US 8,410,142 B2Granted

Bipyridine carboxamide orexin receptor antagonists

AssigneeMerck Sharp & Dohme Corp.

InventorsPaul J. Coleman, Swati P. Mercer, Anthony J. Roecker

Life of this patent

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Abstract

The present invention is directed to bipyridyl carboxamide compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

Claims18

Dependent claims

A compound of the formula I:

A1 is selected from the group consisting of phenyl or naphthyl;
A2 is selected from the group consisting of phenyl or naphthyl;
R1a, R1b and R1c are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4)—(C═O)m—On—C1-6alkyl, where m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,
(5)—(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,
(6)—(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,
(7)—(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R13,
(8)—(C═O)m—On-phenyl or —(C═O)m—On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R13,
(9)—(C═O)m—NR10R11, wherein R10 and R11 are independently selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkyl, which is unsubstituted or substituted with R13,
(c) C3-6alkenyl, which is unsubstituted or substituted with R13,
(d) C3-6alkynyl, which is unsubstituted or substituted with R13,
(e) C3-6cycloalkyl which is unsubstituted or substituted with R13, and
(f) phenyl, which is unsubstituted or substituted with R13,
(10)—S(O)2—NR10R11,
(11)—S(O)q—R12, where q is 0, 1 or 2 and where R12 is selected from the definitions of R10 and R11,
(12)—CO2H,
(13)—CN, and
(14)—NO2;
R2a, R2b and R2c are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4)—(C═O)m—On—C1-6alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,
(5)—(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,
(6)—(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,
(7)—(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R13,
(8)—(C═O)m—On-phenyl or —(C═O)m—On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R13,
(9)—(C═O)m—NR10R11,
(10)—S(O)2—NR10R11,
(11)—S(O)q—R12,
(12)—CO2H,
(13)—CN, and
(14)—NO2;
R3 is hydrogen, C1-6alkyl or C3-6cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R13;
R4 and R5 are independently selected from hydrogen and C1-6alkyl, which is unsubstituted or substituted with one or more substituents selected from R13, or R4 and R5 may be joined together to form a C3-6cycloalkyl with the carbon atom to which they are attached, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13;
R13 is selected from the group consisting of:
(1) halogen,
(2) hydroxyl,
(3)—(C═O)m—On—C1-6alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R14,
(4)—On—(C1-3)perfluoroalkyl,
(5)—(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R14,
(6)—(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R14,
(7)—(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R14,
(8)—(C═O)m—On-phenyl or —(C═O)m—On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R14,
(9)—(C═O)m—NR10R11,
(10)—S(O)2—NR10R11,
(11)—S(O)q—R12,
(12)—CO2H,
(13)—CN, and
(14)—NO2;
R14 is selected from the group consisting of:
(1) hydroxyl,
(2) halogen,
(3) C1-6alkyl,
(4)—C3-6cycloalkyl,
(5)—O—C1-6alkyl,
(6)—O(C═O)—C1-6alkyl,
(7)—NH—C1-6alkyl,
(8) phenyl,
(9)—CO2H, and
(10)—CN;
or a pharmaceutically acceptable salt thereof.

64 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/528,142Filed 29 Feb 2008 · us provisional application
Priority: 2 Mar 2007
Published: US 2010/0063056 A111 Mar 2010
Granted: 2 Apr 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07D 213/82
Amides; Imides: in position 3
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids

Family

Application60/904,511Us provisional application · filed 2 Mar 2007
US 2010/0063056 A1Pre-grant publication · published 11 Mar 2010
US 8,410,142 B2This patent

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

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Abstract

A compound of the formula I:

A1 is selected from the group consisting of phenyl or naphthyl;
A2 is selected from the group consisting of phenyl or naphthyl;
R1a, R1b and R1c are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4)—(C═O)m—On—C1-6alkyl, where m is 0 or 1, n is 0 or 1 (wherein if m is 0 or n is 0, a bond is present) and where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,
(5)—(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,
(6)—(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,
(7)—(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R13,
(8)—(C═O)m—On-phenyl or —(C═O)m—On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R13,
(9)—(C═O)m—NR10R11, wherein R10 and R11 are independently selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkyl, which is unsubstituted or substituted with R13,
(c) C3-6alkenyl, which is unsubstituted or substituted with R13,
(d) C3-6alkynyl, which is unsubstituted or substituted with R13,
(e) C3-6cycloalkyl which is unsubstituted or substituted with R13, and
(f) phenyl, which is unsubstituted or substituted with R13,
(10)—S(O)2—NR10R11,
(11)—S(O)q—R12, where q is 0, 1 or 2 and where R12 is selected from the definitions of R10 and R11,
(12)—CO2H,
(13)—CN, and
(14)—NO2;
R2a, R2b and R2c are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4)—(C═O)m—On—C1-6alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R13,
(5)—(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13,
(6)—(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R13,
(7)—(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R13,
(8)—(C═O)m—On-phenyl or —(C═O)m—On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R13,
(9)—(C═O)m—NR10R11,
(10)—S(O)2—NR10R11,
(11)—S(O)q—R12,
(12)—CO2H,
(13)—CN, and
(14)—NO2;
R3 is hydrogen, C1-6alkyl or C3-6cycloalkyl, which is unsubstituted or substituted with one or more substituents selected from R13;
R4 and R5 are independently selected from hydrogen and C1-6alkyl, which is unsubstituted or substituted with one or more substituents selected from R13, or R4 and R5 may be joined together to form a C3-6cycloalkyl with the carbon atom to which they are attached, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R13;
R13 is selected from the group consisting of:
(1) halogen,
(2) hydroxyl,
(3)—(C═O)m—On—C1-6alkyl, where the alkyl is unsubstituted or substituted with one or more substituents selected from R14,
(4)—On—(C1-3)perfluoroalkyl,
(5)—(C═O)m—On—C3-6cycloalkyl, where the cycloalkyl is unsubstituted or substituted with one or more substituents selected from R14,
(6)—(C═O)m—C2-4alkenyl, where the alkenyl is unsubstituted or substituted with one or more substituents selected from R14,
(7)—(C═O)m—C2-4alkynyl, where the alkynyl is unsubstituted or substituted with one or more substituents selected from R14,
(8)—(C═O)m—On-phenyl or —(C═O)m—On-naphthyl, where the phenyl or naphthyl is unsubstituted or substituted with one or more substituents selected from R14,
(9)—(C═O)m—NR10R11,
(10)—S(O)2—NR10R11,
(11)—S(O)q—R12,
(12)—CO2H,
(13)—CN, and
(14)—NO2;
R14 is selected from the group consisting of:
(1) hydroxyl,
(2) halogen,
(3) C1-6alkyl,
(4)—C3-6cycloalkyl,
(5)—O—C1-6alkyl,
(6)—O(C═O)—C1-6alkyl,
(7)—NH—C1-6alkyl,
(8) phenyl,
(9)—CO2H, and
(10)—CN;
or a pharmaceutically acceptable salt thereof.

64 more elements

Facts

Application

12/528,142Filed 29 Feb 2008 · us provisional application

Priority

2 Mar 2007

Published

US 2010/0063056 A111 Mar 2010

Granted

2 Apr 2013

Term ends

Not estimatedThe source records don’t support an estimate.

Classification15 codes

C07D 213/82
Amides; Imides: in position 3
A61P 3/04
Drugs for disorders of the metabolism: anorexiants; Antiobesity agents
A61P 25/00
Drugs for disorders of the nervous system
A61P 25/04
Drugs for disorders of the nervous system: centrally acting analgesics, e.g. opioids