Substituted pyrrolo[1,2-a][1,2,4]triazolo-([1,2,4]triazino-)[c]quinazoline-4a(5a)-propanoic acids: synthesis, spectral characteristics and anti-inflammatory activity
Authors: V. Stavytskyi, О. Voskoboinik, М. Kazunin, I. Nosulenko, S. Shishkina, S. Kovalenko
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The heterocyclization of 3-(2-aminophenyl)-6-(4-isopropylphenyl)-1,2,4-triazin-5(2H)-one with 4-oxoheptanedioic acid was studied in this work. It was shown that this reaction yielded partial hydrogenated [1,2,4]triazino[2,3-c]quinazoline, pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline-5a(6H)-yl)propanoic acid or their mixture depending on the reaction condition (the nature of a solvent, the temperature, and the process duration). It was found that the refluxing of initial compounds in acetic acid was the most suitable in the case of the synthesis of 3-(3-(4-isopropylphenyl)-2,8-dioxo-7,8-dihydro-2H-pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazolin-5a(6H)-yl)propanoic acid. The found optimal conditions were used for the condensation of 2-azaheterylanilines with 4-oxoheptanedioic acid. These conditions created the basis for preparative methods for the synthesis of tetracyclic derivatives series. The structure and purity of the obtained compounds were determined by a complex of appropriate physicochemical methods, including 1Н and 13С NMR, IR, chromatography-mass, mass-spectroscopies and X-ray diffraction analysis. The features of the fragmentation of different heterocycles molecular ions under electronic ionization were discussed. It was established that the destruction of pyrrolidone cycle caused higher fragmentation of aromatic pyrrolo[1,2-a][1,2,4]triazоlo[1,5-c]quinazoline system. It was found that the introduction of carboxyethyl fragment into the pyrrolo[1,2-a][1,2,4]triazino-)[2,3-c]quinazoline system was favorable for the formation of anti-inflammatory agents. Pharmacological studies revealed that only substituted pyrrolo[1,2-a][1,2,4]triazino[2,3-c]quinazoline-5a(6H)-propanoic acids showed high anti-inflammatory activity. The series of the obtained compounds demonstrated an anti-inflammatory activity that was comparable to or higher than the pharmacological effect of the reference compound "diclofenac". The essential role of the presence of fluorine atom in the anti-inflammatory activity of the synthesized compounds was discussed.