MXPA97007191A - Compound useful trikicicles to inhibit the function of protein g and for treatment of proliferati diseases - Google Patents

Abstract

A method of inhibition of Ras function and thus inhibition of cell growth is disclosed. The method comprises the administration of a new compound of the formula (Ia), (Ib) or (Ic) wherein: R and R 1 H, alkyl, halogen, OH, alkoxy, NH 2; alkylamino, dialkylamino; CF 3; SO 3 H; CO 2 R 3; NO2; SO2NH2; or CONHR4; n represents 0 or 1; R2 is a group of the formula R5C (O) -, R5CH2C (O) -, R5C (R6) 2C (O) -, R5S = 2-, R5CH2SO2-, R5SCH2C (O) -, R5OC (O) -, R5NHC (O) -, R5NHC (O) -, R5C (O) C (O) -, R5SC (O); R5 represents alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl , heteroarylalkyl, heteroarylalkenyl or heterocycloalkyl, and R6 represents alkyl or C (R6) 2 is a carbocyclic ring, or pharmaceutically acceptable salts thereof.

Description

OF PROTEIN G AND FOR THE TREATMENT OF PROLIFERATIVE DISEASES. The international publication number WO92 / 11034, published on July 9, 1992, discloses a method for increasing the sensitivity of a tumor to an antineoplastic agent, where the tumor is resistant to the antineoplastic agent, by concurrent administration of the antineoplastic agent and a Formula enhancing agent: where Y 'is hydrogen, substituted carboxylate or substituted sulfonyl. Examples of such potentiating agents include 11- (4-piperidilidene) -5H-benzo [5,6] cyclohep-ta [1,2-b] pyridines such as Loratadine. To acquire a transforming potential, it is necessary that the Ras oncogene precursor is subjected to a farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Inhibitors of the enzyme that catalyze 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, although more notably in more than 50% of colon and pancreatic carcinomas (Kohl et al., Science, Vol. 260, 1834 to 1837, 1993). A desired contribution to the art would be useful compounds for the inhibition of farnesyl transferase. Through this invention this contribution is provided. This invention provides a method for inhibiting farnesyl protein transferase (FPT) using the tricyclic compounds described below which: (i) potently inhibit FPT, but not geranylgeranyl protein transferase I, in vitro: (ii) block the change phenotypic induced by a form of transforming Ras that is a farnesyl acceptor, but not by a form of transforming Ras that was converted into a geranylgeranyl acceptor by genetic engineering; (iii) they block the intracellular processing of Ras which is a farnesyl acceptor, but not of Ras prepared by genetic engineering to be a geranylgeranium acceptor, and (iv) they block abnormal cell growth in culture induced by transforming gas. This invention also provides a method for inhibiting the normal growth of cells, including transformed cells, by administering an effective amount of a compound of the present invention. Normal growth of cells means cell growth independent of normal regulatory mechanisms (eg, loss of contact inhibition), including abnormal growth of: (1) tumor cells (tumors) expressing 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 aberrant activation of Ras occurs. This invention provides compounds of the formula (la), (Ib) and (le) Oa) (Ib) where: R and R1 independently from each other are selected from H, alkyl (CrC6). halogen OH, alkoxy (C C6); NH2; alkylamino (C Cß); di (alkyl (CrC6)) amino; CF3; SO3H; CO2R3; NO2; SO2NH2; and CONHR4; R2 represents R5C (O) -, R5CH2C (O) -, R5C (R6) 2C (O) -, R5SO2-, R5CH2SO2-, R5SCH2C (O) -, R5OC (O) -, RdNHC (O) -, R5C (O) C (O) - or R5OC (S) -; R3 represents alkyl (Cr6) aryl; R represents alkyl (C ^ Ce); R5 represents alkyl (CrC6); aryl, arylalkyl (C C6), arylalkenyl (C2-C6), heteroaryl, heteroarylalkyl-Ce), heteroarylalkenyl (C2-C6) or heterocycloalkyl; Each R6 independently represents alkyl (C ^ Ce), or both R4 groups together with the carbon atom to which they are attached comprise a carbocyclic ring (C3-C7); n represents 0 or 1; and the dotted line represents an optional double link; and the pharmaceutically acceptable salts thereof. This invention also provides a method for inhibiting tumor growth by administering an effective amount of the tricyclic compounds, which are described herein, to a mammal (for example a man) that requires such treatment. In particular, this invention provides a method for inhibiting the growth of tumors expressing an activated Ras oncogene by administering an effective amount of the compounds described above. Examples of tumors that can be inhibited include, but are not limited to, lung cancer (e.g., lung adenocarcinoma), pancreatic cancers (e.g., pancreatic carcinoma such as, e.g., exocrine pancreatic carcinoma), colon cancers ( for example, colorectal carcinomas such as, for example, colon adenocarcinomas and colon adenoma), myeloid leukemias (e.g., acute myelogenous leukemia (AML)), follicular thyroid cancer, bladder carcinoma, and myelodiplasmic syndrome (MDS). It is believed that this invention also provides a method for inhibiting both benign and malignant proliferative diseases, in which the Ras proteins are aberrantly activated as a result of an oncogenic mutation in other genes, that is, the Ras gene itself it is not activated by mutation to an oncogenic form, where said inhibition is achieved by means of the administration of an effective amount of the tricyclic compounds described herein, to a mammal (e.g., a man) that requires such treatment. For example, it is possible to inhibit benign proliferative disorder, neurofibromatosis, or tumors in which Ras is activated due to mutation or overexpression of tyrosine kinase oncogenes (eg neu, src, abl, Ick, lyn, fyn), by means of the tricyclic compounds described herein. The compounds of this invention inhibit the farnesyl protein transferase and the farnesyl action of the Ras oncogene protein. This invention further provides a method of inhibiting Ras farnesyl protein transferase in mammals, especially man, by administering an effective amount of the tricyclic compounds described above. The administration of the compounds of this invention to patients to inhibit farnesyl protein transferase is useful in the treatment of the cancers described above. The tricyclic compounds useful in the methods of this invention inhibit abnormal cell growth. Without wishing to be bound by a theory, it is considered that these compounds can function through the inhibition of the function of the G protein, such as Ras p21, by blocking the isoprenylation of the G protein, making them then useful in the treatment of proliferative diseases such as tumor growth and cancer. Without wishing to be bound by a theory, these compounds are considered to inhibit Ras farnesyl protein transferase and, therefore, have an antiproliferative activity against cells transformed by Ras. As used herein, the following terms are used as defined below unless otherwise indicated: "alkyl", including the alkyl portions of alkoxy, alkylamino, and dialkylamino, means a straight or branched chain of carbon containing 1 to 1 carbon. and 20 carbon atoms, preferably between 1 and 6 carbon atoms; "alkenyl" means an alkyl group containing 1 or 2 double bonds; "heterocycloalkyl", means a saturated carbocyclic ring containing between 3 and 7 carbon atoms, preferably between 4 and 6 carbon atoms, wherein the carbocyclic ring is interrupted by 1 to 3 heteroatoms selected from O, S and N, and includes heterocycloalkyls as 2- or 3-tetrahydrofuranyl, 2-, 3- or 4-tetrahydropranyl, 2- or 3-tetrahydrothienyl, 2-, 3- or 4-piperidinyl, 2- or 3-pyrrolidinyl, 2- or 3-piperazinyl and - or 3-dioxanil; "Aryl" represents a carbocyclic aromatic group containing between 6 and 10 carbon atoms, such as phenyl or naphthyl, wherein said carbocyclic group may be optionally substituted with 1 to 3 substituents selected from halogen, alkyl (CrC6), hydroxy, akoxy (^ -Ce), phenoxy, CF3, amino, alkylamino, dialkylamino, CH3C (O) NH-, CH3C (O) O-, NO2 and -COOR8, where R8 represents H or alkyl (CrC6); "halogen" represents fluorine, chlorine, bromine and iodine; "heteroaryl" means a cyclic aromatic group, containing 5 to 10 members in the ring, comprising 2 to 9 carbon atoms and 1 to 3 heteroatoms selected from O, S, N and N? O, where N? O represents an N -oxide, and includes heteroaryls such as 2-, 3- or 4-pyridyl, 2-, 3- or 4-pyridyl N-oxide, imidazole, pyrazolyl, triazolyl, thienyl and furanyl, where the heteroaryl group is optionally substituted with to 3 substituents selected from halogen, alkyl (C, -C6), alkoxy (C ^ Ce), amino, alkylamino, dialkylamino, C6H5C (O) NHCH2- and -COOR8, where R8 represents H or alkyl (CrC6). The lines drawn within the ring systems indicate that the indicated bond may be attached to any of the ring substitutable carbon atoms. Certain compounds of the invention can exist in different isomeric forms (e.g., enantiomers and diastereomers). The invention contemplates all such isomers in both pure form and mixed form, including racemic mixtures. Enolic forms are also included. The compounds of the invention can exist in unsolvated and soivated forms, including hydrated forms, for example hemihydrates. In general, the solvated form with pharmaceutically acceptable solvents such as water, ethanol and the like are equivalent to unsolvated forms for the purposes of the invention. Certain tricyclic compounds will be acidic in nature, for example, those compounds which possess a carboxyl or phenolic hydroxyl group. These compounds can form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts.

Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonium, alkylamines, hydroxyalkylamines, N-methylglucamines and the like. Certain basic tricyclic compounds also form pharmaceutically acceptable salts, for example acid addition salts. For example, pyrido-nitrogen atoms can form salts with strong acids, while compounds having basic substituents such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesulfonic and other mineral and carboxylic acids known to those skilled in the art. in art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms can be regenerated by treating the salt with a suitable dilute aqueous solution of the base, such as dilute aqueous sodium hydroxide, potassium carbonate, ammonium and dilute sodium bicarbonate. The free base forms differ from their respective salt forms in some way in certain physical properties, such as solubility in polar solvents, but the salts of acids and base are otherwise equivalent to their respective free base forms for the purposes of the invention. All these salts of acids and bases are intended to be pharmaceutically acceptable salts within the scope of the invention and all salts of acids and bases are considered equivalent to the free forms of the corresponding compounds for the purposes of this invention. Hereinafter reference is made to the following compounds and reagents with the abbreviations indicated below: trifluoroacetic anhydride (TFAA); 4-dimethylaminopyridine (DMAP); methanol (MeOH); Ethanol (EtOH); diethyl ether (Et2O); triethylamine (Et3N), ethyl acetate (EtOAc); acetic acid (HOAc); m-chloroperbenzoic acid (MCPBA); dichlorohexylcarbodiimide (DCC); 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydroxychloride (DEC); 1-hydroxybenzotriazole (HOBT); N-methylmorpholine (NMM); dimethylformamide (DMF). The compounds of formula (Ia) and (Ib) can be prepared by means of the process shown in Reaction Scheme 1. SCHEME DF RFACClf) N 1 Stage (TU) Stage (b) (IV) Stage (c) Stage Stage ( In Step (a) of Reaction Scheme 1, a protected lactam A of the formula (III) is treated, where P is an amine protecting group, such as CH 3, benzyl or C 6 H 5 SO 2 -, and n has the definition indicated above, with LDA, then it is reacted with a ketone of the formula (II) where R and R1 have the definition indicated above and the dotted line represents an optional double bond, at -100 to 0 ° C, preferably at a temperature between - 80 ° and -20 ° C, to form an alcohol of the formula (IV). In Step (b) the alcohol (IV) of Step (a) is dehydrated by means of treatment with concentrated H2SO4 to form a mixture of isomeric compounds (Va) and (Vb). Compounds (Va) and (Vb) are separated, for example, by column chromatography, and a single isomer (Va) or (Vb) is used in Step (c). In Step (c) the compound (Va) or (Vb) is treated with LiAIH4, at a temperature between -40 ° and 40 ° C, preferably between -10 ° and 20 ° c, and more preferably at a temperature of about 0 ° C, in a suitable solvent, such as THF or Et2O, to form a mixture of the compounds of the formula (Via) and (Vla-1) or of a compound of the formula (Vlb) respectively. In Step (b) the compound (Via) or (Vlb) is deprotected using reagents and reaction conditions appropriate for the specific protecting group (P), k as those described in Greene, and others, "Protective Groups in Organic Synthesis, 2nd Ed. ", Pag. 315-385, John Wiley & amp;; Sons, New York (1991), to form an amine of the formula (Vlla) or (Vllb). In Step E the amine (Vlla) or (Vllb) is treated with a compound of the formula R -OH, where R 2 has the definition indicated above, in a suitable solvent, such as DMF or CH 2 Cl 2, in the presence of an agent of coupling, such as DCC or DEC, to form a compound of the formula (la) or (Ib) respectively. Alternatively, the amine (Vlla) or (Vllb) is reacted with a compound of the formula R2-CI, where R2 has the definition indicated above, in the presence of a tertiary amine base, such as DMAP or pyridine, to form a compound of the formula (la) or (Ib) respectively. The compounds of the formula (le) can be prepared by means of processes shown in Reaction Scheme 2.

SCHEME PE REA £ Cj & ü Stage (b): Eta In step (a) of Reaction Scheme 2 the mixture of the compounds of the formula (Via) or (Vla-1) of Step (c) of Reaction Scheme 1 is reacted, where P represents CH3, and R , R1 and n have the definition indicated above, and the optional double bond is not present, with a compound of the formula CICO2R7, where R7 represents alkyl (C -, - C6), (ie an alkyl chloroformate), preferably ethyl chloroformate , in the presence of a tertiary amine base, preferably ET3N, in a suitable solvent, such as toluene, at a temperature between 40 ° and 110 ° C, preferably between 60 ° and 90 ° C, to form a mixture of the compounds (VIII), (IX) and (X). The compounds (VIII) and (X) are formed from the compound (Vlla) while the compound (IX) is formed from the compound (Vlla-1). The compounds (VIII), (IX) and (X) are separated, for example, by chromatography. In Step (b) a compound of the formula (VIII) or (IX) is reacted with concentrated HCl at a temperature between 40 ° and 110 ° C, preferably between 70 ° and 90 ° C, to form an amine of formula (XI) or (XII). Alternatively, in Step (b) a compound of the formula (VIII) or (IX) is reacted with a hydroxide base, such as NaOH or KOH, preferably KOH, in the presence of a suitable solvent such as a mixture of an alcohol C ^ Ce and water, preferably a mixture of EtOH and water or PrOH and water, at a temperature between 40 ° and 100 ° C, preferably between 50 ° to 80 ° C, to form a compound of the formula (XI) ) or (XII), respectively. In Step (c) a compound of formula (XI) or (XII) is reacted with either R2OH and a coupling agent, or with R2CI and a base, substantially by means of the same procedures as described above. Scheme 1, Step (e), to form a compound of the formula (le). An alternative process for the preparation of the compounds of the formula (le) is described in Reaction Scheme 3.

