HK1078034A - Piperidin-2,6-dione pamoate salts and their use for the treatment of stress-related affective disorders - Google Patents

Description

Piperidine-2, 6-dione pamoate salts and their use in the treatment of stress-related affective disorders

The present invention relates to pamoate salts of certain 3-phenyl-3-dimethylaminoalkyl-4, 4-dimethylpiperidin-2, 6-dione compounds and their use in the treatment of stress-related affective disorders. The term "stress-induced affective disorders" as used herein includes any condition associated with increased levels of 5-HT (5-hydroxytryptamine; serotonin) due to newly synthesized 5-HT.

3-phenyl-3-dimethylaminoalkyl-4, 4-dimethylpiperidin-2, 6-dione compounds of the formulA I below and their acid addition salts have been known since 1974 (cf. BE-A-808,958; corresponding to GB-A-1,455-687 and U.S. Pat. No. 3, 3,963,729):

wherein R is₁Represents methoxy, ethoxy or hydroxy;

R₂represents methoxy, ethoxy, hydroxy or hydrogen; and is

n represents 2 or 3.

They are reported to possess A variety of pharmacological activities (see USA-3,963,729; US-A-4,461,771; US-A-4,738,973; US-A-4,835,151; US-A-4,835,151; USA-4,918,084; US-A-4,994,475; US-A-5,1177,086; GB-A-2,196,251& GB-A-2,206,491), but are of major interest for the treatment of stress-related affective disorders, especially anxiety and depression, which are the only compounds currently known to selectively block activation of tryptophan hydroxylase due to depolarization, metabolic inhibitors, methylxanthines or stress. The compound selected for clinical evaluation was 3- (3-methoxyphenyl) -3- (3-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione, which is also known as AGN2979 (the name will be used in this application); BTG 1501; MDL 72415 and SC 48274. A number of acid addition salts of AGN2979 have been tried, but the hydrochloride salt has always been the salt of choice, since the hydrochloride salt is the most commonly used acid addition salt, is easy to prepare, is inexpensive, and there is no reason to believe that any other salt will be superior to the hydrochloride salt. The use of AGN2979 or the pamoate salts of 3-dialkylaminoalkyl-4, 4-dialkylpiperidine-2, 6-diones of the formula I or other 3-phenyl-substituted 3-dialkylaminoalkyl-4, 4-diones of any other base has never before been proposed or suggested for any reason.

Many studies on clinical trials of AGN2979 hydrochloride have been carried out and the results published. These clinical trials indicate that the salt is effective at a dose of about 4 mg/kg/day (200 and 400 mg/day for humans) in the treatment of anxiety and depression. However, a one-year subacute toxicity test of this hydrochloride salt (200 mg/kg/day, oral (p.o.) (i.e. via oral administration)) in rats showed that during this year the animals experienced an immediate and sustained weight loss (40% over 1 year) as well as changes in hepatocytes that could not be found by conventional transaminase assays as indicated by post-mortem examination. Results the united states food and drug administration ("f.d.a") prohibited the use of dosage levels previously used in clinical trials. Clinical trials by Cutler et al later using the f.d.a. approved dose-1 mg b.i.d. (i.e. twice daily) (about 30 μ g/kg/day) showed that AGN2979 hydrochloride had only a weakly potent anxiolytic effect at FDA approved dose levels.

It has now surprisingly been found that the above-mentioned problems of weight loss and hepatocyte changes can be overcome by replacing the hydrochloride or other previously disclosed salts with the pamoate salts of the compounds of formula I. Over time, these pamoate salts did not cause weight loss and were shown not to cause hepatocyte changes. In addition, it has been found that the pamoate salts of the compounds of formula I, in contrast to the known salts, are tasteless and can be prepared as pharmaceutical compositions for oral administration, especially in the form of suspensions, syrups or the like. Accordingly, in a first aspect, the present invention provides a pamoate salt of 3-phenyl-3-dimethylaminoalkyl-4, 4-dimethylpiperidin-2, 6-dione represented by formula I:

wherein

R₁Represents methoxy, ethoxy or hydroxy;

R₂represents methoxy, ethoxy, hydroxy or hydrogen; and is

n represents 2 or 3.

