US 2010/0305140 A1Published application

Benzimidazole derivatives which are to be used as antagonist for the cb1-receptor

AssigneeAstraZeneca AB

InventorsWilliam Brown, Daniel Page, Sanjay Srivastava, Christopher Walpole, Zhong-Yong Wei, Hua Yang

Life of this patent

Estimating the term…

Abstract

Compounds of formula I or pharmaceutically acceptable salts thereof: wherein X, A, R1, R2, R3 and R4 are as defined in the specification as well as salts and pharmaceutical compositions including the compounds are prepared. They are useful in therapy, in particular in the management of pain.

Claims22

Dependent claims

A compound of formula I, a pharmaceutically acceptable salt thereof, a diastereomer, an enantiomer, or a mixture thereof:

wherein:
R1 is selected from C1-10alkyl, C2-10alkenyl, C1-10alkoxy, C6-10aryl-C1-6alkyl, C6-10aryl-C(═O)-C1-6alkyl, C3-10cycloalkyl-C1-6alkyl, C4-8cycloalkenyl-C1-6alkyl, C3-6heterocyclyl-C1-6alkyl, C3-6heterocyclyl-C(═O)—C1-6alkyl, C6-10aryl, C6-10aryl-C(═O)—, C3-10cycloalkyl, C4-8cycloalkenyl, C3-6heterocyclyl and C3-6heterocyclyl-C(═O)—;
wherein said C1-10alkyl, C2-10alkenyl, C1-10alkoxy, C6-10aryl-C1-6alkyl, C6-10aryl-C(═O)—C1-6alkyl, C3-10cycloalkyl-C1-6alkyl, C4-8cycloalkenyl-C1-6alkyl, C3-6heterocyclyl-C1-6alkyl, C3-6heterocyclyl-C(═O)—C1-6alkyl, C6-10aryl, C6-10aryl-C(═O)—, C3-10cycloalkyl, C4-8cycloalkenyl, C3-6heterocyclyl or C3-6heterocyclyl-C(═O)— is optionally substituted by one or more groups selected from carboxy, —(C═O)—NH2, halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, —N(R6)—C(═O)R5, —S(═O)2—NR5R6, —C(═O)—NR5R6, —NH—C(═O)—NR5R6 and —NR5R6;
R2 is selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, C4-8cycloalkenyl-C1-6alkyl, C3-6heterocycloalkyl-C1-6alkyl, C4-8cycloalkenyl and C3-6heterocycloalkyl, wherein said C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, C4-8cycloalkenyl-C1-6alkyl, C3-6heterocycloalkyl-C1-6alkyl, C4-8cycloalkenyl or C3-6heterocycloalkyl used in defining R2 is optionally substituted by one or more groups selected from carboxy, —(C═O)—NH2, halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and —NR5R6;
R3 is selected from C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl, C2-5heteroaryl, C2-5heteroaryl-C1-4alkyl, C2-5heterocycloalkyl, C2-5heterocycloalkyl-C1-4alkyl, phenyl and benzyl, wherein said C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl, C2-5heteroaryl, C2-5heteroaryl-C1-4alkyl, C2-5heterocycloalkyl, C2-5heterocycloalkyl-C1-4alkyl, phenyl or benzyl is optionally substituted by one or more groups selected from C1-6alkyl, carboxy, halogen, cyano, nitro, methoxy, ethoxy, hydroxy, and —NR5R6;
and
R4 is selected from C1-6alkyl, carboxy, halogen, cyano, nitro, methoxy, ethoxy, hydroxy, and —NR5R6;
is a 4, 5 or 6-membered heterocycle which optionally contains one or two additional heteroatoms selected from O, S and N on its ring in addition to the nitrogen shown;
X is selected from —O—C(═O)—, —C(═O)—NH—, —NH—C(═O)—, —NHR7—C(═O)—, —C(═O)—NHCH2—, —NH—C(═O)CH2—, —NH—C(═O)—NH—, —O—C(═O)—NH—, —NH—(CH2)m—, —O—(CH2)m—, —C(═O)—O—, and —NH—C(═O)—O—;
wherein R5 and R6 are independently selected from —H, C1-6alkyl optionally substituted with —OH, methoxy, ethoxy or halogen, C3-6cycloalkyl-C0-malkyl optionally substituted with —OH, methoxy, ethoxy or halogen, C2-6alkenyl optionally substituted with —OH, methoxy, ethoxy or halogen, and a divalent C1-6alkylene optionally substituted with —OH, methoxy, ethoxy or halogen that together with another divalent R5 or R6 form a portion of a ring;
R7 is C1-6alkyl, and
m is 0, 1, 2 or 3.

