MXPA96004390A - Complexes of cationic platinum trinucleares antitumoral conactivity and pharmaceutical compositions that contains them - Google Patents

Abstract

The present invention relates to a compound of the general formula (I) wherein: n is an integer from 2 to 7 included; Z-m is an anion selected from chloride, bromide, iodide, nitrate, sulfate; m is the integer 1

Description

COMPLEXES OF TRYUCLEAR CATIONIC PLATINUM WITH ANTITU ORAL ACTIVITY AND COMPOSITIONS PHARMACEUTICALS CONTAINING THEM The present invention relates to platinum complexes having antitumor activity, processes for the preparation thereof and pharmaceutical compositions containing them. Technological Background The use of platinum complexes such as cisplatin and carboplatin in cancer chemotherapy is well established in the field. A number of platinum complexes, such as cis-platin, are used to treat testicular, ovarian, head and neck carcinomas, and small lung cells. However, treatment with cisplatin can result in severe nephrotoxicity. An additional clinical disadvantage is the problem of acquired resistance to the drug, which results in the tumor becoming refractory to treatment by the agent. It is generally believed that platinum complexes such as cisplatin manifest their biological activity through covalent interaction with DNA. In particular, cisplatin induces the formation of a range of adducts in the DNA, including monodentate adducts, bidentate adducts, such as intratranded transverse ligations of GG or AG, and GNG [Reedijk et al., Structure and Bonding, (1987) 67 , 53-89]. To a lesser degree, cisplatin also results in intra-braced transverse GG ligatures and transverse DNA protein ligations [Rahmouni et al., Biochemistry, (1987) 26, 7229-7234]. These DNA lesions result in conformational changes that are reflected in the curving and local development of DNA. It has been reported that these DNA lesions inhibit the activity of various DNA polymerases [Vallan et al., Nucí. Acids Res., (1988) 16, 4407-4418; Pinto and others, Proc. Nati Acad. Sci., (1985) 82, 4616-4619; and Gralla et al., Cancer Res., (1987) 47, 5092-5096]. It has also been shown that the crosslinked transverse ligature between two guanine bases surrounding it inhibits the function of the RNA polymerase. [Lemaire et al., Proc. Nati Acad. Sci., (1991) 88, 1982-1985]. According to the above, the cytotoxic effects of cisplatin are most likely attributed to the combined effects of these DNA lesions, rather than the result of any of the cases of specific lesions. The mono (platinum) and bis (platinum) complexes containing respectively one or two platinum atoms are known in the art (US Pat. Nos. 4,225,529, 4,250,189, 4,533,502, 4,565,884, 4,571,335 and 4,797,393). For example, mono (platinum) complexes include monomeric chloramine-squared Pt (II) compounds which are four coordinated. The relative number of chloride and ammonia groups in such compounds can vary and therefore these compounds can be described by the general formula: [PtClm (NH3) 4-m] (2_m + In this way, the structure of these compounds can vary from [Pt (NH3)] 2+ where m = 0 for PtCl4> where m-4 Since Cl is more labile in substitution compared to ammonia, the complexes [PtCl (NH3) 2] and [PtCl (NH3) 3] Cl are considered bifunctional and monofunctional, respectively, where the prefixes "bi" and "mono" refer to the number of output binders.

