US 6,888,004 B2Granted

Imidazolyl derivatives as corticotropin releasing factor inhibitors

AssigneeBristol-Myers Squibb Company

InventorsGene M. Dubowchik, Vivekananda M. Vrudhula, Dmitry Zuev, Bireshwar Dasgupta, John E. Macor

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Abstract

The present invention relates to novel heterocyclic antagonists of Formula (I) and pharmaceutical compositions comprising said antagonists of the corticotropin releasing factor receptor (“CRF receptor”) useful for the treatment of depression, anxiety, affective disorders, feeding disorders, post-traumatic stress disorder, headache, drug addiction, inflammatory disorders, drug or alcohol withdrawal symptoms and other conditions the treatment of which can be effected by the antagonism of the CRF-1 receptor.

Claims23

Dependent claims

A compound of Formula (I)

or a pharmaceutically acceptable salt or solvate thereof wherein
R1 is H, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6thioalkyl, cyano, halo, C3-7cycloalkyl, —C1-6alkylene-C3-7cycloalkyl, C2-6alkenyl or C3-6alkynyl;
R2 is C(D)NR3R4, D′—D″(R3)(R4) or CH2N R3R4
D′ is CH2 or a bond:
D″ is C, C—OH or CH
wherein
said C is attached to R3 by a single or double bond;
said C is attached to R4 by a single or double bond;
provided that
C is not attached to both R3 and R4 by double bonds;
said CH is attached to R3 and R4 by single bonds;
said C of C—OH is attached to R3 and R4 by single bonds;
D is O or S;
R3 and R4 are each independently selected from the group consisting of H, C1-6alkyl, C1-6haloalkyl, —C1-6hydroxyalkyl, —C1-4alkylene-O—C1-4alkyl, —C1-3alkylene-C1-6thioalkyl, —C2-6alkylidene-(C1-4alkoxy)2, C3-7cycloalkyl, —C1-6alkylene-C3-7cycloalkyl, C2-6alkenyl, C3-6alkynyl, —C1-6alkylene-CN, —C1-6alkylene-heterocycle and —C1-6alkylene-aryl;
wherein said aryl of said —C1-6alkylene-aryl is optionally substituted with one to three of the same or different substituents selected from the group consisting of fluoro, chloro, bromo, cyano, nitro, C1-4alkyl and C1-3alkoxy;
or
R3 and R4 together with the nitrogen to which they ace attached form a five or six-membered heterocycle,
said heterocycle optionally containing one additional heteroatom selected from the group consisting of N, S and O;
and
said heterocycle optionally substituted with one or more groups selected from the group consisting of C1-6alkyl, C1-6alkoxy, aryl, —C1-4alkylene-aryl, pyridyl and halogen;
wherein said aryl of said —C1-4alkylene-aryl is optionally substituted with one to three of the same or different substituents selected from the group consisting of fluoro, chloro, bromo, cyano, nitro and C1-3alkoxy;
X is C;
Y is C;
A is
wherein
X1 is N and is attached to X;
Y1 is N and is attached to Y;
G is
wherein
Y2 is CH, CH2, (C(O), C(S), CR5, or CHR5 and is attached to Y1;
J is a bond;
Z1 is CH, CH2, C(O), C(S), CR7, or CHR7 and is attached to Z;
wherein
R5, and R7 are each independently selected from the group consisting of —CN, —C1-4alk(en)ylene-CN, halo, C1-6alkyl, C2-6alkenyl, C3-6alkynyl, C1-6haloalkyl, aryl, —C1-4alk(en)ylene-aryl, —C1-4alk(en)ylene-heterocyclo, heterocyclo, —C1-4alk(en)ylene-amino, —C1-4alkylene-amino-C1-4alkyl, aryl-amino, -amino-(C1-6alk(en)yl)1-2, -amino-aryl, -amino-heterocyclo, 1-6alkoxy, —O— aryl and -O-heterocyclo;
and
Z is N—V, wherein V is phenyl, 2-pyridyl or 3-pyridyl substituted with two to three of the same or different substituents selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-6thioalkyl, C1-4haloalkyl, halogen, N(C1-C4alkyl)2 and CN.

