2-amino-4-acetyl-7-bromo-8б-hydroxy-3а,8б-dihydrothiazolo[5,4-b]indole hydrobromide protecting body against hypoxia and liver against poisoning with carbon tetrachloride

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a new 2-amino-4-acetyl-7-bromo-8b-hydroxy-3a,8b-dihydrothiazolo[5,4-b]indole hydrobromide of the formula (1) that is able to protect body against hypoxia and liver against poisoning with carbon tetrachloride. The melting point of this compound is 266-267°C (with decomposition). The compound is synthesized from 1-acetyl-5-bromo-3-indolinone and elemental bromine in dioxane medium followed by addition of thiourea in isopropyl alcohol.

EFFECT: valuable medicinal properties of compound.

2 tbl, 1 ex

 

The invention relates to the chemistry of the condensed nitrogen-containing heterocyclic systems and specifically relates to compounds of formula 1

Previously installed hepatoprotective activity of the hydrobromide of 2-amino-4-acetyl-8b-hydroxy-3a,8b-dihydrothiazolo[5,4-b]indole, and other information on the biological activity of derivatives of this heterocyclic system missing (Patent 2009127 RF, MKI35 07 D 209/36, a 61 K 31/395. The hydrobromide of 1-acetyl-2-isothiourea-3-indolinone, protecting the liver from poisoning by carbon tetrachloride / Velieva B.C., Melman A.I., Tomchin A.B., Marysheva V.V., Smirnov A.V., acavity SV, Gaivoronsky V.V. (Russia). - 5018404/04; Claimed 03.07.91.). The original compound 2 was attributed to the chain structure, it was later established that he meets the ringed tautomeric form (Imidazo[4,5-b]indoles / Vasilieva, Abomin, Aiello, WMV // Zhur.org.chem., 1998. - t No. 4. - S-617.),

A similar action is reference antihypoxic drug antizol formula 3 (Methodological guidelines for experimental study of drugs proposed for clinical studies as antihypoxic tools / edited by Ludlowkoeni. - M: BI, 1990. - 18 C.).

The purpose of this innovation is about of the invention is the expansion of the means, effectively protect the body from hypoxic exposure and protects the liver from carbon tetrachloride poisoning.

In the study of biological activity of the claimed compounds is established that protects the body from exposure to hypobaric hypoxic hypoxia. This, in turn, suggests the possibility of using it to prevent the harmful effects of factor hypoxia on people.

A protective effect on the liver suggests the possibility of using this compound for prevention and treatment in humans acute inhalation poisoning pairs of carbon tetrachloride. Widespread use of carbon tetrachloride in industry, agriculture and military Affairs that makes urgent the search for pharmacological agents that protect the body from exposure to this toxicant. To restore liver function used in the preparation of essential phospholipids Essentiale, but its activity is insufficient.

This goal is achieved by the chemical structure of the compound 1 having the above property.

The hydrobromide of 2-amino-4-acetyl-7-bromo-8b-hydroxy-3and,8b-dihydrothiazolo[5,4-b]indole is a white crystalline substance, cold difficultly soluble in water, ethyl and isopropyl alcohols, formed what about soluble in dimethyl sulfoxide and dimethylformamide, when boiling is easily soluble in alcohols. The substance is unstable to heat.

The claimed substance receive under the scheme:

Example. To a suspension of 17.3 g (68,1 mmol) 1-acetyl-5-bromo-3-indolinone in 170 ml of dioxane with stirring, add the solution to 3.36 ml (71,5 mmol) of bromine in 90 ml of dioxane. The reaction mass becomes transparent after 3 minutes add cooked by heating and cooled to 25°With a supersaturated solution of 6.2 g (81,7 mmol) of thiourea in 180 ml of isopropyl alcohol. Stirred for 10 min and then bring the reaction mass to a boil. Filtered hot, the residue is washed with 2×30 ml of dioxane, 4×30 ml of ether. Dried in vacuo over calcium chloride. The weight of white crystals of 21.5 g (77%). TPL 266-267°C (decomp.). The substance is homogeneous according to TLC in Silufol-254, put in methanol, eluent ethyl acetate : hexane 3:1, Rf0,21.

