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US 7,888,347 B2Granted
Pyrazolo [3,4-D]azepine derivatives as histamine H3 antagonists
AssigneeGlaxo Group Limited
InventorsMark James Bamford, David Matthew Wilson
Life of this patent
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Abstract
The present invention relates to novel pyrazole derivatives of formula I having pharmacological activity as H3 antagonists processes for their preparation, to compositions containing them and to their use in the treatment of neurological and psychiatric disorders.
Claims11
A compound of formula (I) or a pharmaceutically acceptable salt thereof:
- wherein:
- R1 represents —C1-6 alkyl, —C3-7 cycloalkyl or —CH2—C3-7 cycloalkyl, wherein said cycloalkyl groups may be optionally substituted by C1-3 alkyl;
- X represents a bond or —CH2—,
- R2 represents -aryl, -aryl-aryl, -aryl-heteroaryl, -aryl-heterocyclyl, -heteroaryl, -heteroaryl-aryl, -heteroaryl-heteroaryl, -heteroaryl-heterocyclyl, -heterocyclyl, -heterocyclyl-aryl, -heterocyclyl-heteroaryl or -heterocyclyl-heterocyclyl;
- wherein said aryl, heteroaryl and heterocyclyl groups of R2 may be optionally substituted by one or more substituents which may be the same or different, and which are selected from the group consisting of halogen, hydroxy, cyano, nitro, ═O, C1-6 alkyl, haloC1-6 alkyl, —O-haloC1-6 alkyl, —O—C1-6 alkyl, —C1-6 alkyl-O—C1-6 alkyl, —CO2R4, —COR4, —C1-6 alkyl-COR4, —SR4, —SO2R4, —SOR4, —OSO2R4, —C1-6 alkyl-SO2R4, —C1-6 alkyl-NR4SO2R5, —C1-6 alkyl-SO2NR4R5, —NR4R5, —C1-6 alkyl-NR4R5, —C3-8 cycloalkyl-NR4R5, —CONR4R5, —NR4COR5, —C1-6 alkyl-NR4COR5, —C1-6 alkyl-CONR4R5, —NR4SO2R5, —OCONR4R5, —NR4CO2R5, —NR6CONR4R5 and —SO2NR4R5, wherein R4, R5 and R6 independently represent hydrogen, C1-6 alkyl, or wherein —NR4R5 may represent a nitrogen containing heterocyclyl group;
- and
- wherein R4, R5 and R6 may be optionally substituted by one or more substituents which may be the same or different, and which are selected from the group consisting of halogen, hydroxy, cyano, amino, nitro and ═O.
4 more elements
A compound which is:
- N,N-Dimethyl-4-[6-(2-methylpropyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzamide;
- N,N-Dimethyl-4-[6-(1-methylethyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzamide;
- 4-(6-Cyclobutyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)-N,N-dimethylbenzamide;
- 4-(6-Cyclopentyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)-N,N-dimethylbenzamide;
- N-Methyl-4-[6-(2-methylpropyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzamide;
- N-Methyl -4-[6-(1-methylethyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzamide;
- 4-(6-Cyclobutyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)-N-methylbenzamide;
- 4-(6-Cyclopentyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)-N-methylbenzamide;
- 3-{4-[6-(1-Methylethyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]phenyl}-1,3-oxazolidin-2-one;
- 1-Methyl-3-{4-[6-(1-methylethyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]phenyl}-2-imidazolidinone;
- 1-Methyl-3-{4-[6-(2-methylpropyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]phenyl}-2-imidazolidinone
- 1-[5-(6-Cyclobutyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)-2-pyridinyl]-2-pyrrolidinone;
- 1-[4-(6-Cyclobutyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl) phenyl]-2-pyrrolidinone;
- 1-{4-[6-(1-Methylethyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]phenyl}-2-pyrrolidinone;
- 6-(1-Methylethyl)-2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine;
- 4-[6-(2-Methylpropyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzamide;
- 4-[6-(1-Methylethyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzamide;
- 1-[4-(6-Ethyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-2-pyrrolidinone;
- 1-{4-[6-(Cyclopropylmethyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]phenyl}-2-pyrrolidinone;
- 1-{4-[6-(2-Methylpropyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]phenyl}-2-pyrrolidinone;
- 2-[4-(3-Methyl-1,2,4-oxadiazol-5-yl)phenyl]-6-(2-methylpropyl)-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine;
- 1-[4-(6-Cyclohexyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-2-pyrrolidinone;
- 4-(6-Cyclopentyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzamide;
- 1-[4-(6-Cyclopentyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-2-pyrrolidinone;
- 6-Cyclobutyl-2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo azepine;
- 4-(6-Cyclobutyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzamide;
- 6-Cyclopentyl-2-[4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine;
- 6-Cyclobutyl-2-[4-(methylsulfonyl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine;
- N-[4-(6-Cyclobutyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]methanesulfonamide;
- 3-[4-(6-Cyclopentyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-1,3-oxazolidin-2-one ;
- 1-[4-(6-Cyclopentyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-3-methyl-2-imidazolidinone;
- 4-(6-Cyclobutyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)benzonitrile;
- 4-[6-(2-Methylpropyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzonitrile;
- 4-[6-(1-Methylethyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzonitrile;
- 2-(4-Bromophenyl)-6-cyclobutyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine;
- 1-[4-(6-Cyclobutyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-3-methyl-2-imidazolidinone;
- 3-[4-(6-Cyclobutyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-1,3-oxazolidin-2-one;
- 3-[4-(6-Cyclobutyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)phenyl]-1-methyl-2,4-imidazolidinedione;
- 6-Cyclobutyl-2-[4-(4-morpholinyl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine;
- 6-Cyclobutyl-2-[4-(1-piperidinyl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine;
- 6-Cyclobutyl-2-[4-(1-pyrrolidinyl)phenyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine;
- 3-{4-[6-(2-Methylpropyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]phenyl}-1,3-oxazolidin-2-one;
- 1-{5-[6-(1-Methylethyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]-2-pyridinyl}-2-pyrrolidinone;
- 6-Cyclobutyl-2-[1-(6-methyl-3-pyridinyl)-4-piperidinyl]-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine;
- 6-Cyclobutyl-2-phenyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepine;
- or
- 4-[(6-Cyclobutyl-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl)methyl]benzonitrile;
- or a pharmaceutically acceptable salt thereof.
45 more elements
A compound which is N-Methyl-4-[6-(2-methylpropyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzamide, having the following structure:
- or a pharmaceutically acceptable salt thereof.
A compound which is N-Methyl-4-[6-(1-methylethyl)-5,6,7,8-tetrahydropyrazolo[3,4-d]azepin-2(4H)-yl]benzamide, having the following structure:
- or a pharmaceutically acceptable salt thereof.
Dependencies are inferred from the claim text.