Studies on 2-benzyloxy-4H-3,1-benzoxazin-4-ones as serine protease inhibitors

Abstract

The class of 3,1-benzoxazin-4-ones includes potent inhibitors of various serine proteases. Structural investigations on three 2-benzyloxy-4H-3,1-benzoxazin-4-ones (1–3) are described with respect to their reactivity to alkaline hydrolysis. The 13CNMR data of 2-benzyloxy-5-methyl-4H-3,1-benzoxazin-4-one 3 are discussed. This peri substituted compound was subjected to a crystal structure analysis. The heterocyclic skeleton together with the carbonyl oxygen and the methyl carbon is planar, and only small angle distortions occurred. The inhibition of neutrophil serine proteases by 1–3 is reported. The different reactivity of the 5-methyl derivative 3 towards serine proteases is mainly influenced by specific interactions within the active sites. Thus, 3 was found to rapidly acylate human leukocyte proteinase 3 and exhibited a Ki value of 1.8 nM.