MXPA99011798A - FARNESYL TRANSFERASE INHIBITORS IN COMBINATION WITH HMG CoA REDUCTASE INHIBITORS FOR THE TREATMENT OF CANCER - Google Patents

Abstract

The present invention relates to a method of treating cancer in a mammal, including a human, by administering to the mammal a FTase inhibitor in combination with an HMG CoA reductase inhibitor.

Description

INHIBITORS OF FARNES1L TRANSFERASA COMBINED WITH INHYIDS OF HMG CoA REDUCTASA FOR THE TREATMENT OF CANCER This invention relates to the use of a farnesyl transferase inhibitor (FTase) combined with an inhibitor of hydroxymethylglutaryl-i coenzyme A (HMG CoA) reductase to treat cancer in a mammal. ^ Oncogenes are genes that, when activated, encode protein components of signal transduction pathways, which cause the abnormal stimulation of cell development and mitogenesis. The expression of oncogenes in cultured cells causes a cellular transformation, = z. 'characterized by the ability to develop cells in soft agar and by the development of cells as dense foci without the inhibition by contact f that have non-transformed cells. __ Mutation and / or overexpression of certain oncogenes is frequently associated with human cancers and other disorders that involve abnormal (ie, unregulated) cell development. For example, the development of benign or malignant tumors may be caused by the expression of an activated Ras oncogene or by activation of the Ras protein by another gene that has undergone an oncogenic mutation. The abnormal development of T cells that occur in the benign or malignant cells of other proliferative I disorders may be caused by aberrant activation of Ras. HE they frequently report mutant oncogenic forms of Ras in many human cancers, most notably in more than 50% of pancreatic and colon carcinomas (Kohl et al., Science, vol 260, 1834-1837, 1993). The oncogene in Ras is expressed in approximately 40% of malignant solid tumors that do not respond to conventional chemotherapies. The K- isoform! Ras is expressed in approximately 90% of pancreatic tumors and in approximately 40% of cancers of the lung and colon-rectum. The isoform l H-Ras is expressed in approximately 40% of head and throat cancers. The N-Ras isoform is expressed in most thyroid cancers and in approximately 25% of acute myeloid leukemias. In order to acquire the potential of transforming normal cells into cancer cells or i into benign cells having an abnormal development, defined below, the precursor of the Ras oncoprotein must undergo famesilation of the cysteine residue located in a carboxyl-terminated tetrapeptide. Therefore, the inhibitors of the enzyme that catalyzes this modification, the protein farnesyl transferase, are useful as anticancer agents in tumors in which Ras contributes to the transformation. ^ The K-Ras isoform can be farnesylated and geranylgeranylated in intact cells. Potent inhibitors of the enzyme farnesyl transferase (FTase) and which are highly selective for FTase versus geranylgeranyl transferase I (GGTase I) may be unable to block the prenylation of mutant K-Ras and, therefore, be ineffective in inhibiting the development of K-Ras expressing tumor cells.

The author of the present invention has found that the administration of a low dose of an HMG CoA reductase inhibitor, combined with a potent selective inhibitor of FTase, blocks the prenylation of K-Ras and the function of K-ras. , as well as prenylation and function of H-Ras. The activity of the prenyl transferase proteins FTase and GGTase I 1 _ I depends on the concentrations of the isoprenoid substrates, farnesyl pyrophosphates and geranylgeranil, respectively. Mevalonate is the first intermediate involved in the isoprenoid route and its synthesis depends on the activity of HMG CoA reductase. Compounds such as lovastatin and compactin, which are strong binding inhibitors of HMG CoA reductase, block the formation of mevalonate and thus block the soprenoid pathway. Therefore, they inhibit FTase and GGTase I. It is believed that the therapeutic effect of compounds of the two previous classes of drugs (FTase inhibitor and HMG CoA reductase inhibitor) is synergistic. The author of the present invention has found that the combined administration of a FTase inhibitor and an HMG CoA reductase inhibitor solves the limitations of each of them given separately. Thus, it is assumed that the combination is effective in cases in which only one of the agents would not be effective. Japanese patent application JP7316076 published December 5, 1995, relates to an anticancer pharmaceutical composition containing limonene which, although not an inhibitor of FTase, has been shown to prevent the incorporation of isoprene compounds derived from mevalonic acid in Ras and in proteins derived from Ras and from praváStatina which is an inhibitor of HMG CoA reductase. The present invention relates to a pharmaceutical composition for the treatment of cancer or of a benign proliferative disorder in a mammal, including a human being, comprising an inhibitor of FTase, an inhibitor of HMG CoA reductase and a vehicle pharmaceutically acceptable, wherein the active ingredients of said composition (ie, the FTase inhibitor and the HMG CoA reductase inhibitor) are present * = f in amounts that make the composition effective in the treatment of the = »1 cancer or a benign proliferative disorder. ! This invention also relates to a method for treating cancer or a benign proliferative disorder in a mammal, including a human, which comprises administering to said mammal an anticancer or antiproliferative effective amount of a pharmaceutical composition comprising an inhibitor of the invention. FTase, an inhibitor of HMG CoA reductase and a pharmaceutically acceptable vehicle. This invention also relates to a method of treating cancer or a benign proliferative disorder in a mammal, including a human, which comprises administering to said mammal an inhibitor of Ftase and an inhibitor of HMG CoA reductase in amounts which cause the combination of said two active agents is effective in the treatment of cancer or of a benign proliferative disorder.

This invention also relates to a pharmaceutical composition for inhibiting the abnormal development of cells in a mammal, including a human being, comprising an inhibitor of FTase, an inhibitor of HMG CoA reductase and a pharmaceutically acceptable carrier, wherein Active ingredients of said composition (ie, the FTase inhibitor and the HMG CoA reductase inhibitor) are present in amounts which make the composition effective to inhibit the abnormal development of I cells. _, This invention also relates to a method for inhibiting the abnormal development of cells in a mammal, including a human being, which comprises administering to said mammal an inhibitor of FTase and an inhibitor of HMG CoA reductase in amounts which cause the combination of said two active ingredients is effective to inhibit the abnormal development of cells. The term "treat", as used herein, refers to preventing or delaying or inhibiting the progress of the disorder to which that term applies. "Abnormal cell development," as used herein, refers to the development of cells that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This term includes the abnormal development of (1) tumor cells (tumors) that express an activated Ras oncogene, (2) tumor cells in which the Ras protein is activated as a result of oncogenic mutation in another gene and (3) benign cells and malignancies of other proliferative diseases in which ab aberrant activation of Ras occurs. Examples of such benign proliferative diseases are I psoriasis, benign prostatic hypertrophy and restenosis. Patients who can be treated with an inhibitor of FTase t combined with an HMG CoA reductase inhibitor according to the methods of this invention or using the pharmaceutical compositions of the invention include, for example, patients who have been I have been diagnosed with lung cancer, bone cancer, cancer? pancreas, skin cancer, head and throat cancer, cutaneous or infra-ocular melanoma, cancer of the uterus, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecological tumors ( for example, uterine sarcomas, carcinoma of the tubes - I Fallopian, endometrial carcinoma, cervical carcinoma, vaginal carcinoma or vulvar carcinoma), Hodgkin's disease, esophageal cancer, small bowel cancer, cancer of the endocrine system (for example, thyroid, parathyroid or adrenal gland cancer), soft tissue sarcomas, urethral cancer, cancer of the penis, prostate cancer, acute or chronic leukemia, solid tumors of childhood, lymphocytic lymphomas, bladder cancer, kidney or ureter cancer (eg, renal cell carcinoma, carcinoma of the renal pelvis) or neoplasms of the central nervous system (CNS) (for example, primary CNS lymphoma, spinal cord tumors, brainstem gliomas, or pituitary adenomas).

