Research and Development of Beraprost Sodium, a New Stable PGI₂ Analogue

Abstract

A novel prostaglandin I₂ (PGI₂) analogue, beraprost sodium, is the first launched drug as an orally active PGI₂. PGI₂ was discovered in 1976, and has attracted much attention as a medicine for cardiovascular diseases such as strokes and heart attacks because of its potent antiplatelet and vasodilating effect. However, PGI₂ is extremely unstable for the use as practical medicines. Thus, stable PGI₂ analogues have been explored by a large number of researchers in the world. Just after the discovery of PGI₂, we started a research on chemically and metabolically stable PGI₂ derivatives with longer duration of action and less adverse reaction. We invented a novel class of stable PGI₂, 5, 6, 7-trinor-4, 8-infer-m-phenylenePGI₂ analogues that have the phenol moiety instead of the enolether moiety of PGI₂. Further efforts were devoted to enhance the efficacy of the PGI₂. analogues and to eliminate their side effects, and an orally active analogue, beraprost sodium, was obtained. In order to establish the synthetic route of beraprost sodium, various novel processes were invented, including ortho-selective metalation of bromoanisoles by means of Grignard reagents, copper-catalyzed S_N2' cyclization to prepare cyclopenta [b] benzofuran, and stereo-selective elongation of the omega-side chain by Prins reaction. Beraprost sodium inhibited platelet aggregation induced by adenosine 5'-diphosphate (ADP), collagen and arachidonic acid. It was shown that the drug