IP Library › Granted Patent US 8,604,074

Granted Patent B2

US 8,604,074 · App. 12/685,652 · Granted Dec 10, 2013

Pro-neurogenic compounds

Inventors: Steven L. McKnight (Dallas, TX); Andrew A. Pieper (Plano, TX); Joseph M. Ready (Carrollton, TX); Jef K. De Brabander (Flower Mound, TX)

Assignee: Board of Regents of The University of Texas System

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Quick Facts

Patent No.: US 8,604,074
App. No.: 12/685,652
Granted: Dec 10, 2013
Kind: B2

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Abstract

This invention relates generally to stimulating neurogenesis (e.g., post-natal neurogenesis, e.g., post-natal hippocampal neurogenesis) and protecting from neuron cell death.

Claims (248)

1. A method for promoting post-natal mammalian neurogenesis and/or reducing neuronal cell death in a subject in need thereof, the method comprising administering an effective amount of a compound having the following formula or a pharmaceutically acceptable salt thereof:

wherein:

R 3 and R 6 are each independently selected from halo, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , and cyano;

A is CR A1 R A2 , wherein R A1 is selected from hydrogen, halo, C 1 -C 3 alkyl, and OR 9 , and R A2 is selected from halo, C 1 -C 3 alkyl, and OR 9 ;

Z is selected from —NHR 10 ; —N(CH 3 )R 11 ; —OR 12 ; and —S(O) n R 13 , wherein n is 0, 1, or 2;

R 9 is hydrogen or C 1 -C 3 alkyl that is optionally substituted with hydroxyl or C 1 -C 3 alkoxy;

R 10 , R 11 , R 12 and R 13 are each independently selected from:

(a) C 6 -C 10 aryl that is optionally substituted with 1 to 4 R b ; or

(b) heteroaryl containing from 6-14 ring atoms, wherein from 1-6 of the ring atoms are independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1 to 4 R b ;

R b at each occurrence is independently selected from:

(aa) C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 thiohaloalkoxy; —O—(CH 2 ) 1-3 —[O(CH 2 ) 1-3 ] 1-3 —H; C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl);

(bb) halo; hydroxyl; cyano; nitro; —NH 2 ; azido; sulfhydryl; C 2 -C 6 alkenyl; C 2 -C 6 alkynyl; —C(O)H; —C(O)(C 1 -C 6 alkyl); —C(O)(C 1 -C 6 haloalkyl); C(O)OH; —C(O)O(C 1 -C 6 alkyl); —C(O)NH 2 ; —C(O)NH(C 1 -C 6 alkyl); C(O)N(C 1 -C 6 alkyl) 2 ; —SO 2 (C 1 -C 6 alkyl); —SO 2 NH 2 ; —SO 2 NH(C 1 -C 6 alkyl); —SO 2 N(C 1 -C 6 alkyl) 2 ;

(cc) C 3 -C 6 cycloalkyl or heterocyclyl containing from 5 to 6 ring atoms, wherein from 1 to 2 of the ring atoms of the heterocyclyl is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S; and

(dd) phenyl or heteroaryl containing from 5 to 6 ring atoms, wherein from 1 to 2 of the ring atoms of the heteroaryl is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; wherein each of said phenyl and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected from halo; hydroxyl; cyano; nitro; —NH 2 ; —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), C 1 -C 6 alkoxy; C 1 -C 6 haloalkoxy; C 1 -C 6 thioalkoxy; C 1 -C 6 thiohaloalkoxy; C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl.

2. A method for promoting post-natal mammalian neurogenesis and/or reducing neuronal cell death in a subject in need thereof, the method comprising administering an effective amount of a compound having the following formula or a pharmaceutically acceptable salt thereof:

wherein

R 3 and R 6 are each independently selected from halo, CH 3 , ethynyl, cyclopropyl, —N 3 , and cyano;

R A1 and R A2 are each independently selected from hydrogen, halo, CH 3 , and OR 9 , wherein one of R A1 and R A2 is halo or OR 9 ;

Z is selected from —NHR 10 ; —N(CH 3 )R 11 ; —OR 12 ; and —S(O) n R 13 , wherein n is 0, 1, or 2;

R 9 is hydrogen or C 1 -C 3 alkyl that is optionally substituted with hydroxyl or C 1 -C 3 alkoxy;

R 10 , R 11 , R 12 and R 13 are each independently selected from:

(a) C 6 -C 10 aryl that is optionally substituted with 1 to 4 R b ; or

R b at each occurrence is independently selected from:

3. The method of claim 1 , wherein R A2 is fluoro, and R A1 is hydrogen.

4. The method of claim 3 , wherein each of R 3 and R 6 is halo.

5. The method of claim 3 , wherein each of R 3 and R 6 is bromo.

6. The method of claim 1 , wherein Z is —NHR 10 .

7. The method of claim 6 , wherein R 10 is unsubstituted phenyl.

8. The method of claim 6 , wherein R 10 is phenyl that is substituted with 1 R b .

9. The method of claim 8 , wherein R b is C 1 -C 6 alkoxy.

10. The method of claim 9 , wherein R b is OCH 3 .

11. The method of claim 8 , wherein R 10 is 3-methoxyphenyl.

12. The method of claim 1 , wherein Z is —OR 12 or —S(O) n R 13 .

13. The method of claim 12 , wherein R 12 is C 6 -C 10 aryl that is optionally substituted with 1 to 4 R b .

14. The method of claim 1 , wherein R A2 is OR 9 , and R A1 is hydrogen.

15. The method of claim 14 , wherein R 9 is hydrogen.

16. The method of claim 15 , wherein Z is —NHR 10 .

17. The method of claim 16 , wherein R 10 is unsubstituted phenyl.

18. The method of claim 16 , wherein R 10 is phenyl that is substituted with 1 R b .

19. The method of claim 18 , wherein each of R 3 and R 6 is halo.

20. The method of claim 18 , wherein each of R 3 and R 6 is bromo.

21. The method of claim 1 , wherein the compound is selected from:

R-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol;

