RU2653511C2 - 4-methyl-n-2,4-dimethylphenyl-6-(3-fluorophenyl)-2-thyoxo-1,2,3,6-tetragydropyrimidine-5-carboxamide that has analgetic action - Google Patents

Abstract

FIELD: biochemistry.

SUBSTANCE: invention relates to a novel pyrimidine-4-methyl-N-2,4-dimethylphenyl-6-(3-fluorophenyl)-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide derivative of formula (1)

. Compound has an analgesic effect, which suggests its use in medicine as an analgesic. Compound 1 is prepared by reacting a three-component condensation of 2,4-dimethylacetoacetanilide, 3-fluorobenzaldehyde and thiourea while maintaining the reagents at a temperature of 120–150 °C until the gas evolution ceases and the reaction mixture solidifies, after cooling, the residue is treated with ethanol. Claimed compound is a colorless crystalline substance with T_pl. 236–238 °C, soluble in dimethylformamide, acetic acid, when heated – in ethanol, stable during storage. LD₅₀ of the compound when administered intraperitoneally to non-linear mice is > 5100 mg/kg.

EFFECT: activity of compound 1 surpasses the activity of metamizole sodium.

1 cl, 1 tbl

Description

The invention relates to the field of organic chemistry, derivatives of pyrimidine, namely the new biologically active 4-methyl-N-2,4-dimethylphenyl-6- (3-fluorophenyl) -2-thioxo-1,2,3,6-tetrahydropyrimidine-5 -carboxamide (1) of the formula:

possessing an analgesic effect, which suggests its use in medical practice as an analgesic.

The closest structural analogs to the claimed compound are compounds of the general formula 2 exhibiting antimicrobial activity [Synthesis of Some New Dihydropyrimidines by Iodine as a Catalyst at Ambient Temperature and Evaluation of Their Biological Activity / P.D. Zalavadiya, R.M. Ghetiya, B.L. Dodiya [et al.] // J. Heterocyclic Chem. - 2013 .-- Vol. 50. - P. 973-978].

The aim of the invention is to search among derivatives of pyrimidine compounds with analgesic activity.

This goal is achieved by obtaining 4-methyl-N-2,4-dimethylphenyl-6- (3-fluorophenyl) -2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide (1), which is synthesized by a three-component reaction 2 , 4-dimethylacetoacetanilide, 3-fluorobenzaldehyde, thiourea [Synthesis of N, 6-diaryl-4-methyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides / V.L. Gein, T.M. Zamaraeva, A.A. Zorina [et al.] // Journal. organic chemistry. - 2009. - Vol. 45, no. 10. - S. 1591-1592]

The method of obtaining 4-methyl-N-2,4-dimethylphenyl-6- (3-fluorophenyl) -2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide

A mixture of 2.05 g (0.01 mol) of 2,4-dimethylacetoacetanilide, 1 ml (0.01 mol) of 3-fluorobenzaldehyde and 0.76 (0.01 mol) of thiourea was kept at a temperature of 120-150 ° С until gas evolution ceased and the reaction mixture solidified, after cooling, the residue was treated with ethanol were filtered off and recrystallized from ethanol. Yield 1 is 3.28 g (89%).

The inventive compound is a colorless crystalline substance soluble in DMF, acetic acid, when heated in ethanol, stable during storage. T _pl. 236-238 ° C. Calculated,% C 65.02; H 5.46; N, 11.37. C ₂₀ H ₂₀ FN ₃ OS. Found,% C 65.14, 64.91; H 5.54, 5.37; N 11.50, 11.26.

The ¹ H NMR spectrum of compound 1 was recorded at an operating frequency of 300 MHz, and the internal standard was TMS. ¹ H NMR spectrum, δ, ppm J, Hz: 1.89 s (3H, 4-CH ₃ ), 2.13 and 2.21 2 s (6H, ( CH ₃ ) ₂ C ₆ H ₃ ), 5.41 d (1H, 6-CH, J = 2.1 Hz), 6.91 -7.47 m (7H, FC ₆ H ₄ , (CH ₃ ) ₂ C ₆ H ₃ ), 9.17 s (1H, NH), 9.44 d (1H, 1-NH, J = 2.1 Hz), 10.02 2c (1H, 3-NH, 2-SH).

In the IR spectrum of compound 1, bands are observed due to stretching vibrations of the amide group (1678 cm ^-1 ), NH bonds (3158 cm ^-1 ), and also the C = C band in the region of 1608 cm ^-1 .

The IR spectrum of the compound was recorded on a Specord M-80 spectrophotometer in liquid paraffin, ¹ H NMR spectra were recorded on a Bruker 300 spectrometer (operating frequency 300 MHz) in DMSO-d ₆ , and the internal standard was TMS. Elemental analysis was performed on a Perkin Elmer 2400 instrument. Melting point was determined on an M-565 instrument.

Compound 1 was tested for analgesic activity. Analgesic activity was studied by the method of "vinegar cramps." Non-linear mice weighing 20.0-30.0 g were used for the experiment. The test compound was administered at a dose of 50 mg / kg intraperitoneally as a suspension in 2% starch mucus. After 30 minutes, 0.75% acetic acid was administered to the same mice at the rate of 0.1 ml per 10 g of animal weight. An indicator of pain sensitivity was the number of cramps in the animal, calculated within 15 minutes from the moment of the introduction of acetic acid. The results are statistically processed with the calculation of the Fisher-Student test. The effect was considered significant at P <0.05.

Metamizole sodium was used as a reference standard.

Acute toxicity was determined by intraperitoneal administration to nonlinear mice weighing 20-25 g. The results were processed according to Prozorovsky with the calculation of the average lethal dose (DD ₅₀ ) [Prozorovsky VV, Prozorovskaya MP, Demchenko VM // Pharmacology and toxicology. - 1978. - T. 41. - No. 4. - S. 497-502]. Acute toxicity (LD ₅₀ ) of the claimed compound was> 5100 mg / kg The results of the study are shown in table 1.

P - in comparison with the control.

Thus, the claimed compound 1 - 4-methyl-N-2,4-dimethylphenyl-6- (3-fluorophenyl) -2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide exhibits an analgesic effect that exceeds the activity metamizole sodium and less toxic 2 times.

Information sources

1. Synthesis of Some New Dihydropyrimidines by Iodine as a Catalyst at Ambient Temperature and Evaluation of Their Biological Activity / P.D. Zalavadiya, R.M. Ghetiya, B.L. Dodiya [et al.] // J. Heterocyclic Chem. - 2013 .-- Vol. 50. - P. 973-978.

2. Synthesis of N, 6-diaryl-4-methyl-2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamides / V.L. Gein, T.M. Zamaraeva, A.A. Zorina [et al.] // Journal. organic chemistry. - 2009. - T. 45, no. 10. - S. 1591-1592.

3. Prozorovsky V.V., Prozorovskaya M.P., Demchenko V.M. // Pharmacology and toxicology. - 1978. - T. 41. - No. 4. - S. 497-502.

Claims (2)

4-Methyl-N-2,4-dimethylphenyl-6- (3-fluorophenyl) -2-thioxo-1,2,3,6-tetrahydropyrimidine-5-carboxamide

showing an analgesic effect.