MXPA94001344A - Inhibitors of farnesil: protein transferasacomo agents anticancero - Google Patents

Abstract

The present invention relates to certain inhibitors of farnesyl: protein transferase, which are useful as antineoplastic agents

Description

INHIBITORS OF FARNESIL: PROTEIN TO TRANSFERASE AS ANTICANCER AGENTS OWNER: MERRELL DOW PHARMACEUTICALS INC., A company of North American nationality, located at: 2110 East Galbraith Road, Cincinnati, Ohio 45215, E.U.A. INVENTOR: DAVID MARTIN STEMERICK, of North American nationality, domiciled at: 5598 Carlsbad Court Fairfield, Ohio 45014, E.U.A.

SUMMARY OF THE INVENTION The present invention relates to certain inhibitors of farnesyl: protein transferase, which are useful as antineoplastic agents.

BACKGROUND OF THE INVENTION The ras family of the proto-oncogene oncogenes codes for certain proteins, which are involved in the control of the proliferation of eukaryotic cells. These genes, by means of the processes of normal transcription and translation, provide proteins called ras proteins, which can interact with molecules made for the control of cell division. Ras proteins are produced initially in the cell in an inactive state and must support several post-translational modifications to become activated. As part of the activation process, ras proteins support farnesylation at a cysteine residue located near the C-terminus. This farnesylation facilitates the association of ras protein with the inner surface of the plasmic membrane. The association of the membrane is critical for the onsogenic transformation caused by the activated ras proteins. See Schafer et al., Science 245. 379 (1989). Farnesylation of ras proteins is catalyzed by ras rasnesyl: transferase protein, also known as FPTase. By means of that enzymatic reaction, the farnesyl portion of the cholesterol biosynthetic intermediate, farnesyl diphosphate, is raised by means of a thioether bond to a cysteine residue located near the C-terminus of the ras protein. Activated ras proteins are found in a variety of human cancers, including colon and pancreatic carcinomas. The interference of the membrane in the location by the ras proteins by the inhibition of the FPTase-mediated farnesylation of the inactive ras proteins, will present inhibited cell proliferation, caused by the activated ras proteins, and in this way provides an anticancer effect. The present invention provides compounds, which are inhibitors of ras FPTase and as such are useful as anticancer agents.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides compounds having the following general formula: -OR2 Formula I OR wherein X is CH2, CC12 or CF2, R-] and 2 are each independently H; alkyl of C1-C4 '^ CH2 ^ n-Z' in e- ^ < 3 n is e ^ - integer 0, 1, 2, 3 or 4 and Z is phenyl or naphthyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 4 alkyl, C 1 alkoxy | -C4, halogen, CF3, OCF3, OH, CN, N02 and NH2; or a pharmaceutically acceptable cation, and A is a radical selected from the group consisting of wherein R3 is C- | -C- | g alkyl, which may be saturated or unsaturated, having 1 to 9 double bonds.

The present invention provides compounds having the following general formula: O O - IPI AND IPI OR3 Formula II wherein X is CH2, CC12 / or CF2, Y is CH2 or CF2, R- | and R2 are each independently H; alkyl of C-j-C ^ (CH2) n -Z, where n is the integer 0, 1, 2, 3 or 4 and Z is phenyl or naphthyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C-, C4, alkoxy, C.] - C4, halogen, CF, OCF3, OH, CN, N02 and H2; or a pharmaceutically acceptable cation, and A is a radical selected from the group consisting of wherein R 4 is C 1 -C 4 alkyl, which may be saturated or unsaturated, having 1 to 9 double bonds.

Another embodiment of the present invention is a method for the treatment of a patient suffering from a neoplastic disease or to control the growth of a neoplasm in a patient suffering from a neoplastic disease, which consists of administering a therapeutically antineoplastic amount. effective of a compound of Formula I or II.

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "C-j-C ^ alkyl" refers to a straight or branched chain hydrocarbon radical, saturated from one to four carbon atoms. Included within the scope of this term are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and the like. The term "C 1 -C 4 alkoxy" refers to an alkyloxy radical formed on an oxygen radical having a straight or branched chain saturated hydrocarbon radical of one to four carbon atoms. Included within the scope of this term are methoxy, ethoxy, propyloxy, isopropyloxy-, n-butyloxy, isobutyloxy, sec-butyloxy, t-butyloxy and the like. The term "C-i-C-jg alkyl, which may be saturated or unsaturated, having 1 to 9 double bonds" refers to a straight or branched chain hydrocarbon radical of one to nineteen carbon atoms. Specifically included within the scope of this term are methyl, ethyl, n-propyl, isopro-pyl, n-butyl, isobutyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl. , heptadecyl, octadecyl, nonadecyl, farnesyl, geranyl, neryl, 3-methyl-2-butenyl and the like. The term "halogen" refers to a chlorine, bromine or iodine atom. The term "Pg" refers to a protecting group. The term "pharmaceutically acceptable cation" refers to those cations that are not substantially toxic at the dose administered, to achieve the desired effect and do not possess significant independent pharmacological activity. The salts included within the scope of this term are those of alkali metals, for example, sodium and potassium; alkaline earth metals such as calcium and magnesium; light metals of Group IIIA, including aluminum; and primary, secondary and tertiary organic amines such as, for example, triethylamine, dibenzylamine, N, N'-dibenzylethylenediamine, diisopropyletileamine and the like. Sodium salts are preferred. The compounds of Formula I can be prepared as described in Scheme I. • All substituents, unless otherwise indicated, are those previously defined. Reagents and starting materials are readily available to an expert skilled in the art. Scheme I Stage c Optional Hydrolysis R5 = R1 and R2 with the proviso that R5 is not hydrogen or a pharmaceutically acceptable cation Z = hydrogen or a pharmaceutically acceptable cation.

