Means inhibiting the proliferation of lymphocytes


(57) Abstract:

The invention relates to medicine and organic chemistry and relates to the problem of creating new drugs, inhibiting the proliferation of lymphocytes. Such drugs could be used in practical medicine for immunosuppressive and anti-leukemia therapy. The purpose of the invention is a new biologically active compound 2-amino-6-/1-ethyl-2-methyl-4-nitroimidazole-5/-thiopurin, inhibiting the proliferation of lymphocytes. 2-Amino-6-/1-ethyl-2-methyl-4-nitroimidazole-5/-thiopurin inhibits primary immune response of animals to thymusdependent and timecategory antigens and has a great breadth of therapeutic action. 3 Il.

The invention relates to the problem of creating new drugs, inhibiting the proliferation of lymphocytes, which could be used in practical medicine for immunosuppressive and anti-leukemia therapy.

The object of the invention is a new purine derivative - compound s-1 (formula-1 and its structural analogues are presented below:

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The specified connection and its properties are not described in literature.

Immunodepression studied 6-mercaptopurine, azathioprine, 8-azaguanine, guanren and others. One of the most effective modern immunosuppressants is azathioprine, which is widely used in the treatment of autoimmune and rheumatic diseases (E. Berger, L. Rumbach, Rev. Med. Interne, 1999, 20, 346S-350S; So Munster, D. E. Furst, Clin. Exp. Rhewnatol. , 1999, 17 (6), S29 - S36), the treatment of idiopathic pulmonary fibrosis (R. P. Baughman, E. E. Lower, Clin. lmmunotherap. , 1996, 6 (6), 431-442), clinical transplantation (C. G. Groth, L. Backman, J. M. Morales et al. , Transplantation, 1999, 67 (7), 1036-1042; N. Perico, G. Remuzzi, Drugs, 1999, 54 (4), 533-570; G. N. Pershin, Journal of WMO them. D. I. Mendeleev, 1970, 15 (2), 216-222; ) etc. However, this drug has a low therapeutic latitude (L. N. Felicis, Y. A. Sorkin, G. N. Pershin and other Pharmacology and toxicology, 1971, 34 (6), 708-713) and gives serious side effects (J. N. Stolk, A. M. Boerbooms, R. A. de Abreu et al. , Arthritis Rheum. , 1998, 41 (10), 1858-1866; M. F. Neurath, R. Wanitschke, M. Peters et al. , Gut, 1999, 44 (5), 625-628). Therefore, the search of new immunosuppressive compounds remains a challenge for theoretical and practical medicine.

In the Handbook (R. C. Petrov, V. M. Manko, Immunodepression, M. : Medicine, 1971, S. 31), and also (L. N. Felicis, Y. A. Sorkin, G. N. Pershin and others , Pharmacology and toxicology, 1971, 34 (6), 708-713) described immunosuppressive properties thioguanine analogue of azathioprine-and humoral immune response, however, this compound had relatively high toxicity and therefore has not found wide application.

The aim of the invention is a new compound 2-amino-6-(1-ethyl-2-methyl-4-nitroimidazole-5)-thiopurin, having advantages over known drug azathioprine.

The synthesis of new compounds is our proposed method. The proposed method is illustrated by the following example.

Example. A mixture of 23.8 g (0,143 mol) Tg, of 27.0 g (0,143 mol) of 1-ethyl-2-methyl-4-nitro-chlor-imidazole, 1 l of water and 14.5 g (0,145 mol) of 40% aqueous sodium hydroxide solution is stirred for 3-3,5 hours at 70oC, this results in the release of sediment. To the hot reaction mass add 4-5 ml of glacial acetic acid until the acid reaction of the aqueous layer, the mixture is cooled to 15-20oC, the precipitate is filtered off, washed on the filter with water until the disappearance of the chloride, dried at 70oC to constant weight. Get 46.2 g (96% yield) of the terms of substance So pl. 232-233oC (decomposition). The product purified by crystallization from distilled water 1: 150 with the addition of 2-3 g of activated charcoal. The yield of pure substance with So pl. 236-237 - to 39.6 g (82%), So pl.oC (decomposition) is to 39.6 g (79%).

Found The H 4,17; N 33,12; S FOR 9.47; H2O 5,32.

Rf= 0,45 (system butanol-water-acetic acid 5: 4: 1).

The study of toxic and immunosuppressive actions of the new compound was carried out in comparison with azathioprine. Both drugs are used in the form of a suspension in 1% starch gel, which was administered to the animals intraperitoneally.

Determination of acute toxicity was carried out according to Litchfield and Wilcoxon signed. Within 14 days recorded appearance, behavior, and death of animals. Clinic poisoning by both drugs was the same: with the introduction of toxic doses of the mouse in both cases on day 3 began sharply to lose weight and were killed on day 7 to day 9. At the opening of the spleen thinned, the lymph nodes are absent, there are hemorrhages in internal organs. Were obtained the following values LD50: S-1 80 mg/kg (62,2-97,5), for azathioprine - 350 mg/kg (286 - 428). Curve toxicity of azathioprine was more gentle, which indicates different toxicodynamic study drug.

In the study of suppression of the primary immune response as antigens used sheep erythrocytes (EB) at a dose of 5x108cells and polysaccharide Vi antigen (Vi-AG) in the dose of 5 mg, which were injected into mice intravenously entom volume. Immune response in experimental and control animals were evaluated at 4 days after immunization by the number of antibody productive cells (AFC) in the spleen by the method of local hemolysis in gel. therapeutic index, TI was calculated by the formula T = LD50/ED50. In preliminary experiments, we determined the optimal time of introduction of both drugs in relation to antigenic stimulus: the immune response of mice EB and Vi-AG under the action of both drugs were oppressed in the highest degree in their introduction twenty-four hours after antigen.

After determining the optimal time of introduction of s-1, we conducted a comparative study of the suppression of the immune response to unit depending on the dose of the compounds. The results of the experiments shown in Fig. 1, which shows that the new drug significantly stronger inhibited the immune response of the animals compared with azathioprine. The strongest inhibition of immunogenesis new drug was observed in the range of doses of 30-50 mg/kg (number of AFC in the spleen < 10% of control). It should also be noted that therapeutic index-1 was significantly higher than that of azathioprine (respectively, 13.3-inch and 8.0).

At the final stage of our work we conducted a one-off Stavisky (Vi-AG, Fig. 3) immune response. As in the previous section, a new connection is more effectively inhibited the immune response of mice to both antigen than azathioprine. Differences were highly reliable.

Summing up, it should be noted that the above drug s-1 can be used as an immunosuppressant. Anyway, on this indicator, it is superior to azathioprine in spite of greater toxicity. As already noted, the breadth of therapeutic action of a new drug is higher than that of azathioprine, which characterizes it as a more secure means and refers to the perspective of its further study.

2-Amino-6-/1-ethyl-2-methyl-4-nitroimidazole-5/-thiopurin formula

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inhibiting the proliferation of lymphocytes.


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