Organic compounds

Patent metadata

Field	Value
Publication number	US-9242963-B2
Application number	US-201514677260-A
Country	US
Kind code	B2
Filing date	Apr 2, 2015
Priority date	Jun 27, 2008
Publication date	Jan 26, 2016
Grant date	Jan 26, 2016

Abstract

The present invention provides novel organic compounds of Formula (I): methods of use, and pharmaceutical compositions thereof.

First claim

We claim:

1. A compound of Formula I:

wherein:
R 1a is hydrogen;
R 2a is hydrogen, halogen, or hydroxy;
R 3a is hydrogen, halogen, cyano, or alkoxy;
R 4a is hydrogen or halogen;
R 5a is hydrogen or alkyl;
R 6a and R 7a are hydrogen;
R 8a is:

L is carbonyl or sulfonyl; and
R 11a , R 12a , R 13a , R 14a , and R 15a are each independently hydrogen, alkyl, cyano, halogen, alkoxy, alkoxycarbonyl, carboxylate, heteroaryl, or sulfonyl; with the proviso that at least one of R 2a -R 5a is other than hydrogen; or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 wherein the compound is selected from:
(3-Methyl-2-pyridin-3-yl-indol-1-yl)-phenyl-methanone;
1-(4-cyano-3-methyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile;
3-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid tert-butyl ester;
1-(3-Methyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile;
1-(3,4-Dimethyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile;
1-(4-Methoxy-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile
1-(3-Methoxy-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile;
1-(3,4-Dimethoxy-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile;
1-(3-Ethyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile;
1-(3,5-Dimethyl-benzoyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile;
5-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-2-methyl-benzoic acid;
3-(5-Cyano-2-pyridin-3-yl-indole-1-carbonyl)-benzoic acid; and
1-(3-Cyano-benzenesulfonyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile;
or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition, comprising
an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.

4. The pharmaceutical composition of claim 3 , further comprising a second agent.

5. The pharmaceutical composition of claim 4 , wherein said second agent is an HMG-Co-A reductase inhibitor, an angiotensin II receptor antagonist, angiotensin converting enzyme (ACE) Inhibitor, a calcium channel blocker (CCB), a dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, an endothelin antagonist, a renin inhibitor, a diuretic, an ApoA-I mimic, an anti-diabetic agent, an obesity-reducing agent, an aldosterone receptor blocker, an endothelin receptor blocker, or a CETP inhibitor.

6. A pharmaceutical composition, comprising
an effective amount of a compound according to claim 2 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or diluent.

7. The pharmaceutical composition of claim 6 , further comprising a second agent.

8. The pharmaceutical composition of claim 7 , wherein said second agent is an HMG-Co-A reductase inhibitor, an angiotensin II receptor antagonist, angiotensin converting enzyme (ACE) Inhibitor, a calcium channel blocker (CCB), a dual angiotensin converting enzyme/neutral endopeptidase (ACE/NEP) inhibitor, an endothelin antagonist, a renin inhibitor, a diuretic, an ApoA-I mimic, an anti-diabetic agent, an obesity-reducing agent, an aldosterone receptor blocker, an endothelin receptor blocker, or a CETP inhibitor.

9. A method of alleviating or ameliorating at least one symptom of an aldosterone synthase associated state in a subject, comprising administering to said subject a therapeutically effective amount of a compound according to claim 1 ; or a pharmaceutically acceptable salt thereof; wherein the aldosterone synthase associated state is hypertension.

10. A method of alleviating or ameliorating at least one symptom of an aldosterone synthase associated state in a subject, comprising administering to said subject a therapeutically effective amount of a compound of Formula I:

wherein:
R 1a is hydrogen;
R 2a is hydrogen, halogen, or hydroxy;
R 3a is hydrogen, halogen, cyano, or alkoxy;
R 4a is hydrogen or halogen;
R 5a is hydrogen or alkyl;
R 6a and R 7a are hydrogen;
R 8a is:

L is alkyl, carbonyl, sulfonyl, or —(CH 2 ) 2 —O—; and
R 11a , R 12a , R 13a , R 14a , and R 15a are each independently hydrogen, alkyl, cyano, halogen, alkoxy, or sulfonyl; with the proviso that at least one of R 2a -R 5a is other than hydrogen; or a pharmaceutically acceptable salt thereof; wherein the aldosterone associated state is hypertension.

11. The method according to claim 10 wherein the compound of Formula I is selected from:
1-Benzyl-3-methyl-2-pyridin-3-yl-1H-indole;
3-(5-Chloro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile;
3-(6-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile hydrochloride;
3-(4-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile hydrochloride;
4-(4-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile hydrochloride;
4-(6-Fluoro-3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile;
3-Fluoro-4-(3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile;
3-(3-methyl-2-pyridin-3-yl-1H-indol-1-ylmethyl)-benzonitrile;
1-(2-Fluoro-4-methoxy-benzyl)-3-methyl-2-pyridin-3-yl-1H-indole hydrochloride;
3-(3-Methyl-2-pyridin-3-yl-indole-1-carbonyl)-benzonitrile;
3-Methyl-1-(2-phenoxy-ethyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile;
1-(2-Phenoxy-ethyl)-2-pyridin-3-yl-1H-indole-5-carbonitrile;
3-Methyl-1-(2-phenoxy-ethyl)-2-pyridin-3-yl-1H-indole;
4-(3-Methyl-2-pyridin-3-yl-indole-1-carbonyl)-benzonitrile; and
3-(5-Cyano-3-methyl-2-pyridin-3-yl-indole-1-carbonyl)-benzonitrile; or a pharmaceutically acceptable salt thereof.

Assignees

• Adams Christopher Michael
• Hu Qi-Ying
• Mcquire Leslie Wighton
• Papillon Julien
• Novartis Ag

Inventors

• Adams Christopher Michael
• Hu Qi-Ying
• Mcquire Leslie Wighton
• Papillon Julien

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/08

  Vasodilators for multiple indications · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title