Estrogen receptor ligands. 12. Synthesis of the major metabolites of an ERalpha-selective, dihydrobenzoxathiin antagonist for osteoporosis.
[reaction: see text] During the course of drug metabolism studies, a major metabolite of compound 1 was detected in rhesus monkeys and assigned structure 4. The intriguing biotransformation of 1 leading to 4 was confirmed by a 19-step total synthesis starting from resorcinol (11), the key feature of which was the construction of the oxygen bridge utilizing a phenolic oxidation and trapping sequence. In addition, the synthesis of a related metabolite (5) is described.
Kim
Seongkon
S
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000 (800B-109), Rahway, NJ 07065, USA. seongkon_kim@merck.com
Wu
Jane Y
JY
Zhang
Zhoupeng
Z
Tang
Wei
W
Doss
George A
GA
Dean
Brian J
BJ
Dininno
Frank
F
Hammond
Milton L
ML
D000818:Animals; D001711:Biotransformation; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors*; D008253:Macaca mulatta; D008958:Models, Molecular; D008968:Molecular Conformation; D010024:Osteoporosis / Q000188:drug therapy*; D010075:Oxathiins / Q000138:chemical synthesis* / Q000494:pharmacology*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry; D012118:Resorcinols / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000138:chemical synthesis* / Q000494:pharmacology*
D047628:Estrogen Receptor alpha; D010075:Oxathiins; D012118:Resorcinols; D020845:Selective Estrogen Receptor Modulators; C500019:dihydrobenzoxathiin; D010100:Oxygen