U.S. patent application number 15/627475 was filed with the patent office on 2018-02-01 for drug combinations comprising a dgat inhibitor and a ppar-agonist.
The applicant listed for this patent is Janssen Pharmaceutica NV. Invention is credited to Brian Joel Hrupka, Joannes Theodorus Maria Linders, Peter Walter Maria Roevens.
Application Number | 20180028660 15/627475 |
Document ID | / |
Family ID | 40640200 |
Filed Date | 2018-02-01 |
United States Patent
Application |
20180028660 |
Kind Code |
A1 |
Linders; Joannes Theodorus Maria ;
et al. |
February 1, 2018 |
DRUG COMBINATIONS COMPRISING A DGAT INHIBITOR AND A
PPAR-AGONIST
Abstract
The present invention relates to combinations of a DGAT
inhibitor and a peroxisome proliferator-activator receptor (PPAR)
agonist or a prodrug thereof. The invention further relates to
methods for preparing such combinations, pharmaceutical
compositions comprising said combinations as well as the use as a
medicament of said combinations. The present invention also relates
to novel DGAT inhibitors. The invention further relates to methods
for preparing such compounds, pharmaceutical compositions
comprising said compounds as well as the use as a medicament of
said compounds.
Inventors: |
Linders; Joannes Theodorus
Maria; (Eindhoven, NL) ; Roevens; Peter Walter
Maria; (Malle, BE) ; Hrupka; Brian Joel;
(Beerse, BE) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Janssen Pharmaceutica NV |
Beerse |
|
BE |
|
|
Family ID: |
40640200 |
Appl. No.: |
15/627475 |
Filed: |
June 20, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
14793896 |
Jul 8, 2015 |
9724418 |
|
|
15627475 |
|
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|
12993491 |
Nov 19, 2010 |
9107946 |
|
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PCT/EP2009/056800 |
Jun 3, 2009 |
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14793896 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 3/10 20180101; A61P
35/00 20180101; A61P 3/00 20180101; A61P 1/18 20180101; A61P 9/10
20180101; A61K 31/216 20130101; A61K 31/216 20130101; A61P 13/12
20180101; A61P 3/04 20180101; A61P 27/02 20180101; A61K 45/06
20130101; A61P 17/06 20180101; A61P 25/00 20180101; A61P 3/06
20180101; A61P 25/28 20180101; A61K 2300/00 20130101; A61K 2300/00
20130101; C07D 295/192 20130101; A61K 31/496 20130101; A61P 17/10
20180101; A61K 31/496 20130101; A61P 1/16 20180101; A61P 19/06
20180101; A61P 9/12 20180101; A61P 9/04 20180101; A61P 9/00
20180101 |
International
Class: |
A61K 45/06 20060101
A61K045/06; A61K 31/216 20060101 A61K031/216; A61K 31/496 20060101
A61K031/496; C07D 295/192 20060101 C07D295/192 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 5, 2008 |
EP |
PCT/EP2008/056983 |
Jun 5, 2008 |
EP |
PCT/EP2008/057008 |
Jun 5, 2008 |
EP |
PCT/EP2008/057011 |
Jun 6, 2008 |
EP |
PCT/EP2008/057060 |
Dec 5, 2008 |
EP |
08170780.4 |
Claims
1. A combination of a PPAR-.alpha. agonist or a prodrug thereof and
a DGAT inhibitor wherein the DGAT inhibitor is selected from a) a
compound having the formula ##STR00899## including any
stereochemically isomeric form thereof, wherein A represents CH or
N; X represents O or NR.sup.x; the dotted line represents an
optional bond in case A represents a carbon atom; Y represents a
direct bond; --NR.sup.x--C(.dbd.O)--; --C(.dbd.O)--NR.sup.x--;
--NR.sup.x--C(.dbd.O)--Z--; --NR.sup.x--C(.dbd.O)--Z--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z--O--;
--NR.sup.x--C(.dbd.O)--Z--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--O--Z--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z--; --C(.dbd.O)--Z--O--; --C(.dbd.O)--NR.sup.x--Z--;
--C(.dbd.O)--NR.sup.x--Z--O--;
--C(.dbd.O)--NR.sup.x--Z--C(.dbd.O)--O--;
--C(.dbd.O)--NR.sup.x--Z--O--C(.dbd.O)--;
--C(.dbd.O)--NR.sup.x--O--Z--;
--C(.dbd.O)--NR.sup.x--Z--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z--NR.sup.y--C(.dbd.O)--; or
--C(.dbd.O)--NR.sup.x--Z--NR.sup.y--C(.dbd.O)--O--; Z represents a
bivalent radical selected from C.sub.1-6alkanediyl,
C.sub.2-6alkenediyl or C.sub.2-6alkynediyl; wherein each of said
C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or C.sub.2-6alkynediyl may
optionally be substituted with C.sub.1-4alkyloxy,
C.sub.1-4alkylthio, hydroxyl, cyano or aryl; and wherein two
hydrogen atoms attached to the same carbon atom in the definition
of Z may optionally be replaced by C.sub.1-6alkanediyl; R.sup.x
represents hydrogen or C.sub.1-4alkyl; R.sup.y represents hydrogen;
C.sub.1-4alkyl optionally substituted with C.sub.3-6cycloalkyl or
aryl or Het; C.sub.2-4alkenyl; or S(.dbd.O).sub.p-aryl; R.sup.1
represents C.sub.1-12alkyl optionally substituted with cyano,
C.sub.1-4alkyloxy, C.sub.1-4alkyl-oxyC.sub.1-4alkyloxy,
C.sub.3-6cycloalkyl or aryl; C.sub.2-6alkenyl; C.sub.2-6alkynyl;
C.sub.3-6cycloalkyl; aryls; aryl.sup.1C.sub.1-6alkyl; Het.sup.1; or
Het.sup.1C.sub.1-6alkyl; provided that when Y represents
--NR.sup.x--C(.dbd.O)--Z--; --NR.sup.x--C(.dbd.O)--Z--NR.sup.y;
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--NR.sup.y--; --C(.dbd.O)--Z--;
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z--; --C(.dbd.O)--NR.sup.x--O--Z--; or
--C(.dbd.O)--NR.sup.x--Z--NR.sup.y--; then R.sup.1 may also
represent hydrogen; R.sup.2 and R.sup.3 each independently
represent hydrogen; hydroxyl; carboxyl; halo; C.sub.1-6alkyl;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; or --S(.dbd.O).sub.p--C.sub.1-4alkyl;
R.sup.4 represents hydrogen; hydroxyl; carboxyl; halo;
C.sub.1-6alkyl; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; C.sub.1-4alkylcarbonylamino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; R.sup.6R.sup.5N--C(.dbd.O)--;
R.sup.6R.sup.5N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl; aryl;
aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; or Het-O--; R.sup.5
represents hydrogen; C.sub.1-4alkyl optionally substituted with
hydroxyl or C.sub.1-4alkyloxy; R.sup.8R.sup.7N--C.sub.1-4alkyl;
C.sub.1-4alkyloxy; Het; aryl; or
R.sup.8R.sup.7N--C(.dbd.O)--C.sub.1-4alkyl; R.sup.6 represents
hydrogen or C.sub.1-4alkyl; R.sup.7 represents hydrogen;
C.sub.1-4alkyl; or C.sub.1-4alkylcarbonyl; R.sup.8 represents
hydrogen or C.sub.1-4alkyl; or R.sup.7 and R.sup.8 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(.dbd.O).sub.p and N; and which
heterocycle may optionally be substituted with C.sub.1-4alkyl;
R.sup.9 represents hydrogen; halo; C.sub.1-4alkyl; or
C.sub.1-4alkyl 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.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; and --S(.dbd.O).sub.p--C.sub.1-4alkyl;
aryl.sup.1 represents phenyl, naphthalenyl or fluorenyl; each of
said phenyl, naphthalenyl or fluorenyl optionally substituted with
at least one substituent, each substituent independently being
selected from the group consisting of hydroxyl; oxo; carboxyl;
halo; C.sub.1-6alkyl optionally substituted with carboxyl,
C.sub.1-4 alkyloxycarbonyl or aryl-C(.dbd.O)--; hydroxyC.sub.1-6
alkyl optionally substituted with aryl or aryl-C(.dbd.O)--;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; amino; mono- or di(C.sub.1-6alkyl)amino;
R.sup.6R.sup.5N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--;
aryl-C(.dbd.O)--C.sub.1-4alkyl; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--; Het-C(.dbd.O)--C.sub.1-4alkyl; and Het-O--; 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(.dbd.O).sub.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(.dbd.O).sub.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.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyl-oxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; and --S(.dbd.O).sub.p--C.sub.1-4alkyl;
Het.sup.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(.dbd.O).sub.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(.dbd.O).sub.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.sub.1-6alkyl optionally
substituted with carboxyl, C.sub.1-4alkyloxycarbonyl or
aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally substituted with
aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6
alkyloxy optionally substituted with C.sub.1-4 alkyloxy; C.sub.1-6
alkylthio; polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl
wherein C.sub.1-6alkyl may optionally be substituted with aryl;
cyano; aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; amino; mono- or di(C.sub.1-6alkyl)amino;
R.sup.6R.sup.5N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--;
aryl-C(.dbd.O)--C.sub.1-4alkyl; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--; Het-C(.dbd.O)--C.sub.1-4alkyl; and Het-O--; p
represents 1 or 2; a N-oxide thereof, a pharmaceutically acceptable
salt thereof or a solvate thereof; b) a compound having the formula
##STR00900## 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
--NR.sup.x--C(.dbd.O)--; --Z--C(.dbd.O)--;
--Z--NR.sup.x--C(.dbd.O)--; --S(.dbd.O).sub.p--; C(.dbd.S)--;
--NR.sup.x--C(.dbd.S)--; --Z--C(.dbd.S)--;
--Z--NR.sup.x--C(.dbd.S)--; --O--C(.dbd.O)--; or
--C(.dbd.O)--C(.dbd.O)--; Z represents a bivalent radical selected
from C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or
C.sub.2-6alkynediyl; wherein each of said C.sub.1-6alkanediyl,
C.sub.2-6alkenediyl or C.sub.2-6alkynediyl may optionally be
substituted with hydroxyl or amino; and wherein two hydrogen atoms
attached to the same carbon atom in C.sub.1-6alkanediyl may
optionally be replaced by C.sub.1-6alkanediyl; R.sup.x represents
hydrogen or C.sub.1-4alkyl; R.sup.1-- represents a 5-membered
monocyclic heterocycle containing at least 2 heteroatoms; a
6-membered aromatic monocyclic heterocycle; or a 5-membered
heterocycle containing at least 2 heteroatoms fused with phenyl,
cyclohexyl or a 5- or 6-membered heterocycle; wherein each of said
heterocycles may optionally be substituted with at least one
substituent, each substituent independently being selected from the
group consisting of hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl
optionally substituted with carboxyl, C.sub.1-4alkyloxycarbonyl or
aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally substituted with
aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)-aminocarbonyl;
C.sub.1-6alkylcarbonyl; amino; mono- or di(C.sub.1-6alkyl)amino;
R.sup.5R.sup.4N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkyl-C.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--;
aryl-C(.dbd.O)--C.sub.1-4alkyl; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--; Het-C(.dbd.O)--C.sub.1-4alkyl; and Het-O--;
R.sup.2 represents R.sup.3; R.sup.3 represents C.sub.3-6cycloalkyl,
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.sub.3-6cycloalkyl, phenyl, naphtalenyl,
2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl,
2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle may
optionally be substituted with at least one substituent, each
substituent independently selected from the group consisting of
hydroxyl; carboxyl; halo; C.sub.1-6alkyl optionally substituted
with hydroxy; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally
substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; C.sub.1-4alkylcarbonylamino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; R.sup.5R.sup.4N--C(.dbd.O)--;
R.sup.5R.sup.4N--C.sub.1-6alkyl; C.sub.3-6cycloalkyk
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; and Het-O--;
R.sup.4 represents hydrogen; C.sub.1-4alkyl optionally substituted
with hydroxyl or C.sub.1-4alkyloxy;
R.sup.7R.sup.6N--C.sub.1-4alkyl; C.sub.1-4alkyloxy; Het; aryl; or
R.sup.7R.sup.6N--C(.dbd.O)--C.sub.1-4alkyl; R.sup.5 represents
hydrogen or C.sub.1-4alkyl; R.sup.6 represents hydrogen;
C.sub.1-4alkyl; or C.sub.1-4alkylcarbonyl; R.sup.7 represents
hydrogen or C.sub.1-4alkyl; or R.sup.6 and R.sup.7 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 selected from the group
consisting of O, S, S(.dbd.O).sub.p and N; and which heterocycle
may optionally be substituted with C.sub.1-4alkyl; R.sup.8
represents hydrogen halo C.sub.1-4alkyl; or C.sub.1-4alkyl
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.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; and --S(.dbd.O).sub.p--C.sub.1-4alkyl; Het
represents a monocyclic non-aromatic or aromatic heterocycle
containing at least one heteroatom selected from the group
consisting of O, S, S(.dbd.O).sub.p and N; or a bicyclic or
tricyclic non-aromatic or aromatic heterocycle containing at least
one heteroatom selected from the group consisting of O, S,
S(.dbd.O).sub.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.sub.1-6
alkyl optionally substituted with C.sub.1-4alkyloxy, amino or mono-
or di(C.sub.1-4alkyl)amino; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyloxy optionally substituted with C.sub.1-4alkyloxy;
C.sub.1-6alkylthio; polyhaloC.sub.1-6alkyloxy;
C.sub.1-6alkyl-oxycarbonyl; cyano; aminocarbonyl; mono- or
di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkylcarbonyl; nitro;
amino; mono- or di(C.sub.1-4alkyl)amino; and
--S(.dbd.O).sub.p--C.sub.1-4alkyl p represents 1 or 2; a N-oxide
thereof, a pharmaceutically acceptable salt thereof or a solvate
thereof; c) a compound having the formula ##STR00901## 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(.dbd.O)--;
--C(.dbd.O)--C(.dbd.O)--; --NR.sup.x--C(.dbd.O)--;
--Z--C(.dbd.O)--; --Z--NR.sup.x--C(.dbd.O)--; --C(.dbd.O)--Z--;
--NR.sup.x--C(.dbd.O)--Z--; C(.dbd.S)--; --S(.dbd.O).sub.p--;
--NR.sup.x--C(.dbd.S)--; --Z--C(.dbd.S)--;
--Z--NR.sup.x--C(.dbd.S)--; --C(.dbd.S)--Z--; or
--NR.sup.x--C(.dbd.S)--Z--; Z represents a bivalent radical
selected from C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or
C.sub.2-6alkynediyl; wherein each of said C.sub.1-6alkanediyl,
C.sub.2-6alkenediyl or C.sub.2-6alkynediyl may optionally be
substituted with hydroxyl or amino; and wherein two hydrogen atoms
attached to the same carbon atom in C.sub.1-6alkanediyl may
optionally be replaced by C.sub.1-6alkanediyl; R.sup.x represents
hydrogen or C.sub.1-4alkyl; Y represents C(.dbd.O)--NR.sup.x-- or
--NR.sup.x--C(.dbd.O)--; R.sup.1 represents adamantanyl;
C.sub.3-6cycloalkyl; aryl.sup.1 or Het.sup.1; R.sup.2 represents
hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl,
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.sub.3-6cycloalkyl, phenyl, naphtalenyl,
2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or 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.sub.1-6 alkyl optionally substituted with
hydroxy; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally
substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; C.sub.1-4alkylcarbonylamino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; R.sup.4R.sup.3N--C(.dbd.O)--;
R.sup.4R.sup.3N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; and Het-O--;
R.sup.3 represents hydrogen; C.sub.1-4alkyl optionally substituted
with hydroxyl or C.sub.1-4alkyloxy;
R.sup.6R.sup.5N--C.sub.1-4alkyl; C.sub.1-4alkyloxy; Het;
Het-C.sub.1-4alkyl; aryl; or
R.sup.6R.sup.5N--C(.dbd.O)--C.sub.1-4alkyl; R.sup.4 represents
hydrogen or C.sub.1-4alkyl; R.sup.5 represents hydrogen;
C.sub.1-4alkyl; or C.sub.1-4alkylcarbonyl; R.sup.6 represents
hydrogen or C.sub.1-4alkyl; or R.sup.5 and R.sup.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(.dbd.O).sub.p Of and N; and
which heterocycle may optionally be substituted with
C.sub.1-4alkyl; R.sup.7 represents hydrogen; halo;
C.sub.1-4alkyl.sub.7 or C.sub.1-4alkyl 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.sub.1-6alkyl
optionally substituted with C.sub.1-4alkyloxy, amino or mono- or
di(C.sub.1-4alkyl)amino; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; and --S(.dbd.O).sub.p--C.sub.1-4alkyl;
aryl.sup.1 represents phenyl, naphthalenyl or fluorenyl; each of
said phenyl, naphthalenyl or fluorenyl optionally substituted with
at least one substituent, each substituent independently being
selected from the group consisting of hydroxyl; oxo; carboxyl;
halo; C.sub.1-6alkyl optionally substituted with carboxyl,
C.sub.1-4 alkyloxycarbonyl or aryl-C(.dbd.O)--; hydroxyC.sub.1-6
alkyl optionally substituted with aryl or aryl-C(.dbd.O)--;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-6alkyl)amino; R.sup.4R.sup.3N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl-NR.sup.x--; aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; and Het-O--; 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(.dbd.O).sub.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(.dbd.O).sub.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.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; and --S(.dbd.O).sub.p--C.sub.1-4alkyl;
Het.sup.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(.dbd.O).sub.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(.dbd.O).sub.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.sub.1-6alkyl optionally
substituted with aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally
