RU2389724C1 - 4-(4-methylphenyl)-4-oxo-2-[3-(ethoxycarbonyl-4,5-r2,r1-thiophen-2-ylamino]but-2-enoic acid, having anti-inflammatory and analgesic activity - Google Patents

Abstract

FIELD: chemistry. ^ SUBSTANCE: invention relates to new biologically active substances and specifically to 4-(methylphenyl)-4-oxo-2-[3-ethoxycarbonyl-4,5-R2,R1-thiophen-2-ylamino]but-2-enoic acid of general formula: R1,R2=CH3 R1+R2=(CH2)3. ^ EFFECT: obtaining new compounds having anti-inflammatory and analgesic activity, as well as low toxicity, which can be used as medicinal agents. ^ 1 cl, 1 tbl, 4 ex

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-methylphenyl) -4-oxo-2- [3-ethoxycarbonyl-4,5- R ² , R ¹ -thiophen-2-ylamino] but-2-ene acids of the general formula

possessing anti-inflammatory and analgesic activity, which suggests their use in medicine as medicines, with anti-inflammatory and analgesic properties.

The structural analogue of the claimed compounds is 2- (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-ylamino) -4- (4-methoxyphenyl) -4-oxobut- 2-enic acid (3) [Rubtsov A.E., Makhmudov PP, Kovylyaeva N.V., Prosyanik N.I., Bobrov A.V., Zalesov V.V. Synthesis, anti-inflammatory and analgesic activity of 4-aminoantipyrine derivatives. Chem farm. Zh., 2002, t. 36, No. 11, pp. 31-351] of the formula

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-methylphenyl) -4-oxo-2 - {[3- (ethoxycarbonyl) -4,5-dimethyl-2-thienyl] amino} -2-butene and (4- (4-methylphenyl ) -4-oxo-2 - {[3- (ethoxycarbonyl) -5,6-dihydro-4H-dihydrocyclopenta [b] thiophen-2-yl] amino} -2-butenoic acids, which have anti-inflammatory and analgesic activity. Compounds 1,2 are synthesized by reacting 4- (4-methylphenyl) -2,4-dioxobutanoic acid with 4,5-disubstituted ethyl 2-amino-thiophene-3-carboxylic acid in ethyl alcohol at 60 ° C, followed by isolation of the target product KTA by known methods according to the scheme

Example 1. Preparation of compound 1. To a solution of 2.06 g (0.01 mol) of 4- (4-methylphenyl) -2,4-dioxobutanoic acid in 20 ml of ethyl alcohol, a solution of 1.85 g (0.01 mol) of 2-amino-4 ethyl ester is added. 5-dimethyl [b] thiophene-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 2.91 g (78%). Mp 167-168 ° C. Found,%: C 61.13; H 5.11; N, 3.74; O 21.43; S 8.57. C ₁₉ H ₁₉ NO ₅ S. Calculated,%: C 61.11; H 5.13; N, 3.75; O 21.42; S 8.59. IR spectrum (FSM 1201, liquid paraffin, ν, cm ^-1 ): 2953.94 (NH), 1675 (COO). ¹ H NMR Spectrum (Varian Mercury300 (300 MHz), DMSO-d ₆ , HMDS, δ, ppm): 12.65 s (1H, NH); 7.88 m (4H, arom); 6.46 s (1H, C = CH); 4.32 q (2H, OCH ₂ CH ₃ ); 2.36 s, 2.2 s, 2.18 s (9H, 3CH ₃ ) 1.32 t (3H, OCH ₂ CH ₃ ).

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

Example 2. Compound 2 was prepared analogously. Yield 2.96 g (77%). Mp 180-181 ° C. Found,%: C 62.30; H 4.99; N, 3.61; O 20.73; S 8.31. Calculated,%: C 62.32; H 4.97; N, 3.63; About 20.75; S 8.32. IR spectrum (FSM 1201, liquid paraffin, ν, cm ^-1 ): 3405 (NH), 1678 (СО). ¹ H NMR spectrum (Varian Mercury300 (300 MHz), DMSo-d ₆ , HMDS, δ, ppm): 12.72 s (1H, NH), 7.89-7.3 2d (4H, C ₆ H ₄ ), 6.5 s (1H, CH), 4.24-4.31 q (2H, OCH ₂ CH ₃ ), 2.86-2.79 m (2H, CH ₂ ), 1.3 t (3H, OCH ₂ CH ₃ ).

The resulting compound 2 is a dark red crystalline substance, soluble in chloroform, toluene, acetone, insoluble in water and hexane.

Example 3. Anti-inflammatory activity was studied in experiments on 30 white outbred rats of both sexes weighing 220-260 g. Compounds 1,2 were administered intraperitoneally at a dose of 50 mg / kg in suspension in 2% starch solution an hour before modeling acute carrageenin inflammation. Carrageenin edema was caused by subplant implantation of 0.1 ml of a 1% phlogogen solution in the hind paw of a rat. Anti-inflammatory activity was judged by the change in the severity of inflammation in dynamics, which was recorded oncometrically 2 and 4 hours after modeling 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)] . Equivolume amount of 2% starch solution was administered to control animals. Orthophene at a dose of 10 mg / kg served as a comparison drug.

Example 4. The analgesic activity of compounds 1,2 was studied on 12 white mice males weighing 20-25 g by the method of thermal irritation [NB, Eddy, D. Leimbach, Pharmacology and Toxicology, 1960, No. 4, p. 311-315] . The studied compounds 1,2 were administered at a dose of 50 mg / kg intraperitoneally in the form of a suspension in a 2% starch solution 1 hour before placing the animals on a hot plate. An indicator of pain sensitivity was the length of time the mice stay on the plate until the onset of the defensive reflex - licking the paws. Equivolume amount of 2% starch solution was administered to control animals. Orthophene at a dose of 10 mg / kg served as a comparison drug.

Acute toxicity (LD ₅₀ ) of the claimed compounds 1.2 was determined on 24 white mongrel mice of both sexes weighing 18-22 g with an intraperitoneal route of administration in the form of a suspension in a 2% starch solution according to the express method of VB Prozorovsky [Prozorovsky VB ., Prozorovskaya M.P., Demchenko V.I. Pharmacology and Toxicology, 1978, No. 4, p. 497-502]. It was found that the LD _{50 of} compounds 1.2 is more than 1000 mg / kg. According to the classification of toxicity of drugs, compounds 1.2 belong to the class of practically non-toxic substances [Izmerov I.F., Sanotsky I.V., Sidorov K.K., Toxicometry parameters of industrial poisons. M .: Medicine, 1977, p.196-197]. They are 14 times less toxic than orthophene.

Table Anti-inflammatory, analgesic activity and acute toxicity of compound 1.2 Compound Dose mg / kg LD ₅₀ mg / kg % inhibition * carrageenin edema Latent period of the defensive reflex, s 4 hours 2.5 hours The control - - 0,0 ± 0,0 10.0 ± 0.5 one fifty > 1000 35.27 23.52 ± 2.12 2 fifty > 1000 39.95 18.58 ± 1.11 3 fifty > 1000 106.2 ± 7.5 15.2 ± 1.25 Ortofen 10 74 61.0 ± 1.51 26.2 ± 0.61 * compared to control

As can be seen from the table, compounds 1,2 exhibit pronounced anti-inflammatory activity. In addition, compounds 1,2 showed significant analgesic activity, comparable to the standard and superior to the activity of the analogue in structure (3). It should be noted that the effective dose of orthophene is 0.14 of its LD ₅₀ , and for the claimed compounds - 0.05 of its LD ₅₀ , which indicates certain advantages of compounds 1.2 over orthophene in terms of their safety and effectiveness.

Claims (1)

4- (4-Methylphenyl) -4-oxo-2- [3-ethoxycarbonyl-4,5-R ² , R ¹ -thiophen-2-ylamino] but-2-enoic acids of the general formula:

possessing anti-inflammatory and analgesic activity.