MXPA96003797A - Therapeutic agents for use in can therapy - Google Patents

Abstract

This invention relates to a method for the treatment of cancer by administering a compound of the formula (See Formula) wherein A, X, G, Z, R3, R4, R5, R6, R7, R8, R9, R10, E1 , E2 p, Het ', het "are defined as indicated in the description. New compounds of the formula are also claimed

Description

THERAPEUTIC AGENTS FOR USE IN C NCER THERAPY This invention relates to the use of certain substituted heterocyclic compounds for the treatment of cancer. The therapeutically active agents of this invention show activity as inhibitors of the farnesyl protein transaserase enzyme and are believed to be useful as anticancer and antitumor agents. The therapeutic agents of this invention, ie, the compounds of formula I, IIA and 1IB, as described below, and their pharmaceutically acceptable salts, as well as the methods for their preparation, are described in the International Patent Application. PCT / US 92/11292 which designates the United States and which was published on July 22, 1993 as WO 93 / l «+ 0fi5, United States patent? +. ß76.259, which was issued on 2« + October 19, 9, International Patent Application PCT / IB 95/001 &9, which designates the United States and which was filed on March 20, 1995, and United States Patent Application 0 / 236.7i + 3 , which was presented on April 29, 199I +. The above patent and patent applications are incorporated herein by reference in their entirety. Oncogenes often encode protein components of the transduction signal pathways that lead to stimulation of cell growth and itogenesis. The oncogenic expression in culture cells leads to a cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci, lacking the contact inhibition that appears in non-transformed cells. The mutation and / or overexpression of certain oncogenes is frequently associated with human cancer. In order to acquire the transformation potential, the precursor of the Ras oncoprotein must undergo a phresolysis of the cysteine residue located in a carboxyl terminal tetrapeptide. The inhibitors of the enzyme that catalyzes this modification, farnesyl protein transferase, have therefore been suggested as anticancer agents for tumors in which Ras contributes to the transformation. Mutated oncogenic forms of Ras are frequently found in many human cancers, most notably in more than 5 of colon and pancreatic carcinomas (Kohl et al., Science, vol 260, 1A34 to 1A37, 1993).

DESCRIPTION OF THE INVENTION This invention relates to a method of treating cancer in mammals, including man, which comprises administering to said mammals an amount of the compound of the formula in which both dotted lines represent optional double links; Z is oxygen or sulfur when it has a double bond with ring A and Z is hydroxyl, (C -Cx) alkyl-SO-, (C., .- CXo > alqui 1-SO.j, -, adamant-2-i 1-S-, naphthyl-S-, benzyl-S-, phenyl-C (= 0) CH3.-S-, (C ^ -CA) alkyl-0-C <= 0) - CHSB ~ So (H, H) (that is, Z represents 2 hydrogen atoms, each of which has a single bond with the same carbon atom of ring A) when Z has a single bond with ring A, and wherein said naphthyl and phenyl and the phenyl radical of said benzyl can optionally be substituted with one to three substituents independently selected from (C ^ -CA) alkyl optionally substituted with one to three fluorine atoms, (C ^ - C3,) alkoxy optionally substituted with one to three fluorine atoms, halogen (e.g., chloro, fluoro, bromo or iodo), amino, < CX-CA) rents ino, Cdi-Ci-C,.,) AlkylDamino, cyano, nitro, (Cl.-C?) Alkyl-SOr, - where n is zero, one or two, -C00H, -COOCCÍ -CA) alkyl and -CÍO) NH (C ^ -C ,,,) alkyl; X is NR or CHR1-; R is hydrogen, (C ^ -C ^) alkyl or (CA-C?) Alkylphenyl when ring A is saturated (ie, when ring A does not contain double bonds) and R does not exist when ring A contains a double link; R3 is selected from naphthyl, phenyl, (Ci-C *) alkylphenyl, 1-adamantyl, 2-adamantyl, (CA-C?) Straight or branched chain alkyl, and (C? -Cao) bicyclic or tricyclic alkyl; wherein said < C; 3-C10 cycloalkyl and said (C? -Cao) bicyclic or tricyclic alkyl may be optionally substituted by a hydroxy group; and wherein said ada nyl groups can be optionally substituted with one to three substituents independently selected from (CA-C?) alkyl, halo and hydroxy; and R3 and R4 * are independently selected from benzyl, wherein the phenyl radical of said benzyl can be optionally substituted with an amino or nitro group; hydrogen, phenyl, < NsC) - (Cj.-CA) alkyl, 0 ^ .- 0 ^) alkyl-0-CÍSOJ-ÍCI-CA) alkyl and Het-CH », where Het is selected from 2-, 3- or? + - 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 compound, (b) when Z is (H, H), X is CHa, (c) when Z is oxygen or (H, H) and X is CHR *, A should be hydrogen, (d> when Z is sulfur and X is NR x, R should be hydrogen, and (e) one of the Ra and RL * should be Het-CH; B; or a pharmaceutically acceptable salt thereof that is effective in the treatment of cancer.Preferred embodiments of this invention include those methods already described wherein the compound of formula I which is employed is a compound wherein one of Rx and R are L-pyridinylmethyl Other preferred embodiments of this invention include the above methods wherein the compound of formula I which is employed is a compound wherein Z = (bepcyl) -S-, in the that the phenyl radical of said benzyl can be optionally substituted as defined above, and Ra is a cycloalkyl group. Also refers to a method of treating cancer in mammals, including man, which comprises administering to the said mammal an amount of the compound of the formula IIB in which R? is 4-, 3--, or 2-pyridyl, pyridyl, pyrazinyl, 2-f luora-4-pyridyl or 3-fluoro-4-pyridyl la; R7 is (CÍ-CÍQ) straight or branched chain alkyl, (C3 ~ C?) Cycloalkyl, 2-, 3-, or 4-pyridyl, phenyl or phenyl substituted with W; each W is, independently, chloro, fluoro, bromo, R ", -OH, -0R * \ - N0.B, NHa, -NHR '-NR ^ R *», -CN or -S (0) m-R '*; RA is hydrogen, chlorine, fluorine, bromine, -CN, -OH, -N0a, -CFa, -NHR **, -NR "R", R ", -OR * or -S (0) mR" each R ** is, independently, (C ^ -C ^ straight or branched chain alkyl, phenyl or benzylated, in which the aforementioned phenyl and phenyl radical of said benzyl can optionally be substituted with chlorine, fluorine, bromine, - CN, -OH, NO », -CF.3, -NH.J ,, alkyl! Amino or -S (0) m - (Ci-Ci *) alkyl; R» is - (CHa) nY or -OC0R * *; Y is hydrogen, OH, NHg., -NHR ", -NR-'R", -NHC0R ", -NHC0aR **, chlorine, fluorine, bromine, 0R *", -S (0) mRs > -C0aH, -CO-aR '", -CN, -CO R ^ R *, -CDNHR", -CONH. ,,, - COR ", -CH = CHC0aR **, -OCOR"', phenyl, substituted phenyl with W, -C = CC0aR '', -CHsCHR * »or -C = CR '*; m is 0, 1 or 2, n is 1 to 7, p is 0 or 1, G is oxygen or sulfur; R1-0 is (CA-C10) straight or branched chain alkyl, (C3-Ca) cycloalkyl, 2-, 3 ~ or 4-pyridyl or E *, E52, E3 and E1 * are independently selected from hydrogen, halogen (ie, chlorine, fluorine, bromine or iodine), (CA-C: B) alkyl, -OH, (C. C3) alkoxy, -N0a-CF3-CN, -NHa, (CA-C: a) alkynyl and diC (Ca.-C3) alkyl-lamino; He 'and Het "are independently selected from 6 heterocyclic rings of six members containing at least one nitrogen atom as part of the ring, optionally substituted with a substituent selected from (Ct-Ca) alkyl, halogen, -OH, (Ca.-C: B) alkoxy, -NHg ,, ( C ^ -Ca) alkylamino and di (CA-Ca) alkylDa ino, or a pharmaceutically acceptable salt thereof, which is effective in the treatment or prevention of cancer. More specific embodiments of this invention include methods for the treatment of cancer. cancer, as described above, wherein the compounds administered are respectively: (a) a compound of formula IIA; & (b) a compound of formula 1IB; (c) a compound of formula IIA wherein RA is hydrogen; (d) a compound of formula IIA wherein RB is (CH; a) n-Y; (e) a compound of formula IIA wherein RB is -OCORs >; (f) a compound of formula IIA wherein Ra ee 4-, 3- or 2-pyridyl; (g) a compound of formula IIA wherein R is 4-, 3- or 2-pyridyl; (h) a compound of formula I1B wherein E1 and E3 * are both hydrogen; (i) a compound of formula 1IB wherein RÍO is 2-, 3- or 4-pyridyl, (j) a compound of formula 1IB in which one or both Het 'and Het' 'is 2-, 3- or 4-pyridyl; (k) a compound of formula 1IB wherein one or both Het 'and He "is pyretyl; and (1) a compound of formula 1IB wherein each Het 'and Het '' contain one to three nitrogen atoms in the ring. This invention also relates to a method of inhibiting the abnormal growth of cells in a mammal, including man, comprising administering to said mammal an effective inhibitory amount of farnesyl protein transferase of a compound of formula I, IIA or 1IB, as defined above, or a pharmaceutically acceptable salt of such compound.

