17-Heteroaroyl Esters of Corticosteroids. 2. 11β-Hydroxy Series

Article abstract of DOI:10.1021/jm00392a010

The preparation and topical antiinflammatory potencies of a series of 17-furoyl and -thenoyl esters of 9α-fluoro-11β-hydroxy-16-methyl and 9α-chloro-11β-hydroxy-16-methyl corticosteroids are described.The 17α-esters were introduced to the 9α-fluoro 11-ketones or the appropriate Δ⁹⁽¹¹⁾ compounds by direct acylation with the appropriate heteroaryl carbonyl chloride in the presence of 4-(dimethylamino)pyridine.Functionalization of the C ring was completed by standard methods.The most extensively studied heterocyclic acyl group was 2-furoyl, but 3-furoyl and 2- and 3-thienoyl derivatives were also investigated.Antiinflammatory potencies were measured in mice by a 5-day modification of the Tonelli croton oil ear assay.The most potent topical antiinflammatory agents were 1e, dexamethasone 17-(2'-furoate)-21-propionate, and 2c, the 21-chloro 17-(2'-furoate) in the 9α-chloro series, both being 6 times as potent as betamethasone 17-valerate.Several other 9α-chloro-11β-hydroxy-17-heteroaryl carboxylates (2a, 2b, 2d and 2g) were at least 4 times as potent as betamethasone 17-valerate.Evaluation of 2c in the clinic confirmed that the compound is a potent topical antiinflammatory agent in humans.