Spiroazacyclic compounds as monoamine receptor modulators

• US 7,217,719 B2
• Filed: 06/16/2005
• Issued: 05/15/2007
• Est. Priority Date: 12/28/2001
• Status: Expired due to Fees

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Schlienger, Nathalie
• Primary Examiner(s): Habte; Kahsay
• Application Number:
  US11/154,083
• Publication Number:
  US 20050256108A1
• Time in Patent Office: 698 Days
• Field of Search: 546/17, 546/18, 514/278
• US Class Current: 514/278
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• 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 25/32 Alcohol-abuse
• 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 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• 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: A61P 9/12 Antihypertensives
• CPC Class Codes: C07D 471/10 Spiro-condensed systems
• CPC Class Codes: C07D 491/10 Spiro-condensed systems
• CPC Class Codes: C07D 498/10 : Spiro-condensed systems

Abstract

The present invention relates to 1,3,8-triara-spiro[4.5]decan-2-one compounds as monoamine receptor modulators; compositions comprising the same; methods of inhibiting an activity of a monoamine receptor with said compounds; methods of treating a disease condition associated with a monoamine receptor using said compounds; and methods for identifying a subject suitable for treatment using said compounds.

Claims

1. A compound of formula I, salts and stereoisomers thereof

2. The compound of claim 1, wherein said optionally substituted aryl(C_1-6 alkyl) is (4-substituted)-aryl(C_1-6 alkyl).

3. The compound of claim 1, wherein at least one of R⁵ and R⁶ is selected from the group consisting of fluoro-substituted-aryl (C_1-6 alkyl), and fluoro-substituted-heteroaryl (C_1-6 alkyl).

4. The compound of claim 1, wherein R⁵ and R⁶ are independently substituted 1, 2, or 3 times with a substituent independently selected from the group consisting of halogen and optionally substituted O—

C_1-6-alkyl.

5. The compound of claim 4, wherein the halogen is fluorine and the optionally substituted O—

C_1-6-alkyl is an unsubstituted or fluorinated O—

C_1-6-alkyl.

6. The compound of claim 1, wherein the compound of formula I is an optionally substituted 1,3,8-triaza-spiro[4.5]decan-2-one.

7. The compound of claim 6 selected from the group consisting of:

3 -(4-Difluoromethoxybenzyl)-4-(4-fluorobenzyl)-8-methyl- 1,3,8-triaza-spiro[4.5]decan-2-one;

4-(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-8-methyl- 1,3,8-triaza-spiro[4.5]decan-2-one;

3-(4-Cyclopropylmethoxybenzyl)-4-(4-fluorobenzyl)-8-methyl- 1,3,8 -triaza-spiro [4.5]decan-2-one;

8-Ethyl-4-(4-fluorobenzyl)- 3-(4-isobutoxybenzyl)- 1,3,8-triaza-spiro[4.5]decan-2-one; and

8-(2-[1,3]Dioxolan-2-yl-ethyl)-4-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1,3,8-triaza-spiro [4.5]decan-2-one.

8. A composition comprising:

i) one or more compounds claim 1; and

ii) at least one pharmaceutically acceptable excipient or carrier.

9. A method of inhibiting 5-HT_2A receptor signaling activity in vitro, the method comprising contacting the 5-HT_2A receptor with an effective amount of one or more of the compounds according to claim 1.

10. A method of treating a disease condition or symptom of a disease condition associated 5-HT_2A receptor signaling activity comprising administering to a subject in need of such treatment a therapeutically effective amount of one or more of the compounds of claim 1, wherein the disease condition is selected from the group consisting of schizophrenia, psychosis, drug-induced psychosis, treatment-induced psychosis, migraine, hypertension, thrombosis, vasospasm, depression, anxiety, sleep disorders and appetite disorders.

11. The method of claim 9, wherein the 5-HT_2A receptor signaling activity is constitutive activity.

12. The method of claim 9, wherein the 5-HT_2A receptor signaling activity is agonist-mediated activity.

13. The method of claim 10, the disease or condition is schizophrenia.

14. The method of claim 10, wherein the disease or condition is psychosis.

15. The method of claim 14, wherein the disease or condition is selected from the group consisting of:

drug-induced psychosis and treatment-induced psychosis.

16. The method of claim 10, wherein the 5-HT_2A receptor signaling activity is constitutive activity.

17. The method of claim 10, wherein the 5-HT_2A receptor signaling activity is agonist-mediated activity.

18. The method of claim 10, wherein the disease condition or the symptom of a disease condition is associated with elevated 5-HT_2A receptor signaling activity.

