IP Library › Granted Patent US 9,446,042

Granted Patent B2

US 9,446,042 · App. 14/750,119 · Granted Sep 20, 2016

Pro-neurogenic compounds

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

Assignee: Board of Regents of The University of Texas System

A61K31/506 A61K31/403 A61K31/404 A61K31/4035 A61K31/4045 A61K31/4155 A61K31/4192 A61K31/422 A61K31/437 A61K31/4439 C07D209/08 C07D209/14 C07D209/88 C07D401/06 C07D401/12 C07D403/06 C07D403/12 C07D413/06 C07D471/04

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Quick Facts

Patent No.: US 9,446,042
App. No.: 14/750,119
Granted: Sep 20, 2016
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 (129)

1. A method for the treatment of a disease, disorder, or condition caused by or associated with insufficient neurogenesis or unwanted neuronal cell death in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof, having formula (III):

wherein:

each of R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , and R 8 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro;

R 6 is selected from fluoro, bromo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro;

each of L 1 and L 2 is, independently, C 1 -C 3 alkylene, which is optionally substituted with from 1-2 independently selected R c ;

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

Z is:

(i) —NR 10 R 11 ; or

(ii) —OR 12 ; or

(iii) —S(O) n R 13 , wherein n is 0, 1, or 2;

each of R 10 and R 11 is independently selected from:

(a) hydrogen;

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

(d) C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, each of which is optionally substituted with from 1-3 R d ; and

(e) —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), or —C(O)O(C 1 -C 6 alkyl);

wherein one of R 10 and R 11 is selected from (b) or (c);

R 12 is:

C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ;

R 13 is:

C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ;

R b at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:

(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) 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 5-6 ring atoms, wherein from 1-2 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 5-6 ring atoms, wherein from 1-2 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 1-3 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;

R c at each occurrence is, independently selected from halo, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and cyano; and

R d at each occurrence is, independently selected from hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and cyano.

2. The method of claim 1 , wherein R A1 is selected from hydrogen, halo, and C 1 -C 3 alkyl, and R A2 is halo.

3. The method of claim 1 , wherein R A1 is hydrogen or C 1 -C 3 alkyl, and R A2 is halo.

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

5. The method of claim 1 , wherein the carbon attached to R A1 and R A2 is substituted with four different substituents, and is (R) or (S) configured.

6. The method of claim 1 , wherein the compound is (+) (dextrorotatory) or (−) (levororotatory).

7. The method of claim 1 , wherein R 3 and R 6 are each independently selected from fluoro, bromo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro.

8. The method of claim 1 , wherein Z is:

—OR 12 ; or

—S(O) n R 13 , wherein n is 0, 1, or 2.

9. The method of claim 1 , wherein Z is —NR 10 R 11 , wherein one of R 10 and R 11 is:

C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ; or pyridyl;

and the other of R 10 and R 11 is hydrogen or C 1 -C 6 alkyl.

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

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

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

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

3,6-dibromo-9-(2-fluoro-3-phenoxypropyl)-9H-carbazole;

3,6-dibromo-9-(2-fluoro-3-(phenylsulfonyl)propyl)-9H-carbazole;

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

3,6-dibromo-9-(2,2-difluoro-3-phenoxypropyl)-9H-carbazole;

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-4-methoxyaniline;

N-(2-bromo-3-(3,6-dibromo-9H-carbazol-9-yl)propyl)-N-(4-methoxyphenyl)-4-nitrobenzenesulfonamide;

Ethyl 2-(4-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropylamino)phenoxy)acetate; and

N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-4-(2-(2-methoxyethoxy)ethoxy)aniline;

or a pharmaceutically acceptable salt thereof.

11. The method of claim 1 , wherein the compound is N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxyaniline.

12. A method for the treatment of a disease, disorder, or condition caused by or associated with insufficient neurogenesis or unwanted neuronal cell death in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof, having formula (III):

wherein:

each of L 1 and L 2 is, independently, C 1 -C 3 alkylene, which is optionally substituted with from 1-2 independently selected R c ;

A is CR A1 R A2 , wherein R A1 is selected from hydrogen and C 1 -C 3 alkyl; and R A2 is selected from halo and OR 9 ; wherein R 9 is hydrogen or C 1 -C 3 alkyl that is optionally substituted with hydroxyl or C 1 -C 3 alkoxy;

Z is:

(i) —NR 10 R 11 ; or

(ii) —OR 12 ;

each of R 10 and R 11 is independently selected from:

(a) hydrogen;

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

(d) C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, each of which is optionally substituted with from 1-3 R d ; and

(e) —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), or —C(O)O(C 1 -C 6 alkyl);

wherein one of R 10 and R 11 is (c);

R 12 is:

C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ;

R b at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:

13. The method of claim 12 , wherein when A is CHOH and Z is NR 10 R 11 , one or more of the following apply:

each of R 3 and R 6 is CH 3 ;

one of R 3 and R 6 is CH 3 and the other of R 3 and R 6 is bromo; or

L 1 and/or L 2 is C 2 -C 3 alkylene that is optionally substituted with from 1-2 independently selected R c .