In Scheme I, step a, the aldehyde defined by structure (2) is treated with the phosphate anion defined by structure (1) to provide defined by structure (3). For example, an equivalent of the appropriately substituted phosphonate (1), such as dimethyl difluoromethylphosphonate dissolved in a suitable organic solvent, such as tetrahydrofuran, is added dropwise to a stirred solution of the lithium diisopropylamide at about -78 ° C. The mixture is stirred for 2 minutes to 2 hours. An aldehyde (2) appropriately substituted, such as farnesal [prepared by Swern oxidation of trans, trans-farnesol following the procedure of Biller, S.A. and Forster, C., Tetrahedron 1990, 46 (19), 6645] dissolved in a suitable organic solvent such as tetrahydrofuran, is slowly added to the anion of (1) which maintains the reaction temperature below -72 ° C. After about 2 hours, the reaction is poured into a suitable aqueous acid, such as 0.1 N hydrochloric acid and extracted with a suitable organic solvent such as diethyl ether. The organic phase is dried over a suitable drying agent such as anhydrous magnesium sulfate, filtered and concentrated under vacuum. Then the residue is purified by techniques well known in the art. For example, the residue can be purified by flash chromatography using a suitable organic eluent, such as 40% ethyl acetate / hexane to provide the, Dimethyl-1-difluoro-2-hydroxy-4, 8,12-trimethyl-3, 7,11 -tridecatrienylphosphonate. In Scheme I, step b, the alcohol (3) is oxidized to the ketone described by the structure (5. For example, one equivalent of the trifluoroacetic acid anhydride is added in drops to 2 equivalents of dimethylsulfoxide in a suitable organic solvent. , such as dichloromethane at about 60 ° C. After the addition is complete, the reaction is stirred for about 2 minutes.One equivalent of an alcohol (3), appropriately substituted, such as 1,1-difluoro-2-hydroxy Dimethyl-4, 8,12-trimethyl-3,7,11-tridecatrienylphosphonate, dissolved in a suitable organic solvent, such as dichloromethane-QO, is added to the reaction in droplets. After the addition is complete, the reaction The reaction is cooled to -78 ° C and an excess of triethylamine is added in drops, then the reaction is allowed to warm to room temperature and is stirred for about 45 minutes. in water and extracted with a suitable organic solvent, such as diethyl ether. The organic phase is dried over a suitable drying agent, such as anhydrous magnesium sulfate, filtered and concentrated under vacuum. Then the residue is purified by techniques well known in the art. For example, the residue can be purified by flash chromatography using a suitable organic eluent, such as 20% ethyl acetate / hexane to provide 1,1-difluoro-2-oxo-4,8,13-trimethyl-3, 7,11-dimethyltridecatrienylphosphonate. In Scheme I, step c, the alcohol defined by structure (3) is hydrolyzed to the diacid or diacid salt defined by structure (4). For example, an appropriately substituted alcohol (3), such as 1,1-difluoro-2-hydroxy-4,8,12-trimethyl-3,7,11-tridecatrienylphosphonate dimethyl, is combined with about 2 equivalents of collidine in a suitable organic solvent, such as dichloromethane and cooled to about 0 ° C. Approximately 4 equivalents of a suitable trialkylsilyl halide, such as trimethylsilyl iodide, is added dropwise to the above solution. After stirring for about 2 hours, the reaction is diluted with a suitable organic solvent, such as diethyl ether, and rinsed with a suitable aqueous acid, such as 1N hydrochloric acid. The organic phase is dried over a suitable drying agent, such as anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the unpurified diacid. This is treated with a suitable base, such as 0.1N sodium hydroxide and then lyophilized to remove the water. Then the product is purified by techniques well known in the art. For example, the product can be purified by chromatography on a suitable stationary phase, such as CHP20P (a divinylbenzene / styrene copolymer) with a suitable eluent, such as a gradient of water to methanol, to provide the disodium salt of acid 1, 1-difluoro-2-hydroxy-4,8,12-trimethyl-3,7,11 -tridecatrienylphosphonic acid. In Scheme I, step c, the ketone defined by structure (5) is hydrolyzed to the diacid or diacid salt defined by structure (6). For example, an appropriately substituted ketone (5), such as 1,1-difluoro-2-oxo-4, 8,12-trimethyl-3,7,11-tridecatrienylphosphonate dimethyl, is combined with about 2 equivalents of collidine in a suitable organic solvent, such as dichloromethane, and cooled to about 0 ° C. Approximately 3 to 4 equivalents of a suitable trialkylsilyl halide, such as trimethylsilyl bromide, is added dropwise to the above solution. Then the reaction is allowed to warm to room temperature. After stirring for 5 hours, the reaction is diluted with a suitable organic solvent, such as toluene. The solvent is removed under vacuum and the residue is dissolved in a suitable organic solvent, such as diethyl ether and rinsed with a suitable aqueous acid., such as 1N hydrochloric acid. This is treated with an excess of a suitable base, such as 0.1N sodium hydroxide concentrated under vacuum to remove the organic solvents, and then lyophilized to remove the water. Then the product is purified by techniques well known in the art. For example, the product can be purified by chromatography on a suitable stationary phase, such as CHP20P (a divi-nilbenzene / styrene copolymer) with a suitable eluent, such as a gradient of water to methanol, to provide the disodium salt of the acid 1, 1-difluoro-2-oxo-4, 8, 12-trimethyl-3,7,11-tridecatrienyl-phosphonic acid. The compounds of Formula II can be prepared as described in Scheme II. All substituents, unless indicated otherwise, were previously defined. Reagents and starting materials are readily available to an expert with ordinary skill in the art.

