2-amino-4-acetyl-7-bromo-8b-hydroxy-3a,8b-dihydroxytiazolo[5,4-b]indole for liver protection from poisoning with carbon tetrachloride

FIELD: organic chemistry.

SUBSTANCE: invention relates to new 2-amino-4-acetyl-7-bromo-8b-hydroxy-3a,8b-dihydroxytiazolo[5,4-b]indole of formula useful in liver protection from poisoning with carbon tetrachloride. Said compound has boiling point of 174-175°C (decomposition) and LD50 of 1950±180 mg/kg. Method for production of claimed compound also is disclosed.

EFFECT: new compound for liver protection from poisoning with carbon tetrachloride.

2 ex, 1 tbl

 

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-3and,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, haivoron-Skye 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)

Known hepatoprotective properties hydrobromide 4-acetylthiazole[5,4-b]indole (Patent 2076867 RF, MKI36 07 D 487/04, a 61 K 31/40. The hydrobromide 4-acetylthiazole[5,4-b]indole protecting the liver from carbon tetrachloride poisoning and how to obtain it / Velieva B.C., Melman A.I., Tomchin A.B., Smirnov A.V., acavity SV, Gaivoronsky V (RF) - 5042409/04; Claimed 19.05.1992) - 3 connection.

This property 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 Essentiale, but its activity is insufficient.

This goal is achieved by the chemical structure of the new compounds of formula 1 having the above properties.

The inventive compound is a white crystalline substance, insoluble in water, soluble in methyl and ethyl alcohols, acetone and slightly soluble in dimethylformamide and dimethylsulfoxide. The inventive compound is produced by the action of 30%aqueous sodium acetate to the hydrobromide of 2-amino-4-acetyl-7-bromo-8b-hydroxy-3and,8b-dihydrothiazolo[5,4-b]indole.

Example 1. The hydrobromide of 2-Amio-4-acetyl-7-bromo-8b-hydroxy-3and,8b-dihydrothiazolo-[5,4-b]indole. To a solution of 17.3 g (0.068 mol) of 5-bromo-N-acetylindole in 170 ml of dioxane at 20°With added solution to 3.36 ml (0,0715 mol) of bromine in 90 ml of dioxane and kept at the remesiana for 1 minutes Added prepared by heating and cooled to 25°With a supersaturated solution of 6.2 g (0,0817 mol) of thiourea in 180 ml of 2-propanol and heated under reflux for 5 min. was Filtered in hot condition, the precipitate was washed with 2-propanol (2×30 ml), dioxane (2×30 ml) and ether (4×30 ml), dried in vacuum over phosphorus pentoxide. Got a connection in the form of a grayish-white crystals, weight 22,68 g (81,4%). According to TLC individual substance is applied in DMF, dried at 60°30 min, eluent ethyl acetate : acetone, Rf=0,21, So pl. 266-267°C (decomp.).

Example 2. 2.0 g (4,88 mmol) to the hydrobromide of 2-amino-4-acetyl-7-bromo-8b-hydroxy-3and,8b-dihydrothiazolo[5,4-b]indole are dissolved at 50°With 150 ml of water, filtered from the suspension and to the filtrate add 30%sodium acetate to pH 6 by the universal indicator. Gradually throughout the volume begin to fall white crystals, which after 1 hour, filtered off, washed with alcohol and ether. Air-dried, yield 1.0 g (62,5%). For analytical purposes the substance crystallized from methanol. Get shiny white crystals. Sample Beylshtein negative. The melting temperature depends on the temperature entered into the device. In case you make at 160°With the substance melts at 174-175°C (decomposition).

The substance is homogeneous according to TLC. The adsorbent - Silufol UV-254, actuarial for application - dimethylformamide, eluent is acetone: hexane=1:1; Rf0,28.

Range of PMR in DMSO d6. 300 MHz, ppm: 2.25 + 2.40 (3H, CH3), 5.77 + 6.10 (1H, H3a), 6.65 (m, 3H, NH2, OH), 7.30 (1H, H6), 7.45 (1H, H8), 8.03 (1H, H5).

Study of biological activity of the claimed compounds.

Acute toxicity was determined on outbred mice-males weighing 18-22 g by well-known methods (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-502). The target compound was administered intraperitoneally once in suspension in water with the addition of tween-80. LD501950±180 mg/kg, which can be attributed to the claimed connection to toxic substances.

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 71,0 mg/kg intraperitoneally. It was compared with the known hepatoprotector Essentiale and prototypes in the equimolar dose of compound 2 at a dose of 71.4 mg/kg and compound 3 at a dose of 67.5 mg/kg

The clinical picture of poisoning CCl4develops slowly. The main symptoms of severe intoxication is manifested only at the end of 2 suteki 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 alanine transferase (Alt) and aspartate aminotransferase (AST) in the serum. The change in the activity of Alt and AST in the serum indicates deleterious effects CCl4on the cell membrane and organelles of the cell. The results of the experiments are shown in table 1.

Table 1.

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+Essentiale127*105*
CCl4+connection 1112**111*
CCl4+connection 2151*120
CCl4+connection 3136*110*
Note. *p<0,05; **p<0,01 compared to the group treated with CCl4.

The data obtained indicate that the use with the organisations 1 2.5 times reduces the concentration of Alt and 1.36 times the concentration of AST. Thus, the ability to protect the liver from poisoning by carbon tetrachloride connection exceeds 1 analogues 2 and 3, and Essentiale reduction Alat.

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

protects the liver from carbon tetrachloride poisoning.



 

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