This invention also relates to a method for the inhibition of abnormal cell growth in a mammal, including a human, which comprises administering to said mammal an amount effective for the inhibition of abnormal cell growth of a compound of formula I , IIA or 1IB, as defined above, or a pharmaceutically acceptable salt of that compound. "Abnormal cell growth," as used herein, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). This includes the abnormal growth 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 an oncogenic mutation in another gene; and (3) benign and malignant cells of other proliferative diseases in which the activation of aberrant Ras occurs. Examples of such benign proliferative diseases are psoriasis, benign prostatic hypertrophy and restinosis. The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic radicals or combinations thereof. The term "halogen" as used herein, refers to chlorine, fluorine, bromine or iodine.

The compounds of formulas I, IIA and 1IB which are basic in nature are capable of forming a wide variety of salts with various organic and inorganic acids. Acids which can be used to prepare pharmaceutically acceptable acid addition salts of those compounds of formulas I, IIA and 1IB which are basic in nature are those which form non-toxic acid addition salts, that is, salts containing pharmacologically anions acceptable, such as the hydrochloride, hydroiodide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate Cesto es, 1,1'-meleno-bis- (2-hydroxy-3-naf or o] The above-mentioned compounds of formula I, IIA and IIB may contain chiral centers and therefore may exist in different pendant forms. This invention relates to any of the methods described above using any of the optical isomers or other stereoisomers of the compounds of formulas I, IIA and IIB and mixtures thereof. Patients who can be treated with compounds of formula I, IIA or 1IB according to the methods of this invention include, for example, patients who have been diagnosed with lung cancer, bone cancer, pancreatic cancer, cancer of the skin, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecological tumors (for example, uterine sarcomas, carcinoma of the fallopian tubes, endometrial carcinoma, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (for example, thyroid cancer , parathyroid glands or adrenal glands), soft tissue sarcomas, urethral cancer, penile cancer, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphoma s lymphocytes, bladder cancer, rickettsia or urethra (eg, renal cell carcinoma, renal pelvis carcinoma), or neoplasms of the central nervous system (eg, primary CNS lymphoma, spinal cord tumors, guams brain stem or pituitary adenomas). Patients who can be treated with the compounds of formula I, IIA or 1IB according to the methods of the present invention also include patients suffering from abnormal cell growth as described above.

