Prostaglandin Prodrugs III: Synthesis and Biological Properties of C9- and C15CIS-Monoesters of Dinoprost (Prostaglandin F2α)

• Published in: Journal of pharmaceutical sciences 1979-08, Vol.68 (8), p.949-951
• Main Authors: Morozowich, W., Oesterling, T.O., Miller, W.L., Lawson, C.F., Cornette, J.C., Weeks, J.R., Douglas, S.L.
• Format: Article
• Language: English
• Subjects: Dinoprost—prodrugs, C9‐ and C15‐monoesters, synthesis, bioactivity; Prodrugs—dinoprost, C9‐ and C15‐mnonoesters, synthesis, bioactivity; Prostaglandins—dinoprost ,prodrugs ,C9‐ and C15‐monoesters, synthesis, bioaclivity
• ISSN: 0022-3549; 1520-6017
• DOI: 10.1002/jps.2600680808

Methods are described for the synthesis of dinoprost C9‐ and C15‐monoesters using protective groups. Esters at C9were synthesized by acylation of dinoprost 11,15‐bis(tetrahydropyran‐2‐yl)ether followed by acid‐catalyzed protective group removal. Esters at C15were synthesized by initial formation of the protected intermediate, dinoprost 9,11‐n‐butylboronate, followed by acylation and hydrolytic protective group removal. Many esters were activein vivoin the hamster antifertility screen. Plasma hydrolysis studies showed that the C15‐esters were more readily cleaved than the C9‐esters.In vivostudies in the rat showed that both the C9‐ and C15‐esters resulted in urinary excretion of 5α,7α‐dihydroxy‐11‐ketotetranorprosta‐l, 16‐dioic acid in amounts comparable to those obtained after dosing with dinoprost, indicating that ester hydrolysis occurredin vivo.