium hydroxide and non-toxic organic bases such as triethylamine, butylamine, dimethylethanolamine, diethanolamine, triethanolamine and 2-ethyl-6-methyl-3-hydroxypyridine, as well as choline.

In a preferred embodiment of the invention, the pharmaceutically acceptable salt of the invention is succinic acid bis-choline salt of formula (II):

as used herein, the term "effective amount" refers to the amount of succinic acid or a pharmaceutically acceptable salt thereof required to treat depression, anxiety, schizophrenia, sleep disorders, or epilepsy in a subject in need thereof. As is well known to those skilled in the art, the effective amount may vary depending on the route of administration, the use of excipients, and the combination with other agents.

Preferably, the effective amount of the monocholine succinate salt of formula (I) or a pharmaceutically acceptable salt thereof for use in the method of the invention is 0.1-100 mg/kg body weight per day:

more preferably, the effective amount of the monocholine succinate salt of formula (I) or a pharmaceutically acceptable salt thereof for use in the method of the invention is 1-10 mg/kg body weight per day.

The monocholine succinate salt of formula (I) or a pharmaceutically acceptable salt thereof can be administered to mammals by various routes. Preferably, the monocholine succinate salt of formula (I) or its pharmaceutically acceptable salt is administered in various dosage forms by a route selected from oral, submucosal, sublingual, buccal, intranasal, epidermal, parenteral, intraocular, intramuscular, subcutaneous, intravenous and intraperitoneal administration. Such dosage forms include, but are not limited to: tablets, capsules, powders, solutions, aqueous solutions, aerosols, elixirs, syrups and injections.

Preferably, the monocholine succinate salt of formula (I) or a pharmaceutically acceptable salt thereof is administered for one day or more. More preferably, the monocholine succinate salt of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily for a course of 5-7 days with a rest period of 2-4 weeks between courses.

Preferably, the mammal is a human.

Further, the present invention provides the use of a monocholine succinate salt of formula (I) or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the prevention or treatment of depression, anxiety, schizophrenia, sleep disorders or epilepsy in a mammal in need thereof:

further, the present invention provides a pharmaceutical composition for preventing or treating depression, anxiety, schizophrenia, sleep disorder or epilepsy, comprising: (a) a mono-choline salt of succinic acid of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier:

preferably, the pharmaceutically acceptable salt is succinic acid biliine salt of formula (II):

as used herein, the term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, component or carrier, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting a chemical agent from one organ or part of the body to another organ or part of the body. Some examples of pharmaceutically acceptable carriers that may be used include: sugars such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; tragacanth powder; malt; gelatin; talc powder; excipients, such as cocoa butter and suppository waxes (suppository wax); oils, such as sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol; polyols such as glycerol, sorbitol, mannitol and polyethylene glycol; esters, such as ethyl oleate and ethyl dodecanoate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; ringer's solution; ethanol; a phosphate buffer solution; and other non-toxic compatible materials used in pharmaceutical formulations.

The compositions of the present invention are prepared by known processes using known ingredients. The compositions of the present invention may comprise optional components. Each of these optional components is typically used at a level of from about 0.0005% to about 10.0%, preferably from about 0.005% to about 1.0%, by weight of the composition. Examples of suitable optional components include, but are not limited to: buffers, lubricants, colorants, carriers, and the like.

The compositions of the present invention may be administered by various routes. These routes include, but are not limited to: oral, submucosal, sublingual, buccal, intranasal, epidermal, parenteral, intraocular, intramuscular, subcutaneous, intravenous, and intraperitoneal routes of administration.

The following examples serve to demonstrate the invention. These examples are for illustration only and are not intended to limit the scope of the invention in any way.

