Novel aminophenyl piperazine or aminophenyl piperidine derivatives inhibiting prenyl transferase proteins and method for preparing same
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Abstract
The invention concerns compounds corresponding to general formula (I), wherein, in particular: W represents hydrogen, COR6, CSR6, SO2R6, CO(CH2)nR6, (CH2)nR7; X represents CH or N; Y represents (CH2)n, CO, CH2CO, CH═CHCO, CH2CH2CO; Z represents a heterocycle. When Z=pyridine, then Y is other than CO. R1 represents hydrogen, C1-C6 alkyl, halogen OCH3, CF3; R2 and R3, identical or different, represent hydrogen, C1-C6 alkyl; R4 represents a) hydrogen, b) C1-C6 alkyl, c) an aryl, d) a heterocycle; R5 represents hydrogen, COR7R8, SO2R7, CO(CH2)nSR7, CO(CH2)nOR7, CONR7R8, CO(CH2)mCOR7; R6 represents a) a phenyl or a naphthyl, b) a C1-C6 alkyl, a cycloalkyl, c) a heterocycle, d) NR7R8; R7 and R8, identical or different, represent a) hydrogen, C1-C15 alkyl, b) a heterocycle, c) an aryl; n represents 0 to 10; m represents 2 to 10; provided that when Z represents a quinozaline or benzimidazole group, then R5 is other than CH2Ph or methyl and n is other than zero.
27 Citations
44 Claims
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1. A compound corresponding to the general formula (I):
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22)
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2. The compound as claimed in claim 1, characterized in that R1, R2, R3 and R4 each represent a hydrogen and Y is a methylene (CH2).
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3. The compound as claimed in either of claims 1 and 2, characterized in that Z represents an imidazolyl or pyridyl residue.
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4. The compound as claimed in claim 3, characterized in that Z represents an imidazolyl residue and R4 is a benzyl group substituted with a nitrile, nitro or methoxy group in position 4.
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5. The compound as claimed in one of claims 1 to 4, characterized in that X represents a nitrogen atom.
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6. The compound as claimed in one of claims 1 to 4, characterized in that X represents a carbon atom.
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7. The compound as claimed in one of claims 1 to 6, characterized in that R5 represents 2-thiophenecarbonyl or 5-chloro-2-thiophenecarbonyl.
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8. The compound as claimed in one of claims 1 to 6, characterized in that R5 represents CSNR7R8
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9. The compound as claimed in one of claims 1 to 8, characterized in that W represents COR6.
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10. The compound as claimed in one of claims 1 to 8, characterized in that W represents (CH2)nR7.
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11. The compound as claimed in claim 1, selected from:
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N-(3H-imidazol-4-ylmethyl)-4-nitro-N-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}benzamide 4-{4-[benzenesulfonyl-(3H-imidazol-4-ylmethyl)amino]phenyl}-1-piperazinecarbothioic acid propylamide 4-{4-[benzenesulfonyl-(3H-imidazol-4-ylmethyl)amino]phenyl}-1-piperazinecarbothioic acid cyclohexylamide 4-{4-[benzenesulfonyl-(3H-imidazol-4-ylmethyl)amino]phenyl}-1-piperazinecarbothioic acid cyclohexylmethyl-amide 4-{4-[benzenesulfonyl-(3H-imidazol-4-ylmethyl)amino]phenyl}-1-piperazinecarbothioic acid benzylamide 4-{4-[benzenesulfonyl-(3H-imidazol-4-ylmethyl)amino]phenyl}-1-piperazinecarbothioic acid isobutylamide 4-{4-[benzenesulfonyl-(3H-imidazol-4-ylmethyl)amino]phenyl}-1-piperazinecarbothioic acid (2-methoxyethyl)amide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-3-fluoro-N-(3H-imidazol-4-ylmethyl)benzamide 4-[5-({4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenylamino}methyl)-imidazol-1-ylmethyl]benzonitrile N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]benzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]benzenesulfonamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-4-cyano-N-(3H-imidazol-4-ylmethyl)benzamide thiophene-2-carboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide 2-chloro-N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide 3-chloro-N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide 4-chloro-N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]-2-fluorobenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]-3-fluorobenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]-4-fluorobenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-2-trifluoromethylbenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-2-methoxybenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-methoxybenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-methoxybenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-2-nitrobenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-nitrobenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-nitrobenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-4-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-benzamide cyclohexanecarboxylic acid {4-[4-(5-chloro-thiophene-2-carbonyl)-1-piperazinyl]phenyl}-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-amide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-2-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-benzenesulfonamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-3-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzenesulfonamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-4-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzenesulfonamide 1-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-1-(3H-imidazol-4-ylmethyl)-3-propylurea 1-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-1-(3H-imidazol-4-ylmethyl)-3-(2-methylsulfanylphenyl)urea N-(3H-imidazol4-ylmethyl)-4-nitro-N-[4-(4-propylthiocarbamoyl-1-piperazinyl)phenyl]benzamide N-[4-(4-cyclohexylthiocarbamoyl-1-piperazinyl)phenyl]-N-(3H-imidazol-4-ylmethyl)-4-nitrobenzamide N-(3H-imidazol-4-ylmethyl)-N-[4-(4-isobutylthiocarbamoyl-1-piperazinyl)phenyl]-4-nitrobenzamide 4-{4-[benzenesulfonyl-(3H-imidazol-4-ylmethyl)amino]phenyl}piperidine-1-carbothioic acid isobutylamide N-(3H-imidazol-4-ylmethyl)-N-[4-(1-isobutylthiocarbamoylpiperidin-4-yl)phenyl]-4-nitrobenzamide cyclohexanecarboxylic acid (3H-imidazol-4-ylmethyl)-[4-(1-isobutylthiocarbamoyl-piperidin-4-yl)-phenyl]amide 4-{4-[(4-cyano-benzenesulfonyl)(3H-imidazol-4-ylmethyl)amino]phenyl}piperidine-1-carbothioic acid cyclohexylamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-3-(3H-imidazol-4-yl)acryamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-3-[3-(4-cyano-benzyl)-3H-imidazol-4-yl]propionamide 4-(5-{[{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}(3-fluoro-benzyl)amino]methyl}imidazol-1-ylmethyl)benzonitrile 4-(5-{[{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}(4-fluoro-benzyl)amino]methyl}imidazol-1-ylmethyl)benzonitrile 4-(5-{[{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}(3-hydroxy-benzyl)amino]methyl}imidazol-1-ylmethyl)-benzonitrile 4-(5-{[{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}(3-methoxyl-benzyl)amino]methyl}imidazol-1-ylmethyl)benzonitrile 4-(5-{[{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-(3,4-dichloro-benzyl)amino]methyl}imidazol-1-ylmethyl)benzonitrile 4-{5-[({4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}thiophen-3-ylmethylamino)methyl]imidazol-1-ylmethyl}benzonitrile 4-{5-[(benzo[1,3]dioxol-5-ylmethyl-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}amino)methyl]imidazol-1-ylmethyl}benzonitrile 4-{5-[(butyl-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}amino)-methyl]imidazol-1-ylmethyl}benzonitrile 4-(5-{[{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}(3-phenyl-propyl)amino]methyl}imidazol-1-ylmethyl)benzonitrile 4-{5-[((3-fluorobenzyl)-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}amino)-methyl]imidazol-1-ylmethyl}benzonitrile 4-{5-[((4-fluorobenzyl)-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}amino)-methyl]imidazol-1-ylmethyl}benzonitrile 4-{5-[((4-fluorobenzyl)-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}amino)-methyl]imidazol-1-ylmethyl}benzonitrile 4-{5-[((3-methoxybenzyl)-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}-amino)methyl9 imidazol-1-ylmethyl}benzonitrile 4-{5-[((3,4-dichlorobenzyl)-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}-amino)methyl]imidazol-1-ylmethyl}benzonitrile 4-{5-[({4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}thiophen-3-ylmethyl-amino)methyl]imidazol-1-ylmethyl}benzonitrile 4-{5-[(benzo[1,3]dioxol-5-ylmethyl-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl}amino)methyl]imidazol-1-ylmethyl}benzonitrile 4-{5-[(butyl-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}amino)methyl]-imidazol-1-ylmethyl}benzonitrile 4-{5-[((3-phenylpropyl)-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}-amino)methyl]imidazol-1-ylmethyl}benzonitrile N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-(1-methyl-1H-benzoimidazol-2-ylmethyl)benzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-(2-methyl-3H-imidazol-4-ylmethyl)benzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-thiazol-2-ylmethylbenzamide N-{4-[4-(3-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide N-{4-[4-(benzo[b]thiophene-2-carbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide N-{4-[4-(3-chlorobenzo[b]thiophene-2-carbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(2-thiophen-2-ylacetyl)-1-piperazinyl]phenyl}benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(furan-2-carbonyl)-1-piperazinyl]phenyl}benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(isoxazole-5-carbonyl)-1-piperazinyl]phenyl}benzamide N-(4-{4-[3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl]-1-piperazinyl}phenyl)-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(5-methylthiophene-2-carbonyl)-1-piperazinyl]phenyl}benzamide N-{4-[4-(5-bromothiophene-2-carbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(thiophene-3-carbonyl)-1-piperazinyl]phenyl}benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(2-thiophen-3-ylacetyl)-1-piperazinyl]phenyl}benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(4-thiophen-2-ylbutyryl)-1-piperazinyl]phenyl}benzamide