Cinnoline derivatives useful as cb-1 receptor inverse agonists

Patent metadata

Field	Value
Publication number	US-2016200719-A1
Application number	US-201614992464-A
Country	US
Kind code	A1
Filing date	Jan 11, 2016
Priority date	Jan 12, 2015
Publication date	Jul 14, 2016
Grant date	—

Abstract

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

First claim

We claim:

1 . A compound of formula (I)

wherein
R 1 is selected from the group consisting of hydrogen and hydroxy;

is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, 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 and C 1-4 alkyl; provided that each substituent is bound to a carbon atom of the ring;

is selected from the group consisting of phenyl, furyl, thienyl, thiazolyl, benzothiazolyl and benzo[d][1,3]dioxolyl;
wherein the phenyl, furyl, thienyl, thiazolyl, 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 and C 1-4 alkyl; provided that each substituent is bound to a carbon atom of the ring;
a is an integer from 0 to 1;
L 1 is selected from the group consisting of —N(R 2 )—, —N(R 2 )—CH 2 — and —N(R 2 )—CH 2 CH 2 —; wherein R 2 is selected from the group consisting of hydrogen and C 1-2 alkyl; and wherein the L 1 is bound to the cinnoline core through a nitrogen atom;

is selected from the group consisting of

(wherein X is selected from the group consisting of C and N);
provided that when

is selected from the group consisting of

then a is 0 or a is 1 and L 1 is other than —N(R 2 ) and —N(R 2 )—CH 2 —;
wherein R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, —CO 2 H, —C(O)O—(C 1-4 alkyl), —(C 1-4 alkyl)-CO 2 H, —(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl), —SO 2 —(C 1-4 alkyl) and —SO 2 -(halogenated C 1-4 alkyl);
c is an integer from 0 to 2;
each R 4 is independently selected from the group consisting of halogen, C 1-4 alkyl, halogenated C 1-2 alkyl, C 1-4 alkoxy and halogenated C 1-2 alkoxy;
wherein R 5 is selected from the group consisting of —C(O)—(C 1-4 alkyl), —C(O)O—(C 1-4 alkyl), —SO 2 —(C 1-4 alkyl) and —SO 2 -(halogenated C 1-4 alkyl); and

wherein R 6 is selected from the group consisting of C 1-4 alkyl, halogenated C 1-4 alkyl, —C(O)—NR E1 R F , —NR E —C(O)—(C 1-4 alkyl), —NR E —SO 2 —(C 1-4 alkyl), and

wherein R E and R F are each independently selected from the group consisting of hydrogen, methyl and ethyl;
b is an integer from 0 to 1;
L 2 is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, —NH—, —N(CH 3 )—, —C(O)— and —SO 2 —;
provided that when

is selected from the group consisting of

then b is 0 or b is 1 and L 2 is other than —NH— or —N(CH 3 )—;

is selected from the group consisting of phenyl, furan-2-yl, thien-2-yl;
wherein the phenyl is optionally substituted with a substituent selected from the group consisting of halogen, hydroxy, cyano, C 1-4 alkyl, halogenated C 1-4 alkyl, hydroxy substituted C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, —CO 2 H, —C(O)O—(C 1-4 alkyl), —(C 1-4 alkyl)-CO 2 H, —(C 1-4 alkyl)-C(O)O—(C 1-4 alkyl), —SO 2 —(C 1-4 alkyl) and —SO 2 -(halogenated C 1-4 alkyl); and wherein the phenyl is further optionally substituted with one to two additional substituents independently selected from the group consisting of halogen, C 1-4 alkyl, halogenated C 1-2 alkyl, C 1-4 alkoxy and halogenated C 1-2 alkoxy;
and wherein the furan-2-yl or thien-2-yl is optionally substituted with a substituent selected from the group consisting of halogen, C 1-4 alkyl, halogenated C 1-4 alkyl, C 1-4 alkoxy, halogenated C 1-4 alkoxy, —CO 2 H, —C(O)O—(C 1-4 alkyl) and —C(O)—NR G R H ; wherein R G and R H are each independently selected from the group consisting of hydrogen, methyl and ethyl;
or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof.

2 . A compound as in claim 1 , wherein
R 1 is selected from the group consisting of hydrogen and hydroxy;

is selected from the group consisting of phenyl, furyl, thienyl and thiazolyl;
wherein the phenyl, furyl, thienyl or thiazolyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, fluorinated C 1-2 alkyl, C 1-4 alkoxy, fluorinated C 1-2 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 and C 1-2 alkyl; provided that each substituent is bound to a carbon atom of the ring;

is selected from the group consisting of phenyl, furyl, thienyl and thiazolyl;
wherein the phenyl, furyl, thienyl or thiazolyl is optionally substituted with one to two substituents independently selected from the group consisting of halogen, hydroxy, C 1-4 alkyl, fluorinated C 1-2 alkyl, C 1-4 alkoxy, fluorinated C 1-2 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 and C 1-2 alkyl; provided that each substituent is bound to a carbon atom of the ring;
a is an integer from 0 to 1;
L 1 is selected from the group consisting of —N(R 2 )—, —N(R 2 )—CH 2 — and —N(R 2 )—CH 2 CH 2 —; wherein R 2 is selected from the group consisting of hydrogen and methyl; and wherein the L 1 is bound to the cinnoline core through a nitrogen atom;

is selected from the group consisting of

provided that when

then a is 0 or a is 1 and L 1 is other than —NH— and —NH—CH 2 —
wherein R 3 is selected from the group consisting of halogen, hydroxy,

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Macielag Mark Joseph
• Zhang Yue-Mei
• Decorte Bart L
• Greco Michael N
• Ludovici Donald W
• Parker Michael H

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title