Example 1

This example illustrates the preparation of compounds of formula (I) and (II)

The compound of formula (I) was prepared by mixing 12.1g choline and 11.8g succinic acid at room temperature without solvent. The resulting mixture was dissolved in acetone at room temperatureIn a ketone; and the solution is filtered with a filter; compound (I) is recovered as an ionic liquid by evaporating acetone from the solution. D₂In O¹H NMR: 2.41(9H, s), 3.19(4H, s), 3.49(2H, t), 4.10(2H, t). The molecular formula is as follows: c₉H₁₉NO₅。

The compound of formula (II) was prepared by mixing 2.2g of the compound of formula (I) with 1.1g of choline at room temperature in the absence of solvent. The mixture was dried under vacuum and recrystallized from isopropanol-acetone. Compound (II) was recovered as a white powder. D₂In O¹H NMR：2.35(18H，s)，3.15(4H，s)，3.46(4H，t)，4.00(4H，t)。

Example 2

This example demonstrates that the compounds of the present invention are effective in the treatment of depression.

The effect of the compounds of the present invention on the treatment of depression was evaluated in rodents in (a) forced swim test and (B) model of chronic stress depression.

(A) In forced swim trials, young male CD1 mice were used and housed individually. Mice were treated with saline (control) or 25mg/kg compound (I) or (II) intraperitoneal injection (i.p.) for 7 days, once daily, and tested on day 8. In the control group, mice were treated with 10mg/kg imipramine by intraperitoneal injection 30 min before the swimming test (i.p.). Forced swim test was performed at room temperature in a 17cm diameter glass cylinder filled with 13cm high (7 cm from the cylinder edge) of water. Animals were scored over 6 minutes. The latency of the first floating event was accepted as a measure of forced swim behavior. Statistical analysis as post hoc analysis was performed using ANOVA and the mann-whicker test. The mean of the latencies of the first floating events ± SEM data are listed in table 1.

TABLE 1

^*Significance of control differences (P < 0.05).

(B) In the chronic stress depression model, young male CD1 mice were used and housed alone. Mice were treated with saline (control) or 25mg/kg compound (II) intraperitoneal injection (i.p.) once daily for 7 days before stress initiation. The stress operation is performed for 10 days. In the reference group, mice received imipramine orally for 8mg/kg7 days daily before stress, followed by a full 10 day course of stress. Animals (20 for each group) were tested for sucrose preference on day 10 of stress. Statistical analysis as post hoc analysis was performed using ANOVA and the mann-whicker test. Mean ± SEM data for percentage of sucrose preference are listed in table 2.

TABLE 2

^*Significance of stress control differences (P < 0.05).

Thus, the compounds of the present invention are effective in the treatment of depression.

Example 3

This example demonstrates that the compounds of the present invention are effective in the treatment of anxiety disorders.

The efficacy of the compounds of the invention in treating anxiety disorders was evaluated in rodents in light/dark transillumination tests. Stressed mice from example 2 were tested in a dark/light box as described by Crawley et al, Pharmacol Biochem Behav 13, 167-70 (1980). Animals were scored within 5 minutes for (i) the total time spent in the light box and (ii) the number of exits. Statistical analysis as post hoc analysis was performed using ANOVA and the mann-whicker test. (i) The total time spent in the light box and (ii) the mean of the numbers of the exits ± SEM data are listed in table 3.

TABLE 3

^*Significance of stress control differences (P < 0.05).

Thus, the compounds of the present invention are useful for the treatment of anxiety disorders.

Example 4

This example demonstrates that the compounds of the present invention are effective for the treatment of sleep disorders.

The effect of the compounds of formula II of the present invention on the treatment of sleep disorders (insomnia) was evaluated in a caffeine-induced model of insomnia. Mice were treated with intraperitoneal injections of 25mg/kg of compound II or saline (control) for 7 days, once a day. On day 8, 10mg/kg caffeine significantly extended the Sleep Onset Latency (SOL) compared to vehicle in control mice. In compound II pre-treated mice, caffeine did not prolong SOL compared to vehicle. Thus, the compounds of the present invention are useful for the treatment of sleep disorders.

Example 5

This example demonstrates that the compounds of the present invention are effective in the treatment of schizophrenia.