The charge of the complexes is obtained when considering that the cation Pt (II) has a formal charge of +2 and therefore requires a negative charge of -2 for the neutralization of the charge. For example, when m = 0, neutralization is provided by the presence of two chloride anions outside the coordination sphere. The formation of the bond between platinum and aminiac, which is a neutral binder, can be described as a donation of an electron pair of NH3 to the empty orbits of the Pt (II) atom. In this way, no electron distribution occurs between the Pt and NH3 group. Due to this absence of electron distribution, the number of neutral binders does not affect the total charge in the coordination sphere of the Pt. In this way, [Pt (NH3)] 2+ is formally a cation of 2+ that requires an uncoordinated anion or anions, or counter-ions, that have a net negative charge of 2- for the neutralization of the complex. For example, neutralization can be provided by two mononegative anions charged (eg, N03", Cl", PF6 ~, BF, and mono-carboxylates having the general formula RCOCf) or a single, negatively charged anion (eg, S042). ", dicarboxylates having the general formula [R (COO) 2] 2 ~) Therefore, for the same principles, [PtCl2 (NH3) 2] is a neutral complex.These considerations can be applied not only to ammonia, but also to neutral binders such as primary and secondary amines It is noted that anionic binders such as Cl "" can either bind in a coordinated fashion (ie, forming a Pt-Cl bond) or can act as a counter-anion without No need for covalent bond formation The exact form in which anions such as Cl "are included in a given platinum complex depends both on theoretical considerations (kinetic vs. thermodynamic effects) and on procedures if Real ntéticos used to elaborate the complex (for example, the degree of reaction, acidity, concentration of the particular anion, such as the concentration of Cl "that is contained in the reaction mixture. These considerations are also applicable to other anionic and neutral binders. The fact that the total charge of the monoplatin complexes depends on the relative number of neutral and anionic binders that bind to the metal of Pt (II) is equally applicable to polynuclear complexes (which contain more than one coordinated sphere of Pt (II). )), and for complexes containing Pt (IV) where the oxidation state of the platinum radical is 4+. For example, dinuclear complexes, where two equivalent Pt (II) coordination spheres are linked by a diamine linking agent, can be represented by the general formula [(PtClm (NH3) 3-m) 2 (diamine)] 2 (2"ml + In this way, when m = 2 and two bifunctional coordination spheres are present, the compound is neutral.) In contrast, when m = l, only monofunctional coordination spheres are present and the platinum radical has a charge 2+ formal, which must be compensated by one or more counter-anions that have a net charge of 2. Recently, examples of trinuclear platinum complexes (also called tri-platinum complexes) were reported in the literature [Yun Qu and others, Inorg, Chem., 32, 2591-2593 (1993).] Such compounds, in which the binders have a cis configuration, are neutral complexes or that bear a total charge of +2 and can be represented by the following formula general: X X X X X Pt Pt Pt NH3 NH2 ~ R - H2 NH ^ R ~ "NH2 H3 wherein X means a labile binder (such as a chlorine atom) and R means an alkylene chain. From what is stated above, it is evident that, in the case of complexes with a total charge of +2, said charge is located in the central platinum atom, supporting four neutral ligands, as long as the two atoms of Platinum peripherals are formally neutral and, as defined above, bifunctional. Such complexes are described as possible antitumor agents, but no experimental evidence has been given.

Description of the Invention The present invention relates to tri-platinum complexes in which the three platinum atoms are linked by diamine chains and in which the central platinum atom coordinates four neutral linkers, as long as the two atoms of Platinum peripherals coordinate both three neutral binders and one binder that has a -1 charge. Accordingly, the compounds of the present invention are different from the prior art compounds in having a total charge of +4 and in particular by having the central platinum atom with a formal charge of +2 and each of the two peripheral platinum atoms with a formal charge of +1. In addition, as evidenced above, the two peripheral platinum atoms are monofunctional. A further difference of the tri-platinum complexes described in the prior art is that in the compounds of the present invention