Synthesis and topical antiinflammatory properties of 17,21-bis(acetyloxy)-6beta,9-difluoro-11beta-hydroxypregna-1,4-diene-3,20-dione and related 2-halogenated compounds.
Introduction of a halogen atom at C-2 of steroid 3-ketofluorohydrins, obtained from the corresponding 5alpha,6alpha-epoxides by trans-diaxial opening with hydrofluoric acid, prevents the 6beta-fluorine atom from undergoing rearrangement to the more stable 6alpha configuration when the 5-tert-hydroxyl is split off to yield to yield a conjugated double bond. Two processes were investigated for the synthesis of 17,21-bis(acetyloxy)-6beta-fluoro-1,4,9(11)-triene-3,20-dione (24a) and the related 2-bromo compound 24b starting from the known 21-(acetyloxy)-6beta-fluoro-5alpha,11alpha,17-trihydroxypregnane-3,20-dione (13). Successive reaction with hypobromous acid, epoxidation, and fluorination converted 24a and 24b into the title compound 27a and the analogue 2-bromo compound 27b. In addition, a synthesis of 17,21-bis(acetyloxy)-2-chloro-6beta,9-difluoropregna-1,4-diene-3,20-dione (27c) is reported. The antiinflammatory activity of 17,21-bis-(acetyloxy)-6beta,9-difluoropregna-1,4-diene-3,20-dione (27a) and its 2-halogenated analogues 27b and 27c in comparison with the corresponding 6alpha,9-difluoro epimers was studied. Some 6beta-fluoro compounds displayed high topical antiinflammatory activity without systemic effects.
D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis*; D006099:Granuloma / Q000503:physiopathology; D009929:Organ Size / Q000187:drug effects; D011245:Pregnadienes / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013259:Steroids, Fluorinated / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013950:Thymus Gland / Q000033:anatomy & histology / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D011245:Pregnadienes; D013259:Steroids, Fluorinated