Patients who can be treated with a FTase inhibitor combined with an HMG CoA reductase inhibitor according to the methods of this invention or using the pharmaceutical compositions of the invention also include patients suffering from abnormal cell development, defined above. More specific embodiments of this invention relate to the above pharmaceutical compositions and to methods of treatment in which the FTase inhibitor is selected from:! a) compounds of formula I wherein: I ~ R1 and R2 are independently selected from the group formed ^ - [by - (CH2) P (5-10 membered heterocycles), - (CH2) p- (C6-C? 0 aryl), allyl, propargyl and CrC6 alkyl, wherein p is 0 to 3, said alkyl and alkyl moieties of said groups R1 and R2 are optionally substituted by 1 to 3 substituents R9, and the aryl and heterocyclic moieties of said groups R1 and R2 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), C1-C10 alkyl, wherein m is 0 to 6, and said cycloalkyl and alkyl contain 1 or 2 double or triple bonds; each of X1, X2 and X3 is C? -C7 alkylene optionally containing 1 or 2 double or triple bonds, X4 is a Ci-C7 bond or alkylene optionally containing 1 or 2 double or triple bonds and, in the formula ( B), ejj-this X4 is attached to the remainder X1 at any available carbon of the remainder x1; R 4 is C 1 -C 6 aryl, 5-10 membered heterocycle or C 1 -C 6 alkyl, wherein each of said R 4 groups is optionally substituted by 1 to 3 substituents R 5; 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, -NR8 + C (O) NR8 + R6, -NR8C (O) NR8R6, -NR8C (O) R6, -NR8C (O) O (C4 alkyl), -C (NR8) NR8R6, -C (NCN) NR8R6, -C (NCN) S (CtC4 alkyl), -NR8C (NCN) S (alkyl dC *), -NR8C (NCN) NR8R6, -NR8OR2 (alkyl d-C4), -S (O) n (C C -C alkyl) wherein n is 0 to 2, -NR 8 C (O) C (O) NR 8 R 6, - NR 8 C (O) R 8, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl and C 1 -C 4 alkyl optionally substituted by 1 to 3 fluoro substituents; each of R6 and R7 is independently hydrogen or alkyl ~ i C1-C4; ~~ I each R8 is independently R6 or -OR6; and __ each R9 is independently selected from cyano, R6, -OR6, - OC (0) R6, -C (0) OR6, -C (0) NR6R7, -NR6R7, -NR6R8, -S02NR6R7, and alkyl substituted by hydroxy; and b) compound of formula wherein R1 is hydrogen, halo (e.g., chloro, fluoro, bromo or iodo), cyano "hydroxy, nitro, trifluromethyl, -NHR5, R5, -OR5 or -S (O) mR5; R2 is - (CH2) nY u -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, NHCOsR5, halo, -OR5, -S (O) mR5, -CO2H, -CO2R5, -CONR5R5, -CONHR5, - CONH2, -COR5, -CH = CHCO2R5, -OCOR5, phenyl, phenyl substituted with W, - i C = CCO2R5, -CH = CHR5 or -C = CR5; each R5 is independently linear or branched C1-C4 alkyl, < I phenyl or benzyl, said phenyl and the rest of said benzyl optionally being substituted with halo, hydroxy, nitro, cyano, amino, linear or branched C1-C4 alkyl, linear or branched C1-C4 alkoxy, phenyl, benzyl, ( alkyl d-C4) amino or -S (O) m (C 1 -C 4 alkyl) linear or branched); - I each W is independently halo, R5, hydroxy, -OR5, nitro, amino, -NHR5, -NR5R5, cyano or -S (O) mR5; t m is O, 1 or 2; n is 1 to 7; p is 0 or 1; E1 and E2 are independently selected from hydrogen, halo, C1-C3 alkyl, hydroxy, C1-C3 alkoxy, nitro, trifluoromethyl, cyano, amino, (C?-Cs) amino, and di (alkyl d-C3) -amino; and their pharmaceutically acceptable salts. Het 'and Het "are independently selected from 6-membered heterocyclic rings containing from one to four nitrogen atoms as part of the ring, optionally substituted with a substituent selected from d-C3 alkyl, halo, hydroxy, C1-C3 alkoxy, amino (C 1 -C 3 alkyl) amino ^ and di (C 1 -C 3 alkyl) amino) and (c) compounds of formula III in which the two dotted lines represent optional double links; [Z is oxygen or sulfur when there is a double bond attached to the ring A and Z is hydroxy, (C 1 -C 0 alkyl) -S- (alkyl d-C 10) -SO-, (C 1 -C 6 alkyl) -SO 2 -, adamant-2-yl-S- , naphthyl-S-, benzyl-S-, phenyl-C (= O) CH2-S-, (C1-C6 alkyl) -OC (= O) - l CH2-S- or (H, H) (that is, Z represents two hydrogen atoms, each of which is linked by a single bond to the same carbon of ring A) when Z is linked by a single bond to ring A , wherein said naphthyl and phenyl and the phenyl moiety of said benzyl may be substituted optionally with one to three substituents independently selected from CI-CT alkyl optionally substituted with one or three fluorine atoms, d-C6 alkoxy optionally substituted with one or three fluorine atoms, halo (for example, chloro, fluoro, bromo or iodo), amino, (alkyl d-C6) amino, di (C 1 -C 6 alkyl) amino, cyano, nitro, (C 6 alkyl) ) -SO-n- in which n is cefó, one or two, -COOH, -COO (alkyl d-C6) and -C (O) NH (alkyl d-C6); k. X is NR1 or CHR1; R1 is hydrogen, d-C6 alkyl or (d-C6 alkyl) phenyl when ring A is saturated (that is, when ring A does not contain double bonds) and R1 is missing when ring A contains double bonds; R 2 is selected from naphthyl, phenyl, (CrC 6 alkyl) phenyl, 1-adamantyl, 2-adamantyl, linear or branched C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl and C 8 -C 30 bicyclic or tricyclic alkyl, said cycloalkyl C 3 being able to be -C10 and said C8-C-3o bicyclic or tricyclic alkyl optionally substituted with a hydroxy group, and said adamantyl groups being optionally substituted with one or three substituents independently selected from C? -C6 alkyl, halo and hydroxy; and R3 and R4 are independently selected from benzyl, wherein the phenyl moiety of said benzyl may be optionally substituted with an amino or nitro group; hydrogen, phenyl, (N = C) - (alkyl d-C6), (alkyl d-C6) - z t O-C (= O) - (alkyl d-C6) and Het-CH2 in which Het is selected from 2-, 3- or 4-pyridinyl, furyl, tetrahydrofuryl, pyrimidyl, pyrazinyl, pyrazolyl, isoxazolyl, thiophenyl and triazolyl; 1 with the addition that (a) no more than one of the two dotted lines ^ can represent a double bond in any one of the compounds, (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 and the pharmaceutically acceptable salts of the aforementioned compounds. Other more specific embodiments of this invention relate to any of the above pharmaceutical compositions and to treatment methods in which the FTase inhibitor is selected from compounds of formula I defined above in which R1 and R2 are - ( CH2) p (heterocycles of 5-10 members) in which p is 1 or 2.

Other more specific embodiments of this invention relate to any of the above pharmaceutical compositions and methods of treatment in which the FTase inhibitor is selected from compounds of formula T defined above wherein R3 is a - (CH2) m- pinano in which m is 0, 1 or 2 and, more preferably, those in which R 3 is pinanomethyl. Other more specific embodiments of this invention relate to any of the above pharmaceutical compositions and to methods of treatment in which the FTase inhibitor is selected from compounds (of formula I defined above in which R3 is wherein X r, X v2, X "3 and X are as defined above.

Other more specific embodiments of this invention relate to any of the above pharmaceutical compositions and to methods of treatment in which the FTase inhibitor is selected from compounds of the formula defined above wherein R 4 is phenyl optionally substituted by 1 to 3 substituents R5.

