SUBSTITUTED PHENETHYLAMINES WITH SEROTONINERGIC AND/OR NOREPINEPHRINERGIC ACTIVITY

• US 20090023765A1
• Filed: 09/19/2008
• Published: 01/22/2009
• Est. Priority Date: 12/01/2005
• Status: Active Grant

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Auspex Pharmaceuticals, Inc. (Teva Pharmaceutical Industries Limited)
• Inventors: Sarshar, Sepehr, Gant, Thomas G.
• Granted Patent: US 8,138,226 B2
• Time in Patent Office: Days
• US Class Current: 514/282
• CPC Class Codes: A61K 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07B 2200/05 : Isotopically modified compounds, e.g. labelled
• CPC Class Codes: C07B 59/001 : Acyclic or carbocyclic compounds
• CPC Class Codes: C07C 217/74 : with rings other than six-membered aromatic rings being part of the carbon skeleton
• CPC Class Codes: C07C 235/34 : having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 255/37 : the carbon skeleton being further substituted by etherified hydroxy groups
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 65/21 : containing ether groups, groups, groups, or groups

Abstract

Chemical syntheses and medical uses of novel inhibitors of the uptake of monoamine neurotransmitters and pharmaceutically acceptable salts and prodrugs thereof, for the treatment and/or management of psychotropic disorders, anxiety disorder, generalized anxiety disorder, depression, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, hot flashes, senile dementia, migraine, hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathic pain, painful diabetic retinopathy, bipolar depression, obstructive sleep apnea, psychiatric disorders, premenstrual dysphoric disorder, social phobia, social anxiety disorder, urinary incontinence, anorexia, bulimia nervosa, obesity, ischemia, head injury, calcium overload in brain cells, drug dependence, and/or premature ejaculation are described.

Claims

1-7. -7. (canceled)

8. A method of treating a mammal suffering from a disease or condition involving monoamine reuptake or a monoamine receptor related disorder comprising administering to said mammal a therapeutically effective amount of a compound having structural Formula 1

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₁₈ are independently selected from the group consisting of hydrogen and deuterium;

R₁₉, R₂₀, and R₂₁ are independently selected from the group consisting of —

CH₃ and —

CD₃;

provided that said compound of Formula 1 contains at least one deuterium atom; and

provided that deuterium enrichment in said compound of Formula 1 is at least about 1%.

9. The method of claim 8, wherein said disease, condition, or disorder is selected from the group consisting of a psychotropic disorder, an anxiety disorder, a generalized anxiety disorder, depression, a post-traumatic stress disorder, an obsessive-compulsive disorder, a panic disorder, a hot flash, senile dementia, migraine, hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathic pain, painful diabetic retinopathy, bipolar depression, obstructive sleep apnea, a psychiatric disorder, a premenstrual dysphoric disorder, a social phobia, a social anxiety disorder, urinary incontinence, anorexia, bulimia nervosa, obesity, ischemia, head injury, calcium overload in brain cells, drug dependence, and premature ejaculation.

10. The method of claim 8, wherein the compound of Formula 1 affects decreased inter-individual variation in plasma levels of said compound or a metabolite thereof as compared to the non-isotopically enriched compound.

11. The method of claim 8, wherein the compound of Formula 1 affects increased average plasma levels of said compound per dosage unit thereof as compared to the non-isotopically enriched compound.

12. The method of claim 8, wherein the compound of Formula 1 affects decreased average plasma levels of at least one metabolite of said compound per dosage unit thereof as compared to the non-isotopically enriched compound.

13. The method of claim 8, wherein the compound of Formula 1 affects a decreased metabolism by at least one polymorphically-expressed cytochrome P₄₅₀ isoform in mammalian subjects per dosage unit thereof as compared to the non-isotopically enriched compound.

14. The method of claim 13, wherein said cytochrome P₄₅₀ isoform is selected from the group consisting of CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

15. The method of claim 8, wherein the compound of Formula 1 affects a decreased inhibition of at least one cytochrome P₄₅₀ isoform in mammalian subjects per dosage unit thereof as compared to the non-isotopically enriched compound.

16. The method of claim 15, wherein said cytochrome P₄₅₀ isoform is selected from the group consisting of CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4×

1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51

17. The method of claim 8, wherein the compound of Formula 1 elicits an improved clinical effect during the treatment in said mammal per dosage unit thereof as compared to the non-isotopically enriched compound.

18. The method of claim 17, wherein the said improved clinical effect comprises an effect selected from the group consisting of accelerated rate of healing, accelerated rate of symptom relief, improved patient compliance, and reduced substance abuse withdrawal symptomology during the treatment.

27. The method of claim 8, wherein said compound of Formula 1 has the structural formula:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

28. The method of claim 27, wherein said compound of Formula 1 is a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−

)-enantiomer.

29. The method of claim 27, wherein said compound of Formula 1 is a mixture of about 90% or more by weight of the (−

)-enantiomer and about 10% or less by weight of the (+)-enantiomer.

30. The method of claim 27, wherein said compound of Formula 1 is a hydrochloride salt.

31. The method of claim 30, wherein said hydrochloride salt is a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−

)-enantiomer.

32. The method of claim 30, wherein said hydrochloride salt is a mixture of about 90% or more by weight of the (−

)-enantiomer and about 10% or less by weight of the (+)-enantiomer.

19. A method of treating a mammal for a drug addiction comprising co-administering a first component and a second component, wherein said first component comprises a therapeutically effective amount of a compound of Formula 1, and said second component comprises a therapeutically effective amount of an opioid antagonist, said compound having structural Formula 1

or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, R₁₆, R₁₇, and R₁₈ are independently selected from the group consisting of hydrogen and deuterium;

R₁₉, R₂₀, and R₂₁ are independently selected from the group consisting of —

CH₃, and —

CD₃;

provided that said compound of Formula 1 contains at least one deuterium atom; and

provided that deuterium enrichment in said compound of Formula 1 is at least about 1%.

20. The method of claim 19, wherein said opioid antagonist is selected from the group consisting of nalmefene, naltrexone, and naloxone.

21. The method of claim 19, wherein said drug addiction is selected from the group consisting of tobacco addiction, alcohol addiction, marijuana addiction, and cocaine addiction.

25. The method of claim 19, wherein said first component elicits an improved clinical effect for the treatment of a drug addiction, as compared to the non-isotopically enriched analog of the first component.

26. The method of claim 25, wherein said improved clinical effect is selected from the group consisting of an accelerated rate of healing, an accelerated rate of symptom relief, improved patient compliance, and reduced substance abuse withdrawal symptomatology during the treatment.

33. The method of claim 19, wherein said compound of Formula 1 has the structural formula:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

34. The method of claim 33, wherein said compound of Formula 1 is a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−

)-enantiomer.

35. The method of claim 33, wherein said compound of Formula 1 is a mixture of about 90% or more by weight of the (−

)-enantiomer and about 10% or less by weight of the (+)-enantiomer.

36. The method of claim 33, wherein said compound of Formula 1 is a hydrochloride salt.

37. The method of claim 36, wherein said hydrochloride salt is a mixture of about 90% or more by weight of the (+)-enantiomer and about 10% or less by weight of the (−

)-enantiomer.

38. The method of claim 36, wherein said hydrochloride salt is a mixture of about 90% or more by weight of the (−

)-enantiomer and about 10% or less by weight of the (+)-enantiomer.

22. (canceled)

23. (canceled)

24. (canceled)