Potential anti-inflammatory activity and ulcerogenicity study of some novel pyrimido[4′,5′:4,5]pyrimido[1,6-a]azepine derivatives

Abstract

A series of novel tricyclic pyrimido[4′,5′:4,5]pyrimido[1,6-a]azepine derivatives were synthesized using the starting compound 3-amino-1-oxo-2-phenyl-5-(pyrrolidin-1-yl)-1,2,4a,5,6,7,8,9-octahydropyrimido[1,6-a]azepine-4-carbonitrile 4. This series includes the 3-aryl derivatives 6a, b, the 3-cycloaminoalkyl derivatives 8a–f, the 3-mercaptomethyl derivatives 10 and 11a, b, the 2-cycloaminomethyl derivatives 13a–c, the 1-cycloamino derivatives 15a–c and the 1-amino derivative 16. The structures of the newly synthesized compounds were elucidated by IR, 1H NMR, 13C NMR, mass spectroscopy and elemental analyses. The anti-inflammatory activity of all newly synthesized compounds was evaluated using the carrageenan-induced paw oedema test in rats using diclofenac sodium as the reference drug. Ulcer indices for the most active compounds were calculated. The 3-mercaptomethylacetic acid derivative 10 was the most active compound, showing activity comparable to diclofenac sodium with minimal ulcerogenic effect while the rest of the tested compound exhibited moderate anti-inflammatory activity.