N-(4-{4-[2-(5-chlorobenzo[b]thiophen-3-yl)acetyl]-1-piperazinyl}phenyl)-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(4-oxo4-thiophen-2-ylbutyryl)-1-piperazinyl]phenyl}benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(5-oxo-5-thiophen-2-ylpentanoyl)-1-piperazinyl]phenyl}benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(1-methyl-1H-pyrrole-2-carbonyl)-1-piperazinyl]phenyl}benzamide N-(4-{4-[5-(4-chlorophenyl)-furan-2-carbonyl]-1-piperazinyl}-phenyl)-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(5-methyl-1-phenyl-1H-pyrazole-4-carbonyl)-1-piperazinyl]phenyl}benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(3,5-dimethylisoxazole-4-carbonyl)-1-piperazinyl]phenyl}benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-1-piperazinyl]phenyl}benzamide N-{4-[4-(5-chlorothiophen-2-ylmethyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(3-methylthiophen-2-ylmethyl)-1-piperazinyl]phenyl}benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(5-methylthiophen-2-ylmethyl)-1-piperazinyl]phenyl}benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(5-ethylthiophen-2-ylmethyl)-1-piperazinyl]phenyl}benzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-(2-phenyl-1H-imidazol-4-ylmethyl)benzamide 4-(4-{benzenesulfonyl-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}phenyl)-1-piperazinecarbothioic acid isobutylamide 4-(4-{benzenesulfonyl-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}phenyl)-1-piperazinecarbothioic acid propylamide 4-(4-{benzenesulfonyl-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}phenyl)-1-piperazinecarbothioic acid cyclohexylamide 4-(4-{benzenesulfonyl-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}phenyl)-1-piperazinecarbothioic acid benzylamide 4-(4-{(4-cyanobenzenesulfonyl)-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-amino}phenyl)-1-piperazinecarbothioic acid isobutylamide 4-(4-{(4-cyanobenzenesulfonyl)-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-amino}phenyl)-1-piperazinecarbothioic acid propylamide 4-(4-{(4-cyanobenzenesulfonyl)-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-amino}phenyl)-1-piperazinecarbothioic acid cyclohexylamide 4-(4-{(4-cyanobenzenesulfonyl)-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-amino}phenyl)-1-piperazinecarbothioic acid cyclohexylmethylamide 4-(4-{(4-cyanobenzenesulfonyl)-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-amino}phenyl)-1-piperazinecarbothioic acid benzylamide 4-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-[4-(4-isobutylthiocarbamoyl-1-piperazinyl)phenyl]benzamide 4-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-[4-(4-propylthiocarbamoyl-1-piperazinyl)phenyl]benzamide 4-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-[4-(4-cyclohexylthiocarbamoyl-1-piperazinyl)phenyl]benzamide 4-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(cyclohexylmethylthiocarbamoyl)-1-piperazinyl]phenyl}benzamide N-[4-(4-benzylthiocarbamoyl-1-piperazinyl)-phenyl]-4-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide N-[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]-3-fluoro-N-[4-(4-isobutylthiocarbamoyl-1-piperazinyl)-phenyl]benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-fluoro-N-[4-(4-propylthiocarbamoyl-1-piperazinyl)phenyl]benzamide N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-[4-(4-cyclohexylthiocarbamoyl1-piperazinyl)phenyl]-3-fluorobenzamide N-[4-(4-benzylthiocarbamoyl-1-piperazinyl)phenyl]-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-fluorobenzamide 4-{4-[1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-(2-methylsulfanylphenyl)-ureido]phenyl}-1-piperazinecarbothioic acid propylamide 4-(4-{1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-propylureido}phenyl)-1-piperazinecarbothioic acid isobutylamide 4-(4-{1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-propylureido}phenyl)-1-piperazinecarbothioic acid propylamide 4-(4-{1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-propylureido}phenyl)-1-piperazinecarbothioic acid cyclohexylamide 4-(4-{1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-propylureido}phenyl)-1-piperazinecarbothioic acid cyclohexylmethylamide 4-(4-{1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-propylureido}phenyl)-1-piperazinecarbothioic acid benzylarnide N-(3H-imidazol-4-ylmethyl)-N-[4-(4-isobutylthiocarbamoyl-1-piperazinyl)phenyl]-3-methoxybenzamide 3-fluoro-N-(3H-imidazol-4-ylmethyl)-N-[4-(4-isobutylthiocarbamoyl-1-piperazinyl)phenyl]benzamide cyclopropanecarboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide cyclobutanecarboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide cyclopentanecarboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-cyclopentylpropionamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-2-cyclopentylacetamide naphthalene-1-carboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl]}-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide biphenyl-4-carboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3,5-dimethoxybenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-methylbenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-ethoxybenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-ethylbenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-hexylbenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl-4-methylbenzamide 