111802-47-2

Prednisolone derivatives with a 16α-methyl carboxylate group were synthesized by a novel procedure of 1,3-dipole addition of fulminic acid to 21-acetyloxy-11β-hydroxy-3,20-dioxo-1,4,16-pregnatriene, followed by base-catalyzed ring opening of the resulting

A novel class of steroidal 16-esters and amides, 1-8 has been synthesized and evaluated as safer local antiinflammatory agents. These compounds retain the intact ketol side-chain of prednisolone and have an alkanoate ester or carboxamide function at the C-16 of the steroid nucleus. In the cotton pellet granuloma assay a correlation was observed between the size of the C-16 substituent group and the local antiinflammatory activity. The incorporation of a methyl carboxylate group at the C-16 position of prednisolone as in methyl 11β,17α,21-trihydroxy-3,20-dioxo-pregna-1,4-diene-16α-carboxylate, 5, resulted in an increase in antiinflammatory activity. The 17-deoxy analogue of 5, 1, retained one-half the activity of prednisolone. These two compounds were further evaluated for their effects on plasma corticosterone, adrenal and thymic weights at their ID50 doses for granuloma formation. Neither 5 nor 1 depressed plasma corticosterone levels or significantly altered adrenal weights. Compound 1 was also devoid of thymolytic activity, whereas 5 produced a 33% thymic involution at its ID50 compared to 47% for prednisolone at its equiactive dose.