Quinoline derivatives useful as CB-1 inverse agonists

Patent metadata

Field	Value
Publication number	US-9266835-B2
Application number	US-201514615560-A
Country	US
Kind code	B2
Filing date	Feb 6, 2015
Priority date	Feb 27, 2014
Publication date	Feb 23, 2016
Grant date	Feb 23, 2016

Abstract

The present invention is directed to quinoline derivatives, pharmaceutical compositions containing said derivatives and their use in the treatment of disorders and conditions mediated by the CB-1 receptor; more particularly, in the treatment of disorders and conditions responsive to inverse agonism of the CB-1 receptor. For example, the compounds of the present invention are useful in the treatment of metabolic disorders.

First claim

We claim:

1. A compound of formula (A)

wherein
U 1 is selected from the group consisting of

 and

R 0 is selected from the group consisting of

 and

 provided that
when U 1 is

 , then R 0 is

 is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl or benzo[d][1,3]dioxolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, fluorinated C 1-4 alkyl, C 1-4 alkoxy, fluorinated C 1-4 alkoxy, cyano, —C(O)OH, C(O)O—C 1-4 alkyl and NR A R B ; wherein R A and R B are each independently selected from the group consisting of hydrogen, C 1-4 alkyl and —(C 2-4 alkyl)-O—(C 1-4 alkyl); provided that each substituent is bound to a carbon atom of the ring;
L 1 is selected from the group consisting of —O—, —CH 2 —,

 and

 wherein the azetidin-1,3-diyl, piperidin-1,4-diyl or piperazin-1,4-diyl group is bound to the —CH— portion of the core structure of the compounds of formula (I) at the 1-position;

 is phenyl; wherein the phenyl is optionally substituted with one or more substituents, independently selected from the group consisting of halogen, —OH, —CN, C 1-4 alkyl, fluorinated C 1-2 alkyl, C 1-4 alkoxy and fluorinated C 1-2 alkoxy;

 is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, pyridyl, benzothiazolyl or benzo[d][1,3]dioxolyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, fluorinated C 1-4 alkyl, C 1-4 alkoxy, fluorinated C 1-4 alkoxy, cyano, —C(O)OH, C(O)O—C 1-4 alkyl and NR C R D ; wherein R C and R D are each independently selected from the group consisting of hydrogen, C 1-4 alkyl and —(C 2-4 alkyl)-O—(C 1-4 alkyl); provided that each substituent is bound to a carbon atom of the ring;
R 1 is selected from the group consisting of hydrogen, halogen, —(C 1-4 alkyl)-O—(C 1-2 alkyl), —(C 1-4 alkyl)-OH, —(C 3-4 alkenyl)-O—(C 1-2 alkyl), —(C 3-4 alkenyl)-OH, —OH, —C 1-4 alkyl, —O—(C 1-4 alkyl), —O—(C 1-4 alkyl)-CO 2 H, —O—(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl), —O—(C 2-4 alkyl)-NH 2 , —O—(C 1-4 alkyl)-C(O)—NH 2 , —O—(C 2-4 alkyl)-NH—C(O)—(C 1-2 alkyl), —O—(C 2-4 alkyl)-NH—C(O)O—(C 1-4 alkyl) and —NR E R F ;
wherein R E and R F are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, —(C 1-4 alkyl)-OH, —(C 1-4 alkyl)-CO 2 H, —(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl), —(C 1-4 alkyl)-O—(C 1-4 alkyl) —(C 1-4 alkyl)-NH 2 and 1-((halogenated C 1-2 alkyl)-sulfonyl))-piperidin-4-yl; alternatively, R E and R F are taken together with the nitrogen atom to which they are bound to form a 5 to 6 membered, saturated ring selected from the group consisting of pyrrolidin-1-yl, 1-(pyrrolidin-2-one), piperidin-1-yl, piperazin-1-yl, 4-methyl-piperazin-1-yl and morpholin-4-yl;