Sg? Wepa II Stage d Anionic Addition 14 R5 = R-j. R2 and R3 with the proviso that R5 is not hydrogen or a pharmaceutically acceptable cation Z = hydrogen or a pharmaceutically acceptable cation. Y = CH2 or CF2 In Scheme II, step a, the alcohol (3) is protected with a suitable protecting group, such as t-butyldiphenylsilyl ether or t-butyldimethylsilyl ether, with t-butyldiphenylsilyl ether being most preferred, to provide the appropriately substituted protected alcohol, described by structure (7). For example, following the general procedure described by Hanessian, S. and Lavellee, P., J. Can. Chem. 1975, 5_3, 2975, the alcohol (3) is dissolved in a suitable solvent such as dimethylformamide and treated with about 1.1 equivalents of t-butyldiphenylsilyl chloride and about 2.2 equivalents of imidazole. The reaction is stirred at room temperature for 4 to 24 hours. The reaction is then diluted with diethyl ether, rinsed with water, saturated sodium chloride, diluted in half with water, saturated sodium chloride, dried over a suitable drying agent, such as anhydrous sodium sulfate, filtered and it is concentrated under vacuum. The residue is purified by techniques well known to one skilled in the art. For example, the residue can be purified by flash chromatography with a suitable eluent, such as ethyl acetate / hexane, to provide the protected alcohol described by structure (7). In Scheme II, step b, the protected alcohol (7) is selectively hydrolyzed to provide the appropriately substituted monoacid, described by structure (8). For example, following the general procedure described by Biller, S.A. and Forster, C. Tetrahedron 1990, 46. (19) 6645, the protected alcohol (7) is dissolved in a suitable solvent mixture, such as 1: 1 methanol / water containing a slight excess of potassium hydroxide. The reaction is heated to 65-75 ° C for 1 to 5 hours. Then the methanol is evaporated and methylene chloride is added. The stirring mixture is acidified with potassium acid sulfate. The layers are separated and the aqueous layer is extracted with methylene chloride. The organic extracts are combined, washed with 50% brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give the monoacid (8). In Scheme II, step c, the monoacid (8) is treated with oxalyl chloride to form the appropriately substituted acid chloride, described by structure (9). For example, the monoacid (8) is dissolved in a suitable organic solvent, such as benzene, which contains a catalytic amount of dimethylformamide under a nitrogen atmosphere. An excess of oxalyl chloride is added dropwise at room temperature. After 2 to 4 hours, the solution is concentrated under vacuum. The residue is then dissolved twice in benzene, and concentrated under vacuum to provide the acid chloride (9). In Scheme II, step d, the acid chloride (9) is treated with a suitable anion to provide the appropriately substituted phosphonate, described by structure (10). For example, a solution of about 2.2 equivalents of an appropriately substituted dialkylphosphonate, such as dimethyl methylphosphonate in a suitable organic solvent, such as tetrahydrofuran, is cooled to about -78 ° C and treated in drops with approximately 2.1 equivalents of butyllithium ( 1.6 M in hexane). After stirring for about 15 to 30 minutes, one equivalent of the acid chloride (9) dissolved in tetrahydrofuran is added in drops to the anion formed therein. After stirring at -78 ° C for about 1 hour, the reaction is allowed to warm to 0 ° C and is stirred for an additional 1 hour. The reaction is then diluted with suitable organic solvent, such as diethyl ether and quenched with a suitable aqueous acid, such as 10% hydrochloric acid. The phases are separated and the organic phase is rinsed with water, saturated sodium bicarbonate and brine. The mixture is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified using techniques well known to one skilled in the art. For example, the residue can be purified by flash chromatography on silica gel, using a suitable eluent, such as methanol / methylene chloride, to provide the purified phosphonate (10). In Scheme II, step e, the phosphonate (10) is deprotected under mild conditions, to provide the alcohol described by structure (11). For example, a solution of the phosphonate (10) is dissolved in a suitable organic solvent, such as tetrahydrofuran, and treated with an excess of a suitable fluoride ion source, such as tetra-n-butyl-ammonium fluoride at room temperature. . After about 1-24 hours, the reaction is diluted with a suitable organic solvent, such as diethyl ether. The reaction is then washed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by techniques well known to one skilled in the art. For example, the residue can be purified by flash chromatography on silica gel, using a suitable eluent, such as methanol / methylene chloride, to provide the purified alcohol (11). Scheme II, step f, of the alcohol (11) can be hydrolyzed by following generally a procedure previously described in scheme 1, step c, to provide the compound described by structure (12). In Scheme II, step g, alcohol (11) can be oxidized by following generally the procedure previously described in scheme I, step b to provide the ketone described by structure (13). In Scheme II, step f, the ketone (13) can be hydrolyzed by following generally the procedure previously described in Scheme I, step c, to provide the compound (14) in which R5 = Z. The following examples present typical syntheses as described by Schemes I and II. It is understood that these examples are illustrative only and are not intended to limit the scope of the invention in any way. As used in the following examples, the following terms have the indicated meanings: "eq." refers to equivalents, "g" refers to grams, "mg" refers to milligrams, "mmoles" refers to millimoles, "ml" refers to milliliters, "° C" refers to degrees Celsius, "CCF" refers to thin layer chromatography, "Rf" refers to the retention factor and "LOD" refers to loss during drying.

Example 1 Preparation of dimethyl 1, 1 -difluoro-2-hydroxy-4, 8,12-trimethyl-3, 7, 11 -tridecatrienylphosphonate Scheme I, stage a; The diisopropylamine (22.24 ml, 0.159 mol) is combined with tetrahydrofuran (250 ml) and cooled to -20 ° C. N-Butyllithium (63.3 ml, 2.5 N in hexane, 0.159 mol) is added dropwise to the solution. Stir for 30 minutes and cool to -78 ° C. A solution of dimethyl difluoromethylphosphonate (25.8 g, 0.159 mol) in tetrahydrofuran (20 ml) is added dropwise, while the temperature is maintained below -75 ° C. After the addition is complete, it is stirred for 2 minutes and then a trans-farnesal solution [prepared according to Biller, S.A.; Fors-ter, C. Tetrahedron 1990, 46 (19), 6645] (14 g, 0.0636 moles) prepared in the previous step, in tetrahydrofuran (10 ml), keeping the temperature below -72 ° C. After the addition is complete, it is stirred for an additional 2 hours at -78 ° C and then the reaction is poured into 0.1N hydrochloric acid (500 ml). The reaction is extracted with diethyl ether (2 X 11). The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography [40% ethyl acetate / hexane, Rf (50% ethyl acetate / hexane) = 0.44] to provide the title compound (9.3 g, 39%) as an oil. Analysis Calculated for C-j gH31F204P: C, 56.83; H, 8.21. Found: C, 56.61; H, 8.48.

Preparation? LeJL 1. 1 -dif luoro-2-oxo-4 .8. 1 2-trimethyl- 3.7.11 -tridecatrienylphosphonate dimethyl Scheme I, stage b; Trifluoroacetic acid anhydride (1.30 ml, 0.0096 mole) is combined with dichloromethane (20 ml) and cooled to -60 ° C. A solution of dimethyl sulfoxide (1.30 ml, 0.0183 mol) in dichloromethane (2 ml) is added dropwise, while the temperature is maintained below -55 ° C. After the reaction is complete, stir for 2 minutes. A solution of dimethyl 1,1-difluoro-2-hydroxy-4,8,12-trimethyl-3,7,11-tridecatrienylphosphonate (1.60 g, 0.0042 mole) prepared in Example 1 in dichloromethane (4 ml) is added. and it is stirred for 45 minutes. The reaction is cooled to -78 ° C and triethylamine (3.0 mL, 0.021 moles) is added dropwise. The reaction is allowed to warm to room temperature and is stirred for 45 minutes. The reaction is poured into water (100 ml). The extract is mixed with diethyl ether (400 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography (20% ethyl acetate / hexane, R £ = 0.18) to give the title compound (1.1 g, 69%) as an oil. Analysis calculated for C- | gH29F204P: C, 57.13; H, 7.72.

Found: C, 57.10; H, 7.97.

Example 3 Preparation of the disodium salt of 1,1-difluoro-2-hydroxy-4, 8,12-trimethyl-3, 7,11 -tridecatrienylphosphonate Scheme I, stage c; The dimethyl 1,1-difluoro-2-hydroxy-4,8,12-trimethyl-3,7,11-tridecatrienylphosphonate (0.378 g, 0.001 mole) prepared in Example 1 was combined with collidine (0.44 ml, 0.0033 moles) ) and dichloromethane (5 ml). It is cooled to 0 C. A solution of trimelsilyl iodide (0.56 ml, 0.004 mole) in dichloromethane (0.5 ml) is added dropwise and the reaction is allowed to stir for 2 hours. Diethyl ether (200 ml) is added and washed with 1N hydrochloric acid (3 X 100 ml). The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the phosphonic acid of the title compound. The residue is treated with 0.1N sodium hydroxide (25 ml) and lyophilized to produce an off-white powder. Purify by chromatography on CHP20P (a divinylbenzene / styrene copolymer), eluting with a gradient, starting with water and ending with methanol. The product containing the fractions is lyophilized to provide the title compound (0.17 g, 43%) as a white powder, m.p. 287-289 ° C. Analysis Calculated for C 16 H 25 F 204 PNa 2: C, 48.48; H, 6.36. Found: C, 48.20; H, 6.32.

