Synthesis and structure-activity studies of a series of 7 alpha-halogeno corticosteroids.
The preparation and topical antiinflammatory potencies of a series of 7 alpha-halogeno-16-substituted-prednisolone derivatives are described. The 7 alpha-chloro, 7 alpha-bromo, and 7 alpha-iodo corticosteroids were obtained by addition of hydrogen halide to the 6,7-dehydro compounds. The extent of addition of HCl varied with substitution at C-11, while no addition of HF was observed at all. The 7 alpha-fluoro corticosteroids were prepared by reaction of the appropriate 7 beta-hydroxy compounds with N,N-diethyl(2-chloro-1,1,2-trifluoroethyl)amine. The 7 beta-hydroxy steroids were obtained, in turn, from the 6,7-dehydro compounds via the 6 beta,7 beta-dihydroxy derivatives. Antiinflammatory potencies were measured in mice by the Tonelli croton oil ear assay. The greatest effect of a 7 alpha-halogen was observed in the 16 alpha-methylprednisolone series, where 7 alpha-chloro and 7 alpha-bromo substitution increased potency 2.5- to 3.5-fold. Compounds 4b and 5b were equipotent to betamethasone dipropionate. 7 alpha-Halogen substitution in other series produced more variable effects and sometimes led to a reduction of antiinflammatory potency.
D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis*; D001623:Betamethasone / Q000494:pharmacology; D001624:Betamethasone Valerate / Q000494:pharmacology; D006219:Halogens; D006854:Hydrocortisone / Q000494:pharmacology; D051379:Mice; D013256:Steroids / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D006219:Halogens; D013256:Steroids; D001623:Betamethasone; D001624:Betamethasone Valerate; D006854:Hydrocortisone