ESQUFMA DE REAP, P.ir? Stage (b) Stage (c): Stage ( Stage (e) In Step (a) of Reaction Scheme 3 a compound of the formula (Va) of Step (b) of Reaction Scheme 1 is reacted, where P represents CH 3, and R, R 1 and n have the definition indicated above, and the optional double bond is not present, with Zn powder and glacial HOAc at a temperature between 80 ° and 120 ° C, preferably around 100 ° C, to form a mixture of the compounds (XIII), (XIV) and (XV) The compounds. The compounds (XIII), (XIV) and (XV) are separated, for example, by means of chromatography.

In Step (b) of Reaction Scheme 3, a compound of formula (XIII) or (XIV) is reduced by treatment with a hydride reducing agent, such as LiAl H, substantially in accordance with the same procedure as it has been described for Step (c) of Reaction Scheme 1 to form a compound of formula (XVI), where R, R1 and n have the definition indicated above, and the dotted line represents an optional double bond. In Step (c), a compound of the formula (XVI) is treated with R2OH and a compound of the formula CICO2R7, where R7 has the definition indicated above, substantially by means of the same procedure as described for Step (a) of Reaction Scheme 2, to form a compound of the formula (XVII). In Step (d) a compound of the formula (XVII) is hydrolyzed substantially in accordance with the same procedure as described for Step (b) of Reaction Scheme 2 to form an amine of the formula (XVIII). In Step (e) an amine of formula (XVIII) is reacted with either R2OH and a coupling agent, or R2CI and a base in substantially the same manner as described for Reaction Scheme 1, Step (e), to form a compound of the formula (le). The initial ketones of the formula (II) and the starting compounds of the formula (III) are known or can be prepared by known methods. The compounds of the formula R2OH, R2CI and CICO2R7 are known and are commercially available or can be prepared via established methods. In the above processes, it is sometimes desirable and / or necessary to protect certain groups R1, R2, R3 and R4 etc. during the reactions. Conventional protective groups that are operable are described in Greene, and others, "Protective Groups in Organic Synthesis, 2 Ed.", John Wiley & amp;; Sons, New York (1991). For example, see Table 1 on page 60 of the world patent WO 95/10516. The compounds useful in this invention are exemplified by the following comparative examples, which should not be construed as limiting the scope of the present invention. PREPARATION 1 In a 2-neck flask dried with a flame, THF (400 ml) and dry diisopropylamine (0.135 mol, 13.74 g, 19.0 ml) are combined. The solution is cooled to -78 ° C and n-BuL (2 M, 0.144 mol, 67 ml) is slowly added (under dripping) for 5 minutes. The resulting mixture is stirred at -78 ° C for 45 minutes, then a THF solution of lactam (0.123 mol, 21.6 g, 20 mL) is added slowly (under dripping) for 5 minutes. The reaction mixture is stirred at -78 ° C for 1 hour, then it is increased to 0 ° C for 1 hour, whereby an opaque red solution is obtained. The reaction mixture is again cooled to -78 ° C and added to a THF solution of the ketone (0.123 mol, 30 g in 300 ml THF) Via cannula. When the reaction is complete by TLC analysis (after about 2 hours), the temperature increases to -50 ° C during minutes, then saturated NH4CI (aqueous) is added to cool. The mixture is diluted with additional H2O and extracted repeatedly with EtOAc. The extracts are combined and washed with brine. The extracts are dried over Na 2 SO 4, filtered and concentrated in vacuo, whereby a mixture of diastereomeric alcohols is obtained. The mixture is heated in EtOAc whereupon 19.9 g are obtained (42% yield) of the higher Rf diasteriomer as a solid. Chromatography (silica gel, 2% THF: CH 2 Cl 2 gradually growing to 5% THF: CH 2 Cl 2) of the material obtained from the mother liquor gives 21.3 g (45% yield) of lower Rf diastereomer as a solid and 2, 9 g of unreacted ketone. The analytical data for diastereomers of R, higher are: Mass Spectrum (Cl, M + H) = 385, MP 164-166 ° C, Analysis of Burning Cale: C, 71.51; H, 5.76; N, 6.67; Cl, 8.44. Found: C, 71, 55; H, 5.58; N, 6.67; Cl, 8.49. The analytical data for the lower Rf diastereomer are: Mass Spectrum (Cl, M + H) = 385, Analysis of Combustion Cale: C, 71, 51; H, 5.76; N, 6.67; Cl, 8.44. Found: C, 71, 46; H, 5.57; N, 6.66; Cl, 8.40.

Combine 1.0 g (2.38 mmol) of higher Rf diastereomer from Step A and concentrated H2SO4 at room temperature. The mixture is heated at 60 ° C for 1.5 hours, then cooled to room temperature and poured onto ice in a rozo. The resulting solution is basified to a character of about 10 with 10% Na 2 SO 4 (aqueous) and extracted repeatedly with CH 2 Cl 2 (or EtOAc). The extracts are combined, the extracts are washed with brine, then dried over Na 2 SO 4, filtered and concentrated in vacuo to a residue. Chromatography (silica gel, 5% acetone: CH 2 Cl gradually growing to 5% MeOH: CH 2 Cl 2) gives 200 mg of the E-N-benzyl isomer, and 600 mg of the Z-N-benzyl isomer as solids. The analytical data for the E-N-benzyl isomer are: Mass Spectrum (Cl, M + H) = 401, MP 178-180.5 ° C. Analysis of Burning Cale: C, 74.90; H, 5.28; N, 699; Cl, 8.84. The analytical data for the Z-benzyl isomer are: Mass Spectrum (Cl, M + H) = 401, Analysis of Combustion Cale: C, 74.90; H, 5.28; N, 6.99; Cl, 8.84.

Found: C, 74.78; H, 5.41; N, 6.97; Cl, 8.82 Stage C: Stage C: The Z-N-benzyl isomer from Step B and 5 ml of THF are combined under an atmosphere of N2. The solution is cooled to 0 ° C, and 70 mg of LiAIH4 (1.867 mmol) are added in portions. The mixture is stirred for about 30 minutes at 0 ° C, then cooled with EtOAc and MeOH. it is filtered through celite® to remove the aluminum salts, the filtrate is concentrated and 5% NaOH (aqueous) is added. The aqueous portion is extracted with EtOAc.THF (9: 1), the organic phases are combined and washed with brine. Dry over Na SO4, filter and concentrate the filtrate in vacuo to a residue. Chromatography (silica gel, 10% acetone: hexane gradually increasing to 20% acetone: hexane) gives 175 mg (51% yield) of the Z-N-benzylamine. The analytical data for Z-N-benzylamine are: Mass Spectrum (Cl, M + H) = 387. High resolution MS Cale, for C25H24N2CI: 387.1628. Found: 387.1609. Stage D: 500 mg of the Z-N-benzylamine from Step C (1.29 mmol) MeOH (20 ml), HOAc (5 ml), 1,4 cyclohexadiene (5 ml) and 210 mg 10% are combined.

