RU2798427C1 - 2-(2-(4-nitrobenzoyl)hydrasono)-4-oxo-4-(4-methylphenyl)butanoic acid octyl ether with analgesic activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to 2-(2-(4-nitrobenzoyl)hydrazono)-4-oxo-4-(4-methylphenyl)butanoic acid octyl ester of formula 1, which has analgesic activity, as a drug.

EFFECT: obtaining new compound with a high yield, with a pronounced analgesic activity, as well as low toxicity.

1 cl, 1 tbl, 3 ex

Description

The invention relates to the field of organic chemistry and medicinal chemistry, to new biologically active substances of the class of substituted 2-amino-4-oxobutanoic acids, namely to octyl ester 2-(2-(4-nitrobenzoyl)hydrazono)-4-oxo-4- (4-methylphenyl)butanoic acid 1, formula:

,

,

which has analgesic activity, which suggests its use in medicine as a drug with analgesic properties.

The structural analogue of the claimed compound is ethyl ester 2-[(1,4-dioxo-1-((5-bromopyridin-2-yl)amino)-4-phenylbut-2-en-2-yl)amino]-4, 5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid 2 with analgesic activity [US Pat. RU 2501795 C1 Ros. Federation. No. 2012141788/04; dec. 01.10.12; publ. 20.12.13, Bull. No. 35] formulas:

Data on analgesic activity are given:

Ortofen was chosen as the standard of comparison, the formulas are:

,

,

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-oxobutanoic acids with a pronounced analgesic effect and low toxicity.

This task is achieved by obtaining octyl ester of 2-(2-(4-nitrobenzoyl)hydrazono)-4-oxo-4-(4-methylphenyl)butanoic acid, which has analgesic activity.

The claimed compound 1 is synthesized by the interaction of N-(2-oxo-5-(4-methylphenyl)furan-3(2H)-ylidene)-4-nitrobenzohydrazide with octanol in toluene, with the addition of one equivalent of triethylamine, at a temperature of 100°C, followed by isolation of the target product by known methods according to the scheme:

The objective of the invention is to expand the arsenal of analgesics with low toxicity, and exceeding the specified activity drugs used in medical practice.

Example 1 Preparation of Compound 1 Mixture of N-(2-oxo-5-(4-methylphenyl)furan-3(2H)-ylidene)-4-nitrobenzohydrazide 3.51 g (0.01 mol) and 1.30 g (0.01 mol) of octanol was dissolved in 30 ml of absolute toluene, followed by the addition of 1.01 g (0.01 mol) of triethylamine. The resulting solution was heated to 100°C with vigorous stirring and kept at this temperature for one hour. The mixture is cooled to 0°C, the precipitate formed is filtered off and recrystallized. Yield 3.08 g (64%), mp. 251.0-252.5°C. ¹ H NMR spectrum (DMSO-d6), δ, ppm: 0.87 m (3H, CH ₃ ), 1.28 m (10H, 5CH ₂ ), 1.61 m (2H, CH ₂ ), 2.37 s (3H, CH ₃ ), 3.31 d (J=19.5, 1H, CH ₂ ), 3.61 d (J=19.5, 1H, CH ₂ ), 4.26 m (2H, OCH ₂ ), 7.21 m (2H, H _arom ), 7.87 m (2H, H _arom ), 8.14 m (2H, H _arom ), 8.30 m (2H, H _arom ), 13.70 (1H, NH). Found, %: C, 64.87; H, 6.51; N, 8.71. C ₂₆ H ₃ 1N ₃ O ₆ . Calculated, %: С, 64.85; H, 6.49; N, 8.73.

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 analgesic activity of compound 1 was studied on outbred mice (females) weighing 18-22 g using the "hot plate" test [Radell Z.O., Selitto J.J. A method for measuring analgesic activity on inflamed tissue. // Arch. Intermat. Pharmacodun. Etther. 1957. - Vol.11. - No. 4 - S. 409 -419].

The test compound was administered intraperitoneally in the form of 2% starch mucus at a dose of 50 mg/kg 0.5 h before animals were placed on a metal plate heated to 53.5°C. The duration of the animal's stay on the hot plate until the moment of licking the hind legs, measured in seconds, served as an indicator of pain sensitivity. The effect was compared with ortofen. The test results are presented in the table:

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

Claims (3)

2-(2-(4-nitrobenzoyl)hydrazono)-4-oxo-4-(4-methylphenyl)butanoic acid octyl ester 1:

, having analgesic activity.