Cyclohexyl-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulenes as V1a antagonists

Patent metadata

Field	Value
Publication number	US-9346824-B2
Application number	US-201414245126-A
Country	US
Kind code	B2
Filing date	Apr 4, 2014
Priority date	Oct 5, 2011
Publication date	May 24, 2016
Grant date	May 24, 2016

Abstract

The present invention provides 4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulenes, which act as V1a receptor modulators, and in particular as V1a receptor antagonists, their manufacture, pharmaceutical compositions containing them and their use as medicaments. The active compounds of the present invention are useful as therapeutics acting peripherally and centrally in the conditions of dysmenorrhea, male or female sexual dysfunction, hypertension, chronic heart failure, inappropriate secretion of vasopressin, liver cirrhosis, nephrotic syndrome, anxiety, depressive disorders, obsessive compulsive disorder, autistic spectrum disorders, schizophrenia, and aggressive behavior.

First claim

The invention claimed is:

1. A compound of formula I,

wherein
R 1 is halogen;
R 2 is selected from the group consisting of
i) heteroaryl, unsubstituted or substituted by 1 to 3 substituents individually selected from the group consisting of OH, halogen, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, halogen-C 1-6 -alkyl, halogen-C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl and hydroxy-C 1-6 -alkyl;
ii) aryl, unsubstituted or substituted by 1 to 3 substituents individually selected from the group consisting of OH, halogen, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, halogen-C 1-6 -alkyl, halogen-C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl and hydroxy-C 1-6 -alkyl;
iii) C 3-7 -cycloalkyl, unsubstituted or substituted by 1 to 3 substituents individually selected from the group consisting of OH, halogen, cyano, C 1-6 -alkyl, C 1-6 -alkoxy, halogen-C 1-6 -alkyl, halogen-C 1-6 -alkoxy, C 1-6 -alkoxy-C 1-6 -alkyl and hydroxy-C 1-6 -alkyl; and
iv) C 1-6 -alkyl, unsubstituted or substituted by 1 to 3 substituents individually selected from the group consisting of OH, halogen, cyano, C 3-7 -cycloalkyl, C 1-6 -alkoxy and halogen-C 1-6 -alkoxy;

or pharmaceutically acceptable salts thereof.

2. A compound according to claim 1 , wherein R 1 is chloro.

3. A compound of claim 1 , wherein R 2 is selected from the group consisting of unsubstituted heteroaryl, heteroaryl substituted by halogen or C 1-6 -alkyl, unsubstituted C 1-6 -alkyl and C 1-6 -alkyl substituted by halogen and C 3-7 -cycloalkyl.

4. A compound of claim 1 , wherein R 2 is selected from the group consisting of 3-fluoro-pyridinyl, 4-benzo[d]isothiazolyl, 5-methyl-[1,2,4]oxadiazolyl, 5-methyl-isoxazolyl, 4,5,6,7-tetrahydro-benzo[c]isoxazolyl, 4, 5, 6,7-tetrahydro-1H-indazolyl, isobutyl, cyclopentyl-difluoro-methyl and 4-benzo[d]isoxazolyl.

5. A compound of claim 1 , selected from the group consisting of
8-Chloro-1-[4-(3-fluoro-pyridin-2-yl)-cyclohexyl]-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene,
1-(4-Benzo[d]isothiazol-3-yl-cyclohexyl)-8-chloro-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene,
8-Chloro-1-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)-cyclohexyl]-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene,
8-Chloro-1-[4-(5-methyl-isoxazol-3-yl)-cyclohexyl]-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene,
8-Chloro-1-[4-(4,5,6,7-tetrahydro-benzo[c]isoxazol-3-yl)-cyclohexyl]-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene,
8-Chloro-1-[4-(4,5,6,7-tetrahydro-1H-indazol-3-yl)-cyclohexyl]-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene,
8-Chloro-1-(4-isobutyl-cyclohexyl)-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene,
8-Chloro-1-[4-(cyclopentyl-difluoro-methyl)-cyclohexyl]-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene, and
1-(4-Benzo[d]isoxazol-3-yl-cyclohexyl)-8-chloro-4H,6H-5-oxa-2,3,10b-triaza-benzo[e]azulene,
or pharmaceutically acceptable salts thereof.

6. A process for preparing a compound of claim 1 , which process comprises reacting a compound of formula II with a compound of formula III to a compound of formula I

wherein R 1 and R 2 are as defined in claim 1 .

7. A compound prepared by a process as defined in claim 6 .

8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable auxiliary substance.

Assignees

• Hoffmann La Roche
• Hoffmann La Roche

Inventors

• Dolente Cosimo
• Schnider Patrick

Classifications

• A61P5/24

  of the sex hormones · CPC title

• A61P43/00

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

• A61P9/04

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

• A61P9/12

  Antihypertensives · CPC title

• A61P9/08

  Vasodilators for multiple indications · CPC title