DETAILED DESCRIPTION OF THE INVENTION The preparation of the compounds of the formulas I, IIA, and 1IB is described with inuit. In the reaction schemes and in the discussion that follows, X, Y, Z, W, A, RA ', R52, R3 », R1 *, RB, RA, R7, R ?, R", RIO, E *, E52, E3, E1 *, G, Het, Het ', Het' 'are defined as indicated above. i r I V r Scheme 1 (continuous ion) VI 10 IB Scheme 2 r i VII 10 IC (Q- (CrC10) alkyl or 2-adamantyl) Scheme 3 • / I I I [X 1E XI I XI Scheme 3 (with inuación) XI I \ R1 IF With respect to scheme 1, a compound of formula III is reacted with potassium bis (trimethylsilyl1) amide in THF (tetrahydrofuran) at a temperature of about -70 ° C. After stirring for about 30 minutes, a compound of formula 2-, 3- or 4-pyridinylmethyl-X, in which X is an appropriate leaving group (eg chloride or bromide), is added and the mixture of The reaction is allowed to warm up to room temperature. This reaction yields a compound of the formula IV in which R1 * is 2-, 3- or 4-pyridinium, which can be isolated or reacted in situ to form a compound of the formula V. The addition of the substituent R3 to the compound of formula IV gives a compound of formula V. This is carried out by the same procedure as described above to produce the compound of formula IV, with the exception that a compound of formula RaX is used instead of 2-, 3- or 4-pyridinyl eti 1-X (RaX can be, however, as indicated above, 2-, 3- or 4-pyridinylmethyl-X). The compounds of formula II can be formed by reaction of the corresponding compounds of formula V with an acid. The acid is preferably a mineral acid such as hydrochloric, nitric or sulfuric acid. This reaction is typically carried out using an organic cosolvent such as ethyl ether, tetrahydrofuran (THF) or acetonitrile, preferably THF. The reaction temperature varies from -5 ° C to to about 35 ° C, and is preferably between about 0 ° C and about room temperature. Reaction of the resulting compound of formula II with an isocyanate of the formula RaNCO gives the corresponding urea of formula VI. Generally, this reaction is carried out in a protic solvent such as methanol, ethanol or methylene chloride, with methanol and ethanol being preferred, at a temperature of about room temperature to approximately 7 ° C, preferably at about the temperature of reflux of the solvent. The reaction is preferably carried out for approximately six to eight hours, but can be carried out for a longer or shorter period of time (eg, from about half a day to about two days). Urea of formula VI it can be isolated or converted in situ to the corresponding hydaptoine derivative of formula IA. (Thin layer chromatography (TLC) can be used to determine when the starting material of the previous reaction has been consumed). The conversion is effected by heating the compound of formula VI in the presence of a catalytic amount of potassium cyanide in a reaction with inert solvent which is the same or similar to that used in the previous reaction. This reaction is preferably carried out at the reflux temperature of the solvent, although lower temperatures (eg, approximatively room temperature to approximately 7 ° C) are also suitable. The compounds of formula IB can be formed by reacting the corresponding compounds of formula IA with a strong base (eg, sodium hydride, lithium diisopropylamide, lithium hydride or potassium hydride), followed by a compound of formula R ^ X , wherein X is a leaving group (eg, chloride, iodide or bromide), and the preferred base is sodium hydride and the preferred leaving group is iodide or bromide. The solvent is typically an aprotic solvent such as THF, dimethylformamide (DMF) or an ether such as ethyl ether. It is preferably DMF. The reaction temperature can vary from about -7 ° C to about 70 ° C. A temperature of about 0 ° G to about room temperature is preferred. In relation to Scheme 2, the compounds of formula IC and ID can be formed as indicated below. A compound of formula II is reacted with a compound of formula RaNCS to form the corresponding compound of formula IC. This reaction, which occurs through an intermediate of formula VII, is generally carried out using similar solvents and under conditions similar to those described above for the formation of urea of formula VI. When R2 is adamantyl, it is preferable to use a large excess of RffiNCS reagent and let the reaction proceed for a period of about two days to a week. The resulting compound of formula IC can then be converted to the corresponding compound of formula ID by reacting it with a compound of formula QX wherein Q is (Ca.-Cj,) alkyl, 2-adamantyl, phenyl-C (= 0) CH2- or (Ci-C,.,) Alkyl-0-C < = 0) CH2 and X is the leaving group, as defined above. This reaction is typically carried out in a polar solvent such as THF, DMF or acetonitrile or acetone, preferably acetone, in the presence of a base scavenger such as a carbonate or a tertiary organic amine. Potassium carbonate is preferred. The reaction temperature may vary from about -7 ° C to about 140 ° C, with the preferred being from about 0 ° C to about room temperature. When Q is adamantyl or any other bulky substituent such as cyclohexyl, the reaction is preferably carried out in DMF at a temperature of about 25 ° C to about the reflux temperature. With reference to Scheme 3, the compounds of formula IX can be prepared by reacting diethylonate with sodium ethoxide, followed by 2-, 3- or 4-pyridinylmet-il-X, wherein X is the leaving group (eg, chlorine or bromine) The monoalkyl product is then reacted with sodium ethoxide, followed by a compound of the RSX formula, in which X is the outgoing group, as defined above. (The reactions with 2-, 3- or 4-piridilmet i 1-X and R 3 X can be carried out simultaneously or sequentially. However, when Ra and R1 * are different, it is preferable to isolate and purify the monoalkylated product prior to formation of the dialkylated product with RaX). The bis ester is then hydrolyzed with two or three equivalents of sodium or potassium hydroxide. Preferably, after the addition of sodium or potassium hydroxide, the reaction mixture is stirred for approximately 4 hours. These ester hydrolysis reactions are generally carried out at a temperature from about 0 ° C to about 60 ° C in an ether / alcohol / water solvent, preferably a THF: methanol: water mixture. The compound of formula IX can be converted to the corresponding compound of formula X by reacting it at a temperature of about 0 ° C to about 50 ° C with an excess of anhydrous acid such as hydrochloric or hydrobromic acid, in the amount of one equivalent of acid by basic function in the compound of formula IX (e.g., four equivalents of acid if both R3 and R1 * are 4-pyridinyl and yl), and with an alcohol of the formula Rr OH and then evaporating the reaction mixture to dryness Alternatively, when R3 and R are acid sensitive, the compounds of formula X can be prepared as described by Krapcho et al. 3. Orq. Chem, 43, 13A (1976). This process involves the treatment of bis-alkylated malonate with dimethyl sulfoxide (DMSO), lithium