Azetidine compounds, compositions and methods of use

Patent metadata

Field	Value
Publication number	US-9139593-B2
Application number	US-201414328033-A
Country	US
Kind code	B2
Filing date	Jul 10, 2014
Priority date	Nov 1, 2011
Publication date	Sep 22, 2015
Grant date	Sep 22, 2015

Abstract

Provided are compounds of Formula I,

R 1 -L 1 -A-L 2 -R 2   (I),

and stereoisomers, tautomers and pharmaceutically acceptable salts thereof, wherein A, L 1 , L 2 , R 1 and R 2 are defined herein. The present invention also provides a pharmaceutical composition and methods of using such compounds. The compounds are useful for therapy and/or prophylaxis in a patient, and in particular to inhibitors of Soluble Epoxide Hydrolase (sEH).

First claim

The invention claimed is:

1. A compound of Formula (I):
R 1 -L 1 -A-L 2 -R 2   (I)

wherein
A is selected from the group consisting of Ia, and Ic:

wherein
X is N or CH;
Y is NH or CH 2 ; and

wherein
L 1 is selected from the group consisting of a bond, —(CH 2 ) 1-3 —, —NH—(CH 2 ) 0-3 —C(O)—, —(CH 2 ) 0-3 —C(O)—, —(CH 2 ) 0-3 —SO 2 — and —(CH 2 ) 0-3 —NR 3 —C(O)—;
L 2 is selected from the group consisting of a bond, —(CH 2 ) 1-3 —, —(CH 2 ) 0-3 —C(O)—NH—, —NH—(CH 2 ) 0-3 —C(O)—NH—, —(CH 2 ) 0-3 —C(O)—, —(CH 2 ) 0-3 —SO 2 — and —(CH 2 ) 0-3 —NR 3 —C(O)—;
R 1 is selected from the group consisting of phenyl, 5- or 6-membered heteroaryl, adamantyl and —(CH 2 ) 1-3 -phenyl, wherein said phenyl, heteroaryl or adamantyl is unsubstituted or substituted by one to three R 5 groups;
R 2 is selected from the group consisting of phenyl, 5- or 6-membered heteroaryl and —(CH 2 ) 1-3 -phenyl, wherein said phenyl or heteroaryl is unsubstituted or substituted by one to three R 5 groups;
R 3 is hydrogen or lower alkyl;
R 4 is hydrogen or lower alkyl; and
R 5 is selected from the group consisting of halogen, lower alkyl, lower haloalkyl, lower haloalkoxy, and —C(O)OR 4 , or
a stereoisomer, tautomer or pharmaceutically acceptable salt thereof,
with the proviso that said compound is not 2,6-bis[(4-methylphenyl)sulfonyl]-2,6-diazaspiro[3,3]heptane or 2-phenyl-6-(phenylmethyl)-2,6-diazaspiro[3,3]heptane,
and the further provisos that when L 2 is —C(O)—NH—, L 1 is not —CH 2 —; when L 2 is —CH 2 —, L 1 is not a bond; when L 2 is —SO 2 —, L 1 is not —CH 2 —; and L 1 and L 2 are different.

2. The compound according to claim 1 selected from the group consisting of:
6-Benzoyl-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid 2,4-dichloro-benzylamide;
4-[6-(2,4-Dichloro-benzylcarbamoyl)-2,6-diaza-spiro[3.3]hept-2-yl]-benzoic acid;
6-(2,4-Dichloro-benzenesulfonyl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid benzylamide;
6-Pyrimidin-2-yl-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid 2,4-dichloro-benzylamide;
rac-6-Benzoyl-3,6-diaza-bicyclo[3.2.0]heptane-3-carboxylic acid 2,4-dichloro-benzylamide;
rac-6-Benzenesulfonyl-3,6-diaza-bicyclo[3.2.0]heptane-3-carboxylic acid 2,4-dichloro-benzylamide;
rac-6-Pyrimidin-2-yl-3,6-diaza-bicyclo[3.2.0]heptane-3-carboxylic acid 2,4-dichloro-benzylamide; and
rac-4-[3-(2,4-Dichloro-benzylcarbamoyl)-3,6-diaza-bicyclo[3.2.0]hept-6-yl]-benzoic acid, and
pharmaceutically acceptable salts thereof.

