Merck Sharp + Dohme Corp.

Merck Sharp + Dohme B.v.

Scott James Lusher

Adrianus Petrus Antonius De Man

Gerrit Herman Veeneman

Christiaan Gerardus Johannes Maria Jans

Guido Jenny Rudolf Zaman

Arthur A Oubrie

Rogier Christian Buijsman

Pedro Harold Han Hermkens

Ralf Plate

Herman Thijs Stock

Fredericus Antonius Dijcks

Paolo Giovanni Martino Conti

Willem Hendrik Abraham Dokter

Fredricus Antonius Dijcks

The present invention relates to novel N-substituted azetidine derivatives &#x3c; of the formula (I); wherein SERMF is a Selective Estrogen Receptor Modilator fragment; X is no atom, O, S, CH2, carbonyl, N&#x2014;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, &#x3e; 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&#x2014;in certain embodiments&#x2014;selective estrogen receptor downregulating (SERD) activity in ER-positive breast cancer cells. 

N-substituted azetidine derivatives

The present invention relates to compounds having general Formula (I) or a pharmaceutically acceptable salt thereof. The present invention also relates to pharmaceutical compositions comprising said compounds and the use of these derivatives to modulate glucocorticoid receptor activity. 

Non steroidal glucocorticoid receptor modulators

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Den Bosch, Netherlands

Scott James Lusher