New steroidal antiinflammatory agents: prednisolone derivatives with an isoxazoline fusion at the 16- and 17-carbons and an alkyl carboxylate at the 16 alpha-position.

In a continuing effort to synthesize potent antiinflammatory steroids without systemic side effects based on the antedrug concept, prednisolone derivatives with a carboxylate ester group at the C-16 and isoxazoline rings at the C-16 and C-17 were obtained by 1,3-dipolar cycloaddition of nitrile oxides to 1,4,16-pregnatriene-3,20-diones. Most of the new steroids retained the antiinflammatory activities of their parent compounds as evidenced by the croton oil-induced ear edema assay. They also demonstrated substantial or almost complete reductions in systemic side effects as shown by the 5-day ear edema and cotton pellet bioassays. In the case of the new steroids with alkyl carboxylate groups, the improved pharmacological profile is ascribed to their metabolically labile ester function which should be readily hydrolyzed to inactive carboxylic acid, thus eliminating the systemic side effects. The pharmacological profiles of the isoxazoline derivatives remain to be explained, partly due to insufficient information on the metabolic fate of these compounds.