the binders are in trans configuration. Particularly, the invention relates to tri-platinum complexes of the formula (I): where n is an integer from 2 to 7 included; z "m is an anion selected from chloride, bromide, iodide, nitrate, sulfate (m = 2); m is the integer 1 or 2. Preferred compounds of formula (I) are those in which n is the integer 6 The particularly preferred compounds of the formula (I) are those in which n is the integer 6, z "is a chloride or nitrate anion, and m is 1. The present invention also relates to the processes for the preparation of the compounds of the formula (I). A method for the preparation of the compounds of the formula (I) is that which involves the synthesis of the intermediate (III) starting from trans-platinum, previously activated by the substitution of a chlorine atom with dimethylformamide, by means of the reaction with an amine of the formula (II), as shown in the following scheme: trans-platinum (III) wherein P is a suitable conventional protection group such as a tert-butoxycarbonyl or p-methoxybenzyloxycarbonyl, n is as described above. The intermediate of the formula (III) produces, after the dissociation of the protection group P, the intermediate of the formula (IV): where n is as defined above, Q "m is a counter-ion that depends on the dissociation conditions of the group P. For example, if P is a tert-butoxycarbonyl group, Q" m can be a chloride anion or of trifluoroacetate. The intermediate (IV) is then transformed into the intermediate (V): where n is as defined above, by means of an exchange reaction between the ion Q "m and the nitrate ion When Q" m is a chloride anion, said exchange reaction can be carried out in the presence of nitrate of silver and in solvents such as water or alcohols (methanol, ethanol). The intermediate (V) is then reacted with half a mole of trans-platinum, previously activated by the substitution of both chlorine atoms with two molecules of dimethylformamide, to give the compounds of the formula (I): (V) NaCH CK ^ 3 NH ^ m ^ 2 ^ CH2 n -lM2 ^ 3 4 + 4 / mZ "NH NH - (CH) n- ^ 4H NH 3 2 2 '2 3 NH, Cl (I) in which z "m is a nitrate anion These compounds can then be transformed into the compounds of the formula (I) in which z" ra is a halide or sulfate by conventional exchange reactions, widely reported in the literature, such as treatment with an alkaline or alkaline earth metal halide or sulfate. Alternatively, the compounds of the formula (I), in which z "m is a sulfate anion, can be obtained from the corresponding compounds of the formula (I) with z" m = halide, by treatment with sulfate silver. A preferred method for preparing the compounds (I) with z "m = chloride from the compounds (I) with z" m = nitrate is the reaction with a molar excess of hydrochloric acid at a temperature ranging from 0 ° C to 50 ° C. Another method for the preparation of the compounds of the formula (I) consists in first reacting two moles of the amine of the formula (II) with trans-platinum, previously activated by the substitution of both chlorine atoms with two molecules of dimethylformamide. , to give the intermediate of the formula (VI): P-NH-ICH? where P has the meanings defined above. The dissociation of the groups P leads to the intermediate of the formula (VII), where Q ~ m has the meanings defined above, which is subsequently transformed into the intermediate of the formula (VIII): (VII) (VIII) Said transformation is carried out by means of an exchange reaction between the ion of Q "m and the nitrate ion When Q" m is a chloride anion, said exchange reaction is carried out in the presence of silver nitrate and in solvents such as water or alcohols (methanol, ethanol). The intermediate (VIII) is then reacted with two moles of trans-platinum, previously activated by the substitution of a chlorine atom with dimethylformamide, to give the compounds of the formula (I): p4 + Cl NH3 NH, NH2 ~ (CH2) n-lNH2 NH3 ^ Pt \ Pt \ Pt 4 / mz " NH3 NH2 ~~ (CH2) n ~ NH2 NH3 NH3"Cl (i) wherein z "m is a nitrate anion, which compounds can then be transformed into the compounds of the formula (I) in which z" m is a halide or sulfate by conventional exchange reactions widely reported in the literature, such as the treatment with an alkaline or alkaline earth metal halide or sulphate. Alternatively, the compounds of the formula (I), in which z "m is a sulfate anion, can be obtained from the corresponding compounds of the formula (I) with z" m = halide, by treatment with sulfate silver. A preferred method for preparing the compounds (I) with z "m = chloride from the compounds (I) with z" m = nitrate is the reaction with a molar excess of