4-Aminosubstituted 1,6-dyhidropyrazolo[3,4-e][1,4] diazepines: the synthesis, NMR-spectral and quantum-chemical study

S. V. Kemskіі, Yu. S. Boyko, A. V. Bolbut, S. Yu. Suykov, A. A. Kyrylchuk, M. V. Vovk


The role of the structural modification of 1,4-benzodiazepine systems with dialkylamino groups previously used successfully for a number of important derivatives possessing a complex of specific biological properties has been noted. This paper significantly expands the variety of hetero-annelated diazepines by developing a preparatively convenient synthetic route of new amino substituted pyrazol[3,4-e][1,4]diazepines. For this purpose, the reaction of 4-chloro-1,6-dihydropyrazolo[3,4-e][1,4]diazepines with the primary alkyl (aryl) amines and the secon- dary cycloalkylamines has been studied in detail. It has been found that this interaction occurs under 8-10 hour reflux in ethanol and for the primary and secondary alkylamines it leads to 4-amino-1,6-dihydropyrazolo[3,4-e] [1,4]diazepine hydrochlorides, and in case of aryl amines – to their corresponding free bases with high yields. The reaction of the secondary amines has been shown to be very sensitive to their steric parameters: dietyl- or diisopropylamines do not interact with 4-chloro derivatives of 1,6-dihydropyrazolo[3,4-e][1,4]diazepines. The structure of the compounds synthesized is consistent with the results of elemental analysis, LS/MS-, IR- and NMR-spectra. The COSY and EXSY methods were used for reliable identification of signals of cycloalkylamino substituents of 1,6 dihydropyrazolo[3,4-e][1,4]diazepines. Changes in NMR-spectra during protonation of 5-cycloalkylaminopyrazolodiazepines correspond to the results of quantum chemical simulations, according to them the preferred structure is the one with the protonated nitrogen atom in position 5 of the pyrazolodiazepine system.


4-aminosubstituted 1,6-dyhidropyrazolo[3,4-e][1,4]diazepines; structural modification; bioactive compounds


Ramajayam R., Girdhar R., Yadav M. R. Mini-Rev. Med. Chem., 2007, Vol. 7, pp.793-812.

Insuasty B., Ramirez J., Becerra D., Echeverry C., Quiroga J., Abonia R., Robledo S. M., Velez I. D., Upegui Y., Munoz J. A., Ospina V., Nogueras M., Cobo J. Eur. J. Med. Chem., 2015, Vol. 93, pp.401-413.

Pertejo P., Garcia-Valverde M., Pena P., Cordero N. A., Torroba T., Gonzalez-Ortega A. Org. Biomol. Chem., 2014, Vol. 12, pp.4905-4916.

El-Subbaghv H. I., Hassan G. S., El-Messery S. M., T. Al-Rashood S. T., Al-Omary F. A. M., Abulfadl Y. S., Shabayek M. I. Eur. J. Med. Chem., 2014, Vol. 74, pp.234-245.

Hernandez S., Moreno I., SanMartin R., Herrero M. T., Dominguez E. Org. Biomol. Chem., 2011, Vol. 9, pp.2251-2257.

Showell G. A., Bourrain S., Neduvelil J. G., Fletcher S. R., Baker R., Watt A. P., Fletcher A. E., Freedman S. B., Kemp J. A., Morshall G. R., Patel S., Smitn A., Matossa V. G. J. Med. Chem., 1994, Vol. 37, pp.719-721.

Пат. US 5696110(A)(1997). Заявл.: 09.05.1995. Опубл.: 09.12.1997 [Електроний ресурс]. Режим доступу http:worldwide.espacent.com

Пат. US 5618812(1997). Заявл.: 26.07.1995. Опубл.: 08.04.1997 [Електроний ресурс]. Режим доступу http:worldwide.espacent.com

Bihel F. J. J., Justiniano H., Schmitt M., Hellal M., Mohamed A. Ibrahim M. A., Lugnier C., Bourguignon J.-J. Bioorg. Med. Chem. Lett., 2011, Vol. 21, pp.6567-6572.