Example4 Preparation of the disodium salt of 1,1-difluoro-2-oxo-4,8,12-trimethyl-3, 7,11 -tridecatrienylphosphonate Scheme I, stage d; The 1,1-dimethyl-ro-2-oxo-4, 8,12-trimethyl-3,7,11-tpdecatrienylphosphonate (1.2 g, 0.0032 mol), prepared in Example 2, is combined with collidine (0.85). ml, 0.0064 moles) and dichloromethane (5 ml). It is cooled to 0 ° C. Trimethylsilyl bromide (0.92 ml, 0.007 moles) is added, warmed to room temperature and stirred for 5 hours. Toluene (20 ml) is added and concentrated under vacuum. Diethyl ether (200 ml) is added and washed with 1N hydrochloric acid (3 x 50 ml). The organic phase is treated with 0.1N sodium hydroxide (64 ml), concentrated in vacuo to remove the organic solvents and lyophilized to remove the water. Purify by chromatography as in Example 3, and freeze-dry the product containing the fractions to give the title compound (0.32 g, 25%) as a white powder, m.p. 247.5-249 ° C (decomposition). Analysis Calculated for C-] 6H2 F2O4PNa »0.8H20: C, 47.02; H, 6.09, LOD = 3.7. Found: C, 47.05; H, 6.07, LOD = 3.7.

Example 5 Preparation of dimethyl 2-hydroxy-4, 8,12-trimethyl-3, 7,11-tridecatrienylphosphonate Scheme I, step a: The diisopropylamine (2.80 ml, 0.02 mole) is combined with tetrahydrofuran (40 ml) and cooled to -20 ° C. N-Butyllithium (8.0 ml, in 2.5 N hexane, 0.02 mole) is added dropwise to the solution. Stir for 20 minutes, and cool to 70 ° C. A solution of dimethyl methylphosphonate (2.48 g, 0.020 mol) in tetrahydrofuran (20 ml) is added dropwise while keeping the temperature below -70 ° C. After the addition is complete, stir for 1 hour, and then slowly add a solution of trans, trans-farnesaldehyde [prepared as in example 1] (2.2 g, 0.01 mol) in tetrahydrofuran (4 ml) maintaining the temperature below -72 ° C. After the addition is complete, it is stirred for an additional 1 hour at -70 ° C, and then the reaction is poured into saturated ammonium chloride (100 ml). The reaction is extracted with diethyl ether (400 ml). The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (50% ethyl acetate / hexane, Rf = 0.083) to give the title compound (1.97 g, 57%) as an oil; MS (El) M + = 344. Analysis Calculated for C-jgHß ^ O ^ P: C, 62.77; Hf 9.66. Found: C, 62.75; H, 9.74.

Example 6 Preparation of dimethyl 2-OXO-4.8.12-trimethyl-3, 7.11-tridecatrienylphosphonate Scheme I, stage b; The dimethyl 2-hydroxy-4,8,12-trimethyl-3,7,11-tridecatrienylphosphonate (1.03 g, 0.003 mole) prepared in Example 5 is combined with barium permanganate (2.30 g, 0.009 mole) and dichloromethane ( 18 ml) under a nitrogen atmosphere. It is stirred for 6 days.- The solids are removed by filtration and the filtrate is concentrated under vacuum. The residue is purified by flash chromatography (75% ethyl acetate / hexane, R.sup.- = 0.51) to give the title compound (0.3 g, 30%) as an oil; MS (CI / CH4) M + H = 343. Analysis Calculated for C-jg ^ -jO ^ P: C, 63.13; H, 9.13. Found: C, 61.96; H, 9.22.

Example 7 Preparation of the disodium salt of 2-hydroxy-4.8.12-trimethyl-3,7,11-tridecatrienylphosphonate.

Scheme I, stage c; Combine dimethyl 2-hydroxy-4,8,12-trimethyl-3,7,11-tridecatrienylphosphonate (0.95 g, 0.0027 mol) with collidine (0.73 ml, 0.0055 mol) and dichloromethane (7.5 ml). It is cooled to 0 ° C. Trimethylsilyl bromide (1.44 ml, 0.011 mole) is added and heated to room temperature. Stir for 5 hours and add toluene (20 ml). Concentrate in vacuo and dissolve the residue in diethyl ether (200 ml). Rinse with 1N hydrochloric acid (3 X 50 ml). 0.1N sodium hydroxide (54 ml) is added to the organic phase, the organic solvents are removed under vacuum and lyophilized to remove the water. Purity by chromatography as in Example 3, gives the title compound (0.35 g, 35%) as a white lyophilizate, m.p. > 350 ° C. Calculated Analysis for C- | 6H27O4PNa2 «0.6H20: C, 51.78; H, 7.66, LOD 2.9. Found: C, 51.48; H, 7.66, LOD 2.9.

Preparation of the disodium salt of 2-oxo-4,8,13-trimethyl-3,7,11-tridecatrienylphosphonate.

