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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

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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-tetrahydro[1, 3]diazepino[1, 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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Authors and Affiliations

  1. Institute of Physical and Organic Chemistry, Southern Federal University, 194/2 prosp. Stachki, 344090, Rostov on Don, Russian Federation

    A. S. Morkovnik, T. A. Kuz’menko, L. N. Divaeva, Yu. V. Koshchienko, V. A. Anisimova & M. V. Bogoslavtseva

  2. Volgograd State Medical University, 1 pl. Pavshikh Bortsov, 400131, Volgograd, Russian Federation

    A. A. Spasov, A. F. Kucheryavenko, 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

  3. N. S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, 31 Leninsky prosp., 119991, Moscow, Russian Federation

    L. G. Kuzmina

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  1. A. S. Morkovnik
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  7. V. A. Anisimova
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Correspondence to A. S. Morkovnik.

Additional information

Dedicated to Academician of the Russian Academy of Sciences N. S. Zefirov on the occasion of his 80th birthday.

Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 11, pp. 2622—2631, November, 2015.

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Morkovnik, A.S., Spasov, A.A., Kuz’menko, T.A. et al. 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. Russ Chem Bull 64, 2622–2631 (2015). https://doi.org/10.1007/s11172-015-1200-3

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  • DOI: https://doi.org/10.1007/s11172-015-1200-3

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