4-butyl-N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3,4-difluorobenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-trifluoromethoxybenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]acetamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-2-phenoxyacetamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-2-phenylacetamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]propinamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]butyramide furan-2-carboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-2-thiophen-2-ylacetamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-methanesulfonamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3,4-dimethylbenzamide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-fluoro-4-methylbenzamide 2-chloro-N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-5-methylsulfanylbenzamide 3-methoxycyclohexanecarboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide 4-methylcyclohexanecarboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide 1-methylcyclohexanecarboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-2-naphthalen-1-ylacetamide 2-phenylcyclopropanecarboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide 4-{5-[(benzyl-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}amino)-methy]imidazol-1-ylmethyl}benzonitrile, and also the therapeutically acceptable salts and solvates thereof.
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12. A process for preparing the compounds of general formula (I) as claimed in one of claims 1 to 11, characterized in that an intermediate of general formula (V)
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13. The process for preparing the compounds of general formula (I) as claimed in one of claims 1 to 11, characterized in that an intermediate of general formula (VIII)
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14. A pharmaceutical composition containing, as active substance, a compound as claimed in one of claims 1 to 11 in combination with an acceptable pharmaceutical vehicle.
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15. A pharmaceutical composition containing, as active substance, a compound as claimed in one of claims 1 to 11 in combination with an acceptable pharmaceutical vehicle, for the curative or preventive treatment of disorders associated with farnesylation and/or geranylgeranylation of proteins.
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16. A pharmaceutical composition containing, as active substance, a compound as claimed in claims 1 to 11 in combination with an acceptable pharmaceutical vehicle, for treating or preventing cancers such as cancer of the lung, of the pancreas, of the skin, of the head, of the neck, of the uterus, of the ovaries, anal cancer, cancer of the stomach, of the colon, of the breast, of the esophagus, of the small intestine, of the thyroid gland, of the prostate, of the kidney, of the bladder, acute or chronic leukemia, or a combination of two or more of these cancers.
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17. A pharmaceutical composition as claimed in one of claims 14 to 16 in combination especially with an anticancer agent such as cytotoxic anticancer agents, especially navelbine, vinflunine, taxol, taxotere, 5-fluorouracil, le methotrexate, doxorubicin, camptothecin, gemcitabine, etoposide, cisplatin or BCNU, or hormonal anticancer agents, for instance tamoxifen or medroxyprogesterone, for their simultaneous, separate or sequential use, for the treatment or prevention of cancers.
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18. The pharmaceutical composition as claimed in one of claims 14 to 16, in combination with an agent for inhibiting the biosynthesis of farnesyl and geranylgeranyl pyrophosphates, such as an HMG-CoA reductase inhibitor, for instance lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or cerivastatin, for their simultaneous, separate or sequential use.
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19. The pharmaceutical composition as claimed in one of claims 14 to 16, in combination with a treatment with radiation (X-rays or gamma rays) for their simultaneous, separate or sequential use for treating or preventing cancers.
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20. The pharmaceutical composition as claimed in one of claims 14 to 16, for treating or preventing restenosis or atherosclerosis.
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21. The pharmaceutical composition as claimed in one of claims 14 to 16, for treating or preventing infections associated with PFTase such as delta hepatitis.
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22. The pharmaceutical composition as claimed in one of claims 14 to 16, for treating or preventing benign proliferative disorders.
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2. The compound as claimed in claim 1, characterized in that R1, R2, R3 and R4 each represent a hydrogen and Y is a methylene (CH2).
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23. A compound of formula (I):
- View Dependent Claims (24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44)
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24. A compound of claim 23, wherein R1, R2, R3 and R4 each represent a hydrogen and Y is a methylene (CH2).