substituted with aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyloxy optionally substituted with C.sub.1-4alkyloxy;
C.sub.1-6alkylthio; polyhaloC.sub.1-6alkyloxy;
C.sub.1-6alkyloxy-carbonyl wherein C.sub.1-6alkyl may optionally be
substituted with aryl; cyano; aminocarbonyl; mono- or
di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkylcarbonyl; nitro;
amino; mono- or di(C.sub.1-6alkyl)amino;
R.sup.4R.sup.3N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; and Het-O--; p
represents 1 or 2; a N-oxide thereof, a pharmaceutically acceptable
salt thereof or a solvate thereof; or d) a compound having the
formula ##STR00902## 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
C(.dbd.O)--; --O--C(.dbd.O)--; --C(.dbd.O)--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--; --Z.sup.1--C(.dbd.O)--;
--Z.sup.1--NR.sup.x--C(.dbd.O)--; --C(.dbd.O)--Z.sup.1--;
--NR.sup.x--C(.dbd.O)--Z.sup.1--; --S(.dbd.O).sub.p--; C(.dbd.S)--;
--NR.sup.x--C(.dbd.S)--; --Z.sup.1--C(.dbd.S)--;
--Z.sup.1--NR.sup.x--C(.dbd.S)--; --C(.dbd.S)--Z.sup.1--; or
--NR.sup.x--C(.dbd.S)--Z.sup.1--; Z.sup.1 represents a bivalent
radical selected from C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or
C.sub.2-6alkynediyl; wherein each of said C.sub.1-6alkanediyl,
C.sub.2-6alkenediyl or C.sub.2-6alkynediyl may optionally be
substituted with hydroxyl or amino; and wherein two hydrogen atoms
attached to the same carbon atom in C.sub.1-6alkanediyl may
optionally be replaced by C.sub.1-6alkanediyl; Y represents
NR.sup.x--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2-0--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z.sup.2--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--O--Z.sup.2--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z.sup.2--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z.sup.2--; --C(.dbd.O)--Z.sup.2--O--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--O--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--C(.dbd.O)--O--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--O--C(.dbd.O)--;
--C(.dbd.O)--NR.sup.x--O--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--C(.dbd.O)--; or
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--C(.dbd.O)--O--; Z.sup.2
represents a bivalent radical selected from C.sub.1-6alkanediyl,
C.sub.2-6alkenediyl or C.sub.2-6alkynediyl; wherein each of said
C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or C.sub.2-6alkynediyl may
optionally be substituted with C.sub.1-4alkyloxy,
C.sub.1-4alkylthio, hydroxyl, cyano or aryl; and wherein two
hydrogen atoms attached to the same carbon atom in the definition
of Z.sup.2 may optionally be replaced by C.sub.1-6alkanediyl;
R.sup.x represents hydrogen or C.sub.1-4alkyl; R.sup.y represents
hydrogen; C.sub.1-4alkyl optionally substituted with
C.sub.3-6cycloalkyl or aryl or Het; C.sub.2-4alkenyl; or
S(.dbd.O).sub.p-aryl; R.sup.1 represents C.sub.1-12alkyl optionally
substituted with cyano, C.sub.1-4alkyloxy,
C.sub.1-4alkyl-oxyC.sub.1-4alkyloxy, C.sub.3-6cycloalkyl or aryl;
C.sub.2-6alkenyl; C.sub.2-6alkynyl; C.sub.3-6cycloalkyl;
adamantanyl; aryls; aryl.sup.1C.sub.1-6alkyl; Het.sup.1; or
Het.sup.1C.sub.1-6alkyl; provided that when Y represents
--NR.sup.x--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--O--Z.sup.2--; or
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--; then R.sup.1 may also
represent hydrogen; R.sup.2 represents hydrogen; C.sub.1-12alkyl;
C.sub.2-6alkenyl; or R.sup.3; R.sup.3 represents
C.sub.3-6cycloalkyl, 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.sub.3-6cycloalkyl,
phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,
1,3-benzodioxolyl or 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.sub.1-6alkyl optionally
substituted with hydroxy; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; C.sub.1-4alkylcarbonylamino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; R.sup.5R.sup.4N--C(.dbd.O)--;
R.sup.5R.sup.4N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; and Het-O--;
R.sup.4 represents hydrogen; C.sub.1-4alkyl optionally substituted
with hydroxyl or C.sub.1-4alkyloxy;
R.sup.7R.sup.6N--C.sub.1-4alkyl; C.sub.1-4alkyloxy; Het;
Het-C.sub.1-4alkyl; aryl; or
R.sup.7R.sup.6N--C(.dbd.O)--C.sub.1-4alkyl; R.sup.5 represents
hydrogen or C.sub.1-4alkyl; R.sup.6 represents hydrogen;
C.sub.1-4alkyl; or C.sub.1-4alkylcarbonyl; R.sup.7 represents
hydrogen or C.sub.1-4alkyl; or R.sup.6 and R.sup.7 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(.dbd.O).sub.p and N; and which
heterocycle may optionally be substituted with C.sub.1-4alkyl;
R.sup.8 represents hydrogen; halo; C.sub.1-4alkyl; or
C.sub.1-4alkyl 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.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; and --S(.dbd.O).sub.p--C.sub.1-4alkyl;
aryl.sup.1 represents phenyl, naphthalenyl or fluorenyl; each of
said phenyl, naphthalenyl or fluorenyl optionally substituted with
at least one substituent, each substituent independently being
selected from the group consisting of hydroxyl; oxo; carboxyl;
halo; C
.sub.1-6alkyl optionally substituted with carboxyl,
C.sub.1-4alkyloxycarbonyl or aryl-C(.dbd.O)--;
hydroxyC.sub.1-6alkyl optionally substituted with aryl or
aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-6alkyl)amino; R.sup.5R.sup.4N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl-NR.sup.x--; aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; and Het-O--; 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(.dbd.O).sub.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(.dbd.O).sub.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.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; and --S(.dbd.O).sub.p--C.sub.1-4alkyl;
Het.sup.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(.dbd.O).sub.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(.dbd.O).sub.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.sub.1-6alkyl optionally
substituted with carboxyl, C.sub.1-4alkyloxycarbonyl or
aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally substituted with
aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-6alkyl)amino; R.sup.5R.sup.4N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl-NR.sup.x--; aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; and Het-O--; p
represents 1 or 2; provided that if X represents O--C(.dbd.O)--,
then R.sup.2 represents R.sup.3; a N-oxide thereof, a
pharmaceutically acceptable salt thereof or a solvate thereof
2. The combination according to claim 1 wherein the DGAT inhibitor
has the following formula ##STR00903## including any
stereochemically isomeric form thereof, wherein A represents CH or
N; X represents O or NR.sup.x; the dotted line represents an
optional bond in case A represents a carbon atom; Y represents a
direct bond; --NR.sup.x--C(.dbd.O)--; --C(.dbd.O)--NR.sup.x--;
--NR.sup.x--C(.dbd.O)--Z--; --NR.sup.x--C(.dbd.O)--Z--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z--O--;
--NR.sup.x--C(.dbd.O)--Z--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--O--Z--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z--; --C(.dbd.O)--Z--O--; --C(.dbd.O)--NR.sup.x--Z--;
--C(.dbd.O)--NR.sup.x--Z--O--;
--C(.dbd.O)--NR.sup.x--Z--C(.dbd.O)--O--;
--C(.dbd.O)--NR.sup.x--Z--O--C(.dbd.O)--;
--C(.dbd.O)--NR.sup.x--O--Z--;
--C(.dbd.O)--NR.sup.x--Z--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z--NR.sup.y--C(.dbd.O)--; or
--C(.dbd.O)--NR.sup.x--Z--NR.sup.y--C(.dbd.O)--O--; Z represents a
bivalent radical selected from C.sub.1-6alkanediyl,
C.sub.2-6alkenediyl or C.sub.2-6alkynediyl; wherein each of said
C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or C.sub.2-6alkynediyl may
optionally be substituted with C.sub.1-4alkyloxy,
C.sub.1-4alkylthio, hydroxyl, cyano or aryl; and wherein two
hydrogen atoms attached to the same carbon atom in the definition
of Z may optionally be replaced by C.sub.1-6alkanediyl; R.sup.x
represents hydrogen or C.sub.1-4alkyl; R.sup.y represents hydrogen;
C.sub.1-4alkyl optionally substituted with C.sub.3-6cycloalkyl or
aryl or Het; C.sub.2-4alkenyl; or S(.dbd.O).sub.p-aryl; R.sup.1
represents C.sub.1-12alkyl optionally substituted with cyano,
C.sub.1-4alkyloxy, C.sub.1-4alkyl-oxyC.sub.1-4alkyloxy,
C.sub.3-6cycloalkyl or aryl; C.sub.2-6alkenyl; C.sub.2-6alkynyl;
C.sub.3-6cycloalkyl; aryls; aryl.sup.1 C.sub.1-6alkyl; Het.sup.1;
or Het'C.sub.1-6alkyl; provided that when Y represents
--NR.sup.x--C(.dbd.O)--Z--; --NR.sup.x--C(.dbd.O)--Z--NR.sup.y;
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--NR.sup.y--; --C(.dbd.O)--Z--;
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z--; --C(.dbd.O)--NR.sup.x--O--Z--; or
--C(.dbd.O)--NR.sup.x--Z--NR.sup.y--; then R.sup.1 may also
represent hydrogen; R.sup.2 and R.sup.3 each independently
represent hydrogen; hydroxyl; carboxyl; halo; C.sub.1-6alkyl;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; or --S(.dbd.O).sub.p--C.sub.1-4alkyl;
R.sup.4 represents hydrogen; hydroxyl; carboxyl; halo;
C.sub.1-6alkyl; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; C.sub.1-4alkylcarbonylamino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; R.sup.6R.sup.5N--C(.dbd.O)--;
R.sup.6R.sup.5N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl; aryl;
aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; or Het-O--; R.sup.5
represents hydrogen; C.sub.1-4alkyl optionally substituted with
hydroxyl or C.sub.1-4alkyloxy; R.sup.8R.sup.7N--C.sub.1-4alkyl;
C.sub.1-4alkyloxy; Het; aryl; or
R.sup.8R.sup.7N--C(.dbd.O)--C.sub.1-4alkyl; R.sup.6 represents
hydrogen or C.sub.1-4alkyl; R.sup.7 represents hydrogen;
C.sub.1-4alkyl; or C.sub.1-4alkylcarbonyl; R.sup.8 represents
hydrogen or C.sub.1-4alkyl; or R.sup.7 and R.sup.8 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(.dbd.O).sub.p and N; and which
heterocycle may optionally be substituted with C.sub.1-4alkyl;
R.sup.9 represents hydrogen; halo; C.sub.1-4alkyl; or
C.sub.1-4alkyl 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.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; and --S(.dbd.O).sub.p--C.sub.1-4alkyl;
aryl.sup.1 represents phenyl, naphthalenyl or fluorenyl; each of
said phenyl, naphthalenyl or fluorenyl optionally substituted with
at least one substituent, each substituent independently being
selected from the group consisting of hydroxyl; oxo; carboxyl;
halo; C.sub.1-6alkyl optionally substituted with carboxyl,
C.sub.1-4 alkyloxycarbonyl or aryl-C(.dbd.O)--; hydroxyC.sub.1-6
alkyl optionally substituted with aryl or aryl-C(.dbd.O)--;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; amino; mono- or di(C.sub.1-6alkyl)amino;
R.sup.6R.sup.5N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--;
aryl-C(.dbd.O)--C.sub.1-4alkyl; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--; Het-C(.dbd.O)--C.sub.1-4alkyl; and Het-O--; 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(.dbd.O).sub.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(.dbd.O).sub.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.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyl-oxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; and --S(.dbd.O).sub.p--C.sub.1-4alkyl;
Het.sup.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(.dbd.O).sub.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(.dbd.O).sub.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.sub.1-6alkyl optionally
substituted with carboxyl, C.sub.1-4alkyloxycarbonyl or
aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally substituted with
aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6
alkyloxy optionally substituted with C.sub.1-4 alkyloxy; C.sub.1-6
alkylthio; polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl
wherein C.sub.1-6alkyl may optionally be substituted with aryl;
cyano; aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; amino; mono- or di(C.sub.1-6alkyl)amino;
R.sup.6R.sup.5N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--;
aryl-C(.dbd.O)--C.sub.1-4alkyl; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--; Het-C(.dbd.O)--C.sub.1-4alkyl; and Het-O--; p
represents 1 or 2; a N-oxide thereof, a pharmaceutically acceptable
salt thereof or a solvate thereof
3. The combination according to claim 1 wherein the DGAT inhibitor
has the following formula ##STR00904## 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 --NR.sup.x--C(.dbd.O)--;
--Z--C(.dbd.O)--; --Z--NR.sup.x--C(.dbd.O)--; --S(.dbd.O).sub.p--;
C(.dbd.S)--; --NR.sup.x--C(.dbd.S)--; --Z--C(.dbd.S)--;
--Z--NR.sup.x--C(.dbd.S)--; --O--C(.dbd.O)--; or
--C(.dbd.O)--C(.dbd.O)--; Z represents a bivalent radical selected
from C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or
C.sub.2-6alkynediyl; wherein each of said C.sub.1-6alkanediyl,
C.sub.2-6alkenediyl or C.sub.2-6alkynediyl may optionally be
substituted with hydroxyl or amino; and wherein two hydrogen atoms
attached to the same carbon atom in C.sub.1-6alkanediyl may
optionally be replaced by C.sub.1-6alkanediyl; R.sup.x represents
hydrogen or C.sub.1-4alkyl; R.sup.1 represents a 5-membered
monocyclic heterocycle containing at least 2 heteroatoms; a
6-membered aromatic monocyclic heterocycle; or a 5-membered
heterocycle containing at least 2 heteroatoms fused with phenyl,
cyclohexyl or a 5- or 6-membered heterocycle; wherein each of said
heterocycles may optionally be substituted with at least one
substituent, each substituent independently being selected from the
group consisting of hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl
optionally substituted with carboxyl, C.sub.1-4alkyloxycarbonyl or
aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally substituted with
aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)-aminocarbonyl;
C.sub.1-6alkylcarbonyl; amino; mono- or di(C.sub.1-6alkyl)amino;
R.sup.5R.sup.4N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkyl-C.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--;
aryl-C(.dbd.O)--C.sub.1-4alkyl; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--; Het-C(.dbd.O)--C.sub.1-4alkyl; and Het-O--;
R.sup.2 represents R.sup.3; R.sup.3 represents C.sub.3-6cycloalkyl,
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.sub.3-6cycloalkyl, phenyl, naphtalenyl,
2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl,
2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle may
optionally be substituted with at least one substituent, each
substituent independently selected from the group consisting of
hydroxyl; carboxyl; halo; C.sub.1-6alkyl optionally substituted
with hydroxy; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally
substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; C.sub.1-4alkylcarbonylamino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; R.sup.5R.sup.4N--C(.dbd.O)--;
R.sup.5R.sup.4N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; and Het-O--;
R.sup.4 represents hydrogen; C.sub.1-4alkyl optionally substituted
with hydroxyl or C.sub.1-4alkyloxy;
R.sup.7R.sup.6N--C.sub.1-4alkyl; C.sub.1-4alkyloxy; Het; aryl; or
R.sup.7R.sup.6N--C(.dbd.O)--C.sub.1-4alkyl; R.sup.5 represents
hydrogen or C.sub.1-4alkyl; R.sup.6 represents hydrogen;
C.sub.1-4alkyl; or C.sub.1-4alkylcarbonyl; R.sup.7 represents
hydrogen or C.sub.1-4alkyl; or R.sup.6 and R.sup.7 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 selected from the group
consisting of O, S, S(.dbd.O).sub.p and N; and which heterocycle
may optionally be substituted with C.sub.1-4alkyl; R.sup.8
represents hydrogen halo; C.sub.1-4alkyl; or C.sub.1-4alkyl
substituted with hydroxyl; aryl represents phenyl or phenyl
substituted with at least one substituent, one, two, three, four or
five substituents, each substituent independently being each
substituent independently being selected the group consisting of
from hydroxyl; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with C.sub.1-4alkyloxy, amino or mono- or
di(C.sub.1-4alkyl)amino; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; and --S(.dbd.O).sub.p--C.sub.1-4alkyl; Het
represents a monocyclic non-aromatic or aromatic heterocycle
containing at least one heteroatom selected from the group
consisting of O, S, S(.dbd.O).sub.p and N; or a bicyclic or
tricyclic non-aromatic or aromatic heterocycle containing at least
one heteroatom selected from the group consisting of O, S,
S(.dbd.O).sub.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.sub.1-6alkyl optionally substituted with C.sub.1-4alkyloxy, amino
or mono- or di(C.sub.1-4alkyl)amino; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyloxy optionally substituted with C.sub.1-4alkyloxy;
C.sub.1-6alkylthio; polyhaloC.sub.1-6alkyloxy;
C.sub.1-6alkyl-oxycarbonyl; cyano; aminocarbonyl; mono- or
di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkylcarbonyl; nitro;
amino; mono- or di(C.sub.1-4alkyl)amino; and
--S(.dbd.O).sub.p--C.sub.1-4alkyl p represents 1 or 2; a N-oxide
thereof, a pharmaceutically acceptable salt thereof or a solvate
thereof.