Pamoic acid is 4, 4' -methylenebis [ 3-hydroxy-2-naphthoic acid ], and is also known as embonic acid.

The compounds of formula I exist in the form of optical isomers, and the pamoate salts can therefore be used in racemic form or as individual (+) or (-) isomers. In the present invention, the (-) isomer is preferred. The salt may exist in the form of a solvate, especially a hydrate, and may therefore form a hydrate on storage in a non-airtight environment.

In a second aspect, the present invention provides a method of treatment or prophylaxis of stress-related affective disorders which comprises administering to a human or animal patient an effective amount of a pamoate salt of a compound of formula I or a pharmaceutically acceptable solvate thereof.

In a third aspect, the present invention provides a pharmaceutical composition comprising a pamoate salt of a compound of formula I or a pharmaceutically acceptable solvate thereof in association with a pharmaceutically acceptable diluent or carrier.

In a fourth aspect, the present invention provides pamoate salts of compounds of formula I and pharmaceutically acceptable solvates thereof for use in the treatment of the human or animal body by therapy or diagnosis carried out on the human or animal body.

In a fifth aspect, the present invention provides the use of the pamoate salts of compounds of formula I and pharmaceutically acceptable solvates thereof in the manufacture of a medicament for the treatment or prevention of stress-related affective disorders.

Examples of pamoate salts of compounds of formula I include:

3- (3' -methoxyphenyl) -3- (2 "-N, N-dimethylaminoethyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate;

3- (3' -methoxyphenyl) -3- (3 "-N, N-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate;

3- (3' -hydroxyphenyl) -3- (2 "-N, N-dimethylaminoethyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate;

3- (3' -hydroxyphenyl) -3- (3 "-N, N-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate;

3- (3' -ethoxyphenyl) -3- (3 "-N, N-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate;

3- (3 ', 5' -dimethoxyphenyl) -3- (3 "-N, N-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate;

3- (3 ', 5' -dihydroxy) -3- (3 "-N, N-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate; and

3- (3 ', 5 ' -diethoxy) -3- (3 ' -N, N-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate.

A preferred pamoate salt is that wherein R is₁Represents methoxy, and R₂Those salts of compounds of formula I which represent methoxy or hydrogen. The most preferred salts are 3- (3, 5-dimethoxyphenyl) -3- (3-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate, and especially 3- (3-methoxyphenyl) -3- (3-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione (AGN 2979) pamoate.

The pamoate salts of the invention can be prepared by conventional techniques for converting the free base into an acid addition salt or for converting one acid addition salt into another. For example, pamoate salts are prepared by: treating an ethanol solution of a compound of formula I with a cold solution of pamoic acid in ethanol; the solvent was evaporated under reduced pressure and the residue was recrystallized from ethanol.

Alternatively, the salts of the compounds of formula I may be converted to the pamoate salts by neutralization with, for example, ammonium hydroxide, followed by treatment with pamoic acid.

The compounds of formulA I may be prepared by the methods disclosed in US-A-3,963,729 or US-A-5,104,990, the disclosures of both documents being incorporated herein by reference. The optical isomers can be isolated by conventional methods, for example, the (-) isomer can be isolated by crystallizing its (+) binaphthyl phosphate salt (binaphthyl phosphoric acid salts) from a suitable solvent such as ethanol.

