Immunomodulator with antimycobacterial activity "isoton", the method of its production and use

C07D213/44 - Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom


(57) Abstract:

The invention relates to the field of medicine and relates to a new medicinal product - immunomodulator with antimycobacterial activity "Isoton", method of its production and application. The invention consists in the interaction equimolecular quantities 6 methyluracil-5-sulfochloride and the hydrazide of isonicotinic acid in absolute acetonitrile at 81C, filtering, dissolving the precipitate in hot water, filtration, deposition of sediment after adding to the filtrate NH4OH to pH 7 and crystallization from DMF. The resulting material is a N - (6-methyl-2,4,dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N'-isonicotinohydrazide hydrate, which in oral administration and parenteral has antimicrobacterial activity. The technical result is the creation of a new immunomodulator with antimycobacterial activity, also used in secondary immunodeficiencies and mycobacteriosis. 3 C. p. F.-ly, 3 tables.

The present invention relates to the field of medicine, more precisely relates to a new medicinal product - isotone, immunocorrector with antimycobacterial activity, of the formula 1:

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--- oborowsky properties /2/ and has an immunostimulatory effect on humoral and cellular immunity /3 - 5/. However, he lacks mitogenic activity and capable of increasing the proliferation of T-cells only in response to PHA. The toxicity of diacetone 2600 mg/kg

The purpose of the invention to provide a new immunomodulator with antimycobacterial activity, including HIV - carriage, active not only against mycobacteria, leprosy, and tuberculosis, and other diseases that occur on the background of immunodeficiency.

We derived earlier N-/6-methyl-2,4-dioxo-1,2,3,4 - Tetra-hydro-5-pyrimidinone/-N'-isonicotinohydrazide /6/, though he had antimycobacterial action, but immunotropic activity not possessed, moreover, it can not withstand long periods of storage because of the contained impurities.

Therefore, it was necessary to find a new way to obtain this substance, a pharmacologically pure samples which is devoid of the above disadvantages.

This goal is achieved by the compound of formula 1 "isoform".

ISOPON get boiling equimolecular amounts of the hydrazide of isonicotinic acid and 6-methyluracil-5-sulfochloride in anhydrous acetonitrile. Samples isotone retain their properties over 3 years.

Kah Russia, showed that ISOPON normalizes the immune status of patients with leprosy, tuberculosis, chronic nonspecific pneumonia and chlamydia, including the body in fighting disease, but also penetrate into the cells and stimulates its function and brings effective start up of the pathogen destroys it. It is not excluded the possibility of a direct effect on pathogens, sexually transmitted diseases, chlamydia, Trichomonas, Ureaplasma infection.

It is necessary to emphasize the good tolerability of Isopoda, no side effects and is compatible with modern antimycobacterial tools /ethionamide, rifamycin, and others), which is confirmed when examining patients with leprosy and tuberculosis.

Toxicity isotone was determined on outbred mice weighing 18-20 g in the acute experience of the method of Litchfield - Wilcoxon signed and amounted to more than 7000 mg/kg

The invention is illustrated by the following examples.

Example 1. N - 6- /Methyl-2,4-dioxo-1,2,3,4-tetrahydro - 5H-pyrimidine-4-sulfon/ -N'- isonicotinohydrazide /Ia/, hydrate.

The mixture is 2.74 g /0.02 mol/ hydrazide of isonicotinic acid and of 4.49 g /0.02 mol/ 6-methyluracil-5-sulfochloride in 50 ml of absolute and the sludge, alcohol, air-dried. Get 7,27 g yellowish fine powder. The resulting product was dissolved in minimum amount of hot water, filtered and to the filtrate add NH4OH to pH 7. Precipitated white precipitate is separated, well washed on the filter with water and alcohol and crystallized from DMF with water.

Get 4.94 g /76%/ white light crystals, etc., 255-6oC.

Found,%: C 38,3, H, 4,0, S 9,2, N 20,2,


Calculated,%: C 38,5, H 3,8, S 9,4, N 20,4.

PMR spectrum in DMSO: /3H, uracil/, 2,36 M. D./ 4H, pyridine/, 7,7 M. D. 8,65 M. D., /2H NH uracil/ 8,98 M. D. 10,9 M. D. /2H NH chain/ 11,42 M. D. 11,53 M. D./2H, H2O/ 3,18 M. D.

Example 2. The definition of immunotropic activity of isotone. Immunotropic activity isotone was determined on the model of immunodeficiency caused by irradiation.

To create immunodeficiency mice F1(CBAxC57BZ/6) were irradiated with gamma rays in radiotherapy apparatus BEAM-1 at a dose of 4 Gy at a dose rate of 0.55 G/ml, the Amount of antibody productive cells in the spleens was determined by the method of EPHE-Nordin.

ISOPON and diazepan is administered orally in a wide range of doses. The results are shown in table 1.