S-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(2-iminopyridin-1(2H)-yl)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylthio)propan-2-ol;

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-N-(3-methoxyphenyl)acetamide;

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxyaniline;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-one;

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-methoxypropyl)-3-methoxyaniline;

1-(3,6-Dimethyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;

1-(3-Bromo-6-methyl-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol;

1-(3,6-Dichloro-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;

1-(3-Azidophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;

1,3-Bis(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;

1-(9H-Carbazol-9-yl)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;

3-(3,6-Dibromo-9H-carbazol-9-yl)-2-hydroxy-N-(3-methoxyphenyl)-propanamide;

4-(3,6-dibromo-9H-carbazol-9-yl)-1-(phenylamino)butan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-4-(phenylamino)butan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-2-ylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-((3-methoxyphenyl)(methyl)-amino)propan-2-ol;

3-amino-1-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)pyridinium;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyrimidin-2-ylamino)propan-2-ol;

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxy-N-methylaniline;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-methoxypropan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(1H-indol-1-yl)propan-2-ol;

3-(1-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropyl)-1H-1,2,3-triazol-4-yl)propan-1-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-ethoxyphenylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3,5-dimethyl-1H-pyrazol-1-yl)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfinyl)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylsulfonyl)propan-2-ol;

1-(3-bromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-phenoxypropan-2-ol;

N-(2-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-hydroxypropoxy)ethyl)-acetamide;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-3-ylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-4-ylamino)propan-2-ol;

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2,2-difluoropropyl)-3-methoxyaniline;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(o-tolylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(m-tolylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(2-methoxyphenylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(naphthalen-1-ylamino)propan-2-ol;

1-(4-bromophenylamino)-3-(3,6-dichloro-9H-carbazol-9-yl)propan-2-ol;

1-(4-bromophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(4-ethoxyphenylamino)propan-2-ol;

1-(4-chlorophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(2-hydroxyethylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(2,4-dimethoxyphenylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(2,3-dimethylphenylamino)propan-2-ol;

1-(2-chlorophenylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;

1-(tert-butylamino)-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(isopropylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(4-methoxyphenylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(m-tolylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3,5-dimethylphenylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(3,4-dimethylphenylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(2,5-dimethylphenylamino)propan-2-ol;

1-(9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol;

1-(3,6-dichloro-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol;

1-(9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol;

1-(3,6-dichloro-9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol;

1-(3,6-dibromo-9H-carbazol-9-yl)-3-(p-tolylamino)propan-2-ol;

N-(4-(3-(9H-carbazol-9-yl)-2-hydroxypropoxy)phenyl)acetamide;

1-(9H-carbazol-9-yl)-3-phenoxypropan-2-ol;

1-(9H-carbazol-9-yl)-3-(4-methoxyphenylamino)propan-2-ol;

1-(benzylamino)-3-(9H-carbazol-9-yl)propan-2-ol;

methyl 4-(3-(9H-carbazol-9-yl)-2-hydroxypropoxy)benzoate;

1-(9H-carbazol-9-yl)-3-(4-methoxyphenoxy)propan-2-ol; and

1-amino-3-(3,6-dibromo-9H-carbazol-9-yl)propan-2-ol;

or a pharmaceutically acceptable salt thereof.

22. The method of claim 1 , wherein the compound is selected from S-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol; R-1-(3,6-Dibromo-9H-carbazol-9-yl)-3-(3-methoxyphenylamino)-propan-2-ol; or 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(phenylamino)propan-2-ol.

23. The method of claim 2 , wherein R A2 is fluoro, and R A1 is hydrogen.

24. The method of claim 23 , wherein each of R 3 and R 6 is halo.

25. The method of claim 23 , wherein each of R 3 and R 6 is bromo.

26. The method of claim 2 , wherein Z is —NHR 10 .

27. The method of claim 26 , wherein R 10 is unsubstituted phenyl.

28. The method of claim 26 , wherein R 10 is phenyl that is substituted with 1 R b .

29. The method of claim 28 , wherein R b is C 1 -C 6 alkoxy.

30. The method of claim 29 , wherein R b is OCH 3 .

31. The method of claim 28 , wherein R 10 is 3-methoxyphenyl.

32. The method of claim 2 , wherein Z is —OR 12 or —S(O) n R 13 .

33. The method of claim 32 , wherein R 12 is C 6 -C 10 aryl that is optionally substituted with 1 to 4 R b .

34. The method of claim 2 , wherein R A2 is OR 9 , and R A1 is hydrogen.

35. The method of claim 34 , wherein R 9 is hydrogen.

36. The method of claim 35 , wherein Z is —NHR 10 .

37. The method of claim 36 , wherein R 10 is unsubstituted phenyl.

38. The method of claim 36 , wherein R 10 is phenyl that is substituted with 1 R b .

39. The method of claim 38 , wherein each of R 3 and R 6 is halo.

40. The method of claim 38 , wherein each of R 3 and R 6 is bromo.

41. The method of claim 2 , wherein the compound is selected from: