Compounds and methods for the treatment of cardiovascular,...

C - Chemistry – Metallurgy – 07 – D

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C07D 307/14 (2006.01) A61K 31/341 (2006.01) A61P 9/00 (2006.01) A61P 29/00 (2006.01)

Patent

CA 2194064

Tetrahydrofurans, tetrahydrothiophenes, pyrrolidines and cyclopentanes are disclosed that reduce the chemotaxis and respiratory burst leading to the formation of damaging oxygen radicals of polymorphonuclear leukocytes during an inflammatory or immune response. The compounds exhibit this biological activity by acting as PAF receptor antagonists, by inhibiting the enzyme 5-lipoxygenase, or by exhibiting dual activity, i.e., by acting as both a PAF receptor antagonist and inhibitor of 5-lipoxygenase. It has been determined that 5-lipoxygenase activity, oral availability, and stability in vivo (for example, glucuronidation rate) can vary significantly among the optical isomers of the disclosed compounds.

L'invention concerne des tétrahydrofurannes, des tétrahydrothiophènes, des pyrrolidines et des cyclopentanes qui réduisent le chimiotactisme et l'activation métabolique respiratoire entraînant la formation de radicaux oxygène dommageables de leucocytes polymorphonucléaires lors d'une réaction inflammatoire ou immunitaire. Ces composés présentent cette activité biologique en agissant comme antagonistes du récepteur du facteur d'activation des plaquettes, en inhibant la 5-lipoxygénase, ou bien en présentant une activité double, c'est-à-dire en agissant à la fois comme antagonistes du récepteur du facteur d'activation des plaquettes et comme inhibiteur de la 5-lipoxygénase. Il a été déterminé que l'activité 5-lipoxygénase, la disponibilité orale, et la stabilité in vivo(par exemple le taux de glucuronidation) peuvent varier substantiellement parmi les isomères optiques descomposés décrits.

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