Scheme I, step c: Combine dimethyl 2-oxo-4,8, 12-trimethyl-3,7, 11 -tridecatrienylphosphonate (0.692 g, 0.002 mole) with collidine (0.53 ml, 0.004 mole) and dichloromethane (5 ml). It is cooled to 0 ° C. Tri-ethylsilyl bromide (1.05 ml, 0.008 mole) is added and heated to room temperature. It is stirred for 4 hours and then concentrated under vacuum. The residue is dissolved in diethyl ether (100 ml) and rinsed with 1N hydrochloric acid (3 X 50 ml). 0.1N sodium hydroxide (40 ml) is added to the organic phase, the organic solvents are removed under vacuum and lyophilized to remove the water, to provide a white powder. Purify by chromatography as described in Example 3, to provide the title compound (0.34 g, 44%) as a white powder, m.p. > 360 ° C. Analysis Calculated for C-gH2504PNa2 »1.15H20: C, 50.69; H, 7.26, LOD 5.5. Found: C, 50.54; H, 7.53, LOD 5.5. Example 9 Preparation of methyl (1,1-difluoro-2-hydroxy-4, 8,12-trimethyl-3, 7,11 -tridecatrienyl) methylol phosphinate rdimethyl ester Scheme II, stage a; Dissolve dimethyl 1,1-difluoro-2-hydroxy-4,8,12-trimethyl-3,7,11-tridecatrienylphosphonate (1.0 eq.) Prepared in Example 1 in tetrahydrofuran. It is treated with t-butyldiphenylsilyl chloride (1.1 eq.) And imidazole (2.2 eq.) At room temperature with stirring. After 8 hours, the reaction is diluted with ether and rinsed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography on silica gel (ethyl acetate / hexane) to provide the protected alcohol. Scheme II, stage b; The protected alcohol formed in the above (1.0 eq.) In methanol / water, 1: 1, which contains potassium hydroxide (1.1 eq.) Is dissolved and the reaction is heated at 65 ° C for 1 hour. The methanol is evaporated and an equivalent amount of methylene chloride is added. The mixture is acidified with stirring with potassium acid sulfate. The layers are separated and the aqueous layer is extracted with methylene chloride. Combine the organic extracts, wash with 50% brine, dry over anhydrous magnesium sulfate, filter and concentrate under vacuum to provide the monoacid. Scheme II, stage c; The monoacid formed in the above (1.0 eq.) Is dissolved in dry benzene under nitrogen and a catalytic amount of dimethylformamide is added. The solution is treated with oxalyl chloride (3.0 eq.) In drops at room temperature, and stirred for 4 hours. The reaction is concentrated under vacuum, an equivalent amount of benzene is added as above, it is concentrated under vacuum and this process is repeated once more to provide the acid chloride. Scheme II, stage d; The dimethyl methylphosphonate (2.2 eq.) Is dissolved in dry tetrahydrofuran and cooled to -78 ° C. It is added in drops to the solution butyllithium (2.1 eq of a 1.6 M solution in hexane). After the addition is complete, the reaction is stirred for 30 minutes. The above is dissolved in acid chloride (1.0 eq.) In dry tetrahydrofuran and added dropwise to the anion. After the addition is complete, the reaction is stirred for 1 hour at -78 ° C, warmed to 0 ° C and stirred for an additional hour. The reaction is diluted with diethyl ether and the reaction is stopped with 10% hydrochloric acid. The phases are separated and the organic phase is washed with water, saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography on silica gel (methanol / methylene chloride) to provide the methyl phosphinate-methyl phosphonate. Scheme II, stage e; The methylphosphinate-methylphosphonate formed in the above (1.0 eq.) Is dissolved in tetrahydrofuran and tetrabutylammonium fluoride (2.0 eq.) Of a 1M solution in tetrahydrofuran is added. The reaction is stirred at room temperature for 20 hours and diluted with diethyl ether. The organic material is rinsed with water, brine, dried anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography on silica gel (methanol / methylene chloride) to give the title compound.

Example10 Preparation of sodium salt of disodium salt of T (1,1-difluoro-2-hydroxy-4.8,12-trimethyl-3,7,11 -tride-catrienyl) methyl osphonol phosphinate.

Scheme II, stage f; The methyl phosphinate-dimethyl phosphonate (1. eq.) Prepared in Example 9 is combined with collidine (3.3 eq.) And dichloromethane. It is cooled to 0 ° C and a solution of trimethylsilyl iodide (4 eq.) In dichloromethane is added dropwise. The reaction is allowed to stir for 2 hours. Diethyl ether is added and washed with 1 N hydrochloric acid. The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the triacid of the title compound. The residue is treated with an excess of 0.1N sodium hydroxide and lyophilized. Purify by chromatography on CHP20P (divinylbenzene / styrene copolymer) eluting with a gradient, starting with water and ending with methanol. The product containing the fractions is lyophilized to provide the title compound.

Example 11 Preparation of the di-ethyl ester of f (1,1-difluoro-2-oxo-4,8,12-trimethyl-3, 7,11 -tridecatrienyl) methylphosphathatolumino methyl.

Scheme II, stage g; Trifluoroacetic acid anhydride (1.0 eq.) Is combined with dichloromethane and cooled to -60 ° C. A solution of dimethyl sulfoxide (2.0 eq.) In dichloromethane is added dropwise, while keeping the temperature below ~ -55 ° C. After the addition is complete, stir for 2 minutes. A solution of the dimethyl methylphosphonate phosphinate (1 eq.) Prepared in Example 9 in dichloromethane is added and stirred for 45 minutes. The reaction is cooled to -78 ° C and triethylamine (3 eq.) Is added in drops. The reaction is allowed to warm to room temperature and is stirred for 45 minutes. The reaction is poured into water. This mixture is extracted with diethyl ether. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography (ethyl acetate / hexane) to give the title compound. Example 12 Preparation of the sodium salt of disodium salt of f (1,1-difluoro-2-oxo-4, 8,12-trimethyl-3.7.11-tridecatrienyl) methylphosphonatol phosphinate.

Scheme II, stage f; The methyl phosphinate-dimethyl phosphonate (1.0 eq.), Prepared in example 11, is combined with collidine (2.0 eq.) And dichloromethane. It is cooled to 0 ° C and trimethylsilyl bromide (2.1 eq.) Is added. Warm to room temperature and stir for 5 hours. Toluene is added and concentrated under vacuum. Diethyl ether is added and washed with 1 N hydrochloric acid. The organic phase is treated with excess 0.1 N sodium hydroxide, concentrated in vacuo to remove the organic solvents and lyophilized to remove the water. Purify by chromatography as in Example 10 and lyophilize the product containing the fractions, to provide the title compound.

Example 13 Preparation of the dimethyl ester of methyl (1,1-difluoro-2-hydroxy-4,8,12-trimethyl-3,7,11 -tridecatrienyl) difluoromethylphosphonic acid 1-phosphinate.

Scheme II, stage d; Difluoromethylphosphonate in dry tetrahydrofuran is added to a solution of lithium diisopropylamide (1.05 eq.) At -78 ° C. After the addition is complete, the reaction is stirred for 30 minutes. The acid chloride (1.0 eq.) [Formed in example 9, steps a to c] is dissolved in dry tetrahydrofuran and added dropwise to the anion. After the addition is complete, the reaction is stirred for 1 hour at -78 ° C, warmed to 0 ° C and stirred for an additional hour. The reaction is diluted with diethyl ether and the reaction is stopped with 10% hydrochloric acid. The phases are separated and the organic phase is washed with water, saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography on silica gel (methanol / methylene chloride) to provide dimethyl difluoromethylphosphonate phosphinate. Scheme II, stage e; The dimethyl difluoromethylphosphonate phosphinate, formed in the above (1.0 eq.) In tetrahydrofuran, is dissolved and tetrabutylamino fluoride (2.0 eq.) Of a 1M solution in tetrahydrofuran is added). The reaction is stirred at room temperature for 20 hours and diluted with diethyl ether. The organic material is rinsed with water, brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography on silica gel (methanol / methylene chloride) to provide the title compound. Example 14 Preparation of the sodium salt of the acid disodium salt of r (1,1-difluoro-2-hydroxy-, 8, 12-trimethyl-3,7,11 -tridecatrienyl) difluoromethylphosphonicol phosphinic acid.

