Tricyclic compounds that inhibits farnesyl protein transferase I but not geranylgeranyl protein transferase I in the treatment of cancer or cancer-like conditions

摘要

The use of compounds represented by formula I as farnesyl transferase protein inhibitors. The tricyclic compounds disclosed does not inhibit geranylgeranyl protein transferase I, in vitro, as it appears to block the phenotypic change induced by a form of transforming Ras engineered to be a geranylgeranyl acceptor, blocks intracellular processing of Ras which is a farnesyl acceptor but not of a Ras engineered to be a geranylgeranyl acceptor and it blocks abnormal cell growth in cell culture induced by transforming Ras. The pharmaceutical composition is useful for inhibiting abnormal cell growth, such as tumours. Wherein; One of a, b, c and d represents N or NR9 wherein R9 is O-, -CH3 or -(CH2)nCO2H wherein n is 1 to 3, and the remaining a, b, c and d groups represent CR1 or CR2; or a, b, c, and d are independently selected from the group consisting of CR1 and CR2; wherein R1 and R2 are independently selected from the group consisting of H, halo, -CF3, -OR10, -COR10, -SR10, -S(O)tR11 wherein t is 0,1 or 2, -SCN, -N(R10)2, -NR10R11, -NO2, -OC(O)R10, -C02R10, -OCO2R11, -CN, -NHC(O)R10, -NHSO2R10, -CONHR10, -CONHCH2CH2OH, -NR10COOR11, Formula II, -SR11C(O)OR11, -SR11N(R75)2, wherein each R75 is independently selected from H and -C(O)OR11, benzotriazol-1-yloxy, tetrazol-5-ylthio, substituted tetrazol-5-ylthio, alkynyl, alkenyl and alkyl, R3 and R4 are independently selected from the group consisting of H, R1 and R2, or R3 and R4 taken together represent a saturated or unsaturated C5-C7 fused ring to the benzene ring; R5, R6, R7 and R8 are independently selected from the group consisting of H, -CF3, -COR10, alkyl and aryl, and R10 represents H, alkyl, aryl, or aralkyl; X represents N, CH or C, which C may contain an optional double bond (represented by the dotted line) to carbon atom 11; the dotted line between carbon atoms 5 and 6 represents an optional double bond, such that when a double bond is present, A and B independently are selected from the group consisting of -R10, halo, -OR11, -OC02R11 and -OC(O)R10, and when no double bond is present between carbon atoms 5 and 6, A and B each independently represent (H, H), (OR11, -OR11), (H, halo), (halo, halo), (alkyl, H), (alkyl, alkyl), (H, -OC(O)R10), (H, -OR10), =O, (aryl, H) and =NOR10, or A and B together are -O-(CH2)p-O- wherein p is 2, 3 or 4; and R represents: (1) -C(O)N(R10)2; (2) -CH2C(O)N(R1 )2; (3) -SO2-alkyl, -SO2-aryl, -S02-aralkyl, -SO2-heteroaryl or -SO2 heterocycloalkyl; (4) cyano; (5) an imidate represented by the formula III; (6) an imidamido group of the formula IV; (7) a 1-amino-2-nitroethylene derivative of the formula V; (8) -C(O)R16; (9) -O(O)-O-R16; (10) Formula VI; (11) alkyl, aryl. aralkyl, cycloalkyl, heterocycloalkyl or heteroaryl; (12) -S02NR10R14; (13) -P(O)(R10)2; (14) a sugar group of the formula VII, VIII, IX; (15) -CH2C(O)OR28.