Derived 4-oxo-1,4-dihydropyrimidin having immunosuppressive activity


(57) Abstract:

The invention relates to a new derivative of 4-oxo-1,4-dihydropyrimidin, specifically: 2,6-diethyl-5-phenyl-1(5,6-dimethylbenzimidazolyl-1)-4-oxo-1,4-dihydropyrimidine (I) having immunosuppressive activity, which can find application in medicine. This derivative is obtained by condensation of the corresponding derivative of 2-phenylacetophenone with amino derivatives of benzimidazole in the environment of glacial acetic acid in the presence of DMF. The compound (I) has an immunosuppressive effect on the organism of an animal, inhibiting both cellular and humoral form the primary response. table 2.

The invention relates to new synthetic derivatives of 4-oxo-1,4-dihydropyrimidin. Known derivatives of 4 - oxopyrimidine series containing heterocyclic substituents, namely, imidazole, pyrimidine and pyridine together with diazolinum [Spngier J. P. Schurack W. //Arch. Pharm-1983 - Vol.316-p. 82-83: C. A.-1983-Vol. 98-125979 f] with antihistaminic activity.

Also known derivatives of 4(3H)- pyrimidine, possessing anxiolytic [Sidney S. G. // Eur. Path.AppI. E. R. 107914 07 D 401/02090584; C. A. 1984-Vol. 101 - 1919537z] and salts 4-oxo-1,4-dihydropyrimidin have tallurgical and immunostimulatory activity [Prediction of biological activity and synthesis of new N-heteroplastic 4-oxo-1,4-dihydropyrimidin. Pyatigorsk. 1995, S. 22-Dept. in VINITI N 2796 - In-95 23.10.95].

The closest structure to the claimed connection are: 2,6-dimethyl-5-phenyl-1-(5,6-dimethylbenzimidazolyl-1-)-4-oxo-1,4 - dihydropyrimidin and 2,6-diethyl-5-phenyl-1-(2-methylbenzimidazolyl-1)- 4-oxo-1,4-dihydropyrimidin having immunostimulatory activity [Patent N2037491.].

The purpose of this invention to provide a new derivative of 4-oxo-1,4-dihydropyrimidin with more pronounced immunosuppressive activity compared to known substances.

The inventive object is a derivative of pyrimidine 4-oxo-1,4-dihydropyrimidin and its biological properties in the available literature are not described. This new substance refers to a derivative of pyrimidine containing heterocyclic Deputy and with immunotropic effect.

This goal is achieved in the synthesis of compounds of the following structure:

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having immunosuppressive activity

The described connection is obtained by boiling N-propionyl - 2 phenylacetophenone with 1-amino-5,6-dimethylbenzimidazole in glacial acetic acid according to the scheme:

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Example. Obtaining 2,6-diethyl-5-phenyl-1 -(5,6 - DIMET is 7 g (0.01 mol) of N-propionyl-2-phenylacetophenone and 1.61 g (0.01 mol) of 1 - amino-5,6-dimethylbenzimidazole. The reaction mixture boil for 1 hour, then cooled and poured into 100 ml of ether. The residue is filtered and washed with benzene. Exit 49% (1,99 g). TPL=149-150oC (from ethanol). Found,%: C 74,23; H Is 6.61; N 15,56; 3,60. Calculated %: 74,21; H 6,53; N 15,64; 3,62.

The infrared spectrum, cm-1: 1705, 1653, 1570, 1535 (vaseline oil).

UV spectrummax: 207 nm; 252; 278 nm (1105mol/l in ethanol).

The study immunotropic action derived 4-oxo-1,4 - dihydropyrimidin conducted on the model of hypersensitivity reactions of the delayed type (GST), which is one of the most frequently used methods to assess cellular immunity [Immunological methods, Ed. of Primes, M , Medicine, 1987, S. 346 and C. 64.]. 45 mice of both sexes lines IAS weighing 18-20 g were immunized intraperitoneally with sheep erythrocytes (DL) number 2109cells/ml. All animals were divided into 3 groups of 25 mice: 1 gr. control; gr 2 - product comparison - methyluracil; 3 gr. - experience, i.e., investigational new substance (I). Each group was held on 5 series of studies that used 5 mice in the series. To determine the reaction GST 4 days introduced which permits suspension dose unit in an amount of 0.01 ml subcutaneously in arnosti reaction GST to DL was evaluated by the degree of swelling experienced paws compared to the control by measuring the mass of legs and was calculated index response (IR) in percent

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where - Pabout- weight experienced tabs;

Pto- weight control tabs,

The introduction of the analyte causes a shift in the index. The tested substances were administered a single dose of 25 mg/kg of body weight of mice in the 1% starch suspension into the stomach using a special probe for 2 days before the antigenic load. As a comparison object used officinal drug methyluracil with immunotropic activity. Methyluracil was administered in the same dose and the same pattern as the test substance.

Control animals received 1% starch suspended in an appropriate amount and immunotherapies according to the same scheme, and experimental animals.

The results of the experiments are statistically processed and presented in table 1.

