Prostaglandin prodrugs. 5. Prostaglandin E2 ethylene ketal

Abstract

In order to improve chemical stability of prostaglandin[PG]E2 (2) PG E2 ethylene ketal (1) was prepared by direct ketalization of 2 with ethylene glycol in benzene. To establish a quantitative assessment of 1 as a chemically stable and orally active prodrug of 2, the hydrolysis of 1 to 2 and the subsequent dehydration of 2 to PG A2 (3) were followed at 25.degree. C and 6 pH''s ranging from 2.0-6.5 by a high-pressure liquid chromatographic procedure. Kinetic results clearly indicate that 1 should be quantitatively hydrolyzed back to the parent drug 2 under stomach conditions without loss to 3. At pH 2 and 25.degree. C, half-lives of hydrolysis of 1 to 2 and dehydration of 2 to 3 are in the order of 1 h and 14 days, respectively. Preliminary data on the biological response [uterine activity of Macaca mulatta] after oral administration of 1 appeared to indicate that 1 is bioequivalent to 2.