Derivatives of 4-oxo-1,4-dihydropyrimidin with anti-allergic and immunotropic activity


(57) Abstract:

Purpose: used in pharmaceutical industry and medicine. The essence of the invention: derivatives of 4-oxo-1,4-dihydropyrimidin formula has anti-allergic and immunotropic activity. Reagent 1 : 2,6-dimethyl-1,5-diphenyl-4-oxo-1,4-dihydropyrimidin or 2,6-dimethyl-5-phenyl-1-(3-pyridinyl)-4-oxo-1,4-dihydropyrimidin. Reagent II: 4-methoxybenzaldehyde, 4-hydroxybenzaldehyde. The process is conducted in a mixture of dimethyl sulfoxide and ethanol by boiling, exit 53 - 71%. R1-C6H5, R2-OCH3; mol.m. 394, so pl. 261-263°C, C20H19N2O, R1-C6H5, R2-OH mol. m 380, so pl. 317-319°C, C19H17N2O2, R1-C6H5, R2-3-pyridyl, mol.m. 395, so pl. 238-241°C. C27H18N3O, the compounds are non-toxic(LD501200 mg/kg) have a pronounced anti-allergic and immune stimulating effects. 3 table.

The invention relates to new biologically active compounds derived from 4-oxo-1,4-dihydropyrimidin with anti-allergic and immunological activity, which can find application in pharmaceutical industry and medicine.

Also known derivatives of 4(3H)-pyrimidine, possessing anxiolytic action (2), and salts of 4-oxo-1 4-dihydropyrimidine with psycho-stimulant, antidepressant and anxiolytic activity (3).

However, the described connection, first, different from the specified number of structural characteristics, secondly, to have a more pronounced anti-allergic effect.

The aim of the invention is the finding in a series of new derivatives of pyrimidine low-toxic and has a more pronounced anti-allergic and immunotropic activity.

This goal is achieved by the described derivatives of 4-oxo-1,4-dihydropyrimidin General formula 1

< / BR>
< / BR>
having antiallergic and immunotropic activity.

The described connection get the pattern

+ C-R2< / BR>
P R I m e R 1. Obtaining 1,5-diphenyl-6-methyl-2(4-methoxytrityl)-4-oxo-1,4-dihydropyrimidin.

In a mixture of 2 ml of dimethyl sulfoxide and 3/5 ml of ethanol is dissolved 2.76 g (0.01 mol) of 2,6-dimethyl-1/5-phenyl-4-oxo-1,4-dihydropyrimidin and 1.36 g (0.01 mol) of 4-methoxybenzaldehyde. Reaction% (2,79)g So pl. 261-263aboutWith from ethanol. Found, %: C 79,15; H 5,61; N 7,09; O 8,14 Calculated, %: C 79,19; H 5,58; N 7,11; O 8,12

Mol.m. 394.

IR spectrum: cm-11646, 1598, 1518, 1251, 1173 (vaseline oil)

UV spectrum:max206 nm 243 nm, 349 nm/ (5x10-6mol/l in ethanol).

P R I m m e R 2. Obtaining 1,5-diphenyl-6-methyl-2-(4-methoxytrityl)-4-oxo-1,4-dihydropyrimidin.

In a mixture of 1 ml DMSO and 4 ml of ethanol is dissolved 2.76 g (0.01 mol) of 2,6-dimethyl-1/5-phenyl-4-oxo-1,4-dihydropyrimidin and 1.22 g (0.01 mol) of 4-methoxybenzaldehyde. The reaction mixture is boiled for 1 h, then cooled and poured into 100 ml of ether. Stands out sediment. Exit 67% (2,54)g So pl. 317-319aboutWith from ethanol. Found, %: C 78,93; H 5,27; N 7,32; O 8,39 Calculated, %: C 79,96; H 5,26; N 7,37; O 8,42

Mol.m. 380.

IR spectrum: cm-11638, 1611, 1572, 1490, 1292 . UV spectrum:max203 nm, 248 nm, 356 nm/ (1x10-6mol/l in ethanol).

P R I m e R 3. Getting 6-methyl-2(4-methoxytrityl)-5-phenyl-1-(3 - pyridinyl)-4-oxo-1,4-dihydropyrimidin.

In a mixture of 2 ml DMSO and 4 ml of ethanol is dissolved 2,77 g (0.01 mol) of 2,6-dimethyl-5-phenyl-1-(3-pyridinyl)-4-oxo-1,4-dihydropyrimidin and 1.36 g (0.01 mol) of 4-methoxybenzaldehyde. The reaction mixture is boiled 1.1 h, then cooled t and poured into 100 ml of ether. Released on the 8,04 Calculated %: C 75,95; H 5,32; N TO 10.62; O 8,01

Mol.m. 395

IR spectrum: cm-11645, 1611, 1518, 1385, 1252

UV spectrum:max204 nm, 250 nm, 354 nm.