The pamoate salts of the compounds of formula I have the same qualitative pharmacological activity as previously reported for the free base and other acid addition salts, especially the hydrochloride salt, and are particularly useful for the treatment or prevention of any stress-induced affective disorder. As mentioned above, the term "stress-induced affective disorder" as used herein includes any condition associated with increased levels of 5-HT (5-hydroxytryptamine; serotonin) due to newly synthesized 5-HT. In particular, the pamoate salts of the invention are useful in the treatment or prevention of neurological and psychological diseases and conditions in which newly synthesized 5-HT is implicated, as well as being currently addressed by antidepressants, anxiolytics and antipsychotics. Non-limiting examples of such diseases or disorders are agoraphobia; anorexia nervosa; anxiety disorders; anxiety associated with withdrawal from drug abuse (anxiety); bulimia nervosa; chronic paroxysmal migraine; depression (including prevention of depression recurrence); a decline in immune responses associated with anxiety, depression or loss of decline; sleep onset or maintenance disorders; sleep arousal disorder; dream anxiety episodes (dreamanoxiety attacks); huntington's chorea; the syndrome of Kleine-Levin; memory impairment; meniere's disease, menstrual-related sleep syndrome; migraine headache; motion sickness; by administration of 5HT₃Nausea, neurogenic pain (neurogenic pain) with incomplete relief of the antagonist; neuropathic pain; obsessive compulsive disorder; panic attacks (panical attacks); post-traumatic stress disorder; premenstrual dysphoric disorder (pre-menstrual dyssphoriciditter); recurrent transient depression; restless legs syndrome, schizophrenia, senile dementia; serotonin stimulation syndrome; sleep apnea (sleep apnoea); cardiovascular symptoms associated with sleep; sleep-related seizures; cluster headache associated with sleep; sleep-related myoclonus syndrome (myoclonus syndrome); social phobia; sudden infant death syndrome; and tinnitus.

It is believed that the antidepressant effect of AGN2979 pamoate results from the inhibition of tryptophan hydroxylase activation. The mechanism of this effect may beTo K⁺Closure of the passage, since it is known to open K⁺Other metabolic inhibitors of the channel, such as guanidine and sodium cyanide, are capable of activating tryptophan hydroxylase and this activation can be blocked by AGN2979 pamoate.

The pamoate salts of the present invention can be administered by any of the means previously proposed for the hydrochloride salt. They can be administered to the patient to be treated by oral or parenteral routes, such as subcutaneous or intravenous routes, alone or in the form of pharmaceutical preparations. The amount of pamoate salt administered can vary and can be any effective amount. The amount of pamoate salt administered may vary over a wide range depending on the patient and the mode of administration, providing from about 0.1mg/kg to about 20mg/kg, usually from about 0.5mg/kg to about 10mg/kg, preferably from about 1 to about 5mg/kg of patient body weight per dose. The unit dose of these salts may contain, for example, from about 10mg to about 500mg, advantageously from about 25 to about 200mg, usually from about 50 to about 100mg of the pamoate salt and may be administered 1 to 4 times per day. The term "unit dosage form" as used herein refers to a single or multiple dosage form containing an amount of active ingredient admixed or otherwise associated with a diluent or carrier, such that one or more predetermined units are typically required for a single therapeutic administration. For multiple dosage forms, such as liquid or scored tablets, the predetermined unit will be a fraction of the multiple dosage form, such as a 5ml (teaspoonful) quantity of liquid or a half or quarter scored tablet.

Pharmaceutical formulations employing the commonly employed forms of pamoate salts of the invention can be prepared by methods well known in the pharmaceutical art and typically comprise at least one active pamoate salt of the invention in admixture or otherwise in association with a pharmaceutically acceptable carrier or diluent. To prepare these formulations, the active ingredient is typically mixed with a carrier, or diluted with a diluent, or enclosed or encapsulated in a capsule, sachet, paper or other container. The carrier or diluent may be a solid, semi-solid, or liquid material that acts as a carrier, excipient, or medium for the active ingredient. Suitable carriers or diluents are well known per se. The formulations may be adapted for enteral or parenteral use and may be administered in the form of tablets, capsules, lozenges, suppositories, syrups, suspensions and the like.

The invention is illustrated in the following non-limiting examples.

Example 1

Preparation of 3- (3-methoxyphenyl) -3- (3-dimethylaminopropyl) -4, 4-dimethyl-piperidine

-2, 6-diketo-pamoate (AGN 2979 pamoate)

(A) Preparation of diethyl 2- [ 2-cyano-5- (dimethylamino) -2- (3-methoxyphenyl) -1, 1-dimethylpentyl ] malonate monohydrochloride

