Trinuclear cationic platinum complexes exhibiting antitumor activity, method for their production and pharmaceutical compositions containing these complexes

 

(57) Abstract:

Trinuclear cationic platinum complexes of the formula I, where n = 2, -7, integer; Z-m- chlorine anion, bromine, iodine, nitrate or sulfate; m = 1 or 2, have antitumor activity. 3 S. and 19 C.p. f-crystals.

The invention relates to platinum complexes with antitumor activity, to processes for their preparation and to pharmaceutical compositions containing said complexes.

The use of complexes of patina, such as cisplatin and carboplatin, anti-cancer chemotherapy is well known to specialists. For example, the number of complexes plate, such as cisplatin, used for the treatment of testicular cancer, ovarian cancer, head and neck tumors and squamous cell lung cancer. However, treatment with cisplatin can lead to severe nephrotoxicity. Another drawback of this tool is the acquisition of resistance to it, resulting in the tumor becomes resistant to the treatment of this drug.

I believe that, in General, the biological activity of complex compounds patina, such as cisplatin, due to covalent interaction with DNA. In particular, cisplatin is chained cross-stitching GG or AG, and GG (Reedijk et al., Structure and Bonding, (1987) 67, 53-89). To a lesser extent, cisplatin also leads to the formation of interchain cross-links GG and crosslinking of DNA-protein (Rahmouni et al., Biochemistry, (1987) 26, 7229-7234). Such DNA damage lead to conformational changes that affect the twisting and local "Raspletina DNA. There is an opinion that such DNA damage inhibit the activity of various DNA polymers (Vallan et al., Nuel. Acids.Res. , (1988) 16, 4407-4418; Pinto et al., Proc, Natl. Acad.Sci., (1985) 82, 4616-4619 and Gralla et al., Cancer Res., (1987) 47, 5092-5096). It was also shown that interchain cross-linking between two adjacent goinnovate grounds also inhibit the action of RNA polymerase (Lemaire et al. , Proc. Natl. Acad. Sci. (1991) 88, 1982-1985). Hence we can conclude that the cytotoxic action of cisplatin, in all probability, due to the integrated effect of these DNA damage and is not the result of any specific damage.

Complexes of mono(platinum) and bis(platinum), containing, respectively, one or two atoms of platinum, known in the art and are described in U.S. patents NN 4225529, 4250189, 4533502, 4565884, 4571335 and 4797393. So, for example, complexes of mono(platinum) are Monomeric chloramine platinum compounds (11) is p such compounds may vary therefore, these compounds can be represented by the General formula.

[PtClm(NH3)4-m](2-m)+< / BR>
Thus, the structure of these compounds can vary from [Pt(NH3)4]2+where m= 0 to PtCl2-4where m=4. Because Cl is more labile in relation to substitution than ammonia, the complexes [PtCl2(NH3)2] and [PtCl2(NH3)3] Cl are bifunctional and monofunctional, respectively, where the prefix "bi" and "mono" refers to the number of the leaving ligands. The charge of the complex is determined proceeding from the fact that the cation Pt(11) has a formal charge of +2, and therefore the charge neutralization requires a negative charge -2. For example, if m=0, then neutralization is provided by the presence of two chloride anions in the outer coordination sphere.

The bond formation between platinum and ammonia, which is a neutral ligand, it is fashionable to describe how e-pairs from the NH3on the vacant orbitals of the atom (Pt(11). Thus, generalization of the electron pair between Pt and NH3the group does not occur. Because this summary of electrons is absent, the number of neutral ligands does not affect the total charge in coordinat is that to neutralize the complex requires the presence of necoordonarea anion, either anions or counterions, with a full negative charge of 2-. For example, neutralization of the complex can be provided with two singly charged anions (e.g., NO-3, Cl-PF-6BF-4and monocarboxylate General formula RCoo-or one double anion (e.g., SO2-4, dicarboxylate having the General formula [R(COO)2]-2). Based on these considerations, [PtCl2(NH3)2] is a neutral complex.

This same principle can be applied not only to ammonia, but also to the neutral ligands, such as primary or secondary amines.

