The method of obtaining n-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5 - pyrimidinylidene)-n`-isonicotinohydrazide

 

(57) Abstract:

The invention relates to a method for producing N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N’-isonicotinohydrazide by reacting 6-methyluracil-5-sulfochloride with isonicotinic acid hydrazide in the presence of dioxane as an activator of the reaction at a molar ratio of reactants is 1:1,5:2,5 respectively, in the medium of anhydrous ethyl acetate at a temperature of 50-75°C for at least 6 hours followed by treatment of the resulting product is water-dimethylformamide at 70-80°C and pH 6, the allocation and dehydration of the target product. N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N’-isonicotinohydrazide finds its application in medicine as an active principle of a drug for prevention and treatment of secondary immunodeficiencies in infectious and somatic diseases, treatment of mycobacterial and viral infections. The technical result is an increase in the yield of the target product, as well as reducing the process time and reduce labor costs to the target product. table 4.

The technical field to which the invention relates

The present invention relates to the field of chemistry, in particular to a new soabantengikictolm, immunomodulatory, antiviral and anabolic activity. Due to the wide range of actions specified connection can be used in medicine as an active principle of a drug for prevention and treatment of secondary immunodeficiencies in infectious and somatic diseases, treatment of mycobacterial and viral infections.

The level of technology

Currently known way to obtain N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N'-isonicotinohydrazide in hydrated form, which lies in the interaction of equimolar amounts of 6-methyluracil-5-sulfochloride and the hydrazide of isonicotinic acid in acetonitrile at 81s with, filtering, dissolving the precipitate in water, filtration, deposition of sediment after adding to the filtrate NH4OH to pH 7 and crystallization from DMF with water (EN 2141322). Obtaining N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N'-isonicotinohydrazide hydrated form impedes the release of the current start in the body and reduces its effectiveness.

The invention

The present invention is to develop a method of obtaining N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl what ispolzovaniem as initial reagents 6-methyluracil-5-sulfochloride and the hydrazide of isonicotinic acid in the presence of as activator reaction dioxane, taken in a molar ratio of 1:1,5:2,5 respectively, in the medium of organic solvent, which is anhydrous ethyl acetate at a temperature of 50-75°C., for at least 6 hours, followed by treatment of the resulting product is water-dimethylformamide at 70-80°C and pH 6, the allocation and dehydration of the target product.

In the processing phase, the resulting reaction product with an aqueous solution of dimethylformamide are extracted contained in the product impurities, allowing the result to obtain the desired product of high purity. The extraction was carried out with an aqueous solution of dimethylformamide in which dimethylformamide is present preferably in an amount of 3 mol per 1 mol of the original 6-methyluracil-5-sulfochloride.

Stage dehydration carried out using known methods, it is preferable to first carry out the drying of the selected product at 100-105C to constant weight with subsequent processing dehydrating reagent by capillary-sorption drying in the presence of Aerosila S-1 and a branch of the sorbent.

This method allows you to obtain N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N’-isonicotinohydrazide ethyl acetate instead of expensive acetonitrile can significantly reduce the cost of raw materials.

The use of dioxane as an activator of the reaction between reagents allows to increase the yield of the target product, to reduce the process time and reduce labor costs to the target product.

Information confirming the possibility of carrying out the invention

Below is an example illustrating a specific implementation of the invention.

Example 1

N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N’-isonicotinohydrazide (ISOFON)

To a mixture of 250 ml of dry ethyl acetate and 20.5 ml (0.25 mol) of dioxane at a temperature of 50-60C consistently metered portions of 20.6 grams (0.15 mole) of the hydrazide of isonicotinic acid and 22.4 g (0.1 mol) of 6-methyluracil-5-sulfochloride. The reaction mass with stirring is heated to 73-75S and maintained at this temperature for 6 hours. The reaction mass is then cooled to 40-50°C, the resulting product is filtered off, washed on the vacuum advance filter twice with ethyl alcohol (20 ml) and dried on the vacuum filter, then the product is placed in a mixture of 250 ml of water and 25 ml (0.3 mol) of dimethylformamide. The suspension is heated under stirring up to 70-80°C, adjusted pH to 6 and give a one-hour exposure. Nerastvorim precipitate are filtered from gorock reaction dried on the vacuum filter, dried at 100-105C to constant mass and then treated by the method of capillary-sorption drying in the presence of Aerosila S-1 and a subsequent separation of the sorbent. Get to 27.7 g (85%) of N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N’-isonicotinohydrazide tpl.(decomp.)=253-S.