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25. A compound of claim 23, wherein Z represents an imidazolyl or pyridyl residue.
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26. A compound of claim 25, wherein Z represents an imidazolyl residue and R4 is a benzyl group substituted with a nitrile, nitro or methoxy group in position 4.
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27. A compound of claim 23, wherein X represents a nitrogen atom.
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28. A compound of claim 23, wherein X represents a carbon atom.
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29. A compound of claim 23, wherein R5 represents 2-thiophenecarbonyl or 5-chloro-2-thiophenecarbonyl.
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30. A compound of claim 23, wherein R5 represents CSNR7R8
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31. A compound of claim 23, wherein W represents COR6.
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32. A compound of claim 23, wherein W represents (CH2)nR7.
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33. A compound of claim 23, selected from:
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N-(3H-imidazol-4-ylmethyl)-4-nitro-N-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}benzamide, 4-{4-[benzenesulfonyl-(3H-imidazol-4-ylmethyl)amino]phenyl}-1-piperazinecarbothioic acid propylamide, 4-{4-[benzenesulfonyl-(3H-imidazol-4-ylmethyl)amino]phenyl}-1-piperazinecarbothioic acid cyclohexylamide, 4-{4-[benzenesulfonyl-(3H-imidazol-4-ylmethyl)amino]phenyl}-1-piperazinecarbothioic acid cyclohexylmethyl-amide, 4-{4-[benzenesulfonyl-(3H-imidazol-4-ylmethyl)amino]phenyl}-1-piperazinecarbothioic acid benzylamide, 4-{4-[benzenesulfonyl-(3H-imidazol-4-ylmethyl)amino]phenyl}-1-piperazinecarbothioic acid isobutylamide, 4-{4-[benzenesulfonyl-(3H-imidazol-4-ylmethyl)amino]phenyl}-1-piperazinecarbothioic acid (2-methoxyethyl)amide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-3-fluoro-N-(3H-imidazol-4-ylmethyl)benzamide, 4-[5-({4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenylamino}methyl)-imidazol-1-ylmethyl]benzonitrile, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzenesulfonamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-4-cyano-N-(3H-imidazol-4-ylmethyl)benzamide, thiophene-2-carboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide, 2-chloro-N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide, 3-chloro-N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide, 4-chloro-N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-2-fluorobenzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-fluorobenzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-fluorobenzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-2-trifluoromethylbenzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-2-methoxybenzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-methoxybenzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-methoxybenzamide, N-{4-[45-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-2-nitrobenzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-nitrobenzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-nitrobenzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-4-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-benzamide, cyclohexanecarboxylic acid {4-[4-(5-chloro-thiophene-2-carbonyl)-1-piperazinyl]phenyl}-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-amide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-2-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-benzenesulfonamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-3-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzenesulfonamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-4-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzenesulfonamide, 1-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-1-(3H-imidazol-4-ylmethyl)-3propylurea, 1-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-1-(3H-imidazol-4-ylmethyl)-3-(2-methylsulfanylphenyl)urea, N-(3H-imidazol-4-ylmethyl)-4-nitro-N-[4-(4-propylthiocarbamoyl-1-piperazinyl)phenyl]benzamide, N-[4-(4-cyclohexylthiocarbamoyl-1-piperazinyl)phenyl]-N-(3H-imidazol-4-ylmethyl)-4-nitrobenzamide, N-(3H-imidazol-4-ylmethyl)-N-[4-(4-isobutylthiocarbamoyl-1-piperazinyl)phenyl]-4-nitrobenzamide, 4-{4-[benzenesulfonyl-(3H-imidazol-4-ylmethyl)amino]phenyl}piperidine-1-carbothioic acid isobutylamide, N-(3H-imidazol-4-ylmethyl)-N-[4-(1-isobutylthiocarbamoylpiperidin-4-yl)phenyl]-4-nitrobenzamide, cyclohexanecarboxylic acid (3H-imidazol-4-ylmethyl)-[4-(1-isobutylthiocarbamoyl-piperidin-4-yl)-phenyl]amide, 4-{4-[(4-cyano-benzenesulfonyl)(3H-imidazol-4-ylmethyl)amino]phenyl}piperidine-1-carbothioic acid cyclohexylamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-3-(3H-imidazol-4-yl)acrylamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-3-[3-(4-cyano-benzyl)-3H-imidazol-4-yl]propionamide, 4-(5-{[{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}(3-fluoro-benzyl)amino]methyl}imidazol-1-ylmethyl)benzonitrile, 4-(5-{[{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}(4-fluoro-benzyl)amino]methyl}imidazol-1-ylmethyl)benzonitrile, 