Synthesis, structure and properties of N-R-amides and hydrazides of 2-[4-R-5-(theophylline-7ʹ-yl)-1,2,4-triazole-3-ylthio]acetic acid

One of the most important tasks of modern pharmaceutical science is the search for new biologically active substances, which have high efficacy and low toxicity. Derivatives of 1,2,4-triazole and theophylline are a promising class of compounds for synthesis of biologically active substances on their basis, due to a wide range of biological activity of these heterocycles’ derivatives. The purpose of work is the development of efficient methods for synthesis of new amides and hydrazides of 2-[4-R-5-(theophylline7’-yl)-1,2,4-triazole-3-ylthio]acetic acid (R = CH3, C2H5, C6H5) with variation of the reactions conditions and the study of physical properties of the obtained compounds. Materials and methods. As a key source of reagents we used 7’-((3-thio-4-R-4H-1,2,4-triazole-5-yl)methyl)theophylline and esters of 2-[4-R-5-(theophylline-7’-yl)-1,2,4-triazole-3-ylthio]acetic acid, which were obtained by known methods from readily available raw materials. By heating in ethanol medium the corresponding amines (ammonia, methylamine, ethylamine, monoethanolamine, diethanolamine), n-propyl ether 2-[4-R-5-(theophylline-7’-yl)-1,2,4-triazole-3-ylthio]acetic acid a series of amides of 2-[4-R-5(theophylline-7’-yl)-1,2,4-triazole-3-ylthio]acetic acid were obtained. Hydrazide of 2-[4-R-5-(theophylline-7’-yl)-1,2,4-triazole-3ylthio]acetic acid was synthesized by interaction of corresponding esters of 2-[4-R-5-(theophylline-7’-yl)-1,2,4-triazole-3-ylthio]acetic acid with an aqueous solution of hydrazine hydrate in ethanol medium. The structure of the obtained compounds is confirmed by data of elemental analysis, 1H NMR spectroscopy and IR-spectrophotometry. The individuality of substances is established by using high performance liquid chromatography with diode-array and mass spectrometric detection. Results. Optimal methods of obtaining amides and hydrazides of 2-[4-R-5-(theophylline-7’-yl)-1,2,4-triazole-3-ylthio]acetic acid have been developed. Getting investigated amides by two alternative ways of synthesis, it was established that the initial interaction of thiol with 2-chloracetamide proceeds with high yield product of the reaction compared to the reaction between a corresponding ester with ammonia. Conclusions. 15 amide and 3 hydrazide 2-[4-R-5-(theophylline-7’-yl)-1,2,4-triazole-3-ylthio]acetic acids have been synthesized, their structure has been established and physical properties have been studied.


The purpose of the work
The purpose of the work is the synthesis of new amides and hydrazides of 2-[4-R-5-(theophylline-7'-yl)-1,2,4-triazol-3ylthio]acetic acid and the study of their physical properties.
The study of physical-chemical properties of the obtained compounds was carried out using methods listed in the State Pharmacopoeia of Ukraine. The melting point was determined using capillary method on Stanford Research Systems Melting Point Apparatus 100 (SRS, USA). The structure of the compounds was confirmed with elemental analysis on Elemental Vario EL cube (Elementar Analysensysteme, Germany), IR spectra (4000-400 cm -1 ) were taken off the module ALPHA-T of Bruker ALPHA FT-IR spectrometer (Bruker optics, Germany). Chromato-mass-spectral studies were carried out on the instrument Agilent 1260 Series LC/MSD System, method of ionization -electrospray (ESI).

Results and their discussion
The presence of the amide group in the IR-spectrum of the obtained compounds was confirmed by the presence of characteristic absorption bands in the region of 3132-3370 cm -1 (СОNH 2 ) and in the region 1630-1675 cm -1 (СОNH 2 ). The absorption band of the secondary amino group was observed in the range of 3165-3200 cm -1 . The IR-spectrum of compounds 4, 5, 11, 12, 17, 18 in addition to the above has an additional absorption band within 950-890 cm -1 , indicating the presence of OH-groups.
In the NMR 1 H synthesized compounds, signals of protons with chemical displacements are present, which confirm the structure of the resulting compounds. Signals of protons of methylene groups (3.75-3.85 ppm), aromatic prototype multiplets -for compounds 13-18 (7.25-8.16 ppm). In addition, proton of amide NH-group (7.65-7.93 ppm), a proton of the hydroxyl group (2.09-4.71 ppm). Intense signals of protons of methyl groups of the xanthine fragment are recorded in intervals at 3.15-3.30 ppm, and at 3.50-3.60 ppm. The signal of the methyl proton of the indicated fragment is registered in the form of a singlet in the range of 8.30-8.43 ppm. The protons of the thiomethylene moiety resonate at 3.88 ppm in the form of a singlet. In compound 13, the magnetic properties of the protons of the phenyl substituent and the amide group were so close that their resonance frequencies practically coincided: in spectra for protons signals of these two groups one single multiplier with a total intensity of 7H can be observed at 6.65-7.75 ppm.
In the mass spectrum, there is a peak of the molecular ion and peaks of fragment ions, which confirm this structure.

Conclusions
A universal method for the preparation of 2-[4-R-5-(theophylline-7'-yl)-1,2,4-triazol-3-ylthio]acetic acid amides and hydrazides was developed. It was established that while the interaction of the starting thiol with 2-chloroacetamide the product yields of the reaction are greater than in the reaction of the corresponding ester with ammonia.