Pro-neurogenic compounds

Patent metadata

Field	Value
Publication number	US-9156787-B2
Application number	US-201414339742-A
Country	US
Kind code	B2
Filing date	Jul 24, 2014
Priority date	Jan 9, 2009
Publication date	Oct 13, 2015
Grant date	Oct 13, 2015

Abstract

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

First claim

The invention claimed is:

1. A method for treating major depression comprising: administering to a subject in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the following formula:

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 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) 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;
wherein when R 3 and R 6 are both halo, one of R A1 and R A2 is OH and the other is hydrogen, Z is —NHR 10 , and R 10 is C 6 -C 10 aryl that is optionally substituted with 1 to 4 R b , then R 10 is unsubstituted phenyl or phenyl substituted with 1 R b .

2. 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.

3. The method of claim 2 , wherein the compound or salt is (+) (dextrorotatory) or (−) (levororotatory).

4. The method of claim 1 , wherein the effective amount of the compound or salt reduces neuron cell death.

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

6. A method for treating major depression comprising: administering to a subject in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the following formula:

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)—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 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) 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;
wherein when R 3 and R 6 are both halo, one of R A1 and R A2 is OH and the other is hydrogen, Z is —NHR 10 , and R 10 is C 6 -C 10 aryl that is optionally substituted with 1 to 4 R b , then R 10 is unsubstituted phenyl or phenyl substituted with 1 R b .

7. The method of claim 6 , wherein the carbon attached to R A1 and R A2 is substituted with four different substituents, and is (R) or (S) configured.

8. The method of claim 6 , wherein the effective amount of the compound or salt reduces neuron cell death.

9. A method for treating major depression comprising: administering to a subject in need thereof an effective amount of a compound, or a pharmaceutically acceptable salt thereof, having the following formula:

wherein:
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 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 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-

Assignees

• Univ Texas

Inventors

• Mcknight Steven L
• Ready Joseph M
• Pieper Andew A
• De Brabander Jef K

Classifications

• C07D209/86

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system · CPC title

• A61P25/28

  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 title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title

• A61K31/403 Primary

  condensed with carbocyclic rings, e.g. carbazole · CPC title