It should be noted that the negatively charged ligands, such as Cl-or can form a coordination bond (i.e., communication Pt-Cl), or can act as a counterion without any need to form a covalent bond. The exact form, which are anions, such as CL-in this complex of platinum depends on specifically the present theory (kinetic or thermodynamic) and from the method of synthesis used to obtain the complex (e.g., degree of reaction, acidity and concentration is to be attributed to other negatively charged or neutral ligands.

The fact that a full charge monoplatinum complexes depends on the relative number of neutral ligands and ligand-anion associated with the metal Pt(11) equally applies to multi-core systems (which contain more than one coordination sphere Pt(11)) and Pt(IV)-containing complexes, where the degree of oxidation of an atom of platinum is +4. For example, dual core complexes, where two equivalent coordination Pt(11) relate Daminova bridging group can be represented by the General formula

[PtClm(NH3)3-m)2(diamine)]2(2-m)+.

Thus, if m=2 and there are two bifunctional coordination sphere, the compound is neutral. In contrast, if m= 1, then there is no uni-functional coordination, and the atom of platinum, which has a formal charge of 2+, must be balanced by one or more counterions having a total charge of -2.

Examples of trinuclear platinum (also known as the three complexes of platinum) were recently described in the literature (Yun Qu et al., Inorg.Chem., 32, 2591-2593 (1993)). These compounds in which the ligands are CIS-configuration, are neutral Sands/BR>< / BR>
< / BR>
where X is a labile ligand (such as a chlorine atom);

R represents alkylenes chain.

Based on the above it is obvious that if the complexes have a total charge of +2, the charge is localized on the Central atom of platinum, associated with four neutral ligands, while the two peripheral atom of platinum are formally neutral and, as described above, the bifunctional. It has been suggested that these complexes possess anti-tumor activity, however, this assumption was not confirmed experimentally.

The present invention relates to three-and-platinum complexes, where three atoms of platinum bound demonovyn chains and where around a Central atom of platinum coordinated four neutral ligand, and around each of the two peripheral platinum atoms coordinated three neutral ligand and one ligand having a charge of -1.

Therefore, the compounds of the present invention differ from the compounds of the prototype that their total charge is +4, and in particular, the Central platinum atom has a formal charge of +2, and each of the two peripheral atoms of platinum has a formal Hnctional.

Another difference from the three-platinum complexes of prototypes is that the ligands in the compounds of the present invention are present in the TRANS configuration.

More specifically, the present invention relates to theplatinum complexes of formula 1

< / BR>
where n is an integer from 2 to 7 inclusive;

Z-mrepresents an anion selected from chloride, bromide, iodide, nitrate and sulfate (m=2);

m= 1 or 2.

Preferred compounds of formula 1 are compounds in which n=6.

Especially preferred compounds of formula 1 are compounds in which n=6, Z-mrepresents an anion, such as chloride or nitrate, and m = 1.

The present invention also relates to methods of preparing compounds of formula 1.

The method of obtaining compounds of formula 1 provides the synthesis of the intermediate compound III on the basis of TRANS-platinum (pre-activated by substitution of the chlorine atom dimethylformamide) by reaction with an amine of the formula II, as shown in the following diagram:

< / BR>
where P is a suitable standard protecting group such as tert-butoxycarbonyl or p-methoxybenzyloxy PPI P receive the intermediate compound of formula IV

< / BR>
where n is defined above;

Q-mis a counterion, the type of which depends on the conditions of the cleavage of the group P. for Example, if P is tert-butoxycarbonyl group, then Q-mmay be the chloride anion or triftoratsetofenona.

Then the intermediate compound (IV) is transformed into the intermediate compound (V)

< / BR>
where n is defined above,

through exchange reactions between the ion Q-mand the nitrate ion.

Specified exchange reaction, in the case when Q-mis the chloride anion, can be carried out in the presence of silver nitrate in a solvent such as water or alcohols (methanol, ethanol).

Then, the intermediate compound (V) is subjected to reaction with 0.5 mol of TRANS-platinum, pre-activated by substitution of the two chlorine atoms in two molecules of dimethylformamide, resulting in a gain of compounds of formula 1

< / BR>
< / BR>
where Z-mis the nitrate anion.

