Potential steroidal antiestrogens

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Abstract
A series of analogues of 17.beta.-estradiol were synthesized and the compounds were tested, using sucrose density gradient analysis, for their ability to compete with 6,7-3H-17.beta.-estradiol for the estrogen-receptor protein from mouse uterine homogenates. Active compounds were also tested for antiuterotrophic activity in immature rats and/or mice. 3,17.beta.-Dihydroxy-6-phenylestra-1,3,5(10),6-tetrene (14) was the most active new compound in the in vitro test, suppressing the binding of 17.beta.-estradiol by 34 and 87%, respectively, at molar ratios of 1 and 3.16. It was significantly more potent than the intermediate 6-oxoestradiol which produced a 52% inhibition of binding at a molar ratio of 3.16. The thiosemicarbazone of 6-oxoestradiol and the derived 3,17.beta.-dihydroxy-6-(2-imino-4-oxothiazolidinyl-1-imino)estra-1,3,5(10)-triene produced, respectively, only 46 and 16% inhibition of binding at a molar ratio of 10. Introduction of a 1-methyl substituent into either 6-oxo or 6-phenyl compounds reduced affinity for the receptor significantly (compounds 5 and 15) and conversion of the 3-OH into a .beta.-dialkylaminoethoxy group virtually destroyed all binding activity. At a molar ratio of 10, compound 14 failed to suppress the uterine weight response of immature rats to 17.beta.-estradiol; compound 15, at a molar ratio of 200, produced a significant increase in the uterine weight of immature rats, but not of immature mice even at a molar ratio of 1000.

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