Synthesis, estrogen receptor binding affinity and biological evaluation of some 2-substituted estrone derivatives

This report details the preparation of modified estrogens which are structurally designed to possess estrogenic and/or antiestrogenic activity. The prominent feature of these estrogens is the introduction of a novel side chain in the 2-position of ring A of the steroid nucleus. Their synthesis includes the use of transformations based upon Mannich base chemistry: preparation of the intermediate 2-dimethylamino-methylestrone via aminomethylation of estrone and introduction of various functionalities via reaction of this Mannich base with different reagents. When evaluated for their interaction with the estrogen receptor by competitive binding assays, the tested products were found to be relatively weak competitors at 0 degree C. The uterotrophic and post-coital antifertility assays indicated effects varying in magnitude relative to estradiol. Ethyl[(2'-acetyl-3'-(3-hydroxyestra-17-oxo-1,3,5 (10)-trien-2-yl)]propionate (15) showed uterotrophic and antiimplantation activities of 95% and 20% respectively.