RU2485112C1 - 4-(4-bromophenyl)-4-oxo-2-{[3-ethoxycarbonyl)-4,5-dimethylthien-2-yl]amino}-2-butenoic acid, having anti-inflammatory and analgesic activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to novel biologically active substances of the class of 4-aryl-2,4-dioxobutanoic acids. Disclosed is 4-(4-bromophenyl)-4-oxo-2-{[3-ethoxycarbonyl)-4,5-dimethylthien-2-yl]amino}-2-butenoic acid, having anti-inflammatory and analgesic activity, of formula (1):

.

EFFECT: obtaining a compound with high output, having marked anti-inflammatory and analgesic activity as well as low toxicity.

1 cl, 1 tbl

Description

The invention relates to the field of organic chemistry, to new biologically active substances of the class of 4-aryl-2,4-dioxobutanoic acids, namely to 4- (4-bromophenyl) -4-oxo-2 - {[3- (ethoxycarbonyl) -4 , 5-dimethylthien-2-yl] amino} -2-butenoic acid (1) of the formula:

It has anti-inflammatory and analgesic activity, which suggests its use in medicine as medicines with anti-inflammatory and analgesic properties.

The structural analogue of the claimed compounds is 4- (4-methylphenyl) -4-oxo-2- [3-ethoxycarbonyl-4,5-dimethylthiophen-2-ylamino] but-2-enoic acid (2) [4- (4- methylphenyl) -4-oxo-2- [3-ethoxycarbonyl-4,5-dimethylthiophen-2-ylamino] but-2-enoic acids having anti-inflammatory and analgesic activity: US Pat. 2389724 ROS. Federation. No. 2008151813/04; declared 12/25/08; publ. 05/20/10, bull. No. 14] formulas:

The data on anti-inflammatory and analgesic activity are given:

Compound % inhibition of carrageenan edema after 4 hours Latent period of a defensive reflex, in 2 hours in with 2 35.3 23.5

The orthophene formula is chosen as the reference standard:

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

The objective of the invention is to search for a series of derivatives of 4-aryl-2,4-dioxobutanoic acids substances with a pronounced anti-inflammatory and analgesic effect and low toxicity.

The problem is achieved by obtaining 4- (4-bromophenyl) -4-oxo-2 - {[3- (ethoxycarbonyl) -4,5-dimethylthien-2-yl] amino} -2-butenoic acid, which has anti-inflammatory and analgesic activity . The claimed compound 1 is synthesized by the interaction of 4- (4-bromophenyl) -2,4-dioxobutanoic acid with ethyl 2-amino-4,5-dimethylthiophene-3-carboxylic acid in ethyl alcohol at 60 ° C followed by isolation of the target product by known methods according to the scheme:

An example of the preparation of compound 1. To a solution of 2.7 g (0.01 mol) of 4- (4-bromophenyl) -2,4-dioxobutanoic acid in 20 ml of ethyl alcohol, a solution of 1.85 g (0.01 mol) of 2-amino-4,5- ethyl ester is added. dimethylthiophene-3-carboxylic acid in 20 ml of the same solvent and incubated at room temperature for 24 hours. The mixture was cooled to 0 ° C, the precipitate formed was filtered off and recrystallized from acetonitrile. Yield 2.00 g (92.17%). Mp 179-180 ° C. Found,%: C 49.35; H 3.69; N 3.22; O 18.23; S 67.29; Br 18.23 C18H16BrNO ₅ S. Calculated,%: C 49.33; H 3.68; N, 3.20; O 18.25; S 67.32; Br 18.23. IR spectrum (FSM 1201, liquid paraffin, ν, cm ^-1 ): 3189.39 (NH), 1676.30 (COO). ¹ H NMR spectrum (Varian Mercury300 (300 MHz), DMSO-d ₆ , HMDS, δ, ppm): 1.33 (t, J 7.2 Hz, 3H, Me), 2.19 (s, 3H, Me), 2.24 (s, 3H, Me), 4.33 (q, J 7.2 Hz, 2H, CH ₂ O), 6.47 (s, 1H, C = CH), 7, 72 (d, J 8.7 Hz, 2H, arom.), 7.43 (d, J 8.7 Hz, 2H, arom.), 12.71 (s, 1H, NH).

The resulting compound 1 is a bright red crystalline substance, soluble in chloroform, toluene, acetone, insoluble in water and hexane.

The study of anti-inflammatory, analgesic activity and acute toxicity was carried out in the research laboratory of BAS Natural Sciences Institute of Perm State National Research University

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 in the form of a suspension in 2% starch mucus. For test compound (1), LD ₅₀ 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., Sapotsky I.V., Sidorov K.K. Toxicometry parameters of industrial poisons. - M .: Medicine, 1977. - p.196].

The anti-inflammatory activity was studied on white Wistar rats weighing 170-200 g. The antiexudative effect of compounds (I) was evaluated on a model of acute inflammatory paw edema caused by subplanetary administration of 0.1 ml of 1% carrageenin solution. An indicator of the action of the studied compounds, administered orally at a dose of 50 mg / kg in a 2% starch mucus solution, was the size of the swelling of the paw, determined oncometrically. The strength of the antiexudative effect was judged by the degree of inhibition of the inflammatory response in% of control [Methodological recommendations for experimental preclinical study of non-steroidal anti-inflammatory pharmacological substances. - M., 1982. - 17 p. Approved by the Pharmacological Committee of the Ministry of Health of the USSR on November 11, 1992, Protocol No. 22]. The effect was compared with orthophene at a dose of 10 mg / kg [Neugodova VP, Tsarichenko GV, Ryndina S.E. Toxicological evaluation of voltaren // Pharmacologist, and toxicologist. - 1986.V.49. - No. 1. P.123].

The analgesic activity of the compound (I was studied on outbred mice weighing 18-22 g using the hot plate test [Radell ZO, Selitto JJ A method for measurement of analgesic activity on inflamed tissue. // Arch. Intermat. Pharmacodun. Et ther. 1957 . - Vol.11. - No. 4 - S.409-419].

The studied compounds were administered intraperitoneally in the form of 2% starch mucus at a dose of 50 mg / kg 0.5 h before the animals were placed on a metal plate heated to 53.5 ° C. An indicator of pain sensitivity was the duration of the animal’s stay on the hot plate until the hind legs were licked, measured in seconds.

The test results are presented in the table.

Anti-inflammatory, analgesic activity and acute toxicity of compound 1 Compound Dose mg / kg LD ₅₀ mg / kg % inhibition * carrageenin edema Latent period of the defensive reflex, s 4 hours 1,5 hour The control - - 0,0 10.0 one fifty > 1000 44.0 29.5 Ortofen 10 74 61.0 26.2 * compared to control

As can be seen from the table, the claimed compound (1) exhibits pronounced anti-inflammatory and analgesic activity and is less toxic than the reference drug, orthophene. Therefore, the claimed compound (I) may find application in medical practice as an anti-inflammatory and analgesic drug.

Claims (1)

4- (4-Bromophenyl) -4-oxo-2 - {[3- (ethoxycarbonyl) -4,5-dimethylthien-2-yl] amino} -2-butenoic acid

possessing anti-inflammatory and analgesic activity.