Pd / C under N2 atmosphere. The mixture is carefully heated to 70 ° C at which time hydrogen begins to evolve. After 1 hour hydrogen is added and heating is continued at about 40 ° C for an additional 1 hour. The mixture is filtered through celite®, and the filtrate is concentrated in vacuo to a residue. Toluene is added and concentrated in vacuo again to remove residual HOAc. Chromatography (silica gel, 5% MeOH: CH 2 Cl 2) gradually growing to 10% MeOH: CH 2 Cl 2: 1% NH 4 OH) gives 221 mg (58% yield) of the product of Z-amine (P-1). The analytical data for the Z-amine are: Mass Spectrum (Cl, M + H) = 296. Using the indicated initial ketone and substantially substituting the same procedure as that described in Preparation 1, the following amine was prepared: PREPARATION 2 Combine 1.04 g of UAIH4 (27.7 mmol) and 75 ml of Et2O under N2 atmosphere. The mixture is cooled to 0 ° and a THF solution of 2.2 g (5.49 mmol) of the E-N-benzyl isomer from Step B of Preparation 1 is added with a syringe. After 120 minutes the reaction mixture is cooled with EtOAc and MeOH, followed by the addition of 1% NaOH (aqueous). The aqueous portion is extracted with EtOAc (4 x 75 mL), then with EtOAc: THF (4: 1), and the extracts are combined. The extracts are washed with brine, dried over MgSO 4, filtered and concentrated in vacuo to a residue. Chromatography (silica gel, 15% acetone: EtOAc gradually growing to 5% MeOH: EtOAc) gives 1.08 g (51% yield of the EN-benzylamine product) The analytical data for the N-benzylamine are: Mass (Cl, M + H) = 387, Analysis of Combustion Cale: C, 77.61, H, 5.99, N, 7.24, Cl, 9.16, Found: C, 77.80, H, 6.07; N, 7.20; Cl, 8.94, Stage B: -amine The E-N-benzylamine of Step A is hydrogenated using Pd / C essentially by the same procedure as that described for Z-isomer in Step D of Preparation 1 to give the product of amine E (P-2). Using the indicated initial ketone and following substantially the same procedure as that described in Preparation 2, the following amine was prepared.

Combine 10 g (41.03 mmol) of ketone and 100 ml of CH2Cl2 and cool to -5 ° C. 7.0 mL (49.5 mmol) of TFAA is added, then 3.7 g (43.5 mmol) of NaNO3 are added to the stirred mixture. The mixture is allowed to warm to 20 ° C and is stirred for 30 hours. The mixture is cooled to 0 ° C and a solution of 30 ml of concentrated NH4 or H (aqueous) in 100 ml of water is slowly added, stirred for 30 minutes, then 300 ml of CH CI2 and 200 ml of water are added. . The layers are separated and the organic phase is dried over MgSO 4. It is filtered and concentrated in vacuo to a solid residue. The solid is stirred in 100 ml of warm MeOH for 30 minutes, then the mixture is allowed to cool to room temperature. It is filtered, the solid is washed with 20 ml of MeOH and dried under vacuum (0.2 mm Hg) at room temperature, whereby 4.9 g (41.4% yield) of the nitroketone product are obtained. Stage B: g (17.3 mmol) of the nitroketone from Step A, 140 ml of EtOH and 15 ml of water are combined at room temperature, then 3 g (54.5 mmol) of iron powder are added. 1 ml of concentrated HCl is added and the mixture is heated at reflux for 4 hours. The mixture is cooled to room temperature and concentrated in vacuo to a volume of about 20 ml. 100 ml of water, 200 ml of CH2Cl2 and 30 ml of 20% NaOH are added (aqueous). The layers are separated and the aqueous phase is extracted with 200 ml of CH2Cl2. The organic extracts are combined, stepped on and washed with 100 ml of water. It is then dried over MgSO 4, then concentrated in vacuo to a residue. The residue is stirred in a mixture of 20 ml of acetone and 100 ml of Et O to form a solid. The solid is filtered and washed with 20 ml of Et2O, then dried under vacuum at 20 ° C and 4.0 g (89.5% yield) of the aminoacetone product are obtained.

The analytical data for the aminoacetopa are: p. F. = 199 ° -200 ° C; Mass Spectrum (Cl) = 259, 261; Analysis of Burning Cale: -C, 64.99; H, 4.28; N, 10.83; Found - C, 64.79; H, 4.41; N, 10.58. Stage C: Combine 10 g (0.386 mol) of the amino ketone from Step B and 300 ml of 48% HBr at -5 ° C, then add 9.0 ml (1.74 mol) of Br2 and stir to -5. ° C for 20 minutes. Slowly add (under dripping) a solution of 10.5 g (1.52 mol) NaNO2 in 25 ml of water, maintaining the temperature at -5 ° C. Stir for 1 hour at -5 ° C, allow the mixture to warm to 20 ° C for 1 hour and stir at 20 ° C for 4 hours. The mixture is poured into 300 g of ice and 40% NaOH (aqueous) is added to the ice-cooled mixture to adjust the pH to 14. It is extracted with CH 2 Cl 2 (2 x 300 ml), the extracts are combined and dry over MgSO4. It is filtered and concentrated in vacuo until a residue is obtained. Chromatography of the residue (silica gel, 25% EtOAc / hexanes) gives 8.7 g (69.9% yield) of the bromoketone product. The analytical data for bromoketone are: Mass Spectrum (Cl) = 322, 324.

Slowly add (dropwise) 18 ml (45.0 mmol) of 2.5 M N-butyl lithium in hexanes to a solution of 7.0 ml (49.41 mmol) of diisopropylamine in 100 ml of THF at -78 ° C. Stir at -78 ° C for 15 minutes, then add 7.0 mL (64 mmol) of N-methyl-2-piperidone. The mixture is stirred at -78 ° C for 30 minutes, then heated at -5 ° C for a period of 1 hour. Cool to -78 ° C and slowly add (dropwise) a solution of 12 g (27.2 mmol) of the bromo ketone from Step C in 200 ml of dry THF. The mixture is stirred at -78 ° C for 1 hour, then heated at -10 ° C for 1.5 hours. 25 ml of water are added and concentrated in vacuo to remove about 200 ml of solvent. Extract with 300 ml of CH2CI2 and 300 ml of brine and dry the organic extract over MgSO4. It is filtered, concentrated in vacuo to a residue and the residue is stirred in a mixture of 30 ml of acetone and 20 ml of Et 2 O to form a solid. Filter, wash the solid with 10 ml of Et2O and dry at 20 ° C, 0.2 mm Hg, overnight to obtain 11.89 g of product with a mixture of diastereomers. Chromatography (silica gel, 25% EtOAc / hexanes) of the mother liquor and Et2O wash gives an additional 1.0 g of the product (79.56% of total yield) Analytical data of the product of Stage D: Mass Spectrum (Cl, M + H) = 437, Analysis of Combustion Cale: -C, 55.12, H, 4.62, N, 6.43, Found: C, 54.70, H, 4.57, N, 6.26 Stage E: Combine 11.4 g (26.1 mmol) of the product of Step D and 100 mL of concentrated H2SO and heat at 80 ° C for 4 hours. The mixture is cooled to 20 ° C, poured into 300 g of ice and 50% NaOH (aqueous) is added to the ice-cooled mixture to adjust the pH to 14. It is filtered to collect the resulting solid, washed the solid with 300 ml of water, then dried at 20 ° C overnight, 0.2 mm Hg. Chromatograph the solid (silica gel, 2% MeOH / EtOAc) to give 4.48 g of the Z isomer and 4.68 g of the E isomer of the product (total yield 84%). The analytical data for the Z isomer are: Mass Spectrum (Cl, M + H) = 417, 419; Combustion Analysis: Cale. -C, 57.50; H, 4.34; N, 6.70, Found: C, 57.99; H, 4.76; N, 6.66. The analytical data for the E isomer are: Mass Spectrum (Cl, M + H) = 417, 419; Combustion Analysis: Cale. -C, 57.50; H, 4.34; N, 6.70, Found: C, 57.23; H, 4.43; N, 6.65. Stage F: Combine 1.0 g (2.39 mmol) of the product of the Z-isomer of Step E and ml of dry THF at -10 ° C and 110 mg (2.78 mmol) of LiAIH4 are added. The mixture is stirred at -10 ° and -5 ° C for 2 hours, then 2 ml of EtOAc are added followed by 20 ml of sodium potassium tartrate, tetrahydrate (aqueous), 5 ml of 10% NaOH (aqueous). and 150 ml of CH2Cl2. The layers are prepared and the organic phase is dried over MgSO4. It is filtered and concentrated in vacuo to a residue, the residue is chromatographed (silica gel, first 25% EtOAc / hexanes, then 3% MeOH / EtOAc containing 1% concentrated NH 4 OH), whereby 480 mg (50% of Product performance of Z-methylamine The analytical data for methylamine Z are: pf = 160 ° -161 ° C, Mass Spectrum (Cl, M + H) = 403, 405; 59.49; H, 4.99; N, 6.94, Found: C, 59.75; H, 5.43; N, 6.79. Step G: Combine 1.1 g (2.72 mmol) of the Z-methylamine from Step F and 20 ml of toluene at 0 ° C and add 1.0 ml (10.4 mmol) of CICO2C2H6. 1.0 mL (13.6 mmol) of Et3N is added and the mixture is heated at 70 ° C for 3 hours. The mixture is cooled and concentrated in vacuo to a residue. The residue is extracted with 50 ml of CH 2 Cl 2 and the extract is washed with 30 ml of water. Dry MgSO 4, filter and concentrate in vacuo to a residue. Chromatography of the residue (silica gel, 20% EtOAc / hexanes) gives the crude product. It is crystallized from a mixture of EtO and CH 2 Cl 2 whereby 510 mg (40.8% yield) of the Z-ethylcarbamate product is obtained. The analytical data for the Z-ethylcarbamate are: p.f. = 182 ° -183 ° C; Mass Spectrum (Cl, M + H) = 461, 463; Analysis of combustion: cale. -C, 57.29; H, 4.80; N, 6.06, Found: C, 57.38; H, 4.72; N, 6.08. Stage H: Combine 400 g (0.866 mmol) of the Z-methylarbamate from Step G and 5 ml of concentrated HCl and heat at 100 ° C overnight. Cool to 0 ° C and slowly add 30% NaOH (aqueous) to basify the mixture. Extract with CH2Cl2 (2 x 50 mL) and dry the extract over MgSO4. Filter and concentrate in vacuo to yield 320 mg (94.86% yield) of the Z-amine product (P-3). The analytical data for Z-amine (P-3) are: Mass Spectrum (FAB, M + H) * 389, 391. Using the indicated initial ketone and following substantially the same procedure as that described in Steps D to H of preparation 3, the following amine was prepared: Initial ketone Amine (P-3A), p.f. = 169 ° -170 ° C PREPARATION A Combine 3.4 g (8.15 mmol) of the E-isomer product from Step E of Preparation 3 and 40 mL of dry THF at -5 ° C and add 470 mg (11.9 mmol) of LiAIH4. The mixture is stirred at 0 ° C for 5 hours, then 5 ml of water, 20 ml of potassium sodium tartrate, 10% tetrahydrate (aqueous), 5 ml of 10% NaOH (aqueous) and 150 ml are added. of CH2Cl2. The layers are separated and the organic phase is dried over MgSO4. It is filtered and concentrated in vacuo to obtain a residue. The residue is a mixture of the compound of the product and a compound of the formula The residue is chromatographed (silica gel, 5% MeOH / EtOAc) whereby 1.3 g (40% yield) of the product of E-methylamine is obtained. The analytical data for E-methylamine are: p.f. = 140 ° -141 ° C; Mass Spectrum (Cl, M + H) = 403, 405; Analysis of Cale Burning: -C, 59.49; H, 4.99; N, 6.94; Found: C, 59.11; H, 4.75; N, 6.98. Stage B: Using 0.4 g (0.99 mmol) of the E-methylamine from step A, 15 ml of toluene, 0.5 ml (5.2 mmol) of CICO2C2H5, and 0.5 ml (6.8 mmol) of Et3N , and substantially the same procedure as that described in Preparation 3, Step G, 230 mg (51.5% yield) of the E-methylcarbamate product was prepared. The analytical data for E-methylcarbamate are: Melting point = 186 ° -187 ° C; Mass Spectrum (Cl, M + H) = 463, 464; Combustion Analysis: Cale. C, 57.29; H, 4.80; N, 6.06; Found: C, 57.43; H, 5.11; N, 6.09. Stage C: The E-ethylcarbamate from Step B is converted to E-amine (P-4) in 97.8% yield) using substantially the same procedure as that described in Preparation 3, Step H. Analytical data for the amine E (P-4) are: pf 166 ° -167 ° C; Mass Spectrum (Cl) = 389, 391; Heating Analysis Cale: - C, 57.88; H, 4.66; N, 7.10; Found: - C, 57.63; H, 4.61; N, 7.03. Using the initial ketone indicated to prepare the appropriate E-isomer via the procedures described in Steps D and E of Preparation 3, Steps AE, the following amines were prepared substantially in accordance with the same procedure as that described in Steps AC of Preparation 4: - Initial ketone Amine (P-A). P- f • = 140 ° -141 ° C g (61.5 mmol) of the crude (non-chromatographed) E-methyl-amine obtained from Preparation 4 are combined., step A (using the appropriate initial ketone) and 200 ml of toluene at 0 ° C and add 20 ml (208 mmol) of CICO2C2H5. 20 ml (272 mmol) of Et 3 N are added, then heated to 80 ° C and stirred for 4 hours. It is cooled to room temperature and concentrated in vacuo to a residue. The residue is extracted with 300 ml of CH2CI2, the extract is washed with 200 ml of water, then dried over MgSO4. Filter, concentrate in vacuo to a residue, then chromatograph the residue (silica gel, 70% EtOAc / hexanes) to give 5.0 g of the product (a), 4.2 g of the product (b), and 300 mg of the product (c). Analytical Data: Mass Spectrum (Cl, M + H) product (a) = 383, product (b) = 383, product (c) = 385. Stage B: Combine 4.0 g (10.4 mmol) of product (b) from Step A and 20 ml of concentrated HCl and heat at 80 ° C overnight. It is cooled to 20 ° C, basified to pH 14 with 20% NaOH (aqueous) and extracted with 200 ml of CH 2 Cl 2. The extract is washed with 25 ml of water, dried over MgSO 4, filtered and concentrated in vacuo to a residue. The residue is chromatographed (silica gel, 10% MeOH / EtOAc + 2% NH 4 OH (aqueous)), then triturated with 15 ml of acetone / Et 2 O to give 1.96 g (60.5% yield) of the product of amine (P-5). The analytical data for the amine (P-5) are: p.f. = 157 ° -158 ° C; Mass Spectrum (Cl, M + H) = 311, 313. PREPARATION 6 Combine 400 mg (1.03 mmol) of product (c) from Preparation 5, Step A, and 5 ml of EtOH at 20 ° C, then a solution of 0.23 g (4.15 mmol) of KOH in 10 ml of water is added. The mixture is refluxed for 3 days, cooled to room temperature and concentrated in vacuo to a residue. The residue is extracted with 80 ml of CH2Cl2 and the extract is washed with 50 ml of water. Dry over MgSO 4 1, filter and concentrate in vacuo to a residue. The residue is chromatographed (silica gel, 10% MeOH / EtOAc + 2% NH 4 OH (aqueous)), then triturated with 10 ml of Et 2 O to give 200 mg (61.5% yield) of the amine (P-6). ). The analytical data for the amine (P-6) are: Mass Spectrum (Cl, M + H) = 313, 315.

