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1. WO2012084711 - N-SUBSTITUTED AZETIDINE DERIVATIVES

Publication Number WO/2012/084711
Publication Date 28.06.2012
International Application No. PCT/EP2011/073041
International Filing Date 16.12.2011
IPC
C07D 409/12 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
409Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
02containing two hetero rings
12linked by a chain containing hetero atoms as chain links
C07D 413/12 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
413Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
02containing two hetero rings
12linked by a chain containing hetero atoms as chain links
C07D 405/12 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
405Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
02containing two hetero rings
12linked by a chain containing hetero atoms as chain links
C07D 205/04 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
205Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
02not condensed with other rings
04having no double bonds between ring members or between ring members and non-ring members
C07D 409/14 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
409Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
14containing three or more hetero rings
C07D 417/14 2006.01
CCHEMISTRY; METALLURGY
07ORGANIC CHEMISTRY
DHETEROCYCLIC COMPOUNDS
417Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/196
14containing three or more hetero rings
CPC
A61P 13/08
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
13Drugs for disorders of the urinary system
08of the prostate
A61P 15/00
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
15Drugs for genital or sexual disorders
A61P 19/00
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
19Drugs for skeletal disorders
A61P 35/00
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
35Antineoplastic agents
A61P 43/00
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
43Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
A61P 5/30
AHUMAN NECESSITIES
61MEDICAL OR VETERINARY SCIENCE; HYGIENE
PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
5Drugs for disorders of the endocrine system
24of the sex hormones
30Oestrogens
Applicants
  • MERCK SHARP & DOHME B.V. [NL]/[NL] (AllExceptUS)
  • DIJCKS, Fredricus Antonius [NL]/[NL] (UsOnly)
  • LUSHER, Scott James [GB]/[NL] (UsOnly)
  • STOCK, Herman Thijs [NL]/[NL] (UsOnly)
  • VEENEMAN, Gerrit Herman [NL]/[NL] (UsOnly)
Inventors
  • DIJCKS, Fredricus Antonius
  • LUSHER, Scott James
  • STOCK, Herman Thijs
  • VEENEMAN, Gerrit Herman
Agents
  • JAAP, David Robert
Priority Data
10196960.824.12.2010EP
Publication Language English (EN)
Filing Language English (EN)
Designated States
Title
(EN) N-SUBSTITUTED AZETIDINE DERIVATIVES
(FR) DÉRIVÉS D'AZÉTIDINE N-SUBSTITUÉS
Abstract
(EN)
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.
(FR)
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)(alkyle en C1-3), chacun étant éventuellement indépendamment substitué par un ou plusieurs atomes d'halogène ou groupes nitrile, hydroxyle ou alkyle en C1-2; R5 représente H ou un groupe alkyle en C1-3, éventuellement substitué par un ou plusieurs atomes de fluor; R17, R18 et R19 représentent chacun indépendamment des autres H, l'atome de fluor, le groupe nitrile ou un groupe alkyle en C1-3, éventuellement substitué par un ou plusieurs atomes de fluor; ou sur un promédicament, un dérivé isotopiquement marqué ou un sel pharmaceutiquement acceptable de ceux-ci, sur des compositions pharmaceutiques comprenant ces composés et sur leur utilisation en thérapie, en particulier sur leur utilisation pour la prévention ou le traitement d'un dysfonctionnement de l'ovulation, du cancer de l'utérus, du cancer de l'endomètre, du cancer de l'ovaire, de l'endométriose, de l'ostéoporose, du cancer de la prostate, de l'hypertrophie bénigne de la prostate et du cancer du sein, en particulier du cancer du sein RE-positif, plus particulièrement du cancer du sein RE-positif résistant au traitement par des hormones. Lesdits dérivés d'azétidine N-substitués ont une activité antagoniste des récepteurs des œstrogènes alpha (REα) et, dans certains modes de réalisation, de frénation sélective des récepteurs des œstrogènes (SERD) dans des cellules de cancer du sein RE-positif.
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