Other more specific embodiments of this invention relate to any of the above pharmaceutical compositions and to methods of treatment in which the FTase inhibitor is selected from the compounds listed below: 2- [2- (4-bromophenyl) -2- oxoethylidene] -5,5-bispyridin-4-ylmethyl-3- (2,6,6-trimethylbicyclo [3.1.1] hept-3-ylmethyl) imidazolidin-4-one, 4-. { [5-oxo-4,4-bispyridin-4-ylmethyl-1- (2,6,6-trimethyl-bicyclo [3.1.1] hept-3-ylmethyl) midazolidin-2-ylidene] acetyl } benzonitrile, - = - 2- [2- (4-chlorophenyl) -2-oxoetylidene] -5,5-bispyridin-4-ylmethyl-3- (2,6,6-trimethylbicyclo [3.1.1] hept- 3-ylmethyl) imidazolidin-4-one, 2- [2- (3,4-dichlorophenyl) -2-oxoethyl] deno] -5,5-bispyridin-4-ylmethyl-3- (2,6 -6-trimethylbicyclo [3.1.1] hept-3-ylmethyl) imidazolidin-4-one, 2- [2- (3-nitrophenyl) -2-oxoethylidene] 5,5-bispyridin-4-ylmethyl-3- (2 , 6,6-trimethylbicyclo [3.1.1] hept-3-methylmethyl) imidazolidin-4-one, 2- [2- (4-methoxyphenyl) -2-oxoethylidene] -5,5-bispyridin-4-ylmethyl- 3- (2,6,6-rimethylbicyclo [3.1.1] hept-3-ylmethyl) imidazolidin-4-one, 2- [2- (3-methoxyphenyl) -2-oxoethylidene] -5,5- bispyridin-4-ylmethyl-3- (2> 6,6-trimethylbicyclo [3.1.1] hept-3-ylmethyl) imidazolidin-4-one, 2- [2- (2-methoxyphenyl) -2-oxoethylidene] -5,5-bispyridin-4-ylmethyl-3- \ (2,6,6-trimethylbicyclo [3.1.1] hept-3-ylmethyl) imidazolidin-4-one, 2- (2-biphenyl-4-yl-2-oxoethylidene) -5,5-bispyridin-4-ylmethyl-3- (2,6,6-trimethylbicyclo [3.1 .1] hept-3-ylmethyl) imidazole? Din-4-one, 2- (2-naphthalen-2-yl-2-oxoethylidene) -5,5-bispyridin-4-ylmethyl-3- (2,6, 6-trimethylbicyclo [3.1.11hept-3-ylmethyl) imidazolidin-4-one, f 2- [2- (4-fluorophenyl) -2-oxoethylen] -5,5-bispyridin-4-ylmethyl-3- (2,6,6-I trimethylbicyclo [3.1.1] hept-3-ylmethyl) imidazoIidin-4-one, 2- [2- (2,4-difluorophenyl) -2-oxoethylidene] -5,5-bispyridin- 4-ylmethyl-3- (2,6,6-rimethylbicyclo [3.1.1] hept-3-ylmethyl) imidazolidin-4-one, 4-. { [5-oxo-4,4-bispyridin-4-ylmethyl-1- (2,6-6-trimethyl-bicyclo [3.1.1] hept-3-yl) imidazoIidin-2-ylidene] acetyl} benzonitrile, 2- [2- (4-nitrophenol) -2-oxoethylidene] -5,5-bispyridin-4-ylmethyl-3- (2,6,6-trimethylbicyclo [3.1.1] hept-3-ylmethyl) imidazolidin -4-one, * _ 2- [2-oxo-2-phenylethyldene] 5,5-bispyridin-4-ylmethyl-3- (2,6,6-trimethoxybicyclo [3.1.1] hept-3-ylmethyl) imidazolidin-4-one, l 2-. { 2-oxo-2- [4-2H-tetrazol-5-yl) phenyl] ethylidene} -5) 5-bispyridin-4-ylmethyl-3- (2,6,6-trimethylocyclo [3.1.1] hept-3-ylmethyl) imidazolidin-4-one, f 3-. { [5-oxo-4,4-b¡sp¡ridin-4-ylmethyl-1- (2,6,6-trimethyl-bicyclo [3.1.1] hept | f 3-ylmethyl) imidazolidin-2-ylidene] acetyl} benzonitrile, ethyl ester of 4- acid. { [5-oxo-4,4-bispyridin-4-ylmethyl-1 - (2,6,6 trimethylbicyclo [3.1.1] hept-3-ylmethyl) imidazolidin-2-yldene] acetyl} benzoic acid, 2- [2-oxo-2- (4-trifluoromethyl-phenyl) -etilide] -5,5-bispyridin-4-ylmethyl-3- (2,6,6-trimethylbicyclo [3.1.1] ] hept-3-ylmethyl) imidazolidin-4-one, 2- [2- (4-methanesulfonylphenyl) -2-oxoethylidene] -5,5-bispyridin-4-ylmethyl-3- ( 2,6,6-trimethylbicyclo [3.1.1] hept-3-ylmethyl) -midazolidin-4-one, 4-. { [1- (6,6-Dimethyl-cyclo [3.1.i] hept-2-ylmethyl) -5-oxo-4,4-bispyridin-4-ylmethylimidazolidin-2-ylidene] acetyl} benzonytryl, 4 - [(1-bicyclo [2.2.2] oct-1-methyl-5-oxo-4,4-bispyridin-4-JI-ilmethyl-midazolidin-2-ylidene) acetyl] benzonthril, 4-. { [1 - (2-ethyl-6,6-dimethyl-cyclo [3.1.1] hept-3-ylmethyl) -5-oxo-4,4-b.spyridin-4-methylmethylimidazoid-2- Lead] acetyl } benzonitrile, 4-. { [1- (2-Benzyl-6,6-dimethylbicyclo [3.1.1] hept-3-ylmethyl) -5-oxo-4,4-bispyridin-4-ylmethyllimidazolidin-2-ylidene] -acetyl } benzonitrile, Z. 4-. { [1- (2-isopropenyl-6,6-dimethylbicyclo [3.1.1] hept-3-ylmethyl) -5-oxo-4,4-bispyridin-4-ylmethylimidazolidin-2-ylidene] acetyl} benzonitriIo,: 4-. { [1- (2-isopropyl-6,6-dimethyl-cyclo [3.1.1] hept-3-ylmethyl) -5-oxo-4,4-bispyridin-4-ylmethylimidazolidin-2-ylidene] acetyl } benzonitrile,! 4- ( { 1- [2- (1-methoxyiminoethyl) -6,6-dimethylbicyclo [3.1.1] hept-3-ylmethyl] -5-oxo-4,4-bispyridin-4-ylmethylimidazolidin- 2-ylidene.} Acetyl) benzonitrile, "4- { [1- (6,6-dimethyl-2-methylenebicyclo [3.1.1] hept-3-ylmethyl) -5-oxo-4.4 -? bispyridin-4-ylmethyl-1,4-amino-2-ylidene] acetyl} benzonitrile, 4- { [1- (2-hydroxy-2-hydroxymethyl-6, 6-dimethylbicyclo [3.1.1] hept-3-ylmethyl) -5-oxo-4,4-bispyridin-4-ylmethyl-lidazolidin-2-ylidene] acetyl} benzontrile, 4-. { [1- (6,6-dimethyl-2-oxo-bicyclo [3.1.1] hept-3-ylmethyl) -5-oxo-4,4-bispyridin-4-ylmethylimidazolidin-2-yldene] acet L} benzonyl ether, 3-tert-butyl-2- (2-oxo-2-phenylethylidene) -5,5-bispyridin-4-ylmethylimidazolidin-4-one, 4-. { [1- (2,2-Dimethyl-propyl) -5-oxo-4,4-bispyridin-4-ylmethyl-imidazolidin-2-ylidene] acetyl} benzonitrile, 4-. { [1 - (2-adamantan-1-ethyl) -5-oxo-4,4-bispyridin-4-ylmethylimidazolidin-2-ylidene] acetyl} benzonitrile, 3-cyclohexyl] -2- (2-oxo-2-phenylethylidene) -5,5-bispyridin-4-ylmethylimidazolidin-4-one, 4-. { (1-adamantan-1-methylmethyl-5-oxo-4,4-bispyridin-4-ylmethylimidazolidin-2-ylidene) acetyl] benzonitrile, T 4 - [(1-cyclohexylmethyl-5-oxo-4,4-bispyridin- 4-ylmethylimidazolidin-2-ylidene) acetyl] benzonitrile, 3-hexyl-2- (2-oxo-2-phenylethylidene) -5,5-bispyridin-4-ylmethipidazolidin-4-one, - i 3-naphthalen-1-yl-2- (2-oxo-2-phenylethylidene) -5,5-bispyridin-4-ylmethylimidazolidin-4-one, 3-adamantan-1-yl-2- (2 -oxo-2-phenylethylidene) -5,5-bispyridin-4-ylmethylimidazolidin-4-one, 3-adamantan-1-yl-2- [2- (4-nitrophenol) -2-oxoethylidene] -5,5-bispyridin-4-ylmethylimidazolidin-4-one, 4 - [(1-benzyl-5-oxo-4,4-bispyriclun-4-ylmethylimidazoylidin-2-ylidene acetyl] benzonitrile, 4 - [(1-allyl-5-oxo-4,4-bispyridin-4-ylmethylimidazolidin-2-L-ylidene) acetyl] benzonitrile, 4 - [(1-methyl-) 5-oxo-4,4-bispyridin-4-ylmethylimidazolidin-2-ylidend) acetyl] benzonitrile, 4-. { [1 - (2,2-diethoxyethyl) -5-oxo-4,4-bispyridin-4-ylmethyllimidazolidin-2-ylidene] acetyl} benzonitrile, 4-. { (1-adamantan-2-ylmethyl-5-oxo-4,4-bispyridin-4-ylmethyl-thidazolidin-2-ylidene) acetyl] benzonyl, 4 - [(1-adamantan-2-yl-5-oxo 4,4-bispyridin-4-ylmethylimidazolidin-2-ylidene) acetyl] benzonitrile, 4 - [(5-oxo-1-phenyl-4,4-bispyridin-4-ylmethylimidazoidin-2-ylidene) acetyl] benzonitrile and 4-. { [4-tert-Butylpheni-5-oxo-4,4-bispyridin-4-ylmethylimidazolidin-2-ylidene) acetyl] benzonitrile I and the pharmaceutically acceptable salts of said compounds. Other more specific embodiments of this invention are: refer to any of the above pharmaceutical compositions and treatment methods in which the HMG CoA reductase inhibitor contained in said composition or used in said method is selected from the group consisting of atorvastatin, pravastatin, niacin, gemfibrozil, chlorofibrate, lovastatin, fluvastatin , simvastatin and compactin and the pharmaceutically acceptable salts of the aforementioned compounds. Other more specific embodiments of this invention relate to any of the above pharmaceutical compositions and to methods of treatment in which the HMG CoA reductase inhibitor contained in said composition or used in said process in atorvastatin. Other more specific embodiments of this invention relate to any of the above pharmaceutical compositions and to methods of treatment in which the HMG CoA reductase inhibitor contained in said composition or used in said process is i lovastatin.

