Patent ID: 6541491
Filing Date: 2003-04-01
Classification: A61P,C07D

Abstract:
A pharmaceutical composition comprising an inhibitor of ras farnesylation of Formula I wherein:R1 is selected from H; â€”C1-4alkyl; â€”C1-3alkylene-Ph optionally mono or di-substituted on Ph with substituents selected from C1-4alkyl, halogen, OH, C1-4alkoxy, C1-4alkanoyl, C1-4alkanoyloxy, amino, C1-4alkylamino, di(C1-4alkyl)amino, C1-4alkanoylamino, nitro, cyano, carboxy, carbamoyl, C1-4alkoxycarbonyl, thiol, C1-4alkylsulfanyl, C1-4alkylsulfinyl, C1-4alkylsulfonyl and sulfonamido; â€”COâ€”C1-4alkyl; â€”COâ€”Oâ€”C1-4alkyl; â€”COâ€”Oâ€”C2-4alkenyl; â€”COOâ€”(CH2)nPh optionally substituted on Ph as defined for substitution on Ph in R1=â€”C1-3alkylene-Ph in this claim 1 and n=0-4; â€”C1-4alkylene-CONR4R5 where R4 and R5 are independently selected from H, C1-4alkyl; and â€”C1-4alkylene-COOR6 where R6 is selected from H, C1-4alkyl; R2 is selected from H; â€”C1-4alkyl, â€”C1-3 alkylene-Ph optionally substituted on Ph as defined for substitution on Ph in R1=â€”C1-3 alkylene-Ph in this claim 1; â€”COC1-4alkyl; and â€”COOC1-4alkyl; R3 is selected from H; OH; CN; CF3; NO2: â€”C1-4alkyl; â€”C1-4alkylene-R7 where R7 is selected from phenyl, naphthyl, and a 5-10 membered monocyclic or bicyclic heteroaryl ring containing up to 5 heteroatoms selected from O, N and S and any aryl ring in R7 is optionally substituted as defined for substitution on the Ph group in R1=â€”C1-3alkylene-Ph in claim 1; R7; C2-4alkenyl; halogen; â€”(CH2)nCOOR8 where n=0-3 and R8 represents H, C1-4alkyl, C2-4alkenyl; â€”CONR9 R10 where R9 and R10 independently represent H, C1-4alkyl, C2-4alkenyl, â€”Oâ€”C1-4alkyl, â€”Oâ€”C2-4alkenyl, or â€”C1-3alkylenePh optionally substituted as defined for this group for R1 in this claim 1; â€”CON(R11)OR12 where R11 and R12 independently represent H, C1-4alkyl and C2-4alkenyl; a group of Formula II, â€”CONR13 CHR14 COOR17, where R13 is H or C1-4alkyl, R17 is H or C1-6alkyl, R14 is selected from the side chain of a lipophilic amino acid, carbamoylC1-4alkyl, N-(monoC1-4alkyl)carbamoylC1-4alkyl and N-(diC1-4alkyl)carbamoylC1-4alkyl; the group of Formula II having L or D configuration at the chiral alpha carbon in the corresponding free amino acid; a lactone of formula C1-4alkyl monosubstituted on carbon with &boxH;Nâ€”OH; a group of Formula â€”Xâ€”R15 where X is selected from 0, CO, CH2, S, SO, SO2 and R15 is selected from C1-6alkyl, phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms selected from O, N and S and any aryl ring in R15 is optionally substituted as defined for the Ph group in R1=â€”C1-3alkylene-Ph in this claim 1;p is 0-3 in which R3values can be the same or different; L is a linking moiety selected from the following groups written from left to right in Formula I: â€”COâ€”NR16-where R16 is selected from H, C1-4alkyl, C1-4alkylene-Z, â€”COâ€”C1-4alkylene-Z, â€”COâ€”C1-6alkyl, â€”COZ, and Z, and Z is selected from 0-C1-4alkyl, phenyl, naphthyl, a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms selected from O, N and S and any aryl ring in R16 is optionally substituted as defined for the Ph group in R1=â€”C1-3alkylene-Ph in this claim 1 â€”CH2â€”NR18â€” where R18 represents any value defined for R16; â€”CH2Sâ€”; â€”CH2Oâ€”; â€”CH2â€”CHR19â€” where R19 represents any value defined for R16; â€”CH2Sâ€”; â€”CH2Oâ€”; â€”CH2CHR19â€” where R19 represents any value defined for R16; â€”CH&boxH;CR20â€” where R20 represents any value defined for R16; â€”CH2NR21â€”Tâ€” where R21 represents any value defined for R16, T represents â€”(CH2)nâ€” where n is 1-4 and T is optionally monosubstituted with R22 where R22 represents any value for R16 other than H; â€”CH2NR23â€”SO2â€” where R23 represents any value defined for R16; where n is 0-4 and T is optionally monosubstituted with R29 where R29 represents any value for R16 other than H; â€”COâ€”NR25 â€”Tâ€” where R25 represents any value defined for R16, T represents â€”(CH2)nâ€” where n is 1-4 and T is optionally monosubstituted with R26 where R26 represents any value for R16 other than H; â€”CH2Sâ€”Tâ€” where T represents â€”(CH2)nâ€” where n is 1-4 and T is optionally monosubstituted with R27 where R27 represents any value for R16 other than H; â€”CH2Oâ€”Tâ€” where T represents â€”(CH2)nâ€” where n is 1-4 and T is optionally monosubstituted with R28 where R28 represents any value for R16 other than H; A is selected from phenyl; naphthyl; a 5-10 membered monocyclic or bicyclic heteroaryl ring containing upto 5 heteroatoms where the heteroatoms are independently selected from O, N and S; or a â€”Sâ€”Sâ€” dimer thereof when R2=H; or a N-oxide thereof, or an enantiomer, diastereoisomer, pharmaceutically acceptable salt, prodrug or solvate thereof together with a pharmaceutically acceptable diluent or carrier.