The reaction vessel was nitrogen-purged and 50ml of anhydrous tetrahydrofuran was added. The solvent was cooled to below-40 ℃ and 32mmol of lithium diisopropylamide in tetrahydrofuran-heptane (16ml, 2M solution) were added. A solution of 6.97g (30mmol) of alpha- [3- (dimethylamino) propyl ] -3-methoxybenzylacetonitrile in 30ml of tetrahydrofuran is added below-20 ℃ and left at this temperature for 30 minutes. The mixture was then cooled to-50 ℃ and a solution of 6.62g (33mmol) of isopropylidene diethyl malonate in 30ml of tetrahydrofuran was added to the reaction mixture at such a rate that the temperature did not exceed-50 ℃. The mixture was stirred at-50 ℃ for 30 minutes and the cold reaction mixture was added to a stirred solution of 30ml aqueous hydrochloric acid (36% w/w) in 100ml water cooled to 10 ℃. The mixture was extracted 2 times with toluene and the toluene phase was back-extracted with a solution of 2ml of hydrochloric acid (36% w/w) in 8ml of water. The aqueous acidic extract was combined with the above aqueous acidic phase and extracted 2 times with 50ml portions of dichloromethane. The combined dichloromethane extracts were washed with water, the dichloromethane phase was filtered and concentrated to a small volume by distillation at atmospheric pressure. 100ml of ethyl acetate were added and the resulting slurry was cooled to 5-10 ℃. The resulting solid was collected by filtration, washed with ethyl acetate and dried at 50 ℃ to obtain 10.1g of a white powder.

(B) Preparation of 3- (3-methoxyphenyl) -3- (3-dimethylaminopropyl) -4, 4-dimethyl-piperidine-2, 6-dione hydrogensulfate (anhydrous)

To a 250ml round bottom flask was added 10g of diethyl 2- [ 2-cyano-5- (dimethylamino) -2- (3-methoxyphenyl) -1, 1-dimethylpentyl ] malonate monohydrochloride prepared above, and a solution of 10.2g sulfuric acid (96% w/w) in 90ml was added. The reaction mixture was refluxed for about 54 hours. When the reaction was complete (as confirmed by thin layer chromatography), the solution was cooled to 25 ℃. The aqueous solution was washed with dichloromethane, the aqueous phase was mixed with dichloromethane and basified with aqueous ammonium hydroxide (29% w/w) while maintaining the temperature below 30 ℃. After separation of the layers, the aqueous phase was extracted 2 times with dichloromethane, the combined organic phases were concentrated and the residue was crystallized from tert-butyl methyl ether to give 5.7 white powder. The crude product was suspended in 200ml of anhydrous ethanol, 1 equivalent of concentrated sulfuric acid was added, and the mixture was heated under reflux for 30 minutes to dissolve the salt. After cooling, most of the solvent was evaporated under reduced pressure, and the residue was crystallized from 50/50 mixture of diethyl ether and ethanol to obtain 6g of a white powder (melting point 159-.

(C) Preparation of 3- (3-methoxyphenyl) -3- (3-dimethylaminopropyl) -4, 4-dimethyl-piperidine-2, 6-dione pamoate (Anhydrous)

AGN-2979 bisulphate solution (1mmole, 430mg in 10ml water) obtained in step B was mixed with 20ml dichloromethane and basified with aqueous ammonium hydroxide (29% w/w). After separation of the layers, the aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was dissolved in 10ml of ethanol and mixed with a solution of hot pamoic acid (embonic acid, 390mg, 1mmole) in 30ml of hot ethanol and the mixture was heated to reflux. After cooling, the pamoate salt crystallized and the salt recrystallized in hot ethanol to give a pale yellow powder with a melting point of 146-.

Example 2

Tablets each having the following composition were prepared by conventional tableting techniques:

components mg/tablet

(a) AGN2979 pamoate salt 50

(b) Lactose 51.5

(c) Dried corn starch 45

(d) Magnesium stearate 1.5

Example 3

The suppository is formed from:

components mg/suppository

(a) AGN2979 pamoate 20

(b) Cocoa butter (cacao butter) 980

Compound (a) was powdered, sieved through a BS No.100 sieve (0.125mm) and triturated with molten cocoa butter at 45 ℃ to form a smooth suspension. The mixture was sufficiently stirred and poured into molds each having a standard capacity of 1g to prepare suppositories.