hydrochloric acid at a temperature ranging from 0 ° C to 50 ° C. Possible methods for removing the P groups involve treatment with inorganic acid (such as aqueous hydrochloric acid or in an alcohol or ether solution) or organic (such as trifluoroacetic acid). When P is a tert-butoxycarbonyl group, the preferred conditions for its dissociation are those that contemplate the use of hydrogen chloride in alcohol solution. In this case, as stated above, the counter ion Q ~ rn will be the chloride ion. The compounds of the invention generally have a good solubility in water, in physiological solvents and miscible with water. The compounds of the invention not only have a marked antitumor activity, but also a low toxicity, therefore their therapeutic index is particularly favorable. In addition, the high solubility in water of the tri-platinum complexes of the present invention makes the preparation of oral and parenteral dosage forms easy. The cytotoxic effect of the compounds of the invention was examined in vitro on various tumor cell lines including L-1210 murine leukemia, human ovarian carcinoma A2780 or the sub-lines resistant to cis-platin L-1210 / CDDP and A2780 / CDDP , respective. The examination in the A2780 cell line is an established method for the evaluation of platinum complexes as antitumor agents. In addition, the compounds of the invention were examined in an in vivo test in which the tumor cells L-1210 are inoculated intraperitoneally in a mouse and the compound is administered intraperitoneally 24, 120 and 216 hours after the inoculation of the tumor. The compounds of the invention show a high antitumor effect in the experimental models above. When the compounds of formula (I) are administered to humans and animals that have tumors that can be treated with platinum complexes, in doses ranging from 0.1 mg to 1.2 g per square meter of body area, they are capable of inducing regression of said tumors. Accordingly, another object of the present invention is the use of the compounds of the formula (I) for the preparation of a medicament useful for the treatment of tumors. The effective dose of the compounds of the invention can be determined by skilled clinicians according to conventional methods. The relationship between the doses used for animals of various species and sizes and those for humans (based on mg / m2 of body area) is described by Freirech, E.J. and others, Quantitative Comparison of Toxicity of Anticancer Agents in Mouse, Rat, Hamster, Dog, Monkey and Man, Cancer Chemother. Rep., 50, N. 4, 219-244 (1966). However, normally, the patient will receive doses from 0.1 to 1200 mg / kg of body weight of the complex, with a dose regimen that will vary depending on various factors that are well known to expert clinicians. Sometimes one can take advantage of administering the platinum complexes of the present invention together with one or more agents that enhance antitumor activity or that alleviate the undesirable side effects of the platinum complex. For example, the platinum complexes of the present invention can be administered together with reduced glutathione, as disclosed in GB 2174905 and U.S. 4,871,528. In addition, it may be advantageous to administer the platinum complexes of the present invention in combination with other platinum complexes having antitumor activity. A further object of the present invention is a pharmaceutical composition containing at least one compound of the formula (I) in combination with a platinum complex having antitumor activity. Tumors in patients that can be treated with the platinum complexes of the present invention are those tumors known to be susceptible to cis-platinum therapy. The complexes of the present invention are also active against some tumors resistant to cis-platinum. More generally, the compounds of the invention can be used for the treatment of the same pathological forms for which cis-platinum is used. These include the treatment of tumors, sensitization or enhancement of radiation [Douple et al., Cisplatin Current Status and Developments, Ed. A.W. Prestayk et al., Academic Press, 125 (1980); Douple et al., Platinum Metals Res., 29, 118 (1985)] and the treatment of parasitic diseases such as African sleeping sickness [Farrell et al., Biochem. Pharmacol., 33, 961 (1984)]. The treatment regimen can vary appropriately, as is well known to the clinical expert, according to the type of tumor to be treated and the patient's conditions. A further object of the present invention are pharmaceutical compositions containing a therapeutically effective amount of at least one compound of the formula (I) in admixture