Potent fluorinated corticosteroids

Clobetasol propionate at concentrations up to % did not increase the rate of formation of ultra violet light-induced skin tumors when topically applied to hairless mice 5 days per week for a period of 40 weeks.
Clobetasol propionate was negative in the in vitro mammalian chromosomal aberration test and in the in vivo mammalian erythrocyte micronucleus test

The effect of subcutaneously administered clobetasol propionate on fertility and general reproductive toxicity was studied in rats at doses of 0, , 25, and 50 μg/kg/day. Males were treated beginning 70 days before mating and females beginning 15 days before mating through day 7 of gestation. A dosage level of less than μg/kg/day clobetasol propionate was considered to be the no-observed-effect-level (NOEL) for paternal and maternal general toxicity based on decreased weight gain and for male reproductive toxicity based on increased weights of the seminal vesicles with fluid. The female reproductive NOEL was μg/kg/day (ratio of animal dose to proposed human dose of on a mg/m 2 /day basis) based on reduction in the numbers of estrous cycles during the pre-cohabitation period and an increase in the number of nonviable embryos at higher doses.

Using cyclic ketone scaffolds, several novel trifluoroacetylated 1,3-diketones and selectively α-fluorinated ketones have been prepared in yields ranging from 20-77% using the Claisen condensation and electrophilic fluorination by the Selectfluor ® reagent, respectively. We report tendencies in the difluorinated and trifluoroacetylated products to form hydrates as well as an unusual range of substrate reactivity toward the Selectfluor ® reagent. In general, initial spectroscopic studies suggest that cyclic 2-trifluoroacetylated-1,3-diketones undergo rapid hydration resulting in an equilibrium mixture favoring the diketo hydrate over the keto-enol hydrate. Fluorination of ketone species by Selectfluor ® was found to be governed by a combination of steric and electronic effects. Plausible mechanisms for both mono- and difluorination, involving a keto-enol or enolic tautomer, are proposed.

Potent fluorinated corticosteroids

potent fluorinated corticosteroids


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