Example 4

Pellets each having the following composition were prepared by the following method: mixing the active ingredient (a) with corn starch (b), then adding liquid glucose (c), kneading thoroughly to form a plastic mass from which pellets are cut and formed:

components Each pill

(a) AGN2979 pamoate salt 50mg

(b) Corn starch 45mg

(c) Liquid glucose 7cm³

Example 5

Gelatin capsules containing 50mg of AGN2979 pamoate and 20mg of talc, respectively, were prepared by the following method: AGN2979 and talc were separately sieved through a fine mesh screen, the sieved powders were mixed, and the mixed powders were filled into hard gelatin capsules at a net fill of 70 mg/capsule.

Claims (33)

1. A pamoate salt of 3-phenyl-3-dimethylaminoalkyl-4, 4-dimethylpiperidin-2, 6-dione represented by formula I:

wherein

R₁Represents methoxy, ethoxy or hydroxy;

R₂represents methoxy, ethoxy, hydroxy or hydrogen; and is

n represents 2 or 3.

2. The pamoate salt of claim 1, wherein R₁Represents methoxy, and R₂Represents methoxy or hydrogen.

3. The pamoate salt of claim 2, wherein the pamoate salt is 3- (3-methoxyphenyl) -3- (3-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate.

4. The pamoate salt of claim 2, wherein the pamoate salt is 3- (3, 5-dimethoxyphenyl) -3- (3-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate.

5. The pamoate salt of any one of the preceding claims, wherein the pamoate salt is the (-) isomer thereof.

6. The pamoate salt of any one of the preceding claims, wherein the pamoate salt is in the form of a hydrate.

7. A pharmaceutical composition comprising a pamoate salt of 3-phenyl-3-dimethylaminoalkyl-4, 4-dimethylpiperidin-2, 6-dione represented by formula I:

wherein

R₁Represents methoxy, ethoxy or hydroxy;

R₂represents methoxy, ethoxy, hydroxy or hydrogen; and is

n represents a number of 2 or 3,

and a pharmaceutically acceptable diluent or carrier.

8. The pharmaceutical composition according to claim 7 for use in the treatment or prevention of stress-related affective disorders.

9. The pharmaceutical composition according to claim 7 or 8, wherein the 3-phenyl-3-dimethylaminoalkyl-4, 4-dimethylpiperidin-2, 6-dione is as defined in any one of claims 2, 5 and 6.

10. The pharmaceutical composition of claim 9, wherein the pamoate salt is 3- (3-methoxyphenyl) -3- (3-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate.

11. The pharmaceutical composition of claim 9, wherein the pamoate salt is 3- (3, 5-dimethoxyphenyl) -3- (3-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate.

12. A pamoate salt of 3-phenyl-3-dimethylaminoalkyl-4, 4-dimethylpiperidin-2, 6-dione of formula I:

wherein:

R₁represents methoxy, ethoxy or hydroxy;

R₂represents methoxy, ethoxy, hydroxy or hydrogen; and is

n represents 2 or 3.

13. A pamoate salt as claimed in claim 12, wherein the 3-phenyl-3-dimethylaminoalkyl-4, 4-dimethylpiperidin-2, 6-dione is as defined in any one of claims 2, 5 and 6.

14. The pamoate salt of claim 13, wherein the pamoate salt is 3- (3-methoxyphenyl) -3- (3-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate.

15. The pamoate salt of claim 13, wherein the pamoate salt is 3- (3, 5-dimethoxyphenyl) -3- (3-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate.

16. Use of a pamoate salt of 3-phenyl-3-dimethylaminoalkyl-4, 4-dimethylpiperidin-2, 6-dione of formula I or a pharmaceutically acceptable solvate thereof for the preparation of a medicament for the treatment or prophylaxis of stress-related affective disorders:

wherein

R₁Represents methoxy, ethoxy or hydroxy;

R₂represents methoxy, ethoxy, hydroxy or hydrogen; and is

n represents 2 or 3.