Пат. US 2004152888(A1)(2004). Заявл.: 07.06.2002. Опубл.: 08.05.2004 [Електроний ресурс]. Режим доступу http:worldwide.espacent.com

Пат. WO2010121164(A2)(2010). Заявл.: 17.04.2009. Опубл.: 21.10.2010 [Електроний ресурс]. Режим доступу http:worldwide.espacent.com

Пат. US 2002045747(A1)(2002). Заявл.: 30.07.2001. Опубл.: 18.04.2002 [Електроний ресурс]. Режим доступу http:worldwide.espacent.com

Пат. US 5595990(1997). Заявл.: 27.03.1995. Опубл.: 21.01.1997 [Електроний ресурс]. Режим доступу http:worldwide.espacent.com

Пат. US 20030171364(A1)(2003). Заявл.: 27.12.2002. Опубл.: 11.09.2003 [Електроний ресурс]. Режим доступу http:worldwide.espacent.com

Kemskii S. V., Bol’but A. V., Vovk M. V. Russ. J. Org. Chem., 2015, Vol. 51, pp.1481-1487.

Hyunter Kh. Vvedeniye v kurs spektroskopii YaMR. Perevod s angliyskoho. Moskwa, 1984.

Ahlrichs R., Bär M., Häser M., Horn H., Kölmel C. Chem. Phys. Lett., 1989, Vol. 162, pp.165–169.

Furche F., Ahlrichs R., Hättig C., Klopper W., Sierka M., Weigend F. Wiley Interdiscip. Rev. Comput. Mol. Scі., 2014, Vol. 4, pp.91-100.

Whitten J. L. J. Chem. Phys., 1973, Vol. 58, pp.4496.

Dunlap B. I., Connolly J. W. D., Sabin J. R. J. Chem. Phys., 1979, Vol. 71, pp.3396.

Vahtra O., Almlöf J., Feyereise M. W. Chem. Phys. Lett., 1993, pp.514-518.

Eichkor K., Treutler O., Öhm H., Häser M., Ahlrichs R. Chem. Phys. Lett., 1995, Vol. 240, pp.283-289.

Grimme S., Antony J., Schwabe T., Mück-Lichtenfeld C. Org. Biomol. Chem., 2007, Vol. 5, pp.741-758.

Schäfer A., Huber C., Ahlrichs R. J. Chem. Phys., 1994, Vol. 100, pp.5829-5835.

Frisch M. J., Trucks G. W., Schlegel H. B., Robb M. A., Cheesema J. R., Scalmani G., Barone V., Petersson G. A., Nakatsuji H., Caricato M., Li X., Izmaylov A. F., Bloino J., Zheng G., Sonnenberg J. L., Ehara M., Toyota K., Fukuda R., Hasegawa J., Ishida M., Honda Y., Kitao O., Nakai H., Vreven T., Montgomery J. A., Peralta E., Ogliaro F., Bearpark M., Heyd J. J., Kudin K. N., Staroverov V. N., Keith T., Kobayashi R., Raghavachari K., Rendel A. l, Burant J. C., Iyengar S. S., Cossi M., Rega N., Millam J. M., Klene M., Knox J. E., Bakken V., Adamo C., Jaramillo J., Gomperts R., Yazyev O., Austin A. J., Cammi R., Pomelli C., Martin R. L., Morokuma K., Zakrzewski V. G.,. Salvador P., Dannenberg J. J., Dapprich S., Farkas O., Foresman B., Ortiz J. V., Fox J. C., Gaussian, Inc., Wallingford CT 2010.

Becke A. D. Phys. Rev. A, 1988, Vol. 3, pp.3098-3100.

Perdew J. P. Phys. Rev. B, 1986, Vol. 33, pp.8822-8824.

Ditchfield R., Hehre W. J., Pople J. A. J. Chem. Phys., 1971, Vol. 54, pp.724-728.

Hariharan P. C., Pople J. A. Theor. Chim. Acta, 1973, Vol. 28, pp.213-222.

Hariharan P. C., Pople, J. A. Mol. Phys., 1974, Vol. 27, pp.209-214.

Hehre W. J. Ditchfield R., Pople J. A. J. Chem. Phys., 1972, Vol. 56, pp.2257-2261.

Frisch M. J. Pople J. A., Binkley J. S. J. Chem. Phys., 1984, Vol. 80, pp.3265.

Klamt A., Schüürmann G. J. Chem. Soc. Perkin Trans. 2., 1993, pp.799-805.

Schäfer A., Klamt A., Sattel D., Lohrenz J. C. W., Eckert F. Phys. Chem. Chem. Phys., 2000, Vol. 2, pp.2187-2193.

Klamt A. Wiley Interdiscip. Rev. Comput. Mol. Sci., 2011, Vol. 1, pp.699-709.

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DOI: https://doi.org/10.24959/ophcj.16.896

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