14. The method of claim 12 , wherein R A1 is hydrogen, and R A2 is halo or OR 9 .

15. The method of claim 12 , wherein R A1 is hydrogen, and R A2 is halo.

16. The method of claim 12 , wherein R A1 is hydrogen, and R A2 is fluoro.

17. The method of claim 12 , wherein R A1 is hydrogen, and R A2 is OR 9 .

18. The method of claim 12 , wherein R A1 is hydrogen, and R A2 is OH.

19. The method of claim 12 , wherein R 3 and R 6 are each independently selected from fluoro, bromo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro.

20. The method of claim 12 , wherein R 3 and R 6 are bromo.

21. The method of claim 12 , wherein R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 are hydrogen.

22. The method of claim 20 , wherein R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 are hydrogen.

23. The method of claim 12 , wherein Z is —NR 10 R 11 , wherein one of R 10 and R 11 is (c) and the other of R 10 and R 11 is hydrogen.

24. The method of claim 12 , wherein Z is —NR 10 R 11 , wherein one of R 10 and R 11 is pyridyl and the other of R 10 and R 11 is hydrogen.

25. A method for the treatment of a disease, disorder, or condition caused by or associated with insufficient neurogenesis or unwanted neuronal cell death in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound or a pharmaceutically acceptable salt thereof, having formula (III):

wherein:

each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is independently selected from hydrogen, halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro;

each of L 1 and L 2 is, independently, C 1 -C 3 alkylene;

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

Z is:

(i) —NR 10 R 11 ;

(ii) —OR 12 ; or

(iii) —S(O) n R 13 , wherein n is 0, 1, or 2;

each of R 10 and R 11 is independently selected from:

(a) hydrogen;

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

(d) C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, each of which is optionally substituted with from 1-3 R d ; and

(e) —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), or —C(O)O(C 1 -C 6 alkyl);

wherein one of R 10 and R 11 is selected from (b) or (c);

R 12 is:

C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ;

R 13 is:

C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ;

R b at each occurrence is independently selected from the substituents delineated in (aa) through (dd) below:

and R d at each occurrence is, independently selected from hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —NH 2 , —NH(C 1 -C 6 alkyl), N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and cyano.

26. The method of claim 25 , wherein R A1 is hydrogen, and R A2 is halo.

27. The method of claim 25 , wherein R A1 is hydrogen, and R A2 is fluoro.

28. The method of claim 25 , wherein R 3 and R 6 are each independently selected from halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 thiohaloalkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkynyl, cyclopropyl, —N 3 , cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , —NHC(O)(C 1 -C 6 alkyl), and nitro.

29. The method of claim 25 , wherein R 3 and R 6 are bromo.

30. The method of claim 25 , wherein R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 are hydrogen.

31. The compound or salt of claim 29 , wherein R 1 , R 2 , R 4 , R 5 , R 7 , and R 8 are hydrogen.

32. The method of claim 25 , wherein Z is —NR 10 R 11 , wherein one of R 10 and R 11 is (c) and the other of R 10 and R 11 is hydrogen.

33. The method of claim 25 , wherein Z is —NR 10 R 11 , wherein one of R 10 and R 11 is pyridyl and the other of R 10 and R 11 is hydrogen.

34. The method of claim 25 , wherein the compound is 1-(3,6-dibromo-9H-carbazol-9-yl)-3-(pyridin-2-ylamino)propan-2-ol.

Assignments (1)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 1, 2016

From: MCKNIGHT, STEVEN L.; PIEPER, ANDREW A.; READY, JOSEPH M.; DE BRABANDER, JEF K.

To: BOARD OF REGENTS OF THE UNIVERSITY OF TEXAS SYSTEM

Reel/Frame 038763/0840 →

Continuity (5)

Division 13709531 · Dec 10, 2012

Continuation 12832056 · Jul 7, 2010

Continuation In Part 12685652 · Jan 11, 2010

Provisional Application 61143755 · Jan 9, 2009

Related Publication 20150290195A1 · Oct 15, 2015