- PREPARATION 7 Zn / AcOH 100 ° C Combine 1.0 g (2.95 mmol) of the E-isomer product (obtained using the appropriate ketone) of Preparation 3, Step E, 30 mL of glacial HOAc and 1.0 g (15.29 mmol) of powder of Zn and the mixture is heated at 100 ° C overnight. Filter through celite®, wash the filter cake with 20 ml of glacial HOAc, then concentrate the filtrate in vacuo to a residue. The residue is basified with 15 ml of concentrated NH 4 OH (aqueous), 50 ml of water are added and extracted with CH 2 Cl 2 (2 x 100 ml). The combined extracts are dried over MgSO 4, filtered and concentrated in vacuo to a residue. The residue is chromatographed (silica gel, 5% MeOH / EtOAc + 2% NH 4 OH (aqueous)), whereby three products are obtained: 300 mg (30% yield) of the product (a); 250 mg (25% yield) of the product (b); and 250 mg (25% yield) of the product (c). The analytical data for the product (c): p.f. = 142 ° -144 ° C, Mass Spectrum (Cl, M + H) = 339, 341. EXAMPLE 1 115 mg of the product of the Z-amine (P-1) of Preparation 1 are combined, (0.389 mmol), 5 ml of pyridine (5 ml) and a catalytic amount (15 mg) of DMAP under an atmosphere of N2. The solution is cooled to 0 ° C and 175 mg of 2-thienylsulfonyl chloride (0.961 mmol) are added. It is stirred for 10 minutes at 0 ° C, then warmed to room temperature and stirred for 17 hours. The reaction mixture is cooled by adding a solution of NaHCO4 (aqueous), and the aqueous layer is extracted with EtOAc-THF (20: 1). The extracts are combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to a residue. Chromatograph (silica gel, 25% EtOAc: hexane gradually growing to 35% EtOAc: hexane) whereby 65 mg (29% yield) of the product of Z-N- (2-thienyl) sulfonamide (E-1) is obtained. The analytical data for ZN- (2-thienyl) sulfonamide: are Mass Spectrum (Cl, M + H) = 443. Using the appropriate sulfonyl chloride and the indicated amine and following substantially the same procedure as that described for Example 1, the following sulfonamide compounds are obtained.

EXAMPLE 2 Combine 110 mg of the Z-amine product (P-1) of Preparation 1 (0.339 mmol), 5 ml of pyridine and a catalytic amount (10 mg) of DMAP under a nitrogen atmosphere. The solution is cooled to 0 ° C and C6H5SO2CI (1.17 mmol, 207 mg) is added. The mixture is stirred for 10 minutes at 0 ° C, then warmed to room temperature and stirred for 17 hours. A solution of NaHCO3 (aqueous) is added to cool the reaction mixture, then the aqueous layer is extracted with EtOAc-THF (20: 1). The extracts are combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to a residue. Chromatograph (silica gel, 25% EtOAc: hexane gradually growing to 35% EtOAc: hexane) whereby 80 mg (54% yield) of the product of Z-benzenesulfonamide (E-2) is obtained. Analytical data for ZN-benzenesulfonamide are: Mass Spectrum (Cl, M + H) = 437. Using the appropriate sulfonyl chloride and the indicated amine and following substantially the same procedure as that described by Example 2, the following sulfonamide compounds: - EXAMPLE 3 80 mg of the product of E-amine (P-2) of preparation 2 (0.270 mmol) are combined 3 ml of DMF and 2 ml of NMM under a nitrogen atmosphere. The mixture is cooled to 0 ° C and 110 mg of HOBT (0.888 mmol), 250 mg of DEC (1.31 mmol), and 0.651 mmol of (4-pyridylthio) acetic acid are added. After 30 minutes, it is warmed to room temperature and stirred for 24 hours. Concentrate in vacuo to a residue, dilute the residue with NaHCO3 (aqueous), and extract with CH2Cl2. The extracts are combined, washed with brine, dried over Na 2 SO 4, filtered and concentrated in vacuo to give a residue. It was decolorized with activated carbon and chromatographed (silica gel, 5% MeOH: CH 2 Cl 2 gradually growing to 10% MeOH: CH 2 Cl 2) whereby 45 mg (37% yield) of the E- (4-pyridylthio) amide product was obtained. (E-3). The analytical data for E- (4-pyridylthio) amide are: Mass Spectrum (Cl, M + H) - using the appropriate carboxylic acid and the indicated amine and following substantially the same procedure as that described for Example 3, the following amide compounds were prepared: - EXAMPLE 4 Combine 100 mg (0.626 mmol) of 3-pyridine sulfonic acid and 3 mL of anhydrous pyridine at 0 ° C and add 100 mg (0.406 mmol) of methylene chloride and 4-nitrobenzensulfonyl. 5 mg of DMAP are added and the mixture is stirred at 0 ° C for 7 hours. 80 mg (0.258 mmol) of Z-amine (P-3A) from Preparation 3 are added and the mixture is stirred for 1 hour at 0 ° C, and then overnight at 20 ° C. 50 ml of CH2Cl2 and 20 ml of water are added, the phases are separated and the organic phase is washed with water. Dry over MgSO 4, filter and concentrate in vacuo to a residue. The residue is chromatographed (silica gel, 5% MeOH / EtOAc + 1% concentrated NH4OH (aqueous), crystallized from 10 ml of Et20 and the resulting solid is dried at 60 ° C under vacuum to obtain 180 mg (68.9% yield) of the product of Z-3-pyridinesulfonamide (E-4) The analytical data for Z-3-pyridinesulfonamide (E-4) are: mp = 158 ° -159 ° C; Mass Spectrum (Cl) = 452, 454. Using the indicated E- or Z-amide, and following substantially the same procedure as that described for Example 4, the following sulfonamide compounds were prepared: Combine 70 mg (0.225 mmol) of Z-amine (P-3A) from preparation 3, 0.2 ml (1.53 mmol) of C6H5N = C = O and 15 ml of CH2Cl2 at 0 ° C, add 0.2 ml (2.72 mmol) of Et 3 N and stir at 20 ° C overnight. Additional 20 ml of water and 25 ml of CH2Cl2 are added, the layers are separated and the organic phase is dried over MgSO4. It is filtered, concentrated in vacuo to a residue, the residue chromatographed (silica gel, 20% EtOAc / hexanes) and crystallized from 10 ml of Et2O. The resulting solid is dried in vacuo at 20 ° C, whereby 75 mg (78% yield) of the product of Z-phenylurea (E-5) is obtained. Analytical data for Z-phenylurea (E-5) are: p.f. = 184 ° -185 ° C; Mass Spectrum (Cl, M + H) = 430, 432. EXAMPLE 6 Combine 25 mg (0.08 mmol) of the Z-amine (P-3A) of Preparation 3, 0.2 ml (2.72 mmol) and Et3N and 2 ml of anhydrous pyridine and add 0.2 g. (1.13 mmol) of phenyl chlorothioformate. 5 mg (0.04 mmol) of DMAP are added and the mixture is stirred overnight. Concentrate in vacuo to a residue and partition the residue between 25 ml EtOAc and 20 ml water. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo to a residue. The residue is chromatographed (silica gel, 5% MeOH / EtOAc), triturated with hexanes and the resulting solid is dried at 20 ° C under vacuum to give 30 mg (83.6% yield) of the product of Z-phenylthiocarbamate. (E-6). The analytical data for Z-phenylthiocarbamate (E-6) are: p.f. = 187 ° -188 ° C; Mass Spectrum (Cl) = 447.