These compounds can then be converted into compounds of formula 1 where Z-mis a halide or sulfate, using the standard exchange reactions, widely described in the literature, such as processing ha is s Z-mis the sulfate anion, can be obtained from corresponding compounds of formula 1 where Z-mis a halogen, by treatment with sulphate of silver.

A preferred method of preparing compounds of formula 1 where Z-mis a chloride, of the compounds of formula 1 where Z-mis nitrate, involves the reaction of these compounds with a molar excess of hydrochloric acid at a temperature in the range from 0 to 50oC.

Another method of preparing compounds of formula I is that the first two mol of amine of formula II is subjected to reaction with TRANS-platinum, pre-activated by substitution of two chlorine atoms in two molecules of dimethylformamide, resulting in a gain of the intermediate compound of formula VI

< / BR>
where P has the values defined above.

After removal of the P gain of the intermediate compound of formula VII, where Q-mdefined above, which is then converted into an intermediate compound of formula VIII

< / BR>
< / BR>
This transformation is performed using the exchange reactions between the ion Q-mand nitrate-ion. If Q-mis the chloride anion, the reaction can be carried out in the presence of nitrate Snee (VIII) is subjected to reaction with two moles of TRANS-platinum, pre-activated by substitution of the chlorine atom molecule of dimethylformamide, resulting in the receive connection of the formula I

< / BR>
where Z-mis nitrate-anion.

These compounds can then be converted into the compounds of formula I, where Z-mis a halide or sulfate, using the standard exchange reactions, widely described in the literature, such as processing a halide or sulfate of an alkaline or alkaline earth metal. Alternative compounds of formula I in which Z-mis the sulfate anion, can be obtained from corresponding compounds of formula I in which Z-mis a halogen, by treatment with sulphate of silver.

A preferred method of preparing compounds of formula I, where Z-mis chloride, involves the reaction of compounds of formula I, where Z-mis nitrate, a molar excess of hydrochloric acid at a temperature in the range from 0 to 50oC.

A suitable method of removing the group P can be processed inorganic acid (such as aqueous, alcoholic or ethereal solution of hydrochloric acid) or organic acid (such as triperoxonane using hydrogen chloride in ethanol solution. In this case, as mentioned above, the counterion Q-mwill be a chloride ion.

Compounds of the present invention is well soluble in water, physiological solution and miscible with water solvents.

Compounds of the present invention have not only a notable antitumor activity, but also low toxicity, and therefore their therapeutic index is particularly favorable.

In addition, the high solubility of the three-platinum complexes of the present invention facilitates the receipt of oral and parenteral pharmaceutical forms.

Compounds of the present invention were tested for their cytotoxic activity in vitro using different tumor cell lines, including cell line murine leukemia L-1210 cell line carcinoma human ovarian A, or the corresponding resistant to this drug called cisplatin as compared to the L-1210/CDDP and A2780/CDDP. The test cell line A is a traditional method for assessing the platinum complexes on their antitumor activity. In addition, we conducted in vivo testing of compounds of the present invention, in which mice vnutribruchinno have introduced the connection. Compounds of the present invention was found high antitumor activity in these experimental models.

If the compounds of formula I can enter the human or animal suffering from tumors susceptible to treatment with platinum complexes, in doses, comprising in the range from 0.1 mg to 1.2 g per square meter of body surface, these compounds are able to cause regression of these tumors.

Therefore, another objective of the present invention is the use of compounds of formula I for the manufacture of a medicinal product for the treatment of tumors.

The effective dose of the compounds of the present invention can be determined by the attending physician in accordance with a standard technique. The magnitude of the doses used for the introduction of animals of different species, as well as for the introduction of man (in milligrams per square meter of body surface) is described Freirech, E. J., and others (Quantitative Comparison of Toxicity of Anticancer Agents in Mouse, Rat, Hamster, Dog, Monkey and Man, Cancer Chemother. Rep., 50, N4, 219-244 (1966)).

