Synthesis and antinociceptive activity of 2,2’-(1,4-phenylene)bis[3-aryl-2-azaspiro[3.5]nonan-1-ones]

Abstract

Over the years, azetidin-2-ones, or β-lactams, have received a lot of attention from scientists as potential drug candidates due to their diverse biological activity. Spiro-β-lactams also exhibit biological activity; therefore, it is of interest to synthesize and study the properties of new compounds belonging to this class. The study aims to examine the antinociceptive activity of several synthesized bis(spirolactams), specifically 2,2’-(1,4-phenylene)bis[3-aryl-2azaspiro[3.5]nonan-1-ones]. These bis(spiroazetidine-2-ones) were obtained in the interaction of a twofold excess of the Reformatsky reagent, derived from methyl 1-bromocyclohexane carboxylate and zinc, with N,N-(1,4-phenyle- ne)bis(1-arylmethanimines) by means of boiling them in a 10:1 mixture of toluene and hexamethylphosphorictriamide for four hours. Bis(spiro-β-lactams) on the basis of diimines derived from p-phenylenediamine, 2-methoxybenzaldehyde, p-tolualdehyde, and 3-bromobenzoic aldehyde were synthesized for the first time. The composition and structure of the previously undescribed products were established using IR, [1]H, and 13C NMR spectroscopy and elemental analysis. The antinociceptive activity of the obtained compounds was studied on outbred white mice of both sexes via the hot plate test with an intraperitoneal injection. The effect was estimated two hours after administration. Several synthesized compounds were found to exhibit antinociceptive activity at or above the level of the comparator product – metamizole sodium. Nerve endings can be considered the target of the antinociceptive activity of examined substances since under the effect of these substances, no signs of central action are observed in the behavior of animals. Thus, the conducted studies showed the promise of further search for biologically active substances among the compounds of this series.