NEW DERIVATIVES OF 2-OXOINDOLIN-3-GLYOXYLIC ACID-AMID AND ETHER, AND THEIR COMPARATIVE ANTIHYPOXIC ACTIVITY

Results of comparative antihypoxic activity of amid and ether – new derivatives of 2-oxoindolin-3-glyoxilic acid among various types of hypoxia are suggested in the article. It is indicated that they give evidence of antihypoxic property among all basic types of hypoxia. When acute hystotoxical and acute hemic hypoxias existed their effectiveness was higher than effectiveness of medicine of comparison of mexidol. Antihypoxic activity of ether, amid and mexidol was almost identical on experimental models of acute normobaric hypoxia and acute hypobaric hypoxia. It is suggested that mechanism of antihypoxic activity of new derivatives of 2-oxoindolin-3-glyoxylic acid is stipulated by means of stabilization of cellular membrances, optimisation of cellular respiration and reduction of sensitivity of tissues and oxygen deficiency.


INTRODUCTION
The pharmacological medicines have been applied in therapeutic practice since ancient times, which improve the utilization of a circulating oxygen, reduce a need of it for organs and tissues, and in such a way they enable the reducion of an hypoxia and the increase of a steadfastness of an organism to an oxygen deficiency. The frequency of the hypoxic conditions, a polymorphism of their appearance affects the necessity of a search for the methods and the means of struggle with an oxygen deficiency. At least, the contents of the antihypoxic means remain slight. We learned 10 etheres and 10 amids -new derivatives of 2-oxoindolin-3-glyoxylic acid for the period of screening reaserches, among which one amid and one ether were selected for further preclinic research, which gave evidence of the most antihypoxic activity.
Aim of research. To carry out a research in the comparative aspect of antihypoxic action of ether and amidnew derivatives of 2-oxoindolin-3-glyoxylic acid in different experimental models of oxygenous hunger.

MATERIALS AND METHODS
The experiments were carried out on the nonlineal white mice of the different weight 18-22 grams in the cases of different types of hypoxias [2]. The acute hypobaric hypoxia was created by means of lifting of the animals at the height of 11.000 metres with speed of 50 metres per second by means of the device Komovsky; the hypoxic hypoxia was created by means of arranging the animals in hermochamber 200 mililiters; the acute hemic hypoxia was obtained by means of injection of nitrite sodium 200 mg/kg within a skin; hystotoxic hypoxia -by means of injection of sodium nytroprusid 25 mg/kg within stomach [1]. The mexodil as antyhipoxant of new generation was selected as medicine of comparison [3]. The control and experiments carried out and registered simultaniuosly the duration of life per minutes. The mexidol 100 mg/kg and experimental substances (ether -13.9 mg/kg, amid -18.6 mg/kg) were injected within a stomach before half an hour of the beginning of an experiment. All obtained results were processed by means of methods of nonparametric statistics by means of the application of the assessment of Student [4]. In all cases differences were thought to be obvious under p < 0.05.

RESULTS AND DISCUSSION
According to the researches, ether and amid -derivatives of 2-oxoindolin-3-glyoxylic acid practically gave evidence of the identical antihypoxic property in all experimental models (Table). However their effectiveness was higher than mexidol in the cases of the acute hystotoxic (327.9 % and 290.2 %) and the acute hemic hypoxia (197.0 % and 165.9 % correspondenly). The antihypoxic activity of ether, amid and mexidol was almost identical in the experimental models of the acute normobaric hypoxia and acute hypobaric hypoxia. One should remark, in the case of hemic hypoxia we watched relatively low antihypoxic activity of ether, amid and mexidol (26.2 ± 2.2 min, 26.6 ± 2.1 min and 22.4 ± 1.9 min correspondenly) as compared with different types of hypoxias. We obtained data of mexidol they coincide with results of other scientists [2]. © Toryanik E. L., 2016 One can arrange the models in such an order by means of antihypoxic activity of ether and amid: acute hystotoxic hypoxia > normobaric hypercapnical hypoxia > acute hypobaric hypoxia > acute hemic hypoxia.
The mexidol as antihypoxant of new generation, we chose it as a medicine of comparison, in some way studied in the experimental models of the acute oxygenous hunger as well as in clinics of the Russian Federation in the cases of the different illnesses. For all it every single type of hypoxia has its "launch" mechanism of the development, one can carry one's point of view quite clearly concerning the possible mechanisms of antihypoxic action of new substance separately in every single case.
According to the references it is noted that hystotoxic hypoxia appears in the case of failures in the system of utilization of oxygen when enough supply of its to the tissues happens. Under these circumstances the ferments of the biological oxygenation inhibite that enables the disconnecton of the oxygenation and phosphoration to the energetic hunger of tissues.
[5] The mechanisms of antihypoxic activity of mexidol are studied and bring about an effect on the stabilization of the biological membrances and energetic exchange of tissues, an activization of the energo -synthetic functions of mitohondrias, an increase of an effectiveness of the reactions of a chain of respiration by means of sycsinate [6]. Considering that new derivatives of 2-oxoindolin-3-glyoxylic acid and a mexidol gave evidence of rather high activity on a current model of oxygenous hunger, one can suggest, that new substances have such mechanisms of realization of antihypoxic effect as well as a medicine of comparison.
One of the main pathogenetic chains of an acute normobaric and acute hypobaric hypoxia is hypoxemia and hyper or hypocapnia [6]. We think that a discovery of enough activity of research substances can have to do with a reduction of the sensitivity of tissues to oxygen deficiency.
Addition of methgemoglobincreator in the case of gemic hypoxia causes the reduction of oxygenous volume of blood because of inability of methgemoglobin to transport oxygen [5]. However one of a mechanism of antihypoxic action of mexidol is impact on the level of gemoglobin of blood by means of a stabilization of the biological membrances of erithrositos [6], one can suggest, that effectiveness of new derivatives of 2-oxoindolin-3-gly-oxylic acid which exceeded an effectiveness of medicine of comparison in the experiment having to do with the identical mechanism which optimizes the cellular respiration.

CONCLUSIONS
1. Ether and amid -new derivatives of 2-oxsoindolin-3glyoxylic acid -gave evidence of antihypoxic acivity in all experimental models of hypoxia. 2. In the cases of an acute hystotoxic and acute gemic hypoxia an effectiveness of the research substances was higher than an effectiveness of the research substances of medicine of comparison -mexidol. An antihypoxic activity of ether, amid and mexidol are almost identical in the experimental models of an acute normobaric hypoxia and acute hypobaric hypoxia. 3. When the reduction of an antihypoxic effect of ether and amid -derivatives of 2-oxoindolin-3-glyoxylic acid happens -one can arrange types of hypoxias in such an order: acute hystotoxic hypoxia > normobaric hypercapnic hypoxia > acute hypobaric hypoxia > acute gemic hypoxia. Prospects of further researches. Prospective is further preclinic study of new derivatives of 2-oxoindolin-3-glyoxylic acid and precision of mechanisms of their antihypoxic action.