19. The compound of claim 1, wherein said compound is racemic (4S)/(4R)-4-(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-8-methyl-1,3,8-triaza-spiro [4.5]decan-2-one.

20. The compound of claim 1, wherein said compound is enantio-pure or enantio-enriched (4S)- 4-(4-Fluorobenzyl)-3-(4-isobutoxybenzyl)-8-methyl-1,3,8-triaza-spiro[4.5]decan-2-one or (4R)-4-(4-Fluorobenzyl)-3-(4-isobutoxsybenzyl)-8-methyl -1,3,8-triaza-spiro[4.5]decan-2-one.

21. The compound of claim 1, wherein said compound is racemic (4S)/(4R)-3-(4-Cycloprapylmethoxybenzyl)4-(4-fluorobenzyl)-8-methyl-1,3,8-triaza -spiro[4.5]decan-2-one.

22. The compound of claim 1, wherein said compound is enantio-pure or enantio-eririched (4S)-3-(4-Cyclopropylmethoxybenzyl)-4-(4-fluorobenzyl)-8-methyl-1,3,8-triaza-spiro[4.5]decan-2-one or (4R)-3-(4-Cyclopropylmethoxybenzyl)-4-(4-fluorobenzyl) -8-methyl-1,3,8-triaza-spiro[4.5]decan-2-one.

23. The compound of claim 1, wherein said compound is racemic (4S)/(4R)-3(4-Difluoromethoxybenzyl)-4-(4-fluorobenzyl)-8-methyl-1,3,8-triaza-spiro [4.5]decan-2-one.

24. The compound of claim 1, wherein said compound is enantio-pure or enantio-enriched (4S )-3-(4-Difluoromethoxybenzyl)-4-(4-fluorobenzyl)-8-methyl-1,3,8-triaza-spiro[4.5]decan-2-one or (4R)-3-(4-Difluoromethoxybenzyl)-4-(4-fluorobenzyl)-8-methyl-1,3,8,-triaza-spiro[4.5]decan-2-one.

25. The compound of claim 1, wherein said compound is racemic (4S)/(4R)-8-Ethyl-4-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1,3,8-triaza-spiro[4.5]decan-2-one.

26. The compound of claim 1, wherein said compound is enantio-pure or enantio-enriched (4S)-8-Ethyl-4-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1,3,8-triaza-spiro[4.5]decan-2-one or (4R)-8-Ethyl-4-(4-fluorobenzyl)-3-(4-isobutoxybenzyl) 1,3,8-triaza-spiro [4.5]decan-2-one.

27. The compound of claim 1, wherein said compound is racemic (4S)/(4R)-(2-[1,3]Dioxolan-2-yl-ethyl)-4-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1,3,8-triaza-spiro[4.5]decan-2-one.

28. The compound of claim 1, wherein said compound is enantio-pure or enantio-enriched 4S)-8-(2-[1,3]Dioxolan-2-yl-ethyl)-4-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1,3,8-triaza-spiro[4.5]decan-2-one or (R)-8-(2-[1,3]Dioxolan-2-yl-ethyl)-4-(4-fluorobenzyl)-3-(4-isobutoxybenzyl)-1,3,8-triaza-spiro[4.5]decan-2-one.

29. The compound of claim 1, wherein R¹ is an optionally substituted substituent selected from the group consisting of C_1-6 alkyl, C_2-8 alkenyl, C_2-8 alkynyl, C_3-8 cyoloalkyl, aryl, heteroaryl, aryl(C_1-6 alkyl), and heterocyclyl(C_1-6 alkyl).

30. The compound of claim 1, wherein R¹ is an optionally substituted substituent selected from the group consisting of C_1-6 alkyl and heterocyclyl(C_1-6 alkyl).

31. The compound of claim 30, wherein the C_1-6 alkyl is methyl or ethyl.

32. The compound of claim 30, wherein the heterocyclyl(C_1-6 alkyl) is -[1,3]Dioxolan-2-yl(C_1-6 alkyl).

33. The compound of claim 1, wherein the compound of formula I is an optionally substituted 1,2,4,8-tetraaza-spiro[4.5]decan-3-one.

34. The compound of claim 33 selected from the group consisting of:

2-(4-Ethoxybenzyl)-1-(4-fluorobenzyl)-8-methyl-1,2,4,8-tetraaza-spiro[4.5]decan-3-one; and

1-(4-Fluorobenzyl)-2-(4-isobutoxybenzyl)-8-methyl-1,2,4,8-tetraaza-spiro[4.5]decan-3-one.

35. A method of inhibiting an activation of a 5-HT_2A receptor in vitro, the method comprising contacting the 5-HT_2A receptor with an effective amount of one or more of the compounds according to claim 1.