9 more elements

A compound selected from:

1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)-N-methylazetidine-3-carboxamide;
1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)-N-cyclopropylpiperidine-3-carboxamide;
1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)-N-ethylpipendine-3-carboxamide;
1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)-N-cyclopropylpiperidine-4-carboxamide;
1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)-N-ethylpipendine-4-carboxamide;
1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)-N-methylpipendine-4-carboxamide;
N-(tert-Butyl)-1-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)pipendine-4-carboxamide;
1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)-N-cyclobutylpiperidine-4-carboxamide;
s1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)-N-isoxazol-3-ylpipendine-4-carboxamide;
1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)-N-1,3-thiazol-2-ylpipendine-4-carboxamide;
1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)-N-(5-methylisoxazol-3-yl)pipendine-4-carboxamide;
1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)-N-ethyl-N-methylpipendine-4-carboxamide;
1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)-N-(cyclopropylmethyl)piperidine-4-carboxamide;
1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)-N-cyclopropylpyrrolidine-3-carboxamide;
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-5-[(4-methoxypipendin-1-yl)carbonyl]-1H-benzimidazole;
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-5-[(4-ethoxypipendin-1-yl)carbonyl]-1H-benzimidazole;
2-tert-Butyl-5-{[4-(cyclopropylmethoxy)piperidin-1-yl]carbonyl}-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole;
2-tert-Butyl-5-{[4-(cyclobutylmethoxy)pipendin-1-yl]carbonyl}-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole;
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-5-[(4-propoxypiperidin-1-yl)carbonyl]-1H-benzimidazole;
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-5-[(4-isopropoxypiperidin-1-yl)carbonyl]-1H-benzimidazole;
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-5-{[4-(2,2-dimethylpropoxy)piperidin-1-yl]carbonyl}-1H-benzimidazole;
5-{[4-(Benzyloxy)piperidin-1-yl]carbonyl}-2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole;
2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-5-[(4-isobutoxypiperidin-1-yl)carbonyl]-1H-benzimidazole;
2-[1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)azetidin-3-yl]-N-cyclopropylacetamide;
N-[1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)piperidin-4-yl]cyclopropanecarboxamide;
1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)-N-(cyclopropylmethyl)piperidin-4-amine;
4-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)-N-cyclopropylpiperazine-1-carboxamide;
2-tert-Butyl-5-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole;
2-[1-({2-tert-Butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}carbonyl)piperidin-4-yl]-N-cyclopropylacetamide;
2-tert-Butyl-5-{[3-(cyclopropylmethoxy)azetidin-1-yl]carbonyl}-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazole;
1-{[2-tert-Butyl-1-(cyclohexylmethyl)-1H-benzimidazol-5-yl]carbonyl}-N-cyclopropylpiperidine-4-carboxamide;
and pharmaceutically acceptable salts thereof.

