Granted Patent B2

US 9,597,315 · App. 14/802,802 · Granted Mar 21, 2017

Inventors: Phil Skolnick (Edgewater, NJ); Zhengming Chen (Belle Meade, NJ)

Assignee: EUTHYMICS BIOSCIENCE, INC.

A61K31/403A61K31/00A61K31/404A61K31/428A61K31/4439A61K31/4709C07D401/04C07D403/04C07D405/04C07D409/04C07D417/04

Abstract

Claims (91)

1. A method for treating a central nervous system (CNS) disorder, or to alleviate one or more symptom(s) associated with the CNS disorder, in a mammalian subject, comprising administering to said subject an effective amount of a compound of the following Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Ar is a heterocyclic aryl group selected from furan, methylfuran, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, isothiazole, methoxypyridine, pyridazine, pyrazine, triazine, indole, methylindole, benzofuran, benzothiophene, benzothiazole, isoquinoline, cinnoline, phthalazine, quinazoline, chromane and isochromane, and Ar is either unsubstituted or substituted with one or more substituents independently selected from fluoro, chloro, bromo, iodo, —NO 2 , —CN, —NH 2 , carboxy, C 2-8 alkenyl, C 2-8 alkynyl, halo(C 1-8 )alkyl, hydroxy, trifluoromethyl, C 3-8 cycloalkyl, C 1-3 alkoxy, C 1-3 alkoxy(C 1-3 )alkyl, carboxy(C 1-3 )alkyl, C 1-3 alkanoyl, halo(C 1-3 )alkoxyl, C 1-8 alkylamino, and di(C 1-8 )alkylamino; and

R 1 is selected from hydrogen, unsubstituted C 1-10 alkyl, C 3-8 cycloalkyl, C 2-10 alkenyl, and C 3-10 alkynyl, and substituted C 1-10 alkyl, C 3-10 alkenyl and C 3-10 alkynyl wherein the substituent is one or more of hydroxy, cyano, halogen, C 1-6 alkoxy, aryl substituted C 1-6 alkoxy, aryloxy, aryloxy substituted with one or more halogens, C 1-6 alkyl, C 1-6 alkyl independently substituted with one or more of cyano and halogen, C 1-4 alkoxy, and C 1-4 haloalkoxy, and

wherein the CNS disorder is selected from depression, an anxiety disorder, an attention deficit disorder, obesity, substance abuse, PMDD (Premenstrual dysphoric disorder) and a cognitive disorder.

2. The method according to claim 1 , wherein the compound has the following Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:

Ar is furan, methylfuran, fluorobenzothiophene, methoxypyridine, benzofuran, benzothiophene, chlorobenzothiophene, benzothiazole, indole, or methylindole; and

R 1 is hydrogen, methyl, ethyl, propyl, or isopropyl.

3. The method according to claim 2 , wherein the compound is selected from the group consisting of:

1-(5-methylfuran-2-yl)-3-azabicyclo[3.1.0]hexane;

1-(6-methoxypyridin-3-yl)-3-azabicyclo[3.1.0]hexane;

1-(6-methoxypyridin-3-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

1-(benzofuran-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

1-(benzofuran-3-yl)-3-azabicyclo[3.1.0]hexane;

1-(benzofuran-3-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

1-methyl-2-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indole;

2-(3-ethyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-methyl-1H-indole;

2-(3-isopropyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-methyl-1H-indole;

1-methyl-5-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)-1H-indole;

5-(3-ethyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-methyl-1H-indole;

5-(3-isopropyl-3-azabicyclo[3.1.0]hexan-1-yl)-1-methyl-1H-indole;

1-(5-chlorobenzo[b]thiophen-3-yl)-3-azabicyclo[3.1.0]hexane;

1-(5-chlorobenzo[b]thiophen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

1-(5-chlorobenzo[b]thiophen-3-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

1-(benzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane;

1-(benzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;

1-(6-fluorobenzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane;

1-(6-fluorobenzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;

1-(5-fluorobenzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane;

1-(5-fluorobenzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane; and

2-(3-azabicyclo[3.1.0]hexan-1-yl)-benzo[d]thiazole;

or a pharmaceutically acceptable salt thereof.

4. The method according to claim 2 or a pharmaceutically acceptable salt thereof, wherein Ar is benzothiophene, fluorobenzothiophene, or chlorobenzothiophene.

5. The method according to claim 2 , wherein the compound is selected from the group consisting of:

1-(5-chlorobenzo[b]thiophen-3-yl)-3-azabicyclo[3.1.0]hexane;

1-(5-chlorobenzo[b]thiophen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

1-(5-chlorobenzo[b]thiophen-3-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

1-(benzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane;

1-(benzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;

1-(6-fluorobenzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane;

1-(6-fluorobenzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;

1-(5-fluorobenzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane; and

1-(5-fluorobenzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane;

or a pharmaceutically acceptable salt thereof.

