RU2432355C2 - Bis[3-(4-chlorophenyl)-1-(4-methylphenyl)carboxamido-1,3-propanedionato]oxovanadium, having hypoglycemic and antihypoxic activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to bis[3-(4-chlorophenyl)-1-(4-methylphenyl)carboxamido-1,3-propanedionato]oxovanadium of formula:

. The compound has hypoglycemic and antihypoxic activity.

EFFECT: obtaining a compound having high hypoglycaemic and antihypoxic activity and low toxicity.

1 ex, 2 tbl

Description

The invention relates to the field of organic chemistry, to new biologically active substances of the class of complex compounds of arylamides 4-aryl-2-hydroxy-4-oxo-2-butenoic acids, namely to bis [3- (4-chlorophenyl) -1- (4 methylphenyl) carboxamido-1,3-propanedionato] oxovanadium (1) of the formula

possessing hypoglycemic and antihypoxic activity, which suggests its use in medicine as a hypoglycemic agent with concomitant antihypoxic activity.

The closest analogue in structure to the claimed compound is 4-methylphenylamide 2-hydroxy-4-oxo-4-phenyl-2-butenoic acid (2) [Andreichikov Yu.S., Nalimova Yu.A., Tendryakova SP, Vilenchik Ya .M. Chemistry of oxalyl derivatives of methyl ketones. IX. The interaction of 5-aryl-2,3-dihydrofuran-2,3-diones with ammonia and aromatic amines // Journal of Organic Chemistry. - 1978. - T. 14, No. 1. - S.160-163] formulas

Structural analogue 2 does not have hypoglycemic and antihypoxic activity.

Reference standards selected:

1. Sugar-lowering drug metformin (3), widely used in medical practice and which is an analogue in action [Mashkovsky MD Medicines - 15th ed., Rev., Rev. and add. - M .: New Wave LLC, 2005. - T.2. - S.562-563].

2. Angipoxic drug piracetam (4), widely used in medical practice and which is an analogue in action [Mashkovsky MD Medicines - 15th ed., Rev., Rev. and add. - M.: Publishing House New Wave LLC, 2005. - p.113-115].

The objective of the invention is to search for a number of complex compounds of arylamides of 4-aryl-2-hydroxy-4-oxo-2-butenoic acids substances with pronounced hypoglycemic and antihypoxic activity, as well as low toxicity.

The problem is achieved by obtaining bis [3- (4-chlorophenyl) -1- (4-methylphenyl) carboxamido-1,3-propanedione] oxovanadium (1), which has hypoglycemic and antihypoxic activity.

The claimed compound 1 is synthesized by the interaction of 4-methylphenylamide 2-hydroxy-4-oxo-4- (4-chlorophenyl) -2-butenoic acid (5) with vanadyl sulfate, with a reagent ratio of 2: 1 in ethyl alcohol at room temperature followed by the selection of the target product by known methods according to the scheme:

Preparation Example 1 for compound 1. To a suspension of 6.32 g (0.02 mol) of 4-methylphenylamide 2-hydroxy-4-oxo-4- (4-chlorophenyl) -2-butenoic acid in 40 ml of ethyl alcohol, solution 1 was added. 63 g (0.01 mol) (VO) SO ₄ in 25 ml of water, stirred until complete dissolution of the reagent and kept at room temperature for 12 hours. The precipitate formed is filtered off, washed with hot toluene and dried. Yield 6.19 g (89%). Mp = 325-327 ° C. Found,%: C 58.53; H 3.69; C1 10.24; N, 4.09; V 7.27. C ₃₄ H ₂₆ C ₁₂ N ₂ O ₇ V. Calculated,%: C 58.64; H 3.76; C1 10.18; N, 4.02; V 7.31.

IR (Specord M80, liquid paraffin, ν, cm ^-1 ): 3275 ( NH CO), 1665 ( CO NH), 1605, 1580 (C = O, C = C, C = N). ¹ H NMR spectrum (Bruker DRX 500, DMSO-d ₆ , HMDS, δ, ppm): 3.15 s (6H, 2CH ₃ ), 7.12-8.08 m (18H, 4C ₆ H ₄ , 2CH), 8.92 br. . c (2H, 2NH).

The inventive compound 1 is a dark green crystalline substance, soluble in dimethyl sulfoxide and dimethylformamide, insoluble in water, chloroform, alkanes.

The hypoglycemic activity of compound 1 was studied in a model of alloxan diabetes. The experiments were performed on outbred white rats of both sexes weighing 180-200 g. Experimental hyperglycemia was simulated by intraperitoneal administration of alloxan at a dose of 160 mg / kg. Compound 1 was administered orally to rats with alloxan diabetes at a dose of 50 mg / kg as a suspension in a 2% starch solution. Equivolume amount of 2% starch solution was administered to control animals. The glucose concentration in the blood of animals was determined by the glucose oxidase method [Volchegorsky I.A., Rassokhina L.M., Miroshnichenko I.Yu. Antioxidants in experimental diabetes mellitus // Problems of Endocrinology, 2008. - V. 54. - No. 5. - S.43-50] before the administration of test compound 1, as well as 30 and 120 minutes after it. Rats were deprived of food 16 hours before the experiment and for the duration of the experiment. The degree of hypoglycemic activity of the studied compound 1 after 30 and 120 minutes after its administration was compared with the activity of metformin at a dose of 50 mg / kg.

Antihypoxic activity was studied on the model of normobaric hypercapnia. To reproduce this form of hypoxia in mice, compound 1 was administered at a dose of 50 mg / kg, after an hour the animals were individually placed in hermetically sealed vessels (200 cm ³ ). As animals consume oxygen, their concentration in the vessel decreases, which leads to their death. The life span of the animals was recorded, which was used to judge the effectiveness of the test substance. Placebo (water) was administered to the control group mice in the same volume. Comparison drug was piracetam at a dose of 50 mg / kg [Methodological recommendations for the experimental study of drugs proposed for clinical study as antihypoxic agents. / Ed. L.D. Lukyanova. - M., 1990. - 19 p.].

The results are processed statistically using the student coefficient and are presented in tables 1, 2.

The acute toxicity of the claimed compound 1 when administered orally was studied on white mice of both sexes weighing 18-20 g with a determination of LD ₅₀ [Guidelines for the study of the general toxic effects of pharmacological substances // Guide to the experimental (preclinical) study of new pharmacological substances. / Under the general editorship of Corr. RAMS, prof. R.U. Khabrieva. - 2-ed., Revised., And additional .. - M .: OJSC "Publishing house" Medicine ", 2005. - P.41-54]. In each series, 6 animals were used. Observation was carried out hourly during the day after the introduction of compound 1 in the form of a suspension in a 2% starch solution. The control animals were injected with an equivolume amount of 2% starch solution. The results were processed according to Prozorovsky with the calculation of the average lethal dose (LD ₅₀ ) at P = 0.05 [Prozorovsky VB, Prozorovskaya MP, Demchenko V.I. Express method for determining the average effective dose and its errors // Pharmacology and Toxicology. - 1978. - No. 4. - S.497-502].

It was found that the LD _{50 of} compound 1 is 2800 mg / kg. According to the classification of toxicity of drugs, compound 1 belongs to the class of low toxic substances [Izmerov I.F., Sanotsky I.V., Sidorov K.K., Toxicometry parameters of industrial poisons. - M .: Medicine, 1977. - p.196-197].

Table 1 Hypoglycemic effect in alloxan diabetes and acute toxicity of compound 1 Series of experiments LD ₅₀ Dose mg / kg Number of animals Glucose level, mmol / l 30 minutes 120 min Control ₁ - - 6 4.38 ± 0.09 4.74 ± 0.06 Control ₂ - - 6 14.63 ± 1.83 *** ¹ 14.28 ± 0.38 ^{*** 1} Compound 1 2800 fifty 6 7.43 ± 0.99 * ¹ * ² *** ³ 4.43 ± 0.59 ** ² *** ³ Metformin 1266 (1050-1485) fifty 6 8.62 ± 0.34 *** ¹ *** ² 4.34 ± 0.23 *** ² Note: ^* = p <0.05 ^** , = p <0.01, ^*** = p <0.001; 1 - in relation to control - 1 2 - in relation to control - 2 3 - in relation to metformin

table 2 Antihypoxic effect of compound 1 Series of experiments Normobaric hypercapnia (mice) Life time, s % increase in life expectancy Compound 1 2633.3 ± 106.0 *** ¹ ** ² 70,2 metformin 1728.9 ± 113.4 1.3 piracetam 3200.0 ± 168.8 ** ³ 92.3 the control 1706.7 ± 129.1 - Note ^* : = p <0.05, ^** = p <0.01, ^*** = p <0.001; 1 - in relation to control 2 - in relation to piracetam 3 - with respect to compound 1

As can be seen from table 1, compound 1 showed hypoglycemic activity in the model of alloxan diabetes during the entire observation period, and it is not inferior in action to metformin. Compound 1 also has a high antihypoxic activity (see table 2), while metformin does not have this type of activity. This type of activity is a positive factor, since in diabetes there is almost always hypoxia, the severity of which increases significantly with decompensation of the disease and the development of vascular complications. Moreover, the claimed substance 1 is 2.2 times less toxic than metformin.

Thus, bis [3- (4-chlorophenyl) -1- (4-methylphenyl) carboxamido-1,3-propanedionato] oxovanadium (1) exhibits high hypoglycemic and antihypoxic activity and has significantly lower toxicity compared to metformin, which makes it can be used in medicine to create new drugs with hypoglycemic and antihypoxic activity.

LITERATURE

1. Andreichikov Yu.S., Nalimova Yu.A., Tendryakova S.P., Vilenchik Y.M. Chemistry of oxalyl derivatives of methyl ketones. IX. The interaction of 5-aryl-2,3-dihydrofuran-2,3-diones with ammonia and aromatic amines // Journal of Organic Chemistry. - 1978. - T. 14, No. 1. - S.160-163.

2. Mashkovsky M.D. Medicines, - 15th ed., Revised., Rev. and add. - M .: New Wave LLC, 2005. - T.2. - S.113-115, 562-563.

3. Volchegorsky I.A., Rassokhina L.M., Miroshnichenko I.Yu. Antioxidants in experimental diabetes mellitus // Problems of Endocrinology, 2008. - T. 54. - No. 5. - S. 43-50.

4. Methodological recommendations for the experimental study of drugs proposed for clinical study as antihypoxic drugs / Ed. L.D. Lukyanova. - M., 1990. - 19 p.

5. Guidelines for the study of the general toxic effects of pharmacological substances // Guide to the experimental (preclinical) study of new pharmacological substances / Edited by the corr. RAMS, prof. R.U. Khabrieva. - 2-ed., Revised. and add. - M .: OJSC "Publishing house" Medicine ", 2005. - P.41-54.

6. 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.

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

Claims (1)

Bis [3- (4-chlorophenyl) -1- (4-methylphenyl) carboxamido-1,3-propanedione] oxovanadium of the formula:

possessing hypoglycemic and antihypoxic activity.