SYNTHESIS OF THE ROW OF NEW FUNCTIONAL DERIVATIVES OF 7-ARYLALKYL -8-HYDRAZINE THEOPHYLLINES

Hydrazine functional derivatives are widely used in medical practice as remedies applied for pharmacotherapy of depression, infection diseases, hypertension, diabetes, etc. It is worth mentioning that among obtained 7-R-8-hydrazine derivatives of 1,3-dimethylxantine promising substances have been identified. Due to the fact that literature sources display only results of occasional studies of the reactions between 7-R-8-hydrazine theophyllines and mono- or dicarbonyle substances, the use of other keto reagents for xanthine bicycle at 8 th position function-alization will allow to explore synthetic potential of the last one, and with high probability may lead to obtaining original biologically active substances. Aim. To study types of reaction between 8- hydrazinyl-1,3-dimethyl-7-aryl alkyl-1H-purine-2,6(3H,7H)-diones and a number of carbonyl containing reagents. Methods. A nucleophilic addition reaction followed by dehydration or ethanol splitting was used, as well as the complex of the modern analysis methods to confirm the structure and individuality of the synthesized substances. Results. Different directions of 8-hydrazinyl-1,3,-dimethyl-7(fenetyl-, 3-phenylpropyl-, 3-phenylalyl)- 1H-purine-2,6(3H,7H)-diones chemical transformations in reactions with the appropriate carbonyl containing compounds have been studied experimentally. The structure of synthesized substances was confirmed by chromatog-raphy/mass and 1 H NMR spectroscopy. Conclusion. The group of 7-arylalkyl-8-(3,5-R,R 1 -pyrazole-1-yl)theophyllines, consisting of two functionally substituted bioactive heterocycles, has been synthesized by reaction between initial substances and selected mono- and dicarbonyl compounds


Introduction
Hydrazine functional derivatives are widely used in medical practice as remedies applied for pharmacotherapy of depression, infection diseases, hypertension, diabetes, etc [1][2][3]. Leading scientific journals constantly show new publications displaying results of both research in the area of hydrazine containing substances synthesis, and biological study for detection of original substances with promising pharmacological effects in the given group of compounds [4,5]. It is worth mentioning that theophylline molecule is also pharmacologically active. Its combination with different substituents, including heterocyclic number, may lead to increasing of both the severity and range of biological effects of the synthesized compounds. In this respect, a significant attention of scientists from different countries [6][7][8] is drawn to some 7-R-8-hydrazine derivatives of 1,3-dimethylxanthine, as basic structures for different chemical transformations.

Formulation of the problem in a general way, the relevance of the theme and its connection with important scientific and practical issues
Despite the large number of registered in Ukraine remedies, the need of original substances for treatment of different disorders of human's organism remains relevant. Therefore, the synthesis of new molecules (including different azaheterocycles derivatives) based on the use of already established «structure-activity» relationship is highly important for modern pharmaceutical and medical chemistry.

Analysis of recent studies and publications in which a solution of the problem and which draws on the author
Literature sources [2, 3] describe a pronounced biological activity of the relevant xanthine and pyrazole methylated derivatives. Some representatives of these compounds have been successfully used in medical practice, but their synthetic and pharmacological potentials are far from being exhausted.

Allocation of unsolved parts of the general problem, which is dedicated to the article
Considering the theophylline derivatives' high reaction ability and versatile biological activity, the synthesis of the number of original 7,8-disubstituted of 1,3dimethylxantine was reasonable.
The reaction of 5-7 compounds with methyl 4-(4methyl-(metoxy-,chloro-)phenyl)-2,4-dioxobutanoate and ethyl 3-(furan-2-yl)-3-oxopropanoate has been studied under different conditions of chemical process. The given reagents have not been chosen randomly, since they contain functional components, which adding to other heterocyclic systems led to strengthening of pharmacological activity of the last ones [10].
However, in the case of the use of above mentioned esters as reagents, as results of analysis of the Reaxys Elsevier database relevant part show, reaction with 5-7 substances by the given method can be accompanied by the formation of a complex mixture of products.
In 1 H NMR spectra of compounds 8 and 9 double signals of protons of -NH-, -СН 2 -та -ОСН 3 -groups were registered, indicating possible existence of these substances as mixtures of E-and Z-isomers. Due to OHgroup presence, in weak fields of 1 H NMR spectra of 19-21 compounds expanded one proton singlets were identified, which confirmes the presence of the given compounds in enol form.
Chromatography/mass spectroscopy research of the obtained substances were carried out using HPLC Agilent 1100 Series, equipped with diode matrix and mass-selective Agilent LC/MSD SL detectors. Chemical ionization at atmospheric pressure was chosen as ionisation method. The 1 H NMR spectra of synthesized compounds were recorded by using Varian Mercury 400 (400 MHz) spectrometer, DMSO-d 6 solvent, internal standardtetrametylsylan. IR spetra (in area of 4000-600 sm -1 ) were recorded by using Bruker ALPHA FT-ІR spectrometer on the ATR console (soothing a general display).
Add 0.0027 mole of relevant methyl 2,4-dioxo-4-R-phenylbutanoate (R=СН 3 , ОСН 3 , Cl) to suspension of 0.0027 mole of substances 5-7 in 7 ml of glacial acetic acid and boil for 8 hours. Obtained solutions with intensive colors are cooled and poured into water. Formed precipitates are filtered, dried, and purified by recrystallization from ethanol.