4-(5-{[{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}(3-hydroxy-benzyl)amino]methyl}imidazol-1-ylmethyl)-benzonitrile, 4-(5-{[{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}(3-methoxy-benzyl)amino]methyl}imidazol-1-ylmethyl)benzonitrile, 4-(5-{[{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-(3,4-dichloro-benzyl)amino methyl}imidazol-1-ylmethyl)benzonitrile, 4-{5-[({4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}thiophen-3-ylmethylamino)methyl]imidazol-1-ylmethyl}benzonitrile, 4-{5-[(benzo[1,3]dioxol-5-ylmethyl-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}amino)methyl]imidazol-1-ylmethyl}benzonitrile, 4-{5-[(butyl-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}amino)-methyl]imidazol-1-ylmethyl}benzonitrile, 4-(5-{[{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}(3-phenyl-propyl)amino]methyl}imidazol-1-ylmethyl)benzonitrile, 4-{5-[((3-fluorobenzyl)-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}amino)-methyl]imidazol-1-ylmethyl}benzonitrile, 4-{5-[((4-fluorobenzyl)-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}amino)-methyl]imidazol-1-ylmethyl}benzonitrile, 4-{5-[((4-fluorobenzyl)-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}amino)-methyl]imidazol-1-ylmethyl}benzonitrile, 4-{5-[((3-methoxybenzyl)-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}-amino)-methyl]imidazol-1-ylmethyl}benzonitrile, 4-{5-[((3,4-dichlorobenzyl)-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}-amino)methyl]imidazol-1-ylmethyl}benzonitrile, 4-{5-[({4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}thiophen-3-ylmethyl-amino)methyl]imidazol-1-ylmethyl}benzonitrile, 4-{5-[(benzo[1,3]dioxol-5-ylmethyl-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}amino)methyl]imidazol-1-ylmethyl}benzonitrile, 4-{5-[(butyl-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}amino)methyl]-imidazol-1-ylmethyl}benzonitrile, 4-{5-[((3-phenylpropyl)-{4-[4-(thiophene-2-carbonyl)-1-piperazinyl]phenyl}-amino)methyl]imidazol-1-ylmethyl}benzonitrile, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-(1-methyl-1H-benzoimidazol-2-ylmethyl)benzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-(2-methyl-3H-imidazol-4-ylmethyl)benzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-thiazol-2-ylmethylbenzamide, N-{4-[4-(3-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide, N-{4-[4-(benzo[b]thiophene-2-carbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide, N-{4-[4-(3-chlorobenzo[b]thiophene-2-carbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(2-thiophen-2-ylacetyl)-1-piperazinyl]phenyl}benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(furan-2-carbonyl)-1piperazinyl]phenyl}benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(isoxazole-5-carbonyl)-1-piperazinyl]phenyl}benzamide, N-(4-{4-[3-(2-chlorophenyl)-5-methylisoxazole-4-carbonyl]-1-piperazinyl}phenyl)-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(5-methylthiophene-2-carbonyl)-1-piperazinyl]phenyl}benzamide, N-{4-[4-(5-bromothiophene-2-carbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(thiophene-3-carbonyl)-1-piperazinyl]phenyl}benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(2-thiophen-3-ylacetyl)-1-piperazinyl]phenyl}benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(4-thiophen-2-ylbutyryl)-1-piperazinyl]phenyl}benzamide, N-(4-{4-[2-(5-chlorobenzo[b]thiophen-3-yl)acetyl]-1-piperazinyl}phenyl)-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(4-oxo-4-thiophen-2-ylbutyryl)-1-piperazinyl]phenyl}benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(5-oxo-5-thiophen-2-ylpentanoyl)-1-piperazinyl]phenyl}benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(1-methyl-1H-pyrrole-2-carbonyl)-1-piperazinyl]phenyl}benzamide, N-(4-{4-[5-(4-chlorophenyl)-furan-2-carbonyl]-1-piperazinyl}-phenyl)-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(5-methyl-1-phenyl-1H-pyazole-4-carbonyl)-1-piperazinyl]phenyl}benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(3,5-dimethylisoxazole-4-carbonyl)-1-piperazinyl]phenyl}benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(5-methyl-2-phenyl-2H-[1,2,3]triazole-4-carbonyl)-1-piperazinyl]phenyl}benzamide, N-{4-[4-(5-chlorothiophen-2-ylmethyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(3-methylthiophen-2-ylmethyl)-1-piperazinyl]phenyl}benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(5-methylthiophen-2-ylmethyl)-1-piperazinyl]phenyl}benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(5-ethylthiophen-2-ylmethyl)-1-piperazinyl]phenyl}benzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-(2-phenyl-1-Himidazol-4-ylmethyl)benzamide, 4-(4-{benzenesulfonyl-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}phenyl)-1-piperazinecarbothioic acid isobutylamide, 4-(4-{benzenesulfonyl-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}phenyl)-1-piperazinecarbothioic acid propylamide, 4-(4-{benzenesulfonyl-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}phenyl)-1-piperazinecarbothioic acid cyclohexylamide, 4-(4-{benzenesulfonyl-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}phenyl)-1-piperazinecarbothioic acid benzylamide, 4-(4-{(4-cyanobenzenesulfonyl)-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}phenyl)-1-piperazinecarbothioic acid isobutylamide, 