Cyclohexylamin chinoline (2,1-b) hinzelin-12-he-5 - carboxylic acid, manifesting antiflamitory activity

 

(57) Abstract:

Cyclohexylamin chinoline (2,1-b)hinzelin-12-he-5-carboxylic acid of formula (1) can be used in medicine as a treatment for spring-summer encephalitis. The connection has antireverse activity, not inferior to tick the immunoglobulin that can help expand the Arsenal of drugs used for the treatment of tick-borne encephalitis. table 2.

The invention relates to biologically active compounds, namely cyclohexylamino chinoline[2,1-b]hinzelin-12-he-5-carboxylic acid formula

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with antireverse activity, suggesting the possibility of its use in medicine as a drug for the treatment of tick-borne encephalitis.

The closest analogue to the structure of the claimed compounds is chinoline[2,1-b] hinzelin-12-it [1] (Zayed O. A., Chelintsev Century, About the action of chloropyridine on Anthranilic acid. Journal of organic chemistry, 1937, No. 7, S. 2318 - 2323).

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Information about its biological activity are missing.

In medical practice for the treatment of diseases caused in which prigotovleniya, analysis and use of medications. -M.: the USSR Ministry of health, Union information Bureau, 1988, vol. 4, S. 49), which is taken by us as the standard of comparison antireverse activity.

The aim of the invention is search in the row chinoline[2,1-b]hintline, compounds with pronounced antireverse activity with low toxicity.

This goal is achieved by the synthesis of cyclohexylamine[2,1-b]hinzelin-12-he-5-carboxylic acid by the interaction of cyclohexylamine 2-horseshoebay acid [3] (Yanborisova O. A., Collet C. E., S. Vikharev, A., Konshin M. E. Synthesis, properties and biological activity of amides of 2-horseshoebay acid Dept. in VINITI, 1990, N 3119-V) with Anthranilic acid according to the following scheme:

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An example of obtaining the claimed compounds.

A solution of 2.9 g (0.01 mol) of cyclohexylamine 2-horseshoebay acid and of 1.37 g (0.01 mol) of Anthranilic acid in 10 ml of glacial acetic acid is boiled for 10 h, cooled, poured into 100 ml of water, neutralized with 10% sodium carbonate solution, the precipitate is filtered off and crystallized from DMF. Output 3,19 g ( 86%).

So pl. 285 - 286oC. C23H21N3O2.

Found, %: C 74,52; H Lower Than The 5.37; N 11,03.

Wycislo, DMSO-d6, GMDS, , M. D.): 2.4 m (10H, 5CH2), 3.2 m (1H, CH), to 7.77 m (9H, ArH), 9.4 (1H, NH).

The inventive compound is a light yellow crystalline substance, soluble in DMF, DMSO, insoluble in water, ethanol. When stored in air connection stable.

Previously the biological tests showed that cyclohexylamin chinoline(2,1-b)hinzelin-12-he-5-carboxylic acid exhibit high anti-inflammatory and analgesic activity and low toxicity [4] (Mikhalev A. I., Yanborisova O. A., Sachs, A. S., Yushkov centuries, Konshin M. E. Cyclohexylamin chinoline(2,1-b)hinzelin-12-he-5 - carboxylic acid, exhibiting anti-inflammatory and analgesic activity. USSR author's certificate N 1713248, C 07 D 471/04, 1991).

Acute toxicity was studied on white mice by the method of G. N. Pershina [5] (Pershin, N. Methods of experimental chemotherapy, M, Medicine, 1959, S. 456 - 462) intraperitoneal injection, and found that LD50for the claimed compound is 1890 mg/kg

The claimed compound was tested for the presence antireverse activity on outbred white rats weighing 120-160 g according to the method of [6] (Yushkova T. A., Yushkov centuries Reaction of Central and immune the AI. Perm, 1994, S. 87 - 90) with intraperitoneal injection of a substance at a dose of 0.1 LD50for 1 h before the injection of the antigen.

Antigen tick-borne encephalitis virus was injected once intraperitoneally at the rate of 0.5 ml per 100 g weight of the animal in titer of 1:80.

As a matter of standard of comparison was used immunoglobulin against tick-borne encephalitis, which was administered intraperitoneally at a dose of 0.005 ml per 100 g of rat in titer of 1:80 for 1 h before the injection of the antigen.

Antiviral effect was judged by the change in the response of cellular immunity to an antigen of the virus of tick-borne encephalitis [7] (Yushkova T. A. methodology of the search for substances that have chemotherapeutic activity against tick-borne encephalitis virus. Mat. Dokl. 50-th scientific-practical conference Perm filminstitut, Perm, 1994, S. 47). Proven connection intensified specific phagocytosis premirovany antigen of the virus of tick-borne encephalitis of sheep red blood cells (PL. 1), reduced expression of the receptor, affinity flaviramea antigen and interferon. Simultaneously tested the connection was eliminated immunodeficiency, as evidenced by the restoration of the level of T - and b-lymphocytes.

From the data table. 1 victa it is not inferior to the immunoglobulin against tick-borne encephalitis virus.

The antigen of the virus of tick-borne encephalitis caused leuko - and lymphopenia, neutrophilia and monocytosis. The claimed connection restored the blood to a level detected in the intact rats (table. 2) not giving the standard - immunoglobulin against tick-borne encephalitis.

Thus, cyclohexylamin[2,1-b]hinzelin-12-he-5-carboxylic acid, has antireverse activity that demonstrates the feasibility of in-depth study of its activity with the purpose of creation on its basis of medicines used to treat spring-summer encephalitis.

Sources of information

1. The Zayed O. A., Chelintsev Century, About the action of chloropyridine on Anthranilic acid. Journal of organic chemistry, 1937, No. 7, S. 2318-2323.

2. Methodical recommendations on preparation, analysis and use of medications, M., Ministry of health of the USSR, all-Union information Bureau, 1988, vol.4, S. 49.

3. Yanborisova O. A. , Collet C. E., S. Vikharev, A., Konshin M. E. Synthesis, properties and biological activity of amides of 2-horseshoebay acid. Dept. in VINITI, 1990, N 3119-B90.

4. Mikhalev A. I., Konshin M. E., Yanborisova O. A., Sachs, A. S., Yushkov Century. Century. Cyclohexylamin chinoline(2,1-b)hinzelin-elsto the USSR, N 1713248, C 07 D 471/04, 1991.

5. Pershin, N. Methods of experimental chemotherapy. - M.: Medicine, 1959, S. 456-462.

6. Yushkova T. A. , Yushkov centuries Reaction of Central and immune system to an antigen of the virus of tick-borne encephalitis. Actual problems of theoretical and applied immunology. Perm, 1994, S. 87-90.

7. Yushkova T. A. methodology of the search for substances that have chemotherapeutic activity against tick-borne encephalitis virus. Mat. Dokl. 50-th scientific-practical conference Perm filminstitut, Perm, 1994, S. 47.

Cyclohexylamin chinoline [2,1-b] hinzelin-12-he-5-carboxylic acid formula

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showing antiflamitory activity.

 

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16 cl, 1 tbl, 86 ex

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