N-substituted piperidine derivatives as serotonin receptor agents

• US 7,253,186 B2
• Filed: 06/20/2003
• Issued: 08/07/2007
• Est. Priority Date: 06/24/2002
• Status: Expired due to Fees

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Andersson, Carl-Magnus, Schlienger, Nathalie, Fejzic, Alma, Hansen, Eva Louise, Pawlas, Jan
• Primary Examiner(s): AULAKH, CHARANJIT
• Application Number:
  US10/601,070
• Publication Number:
  US 20040106600A1
• Time in Patent Office: 1,509 Days
• Field of Search: 514/326, 514/316, 514/235.5, 546/207, 546/208, 546/209, 546/210, 546/211, 546/190, 544/129, 544/283, 435/7.2
• US Class Current: 514/326
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Disclosed herein are compounds of Formula I,

or a pharmaceutically acceptable salt, amide, ester, or prodrug thereof. Also disclosed are methods of inhibiting an activity of a monoamine receptor comprising contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of one or more of the compounds of Formula I. Disclosed are also methods of inhibiting an activation of a monoamine receptor comprising contacting the monoamine receptor or a system containing the monoamine receptor with an effective amount of one or more of the compounds of Formula I. Furthermore, methods of treating psychotic disease using a compound of Formula I are disclosed.

Claims

1. A compound of Formula I

2. The compound of claim 1, wherein said heterocyclyl is optionally substituted with one or more groups selected from the group consisting of hydrogen, halogen, hydroxy, alkoxy, alkyl, and amino.

3. The compound of claim 1, wherein said heterocyclyl is selected from the group consisting of tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline;

pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, and 1,3-oxathiolane.

4. The compound of claim 3, wherein said heterocyclyl is selected from the group consisting of 1,3-dioxane, 1,3-dioxolane, and tetrahydropyran.

5. The compound of claim 1, wherein R² and R³ are hydrogen.

6. The compound of claim 1, wherein n is 1.

7. The compound of claim 1, wherein W is oxygen.

8. The compound of claim 1, wherein Ar¹ is an optionally substituted aryl.

9. The compound of claim 1, wherein Ar¹ is 4-substituted aryl.

10. The compound of claim 1, wherein Ar¹ is selected from the group consisting of alkyl-substituted phenyl, alkoxy-substituted phenyl, halogen-substituted phenyl, hydroxy-substituted phenyl and amino-substituted phenyl.

11. The compound of claim 10, wherein said alkyl is selected from the group consisting of methyl, ethyl, propyl, n-butyl, sec-butyl and tert-butyl, and said alkoxy is selected from the group consisting of methoxy, ethoxy, propxy, n-butoxy, sec-butoxy, and tert-butoxy.

12. The compound of claim 10, wherein Ar¹ is halogen-substituted phenyl.

13. The compound of claim 12, wherein said halogen is fluoro.

14. The compound of claim 1, wherein X is selected from the group consisting of optionally substituted methylene, optionally substituted ethylene, and CH₂N(R^N).

15. The compound of claim 14, wherein X is an optionally substituted methylene.

16. The compound of claim 14, wherein X is CH₂N(R^N).

17. The compound of claim 1, wherein Ar² is an optionally substituted aryl.

18. The compound of claim 1, wherein Ar² is 4-substituted aryl.

19. The compound of claim 17, wherein said substituent on Ar² is selected from the group consisting of alkyl, alkoxy, halogen, hydroxy, amino, alkylamino, heteroaryl, and heterocyclyl.

20. The compound of claim 17, wherein said substituent on Ar² is selected from the group consisting of chloro, fluoro, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, see-butoxy, tert-butoxy, trifluoromethoxy, N-morpholinyl, N-pyrrolidinyl, N-pyrazolyl, N-triazolyl and 2-oxopyrrolidinyl.

22. A method of inhibiting an activity of a 5HT2A receptor in vitro comprising contacting the 5HT2A receptor with a compound of claim 1.

23. A method of inhibiting an activation of a 5HT2A receptor in vitro comprising contacting the 5HT2A receptor with a compound of claim 1.

24. A method of treating psychosis comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1.

25. The method of claim 22, wherein the 5HT2A receptor is mutated or modified.

26. The method of claim 22, wherein the activity is signaling activity.

27. The method of claim 22, wherein the activity is constitutive.

28. The method of claim 22, wherein the activity is associated with serotonin receptor activation.

29. The method of claim 23, wherein the activation is by an agonistic agent.

30. The method of claim 29, wherein the agonistic agent is exogenous.

31. The method of claim 29, wherein the agonistic agent is endogenous.

32. The method of claim 23, wherein the activation is constitutive.

33. The method of claim 23, wherein the 5HT2A receptor is mutated or modified.

21. A compound selected from the group consisting of:

N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzyl)-N′

-(4-isopropoxybenzyl)carbamide, oxalate;

N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide, oxalate;

N-[1-(1,3-Dioxan-5-yl)-piperidin-4-yl)-N-(4-fluorobenzyl)-2-(4-isobutoxyphenyl)acetamide, tartrate;

N-[1-(2,2-Dimethyl-1,3-dioxan-5-yl)piperidin-4-yl]-N-(4-fluorobenzyl)-2-(4-fluorophenyl)acetamide, tartrate;

N-(4-Fluorobenzyl)-2-(4-isobutoxyphenyl)-N-[1-(tetrahydropyran-4-yl)piperidin-4-yl]acetamide, tartrate;

N-(4-Fluorobenzyl)-2-(4-fluorophenyl)-N-[1-(tetrahydropyran-4-yl)piperidin-4-yl]acetamide, tartrate.