The optimal concentration for isotone 1-0,03 ug/ml

Diucifon has the ability to increase the proliferation of T - cells only in response to PHA, but lacks mitogenic activity, the optimal concentration for diacetone of 0.1 and 0.03 g/ml.

Thus, the range of isotone on T-lymphocytes wider than dialtone.

Example 3. The results of clinical application of isotone in clinic patients with leprosy /report attached).

Ision was studied in the clinic for patients with leprosy in comparison with Deuteronomy. Daily dose of 0.6 g

Within 3-4 weeks, patients receiving ISOPON noted improvement in General condition, decrease in inflammatory infiltrates in the skin, softening laprom and nodes, change their color from rusty brown to pale pink.

3 months have gone the causative agent of leprosy in scrapings from the mucous membrane of the nose and smear the index sharply declined.

Casings 5-6 months, the causative agent of leprosy in the reading and histological examination were not found. Patients who received diazipan, passed through the same stages of clinical recovery, but more lithological study were not found. The results obtained are presented in table 2.

The results of immunological examination of patients with leprosy who received ISOPON and diazepan showed that both drugs normalize the immune status of the patient: increases the total number of T-lymphocytes, the number of T-helper cells, normal immunoregulatory index/, the relation of Tx/Twiththat has been reduced.

It should be noted that the normalization of immunological parameters proceeds more smoothly when applying Isopoda, probably due to its impact on other mechanisms of immunity than dialtone.

Thus, isophon showed marked clinical antimycobacterial and immunotropic effect, superior to diazepan.

The use of isophane allowed to shorten inpatient treatment of leprosy in 2 times.

Example 4. The results of clinical application of Isopoda in the clinic TB /preliminary report is attached).

Ision was applied in patients with pulmonary tuberculosis. A dose of 0.6 g per day.

Patients admitted with symptoms of intoxication during treatment noted improvement in health, normalization those who Eskom the survey was an increase in the number of T-lymphocytes, T-helper cells, reducing the high number of T-suppressors (see table 3).

When the control x-ray examination of the lungs marked by a positive trend in the reduction perifocal ipricewaterho infiltration. The results are presented in table 3.

Thus, when applied in patients with tuberculosis ision has proven itself as an effective immunomodulator with a strong antimycobacterial activity.

Considering the small low toxicity isotone currently being considered for the replacement of tubazide as the main leprosy with toxicity 150 mg/kg, on a new ISOPON.

Example 5. The results of chemical application isotone in clinic patients with chlamydia.

Ision was applied in patients with chlamydial infection in a daily dose of 0.4 g in patients with newly diagnosed chlamydia, isophon was appointed as monotherapy. And in 9 of 11 patients of this group marked improvement in the absence of local signs of inflammation and negative tests for detection of the pathogen. And all 11 patients identified improvement and normalization of hematological immunological and biochemical parameters.

The clinical effect was achieved in both groups, but patients receiving isophon, recovery occurred faster: 7-8 day patients reported improvement of health, reduction of inflammation and 15-17 day of treatment, the pathogen was not found.

In the group without isotone this effect was achieved not less than a month of treatment.

Thus, a high clinical effect of isophone is achieved through two steps, immunostimulating and antichlamydial.

Currently completed the study of the direct effects of isotone for chlamydia, Trichomonas and Ureaplasma infections.

Given the wide range of immunotropic activity of Isopoda and its antimycobacterial activity and very low toxicity to recommend this drug for use in General medical practice in the treatment of various diseases occurring on the background of immunodeficiency, including HIV infection, and also when mycobacteriosis (tuberculosis, leprosy and others).


1. N. M.The Goloshchapov, A. A. Yushchenko, J., Umerov, C. A. Evstratova, T. C. Grenuk, B. E. Ivanov, V. S. Reznik, N. G.Pushkarov, C. S. Lieberman, S. A. Sharov, A. S. USSR N 606242.

2. N. M. Gol

3. B. N. Leskov, Bulletin of experimental biology, 1985, XXVII, No. 12, S. 738.

4. C. S. prozorovskii, D. Thesis M. H. 1991

5. L. E. Kostyuk, Dissertation K. B. N., Moscow 1986

6. N. M.The Goloshchapov, Etc. Filipski, V. D. Smirnov, G. R. Uncur, M. A. Irina A. S. USSR N 768186.

1. Immunomodulator with antimycobacterial activity, representing N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N'-isonicotinohydrazide hydrate formula

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2. The method of obtaining immunomodulator under item 1, characterized in that the interaction equimolecular quantities of 6-methyluracil-5-sulfochloride and isoniazid is carried out in acetonitrile at a temperature of 81oC, dissolved in water, to the filtrate add NH4OH, the precipitate was separated and crystallized from DMF with water.

3. Immunomodulator with antimycobacterial activity under item 1 for oral administration and parenteral in secondary immunodeficiencies and mycobacteriosis.


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9 cl, 1 tbl, 8 ex