29 more elements

A method for preparing a compound of formula I,

comprising the step of reacting a compound of formula II,
with a compound of formula III,
wherein
Y is selected from Cl, Br, F and OH;
R1 is selected from C1-10alkyl, C2-10alkenyl, C1-10alkoxy, C6-10aryl-C1-6alkyl, C6-10aryl-C(═O)—C1-6alkyl, C3-10cycloalkyl-C1-6alkyl, C4-8cycloalkenyl-C1-6alkyl, C3-6heterocyclyl-C1-6alkyl, C3-6heterocyclyl-C(═O)—C1-6alkyl, C6-10aryl, C6-10aryl-C(═O)—, C3-10cycloalkyl, C4-8cycloalkenyl, C3-6heterocyclyl and C3-6heterocyclyl-C(═O)—;
wherein said C1-10alkyl, C2-10alkenyl, C1-10alkoxy, C6-10aryl-C1-6alkyl, C6-10aryl-C(═O)—C1-6alkyl, C3-10cycloalkyl-C1-6alkyl, C4-8cycloalkenyl-C1-6alkyl, C3-6heterocyclyl-C1-6alkyl, C3-6heterocyclyl-C(═O)—C1-6alkyl, C6-10aryl, C6-10aryl-C(═O)—, C3-10cycloalkyl, C4-8cycloalkenyl, C3-6heterocyclyl or C3-6heterocyclyl-C(═O)— is optionally substituted by one or more groups selected from carboxy, —(C═O)—NH2, halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, —N(R6)—C(═O)R5, —S(═O)2—NR5R6, —C(═O)—NR5R6, —NH—C(═O)—NR5R6 and —NR5R6;
R2 is selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, C4-8cycloalkenyl-C1-6alkyl, C3-6heterocycloalkyl-C1-6alkyl, C4-8cycloalkenyl and C3-6heterocycloalkyl, wherein said C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, C4-8cycloalkenyl-C1-6alkyl, C3-6heterocycloalkyl-C1-6alkyl, C4-8cycloalkenyl or C3-6heterocycloalkyl used in defining R2 is optionally substituted by one or more groups selected from carboxy, —(C═O)—NH2, halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and —NR5R6;
R3 is selected from C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl, C2-5heteroaryl, C2-5heteroaryl-C1-4alkyl, C2-5heterocycloalkyl, C2-5heterocycloalkyl-C1-4alkyl, phenyl and benzyl, wherein said C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl, C2-5heteroaryl, C2-5heteroaryl-C1-4alkyl, C2-5heterocycloalkyl, C2-5heterocycloalkyl-C1-4alkyl, phenyl or benzyl is optionally substituted by one or more groups selected from C1-6alkyl, carboxy, halogen, cyano, nitro, methoxy, ethoxy, hydroxy, and —NR5R6;
and
R4 is selected from C1-6alkyl, carboxy, halogen, cyano, nitro, methoxy, ethoxy, hydroxy, and —NR5R6;
is a 4, 5 or 6-membered heterocycle which optionally contains one or two additional heteroatoms selected from O, S and N on its ring in addition to the nitrogen shown;
X is selected from —O—C(═O)—, —C(═O)—NH—, —NH—C(═O)—, —NHR7—C(═O)—, —C(═O)—NHCH2—, —NH—C(═O)CH2—, —NH—C(═O)—NH—, —O—C(═O)—NH—, —O—(CH2)m—, —C(═O)—O—, and —NH—C(═O)—O—;
wherein R5 and R6 are independently selected from —H, C1-6alkyl optionally substituted with —OH, methoxy, ethoxy or halogen, C3-6cycloalkyl-C0-malkyl optionally substituted with —OH, methoxy, ethoxy or halogen, C2-6alkenyl optionally substituted with —OH, methoxy, ethoxy or halogen, and a divalent C1-6alkylene optionally substituted with —OH, methoxy, ethoxy or halogen that together with another divalent R5 or R6 form a portion of a ring;
R7 is C1-6alkyl, and
m is 0, 1, 2 or 3.

12 more elements

Dependencies are inferred from the claim text.

Facts

Application: 12/303,643Filed 11 Jun 2007
Priority: 13 Jun 2006
Published: 2 Dec 2010
Term ends: Not estimatedThe source records don’t support an estimate.

Classification34 codes

C07D 413/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms:…
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 1/10
Drugs for disorders of the alimentary tract or the digestive system: laxatives

Family

Application60/804,599Us provisional application · filed 13 Jun 2006
US 2010/0305140 A1This patent

