Derivatives of ethynylestradiol with oxygenated 17 alpha-alkyl side chain: synthesis and biological activity

The coupling reaction of an acetylide ion with alkyl bromide or delta-valerolactone was used to synthesize twelve 17 alpha-derivatives of ethynylestradiol having various 17 alpha-side chain lengths and, except one, having mono- or di-oxygenated function on the side chain. All compounds had low (0.01-1.79%) relative binding affinity (RBA) for the rat uterine estrogen receptor. The highest RBA were obtained for compounds 26 (1.79%), 30 (1.55%) and 19 (0.42%). The length and polarity of the side chain decreases the affinity for the estrogen receptor. The in vivo estrogenic activity was measured on mouse uterine weight and was found to range from 0 to 35%, except for compound 30 (100%). The antiuterotrophic activity was measured by inhibition of estradiol-induced stimulation of uterine weight and was found to be 39% for compound 19, 25% for compound 26 and 0% for all other compounds. These two compounds (19 and 26) possess mixed agonist and antagonist activity.