Cinnoline derivatives useful as CB-1 receptor inverse agonists

Patent metadata

Field	Value
Publication number	US-9732061-B2
Application number	US-201614992464-A
Country	US
Kind code	B2
Filing date	Jan 11, 2016
Priority date	Jan 12, 2015
Publication date	Aug 15, 2017
Grant date	Aug 15, 2017

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

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, cyano, C 1-4 alkyl, fluorinated C 1-4 alkyl, hydroxy subs

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

• C07D401/04

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

• C07D417/14

  containing three or more hetero rings · CPC title