RU2503671C1 - (Z)-2-[(3-CARBAMOYL-4,5,6,7-TETRAHYDROBENZO[b]THIEN-2-YL)AMINO]-4-(4-R-PHENYL)-4-OXOBUT-2-ENOIC ACIDS, HAVING ANALGESIC ACTIVITY - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to biologically active substances which are (Z)-2-[(3-carbamoyl-4,5,6,7-tetrahydrobenzo [b]thien-2-yl)amino]-4-(4-R-phenyl)-4-oxobut-2-enoic acids of general formula (1-3)

. The acids (1-3) are obtained by reacting 4-(4-R-phenyl)-2,4-dioxobutanoic acid with an amide of 2-amino-4,5,6,7-tetrahydro[b]thiophene-3-carboxylic acid in a medium of ethyl alcohol at 60°C, followed by extraction of the end product using existing methods.

EFFECT: obtaining novel compounds with high output, having marked analgesic activity and low toxicity.

1 tbl, 4 ex

Description

The invention relates to the field of organic chemistry, to new biologically active substances of the class 2-amino-4-aryl-4-dioxobutanoic acids, namely to (Z) -2 - [(3-carbamoyl-4,5,6,7-tetrahydrobenzo [b] thien-2-yl) amino] -4- (4-R-phenyl) -4-oxobut-2-enoic acids (1-3) of the general formula

possessing analgesic activity, which suggests their use in medicine as medicines with analgesic properties.

An analogue in structure to the claimed compounds is 4- (4-methylphenyl) -4-oxo-2- [3-ethoxycarbonyl-4,5-dimethylthiophen-2-ylamino] but-2-enoic acid (4), which has 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:

Data on analgesic activity are given:

Compound Latent period of a defensive reflex, in 2 hours in with four 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 2-amino-4-aryl-4-dioxobutanoic acids substances with a pronounced analgesic effect and low toxicity.

The problem is achieved by obtaining (Z) -2 - [(3-carbamoyl-4,5,6,7-tetrahydrobenzo [b] thien-2-yl) amino] -4- (4-R-phenyl) -4-oxobut -2-eno acids, which have analgesic activity.

The claimed compounds (1-3) are synthesized by the interaction of 4- (4-R-phenyl) -2,4-dioxobutanoic acid with the amide of 2-amino-4,5,6,7-tetrahydro [b] thiophene-3-carboxylic acid in ethyl alcohol at 60 ° C followed by isolation of the target product by known methods according to the scheme

Example 1. Obtaining (Z) -2 - [(3-carbamoyl-4,5,6,7-tetrahydrobenzo [b] thien-2-yl) amino] -4-phenyl-4-oxobut-2-enoic acid ( one). To a solution of 1.92 g (0.01 mol) of 4-phenyl-2,4-dioxobutanoic acid in 20 ml of ethyl alcohol is added a solution of 1.96 g (0.01 mol) of 2-amino-4,5,6,7-tetrahydro [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 3.35 g (90.48%). Mp 166-167 ° C. Found,%: C 61.60; H 4.93; N, 7.58; O 17.29; S 8.64 C ₁₉ H ₁₈ N ₂ O ₄ S. Calculated,%: C 61.61; H 4.90; N 7.56; O 17.28; S 8.66. IR spectrum (FSM 1202, liquid paraffin, ν, cm ^-1 ): 3400 (NH ₂ , 3184 (br. NH), 1706 (COO), 1567. ¹ H NMR spectrum (Varian Mercury 300 (300 MHz), DMSO- d ₆ , HMDS, δ, ppm): 1.79 (m, 4H, (CH ₂ ) ₄ ), 2.66 (m, 4H, (CH ₂ ) ₄ ), 6.41 (s, 1H , C = CH), 7.47 (br s, 2H, NH ₂ ), 7.59-8.05 (m, 5H, arom.), 12.33 (s, 1H, NH).

