SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS IN A SERIES OF ANTIINFLAMMATORY CORTICOSTEROID ANALOGS, HALOMETHYL ANDROSTANE-17-BETA-CARBOTHIOATES AND ANDROSTANE-17-BETA-CARBOSELENOATES

The preparation and topical antiinflammatory potencies of a series of halomethyl 17 alpha-(acyloxy)11 beta-hydroxy-3 -oxoandrosta-1,4-diene- 17 beta-carbothioates, carrying combinations of 6 alpha-fluoro, 9 alph a-fluoro, 16-methyl, and 16-methylene substituents, are described. Key synthetic stages were the preparation of carbothioic acids and their reaction with dihalomethanes. The carbothioic acids were formed from 1 7 beta-carboxylic acids by initial reaction with dimethylthiocarbamoyl chloride followed by aminolysis of the resulting rearranged mixed anh ydride with diethylamine, or by carboxyl activation with 1,1'-carbonyl diimidazole (CDI) or 2-fluoro-N-methylpyridinium tosylate (FMPT) and r eaction with hydrogen sulfide, the choice of reagent being governed by the 17 alpha-substituent. Carboxyl activation with FMPT and reaction with sodium hydrogen selenide led to the halomethyl 16-methyleneandros tane-17 beta-carboselenoat analogues. Antiinflammatory potencies were measured in humans using the vasoconstriction assay and in rats and mi ce by a modification the Tonelli croton oil ear assay. Best activities were shown by fluoromethyl and chloromethyl carbothioates with a 17 a lpha-propionyloxy group. S-Fluoromethyl 6(alpha,9 alpha-difluoro-11 be ta-hydroxy-16 alpha-methyl-3-oxo-17 alpha-(propionyloxy)androsta-1,4-d iene-17 beta-carbothioate (fluticasone propionate, FP) was selected fo r clinical study as it showed high topical antiinflammatory activity b ut caused little hypothalamic-pituitary-adrenal suppression after topi cal or oral administration to rodents.