The therapeutic effect of the compounds of the present invention on schizophrenia was evaluated in mice kept in social Isolation (ISO). Isolated feeding of mice is a non-injurious treatment that results in a deficiency in PPI (prepulse inhibition) of the startle reflex and other behavioral and neurochemical alterations similar to those observed in schizophrenic patients. Weiss IC and Feldon J, Psychopharmacology, 2001, 156: 305-326, Harte MK et al, schizophor. res.2006, 81: 210-211, Swerdlow NR et al, Arch Gen Psych. December, 2006, 63: 1325-1335. Mice were treated with intraperitoneal injections of 25mg/kg of compound II or saline (control) for 7 days, once a day. Mice were socially isolated and prepulse inhibition of startle response was measured at 80dB prepulse and 110dB pulse intensity with a prepulse latency of 100 ms. PPI ratios were calculated as the response amplitude reduction (%) of the stimulus delivered with pre-pulses, relative to those without pre-pulses. Statistical analysis as post hoc analysis was performed using ANOVA and the mann-whicker test. Mean ± SEM data for% prepulse inhibition are listed in table 4.

TABLE 4

^*Significance of control (social isolation) differences (P < 0.05).

Thus, the compounds of the present invention are useful for the treatment of schizophrenia in animal models.

Example 6

This example demonstrates that the compounds of the present invention are effective in the treatment of epilepsy.

The effect of treatment of epilepsy with the compounds of the present invention was evaluated in mice with pentylenetetrazol-induced seizures. Loscher et al, Epilepsy Res 1991, 8: 171-189. Mice were treated with intraperitoneal injections of 10mg/kg of compound II or saline (control) for 7 days, once a day. Pentylenetetrazole was administered. The onset was significantly reduced after treatment with compound II compared to the control.

Example 7

This example shows an injection comprising a compound of formula (I).

The compound of formula (I) is dissolved in water for injection to the desired volume. 0.4M disodium hydrogen phosphate was added to a pH of 5.0. In this way, a 5% strength solution of the compound of the formula (I) is prepared. The solution was filtered through a sterile grade filter (0.2 μm) and then filled into ampoules.

Example 8

The present invention shows an injection comprising a compound of formula (II).

The compound of formula (II) is dissolved in water for injection to the desired volume. 0.4M disodium hydrogen phosphate was added to a pH of 5.0. Thus, a 5% strength solution of the compound of formula (II) was prepared. The solution was filtered through a sterile grade filter (0.2 μm) and then filled into ampoules.

Claims (12)

1. A method of treating depression, anxiety, schizophrenia, sleep disorders, or epilepsy, comprising administering to a mammal in need thereof an effective amount of a monocholine succinate salt of formula (I):

2. the method of claim 1, wherein the pharmaceutically acceptable salt is succinic acid bis-choline salt of formula (II):

3. the method according to claim 1, wherein the effective amount of the monocholine succinate salt of formula (I) or its pharmaceutically acceptable salt is 0.1-100 mg/kg body weight per day.

4. The method of claim 1, wherein the monocholine succinate salt of formula (I), or a pharmaceutically acceptable salt thereof, is administered by a route selected from the group consisting of: oral, submucosal, sublingual, buccal, intranasal, epidermal, parenteral, intraocular, intramuscular, subcutaneous, intravenous, and intraperitoneal.

5. The method of claim 1, wherein the monocholine succinate salt of formula (I) or a pharmaceutically acceptable salt thereof is administered for one day or more.

6. The method of claim 1, wherein the mammal is a human.

7. Use of a monocholine succinate salt of formula (I) or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for the treatment of depression, anxiety, schizophrenia, sleep disorders or epilepsy in a mammal in need thereof:

8. the use of claim 7, wherein the pharmaceutically acceptable salt is succinic acid bis-choline salt of formula (II):

9. a pharmaceutical composition for treating depression, anxiety, schizophrenia, sleep disorders, or epilepsy, comprising: (a) a monocholine succinate salt of formula (I) or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier:

10. a pharmaceutical composition according to claim 9, wherein the composition comprises 1-1000 mg of the monocholine succinate salt of formula (I) per unit dosage form of the composition.

11. The pharmaceutical composition of claim 9, wherein the pharmaceutically acceptable salt is succinic acid bis-choline salt of formula (II):

12. the pharmaceutical composition of claim 9, wherein the composition is administered by a route selected from the group consisting of: oral, submucosal, sublingual, buccal, intranasal, epidermal, parenteral, intraocular, intramuscular, subcutaneous, intravenous, and intraperitoneal.