33 more elements

A compound selected from the group consisting of 6-Chloro-2-methyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid cyclopropylmethyl-propyl-amide;

[6-Chloro-2-methyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclopropylmethyl-propyl-amine;
6-Chloro-2-ethyl-7-(2-bromo-4-isopropylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid N-cyclopropylmethyl-N-propylamide;
6-Chloro-2-ethyl-7-(2,4-dichlorophenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid N-cyclopropylmethyl-N-(2,2,2-trifluoroethyl)amide;
6-Chloro-2-ethyl-7-(2,4-dichlorophenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid N,N-dipropylamide;
3-[(N,N-Dipropylamino)methyl]-6-chloro-2-ethyl-7-(2,4-diclorophenyl)-7H-imidazo[1,2-a]imidazole;
3-[(N-Cyclopropylmethyl-N-(2,2,2-trifluoroethyl)amino)methyl]-6-chloro-2-ethyl-7-(2,4-diclorophenyl)-7H-imidazo[1,2-a]imidazole;
6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid N-cyclopropylmethyl-N-propylamide;
6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid N-butyl-N-ethylamide;
6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid N,N-dipropylamide;
6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid N,N-diethylamide;
3-[(N-Butyl-N-ethylamino)methyl]-6-chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole;
6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid N,N-diallylamide;
6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid N-cyclopropylmethyl-N-(2,2,2-trifluoroethyl)amide;
6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid N-ethyl-N-pyridin-4-yl)methylamide;
6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid N-cyclopropylmethyl-N-ethylamide;
3-[(N-Cyclopropylmethyl-N-ethylamino)methyl-6-chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole;
6-Chloro-2-ethyl-7-(2,4,6-trimethylphenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid (3,5-dimethylpiperidin-1-yl)amide;
6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazole-3-carboxylic acid cyclopropylmethyl-propyl-amide;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclopropylmethyl-propyl-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclopropylmethyl-(2,2,2-trifluoro-ethyl)-amine;
Benzyl-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo(1,2-a]imidazol-3-ylmethyl]-methyl-amine;
6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-methyl-phenethyl-amine;
Benzyl-6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-ethyl-amine;
Butyl-6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-methyl-amine;
Benzyl-butyl-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl)-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-ethyl-(2-methyl-allyl)-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl-(4-nitro-benzyl)-propyl-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-furan-2-ylmethyl-methyl-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(3,4-dichloro-benzyl)-ethyl-amine;
6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazo-3-ylmethyl]-cyclopropylmethyl-(2,2,3,3,3-pentafluoro-propyl)-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclopropylmethyl-ethyl-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclobutylmethyl-(2,2,2-trifluoro-ethyl)-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-propyl-(3,3,3-trifluoro-propyl)-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-propyl-(2,2,2-trifluoro-ethyl)-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(2,2,3,3,3-pentafluoro-propyl)-propyl-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-phenethyl-(2,2,2-trifluoro-ethyl)-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-phenethyl-propyl-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-ethyl-phenethyl-amine;
Benzyl-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(2-cyclopropyl-ethyl)-propyl-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(2-cyclopropyl-ethyl)-ethyl-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(2-cyclopropyl-ethyl)-(3,3,3-trifluoro-propyl)-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(2-cyclopropyl-ethyl)-(2,2,2-trifluoro-ethyl)-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(4-fluoro-benzyl)-(2,2,2-trifluoro-ethyl)-amine;
-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(4-fluoro-benzyl)-(3,3,3-trifluoro-propyl)-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(4-fluoro-benzyl)-propyl-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclobutymethyl-propyl-amine;
(4-Chloro-benzyl)-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(3,3,3-trifluoro-propyl)-amine;
(4-Chloro-benzyl)-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-propyl-amine;
Benzyl-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-propyl-amine;
Allyl-[6-chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-propyl-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(3-fluoro-benzyl)-propyl-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-cyclobutylmethyl-ethyl-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(2-methoxy-ethyl)-propyl-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-(3-fluoro-benzyl)-(3,3,3-trifluoro-propyl)-amine;
[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-dipropyl-amine;
Diallyl-[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-amine;
and
Butyl-[6-Chloro-2-trifluoromethyl-7-(2,4,6-trimethyl-phenyl)-7H-imidazo[1,2-a]imidazol-3-ylmethyl]-ethyl-amine or a pharmaceutically acceptable salt or solvate thereof.

56 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/044,183Filed 11 Jan 2002 · us provisional application
Priority: 26 Jan 2001
Published: US 2002/0183375 A15 Dec 2002
Granted: 3 May 2005
Term ends: Not estimatedThe source records don’t support an estimate.