chloride and water. Derivative pyrrole idina-2, 5-dione of formula IE can be prepared by reacting the corresponding compound of formula X with an amide base followed by a compound of formula RsaNHCOCHa, X, wherein X is the leaving group, as It was defined earlier. Suitable bases include lithium diisopropylamide, lithium hexamethyldisilazide and lithium diethylaryl. Suitable solvents include aprotic solvents such as THF, ethyl ether, DMF, benzene and toluene. The reaction can be carried out at temperatures ranging from about -7 &; ° C to approximately room temperature. Preferably, this reaction is carried out in THF, using lithium diisopropylamide as the base and bromide as the leaving group, at a temperature ranging from about -7 ° C to about room temperature. Reaction of the resulting compound of formula IB with a borohydride gives the corresponding compounds of formulas XII and XI. The major product formed is the compound of formula XII. This reaction is generally carried out in a protic solvent such as a lower alcohol, preferably isopropanol, at a temperature from about -20 ° C to about 50 ° C, preferably at about room temperature, using a large excess of borohydride. Sodium borohydride is the preferred reagent, although other borohydrides (eg, lithium borohydride) may also be used. The compounds of formula XII formed in the previous step can be converted into the corresponding compounds of formula IF by reacting them with a phosphine (eg, tributylphosphine or triphenylphosphine) and an azodicarboxylate (eg, di isopropylazodicarboxylate). or diethylazodicarboxylate). Suitable solvents for this reaction (Mitsunobu reaction) include aprotic solvents such as THF, methylene chloride or acetonitr with THF being preferred. Suitable temperatures range from about 00C to about 400C, with about room temperature being preferred. International Patent Application WO 93/14065, referred to above and incorporated herein by reference in its entirety, describes a method of preparing the compounds of formula IIA. U.S. Patent Application 4,676,259, also cited above and incorporated herein by reference in its entirety, describes methods of synthesis of compounds of formula 1IB. The compounds of formulas 1, IIA and 1IB which are basic in nature are capable of forming a wide variety of different salts with various organic and inorganic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of formula I, IIA and 1IB from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter into the free base compound by treatment with an alkaline reagent and then converting the latter free base into a pharmaceutically acceptable acid addition salt. The acid-base salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt is easily obtained. The desired acid salt can also be precipitated from a solution of a free base in an organic solvent by adding an appropriate mineral or organic acid to the solution. The compounds of formulas 1, IIA and 1IB exhibit activity of Ras farnesylation inhibitors and are useful in the treatment of cancer and inhibition of abnormal cell growth in mammals, including man. Patients who can be treated with the compounds of formula I, IIA or 1IB according to the methods of the present invention include, for example, patients who have been diagnosed with lung cancer, bone cancer, pancreatic cancer, cancer of skin, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, gynecological tumors (eg, uterine sarcomas, carcinoma of the fallopian tubes, endometrial carcinoma, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, esophageal cancer, small bowel cancer, cancer of the endocrine system (eg, thyroid cancer, parathyroids or adrenal glands), soft tissue sarcomas, cancer of the urethra, cancer of the penis, cancer of prostate, acute or chronic leukemia, solid tumors of childhood, lymphocytic lymphomas, bladder cancer, kidney or ureter cancer (eg, renal cell carcinoma, renal pelvis carcinoma), or neoplasms of the nervous system central lymphoma of the primary CNS, spinal axis tumors, brainstem gliomas or pituitary adenomas). The compounds of the formulas 1, IIA or 1IB and their pharmaceutically acceptable salts (hereinafter collectively referred to as "the therapeutic compounds") can be administered orally, transdermally (e.g. through the use of a patch) , parenteral or topical. Oral administration is preferred. In general, the formula I axis compounds and their pharmaceutically acceptable salts are administered Preferably in doses ranging from approximately 1.0 mg to approximately 500 mg per day, preferably from approximately 1 to approximately 100 mg per day in single or divided doses (i.e. , multiple). The compounds of the formulas IIA and 1IB and their pharmaceutically acceptable salts will generally be administered in daily doses ranging from approximately 0.01 to approximately 10 mg per kg of body weight per day, in single or divided doses. Variations may occur depending on the weight and condition of the person treated and the particular route of administration chosen. In some cases, dosage levels below the lower limit of the aforementioned range may be more than adequate, while in other cases even higher doses may be used without causing any side effects, provided that said higher doses are divided into small doses for administration throughout the day. The therapeutic compounds can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the two routes previously indicated, and said administration can be carried out in a single dose or in multiple doses. More particularly, the novel therapeutic compounds of this invention can be administered in a wide variety of different dosage forms, that is, they can be combined with different inert pharmaceutically acceptable carriers in the form of tablets, capsules, lozenges, tablets to dissolve in the mouth, hard candies, powders, sprays, creams, balsams, suppositories, jellies, gels, pastes, lotions, ointments, elixirs, syrups and the like. Such vehicles include solid diluents or fillers, sterile aqueous medium and various non-toxic organic solvents, etc. In addition, oral pharmaceutical compositions can be suitably sweetened and / or flavored. For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine can be employed with various disintegrants such as starch (and preferably corn starch, potato or tapioca), acid alginic and certain complex silicates, together with granulating aggregates such as polyvinylpyrrolinone, sucrose, gelatin and gum arabic. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc can often be very useful for tabletting purposes. Solid compositions of similar type can also be used as fillers in gelatin capsules; the preferred materials in this respect also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient may be combined with various sweetening agents or aromatics before, coloring matter or dyes, and, if desired, emulsifiers and / or suspending agents as well as together with certain diluepts such as water, ethanol, propylene glycol, glycerin and various similar combinations thereof.