Other more specific embodiments of this invention refer to any - i of the above pharmaceutical compositions and to treatment methods in which the FTase inhibitor contained in said ; - I composition or used in said process is selected from: - - I _ (a) compounds of the formula NA defined above in I that R3 is 4-pyridyl, 4-pyrimidyl or 2-fluoro-4-pyridyl , (b) compounds of the formula HA defined above in which R2 is - (CH2) nY, (c) compounds of the formula HA defined above in which Z - í R2 is - (CH2) nY and n is an integer from 1 to 5, - i (d) compounds of the formula NA or I IB defined above in - - * that each of R1 E1, E2 and R4, if present, is hydrogen and (e) compounds of the formula NA defined above where R2 is - (CH2) nY, R1 is 4-pyridyl, 4-pyrimidyl or 2-fluoro-4-pyridyl, R5 is "C" -C2 alkyl and Y is -CO2R5, cyano, -CONHR4, CH = CHCO2R5 or -OCOR 5. Other more specific embodiments of this invention refer to any of the above pharmaceutical compositions and treatment methods in which the FTase inhibitor contained in said composition or used in said process is not limonene or d-limonene. = The term "alkyl", as used herein, unless otherwise indicated otherwise, it includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.

The term "halo", as used herein, refers to chlorine, fluoro, bromo or iodo. 1 r i The above compounds of formulas I, HA, I IB, III and IV can! contain one or more chiral centers and, therefore, may exist in 2 or more enantiomeric or diastereomeric forms. The above definitions of i compounds that have the formulas I, NA, I IB, III and IV include all r r * enantiomers, diastereomers and other stereoisomers of these compounds, as well as mixtures thereof. The following references refer to compounds that exhibit activity as inhibitors of FTase and that can be used, combined with an HMG CoA reductase inhibitor, in the pharmaceutical compositions and methods of this invention, and to processes for preparing the same: International Patent PCT / US-92/1292, which: I designates the United States and published on July 22, 1993 as WO 93/14085; U.S. Patent 4,876,259 issued October 24, 1989; U.S. Patent H1345 granted August 2, 1994; world patent application WO 93/24633 published December 9, 1993; U.S. Patent 5,260,332 issued November 9, 1993; U.S. Patent 5,262,435 issued November 16, 1993; U.S. Patent 5,369,125 issued November 29, 1994; world patent application WO 94/03597 published February 17, 1994; world patent application WO 94/16069 published June 21, 1994; G.L. Bulton et al., 209th Meeting of the American Chem. Soc, Anaheim, CA, April 2-6, 1995, Division of Medical Chemistry, Abs. No. 032; world patent application WO 95/00497 published January 5, 1995; U.S. Patent 5,260,479 and published November 9, 1993; world patent application WO 95/10514; world patent application WO 95/10515; world patent application WO 95/10516; World Patent Application WO 95/12572 published May 11, 1995; world patent application WO 95/11917 published May 4, 1995; World Patent Application WO 94/26723 published on November 24, 1994; world patent application WO 95/25086 published September 21, 1995; Kanda and others, AFMC, Symposium International Medical Chemistry AIMECS 95, Tokyo, Japan, Poster, P7M153, September 4, 1995; world patent application WO 96/10037 I I published on April 4, 1996; world patent application WO 96/10035 published April 4, 1996; world patent application WO 96/10034 published April 4, 1996; world patent application WO 96/10011 i published on April 6, 1996; world patent application WO 96/09821 published April 4, 1996; world patent application WO 96/09820 published April 4, 1996; Quin et al., 211st National Meeting of the American Chemical Society, New Orleans, LA, 24-28 March 1996, - Conference, COMP 012, March 24, 1996; worldwide patent applications WO 96/06609 and WO 06/06604 both published on March 7, 1996; European patent application EP 696,593 published February 14, 1996; G.D. Hartman, 14th International Symposium on Medical Chemistry, Maastricht, The Netherlands, 8-12 September 1996, Conference, SL-083, 10 de! September 1996; world patent application WO 96/30363 published October 3, 1996; world patent application WO 96/30343 published October 3, 1996; world patent application WO 97/03050; application for 1 t I world patent WO 94/26723 published on November 24, 1994; i international patent application PCT / IB-95/00189, which designates the United States and filed on March 20, 1995; patent application of the United States 08 / 236,743 filed on April 29, 1994; provisional application of the United States patent entitled "Adamantyl substituted oxindoles as pharmaceutical agents", filed on May 28, 1996 on behalf of R.A. Volkmann and J.P. Lyssikatos; U.S. Patent 5,350,867 issued September 27, 1994; U.S. Patent 5,352,705 issued October 4, 1994; U.S. Patent 5,565,489 issued October 15, 1996; European patent application EP 750,609 published on January 2, 1997; European patent application 461,869 published on December 18, 1991; and world patent application 96/21456 published July 18, 1996. The following references refer to compounds that exhibit activity as inhibitors of HMG CoA reductase and that can be used, combined with an inhibitor of FTase, in the pharmaceutical compositions and methods of this invention, and methods for preparing the same: United States Patent 4,681,893 issued July 21, 1987; U.S. Patent 5,273,995 issued December 28, 1993; U.S. Patent 5,385,929 issued January 31, 1995; United States Patent 4,957,971 issued on September 18, 1990; U.S. Patent 5,102,893 issued April 7, 1992; U.S. Patent 4,957,940 issued September 18, 1990; United States patent 4. 950,675 granted on August 21, 1990; U.S. Patent No. 4,929,620 issued May 29, 1990; United States patent 4. 923,861 issued May 8, 1990; patent of the United States l 4. 9067657 granted March 6, 1990; U.S. Patent 4,868,185 issued September 19, 1989; patent of the States United 5,124,482 issued June 23, 1992; U.S. Patent 5,003,080 issued March 26, 1991; patent of the States U.S. 5,097,045 issued March 17, 1992; patent of the States United 5,149,837 issued September 22, 1992; U.S. Patent 4,906,624 issued March 1, 1990; U.S. Patent 4,761,419 issued August 2, 1988; U.S. Patent 4,735,950 issued April 5, 1998; U.S. Patent 4,808,621 issued February 28, 1989; U.S. Patent 4,647,576 issued March 3, 1987; U.S. Patent 5.1 18,882 issued June 2, 1992; U.S. Patent 5,214,197 issued May 25, 1993; patent of the United States 5,321,046 issued June 14, 1994; U.S. Patent 5,260,440 issued November 9, 1993; U.S. Patent 5,208,258 issued May 4, 1993; U.S. Patent 5,369,125 issued November 29, 1994; U.S. Patent H1345 granted August 2, 1994; patent of the United States 5,262,435 issued November 16, 1993; United States patent 5,260,332 issued November 9, 1993; British Patent Application GB 2,055,100 published February 25, 1981 U.S. Patent 4,499,289 issued February 12, 1983 U.S. Patent 4,645,854 issued February 24, 1987 U.S. patent United States 4,613,610 issued September 23, 1986; United States Patent 4,668,699 issued May 26, 1987; U.S. Patent 4,851,436 issued July 25, 1989; U.S. Patent 4,678,806 issued July 7, 1987; U.S. Patent 4,772,626 issued September 20, 1988; U.S. Patent 4,855,321 issued August 8, 1989; European