4. The combination according to claim 1 wherein the DGAT inhibitor
has the following formula ##STR00905## 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(.dbd.O)--;
--C(.dbd.O)--C(.dbd.O)--; --NR.sup.x--C(.dbd.O)--;
--Z--C(.dbd.O)--; --Z--NR.sup.x--C(.dbd.O)--; --C(.dbd.O)--Z--;
--NR.sup.x--C(.dbd.O)--Z--; C(.dbd.S)--; --S(.dbd.O).sub.p--;
--NR.sup.x--C(.dbd.S)--; --Z--C(.dbd.S)--;
--Z--NR.sup.x--C(.dbd.S)--; --C(.dbd.S)--Z--; or
--NR.sup.x--C(.dbd.S)--Z--; Z represents a bivalent radical
selected from C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or
C.sub.2-6alkynediyl; wherein each of said C.sub.1-6alkanediyl,
C.sub.2-6alkenediyl or C.sub.2-6alkynediyl may optionally be
substituted with hydroxyl or amino; and wherein two hydrogen atoms
attached to the same carbon atom in C.sub.1-6alkanediyl may
optionally be replaced by C.sub.1-6alkanediyl; R.sup.x represents
hydrogen or C.sub.1-4alkyl; Y represents C(.dbd.O)--NR.sup.x-- or
--NR.sup.x--C(.dbd.O)--; R.sup.1 represents adamantanyl,
C.sub.3-6cycloalkyl; aryl.sup.1 or Het.sup.1; R.sup.2 represents
hydrogen, C.sub.1-6alkyl, C.sub.2-6alkenyl, C.sub.3-6cycloalkyl,
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.sub.3-6cycloalkyl, phenyl, naphtalenyl,
2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl or 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.sub.1-6alkyl optionally substituted with hydroxy;
polyhaloC.sub.1-6 alkyl; C.sub.1-6 alkyloxy optionally substituted
with C.sub.1-4 alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; C.sub.1-4alkylcarbonylamino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; R.sup.4R.sup.3N--C(.dbd.O)--;
R.sup.4R.sup.3N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
et-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; and Het-O--; R.sup.3
represents hydrogen; C.sub.1-4alkyl optionally substituted with
hydroxyl or C.sub.1-4alkyloxy; R.sup.6R.sup.5N--C.sub.1-4alkyl;
C.sub.1-4alkyloxy; Het; Het-C.sub.1-4alkyl; aryl; or
R.sup.6R.sup.5N--C(.dbd.O)--C.sub.1-4alkyl; R.sup.4 represents
hydrogen or C.sub.1-4alkyl; R.sup.5 represents hydrogen;
C.sub.1-4alkyl; or C.sub.1-4alkylcarbonyl; R.sup.6 represents
hydrogen or C.sub.1-4alkyl; or R.sup.5 and R.sup.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(.dbd.O).sub.p and N; and which
heterocycle may optionally be substituted with C.sub.1-4alkyl;
R.sup.7 represents hydrogen halo; C.sub.1-4alkyl; or C.sub.1-4alkyl
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.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; and --S(.dbd.O).sub.p--C.sub.1-4alkyl;
aryl.sup.1 represents phenyl, naphthalenyl or fluorenyl; each of
said phenyl, naphthalenyl or fluorenyl optionally substituted with
at least one substituent, each substituent independently being
selected from the group consisting of hydroxyl; oxo; carboxyl;
halo; C.sub.1-6alkyl optionally substituted with carboxyl,
C.sub.1-4alkyloxycarbonyl or aryl-C(.dbd.O)--;
hydroxyC.sub.1-6alkyl optionally substituted with aryl or
aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-6alkyl)amino; R.sup.4R.sup.3N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl-NR.sup.x--; aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; and Het-O--; 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(.dbd.O).sub.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(.dbd.O).sub.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.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; and --S(.dbd.O).sub.p--C.sub.1-4alkyl;
Het.sup.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(.dbd.O).sub.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(.dbd.O).sub.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.sub.1-6alkyl optionally
substituted with aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally
substituted with aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyloxy optionally substituted with C.sub.1-4alkyloxy;
C.sub.1-6alkylthio; polyhaloC.sub.1-6alkyloxy;
C.sub.1-6alkyloxy-carbonyl wherein C.sub.1-6alkyl may optionally be
substituted with aryl; cyano; aminocarbonyl; mono- or
di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkylcarbonyl; nitro;
amino; mono- or di(C.sub.1-6alkyl)amino;
R.sup.4R.sup.3N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; and Het-O--; p
represents 1 or 2; a N-oxide thereof, a pharmaceutically acceptable
salt thereof or a solvate thereof
5. The combination according to claim 1 wherein the DGAT inhibitor
has the following formula ##STR00906## 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 C(.dbd.O)--; --O--C(.dbd.O)--;
--C(.dbd.O)--C(.dbd.O)--; --NR.sup.x--C(.dbd.O)--;
--Z.sup.1--C(.dbd.O)--; --Z.sup.1--NR.sup.x--C(.dbd.O)--;
--C(.dbd.O)--Z.sup.1--; --NR.sup.x--C(.dbd.O)--Z.sup.1--;
--S(.dbd.O).sub.p--; C(.dbd.S)--; --NR.sup.x--C(.dbd.S)--;
--Z.sup.1--C(.dbd.S)--; --Z.sup.1--NR.sup.x--C(.dbd.S)--;
--C(.dbd.S)--Z.sup.1--; or --NR.sup.x--C(.dbd.S)--Z.sup.1--;
Z.sup.1 represents a bivalent radical selected from
C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or C.sub.2-6alkynediyl;
wherein each of said C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or
C.sub.2-6alkynediyl may optionally be substituted with hydroxyl or
amino; and wherein two hydrogen atoms attached to the same carbon
atom in C.sub.1-6alkanediyl may optionally be replaced by
C.sub.1-6alkanediyl; Y represents NR.sup.x--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2-0--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z.sup.2--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--O--Z.sup.2--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z.sup.2--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z.sup.2--; --C(.dbd.O)--Z.sup.2--O--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--O--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--C(.dbd.O)--O--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--O--C(.dbd.O)--;
--C(.dbd.O)--NR.sup.x--O--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--C(.dbd.O)--; or
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--C(.dbd.O)--O--; Z.sup.2
represents a bivalent radical selected from C.sub.1-6alkanediyl,
C.sub.2-6alkenediyl or C.sub.2-6alkynediyl; wherein each of said
C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or C.sub.2-6alkynediyl may
optionally be substituted with C.sub.1-4alkyloxy,
C.sub.1-4alkylthio, hydroxyl, cyano or aryl; and wherein two
hydrogen atoms attached to the same carbon atom in the definition
of Z.sup.2 may optionally be replaced by C.sub.1-6alkanediyl;
R.sup.x represents hydrogen or C.sub.1-4alkyl; R.sup.y represents
hydrogen; C.sub.1-4alkyl optionally substituted with
C.sub.3-6cycloalkyl or aryl or Het; C.sub.2-4alkenyl; or
S(.dbd.O).sub.p-aryl; R.sup.1 represents C.sub.1-12alkyl optionally
substituted with cyano, C.sub.1-4alkyloxy,
C.sub.1-4alkyl-oxyC.sub.1-4alkyloxy, C.sub.3-6cycloalkyl or aryl;
C.sub.2-6alkenyl; C.sub.2-6alkynyl; C.sub.3-6cycloalkyl;
adamantanyl; aryls; aryl.sup.1C.sub.1-6alkyl; Hee; or
Het.sup.1C.sub.1-6alkyl; provided that when Y represents
--NR.sup.x--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--O--Z.sup.2--; or
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--; then RI- may also
represent hydrogen; R.sup.2 represents hydrogen, C.sub.1-12alkyl,
C.sub.2-6alkenyl or R.sup.3; R.sup.3 represents
C.sub.3-6cycloalkyl, 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.sub.3-6cycloalkyl,
phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,
1,3-benzodioxolyl or 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.sub.1-6alkyl optionally
substituted with hydroxy; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; and C.sub.1-4alkylcarbonylamino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; R.sup.5R.sup.4N--C(.dbd.O)--;
R.sup.5R.sup.4N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; and Het-O--;
R.sup.4 represents hydrogen; C.sub.1-4alkyl optionally substituted
with hydroxyl or C.sub.1-4alkyloxy;
R.sup.7R.sup.6N--C.sub.1-4alkyl; C.sub.1-4alkyloxy; Het;
Het-C.sub.1-4alkyl; aryl; or
R.sup.7R.sup.6N--C(.dbd.O)--C.sub.1-4alkyl; R.sup.5 represents
hydrogen or C.sub.1-4alkyl; R.sup.6 represents hydrogen;
C.sub.1-4alkyl; or C.sub.1-4alkylcarbonyl; R.sup.7 represents
hydrogen or C.sub.1-4alkyl; or R.sup.6 and R.sup.7 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(.dbd.O).sub.p and N; and which
heterocycle may optionally be substituted with C.sub.1-4alkyl;
R.sup.8 represents hydrogen halo; C.sub.1-4alkyl; or C.sub.1-4alkyl
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.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; and --S(.dbd.O).sub.p--C.sub.1-4alkyl;
aryl.sup.1 represents phenyl, naphthalenyl or fluorenyl; each of
said phenyl, naphthalenyl or fluorenyl optionally substituted with
at least one substituent, each substituent independently being
selected from the group consisting of hydroxyl; oxo; carboxyl;
halo; C.sub.1-6alkyl optionally substituted with carboxyl,
C.sub.1-4 alkyloxycarbonyl or aryl-C(.dbd.O)--;
hydroxyC.sub.1-6alkyl optionally substituted with aryl or
aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-6alkyl)amino; R.sup.5R.sup.4N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl-NR.sup.x--; aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; and Het-O--; 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(.dbd.O).sub.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(.dbd.O).sub.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.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; and --S(.dbd.O).sub.p--C.sub.1-4alkyl;
Het.sup.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(.dbd.O).sub.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(.dbd.O).sub.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.sub.1-6alkyl optionally
substituted with carboxyl, C.sub.1-4alkyloxycarbonyl or
aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally substituted with
aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-6alkyl)amino; R.sup.5R.sup.4N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl-NR.sup.x--; aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; and Het-O--; p
represents 1 or 2; provided that if X represents O--C(.dbd.O)--,
then R.sup.2 represents R.sup.3; a N-oxide thereof, a
pharmaceutically acceptable salt thereof or a solvate thereof
6. The combination according to claim 4 wherein the DGAT inhibitor
is selected from:
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[-
3-(1-pyrrolidinyl)phenyl]-benzamide;
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazin-
yl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide;
4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-
-N-[3-(1-pyrrolidinyl)phenyl]-benzamide;
4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]ac-
etyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide;
4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-pi-
perazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide;
4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-pip-
erazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide; including any
stereochemically isomeric form thereof; a N-oxide thereof, a
pharmaceutically acceptable salt thereof or a solvate thereof.
7. The combination according to claim 5 wherein the DGAT inhibitor
is selected from:
N4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]phe-
nyl]-4-methoxy-benzeneacetamide;
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[-
[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazin-
yl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;
4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-
-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[-
(3,5-dimethoxyphenyl)methyl]-benzamide;
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazin-
yl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;
4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-pip-
erazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;
4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-pip-
erazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;
4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]ac-
etyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;
4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-pi-
perazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;
4-[4-[[2,6-dichloro-4-[[4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]ac-
etyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide;
4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-pi-
perazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide;
N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-pipera-
zinyl]phenyl]-4-methoxy-benzeneacetamide;
N4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl-
]phenyl]-4-methoxy-benzeneacetamide;
4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-
-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide; including any
stereochemically isomeric form thereof; a N-oxide thereof, a
pharmaceutically acceptable salt thereof or a solvate thereof.
8. The combination according to claim 1 wherein the PPAR-.alpha.
agonist or a prodrug thereof is a fibrate.
9. The combination according to claim 8 wherein the fibrate is
fenofibrate.
10. A combination according to claim 1 for reducing food intake,
for reducing weight, for suppressing appetite, for inducing
satiety; or for the treatment or prevention, in particular
treatment, of metabolic disorders, such as obesity and/or obesity
related disorders (including, but not limited to, peripheral
vascular disease, cardiac failure, myocardial ischaemia, cerebral
ischaemia, cardiac myopathies), diabetes, in particular type II
diabetes mellitus, and/or complications arising therefrom (such as
retinopathy, neuropathy, nephropathy), syndrome X, insulin
resistance, impaired glucose tolerance, conditions of impaired
fasting glucose, hypoglycemia, hyperglycemia, hyperuricemia,
hyperinsulinemia, pancreatitis, hypercholesterolemia,
hyperlipidemia, dyslipidemia, mixed dyslipidemia,
hypertriglyceridemia, nonalcoholic fatty liver disease, fatty
liver, increased mesenteric fat, non-alcoholic steatohepatitis,
liver fibrosis, metabolic acidosis, ketosis, dysmetabolic syndrome;
dermatological conditions such as acne, psoriasis; cardiovascular
diseases, such as atherosclerosis, arteriosclerosis, acute heart
failure, congestive heart failure, coronary artery disease,
cardiomyopathy, myocardial infarction, angina pectoris,
hypertension, hypotension, stroke, ischemia, ischemic reperfusion
injury, aneurysm, restenosis or vascular stenosis; alzheimer's
disease; neoplastic diseases, such as solid tumors, skin cancer,
melanoma, lymphoma or endothelial cancers, e.g., breast cancer,
lung cancer, colorectal cancer, stomach cancer, other cancers of
the gastrointestinal tract (e.g., esophageal cancer or pancreatic
cancer), prostate cancer, kidney cancer, liver cancer, bladder
cancer, cervical cancer, uterine cancer, testicular cancer or
ovarian cancer.
11. The combination according to claim 10 for reducing food intake,
for reducing weight, for suppressing appetite, for inducing
satiety; for the treatment or prevention of obesity and/or obesity
related disorders, diabetes or cardiovascular diseases.
12-15. (canceled)
16. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a therapeutically effective amount of a
combination according to claim 1.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application a divisional application of U.S. patent
application Ser. No. 14/793,896, filed Jul. 8, 2015, currently
pending, which is a continuation application of U.S. patent
application Ser. No. 12/993,491, filed Nov. 19, 2010, now U.S. Pat.
No. 9,107,946, the disclosure of which is hereby incorporated by
reference, which is the U.S. national stage of Application No.
PCT/EP2009/ 056800, filed Jun. 3, 2009, which application claims
priority from PCT/EP2008/057060, filed Jun. 6, 2008;
PCT/EP2008/057008, filed Jun. 5, 2008; PCT/EP/056983, filed Jun. 5,
2008; PCT/EP2008/057011, filed Jun. 5, 2008 and EP 08170780.4,
filed Dec. 5, 2008.
FIELD OF THE INVENTION
[0002] This invention concerns novel drug combinations comprising
an acyl CoA:diacylglycerol acyltransferase (DGAT) inhibitor, in
particular a DGAT1 inhibitor, and a peroxisome
proliferator-activated receptor (PPAR) agonist, in particular a
PPAR-.alpha. agonist, pharmaceutical compositions comprising said
novel drug combinations as active ingredients, as well as the use
of said combinations as a medicament and for the manufacture of a
medicament.
[0003] The present invention also concerns new
piperidine/piperazine derivatives having DGAT inhibitory activity,
in particular DGAT1 inhibitory activity. The invention further
relates to methods for their preparation and pharmaceutical
compositions comprising them. The invention also relates to the use
of said compounds for the manufacture of a medicament for the
prevention or the treatment of a disease mediated by DGAT, in
particular DGAT 1.
BACKGROUND OF THE INVENTION
[0004] Triglycerides represent the major form of energy stored in
eukaryotes. Disorders or imbalances in triglyceride metabolism are
implicated in the pathogenesis of and increased risk for obesity,
insulin resistance syndrome and type II diabetes, nonalcoholic
fatty liver disease and coronary heart disease (see, Lewis, et al,
Endocrine Reviews (2002) 23:201 and Malloy and Kane, Adv. Intern.
Med. (2001) 47:11 1). Additionally, hypertriglyceridemia is often
an adverse consequence of cancer therapy (see, Bast, et al. Cancer
Medicament, 5th Ed., (2000) B. C. Decker, Hamilton, Ontario,
CA).
[0005] A key enzyme in the synthesis of triglycerides is acyl
CoA:diacylglycerol acyltransferase, or DGAT. DGAT is a microsomal
enzyme that is widely expressed in mammalian tissues and that
catalyzes the joining of 1,2-diacylglycerol (DAG) and fatty acyl
CoA to form triglycerides (TG) at the endoplasmic reticulum
(reviewed in Chen and Farese, Trends Cardiovasc. Med. (2000) 10:
188 and Farese, et al, Curr. Opin. Lipidol. (2000) 11:229). It was
originally thought that DGAT uniquely controlled the catalysis of
the final step of acylation of diacylglycerol to triglyceride in
the two major pathways for triglyceride synthesis, the glycerol
phosphate and monoacylglycerol pathways. Because triglycerides are
considered essential for survival, and their synthesis was thought
to occur through a single mechanism, inhibition of triglyceride
synthesis through inhibiting the activity of DGAT has been largely
unexplored.
[0006] Genes encoding mouse DGAT1 and the related human homologs
ARGP1 (human DGAT1) and ARGP2 (human ACAT2) now have been cloned
and characterized (Cases, et al, Proc. Natl Acad. Sci. (1998)
95:13018; Oelkers, et al, J. Biol. Chem. (1998) 273:26765). The
gene for mouse DGAT1 has been used to create DGAT knock-out mice to
better elucidate the function of the DGAT gene.
[0007] Unexpectedly, mice unable to express a functional DGAT1
enzyme (Dgat1-/- mice) are viable and still able to synthesize
triglycerides, indicating that multiple catalytic mechanisms
contribute to triglyceride synthesis (Smith, et al, Nature Genetics
(2000) 25:87). Other enzymes that catalyze triglyceride synthesis,
for example, DGAT2 and diacylglycerol transacylase, also have been
identified (Cases, et al, J. Biol. Chem. (2001) 276:38870). Gene
knockout studies in mice have revealed that DGAT2 .mu.lays a
fundamental role in mammalian triglyceride synthesis and is
required for survival. DGAT2 deficient mice are lipopenic and die
soon after birth, apparently from profound reductions in substrates
for energy metabolism and from impaired permeability barrier
function in the skin. (Farese, et al., J. Biol. Chem. (2004) 279:
11767).
[0008] Significantly, Dgat1-/- mice are resistant to diet-induced
obesity and remain lean. Even when fed a high fat diet (21% fat)
Dgat1-/- mice maintain weights comparable to mice fed a regular
diet (4% fat) and have lower total body triglyceride levels. The
obesity resistance in Dgat1-/- mice is not due to decreased caloric
intake, but the result of increased energy expenditure and
decreased resistance to insulin and leptin (Smith, et al, Nature
Genetics (2000) 25:87; Chen and Farese, Trends Cardiovasc. Med.
(2000) 10: 188; and Chen, et al, J. Clin. Invest. (2002) 109:1049).
Additionally, Dgat1-/- mice have reduced rates of triglyceride
absorption (Buhman, et al, J. Biol. Chem. (2002) 277:25474). In
addition to improved triglyceride metabolism, Dgat1-/- mice also
have improved glucose metabolism, with lower glucose and insulin
levels following a glucose load, in comparison to wild-type mice
(Chen and Farese, Trends Cardiovasc. Med. (2000) 10: 188).
[0009] The finding that multiple enzymes contribute to catalyzing
the synthesis of triglyceride from diacylglycerol is significant,
because it presents the opportunity to modulate one catalytic
mechanism of this biochemical reaction to achieve therapeutic
results in an individual with minimal adverse side effects.
Compounds that inhibit the conversion of diacylglycerol to
triglyceride, for instance by specifically inhibiting the activity
of DGAT1, will find use in lowering corporeal concentrations and
absorption of triglycerides to therapeutically counteract the
pathogenic effects caused by abnormal metabolism of triglycerides
in obesity, insulin resistance syndrome and overt type II diabetes,
congestive heart failure and atherosclerosis, and as a consequence
of cancer therapy.
[0010] Because of the ever increasing prevalence of obesity, type
II diabetes, heart disease and cancer in societies throughout the
world, there is a pressing need in developing new therapies to
effectively treat and prevent these diseases. Therefore there is an
interest in developing compounds that can potently and specifically
inhibit the catalytic activity of DGAT, in particular DGAT1.
[0011] We have now unexpectedly found that novel compounds
exhibiting DGAT inhibitory activity, in particular DGAT1 inhibitory
activity, and these compounds can therefore be used to prevent or
treat a disease associated with or mediated by DGAT, such as for
example obesity, type II diabetes, heart disease and cancer. The
compounds of the invention differ from the prior art compounds in
structure, in their pharmacological activity, pharmacological
potency, and/or pharmacological profile.