Study of the biological activity of the claimed compounds.

Study of the protective effect of compound 1 when exposed to hypobaric hypoxic hypoxia. Experiments were performed on outbred mice weighing 18-20 g of the Inventive compound was administered intraperitoneally in the form of a thin slurry with Tween-20 at a dose of at 88.5 mg/kg 30 minutes prior to the hypoxic episode. The optimal dose was chosen based on preliminary experiments. The effect of the drug was compared izvestnym the antihypoxic drug-antisolar in equimolar dose of 25 mg/kg Mice in the control were treated with equivalent volumes of saline.

Hypoxia was simulated in the chamber "lifting" of the animals at the altitude of 10,000 m with a speed of 50 m/s and an exposure time within 90 minutes assessment of the protective effect was studied by life expectancy and survival of animals after a hypoxic episode. The activity of the claimed compounds 1 in comparison with the known analogue presented in table 1.

Table 1

Antihypoxic activity of the claimed compounds
ConnectionThe number of animalsThe average life expectancy minThe increase in survival rate, %
Control10to 3.92±2,12-
Antizol910,1689,0**
Connection 18a 4.83±1,0162,5*
Note. The difference is significant in comparison to the control animals at *R≤0,05; **-R≤0,01

According to table 1 it is evident that the claimed compound improves the survival of animals by 62.5% compared to the control. This is more than 2/3 of the activity pattern. We can say that the connection 1 shows antihypoxic the th activity.

Acute toxicity was determined on nonlinear white mice-males weighing 18-22 g (Prozorovsky V.B. have been and others, "rapid method for determining the average effective dose and its errors, Pharmacology and toxicology, 1978, No. 4, S. 494-502.). The target compound was administered intraperitoneally once in suspension in water with the addition of Tween-80. The value of LD50amounted to 309±29 mg/kg

Hepatotropic action was studied on rats male weight 140-170, carbon Tetrachloride was administered subcutaneously daily in 50% solution in liquid paraffin for 4 days in a row in an amount of 0.4 ml/100 g mass. Simultaneously with CCl4introduced compound 1 at a dose of at 88.5 mg/kg intraperitoneally. It was compared with the known hepatoprotector Essentiale and compound 2, which was investigated in equimolarly dose of 67.6 mg/kg

The clinical picture of poisoning CCl4develops slowly. The main symptoms of severe intoxication is manifested only at the end of 2 days, and in 4 to 7 days lead to a lethal outcome. All the patients had severe liver damage up to fatty degeneration of the body. Evaluation of the protective effect of compounds 1 and analogues was performed by examining the activity specific for liver alanineaminotransferase (Alat) and aspartate aminotransferase (AST) in the serum. The change in the activity of Alt and AST in the serum svidetelstvuet deleterious effects CCl 4on the cell membrane and organelles of the cell. The results of the experiments are given in table 2.

Table 2

The change in the activity of Alt and AST in the serum on the seventh day of the experiment.
Groups of animalsB %AST, %
The intact100100
CCl4281151
CCl4+ Essentiale127105
CCl4+ connection 1109107
CCl4+ connection 2137110

The data obtained indicate that the use of compound 1 in 2.6 times reduces the concentration of Alt and 1.4 times the concentration of AST. Thus, the ability to protect the liver from poisoning by carbon tetrachloride connection exceeds 1 connection 2 and table.

The hydrobromide of 2-amino-4-acetyl-7-bromo-8b-hydroxy-3a,8b-dihydrothiazolo[5,4-b]indole of the formula

protect the body from hypoxia and liver from poisoning by carbon tetrachloride.



 

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