Synthesis and structure-activity studies in a series of 7.alpha.-halogeno corticosteroids

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Abstract
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.-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 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 [7.alpha.-chloro-16.alpha.-methyl-11.beta.,17.alpha.,21-trihydroxy-1,4-pregnadiene-3,20-dione 17,21-dipropionate] and [.alpha.-bromo-16.alpha.-methyl-11.beta.,17.alpha.,21-trihydroxy-1,4-pregnadiene-3,20-dione- 17,21-dipropionate] 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.