Pro-neurogenic compounds

Patent metadata

Field	Value
Publication number	US-9278923-B2
Application number	US-201314100515-A
Country	US
Kind code	B2
Filing date	Dec 9, 2013
Priority date	Jan 9, 2009
Publication date	Mar 8, 2016
Grant date	Mar 8, 2016

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

What is claimed is:

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

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, 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 CH 2 ;.
A is CR A1 R A2 , wherein one of R A1 and R A2 is halo or OR 9 , and the other of R A1 and R A2 is hydrogen, halo, OR 9 or C 1 -C 3 alkyl; wherein R 9 is C 1 -C 3 alkyl that is optionally substituted with hydroxyl or C 1 -C 3 alkoxy;
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 ;
(c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S, wherein said heteroaryl 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 1-3R d ;
(e) —C(O)(C 1 -C 6 alkyl), —C(O)(C 1 -C 6 haloalkyl), or —C(O)O(C 1 -C 6 alkyl);
(f) C 2 -C 6 alkenyl or C 2 -C 6 alkenyl;
wherein one of R 10 and R 11 is (b) or (c);

R 12 1s:
(i) C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ; or
(ii) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 R b ;

R 13 is:
(i) C 6 -C 10 aryl that is optionally substituted with from 1-4 R b ; or
(ii) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C 13 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with from 1-4 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; 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);
wherein the alkyl portion of each is optionally substituted with from 1-3 independently selected R e ;
(bb) halo; hydroxyl; cyano; nitro; —NH 2 ; azido; sulfhydryl; C 2 -C 6 alkenyl; C 2 -C 6 alkenyl;
—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; and
R e 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; —NH 2 ; —NH(C 1 -C 6 alkyl); N(C 1 -C 6 alkyl) 2 ;—NHC(O)(C 1 -C 6 alkyl); cyano; —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) 22 n-C 6 alkyl); —SO 2 NH 2 ; —SO 2 NH(C 1 -C 6 alkyl); -SO 2 N(C 1 -C 6 alkyl) 2 ; and L 3 -(C 1 -C 6 alkylene)-Cy, where in L 3 is a —O—, —NH—, —NCH 3 -, —C(O)—, —C(O)NH—, —C(O)NCH 3 -, —NHC(O)—, or —NCH 1 C(O)—, and Cy is a saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring system.

2. The method of claim 1 , wherein the disease, disorder, or condition is selected from the group consisting of:
schizophrenia, major depression, bipolar disorder, normal aging, epilepsy, traumatic brain injury, post-traumatic stress disorder, Parkinson's disease, Alzheimer's disease, Down syndrome, spinocerebellar ataxia, amyotrophic lateral sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, and abuse of a neuro-active drug.

3. The method of claim 1 , wherein R 3 is halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , or nitro; and each of R 1 , R 2 , and R 4 is hydrogen.

4. The method of claim 3 , wherein R 6 is halo, hydroxyl, sulfhydryl, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cyano, —NH 2 , —NH(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl) 2 , or nitro; and each of R 5 , R 7 , and R 8 is hydrogen.

5. The method of claim 1 , wherein Z is —NR 10 R 11 .

6. The method of claim 5 , wherein one of R 10 and R 11 is (b) C 6 -C 10 aryl that is optionally substituted with from 1-4 R b , and the other is hydrogen or C 1 -C 6 alkyl.

7. The method of claim 5 , wherein one of R 10 and R 11 is (c) heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S, wherein said heteroaryl is optionally substituted with from 1-4 R b ; and the other is hydrogen or C 1 -C 6 alkyl.

8. The method of claim 1 , wherein Z is —OR 12 .

9. The method of claim 8 , wherein R 12 is C 6 -C 10 aryl that is optionally substituted with 1 R b .

10. The method of claim 1 , wherein R 12 is heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with 1 R b .

11. The method of claim 1 , wherein Z is —S(O) n R 13 , wherein n is 0 or 2.

12. The method of claim 11 , wherein R 13 is C 6 -C, 10 aryl that is optionally substituted with 1 R b .

13. The method of claim 11 , wherein R 13 is heteroaryl containing from 5-14 ring atoms, wherein from 1-6 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; and wherein said heteroaryl is optionally substituted with 1 R b .

14. 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-methoxypropyl)-3-methoxyaniline;
N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-3-methoxy-N-methylaniline; and
N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2,2-difluoropropyl)-3-methoxyaniline.

15. A method of treating a disease, disorder, or condition associated with insufficient neurogenesis or unwanted neuronal cell death in a subject in need thereof, comprising administering a

Assignees

• Univ Texas

Inventors

• Mcknight Steven L
• Ready Joseph M
• Pieper Andrew 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