However, in General, complex dose that can be administered to the patient is from 0.1 to 1200 mg per kg of body weight, and the circuit introduction this dose may vary depending on various f the new complexes of the present invention together with one or more agents, enhancing antitumor activity or eliminating unwanted side effects of these complexes.

So, for example, platinum complexes of the present invention can be introduced together with the restored glutathione, as described in UK patent 214905 and U.S. patent 4871528.

In addition, it may be preferable to introduce the platinum complexes of the present invention in combination with other platinum complexes with antitumor activity.

Therefore, another objective of the present invention to provide a pharmaceutical composition containing at least one compound of formula I in combination with a platinum complex having antitumor activity.

Platinum complexes of the present invention can be used for the treatment of neoplastic diseases, which are known to be susceptible to therapy with the use of CIS-platinum. The complexes of the present invention also have activity against certain tumors that are resistant to CIS-platinum.

Generally speaking, the compounds of the present invention can be used for Vlada tumor, sensitization of the body, or exposure to high doses of radiation (Douple et al., Cisplatin Current Status and Development, Ed. A. W. Prestayk et al., Academic Press, 125(1980); Douple et al. Platinum Metals Res., 29, 118 (1985)), as well as parasitic infestations, such as African sleeping sickness (Farrel et al., Biochem. Pharmacol., 33, 961 (1984)).

As is well known to specialists, the treatment regimen may appropriately vary depending on the type of tumor and the patient's condition.

Another objective of the present invention to provide pharmaceutical compositions containing a therapeutically effective amount of at least one of the compounds of formula I in combination with standard carriers and fillers.

Preferably, if the compounds of the present invention is administered in the form of sterile aqueous solutions, optionally containing sodium chloride in an appropriate concentration (0.1 to 0.9 mg/ml). These solutions are preferably injected intravenously or intraarterially, although in some cases can be used and other ways of introduction.

Pharmaceutical compositions for parenteral administration are sterile physiological solutions described above, or sterile powders which is whether intraperitoneal administration.

Other pharmaceutical compositions can be manufactured in the form of syrups or similar liquid forms, as well as solid forms such as tablets, capsules, etc.

The pharmaceutical compositions of the present invention can be obtained by well known methods, for example methods described in "Remington''s Pharmaceutical Sciences Handbook, XVII Ed., Mack. Pub., N. Y., USA.

The present invention, also illustrated by the following examples.

Receiving 1.

N - BOC-hexanediamine received from him cleaners containing hydrochloride salt, which is a commercial product.

2.1 g of the hydrochloride of N - BOC-hexanediamine was dissolved in diethyl ether (20 ml) and the resulting solution was treated while stirring with 16 milliliters of 1 n aqueous sodium hydroxide solution.

The organic phase is washed with saline, dried with sodium sulfate and the solvent evaporated under reduced pressure, resulting in a received N - BOC-hexanediamine in the form of the free base with theoretical output.

Example 1. Getting t-[PtCl(NH3)2H2N- (CH2)6- NH-BOC]++ NO-3.

2 g of TRANS-platinum was dissolved in 133 ml of anhydrous dimethylforamide protecting it from exposure to light, kept for 18 hours. After that, the precipitated silver chloride was filtered, the clear filtrate was cooled to a temperature of -20oC, and the solution was added N-BOC-1,6-hexanediamine (1,36 g) in 40 ml of anhydrous dimethylformamide. The addition was continued for approximately 30 minutes. The resulting solution was kept under stirring and at a temperature of -20oC for 3 hours, and then for a further one hour at a constant temperature. The solvent is evaporated under reduced pressure while maintaining the temperature of the solution not exceeding 40oC, after which the resulting residue was dissolved in 200 milliliters of ethyl ether with stirring for 20 minutes and filtered. The obtained solid substance was dissolved in 200 ml of methanol and left for 15 hours under stirring to precipitate the existing trace amounts of TRANS-platinum. Isolated TRANS-platinum was filtered, and the solution was treated with activated charcoal (1 g) was again filtered and finally the solvent is evaporated under reduced pressure. The residue was purified by his suspension in 100 ml of acetone under stirring for 30 minutes. After filtration were obtained 2.3 g of product.