with conventional vehicles and excipients. The compounds of the invention are preferably administered as sterile aqueous solutions, which optionally contain sodium chloride in suitable concentration (0.1-0.9 mg / ml). The solutions are preferably administered by intravenous or intra-arterial routes, although other forms of administration may be used in particular cases. Pharmaceutical compositions for parenteral administration comprise sterile saline solutions, as defined above, or sterile powders for the extemporaneous preparation of the solutions, as well as oily preparations for intramuscular or intraperitoneal administrations. Other useful pharmaceutical compositions may be syrups or similar liquid forms, as well as solid forms such as tablets, capsules and the like. The pharmaceutical compositions according to the present invention are prepared according to known methods, such as those reported in Remingston's Pharmaceutical Sciences Handbook, XVII De., Mack Pub., N.Y. , USES..

The following examples further illustrate the invention. Preparation 1 Hexanediamine N-BOC is prepared starting from its hydrochloric salt, which is a commercial product. 2.1 g of N-BOC hexanediamine hydrochloride are dissolved in diethyl ether (20 ml) and treated with 16 ml of a 1 N aqueous solution of sodium hydroxide under stirring. The organic phase is then rinsed with saline, dried over sodium sulfate and the solvent is evaporated under reduced pressure to give a hexane diamine free base of N-BOC, with a theoretical yield. EXAMPLE 1 Preparation of t- [PtCl (NH3) 2H2N- (CH2) 6-NH-BOC] + N03"2 g of trans-platinum were dissolved in 133 ml of anhydrous dimethylformamide (DMF) and added with 1.13 g of nitrate The reaction mixture was kept under stirring, protected from light for 18 hours, after which the precipitated silver chloride was separated by filtration and the clear filtrate was cooled to -20 ° C and added with a solution of N-BOC-1, 6-hexanediamine (1.36 g) in 40 ml of anhydrous DMF. The addition lasted approximately 30 minutes. The solution was kept under stirring at -20 ° C for 3 hours and for one hour at room temperature. The solvent was then evaporated under reduced pressure, maintaining the temperature of the solution without passing over 40 ° C and the residue was taken up in 200 ml of ethyl ether, kept under stirring for 20 minutes, then filtered. The resulting solid was dissolved in 200 ml of methanol and kept under stirring for 15 hours to precipitate any trace of transplatin. The separated trans-platinum was filtered and the solution was treated with active carbon (1 g), filtered again and finally the solvent was evaporated under reduced pressure. The residue was purified by suspending it in acetone (100 ml) under stirring for 30 minutes. After filtration, 2.3 g of product were obtained. Elemental analysis (% calculated / found): C 24.33 / 24.05; H 5.57 / 5.64; N 12.90 / 12.84; Cl 6.53 / 6.40; Pt 35.93 / 36.06. 195Pt-NMR in DMF / d7-DMF: -2433 ppm. EXAMPLE 2 Preparation of t- [PtCl (NH3) 2H2N- (CH2) 6-NH3] 2 + 2N03"A solution of 1.5 g of t- [PtCl (NH3) 2H2N- (CH2) 6-NH-BOC] was added] + N03 ~ in 150 ml of methanol with 21 ml of a 6.5 M solution of hydrogen chloride in ethanol The reaction mixture was kept under stirring for 24 hours at room temperature, then the solid was filtered, the filter was washed with methanol and ethyl ether and finally dried The resulting solid was dissolved in 180 ml of methanol and added with a solution of silver nitrate (0.825 g) in 45 ml of methanol.The reaction mixture was kept under stirring at room temperature. At room temperature for 30 minutes, the silver chloride was separated by filtration and the clear filtrate was evaporated to dryness, the residue was taken up in acetone, kept under stirring for 15 minutes, filtered and dried to obtain 0.925 g of product. Elementary analysis (% calculated / found): C 14.65 / 14.19; H 4.71 / 4.66; N 14.24 / 16.62; Cl 7.21 / 6.91; Pt 39.67 / 36.10. 195Pt-NMR in DMF / d7-DMF: -2433 pp. EXAMPLE 3 Preparation of t, t, t- [PtCl (NH3) 2H2N- (CH2) 6-NH2-Pt (NH3) 2H2N- (CH2) 6-NH2PtCl (NH3) 2] 4 + 4N03 ~ 61 mg of trans-platinum in 2 ml of anhydrous dimethylformamide and added with 69.1 mg of silver nitrate. The reaction mixture was kept under stirring and at 65 ° C for 6 hours, then it was cooled to room temperature and the silver chloride precipitate was separated by filtration. The filtrate was added with a solution of t- [PtCl (NH3) 2H2N- (CH2) 6-NH3] 2 + 2N03 ~ (200 mg) in 2 ml of dimethylformamide and with 0.4 ml of a sodium hydroxide solution of 1 ml. N in methanol. The resulting reaction mixture was kept at room temperature overnight, then it was diluted with ethyl ether until the solid was separated, which was filtered, washed with ethyl ether, then with acetone and finally dried to obtain 220 mg of ethyl acetate. product. Said product was suspended in DMF (5 ml) and kept under stirring for 10 minutes, then it was recovered by filtration and resuspended in acetone (10 ml), keeping it under stirring for an additional 30 minutes. After filtration and drying 150 mg of product are obtained. Elementary analysis (% calculated / found): C 11.63 / 11.70; H 4.07 / 3.95; N 15.83 / 15.20; Cl 5.72 / 4.60; Pt 47.24 / 47.10. 