RU2342364C1 - Bis{3-phenyl-1-[n-(3-pyridyl)carboxamido]-1,3-propandionato} cadmium, which has anti-flammatory activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely described is bis{3-phenyl-1-[N-(3-pyridyl)carboxamido]-1,3-propandionato}cadmium, which has anti-inflammatory activity, of formula:

.

EFFECT: obtainin compound with high output, which has expressed anti-inflammatory 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 of complex compounds of heterylamides of 4-aryl-2,4-dioxobutanoic acids, namely to bis {3-phenyl-1- [N- (3-pyridyl) carboxamido] -1 , 3-propanedionato} cadmium of the formula (1):

possessing anti-inflammatory activity, which suggests its use in medicine as an anti-inflammatory drug.

The closest analogue in structure and action of the claimed compound is 3-pyridylamide 4-phenyl-2,4-dioxobutanoic acid (2) [Milyutin A.V., Amirova L.R., Krylova I.V., Nazmetdinov F.Ya., Novoselova G.N., Andreichikov Yu.S., Calla V.E. Synthesis, properties and biological activity of 4-aryl-2-hydroxy-4-oxo-2-butenoic (aroylpyruvic) acids 3-pyridylamides. Chem.-farm. J., 1996, No. 1, p. 32-35] formulas:

Structural analogue 2 has a weak anti-inflammatory effect, insufficient for practical health care.

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

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 the search in a series of complex compounds of heterylamides of 4-aryl-2,4-dioxobutanoic acids for substances with pronounced anti-inflammatory activity and low toxicity.

The problem is achieved by obtaining bis {3-phenyl-1- [N- (2-pyridyl) carboxamido] -1,3-propanedione} cadmium (1), which has anti-inflammatory activity.

The claimed compound 1 is synthesized by the interaction of 4-phenyl-2,4-dioxobutanoic acid 3-pyridylamide (2) with cadmium dichloride, at a reagent ratio of 2: 1 in ethyl alcohol at room temperature, followed by isolation of the target product by known methods according to the scheme:

Compound preparation example 1 1. To a suspension of 5.36 g (0.02 mol) of 4-phenyl-2,4-dioxobutanoic acid 3-pyridylamide in 40 ml of ethyl alcohol, a solution of 2.28 g (0.01 mol) of CdCl ₂ · 2.5 is added H ₂ O in 25 ml of the same solvent, stirred until complete dissolution of the reagent and incubated at room temperature for 12 hours. The precipitate formed is filtered off, washed with hot toluene and dried. Yield 5.63 g (87%). T. pl. 322-324 ° C. Found,%: C 55.73; H 3.40; N, 8.71. C ₃₀ H ₂₂ N ₄ O ₆ Cd. Calculated,%: C 55.69; H 3.43; N, 8.65.

IR spectrum (Specord M80, liquid paraffin, ν, cm ^-1 ): 3355 (NH), 1705 ( CO NH), 1610, 1600, 1580 (C = O, C = C, C = N). ¹ H NMR spectrum (Bruker DRX 500, DMSO-d ₆ GMDS, δ, ppm): 7.13-8.82 (m, 20H, 2C ₆ H ₅ , 2C ₅ H ₄ N, 2CH); 10.75 (br.s, 2H, 2NH).

The inventive compound 1 is a light yellow crystalline substance, soluble in dimethyl sulfoxide and dimethylformamide, insoluble in chloroform, hexane and water.

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 into the rat hind paw. 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 Ministry of Health of the USSR, 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 Excel 2000 and presented in the table.

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 1500 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 20 times less toxic than 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 practically not inferior to orthophene. In addition, the effective dose of orthophene is 0.14 from its LD ₅₀ , and the claimed compound is 0.03 from its LD ₅₀ , which indicates certain advantages of compound 1 over orthophene in terms of its safety and effectiveness.

Thus, bis {3-phenyl-1- [N- (3-pyridyl) carboxamido] -1,3-propanedione} cadmium (1) is more effective and less toxic than orthophene, which makes it possible to use it to create new drugs with anti-inflammatory activity.

LITERATURE

1. Milyutin A.V., Amirova L.R., Krylova I.V., Nazmetdinov F.Ya., Novoselova G.N., Andreichikov Yu.S., Calla V.E. Synthesis, properties and biological activity of 4-aryl-2-hydroxy-4-oxo-2-butenoic (aroylpyruvic) acids 3-pyridylamides // Chem.-Pharm. g. - 1996. - No. 1, p. 32-35.

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. Prozorovsky V. B., Prozorovskaya M. P., Demchenko V. I. The express method for determining the average effective dose and its errors // Pharmacology and Toxicology. - 1978. - No. 4. - S.497-502.

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

Claims (1)

Bis {3-phenyl-1- [N- (3-pyridyl) carboxamido] -1,3-propanedione} cadmium of the formula:

possessing anti-inflammatory activity.