Found, %: C 40,83; N 33,31; N 21,3; S 9,89.

C11H11O5N5S

Calculated, %: C 40,61; N 33,38; N 21,54; S 9,85.

Biamperometricheskoi method for the determination of water content using Fischer reagent showed the lack of it in the samples of compound I obtained in accordance with the proposed method.

N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N’-isonicotinohydrazide insoluble in most organic solvents, unstable, collapses both in main and in an acid environment with formation of 6-methyluracil, 6-methylenecyclobutane, 4-pyridineboronic acid. For cleaning substance to the Pharmacopoeia purity of 99.5-100%) carry out additional crystallization. As the environment for crystallization using high-boiling solvents are: dimethylformamide, dimethylacetamide, dimethylsulfoxide, by dissolving in which the compounds I according to the liquid the value of I is 60-70% (from the crystallization of N’-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N’-isonicotinohydrazide).

To get dosage forms using anhydrous chromatographically pure N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N’-isonicotinohydrazide received in accordance with the above method. Unlike known from RU 2141322 hydrate (ISION) obtained according to the invention pure anhydrous N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N’-isonicotinohydrazide (ISOPON) nontoxic for white mice in a dose of more than 7500 mg/kg (determined by the method of Litchfield-Wilkinson) and does not lead to death or loss of mass. Macro-and microscopic examination of internal organs showed no differences between the animals in the experiment and the control.

The content of N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N’-isonicotinohydrazide obtained according to the invention, in the pharmaceutical composition in unit form is 100-400 µg and 100% auxiliary substances. The pharmaceutical composition may be in the form of hard gelatin capsules, in the form of tablets with acid-resistant shell or without shell, in the form of suppositories containing substance in microencapsulated form. Dosage forms get using known for supporting them oshopey activity of microencapsulated substance N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N’-isonicotinohydrazide (ISOFON)

Immunotropic activity of microencapsulated substance was estimated by the method of local hemolysis on EPHE education antibody productive cells (AFC) in the spleen of mice immunized with sheep erythrocytes (EB) (guidelines for the definition of immunotropic activity of pharmacological substances. Manual on experimental (preclinical) study of new pharmacological substances. M, 2000, S. 257-264). Comparators were sulphite and immunomodulator N-(6-methyl-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinylidene)-N-isonicotinohydrazide hydrate (ISION).

The results presented in table. 1, show that the microencapsulated substance (ISOFON) has a significantly greater immunotropic activity than the Comparators.

Example 3

Antiviral activity of the drug ISOFON was evaluated in vitro on cell cultures of chicken fibroblasts and in vivo influence on clinical and virological parameters in infected Guinea pigs.

In vitro antiviral activity of the drug ISOFON (invention) tested under the action of the drug in doses of 10-1000 μg/ml for 1 hour at C virus VAL strain 15 (PL.2). Found that at doses of 500-1000 µg/ml ISOivo Guinea pigs for 3 days 2 times a day was administered ISOFON in the dose of 0.5 and then vaccinated with live vaccine VAL (strain 15) with follow-up care within 7 days. Results table. 3 shows that the introduction of the drug ISOFON (invention) leads to a significant reduction of clinical manifestations of infection in both the number of febrile animals, and the duration and height of fever with significantly less levels of viraemia in infected Guinea pigs.

Example 5

The anabolic drug activity ISOFON (invention) was studied on white mice at the age of one month, which was within 10 days of partial fasting and meals at the standard norms. The experimental group daily for 14 days inside were injected with 0.2 g of the drug ISOFON. The data presented in the table. 4 shows that the experimental animals was observed significantly more rapid recovery of parameters of the internal environment of the body with significant weight gain and liver. Histological assessment of the liver noted that after fasting in the liver observed degenerative changes, as evidenced by the reduction of its weight with a decrease in glycogen content. The introduction of the drug ISOFON in the diet of animals contributed to the acceleration of reparative processes and to restore normal levels of glycogen and the-isonicotinohydrazide by reacting 6-methyluracil-5-sulfochloride with isonicotinic acid hydrazide in the presence of dioxane as an activator of the reaction at a molar ratio of reagents, equal to 1:1,5:2,5 respectively, in the medium of anhydrous ethyl acetate at a temperature of 50-75°C for at least 6 h, followed by treatment of the resulting product is water-dimethylformamide at 70-80°C and pH 6, the allocation and dehydration of the target product.

 

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