For parenteral administration, solutions of a therapeutic compound in either peanut or sesame oil or in aqueous propylene glycol can be employed. The aqueous solutions should be suitably buffered if necessary and the diluent liquid previously made isotonic. These aqueous solutions are suitable for intravenous injection purposes. Oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. The sterile preparation of all these solutions is easily carried out by conventional pharmaceutical techniques well known to those having preparation in the art. Additionally, it is also possible to administer the therapeutic compounds topically and this may be preferably carried out in the form of creams, gelatins, gels, pastes, ointments and the like, in accordance with conventional pharmaceutical practice. The activity of the therapeutic compounds as inhibitors of ras farnesylation can be determined by their ability, relative to a control, to inhibit ras farnesyl transferase in vitro. This procedure is described below. A crude preparation of human farnesyl transferase (FTase) comprising the cytosolic fraction of homogenized brain tissue is used to search for compounds in a 96-well format assay. The citaolic fraction is prepared by homogenizing approximately 40 grams of fresh tissue in 100 ml of sucrose / MgCliB / EDTA buffer (using a Dounce homogenizer, 10-15 strokes), centrifuging the homogenates at 1000 g for 10 minutes, centrifuging again the supernatant at 17,000 grams for 15 minutes at 4G, and then collecting the supernatant formed. This supernatant is diluted to a final concentration of 50 mM Tris HCl (pH 7.5), 5 mN DTT, 0.2 M KC1, 20 μM ZnC12, 1 mM PMSF and centrifuged again at 176,000 grams for 90 minutes at 4G. The supernatant, called "crude FTase" was treated for protein concentration, aliquoted and stored at -70 ° C. The assay used to measure the inhibition of human FTase in vitro is a modification of the method described by Amersham LifeScience to use its Proximal Scintillation Assay (SPA) Farnesyl Transferase (3H) kit (TRKQ 7010). The activity of the enzyme Ftase is determined in a volume of 100 μl containing N- (2-hydroxy et i 1) piperazine-N '- (2-ethane sulfonic acid) 50 mM (HEPES) pH 7.5, MgC12 30 M , KC1 20 μM, Na »HP0n. 5mM, dithiothreitol (DTT) 5mM, Triton X-100 0.01%, dimethyl sulfoxide (DMS0) 5%, 20μg crude FTase, C3H1-farnesyl pyrophosphate 0.12μM C3H.I -FPP; Amersham Lifescience 36000 dpm / pmal), and Biotinylated Ras Peptide KT CVIS (Bt-KTKCVIS) 0.2 μM which is biotinylated N-terminally in its alpha amino group and was synthesized and purified by in situ HPLC. The reaction is initiated by the addition of the enzyme and terminated by the addition of EDTA (supplied as the STOP reagent in the TRKQ 7010 kit) followed by an incubation at 37 ° C for 45 minutes. Bt-KTKCVIS prenated and pre-prenylated is collected by adding 10 μl of SPA beads with a layer of Steptavidin (TRKQ 7010) per well and incubated the reaction mixture for 30 minutes at room temperature. The amount of radioactivity due to the SPA beads is determined using a MicroBeta 1450 counting plate. Under these test conditions, the activity of the enzyme is linear with respect to the concentrations of the prenyl group acceptor, Bt-KTKCVIS, and gross FTase , but saturating with respect to the giver of prenilos, FPP. The reaction time of the test is also in the linear range. The compounds to be analyzed are routinely dissolved in 100% DMS0. The inhibition of farnesyl transferase activity is determined by calculating the percentage of incorporation of the tritiated in the presence of the compound to be analyzed against its incorporation in control wells (absence of inhibitor). IC.sub.i.sup.-values, that is, the concentration required to produce half of the maximum farnethylation of Bt-KTKCVIS, are determined from the response doses obtained. Having described the invention as above, the contents of the following are declared as property

