Robert L. Tiberi

SYNTHESIS AND STRUCTURE–ACTIVITY RELATIONSHIPS IN A NOVEL SERIES OF TOPICALLY ACTIVE CORTICOSTEROIDS

Abstract The influence of 7α-halogeno substitution on topical anti-inflammatory potency was studied in a series of prednisolone derivatives. 7α-Chloro, bromo and iodocorticosteroids were synthesized by hydrogen halide addition to the 6,7-dehydro compounds. 7α-Fluoro substituted steroids were obtained by reaction of the appropriate 7β-hydroxy compounds with N,N-diethyl(2-chloro-1,1,2-trifluoroethyl)amine. Antiinflammatory potencies were obtained using a modification of the croton oil ear test in mice. The greatest effect of a 7α-halogen was observed in the 16α-methylprednisolone series, where both 7α-chloro and 7α-bromo substitution yielded compounds equivalent in potency to betamethasone dipropionate. The enhancing effect of this substitution in other series was variable and less marked.

Recent advances in the structure-activity relationships of substituted corticosteroids

Abstract The influence of the 6-azido-6-ene grouping on corticosteroid activity has been studied. The 6-azido-6-ene-corticosteroids were synthesized by reaction of the methanesulfonate esters of 6β,7β-dihydroxycorti-costeroids with azide ion. These diols were the unexpected products of the reaction between OsO 4 and 6-ene-corticosteroids. Their β-stereochemistry was assigned unambiguously from their n.m.r. spectra and is contrary to that of some published assignments. Anti-inflammatory activity was measured by the suppression of exudate in the rat granuloma pouch assay. Potency of 9α-unsubstituted corticosteroids was found to be increased by 5–8 times on introduction of the 6-azido-6-ene group. Introduction of this modification into 9α-fluorocorticosteroids enhanced potency in the absence of a 1,2-double bond and left the potency substantially unchanged in the presence of a 1,2-double bond.

RECENT ADVANCES IN THE STRUCTURE–ACTIVITY RELATIONSHIPS OF SUBSTITUTED CORTICOSTEROIDS

The influence of the 6-azido-6-ene grouping on corticosteroid activity has been studied. The 6-azido-6-ene-corticosteroids were synthesized by reaction of the methanesulfonate esters of 6β,7β-dihydroxycorti-costeroids with azide ion. These diols were the unexpected products of the reaction between OsO4 and 6-ene-corticosteroids. Their β-stereochemistry was assigned unambiguously from their n.m.r. spectra and is contrary to that of some published assignments. Anti-inflammatory activity was measured by the suppression of exudate in the rat granuloma pouch assay. Potency of 9α-unsubstituted corticosteroids was found to be increased by 5–8 times on introduction of the 6-azido-6-ene group. Introduction of this modification into 9α-fluorocorticosteroids enhanced potency in the absence of a 1,2-double bond and left the potency substantially unchanged in the presence of a 1,2-double bond.