Scheme II, stage f; The difluoromethyl phosphonate dimethyl phosphonate (1 eq.) Prepared in Example 17 is combined with collidine (4.0 eq.) And dichloromethane. It is cooled to 0 ° C and a solution of trimethylsilyl bromide (5 eq.) Is added dropwise. The reaction is allowed to stir for 5 hours. At room temperature, diethyl ether is added and washed with 1 N hydrochloric acid. The organic phase is dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to provide the triacid of the title compound. The residue is treated with excess 0.1 N sodium hydroxide and lyophilized. Purify by chromatography on CHP20P (a divinylbenzene / styrene-no copolymer) eluting with a gradient, starting with water and ending with methanol. The product containing the fractions is lyophilized to provide the title compound.

Example 15 Preparation of the dimethyl ester of f (1,1-difluoro-2-oxo-4,8,12-trimethyl-3, 7,11 -tridecatrienyl) difluoromethylphosphonatungosphthalic acid methyl ester.

Scheme II, stage g; Trifluoroacetic anhydride (1.0 eq.) Is combined with dichloromethane and cooled to -60 ° C. A solution of dimethyl sulfoxide (2.0 eq.) In dichloromethane is added dropwise, while the temperature is maintained at less than 55 ° C. After the addition is complete, stir for 2 minutes. A solution of difluoromethyl phosphonate dimethyl phosphonate (1 eq.) Prepared in Example 17, in dichloromethane, is added and stirred for 45 minutes. The reaction is cooled to -78 ° C and triethylamine (3 eq.) Is added in drops. The reaction is allowed to warm to room temperature and is stirred for 45 minutes. The reaction is poured into water. That mixture is extracted with diethyl ether. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by flash chromatography (ethyl acetate / hexane) to give the title compound.

Example 16 Preparation of the sodium salt of the disodium salt acid of f (1,1-difluoro-2-oxo-4.8.12-trimethyl-3.7.11-tridecatrienyl) difluoromethylphosphonic-1-phosphinic acid.

Scheme II, stage f; The difluoromethyl phosphonate-dimethyl phosphonate (1.0 eq.), Prepared in Example 19, is combined with collidine (2.0 eq.) And dichloromethane. It is cooled to 0 ° C and trimethylsilyl bromide (2.1 eq.) Is added. Warm to room temperature and stir for 5 hours. Toluene is added and concentrated under vacuum. Diethyl ether is added and washed with 1 N hydrochloric acid. The organic phase is treated with excess 0.1N sodium hydroxide, concentrated under vacuum to remove organic solvents and lyophilized to remove water. Purify by chromatography as in Example 10 and lyophilize the product containing the fractions, to provide the title compound. In another embodiment, the present invention provides a method for the treatment of a patient attacked by a neoplastic disease, comprising administering an antineoplastic, therapeutically effective amount of a compound of the formula I or II. The term, "neoplastic disease" as used herein, refers to an abnormal state or condition characterized by rapid proliferation of cell growth or neoplasm. The neoplastic disease for which treatment with a compound of Formula I or II, will be particularly useful, includes: leukemias such as, but not limited to, acute lymphoblastic, chronic lymphocytic, acute myeloblastic, and chronic myelocytic leukemia; Carcinomas such as, but not limited to those of the cervix, esophagus, stomach, small intestine, pancreas, colon and lungs; Sarcomas, such as, but not limited to, west-roma, osteosarcoma, lepoma, liposarcoma, hemangioma, and hemangiosarcoma; Melanomas, including amelanotic and melanotic; and mixed types of neoplasms such as, but not limited to, carcinosarcoma, lymphoid tissue type, follicular reticulum, cellular sarcoma, and Hodgkin's disease. As used herein, the term "patient" refers to a warm-blooded animal, such as a human, which is attacked with the particular neoplastic disease. A therapeutically effective antineoplastic amount of the compound of Formula I or II refers to an amount which is effective, by administering a single dose or multiple doses to the patient, to control the growth of the neoplasm or to prolong the survival of the patient, beyond what was expected in the absence of such treatment. As used herein, the "growth control" of the neoplasm refers to the decrease, interruption, arrest, elimination of its growth and metastasis and does not necessarily indicate a total elimination of the neoplasm. As used herein, the term "therapeutically effective amount" refers to an antineoplastic, therapeutically effective amount of a compound of Formula I or II. A therapeutically effective amount can be easily determined by the diagnosis of the attending physician, as one skilled in the art, by the use of known techniques and observation of the results obtained under analogous circumstances. To determine the therapeutically effective amount or dose, a number of factors are considered by the attending physician, including but not limited to, the mammalian species; its size, age and general health; the specific disease involved; the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the form of administration; the bioavailability characteristics of the preparation administered; the selected dose regimen; the use of the concomitant medication; and other important circumstances.

