Development of 3,4-dihydro-2H-benzo[1,4]oxazine derivatives as dual thromboxane A2 receptor antagonists and prostacyclin receptor agonists

We discovered a novel series of 3,4-dihydro-2H-benzo[1,4]oxazin-8-yloxyacetic acid derivatives as potent dual-acting agents to block the TXA2 receptor and to activate the PGI2 receptor. We report the synthesis, structure–activity relationship, and in vitro, ex vivo, and in vivo pharmacology of this series of compounds. 4-[2-(1,1-Diphenylethylsulfanyl)ethyl]-3,4-dihydro-2H-benzo[1,4]oxazin-8-yloxyacetic acid N-methyl-d-glucamine salt (7) is a promising candidate for a novel treatment in the anti-thrombotic and the cardiovascular fields avoiding hypotensive side effects.

A novel series of 3,4-dihydro-2H-benzo[1,4]oxazin-8-yloxyacetic acid derivatives was discovered as potent dual-acting agents to block the thromboxane A2 receptor and to activate prostacyclin receptor. Synthesis, structure–activity relationship, in vitro, ex vivo, and in vivo pharmacology of this series of compounds are described.Figure optionsDownload as PowerPoint slide