patent application EP 244364 published on November 4, 1987; U.S. Patent 4,766,145 issued August 23, 1988; U.S. Patent 4,876,279 issued October 24, 1989; U.S. Patent 4,847,306 issued July 1, 1989; U.S. Patent 5,049,696 issued September 17, 1991; European patent application EP 245,990 published November 19, 1987; European patent application EP 251,625 published on January 7, 1988; U.S. Patent 4,719,229 issued January 12, 1988; Japanese patent application 63014722 published January 21, 1988; U.S. Patent 4,736,064 issued April 5, 1988; U.S. Patent 4,738,982 issued April 19, 1988; U.S. Patent 4,845,237 issued July 4, 1915; European Patent EP 306263"issued March 18, 1992; United States Patent 5,026,708 issued June 25, 1991; and United States Patent 4,863,957 issued September 5, 1992; 1989; U.S. Patent 4,946,841 issued August 7, 1990; European patent 339358 granted on July 13, 1994; patent of the United States 4,937,264 issued June 26, 1998; US Pat. No. 4,876,366 issued October 2, 1989; U.S. Patent 4,921,974 issued May 1, 1990; U.S. Patent 4,963,538 issued October 16, 1990; patent of the United States 5,130,306 on July 14, 1992; U.S. Patent 4,900,754 issued February 13, 1990; U.S. Patent 5,026,698 issued June 25, 1991; U.S. Patent 4,977,161 issued December 11, 1990; U.S. Patent 4,927,851 issued May 22, 1990; European patent application EP 373,507 published on June 20, 1990; U.S. Patent 4,939,143 issued July 3, 1990; U.S. Patent 4,939,159 granted "July 3, 1990; U.S. Patent 4,940,727 issued July 0, 1990; U.S. Patent 5,116,870 granted;" I May 26, 1992; Australian Patent 635,545 issued March 25, 1993; United States Patent 5,098,391 issued March 24, 1992; United States 5,294,724 issued March 15, 1994; patent of the i United States 5,001,255 issued March 19, 1991; U.S. Patent 5,149,834 issued September 22, 1992; U.S. Patent 5,089,523 issued February 18, 1992; European patent application EP 465,265 published on January 8, 1992; U.S. Patent 5,476,848 issued December 19, 1995; U.S. Patent 5,321,046 issued June 14, 1994; U.S. Patent 5,106,992 issued April 21, 1992; US Pat. No. 5,347,039 issued September 13, 1994, application I of Japanese Patent 4193836 published July 13, 1992, British Patent Application 2253787 published September 23, 1992; United States 5.41-1969 issued May 2, 1995; Japanese Patent Application 4,356,435 issued December 10, 1992; United States Patent 5,266,707 issued November 30, 1992; 1993; U.S. Patent 5,455,247 issued October 3, = _. -! nineteen ninety five; U.S. Patent 5,475,029 issued December 12, 1995; U.S. Patent 5,591,772 issued January 7, 1997; U.S. Patent 5,286,746 issued February 15, 1994; Japanese patent application JP 7089898 published on April 4, - i i nineteen ninety five; European patent application EP 677,039 published October 18, 1995; and world patent application 96/08248 published March 21, 1996.

The invention relates to methods of treating cancer in which the inhibitor of FTase and the HMG CoA reductase inhibitor are administered together as part of the same pharmaceutical composition, as well as to processes in which these two active agents are administered separately as part of an appropriate dosing regimen designed to reap the benefits of combination therapy. The appropriate dosage regimen, amount of each dose administered and specific intervals between doses of each active agent will depend on the patient being treated, type of cancer or abnormal cell development and severity of the condition. To perform the methods of this invention, the FTase inhibitor will administer in amounts described in the literature, or in amounts that are believed to be effective, for the administration of said compound as the sole active agent for the treatment of cancer or the inhibition of development. Abnormality of cells, and the HMG CoA reductase inhibitor will be administered in an amount that is approximately one quarter or one half of the amount described in the literature, or in an amount believed to be effective, for the administration of said compound as only agent for the treatment of hypercholesterolemia. For example, to perform the present invention, the FTase inhibitors of formulas J, HA, IIB and III will typically be administered to an adult of 70 kg in an amount ranging from about 0.005 to about 0.6 mg per day and kg of body weight of the patient being treated, in a single dose or in divided doses, and atorvastatin, HMG CoA reductase inhibitor, will typically be administered in an amount ranging from about 0.07 L to about 3.6 mg per day and kg of body weight, in a single dose t (or in divided doses), however, variations may occur depending on the species of animal being treated and their individual response to the aforementioned drugs, as well as the type of pharmaceutical formulation chosen and period of time and interval in which said administration is carried out. 7 some cases may be more suitable dosage levels below the lower limit of the previous interval, while in other cases higher dosage levels than the previous upper daily limit may be used without causing a detrimental side effect, provided that such higher dosages are administered as several small doses administered throughout the day ^ ^ The FTase inhibitors and HMG CoA reductase inhibitors which are employed in the pharmaceutical compositions and methods of this invention are also referred to hereinbelow. "therapeutic agents". Therapeutic agents can be administered by «= t orally or parenterally. Generally, compositions containing an inhibitor of FTase and an inhibitor of HMG CoA reductase will be administered daily orally or parenterally, in a single dose or in divided doses, so that the total amount of each active agent administered falls within. of the previous pattern. The therapeutic agents can be administered alone or in combination with pharmaceutically acceptable carriers or diluents, by any of the routes indicated above, and said administration can be carried out in a single dose or in divided doses. More particularly, the novel therapeutic agents of this invention can be administered in a wide variety of different dosage forms, that is, they can be combined with various inert, pharmaceutically acceptable carriers, in the form of tablets, capsules, lozenges, troches, hard candies, suppositories, aqueous suspensions, injectable solutions, elixirs, syrups and similar forms. Such vehicles include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. In addition, oral pharmaceutical compositions can be sweetened and / or flavored. In general, the therapeutic compounds of this invention, when administered separately (ie, not in the same pharmaceutical composition) are present in said dosage forms at concentration levels ranging from about 5.0% to about 70% by weight. For oral administration, tablets containing various excipients may be used, such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, together with various disintegrants, such as starch (and preferably corn starch, potato or tapioca), alginic acid and certain complex silicates, together with granulation binders, such as polyvinylpyrrolidone, gelatin and gum arabic. Additionally, lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc, are often very useful for manufacturing the tablets.

