Derivatives of 4-oxo-1,4-dihydropyrimidin having antiallergic activity

 

(57) Abstract:

Use: chemical farmatsevticheskii industry and medicine. The inventive products are derivatives of 4-oxo-1,4-dihydropyrimidin f-ly I, having antiallergic activity: (a) BF C21H2ON4O4S, exit 69% so pl. 255-257°C, b) BF C19H16N4O, the yield was 73% so pl. 179-180°C. Reagent 1: N-acetyl-2-phenyl-acetoacetamide f-crystals 2: On/double bond/CR-CH(phenyl)-C(O)-NH-CR/double bond/O, where R and R the following values. Reagent 2: aminoethanol f-crystals 3: NH-Het, where Het is the following. Reaction conditions: boiling in a mixture of dimethylformamide and glacial acetic acid for 1 h, the connection Structure of f-crystals 1: R1-R2-C2H5R1-R2-CH3. table 1.

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

Known derivatives of 4-oxopyrimidine series containing heterocyclic substituents, namely, imidazole, pyridine and pyridine together with the thiazole [1] with antihistamine and salt 4-oxo-1,4-dihydro - pyrimidine, with psycho-stimulant, antidepressant and anxiolytic activity [3]

Known derivatives of 4-oxo-1,4-dihydropyrimidin possessing anxiolytic, anti-hypertensive, immunostim - stimulating and anti-allergic action. However, the proposed connection first, differ from the above a number of structural characteristics, secondly, to have a more pronounced anti-allergic effect.

The purpose of the invention to obtain new derivatives of 4-oxo-1,4-dihydropyrimidin, with a more pronounced anti-allergic activity compared with the previously stated compounds.

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

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I Het ; R1R2-C2H5< / BR>
II Het ; R1R2-CH3having antiallergic activity.

The described connection is produced by boiling N-acetyl-2-phenyl-acetoacetamide c aminoheterocycles in a mixture of dimethylformamide and glacial acetic acid according to the scheme:

+ H2N-Het

P R I m e R 1. Obtaining 2,6-diethyl-5-phenyl-1-2-sulfabenzamide-1-4-oxo - 1,4-dihydropyrimidin.

In a mixture of 2 ml of glacial acetic acid and 2 ml of DMF restore the mixture is boiled for 1 h, and then cooled and poured into 100 ml of ether. The residue is filtered and washed with benzene.

Yield 69% (2,92 g).

So pl. 255-257aboutC (from ethanol).

Calculated C 59,43; H 4,72; N 13,21; O 15,09; S 7,55

Found, C 59,38; H Of 4.67; N Of 13.27; O 15,11; S 7,49.

M m 424

The infrared spectrum, cm-1: 1631; 1233; 1196; 1035 (vaseline oil).

UV spectrum:max208 nm; 263 nm (5x10-6mol/l in ethanol)

P R I m m e R 2. Obtaining 2,6-dimethyl-5-phenyl-1-1-respiratory-4-oxo-1,4-dihydropyrimidin.

In a mixture of 2 ml of glacial acetic acid and 2 ml of DMF is dissolved 2,19 g (0.01 mol/l) of 11-acetyl-2-phenylacetamide and of 1.33 g (0.01 mol) of 1-aminobenzimidazole. The reaction mixture is boiled for 1 h, then cooled and poured into 100 ml of ether. The residue is filtered and washed with benzene.

The yield was 73% (2,31 g)

So pl. 179-180aboutC (from ethanol).

Calculated With 72,15; N Is 5.06; N 17,72; O Is 5.06.

Found, C 72,07; H 5,12; N 17,69; O 5,01.

M m 316

The infrared spectrum, cm-1: 1629; 1580; 1500; 1050 (vaseline oil)

UV spectrum: 207 nm; 257 nm (1x10-5mol/l in ethanol)

Study of the anti-allergic effects of the substances was carried out on the model reaction of passive cutaneous anaphylaxis (Russian perfumery-cosmetic Association), mediated Julian compounds [9-10]

Serum containing specific gemcitabine antibodies, received the third week after sensitization of mice CBA with ovalbumin (0.5 μg) with aluminum hydroxide (2.5 mg/mouse). Obtained serum dilution of 1:200 was injected intradermally in 6 clipped skin of the back of white rats-males line (160-180 g) in an amount of 50 μl. 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 was decapotable, the skin turned inside out, stained sections were cut and were extracted dye-formamide at 37aboutC for 4 days. The amount of dye in extravasate was determined spectrophotometrically at 600 nm on a calibration curve [12]

The analyte was injected at a dose of 10 mg/kg over 90 min to a resolution of the dose of antigen. As a comparison object used antiallergic drug diasorin [4]

Diasorin was administered at a dose of 10 mg/kg intraperitoneally for 90 min to resolving dose. Control rats were injected intraperitoneally with saline. The percentage of inhibition of the reaction was calculated by the formula

And 100 where As the percentage of inhibition of the Russian perfumery-cosmetic Association;

With mcg x rats.

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

Determination of acute toxicity and calculations LD50carried out according to the method of Cerberus [6] White mice weighing 18-20 g were injected intraperitoneally 0.5 ml of the suspension of the analyte prepared by adding 1-2 drops of Tween-80. At each dose in the experience took 6 mice. It was established that 50 of the investigated substances is more than 1200 mg/kg, therefore, these substances belong to the class of practically non-toxic substances.

The research results show that the proposed compounds have a pronounced anti-allergic action, exceeding the activity of a drug of diesoline.

This indicates the feasibility of further research of these substances with the aim of creating effective drug.

Derivatives of 4-oxo-1,4-dihydropyrimidin General formula

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< / BR>
having antiallergic activity.

 

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