Prostaglandin prodrugs III: Synthesis and biological properties of C9- and C15-monoesters of dinoprost (prostaglandin F2 alpha).

Methods are described for the synthesis of dinoprost C9- and C15-monoesters using protective groups. Esters at C9 were synthesized by acylation of dinoprost 11,15-bis(tetrahydropyran-2-yl)ether followed by acid-catalyzed protective group removal. Esters at C15 were synthesized by initial formation of the protected intermediate, dinoprost 9,11-n-butylboronate, followed by acylation and hydrolytic protective group removal. Many esters were active in vivo in the hamster antifertility screen. Plasma hydrolysis studies showed that the C15-esters were more readily cleaved than the C9-esters. In vivo studies in the rat showed that both the C9- and C15-esters resulted in urinary excretion of 5 alpha, 7 alpha-dihydroxy-11-ketotetranorprosta-1,16-dioic acid in amounts comparable to those obtained after dosing with dinoprost, indicating that ester hydrolysis occurred in vivo.