3. The compound according to claim 1 selected from the group consisting of:
6-Benzoyl-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid 2,4-dichloro-benzylamide;
6-(2,4-Dichloro-benzenesulfonyl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid benzylamide; [3.3]heptane-5-carboxamide;
rac-6-Benzoyl-3,6-diaza-bicyclo[3.2.0]heptane-3-carboxylic acid 2,4-dichloro-benzylamide; and
rac-6-Benzenesulfonyl-3,6-diaza-bicyclo[3.2.0]heptane-3-carboxylic acid 2,4-dichloro-benzylamide;
and pharmaceutically acceptable salts thereof.

4. The compound according to claim 1 wherein said compound is a compound according to formula IAa,

wherein
L 1 is selected from the group consisting of a bond, —(CH 2 ) 0-3 —C(O)—, and —(CH 2 ) 0-3 —SO 2 —;
L 2 is —C(O)—(CH 2 ) 0-3 —NH—;
R 1 is phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or heteroaryl is unsubstituted or substituted by one R 5 group;
R 2 is phenyl or —(CH 2 ) 1-3 -phenyl, wherein said phenyl is unsubstituted or substituted by two R 5 groups;
R 4 is hydrogen; and
R 5 is —C(O)OR 4 ; or
a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

5. The compound of according to claim 4 selected from the group consisting of:
6-Benzoyl-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid 2,4-dichloro-benzylamide;
4-[6-(2,4-Dichloro-benzylcarbamoyl)-2,6-diaza-spiro[3.3]hept-2-yl]-benzoic acid;
6-(2,4-Dichloro-benzenesulfonyl)-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid benzylamide;
6-Pyrimidin-2-yl-2,6-diaza-spiro[3.3]heptane-2-carboxylic acid 2,4-dichloro-benzylamide; and
pharmaceutically acceptable salts thereof.

6. The compound according to claim 1 wherein said compound is a compound according to Formula IAc,

wherein:
L 1 is selected from the group consisting of a bond, —(CH 2 ) 0-3 —C(O)— and —(CH 2 ) 0-3 —SO 2 —;
L 2 is —(CH 2 ) 1-3 —;
R 1 is phenyl or 5- or 6-membered heteroaryl, wherein said phenyl or heteroaryl is unsubstituted or substituted by one R 5 group;
R 2 is phenyl, wherein said phenyl is unsubstituted or substituted by two R 5 groups;
R 4 is hydrogen or lower alkyl; and
R 5 is halogen or —C(O)OR 4 , or
a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

7. The compound according to claim 6 selected from the group consisting of:
rac-6-Benzoyl-3,6-diaza-bicyclo[3.2.0]heptane-3-carboxylic acid 2,4-dichloro-benzylamide;
rac-6-Benzenesulfonyl-3,6-diaza-bicyclo[3.2.0]heptane-3-carboxylic acid 2,4-dichloro-benzylamide;
rac-6-Pyrimidin-2-yl-3,6-diaza-bicyclo[3.2.0]heptane-3-carboxylic acid 2,4-dichloro-benzylamide;
rac-4-[3-(2,4-Dichloro-benzylcarbamoyl)-3,6-diaza-bicyclo[3.2.0]hept-6-yl]-benzoic acid; and
pharmaceutically acceptable salts thereof.

8. A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable carrier.

Assignees

• Hoffmann La Roche
• Hoffmann La Roche

Inventors

• Ceccarelli Simona M
• Guerot Carine
• Knust Henner

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title