Elemental analysis (%):

Calculated: C 24,33; H="ptx2">

Example 2. Getting t-[PtCl(NH3)2H2N-(CH2)6- NH3]2+2NO-3.

To a solution containing 1.5 g t-[PtCl(NH3)2H2N-(CH2)6- NH-BOC]+NO-3and 150 ml of methanol, was added 21 ml (6.5 mol) of a solution of hydrogen chloride in ethanol. The resulting reaction mixture was stirred for 24 hours at room temperature, and then the solid residue was filtered off, washed on the filter with ethyl ether and finally dried off.

The obtained solid substance was dissolved in 180 ml of methanol, and then was added a solution of silver nitrate (0,825 g) in 45 ml of methanol. This reaction mixture was stirred for 30 minutes at room temperature, after which the precipitated silver chloride was filtered and the clear filtrate evaporated to dryness. The residue was dissolved in acetone, stirred for 15 minutes, filtered and dried, resulting in a received 0,925 g of the product.

Elemental analysis (%):

Calculated: C 14,65; H 4,71; N, 14.24 From; Cl 7,21; Pt 39,67;

Found: C 14,19; H Of 4.66; N 16,62; Cl 6,91; Pt 36,10.

195Pt-NMR in DMF/d7-DMF): -2433 million D.

Example 3. Receive so so t -[PtCl(NH3)2H2N-(CH2)6- NH2-Pt(NH3)2Tina suspended in 2 ml of anhydrous dimethylformamide, and then added 69,1 mg of silver nitrate. The resulting reaction mixture was stirred for six hours at a temperature of 65oC, cooled to room temperature and the precipitated silver chloride was filtered. To the filtrate was added to the solution and [PtCl(NH3)2H2N-(CH2)6NH3]+22NO3(200 mg) in 2 ml of dimethylformamide and 0.4 ml of 1N sodium hydroxide in methanol. The resulting reaction mixture was left overnight at room temperature, and then diluted with ethyl ether until then, have not yet been allocated a solid substance, then the substance was filtered, washed with ethyl ether and acetone and finally dried off, resulting in a received 220 mg of product.

The resulting product is suspended in dimethylformamide (5 ml) and was stirred for 10 minutes and then was isolated by filtration and resuspendable in acetone (10 ml), stirring for another 30 minutes. After filtration and drying there was obtained 150 mg of product.

Elemental analysis (%):

Calculated: C 11,63; H 4,07; N 15,83; Cl 5,72; Pt is 47.24;

Found: C 11,70; H 3,95; N 15,20; Cl 4,60; Pt 47,10.

195Pt-NMR in NaCl (0.35% in water): - 2416 million days; - 2667 million D.

1H-NMR (200 MHz) in D2O: 1.35 million days(m, 8H), 1.68 million d>N- (CH2)6-NH-BOC]+2- 2NO-3.

To a suspension containing 1,028 g of TRANS-platinum in 35 ml of anhydrous dimethylformamide, was added to 1.16 g of silver nitrate. The resulting reaction mixture was heated to a temperature of 60oC in the dark for 5 hours, and then precipitated silver chloride was filtered. After adding a solution of N-BOC-1,6-hexanediamine (1.48 g) in 5 ml of dimethylformamide, the resulting reaction mixture was stirred over night at room temperature. This mixture was diluted with 300 milliliters of ethyl ether until then, until it was highlighted white solid, after which the substance was filtered, re-dissolved in methanol and finally filtered through a Millex filter of 0.2 μm to remove trace quantities of silver salts. The methanol solution was diluted with ethyl ether. White solid was led, and then filtered and dried, resulting in received of 1.94 g of the product.

Elemental analysis (%):

Calculated: C 33,63; H 6,93; N 14,26; Pt 24,83;

Found: C 33,44; H 7,00; N 14,30; Pt 25,06.

195Pt-NMR in DMF/d7-DMF): - 2687 million D.

Example 5. Obtaining and-[NH3-(CH2)6-NH2-Pt(NH3)2H2N- (CH2)6-NH<>)6-NH-BOC]2+2NO-3was dissolved in 50 ml of methanol, and then added 5 ml (6.5 mol) of a solution of hydrogen chloride in ethanol. The resulting reaction mixture was left under stirring for 42 hours at room temperature and the resulting solid was filtered and washed with ethyl ether, the resulting received 340 mg of product.