Claims (7)

1. The new use of a compound of the formula in which both dotted lines represent optional double links; Z is oxygen or sulfur when it has a double bond with the ring A and Z is the hydroxyl, (Ca.-C10) alkyl-S-, (C ^ -CÍO) alkyl-SO-, (C ± -C ± o) alkyi-S0.?-, adamant-2-yl-S-, naphthyl-S-, benzyl-S-, phenyl-C (= 0) CHa-S-, 1 ^ - ^) alkyl-0-C ( = 0) -CHa-So (H, H) when Z has a single bond with ring A, and wherein said naphthyl and phenyl and the phenyl radical of said benzyl can optionally be substituted with one to three independently selected substituents (CX-CA) alkyl optionally substituted with one to three fluorine atoms, (Cx-C ^,) alco? i optionally substituted with one to three fluorine atoms, halogen, amino, (C ^ -C ^ alkylamino) , Cdi-ÍCj.-Cs,) alquillamino, cyano, nitro, (C ^ -C ^) alkyl-SO, -, - where n is zero, one or two, -C00H, -C00 (C ,, - CA) alkyl and -C (0) NH (C ^ -CA) alkyl; X is NRA or CHRA; RA is hydrogen, C ^ -C ^) alkyl or (Ci-C? ') Alkylphenyl when ring A is saturated (ie, when ring A does not contain double bonds) and 1 does not exist when ring A contains a double link; Ra is selected from naphthyl, phenyl, (C ^ -C ^) alkylphenyl, 1-adamantyl, 2-adamantyl, (CA-C?) Straight or branched chain alkyl, (Ca ~ CJLO) cycloalkyl and (Cfl-C3o) alkyl bicyclic or tricyclic, wherein said (C3-C10) cycloalkyl and said < CA-C30) bicyclic or tricyclic alkyl may be optionally substituted by a hydroxy group; and wherein said adamantyl groups can be optionally substituted with one to three substituents independently selected from (CA-C?) alkyl, halo and hydroxy; and Ra and R1 * are independently selected from benzyl, wherein the phenyl radical of said benzyl may be optionally substituted with an amino or nitro group; hydrogen, phenyl, (N = C) - (C x ~ C¿,) alkyl, (C ^ -C,) alkyl-0-C (= 0) - (Ca.-CA) alkyl and Het-CHa, where Het is selected from 2-, 3- or 4-pyridinyl, furyl, tetrahydrofuryl, pyrimidyl, pyrazinyl, pyrazolyl, isoxazalyl, thiophenyl and triazolyl; with the proviso that (a) no more than one of the two dotted lines can represent a double bond in any compound, (b) when Z is (H, H), X is CH ^, (c) when Z is oxygen or (H, H) and X is CHR * -, RA should be hydrogen, (d) when Z is sulfur and X is NRA, R should be hydrogen, and (e) one of Ra and R1 * should be Het-CH =; or a pharmaceutically acceptable salt thereof; in the preparation of compositions for the treatment or prevention of cancer in mammals.

2. The new use of a compound of the formula in which both dotted lines represent optional double links; Z is oxygen or sulfur when it has a double bond with ring A and Z is hydroxyl, (CjL-C10> alkyl-S-, (Cx-Cxo) alkyl-SO-, (Ca.-C10) alkyl- S0a-, adamant-2-yl-S-, naphthyl-S-, ben-il-S-, phenyl-C (= 0) CHa-S-, (C ^ -C ^) alkyl-0-C (= 0) ) -CHSB-So (H, H) when Z has a single bond with ring A, and wherein said naphthyl and phenyl and the phenyl radical of said benzyl can optionally be substituted with one to three substituents independently selected from ( CA-CA) alkyl optionally substituted with one to three fluorine atoms, (CX-C?) Alkoxy optionally substituted with one to three fluorine atoms, halogen, amino, (C ^ -C,.,) Alkylamino, Cdi - (Ca.-CA) alkyl lamino, cyano, nitro, (Cl-CA) alkyl-SO,., - wherein n is wax, one or two, -COOH, -C00 (Ca.-Ca,) alkyl and -C (0) NH (Ct-C.5, alkyl; X is NR * or CHR * i RA is hydrogen, (C? - C6) alkyl or (C? - C6) alkylphenyl when ring A is saturated (that is, when ring A does not contain double bonds) and R does not exist when ring A contains a double bond; Ra is selected from naphthyl, phenyl, (C ^ -C ,,,) alkylphenyl, 1-adamantyl, 2-adamantyl, (Ca.-C?) Straight or branched chain alkyl, (C3-C10> cycloalkyl and < C? -C30) bicyclic or tricyclic alkyl; wherein said (Ci-Ci) cycloalkyl and said (C? -C30) bicyclic or tricyclic alkyl may be optionally substituted by a hydro? i group; and wherein said adamantyl groups can be optionally substituted with one to three substituents independently selected from alkyl, halo and hydroxy; and Rs > and RI * are independently selected from benzyl, wherein the phenyl radical of said benzyl can be optionally substituted with an amino or nitro group; hydrogen, phenyl, (NsO-iC ^ -C ,,,) alkyl, (C ^ -C ^) alkyl-0-C (= 0) - (C1-C < b) alkyl and Het-CH- ,. , wherein Het is selected from 2-, 3- or 4-pyridinyl, furyl, tetrahydrofuryl, pyrimidyl, pyrazinyl, pyrazolyl, iso? azolyl, thiophenyl and triazolyl; with the proviso that (a) no more than one of the two dotted lines can represent a double bond in any compound, (b) when Z is (H, H), X is CHa, (c) when Z is oxygen or (H, H) and X is CHRA, R should be hydrogen, (d) when Z is sulfur and X is NRX, R1 should be hydrogen, and (e) one of R3 and Rl * should be Het-CHa; or a pharmaceutically acceptable salt thereof;