4-(4-{(4-cyanobenzenesulfonyl)-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}phenyl)-1-piperazinecarbothioic acid propylamide, 4-(4-{(4-cyanobenzenesulfonyl)-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}phenyl)-1-piperazinecarbothioic acid cyclohexylamide, 4-(4-{(4-cyanobenzenesulfonyl)-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}phenyl)-1-piperazinecarbothioic acid cyclohexylmethylamide, 4-(4-{(4-cyanobenzenesulfonyl)-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amino}phenyl)-1-piperazinecarbothioic acid benzylamide, 4-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-[4-(4-isobutylthiocarbamoyl-1-piperazinyl)phenyl]benzamide, 4-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-[4-(4-propylthiocarbamoyl-1-piperazinyl)phenyl]benzamide, 4-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-[4-(4-cyclohexylthiocarbamoyl-1-piperazinyl)phenyl]benzamide, 4-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-{4-[4-(cyclohexylmethylthiocarbamoyl)-1-piperazinyl]phenyl}benzamide, N-[4-(4-benzylthiocarbamoyl-1-piperazinyl)-phenyl]-4-cyano-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide, N-[3-(4-cyano-benzyl)-3H-imidazol-4-ylmethyl]-3-fluoro-N-[4-(4-isobutylthiocarbamoyl-1-piperazinyl)-phenyl]benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-fluoro-N-[4-(4-propylthiocarbamoyl-1-piperazinyl)phenyl]benzamide, N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-N-[4-(4-cyclohexylthiocarbamoyl1-piperazinyl)phenyl]-3-fluorobenzamide, N-[4-(4-benzylthiocarbamoyl-1-piperazinyl)phenyl]-N-[3-(4-cyanobenzyl)-3-Himidazol-4-ylmethyl]-3-fluorobenzamide, 4-{4-[1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-(2-methylsulfanylpheenyl)-ureido]phenyl}-1-piperazinecarbothioic acid propylamide, 4-(4-{1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-propylureido}phenyl)-1-piperazinecarbothioic acid isobutylamide, 4-(4-{1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-propylureido}phenyl)-1-piperzinecarbothioic acid propylamide, 4-(4-{1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-propylureido}phenyl)-1-piperzinecarbothioic acid cyclohexylamide, 4-(4-{1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-propylureido}phenyl)-1-piperzinecarbothioic acid cyclohexylmethylamide, 4-(4-{1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-propylureido}phenyl)-1-piperazinecarbothioic acid benzylamide, N-(3H-imidazol-4-ylmethyl)-N-[4-(4-isobutylthiocarbamoyl-1-piperazinyl)phenyl]-3-methoxybenzamide, 3-fluoro-N-(3H-imidazol-4-ylmethyl)-N-[4-(4-isobutylthiocarbamoyl-1-piperazinyl)phenyl]benzamide, cyclopropanecarboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-]3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide, cyclobutanecarboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide, cyclopentanecarboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-[3-(4-cyanobezyl)-3H-imidazol-4-ylmethyl]amide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-cyclopentylpropionamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-2-cyclopentylacetamide, naphthalene-1-carboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide, biphenyl-4-carboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3-H-imidazol-4-ylmethyl]-3,5-dimethoxybenzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-methylbenzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-etoxybenzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3-H-imidazol-4-ylmethyl]-4-ethylbenzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-9-hexylbenzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-4-methylbenzamide, 4-butyl-N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]benzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3,4-difluorobenzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-trifluoromethoxybenzamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]acetamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3-imidazol-4-ylmethyl]-2-phenoxyacetamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-2-phenylacetamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]propionamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]butyramide, furan-2-carboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-2-thiophen-2-ylacetamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-methanesulfonamide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3,4-dimethylbenzarnide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-3-fluoro-4-methylbenzamide, 2-chloro-N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-5-methylsulfanylbenzamide, 3-methoxycyclohexanecarboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide, 4-methylcyclohexanecarboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide, 1-methylcyclohexanecarboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide, N-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}-N-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-2-naphthalen-1-ylacetamide, 2-phenylcyclopropanecarboxylic acid {4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]amide, 4-{5-[(benzyl-{4-[4-(5-chloro-2-thiophenecarbonyl)-1-piperazinyl]phenyl}amino)-methyl]imidazol-1-ylmethyl}benzonitrile, and the therapeutically acceptable salts and solvates thereof.