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

Example 2. Obtaining (Z) -2 - [(3-carbamoyl-4,5,6,7-tetrahydrobenzo [b] thien-2-yl) amino] -4- (4-chlorophenyl) -4-oxobut-2 -enoic acid (2). Yield 3.67 g (90.64%). Mp 183-184 ° C. Found,%: C 56.37; H 4.22; N, 6.91; About 15.84; S 7.90; Cl 8.75 C ₁₉ H ₁₇ ClN ₂ O ₄ S. Calculated,%: C 56.37; H 4.23; N, 6.92; O 15.81; S 7.92; Cl 8.76. IR spectrum (FSM 1202, liquid paraffin, ν, cm ^-1 ): 3390 (NH ₂ ), 3186 (br. NH), 1709 (COO), 1577. ¹ H NMR spectrum (Varian Mercury 300 (300 MHz), DMSO -d ₆ , HMDS, δ, ppm): 1.78 (m, 4H, (CH ₂ ) ₄ ), 2.66 (m, 4H, (CH ₂ ) ₄ ), 6.44 (s, 1H, C = CH), 7.46 (br s, 2H, NH ₂ ), 7.57 (d, J 7.5, 2H, arom.), 8.01 (d, J 7.5, 2H, arom.) 12.31 (s, 1H, NH).

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

Example 3. Obtaining (Z) -2 - [(3-carbamoyl-4,5,6,7-tetrahydrobenzo [b] thien-2-yl) amino] -4- (4-methylphenyl) -4-oxobut-2 -enoic acid (3). Yield 3.09 g (80.47%). Mp 150-151 ° C. Found,%: C 62.45; H 5.25; N, 7.31; O 16.65; S 8.36 C ₂₀ H ₂₀ N ₂ O ₄ S. Calculated,%: C 62.48; H 5.24; N, 7.29; O 16.65; S 8.34. IR spectrum (FSM 1202, liquid paraffin, ν, cm ^-1 ): 3343 (NH ₂ ), 3131 (br. NH), 1708 (COO), 1574. ¹ H NMR spectrum (Varian Mercury 300 (300 MHz), DCCl ₃ , HMDS, δ, ppm): 1.57 (m, 4H, (CH ₂ ) ₄ ), 1.91 (m, 2H, (CH ₂ ) ₄ ), 2.45 (s, 3H, Me), 2.79 (m, 2H, (CH ₂ ) ₄ ), 5.89 (br s, 2H, NH ₂ ), 7.09 (s, 1H, C = CH), 7.33 (d J 8.1, 2H, arom.), 7.94 (d, J 8.1, 2H, arom.), 12.65 (s, 1H, NH).

The resulting compound 3 is a bright red crystalline substance, soluble in chloroform, toluene, acetone, insoluble in water and hexane.

Example 4. The biological activity of the compounds (1-3). Acute toxicity (LD ₅₀ , mg / ml) of compound (1-3) was determined by the method of G. N. Pershin [Pershin G. N. Methods of experimental chemotherapy. M., S. 100, 109-117 (1971)]. Compounds (1-3) were administered intraperitoneally to white mice weighing 16-18 g in the form of a suspension in 2% starch mucus and observed the behavior and death of animals for 10 days. For the studied compounds (1-3), the LD ₅₀ is> 1500 mg / kg

According to the classification of toxicity of drugs, compounds (1-3) belong to class V of practically non-toxic drugs [Izmerov N.F., Sanotsky I.V., Sidorov K.K. Toxicometry parameters of industrial poisons in a single exposure: Reference. M., 1977. - P.196].

The analgesic activity of compounds (1-3) was studied on outbred mice (females) weighing 18-22 g using the "hot plate" test [Radell Z.O., Selitto J.J. A method for measurement of analgesic activity on inflamed tissue // Arch. Intermat. Pharmacodun Et ther. 1957. - Vol. 11. - No. 4 - S.409-419].

The test 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 effect was compared with orthophene.

The test results are presented in the table.

Table Analgesic activity and acute toxicity of compounds (1-3) Connections Dose mg / kg LD ₅₀ , mg / kg Latent period of the defensive reflex, s 1,5 hour The control 10.0 Ortofen 10 [ED ₅₀ ] 74 26.2 one fifty > 1500 22.6 2 fifty > 1500 26.0 3 fifty > 1500 24.4

As can be seen from the table, the claimed compounds (1-3) exhibit pronounced analgesic activity and are less toxic than the reference drug, orthophene. Therefore, the claimed compounds (1-3) can find application in medical practice as an analgesic drug.

Claims (1)

(Z) -2 - [(3-carbamoyl-4,5,6,7-tetrahydrobenzo [b] thien-2-yl) amino] -4- (4-R-phenyl) -4-oxobut-2-ene acids (1-3) of the general formula:

possessing analgesic activity.