7-bromo-4-acetylthiazolo[5,4-b]indol-2-succinimide protecting body against hypoxia and possessing curative effect in lung toxic edema

FIELD: organic chemistry, medicine, pulmonology.

SUBSTANCE: invention relates to a new chemical compound, namely, 7-bromo-4-acetylthiazolo[5,4-b]indol-2-succinimide of the formula: that is able to protect body against hypoxia and possesses the curative effect in lung toxic edema. The melting point of this compound is 267-269°.

EFFECT: valuable medicinal properties of compound.

2 tbl, 1 ex

 

The invention relates to the chemistry of condensed compounds of indole with other compounds, specifically with thiazole concerns the compounds of formula 1.

Analog antihypoxic action is the reference drug antizol formula 2 (methodical recommendations for a pilot study of drugs. the proposed clinical study as a antihypoxic tools / edited by Ludlowkoeni. - M, BI, 1990. - 18 C.).

Pulmonary edema is a fairly widespread pathology in emergency practice. associated with effects on the body, prooxidant toxicants used in industry and defense facilities (hydrogen peroxide, acids, oxides of nitrogen, hydrazine, a component of rocket fuel etc). This pathology aleeya life-threatening. Etiotropic treatment of this disease at the present time octuplet. As a rule, we use high-dose hormone therapy (e.g., up to 1000 mg of hydrocortisone or 100 mg of prednisolone per day), cardiac glycosides, vasoactive funds. Lack of funds specific treatment of pulmonary edema substantiates the relevance and practical importance of the discovery and development of drugs for the correction of pulmonary edema, especially of toxic origin.

The purpose of this innovation is about of the invention is the creation of new connections number of thiazolo[5,4-b]indole, effectively protect the body from hypoxia and toxic edema.

This goal is achieved by the chemical structure 1 having the above properties. In the study of biological activity of the claimed compounds is established that protects the body from exposure to hypobaric hypoxic hypoxia and effective for the prevention and treatment of toxic lung edema. This, in turn, suggests the possibility of using it to prevent the harmful effects of factors hypoxia and prooxidant toxicants.

The inventive compound is a grayish-white crystals, difficultly soluble in water, acetone and alcohol, soluble in acetonitrile by heating, dimethylformamide and dimethyl sulfoxide. The structure of the compounds is confirmed by the data of elemental analysis and spectral characteristics shown in the sample text.

EXAMPLE. In the melt 4.5 g of succinic anhydride added 1.0 g (3.8 mmol) of 2-amino-7-bromo-4-acetylthiazole[5,4-b]indole and maintained at 150°C for 0.5 hours and Then cooled mass is treated with acetone, the precipitate is filtered off and crystallized from 100 ml of acetonitrile. The next day sucked slightly beige shiny crystals of compounds 1A, the yield of 63.5%. TPL 267-269°With, the substance is homogeneous according to TLC, the adsorbent of Silufol UV, the solvent for the application of dimethylformamide, eluent acetone-hexane 1:1, Rf0,67.

Range of PMR in DMSO d6, 300 MHz, ppm: 2.90 l (7H, CH3CH2), 7.50 (1H, H6), 8.00 ush. (1H, H5), 8.08 (1H, H5).

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. LD50connection 1 is greater than 1000 mg/kg, which can be attributed to the claimed connection to toxic substances.

Study of the protective effect of compound 1 when exposed to hypobaric hypoxic hypoxia performed on outbred mice weighing 18-20 g of the Inventive compound was administered intraperitoneally in the form of a thin slurry with wine-20 dose of 84.8 mg/kg, which is equimolar 25 mg/kg of the drug (antizol). 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 rates, and animals after a hypoxic episode. The asset is ity of the claimed compounds 1 in comparison with the known analogue is presented in table 1

From table 1 it is seen that compound 1 possesses significant antihypoxic activity: increases relative to control lifespan of experimental animals 3.5 times the survival rate of 67%, and the second activity to reference the antihypoxic drug antipolo quite a bit (statistical differences between groups of animals treated with antizol or connection 1, not received).

Table 1
Antihypoxic activity of the investigated compounds on the model of hypoxic hypoxia in mice
ConnectionThe average life expectancy minLife expectancy % compared to the controlThe increase in survival rate, %
Control5,06±2,17--
Antizol21,04±15,97**415,875,0*
Connection 118,00±4,60*355,866,7*

Note: * R≤0,01, ** p≤0,001 compared to control.

Experiments with toxic pulmonary edema were carried out on outbred mice-males weighing 18-24, pulmonary Edema was modeled by inhalation to mice phosgene at a dose of 4.2 mg×min/l, ACC is tstuat the lesion level LCt 50-84. The lesion level was determined by the actual death of the animals of the control group at 24 h after poisoning. Evaluation of results was performed after 3 and 24 h after poisoning. Determined pulmonary coefficient (LC), which judged the severity of pulmonary edema, and survival of animals after 24 h after poisoning. Luke was calculated by the formula

The drug was administered intraperitoneally in the form of a fine suspension in tween-80 at a dose of 25 mg/kg in a volume of 0.2 ml for 30-60 minutes before poisoning (preventive action) or 20-30 min after poisoning animals (therapeutic effect). Control animals received an injection of solvent (distilled water). The sample for each group consisted of 6 animals. The results were processed statistically using t-student criterion (for life expectancy and value of LK) and Fisher's exact method (for survival).

Table 2

Protivopedikulezna activity of the investigated compounds on the model of toxic pulmonary oedema in mice
GroupPulmonary coefficient, Rel. unitsThe survival rate. %
3 hours24 hours
To ntrol 12,3±1,719,4±1,525
Connection 1, prophylaxis9,2±0,415,4±0,6*25
Compound 1 treatment8,0±0,7*16,7±1,567*

Note: * R≤0,05 compared to the control group.

The use of compound 1 did not show any pronounced prophylactic efficacy. Analysis of therapeutic action showed that compound 1 contributes to the reduction LK poisoned animals to the 3rd hour of the experiment (8,0±0,7 to compared to 12.3±1.7 in the control group, p≤0.05) and a significant increase in survival to 67%. Antizol does not show protivopedikuleznogo actions.

7-Bromo-4-acetylthiazole [5,4-b] indole-2-succinimide formula

protect the body from hypoxia and has a curing effect in toxic lung edema.



 

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EFFECT: valuable medicinal properties of compound.

2 tbl, 1 ex

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