Derived 4-oxo-1,4-dihydropyrimidin having antihypoxic, cerebroprotective and immunotropic activity

 

(57) Abstract:

The invention relates to a new compound - derived 4-oxo-1,4-dihydropyrimidin formula I, having antihypoxic, cerebroprotective and immunotropic activity, and may find application in medicine. The compound of formula I is produced by boiling N-acetyl-2-phenylacetamide C-aminobutyric acid in glacial acetic acid in a mixture with dimethylformamide. table 4.

The invention relates to new synthetic derivatives of 4-oxo-1,4-dihydropyrimidin.

Also known derivatives of pyrimidines having psychotropic activity [Igrashi, Jim-Etsu, Nishimura.// PCT Jnt Appl. WO 963/488 A1, 10 Oct. 1996, 116 p.] and salts of 4-oxo-1,4-dihydropyrimidin with psycho-stimulant, antidepressant [Cashyap M. M.// J. labelled Compd. Radiophann, 1989, v. 22, 12, p. l239,1250; C. A. 1987, v. 106 -18475 a], anti-allergic and immunostimulatory activity [Patent 2015975].

The closest structure to the claimed compound is 2,6-dimethyl-5-phenyl-1-(1-phenyl-1-2,3-dimethyl-5-oxadiazolyl-4)-4-oxo-1,4-dihydropyrimidin hydrochloride having antihypoxic activity [Prediction of biological activity and synthesis of new N-heteroplastic 4-oxo-1,4-dihydropyri is the PTO connection.

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

An important advantage of the inventive object is the simultaneous manifestation of these types of biological activity.

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 the balance of amino acids, has antihypoxic, cerebroprotective and immunostimulating action.

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

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having antihypoxic, cerebroprotective and immunotropic activity.

The described connection is obtained by boiling N-acetyl-2-phenylacetamide C-aminobutyric acid in glacial acetic acid according to scheme 1, is given at the end of the description.

Example. Getting 4-(2,6-dimethyl-5-phenyl-4-oxo-1,4-dihydropyrimidin-1)-butane acid. In a mixture of 2 ml of glacial acetic acid ment of the mixture is boiled for 1 hour, then cooled and poured into 100 ml of ether. The residue is filtered and washed with ether. Yield 53% (1,99 g). TPL=140-141oC (from ethanol). Found, %: C-67,13; N-6,29; N-9,80; O-16.78 In. Calculated %: C-67,17, N-6.35mm; N-9,73; O-For 6.81.

The infrared spectrum, cm-1: 1710, 1647, 1590 cm-1(vaseline oil).

UV-spectrum of lmax: 225 nm and 254 nm; 276 nm; 305 nm ( S-110-5mol/l in ethanol).

On the model of antihypoxic activity (hypoxic hypoxia) studied substance 1. The experiment was conducted at 90 mice CBA male, weight 20-21 grams of 6 animals in each series. Mice were placed in a closed space and recorded life time. The substance was administered in the dose of 10 mg/kg body weight 30 minutes prior to the start of the experiment. In control experiments were injected with saline in the same volume. Statistical processing of data was performed using student's criterion (see table.1).

Thus, agent 1 has antihypoxic activity, which is statically significantly exceeds the value of the control experiments and the reference drug.

Study of the anti-ischemic action of an arbitrary 4-oxopyrimidine reproduced on the model of one-component occlusion of both carotid art is Narodnoe starvation of the brain (experimental materials). - L.: Medgiz, 1949, 48 S.].

All animals were divided into 5 groups: 1 gr. control; 2 gr. -product comparison GABA /50 mg/ kg; 3 gr. - product comparison GABA /75mg/ kg; 4 gr. - agent 1 at a dose of 50 mg/kg; 5 gr. - agent 1 at a dose of 75mg/kg In each group was held on 5 series of studies that used for 8 rats in the series. To determine circulatory activity of new substances / 1/ and the comparison drug GABA was injected in doses of 50 and 75 mg/kg intraperitoneally for 45-60 min before ligation of the carotid arteries.

The severity of circulatory activity was assessed by the number of surviving animals after 72 hours after playing ischemia.

Control animals received an equivalent volume of isotonic sodium chloride solution vnutribruchinno.

The results of the experiments are statistically processed and presented in table 2.

The research results show that the studied compound causes cerebroprotective action.

Compound 1 at a dose of 75 mg/kg increases the survival of animals in the conditions of circulatory hypoxia by 65.2% compared with control,

The study immunotropic action derived 4-oxo-1,4-dihydropyrimidin conducted on the model of the methods for assessment of cellular immunity [Immunological methods /edited Field, - M. : Medicine, 1987, S. 346.] 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; 2 gr. - product comparison - methyluracil; 3 gr. - experience, i.e., investigational new substance (1). 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 the right hurt the foot, and in another control, the same amount of sterile saline. The severity of the 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 - Rabout- mass, experienced tabs;

Pto- weight control tabs.

The introduction of the analyte causes a shift in the index. The test substance was administered once at a 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 to the VA. - M.: Medicine, 1985, S. 138]. 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 3.

Influence of material (1) 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 Medicines. - M.: Medicine, 1971, S. 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; 2 gr. - product comparison - methyluracil; 3 gr. - experience, i.e., investigational new substance (1). Each group was held on 5 series of studies that used 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 (1) (group 3) and m is zerouali according to the same scheme, as experimental animals, were injected them with 1% starch suspended in an appropriate amount. The experimental results are statistically processed and presented in table 4.

Thus, the compound (1) inhibits cell-mediated immunity, tested in the reaction GST to sheep erythrocytes, 19,57% compared to control.

A significant increase in humoral immunity was manifested in the increase in the number of AFC in the spleen of mice. The compound (1) in its activity stimulated antilogies 59.4% compared to control.

Determination of acute toxicity and calculation of LD50carried out according to the method of Cerberus and found that for compound (1) LD50is 1700 mg/kg of body weight of the animals. Thus, the analyzed compound (1) has low toxicity.

The research results show that the studied compound has antihypoxic, cerebroprotective activity, has an impact on cellular and humoral immunity.

Derivative of 4-(2,6-dimethyl-5-phenyl-4-oxo-1,4-dihydropyrimidin-1)-butane acid

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showing antigipoksicheskoe, cerebroprotective and immunotropic activity.

 

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