Monoethanolammonium salt of 6-nitro-3h-gynazole-4-yl-3 - acetic acid, exhibiting antioxidant and anti-ischemic activity


(57) Abstract:

The invention relates to a new compound - monoethanolammonium salt of 6-nitro-3H-gynazole-4-yl-3-acetic acid f-crystals (I), which is antioxidant and anti-ischemic activity and may find application in medicine. table 4.

The invention relates to new biologically active compounds and can be used in medicine.

Known structural analogues: derivatives (3,4-dihydroquinazolin-3-he-4)- carboxylic acid, exhibiting antioxidant activity (Ukraine, Farmaceutyczny magazine.- 1995.- N1.- S. 80-82), of the formula:

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n=0,1; R=OH, OALk, other2; R1=H, CH3WITH2H5; R2= Alk, Het

The disadvantage of analogue is the lack of anti-ischemic activity.

Known structural analogue (prototype): monoethanolammonium salt (3,4-dihydroquinazolin-3-he-4)-- propionic acid of the formula:

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exhibiting antioxidant activity (Ukraine, Bulletin Of formats.-1995.- N3-4.-S. 29-34).

The disadvantage of this analogue is the lack of anti-ischemic activity.

The basis of the invention the goal is to create new biologically AK anti-ischemic effect on the brain tissue.

The solution to this problem provides monoethanolammonium salt of 6-nitro-3H-gynazole-4-yl-3-acetic acid, of the formula:

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exhibiting antioxidant and anti-ischemic activity.

Monoethanolammonium salt of 6-nitro-3H-gynazole-4-yl-3 - acetic acid in contrast to the known analogues contains at position 6 (six) chineselanguage nucleus of the nitrogroup and is a water-soluble salt, which leads to improvement pharmacotechnology properties and more pronounced antioxidant and anti-ischemic action.

Unlike other well-known biological analogues of (-tocopherol acetate, BHT, piracetam) connection according to the invention has an antioxidant effect at all stages of the development of ischemia, increasing the activity of antioxidant enzymes, the level of endogenous-tocopherol and reducing the accumulation of products of lipid peroxidation (LPO) with a simultaneous decrease consumption of high energy phosphates and carbohydrates.

Get the claimed connection with the interaction of 6-nitro-3H-gynazole-4-yl-3-acetic acid with monoethanolamine in an ethanol medium.

Example: 2,49 g (0.01 mol) of 6-nitro-3H-gynazole-4-yl-3-acetic acid dissolve the mine and the reaction mixture is boiled for 10-15 minutes, the last 3 minutes with activated charcoal.

The charcoal is filtered off, the solution is cooled, the precipitate is filtered off, the filter is washed with acetone and dried. Get the target product with a yield of 89%. A yellow crystalline substance with Tplvl.= 191-196oC (the melting interval 2oC) (of alcohol), soluble in water, alcohol, dioxane, DMF.

Found, %: From 46.9, H is 4.9; N 17,7,

Calculated, %: 46.5 H 4,6; N 18,1; C12H14N4O6.

In the IR spectra are observed characteristic absorption bands of the carbonyl groups in the area 1720-1600 cm1and stretching vibrations of the nitro group in the region of 1500 cm'1(assim.) and 1450 cm'1(SIM.).

The identity of the compounds was confirmed by thin layer chromatography on plates "Silufol" in the solvent system: benzene - acetic acid - water (2:8:1), butanol - acetic acid - water (4:1:5). The value of Rf100 is 74 and 78 units, respectively.

Acute toxicity of compounds with intraperitoneal administration to mice of equal 2890 mg/kg

Antioxidant and anti-ischemic activity of the synthesized compounds was studied on a model of acute disorders of cerebral circulation on b is for 6 animals in each group. Unilateral ligation of the common carotid artery was performed under eleminal-sodium anesthesia (eleminal-sodium was administered in the dose of 40 mg/kg) by vessel selection and imposition of a ligature. The test substance was administered in the dose of 1/100 LD50, BHT and piracetam in doses of 50 mg/kg and 100 mg/kg, respectively, intraperitoneally, a-tocopherol at a dose of 50 mg/kg subcutaneously, 1 time per day for 4 days in parallel with the formation of ischemia. 2 hours after the last injection of the analyte animals were sacrificed experiment by decapitate.

In brain tissues was determined by the content of initial and final peroxidation, activity of antioxidant enzymes, the level of endogenous-tocopherol, the intensity of the carbohydrate and energy metabolism.

We used the following research methods: determination of the level of diene conjugates (DC) by the method of direct spectrophotometry heptane extract (C. S. Kogan, etc. the Problem of analysis of endogenous products of lipid peroxidation. - M. ; Medicine, 1986); determination of malondialdehyde (MDA) test with thiobarbituric acid (L. I. Andreeva and other Modification of the method of determination of lipid peroxides in the test with thiobarbiturate acid //lab. case.-the processes of cells and the method of its determination //lab. case.- 1985.- N11.- C. 678-681); the determination of the activity of glutathione peroxidase (AWP) (Gavrilov A. R. and other Determination of the activity of glutathione peroxidase in erythrocytes in saturating concentrations of substrate //lab. case. - 1986. - N12.- C. 721-723): determination of catalase (Korolyuk M. A. and other Method for the determination of catalase activity //laboratory. case.- 1988.- N1.- C. 16-19): determination of substrates carbohydrate metabolism (biochemical Methods of research /edited Prokhorova, M. I. - L.: in Leningrad, 1982.- 278 C.); the determination of the content of high energy phosphates chromatographic (Zakharova N. B. , Rubin C. I. Thin-layer chromatography of nucleotides on the plates "Silufol" //lab. case.- 1980.- N12.-C. 735-738.); the definition of a-tocopherol spectrophotometric (Method definitions-tocopherol in biological material /I. F. Alenichev etc. //proc. Dokl. IV scientific Congress of experts in the clinical lab. diagnosis of the Republic. Belarus, Grodno.- 1992.-S. 182.).

The results of the experiments are shown in tables 1,2,3,4, show that in conditions of unilateral ligation of the common carotid artery is the inhibition of the activity of antioxidant enzymes in brain tissue, the accumulation in it of LPO products, violation of anaerobic and aerobic pathways obrada energieproductie systems and the acceleration of the processes of free radical oxidation (CPO).

The introduction of the inventive compounds on the background cerebral ischemia led to activation of the antioxidant defense systems, which showed an increase in activities of SOD 2.9 times, catalase 1.9 times, HLOOKUP 0.68 times that distinguishes the target connection from antioxidants "direct" actions - dibunola and tocopherol acetate (table 1). Under the influence of the compounds significantly decreased the LPO on 45-54% (table 2).

As the results of the research, the connection activates both the anaerobic and aerobic pathway of energy (increasing the level of pyruvate and malate by 58.3, 43.7%, respectively, table 3), while there was a trend toward higher levels Danilovich nucleotides (ATP and AMP by 42.7%, 54.5 per cent, respectively, table 4).

The inhibition of peroxidation processes and normalizing the individual links carbohydrate metabolism, the synthesized compound has a pronounced antioxidant and protective effects on brain cells, exceeding the effect of these antioxidants, such as tocopherol acetate and BHT, closer in potency to the piracetam - anti-ischemic drug.

Monoethanolammonium salt of 6-nitro-3H-gynazole-4-yl-3-acetic acid formula

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