Synthesis and antiinflammatory activity of novel 12 beta-substituted analogues of betamethasone.

A series of 9 alpha-halo-12 beta-hydroxy and 12 beta-acyloxy analogues of betamethasone 17,21-dipropionate were synthesized and tested for topical antiinflammatory potency in the croton oil ear assay. The compounds were assayed for systemic absorption in the contralateral ear assay, in which it was found that 12 beta-hydroxy analogues 9, 13, and 15 were all absorbed but the corresponding 12 beta-esters 11a-e, 14, and 16 were not. On repeated high-dose applications to the mouse ear, there was no evidence of systemic absorption of any 12 beta-propionate ester as gauged by thymus weights (thymic involution) and plasma cortisol levels (adrenal suppression). Results of limited SAR studies showed that topical antiinflammatory activity and systemic absorption were not greatly influenced by the 9 alpha-halogen but were largely dependent on the polarity and size of the 12 substituent. While the optimal compounds 14 and 16 were less topically active than the controls beta- and beclomethasone dipropionate, unlike the controls, they displayed no systemic effects, even after repeated high-dose applications. Surprisingly, propionate 14 was devoid of atrophogenic activity.

Synthesis and testing of 17a beta-hydroxy-7 alpha-methyl-D-homoestra-4,16-dien-3-one: a highly potent orally active androgen.

The title compound, 17a beta-hydroxy-7 alpha-methyl-D-homoestra-4,16-dien-3-one (3), was synthesized in five steps (17% overall yield) from 7 alpha-methylestrone methyl ether (5) and was found to possess oral androgenic activity, in excess of other known androgens, without using 17 alpha-alkyl substitution.