The study antiallergic activity carried out on the model reaction of passive cutaneous anaphylaxis (Russian perfumery-cosmetic Association) in rats is mediated by antibodies of the IgE class. This experimental model is most frequently used to search for and identify new compounds with anti-allergic activity.

Serum containing specific homotaurine antibodies, receive the third week after sensitization of mice CBA with ovalbumin (0.5 μg) with aluminum hydroxide (2.5 mg/mouse). The resulting serum at a dilution of 1: 200 injected intradermally in the amount of 50 ml per 6 clipped skin of the back of Wistar rats male Wistar (160-180 g). After 24 h, rats intravenously injected resolving dose of ovalbumin (1 mg/kg) in 1 ml of 0.5% solution of the dye Evans blue in saline. After 30 min the rats under ether anesthesia decapitat, leather turn, dyed areas cut out and extracted the dye formamide at 37aboutC for 4 days. The amount of dye in extravasate determined spectrophotometrically at 600 nm on a calibration curve. Issleduite of the comparison object used antiallergic drug diasorin (4), which is injected animals in the same dose (25 mg/kg) for 90 min before the introduction of antibodies. Control rats intraperitoneally injected with saline. The percentage of inhibition of the reaction is calculated by the formula:

A = 100 - where a is the percentage of inhibition of the Russian perfumery-cosmetic Association,

With - mcg Evans blue in the skin of rats treated with the drug;

In - ICG Evans blue in the skin of control rats.

The experimental results are processed statistically and presented in table.1 in the form of average values of root mean square error of the mean.

The study immunotropic action of one of the described compounds - 1 is performed on the model reaction of hypersensitivity of the delayed type (GTZ), which is one of the most commonly used methods to assess cellular immunity.

Mice of CBA, weighing 14-16 g were immunized with sheep red blood cells 2 109cells/ml intraperitoneally. To determine the reaction GST 4 days a resolving dose of suspension of sheep erythrocytes in the amount of 0.01 ml injected subcutaneously in the right hind leg, the other control - injected the same amount of sterile saline. The severity GST to erythrocytes drum assess the degree OTE>/BR>IL = 100%, where Rabout- the weight of the pilot's feet,

Pto- weight control tabs.

The introduction of the drug, affecting cellular immunity, causes a shift in the index.

The substance 1 is administered a single dose of 25 mg/kg in 2% starch suspension into the stomach using a special probe for 2 days before immunization. The control group immunized animals according to the same scheme to impose 2% starch suspension.

As a comparison object used official drug methyluracil (similar in structure and similar in action), having an immunostimulating action. Methyluracil administered in the same dose of 25 mg/kg for 2 days before the antigenic load.

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

Influence of material 1 on the humoral immune response assessed by the number of antibody productive cells (AFC) in the spleen method batagarawa local hemolysis in monocle erythrocytes. In the experiments used mice-female lines IAS weighing 18-22, Animals subjected to immunization with sheep red blood cells intraperitoneally (2 of 109cells/ml). The number of AFC in the spleen was determined on the fifth day after immunization and count to 106the splenocytes (automaticall at a dose of 25 mg/kg in 2% starch suspension. Control immunized animals injected in the amount of 2% solution of starch suspensions. The experimental results are statistically processed and presented in table.3.

Determination of acute toxicity and calculation of LD50carried out according to the method of Cerberus. White mice weighing 18-20 g intraperitoneally injected with 0.5 ml of a suspension of the investigated substances prepared by adding 1-2 drops of tween. At each dose in the experience of take 6 mice. The result found that LD50the described compounds are more equal than 1200 mg/kg and according to the classification they are considered practically non-toxic substances.

The results of this research show that all of the described compounds have grown antiallergic activity, 2 or more times greater than the activity of the anti-allergic drug diazoline and previously described derivatives of 4-oxo-1,4-dihydropyrimidin, being practically non-toxic. In addition, the connection 1 has a pronounced immunostimulating action, affects cellular and humoral immunity, which leads to stimulation of the reaction GST and improvement of AFC in the spleen. Active substances 1 to stimulate the number of AFC in the spleen of mice is
< / BR>
where R1- phenyl, R2- - OCH3;

R1- phenyl, R2- HE;

R ,

R2- OCH3,

having antiallergic and immunotropic activity.


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