Derivatives dichloride, cis-dimentionality platinum exhibiting antiproliferative activity, and method of production thereof

 

(57) Abstract:

The invention relates to biologically active agents with antiproliferative and cytotoxic activity and can be used in pharmaceutical, chemical industry and in medicine. The invention consists in the use of derivatives dichloride, CIS-dimentionality platinum General formula given in the description, as a biologically active substance with antiproliferative activity. The method of obtaining biologically active substances lies in the interaction dichloride CIS-diimidazole platinum with 25% aqueous ammonia solution under heating and vigorous stirring until complete dissolution, followed by cooling and isolation of the target product. 2 S. p. f-crystals, 5 PL.

The invention relates to biologically active substances which possess antiproliferative and cytotoxic activity, and the way they are received, and can be used in pharmaceutical, chemical industry and in medicine.

Known pharmaceutical drugs with anticancer activity based on platinum complexes, amines [1].

However, the known products derived from Mladost the uly (2+[Pt/NH3)2L-CL]) Ct, where L-cytosine, tsitizin, isocytosine, theobromine, theophylline and other with antitumor activity against solid tumors and leukemia [2].

However, the synthesis of known biologically active substances requires rectoscopy and expensive source components.

The closest in technical essence is a biologically active compound, CIS - dichlorodiammineplatinum with antibiotically and cytotoxic activity [3].

However, CIS-dichlorodiammineplatinum has a rather high toxicity and lack of cytotoxic effect on leukemia cells.

Object of the invention is the synthesis of new low-toxic biologically active substances with a higher antiproliferative activity.

The technical result is achieved by the synthesis of derivatives dichloride, CIS-dimentionality platinum General formula (I)

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where

R is hydrogen (1a) or OH-group (1b), showing antiproliferative activity.

The method of obtaining the substance 1a is that dichloride, CIS-imidazolyl platinum treated with 25% aqueous ammonia solution, is heated intensively stirred on the SS="ptx2">

Example 1. CIS-[Pt(NH3)Im2]Cl2(1a).

0.2 g of CIS-diimidazole platinum dissolved in 10 ml of an aqueous solution of 25% aqueous ammonia, heated, stirred on a magnetic stirrer until complete dissolution of the original substance. After complete dissolution of the dichloride CIS-diimidazole platinum, the solution is cooled, the precipitated crystals are filtered.

CIS-[Pt(NH3)2Im2]Cl2(1a) is a white crystals, resistant to air, continued without change for a long time.

Elemental analysis data.

Found, %: N - 19,7; C - 16,4; H - 3,4; calculated, %: N - (Jn 19: 26; C - 16,51; H - 3,21.

Elemental analysis corresponds to the above formula. In IR-spectra (sample in KBr tablet) in the field 3350-2800 cm-1there is a wide laboratoriesa intense band corresponding to N-H stretching vibrations. In the field of 1600-2800 cm-1band deformation vibrations of NH3. The position of the bands suggests the coordination of imidazole molecules and ammonia to platinum.

To prove the structure of the review conducted by the method of proton magnetic resonance. In the PMR spectra of CIS-[Pt(NH3)Im2] Cl2in DMCO (standard HMDS) are the same is the comprehensive decomposition occurs at a temperature of 280oC. solubility in water at 20oC to 0.032 g/ml or 32 g/L.

CIS-[PtNH2(OH)2Im2] Cl2produced by interaction of the CIS platinumdigitalvideo with an aqueous solution of ammonia, only additionally carry out the neutralization equivalent amount of KOH.

Example 2. 1 mol of CIS-[PtIm2Cl2] mixed with 2.1 mmol NH2OH, add 0.1 M aqueous KOH solution, stirred under heating on a magnetic stirrer until complete dissolution of the complex, then filtered, evaporated, get a light gray product is filtered off and washed with a small amount of water and alcohol.

IR Spectro (KBr tablet) in the field of vibrations of N-H and O-H bond (3500-2800 cm-1) observed a very intense band, which indicates the presence of coordinate communication Pt-N. Diffuse band says about the oscillations of the N-H and O-h In the region of 320 cm-1received [PtIm2(NH2(OH)2] Cl2no band corresponding to the oscillations of the Pt-Cl, which is available in the original product CIS-[PtIm2Cl2]. In the area of 620 cm-1there is a strip corresponding to the oscillations of the Pt-n

A comparative study of acute toxicity of the claimed compounds (1a and 1b) is the logical solution at doses of 45 mg/kg to 450 mg/kg for the monitoring of animals within 30 days.

The value of LD50determined by the method of Litchfield and Wilcoxon signed and is 1-318,2 (335,9 - 251,4) mg/kg, maximum tolerated dose (MTD) is to 222.2 mg/kg At MDC LD50is 14 mg/kg Therefore, the magnitude of sredneseriynoe dose acute toxicity of the inventive material 1 more than 20 times smaller than the prototype.

The study of the antiproliferative activity was carried out on suspension culture of leukemia cells K-562 and NIT-102 after 24-48 h of incubation. Efficacy was assessed by the number of pulses per minute to enable ZN-thymidine or ZN-uridine (0,1-1 MCP). The radioactivity determined by scintillation counter MarK(see tab. 1-5).

The table shows that a statistically significant increase (P<0,001) life span in experimental animals after administration of the virus leukemia of Naushera in the dose that causes absolutely lethal effect (LD100), is observed only in the group of animals that received an injection of the proposed drug that confirms his virusinghviru action.

The table shows that the proposed drug is called a two-fold increase in life span of mice-carriers of tumour in comparison with the control (untreated) animals (P< 0,001).

1. Derivatives dichloride, CIS-dimentionality platinum General formula I

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where R is hydrogen (Ia) or OH-group (Ib),

exhibiting antiproliferative activity.

2. The method of producing compound (Ia) under item 1, wherein dichloride, CIS-diimidazole platinum treated with 25% aqueous ammonia solution, is heated intensively stirred until complete dissolution dichloride, CIS-diimidazole platinum, cooled and the precipitated crystals filtered off.

 

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