Synthesis and structure-activity studies of a series of 7α-halogeno corticosteroids

Article abstract of DOI:10.1021/jm00178a015

The preparation and topical antiinflammatory potencies of a series of 7α-halogeno-16-substituted-prednisolone derivatives are described. The 7α-chloro, 7bromo, and 7α-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 7α-fluoro corticosteroids were prepared by reaction of the appropriate 7β-hydroxy compounds with N,N-diethyl(2-chloro-1,1,2-trifluoroethyl)amine. The 7β-hydroxy steroids were obtained, in turn, from the 6,7-dehydro compounds via the 6β,7β-dihydroxy derivatives. Antiinflammatory potencies were measured in mice by the Tonelli croton oil ear assay. The greatest effect of 7α-halogen was observed in the 16α-methylprednisolone series, where 7α-chloro and 7α-bromo substitution increased potency 2.5- to 3.5-fold. Compounds 4b and 5b (the 7α-chloro, respectively 7α-bromo-methyl-prednisolone 17,21-dipropionate, t.w., 7α-chloro,respectively 7α-bromo-16α-methyl-11β,17α,21-trihydroxy-1,4-pregnadiene-3,20-dione 17,21-dipropionate) were equipotent to betamethasone dipropionate. 7α-Halogen substitution in other series produced more variable effects and sometimes led to a reduction of antiinflammatory potency.