Elemental analysis (%):

Calculated: C 23,81; H 6,66; N 13,88; Cl 23,42; Pt 32,23;

Found: C 23,14; H Of 6.73; N 13,51; Cl 22,03; Pt 31,68.

195Pt-NMR in water: - 2674 million D.

Example 6. Getting so so so - - [PtCl(NH3)2H2N- (CH2)6-NH2-Pt(NH3)2H2N- (CH2)6- NH2PtCl(NH3)2]4+4NO-3.

220 mg of t-[NH3-(CH2)6-NH2- Pt(NH3)2H2H-(CH2)6-BH3] 4+-4Cl-was dissolved in 10 ml of distilled water and this solution was treated with 224 milligrams of silver nitrate. The resulting suspension was kept at room temperature under stirring for 10 minutes, and then the precipitated silver chloride was removed by filtration. The filtrate was concentrated almost to dryness and then diluted with acetone. Selected white solid washes the2- Pt(NH3)2H2N-(CH2)6-NH3]4+4NO-3< / BR>
The solution containing 172 mg of TRANS-platinum and 21.5 ml of anhydrous dimethylformamide, treated 98 milligrams of silver nitrate. The resulting suspension was stirred at room temperature overnight, after which the precipitated silver chloride was filtered. The solution containing 204 mg t-[NH3-(CH2)6-NH2--Pt (NH3)2H2N(CH2)6-NH3]+44NO-3in 7 ml of dimethylformamide, treated 0,57 milliliters of a solution of 1 n sodium hydroxide in methanol, and then this solution at room temperature was added to the above filtrate, containing TRANS-platinum, activated by dimethylformamide. After 6 hours the solution was filtered through a Millex filter of 0.2 μm to remove trace quantities of silver salts and the resulting filtrate was diluted with ethyl ether. The precipitated solid was isolated by filtration, resulting in a received 326 mg of product.

195Pt-NMR in NaCl (0.3% in water): - 2416 million days; - 2667 million D.

195H-NMR (200 MHz) in D2O (million days): to 1.35 (m, 8H), by 1.68 (m, 8H), 2,65 (Shir.m., 8H).

Example 7. Getting so so so - - [PtCl(NH3)SUB>3)2]4+4Cl-.

326 mg so so t -[PtCl(NH3)2H2N-(CH2)6-NH2-Pt (NH3)2H2-(CH2)6-NH2PtCl(NH3)2] 4+4NO-3was dissolved in saline solution (0.9% sodium chloride) and the solution was filtered through a Millex filter 90,2 microns), and then concentrated to highlight a white solid. The resulting material was filtered and received 187 mg of the product. Elemental analysis (%):

Calculated: C of 12.73; H of 4.45; N 12,37; Cl 18,78; Pt 51,68;

Found: C 12,60; H Of 4.45; N Is 12.85; Cl 14,77; Pt 48,33.

195Pt-NMR in NaCl (0.3% in water): - 2416 million days; - 2671 million D.

1H-NMR (200 MHz) in D2O (million days): 1,40 (m,8H); to 1.70 (m, 8H), 2,70 (Shir.m. , 8H).

Example 8. In accordance with the methods described in examples 1, 2 and 3, or the alternative methods described in examples 4, 5 and 6, and using the appropriate monoamino diamine were obtained following the TRANS-tri-platinum complexes:

[PtCl(NH3)2H2N-(CH2)5-NH2- Pt(NH3)2H2N-(CH2)5-NH2PtCl- (NH3)2]4+4NO-3;

[PtCl(NH3)2H2N-(CH2)4-NH2- Pt(NH3)2H2N-N-(CH2)3-NH2- Pt(NH3)2H2N-(CH2)3-NH2PtCl- (NH3)2]4+4NO-3;

[PtCl(NH3)2H2N-(CH2)2-NH2- Pt(NH3)2H2N-(CH2)2-NH2PtCl- (NH3)2]4+4NO-3;

[PtCl(NH3)2H2N-(CH2)7-NH2- Pt(NH3)2H2N-(CH2)7-NH2PtCl- (NH3)2]4+4NO-3;

195Pt-NMR in NaCl (0.3% in water): - 2422 million d; - 2670 million D.