Solid compositions of a similar type can also be used as fillers in gelatin capsules; Preferred materials in this regard also include lactose or milk sugar as well as polyethylene glycols of high molecular weight. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient can be combined with various sweetening or flavoring agents, colorants and, if desired, with agents. I emulsifiers and / or suspension, together with diluents such as water, propylene glycol ethanol, glycerol and various combinations thereof. For parenteral administration, t solutions of a therapeutic agent may be employed in sesame or peanut oil or in aqueous propylene glycol. The aqueous solutions must be suitably buffered if necessary and must first be made isotonic to the liquid diluent. These aqueous solutions are suitable for intravenous injections. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injections. The preparation of all these solutions under sterile conditions is easily accomplished by standard pharmaceutical techniques well known to those skilled in the art. ^ The activity of therapeutic compounds as inhibitors of r I FTase can be determined by their capacity, with respect to a control, | to inhibit in vitro FTase. Next, this procedure is described. A crude preparation of FTase, comprising the cytosolic fraction of brain homogenate, is used to select compounds in a 96-well assay format. The cytosolic fraction is prepared by homogenizing approximately 40 grams of fresh tissue in 100 ml of sucrose / MgCl2 / EDTA buffer (using a homogenizer Dounce; 10-15 shakes), centrifuging the homogenates at 1,000 7 -. 7 - i grams for 10 minutes at 4 g, re-centrifuging the supernatant liquid at 17,000 grams for 15 minutes at 4 g and then collecting the resulting supernatant liquid. This liquid supernatant is dilutes to contain a final concentration of 50 mM Tris-HCl (pH 7.5), DTT mN.KCI, 0.2 M, 20 mM ZnCl2 and 1 mM PMSF, and centrifuged again at I 178. 000 grams for 90 minutes at 4 g. The supernatant fluid, called "crude FTase", was assayed for protein concentration, aliquoted and saved. The assay used to measure in vitro the inhibition of human FTase is a modification of the procedure described by Amersham LifeScience using its trihealth proximity test (SPA) kit of 3H-famesyl transferase (TRKQ 7010). The activity of the enzyme FTase is determined in a volume of 100 ml containing N- (2-hydroxyethyl) piperazine-Nc- (2-ethanesulfonic acid (HEPES) 50 mM, pH 7.5, 30 mM MgCl2, KCl μM, 5 mM Na2HPO4, 5 mM dithiothreitol (DTT), 0.01% Triton X-100, 5% dimethylsulfoxide (DMSO), 20 mg crude FTase, [3H] -famesyl pyrophosphate ([3H] -FPP) 0.12 mM; 36,000 dpm / pmol, Amersham LifeScience), and 0.2 mM of biotinylated Ras peptide KTKCVIS (Bt-KTKCVIS) which is biotinylated in the N terminal in its a-amino group and that was synthesized and purified by HPLC in the laboratory. The reaction is initiated by the addition of the enzyme and is terminated by addition of EDTA (supplied in the STOP reagent of the TRKQ 70 10 kit) then incubated at 37 ° C for 45 minutes. Bt-KTKCVIS is taken pre-plied and not pre-coated by adding 10 ml of SPA beads coated with steptavidin (TRKQ 7010) per well and mixing the reaction mixture at room temperature for 30 minutes. The amount of radioactivity bound to the SPA beads is determined using a MicroBeta plate counter 1450. Under these test conditions, the activity of the enzyme is linear with respect to the concentrations of the acceptor of prenyl groups, Bt-KTKCVIS, and the crude FTase, but saturating with respect to the donor of prenyl groups, FPP. The time of the test reaction is also in the linear range. : Test compounds are dissolved routinely in 100% DMSO. The inhibition of farnesyl transferase activity is determined by calculating the percentage of tritiated farnesyl incorporation in the presence of the test compound against its incorporation into control wells (absence of inhibitor). From the responses obtained at the doses the IC50 values are determined, that is, the concentration required to produce half of the maximum famesylation of Bt-KTKCVIS. 7. A fluorescence assay to determine the activity of the FTase, which can be used to select inhibitors of FTase, is described in UK patent application GB 2,267,966 published on December 22, 1993. ^ The activity of certain therapeutic agents as inhibitors of HMG CoA reductase can to be determined by the procedure described; "- [" by Dugan et al., Achiv. Biochem. Biophys., 152, 21-27 (1972). * i procedure, the activity level of the enzyme HMG CoA reductase is increased in standard laboratory rats fed the rats for four days with a dog food containing 5% cholestyramine, after which the rats are sacrificed. The livers of the rats are homogenized and the incorporation of 14C-cholesterol acetate in unsaponified lipid is measured by the liver homogenate of the rats. The micromolar concentration of compound required to inhibit 50% esteral synthesis for a period of one hour is measured and expressed as the IC50 value. A second procedure (designated COR selection) is that described by T. Kita et al., J. Clin. Invést, 66, 1094-1.100 (1980). In this procedure, the amount of 14C-HMG CoA converted to 14C-mevalonate is measured in the presence of a purified HMG CoA reductase enzyme preparation. The micromolar concentration of compound required to inhibit 50% cholesterol synthesis is measured and expressed as the IC 50 value. The various methods of this invention can be practiced as part of a therapy that includes administration of one or more other antitumor substances, for example, those selected from mitotic inhibitors, for example, vinblastine.; alkylating agents, for example, cisplatin, carboplatin and cyclophosphamide; antimetabolites, for example, 5-fluorouracil, cytosine arabinoside and hydroxyurea or, for example, one of the preferred antimetabolites described in the European patent application No. 239362, as the N- acid. { 5- [N- (3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyr) -N-methylamino] -2-tenoyl] -L-glutamic; intercalating antibiotics, for example, adriamycin and bleomycin; enzymes, for example asparaginase; topoisomerase inhibitors, e.g., etoposide; modifiers of t biological responses, for example, interferon; and antihormones, for example, antiestrogens such as "NOLVADEX" (tamoxifen) or antiandrogens as "CASODEX" [4'-cyano-3- (4-fluorophenylsulfonyl) -2-hydroxy-2-methyl-3 '- (trifluoromethyl) propionanimide]. Such therapies can be achieved by dosing the individual components of the therapy simultaneously, sequentially or separately. In accordance with this aspect of the invention, there is provided a pharmaceutical product comprising a pharmaceutically acceptable carrier, such as those described above, one or both of an HMG CoA reductase inhibitor and a FTase inhibitor, and an additional antitumor agent. as those described above. As indicated in the following Table 1, the author of the present invention has shown that the effectiveness of compound 1 having structure it can be increased by a minimally effective dose of lovastatin.

TABLE 1 Synergistic effects of treatment with lovastatin and compound 1 on the prenylation of K-Ras 4B in intact cells * (*) Semi-effluent monolayers of the NIH-3T3 transfectant which over expresses K-Ras 4B mutant were treated for 18 hours at 37 ° C with increasing concentrations of CP-390,392 in the presence and absence of 5 μM of hydrolyzed lovastatin. The cells were lysed in a lysis RIPA buffer [50 mM tris (hydroxymethyl) aminomethane, 0.15 M sodium chloride, 1% sodium deoxycholate, 1% Triton X-100, 0.1% SDS and 0.25% sodium azide; pH 8.5) containing 1 mM of DTT (dithiothreitol, Boehringer Mannheim, Indianapolis, IN) and protease inhibitors (aprotinin, leupeptin, anitpain, pephabloc, at final concentrations of 10 μg / ml, 2 μg / ml, 2 μg / ml and 50 μM, respectively, Boehringer Mannheim, Indianapolis, IN) and boiled for 3 minutes. Equal amounts of protein (100 μg / lane) were resolved by SDS-PAGE on 12.5% gels and transferred to membranes.