3. The new use of a compound according to claim 1, further characterized in that the compound of formula I or a pharmaceutically acceptable salt thereof used is a compound wherein one of R3 and R1 * is 4 -piridini lmet ilo.

4. The new use of a compound according to claim 2, further characterized in that the compound of formula I or a pharmaceutically acceptable salt thereof is a compound in which one of the Ra and R1 * is 4-p go id in i lmet i lo.

5. The new use of a compound according to claim 1, further characterized in that the compound of formula I or a pharmaceutically acceptable salt thereof used is a compound wherein Z is benzyl-S- wherein the The phenyl radical of the benzyl group may be optionally substituted as defined in rei indication 1.

6. The new use of a compound according to claim 2, further characterized in that the compound of formula I or a pharmaceutically acceptable salt thereof it is used is a compound wherein Z is benzyl-S- in which the phenyl radical of the benzyl group can be optionally substituted as defined in claim 2.

7. The new use of a compound according to claim 1 , further characterized in that said compound that is used has the formula P I IB (C3-C6) cycloalkyl, 2-, 3- or 4-pyridyl or EA, E2, E3 and El + are independently selected from hydrogen, halogen (ie, chlorine, fluorine, bromine or iodine>, (Ci-Cg) alkyla, -OH, (d.-Ca) alkoxy, -NO -CF3 -CN, -NHa, (Cx-C3) alkylamino and di [< Ct-C3) alkyl-lamino; Het 'and Het' 'are independently selected from 6 heterocyclic six-membered rings containing at least one nitrogen atom as part of the ring, optionally substituted with a substituent selected from (C ^ -Ca) alkyl, halogen, -OH , (C.-.- Ca) alkoxy, ~ NHa, (C ^ -Ca) alkylamino and diC (Ca.-Ca) alquillamino; or a pharmaceutically acceptable salt thereof, which is effective in the treatment or prevention of cancer. 6. The new use of a compound according to claim 1, further characterized in that said compound that is used has the formula [IB in which R & is 4-, 3-, or 2-pyridyl, pyrimidyl, pyrazinyl, 2-f luoro-4-pyridyl or 3-f luoro-4-pyridyl; R7 is (CJL-CIO) straight or branched chain alkyl, (C3-C?) Cycloalkyl, 2-, 3-, or 4-pyridyl, phenyl or phenyl substituted with W; each W is, independently, fluorine, chlorine, bromine, R **, -OH, -0R », - N0a, NH», -NHR '*, -NR ^ R ", -CN or -S (0) m- R9; RA is hydrogen, fluorine, chlorine, bromine, -CN, -OH, -N0a »-CF3, -NHR **, -NR ^ R *", R ", -OR" or -S (0) mR "; each R'9 is, independently, straight or branched chain alkyl, phenyl or benzylated, wherein said phenyl and phenyl radical of said benzyl can optionally be substituted with chloro, fluoro, bromo, -CN, -OH, NO ^, - CF3, -NHa-, alquil! amino or -S (0) m - (Cx-Cl +) alkyl; R * is - (CH ») n-Y or -aCOR **; Y is hydrogen, OH, NH ^, -NH2-, -NHR4", -NR ^ R" ", -NHCOR **, - NHCOsa" »', fluorine, chlorine, bromine, 0RV, -S < 0) mR * », -C0.?H, -CO ^ R», - CN, -CONR ^ R ", -C0NHR" \ -C0NH *, -COR * ", -CH ^ CHCOaR" », -OCOR" , phenyl, phenyl substituted with W, -CsCCO-jR **, -CH = CHR "or -C = CR *"; m is 0, 1 or 2; n is 1 to 7; p is 0 or 1; it is oxygen or sulfur; RAO is ICP-CÍQ) straight or branched chain alkyl, (C3-C?) Cycloalkyl, 2-, 3- or 4-pyridyl or The, E2, E3 and E4 are independently selected from hydrogen, halogen, (C1-C3) alkyl, hydroxyl, (C1-C3) alkoxy, -N02, -CF3, -CN, -NH2, (C1-C3) alkylamino and diC (Cl-C3) alquillamino; Het 'and Het' 'are independently selected from six-membered heterocyclic rings containing at least one nitrogen atom as part of the ring, optionally substituted with a substituent selected from (C1-C3) alkyl, halogen, -OH, ( Cl-C3) alco-i, -NH2, (Cl-C3) alkylamino and diC (Cl-C3) alkyl-lamino; or a pharmaceutically acceptable salt thereof. 9. The use of a compound according to claims 1, 2, 7 or 6 further characterized in that the compositions obtained are useful for the treatment between breast cancer, bone cancer, lung cancer, pancreatic cancer, cancer skin, prostate cancer, and colon cancer. 10. A method of inhibiting the cellular abnormal growth in mammals, comprising the administration to said mammal of an amount effective for the inhibition of the cellular abnormal growth of a compound of the formula in which both dotted lines represent optional double links; Z is oxygen or sulfur when it has a double bond with ring A and Z is hydroxy, (C1-C10) alkyl-S-, (C1-C10) alkyl-S0-, (Cl-ClO) alkyl-So2 ~, adamant-2-yl-S-, naphthyl-S-, benzyl-S-, phenyl-C (= 0) CH2-S-, (C, .- C6) alkyl-0-C (= 0) -CH2 ~ S ~ o (H, H) when Z has a single bond with ring A, and wherein said naphthyl and phenyl and the phenyl radical of said benzyl can optionally be substituted with one to three substituents independently selected from (Cl-C6) alkyi optionally substituted with one to three fluorine atoms, (Cj.-C6) alco? i optionally substituted with one to three fluorine atoms, halogen, amino, (Cl-C6) alkylamino, [di- (Cl-) C6alkyl3amino, cyano, nitro, (C ^ -C ^ alkyl-SOn where n is zero, one or two, -COOH, -C00 (C1-C6 Jalkyl and C (0) NH (C1-C6) alkyl; X is NR 'or CHR', R1 is hydrogen, (Cl-C6) alkyl or (Cl-C6) alkylphenyl when ring A is saturated and R 'does not exist when ring A contains a double bond; Ra is selected from naft ilo, phenyl, (Cl-C6) alkylphenyl, 1-adamantyl, 2-adamantyl, (C1-C6) straight or branched chain alkyl, (C3-C10) cycloalkyl and (C6-C30) bicyclic or tricyclic alkyl; wherein said (C3-C10) bicycloalkyl and (C6-C30) bicyclic or tricyclic alkyl may be optionally substituted by a hydro? i group; and wherein said adamantyl groups can be optionally substituted with one to three substituents independently selected from (Cl-C6) alkyl, halo and hydroxy; and R3 and R '* are independently selected from benzyl, wherein the phenyl radical of said benzyl may be optionally substituted with an amino or nitro group; hydrogen, phenyl, (N = C) - (Cl-C6) alkyl, (Cl-C6) alkyl ~ 0C (= 0) - (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 compound, (b) when Z is (H, H), X is CH2, (c) when Z is oxygen or (H, H) and X is CHR ', R' shall be hydrogen, (d) when Z is sulfur and X is NR ', R' shall be hydrogen, and (e) one of R3 and R1 * shall be be Het-CH2; or a pharmaceutically acceptable salt thereof. 11. A method of inhibiting abnormal cell growth in a mammal, comprising administering to said mammal an amount effective for inhibiting the abnormal cellular growth of a compound of the formula 118 where R? is 4-, 3-, or 2-pyridyl, pyrimidyl, pyrazinyl, 2-f luoro-4-pyridyl or 3-fluoro-4-pyridyl; R7 is (Cl-ClO) straight or branched chain alkyl, (C3-C6) cycloalkyl, 2-, 3-, or 4-pyridyl, phenyl or phenyl substituted with W; each W is, independently, fluorine, chlorine, bromine, R "*, -OH, -0R" \ -N02, -NH2, -NHR », -NR" R ", - N, or S (0) mR * '; R * is hydrogen, fluorine, chlorine, bromine, -CN, -OH, -N02, -CF3, -NHR ",, - NR9R9, R9 or ~ S (0) m-R9; each R9 is, independently, (C1 -C4) straight or branched chain alkyl, phenyl or benzyl, wherein said phenyl and phenyl radical of said benzyl can optionally be substituted with fluorine, chlorine, bromine, -CN, -OH, N02, -CF31 -NH2, (C1-C4) alkylamino, diCCl-C4) alquillamino or -S (0) m- (C1-C4) alkyl; RB is - (CH2) -Y- or -0C0R9; Y is hydrogen, OH, NH2, -NH2 , -NHR9, -NR9R9, -NHC0R9, -NHCQR9, fluorine, chlorine, bromine, 0R9, S (0) mR9, -C02H, -C02R9, -CN, -C0NR9R9, -C0NHR9, -C0NH2, -C0R9, -CH = CHC02R9, -0C0R9, phenyl, phenyl substituted with W, -C = CC02R9, -CH = CHR9 or C = CR9 m is 0, 1 or 2; n is 1 to 7; p is 0 or 1; G is oxygen or sulfur; RIO is (Cl-ClO) straight or branched chain alkyl, (C3-C6) cycloalkyl, 2-, 3- or 4-pyridyl or E ', E2, E3 and E4 are independently selected from hydrogen, halogen, (C1-C3) alkyl, hydroxyl, (C1-C3) alkoxy, -N02, -CF3, -CN, -NH2, (C1-C3) alkylamino and di C (C1-C3) alquillamino; Het 'and Het' 'are independently selected from six-membered heterocyclic rings containing at least one nitrogen atom as part of the ring, optionally substituted with a substituent selected from (C1-C3) alkyl, halogen, -OH, (C1-) C3) alkoxy, -NH2, (C1-C3) alkylamino and diC (Cl-C3) alkylamino; or a pharmaceutically acceptable salt thereof. 