Prototropic equilibrium in 1(11)<Emphasis Type="Italic">H</Emphasis>-2, 3, 4, 5-tetrahydro[1, 3]diazepino[1, 2-<Emphasis Type="Italic">a</Emphasis>]benzimidazole,synthesis and pharmacological properties of its <Emphasis Type="Italic">N</Emphasis>-substituted derivatives |
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Authors: | A S Morkovnik A A Spasov T A Kuz’menko A F Kucheryavenko L N Divaeva Yu V Koshchienko V A Anisimova L G Kuzmina N V Rogova V A Kuznetsova N I Chepljaeva O A Solovyova A S Taran E S Vorobiev D A Aleshin V S Sirotenko K A Gajdukova M V Bogoslavtseva |
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Institution: | 1.Institute of Physical and Organic Chemistry,Southern Federal University,Rostov on Don,Russian Federation;2.Volgograd State Medical University,Volgograd,Russian Federation;3.N. S. Kurnakov Institute of General and Inorganic Chemistry,Russian Academy of Sciences,Moscow,Russian Federation |
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Abstract: | Based on the X-ray crystallography and 1H NMR spectroscopy data and quantum chemical studies, it was found that 1(11)H-2, 3, 4, 5-tetrahydro1, 3]diazepino1, 2-a]benzimidazole (1) exists almost exclusively in the 1H-prototropic form. To prepare the fixed 11H-diazepinobenzimidazole 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-Rsubstituted 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 α-glucosidase and glycogen phosphorylase. However, they are characterized by a strong antiaggregant effect, making these derivatives promising for further studies. |
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