Prototropic equilibrium in 1(11)H-2,3,4,5-tetrahydro[1,3]diazepino[1,2-a]benzimidazole, synthesis and pharmacological properties of its N-substituted derivatives

摘要

Based on the X-ray crystallography and H-1 NMR spectroscopy data and quantum chemical studies, it was found that 1(11) H-2,3,4,5-tetrahydro[1,3] diazepino[1,2-a]benzimidazole (1) exists almost exclusively in the 1H-prototropic form. To prepare the fixed 11H-diazepinobenz-imidazole forms of 1, 1-R-2-(4-chlorobutylamino) benzimidazoles (R = Me, N= CHAr) were synthesized, which underwent thermal cyclization with the formation of a mixture of 11-R-substituted diazepine 1 and 1-R-2-(pyrrolidin-1-yl) benzimidazole. Alkylation of diazepine 1 in a neutral medium regioselectively gave 11-R-diazepinobenzimidazoles in high yield. Their 1-substituted isomers were obtained by carrying out this reaction in the system NaH-THF. The N(11)-derivatives of diazepinobenzimidazole 1 were found to inhibit dipeptidyl peptidase 4 (DPP-4), but less actively than a comparator drug sitagliptin. The compounds under study did not exhibit antiglycation action in vitro and virtually did not affect activity of a-glucosidase and glycogen phosphorylase. However, they are characterized by a strong antiaggregant effect, making these derivatives promising for further studies.