Piperidine/piperazine derivatives

Patent metadata

Field	Value
Publication number	US-9227935-B2
Application number	US-201414561252-A
Country	US
Kind code	B2
Filing date	Dec 5, 2014
Priority date	Jun 8, 2007
Publication date	Jan 5, 2016
Grant date	Jan 5, 2016

Abstract

The invention relates to a DGAT inhibitor of formula

including any stereochemically isomeric form thereof, wherein A represents CH or N; the dotted line represents an optional bond in case A represents a carbon atom; X represents —O—C(═O)—; —C(═O)—C(═O)—; —NR x —C(═O)—; —Z—C(═O)—; —Z—NR x —C(═O)—; —C(═O)—Z—; —NR x —C(═O)—Z—; —C(═S)—; —NR x —C(═S)—; —Z—C(═S)—; —Z—NR x —C(═S)—; —C(═S)—Z—; —NR x —C(═S)—Z—; Z represents a bivalent radical selected from C 1-6 alkanediyl, C 2-6 alkenediyl or C 2-6 alkynediyl; wherein each of said C 1-6 alkanediyl, C 2-6 alkenediyl or C 2-6 alkynediyl may optionally be substituted; and wherein two hydrogen atoms attached to the same carbon atom in C 1-6 alkanediyl may optionally be replaced by C 1-6 alkanediyl; Y represents —C(═O)—NR x — or —NR x —C(═O)—; R 1 represents adamantanyl, C 3-6 cycloalkyl; aryl 1 or Het 1 ; R 2 represents C 3-6 cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C 3-6 cycloalkyl, phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or heterocycle may optionally be substituted; R 7 represents hydrogen, halo, C 1-4 alkyl, C 1-4 alkyl substituted with hydroxyl;

provided that the following compounds

are excluded;

a N-oxide thereof, a pharmaceutically acceptable salt thereof or a solvate thereof. The invention further relates to methods for preparing such compounds, pharmaceutical compositions comprising said compounds as well as the use as a medicine, as a DGAT inhibitor, of said compounds.

First claim

The invention claimed is:

1. A compound of formula

including any stereochemically isomeric form thereof, wherein
A represents CH;
the dotted line represents an optional bond in case A represents a carbon atom;
X represents —O—C(═O)—; —C(═O)—C(═O)—; —NR x —C(═O)—; —Z—C(═O)—; —Z—NR x —C(═O)—; —C(═O)—Z—; —NR x —C(═O)—Z—; —C(═S)—; —NR x —C(═S)—; —Z—C(═S)—; —Z—NR x —C(═S)—; —C(═S)—Z—; or —NR x —C(═S)—Z—;
Z represents a bivalent radical selected from C 1-6 alkanediyl, C 2-6 alkenediyl or
C 2-6 alkynediyl; wherein each of said C 1-6 alkanediyl, C 2-6 alkenediyl or C 2-6 alkynediyl may optionally be substituted with hydroxyl or amino; and wherein two hydrogen atoms attached to the same carbon atom in C 1-6 alkanediyl may optionally be replaced by C 1-6 alkanediyl;
R x represents hydrogen or C 1-4 alkyl;
Y represents —C(═O)—NR x — or —NR x —C(═O)—;
R 1 represents adamantanyl; C 3-6 cycloalkyl; aryl 1 or Het 1 ;
R 2 represents C 3-6 cycloalkyl, phenyl, naphthalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein said C 3-6 cycloalkyl, phenyl, naphthalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or a 6-membered aromatic heterocycle containing 1 or 2 N atoms may optionally be substituted with at least one substituent, each substituent independently selected from the group consisting of hydroxyl; carboxyl; halo; C 1-6 alkyl optionally substituted with hydroxy; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhalo-C 1-6 alkyloxy; C 1-6 alkyloxycarbonyl wherein C 1-6 alkyl may optionally be substituted with aryl; cyano; C 1-6 alkylcarbonyl; nitro; amino; mono- or di(C 1-4 alkyl)amino; C 1-4 alkylcarbonylamino; —S(═O) p —C 1-4 alkyl; R 4 R 3 N—C(═O)—; R 4 R 3 N—C 1-6 alkyl; C 3-6 cycloalkyl; C 3-6 cycloalkylC 1-4 alkyl; C 3-6 cycloalkyl-C(═O)—; aryl; aryloxy; arylC 1-4 alkyl; aryl-C(═O)—C 1-4 alkyl; aryl-C(═O)—; Het; HetC 1-4 alkyl; Het-C(═O)—C 1-4 alkyl; Het-C(═O)—; and Het-O—;
R 3 represents hydrogen; C 1-4 alkyl optionally substituted with hydroxyl or C 1-4 alkyloxy; R 6 R 5 N—C 1-4 alkyl; C 1-4 alkyloxy; Het; Het-C 1-4 alkyl; aryl; or R 6 R 5 N—C(═O)—C 1-4 alkyl;
R 4 represents hydrogen or C 1-4 alkyl;
R 5 represents hydrogen; C 1-4 alkyl; or C 1-4 alkylcarbonyl;
R 6 represents hydrogen or C 1-4 alkyl; or
R 5 and R 6 may be taken together with the nitrogen to which they are attached to form a saturated monocyclic 5, 6 or 7-membered heterocycle which may further contain one or more heteroatoms each independently selected from the group consisting of O, S, S(═O) p and N; and which heterocycle may optionally be substituted with C 1-4 alkyl;
R 7 represents hydrogen; halo; C 1-4 alkyl; or C 1-4 alkyl substituted with hydroxyl; aryl represents phenyl or phenyl substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; carboxyl; halo; C 1-6 alkyl optionally substituted with
C 1-4 alkyloxy, amino or mono- or di(C 1-4 alkyl)amino; polyhaloC 1-6 alkyl;
C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio;
polyhaloC 1-6 alkyloxy; C 1-6 alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl; C 1-6 alkylcarbonyl; nitro; amino; mono- or di(C 1-4 alkyl)amino; and —S(═O) p —C 1-4 alkyl;
aryl 1 represents phenyl, or fluorenyl; each of said phenyl, or fluorenyl optionally substituted with one or two substituents, each substituent independently being selected from the group consisting of oxo; carboxyl; halo; C 1-6 alkyl optionally substituted with carboxyl or
C 1-4 alkyloxycarbonyl; C 1-6 alkyloxy; C 1-6 alkyloxy-carbonyl; and Het;
Het represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O) p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O) p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C 1-6 alkyl optionally substituted with C 1-4 alkyloxy, amino or mono- or di(C 1-4 alkyl)amino; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy;
C 1-6 alkylthio; polyhaloC 1-6 alkyloxy; C 1-6 alkyloxycarbonyl; cyano; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl; C 1-6 alkylcarbonyl; nitro; amino; mono- or di(C 1-4 alkyl)amino; and —S(═O) p —C 1-4 alkyl;
Het 1 represents a monocyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O) p and N; or a bicyclic or tricyclic non-aromatic or aromatic heterocycle containing at least one heteroatom each independently selected from the group consisting of O, S, S(═O) p and N; said monocyclic heterocycle or said bi- or tricyclic heterocycle optionally being substituted with at least one substituent, each substituent independently being selected from the group consisting of hydroxyl; oxo; carboxyl; halo; C 1-6 alkyl optionally substituted with aryl-C(═O)—; hydroxyC 1-6 alkyl optionally substituted with aryl or aryl-C(═O)—; polyhaloC 1-6 alkyl; C 1-6 alkyloxy optionally substituted with C 1-4 alkyloxy; C 1-6 alkylthio; polyhaloC 1-6 alkyloxy; C 1-6 alkyloxy-carbonyl wherein C 1-6 alkyl may optionally be substituted with aryl; cyano; aminocarbonyl; mono- or di(C 1-4 alkyl)aminocarbonyl; C 1-6 alkylcarbonyl; nitro; amino; mono- or di(C 1-6 alkyl)amino; R 4 R 3 N—C 1-6 alkyl C 3-6 cycloalkyl-NR x —; aryl-NR x —; Het-NR x —; C 3-6 cycloalkylC 1-4 alkyl-NR x —; arylC 1-4 alkyl-NR x —; HetC 1-4 alkyl-NR x —;
—S(═O) p —C 1-4 alkyl; C 3-6 cycloalkyl; C 3-6 cycloalkylC 1-4 alkyl; C 3-6 cycloalkyl-C(═O)—; aryl; aryloxy; arylC 1-4 alkyl; aryl-C(═O)—C 1-4 alkyl; aryl-C(═O)—; Het; HetC 1-4 alkyl; Het-C(═O)—C 1-4 alkyl; Het-C(═O)—; and Het-O—;
p represents 1 or 2;
a N-oxide thereof, or a pharmaceutically acceptable salt thereof.

2. The compound as claimed in claim 1 having the following formula

including any stereochemically isomeric form thereof, wherein
A represents CH;
the dotted line represents an optional bond in case A represents a carbon atom;
X represents —NR x —C(═O)—; —Z—C(═O)—; —Z—NR x —C(═O)—; —C(═O)—Z—; —NR x —C(═O)—Z—; —C(═S)—; —NR x —C(═S)—; —Z—C(═S)—; —Z—NR x —C(═S)—; —C(═S)—Z—; or —NR x —C(═S)—Z—;
Z represents a bivalent radical selected from C 1-6 alkanediyl, C 2-6 alkenediyl or
C 2-6 alkynediyl; wherein each of said C 1-6 alkanediyl, C 2-6 alkenediyl or
C 2-6 alkynediyl may optionally be substituted with hydroxyl;
R x represents hydrogen or C 1-4 alkyl;
Y represents —C(═O)—NR x — or —NR x —C(═O)—;
R 1 represents C 3-6 cycloalkyl; aryl 1 or Het 1 ;
R 2 represents C 3-6 cycloalkyl, phenyl, naphthalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, wherein said C 3-6 cycloalkyl, phenyl, naphthalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl may optionally be substituted with at least one substituent, each substituent independently selected from the group consisting of hydroxyl; carboxyl; halo; C 1-6 al

Assignees

• Janssen Pharmaceutica Nv
• Janssen Pharmaceutica Nv

Inventors

• Bongartz Jean-Pierre Andre Marc
• Linders Joannes Theodorus Maria
• Meerpoel Lieven
• Van Lommen Guy Rosalia Eugeen
• Coesemans Erwin
• Braeken Mirielle
• Buyck Christophe Francis Robert Nestor
• Berwaer Monique Jenny Marie
• De Waepenaert Katharina Antonia Germania J M
• Roevens Peter Walter Maria
• Davidenko Petr Vladimirivich

Classifications

• A61P43/00

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

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title