RU2391334C2 - Water-soluble complex of cis-diaminodichloroplatinum (2+) with isoniaside and method of preparing said complex - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to obtaining physiologically active compounds, particularly to a new water-soluble complex of cis-diaminodichloroplatinum (2+) with isonicotinic acid hydrazide of formula Pt(NH₃)₂Cl₂·2L, where L=INH is isoniaside, isonicotinic acid hydrazide. The method of preparing the complex involves reacting cis-diaminodichloroplatinum (2+) with isonicotinic acid hydrazide with subsequent extraction of the end product.

EFFECT: compound widens the range of water-soluble anti-tumour and anti-metastatic preparations; can be used in medical practice as an analogue of cisplatin on therapeutic effect, but in a more convenient form of administration due to its high solubility and low toxicity.

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Description

The invention relates to physiologically active compounds and can be used in medical practice for the treatment of cancer, both as an independent drug and in a composition with known drugs.

It is known that cisplatin (Cis-Diamindichloroplatin (2+)) (commercial synonyms: Platidiam, Platidiam, Platinol) is widely used in practice for chemotherapy of cancer patients. Cisplatin is a crystalline powder from yellow to yellow-orange in color, which is slowly and very slightly soluble in water and isotonic sodium chloride solution (Mashkovsky M.D. Medicines, ed. 12th. - M .: Medicine, 1992, p. .523-524).

Despite the poor solubility of the compound in water and aqueous solutions, the main method of using cisplatin in therapy is intravenous. To do this, the drug is dissolved at the rate of 10 mg of dry matter per 10 ml of sterile water for injection, and this solution is diluted in 1 liter of isotonic sodium chloride solution or 5% glucose solution. To increase the solubility of cisplatin before administration, the solution is recommended to be preheated to a temperature of 30-36 degrees Celsius. The solution is administered jet (slowly) or in the form of prolonged infusions (within 6-48 hours).

A known method of producing cis-diamindichlorodihydroxoplatinum (4+) from cis-diamindichloroplatinum (2+) by treating a suspension of cisplatin with 30% hydrogen peroxide at 60-80 ° C followed by separation of the solid residue (SU 1137698 A1, N. Zheligovskaya and et al., 10.17.1983). It was shown that during chemical transformations, the built-in hydroxy groups do not affect the steric distribution of chloro and amino groups.

Derivatives of cisplatin are also known, where one of the ligands is replaced by another biogenic ligand in order to reduce the general toxicity of cisplatin (US6548541, Shaw, 04/15/2003; US7160908, Shaw, 01/09/2007) and create its soluble form (RU2151740 C1, N. Zheligovskaya N.N. . et al., June 27, 2000).

The objective of the present invention is to develop a previously unknown complex compound of cisplatin (divalent platinum), namely a complex of cis-diamindichloroplatin (2+) with isonicotinic acid hydrazide (isoniazid), characterized by higher solubility and reduced toxicity, which allows you to abandon the stage of lyophilization in the production process dosage form and facilitates its use, and method for its preparation.

The new complex compound is a derivative of cisplatin (cis-diamindichloroplatin) of the formula: Pt (NH ₃ ) ₂ Cl ₂ · 2L, where L = INH (isoniazid, isonicotinic acid hydrazide).

To obtain compound (1), one part of cisplatin is mixed with 2 parts of isoniazid in solution at a temperature of the solution in the range of 50-80 ° C with constant stirring for 48 hours until a homogeneous solution is formed. The resulting compound is filtered through a standard microbiological filter with a pore size of 0.22 μm for purification from insoluble fractions.

The patented complex compound is new, not described in the literature, and the method for its preparation is not known.

The following is a detailed description of the method for preparing the patented compound, a complex compound of cis-diamindichloroplatinum (2+) with isonicotinic acid hydrazide.

A solution of 0.274 g (0.002 mol) of isonicotinic acid hydrazide in 5 ml of water was prepared. The resulting solution was heated to a temperature of 50 ° C and 0.300 g (0.001 mol) of cis-diamindichloroplatin (2+) was added to it. After mixing the reagents, the reaction mixture was stirred 48 hours at 50 ° C. The resulting solution was filtered through a standard microbiological filter with a pore size of 0.22 μm (Millipore company). The resulting filtrate was concentrated in vacuo. Received 0.563 g (98%) of the substance in the form of a glassy film of light yellow color. The complex is soluble in water, which greatly simplifies the work with it on biological objects, and this is the technical result of the group of inventions.

