Patent NZ-500662-A (NZ)
Title: Farnesyl transferase inhibitors in combination with HMG CoA reductase inhibitors for the treatment of cancer
Inventor: KAJIJI SHAMA MOHAMMED
IPC: A61K45/06
Filed: 1998-06-05
Abstract: A pharmaceutical composition comprising a HMG CoA reductase inhibitor selected from atorvastatin, pravastatin, lovastatin, compactin fluvastatin and simvastatin; and a FTase inhibitor is selected from: (a) compounds of the formula I, wherein: R1 and R2 are independently selected from the group consisting of -(CH2)p-heterocycle, -(CH2)p-aryl, allyl, propargyl and alkyl; wherein the alkyl moieties are optionally substituted by 1 to 3 R9 substituents, and the aryl and heterocyclic moieties are optionally substituted by 1 to 3 substituents independently selected from halo and R9; p is 0 to 3; R3 is -(CH2)m(1- or 2-adamantyl), -(CH2)mcycloalkyl, -(CH2)m-aryl, alkyl or a substituent of formulae (A) or (B), wherein the cycloalkyl and alkyl moieties optionally contain 1 or 2 double or triple bonds; m is 0 to 6, X1, X2, and X3 are each independently alkylene optionally containing 1 or 2 double or triple bonds; X4 is a bond or alkylene optionally containing 1 or 2 double or triple bonds, and, in formula (B), the X4 moiety is attached to the X1 moiety at any available carbon in the X1 moiety; R4 is aryl, heterocyclyl or alkyl wherein each of the R4 groups is optionally substituted by 1 to 3 R5 substituents; each R5 is independently selected from the group consisting of halo, nitro, cyano, phenyl, C(O)OR6, -SO2NR6R7, -NR6R8, -C(O)R6, -OR6, -C(O)NR6R8, -OC(O)NR6R8, -NR8C(O)NR8R6, -NR8C(O)R6, -NR8C(O)O(alkyl), -C(NR8)NR8R6, -C(NCN)NR8R6, -C(NCN)S(alkyl), -NR8C(NCN)S(alkyl), -NR8C(NCN)NR8R6, -NR8SO2(alkyl), -S(O)n(alkyl) wherein n is 0 to 2, -NR8C(O)C(O)NR8R6, -NR8C(O)C(O)R8, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, and alkyl optionally substituted by 1 to 3 fluoro substituents; each R6 and R7 is independently hydrogen or alkyl; each R8 is independently R6 or -OR6; each R9 is independently selected from cyano, R6, -OR6, -OC(O)R6, -C(O)OR6, -C(O)NR6 R7, -NR6R7, -NR6R8, -SO2NR6R7, and alkyl substituted by hydroxy; (b) compounds of formulae IIA or IIB wherein: R1 is hydrogen, halo, cyano, hydroxy, nitro, trifluoromethyl, -NHR5, -NR5R5, R5, -OR5 or -S(O)m-R5; R2 is -(CH2)n-Y or -OCOR5; R3 is 4-, 3-, or 2-pyridyl, pyrimidyl, pyrazinyl, 2- or 3-fluoro-4-pyridyl; R4 is 1- or 2-adamantyl; Y is hydrogen, hydroxy, amino, cyano, -NHR5, -NR5R5, -NHCOR5, -NHCO2R5, halo, OR5, -S(O)mR5, -CO2H, -CO2R5, -CONR5R5, -CONHR5, -CONH2, -COR5, -CH=CHCO2R5, -OCOR5, phenyl, phenyl substituted with W, -C=CCO2R5, -CH=CHR5 or -C=CR5; each R5 is, independently, straight or branched alkyl, phenyl or benzyl, wherein the phenyl and the phenyl moiety of the benzyl may optionally be substituted with halo, hydroxy, nitro, cyano, amino, straight or branched alkyl, straight or branched alkoxy, phenyl, benzyl, alkylamino, dialkylamino, or -S(O)m-alkyl; each W is, independently, halo, R5, hydroxy, -OR5, nitro, amino, -NHR5, -NR5R5, cyano, or S(o)m-R5; m is 0, 1 or 2; n is 1 to 7; p is 0 or 1; E1 and E2 are selected, independently, from hydrogen, halo, alkyl, hydroxy, alkoxy, nitro, trifluoromethyl, cyano, amino, alkylamino and dialkylamino; Het and Het" are independently selected from 6-membered heterocyclic rings containing from one to four nitrogen atoms, optionally substituted with one substituents selected from alkyl, halo, hydroxy, alkoxy, amino, alkylamino and dialkylamino; (c) compounds of the formula III wherein: both dotted lines represent optional double bonds; Z is oxygen or sulfur when it is double bonded to ring A and Z is hydroxy, alkyl-S-, alkyl-SO-, alkyl-SO2-, adamant-2-yl-S-, naphthyl-S-, benzyl-S-, phenyl-C(=O)CH2-S, alkyl-O-C(=O)-CH2-S- or (H,H) when Z is single bonded to ring A; and wherein the naphthyl and phenyl and the phenyl moiety of the benzyl may optionally be substituted with from one to three substituents independently selected from alkyl and alkoxy optionally substituted with from one to three fluorine atoms, halo, amino, alkylamino, dialkylamino, cyano, nitro, alkyl-SOn- wherein n is zero, one or two, -COOH, -COO(C,-C6)alkyl and C(O)NHalkyl; X is NR1or CHR1; R1 is hydrogen, alkyl or alkylphenyl when ring A is saturated and R1 is absent when ring A contains a double bond; R2 is selected from naphthyl, phenyl, alkylphenyl, 1- or 2-adamantyl, straight or branched alkyl; monocyclic, bicyclic or tricyclic alkyl which may optionally be substituted with a hydroxy group; and wherein the adamantyl groups may optionally be substituted with from one to three substituents independently selected from alkyl, halo and hydroxy; R3 and R4 are independently selected from benzyl, wherein the phenyl moiety of the benzyl may optionally be substituted with an amino or nitro group; hydrogen, phenyl, (N=-C)-alkyl, alkyl-O-C(=O)-alkyl and Het-CH2, wherein Het is selected from 2-, 3- or 4-pyridinyl, furyl, tetrahydrofuryl, pyrimidyl, pyrazinyl, pyrazolyl, isoxazolyl, thiophenyl and triazolyl; with the proviso that (i) no more than one of the two dotted lines can represent a double bond in any one compound, (ii) when Z is (H, H), X is CH2, (iii) when Z is oxygen or (H, H) and X is CHR1, R1 must be hydrogen, (iv) when Z is sulfur and X is NR1, R1 must be hydrogen, and (v) one of R3 and R4 must be Het-CH2; and (d) the compound of formula IV. The compositions are useful for the treatment of cancer or a benign proliferative disorder and inhibiting abnormal cell growth.