マクロライド系抗生物質・クラリスロマイシンの合成と次世代マクロライド剤への展開

Abstract

Clarithromycin (CAM), a semi–synthetic 14–membered macrolide antibiotic, has a feature that the 6–hydroxy group of naturally occurring erythromycin A (EM–A) is methylated. Given its potent antibacterial activity against respiratory pathogens and the excellent pharmacokinetic properties by the chemical modification, CAM has been widely prescribed for the initial empirical treatment of respiratory infections. The most challenging task in the drug development was to establish the synthetic route, especially the selective 6–O–methylation against other four hydroxyl groups of EM–A. In this paper we report the synthetic study led to the establishment of chemical process route of CAM and successively our recent drug discovery research on the next generation macrolides exampled by Acylides (3–O–acyl–EM–A derivatives) and Ketolides (3–oxo–EM–A derivatives). Furthermore, as a promising novel series of the next generation macrolides, we refer to 11a–Azalides (11a–aza–11a–homo EM–A derivatives) based on an underexplored strategy consisting of cleavage and reconstruction of the macrolide aglycon.