[0012] We have also unexpectedly found that DGAT inhibitors,
including the DGAT inhibitors of the present invention, can be used
to elevate the levels of one or more satiety hormones, in
particular glucagon-like-peptide-1 (GLP-1) and therefore DGAT
inhibitors, in particular DGAT1 inhibitors, can also be used to
prevent or treat a disease which can benefit from elevated levels
of a satiety hormone, in particular GLP-1. Glucagon-like peptide 1
(GLP-1) is an intestinal hormone which generally stimulates insulin
secretion during hyperglycemia, suppresses glucagon secretion,
stimulates (pro) insulin biosynthesis and decelerates gastric
emptying and acid secretion. GLP-1 is secreted from L cells in the
small and large bowel following the ingestion of fat and proteins.
GLP-1 has been suggested, among other indications, as a possible
therapeutic agent for the management of type II
non-insulin-dependent diabetes mellitus as well as related
metabolic disorders, such as obesity.
[0013] The present novel compounds make it possible to treat a
disease which can benefit from elevated levels of GLP-1 with small
molecules (compared to large molecules such as proteins or
protein-like compounds, e.g. GLP-1 analogues).
[0014] The peroxisome proliferator-activated receptors (PPAR)
belong to the steroid hormone nuclear receptor superfamily of
ligand-activated transcription factors that mediate the specific
effects of small lipophilic compounds, such as steroids, retinoids
and fatty acids, on DNA transcription. They play an important role
in the regulation of lipid metabolism, in the regulation of energy
homeostasis, inflammation, artherosclerosis and glucose control.
Three subtypes are identified so far, namely PPAR-.alpha.,
PPAR-.beta./.delta. and PPAR-.gamma.. The three isoforms exhibit
different tissue distribution as well as different ligand
specificities.
[0015] PPAR-.alpha. plays a crucial role in the intracellular lipid
metabolism. The PPAR-.alpha. subtype is mainly expressed in tissues
with elevated mitochondrial and peroxisomal fatty acid
.beta.-oxidation rates, that efficiently harvest energy from
lipids, including liver, skeletal muscle, heart muscle, proximal
tubular epithelial cells of the kidney, and brown fat (brown
adipose tissue). PPAR-.alpha. is also present in cells of the
arterial wall, in monocytes/macrophages, smooth muscle cells,
endothelial cells, in hepatocytes, and in cardiac myocytes.
[0016] Saturated and unsaturated fatty acids are found to be the
primary natural PPAR-.alpha. ligands. In general, PPAR-.alpha. can
be activated by a heterogeneous group of compounds, which include
natural and synthetic agonists, such as eicosanoids, leukotriene
.beta..sub.4, carbaprostacyclin, nonsteroidal anti-inflammatory
drugs, pirinixic acid (WY-14643; PPAR-.alpha./.gamma. agonist),
phthalate ester plasticizers, pterostilbene, fibrates or active
metabolites thereof, .alpha.-substituted phenyl-propanoic acid
derivatives and isoxazolyl-serine-based compounds. Finally,
PPAR-.alpha. is induced by glucocorticoids in response to stress
and follows a diurnal rhythm.
[0017] Fibrates or active metabolites thereof such as fabric acid
derivatives, are PPAR-.alpha. agonists, and have been used to treat
dyslipidemia for several decades because of their triglyceride
lowering and high-density lipoprotein (HDL) cholesterol elevating
effects. Fibric acid derivatives lower the levels of
triglyceride-rich lipoproteins, such as very low-density
lipoproteins (VLDL), raise HDL levels, and have variable effect on
low-density lipoproteins (LDL) levels. The effects on VLDL levels
appear to result primarily from an increase in lipoprotein lipase
activity, especially in muscle. This leads to enhanced hydrolysis
of VLDL triglyceride content and an enhanced VLDL catabolism.
Fibric acid agents also may alter the composition of the VLDL, for
example, by decreasing hepatic production of apoC-III, an inhibitor
of lipoprotein lipase activity. These compounds are also reported
to decrease hepatic VLDL triglyceride synthesis, possibly by
inhibiting fatty acid synthesis and by promoting fatty acid
oxidation. In addition, they have been documented to be beneficial
in the prevention of ischemic heart disease in individuals with
dyslipidemia and they can also modestly decrease elevated
fibrinogen and PAI-1 levels. Well-known examples of fibrates are
fenofibrate (fenofibric acid as active metabolite), ABT-335 (which
is the choline salt of fenofibric acid), bezafibrate, clofibrate,
ciprofibrate, etofibrate, pirifibrate, beclofibrate and gemfibrozil
(PPAR-.alpha. modulator).
[0018] Because of the ever increasing prevalence of obesity, type
II diabetes, heart disease and cancer in societies throughout the
world, there is a pressing need in developing new therapies to
effectively treat and prevent these diseases.
[0019] We have now unexpectedly found that the combination of a
compound showing DGAT inhibitory activity, in particular DGAT1
inhibitory activity, with a PPAR agonist, in particular a
PPAR-.alpha. agonist, may exhibit an increased and/or accelerated
effect on weight loss, compared to the effect of the DGAT inhibitor
or the PPAR agonist each separately, and additional can decrease
food intake. The combinations of the present invention may show
synergy compared to administration of the composing ingredients
alone.
Background Prior Art
[0020] WO 2006/034441 discloses heterocyclic derivatives and their
use as stearoyl CoA desaturase inhibitors (SCD-1 inhibitors).
[0021] WO 2006/086445 relates to a combination therapy of a SCD-1
inhibitor and another drug to treat adverse weight gain.
[0022] WO 2006/004200 and JP2007131584 relate to urea and amino
derivatives having DGAT inhibitory activity.
[0023] WO 2004/047755 relates to fused bicyclic nitrogen-containing
heterocycles having DGAT inhibitory activity.
[0024] WO2005/072740 relates to an anorectic action of a compound
having DGAT inhibitory activity.
[0025] WO 2007/071966 discloses a conjoint treatment of
pyrimido-[4,5-B]oxazines showing DGAT inhibitory activity together
with anti-dyslipidaemia agents such as PPAR-.alpha. agonists.
[0026] WO2008/148851, WO2008/148840, WO2008/148849 and
WO2008/148868 concern piperidine/piperazine derivatives having DGAT
inhibitory activity.
DESCRIPTION OF THE DRAWINGS
[0027] FIG. 1A shows the food intake of mice treated with a DGAT
inhibitor (compound 223 of Class D--called D in FIG. 1A),
fenofibrate (F) or both, compared to the control group.
[0028] `BL` means baseline food intake.
[0029] FIG. 1B shows the food intake of DIO C57BL/6 mice fed with a
high-fat diet containing fenofibrate (F) and compound 223 of Class
D (D).
[0030] FIG. 1C shows the high fat diet intake (g) of DIO C57BL/6
mice treated with a DGAT inhibitor (compound 358 of Class D),
fenofibrate (F) or both, compared to the control group.
[0031] FIG. 1D shows food intake of lean C57BL/6 mice fed a low-fat
diet containing compound223 of Class D (D) and fenofibrate (F).
[0032] FIG. 2A shows the change in body weight (g) of DIO C57BL/6
mice treated with a DGAT inhibitor (compound 223 of Class D 25
mpk/d), fenofibrate (31 mpk/d) or both.
[0033] FIG. 2B shows the body weight change of DIO C57BL/6 mice fed
with a high-fat diet containing fenofibrate (F) and compound 223 of
Class D (D).
[0034] FIG. 2C shows the change in body weight (g) of DIO C57BL/6
mice fed with a high-fat diet containing DGAT inhibitor (compound
358 of Class D), fenofibrate or both.
[0035] FIG. 2D shows food intake of lean C57BL/6 mice fed a
high-fat diet containing compound 223 of Class D (D) and
fenofibrate (F).
[0036] FIG. 3A shows food intake on day 1 of DIO C57BL/6 mice fed
with a high-fat diet containing compound 223 of Class D and
fenofibrate (D+F).
[0037] FIG. 3B shows day-1 food intake of mice fed a low and
high-fat diet containing 0.01/0.0125 w/w compound 223 of Class
D/fenofibrate (D/F). DIO C57BL/6 mice were acclimated to cages
designed for measuring food intake. After adaptation to either a
lowfat (10 kcal % fat) or high-fat (45 kcal % fat) diet, mice were
switched to a diet with the same fat content (10 kcal % and 45 kcal
% fat respectively), but supplemented with 0.01/0.0125% w/w
D/F.
DESCRIPTION OF THE INVENTION
[0038] The present invention relates to combinations of a DGAT
inhibitor and a peroxisome proliferator-activator receptor (PPAR)
agonist or a prodrug thereof
[0039] In an embodiment, the present invention relates to
combinations of a DGAT inhibitor and a PPAR-.alpha. agonist or a
prodrug thereof.
[0040] In an embodiment, the present invention relates to
combinations of a DGAT1 inhibitor and a PPAR agonist or a prodrug
thereof.
[0041] In an embodiment, the present invention relates to
combinations of a DGAT1 inhibitor and a PPAR-.alpha. agonist or a
prodrug thereof.
[0042] In an embodiment, the present invention relates to
combinations of a DGAT inhibitor, in particular a DGAT1 inhibitor,
and a PPAR-.alpha. agonist or a prodrug thereof selected from the
group of fibrates.
[0043] In an embodiment, the present invention relates to
combinations of a DGAT inhibitor, in particular a DGAT1 inhibitor,
and fenofibrate.
[0044] In an embodiment, the present invention relates to
combinations of a PPAR agonist or a prodrug thereof and a DGAT
inhibitor wherein the DGAT inhibitor is selected from [0045] a) a
compound having the formula
##STR00001##
[0045] including any stereochemically isomeric form thereof,
wherein [0046] A represents CH or N; [0047] X represents O or
NR.sup.x; [0048] the dotted line represents an optional bond in
case A represents a carbon atom; [0049] Y represents a direct bond;
--NR.sup.x--C(.dbd.O)--; --C(.dbd.O)--NR.sup.x--;
--NR.sup.x--C(.dbd.O)--Z--; --NR.sup.x--C(.dbd.O)--Z--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z--O--;
--NR.sup.x--C(.dbd.O)--Z--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--O--Z--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z--; --C(.dbd.O)--Z--O--; --C(.dbd.O)--NR.sup.x--Z--;
--C(.dbd.O)--NR.sup.x--Z--O--;
--C(.dbd.O)--NR.sup.x--Z--C(.dbd.O)--O--;
--C(.dbd.O)--NR.sup.x--Z--O--C(.dbd.O)--;
--C(.dbd.O)--NR.sup.x--O--Z--;
--C(.dbd.O)--NR.sup.x--Z--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z--NR.sup.y--C(.dbd.O)--;
--C(.dbd.O)--NR.sup.x--Z--NR.sup.y--C(.dbd.O)--O--; [0050] Z
represents a bivalent radical selected from C.sub.1-6alkanediyl,
C.sub.2-6alkenediyl or C.sub.2-6alkynediyl; wherein each of said
C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or C.sub.2-6alkynediyl may
optionally be substituted with C.sub.1-4alkyloxy,
C.sub.1-4alkylthio, hydroxyl, cyano or aryl; and wherein two
hydrogen atoms attached to the same carbon atom in the definition
of Z may optionally be replaced by C.sub.1-6alkanediyl; [0051]
R.sup.x represents hydrogen or C.sub.1-4alkyl; [0052] R.sup.y
represents hydrogen; C.sub.1-4alkyl optionally substituted with
C.sub.3-6cycloalkyl or aryl or Het; C.sub.2-4alkenyl; or
--S(.dbd.O).sub.p-aryl; [0053] R.sup.1 represents C.sub.1-12alkyl
optionally substituted with cyano, C.sub.1-4alkyloxy,
C.sub.1-4alkyl-oxyC.sub.1-4alkyloxy, C.sub.3-6cycloalkyl or aryl;
C.sub.2-6alkenyl; C.sub.2-6alkynyl; C.sub.3-6cycloalkyl;
aryl.sup.1; aryl.sup.1C.sub.1-6alkyl; Het.sup.1; or
Het.sup.1C.sub.1-6alkyl; provided that when Y represents
--NR.sup.x--C(.dbd.O)--Z--; --NR.sup.x--C(.dbd.O)--Z--NR.sup.y;
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--NR.sup.y--; --C(.dbd.O)--Z--;
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z--; --C(.dbd.O)--NR.sup.x--O--Z--; or
--C(.dbd.O)--NR.sup.x--Z--NR.sup.y--; then R.sup.1 may also
represent hydrogen; [0054] R.sup.2 and R.sup.3 each independently
represent hydrogen; hydroxyl; carboxyl; halo; C.sub.1-6alkyl;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; [0055]
R.sup.4 represents hydrogen; hydroxyl; carboxyl; halo;
C.sub.1-6alkyl; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; C.sub.1-4alkylcarbonylamino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; R.sup.6R.sup.5N--C(.dbd.O)--;
R.sup.6R.sup.5N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl; aryl;
aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; [0056]
R.sup.5 represents hydrogen; C.sub.1-4alkyl optionally substituted
with hydroxyl or C.sub.1-4alkyloxy;
R.sup.8R.sup.7N--C.sub.1-4alkyl; C.sub.1-4alkyloxy; Het; aryl;
R.sup.8R.sup.7N--C(.dbd.O)--C.sub.1-4alkyl; [0057] R.sup.6
represents hydrogen or C.sub.1-4alkyl; [0058] R.sup.7 represents
hydrogen; C.sub.1-4alkyl; C.sub.1-4alkylcarbonyl; [0059] R.sup.8
represents hydrogen or C.sub.1-4alkyl; or [0060] R.sup.7 and
R.sup.8 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 O, S, S(.dbd.O).sub.p or N; and which
heterocycle may optionally be substituted with C.sub.1-4alkyl;
[0061] R.sup.9 represents hydrogen, halo, C.sub.1-4alkyl,
C.sub.1-4alkyl substituted with hydroxyl; [0062] aryl represents
phenyl or phenyl substituted with at least one substituent, in
particular one, two, three, four or five substituents, each
substituent independently being selected from hydroxyl; carboxyl;
halo; C.sub.1-6alkyl optionally substituted with C.sub.1-4alkyloxy,
amino or mono- or di(C.sub.1-4alkyl)amino; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyloxy optionally substituted with C.sub.1-4alkyloxy;
C.sub.1-6alkylthio; polyhaloC.sub.1-6alkyloxy;
C.sub.1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or
di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkylcarbonyl; nitro;
amino; mono- or di(C.sub.1-4alkyl)amino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; [0063] aryl.sup.1 represents
phenyl, naphthalenyl or fluorenyl; each of said phenyl,
naphthalenyl or fluorenyl optionally substituted with at least one
substituent, in particular one, two, three, four or five
substituents, each substituent independently being selected from
hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with carboxyl, C.sub.1-4alkyloxycarbonyl or
aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally substituted with
aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; amino; mono- or di(C.sub.1-6alkyl)amino;
R.sup.6R.sup.5N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--;
aryl-C(.dbd.O)--C.sub.1-4alkyl; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--; Het-C(.dbd.O)--C.sub.1-4alkyl; Het-O--; [0064] Het
represents a monocyclic non-aromatic or aromatic heterocycle
containing at least one heteroatom each independently selected from
O, S, S(.dbd.O).sub.p or N; or a bicyclic or tricyclic non-aromatic
or aromatic heterocycle containing at least one heteroatom each
independently selected from O, S, S(.dbd.O).sub.p or N; said
monocyclic heterocycle or said bi- or tricyclic heterocycle
optionally being substituted with at least one substituent, in
particular one, two, three, four or five substituents, each
substituent independently being selected from hydroxyl; oxo;
carboxyl; halo; C.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyl-oxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; [0065]
Het.sup.1 represents a monocyclic non-aromatic or aromatic
heterocycle containing at least one heteroatom each independently
selected from O, S, S(.dbd.O).sub.p or N; or a bicyclic or
tricyclic non-aromatic or aromatic heterocycle containing at least
one heteroatom each independently selected from O, S,
S(.dbd.O).sub.p or N; said monocyclic heterocycle or said bi- or
tricyclic heterocycle optionally being substituted with at least
one substituent, in particular one, two, three, four or five
substituents, each substituent independently being selected from
hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with carboxyl, C.sub.1-4alkyloxycarbonyl or
aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally substituted with
aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
[0066] polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl
wherein C.sub.1-6alkyl may optionally be substituted with aryl;
cyano; aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; amino; mono- or di(C.sub.1-6alkyl)amino;
R.sup.6R.sup.5N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--;
aryl-C(.dbd.O)--C.sub.1-4alkyl; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--; Het-C(.dbd.O)--C.sub.1-4alkyl; Het-O--; [0067] p
represents 1 or 2; [0068] a N-oxide thereof, a pharmaceutically
acceptable salt thereof or a solvate thereof; [0069] b) a compound
having the formula
##STR00002##
[0069] including any stereochemically isomeric form thereof,
wherein [0070] A represents CH or N; [0071] the dotted line
represents an optional bond in case A represents a carbon atom;
[0072] X represents --NR.sup.x--C(.dbd.O)--; --Z--C(.dbd.O)--;
--Z--NR.sup.x--C(.dbd.O)--; --S(.dbd.O).sub.p--; C(.dbd.S)--;
--NR.sup.x--C(.dbd.S)--; --Z--C(.dbd.S)--;
--Z--NR.sup.x--C(.dbd.S)--; --O--C(.dbd.O)--;
--C(.dbd.O)--C(.dbd.O)--; [0073] Z represents a bivalent radical
selected from C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or
C.sub.2-6alkynediyl; wherein each of said C.sub.1-6alkanediyl,
C.sub.2-6alkenediyl or C.sub.2-6alkynediyl may optionally be
substituted with hydroxyl or amino; and wherein two hydrogen atoms
attached to the same carbon atom in C.sub.1-6alkanediyl may
optionally be replaced by C.sub.1-6alkanediyl; [0074] R.sup.x
represents hydrogen or C.sub.1-4alkyl; [0075] R.sup.1 represents a
5-membered monocyclic heterocycle containing at least 2
heteroatoms; a 6-membered aromatic monocyclic heterocycle; or a
5-membered heterocycle containing at least 2 heteroatoms fused with
phenyl, cyclohexyl or a 5- or 6-membered heterocycle; wherein each
of said heterocycles may optionally be substituted with at least
one substituent, in particular one, two, three, four or five
substituents, each substituent independently being selected from
hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with carboxyl, C.sub.1-4alkyloxycarbonyl or
aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally substituted with
aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; [0076]
C.sub.1-6alkylthio; polyhaloC.sub.1-6alkyloxy;
C.sub.1-6alkyloxy-carbonyl wherein C.sub.1-6alkyl may optionally be
substituted with aryl; cyano; aminocarbonyl; mono- or
di(C.sub.1-4alkyl)-aminocarbonyl; C.sub.1-6alkylcarbonyl; amino;
mono- or di(C.sub.1-6alkyl)amino; [0077]
R.sup.5R.sup.4N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkyl-C.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--;
aryl-C(.dbd.O)--C.sub.1-4alkyl; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--; Het-C(.dbd.O)--C.sub.1-4alkyl; Het-O--; [0078]
R.sup.2 represents R.sup.3; [0079] R.sup.3 represents
C.sub.3-6cycloalkyl, 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.sub.3-6cycloalkyl,
phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,
1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl or 6-membered aromatic
heterocycle may optionally be substituted with at least one
