The synthesis, analgesic and anti-inflammatory activity of 3-aryl(heteryl)-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)-acrylonitrile derivatives.

Serhii A. Demchenko; Yuliia A. Fedchenkova; Serhii A. Tsyhankov; Оleh E. Yadlovskyi; Volodymyr V. Sukhoveev; Tetiana A. Bukhtiarova; Ludmyla S. Bobkova; Anatolii M. Demchenko

doi:10.24959/ophcj.20.193511

Authors

Serhii A. Demchenko Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine, Ukraine https://orcid.org/0000-0003-2242-0471
Yuliia A. Fedchenkova Nizhyn Mykola Gogol State University, Ukraine https://orcid.org/0000-0003-1240-3053
Serhii A. Tsyhankov Nizhyn Mykola Gogol State University, Ukraine https://orcid.org/0000-0001-6571-8628
Оleh E. Yadlovskyi Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine, Ukraine https://orcid.org/0000-0001-9650-8375
Volodymyr V. Sukhoveev Nizhyn Mykola Gogol State University, Ukraine https://orcid.org/0000-0002-1590-1675
Tetiana A. Bukhtiarova Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine, Ukraine https://orcid.org/0000-0002-2458-8625
Ludmyla S. Bobkova Institute of Pharmacology and Toxicology of the National Academy of Medical Sciences of Ukraine, Ukraine https://orcid.org/0000-0002-6688-2056
Anatolii M. Demchenko Nizhyn Mykola Gogol State University, Ukraine https://orcid.org/0000-0002-2173-3356

DOI:

https://doi.org/10.24959/ophcj.20.193511

Keywords:

3-(het)aryl-2-(6, 7, 8, 9-tetrahydro-5H-[1, 2, 4]triazolo[4, 3-a]azepin-3-yl)acrylonitrile derivatives, ketorolac, analgesic activity, anti-inflammatory activity

Abstract

Aim. To synthesize, prove the structure and study the analgesic and anti-inflammatory activities of 3-(het)-aryl-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acrylonitrile derivatives.

Results and discussion. Condensation of 2-methoxy-3,4,5,6-tetrahydro-7H-azepine with cyanoacetic acid hydrazide leads to formation of 2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acetonitrile. The latter readily reacts with the corresponding (het)arenecarbaldehydes in refluxing ethanol in the presence of catalytic amount of piperidine yielding a series of new 3-(het)aryl-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acrylonitrile derivatives. Further functionalization of 3-(4-hydroxy-3-R-phenyl)-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acrylonitriles has been done by modification of the OH group. One of the compounds synthesized, namely 3-(4-hydroxyphenyl)-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acrylonitrile, exhibits a high level of the analgesic activity on the “hot plate” model, and a similar level of the activity on the model of “acetic acid-induced writhings” as compared to ketorolac. The results obtained indicate the pronounced antinociceptive activity for the test compound.

Experimental part. ¹H NMR spectra of the compounds synthesized were recorded on a Bruker VXR-300 spectrometer (Germany) operating at a frequency of 299.945 MHz, in DMSO-d₆, using tetramethylsilane (TMS) as an internal standard. Melting points were measured using a RNMK 05 device (VEB Analytik,Dresden). The elemental analysis was performed on a EuroEA 3000 elemental analyzer. The analgesic and anti-inflammatory activities of 3-(4-hydroxyphenyl)-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acrylonitrile were determined using models of “carrageenan induced paw edema”, ”hot plate” and “acetic acid-induced writhings”, and compared to the reference drug ketorolac.

Conclusions. A series of new 3-(het)aryl-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acrylonitrile derivatives can be easily synthesized by the interaction of 2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acetonitrile with (het)arenecarbaldehydes. The hydroxy group in 3-(4-hydroxy-3-R-phenyl)-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acrylonitriles can be modified to obtain phenyl esters of aliphatic and aromatic carboxylic acids. The high level of the analgesic activity for 3-(4-hydroxyphenyl)-2-(6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl)acrylonitrile has been determined.

Received: 30.01.2020
Revised: 17.05.2020
Accepted: 29.05.2020

Supporting Agencies

The theme of the NAMS of Ukraine “Pharmaco-mathematical analysis of analgesic and anti-inflammatory action of derivatives of mono-
di- and tricyclic nitrgogen containing heterocycles for directed search for new BAS”

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