Синтез та противірусна активність похідних 1-(4-хлорофеніл)-4-(пара-толіл)-5,6,7,8-тетрагідро-2а,4а-діазациклопента[cd]азулен-2-карбонової кислоти

• Date: 2019
• Main Authors: Demchenko, S. A., Fedchenkova, Yu. A., Sukhoveev, V. V., Bagreeva, O. S., Demchenko, A. M.
• Format: Article
• Language: English
• Published: National University of Pharmacy 2019
• Subjects: заміщені (тіо)аміди 1-(4-хлорофеніл)-4-(пара-толіл)-5; 6; 7; 8-тетрагідро-2а; 4а-діазациклопента[ cd]азулен-2-карбонової кислоти; рибавірин; амізон; противірусна активність; вірус Flu A H1N1 California/07/2009; УДК 54.057; 547.759; 547.327; 615.281; 615.31
• Online Access: https://ophcj.nuph.edu.ua/article/view/ophcj.19.182036
• Journal Title: Journal of Organic and Pharmaceutical Chemistry

Aim. To synthesize, prove the structural framework and study the antiviral activity of 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2a,4a-diazacyclopenta[cd]azulene-2-carboxylic acid derivatives.Results and discussion. The antiviral activity of 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2a,4adiazacyclopenta[cd]azulene-2-carboxylic acid (4-methoxyphenyl)amide was determined in the Southern Research Institute (SRI, Birmingham, Alabama). The efficacy of this compound was expressed by EC50, IC50 and SI values determined in vitro within a range of concentrations of 0.1 – 100 μg/mL. The antiviral drug Ribavirin (Sigma) and the active substance of Amizon – 4-(N-benzyl)aminocarbonyl-1-methylpyridinium iodide were used as the reference drugs.Experimental part. Condensation of 2-methoxy-3,4,5,6-tetrahydro-7H-azepine with α-amino-4-methylacetophenone hydrochloride led to 3-(4-methylphenyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepine. By boiling the latter with α-bromo-4-chloroacetophenone in ethyl acetate 1-[2-(4-chlorophenyl)-2-oxoethyl]-3-(para-tolyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-1-ium bromide was isolated, which in aqueous alkali solution was converted into 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2а,4a-diazacyclopenta[cd]azulene. The latter while reacting with the corresponding aryliso(thio)cyanates in a dry benzene gave 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2a,4a-diazacyclopenta[cd]azulene-2-carboxylic acid (thio)amides. 1H NMR-spectra for the compounds synthesized were recorded on a Bruker VXR-300 spectrometer (Germany) with the operating frequency of 299.945 MHz, and also on a Bruker DRX300 (Germany) spectrometer with the operating frequency of 500.13 MHz, in DMSO-d6 using tetramethylsilane (TMS) as an internal standard. The melting points were measured using a RNMK 05 apparatus (VEB Analytik, Dresden).Conclusions. The series of new 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2a,4a-diazacyclopenta[cd]azulene-2-carboxylic acid (thio)amides has been synthesized. The antiviral activity of 1-(4-chlorophenyl)-4-(para-tolyl)-5,6,7,8-tetrahydro-2a,4a-diazacyclopenta[cd]azulene-2-carboxylic acid (4-methoxyphenyl)amide has been studied in the Southern American Research Institute (SRI, Birmingham, Alabama), and the high level of the antiviral activity has been found against Flu A H1N1 California/07/2009 virus.