Synthesis and antiestrogenic activity of [3,4-dihydro-2-(4-methoxyphenyl)-1-naphthalenyl][4-[2-(1-pyrrolidinyl)ethoxy]phenyl]methanone, methanesulfonic acid salt

Abstract

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.

Identification of pathway-selective estrogen receptor ligands that inhibit NF-κB transcriptional activity

“…A variety of selective ER ligands have been described, and each of them displays an unique biological profile (32,39,40). Whereas both WAY-169916 and E2 can inhibit NF-B functional activity, neither the tissue-selective estrogen receptor modulator, raloxifene, nor the pure ER antagonist, ICI, can promote this activity, which is consistent with previous observations (20).…”

Emerging Therapies for the Prevention or Treatment of Postmenopausal Osteoporosis

“…These data are consistent with in vivo data for ZM189154 in suggesting that not all compounds with high-affinity interactions with the conventional estrogen receptor have beneficial effects on bone. Another member of this family, trioxifene, has also been shown previously to prevent bone loss due to ovariectomy in rats. , However, both nafoxidine and trioxifene were shown to function as partial estrogen agonists on the uterus.

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Application of the McMurry coupling reaction in the synthesis of tri- and tetra-arylethylene analogues as potential cancer chemotherapeutic agents

“…1) inspired us to modify the molecular templates found in certain non-steroidal antiestrogenic compounds to explore the interaction of the resulting new compounds with the tubulin-microtubule protein system. This molecular design strategy proved highly successful for the synthesis of new benzo[ b ]thiophene,4 indole,5 and dihydronaphthalene6 analogues similar to raloxifene,7 nafoxidine,8 and trioxifene 9. Tamoxifen10 is a triarylethylene compound that has been widely used in the treatment of breast cancer, as well as hepatocellular, ovarian, colorectal, and pancreatic carcinomas 11.…”