Immobilon-P (Intergrated Separation Systems, Natick, MA). The membranes were immunoblotted with 5 μg / ml of an anti-Pan-Ras monoclonal antibody (Ab-3) (Calbiochem, La Jolla, CA). The transferred was incubated with secondary antibody conjugated with peroxidase and the immunotransferred Ras protein was detected by enhanced chemiluminesis.

(Amercham Life Products, Arlington Heights, IL). The percentage of prenylated Ras was determined by densitometric scanning using Masterscan 3.0 (Scanalytics, Billerica, Massachusettes).

Claims (6)

NOVELTY OF THE INVENTION CLAIMS

1. - A pharmaceutical composition for the treatment of cancer or a benign proliferative disorder, comprising an inhibitor of FTas, an inhibitor of HMG CoA reductase and a pharmaceutically acceptable carrier, in which the inhibitor of FTase and the inhibitor of HMG CoA reductase are present in amounts that make the composition effective in the treatment of cancer or a benign proliferative disorder, wherein the FTase inhibitor is selected from: (a) compounds of formula I wherein R1 and R2 is independently selected from the group consisting of - (CH2) p (5-10 membered heterocycles), - (CH2) p (Cs-do aryl), allyl, propargyl and C6-C6 alkyl, which p is 0 to 3, said alkyl and the alkyl residues of the __ I mentioned groups R1 and R2 are optionally substituted by 1 to 3 substituents R9, and the aryl and the 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 (aryl C6-C? 0), alkyl d-do, wherein m is 0 to 6 and said cycloalkyl and alkyl optically contain 1 or 2 double or triple bonds; each of X1, X2 and X3 is = -_! independently C? -C7 alkylene optionally containing 1 or 2 double (or triple bonds, X4 is a CrC7 bond or alkylene optionally containing 1 or 2 double or triple bonds and, in the formula (B), the X4 moiety is attached to the X1 residue at any available carbon of the X1 moiety; R4 is C6-C6 aryl, 5-10 membered heterocycle or dC6 alkyl, wherein each of said R4 groups is optionally substituted by 1 to 3 substituents R5 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 (d-C4 alkyl), - C (NR8) NR8R6, -C (NCN) -NR8R6, -C ( NCN) S (alkyl dd),: • _ NR8C (NCN) S (alkyl d-C4), -NR8C (NCN) NR8R6, -NR8SO2 (alkyl C1-C4), -! S (O) n (C 1 -C 4 alkyl) wherein n is 0 to 2, -NR 8 C (O) C (O) NR 8 R 6, -NR 8 C (0) C (0) R 8, thiazolyl, imidazolyl, oxazolyl, pyrazolyl, triazolyl, tetrazolyl and C 1 -C 4 alkyl optionally substituted by 1 to 3 fluoro substituents; each of R6 and R7 are independently hydrogen or C? -C alkyl; each R8 is _. | independently R6 or -OR6; and each R 9 is independently selected from cyano, R 6, -OR 6, -OC (0) R 6, -C (0) OR 6, -C (0) NR 6 R 7, -NR 6 R 7, -NR 6 R 8, - SO 2 NR 6 R 7 and C 1 -C 4 alkyl substituted by hydroxy; and (b) compounds of formula IIA or í? B IIA IIB wherein R1 is hydrogen, halo (eg, chloro, fluoro, bromo or iodo), cyanohydroxy, nitro, trifluoromethyl, -NHR5, -NR5R5, R5, -OR5 or -S (O) m, R5; R2 is - (CH2) nY or -OCOR5; R3 is 4-, 3- or 2-pyridyl, pyrimidyl, pyrazinyl, 2-fluoro-4-pyridyl or 3-fluoro-4-pyridyl; R 4 is 1 -admantyl or 2-adamantyl; Y is hydrogen, hydroxy, amino, cyano, -NHR5 NR5R5, -NHCOR5, halo, OR5, -S (O) mR5, -C02H, -C02R5, -CONR5R5, -CONHR5, -CONH2, -COR5, -CH = CHC02R5 , -OCOR5, phenyl, phenyl substituted with W, -C = CC02R5, or -C = CR5; each R5 is independently linear or branched dC alkyl, phenyl or benzyl, said phenyl and the phenyl moiety of said benzyl optionally being substituted with halo, hydroxy, nitro, cyano, amino, straight or branched C1-C4 alkyl, C4 alkoxy linear or branched, phenyl, benzyl, (C 1 -C 4 alkyl) amino, di (C 1 -C 4 alkyl) amino or -S (0) m- (linear or branched C 1 -C 4 alkyl); each W is independently halo, R5, hydroxy, -OR5, nitro, amino, -NHR5, -NR5R5, cyano or -S (0) mR5; m is 0, 1 or 2; n is 1 to 7; p is 0 or 1; E1 and E2 are independently selected from hydrogen, halo, C1-C3 alkyl, hydroxy, P1-C3 alkoxy, nitro, trifluoromethyl, cyano, amino (C1-C3 alkyl) amino and di (alkyl) C? -C3) -amino; and their pharmaceutically acceptable salts; Het 'and Het' are independently selected from 6-membered heterocyclic rings which contain 1 to 4 nitrogen atoms as part of the ring, i optionally substituted with a substituent selected from C 1 -C 3 alkyl, - • t halo , hydroxy, C1-C3 alkoxy, amino, (C1-C3 alkyl) amino and di (C1-C3 alkyl) amino, and (c) compounds of formula III wherein the two dotted lines represent double bonds optionally; Z is oxygen or sulfur when there is a double bond attached to ring A and Z is hydroxy, (C 1 -C 6 alkyl) -S- (alkyl dC 0) -SO-, (C 1 -C 10 alkyl) -SO 2- , "adamant-2-yl-S, naphthyl-S-, benzyl-S-, phenyl-C (= O) CH2-S-, (alkyl d-C6) -OC (= O) -CH2-S- or (H, H) (that is, Z represents two hydrogen atoms, each of which is linked by a single bond to the same carbon atom of ring A) when Z is attached by a single bond to ring A, and in that the said naphthyl and phenyl and the phenyl moiety of said benzyl can be optionally substituted with one to three substituents independently selected from d-C6 alkyl optionally substituted with one to three fluorine atoms, d-C alco alkoxy substituted by one to three atoms i | fluorine, halo (for example, chloro, fluoro, bromo or iodo), amino, (Ci-Cß alkyl) amino, di (alkyl d-Cß) amino, cyano, nitro, (alkyl d-C6) -SOn- in where n is zero, Juno or two, -COOH, -COO (alkyl "d-Ce) and -C (O) NH (alkyl d-C6); X is NR1 or CHR1; R1 is hydrogen, alkyl d-C6 or (alkyl d-Cß) phenyl when ring A is saturated (that is, when ring A does not contain double bonds) and R1 is missing when ring A contains a double bond; R2 is selected from! naphthyl, phenyl, (alkyl d-C6) phenyl, 1-adamantyl, 2-adamantyl, straight or branched C? -C8 alkyl, C3-C10 cycloalkyl and C8-C3o bicyclic or tricyclic alkyl, said C3-C10 cycloalkyl being able to be and said C8-C30 bicyclic or tricyclic alkyl optionally substituted with a hydroxy group, and it being possible for 1-6 t to be said adamantyl groups optionally substituted with one to three substituents independently selected from d-Cß alkyl, halo and hydroxy; and R3 and R4 are independently selected from benzyl wherein the phenyl moiety of said benzyl may be optionally substituted with a amino or nitro group; hydrogen, phenyl, (Ñ = C) (alkyl d-Ce), (C 1 -C 6 alkyl) -OC (= O) - (alkyl d-Cß) and Het-CH 2, wherein Het is selected from 2- , 3- or 4-pyridinyl, furyl, tetrahydrofuryl, pyrimidiio, 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 of the compounds, (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 X is NR1, R1 must be hydrogen and (e) one of R3 and R4 must be Het-CH2; and (d) the compound and pharmaceutically acceptable salts of the aforementioned compounds I.

