Pentachlorophenate (iv)-4 - methyl-3-[(2 - methyl-4 - hydroxy-5 - pyrimidinyl) methyl]-5-(2-oxyethyl)thiazole exhibiting antitumor activity

 

(57) Abstract:

Use: chemical farmatsevticheskii industry, in particular as a biologically active substance pentachlorophenate (IV) 4-methyl-3'( (2-methyl-4 - hydroxy-5-pyrimidinyl)methyl} -5-(2-oxyethyl)thiazole. The inventive pentachlorphenol (IV) 4-methyl-3-{(2-methyl-4-hydroxy-5-pyrimidinyl) methyl}-5-(2-oxyethyl) thiazole is a crystalline substance is yellow-orange with so pl. of more than 300C and has antitumor activity. table 1.

The invention relates to new biologically active compounds, namely the derived thiazole General formula

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with antitumor activity, and can be used in the pharmaceutical industry. This property suggests the possibility of applying this complex compounds of Occitania with chloride of platinum (IV) in experimental Oncology.

Known toxic compound oksitiamina, which is an antagonist of thiamine (vitamin b1), which is used in experimental Oncology at the dose of 400 mg/kg causes a 3-fold suppression of growth of ascitic Ehrlich carcinoma without changing chromosomal Arata leads to a decrease in body weight of experimental animals, causing diarrhea, lack of appetite, hindering the desired technical result.

The closest set of features and to obtain the desired technical result of the invention is inhibiting tumor growth compound CIS-diamminedichloroplatinum (CIS-platinum, platinum). Well-known compound has activity against experimental strains: sarcoma-180, leukemia P-388 and La; CA-755, melanoma b-16. In other strains, such as sarcoma-37, the effect of CIS-platinum is expressed more weakly [2]

The use of CIS-platinum causes an increase in the number of nursing chromatide exchanges in bone marrow cells of hamsters, mice, spermatocyte males. Introduction CIS-platinum in doses of 1, 2.5 and 5 mg/kg to pregnant females leads to chromosomal aberrations in cells of embryos through 6-18 h [3]

In the clinic CIS-platinum is used for the treatment of tumors of the testis and ovary, head and neck, bladder, etc. widely used in adjuvant chemotherapy with other drugs: etoposide, adriamycin, methotrexate, vincristin, 5-fluorouracil [4]

However, the application of known drug in the clinic cause nephro - and cardiotoxicity, toxic is considered in the expansion of means of influence on a living body by increasing the activity of the substances and reduce its toxicity. This problem is solved by obtaining the complex compounds of Occitania with chloride of platinum (IV) pentachlorophenate (IV) 4-methyl-3-[(2-methyl-4-hydroxy-5-pyrimidinyl)methyl] -5-(2-hydroxy - ethyl)thiazole, with pronounced antitumor activity against, for example, sarcoma-37 and low toxicity. The claimed connection registered in the all-Union scientific center for security biologically active substances as new (N 10363391 from 13.08.91 year).

P R I m e R 1. To 0,1838 g oxydianiline hydrochloride in 1 ml of distilled water add 0,2838 g hexachloroplatinic acid (platinum content of 37.5%). The next day the precipitate is filtered off, washed on the filter with distilled water (2x1 ml) and dried in air. The yield of the target product is 0.3 g (86%). The complex is a crystalline substance is yellow-orange with so pl. > 300aboutSince, it is difficult soluble in water and alcohols, preferably in 0.1 N. Hcl and a mixture of 10% DMSO + 1% DMSO + 1% NaCl, insoluble in acetone and hydrocarbons.

Found, 22,27; N 2,84; S To 5.21; CL To 28.05; Pt 30,88.

WITH12H16N3O2S PtCl5< / BR>
Calculated With 22,56; N 2,53; S 5,02; Cl 27,75; Pt 30,54.

UV-spectrum (Hcl 0.1 N.),max. nm (lg ) 1195, 1125 Wed, 1070 Wed, 1060 Wed, 1040 Wed, 1010 Wed, 925 cf, cf 910, 880 Wed, 830, 795, 600 Wed, 585 Wed, 575, 547 Wed, 535, 470 Wed, 335 S.

The diffraction pattern (SiC radiation), d , (J): 7,90 (41), 6,25 (34), 5,85 (64), 5,70 (24), 5,35 (26), 4,31 (31), 3,94 (100), 3,70 (21), 2,72 (44), 2,63 (25), 2,47 (39), 2,43 (24), 2,21 (21).

