RU2776070C1 - APPLICATION OF AN ANALGESIC AGENT BASED ON POTASSIUM 1,6-DIOXO-6-(4-CHLOROPHENYL)-2-CYANO-1-ETHOXY-4-[((3-ETHOXYCARBONYL)-4,5,6,7-TETRAHYDROBENZO[b]THIOPHENE-2-YL)AMINO]HEXA-2,4-DIENE-3-OLATE - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: invention relates to an application of potassium 1,6-dioxo-6-(4-chlorophenyl)-2-cyano-1-ethoxy-4-[((3-ethoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thi-ophene-2-yl)amino]hexa-2,4-diene-3-olate 1 as an analgesic medicinal product.

EFFECT: provided pronounced analgesic activity and low toxicity.

1 cl, 1 tbl, 1 ex

Description

The invention relates to the field of organic chemistry, to new biologically active substances of the class 1,6-dioxo-6-aryl-2-cyano-4-aminohexa-2,4-diene-3-olate potassium, namely 1,6-dioxo -6-(4-chlorophenyl)-2-cyano-1-ethoxy-4-[((3-ethoxycarbonyl)-4,5 ₎ 6,7-tetrahydrobenzo[b]thiophen-2-yl)amino]hexa-2 ,4-potassium diene-3-olate 1 formula:

Which has analgesic activity, which suggests its use in medicine as medicines 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 2 501 795 С1 Ros. Federation. No. 2012141788/04; dec. 01.10.12; publ. 20.12.13, Bull. No. 35] formulas:

Data on analgesic activity are given:

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 in a series of derivatives of 1,6-dioxo-6-aryl-2-cyano-4-aminohexa-2,4-dien-3-olate potassium substances with a pronounced analgesic effect and low toxicity.

The task is achieved by obtaining 1,6-dioxo-6-(4-chlorophenyl)-2-cyano-1-ethoxy-4-[((3-thoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophene- Potassium 2-yl)amino]hexa-2,4-dien-3-olate, which has analgesic activity, as analgesics.

The claimed compound 1 is synthesized by the interaction of ethyl ester 2-[(2-oxo-5-(4-chlorophenyl)-3(2H)-furanylidene)amino]-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxylic acid with ethyl ester of cyanoacetic acid and potassium tert-butylate in absolute dioxane at 50°C, followed by isolation of the target product by known methods according to the scheme:

Preparation example of compound 1: to a solution of 0.415 g (0.001 mol) of 2-[(2-oxo-5-(4-chlorophenyl)-3(2H)-furanylidene)amino]-4,5,6,7-tetrahydro ethyl ester -1-benzothiophene-3-carboxylic acid in (15 ml) of anhydrous dioxane was added 0.113 g (0.001 mol) of ethyl ester of cyanoacetic acid, 0.112 g (0.001 mol) of t-BuOK was added to the resulting mixture, the resulting solution was heated to 50 ° C and kept for 60 min, the precipitate that formed was filtered off and recrystallized from dioxane. Yield 0.41 g (73%), m.p. 210-212°C (dioxane). IR spectrum, v, cm ^-1 : 1695 br. (COOEt), 2199 (CN), 3364 (NH). 1H NMR spectrum (DMSO-d ₆ ), δ, ppm: A form (74%): 1.04 t (3H, CH ₃ CH ² O, J _{n =} 6.8 Hz), 1.37 m (3H, CH ₃ ), 1.72 m (4H, 2CH ₂ ), 2.55 m (2H, CH ₂ ), 2.66 m (2H, CH ₂ ), 3.86 kv (2H, CH ₃ CH ₂ O, J _n = 6.8 Hz), 4.39 m ( 2Н, CH2O), 5.77 s (1Н, С= CH ), 7.51 m (2Н, _Нarom ), 7.89 m ( _2Н , _Нarom ), 13.67 s (1H, NH); B form (26%): 0.91 t (3H, CH ₃ CH ₂ O, J _n = 7.0 Hz), 1.37 m (3H, CH ₃ ), 1.72 m (4H, 2CH ₂ ), 2.55 m (2H, CH ₂ ), 2.66 m (2H, CH ₂ ), 3.96 m (2H CH ₂ O), 4.39 m (2H, CH ₂ O), 5.89 s (1H, C= CH ), 7.51 m (2H, H _arom ), 7.89 m (2Н, _Нarom ), 13.42 s (1Н, NH). Found, %: С 55.03; H 4.26; No. 4.99; S 5.66. C ₂₆ H ₂₄ ClKN ₂ O ₆ S. Calculated, %: C 55.07; H 4.27; N 4.94; S 5.65.

The resulting compound 1 is a yellow crystalline substance, soluble in water and DMSO, sparingly soluble in acetonitrile and insoluble in alkanes. Compound 1 was obtained according to the previously described method [S.A. Shipilovskikh, A.E. Rubtsov // Journal of General Chemistry. - 2020. - T 90. - No. 5. - S. 708-714.].

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 animals were observed for 10 days. Day of the test compound 1 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].

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 less toxic than the reference drug - ortofen. Therefore, the claimed compound 1 can be used in medical practice as analgesic drugs.

Claims (2)

Application of 1,6-dioxo-6-(4-chlorophenyl)-2-cyano-1-ethoxy-4-[((3-ethoxycarbonyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl )amino]hexa-2,4-potassium diene-3-olate 1 as an analgesic drug: