SU1125957A1 - Ates hydropyridine possessing hepatoprotective activity - Google Patents

Abstract

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Description

The invention relates to new chemical compounds, specifically to 4- (3-methylpyrazolyl-4) -2,6-di-metsht-3, 5-diethoxycarbonyl-1,4-dihydropyridine of the formula G H5 C 200 C, x% COOCHH 5 with hepatoprotective activity. This property suggests the possibility of its use in medicine. 2,6-dimethyl-3,5-diethoxylsarbonyl-1, 4-dihydropyridine (ethidine), which has hepatoprotective activity, is known. The closest in structure to the proposed compound are 4-imidazolyl and 4-thiazolyl-3,5-dialcoxycarbonyl-, 4-dihydropyridines possess cardiovascular activity. The purpose of the invention is to find new substances in the range of 1,4-dihydropyridines with high hepato-protective activity. The goal is achieved by the described 4- (3-methylpyrazolyl-4) -2,6-dimethyl-3, 5-dystoscicarbonyl-1, 4 digipropyridine of the form 1, with hepatoprotective activity. This compound is prepared according to a known procedure by condensation of ethyl acetate with 3-methyl-4-formi-pyrazole and ammonia in a suitable organic solvent at elevated temperature. The starting 3-methyl-4-formylpyrazo is prepared from acetone semicarbazone. Example. 4- (3-Methyl pyrazolyl-4) -2,6-dimethyl-3,5-diethoxycarbonyl-1, 4-dihydropyridine (1). 3 g (0.03 mol) of 3-methyl-4-form of pyrazole, 7.8 g (mol) of acetoacetic acid ethyl ester and 7.5 g (0.225 mol) of 25% aqueous ammonia are dissolved in 20 ml of this 57 . It is cooled and filtered, the precipitate is washed with ether and crystallized from 50% ethanol. 2.25 g (25%) of colorless crystals of compound I are obtained with a mp. 214-215 C. Found,%: C 60.9, H 6.9, N 12.9. Calculated,%: C 61.2, H 7.0, N 12.6. C, H ,, N, 04. UV spectrum (c), / „pjy, nm (igE): 245 (4.25), 270 (3.98), 357 (3.90). IR (nujol), (% absorption): 3355 (84), 3260 (72), 1698 (91), 1680 (91), 1630 (83). PMR spectrum (in (CH}) SO-dg), S, ppm: 1.15 (6 N, t, pCHjCHj), 2.13 (6 H, s, 2,6-СН), 2, 22 (3 H, s, H-CHj), 4.00 (4H, KB, osilen 3), 4.68 (1 H, s, 4-H), 7.04 (1 H, s, 5-H ), 7.71 (1 H, s, NH pyridine), 12.0 (1 H, s, NH pyrazole). The hepatoprotective activity of compound 1 was studied in vitro and in vivo experiments on a model of carbon tetrachloride damage to the liver of rats. Glutathione, vitamin E, cysteamine and ethidium were used as npe.f parates of comparison in in vitro experiments, vitamin E and citedin in in vivo experiments. Experiments were carried out on white outbred rats - males weighing 180-220 g. In experiments in vitro, the livers of rats were homogenized, the resulting homogenate was centrifuged, and the supernatite in an amount containing 3.0 mg of protein was added to the incubation vessels. 6.2 mM NADPH was added to all samples. SSCs (10 μm) and one of the studied substances were added to separate samples.: Glutathione — 0.4 μM, vitamin E, cysteamine, ethidine, and compound 1 10 μM. Samples were incubated at 37 s for 40 min with stirring. Evaluation of lipid peroxidation (sex) was carried out by determining low-M dialdehyde (MDL). When SCC was added to the incubation medium, a sharp increase in the POL process was observed - the amount of MDA increased by 3 times. The introduction of the test compounds into the incubation medium containing the CC1 prevented the POL enhancement (Table 1). The number of experiments is shown in parentheses.

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in in vivo experiments, CCl was injected intraperitoneally at a dose of 0.5 ml / s in the form of a 10% solution in olive oil. The studied compounds were administered orally in the form of an aqueous suspension with the addition of tween-80 at a dose of 200 mg / kg twice - 1 and 24 hours before the injection of SCC-. The control animals were injected with 4.5 ml / kg of olive oil and an aqueous solution of tween-80. Animals were sacrificed by decapitation 24 hours after CC1 administration.

Twenty-four hours after the administration of SCC, a sharp increase in the activity of apanine aminotransferase (AlAT) and aspartate aminotransferase (AsAT) (Table 2) is observed, indicating a serious damage to the liver due to the degradation of hepatocyte membranes. The value of the de Rytis coefficient, reflecting the ratios of the activity of AST and AlAT, is significantly reduced. A decrease in the amount of protein and cytochrome P-450 is observed in the liver (Table 3).

./ Vitamin E use, ethidine

/ Compound 1 prevents significant changes in serum biochemical parameters. Connect:

The effect of the studied compounds on the oxidative effect of carbon tetrachloride in experiments, in vitrot;

The scheme of the experiment

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1 significantly reduces the level of activity of AlAT and AsAT, improves the de Rytis coefficient, and also reliably prevents a decrease in the amount of cytochrome P-450 in the liver.

Compound 1 improves most

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biochemical indices of blood and liver ssh.orotki with lesions of carbon tetrachloride to a greater extent than vitamin Ey ethidine.

Acute toxicity was investigated by intraperitoneal administration to white male mice. for Compound I, it is 1350 (1000-1822) mg / kg.

5 Thus, a positive effect of compound I on structural and functional abnormalities in the liver caused by carbon tetrachloride was revealed. According to the hepatoprotective effect, Compound I is significantly superior to ethidine-compound of the same chemical class.

Low toxicity and high hepatoprotective activity of 4- (C 5 methylcyrazolyl-4) -2, b-dimethyl 3, 5-diethoxycarb-1, 4-dihydropyridine indicate the possibility of its practical application in medicine for the treatment and prevention of liver diseases.

Table 1

Vda

M + (G), nm / mg protein "min I

x) Reliable with respect to control. XX Reliable with respect to the SCC.

The number of experiments is shown in brackets,

 Activity of serum anakirn- and aspartatevminotra spheraei 24 hours after the administration of CC1 and the preliminary administration of the following compounds

) Reliably, it is controlled, t) Reliably in relation to CCli.

Protein and cytochrome P-450 content in the liver 24 hours after administration of CC14 and prior administration of test compounds.

Tables "2

Table 3

Claims (1)

4- (3 ⁷ -Metylpyrazol-4? ·) -2,6 dimethyl-3,5-diethoxycarbonyl-G, 4-dihydropyridine of the formula with hepatoprotective activity. "7yogёgK ^{, p,} T) 5 one