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

Abstract

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-(theophylline-7'-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-3-ylthio]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.

Keywords

• theophylline
• 4-triazole
• amides
• hydrazide
• synthesis
• physical properties