195Pt-NMR in NaCl at 0. 3% in water: -241 6 ppm; -2667 ppm. XH-NMR (200 Mhz) in D20: 1. 35 ppm (m, 8H); 1 . 68 ppm (m, 8H); 2 . 65 ppm (br m, 8H). EXAMPLE 4 Preparation of t- [BOC-NH- (CH2) 6-NH2-Pt (NH3) 2H2N- (CH2) 6-NH-BOC] 2 + 2N03"A suspension of 1.028 g of transplatino in 35 ml of Anhydrous dimethylformamide with 1.16 g of silver nitrate The reaction mixture was heated to 60 ° C, protected from light for 5 hours, then the precipitate of silver chloride was filtered off, after which a solution was added. of N-BOC-1,6-hexanediamine (1.48 g) in 5 ml of dimethylformamide and the resulting reaction mixture was kept at room temperature overnight.Dilute with 300 ml of ethyl ether a white solid was separated, which was filtered, redissolved in methanol and filtered through a 0.2 micron Millex filter to remove any traces of silver salts.The methane solution was then diluted with ethyl ether.A white solid crystallized , which was filtered and dried, to obtain 1.94 g of product, elemental analysis (% ca calculated / found): C 33.63 / 33.44; H 6.93 / 7.00; N 14.26 / 14.30; Pt 24.83 / 25.06. 195Pt-NMR in DMF / d7-DMF: -2687 ppm. EXAMPLE 5 Preparation of t- [NH3- (CH2) 6-NH2-Pt (NH3) 2H2N- (CH2) 6-NH3] 4 + 4Cl "500 mg of t- [BOC-NH- (CH2) 6- was dissolved NH2-Pt (NH3) 2H2N- (CH2) 6-NH-BOC] 2 + 2N03"in 50 ml of methanol and added with 5 ml of a 6.5 M solution of hydrogen chloride in ethanol. The reaction mixture was kept under stirring at room temperature for 42 hours, then the solid was filtered and washed with ethyl ether, to obtain 340 mg of product. Elemental analysis (% calculated / found): C 23.81 / 23.14; H 6.66 / 6.73; N 13.88 / 13.51; Cl 23.42 / 22.03; Pt 32. 23/31.68. 195Pt-NMR in water: -2674 ppm. EXAMPLE 6 Preparation of t, t, t- [PtCl (NH3) 2H2N- (CH2) 6-NH2-Pt (NH3) 2H2N- (CH2) 6-NH2PtCl (NH3) 2] 4 + 4N03"200 mg of t- [NH3- (CH2) 6-NH2-Pt (NH3) 2H2N- (CH2) 6-NH3] 4 + 4Cl "in 10 ml of distilled water and treated with 224 mg of silver nitrate. The resulting suspension was kept at room temperature and under stirring for 10 minutes, then the precipitate of silver chloride was removed by filtration. The filtrate was concentrated almost to dryness, then diluted with acetone. A white solid is separated off, filtered, washed with acetone and dried to obtain 204 mg of t- [NH3- (CH2) 6-NH2-Pt (NH3) 2H2N- (CH2) 6-NH3] 4 + 4N03 A solution of 172 mg of trans-platinum in 21.5 ml of anhydrous dimethylformamide with 98 mg of silver nitrate was treated.The resulting suspension was kept under stirring at room temperature overnight, protected from light, then separated by filtration the precipitate of silver chloride was treated with a solution of 204 mg of t- [NH3- (CH2) 6-NH2-Pt (NH3) 2H2N- (CH2) 6-NH3] 4 + 4No3"in 7 ml of dimethylformamide with 0.57 ml of a 1 N solution of sodium hydroxide in methanol, then said solution was added at room temperature to the previous filtrate containing trans-platinum activated with dimethylformamide. After 6 hours the solution was filtered through a 0.2 micron Millex filter to remove any traces of silver salts, then the filtrate was diluted with ethyl ether. The precipitated solid is separated by filtration to obtain 326 mg of product. 195Pt-NMR in 0.3% NaCl in water: -2416 ppm; -2667 ppm. XH-NMR (200 Mhz) in D20: 1.35 ppm (m, 8H); 1.68 ppm (m, 8H); 2.65 ppm (br m, 8H). EXAMPLE 7 Preparation of t, t, t- [PtCl (NH3) 2H2N- (CH2) 6-NH2-Pt (NH3) 2H2N- (CH2) 6-NH2PtCl (NH3) 2] 4 + 4Cl "326 mg of t, t, t- [PtCl (NH3) 2H2N- (CH2) 6-NH2-Pt (NH3) 2H2N- (CH2) 6-NH2PtCl (NH3) 2] 4 + 4N03"in a saline solution (sodium chloride 0.9%), then the solution was filtered through a 0.2 micron Millex filter and concentrated until a white solid separated, which was filtered to yield 187 mg of product. Elementary analysis (% calculated / found): C 12. 73 / 12.60; H 4.45 / 4.45; N 12.37 / 12.85; Cl 18.78 / 14.77; Pt 51.68 / 48.33. 195Pt-NMR in 0.3% NaCl in water: -2416 ppm; -2671 ppm. 1 H-NMR (200 Mhz) in D20: 1.40 ppm (, 8H); 1.70 ppm (, 8H); 2.70 ppm (br m, 8H).