12. A method for inhibiting the abnormal growth of cells in a mammal, comprising the administration to said mammal of an effective inhibitory amount of farnesyl protein transferase of a compound of the formula in which both dotted lines represent optional double links; Z is oxygen or sulfur when it has a double bond with ring A and Z is hydroyl, (Cl-ClO) alkyl-S-, (C-Cl-C10) alkyl-S0-, (Cl-C10) alkyl- S02-, adamant-2-yl, S-, naphthyl-S, benzyl-S-, phenyl-C (= 0) CH2-S, (Cl-C6) alkyl-oc (= 0) -CH2-S- or (H, H) when Z has a single bond with ring A, and wherein said naphthyl and phenyl and the phenyl radical of said benzyl can optionally be substituted with one to three substituents independently selected from the (Cl-C6) alkyl optionally substituted with one to three fluorine atoms, (C 1 -C 6) alkoxy optionally substituted with one to three fluorine atoms, halogen (eg, chlorine, fluorine, bromine or iodine), amino, (C, -Q) alkylamino, Cdi- (C1-C6) alkyl-lamino, cyano, nitro, (Cl-C6) alkyl-S0n- where n is zero, one or two, -C00H, -C00 (C, -C6) alkyl and -C (0) NH (C1-C6) alkyl; X is NR1 or CHR1 or R1 is hydrogen, (C1-C6) alkyl or (C1-C6) alkylphenyl when ring A is saturated and R1 does not exist when ring A contains a double bond; Ra is selected from naphthyl, phenyl, (C1-C6) alkylphenyl, 1-adamantyl, 2-adamaptyl, (C1-C6) straight or branched chain alkyl, (C3-C10) cycloalkyl and (C6-C30) bicyclic alkyl or tricyclic; wherein said (C3-C10) cycloalkyl and (C6-C30) bicyclic or tricyclic alkyl may be optionally substituted by a hydro-yl group; and wherein said adamantyl groups can be optionally substituted with one to three substituents independently selected from (C 1 -C 6) alkyl, halogen and hydroxyl; and R3 and R1 * are independently selected from benzyl, wherein the phenyl radical of said benzyl can be optionally substituted with an amino or nitro group; hydrogen, phenyl, (N = C) - (Cl-C6) alkyl, (Cl-C6) alkyl-0-C (= 0) - (C1-C6) alkyl and Het-CH2, where Het is selected from 2- , 3- or 4-pyridinyl, furyl, tetrahydrofuryl, pyrimidyl, pyrazinyl, pyrazolyl, isoxazalyl, thiophenyl and thiazolyl; with the proviso that (a) no more than one of the two dotted lines can represent a double bond in any compound, (b) when Z is < H, H), X is CH2, (c) when Z is oxygen or (H, H> and X is CHR *, Rl should be hydrogen, (d) when Z is sulfur and X is NR1, Rl should be hydrogen , and (e) one of R3 and R1"* should be Het-CH2, or a pharmaceutically acceptable salt thereof 12. A method for inhibiting abnormal growth of cells in a mammal, comprising administration to said mammal. mammal of an effective inhibitory amount of farnesyl protein transferase of a compound of the formula [IB where R? is 4-, 3-, or 2-pyridyl, pyrimidyl, pyrazinyl, 2-f luoro-4-pyridyl or 3-f luoro-4-pyridyl; Rt is (CÍ-CÍO) straight or branched chain alkyl, (C3-Cß,) cycloalkyl, 2-, 3-, or 4-pyridyl, phenyl or phenyl substituted with W; each W is, independently, fluorine, chlorine, bromine, R * ", -OH, -0R9, -N02, -NH2, -NHR9, -NR9R9, -CN, or S (0) m-R9; R? is hydrogen, fluorine, chlorine, bromine, -CN, -OH, -N02, -CF3, -NHR9, -NR9R9, R9, -0R "or S (0) m-R9; each R9 is, independently, (Ci- C. * straight or branched chain alkyl, phenyl or benzyl, wherein said phenyl and phenyl radical of benzyl can optionally be substituted with chloro, fluoro, bromo, -CN, -OH, -N02, -CF3, -NH2, ( C1-C4) alkylamino, diC (Cl-C4) alkyl-lamino or-S (0) m- (Ci_c-n.) Alkyl; RB is - (CH2) pY or -0C0R9; Y is hydrogen, OH, NH2, -NH2, -NHR9, -NR9R9, NHC0R9, 5 -NHC02R9, fluorine, chlorine, bromine, OR1 *, -S (0) mR9, -C02H, -C02R9, -CN, -C0NR9R9, -C0NHR9, -C0NH2, -C0R9, -CH = CHC02R9, -0C0R9, phenyl, phenyl substituted with W, -C = CC02R9, CH = CHR9 or -C = CR9; is 0, 1 or 2; n is 1 to 7; p is 0 or 1; G is oxygen or sulfur; R10 is (Ci-C10) straight or branched chain alkyl, (C3-C6) cycloalkyl, 2-, 3-, or 4-pyridyl The, E2, E3 and E4 are independently selected from hydrogen, halogen, (C1-C3) alkylaryl, (CJL-C3) alco? I, -N02, -CF3, -CN, -NH2, (0 ^ -03 alkynyl and d? C (Cx_C3) alkyl-lamino; Het 'and Het' are independently selected from six-membered heterocyclic rings containing at least one nitrogen atom as part of the ring, optionally substituted with a substituent selected from ( CJ.-C3) alkyl, halogen, -OH, (Cj.-C3) alkoxy, -NH2, (Ca.-C3) alkylamino and d? D (Ca.-C3) alkylamino; or a pharmaceutically acceptable salt thereof .. 13.- A compound of the formula in which both dotted lines represent optional double links; Z is (Cl-Clo) alkyl? S02-, naphthyl-S, benzyl-S- or phen? LC (= 0) CH2-S-, where said naphthyl radical of said naphthyl-S- can be optionally substituted and wherein said phenyl and the phenyl radical of said benzyl may optionally be substituted with one to three substituents independently selected from (Cj, -C6) alkyl optionally substituted with one to three fluorine atoms, halogen, amino, ( C ^ -C ^) alkylamino, Cdi- (C-C6) alkyl] amino, cyano, nitro, (Cx, -Cs,) alkyl-SO., - where n is zero, one or two, -C00H, -C00 (C, -Q) alkyl and -C (0) NH (Ca.-C6) alkylene; X is NR * or CHR1; R1 is hydrogen, (Cj.-CA) alkyl or (Cl-C6) alkylphenyl when ring A is saturated and R * does not exist when ring A contains a double bond; Ra is selected from naphthyl, phenyl, (Cx-C6) alkylphenyl, 1-adamantyl, 2-adamantyl, (CA ~ C?) Straight or branched chain alkyl, (C3 ~ C10) cycloalkyl and (C6-C30) alkyl bicyclic or tricyclic; wherein said (C3-C10) cycloalkyl and (C6-C30) bicyclic or tricyclic alkyl may be optionally substituted by a hydroxyl group; and wherein said adamantyl groups can be optionally substituted with one to three substituents independently selected from (Ca.-C6) alkyl, halogen and hydroxyl; and Ra and R1 * are independently selected from benzyl, wherein the phenyl moiety of said benzyl may be optionally substituted with an amino or nitro group; hydrogen, phenyl, (NsO-iCi-CA1alkyl, (C-C6) alkyl-0-C (= 0) - (Ci_c &s,) alkyl and Het-CH21 where Het is selected from 2, 3- or 4-p? P? N? Lo, fuplo, tetrahydrofurall, pipmidil, pyrazinyl, pyrazolyl, iso? Azolyl, thiophenyl, and tpazolyl, with the proviso that one of R3 and R1 * must be Het-CH2; only acceptable of it. SUMMARY OF THE INVENTION This invention relates to a method for the treatment of cancer by administering a compound of the formula where A, X, G, Z, R3, Rl *, Rs, R *, R7, R? , R9, Ric > , E1, E2 p, Het ', Het' 'are defined as indicated in the description. New compounds of formula I are also claimed. P96 / 457 PF