Example 9. In accordance with the method described in example 7, and using the above example 8 TRANS-tri-platinum complexes were obtained the following compounds:

[PtCl(NH3)2H2N-(CH2)5-NH2- Pt(NH3)2H2N-(CH2)5-NH2Pt Cl-(NH3)2]4+4Cl-;

[PtCl(NH3)2H2N(CH2)4-NH2- Pt(NH3)2H2N-(CH2)4-NH2PtCl- (NH3)2]4+4Cl-;

[PtCl(NH3)2H2N(CH2)3-NH2- Pt(NH3)H2H2N-(CH2)3-NH2PtCl- (CH3)2]4+4Cl-;

[PtCl(NH3)2H24Cl-;

[PtCl(NH3)2H2N(CH2)7-NH2- Pt(NH3)2H2N-(CH2)7-NH2-Pt (NH3)2]4+4Cl-;

1H-NMR (200 MHz) in D2O (million days); of 1.39 (s, 12H), 1,68 (Shir. m, 8H), 2,67 (Shir. m, 8H).

Example 10. Getting so so so - -[PtCl(NH3)2-N-(CH2)6-NH2- Pt(NH3)2H2N-(CH2)6-NH2- PtCl(NH3)2]4+4Cl-.

The suspension containing so so so[PtCl(NH3)2H2N- (CH2)6- NH2-Pt(NH3)2H2N-(CH2)6- NH2-PtCl(NH3)2]4+4NO3(1.3 g) and 65 ml of an aqueous solution of 0.1 n hydrochloric acid, was obtained in nitrogen atmosphere, and then was solubilizers with 54oC. After standing for one hour at the same temperature, the solution was cooled at 20oC, and then filtered on a glass fiber filter to remove mechanical impurities; to transparent solution was added 7.8 ml of aqueous solution of 4 n hydrochloric acid and after a few minutes began settling. The resulting suspension was stirred for 30 minutes at a temperature of 20oC, and then another 30 minutes at a temperature of 10oC. the Precipitate was filtered with a thief who has has dried overnight in vacuum at a temperature of 40oC, resulting in received of 1.03 g of the product.

Elemental analysis (calculated/found %) 2H2O: C Of 12.33/-12:34: H 4,65/4,73; N 11,98/12,05; C 18,21/17,55; Pt 50,07/49,97.

Example 11. Solution for injection containing the compound of example 7.

Mix of 0.250 g of the specified connection with 4.5 g of sodium chloride, pH adjusted to approximately 4 (3,5 - 4,2) using a 0.1 n solution of hydrochloric acid and add the ox for injection to a volume of 500 ml. Solution stored in clear glass ampoules of 1 ml, preferably the color of amber.

1. Trinuclear cationic platinum complexes of General formula I

< / BR>
where n = 2 - 7, integer;

Z-mis an anion selected from chloride, bromide, iodide, nitrate and sulfate;

m = 1 or 2.

2. Connection on p. 1, where n = 6.

3. Connection PP.1 and 2, where Z is selected from a chloride or nitrate, and m = 1.

4. The compound according to any one of the preceding paragraphs, selected from the group consisting of

< / BR>
[PtCl(NH3)2H2N-(CH2)6-NH2-Pt(NH3)2H2N-(CH2)6-NH2PtCl-(NH3)2] 4+4Cl-;

< / BR>
5. The method of obtaining the compounds according to paragraphs.1 to 4, comprising the following stages:

a) activation of TRANS-plastie activated intermediate compound with a diamine of the formula II

H2N-(CH2)n-NH-P,

where n = 2 - 7, integer;

P represents a suitable standard protective group;

obtaining after removal of the protective group P of the intermediate compounds of formula IV

< / BR>
where n is as defined above;

m = 1 or 2, integer;

Q-mthe counterion, the type of which depends on the conditions of removal of P;

