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

• Published in: Journal of medicinal chemistry Vol. 30; no. 9; pp. 1581 - 1588
• Main Authors: Shapiro, E L, Gentles, M J, Tiberi, R L, Popper, T L, Berkenkopf, J, Lutsky, B, Watnick, A S
• Format: Journal Article
• Language: English
• Published: United States 01.09.1987
• Subjects: Adrenal Cortex Hormones - therapeutic use; Animals; Anti-Inflammatory Agents - therapeutic use; Croton Oil; Mice; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00392a010

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 1e, 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 antiinflammatory agent in humans.