VEENEMAN, Gerrit Herman;LUSHER, Scott James;DIJCKS, Fredricus Antonius;STOCK, Herman Thijs;MSD OSS B.V.
发明人:
DIJCKS, Fredricus Antonius,LUSHER, Scott James,STOCK, Herman Thijs,VEENEMAN, Gerrit Herman
申请号：
EPEP2011/073041
公开号：
WO2012/084711A1
申请日:
2011.12.16
申请国别(地区):
EP
年份:
2012
代理人:
摘要：
The present invention relates to novel N-substituted azetidine derivatives <； of the formula (I)； wherein SERMF is a Selective Estrogen Receptor Modilator fragment； X is no atom, O, S, CH2, carbonyl, N-R5； R1 is H, (C1 -8)alkyl, (C3-8)cycloalkyl, (C3-6)heterocycloalkyl, (C2-6)alkenyl, (C2- 6)alkynyl, (C1 -4)alkylcarbonyl, (C1 -4)alkoxy(C2-4)alkyl, (C3-6)cycloalkyl(C1 -3)- alkyl, (C3-6)heterocycloalkyl(C1 -3)alkyl, each independently optionally substituted with one or more halogen, nitrile, hydroxyl or (C1 -2)alkyl； R5 is H, (C1 -3)alkyl, optionally substituted with one or more fluorine； R17, R18 and R19 are independently of each other H, fluorine, nitrile or (C1 -3)- alkyl, optionally substituted with one or more fluorine； or a prodrug, isotopically-labelled derivative or pharmaceutically acceptable salt thereof, >； to pharmaceutical compositions comprising these compounds and to their use in therapy, in particular to their use for the prevention or treatment of ovulatory dysfunction, uterine cancer, endometrium cancer, ovarian cancer, endometriosis, osteoporosis, prostate cancer, benign prostatic hypertrophy, and breast cancer, in particular ER-positive breast cancer, more in particular ER- positive, hormone treatment-resistant breast cancer. Said N-substituted azetidine derivatives have estrogen receptor alpha (ERa) antagonistic and - in certain embodiments - selective estrogen receptor downregulating (SERD) activity in ER-positive breast cancer cells.La présente invention porte sur de nouveaux dérivés d'azétidine N-substitués représentés par la formule (I) ； dans laquelle SERMF représente un fragment de modulateur sélectif des récepteurs des œstrogènes ； X représente aucun atome, O, S, CH2, carbonyle, N-R5 ； R1 représente H ou un groupe alkyle en C1-8, cycloalkyle en C3-8, hétérocycloalkyle en C3-6, alcényle en C2-6, alcynyle en C2-6, alkylcarbonyle en C1-4, (alcoxy en C1-4)(alkyle en C2-4), (cycloalkyl en C3-6)(alkyle en C1-3), (hétérocycloalkyl en C3-6)(alk