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

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Abstract

A compound of formula I, a pharmaceutically acceptable salt thereof, a diastereomer, an enantiomer, or a mixture thereof:

wherein:
R1 is selected from C1-10alkyl, C2-10alkenyl, C1-10alkoxy, C6-10aryl-C1-6alkyl, C6-10aryl-C(═O)-C1-6alkyl, C3-10cycloalkyl-C1-6alkyl, C4-8cycloalkenyl-C1-6alkyl, C3-6heterocyclyl-C1-6alkyl, C3-6heterocyclyl-C(═O)—C1-6alkyl, C6-10aryl, C6-10aryl-C(═O)—, C3-10cycloalkyl, C4-8cycloalkenyl, C3-6heterocyclyl and C3-6heterocyclyl-C(═O)—;
wherein said C1-10alkyl, C2-10alkenyl, C1-10alkoxy, C6-10aryl-C1-6alkyl, C6-10aryl-C(═O)—C1-6alkyl, C3-10cycloalkyl-C1-6alkyl, C4-8cycloalkenyl-C1-6alkyl, C3-6heterocyclyl-C1-6alkyl, C3-6heterocyclyl-C(═O)—C1-6alkyl, C6-10aryl, C6-10aryl-C(═O)—, C3-10cycloalkyl, C4-8cycloalkenyl, C3-6heterocyclyl or C3-6heterocyclyl-C(═O)— is optionally substituted by one or more groups selected from carboxy, —(C═O)—NH2, halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, —N(R6)—C(═O)R5, —S(═O)2—NR5R6, —C(═O)—NR5R6, —NH—C(═O)—NR5R6 and —NR5R6;
R2 is selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, C4-8cycloalkenyl-C1-6alkyl, C3-6heterocycloalkyl-C1-6alkyl, C4-8cycloalkenyl and C3-6heterocycloalkyl, wherein said C1-10alkyl, C2-10alkenyl, C2-10alkynyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-6alkyl, C4-8cycloalkenyl-C1-6alkyl, C3-6heterocycloalkyl-C1-6alkyl, C4-8cycloalkenyl or C3-6heterocycloalkyl used in defining R2 is optionally substituted by one or more groups selected from carboxy, —(C═O)—NH2, halogen, cyano, nitro, methoxy, ethoxy, methyl, ethyl, hydroxy, and —NR5R6;
R3 is selected from C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl, C2-5heteroaryl, C2-5heteroaryl-C1-4alkyl, C2-5heterocycloalkyl, C2-5heterocycloalkyl-C1-4alkyl, phenyl and benzyl, wherein said C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl, C2-5heteroaryl, C2-5heteroaryl-C1-4alkyl, C2-5heterocycloalkyl, C2-5heterocycloalkyl-C1-4alkyl, phenyl or benzyl is optionally substituted by one or more groups selected from C1-6alkyl, carboxy, halogen, cyano, nitro, methoxy, ethoxy, hydroxy, and —NR5R6;
and
R4 is selected from C1-6alkyl, carboxy, halogen, cyano, nitro, methoxy, ethoxy, hydroxy, and —NR5R6;
is a 4, 5 or 6-membered heterocycle which optionally contains one or two additional heteroatoms selected from O, S and N on its ring in addition to the nitrogen shown;
X is selected from —O—C(═O)—, —C(═O)—NH—, —NH—C(═O)—, —NHR7—C(═O)—, —C(═O)—NHCH2—, —NH—C(═O)CH2—, —NH—C(═O)—NH—, —O—C(═O)—NH—, —NH—(CH2)m—, —O—(CH2)m—, —C(═O)—O—, and —NH—C(═O)—O—;
wherein R5 and R6 are independently selected from —H, C1-6alkyl optionally substituted with —OH, methoxy, ethoxy or halogen, C3-6cycloalkyl-C0-malkyl optionally substituted with —OH, methoxy, ethoxy or halogen, C2-6alkenyl optionally substituted with —OH, methoxy, ethoxy or halogen, and a divalent C1-6alkylene optionally substituted with —OH, methoxy, ethoxy or halogen that together with another divalent R5 or R6 form a portion of a ring;
R7 is C1-6alkyl, and
m is 0, 1, 2 or 3.

9 more elements

Facts

Application

12/303,643Filed 11 Jun 2007

Priority

13 Jun 2006

Published

2 Dec 2010

Term ends

Not estimatedThe source records don’t support an estimate.

Classification34 codes

C07D 413/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms:…
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 1/10
Drugs for disorders of the alimentary tract or the digestive system: laxatives