substituent, in particular one, two, three, four or five
substituents, each substituent independently selected from
hydroxyl; carboxyl; halo; C.sub.1-6alkyl optionally substituted
with hydroxy; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally
substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; C.sub.1-4alkylcarbonylamino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; R.sup.5R.sup.4N--C(.dbd.O)--;
R.sup.5R.sup.4N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; [0080]
R.sup.4 represents hydrogen; C.sub.1-4alkyl optionally substituted
with hydroxyl or C.sub.1-4alkyloxy;
R.sup.7R.sup.6N--C.sub.1-4alkyl; C.sub.1-4alkyloxy; Het; aryl;
R.sup.7R.sup.6N--C(.dbd.O)--C.sub.1-4alkyl; [0081] R.sup.5
represents hydrogen or C.sub.1-4alkyl; [0082] R.sup.6 represents
hydrogen; C.sub.1-4alkyl; C.sub.1-4alkylcarbonyl; [0083] R.sup.7
represents hydrogen or C.sub.1-4alkyl; or [0084] R.sup.6 and
R.sup.7 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
selected from O, S, S(.dbd.O).sub.p or N; and which heterocycle may
optionally be substituted with C.sub.1-4alkyl; [0085] R.sup.8
represents hydrogen, halo, C.sub.1-4alkyl, C.sub.1-4alkyl
substituted with hydroxyl; aryl represents phenyl or phenyl
substituted with at least one substituent, in particular one, two,
three, four or five substituents, each substituent independently
being selected from hydroxyl; carboxyl; halo; C.sub.1-6alkyl
optionally substituted with C.sub.1-4alkyloxy, amino or mono- or
di(C.sub.1-4alkyl)amino; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; [0086]
Het represents a monocyclic non-aromatic or aromatic heterocycle
containing at least one heteroatom selected from O, S,
S(.dbd.O).sub.p or N; or a bicyclic or tricyclic non-aromatic or
aromatic heterocycle containing at least one heteroatom selected
from O, S, S(.dbd.O).sub.p or N; said monocyclic heterocycle or
said bi- or tricyclic heterocycle optionally being substituted with
at least one substituent, in particular one, two, three, four or
five substituents, each substituent independently being selected
from hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with C.sub.1-4alkyloxy, amino or mono- or
di(C.sub.1-4alkyl)amino; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyl-oxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl [0087] p
represents 1 or 2; [0088] a N-oxide thereof, a pharmaceutically
acceptable salt thereof or a solvate thereof; [0089] c) a compound
having the formula
##STR00003##
[0089] including any stereochemically isomeric form thereof,
wherein [0090] A represents CH or N; [0091] the dotted line
represents an optional bond in case A represents a carbon atom;
[0092] X represents O--C(.dbd.O)--; --C(.dbd.O)--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--; --Z--C(.dbd.O)--;
--Z--NR.sup.x--C(.dbd.O)--; --C(.dbd.O)--Z--;
--NR.sup.x--C(.dbd.O)--Z--; C(.dbd.S)--; --S(.dbd.O).sub.p--;
--NR.sup.x--C(.dbd.S)--; --Z--C(.dbd.S)--;
--Z--NR.sup.x--C(.dbd.S)--; --C(.dbd.S)--Z--;
--NR.sup.x--C(.dbd.S)--Z--; [0093] Z represents a bivalent radical
selected from C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or
C.sub.2-6alkynediyl; wherein each of said C.sub.1-6alkanediyl,
C.sub.2-6alkenediyl or C.sub.2-6alkynediyl may optionally be
substituted with hydroxyl or amino; and wherein two hydrogen atoms
attached to the same carbon atom in C.sub.1-6alkanediyl may
optionally be replaced by C.sub.1-6alkanediyl; [0094] R.sup.x
represents hydrogen or C.sub.1-4alkyl; [0095] Y represents
C(.dbd.O)--NR.sup.x-- or --NR.sup.x--C(.dbd.O)--; [0096] R.sup.1
represents adamantanyl, C.sub.3-6cycloalkyl; aryl.sup.1 or
Het.sup.1; [0097] R.sup.2 represents hydrogen, C.sub.1-6alkyl,
C.sub.2-6alkenyl, C.sub.3-6cycloalkyl, 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.sub.3-6cycloalkyl,
phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,
1,3-benzodioxolyl or 6-membered aromatic heterocycle containing 1
or 2 N atoms may optionally be substituted with at least one
substituent, in particular one, two, three, four or five
substituents, each substituent independently selected from
hydroxyl; carboxyl; halo; C.sub.1-6alkyl optionally substituted
with hydroxy; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally
substituted with C.sub.1-4alkyloxy; [0098] C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; C.sub.1-4alkylcarbonylamino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; R.sup.4R.sup.3N--C(.dbd.O)--;
R.sup.4R.sup.3N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; [0099]
R.sup.3 represents hydrogen; C.sub.1-4alkyl optionally substituted
with hydroxyl or C.sub.1-4alkyloxy;
R.sup.6R.sup.5N--C.sub.1-4alkyl; C.sub.1-4alkyloxy; Het;
Het-C.sub.1-4alkyl; aryl;
R.sup.6R.sup.5N--C(.dbd.O)--C.sub.1-4alkyl; [0100] R.sup.4
represents hydrogen or C.sub.1-4alkyl; [0101] R.sup.5 represents
hydrogen; C.sub.1-4alkyl; C.sub.1-4alkylcarbonyl; [0102] R.sup.6
represents hydrogen or C.sub.1-4alkyl; or [0103] R.sup.5 and
R.sup.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 O, S, S(.dbd.O).sub.p or N; and which
heterocycle may optionally be substituted with C.sub.1-4alkyl;
[0104] R.sup.7 represents hydrogen, halo, C.sub.1-4alkyl,
C.sub.1-4alkyl substituted with hydroxyl; [0105] aryl represents
phenyl or phenyl substituted with at least one substituent, in
particular one, two, three, four or five substituents, each
substituent independently being selected from hydroxyl; carboxyl;
halo; C.sub.1-6alkyl optionally substituted with C.sub.1-4alkyloxy,
amino or mono- or di(C.sub.1-4alkyl)amino; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyloxy optionally substituted with C.sub.1-4alkyloxy;
C.sub.1-6alkylthio; polyhaloC.sub.1-6alkyloxy;
C.sub.1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or
di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkylcarbonyl; nitro;
amino; mono- or di(C.sub.1-4alkyl)amino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; [0106] aryl.sup.1 represents
phenyl, naphthalenyl or fluorenyl; each of said phenyl,
naphthalenyl or fluorenyl optionally substituted with at least one
substituent, in particular one, two, three, four or five
substituents, each substituent independently being selected from
hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with carboxyl, C.sub.1-4alkyloxycarbonyl or
aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally substituted with
aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-6alkyl)amino; R.sup.4R.sup.3N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl-NR.sup.x--; aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; [0107] Het
represents a monocyclic non-aromatic or aromatic heterocycle
containing at least one heteroatom each independently selected from
O, S, S(.dbd.O).sub.p or N; or a bicyclic or tricyclic non-aromatic
or aromatic heterocycle containing at least one heteroatom each
independently selected from O, S, S(.dbd.O).sub.p or N; said
monocyclic heterocycle or said bi- or tricyclic heterocycle
optionally being substituted with at least one substituent, in
particular one, two, three, four or five substituents, each
substituent independently being selected from hydroxyl; oxo;
carboxyl; halo; C.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; [0108] C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; [0109]
Het.sup.1 represents a monocyclic non-aromatic or aromatic
heterocycle containing at least one heteroatom each independently
selected from O, S, S(.dbd.O).sub.p or N; or a bicyclic or
tricyclic non-aromatic or aromatic heterocycle containing at least
one heteroatom each independently selected from O, S,
S(.dbd.O).sub.p or N; said monocyclic heterocycle or said bi- or
tricyclic heterocycle optionally being substituted with at least
one substituent, in particular one, two, three, four or five
substituents, each substituent independently being selected from
hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally
substituted with aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyloxy optionally substituted with C.sub.1-4alkyloxy;
C.sub.1-6alkylthio; polyhaloC.sub.1-6alkyloxy;
C.sub.1-6alkyloxy-carbonyl wherein C.sub.1-6alkyl may optionally be
substituted with aryl; cyano; aminocarbonyl; mono- or
di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkylcarbonyl; nitro;
amino; mono- or di(C.sub.1-6alkyl)amino;
R.sup.4R.sup.3N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; [0110] p
represents 1 or 2; [0111] a N-oxide thereof, a pharmaceutically
acceptable salt thereof or a solvate thereof; [0112] or [0113] d) a
compound having the formula
##STR00004##
[0113] including any stereochemically isomeric form thereof,
wherein [0114] A represents CH or N; [0115] the dotted line
represents an optional bond in case A represents a carbon atom;
[0116] X represents C(.dbd.O)--; --O--C(.dbd.O)--;
--C(.dbd.O)--C(.dbd.O)--; --NR.sup.x--C(.dbd.O)--;
--Z.sup.1--C(.dbd.O)--; --Z.sup.1--NR.sup.x--C(.dbd.O)--;
--C(.dbd.O)--Z.sup.1--; --NR.sup.x--C(.dbd.O)--Z.sup.1--;
--S(.dbd.O).sub.p--; C(.dbd.S)--; --NR.sup.x--C(.dbd.S)--;
--Z.sup.1--C(.dbd.S)--; NR.sup.x--C(.dbd.S)--;
--C(.dbd.S)--Z.sup.1--; --NR.sup.x--C(.dbd.S)--Z.sup.1--; [0117]
Z.sup.1 represents a bivalent radical selected from
C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or C.sub.2-6alkynediyl;
wherein each of said C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or
C.sub.2-6alkynediyl may optionally be substituted with hydroxyl or
amino; and wherein two hydrogen atoms attached to the same carbon
atom in C.sub.1-6alkanediyl may optionally be replaced by
C.sub.1-6alkanediyl; [0118] Y represents
NR.sup.x--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z.sup.2--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--O--Z.sup.2--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z.sup.2--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z.sup.2--; --C(.dbd.O)--Z.sup.2--O--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--O--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--C(.dbd.O)--O--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--O--C(.dbd.O)--;
--C(.dbd.O)--NR.sup.x--O--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--C(.dbd.O)--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--C(.dbd.O)--O--; [0119]
Z.sup.2 represents a bivalent radical selected from
C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or C.sub.2-6alkynediyl;
wherein each of said C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or
C.sub.2-6alkynediyl may optionally be substituted with
C.sub.1-4alkyloxy, C.sub.1-4alkylthio, hydroxyl, cyano or aryl; and
wherein two hydrogen atoms attached to the same carbon atom in the
definition of Z.sup.2 may optionally be replaced by
C.sub.1-6alkanediyl; [0120] R.sup.x represents hydrogen or
C.sub.1-4alkyl; [0121] R.sup.y represents hydrogen; C.sub.1-4alkyl
optionally substituted with C.sub.3-6cycloalkyl or aryl or Het;
C.sub.2-4alkenyl; or S(.dbd.O).sub.p-aryl; [0122] R.sup.1
represents C.sub.1-12alkyl optionally substituted with cyano,
C.sub.1-4alkyloxy, C.sub.1-4alkyl-oxyC.sub.1-4alkyloxy,
C.sub.3-6cycloalkyl or aryl; C.sub.2-6alkenyl; C.sub.2-6alkynyl;
C.sub.3-6cycloalkyl; adamantanyl; aryl.sup.1;
aryl.sup.1C.sub.1-6alkyl; Het.sup.1; or Het.sup.1C.sub.1-6alkyl;
provided that when Y represents --NR.sup.x--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--O--Z.sup.2--; or
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--; then R.sup.1 may also
represent hydrogen; [0123] R.sup.2 represents hydrogen,
C.sub.1-12alkyl, C.sub.2-6alkenyl or R.sup.3; [0124] R.sup.3
represents C.sub.3-6cycloalkyl, 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.sub.3-6cycloalkyl,
phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,
1,3-benzodioxolyl or 6-membered aromatic heterocycle containing 1
or 2 N atoms may optionally be substituted with at least one
substituent, in particular one, two, three, four or five
substituents, each substituent independently selected from
hydroxyl; carboxyl; halo; C.sub.1-6alkyl optionally substituted
with hydroxy; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally
substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; C.sub.1-4alkylcarbonylamino; [0125]
--S(.dbd.O).sub.p--C.sub.1-4alkyl; R.sup.5R.sup.4N--C(.dbd.O)--;
R.sup.5R.sup.4N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; [0126]
R.sup.4 represents hydrogen; C.sub.1-4alkyl optionally substituted
with hydroxyl or C.sub.1-4alkyloxy;
R.sup.7R.sup.6N--C.sub.1-4alkyl; C.sub.1-4alkyloxy; Het;
Het-C.sub.1-4alkyl; aryl;
R.sup.7R.sup.6N--C(.dbd.O)--C.sub.1-4alkyl; [0127] R.sup.5
represents hydrogen or C.sub.1-4alkyl; [0128] R.sup.6 represents
hydrogen; C.sub.1-4alkyl; C.sub.1-4alkylcarbonyl; [0129] R.sup.7
represents hydrogen or C.sub.1-4alkyl; or [0130] R.sup.6 and
R.sup.7 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 O, S, S(.dbd.O).sub.p or N; and which
heterocycle may optionally be substituted with C.sub.1-4alkyl;
[0131] R.sup.8 represents hydrogen, halo, C.sub.1-4alkyl,
C.sub.1-4alkyl substituted with hydroxyl; [0132] aryl represents
phenyl or phenyl substituted with at least one substituent, in
particular one, two, three, four or five substituents, each
substituent independently being selected from hydroxyl; carboxyl;
halo; C.sub.1-6alkyl optionally substituted with C.sub.1-4alkyloxy,
amino or mono- or di(C.sub.1-4alkyl)amino; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyloxy optionally substituted with C.sub.1-4alkyloxy;
C.sub.1-6alkylthio; polyhaloC.sub.1-6alkyloxy;
C.sub.1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or
di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkylcarbonyl; nitro;
amino; mono- or di(C.sub.1-4alkyl)amino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; [0133] aryl.sup.1 represents
phenyl, naphthalenyl or fluorenyl; each of said phenyl,
naphthalenyl or fluorenyl optionally substituted with at least one
substituent, in particular one, two, three, four or five
substituents, each substituent independently being selected from
hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with carboxyl, C.sub.1-4alkyloxycarbonyl or
aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally substituted with
aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-6alkyl)amino; R.sup.5R.sup.4N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl-NR.sup.x--; aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; [0134] Het
represents a monocyclic non-aromatic or aromatic heterocycle
containing at least one heteroatom each independently selected from
O, S, S(.dbd.O).sub.p or N; or a bicyclic or tricyclic non-aromatic
or aromatic heterocycle containing at least one heteroatom each
independently selected from O, S, S(.dbd.O).sub.p or N; said
monocyclic heterocycle or said bi- or tricyclic heterocycle
optionally being substituted with at least one substituent, in
particular one, two, three, four or five substituents, each
substituent independently being selected from hydroxyl; oxo;
carboxyl; halo; C.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; [0135] C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; [0136]
Het.sup.1 represents a monocyclic non-aromatic or aromatic
heterocycle containing at least one heteroatom each independently
selected from O, S, S(.dbd.O).sub.p or N; or a bicyclic or
tricyclic non-aromatic or aromatic heterocycle containing at least
one heteroatom each independently selected from O, S,
S(.dbd.O).sub.p or N; said monocyclic heterocycle or said bi- or
tricyclic heterocycle optionally being substituted with at least
one substituent, in particular one, two, three, four or five
substituents, each substituent independently being selected from
hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with carboxyl, C.sub.1-4alkyloxycarbonyl or
aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally substituted with
aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
[0137] polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl
wherein C.sub.1-6alkyl may optionally be substituted with aryl;
cyano; aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-6alkyl)amino; R.sup.5R.sup.4N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl-NR.sup.x--; aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--C.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; [0138] p
represents 1 or 2; [0139] provided that if X represents
O--C(.dbd.O)--, then R.sup.2 represents R.sup.3; [0140] a N-oxide
thereof, a pharmaceutically acceptable salt thereof or a solvate
thereof
[0141] Hereinafter, the compounds of formula (I) as defined under
a) are indicated as class A compounds, the compounds as defined
under b) are indicated as class B compounds, the compounds as
defined under c) are indicated as class C compounds, and the
compounds as defined under d) are indicated as class D
compounds.
[0142] In an embodiment, the present invention relates to
combinations of a DGAT inhibitor wherein the DGAT inhibitor is
selected from [0143] a) a compound of class A, class B, class C, or
class D; [0144] and [0145] b) a PPAR-.alpha. agonist or a prodrug
thereof.
[0146] In an embodiment, the present invention relates to
combinations of a DGAT inhibitor wherein the DGAT inhibitor is
selected from [0147] a) a compound of class A, class B, class C, or
class D; [0148] and [0149] b) a fibrate.
[0150] In an embodiment, the present invention relates to
combinations of a DGAT inhibitor wherein the DGAT inhibitor is
selected from [0151] a) a compound of class A, class B, class C, or
class D; [0152] and [0153] b) fenofibrate.
[0154] In an embodiment, the present invention relates to any of
the preceding embodiments wherein the DGAT inhibitor is selected
from a compound of Class A.
[0155] In an embodiment, the present invention relates to any of
the preceding embodiments wherein the DGAT inhibitor is selected
from a compound of Class B.
[0156] In an embodiment, the present invention relates to any of
the preceding embodiments wherein the DGAT inhibitor is selected
from a compound of Class C.
[0157] In an embodiment, the present invention relates to any of
the preceding embodiments wherein the DGAT inhibitor is selected
from a compound of Class D.
[0158] In an embodiment, the present invention relates to any of
the preceding or the following embodiments wherein the PPAR agonist
or a prodrug thereof, is a PPAR-.alpha. agonist or a prodrug
thereof, more in particular a fibrate, even more in particular a
fenofibrate.
[0159] In an embodiment, the present invention relates to any of
the preceding or following embodiments wherein the DGAT inhibitor
is a DGAT1 inhibitor.
[0160] The present invention also concerns methods for the
preparation of compounds of class A, class B, class C or class D,
and combinations or pharmaceutical compositions comprising
them.
[0161] The combinations according to the present invention are
suitable for use as a medicament.