6. The method according to claim 5 , wherein the compound is 1-(benzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

7. The method according to claim 6 , wherein the compound is 1-(benzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane hydrochloride.

8. The method according to claim 5 , wherein the compound is (1S,5S)-1-(benzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

9. The method according to claim 8 , wherein the compound is (1S,5S)-1-(benzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

10. The method according to claim 5 , wherein the compound is (1R,5R)-1-(benzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

11. The method according to claim 10 , wherein the compound is (1R,5R)-1-(benzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

12. The method according to claim 5 , wherein the compound is 1-(benzo[b]thiophen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

13. The method according to claim 12 , wherein the compound is 1-(benzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane hydrochloride.

14. The method according to claim 5 , wherein the compound is (1S,5S)-1-(benzo[b]thiophen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

15. The method according to claim 14 , wherein the compound is (1S,5S)-1-(benzo[b]thiophen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride.

16. The method according to claim 5 , wherein the compound is (1R,5R)-1-(benzo[b]thiophen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

17. The method according to claim 16 , wherein the compound is (1R,5R)-1-(benzo[b]thiophen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane hydrochloride.

18. The method according to claim 5 , wherein the compound is 1-(6-fluorobenzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

19. The method according to claim 18 , wherein the compound is 1-(6-fluorobenzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

20. The method according to claim 5 , wherein the compound is (1S,5S)-1-(6-fluorobenzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

21. The method according to claim 20 , wherein the compound is (1S,5S)-1-(6-fluorobenzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

22. The method according to claim 5 , wherein the compound is (1R,5R)-1-(6-fluorobenzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

23. The method according to claim 22 , wherein the compound is (1R,5R)-1-(6-fluorobenzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

24. The method according to claim 5 , wherein the compound is 1-(6-fluorobenzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

25. The method according to claim 5 , wherein the compound is 1-(5-fluorobenzo[b]thiophen-2-yl)-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

26. The method according to claim 5 , wherein the compound is 1-(5-fluorobenzo[b]thiophen-2-yl)-3-methyl-3-aza-bicyclo[3.1.0]hexane or a pharmaceutically acceptable salt thereof.

27. The method according to claim 1 , wherein the compound is selected from the group consisting of:

N,N-dimethyl-2-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)benzo[b]thiophen-5-amine;

1-(5-bromobenzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane;

1-(5-bromobenzo[b]thiophen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

2-(3-azabicyclo[3.1.0]hexan-1-yl)-N,N-dimethylbenzo[b]thiophen-5-amine;

2-(3-ethyl-3-azabicyclo[3.1.0]hexan-1-yl)-N,N-dimethylbenzo[b]thiophen-5-amine;

2-(3-isopropyl-3-azabicyclo[3.1.0]hexan-1-yl)-N,N-dimethylbenzo[b]thiophen-5-amine;

1-(6-bromobenzo[b]thiophen-2-yl)-3-azabicyclo[3.1.0]hexane;

1-(6-bromobenzo[b]thiophen-2-yl)-3-methyl-3-azabicyclo[3.1.0]hexane;

2-(3-azabicyclo[3.1.0]hexan-1-yl)-N,N-dimethylbenzo[b]thiophen-6-amine;

N,N-dimethyl-2-(3-methyl-3-azabicyclo[3.1.0]hexan-1-yl)benzo[b]thiophen-6-amine;

2-(3-ethyl-3-azabicyclo[3.1.0]hexan-1-yl)-N,N-dimethylbenzo[b]thiophen-6-amine; and

2-(3-isopropyl-3-azabicyclo[3.1.0]hexan-1-yl)-N,N-dimethylbenzo[b]thiophen-6-amine;

or a pharmaceutically acceptable salt thereof.

28. The method according to claim 1 , comprising administering to said subject a pharmaceutical composition comprising said compound of Formula I or said pharmaceutically acceptable salt thereof.

29. The method according to claim 2 , comprising administering to said subject a pharmaceutical composition comprising said compound of Formula Ia or said pharmaceutically acceptable salt thereof.

30. The method according to claim 3 , comprising administering to said subject a pharmaceutical composition comprising said compound or said pharmaceutically acceptable salt thereof.

31. The method according to claim 5 , comprising administering to said subject a pharmaceutical composition comprising said compound or said pharmaceutically acceptable salt thereof.

32. The method of claim 2 , wherein the CNS disorder is depression.

33. The method of claim 2 , wherein the CNS disorder is an anxiety disorder.

34. The method of claim 2 , wherein the CNS disorder is an attention deficit disorder.

35. The method of claim 2 , wherein the CNS disorder is obesity.

36. The method of claim 2 , wherein the CNS disorder is substance abuse.

37. The method of claim 2 , wherein the CNS disorder is PMDD (Premenstrual dysphoric disorder).

38. The method of claim 2 , wherein the CNS disorder is a cognitive disorder.

Assignments (3)

Continuity (9)