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

Hidemitsu Nishida; Takafumi Mukaihira; Fumihiko Saitoh; Kousuke Harada; Miyuki Fukui; Tomokazu Matsusue; Atsushi Okamoto; Yoshitaka Hosaka; Miwa Matsumoto; Ikuya Shiromizu; Shuhei Ohnishi; Hidenori Mochizuki

doi:10.1248/cpb.52.406

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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

Hidemitsu Nishida, Takafumi Mukaihira, Fumihiko Saitoh, Kousuke Harada, Miyuki Fukui, Tomokazu Matsusue, Atsushi Okamoto, Yoshitaka Hosaka, Miwa Matsumoto, Ikuya Shiromizu, Shuhei Ohnishi, Hidenori Mochizuki

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Keywords: factor Xa inhibitor, N,O-spiro acetal, M55529, structure–activity relationship, intramolecular cyclization

JOURNAL FREE ACCESS

2004 Volume 52 Issue 4 Pages 406-412

DOI https://doi.org/10.1248/cpb.52.406

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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.

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