Imidazole-containing inhibitors of farnesyl protein transferase.

摘要

Inhibition of farnesyl transferase, which is an enzyme involved in ras oncogene expression, is effected by compounds of the formula their enantiomers, diastereomers, and pharmaceutically acceptable salts, prodrugs, and solvates, wherein: G is G<1> is G<2> is or -NR<1><0>-CH(Q<1>)-; J, K and L are each, independently, N, NR<9>, O, S or CR<1><0> with the provisos that only one of the groups J, K and L can be O or S, and at least one of the groups J or L must be N, NR<9>, O or S to form a fused five-membered heteroring; the bond between J and K or K and L may also form one side of a phenyl ring fused to the fused five-membered heteroring; Q is aryl; Q<1>, A<1> and A<2> are each, independently, H, alkyl, substituted alkyl, phenyl or substituted phenyl; G<3> is R<1><1>, -C(O)OR<1><1>, -C(O)NR<1><1>R<1><2>, 5-tetrazolyl, -C(O)N(R<1><3>)OR<1><1>, -C(O)NHSO2R<1><4> or -CH2OR<1><1>; G<4> is attached at the 1, 2, 4 or 5 position and optionally substituted, at any of the available position or positions on the ring, with halo, alkyl or substituted alkyl having 1 to 20 carbon atoms, alkoxy, aryl, aralkyl, hydroxy, alkanoyl, alkanoyloxy, amino, alkylamino, dialkylamino, alkanoylamino, thiol, alkylthio, alkylthiono, alkylsulfonyl, sulfonamido, nitro, cyano, carboxy, carbamyl, N-hydroxycarbamyl, N-alkylcarbamyl, N-dialkylcarbamyl, alkoxycarbonyl, phenyl, substituted phenyl, or a combinaton of these groups; Y and Z are each, independently, -CH2- or -C(O)-; R<1> - R<1><4> are each, independently, H or alkyl having 1 to 20 carbon atoms; R<7>, R<8> and R<1><4> may also be aryl or aralkyl, and R<3>, R<9>, R<1><1>, R<1><2> and R<1><3> may also be aralkyl; m, n and p are each, independently, 0 or an integer from 1 to 2; q is 0 or an integer from 1 to 4; and the dotted line represents an optional double bond.