RU2798426C1 - N-(5-bromopyridin-2-yl)-4-oxo-4-(p-tolyl)-2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl) )amino)but-2-enamide as an anti-inflammatory drug - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely the use of N-(5-bromopyridin-2-yl)-4-oxo-4-(p-tolyl)-2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)but-2-enamide of formula 1 as a drug having anti-inflammatory activity.

EFFECT: N-(5-bromopyridin-2-yl)-4-oxo-4-(p-tolyl)-2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl) amino)but-2-enamide, which has anti-inflammatory activity and low toxicity.

1 cl, 2 tbl, 3 ex

Description

The invention relates to the field of organic chemistry, to new biologically active substances of the class of substituted 2-amino-4-aryl-4-oxobutanoic acids, namely to N-(5-bromopyridin-2-yl)-4-oxo-4-(p -tolyl)-2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)amino)but-2-enamide 1 formula:

which has anti-inflammatory activity, which suggests its use in medicine as a drug with anti-inflammatory properties and low toxicity.

The structural analogue of the claimed compound is 4-(4-bromophenyl)-2-[(4,5-dimethyl-3-(ethoxycarbonyl)thiophen-2-yl)amino]-4-oxobut-2-enoic acid 2 [Shipilovskikh Sergey Aleksandrovich, synthesis and chemical transformations of substituted 3-(thiophen-2-yl)imino-3H-furan-2-ones, PhD thesis, http://www.chem.msu.ru/rus/theses/2016/2016-04 -02-shipilovskikh/] formulas:

Ortofen of the formula was chosen as the standard of comparison:

which is widely used in medical practice and is an amine derivative of aliphatic acid and analogue in action [Mashkovsky M.D. Medicines. - 15th ed., revised, corrected. and additional - M .: LLC "New Wave", 2005. - p. 170].

The objective of the invention is to search for substances in the series of substituted derivatives of 2-amino-4-aryl-4-oxobutanoic acids with a pronounced anti-inflammatory effect and low toxicity.

The task is achieved by obtaining Na(5-bromopyridin-2-yl)-4-oxo-4-(p-tolyl)-2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-2 -yl)amino)but-2-enamide, which has anti-inflammatory activity.

The claimed compound 1 is synthesized by the interaction of the nitrile 2-[(2-oxo-5-(4-methylphenyl)furan-3(2H)-ylidene)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid with 5-bromopyridine-2-amine in toluene at the boiling point of toluene, followed by isolation of the target product by known methods according to the scheme:

Example 1 Preparation of compound 1: to a solution of 3.48 g (0.01 mol) of nitrile 2-[(2-oxo-5-(4-methylphenyl)furan-3(2H)-ylidene)amino]-4.5 ,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid in 30 ml of absolute toluene is added, 1.73 g (0.01 mol) of 5-bromopyridine-2-amine and kept at the boiling point of toluene for 1 hour. The mixture is cooled to 0°C, the precipitate formed is filtered off and recrystallized. Yield 2.76 g (53%), mp. 170-173°C (from toluene). ^1H NMR spectrum (CDCl ₃ , δ, ppm): 1.88 m (4H, CH ₂ ), 2.50 s (3H, CH ₃ ), 2.69 m (4H, CH ₂ ), 7.30 s (1H, C= CH), 7.35 m (3H, H _arom ), 7.95 m (2H, H _arom ), 8.19 m (1H, H _arom ), 8.44 m (1H, H _arom ), 9.50 s (1H, NH), 10.00 s ( 1H, NH). Found, %: С 57.58; H 4.07; N 10.75; S 6.15. C ₂₅ H ₂₁ BrN ₄ O ₂ S. Calculated, %: C 57.59; H 4.06; N 10.75; S 6.15.

The resulting compound 1 is a yellow crystalline substance, soluble in DMSO, toluene, acetone, insoluble in water and hexane.

Example 2. Acute toxicity (LD ₅₀ , mg/ml) of compound 1 was determined by the method of G. N. Pershin [Pershin G. N. Methods of experimental chemotherapy // M., S. 100, 109-117 (1971)]. Compound 1 was administered intraperitoneally to white mice weighing 16-18 g as a suspension in 2% starch mucus, and the behavior and death of the animals were observed for 10 days. For test compound 1, the LD ₅₀ is > 1500 mg/kg.

According to the toxicity classification of drugs, compound 1 belongs to the V class of practically non-toxic drugs [Izmerov N.F., Sanotsky I.V., Sidorov K.K. Parameters of toxicometry of industrial poisons at a single exposure: a Handbook. M., 1977. - p. 196].

Example 3. The anti-inflammatory activity of compound 1 was studied in experiments on 30 outbred rats of both sexes weighing 220-260 g. Compound 1 was administered intraperitoneally at a dose of 50 mg/kg as a suspension in 2% starch solution one hour before modeling acute carrageenan inflammation. Carrageenan edema was induced by a subplantar injection of 0.1 ml of a 1% phlogogen solution into the hind paw of a rat. The anti-inflammatory activity was judged by the change in the severity of inflammation over time, which was recorded oncometrically 2 and 4 hours after the modeling of inflammation [Methodological recommendations for the experimental study of non-steroidal anti-inflammatory substances, pharmacological committee of the Ministry of Health of the USSR, protocol No. 22 of November 11, 1982. Moscow. 1982]. Control animals were injected with an equivalent volume of 2% starch solution. The reference drug was ortofen at a dose of 10 mg/kg. The test results are presented in the table:

As can be seen from the table, the claimed compound 1 exhibits a pronounced anti-inflammatory activity and is more than 20 times less toxic than the reference drug ortofen. Therefore, the claimed compound 1 can be used in medical practice as an anti-inflammatory drug.

Claims (3)

Application of N-(5-bromopyridin-2-yl)-4-oxo-4-(p-tolyl)-2-((3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl )amino)but-2-enamide

, having anti-inflammatory activity, as a drug.