[0162] The combinations according to the present invention are
suitable for reducing food intake, for reducing weight, for
suppressing appetite, for inducing satiety; or for the treatment or
prevention, in particular treatment, of metabolic disorders, such
as obesity and/or obesity related disorders (including, but not
limited to, peripheral vascular disease, cardiac failure,
myocardial ischaemia, cerebral ischaemia, cardiac myopathies),
diabetes, in particular type II diabetes mellitus, and/or
complications arising therefrom (such as retinopathy, neuropathy,
nephropathy), syndrome X, insulin resistance, impaired glucose
tolerance, conditions of impaired fasting glucose, hypoglycemia,
hyperglycemia, hyperuricemia, hyperinsulinemia, pancreatitis,
hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed
dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver
disease, fatty liver, increased mesenteric fat, non-alcoholic
steatohepatitis, liver fibrosis, metabolic acidosis, ketosis,
dysmetabolic syndrome; dermatological conditions such as acne,
psoriasis; cardiovascular diseases, such as atherosclerosis,
arteriosclerosis, acute heart failure, congestive heart failure,
coronary artery disease, cardiomyopathy, myocardial infarction,
angina pectoris, hypertension, hypotension, stroke, ischemia,
ischemic reperfusion injury, aneurysm, restenosis or vascular
stenosis; alzheimer's disease; neoplastic diseases, such as solid
tumors, skin cancer, melanoma, lymphoma or endothelial cancers,
e.g., breast cancer, lung cancer, colorectal cancer, stomach
cancer, other cancers of the gastrointestinal tract (e.g.,
esophageal cancer or pancreatic cancer), prostate cancer, kidney
cancer, liver cancer, bladder cancer, cervical cancer, uterine
cancer, testicular cancer or ovarian cancer.
[0163] The combinations according to the present invention are
particularly suitable for the treatment of prevention, in
particular treatment, of obesity, type II diabetes mellitus; for
suppressing appetite, for inducing satiety and/or for reducing food
intake.
[0164] The present invention also relates to the use of the
combinations according to the present invention for the manufacture
of a medicament for the treatment or prevention, in particular
treatment, of the above mentioned diseases or conditions.
[0165] The present invention also relates to the use of a
combination of a DGAT inhibitor, in particular a DGAT1 inhibitor,
and a PPAR agonist or a prodrug thereof, in particular a
PPAR-.alpha. agonist or a prodrug thereof, more in particular a
fibrate, even more in particular fenofibrate, for the manufacture
of a medicament for the prevention or the treatment, in particular
for the treatment, of a disease which can benefit from elevated
levels of one or more satiety hormones, in particular GLP-1.
[0166] The present invention also relates to a product containing
a) a DGAT inhibitor, in particular a DGAT1 inhibitor, more in
particular a compound of Class A, Class B, Class C or Class D, and
(b) an agonist of peroxisome proliferators-activator receptor such
as for example fenofibrate, as a combined preparation for
simultaneous, separate or sequential use in the treatment of a
disease which can benefit from an elevated level of GLP-1 or DGAT
inhibition, such as for example diabetes, in particular type II
diabetes mellitus, obesity, for suppressing appetite, inducing
satiety or for reducing food intake.
[0167] In an embodiment, the present invention also relates to
pharmaceutical compositions comprising a pharmaceutically
acceptable carrier, and as active ingredient a therapeutically
effective amount of the combinations mentioned hereinbefore or
hereinafter.
[0168] The present invention further relates to novel compounds,
wherein the compound is selected from: [0169]
N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]p-
henyl]-4-methoxy-benzeneacetamide (compound 355 Class D); [0170]
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[-
3-(1-pyrrolidinyl)phenyl]-benzamide (compound 151 Class C); [0171]
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[-
[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound 354 Class D);
[0172]
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazin-
yl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound 356
Class D); [0173]
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-pi-
perazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 152
Class C); [0174]
4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piper-
azinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 358
Class D); [0175]
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazin-
yl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 353 Class
D); [0176]
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-pi-
perazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 357
Class D); [0177]
4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-
-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 147 Class C);
[0178]
4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-pip-
erazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 360
Class D); [0179]
4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-pip-
erazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound
359 Class D); [0180]
4-[4-[[2,6-dichloro-4-[(4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]ac-
etyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide
(compound 364 Class D); [0181]
4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-pi-
perazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound
361 Class D); [0182]
4-[4-[[2,6-dichloro-4-[(4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]ac-
etyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide
(compound 363 Class D); [0183]
4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-pi-
perazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 362
Class D); [0184]
4-[4-[[2,6-dichloro-4-[(4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]ac-
etyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide
(compound 150 Class C); [0185]
4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-pi-
perazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 149
Class C); [0186]
4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl-
]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound
148 Class C); [0187] including any stereochemically isomeric forms
thereof; [0188] N-oxides thereof, pharmaceutically acceptable salts
thereof or solvates thereof.
[0189] Hereinafter, the novel compounds as defined in the list
hereabove (compounds 147 till 152 from Class C, and compounds 353
till 364 from Class D; including any stereochemically isomeric
forms thereof; N-oxides thereof, pharmaceutically acceptable salts
thereof or solvates thereof), are indicated as compounds of group
Q.
[0190] The present invention further relates to the novel compound
4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-
-N-[(3,5-dimethoxyphenyl) methyl]-benzamide (compound 358 Class D);
including any stereochemically isomeric forms thereof; N-oxides
thereof, pharmaceutically acceptable salts thereof or solvates
thereof.
[0191] The present invention also relates to a compound of group Q
for use as a medicament.
[0192] The present invention also relates to a compound of group Q
for the prevention or the treatment of a disease mediated by DGAT,
in particular the present invention relates to a compound of group
Q for the prevention or the treatment of a disease which can
benefit from inhibition of DGAT, in particular for the treatment of
a disease which can benefit from inhibition of DGAT, in particular
DGAT1.
[0193] The present invention also relates to a compound of group Q
for the prevention or the treatment, in particular for the
treatment, of a disease which can benefit from elevated levels of
one or more satiety hormones, in particular GLP-1.
[0194] The present invention also relates to the use of a compound
of group Q for the manufacture of a medicament for the treatment or
prevention, in particular treatment, of the above mentioned
diseases or conditions.
[0195] In an embodiment, the present invention also relates to
pharmaceutical compositions comprising a pharmaceutically
acceptable carrier, and as active ingredient a therapeutically
effective amount of a compound of group Q.
[0196] The present invention will now be further described. In the
following passages, different aspects of the invention are defined
in more detail.
DETAILED DESCRIPTION
[0197] All terms used are to be construed in accordance with the
following definitions, unless the context indicates otherwise. In
general, the terms are valid for the compounds of class A, class B,
class C and class D, unless it is indicated that a certain
definition for a term is only valid for a certain class or subset
of classes.
[0198] As used hereinbefore or hereinafter C.sub.0-3alkyl as a
group or part of a group defines straight or branched chain
saturated hydrocarbon radicals having from 0 (then it represents a
direct bond) to 3 carbon atoms such as methyl, ethyl, propyl,
1-methylethyl; C.sub.1-2alkyl as a group or part of a group defines
straight or branched chain saturated hydrocarbon radicals having 1
or 2 carbon atoms such as methyl, ethyl;
[0199] C.sub.1-4alkyl as a group or part of a group defines
straight or branched chain saturated hydrocarbon radicals having
from 1 to 4 carbon atoms such as methyl, ethyl, propyl,
1-methylethyl, butyl; C.sub.1-65alkyl as a group or part of a group
defines straight or branched chain saturated hydrocarbon radicals
having from 1 to 5 carbon atoms such as the group defined for
C.sub.1-4alkyl and pentyl, 2-methylbutyl and the like;
C.sub.1-6alkyl as a group or part of a group defines straight or
branched chain saturated hydrocarbon radicals having from 1 to 6
carbon atoms such as the group defined for C.sub.1-4alkyl and for
C.sub.1-5alkyl and hexyl, 2-methylpentyl and the like;
C.sub.1-12alkyl as a group or part of a group defines straight or
branched chain saturated hydrocarbon radicals having from 1 to 12
carbon atoms such as the group defined for C.sub.1-6alkyl and
heptyl, 2-methylheptyl and the like; C.sub.1-6alkanediyl defines
straight or branched chain saturated bivalent hydrocarbon radicals
having from 1 to 6 carbon atoms such as methylene, 1,2-ethanediyl
or 1,2-ethylidene, 1,3-propanediyl or 1,3-propylidene,
1,4-butanediyl or 1,4-butylidene, 1,5-pentanediyl and the like;
C.sub.2-4alkenyl as a group or part of a group defines straight or
branched chain hydrocarbon radicals having from 2 to 4 carbon atoms
and having a double bond such as ethenyl, propenyl, butenyl and the
like; C.sub.2-6alkenyl as a group or part of a group defines
straight or branched chain hydrocarbon radicals having from 2 to 6
carbon atoms and having a double bond such as the group defined for
C.sub.2-4alkenyl and pentenyl, hexenyl, 3-methylbutenyl and the
like; C.sub.2-6alkenediyl defines straight or branched chain
bivalent hydrocarbon radicals having from 2 to 6 carbon atoms and
having a double bond such as 1,2-ethenediyl, 1,3-propenediyl,
1,4-butenediyl, 1,5-pentenediyl and the like; C.sub.2-6alkynyl
defines straight and branched chain hydrocarbon radicals having
from 2 to 6 carbon atoms and having a triple bond such as ethynyl,
propynyl, butynyl, pentynyl, hexynyl and the like;
C.sub.2-6alkynediyl as a group or part of a group defines straight
or branched chain bivalent hydrocarbon radicals having from 2 to 6
carbon atoms and having a triple bond such as 1,2-ethynediyl,
1,3-propynediyl, 1,4-butynediyl, 1,5-pentynediyl and the like;
C.sub.3-6cycloalkyl is generic to cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl.
[0200] The term halo is generic to fluoro, chloro, bromo and iodo.
As used hereinbefore or hereinafter, polyhaloC.sub.1-6alkyl as a
group or part of a group is defined as C.sub.1-6alkyl substituted
with one or more, such as for example 2, 3, 4 or 5 halo atoms, for
example methyl substituted with one or more fluoro atoms, for
example, difluoromethyl or trifluoromethyl, 1,1-difluoro-ethyl,
1,1-difluoro-2,2,2-trifluoro-ethyl and the like. In case more than
one halogen atoms are attached to a C.sub.1-6alkyl group within the
definition of polyhaloC.sub.1-6alkyl, they may be the same or
different.
[0201] As used herein before, the term (.dbd.O) forms a carbonyl
moiety when attached to a carbon atom, a sulfoxide moiety when
attached to a sulfur atom and a sulfonyl moiety when two of said
terms are attached to a sulfur atom. Oxo means .dbd.O.
[0202] The radical R.sup.1, as defined hereinabove for the
compounds of class B, may be an optionally substituted 5-membered
monocyclic heterocycle containing at least 2 heteroatoms, an
optionally substituted 6-membered aromatic monocyclic heterocycle
or an optionally substituted 5-membered heterocycle containing at
least 2 heteroatoms fused with a phenyl, cyclohexyl or a 5- or
6-membered heterocycle.
[0203] A 5-membered monocyclic heterocycle as defined hereinabove
or hereinafter may be a 5-membered monocyclic non-aromatic (fully
saturated or partially saturated) or aromatic heterocycle
containing at least 2 heteroatom, in particular 2 or 3 heteroatoms,
each independently selected from O, S, S(.dbd.O).sub.p or N.
Examples of such unsubstituted monocyclic 5-membered heterocycles
comprise, but are not limited to, non-aromatic (fully saturated or
partially saturated) or aromatic 5-membered monocyclic heterocycles
such as for example 1,3-dioxolanyl, imidazolidinyl, thiazolidinyl,
dihydrooxazolyl, isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl,
triazolidinyl, thiadiazolidinyl, pyrazolidinyl, imidazolinyl,
pyrazolinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl, oxadiazolyl,
tetrazolyl and the like. Optional substituents of the above
heterocycles are hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl
optionally substituted with carboxyl, C.sub.1-4alkyloxy-carbonyl or
aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally substituted with
aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)-aminocarbonyl;
C.sub.1-6alkylcarbonyl; amino; mono- or di(C.sub.1-6alkyl)amino;
R.sup.5R.sup.4N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--;
aryl-C(.dbd.O)--C.sub.1-4alkyl; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--; Het-C(.dbd.O)--C.sub.1-4alkyl; Het-O--.
[0204] A 6-membered aromatic monocyclic heterocycle as defined
hereinabove or hereinafter contains at least one heteroatom, in
particular 1, 2 or 3 heteroatoms, each independently selected from
O, S, S(.dbd.O).sub.p or N. Examples of such unsubstituted
monocyclic 6-membered aromatic heterocycles comprise, but are not
limited to, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,
triazinyl, pyranyl and the like. Optional substituents of the above
heterocycles are hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl
optionally substituted with carboxyl, C.sub.1-4alkyloxycarbonyl or
aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally substituted with
aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; amino; mono- or di(C.sub.1-6alkyl)amino;
R.sup.5R.sup.4N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
[0205] C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--;
aryl-C(.dbd.O)--C.sub.1-4alkyl; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--; Het-C(.dbd.O)--C.sub.1-4alkyl; Het-O--.
[0206] A 5-membered heterocycle containing at least 2 heteroatoms
fused with phenyl, cyclohexyl or a 5- or 6-membered heterocycle as
defined hereinabove or hereinafter may be a non-aromatic (fully
saturated or partially saturated) or aromatic 5-membered
heterocycle containing at least 2 heteroatoms, in particular 2 or 3
heteroatoms, each independently selected from O, S, S(.dbd.O).sub.p
or N, in particular O, S or N, more in particular O or N, fused
with phenyl, cyclohexyl or a 5- or 6-membered non-aromatic (fully
saturated or partially saturated) or aromatic heterocycle
containing at least one heteroatom, in particular 1, 2 or3
heteroatoms, each independently selected from O, S, S(.dbd.O).sub.p
or N. Examples of such unsubstituted bicyclic heterocycles
comprise, but are not limited to, non-aromatic (fully saturated or
partially saturated) or aromatic 8- or 9-membered bicyclic
heterocycles such as for example 1,3-benzodioxolyl, benzoxazolyl,
benzimidazolyl, indazolyl, benzisoxazolyl, benzisothiazolyl,
benzopyrazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl,
purinyl, pyrrolopyridyl, thienopyridyl, furopyridyl,
isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl,
oxazolopyridyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl,
thienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl,
thiazolopyrazinyl, isoxazolopyrazinyl, oxazolopyrazinyl,
pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl,
thienopyrimidinyl, furopyrimidinyl, isothiazolopyrimidinyl,
thiazolopyrimidinyl, isoxazolopyrimidinyl, oxazolopyrimidinyl,
pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyridazinyl,
thienopyridazinyl, furopyridazinyl, isothiazolopyridazinyl,
thiazolopyridazinyl, isoxazolopyridazinyl, oxazolopyridazinyl,
pyrazolopyridazinyl, imidazopyridazinyl, oxadiazolopyridyl,
thiadiazolopyridyl, triazolopyridyl, oxadiazolopyrazinyl,
thiadiazolopyrazinyl, triazolopyrazinyl, oxadiazolopyrimidinyl,
thiadiazolopyrimidinyl, triazolopyrimidinyl, oxadiazolopyridazinyl,
thiadiazolopyridazinyl, triazolopyridazinyl, imidazooxazolyl,
imidazothiazolyl, imidazoimidazolyl, imidazopyrazolyl,
isoxazolotriazinyl, isothiazolotriazinyl, pyrazolotriazinyl,
oxazolotriazinyl, thiazolotriazinyl, imidazotriazinyl,
oxadiazolotriazinyl, thiadiazolotriazinyl, triazolotriazinyl and
the like. Optional substituents of the above heterocycles are
hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with carboxyl, C.sub.1-4alkyloxycarbonyl or
aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally substituted with
aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; amino; mono- or di(C.sub.1-6alkyl)amino;
R.sup.5R.sup.4N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--;
aryl-C(.dbd.O)--C.sub.1-4alkyl; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--; Het-C(.dbd.O)--C.sub.1-4alkyl; Het-O--.
[0207] The radical Het or Het.sup.1 as defined hereinabove may be
an optionally substituted monocyclic non-aromatic or aromatic
heterocycle containing at least one heteroatom, in particular 1, 2
or 3 heteroatoms, each independently selected from O, S,
S(.dbd.O).sub.p or N; or an optionally substituted bi- or tricyclic
non-aromatic or aromatic heterocycle containing at least one
heteroatom, in particular 1, 2, 3, 4 or 5 heteroatoms, each
independently selected from O, S, S(.dbd.O).sub.p or N. Examples of
such unsubstituted monocyclic heterocycles comprise, but are not
limited to, non-aromatic (fully saturated or partially saturated)
or aromatic 4-, 5-, 6- or 7-membered monocyclic heterocycles such
as for example azetidinyl, tetrahydrofuranyl, pyrrolidinyl,
dioxolanyl, imidazolidinyl, thiazolidinyl, tetrahydrothienyl,
dihydrooxazolyl, isothiazolidinyl, isoxazolidinyl, oxadiazolidinyl,
triazolidinyl, thiadiazolidinyl, pyrazolidinyl, piperidinyl,
hexahydropyrimidinyl, hexahydropyrazinyl, dioxanyl, morpholinyl,
dithianyl, thiomorpholinyl, piperazinyl, trithianyl,
hexahydrodiazepinyl, pyrrolinyl, imidazolinyl, pyrazolinyl,
pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl,
thiazolyl, isothiazolyl, pyrazolyl, triazolyl, thiadiazolyl,
oxadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl,
pyridazinyl, triazinyl, pyranyl and the like. Examples of such
unsubstituted bicyclic or tricyclic heterocycles comprise, but are
not limited to, non-aromatic (fully saturated or partially
saturated) or aromatic 8- to 17-membered bicyclic or tricyclic
heterocycles such as for example decahydroquinolinyl,
octahydroindolyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,
2,3-dihydro-1,4-benzodioxinyl, indolinyl, benzofuryl,
isobenzofuryl, benzothienyl, isobenzo-thienyl, indolizinyl,
indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, indazolyl,
benzisoxazolyl, benzisothiazolyl, benzopyrazolyl, benzoxadiazolyl,
benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl,
isoquinolinyl, cinnolinyl, quinolizinyl, phthalazinyl,
quinoxalinyl, quinazolinyl, naphthiridinyl, pteridinyl,
benzopyranyl, pyrrolopyridyl, thienopyridyl, furopyridyl,
isothiazolopyridyl, thiazolopyridyl, isoxazolopyridyl,
oxazolopyridyl, pyrazolopyridyl, imidazopyridyl, pyrrolopyrazinyl,
thienopyrazinyl, furopyrazinyl, isothiazolopyrazinyl,
thiazolopyrazinyl, isoxazolopyrazinyl, oxazolo-pyrazinyl,
pyrazolopyrazinyl, imidazopyrazinyl, pyrrolopyrimidinyl,
thienopyrimidinyl, furopyrimidinyl, isothiazolopyrimidinyl,
thiazolopyrimidinyl, isoxazolopyrimidinyl, oxazolopyrimidinyl,
pyrazolopyrimidinyl, imidazopyrimidinyl, pyrrolopyridazinyl,
thienopyridazinyl, furopyridazinyl, isothiazolopyridazinyl,
thiazolopyridazinyl, isoxazolopyridazinyl, oxazolopyridazinyl,
pyrazolopyridazinyl, imidazopyridazinyl, oxadiazolopyridyl,
thiadiazolopyridyl, triazolopyridyl, oxadiazolopyrazinyl,
thiadiazolopyrazinyl, triazolopyrazinyl, oxadiazolopyrimidinyl,
thiadiazolopyrimidinyl, triazolopyrimidinyl, oxadiazolopyridazinyl,
thiadiazolopyridazinyl, triazolopyridazinyl, imidazooxazolyl,
imidazothiazolyl, imidazoimidazolyl, imidazopyrazolyl;
isoxazolotriazinyl, isothiazolotriazinyl, pyrazolotriazinyl,
oxazolotriazinyl, thiazolotriazinyl, imidazotriazinyl,
oxadiazolotriazinyl, thiadiazolotriazinyl, triazolotriazinyl,
carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl and
the like. Optional substituents for Het heterocycles are hydroxyl;
oxo; carboxyl; halo; C.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyl-oxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl.
