Substituted aza-bicyclic imidazole derivatives useful as trpm8 receptor modulators

Patent metadata

Field	Value
Publication number	US-2016304518-A1
Application number	US-201615196262-A
Country	US
Kind code	A1
Filing date	Jun 29, 2016
Priority date	Mar 5, 2010
Publication date	Oct 20, 2016
Grant date	—

Abstract

The present invention is directed to substituted aza-bicyclic imidazole derivatives, pharmaceutical compositions containing them and their use in the treatment of disorders and conditions modulated by TRP M8, including for example, inflammatory pain, inflammatory hyperalgesia, inflammatory hypersensitivity condition, neuropathic pain, neuropathic cold allodynia, inflammatory somatic hyperalgesia, inflammatory visceral hyperalgesia, cardiovascular disease aggravated by cold and pulmonary disease aggravated by cold.

First claim

1 . A compound of formula (I)

wherein
R 1 is selected from the group consisting of hydrogen, fluoro, chloro, fluorinated C 1-4 alkyl and fluorinated C 1-4 alkoxy;
R 2 is selected from the group consisting of hydrogen, chloro, bromo, C 1-4 alkyl, fluorinated C 1-4 alkyl and fluorinated C 1-4 alkoxy; provided that when R 2 is other than hydrogen, then

is selected from the group consisting of

wherein R 3 is selected from the group consisting of hydrogen, chloro, cyano, C 1-4 alkyl, fluorinated C 1-4 alkyl, C 1-4 alkoxy, fluorinated C 1-4 alkoxy, —O—(CH 2 ) 2 —OH, —O—CH 2 —CO 2 H, —O—(CH 2 ) 2 —O—(C 1-4 alkyl), —O—CH 2 -(fluorinated C 1-2 alkyl), —O—(CH 2 ) 2 —NR R and —NR A R B ;
wherein R and R B are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;
alternatively R A and R B are taken together with the nitrogen atom to which they are bound to form a ring structure selected form the group consisting of pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperidin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl;
Q is an optionally substituted ring structure selected from the group consisting of formulas (a) through (h)

wherein R is C 1-4 alkyl; R 6 is selected from the group consisting of C 1-4 alkyl and fluorinated C 1-4 alkyl; and R 7 is selected from the group consisting of hydrogen, chloro, fluoro, cyano, C 1-4 alkyl and C 1-4 alkoxy;

wherein R 8 and R 9 are each independently selected from the group consisting of C 1-4 alkyl;

wherein R is C 1-4 alkyl; and R 11 is selected from the group consisting of hydrogen and cyano;

wherein R 12 and R 13 are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;

wherein R 14 is C 1-4 alkyl;

wherein R 15 is C 1-4 alkyl; and R 16 is selected from the group consisting of hydrogen, chloro and bromo; and

wherein R 17 is C 1-4 alkyl;
or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.

2 . A compound as in claim 1 , wherein
R 1 is selected from the group consisting of hydrogen, fluoro, chloro, fluorinated C 1-2 alkyl and fluorinated C 1-2 alkoxy; R 2 is selected from the group consisting of hydrogen, chloro, trifluoromethyl and trifluoromethoxy; provided that when R 2 is other than hydrogen, then

is selected from the group consisting of

wherein R 3 is selected from the group consisting of hydrogen, chloro, cyano, C 1-2 alkyl, fluorinated C 1-2 alkyl, C 1-4 alkoxy, fluorinated C 1-2 alkoxy, —O—(CH 2 ) 2 —OH, —O—CH 2 —CO 2 H, —O—(CH 2 ) 2 —O—(C 1-4 alkyl), —O—CH 2 -(fluorinated C 1-2 alkyl),—O—(CH 2 ) 2 —NR A R B and —NR A R B ;
wherein R and R B are each independently selected from the group consisting of hydrogen and C 1-2 alkyl; alternatively R A and R B are taken together with the nitrogen atom to which they are bound to form a ring structure selected from the group consisting of pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl;
Q is an optionally substituted ring structure selected from the group consisting of formulas (a) through (h)

wherein R 5 is C 1-4 alkyl; R 6 is selected from the group consisting of C 1-4 alkyl and fluorinated C 1-4 alkyl; and R 7 is selected from the group consisting of hydrogen, chloro, fluoro, cyano, C 1-2 alkyl and C 1-2 alkoxy;

wherein R 8 and R 9 are each independently selected from the group consisting of C 1-4 alkyl;

wherein R 10 is C 1-4 alkyl; and R 11 is selected from the group consisting of hydrogen and cyano;

wherein R 12 and R 13 are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;

wherein R 14 is selected from the group consisting of C 1-4 alkyl;

wherein R 15 is C 1-4 alkyl; and R 16 is selected from the group consisting of hydrogen, chloro and bromo; and

wherein R 17 is C 1-2 alkyl;
or a solvate, hydrate, tautomer or pharmaceutically acceptable salt thereof.

3 . A compound as in claim 2 , wherein
R 1 is selected from the group consisting of hydrogen, chloro, fluoro, trifluoromethyl and trifluoromethoxy; R 2 is selected from the group consisting of hydrogen and chloro; provided that when R 2 is chloro, then

is selected from the group consisting of

wherein R 3 is selected form the group consisting of hydrogen, chloro, cyano, C 1-2 alkyl, trifluoromethyl, C 1-4 alkoxy, —O—(CH 2 ) 2 —OH, —O—CH 2 —CO 2 H, —O—(CH 2 ) 2 —O—(C 1-2 alkyl), O—CH 2 -(fluorinated C 1-2 alkyl), —O—(CH 2 ) 2 —NR A R B , pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl;
and wherein R A and R B are each an independently selected C 1-2 alkyl; alternatively R A and R B are taken together with the nitrogen atom to which they are bound to form a ring structure selected from the group consisting of pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl;
Q is an optionally substituted ring structure selected from the group consisting of formulas (a) through (h)

wherein R 5 is C 1-4 alkyl; R 6 is selected from the group consisting of C 1-4 alkyl and fluorinated C 1-4 alkyl; and R 7 is selected from the group consisting of hydrogen, chloro, fluoro, cyano, C 1-2 alkyl and C 1-2 alkoxy;

wherein R 8 and R 9 are each in

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Player Mark R
• CALVO Raul
• Chen Jinsheng
• Meegalla Sanath
• Parks Daniel J
• Parsons William J
• Ballentine Scott
• Branum Shawn

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title