EXAMPLE 7 combine 40 mg (0.129 mmol) of the Z-amine (P-3A) of Preparation 3, 0.5 ml (0.391 mmol) of benzoyl chloride and 5 ml of anhydrous pyridine at 0 ° C, add 2 mg of DMAP, the mixture is stirred overnight at 20 ° C. Add to ml of CH2CI2 and 10 ml of water, the phases are separated and the organic phase is washed with 20 ml of brine. The organic phase is dried over MgSO 4, filtered and concentrated in vacuo to a residue. The residue is chromatographed (silica gel, 5% MeOH / EtOAc + 1% concentrated NH4OH (aqueous)), the resulting solid is recrystallized from acetone / hexanes and dried at 60 ° C under vacuum with which to obtain the product of Z-phenylamide (P-7). The analytical data for Z-phenylamide (E-7) are: p.f. = 215 ° -216 ° C; Mass Spectrum (Cl, M + H) = 415, 417.

Using the appropriate acid chloride and the indicated E- or Z-amine and following substantially the same procedure as that described for Example 7, the following amide compounds were prepared: TESTING The IC50 of FPT (farnesyl protein transferase inhibition, in vitro enzyme assay), IC50 of GGPT (inhibition of geranylgeranyl protein transferase, in vitro enzyme assay), IC50 of COS cells (based assay) were determined. in cells) and the Cell Material Test following the test procedures of the worldwide patent WO 95/10516.

TABLE 2 COMPARISON OF THE INHIBITION OF THE FPT AND INHIBITION DF 1 TO GGPT INHIBITION COMPOSITE ENZYMATIC ENZYMATIC INHIBITION FPT IC50 μM GGPT IC50 μM E-2E 0.01 -10 7.4 mM E-1G 0.01- 10 < 13 TABLE 3 INHIBITION OF GROWTH OF TUMOR CELLS - HF MAT TEST RESULTS 1. Epzimology; The data demonstrate that the compounds of the invention are inhibitors of the farnesylation of Ras-CVLS in the partially purified rat farnesyl protein transferase (FPT) and the human brain. The data also show that there are compounds of the invention that can be considered as potent inhibitors (IC50 <10 μM) of the farnesylation of Ras-CVLS in the farnesyl protein transferase of the partially purified rat brain (FPT), see Table 2. The data also demonstrate that the compounds of the invention are somewhat less potent inhibitors of geranylgeranyl protein transferase (GGPT) analyzed using Ras-CVLL as an isoprenol acceptor. The compounds analyzed were inactive or poorly active as inhibitors of geranylgeranyl transferase at a concentration of 20 μg / ml. This selectivity is important for the therapeutic potential of the compounds used in the methods of this invention and increases the potential that the compounds will have as selective inhibitors of growth against cells transformed by Ras. 2. Cell-based: Testing of COS Cells of Cell MAT The analysis of immunomanchons of Ras protein expressed in Ras cells transfected with Ras indicated that the farnesyl transferase inhibitors of this invention inhibit Ras-processing. CVLS, reaching an accumulation of unprocessed Ras (Table 2). For example, compounds E-2 and E-2E inhibit Ras-CVLS processing with IC50 values of > 5 and 2.5 μM, respectively. These results show that the compounds inhibit farnesyl protein transferase in intact cells and indicate their potential to block cell transformation by activated Ras oncogenes. The compounds of this invention also inhibit the growth of tumor cells transformed by Ras in the MAT assay. For example, compound E-2E inhibited with an IC 0 value of < 3.1 μM. This compound only exhibits cytotoxic activity against the monolayer of normal cells at higher concentrations (IC5D of> 50 μM). Antitumor Studies in vivo The antitumor activity of the compounds of the present invention can also be determined by means of the method described in WO 95/10516. for preparing the pharmaceutical compositions of the compounds described by this invention, pharmaceutically acceptable carriers can be solid or liquid. Preparations in solid form include powder, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may comprise between about 5 and about 7% active ingredient. Suitable solid carriers are known in the art, for example magnesium carbonate, magnesium stearate, talc, sugar, lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. For the preparation of the suppositories, a low-melting wax such as, for example, a mixture of fatty acid glycerides or cocoa butter is first melted and the active ingredient is dispersed homogeneously therein such as by stirring. The molten homogeneous mixture is then poured into molds of suitable size, allowed to cool, whereupon it solidifies. Liquid form preparations include solutions, suspensions and emulsions. As an example, water or water-propylene glycol solutions for parenteral infection can be mentioned. Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in the form of powders, which may be found in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas. Also included are solid form preparations, which are intended to be converted, shortly before use, into liquid form preparations, either for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions. The compounds of the invention can also be released transdermally. The transdermal compositions may be in the form of creams, lotions, aerosols and / or emulsions and may be included in a transdermal patch of the matrix or reservoir type as is conventional in the art for this purpose. Preferably the compound is administered orally. Preferably, the pharmaceutical preparation has a unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the active component, for example, an effective amount to achieve the desired purpose. the amount of the active compound in a unit dose of preparation may vary or be adjusted between 0.1 and 100 mg, more preferably between about 1 mg and 300 mg, according to the particular application. The actual dose used can be varied depending on the requirements of the patient and the safety of the condition to be treated. Within the art expertise is the determination of the appropriate dose for a particular application. In general, treatment starts with smaller doses that are less than the optimum dose of the compound, after which the dose is increased by small increments until the optimum effect is reached under the circumstances. For convenience, the total daily dose can be divided and administered in portions during the day, if desired. The amount and frequency of administration of the compounds of the invention and the pharmaceutically acceptable salts thereof will be regulated according to the judgment of the physician in question which considers factors such as the age, condition and size of the patient as well as the severity of the symptoms to be treated. A typical recommended dosage regimen is oral administration between 10 mg and 200 mg per day, preferably between 10 and 100 mg per day, in two to four divided doses to block tumor growth. The compounds are non-toxic when administered within this dose range. The following are examples of pharmaceutical dosage forms containing a compound of the invention. The scope of the invention in its pharmaceutical composition aspect is not limited by the examples provided. Examples of Pharmaceutical Dosage Forms EXAMPLE A-Tgblet3s Manufacturing Method The items n ° 1 and 2 are mixed in a suitable mixer for 10 to 15 minutes, the mixture is granulated with the item No. 3. The granules move through - of a common sieve (eg, 1/4", 0.63 cm) if necessary Dry the damp granules, dry the dried granules if necessary and mix with item No. 4 and mix for 10 to 15 minutes Add Item No. 5 and mix for 1 to 3 minutes Compress the mixture to an appropriate size and weigh it in a suitable tablet machine EXAMPLE B -Capsules Manufacturing Method Mix items 1, 2 and 3 in a suitable mixer for 10 to 15 minutes. Then item No. 4 is added and mixed for 1 to 3 minutes. The mixture is filled into suitable two-piece hard gelatin capsules in an appropriate encapsulation machine. While the present invention has been described in relation to the specific embodiments that have been described above, it will be apparent to any person skilled in the art that many alternatives, modifications and variations thereof may be made. All of these alternatives, modifications and variations are intended to be included within the scope and spirit of the present invention.