The structure and composition of the obtained complex compounds were proved by UV and NMR spectroscopy and elemental analysis, and the obtained spectra are shown in figures 1-6:

figure 1 presents the NMR spectrum of ¹ H source isoniazid;

figure 2 - NMR spectrum of ¹ N mixture of isoniazid + complex;

figure 3 - ¹ H NMR spectrum of a mixture of isoniazid + complex (after a year);

figure 4 - NMR spectrum of ¹ N mixture of isoniazid + complex (80 ° C);

figure 5 - NMR spectrum of ¹ N mixture of isoniazid + complex (after passing through SiO ₂ , eluent - Meon: H ₂ O 3: 1);

figure 6 - absorption spectra of a solution of 10 ^-2 M isoniazid in water (curve 1), solutions of the complex in water with a concentration of 5 · 10 ^-2 M (curve 2) and ≈10 ^-2 M (curve 3) (optical path 0 , 1 cm).

It is seen that in the ¹ H NMR spectrum of the obtained complex, as compared with the spectrum of the initial isoniazid, a shift of the signals of aromatic protons to a weaker field is observed, which indicates the formation of a new compound. The value of the spin – spin interaction constant is 6.3 Hz, which is 1 Hz higher than that of the initial ligand.

The stability of the complex was confirmed by maintaining the NMR spectrum after maintaining the solution of the complex for a year, heating the solution with the complex to 80 ° C and after passing the solution of the complex through a column of silica gel (SiO ₂ ), eluent — CH ₃ OH: H ₂ O = 3: one. The latter shows the possibility of additional purification of the resulting complex.

Elemental analysis.

C ₁₂ H ₂₀ Cl ₂ N ₈ O ₂ Pt

Found 1 (%): C 25.48; H 3.96; Cl 16.13; N, 12.80; Pt 32.29 ;.

Found 2 (%): C 25.18; H 3.70; Cl 14.00; N, 14.86; Pt 33.01 ;.

Calculated (%): С 25.09; H 3.48; Cl 12.37; N, 19.51; Pt. 33.97.

Thus, the proposed method for obtaining the compounds of formula (1) allows to achieve the purpose of the invention and to obtain a previously unknown water-soluble complex compound of cisplatin, namely the complex of cis-diamindichloroplatin (2+) with isonicotinic acid hydrazide. The resulting compound can be used in medical practice both as an independent antitumor and antimetastatic drug, and in a composition with already known drugs.

Tests for acute toxicity were performed by intraperitoneal administration of a solution of the drug to BDFi mice. As a comparison drug, the original cisplatin was used. Tests have shown that the claimed complex, when calculated on the amount of platinum administered, has several times less toxicity compared to the original cisplatin, while the activity against all types of tested tumors that are affected by cisplatin remains the same or increases.

These data prove that the physiological activity of cisplatin bound in the complex with respect to tumor processes has not changed, acute toxicity has decreased, and ease of use during therapy has increased significantly.

Claims (3)

1. A water-soluble complex of cis- [diaminodichloroplatin (2+)] with isonicotinic acid hydrazide of the formula (1)

2. A method of obtaining a water-soluble complex of general formula 1 according to claim 1, characterized in that the treatment of cis-diaminodichloroplatin (2+) is carried out at a temperature of 50-80 ° C with a solution of isonicotinic acid hydrazide at a molar ratio of cis-diaminodichloroplatin (2+) / hydrazide isonicotinic acid, equal to 1: 2, followed by separation of the insoluble residue and the selection of the target product. 3. The method according to claim 2, characterized in that a 0.4 molar aqueous solution of isonicotinic acid hydrazide is first prepared, heated to a temperature of 50 ° C. and 0.001 mol of cis-diaminodichloroplatin (2+) is added to obtain a reaction mixture, then the reaction mixture stirred at a temperature of 50-80 ° C for 48 h and filtered, and the resulting filtrate was concentrated in vacuo to isolate the target product.

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