Synthesis and physical-chemical properties of 3-aryl-( aralkyl )-8-hydrazinemethylxanthines and their N-substituted derivatives

Introduction. Analysis of last years’ literature shows, that the most wide spread drugs are those, which contain in their structures heterocyclic fragment. Such trend could be explained by the fact that, heterocycle containing compounds are the part of the number of substances, which play an important role in the metabolic processes. It should be noted, that most of these drugs have unpleasant side effects and some of them are rather toxic. Xanthine derivatives are low toxic natural compounds with wide spectrum of pronounced pharmacological properties (antioxidant, diuretic, antibacterial, anti-inflammatory etc.) and high variability of chemical modification, that make these compounds handy objects for pharmaceutical research. Thus, synthesis of novel less toxic biologically active compounds – potential medicines – by chemical modification of well-known natural substances, is one of the most important tasks of modern pharmaceutical science. Aim of our research was the development of method of 3-aryl(aralkyl)-8-hydrazinemethylxanthines and their N-substituted derivatives synthesis and studying their physical-chemical properties. Materials and methods. Melting points were determined using capillary method on DMP (M). 1 Н NMR-spectra were recorded by Varian Mercury VX-200 device (company «Varian» – USA) solvent – (DMSO- d 6 ), internal standard – ТМS. Elemental analysis of obtained compounds was produced on device Elementar Vario L cube. Results and discussion.  We selected 3-aryl(aralkyl)-8-chloromethylxanthines as initial compounds for our study. By their interaction with hydrazine hydrate we obtained respective 8-hydrazinemethylxanthines. The next stage of our research was further chemical modification of obtained 8-hydrazinemethylxanthines using the high ability of hydrazine residue for nucleophilic addition reactions. So, we studied the interaction of 3-aryl(aralkyl)-8-hydrazinemethylxanthines with phenylisothiocyanate and carbonyl compounds and synthesized number of N-substituted 8-hydrazinemethylxanthines. The structures of all obtained compounds were proved by the elemental analysis and 1 H NMR-spectroscopy. Conclusions. Obtained results of our work can be used for further search of biological active compounds among xanthine derivatives with hydrazine residue.

A nalysis of last years' literature shows, that the most wide spread drugs are those, which contain in their structures heterocyclic fragment [1].Such trend could be explained by the fact that, heterocycle containing compounds are the part of the number of substances, which play an important role in the metabolic processes.It should be noted, that most of these drugs have unpleasant side effects and some of them are rather toxic [1][2][3].
Thus, synthesis of novel less toxic biological active compounds -potential medicines -by chemical modifi cation of well-known natural substances is one of the most important tasks of modern pharmaceutical science.
Xanthine derivatives are low toxic natural compounds with wide spectrum of pronounced pharmacological properties (antioxidant, diuretic, antibacterial, anti-infl ammatory etc) and high variability of chemical modifi cation [4][5][6][7], that make these compounds handy objects for pharmaceutical research.
One of the most chemically active functional groups is hydrazine group, which easily participate in reactions of nucleophilic addition [8,9].Thus, insertion of such functional fragment in the structure of xanthine molecule could increase its synthetic potential [8][9][10].

Aim of the work
Development of method of 3-aryl(aralkyl)-8-hydrazinemethylxanthines and their N-substituted derivatives synthesis and studying their physical-chemical properties.

Materials and methods
Melting points were determined using capillary method on DMP (M). 1 Н NMR-spectra were recorded by Varian Mercury VX-200 device (company «Varian» -USA) solvent -(DMSO-d6), internal standard -ТМS.Elemental analysis of obtained compounds was produced on device Elementar Vario ЕL cube.

Results and their discussion
As initial compound for synthesis of 8-hydrazinemethylxanthines 3 and 4 we used 8-chloromethylxanthines 1 and 2, which had been obtained by the method described earlier [11].Reaction was taking out by the refl ux of compounds 1 and 2 in the aqueous dioxane with hydrazine hydrate (Fig. 1).
The presence of the hydrazinemethylene fragment in the structure of compounds 3 and 4 was proved by the 1 Н NMR-spectroscopy data.Thus, we registered the signals of protons of hydrazine group in the form of low-intensive multiplet (1H, 11.12 ppm) and doublet (2H, 4.74 ppm) in the spectrum of 3-benzyl-8-hydrazinemethylxanthine 4. The protons of methylene group in position 8 resonated in the form of doublet at 4.32 ppm, that confi rmed substitution of halogen atom on hydrazine group and C-N bond formation.Other signals corresponded to the protons of NH-groups of xanthine heterocycle and CH 2 -and aromatic groups of benzyl residue (Table 1).
The next stage of our research was further chemical modifi cation of obtained compounds 3 and 4 using the high ability of hydrazine residue for nucleophilic addition reactions (Fig. 1).
In the 1 Н NMR-spectrum of compound 5 were registered additional singlet of NH group (9.83 ppm) and multiplets of aromatic group protons at 7.08-6.89ppm (3Н) and 6.59-6.42ppm (2H) in comparison with initial compound 3 (Table 1).Other signals confi rmed the structure of xanthine fragment and substituents in the positions 3 and 8.
Then we study reaction of 8-hydrazinemethylxanthines 3 and 4 with different aromatic and heterocyclic aldehydes and ketones.We found out that interaction of xanthine derivatives 3 or 4 with carbonyl compounds in the aqueous dioxane in the presence of catalytic amount of glacial acetic acid led to formation of respective 8-ylidenhydrazinemethylxanthines 6-17.In the 1 Н NMR-spectra of compounds 6-17 the signals of protons of NH 2 -groups were absent and NH-groups protons resonated in the form of triplets in comparison with 1 Н NMR data of initial compounds 3 and 4. Also we registered signals of azomethine-fragments and aldehyde or ketone residues, which additional confi rm the structures of obtained compounds (Table 1).
Thus, in the 1 Н NMR-spectra of compound 13 proton of azomethine-fragment resonated in the form of intensive singlet at 8.74 ppm (Table 1, fi g. 2).
Presence in the spectra NH-group triplet at 5.50 ppm, CH 2group doublet at 4.28 ppm and aromatic protons multiplet at 7.56-7.31ppm confi rm the structure of substituents in the position 3 and 8 of xanthine system.NH-groups of xanthine heterocycle registered as intensity singlets in the weak fi eld at 13.35 ppm (N 7 H) and 11.22 ppm (N 1 H) respectively.