Synthesis and antiestrogenic activity of [3,4-dihydro-2-(4-methoxyphenyl)-1-naphthalenyl][4-[2-(1-pyrrolidinyl)ethoxy]-phenyl]methanone, methanesulfonic acid salt.
Acylation of the sodio anion of beta-tetralone with phenyl anisoate, followed by a Grignard reaction of the resultant 4 with 4-methoxyphenylmagnesium bromide, gave rise to two novel dihydronaphthalene isomers 5 and 6. Regioselective demethylation of either 5 or 6 by NaSEt produced [3,4-dihydro-2-(4-methoxyphenyl)-1-naphthalenyl](4-hydroxyphenyl)methanone (7). Etherification of the phenolic group of 7 by N-(2-chloroethyl)pyrrolidine and subsequent methanesulfonate salt formation provided [3,4-dihydro-2-(4-methoxyphenyl)-1-maphthalenyl]]4-]2-(1-pyrrolidinyl)ethoxy]phenyl]methanone, methane sulfonic acid salt (3). Potent antiestrogenic activity of 3 was demonstrated by both oral and subcutaneous administration to rats and mice. In vitro binding studies with rat uterine cytosol estrogen receptors indicate compound 3 has a very high binding affinity which exceeds that of estradiol.
D000818:Animals; D002369:Castration; D055598:Chemical Phenomena; D002621:Chemistry; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D004970:Estrone / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D051379:Mice; D009281:Naphthalenes / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D014590:Uterine Contraction / Q000187:drug effects
D004965:Estrogen Antagonists; D009281:Naphthalenes; D011759:Pyrrolidines; D004970:Estrone