Pro-Neurogenic Compounds

Patent metadata

Field	Value
Publication number	US-2016206594-A1
Application number	US-201614996596-A
Country	US
Kind code	A1
Filing date	Jan 15, 2016
Priority date	Jan 9, 2009
Publication date	Jul 21, 2016
Grant date	—

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.

First claim

1 . A compound for promoting post-natal mammalian neurogenesis and/or reducing neuronal cell death in a subject in need thereof, the compound having formula (I) or a pharmaceutically acceptable salt thereof:

wherein:
each of R 1 , R 2 , R 3 , and R 4 is independently selected from hydrogen, halo, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and cyano;
R and R′ are defined according to (1), (2), or (3) below:
(1) R and R′ together with C 2 and C 3 , respectively, form a fused phenyl ring having formula (II):

wherein each of R 5 , R 6 , R 7 , and R 8 is independently selected from hydrogen, halo, C 1 -C 6 alkoxy, C 1 -C 6 alkyl, and cyano;
(2) R and R′ together with C 2 and C 3 , respectively, form a fused heterocyclic ring containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(C 1 -C 6 alkyl), NC(O)(C 1 -C 6 alkyl), O, and S; or
(3) R and R′ together with C 2 and C 3 , respectively, form a fused heteroaryl ring containing from 5-6 ring atoms, wherein from 1-2 of the ring atoms is independently selected from N, NH, N(C 1 -C 3 alkyl), O, and S; and wherein said heteroaryl ring is optionally substituted with from 1-3 independently selected R b ;
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 halo, hydrogen or C 1 -C 3 alkyl;
Z is:
(i) —NR 10 R 11 ;
(ii) —OR 12 ; or
(iii) —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;
each of R 10 and R 1 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 ;
wherein one of R 10 and R 1 is (b) or (c);

R 12 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 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 1 -C 3 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 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 ; 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) 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 ; 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 3 C(O)—, and Cy is a saturated, partially unsaturated or aromatic carbocyclic or heterocyclic ring system.

2 . The compound or salt of claim 1 , wherein Z is —NR 10 R 11 .

3 . The compound or salt of claim 2 , wherein R and R′ together with C 2 and C 3 , respectively, form a fused phenyl ring having formula (II):

4 . The compound or salt of claim 3 , wherein R 3 is halo, C 1 -C 6 alkoxy, or cyano, and each of R 1 , R 2 , R 3 , and R 4 is hydrogen.

5 . The compound or salt of claim 4 , wherein R 6 is halo, C 1 -C 6 alkoxy, or cyano.

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

8 . The compound or salt of claim 5 , wherein one of R 10 and R 11 is unsubstituted phenyl, and the other is hydrogen.

9 . The compound or salt of claim 5 , wherein one of R 10 and R 11 is phenyl that is substituted with 1 R b , and the other is hydrogen.

10 . The compound or salt of claim 9 , wherein R b is C 1 -C 6 alkoxy.

11 . The compound or salt of claim 9 , wherein R b is OCH 3 .

12 . The compound or salt of claim 5 , wherein one of R 10 and R 11 is 3-methoxyphenyl, and the other is hydrogen.

13 . The compound or salt of claim 1 , wherein Z is —OR 12 .

14 . The compound or salt of claim 13 , wherein R 12 is C 6 -C 10 aryl.

15 . The compound or salt of claim 14 , wherein R and R′ together with C 2 and C 3 , respectively, form a fused phenyl ring having formula (II):

16 . The compound or salt of claim 15 , wherein R 3 is halo, C 1 -C 6 alkoxy, or cyano, and each of R 1 , R 2 , R 3 , and R 4 is hydrogen.

17 . The compound or salt of claim 16 , wherein R 6 is halo, C 1 -C 6 alkoxy, or cyano.

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

19 . The compound or salt of claim 1 , 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; 5-((3,6-dibromo-9H-carbazol-9-yl)methyl)-3-(3-methoxyphenyl)-oxazolidin-2-one; 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-(5-bromo-2,3-dimethyl-1H-indol-1-yl)-3-(phenylamino)propan-2-ol; 1-(3,6-Di

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