(C) the exchange reaction between the anion Q-mand anion NO-3in a solvent such as water or alcohol, to obtain the intermediate compounds of formula V

< / BR>
where n is as defined above;

d) interaction of the intermediate compound (V) with TRANS-platinum, pre-activated by substitution of two chlorine atoms in two molecules of dimethylformamide in the presence of silver nitrate in a molar ratio of 1 : 0.5 to obtaining the compounds of formula I, where n is as defined above, m = 1, and Z-mthe nitrate anion, and, if necessary,

e) reaction of the specified currency of the nitrate anion and the other of the anion Z-mwhere Z-mis as it was defined above.

6. The method according to p. 5, where P is chosen from tert-butoxycarbonyl and p-methoxybenzyloxy carried out using hydrochloric acid.

8. The method according to p. 5, where at stage (e) specified the nitrate anion, first replace the chloride anion Z-mand then the chloride anion replace the sulfate anion, and the exchange reaction between the specified chloride and the sulphate is carried out by treatment with sulphate of silver.

9. The method according to p. 5, where at stage (e) specified the nitrate anion replaces the specified chloride anion by exchange reaction using an aqueous solution of hydrochloric acid in a molar excess at 0 - 50oC.

10. The method of obtaining the compounds according to paragraphs.1 to 4, comprising the following stages:

a) interaction of the amine of formula II

H2N-(CH2)n-NH-P,

where n = 2 - 7, integer;

P represents a suitable standard protective group;

with TRANS-platinum, pre-activated by substitution of two chlorine atoms in two molecules of dimethylformamide in the presence of silver nitrate in a molar ratio of 2 : 1 to obtain the intermediate compounds of formula VI

< / BR>
where n and P are as defined above;

b) cleavage of the protective group P with obtaining the intermediate of formula VII

< / BR>
where n is as defined above;

Q-mand the one NO-3to obtain the corresponding nitrate formula VIII

< / BR>
d) interaction of the intermediate compounds of formula VIII with a TRANS-platinum, pre-activated by substitution of the chlorine atom molecule of dimethylformamide, in the presence of silver nitrate in a molar ratio of 1 : 2 to obtain the compounds of formula I

< / BR>
where n is as defined above;

m = 1;

Z-mthe nitrate anion;

and if necessary, (e) the exchange reaction between the nitrate anion and the other anion Z-mwhere Z-mis as it was defined above.

11. The method according to p. 10, where P is chosen from tert-butoxycarbonyl and p-methoxybenzenesulfonyl.

12. The method according to p. 10, where P is tert-butoxycarbonyl, and cleavage of the group P is performed with the use of hydrochloric acid.

13. The method according to p. 10, where at stage (e) specified the nitrate anion, first replace the chloride anion Z-mthen the chloride anion replace the sulfate anion, and the exchange reaction between the chloride and sulfate is carried out by treatment with sulphate of silver.

14. The method according to p. 10, where at stage (e) specified the nitrate anion replace the chloride anion ptx2">

15. Trinuclear cationic platinum complexes of General formula I exhibiting antitumor activity.

16. Pharmaceutical composition having antitumor activity, comprising the active ingredient in a mixture with standard carriers and fillers, wherein the active ingredient contains at least one compound of formula I under item 1 in a therapeutically effective amount.

17. Songs by p. 16, characterized in that contain compounds of formula I on p. 1, where n = 6.

18. The composition of PP.16 and 17, characterized in that contain the compound of the formula I on p. 1, where Z is selected from a chloride or nitrate, m = 1.

19. Songs by p. 16, characterized in that as a connection on p. 1 contain compounds selected from the group:

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[PtCl(NH3)2H2N-(CH2)6-NH2-Pt(NH3)2H2N-(CH2)6-NH2PtCl-(NH3)2] 4+4Cl-;

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20. The composition of PP.16 to 19, characterized in that therapeutically active amount is such that the dose is 0.1 - 1200 mg of active ingredient per 1 kg of body weight.

21. The composition of PP.16 - 20, dedicated to superior quality products is about contain complexes of platinum, with antitumor activity.

 

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EFFECT: higher efficiency of therapy.

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