Synthesis and Evaluation of 1-Arylsulfonyl-3-piperazinone Derivatives as Factor Xa Inhibitors IV.
A Series of New Derivatives Containing a Spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4′-piperidin]-5-one Skeleton

Abstract

In the course of development of factor Xa (FXa) inhibitor in an investigation involving the synthesis of 1-arylsulfonyl-3-piperazinone derivatives, we found new compounds containing a unique spiro skeleton. Among such compounds, (−)-7-[(6-chloro-2-naphthalenyl)sulfonyl]tetrahydro-8a-(methoxymethyl)-1′-(4-pyridinyl)-spiro[5H-oxazolo[3,2-a]pyrazine-2(3H),4′-piperidin]-5-one (28, M55529) had activity more favorable than those of previously reported compounds. The inhibitory activity of M55529 for FXa is IC₅₀=2 nM, with high selectivity for FXa over thrombin and trypsin.