Classification30 codes

C07D 471/14
In which the condensed system contains three hetero rings: ortho-condensed systems
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/12
Drugs for disorders of the alimentary tract or the digestive system: antidiarrhoeals

Family

Application60/264,570Us provisional application · filed 26 Jan 2001
US 2002/0183375 A1Pre-grant publication · published 5 Dec 2002
US 6,888,004 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A compound of Formula (I)

or a pharmaceutically acceptable salt or solvate thereof wherein
R1 is H, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C1-6thioalkyl, cyano, halo, C3-7cycloalkyl, —C1-6alkylene-C3-7cycloalkyl, C2-6alkenyl or C3-6alkynyl;
R2 is C(D)NR3R4, D′—D″(R3)(R4) or CH2N R3R4
D′ is CH2 or a bond:
D″ is C, C—OH or CH
wherein
said C is attached to R3 by a single or double bond;
said C is attached to R4 by a single or double bond;
provided that
C is not attached to both R3 and R4 by double bonds;
said CH is attached to R3 and R4 by single bonds;
said C of C—OH is attached to R3 and R4 by single bonds;
D is O or S;
R3 and R4 are each independently selected from the group consisting of H, C1-6alkyl, C1-6haloalkyl, —C1-6hydroxyalkyl, —C1-4alkylene-O—C1-4alkyl, —C1-3alkylene-C1-6thioalkyl, —C2-6alkylidene-(C1-4alkoxy)2, C3-7cycloalkyl, —C1-6alkylene-C3-7cycloalkyl, C2-6alkenyl, C3-6alkynyl, —C1-6alkylene-CN, —C1-6alkylene-heterocycle and —C1-6alkylene-aryl;
wherein said aryl of said —C1-6alkylene-aryl is optionally substituted with one to three of the same or different substituents selected from the group consisting of fluoro, chloro, bromo, cyano, nitro, C1-4alkyl and C1-3alkoxy;
or
R3 and R4 together with the nitrogen to which they ace attached form a five or six-membered heterocycle,
said heterocycle optionally containing one additional heteroatom selected from the group consisting of N, S and O;
and
said heterocycle optionally substituted with one or more groups selected from the group consisting of C1-6alkyl, C1-6alkoxy, aryl, —C1-4alkylene-aryl, pyridyl and halogen;
wherein said aryl of said —C1-4alkylene-aryl is optionally substituted with one to three of the same or different substituents selected from the group consisting of fluoro, chloro, bromo, cyano, nitro and C1-3alkoxy;
X is C;
Y is C;
A is
wherein
X1 is N and is attached to X;
Y1 is N and is attached to Y;
G is
wherein
Y2 is CH, CH2, (C(O), C(S), CR5, or CHR5 and is attached to Y1;
J is a bond;
Z1 is CH, CH2, C(O), C(S), CR7, or CHR7 and is attached to Z;
wherein
R5, and R7 are each independently selected from the group consisting of —CN, —C1-4alk(en)ylene-CN, halo, C1-6alkyl, C2-6alkenyl, C3-6alkynyl, C1-6haloalkyl, aryl, —C1-4alk(en)ylene-aryl, —C1-4alk(en)ylene-heterocyclo, heterocyclo, —C1-4alk(en)ylene-amino, —C1-4alkylene-amino-C1-4alkyl, aryl-amino, -amino-(C1-6alk(en)yl)1-2, -amino-aryl, -amino-heterocyclo, 1-6alkoxy, —O— aryl and -O-heterocyclo;
and
Z is N—V, wherein V is phenyl, 2-pyridyl or 3-pyridyl substituted with two to three of the same or different substituents selected from the group consisting of C1-4alkyl, C1-4alkoxy, C1-6thioalkyl, C1-4haloalkyl, halogen, N(C1-C4alkyl)2 and CN.

33 more elements

Facts

Application

10/044,183Filed 11 Jan 2002 · us provisional application

Priority

26 Jan 2001

Published

US 2002/0183375 A15 Dec 2002

Granted

3 May 2005

Term ends

Not estimatedThe source records don’t support an estimate.

Classification30 codes

C07D 471/14
In which the condensed system contains three hetero rings: ortho-condensed systems
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/12
Drugs for disorders of the alimentary tract or the digestive system: antidiarrhoeals