 is selected from the group consisting of

 and

R 2 is selected from the group consisting of hydrogen, —(C 1-4 alkyl), —(C 2-4 alkyl)-O—(C 1-4 alkyl) —(C 1-4 alkyl)-CO 2 H, —(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl) and —(C 1-4 alkyl)-C(O)—NR L R M ; wherein R L and R M are each independently selected from the group consisting of hydrogen and C 1-4 alkyl;
R 3 is selected from the group consisting of hydrogen and —OR 4 ;
wherein R 4 is selected from the group consisting of —C 1-12 alkyl, -(hydroxy substituted C 2-12 alkyl), —(C 1-12 alkyl)-N 3 , —(C 2-12 alkyl)-NR J R K , —(C 2-12 alkyl)-O—(C 1-12 alkyl) —(C 2-12 alkyl)-O—(C 1-12 alkyl)-CN, —(C 2-12 alkyl)-O—(C 1-12 alkyl)-CO 2 H, —(C 2-12 alkyl)-O—(C 1-12 alkyl)-C(O)—O—(C 1-6 alkyl), —(C 2-12 alkyl)-O—(C 1-12 alkyl)-C(O)—NR J R K , —(C 1-12 alkyl)-CO 2 H, —(C 1-12 alkyl)-C(O)O—(C 1-6 alkyl), —(C 2-12 alkyl)-OC(O)—(C 1-6 alkyl), —(C 2-12 alkyl)-OC(O)—NR J R K , —(C 1-12 alkyl)-C(O)—NR J R K , —(C 2-12 alkyl)-NR J —C(O)—(C 1-6 alkyl), —(C 2-12 alkyl)-NR J —C(O)—(C 1-12 alkyl)-OH, —(C 2-12 alkyl)-NR J —SO 2 —(C 1-6 alkyl), and —SO 2 -(halogenated C 1-6 alkyl); wherein R J and R K are each independently selected from the group consisting of hydrogen, C 1-6 alkyl and hydroxy substituted C 2-6 alkyl;
provided that when R 1 is selected from the group consisting of —(C 1-4 alkyl)-O—(C 1-2 alkyl), —(C 1-4 alkyl)-OH, —(C 3-4 alkenyl)-O—(C 1-2 alkyl), —(C 3-4 alkenyl)-OH, —O—(C 1-4 alkyl)-CO 2 H, —O—(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl), —O—(C 2-4 alkyl)-NH 2 , —O—(C 1-4 alkyl)-C(O)—NH 2 , —O—(C 2-4 alkyl)-NH—C(O)—(C 1-2 alkyl), —O—(C 2-4 alkyl)-NH—C(O)O—(C 1-4 alkyl) and —NR E R F ; and wherein R E and R F are other than hydrogen or C 1-4 alkyl, then R 3 is selected from the group consisting of hydrogen and —O—C 1-4 alkyl;
provided further that when R 1 is other than hydrogen, then R 2 is hydrogen;
R 5 is selected from the group consisting of hydrogen and C 1-4 alkyl;
b is an integer from 0 to 1;
L 2 is selected from the group consisting of —CH 2 —, —CH 2 CH 2 , —CH(CH 3 )— and cycloprop-1,2-diyl;
R 6 is selected from the group consisting of azetidin-3-yl, pyrrolidin-3-yl, piperidin-4-yl, piperazin-1-yl, morpholin-4-yl, phenyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, thien-2-yl, thien-3-yl, furan-2-yl, furan-3-yl, pyrimidin-2-yl, pyrazin-2-yl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;
wherein any of the R 6 ring structures is optionally substituted with one substituent selected from the group consisting of halogen, hydroxy, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy substituted C 1-12 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, —(C 1-4 alkyl)-CO 2 H, —(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl), —(C 1-4 alkyl)-C(O)—NR P R Q , —O—(C 1-4 alkyl)-O—(C 1-4 alkyl), —O—(C 1-4 alkyl)-CO 2 H, —O—(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl), —O—(C 1-4 alkyl)-C(O)—NR P R Q , —C(O)—(C 1-4 alkyl), —C(O)-(halogenated —C(O)—(C 1-4 alkyl)-CO 2 H, —C(O)—(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl), —

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Decorte Bart
• Macielag Mark
• Greco Michael
• Zhang Yue-Mei
• Teleha Christopher

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D417/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D417/14

  containing three or more hetero rings · CPC title