Abstract
The synthesis of new derivatives of 2-[(1,4-dioxo-1-amino-4-arylbutyl-2-en-2-yl)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid is described. Starting 2-{[5-aryl-2-oxofuran-3(2H)-ylidene]amino}thiophene-3-carboxylic acids were obtained by intramolecular cyclisation of substituted 4-aryl-4-oxo-2-thienylaminobut-2-enoic acids in acetic anhydride. New derivatives of 2-[(1,4-dioxo-1-amino-4-arylbutyl-2-en-2-yl)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acids were obtained via decyclization reaction of 2-{[5-aryl-2-oxofuran-3(2H)-ylidene]amino}thiophene-3-carboxylic acids. The structure of the compounds obtained was confirmed by the 1H and 13C NMR spectroscopy, IR spectrometry and elemental analysis methods. Analgesic activity of new compounds has been studied by the “hot plate” method on outbred white mice of both sexes with intraperitoneal injection. It was found that derivatives of 2-[(1,4-dioxo-1-amino-4-arylbutyl-2-en-2-yl)amino]-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid possess analgesic effect exceeding the effect of the comparison drug metamizole.
Highlights
The Gewald aminothiophene fragment is a promising pharmacophore group, since it was found in both natural and synthetic physiologically active compounds [1,2,3,4,5,6]
The mechanism of the decyclization reaction of 5-aryl2,3-dihydro-2,3-furandiones under the action of nucleophilic reagents was published based on the detailed largescale study of kinetic data [34,35,36] as well as quantum chemical calculations [37]
Assuming the similarity of these structures with the iminofuranones discussed in the current paper, we can assume the validity of this mechanism for the transformations 3-thienylimino-3H-furan-2ones 2a,b under the action of amines as nucleophiles (NuH) described here (Scheme 2)
Summary
The Gewald aminothiophene fragment is a promising pharmacophore group, since it was found in both natural and synthetic physiologically active compounds [1,2,3,4,5,6]. The synthesis of substituted Gewald aminothiophenes can be carried out using the Gewald reaction [7,8,9]. 3imino(hydrazono)-3H-furan-2-ones have high reactivity, leading to the production of compounds of various structures [10,11,12,13,14,15,16,17]. Decyclization reactions of 3-imino-3Hfuran-2-ones lead to the production of 2,4-dioxobutanoic acid derivatives, for which antiviral [18,19,20,21,22], analgesic [23], anti-inflammatory [24], antimicrobial [25] activity was determined. Synthesis and analgesic activity of new 2-[(1,4-dioxo-1-amino-4-arylbutyl-2-en-2-yl)amino]4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid derivatives is discussed
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