The influence of substances (I) on the humoral immune response was assessed by the number of antibody productive cells (AFC) in the spleen of mice by the method batagarawa local hemolysis in a monolayer of red blood cells [M. D. Mashkovsky. Medicinal product. - M.: Medicine, 1971, page 157.]

The experiments were carried out on 75 mice CBA of both sexes weighing 20-22, All animals were divided into 3 groups of 25 mice: 1 gr. control; gr 2 - product comparison - methyluracil; 3 gr. - what was Avalos 5 mice in the series. Animals were immunized EB intraperitoneally (2109cells/ml). The number of AFC in the spleen of mice was determined on the fifth day after immunization and were counted on 106the splenocytes. 2 days before immunization the mice in the stomach with the help of the probe was administered the test substance (I) (group 3) and plastic surgery (2nd group) at doses of 25 mg/kg in 1% starch suspension. Control animals (group 1) were immunized according to the same pattern as the experimental animals were injected them 1% starch suspended in an appropriate amount. The experimental results are statistically processed and presented in table 2.

Determination of acute toxicity and calculation of LD50carried out according to the method of Cerberus and found that for the compound (I) LD50is 1500 mg/kg of body weight of the animals. Thus, the analyzed compound (I) has low toxicity.

The research results show that the studied compound has an effect on cellular and humoral immunity.

Thus, the compound (I) inhibits cell-mediated immunity, tested in the reaction GST to sheep erythrocytes, 24.6% compared to control.

Significant suppression of humoral immunity manifested in o compared to control.


1. Spengler J. P., Schurack W.// Arch. Pharm. - 1983.- Vol. 316.-p. 82-83; C. A. 1983. -Vol. 98 - 125979F.

2. Sidney S. G.//Eur. Path. Appl. E. P. 107914 07 D 401/02090584; C. A. 1984 - Vol. 101 - 1919537z.

3. Cashyap M. M.//J. Labelled. Compd.Radiophann. -1989. - Vol. 22 - N12 p 1239.1250; C. A. 1987. - Vol. 106 - 18475a.

4. Prediction of biological activity and synthesis of new N - getallposts 4-oxo-1,4-dihydropyridine. Pyatigorsk. - 1995. - S. 22. - Dept. in VINITI N 2796 - In-9523.10.95.

5. Patent N 2037491.

6. Immunological methods, Ed. of Primes, M, Medicine, 1987, S. 346 and C. 64.

7. M. D. Mashkovsky. Medicinal product. -M.: Medicine, 1971, page 157.

Derived 4-oxo-1,4-dihydropyrimidin-2,6-diethyl-5-phenyl-1-(5,6-dimethylbenzimidazolyl-1-)-4-oxo-1,4-dihydropyrimidin formula I

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showing immunosuppressive activity.


Same patents:

The invention relates to new substituted pyrrole General formula I

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where R is hydrogen, hydroxyl;

R1and R2- together group of the formula -(CH2)nand R7is hydrogen, or R1and R7- together group of the formula -(CH2)nand R2is hydrogen;

R3is phenyl, naphthyl which may be substituted with halogen, C1-C7- alkoxy, CF3or benzofuranyl, benzo(b)thienyl, indolyl, substituted by 1-3 substituents selected from the group comprising halogen, C1-C7-alkyl, C1-C7-alkoxy; R4, R5and R6is hydrogen, halogen, C1-C4-alkoxy, C1-C7-alkyl,

R8a group of the formula -(CH2)p-R9or -(CH2)q-R100;

R9is hydrogen, C1-C7-alkylsulphonyl, C1-C7-alkylsulfonyl, aminocarbonyl;

R10is hydroxyl, amino, C1-C7-alkylamino, di(C1-C7)-alkylamino, three(C1-C7)-alkylamino, azido, C1-C7-alkoxy-carbylamine, isothiocyanate, C1-C7-alkylcarboxylic, C1-C7-alkylsulfonate, 6-membered nitrogen-containing saturated gets the SUB>2; W is amino; one of X and Y - O-atom, and the other is O or (H,H);

Z - group-CH - or N-atom;

m, p and q is a number from 0 to 5, n is a number from 1 to 5, provided that m and q represent the number from 2 to 5 when Z Is N-atom, and their pharmaceutically acceptable salts

The invention relates to new derivatives of benzimidazole with valuable properties, in particular a derivative of benzimidazole of General formula (I)

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where R1is methyl,

R2- benzimidazole-2-yl, unsubstituted or substituted in position 1 by the stands, imidazol-4-yl substituted in position 1 by alkyl with 1 to 3 carbon atoms, substituted in position 2 by morpholinopropan, 5,6,7,8-tetrahydro-imidazo[1,2 - a]pyridine-2-yl or propanesultone-1-Il,

R3- nonbranched alkyl with 2 to 4 carbon atoms,

R4- amino group, sulfonyl substituted by a residue from the group consisting of dimethylaminopropylamine, cycloalkylcarbonyl, benzylaminocarbonyl in which cycloalkyl part contains 5 or 6 carbon atoms and the phenyl portion may be substituted methoxy group, triptorelin, tert

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