RU2836430C1 - 4-oxo-2-[2-(4-nitrobenzoyl)hydrazinylidene]-4-(4-ethylphenyl)-n-phenethylbutanamide, having anti-inflammatory activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, specifically to 4-oxo-2-[2-(4-nitrobenzoyl)hydrazinylidene]-4-(4-ethylphenyl)-N-phenethylbutanamide, having anti-inflammatory activity.

EFFECT: obtained is a compound with pronounced anti-inflammatory activity, as well as 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-aryl-4-oxobutanoic acids, namely 4-oxo-2-[(2-(4-nitrobenzoyl)hydrazinylidene]-4-(4-ethylphenyl)-N-phenethylbutanamide, of the formula:

,

which has anti-inflammatory activity, which allows us to propose 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 (Compound 2) [Sergey Aleksandrovich Shipilovskikh, 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/], a compound having the formula:

Connections Dose, mg/kg LD ₅₀ mg/kg Inhibition of edema after 2 hours, in % of control 2 50 >1500 44

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-[(2-(4-nitrobenzoyl)hydrazinylidene]-4-(4-ethylphenyl)-N-phenethylbutanamide, which has anti-inflammatory activity.

The claimed compound 1 is synthesized by the interaction of N'-(5-(4-ethylphenyl)-2-oxofuran-3(2H)-ylidene)-4-nitrobenzohydrazide with phenylethylamine under mild conditions with stirring on a magnetic stirrer in toluene for 2 hours to form compound 1, followed by isolation of the target product by known methods according to the scheme:

Example 1. Obtaining compound 1:

To a suspension of 3.65 g (0.01 mol) of N'-(5-(4-ethylphenyl)-2-oxofuran-3(2H)-ylidene)-4-nitrobenzohydrazide in 40 ml of toluene was added 1.21 g (0.01 mol) of phenylethylamine. The resulting mixture was stirred on a magnetic stirrer at room temperature for 2 hours. The solvent was distilled off on a rotary evaporator, and the dry residue was recrystallized from ethanol.

Yield 3.94 g (81%), white crystals, mp 218-219°C (ethanol). IR spectrum, ν, cm ^–1 : 3372 (NH), 3178 (NH), 1663 (C=O), 1604 (C=O, C=N). ^1H NMR spectrum (DMSO _-d6 ) , δ, ppm: 1.22 ( t , 3H, _{CH2CH3 ,} J 7.6 Hz), _2.79 (t, 2H, CH2 _, J 7.3.0 Hz), 3.41 (m, 2H, _CH2 ), 4.57 (s, 2H, _CH2 ), 7.20-8.02 (m, 13H, H _arom ), 8.15 (br. s., 1H, NH), 11.52 (br. s., 1H, NH); Found, %: C 66.68; H 5.41; N 11.49. _{C27H26N4O5 . ​ ​} Calculated, %: C 66.66; H 5.39; N 11.52.

The obtained compound 1 is a white crystalline substance, soluble in DMSO, water, when heated in acetone, alcohols, acetonitrile, insoluble in water and hexane.

Example 2. Acute toxicity (LD₅₀, mg/ml) of compound 1 was determined by the method of G. N. Pershin [Pershin G. N. Methods of experimental chemotherapy // M., pp. 100, 109-117 (1971)]. Compound 1 was administered intraperitoneally to white mice weighing 16-18 g in the form of a 2% suspension starch mucus and observed the behavior and death of animals for 10 days. For the studied compound 1 LD₅₀is > 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 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 increase in swelling of the inflamed foot was calculated in comparison with the initial volume and the inhibition of swelling in comparison with the control - 2% starch mucus. 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 compound 1,2.

Connections Dose, mg/kg LD ₅₀ mg/kg Inhibition of edema after 2 hours, in % of control 1 50 >1500 68 2 50 >1500 44 Control (2% starch mucilage) 0 Ortofen 10[ED ₅₀ ] 74 61

As can be seen from the table, the claimed compound 1 exhibits pronounced anti-inflammatory activity and is more than 20 times less toxic than the comparison drug - orthofen. Consequently, the claimed compound 1 can find application in medical practice as an anti-inflammatory drug.

Claims (3)

4-Oxo-2-[2-(4-nitrobenzoyl)hydrazinylidene]-4-(4-ethylphenyl)-N-phenethylbutanamide possessing anti-inflammatory activity.