A therapeutically effective amount of the compound of the formula I or II is expected to vary from about 0.1 milligrams per kilogram of body weight per day (mg / kg / day) to about 100 mg / kg / day. Preferred amounts are expected to vary from about 0.5 to about 25 mg / kg / day. In effecting the treatment of a patient afflicted with a disease described above, a compound of Formula I or II can be administered in any form or mode which makes the compound bioavailable in effective amounts, including the oral and parenteral routes. For example, the compounds of Formula I or II can be administered orally, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally and the like. Oral administration is generally preferred. A person skilled in the art of preparing formulations can easily select the appropriate form and mode of administration, depending on the particular characteristics of the selected compound, the disease to be treated, the stage of the disease and other important circumstances. The compounds can be administered alone or in the form of a pharmaceutical composition, in combination with pharmaceutically acceptable carriers or excipients, the proportion and nature of which are determined by the solubility and chemical properties of the selected compound, the chosen route of administration and the standard pharmaceutical practice. The compounds of the invention, while effective themselves, can be formulated and administered in the form of pharmaceutically acceptable acid addition salts for the purposes of stability, convenience of crystallization, increased solubility and the like. In another embodiment, the present invention provides compositions comprising a compound of Formula I or II in admixture or in any other association with one or more inert carriers. These compositions are useful, for example, as assay standards as convenient elements for the manufacture of bulk shipments or as pharmaceutical compositions. An assayable amount of a compound of Formula I or II is an amount which is easily measured by standard assay procedures and techniques as is well known and appreciated by those skilled in the art. The assayable amounts of a compound of Formula I or II, will generally vary from about 0.001% to about 75% of the composition 15- by weight. The inert carriers can be any material, which does not degrade or react in any other way covalently with a compound of Formula I or II. Examples of suitable inert carriers are water; aqueous buffers, such as those that are generally useful in the analysis of High Pressure Liquid Chromatography (CLAP); organic solvents, such as acetonitrile, ethyl acetate, hexane and the like; and pharmaceutically acceptable carriers or excipients. More particularly, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I or II in admixture or in any other association with one or more pharmaceutically acceptable carriers or excipients. The pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art. The carrier or excipient may be a solid, semi-solid or liquid material, which may serve as a vehicle or medium for the active ingredient. Such suitable carriers or excipients are well known in the art. The pharmaceutical composition may be adapted for oral or parenteral use and may be administered to the patient in the form of tablets, capsules, suppositories, solution, suspensions and the like. The compounds of the present invention can be administered orally, for example with an inert diluent or with an edible carrier. They can be contained in gelatin capsules or tablets in tablets. For the purpose of oral therapeutic administration, the compounds can be incorporated with excipient, and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gums and the like. These preparations must contain at least 4% of the compound of the invention, the active ingredient, but may be varied depending on the particular form and may conveniently be between 4% to about 70% of the unit's weight. The amount of the compound present in the compositions is such that an adequate dose will be obtained. Preferred compositions and preparations according to the present invention are prepared in such a way that an oral dosage unit form contains between 5.0-300 milligrams of a compound of the invention. Tablets, pills, capsules, troches and the like may also contain one or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex; glidants such as colloidal silicon dioxide; and sweetening agents such as sucrose or saccharin may be added or a flavoring agent such as peppermint flavor, methyl salicylate or orange. When the dosage unit form is a capsule, it may contain in addition to the materials of the above type, a liquid carrier such as polyethylene glycol or a fatty acid. Other dosage unit forms may contain various other materials, which modify the physical form of the dosage unit, for example, as coatings. In this way, the tablets or pills can be coated with sugar, milk gum, or other enteric coating agents. A syrup may contain, in addition to the present compounds, sucrose as a sweetening agent and certain preservatives, dyes and dyes and flavorings. The materials used in the preparation of these various compositions must be pharmaceutically pure and non-toxic in the amounts used. For the purpose of parenteral therapeutic administration, the compounds of the present invention can be incorporated into a solution or suspension. These preparations should contain at least 0.1% of a compound of the invention, but can be varied to between 0.1 to and about 50% of the weight thereof. The amount of the invented compound present in such compositions is such that a suitable dose will be obtained. Suitable compositions and preparations according to the present invention are prepared in such a way that a parenteral dosage unit contains between 5.0 to 100 milligrams of the compound of the invention. The solutions or suspensions may also include one or more of the following adjuvants: sterile diluents such as water for injection, saline, hydrogenated oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium disulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates and phosphates and agents for tonicity adjustment, such as sodium chloride or dextrose. The parenteral preparation can be contained in ampoules, disposable syringes or multiple dose vials, made of glass or plastic. Like any group of structurally related compounds, which possesses a particular generic utility, certain groups and configurations are preferred for the compounds of Formula I or II in their end-use application. With respect to substituent X, compounds of Formula I or II, wherein X is CF2, are generally preferred. With respect to the substituents -j and R, the compounds of Formula I or II, wherein R- and R are Na are generally preferred. With respect to substituent A, compounds of Formula I or II, wherein A is 1 -oxo-farnesyl are generally preferred. The following list identifies the compounds of Formula I or II, which are particularly preferred embodiments of the present invention: 1,1-Difluoro-2-hydroxy-4,8,12-trimethyl-3,7,11-tridecatrienylphosphonate dimethyl; 1, 1-Dimethyl-2-oxo-4,8,12-trimethyl-3,7,11-tridecatrienylphosphonate; Disodium salt of 1,1-difluoro-2-hydroxy-4,8,12-trimethyl-3,7,11-tridecatrienylphosphonate; Disodium salt of 1,1-difluoro-2-oxo-4,8,13-trimethyl-3,7,11-tridecatrienylphosphonate; Dimethyl 2-hydroxy-4,8,12-trimethyl-3,7,1-tridecatrienylphosphonate; Dimethyl 2-OXO-4, 8,12-trimethyl-3,7,11 -tridecatrienylphosphonate; Disodium salt of 2-hydroxy-4,8,8-trimethyl-3,7,11 -tridecatrienylphosphonate; 'Disodium salt of 2-oxo-4,8, 12-trimethyl-3,7,11-tridecatrienylphosphonate; Dimethyl esters of methyl [(1,1-difluoro-2-oxo-4,8,12-trimethyl-3,7,11 -tridecatrienyl) methylphosphonic] -phosphinate and the sodium salts of the corresponding acids; Dimethyl esters of methyl [(1,1-difluoro-2-oxo-4,8, 12-trimethyl-3, 7,11 -tridecatrienyl) difluoromethylphosphonic] phosphinate and the sodium salts of the corresponding acids; Dimethyl esters of methyl [(1,1-difluoro-2-hydroxy-4,8, 12-trimethyl-3,7, 11 -tridecatrienyl) difluoromethylphosphonic] phosphinate and the sodium salts of the corresponding acids; Dimethyl esters of methyl [(1,1-difluoro-2-hydroxy-4,8,1-trimethyl-3,7,1-tridecatrienyl) methylphosphonic] phosphinate and the sodium salts of the corresponding acids;

Claims (23)

[(2-Oxo-4,8,12-trimethyl-3,7,11-tridecatrienyl) methylphosphonic]] phosphinate] methyl dimethyl ester and the sodium salts of the corresponding acids; Dimethyl esters of methyl [(2-oxo-4,8, 12-trimethyl-3,7,11 -tridecatrienyl) difluoromethylphosphonic] phosphinate and the sodium salts of the corresponding acids; Dimethyl esters of methyl [(2-hydroxy-4,8,1-trimethyl-3,7,11 -tridecatrienyl) difluoromethylphosphonic] phosphinate and the sodium salts of the corresponding acids; Dimethyl esters of methyl [(2-hydroxy-4,8, 12-trimethyl-3,7,11 -tridecatrienyl) methylphosphonic] methylphosphinate and the sodium salts of the corresponding acids; Having described the invention as above, it is claimed how property contained in the following: CLAIMS

1. A compound of the formula characterized in that X is CC12, or CF2, R-] and R2 are each independently H; alkyl of C-j-C4; (CH) n-Z, where n is the integer 0, 1, 2, 3 or 4 and Z is phenyl or naphthyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C-] -C4 alkyl, alkoxy C -, - C4, halogen, CF3, 0CF3, OH, CN, N02 and NH2; or a pharmaceutically acceptable cation, and A is a radical selected from the group consisting of wherein R is C- | -C ^ alkyl, which may be saturated or unsaturated, having 1 to 9 double bonds.

2. A compound of the formula characterized in that X is CH2, CC12, or CF2, Y is CH2 or CF2, R, R2 and R are each independently H; C- | -C4 alkyl; (CH) n-Z, where n is the integer 0, 1, 2, 3 or 4 and Z is phenyl or naphthyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C-j -C alkyl, alkoxy C- | -C4, halogen, CF3, OCF3, OH, CN, N02 and NH2; or a pharmaceutically acceptable cation, and A is a radical selected from the group consisting of R4- HR4- -c- II OH O wherein R4 is C-j-C-jg alkyl, which may be saturated or unsaturated, having 1 to 9 double bonds.