EXAMPLE 8 Following the procedures described in Examples 1, 2 and 3, or alternatively the procedures described in Examples 4, 5 and 6, starting from the appropriate monoprotected diamine, the following trans tri-platinum complexes are obtained: [PtCl ( NH3) 2H2N- (CH2) 5-NH2-Pt (NH3) 2H2N- (CH2) 5-NH2PtCl (NH3) 2] 4 + 4N03"; [PtCl (NH3) 2H2N- (CH2) 4-NH2-Pt (NH3 ) 2H2N- (CH2) 4-NH2PtCl (NH3) 2] 4 + 4N03"; [PtCl (NH3) 2H2N- (CH2) 3-NH2-Pt (NH3) 2H2N- (CH2) 3-NH2PtCl (NH3) 2] 4 + 4N03 ~; [PtCl (NH3) 2H2N- (CH2) 2-NH2-Pt (NH3) 2H2N- (CH2) 2-NH2PtCl (NH3) 2] + 4N03"; [PtCl (NH3) 2H2N- (CH2) 7-NH2-Pt (NH3) 2H2N- (CH2) 7-NH2PtCl (NH3) 2] 4 + 4N03". Pt-NMR in 0.3% NaCl in water: -2422 ppm; -2670 ppm. EXAMPLE 9 Following the procedure described in Example 7, starting from the tri-platinum trans complexes obtained according to Example 8, the following compounds are prepared: [PtCl (NH3) 2H2N- (CH2) 5"NH2-Pt (NH3 ) 2H2N- (CH2) 5-NH2PtCl (NH3) 2] 4 + 4Cl "; [PtCl (NH3) 2H2N- (CH2) 4-NH2-Pt (NH3) 2H2N- (CH2) 4-NH2PtCl (NH3) 2] 4 + 4C1"; [PtCl (NH3) 2H2N- (CH2) 3-NH2- Pt (NH 3) 2 H 2 N- (CH 2) 3-NH 2 PtCl (NH 3) 2] + 4 Cl "; [PtCl (NH3) 2H2N- (CH2) 2-NH2-Pt (NH3) 2H2N- (CH2) 2-NH2PtCl (NH3) 2] 4 + 4C1"; [PtCl (NH3) 2H2N- (CH2) 7-NH2- Pt (NH3) 2H2N- (CH2)? -NH2PtCl (NH3) 2] 4 + 4C1". 1 H-NMR (200 Mhz) in D20: 1.39 ppm (s, 12H); 1.68 ppm (br m, 8H); 2.67 ppm (br, m 8H). EXAMPLE 10 Preparation of t, t, t- [PtCl (NH3) 2H2N- (CH2) 6-NH2-Pt (NH3) 2H2N- (CH2) 6-NH2-PtCl (NH3) 2] 4 + 4Cl "One was prepared suspension of t, t, t- [PtCl (NH3) 2H2N- (CH2) 6-NH2-Pt (NH3) 2H2N- (CH2) 6-NH2-PtCl (NH3) 2] 4 + 4N03 (1.3 g) in 0.1 N of aqueous hydrochloric acid (65 ml) under a nitrogen atmosphere and then solubilized at 54 ° C.

After 1 hour at this temperature, the solution was cooled to 20 ° C and filtered on a glass fiber filter to remove the mechanical impurities: to the clear solution 7.8 ml of 4N of aqueous hydrochloric acid were added and in A few minutes began the precipitation. The suspension was stirred at 20 ° C for 30 minutes, then for an additional 30 minutes at 10 ° C. The precipitate was then filtered on a Buckner funnel and rinsed with 0.4 N of aqueous hydrochloric acid (0.5 ml) and acetone. The collected white solid was dried overnight under vacuum at 40 ° C to yield 1.03 g of product. Elemental analysis (% calculated / found) x 2 H20: C 12.33 / 12.34; H 4.65 / 4.73; N 11.98 / 12.05; Cl 18.21 / 17.55; Pt 50.07 / 49.97.

Claims (19)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and therefore the property described in the following claims is claimed as property: 1. The compounds of the general formula (I) where: n is an integer from 2 to 7 included; Z_m is an anion selected from chloride, bromide, iodide, nitrate, sulfate; m is the integer 1 or 2. The compounds according to claim 1, characterized in that n is the integer 6. 3. The compounds according to claims 1-2, characterized in that Z is selected from chloride or nitrate and m is 1. 4 A compound according to the preceding claims, characterized in that it is selected from the group consisting of: [PtCl (NH3) 2H2N- (CH2) 6-NH2-Pt (NH3) 2H2N- (CH2) 6-NH2PtCl (NH3) 2] 4 + 4N03"; [PtCl (NH3) 2H2N- (CH2) 6-NH2-Pt (NH3) 2H2N- (CH2) 6-NH2PtCl (NH3) 2] 4 + 4Cl"; [PtCl (NH3) 2H2N- (CH2) 6-NH2-Pt (NH3) 2H2N- (CH2) 6-NH2PtCl (NH3) 2] 4 + 2S042"5. A process for the preparation of the compounds according to claims 1 -4, characterized in that it comprises the following steps: a) activation of the trans-platinum by means of the substitution of a chlorine atom with dimethylformamide in the presence of silver nitrate, b) reaction of the activated intermediate with a diamine of the formula ( II) H2N- (CH2) n-NH-P (II) where n is an integer from 2 to 7 included, P is a suitable conventional protection group, to give, after the dissociation of said protection group P, the intermediate of the formula (IV) where n is as defined above, Q ~ ra is a counter-ion which depends on the dissociation conditions of the group P. For example, if P is a tert-butoxycarbonyl group, Q "m can be a chloride anion or of trifluoroacetate The intermediate (IV) is then transformed into intermediate (V): where n is as defined above; d) the reaction of the intermediate of formula (V) with trans-platinum, previously activated by the substitution of two chlorine atoms with two molecules of dimethylformamide