Synthesis, physical-chemical properties and the study of anti-hypoxemic activity

Heterocyclic systems, in particular, 1,2,4-triazole derivatives cause great interest in the development of new medicinal substances for the production of highly effective and safe antihypoxants. This fact has created favorable basis for the synthesis of new alkylderivatives 5-(adamantane-1-yl)-4-R-1,2,4-triazole-3-thion, where R is methyl, phenyl. Aim. In order to identify the most promising active compounds the pharmacological screening of anti-hypoxemic activity of synthesized compounds has been carried out. Results. Due to the results of the study a number of compounds with anti-hypoxemic activity have been revealed. Some regularities between structure and pharmacological effect have been established. Conclusion. This demonstrates the prospects of further studies of the obtained compounds.

H ypoxia is a typical pathological process, which occurs as a result of the failure of biological oxidation and due to its energy insecurity of life processes [1]. There is acute and chronic oxygen starvation of cells. Acute hypoxia develops in all types of shock, blood loss, and physical overload. Chronic hypoxia is observed in several pathological conditions: diseases of the respiratory system, cardiovascular system, diseases of the blood, liver, kidneys, and endocrine system [2,3,4].
Various forms of hypoxia, including ischemia are major cause of cerebral stroke and coronary heart disease [5].
To reduce hypoxia, pharmacological means (antihypoxants and antioxidants) and methods are used to enhance the oxygen's delivery into the body and improve the utilization of the body's circulating oxygen, reducing the oxygen demand in the organs and tissues. Drugs contribute to more economical oxygen's expenditure by the tissues, its best utilization and reducing of hypoxia and they also increase the body's resistance to oxygen defi ciency [6,7].
Mexidol, pyracetam, amoxyne, pentoxifilline are most commonly used antihypoxants, which have numerous side effects and they limit their use. Therefore, the development of new medicinal substances for the production of highly effective and safe antihypoxants is one of the most important areas of modern biological, pharmaceutical and medicinal chemistry. Heterocyclic systems call great interest in this direction, in particular, 1,2,4-triazole derivatives.
The obtained compounds are crystalline substances of white color, which were recrystallized from n-butanol for analysis. Physical-chemical constants of the obtained compounds are given in the table 1.
Antihypoxic activity of 5-(adamantane-1-yl)-4-R-1,2,4triazole-3-thion alkylderivatives has been studied [8] to simulate hypoxia with hypercapnia, which was reproduced by placing rats in glass jars of the same size (1330 ml) closed hermetically and turned upside down and placed in a cuvette with water to prevent the admission of air. Mexidol in a dose of 100 mg/kg was used as a comparative drug in the research [9].
Comparative drug Mexidol was injected in aqueous solution. The action of each substance was studied in 7 animals. The control group received isotonic sodium chloride solution. The investigated compounds were administered in a dose of 1/10 of LD50.

Вопросы фармации / Problems of pharmacy
The research results are processed by modern statistical methods of analysis on a personal computer using standard software package Microsoft Offi ce 2010 (Microsoft Excel) and «STATISTICA® for Windows 6.0». Average arithmetics (M) and standard errors of (± m) were calculated. Reliability of inter groups differences according to the experiments were established by using t-Student criterion. 3 levels of statistical signifi cance of differences in the results of the research -p<0.05; p<0.01; and p<0.001 were used [10,11].
The results and their discussion The structure of all synthesized compounds has been confi rmed by the integrated use of modern physical-chemical methods of analysis: elemental, IR spectroscopy and their individuality is detected by thin layer chromatography.
Band oscillations groups characteristic for the nucleus of 1,2,4-triazole: NH-within 3400-3100 cm -1 , -C=N-1690-1620 cm -1 are present in the IR spectra of compounds I, II. There are also present band oscillations groups -C-S in 705-570 cm -1 . There are band oscillations within 2600-2550 cm -1 , which may indicate to the presence of -SН groups in the molecule.
It is established that anti-hypoxemic activity in a series of alkylderivatives 5-(adamantane-1-yl)-4-R-1,2,4-triazole-3-tion (comp. I, II) due to the nature of the substituent at the N 4 atom nitrogen of the nucleus of 1,2,4-triazole and the length of the   Notes: * -p<0.05 relatively to control; ** -p<0.05 relatively to Mexidol; n -the number of animals in each group of the research.
carbon chain alkyl residue with the sulfur atom. The compounds IIc and IIg showed antihypoxic activity, which exceeds the control on 184,47 % (p<0.01) and 180,79 % (p<0.05) and were higher than the activity of the Mexidol on 28,86 and 26,29 %, respectively.
Іb and Ic compounds are close to Mexidol activity, but well worth to note the IIb compound, which 3,12 % less effi cient than Mexidol.
The analysis of the results indicates high antihypoxic activity due to the life expectancy indicator of rats of all studied substances in comparison with the control.
As a result of the studies (ІІ, ІІс, ІІg) compounds were identifi ed, which antihypoxic activity higher than Mexidol the comparison product.
Analyzing the dependence of the chemical structure from antihypoxic activity certain patterns were established between pharmacological activity and chemical structure. Thus, the increase of the alkyl substituent on the sulfur atom to six carbon atoms in the presence, as a methylic (comp. Ic) and phenolic (comp. IIc) radicals at N 4 atoms causes the growth of antihypoxic effect.
It was found that the methyl radical on phenyl substituent replacing at N 4 atom of nitrogen enhances antihypoxic activity of (ІІ, ІІс, ІІg comp.).
A signifi cant reduction of antihypoxic activity is observed with increasing carbon chain to heptile, octile and nonile substituents in the case, as with methyl and phenyl substituents ( IIe, IId, If). But the growth up to ten carbon atoms promotes the growth of antihypoxic activity (comp. IIg).
5. It was established that the methyl radical replacing on phenyl substituent at N 4 atom of nitrogen enhances antihypoxic activity.