P R I m m e R 2. Antitumor activity was studied on white outbred mice-females 3-4 months of age (weight 20-22 g) contained on the regular diet of the vivarium. Animals were divided into control and two experimental groups of 6 mice each. All animals of each group were injected intraperitoneally cells of sarcoma-37 (ascitic version) (12x106cells/mouse). After 48 and 96 h animals one experimental group was injected with 0.2 ml of the proposed drug in a dose of 1.8 mg/kg, other animals of the experimental group was injected with 0.2 ml of CIS-platinum (prototype) in the same dose of 1.8 mg/kg and control group animals 0.2 ml isotonic sodium chloride. On the 7th day of tumor growth, animals were scored, drew ascites and determined the average number of tumor cells per mouse. The results are presented in the table.

The toxicity of the proposed drug for intraperitoneal administration to mice WITH3N, determined by the rapid method (see Frumin, So HFG, 1991, No. 6, S. 15-18), coriden spectroscopic methods and elemental analysis data.

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AND I

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B

In the infrared spectrum has absorption bands, corresponding to stretching vibrations of Oh, NH, CHarene.and CHAlif.(3485, 3175, 3095, 3005, 2910 cm-1), C=O (1745 cm-1), C= N, C=C (1640, 1610, 1555 cm-1),- O (1040 cm-1); Pt-N (375 cm-1), Pt-Cl (335 cm-1). As in the case of Occitania pyrimidine ligand component, judging by spectrum (NH, C=O), there is mainly not in the hydroxy- (A), and in ketoform pyrimidone (B). The presence of the absorption band of the metal-nitrogen indicates that compound I is not ionic associates, and is nutriberry complex, in which the relationship Occitania with platinum via the nitrogen atom. Trivalent chetyrehmagnitnoy the nitrogen atom is linked to a metal ion coordinating communication due to its unshared pair of electrons. Tetravalent become six-coordinated ion Pt(IV) is associated with five chlorine ions and one neutral nitrogen atom of the pyrimidine cycle Occitania and therefore has a charge of -1. This charge is neutralized by the positive charge on the nitrogen atom titlepage fragment of Occitania. In General, the neutral complex I, has zwitterion structure.

Determination of the molecular structure of the complexes of the metal occurs exclusively on atom N-1. Quantum chemical calculations also indicate that the protonation and complexation on atom N-1 energetically most preferable (see A. Adeyemo. R. Oderinde, A. Turner et al.//Bull. Soc. chim. Belg. 1987, v. 96, N 1, p. 15-22; A. Bencini, E. Borchi//Inorg. Chim. Acta. 1987, v. 135, p.85-91; N. Hadjiliadis, J. Markopoulos, G. Pneumatikakis et al.//Inorg. Chim. Acta. 1977, v. 25. p.21-31; A. Marzotto, M. B. Cingi, D. A. Clemente//Inorg. Chim. Acta. 1987, v. 135, p. 37-41; J. Kraut, H. J. Reed//Acta cryst. 1962, v. 15, R. 747). Based on these literature data and taking into consideration the similarity in the molecular structure of thiamine and Occitania (replacement NH2group HE is in position 4 of the pyrimidine cycle) and the electronic distribution in the pyrimidine fragment both connections, I believe that education coordinating communication between Occitania and ion platinum also involved the nitrogen atom N-I. the High frequency stretching vibrations of N-H in the IR spectrum of I is consistent with the conclusion that the nitrogen atom of the N-3 is not involved in coordination with platinum. The formation of ion associates or hydrogen bonds could lead to a decrease of the oscillation frequency N-H, but in this case this is not happening (see, K., Nakamoto. Infrared spectra of inorganic and coordination compounds. M. 1966). Finally, similar conditions of synthesis of the claimed compounds and known also pozvolyaet pattern. Data interplanar distances (d) and relative intensities of the lines (I/Iaboutcommonly used for identification of individual compounds, mixtures, substances and determine their phase composition. There's plenty of background literature on these data, they are used in automated systems rentgenofazovogo analysis. Therefore, we found it possible to lead as one of the physico-chemical characteristics of complex 1 the x-ray data.

Pentachlorophenate (IV) 4-methyl-3-[(2-methyl-4-hydroxy-5-pyrimidinyl)methyl-5-(2-oxyethyl)thiazole formula

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showing antitumor activity.

 

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