Ring-substituted 1,2-dialkylated 1,2-bis(hydroxyphenyl)ethanes. 1. Synthesis and estrogen receptor binding affinity of 2,2'- and 3,3'-disubstituted hexestrols

Abstract

The syntheses of sym. 3,3'- and 2,2'-disubstituted meso hexestrol derivs. (I) are described (3,3'-R = : OH (II) [79199-51-2], F (III) [74536-61-1], Cl (IV) [79140-57-1], Br [74536-64-4], I [55508-15-1], CH2NMe2 [85720-37-2], Me [10465-10-8], CH2OMe [85720-38-3], CH2OEt [85720-40-7], CH2OH [85720-41-8], NO2 [66877-40-5], NH2 [66877-41-6], NMe2 [85720-42-9], Ac [85720-43-0], and Et [85720-45-2]; 2,2'-R = : OH [85720-47-4], F [85720-49-6], Cl [85720-52-1], Br [85720-55-4], Me [85720-57-6], and Et [85720-58-7]). The synthesis of II-IV was accomplished by reductive coupling of the propiophenones with TiCl4/Zn and subsequent hydrogenation of the cis-3,4-diphenylhex-3-enes. The rest of the 3,3'-disubstituted derivs. were obtained by substitution of hexestrol [84-16-2], whereas the 2,2'-disubstituted derivs. were synthesized by coupling the 1-phenyl-1-propanols with TiCl3/LiAlH4 and sepn. of the meso diastereomers. The binding affinity of these compds. to the calf uterine estrogen receptor was measured relative to that of [3H]estradiol by a competitive binding assay. All test compds. showed relative binding affinity (RBA) values between 32 and <0.01% that of estradiol. Only meso-3,4-bis(2,4-dihydroxyphenyl)hexane showed an estrogen receptor binding affinity comparable to that of hexestrol (32 and 27%, resp.). Compds. exhibiting RBA values of >5% were evaluated in the mouse uterine wt. test. All of them showed uterotrophic activity. III and the 3,3'-CH3, 2,2'-OH, 2,2'-F, and 2,2'-CH3 derivs. were strongly active in very small doses (1 micro g/animal/day), whereas II and the 3,3'-NH2 deriv. produced full uterotrophic effects only in high doses and inhibited the estrone-stimulated uterine growth strongly in small doses (59 and 78% inhibition, resp.).