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34. A process for preparing a compound of claim 23, wherein an intermediate of general formula (V)
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35. The process for preparing a compound of claim 23, wherein an intermediate of general formula (VIII)
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36. A pharmaceutical composition containing, as active principal, a compound of claim 23 in combination with a pharmaceutically acceptable vehicle.
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37. A method for treating a living animal body afflicted with a condition selected from disorders associated with farnesylation and/or geranylgeranylation of proteins, comprising the step of administering to the living animal body an effective amount of a compound of claim 23 for alleviation of the condition.
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38. A method for treating a living animal body afflicted with a condition selected from cancers such as cancer of the lung, of the pancreas, of the skin, of the head, of the neck, of the uterus, of the ovaries, anal cancer, cancer of the stomach, of the colon, of the breast, of the esophagus, of the small intestine, of the thyroid gland, of the prostate, of the kidney, of the bladder, acute or chronic leukemia, or a combination of two or more of these cancers, comprising the step of administering to the living animal body an effective amount of a compound of claim 23 for alleviation of the condition.
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39. A pharmaceutical composition of claim 36 in combination especially with an anticancer agent such as cytotoxic anticancer agents, especially navelbine, vinflunine, taxol, taxotere, 5-fluorouracil, le methotrexate, doxorubicin, camptothecin, gemcitabine, etoposide, cisplatin or BCNU, or hormonal anticancer agents, for instance tamoxifen or medroxyprogesterone, for their simultaneous, separate or sequential use, for the treatment or prevention of cancers.
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40. A pharmaceutical composition of claim 36, in combination with an agent for inhibiting the biosynthesis of farnesyl and geranylgeranyl pyrophosphates, such as an HMG-CoA reductase inhibitor, for instance lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin or cerivastatin, for their simultaneous, separate or sequential use.
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41. A pharmaceutical composition of claim 36, in combination with a treatment with radiation (X-rays or gamma rays) for their simultaneous, separate or sequential use for treating or preventing cancers.
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42. A method of preventing or treating restenosis or atherosclerosis in a living animal body, comprising the step of administering to the living animal body a compound of claim 23 which is effective for preventing and treating such affliction.
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43. A method of preventing or treating infections associated with PFTase such as delta hepatitis in a living animal body, comprising the step of administering to the living animal body a compound of claim 23 which is effective for preventing and treating such affliction.
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44. A method of preventing or treating benign proliferative disorders in a living animal body, comprising the step of administering to the living animal body a compound of claim 23 which is effective for preventing and treating such affliction.
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24. A compound of claim 23, wherein R1, R2, R3 and R4 each represent a hydrogen and Y is a methylene (CH2).
Specification
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Current AssigneePierre Fabre Medicament (Fondation Pierre Fabre)
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Original AssigneePierre Fabre Medicament (Fondation Pierre Fabre)
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InventorsHill, Bridget, Perez, Michel, Kruczynski, Anna, Lamothe, Marie
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Application NumberUS10/399,069Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current514/249CPC Class CodesA61P 1/16 for liver or gallbladder di...A61P 31/12 AntiviralsA61P 35/00 Antineoplastic agentsA61P 35/02 specific for leukemiaA61P 43/00 Drugs for specific purposes...A61P 9/10 for treating ischaemic or a...C07D 233/64 with substituted hydrocarbo...C07D 401/12 linked by a chain containin...C07D 405/12 linked by a chain containin...C07D 409/12 linked by a chain containin...C07D 409/14 containing three or more he...C07D 417/12 linked by a chain containin...Y02P 20/55 Design of synthesis routes,...