Claims (18)

1. pFIVINDICATION Having thus specially described and determined the nature of the present invention and the manner in which it is to be carried out in practice, it is declared to claim as property and exclusive right: 1. A method for inhibiting the abnormal growth of cells comprising the administration of an effective amount of a compound of the formula (la), (Ib) or (ic) R and R1 are independently selected from H, C (C6) alkyl, halogen, OH, alkoxy (CrC6); NH2; alkylamino (CrC6); di (alkyl ^ amino; CF3; SO3H; CO2R3; NO2; SO2NH2; and CONHR4; R2 represents R5C (O) -, R5CH2C (O) -, R5C (R6) 2C (O) -, R5SO2-, R5CH2SO2- , R5SCH2C (O) -, R5OC (O) -, R5NHC (O) -, R5C (O) C (O) - or R5SC (O) -; R3 represents (C6) alkyl aryl; R4 represents alkyl (C, -C6), R5 represents (C6) alkyl, aryl, arylalkyl (C | -C6), arylalkenyl (C2-C6), heteroaryl, heteroarylalkylC ^ Ce), heteroarylalkenyl (C2-C6) or heterocycloalkyl; each R6 represents independently of each other alkyl (C ^ Ce), or both groups R4 together with the carbon atom to which they are attached comprise a carbocyclic ring (C3-C7), n represents 0 or 1, and the dotted line represents an optional double bond and pharmaceutically acceptable salts thereof 2. The method of claim 1 wherein the inhibited cells are tumor cells expressing an activated Ras oncogene 3. The method of claim 2 wherein the inhibited cells are pancreatic tumor cells, Morals of lung cancer, tumor cells of epidermal carcinoma, tumor cells of myeloid leukemia, thyroid follicular tumor cells, myelodysplastic cells, bladder carcinoma tumor cells or colon tumor cells. 4. The method of claim 1 wherein the inhibition of abnormal growth of cells occurs by the inhibition of farnesyl protein transferase. The method of claim 1 wherein the inhibition is of tumor cells in which the Ras protein is activated as a result of the oncogenic mutation in genes other than the Ras gene. 6. A compound selected from a compound of the formula (la), (Ib) or (le) (Ib) where: R and R1 are independently selected from H, alkyl (CrC6). halogen OH, alkoxy (C C6); NH2; alkylamino (C C6); di (C 1 -C 6 alkyl) amino; CF3; SO3H; CO2R3; NO2; SO2NH2; and CONHR4; R2 represents R5C (O) -, R5CH2C (O) -, R5C (R6) 2C (O) -, R5SO2-, R6CH2SO2-, R5SCH2C (O) -, R5OC (O) -, R5NHC (O) -, R C (O) C (O) - or R5SC (O) -; R3 represents alkyl (C6) aryl; R4 represents alkyl (C, -C6); R5 represents alkyl (C Ce); aryl, arylalkyl (Ci-Ce), arylalkenyl (C2-C6), heteroaryl, heteroarylalkyl (CrC6), heteroarylalkenyl (C2-C6) or heterocycloalkyl; Each R6 independently represents alkyl (C ^ Ce), or both R6 groups together with the carbon atom to which they are attached comprise a carbocyclic ring (C3-C7); n represents 0 or 1; and the dotted line represents an optional double link; and pharmaceutically acceptable salts thereof. 7. A compound of claim 6 having the structure of (Ib). 8. A compound of claim 6 wherein R and R1 are independently selected from H or halogen. 9. A compound of claim 8 wherein R2 represents R5C (O) -, R5CH2C (O) -, R5SCH2C (O) -, R5SO2-, R5CH2S02-, R5NHC (O) - or R5SC (O) -; 10. A compound of claim 9 wherein R5 represents methyl, phenyl, benzyl, 2-thienyl, 4-pyridyl, 3-pyridyl, 5-chloro-2-thienyl, p-tolyl, p-nitrophenyl, flurorphenyl, p-acetoxyphenyl , 5-chloro-1,3-dimethyl-4-pyrazolyl, 2,4,6-trimethylphenyl, 5- (benzolamino-methyl) -2-tlenyl, 2-methoxycarbonyl-3-thienyl, 4-pyridylthio, 2-furanyl , E- (3-pyridyl) ethenyl, p-methoxyphenyl, p-acetamidophenyl, or the sodium salt of 2-carboxy-3-thienyl. 11. A compound of claim 7 wherein R2 represents R5C (O) -, and R5 is 2-furanyl or E- (3-pyridyl) ethenyl. 12. A compound of claim 7 wherein R2 is R5CH2C (O) -, and R5 is 4-pyridylthio, 4-pyridyl, 3-pyridyl or benzyl. 13. A compound of claim 7 wherein R2 is R5SO2-, and R5 is 2-thienyl, 5-chloro-2-thienyl, 5-chloro-1,3-dimethyl-4-pyrazolyl, 5- (benzoylaminomethyl) -2 -thienyl, 2-methoxycarbonyl-3-thienyl, phenyl, p-nitrophenyl, p-methoxyphenyl, p-fluorophenyl, p-acetamidophenyl, p-tolyl, 2,4,6-trimethylphenyl, methyl, benzyl, 3-pyridyl, or the sodium salt of 2-carboxy-3-thienyl. 14. A compound of claim 7 wherein R2 is selected from R5CH2SO2- where R5 is phenyl; R5NHC (O) - where R5 is phenyl; R5SC (O) -, where R5 is phenyl; R5SO2- where R5 is aryl or heteroaryl; or R5SCH2C (O) -where R5 is heteroaryl. "15. A compound of claim 7 with structural formula 16. A pharmaceutical composition for use in the inhibition of abnormal cell growth comprises a pharmaceutically acceptable carrier and an effective amount of a compound of claim 6. 17. The use of a compound of claim 6 for the manufacture of a medicament. for use in the inhibition of abnormal cell growth. 18. The use of a compound of claim 6 to inhibit abnormal cell growth. p: SCHERING CORPORATION