Synthesis, estrogen receptor binding affinity and biological evaluation of some 2-thiazolylestrone and estratrieno [17,16-d] thiazole derivatives

ABSTRACT

Two series of 2-thiazolyestrone and estratrieno [17,16-d] thiazole derivatives have been designed and synthesized to study the effect of such heterocyclic rings, as modifications of estrone, on the receptor biding affinity, uterotrophic and antiimplantation activities. The key step in the synthesis involved regioselective 16-alpha bromination of 2-acetylestrone with cupric bromide avoiding 2-acetyl bromination. The other key intermediate 2-bromoacetylestrone was prepared by combined Friedel-Crafts reaction and Fries rearrangement of estrone with bromoacetyl chloride and aluminium chloride. The tested products were found to be relatively weak competitors at 0C for estrogen receptor. Uterotrophic and postcoital antifertility assays indicated variable effects relative to estradiol. Some products, particularly compounds IX and XI-XIII, induced significant increase [75-90%] in the rat uterine weight while compounds III, XI and XII displayed notable antiimplantation activity of 69-88% relative to that of estradiol. 2[2-p-chloroanilinothiazol-4-yl] estrone [XIII] had a significant agonist activity eliciting the highest uterotrophic activity [90%] while exhibiting a weak antiimplantation activity [32%]. The p-bromo XII and the p-tolyl XIV derivative imparted strong uterotrophic and antiimplantation activities