Farnesyl transferase inhibitors in combination with HMG CoA reductase inhibitors for the treatment of cancer

A pharmaceutical composition for the treatment of cancer or a benign proliferative disorder in a mammal, comprising an FTase inhibitor, an HMG CoA reductase inhibitor and a pharmaceutically acceptable carrier, wherein the FTase inhibitor and the HMG CoA reductase inhibitor are present in amounts that render the composition effective in the treatment of cancer or a benign proliferative disorder and wherein the FTase inhibitor is selected from:

• (a) compounds of the formula I
• 8
• wherein:
• R1 and R2 are independently selected from the group consisting of —(CH2)p(5-10 membered heterocycles), —(CH2)p(C6-C10 aryl), allyl, propargyl and C1-C6 alkyl wherein p is 0 to 3, said alkyl and the alkyl moieties of said R1 and R2 groups are optionally substituted by 1 to 3 R9 substituents, and the aryl and heterocyclic moieties of said R1 and R2 groups are optionally substituted by 1 to 3 substituents independently selected from halo and R9;
• R3 is —(CH2)m(1- or 2-adamantyl), —(CH2)m(C3-C10 cycloalkyl), —(CH2)m(C6-C10 aryl), C1-C10 alkyl,
• 9
• wherein m is 0 to 6, and said cycloalkyl and alkyl optionally contain 1 or 2 double or triple bonds;
• X1, X2, and X3 are each independently C1-C7 alkylene optionally containing 1 or 2 double or triple bonds, X4 is a bond or C1-C7 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 C6-C10 aryl, 5-10 membered heterocyclyl or C1-C6 alkyl wherein each of said 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(C1-C4 alkyl), —C(NR8)NR8R6, —C(NCN)NR8R6, —C(NCN)S(C1-C4 alkyl), —NR8C(NCN)S(C1-C4 alkyl), —NR8C(NCN)NR8R6, —NR8SO2(C1-C4 alkyl), —S(O)n(C1-C4 alkyl) wherein n is 0 to 2, —NR8C(O)C(O)NR8R6, —NR8C(O)C(O)R8, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl, and C1-C4 alkyl optionally substituted by 1 to 3 fluoro substituents;
• each R6 and R7 is independently hydrogen or C1-C4 alkyl;
• each R8 is independently R6 or —OR6;
• and,
• each R9 is independently selected from cyano, R6, —OR6, —OC(O)R6, —C(O)OR6, —C(O)NR6R7, —NR6R7, —NR6R8, —SO2NR6R7, and C1-C4 alkyl substituted by hydroxy;
• (b) compounds of the formula IIA or IIB
• 10
• wherein:
• R1 is hydrogen, halo (e.g. chloro, fluoro, bromo or iodo), 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-fluoro-4-pyridyl or 3-fluoro-4-pyridyl;
• R4 is 1-adamantyl 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, (C1-C4) straight or branched alkyl, phenyl or benzyl, wherein said phenyl and the phenyl moiety of said benzyl may optionally be substituted with halo, hydroxy, nitro, cyano, amino, (C1-C4) straight or branched alkyl, (C1-C4) straight or branched alkoxy, phenyl, benzyl, (C1-C4) alkylamino, di[(C1-C4)alkyl]amino, or —S(O)m—(C1-C4) straight or branched 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, (C1-C3)alkyl, hydroxy, (C1-C3)alkoxy, nitro, trifluoromethyl, cyano, amino, (C1-C3)alkylamino and di[(C1-C3)alkyl]amino;
• Het′ and Het″ are selected, independently, from 6 membered heterocyclic rings containing from one to four nitrogen atoms as part of the ring, optionally substituted with one substituent selected from (C1-C3)alkyl, halo, hydroxy, (C1-C3) alkoxy, amino, (C1-C3)alkylamino and di[(C1-C3)alkyl]amino;
• (c) compounds of the formula III
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• 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, (C1-C10)alkyl-S—, (C1-C10)alkyl-SO—, (C1-C10)alkyl-SO2—, adamant-2-yl-S—, naphthyl-S—, benzyl-S—, phenyl-C(═O)CH2—S—, (C1-C6)alkyl-O—C(═O)—CH2—S— or (H,H) (i.e., Z represents two hydrogen atoms, each of which is single bonded to the same carbon of ring A) when Z is single bonded to ring A, and wherein said naphthyl and phenyl and the phenyl moiety of said benzyl may optionally be substituted with from one to three substituents independently selected from (C1-C6) alkyl optionally substituted with from one to three fluorine atoms, (C1-C6) alkoxy optionally substituted with from one to three fluorine atoms, halo (e.g., chloro, fluoro, bromo or iodo), amino, (C1-C6)alkylamino, [di-(C1-C6) alkyl]amino, cyano, nitro, (C1-C6)alkyl-SOn— wherein n is zero, one or two, —COOH, —COO(C1-C6)alkyl and —C(O)NH(C1-C6)alkyl;
• X is NR1 or CHR1;
• R1 is hydrogen, (C1-C6)alkyl or (C1-C6)alkylphenyl when ring A is saturated (i.e., when ring A contains no double bonds) and R1 is absent when ring A contains a double bond;
• R2 is selected from naphthyl, phenyl, (C1-C6)alkylphenyl, 1-adamantyl, 2-adamantyl, (C1-C8) straight or branched alkyl, (C3-C10) cycloalkyl and (C8-C30)bicyclic or tricyclic alkyl;
• wherein said (C3-C10)cycloalkyl and said (C8-C30)bicyclic or tricyclic alkyl may optionally be substituted with a hydroxy group;
• and wherein said adamantyl groups may optionally be substituted with from one to three substituents independently selected from (C1-C6)alkyl, halo and hydroxy;
• and
• R3 and R4 are independently selected from benzyl, wherein the phenyl moiety of said benzyl may optionally be substituted with an amino or nitro group;
• hydrogen, phenyl, (N≡C)—(C1-C6)alkyl, (C1-C6)alkyl-O—C(═O)—(C1-C6)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 (a) no more than one of the two dotted lines can represent a double bond in any one compound, (b) when Z is (H, H), X is CH2, (c) when Z is oxygen or (H, H) and X is CHR1, R1 must be hydrogen, (d) when Z is sulfur and X is NR1, R1 must be hydrogen, and (e) one of R3 and R4 must be Het-CH2;
• and
• (d) the compound IV
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• and the pharmaceutically acceptable salts of the foregoing compounds.