2. A pharmaceutical composition according to claim 1, wherein the HMG CoA reductase inhibitor is selected from the group consisting of atorvastatin, pravastatin, lovastatin, compactin, fluvastatin, simvastatin and pharmaceutically acceptable salts of the aforementioned compounds. t

3. The use of a pharmaceutical composition according to any one of claims 1 to 2 for the manufacture of a medicament for treating cancer or a benign proliferative disorder in a mammal.

4. The pharmaceutical composition for the treatment of cancer or a benign proliferative disorder, comprising a FTase inhibitor, an HMG CoA reductase inhibitor and a pharmaceutically acceptable carrier, wherein the inhibitor of the FTase and the inhibitor of the HMG CoA reductase are present in amounts that make the composition effective in the treatment of cancer or a benign proliferative disorder, wherein the FTase inhibitor is selected from: (a) compounds of formula I wherein R1 and R2 is independently selected from the group consisting of - (CH2) p (5-10 membered heterocycles), - (CH2) p (C6-C10 aryl), allyl, propargyl and alkyl- d- alkyl- C6, where p is 0 to 3, said alkyl and alkyl moieties of said groups R1 and R2 are optionally substituted by 1 to 3 substituents R9, and the aryl and the 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-C-? Oaryl aryl), d-Cio alkyl, wherein m is 0 to 6 and the said cycloalkyl and alkyl optionally contain 1 or 2 double or triple bonds; each of X1, X2 and X3 is independently C? -C7 alkylene optionally containing 1 or 2 double or triple bonds, X4 is a bond or alkylene * C? -C7 optionally containing 1 or 2 double or triple bonds and , in formula (B), residue X4 is attached to residue X1 at any available carbon from residue X1; R4 is C6-C10 aryl, 5-10 membered heterocycle or d-C6 alkyl, wherein each of said R4 groups is optionally substituted by 1 to 3 substituents R5; 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 (C, -C) alkyl, -C (NR8) NR8R6, -C (NCN) -NR8R6, -C ( NCN) S (alkyl dd), NR8C (NCN) S (d-C4 alkyl), -NR8C (NCN) NR8R6, -NR8SO2 (d-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 d-C4 alkyl optionally substituted by 1 to 3 fluoro substituents; each of R6 and R7 are independently hydrogen or d-C4 alkyl; each R8 is independently R6 or -OR6; and each R 9 is independently selected from cyano, R 6, -OR 6, -OC (0) R 6, -C (0) OR 6, -C (0) NR 6 R 7, -NR 6 R 7, -NR 6 R 8, -SO 2 NR 6 R 7 and substituted C 1 -C 4 alkyl by hydroxy; and (b) compounds of formula IIA or IGB wherein R1 is hydrogen, halo (e.g., chloro, fluoro, bromo or iodo), i cyano, hydroxy, nitro, trifluoromethyl, -NHR5, -NR5R5, R5, -OR5 or -S (0) m, R5; R2 is - (CH2) nY or -OCOR5; R3 is 4-, 3- or 2-pyridyl, pyrimidyl, pyrazinyl, 2-fluoro-4-pyridyl or 3-fluoro-4-pyridyl; R 4 is 1 -admantyl or 2-adamantyl; Y is hydrogen, hydroxy, amino, cyano, -NHR5, -NR5R5, -NHCOR5, halo, OR5, -S (O) mR5, -C02H, -C02R5, -CONR5R5, -CONHR5, -CONH2, -COR5, -CH = CHC02R5, -OCOR5, phenyl, phenyl substituted with W, -C = CC02R5, or -C = CR5; each R5 is independently linear or branched d-C4 alkyl, phenyl or benzyl, said phenyl and the phenyl moiety of said benzyl optionally being substituted with halo, hydroxy, nitro, cyano, amino, d-linear or branched alkyl, alkoxy d Linear or branched C4, phenyl, benzyl, (C 1 -C) alkyl amino, di (C 1 -C 4 alkyl) amino or -S (0) m- (straight or branched dC 4 alkyl); each W is independently halo, R5, hydroxy, -OR5, nitro, amino, -NHR5, -NR5R5, cyano or -S (0) mR5; m is 0, 1 or 2; n is 1 to 7; p is 0 or 1; E1 and E2 are independently selected from hydrogen, halo, C1-C3 alkyl, hydroxy, C1-C3 alkoxy, nitro, trifluoromethyl, cyano, amino (C1-C3 alkyl) amino and di (CrC3 alkyl) -amino; and their pharmaceutically acceptable salts; Het 'and Het "are independently selected from 6-membered heterocyclic rings containing from one to four nitrogen atoms as part of the ring, optionally substituted with a substituent selected from C 1 -C 3 alkyl, halo, hydroxy, C 1 -C 3 alkoxy, amino , (alkyl dC3) amino and di (alkyl dC3) amino, and (c) compounds of formula III wherein the two dotted lines represent double bonds optionally; Z is oxygen or sulfur when there is a double bond attached to ring A and Z is hydroxy, (alkyl Ci-doJ-S alkyl dC 0) -SO-, (alkyl d-do) - i S02-, adamant-2 il-S, naphthyl-S-, benzyl-S-, phenyl-C (= 0) CH2-S-, (C 1 -C 6 alkyl) -O- 1 C (= O) -CH 2 -S- or (H , H) (that is, Z represents two hydrogen atoms, each of which is linked by a single bond to the same carbon atom of ring A) when Z is linked by a single bond to ring A, and in which Said naphthyl and phenyl and the phenyl moiety of said benzyl may be optionally substituted with one to three substituents independently selected from Ci-Cd alkyl optionally substituted with one to three fluorine atoms, dC 6 alkoxy optionally substituted with one to three carbon atoms. fluorine, halo (for example, chloro, fluoro, bromo or iodo), amino, (alkyl d-C6) amino, di (alkyl d-Cß) amino, cyano, nitro, (alkyl d-C6) -SOn- in the that n is I zero, one or two, -COOH, -COO (alkyl d-C6) and -C (O) NH (alkyl d-C6); X is NR1 or CHR1; R1 is hydrogen, d-C6 alkyl or (d-C6 alkyl) phenyl when ring A is saturated (that is, when ring A does not contain double bonds) and R1 is missing when ring A contains a double bond; R 2 is selected from naphthyl, phenyl, (alkyl d-Cd) phenyl, 1-adamantyl, 2-adamantyl, straight or branched d-Cs alkyl, C3-C10 cycloalkyl, and bicyclic or tricyclic alkyl d-, wherein the cited C3-C10 cycloalkyl and said tricyclic C8-C30 bicyclic alkyl or optionally substituted with a hydroxy group, and said adamantyl groups optionally being substituted with one to three substituents independently selected from alkyl dd, halo and hydroxy; and R3 and R4 are independently selected from benzyl wherein the phenyl moiety of said benzyl may be optionally substituted with an [amino or nitro group; hydrogen, phenyl, (N = C) (alkyl d-C6), (alkyl d-C6) -O- ~ "I C (= O) - (alkyl d-C6) and Het-CH2, wherein Het is selected from 2-, 3- or 4-pyridinyl, furyl, tetrahydrofuryl, pyrimidyl, pyrazinyl, pyrazolyl, isoxazolyl, - I 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 of the - t compounds, (b) when Z is (H, H), X is CH2, (c) when Z is oxygen or I (H, H) and x is CHR1, R1 must be hydrogen, (d) when Z is sulfur X is NR1, R1 must be hydrogen and (e) one of R3 and R4 must be Het-CH2; and (d) the compound and the pharmaceutically acceptable salts of the aforementioned compounds.

5. The pharmaceutical composition according to claim 4, wherein the HMG CoA reductase inhibitor is selected from the group consisting of atorvastatin, pravastatin, lovastatin, compactin, fluvastatin, and simvastatin, or pharmaceutically acceptable salts thereof. the above compounds.

6. The use of a pharmaceutical composition according to any of claims 4 to 5 for the manufacture of a medicament for inhibiting the abnormal development of cells in a mammal.