RU2831129C1 - 4-oxo-2-{[4-phenyl-3-(ethoxycarbonyl)thiophen-2-yl]amino)}-4-(4-fluorophenyl)but-2-enoic acid, having anti-inflammatory activity - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to organic chemistry, specifically to 4-oxo-2-{[4-phenyl-3-(ethoxycarbonyl)thiophen-2-yl]amino)}-4-(4-fluorophenyl)but-2-enoic acid (1).

EFFECT: obtaining a compound of formula 1, having pronounced anti-inflammatory activity and low toxicity.

1 cl, 1 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-dioxobutanoic acids, namely to 4-oxo-2-{[4-phenyl-3-(ethoxycarbonyl)thiophen-2-yl]amino)}-4-(4-fluorophenyl)but-2-enoic acid of the formula:

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

A 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 dissertation, http://www.chem.msu.ru/rus/theses/2016/2016-04-02-shipilovskikh/] of the formula:

The comparison standard chosen was orthofen with the formula:

which is widely used in medical practice and is an amino derivative of an aliphatic acid and an analogue in action [Mashkovsky M.D. Medicines. - 15th ed., revised, corrected and supplemented. - M .: OOO Novaya Volna, 2005. - p. 170].

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

The set task is achieved by obtaining 4-oxo-2-{[4-phenyl-3-(ethoxycarbonyl)thiophen-2-yl]amino)}-4-(4-fluorophenyl)but-2-enoic acid, which has anti-inflammatory activity.

The claimed compound 1 is synthesized by the interaction of 2-hydroxy-4-oxo-4-(4-fluorophenyl)but-2-enoic acid with ethyl ester of 2-amino-4-phenylthiophene-3-carboxylic acid in methanol upon heating to 60°C, followed by isolation of the target product by known methods according to the scheme:

Example 1. Preparation of compound 1: 2.10 g (0.01 mol) of 2-hydroxy-4-oxo-4-(4-fluorophenyl)but-2-enoic acid are added to a solution of 2.47 g (0.01 mol) of ethyl 2-amino-4-phenylthiophene-3-carboxylate in 20 ml of methanol and the mixture is kept at 60°C for 30 minutes. The resulting precipitate is filtered off and washed with cold methanol. Yield 4.26 g (97%), red crystals, mp 174.5-177.0°C (methanol). ¹ H NMR spectrum (DMSO-d ₆ ), δ, ppm: 1.03 (t, 3H, J=7.1 Hz, CH ₃ ), 4.14 (q, 2H, J=7.1 Hz, OCH ₂ ), 6.62 (s, 1H, NC=CH), 7.08 (s, 1H, SC=CH), 7.32 (m, 2H, _Harom ), 7.37 (m, 5H, _Harom ), 8.12 (m, 2H, _Harom ), 12.69 (s, 1H, NH). ^13C NMR spectrum (DMSO- _d6 ), δ, ppm: 14.0, 60.8, 98.9, 115.9, 116.2, 116.4, 117.1, 127.7, 128.2, 128.9, 131.0, 131.1, 135.0, 138.0, 141.1, 148.9, 150.4, 163.5, 164.1, 165.0, 166.6, 189.3. Found, %: C, 62.89; H, 4.16; N, 3.17; S, 7.31. C ₂₃ H ₁₈ FNO ₅ S. Calculated, %: C, 62.86; H, 4.13; N, 3.19; S, 7.30.

The obtained compound 1 is a red crystalline substance, soluble in chloroform, DMSO, toluene, acetone, when heated in alcohols, 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 // Moscow, pp. 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 mortality of the animals were observed for 10 days. For the studied compound 1, LD50 is >1500 mg/kg.

According to the classification of drug toxicity, compound 1 belongs to class V of practically non-toxic drugs [Izmerov N.F., Sanotsky I.V., Sidorov K.K. Toxicometry parameters of industrial poisons with a single exposure: Handbook. Moscow, 1977. - P. 196].

Example 3. The anti-inflammatory activity of compound 1 was studied in experiments on 30 white mongrel rats of both sexes weighing 220-260 g. Compound 1 was administered intraperitoneally at a dose of 50 mg/kg as a suspension in a 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 the rat. The anti-inflammatory activity was judged by changes in the severity of inflammation over time, which were recorded oncometrically 2 and 4 hours after modeling the inflammation [Methodological recommendations for the experimental study of non-steroidal anti-inflammatory substances, Pharmacological Committee of the USSR Ministry of Health, Protocol No. 22 of November 11, 1982. Moscow. 1982]. Control animals were administered an equivolume amount of a 2% starch solution. The comparison drug was orthofen at a dose of 10 mg/kg. The test results are presented in the table:

Table

Anti-inflammatory activity and acute toxicity of compounds 1, 2

Connections Dose,
mg/kg LD ₅₀
mg/kg Latent period of the defensive reflex 2 hours 1 50 >1500 38.60 Ortofen 10 [ED ₅₀ ] 74 61,00

As can be seen from the table, the claimed compound 1 exhibits pronounced anti-inflammatory activity and is twenty times less toxic than the comparison drug - orthofen. Consequently, the claimed compound 1 can find application in medical practice as an anti-inflammatory drug with low toxicity.

Claims (3)

4-oxo-2-{[4-phenyl-3-(ethoxycarbonyl)thiophen-2-yl]amino)}-4-(4-fluorophenyl)but-2-enoic acid , possessing anti-inflammatory activity.