in the presence of silver nitrate, in a ratio of 1: 0.5 moles, to give a compound of the formula (I) wherein n is one defined above, m is 1 and Z "m is the anion nitrate, and if desired, e) the exchange reaction of said nitrate anion and another anion of Z "m, where Z" m is as defined above 6. A process according to claim 5, characterized in that said group P is selected from tert-butoxycarbonyl and P-methoxybenzyloxycarbonyl 7. A process according to claim 5, characterized because said group P is tert-butoxycarbonyl and the dissociation of said group is carried out with hydrochloric acid 8. A process according to claim 5, characterized in that in step e) said nitrate anion is exchanged first with the chloride anion. of Z ~ m, then the a The chloride ion is exchanged with the sulfate anion, in which process the exchange between said chloride and said sulfate takes place by the treatment with silver sulphate. 9. A process according to claim 5, characterized in that in step e) said nitrate anion is exchanged with the chloride anion by means of the reaction with aqueous hydrochloric acid in a molar excess at a temperature ranging from 0 ° C to 50 ° C. 10. A process for the preparation of the compounds of claims 1-4, which comprises the following steps: a) the reaction of an amine of the formula (II) H2N- (CH2) n-NH-P (II) where n is an integer from 2 to 7 included, and P is a suitable conventional protection group, with trans-platinum, previously activated by the substitution of two chlorine atoms with two molecules of dimethylformamide in the presence of silver nitrate, in a molar ratio of 2: 1, to give the intermediate of the formula (VI) P-NH- ICHjn where P has the meanings defined above. The dissociation of the groups P leads to the intermediate of the formula (VII), where Q "m has the meanings defined above, which is subsequently transformed into the intermediate of the formula (VIII): (VII) where n is as defined above and Q "m is an anion derived from the dissociation reaction, c) the exchange reaction between the anion Q" m and the anion N03", to give the corresponding nitrate of the formula (VIII i (VIII) d) the reaction of the intermediate of the formula (VIII) with trans-platinum, previously activated by the substitution of a chlorine atom with a molecule of dimethylformamide in the presence of silver nitrate, in a molar ratio of 1: 2, to give a compound of the formula (I) 4+ NH NH, NH, NH2- (CH2) n- H2 NH, Pt-Pt Pt 4 / mz " NH3 NH2 (CH2) n NH2 NH, NH, Cl (i) where n is as defined above, m is 1 and Z "is the nitrate anion, and, if desired, e) the exchange reaction between said nitrate anion and another anion of Z" m, where Z " This is as defined above 11. A process according to claim 10, characterized in that said group P is selected from tert-butoxycarbonyl and P-methoxybenzyloxycarbonyl 12. A process according to claim 10, characterized in that said group P is tert-butoxycarbonyl and the dissociation of said group is carried out with hydrochloric acid. 13. A process according to claim 10, characterized in that in step e) said nitrate anion is exchanged first with the chloride anion of Z'm, then the chloride anion is exchanged with the sulfate anion, in which process the exchange between said chloride and said sulphate takes place by treatment with silver sulfate. 14. A process according to claim 10, characterized in that in step e) said nitrate anion is exchanged with the chloride anion by means of the reaction with aqueous hydrochloric acid in a molar excess at a temperature ranging from 0 ° C to 50 ° C. 15. The use of the compounds according to claims 1-4 for the preparation of a medicament useful for the treatment of tumors. 16. Pharmaceutical compositions containing a therapeutically effective amount of at least one compound of claims 1-4 as the active ingredient, in admixture with conventional carriers and excipients. 17. The compositions according to claim 16, characterized in that said effective amount is for administering doses of 0.1 to 1200 mg / kg of body weight of the active ingredient. 18. The compositions according to claims 16-17, characterized by parenteral administration. 19. The pharmaceutical composition according to claims 16-18, characterized in that it contains at least one compound of claims 1-4 in combination with a platinum complex having antitumor activity.