17-Heteroaroyl esters of corticosteroids. 2. 11.beta.-Hydroxy series

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Abstract
The preparation and topical antiinflammatory potencies of a series of 17-furoyl and -thenoyl esters of 9.alpha.-fluoro-11.beta.-hydroxy-16-methyl and 9.alpha.-chloro-11.beta.-hydroxy-16-methyl corticosteroids are described. The 17.alpha.-esters were introduced to the 9.alpha.-fluoro 11-ketones or to the appropriate .DELTA.9(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- thenoyl 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 le, dexamethasone 17-(2''-furoate) 21-propionate, and 2c, the 21-chloro 17-(2''-furoate) in the 9.alpha.-chloro series, both being 6 times as potent as betamethasone 17-valerate. Several other 9.alpha.-chloro-11.beta.-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 antiiflammatory agent in humans.