RU2348613C2 - 2-(1,2-diphenyl-2-oxoethylidenehydrazino)-4-(4-methoxyphenyl)-4-oxobut-2-ene acid with anti-inflammatory and analgesic effect - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention concerns new bioactive compound of 4-aryl-2,4dioxybutane acid class, - 2-(1,2-diphenyl-2-oxoethylidenehydrazino)-4-(4-methoxyphenyl)-4-oxobut-2-ene acid of the formula (I)

.

EFFECT: anti-inflammatory and analgesic effect, low toxicity.

1 ex, 1 tbl

Description

The invention relates to the field of organic chemistry, to new biologically active substances of the class 4-aryl-2,4-dioxobutanoic acids, namely 2- (1,2-diphenyl-2-oxoethylidenehydrazino) -4- (4-methoxyphenyl) -4 -oxobut-2-enoic acid (1) of the formula

possessing anti-inflammatory and analgesic activity, which suggests its use in medicine as a medicinal anti-inflammatory and analgesic.

An analogue in structure to the claimed compound is 2-diphenylhydrazino-4- (4-methoxyphenyl) -4-oxobut-2-enoic acid (2) [Rubtsov A.E., Zalesov V.V. Synthesis and intramolecular cyclization of N-substituted 2-amino-4-aryl-4-oxobut-2-enoic acids. ZhORKh, 2003, vol. 39, issue 6, pp. 918-923] formulas

There are no data on the anti-inflammatory and analgesic activity of the structural analogue in the literature.

The sodium salt of 2 - [(2,6-dichlorophenyl) amino] phenylacetic acid (orthophene) (3) of the formula was chosen as the reference standard

which is widely used in medical practice and is 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 2- (1,2-diphenyl-2-oxoethylene ethylene hydrazino) -4- (4-methoxyphenyl) -4-oxobut-2-enoic acid (1), which has anti-inflammatory and analgesic activity.

The claimed compound 1 is synthesized by the interaction of 4- (4-methoxyphenyl) -2,4-dioxobutanoic acid with benzyl monohydrazone in ethyl alcohol at room temperature, followed by isolation of the target product by known methods according to the scheme:

Example 1 for the preparation of compound 1. To a solution of 2.22 g (0.01 mol) of 4- (4-methoxyphenyl) -2,4-dioxobutanoic acid in 20 ml of ethyl alcohol, a solution of 2.24 g (0.01 mol) of benzyl monohydrazone in 20 ml of the same solvent is added 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 3.08 g (72%). Mp 170-171 ° C.

Found,%: C 70.93; H 4.32; N, 6.18. C ₂₅ H ₂₀ N ₂ O ₅ .

Calculated,%: C 70.08; H 4.70; N, 6.54.

IR (Specord M80, liquid paraffin, ν, cm-1): 3275 (NH), 1700 ( CO OH), 1660 (C ₆ H ₅ CO ), 1605 br. (C ⁴ = O, C = C, C = N). ¹ H NMR Spectrum (Bruker DRX 500, DMSO-d ₆ , HMDS, δ, ppm): 3.78 (s, 3H, CH ₃ O); 6.28 (s, 1H, CH); 7.15-7.85 (m, 14H, 2C ₆ H ₅ , C ₆ H ₄ ); 12.92 (s, 1H, NH).

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

Anti-inflammatory activity was studied in experiments on 30 white outbred rats of both sexes weighing 220-260 g. Compound 1 was administered orally at a dose of 50 mg / kg as a 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 the dynamics, which was recorded oncometrically 1, 3 and 5 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. The results were statistically processed using the Exel 2000 program and are presented in the table.

The analgesic activity of compound 1 was studied on 12 white mice of males weighing 20-25 g by the method of thermal irritation [N.B. Eddy, D. Leimbach, Pharmacology and Toxicology, 1960, No. 4, p. 311-315]. Test compound 1 was administered orally at a dose of 50 mg / kg in 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. The results were statistically processed using the Exel 2000 program and are presented in the table.

The acute toxicity (LD ₅₀ ) of the claimed compound 1 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} compound 1 is 1000 mg / kg. According to the classification of toxicity of drugs, compound 1 belongs 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]. It is 14 times less toxic than orthophene.

Table
Anti-inflammatory, analgesic activity and acute toxicity of compound 1 Compound Dose,
mg / kg LD ₅₀ mg / kg % inhibition of carrageenin edema Latent period of the defensive reflex, s 1 hour 3 hours 5 o'clock The control - - 0,0 ± 0,0 0,0 ± 0,0 0,0 ± 0,0 10.0 ± 0.5 one fifty 1000 61.3 ± 3.4 ^{1 ***} 52.0 ± 2.4 ^{1 ***} 46.5 ± 4.7 ^{1 ***}

Ortofen 10 74 22.0 ± 7.4 56.0 ± 7.3 ^{1 ***} 63.0 ± 1.5 ^{1 *} 26.2 ± 0.6 ^{1 *** *} = p <0.05, ^** = p <0.01, ^*** = p <0.001
1 - compared to control; 2-compared with orthophene.

As can be seen from the table, compound 1 showed a pronounced anti-inflammatory activity during the entire observation period, and at the peak of inflammation it is not inferior to orthophene. In addition, compound 1 showed significant analgesic activity in excess of that of the reference standard. It should be noted that the effective dose of orthophene is 0.14 of its LD ₅₀ , and the claimed compound is 0.05 of its LD ₅₀ , which indicates certain advantages of compound 1 over orthophene in terms of its safety and effectiveness.

Thus, 2- (1,2-diphenyl-2-oxoethylidenehydrazino) -4- (4-methoxyphenyl) -4-oxobut-2-enoic acid (1) is more effective and less toxic than orthophene, which makes it possible to use her to create new drugs with anti-inflammatory and analgesic activity.

LITERATURE

1. Rubtsov A.E., Zalesov V.V. Synthesis and intramolecular cyclization of N-substituted 2-amino-4-aryl-4-oxobut-2-enoic acids. ZhORKH, 2003, v. 39, issue 6, S.918-923.

2. Mashkovsky M.D. Medicines - 15th ed., Rev., Rev. and add. - M .: New Wave LLC, 2005. - p. 170.

3. Guidelines for the experimental study of non-steroidal anti-inflammatory substances, pharmacological committee of the Ministry of Health of the USSR, protocol No. 22 of November 11, 1982, Moscow (1982).

4. N.B. Eddie, D. Leimbach, Pharmacology and Toxicology, 1960, No. 4, p. 311-315.

5. Prozorovsky V. B., Prozorovskaya M. P., Demchenko V. I. Pharmacology and Toxicology, 1978, No. 4, pp. 497-502.

6. Izmerov I.F., Sanotsky I.V., Sidorov K.K., Toxicometry parameters of industrial poisons. M .: Medicine, 1977, p.196-197.

Claims (1)

2- (1,2-Diphenyl-2-oxoethylidenehydrazino) -4- (4-methoxyphenyl) -4-oxobut-2-enoic acid, which has anti-inflammatory and analgesic activity