Optional substituents for Het.sup.1 substituents are hydroxyl; oxo;
carboxyl; halo; C.sub.1-6alkyl optionally substituted with
carboxyl, C.sub.1-4alkyloxycarbonyl or aryl-C(.dbd.O)--;
hydroxyC.sub.1-6alkyl optionally substituted with aryl or
aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; amino; mono- or di(C.sub.1-6alkyl)amino;
R.sup.6R.sup.5N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--;
aryl-C(.dbd.O)--C.sub.1-4alkyl; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--; Het-C(.dbd.O)--C.sub.1-4alkyl; Het-O--.
[0208] Examples of a 6-membered aromatic heterocycle containing 1
or 2 N atoms in the definition of R.sup.3 (class B and class D) and
R.sup.2 (class C) are pyridyl, pyrimidinyl, pyridazinyl,
pyrazinyl.
[0209] When any variable occurs more than one time in any
constituent (e.g. aryl, Het), each definition is independent.
[0210] The term Het or Het.sup.1 is meant to include all the
possible isomeric forms of the heterocycles, for instance, pyrrolyl
comprises 1H-pyrrolyl and 2H-pyrrolyl.
[0211] The term R.sup.1 (in class B) is meant to include all the
possible isomeric forms of the heterocycles, for instance, pyrrolyl
comprises 1H-pyrrolyl and 2H-pyrrolyl.
[0212] The carbocycles or heterocycles covered by the terms aryl,
Het, aryl.sup.1, Het.sup.1, R.sup.1 (in class B) or R.sup.3 (in
class B, class C or class D) may be attached to the remainder of
the molecule of formula (I) of class A, class B, class C or class D
through any ring carbon or heteroatom as appropriate, if not
otherwise specified. Thus, for example, when the heterocycle is
imidazolyl, it may be 1-imidazolyl, 2-imidazolyl, 4-imidazolyl and
the like, or when the carbocycle is naphthalenyl, it may be
1-naphthalenyl, 2-naphthalenyl and the like.
[0213] Lines drawn from substituents into ring systems indicate
that the bond may be attached to any of the suitable ring
atoms.
[0214] When X is defined as for instance --NR.sup.x--C(.dbd.O)--,
this means that the nitrogen of NR.sup.x is linked to the R.sup.2
substituent (not applicable for class A) and the carbon atom of
C(.dbd.O) is linked to the nitrogen of the ring
##STR00005##
Thus the left part of the bivalent radical in the definition of X
is linked to the R.sup.2 substituent and the right part of the
bivalent radical in the definition of X is linked to the ring
moiety
##STR00006##
[0215] When Y is defined for instance as --NR.sup.x--C(.dbd.O)-- in
class A or class C, this means that the nitrogen of NR.sup.x is
linked to the phenyl moiety and the carbon atom of C(.dbd.O) is
linked to the R.sup.1 substituent. Thus the left part of the
bivalent radical in the definition of Y is linked to the phenyl
moiety and the right part of the bivalent radical in the definition
of Y is linked to the R.sup.1 substituent.
[0216] When Y is defined as for instance
--NR.sup.x--C(.dbd.O)--Z.sup.2-- in class D, this means that the
nitrogen of NR.sup.x is linked to the phenyl ring and the Z.sup.2
is linked to the R.sup.1 substituent. Thus the left part of the
bivalent radical in the definition of Y is linked to the phenyl
ring and the right part of the bivalent radical in the definition
of Y is linked to R.sup.1 substituent.
[0217] Some of the compounds of class A, class B, class C or class
D may also exist in their tautomeric form. Such forms although not
explicitly indicated in the above formula are intended to be
included within the scope of the present invention.
[0218] Whenever used hereinbefore or hereinafter that substituents
can be selected each independently out of a list of numerous
definitions, such as for example for R.sup.2 and R.sup.3 in class
A, R.sup.4 and R.sup.5 in class B and class D, and R.sup.3 and
R.sup.4 in class C, all possible combinations are intended which
are chemically possible.
[0219] For therapeutic use, salts of the compounds of class A,
class B, class C or class D are those wherein the counterion is
pharmaceutically acceptable. However, salts of acids and bases
which are non-pharmaceutically acceptable may also find use, for
example, in the preparation or purification of a pharmaceutically
acceptable compound. All salts, whether pharmaceutically acceptable
or not are included within the ambit of the present invention.
[0220] The pharmaceutically acceptable salts as mentioned
hereinbefore or hereinafter are meant to comprise the
therapeutically active non-toxic acid addition salt forms which the
compounds of class A, class B, class C or class D are able to form.
The latter can conveniently be obtained by treating the base form
with such appropriate acids as inorganic acids, for example,
hydrohalic acids, e.g. hydrochloric, hydrobromic and the like;
sulfuric acid; nitric acid; phosphoric acid and the like; or
organic acids, for example, acetic, propanoic, hydroxyacetic,
2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic,
maleic, fumaric, malic, tartaric,
2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic,
ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic,
cyclohexanesulfonic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and
the like acids. Conversely the salt form can be converted by
treatment with alkali into the free base form.
[0221] The compounds of class A, class B, class C or class D
containing acidic protons may be converted into their
therapeutically active non-toxic metal or amine addition salt forms
by treatment with appropriate organic and inorganic bases. The
pharmaceutically acceptable salts as mentioned hereinbefore or
hereinafter are meant to also comprise the therapeutically active
non-toxic metal or amine addition salt forms (base addition salt
forms) which the compounds of class A, class B, class C or class D
are able to form. Appropriate base addition salt forms comprise,
for example, the ammonium salts, the alkali and earth alkaline
metal salts, e.g. the lithium, sodium, potassium, magnesium,
calcium salts and the like, salts with organic bases, e.g. primary,
secondary and tertiary aliphatic and aromatic amines such as
methylamine, ethylamine, propylamine, isopropylamine, the four
butylamine isomers, dimethylamine, diethylamine, diethanolamine,
dipropylamine, diisopropylamine, di-n-butylamine, pyrrolidine,
piperidine, morpholine, trimethylamine, triethylamine,
tripropylamine, quinuclidine, pyridine, quinoline and isoquinoline,
the benzathine, N-methyl-D-glucamine,
2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and
salts with amino acids such as, for example, arginine, lysine and
the like.
[0222] Conversely the salt form can be converted by treatment with
acid into the free acid form.
[0223] The term salt also comprises the quaternary ammonium salts
(quaternary amines) which the compounds of class A, class B, class
C or class D are able to form by reaction between a basic nitrogen
of a compound of class A, class B, class C or class D and an
appropriate quaternizing agent, such as, for example, an optionally
substituted C.sub.1-6alkylhalide, arylhalide,
C.sub.1-6alkyl-carbonylhalide, arylcarbonylhalide, or
arylC.sub.1-6alkylhalide, e.g. methyliodide or benzyliodide. Other
reactants with good leaving groups may also be used, such as for
example C.sub.1-6alkyl trifluoromethanesulfonates, C.sub.1-6alkyl
methanesulfonates, and C.sub.1-6alkyl p-toluenesulfonates. A
quaternary amine has a positively charged nitrogen.
Pharmaceutically acceptable counterions include chloro, bromo,
iodo, trifluoroacetate, acetate, triflate, sulfate, sulfonate. The
counterion of choice can be introduced using ion exchange
resins.
[0224] The term solvate comprises the hydrates and solvent addition
forms which the compounds of class A, class B, class C or class D
are able to form, as well as salts thereof Examples of such forms
are e.g. hydrates, alcoholates and the like.
[0225] The N-oxide forms of the present compounds are meant to
comprise the compounds of class A, class B, class C or class D
wherein one or several tertiary nitrogen atoms are oxidized to the
so-called N-oxide.
[0226] It will be appreciated that some of the compounds of class
A, class B, class C or class D may contain one or more centers of
chirality and exist as stereochemically isomeric forms.
[0227] The term "stereochemically isomeric forms" as used
hereinbefore or hereinafter defines all the possible stereoisomeric
forms which the compounds of class A, class B, class C or class D
may possess. Unless otherwise mentioned or indicated, the chemical
designation of compounds denotes the mixture of all possible
stereochemically isomeric forms, said mixtures containing all
diastereomers and enantiomers of the basic molecular structure as
well as each of the individual isomeric forms of the basis
molecular structure and their N-oxides, salts or solvates,
substantially free, i.e. associated with less than 10%, preferably
less than 5%, in particular less than 2% and most preferably less
than 1% of the other isomers. Thus, when a compound of class A,
class B, class C or class D is for instance specified as (E), this
means that the compound is substantially free of the (Z)
isomer.
[0228] In particular, stereogenic centers may have the R- or
S-configuration; substituents on bivalent cyclic (partially)
saturated radicals may have either the cis- or trans-configuration.
Compounds encompassing double bonds can have an E (entgegen) or Z
(zusammen) -stereochemistry at said double bond. The terms cis,
trans, R, S, E and Z are well known to a person skilled in the
art.
[0229] Stereochemically isomeric forms of the compounds of class A,
class B, class C or class D are obviously intended to be embraced
within the scope of this invention.
[0230] Following CAS-nomenclature conventions, when two stereogenic
centers of known absolute configuration are present in a molecule,
an R or S descriptor is assigned (based on Cahn-Ingold-Prelog
sequence rule) to the lowest-numbered chiral center, the reference
center. The configuration of the second stereogenic center is
indicated using relative descriptors [R*,R*] or [R*,S*], where the
first R* is always specified as the reference center and [R*,R*]
indicates centers with the same chirality and [R* ,S*] indicates
centers of unlike chirality. For example, if the lowest-numbered
chiral center in the molecule has an S configuration and the second
center is R, the stereo descriptor would be specified as
S--[R*,S*]. If ".alpha." and ".beta." are used : the position of
the highest priority substituent on the asymmetric carbon atom in
the ring system having the lowest ring number, is arbitrarily
always in the ".alpha." position of the mean plane determined by
the ring system. The position of the highest priority substituent
on the other asymmetric carbon atom in the ring system relative to
the position of the highest priority substituent on the reference
atom is denominated ".alpha.", if it is on the same side of the
mean plane determined by the ring system, or ".beta.", if it is on
the other side of the mean plane determined by the ring system.
[0231] The compounds of (I) may be synthesized in the form of
racemic mixtures of enantiomers which can be separated from one
another following art-known resolution procedures. The racemic
compounds of class A, class B, class C or class D may be converted
into the corresponding diastereomeric salt forms by reaction with a
suitable chiral acid. Said diastereomeric salt forms are
subsequently separated, for example, by selective or fractional
crystallization and the enantiomers are liberated therefrom by
alkali. An alternative manner of separating the enantiomeric forms
of the compounds of class A, class B, class C or class D involves
liquid chromatography using a chiral stationary phase. Said pure
stereochemically isomeric forms may also be derived from the
corresponding pure stereochemically isomeric forms of the
appropriate starting materials, provided that the reaction occurs
stereospecifically. Preferably if a specific stereoisomer is
desired, said compound will be synthesized by stereospecific
methods of preparation. These methods will advantageously employ
enantiomerically pure starting materials.
[0232] Whenever used hereinbefore or hereinafter, the term
"compounds of class A", "compounds of class B", "compounds of class
C" or "compounds of class D" or any subgroup thereof, is meant to
also include their N-oxide forms, their salts, their
stereochemically isomeric forms and their solvates. Of special
interest are those compounds of class A, class B, class C or class
D which are stereochemically pure.
[0233] Whenever used hereinbefore or hereinafter, the term
"compounds of group Q", is meant to also include their N-oxide
forms, their salts, their stereochemically isomeric forms and their
solvates. Of special interest are those compounds group Q which are
stereochemically pure.
[0234] By PPAR agonist, in particular PPAR-.alpha. agonist, is
meant a compound or a prodrug thereof, or a composition containing
said compound or prodrug thereof; which directly or indirectly
stimulates or increases an in vivo or in vitro reaction typical for
the PPAR receptor, in particular the PPAR-.alpha. receptor, e.g.
transcriptional regulation activity, as measured by an assay known
to one skilled in the art such as, for example, described in
Kuwabara K, Murakami K, Todo M, Aoki T, Asaki T, Mura M, and Yano J
(2004) A novel selective peroxisome proliferator-activated receptor
a agonist,
2-methyl-c-5-[4-[5-methyl-2-(4-methylphenyl)-4-oxazolyl]butyl]-1,3-dioxan-
e-r-2-carboxylic acid (NS-220), potently decreases plasma
triglyceride and glucose levels and modifies lipoprotein profiles
in KK-A.sup.y mice. J Pharmacol Exp Ther Vol. 309, No. 3:
970-977.
[0235] Non-limiting examples of PPAR-.alpha. agonists or prodrugs
thereof include natural and synthetic agonists, such as
eicosanoids, leukotriene .beta..sub.4, carbaprostacyclin,
nonsteroidal anti-inflammatory drugs, pirinixic acid (WY-14643;
PPAR-.alpha./.gamma. agonist), phthalate ester plasticizers,
pterostilbene, fibrates or active metabolites thereof,
.alpha.-substituted phenyl-propanoic acid derivatives,
isoxazolyl-serine-based compounds.
[0236] A preferred PPAR-.alpha. agonist or a prodrug thereof is a
fibrate compound including, but not limited to fenofibrate
(fenofibric acid as active metabolite), bezafibrate, clofibrate,
ciprofibrate, etofibrate, ABT-335 (which is the choline salt of
fenofibric acid), pirifibrate, beclofibrate or gemfibrozil (a
PPAR-.alpha. modulator) and analogues, derivatives and
pharmaceutically acceptable salts thereof.
[0237] Whenever the term `prodrug` is used within the context of
this invention, this refers to a pharmacological substance (drug)
that is administered in an inactive or significantly less active
form. Once administered, the prodrug is metabolised in vivo into an
active metabolite. For example, the prodrug fenofibrate (ester) is
metabolised to fenofibric acid which is the active metabolite
(PPAR-.alpha. agonist).
[0238] A preferred fibrate is fenofibrate.
[0239] In the present invention, fibrates include fibric acid
derivatives and pharmaceutically acceptable salts of such fibric
acid derivatives.
[0240] The next embodiments of the present invention are those
combinations of a DGAT inhibitor, more in particular a DGAT1
inhibitor and a PPAR agonist, in particular a PPAR-.alpha. agonist,
more in particular a fibrate, even more in particular fenofibrate;
wherein the DGAT inhibitor is selected from compounds of Class A.
