N-substituted azetidine derivatives

Patent metadata

Field	Value
Publication number	US-9540361-B2
Application number	US-201113995237-A
Country	US
Kind code	B2
Filing date	Dec 16, 2011
Priority date	Dec 24, 2010
Publication date	Jan 10, 2017
Grant date	Jan 10, 2017

Abstract

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.

First claim

What is claimed:

1. N-substituted azetidine derivative of the following Formula 1

wherein
SERMF is a Selective Estrogen Receptor Modulator fragment;
X is no atom, O, S, CH 2 , 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.

2. An N-substituted azetidine derivative according to claim 1 selected from the group consisting of compounds according to any one of Formulae 3

wherein
R1 is (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;
X is no atom, O, S, CH 2 , carbonyl, N—R5;
(h)Ar is a (hetero)aromatic ring, optionally substituted with R12 and R13;
R2 and R3 are independently of each other H, fluorine, chlorine, (C1-3)alkyl, (C1-3)-alkoxy, (C1-3)alkylthio, CF 3 or nitrile;
R4 and R7 are independently of each other H, fluorine, chlorine, (C1-2)alkyl, CF 3 or nitrile;
R12 is H, fluorine, chlorine, (C1-2)alkyl, (C1-2)alkoxy, nitrile or hydroxyl;
R13 is H, fluorine, chlorine, (C1-3)alkyl, (C1-3)alkoxy, (C1-3)alkylthio, CF 3 or nitrile;
R6 is H, hydroxyl, amine or (C1-6)alkoxy;
R6 and R2 may be linked to form a (hetero)aromatic ring which is optionally substituted with fluorine, chlorine or (C1-3)alkyl;
R5 is H, (C1-3)alkyl, optionally substituted with one or more fluorine;
V is O, S, CH 2 , CHOH, CH(C1-3)alkoxy, C═CH 2 , carbonyl, N—R16;
R15 is H, halogen, nitro, nitrile or (C1-6)alkyl, optionally substituted with one or more halogen;
R16 is H, (C1-4)alkyl, (C1-4)alkenyl, optionally substituted with one or more halogen;
R20 is (C1-3)alkyl, optionally substituted with one or more fluorine.

3. An N-substituted azetidine derivative according to claim 1 selected from the group consisting of compounds according to any one of Formulae 4

wherein
R1 is (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;
X is no atom, O, S, CH 2 , carbonyl, N—R5;
(h)Ar is a (hetero)aromatic ring, optionally substituted with R12 and R13;
R2 and R3 are independently of each other H, fluorine, chlorine, (C1-3)alkyl, (C1-3)-alkoxy, (C1-3)alkylthio, CF 3 or nitrile;
R4 and R7 are independently of each other H, fluorine, chlorine, (C1-2)alkyl, CF 3 or nitrile;
R12 is H, fluorine, chlorine, (C1-2)alkyl, (C1-2)alkoxy, nitrile or hydroxyl;
R13 is H, fluorine, chlorine, (C1-3)alkyl, (C1-3)alkoxy, (C1-3)alkylthio, CF 3 or nitrile;
R6 is H, hydroxyl, amine or (C1-6)alkoxy;
R6 and R2 may be linked to form a (hetero)aromatic ring which is optionally substituted with fluorine, chlorine or (C1-3)alkyl;
R5 is H, (C1-3)alkyl, optionally substituted with one or more fluorine;
V is O, S, CH 2 , CHOH, CH(C1-3)alkoxy, C═CH 2 , carbonyl, N—R16;
R15 is H, halogen, nitro, nitrile or (C1-6)alkyl, optionally substituted with one or more halogen;
R16 is H, (C1-4)alkyl, (C1-4)alkenyl, optionally substituted with one or more halogen;
R20 is (C1-3)alkyl, optionally substituted with one or more fluorine.

4. An N-substituted azetidine derivative according to claim 1 selected from the group consisting of compounds according to any one of Formulae 5

wherein
R1 is (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;
(h)Ar is a (hetero)aromatic ring, optionally substituted with R12 and R13;
R2 and R3 are independently of each other H, fluorine, chlorine, (C1-3)alkyl, (C1-3)-alkoxy, (C1-3)alkylthio, CF 3 or nitrile;
R4 and R7 are independently of each other H, fluorine, chlorine, (C1-2)alkyl, CF 3 or nitrile;
R12 is H, fluorine, chlorine, (C1-2)alkyl, (C1-2)alkoxy, nitrile or hydroxyl;
R13 is H, fluorine, chlorine, (C1-3)alkyl, (C1-3)alkoxy, (C1-3)alkylthio, CF 3 or nitrile;
R6 is H, hydroxyl, amine or (C1-6)alkoxy;
R6 and R2 may be linked to form a (hetero)aromatic ring which is optionally substituted with fluorine, chlorine or (C1-3)alkyl.

5. An N-substituted azetidine derivative according to claim 1 selected from the group consisting of compounds according to any one of Formulae 6

6. An N-substituted azetidine de

Assignees

• Dijcks Fredericus Antonius
• Lusher Scott James
• Stock Herman Thijs
• Oubrie Arthur
• Veeneman Gerrit Herman
• Merck Sharp & Dohme

Inventors

• Dijcks Fredericus Antonius
• Lusher Scott James
• Stock Herman Thijs
• Oubrie Arthur
• Veeneman Gerrit Herman

Classifications

• A61P5/30

  Oestrogens · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title