3. A compound according to claim 2, characterized in that X is CF.

4. A compound according to claim 3, characterized in that R-j and R2 are a pharmaceutically acceptable cation.

5. A compound according to claim 4, characterized in that A is the radical R3-C II or

6. A compound according to claim 4, characterized in that A is the radical

7. A compound according to claim 1, characterized in that X is CF2.

8. A compound according to claim 7, characterized in that R- and R2 are a pharmaceutically acceptable cation.

9. A compound according to claim 8, characterized in that A is a radical R3-C II O

10. A compound according to claim 9, characterized in that A is the radical

11. A compound according to claim 1, characterized in that it is 1,1-difluoro-2-hydroxy-4,8,12-trimethyl-3 > 7, 11-dimethyltridecatrienylphosphonate.

12. A compound according to claim 1, characterized in that it is dimethyl 1,1-difluoro-2-oxo-4,8,12-trimethyl-3,7,11 -tridecatrienylphosphonate.

13. A compound according to claim 1, characterized in that it is disodium salt of 1,1-difluoro-2-hydroxy-4,8,12-trimethyl-3,7,11-trideca-trienylphosphonate.

14. A compound according to claim 1, characterized in that it is disodium salt of 1,1-difluoro-2-oxo-4,8,12-trimethyl-3,7,11-tridecatrienylphosphonate.

15. A method for the treatment of a patient affected with a neoplastic disease, characterized by comprising the administration of an antineoplastic, therapeutically effective amount of a compound according to claim 1 or 2.

16. A method for the treatment of a patient affected with a viral infection, characterized in that it comprises the administration of a therapeutically effective antiviral amount of a compound according to claim 1 or 2.

17. A method for controlling the growth of a neoplasm in a patient affected with a neoplastic disease, characterized in that it comprises the administration of a therapeutically effective antineoplastic amount of a compound according to claim 1 or 2.

18. A method for controlling a viral infection in a patient affected with it, characterized in that it comprises the administration of a therapeutically effective antiviral amount of a compound according to claim 1 or 2.

19. A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound of the formula characterized in that X is CC12, or CF- > , R- | and R2 are each independently H; alkyl of C- | -C4; (CH) n-Z, where n is the integer 0, 1, 2, 3 or 4 and Z is phenyl or naphthyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C 1 -C 4 alkyl, C 4 -C 4 alkoxy, halogen, CF 3, OCF 3, OH , CN, N02 and NH2; or a pharmaceutically acceptable cation, and A is a radical selected from the group consisting of R 3 -CH-R 3 -O OH wherein R is C-j-C-j ^ alkyl, which may be saturated or unsaturated, having 1 to 9 double bonds, in admixture or in any other association with one or more pharmaceutically acceptable carriers or excipients.

20. A pharmaceutical composition, characterized in that it comprises a therapeutically effective amount of a compound of the formula characterized in that X is.CH, CC12, or CF, And it is CH2 or CF2, R. | , R2 and R3 are each independently H; C-j-C alkyl; (CH2) nZ, wherein n is the integer 0, 1, 2, 3 or 4 and Z is phenyl or naphthyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C- | - alkyl C4, Cj-C4 alkoxy, halogen, CF3, OCF3, OH, CN, N02 and NH2; or a pharmaceutically acceptable cation, and A is a radical selected from the group consisting of R4-CHR4- -c- II OH O wherein R4 is C- alkyl; -C-j g, which may be saturated or unsaturated, having 1 to 9 double bonds, in admixture or in any other association with one or more pharmaceutically acceptable carriers or excipients.

21. The use in the manufacture of a medicament, for the treatment of a patient afflicted with a neoplastic disease, with a compound of the formula characterized in that X is CC12, or CF2, R. | and R2 are each independently H; alkyl of C -) - C4; ^ H2 ^ n ~ Z 'in e-L < Figure imgf000018_0001 wherein n is e-nr11163 ^ 0 integer 0, 1, 2, 3 or 4 and Z is phenyl or naphthyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of Cj-C4 alkyl, C-alkoxy | -C4, halogen, CF3, OCF3, OH, CN, N02 and NH2T or a pharmaceutically acceptable cation, and A is a radical selected from the group consisting of wherein R is C-j-C-jn alkyl, which may be saturated or unsaturated, having 1 to 9 double bonds.

22. The use in the manufacture of a medicament, for the treatment of a patient afflicted with a neoplastic disease, with a compound of the formula characterized by X is CH2, CC12, or CF, and is CH2 or CF2, R- | , R2 and R3 are each independently H; C- | -C4 alkyl; (CH2) n-Z, where n is the integer 0, 1, 2, 3 or 4 and Z is phenyl or naphthyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C 1 -C alkyl, C 1 -C 4 alkoxy, halogen, CF 3, OCF 3, OH, CN, N02 and NH2; or a pharmaceutically acceptable cation, and A is a radical selected from the group consisting of wherein R is C-α-C- alkyl], which may be saturated or unsaturated, having from 1 to 9 double bonds. 23. The use in the manufacture of a medicament, for the treatment of a patient affected with a viral infection, of a compound of the formula characterized by X X is CC12, or CF, R-j and R2 are each independently H; C- | -C4 alkyl; (CH2) nZ, wherein n is the integer 0, 1, 2, 3 or 4 and Z is phenyl or naphthyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C ^ alkyl; C4, Cj-C4 alkoxy, halogen, CF3, OCF3, OH, CN, N02 and NH2; or a pharmaceutically acceptable cation, and A is a radical selected from the group consisting of wherein R3 is C- | -C- | g alkyl, which may be saturated or unsaturated, having 1 to 9 double bonds.

23. The use in the manufacture of a medicament, for the treatment of a patient afflicted with a viral infection, of a compound of the formula characterized in that X is CH, CC12, or CF2, Y is CH2 or CF2, R-,, R2 and R3 are each independently H; C -? - C4 allyl; (CH2) n-Z, where n is the integer 0, 1, 2, 3 or 4 and Z is phenyl or naphthyl, unsubstituted or substituted with 1 to 3 substituents selected from the group consisting of C-j-C4 alkyl, alkoxy C-j-C4, halogen, CF3, OCF3, OH, CN, N02 and NH; or a pharmaceutically acceptable cation, and A is a radical selected from the group consisting of wherein R4 is C- | -C- | g alkyl, which may be saturated or unsaturated, having from 1 to 9 double bonds. Under the guise of saying the truth, I state that the best known method for carrying out the present invention is the one described in the description of this application. In testimony of which we sign the present in: Mexico, D. F., to February 22, 1994. MERRELL DOW PHARMACEUTICALS,