Synthesis and structure-activity studies of corticosteroid 17-heterocyclic aromatic esters. 1. 9.alpha.,11.beta.-Dichloro series

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Abstract
The preparation and topical antiinflammatory potencies of a series of 9.alpha.,11.beta.-dichloro-16-methyl corticosteroid 17-heteroaryl carboxylates are described. The 17-acyl group was introduced to the 9.alpha.,11.beta.-dichloro 21-acetate by direct acylation with the appropriate heteroaryl carbonyl chloride in the presence of 4-(dimethylamino)pyridine. Alternatively, the 21-functionalized 17-hydroxy .DELTA.9(11) compound was acylated at 17, followed by C-ring chlorination. The most extensively studied heterocyclic acyl functionality was the 2-furoyl, but the 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 compounds were 17-heteroaryl esters in the 16.alpha.-methyl series where the 21-substituent was chloro or fluoro. Thus 2p [21-chloro 17-(2''-furoate)] was 8 times as potent as betamethasone valerate, while 2s [21-fluoro 17-(2''-furoate)], 2r [21-chloro 17-(2''-thenoate)], and 2v [6.alpha.-fluoro 21-chloro 17-(2''-furoate)] were 3 times as potent as betamethasone valerate.