17. The use of claim 16, wherein the stress-related affective disorder is selected from the group consisting of agoraphobia; anorexia nervosa; anxiety disorders; anxiety associated with withdrawal from drug abuse; bulimia nervosa; chronic migraine headache with decreased hair growth; depression (including prevention of depression recurrence); a decline in immune responses associated with anxiety, depression or loss of decline; sleep onset or maintenance disorders; sleep arousal disorder; sleep anxiety attacks; huntington's chorea; Klein-Levin syndrome; memory impairment; meniere's disease, menstrual-related sleep syndrome; migraine headache; motion sickness; by administration of 5HT₃Nausea, neurogenic pain with incomplete relief of the antagonist; neuropathic pain; obsessive compulsive disorder; panic attacks; post-traumatic stress disorder; premenstrual dysphoric disorder; recurrent transient depression; restless legs syndrome, schizophrenia; senile dementia; serotonin stimulation syndrome; sleep apnea; cardiovascular symptoms associated with sleep; sleep-related seizures; sleep-related plexusCluster headache; sleep-related myoclonus syndrome; social phobia; sudden infant death syndrome; and tinnitus.

18. The use according to claim 17, wherein the medicament is for the treatment or prevention of anxiety.

19. The use of claim 17, wherein the medicament is for the treatment or prevention of depression.

20. The use as claimed in claim 17, wherein the medicament is for the treatment or prophylaxis of migraine.

21. The use of claim 17, wherein the medicament is for the treatment or prevention of sleep apnea.

22. Use according to any one of claims 16 to 21, wherein the 3-phenyl-3-dimethylaminoalkyl-4, 4-dimethylpiperidin-2, 6-dione is as defined in any one of claims 2, 5 and 6.

23. The use of claim 22 wherein the pamoate salt is 3- (3-methoxyphenyl) -3- (3-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate.

24. The use of claim 22 wherein the pamoate salt is 3- (3, 5-dimethoxyphenyl) -3- (3-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate.

25. A method for the treatment or prophylaxis of stress-related affective disorders which comprises administering to a human or animal patient an effective amount of a pamoate salt of a 3-phenyl-3-dimethylaminoalkyl-4, 4-dimethylpiperidin-2, 6-dione compound represented by formula I:

wherein

R₁Represents methoxy, ethoxy or hydroxy;

R₂represents methoxy, ethoxy, hydroxy or hydrogen; and is

n represents 2 or 3.

26. The method of claim 25, wherein the stress-related affective disorder is selected from the group consisting of agoraphobia; anorexia nervosa; anxiety disorders; anxiety associated with withdrawal from drug abuse; bulimia nervosa; chronic paroxysmal migraine; depression (including prevention of depression recurrence); a decline in immune responses associated with anxiety, depression or loss of decline; sleep onset or maintenance disorders; sleep arousal disorder; sleep anxiety attacks; huntington's chorea; Klein-Levin syndrome; memory impairment; meniere's disease, menstrual-related sleep syndrome; migraine headache; motion sickness; by administration of 5HT₃Nausea, neurogenic pain with incomplete relief of the antagonist; neuropathic pain; obsessive compulsive disorder; panic attacks; post-traumatic stress disorder; premenstrual dysphoric disorder; recurrent transient depression; restless legs syndrome, schizophrenia; senile dementia; serotonin stimulation syndrome; sleep apnea; cardiovascular symptoms associated with sleep; sleep-related seizures; cluster headaches associated with sleep; sleep-related myoclonus syndrome; social phobia; sudden infant death syndrome; and tinnitus.

27. The method of claim 26, wherein the stress-related affective disorder is anxiety.

28. The method of claim 26, wherein the stress-related affective disorder is depression.

29. The method of claim 26, wherein the stress-related affective disorder is migraine.

30. The method of claim 26, wherein the stress-related affective disorder is sleep apnea.

31. The method of any one of claims 25-30, wherein the 3-phenyl-3-dimethylaminoalkyl-4, 4-dimethylpiperidin-2, 6-dione is as defined in any one of claims 2, 5 and 6.

32. The method of claim 31, wherein the pamoate salt is 3- (3-methoxyphenyl) -3- (3-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate.

33. The method of claim 31, wherein the pamoate salt is 3- (3, 5-dimethoxyphenyl) -3- (3-dimethylaminopropyl) -4, 4-dimethylpiperidine-2, 6-dione pamoate.