Preferred embodiments of compounds of class A are: [0241] A-1)
compounds of class A having the following formula (I)
##STR00007##
[0241] including any stereochemically isomeric form thereof,
wherein [0242] A represents CH or N; [0243] X represents O or
NR.sup.x; [0244] the dotted line represents an optional bond in
case A represents a carbon atom; [0245] Y represents a direct bond;
--NR.sup.x--C(.dbd.O)--; --C(.dbd.O)--NR.sup.x--;
--NR.sup.x--C(.dbd.O)--Z--; --NR.sup.x--C(.dbd.O)--Z--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z--O--;
--NR.sup.x--C(.dbd.O)--Z--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--O--Z--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z--; --C(.dbd.O)--Z--O--; --C(.dbd.O)--NR.sup.x--Z--;
--C(.dbd.O)--NR.sup.x--Z--O--;
--C(.dbd.O)--NR.sup.x--Z--C(.dbd.O)--O--;
--C(.dbd.O)--NR.sup.x--Z--O--C(.dbd.O)--;
--C(.dbd.O)--NR.sup.x--O--Z--;
--C(.dbd.O)--NR.sup.x--Z--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z--NR.sup.y--C(.dbd.O)--;
--C(.dbd.O)--NR.sup.x--Z--NR.sup.y--C(.dbd.O)--O--; [0246] Z
represents a bivalent radical selected from C.sub.1-6alkanediyl,
C.sub.2-6alkenediyl or C.sub.2-6alkynediyl; wherein each of said
C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or C.sub.2-6alkynediyl may
optionally be substituted with C.sub.1-4alkyloxy,
C.sub.1-4alkylthio, hydroxyl, cyano or aryl; and wherein two
hydrogen atoms attached to the same carbon atom in the definition
of Z may optionally be replaced by C.sub.1-6alkanediyl; [0247]
R.sup.x represents hydrogen or C.sub.1-4alkyl; [0248] R.sup.y
represents hydrogen; C.sub.1-4alkyl optionally substituted with
C.sub.3-6cycloalkyl or aryl or Het; C.sub.2-4alkenyl; or
S(.dbd.O).sub.p-aryl; [0249] R.sup.1 represents C.sub.1-12alkyl
optionally substituted with cyano, C.sub.1-4alkyloxy,
C.sub.1-4alkyl-oxyC.sub.1-4alkyloxy, C.sub.3-6cycloalkyl or aryl;
C.sub.2-6alkenyl; C.sub.2-6alkynyl; C.sub.3-6cycloalkyl;
aryl.sup.1; aryl.sup.1C.sub.1-6alkyl; Het.sup.1; or
Het.sup.1C.sub.1-6alkyl; provided that when Y represents
--NR.sup.x--C(.dbd.O)--Z--; --NR.sup.x--C(.dbd.O)--Z--NR.sup.y;
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--NR.sup.y--; --C(.dbd.O)--Z--;
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z--; --C(.dbd.O)--NR.sup.x--O--Z--; or
--C(.dbd.O)--NR.sup.x--Z--NR.sup.y--; then R.sup.1 may also
represent hydrogen; [0250] R.sup.2 and R.sup.3 each independently
represent hydrogen; hydroxyl; carboxyl; halo; C.sub.1-6alkyl;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; [0251]
R.sup.4 represents hydrogen; hydroxyl; carboxyl; halo;
C.sub.1-6alkyl; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl;
R.sup.6R.sup.5N--C(.dbd.O)--; R.sup.6R.sup.5N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl; aryl; aryloxy; arylC.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--;
[0252] R.sup.5 represents hydrogen; C.sub.1-4alkyl optionally
substituted with hydroxyl or C.sub.1-4alkyloxy;
R.sup.8R.sup.7N--C.sub.1-4alkyl; C.sub.1-4alkyloxy; Het; aryl;
R.sup.8R.sup.7N--C(.dbd.O)--C.sub.1-4alkyl; [0253] R.sup.6
represents hydrogen or C.sub.1-4alkyl; [0254] R.sup.7 represents
hydrogen; C.sub.1-4alkyl; C.sub.1-4alkylcarbonyl; [0255] R.sup.8
represents hydrogen or C.sub.1-4alkyl; or [0256] R.sup.7 and
R.sup.8 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
selected from O, S, S(.dbd.O).sub.p or N; and which heterocycle may
optionally be substituted with C.sub.1-4alkyl; [0257] aryl
represents phenyl or phenyl substituted with at least one
substituent, in particular one, two, three, four or five
substituents, each substituent independently being selected from
hydroxyl; carboxyl; halo; C.sub.1-6alkyl optionally substituted
with C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; [0258]
aryl.sup.1 represents phenyl, naphthalenyl or fluorenyl; each of
said phenyl, naphthalenyl or fluorenyl optionally substituted with
at least one substituent, in particular one, two, three, four or
five substituents, each substituent independently being selected
from hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally
substituted with aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyloxy optionally substituted with C.sub.1-4alkyloxy;
C.sub.1-6alkylthio; polyhaloC.sub.1-6alkyloxy;
C.sub.1-6alkyloxy-carbonyl wherein C.sub.1-6alkyl may optionally be
substituted with aryl; cyano; aminocarbonyl; mono- or
di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkylcarbonyl; nitro;
amino; mono- or di(C.sub.1-6alkyl)amino;
C.sub.3-6cycloalkyl-NR.sup.x--; aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--; Het;
HetC.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; [0259] Het represents
a monocyclic non-aromatic or aromatic heterocycle containing at
least one heteroatom selected from O, S, S(.dbd.O).sub.p or N; or a
bicyclic or tricyclic non-aromatic or aromatic heterocycle
containing at least one heteroatom selected from O, S,
S(.dbd.O).sub.p or N; said monocyclic heterocycle or said bi- or
tricyclic heterocycle optionally being substituted with at least
one substituent, in particular one, two, three, four or five
substituents, each substituent independently being selected from
hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with C.sub.1-4alkyloxy, amino or mono- or
di(C.sub.1-4alkyl)amino; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyl-oxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; [0260]
Het.sup.1 represents a monocyclic non-aromatic or aromatic
heterocycle containing at least one heteroatom selected from O, S,
S(.dbd.O).sub.p or N; or a bicyclic or tricyclic non-aromatic or
aromatic heterocycle containing at least one heteroatom selected
from O, S, S(.dbd.O).sub.p or N; said monocyclic heterocycle or
said bi- or tricyclic heterocycle optionally being substituted with
at least one substituent, in particular one, two, three, four or
five substituents, each substituent independently being selected
from hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally
substituted with aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyloxy optionally substituted with C.sub.1-4alkyloxy;
C.sub.1-6alkylthio; polyhaloC.sub.1-6alkyloxy;
C.sub.1-6alkyloxy-carbonyl wherein C.sub.1-6alkyl may optionally be
substituted with aryl; cyano; aminocarbonyl; mono- or
di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkylcarbonyl; nitro;
amino; mono- or di(C.sub.1-6alkyl)amino;
C.sub.3-6cycloalkyl-NR.sup.x--; aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--; Het;
HetC.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; [0261] p represents 1
or 2; [0262] a N-oxide thereof, a pharmaceutically acceptable salt
thereof or a solvate thereof; or [0263] A-2) compounds of class A
or any subgroup thereof as mentioned hereinbefore as embodiment,
wherein X represents NR.sup.x, in particular NH; or [0264] A-3)
compounds of class A or, whenever possible, any subgroup thereof as
mentioned hereinbefore as embodiment, wherein X represents O; or
[0265] A-4) compounds of class A or, whenever possible, any
subgroup thereof as mentioned hereinbefore as embodiment wherein A
represents N; or [0266] A-5) compounds of class A or, whenever
possible, any subgroup thereof as mentioned hereinbefore as
embodiment wherein A represents CH, in particular wherein A
represents CH and the dotted line does not represent a bond; or
[0267] A-6) compounds of class A or any subgroup thereof as
mentioned hereinbefore as embodiment wherein Y represents [0268]
--NR.sup.x--C(.dbd.O)--; --NR.sup.x--C(.dbd.O)--Z--,
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z--O--C(.dbd.O)--; in particular wherein Y
represents --NR.sup.x--C(.dbd.O)-- or --NR.sup.x--C(.dbd.O)--Z--
with Z representing C.sub.1-6alkanediyl; or [0269] A-7) compounds
of class A or, whenever possible, any subgroup thereof as mentioned
hereinbefore as embodiment wherein Y represents a direct bond, in
particular wherein Y represents a direct bond and R.sup.1
represents Het.sup.1; or [0270] A-8) compounds of class A or,
whenever possible, any subgroup thereof as mentioned hereinbefore
as embodiment wherein Y represents --NR.sup.x--C(.dbd.O)--, in
particular wherein Y represents --NR.sup.x--C(.dbd.O)-- and R.sup.1
represents Aryl.sup.1 or Het.sup.1; or [0271] A-9) compounds of
class A or, whenever possible, any subgroup thereof as mentioned
hereinbefore as embodiment wherein Y represents
--NR.sup.x--C(.dbd.O)--Z--NR.sup.y--, in particular wherein Y
represents [0272] --NR.sup.x--C(.dbd.O)--Z--NR.sup.y-- and R.sup.1
represents Aryl.sup.1 or Het.sup.1; or [0273] A-10) compounds of
class A or, whenever possible, any subgroup thereof as mentioned
hereinbefore as embodiment wherein Y represents
--NR.sup.x--C(.dbd.O)--Z--C(.dbd.O)--O-- or
--NR.sup.x--C(.dbd.O)--Z--O--C(.dbd.O)--, in particular
--NR.sup.x--C(.dbd.O)--Z--O--C(.dbd.O)--; or [0274] A-11) compounds
of class A or, whenever possible, any subgroup thereof as mentioned
hereinbefore as embodiment wherein R.sup.2 or R.sup.3 each
independently represent hydrogen, halo or C.sub.1-6alkyl, in
particular both R.sup.2 and R.sup.3 represent halo, more in
particular both R.sup.2 and R.sup.3 represent chloro or fluoro; or
[0275] A-12) compounds of class A or, whenever possible, any
subgroup thereof as mentioned hereinbefore as embodiment wherein
R.sup.4 is placed in para position; or [0276] A-13) compounds of
class A or, whenever possible, any subgroup thereof as mentioned
hereinbefore as embodiment wherein R.sup.4 represents hydrogen;
carboxyl; C.sub.1-6alkyloxycarbonyl; amino; mono- or
di(C.sub.1-4alkyl)amino; R.sup.6R.sup.5N--C(.dbd.O)--;
R.sup.6R.sup.5N--C.sub.1-6alkyl; Het-C(.dbd.O)-- or
HetC.sub.1-4alkyl, in particular Het-C(.dbd.O)-- or
HetC.sub.1-4alkyl; or [0277] A-14) compounds of class A or,
whenever possible, any subgroup thereof as mentioned hereinbefore
as embodiment wherein R.sup.4 is placed in para position and
represents hydrogen; carboxyl; C.sub.1-6alkyloxy-carbonyl; amino;
mono- or di(C.sub.1-4alkyl)amino; R.sup.6R.sup.5N--C(.dbd.O)--;
R.sup.6R.sup.5N--C.sub.1-6alkyl; Het-C(.dbd.O)-- or
HetC.sub.1-4alkyl, in particular Het-C(.dbd.O)-- or
HetC.sub.1-4alkyl; or [0278] A-15) compounds of class A or,
whenever possible, any subgroup thereof as mentioned hereinbefore
as embodiment wherein p represents 2; or [0279] A-16) compounds of
class A or, whenever possible, any subgroup thereof as mentioned
hereinbefore as embodiment wherein R.sup.1 represents hydrogen;
C.sub.1-12alkyl; aryl.sup.1 or Het.sup.1; in particular Aryl.sup.1
or Het.sup.1; more in particular Aryl.sup.1; more in particular
optionally substituted phenyl wherein the optional substituent is
preferably selected from aryl, Het or C.sub.1-6alkyloxy; even more
in particular phenyl; or [0280] A-17) compounds of class A or,
whenever possible, any subgroup thereof as mentioned hereinbefore
as embodiment wherein Z represents C.sub.1-6alkanediyl; or [0281]
A-18) compounds of class A or, whenever possible, any subgroup
thereof as mentioned hereinbefore as embodiment wherein R.sup.x
represents hydrogen; or [0282] A-19) compounds of class A or,
whenever possible, any subgroup thereof as mentioned hereinbefore
as embodiment wherein R.sup.y represents hydrogen; or [0283] A-20)
compounds of class A or, whenever possible, any subgroup thereof as
mentioned hereinbefore as embodiment wherein R.sup.9 represents
hydrogen; or [0284] A-21) compounds of class A or, whenever
possible, any subgroup thereof as mentioned hereinbefore as
embodiment wherein R.sup.9 represents halo, C.sub.1-4alkyl,
C.sub.1-4alkyl substituted with hydroxyl; or [0285] A-22) compounds
of class A or any subgroup thereof as mentioned hereinbefore as
embodiment wherein one or more, preferably all, of the following
restrictions apply: [0286] a) X represents NH; [0287] b) R.sup.2
represents hydrogen, halo or C.sub.1-6alkyl; in particular halo;
more in particular chloro; [0288] c) R.sup.3 represents hydrogen,
halo or C.sub.1-6alkyl; in particular halo; more in particular
chloro; [0289] d) R.sup.4 represents hydrogen; [0290] e) A
represents N; [0291] f) the dotted line does not represent an
additional bond; [0292] g) Y represents --NR.sup.x--C(.dbd.O)--Z--;
[0293] h) Z represents C.sub.1-6alkanediyl; [0294] i) R.sup.1
represents aryl.sup.1; in particular optionally substituted phenyl;
more in particular phenyl. [0295] j) R.sup.x represents hydrogen;
or [0296] A-23) compounds of class A or any subgroup thereof as
mentioned hereinbefore as embodiment wherein one or more,
preferably all, of the following restrictions apply: [0297] a) X
represents NH or O; [0298] b) R.sup.2 represents hydrogen, halo or
C.sub.1-6alkyl; in particular halo; more in particular chloro or
fluoro; [0299] c) R.sup.3 represents hydrogen, halo or
C.sub.1-6alkyl; in particular halo; more in particular chloro or
fluoro; [0300] d) R.sup.4 represents hydrogen; carboxyl;
C.sub.1-6alkyloxycarbonyl; Het-C(.dbd.O)-- or HetC.sub.1-4
alkyl, in particular Het-C(.dbd.O)-- or HetC.sub.1-4alkyl; [0301]
e) A represents N; [0302] f) the dotted line does not represent a
bond; [0303] g) Y represents --NR.sup.x--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z--, --NR.sup.x--C(.dbd.O)--Z--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z--O--C(.dbd.O)--; [0304] h) Z represents
C.sub.1-6alkanediyl; [0305] i) R.sup.1 represents hydrogen;
C.sub.1-12alkyl; aryl.sup.1 or Het.sup.1; in particular aryl.sup.1;
more in particular optionally substituted phenyl wherein the
optional substituent is preferably selected from aryl, Het or
C.sub.1-6alkyloxy; more in particular phenyl; [0306] j) R.sup.x
represents hydrogen; [0307] k) R.sup.y represents hydrogen; [0308]
l) R.sup.9 represents hydrogen; [0309] m) R.sup.4 is placed in para
position; or [0310] A-24) compounds of class A selected from
##STR00008##
[0310] including any stereochemically isomeric form thereof; [0311]
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a
solvate thereof. [0312] The next embodiments of the present
invention are those combinations of a DGAT inhibitor, more in
particular a DGAT1 inhibitor and a PPAR agonist, in particular a
PPAR-.alpha. agonist, more in particular a fibrate, even more in
particular fenofibrate; wherein the DGAT inhibitor is selected from
compounds of Class B. Preferred embodiments of compounds of class B
are: [0313] B-1) compounds of class B having the following formula
(I)
##STR00009##
[0313] including any stereochemically isomeric form thereof,
wherein [0314] A represents CH or N; [0315] the dotted line
represents an optional bond in case A represents a carbon atom;
[0316] X represents --NR.sup.x--C(.dbd.O)--; --Z--C(.dbd.O)--;
--Z--NR.sup.x--C(.dbd.O)--; --S(.dbd.O).sub.p--; C(.dbd.S)--;
--NR.sup.x--C(.dbd.S)--; --Z--C(.dbd.S)--;
--Z--NR.sup.x--C(.dbd.S)--; [0317] Z represents a bivalent radical
selected from C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or
C.sub.2-6alkynediyl; wherein each of said C.sub.1-6alkanediyl,
C.sub.2-6alkenediyl or C.sub.2-6alkynediyl may optionally be
substituted with hydroxyl; [0318] R.sup.x represents hydrogen or
C.sub.1-4alkyl; [0319] R.sup.1 represents a 5-membered monocyclic
heterocycle containing at least 2 heteroatoms; a 6-membered
aromatic monocyclic heterocycle; or a 5-membered heterocycle
containing at least 2 heteroatoms fused with phenyl, cyclohexyl or
a 5- or 6-membered heterocycle; wherein each of said heterocycles
may optionally be substituted with at least one substituent, in
particular one, two, three, four or five substituents, each
substituent independently being selected from hydroxyl; oxo;
carboxyl; halo; C.sub.1-6alkyl optionally substituted with
aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally substituted with
aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; [0320] C.sub.1-6alkyloxy-carbonyl
wherein C.sub.1-6alkyl may optionally be substituted with aryl;
cyano; aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-6alkyl)amino; C.sub.3-6cycloalkyl-NR.sup.x--;
aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--; Het;
HetC.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; [0321] R.sup.2
represents R.sup.3; [0322] R.sup.3 represents C.sub.3-6cycloalkyl,
phenyl, naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl,
1,3-benzodioxolyl, wherein said C.sub.3-6cycloalkyl, phenyl,
naphtalenyl, 2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl may
optionally be substituted with at least one substituent, in
particular one, two, three, four or five substituents, each
substituent independently selected from hydroxyl; carboxyl; halo;
C.sub.1-6alkyl optionally substituted with hydroxy;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl;
R.sup.5R.sup.4N--C(.dbd.O)--; R.sup.5R.sup.4N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl; C.sub.3-6cycloalkylC.sub.1-4alkyl;
C.sub.3-6cycloalkyl-C(.dbd.O)--; aryl; aryloxy; arylC.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--;
[0323] R.sup.4 represents hydrogen; C.sub.1-4alkyl optionally
substituted with hydroxyl or C.sub.1-4alkyloxy;
R.sup.7R.sup.6N--C.sub.1-4alkyl; C.sub.1-4alkyloxy; Het; aryl;
R.sup.7R.sup.6N--C(.dbd.O)--C.sub.1-4alkyl; [0324] R.sup.5
represents hydrogen or C.sub.1-4alkyl; [0325] R.sup.6 represents
hydrogen; C.sub.1-4alkyl; C.sub.1-4alkylcarbonyl; [0326] R.sup.7
represents hydrogen or C.sub.1-4alkyl; or [0327] R.sup.6 and
R.sup.7 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
selected from O, S, S(.dbd.O).sub.p or N; and which heterocycle may
optionally be substituted with C.sub.1-4alkyl; [0328] aryl
represents phenyl or phenyl substituted with at least one
substituent, in particular one, two, three, four or five
substituents, each substituent independently being selected from
hydroxyl; carboxyl; halo; C.sub.1-6alkyl optionally substituted
with C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; [0329]
Het represents a monocyclic non-aromatic or aromatic heterocycle
containing at least one heteroatom selected from O, S,
S(.dbd.O).sub.p or N; or a bicyclic or tricyclic non-aromatic or
aromatic heterocycle containing at least one heteroatom selected
from O, S, S(.dbd.O).sub.p or N; said monocyclic heterocycle or
said bi- or tricyclic heterocycle optionally being substituted with
at least one substituent, in particular one, two, three, four or
five substituents, each substituent independently being selected
from hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with C.sub.1-4alkyloxy, amino or mono- or
di(C.sub.1-4alkyl)amino; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; oxycarbonyl; cyano; aminocarbonyl; mono-
or di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkylcarbonyl; nitro;
amino; mono- or di(C.sub.1-4alkyl)amino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; [0330] p represents 1 or 2;
[0331] a N-oxide thereof, a pharmaceutically acceptable salt
thereof or a solvate thereof; or [0332] B-2) compounds of of class
B or, whenever possible, any subgroup thereof as mentioned
hereinbefore as embodiment wherein X represents
--NR.sup.x--C(.dbd.O)--; --Z--C(.dbd.O)--;
--Z--NR.sup.x--C(.dbd.O)--; --S(.dbd.O).sub.p--;
--NR.sup.x--C(.dbd.S)-- or 0--C(.dbd.O)--; in particular X
represents --NR.sup.x--C(.dbd.O)--; --Z--C(.dbd.O)--;
--Z--NR.sup.x--C(.dbd.O)--; more in particular X represents
--NR.sup.x--C(.dbd.O)-- or --Z--C(.dbd.O)--; or [0333] B-3)
compounds of class B or, whenever possible, any subgroup thereof as
mentioned hereinbefore as embodiment wherein A represents N; or
[0334] B-4) compounds of class B or, whenever possible, any
subgroup thereof as mentioned hereinbefore as embodiment wherein A
represents CH, in particular wherein A represents CH and the dotted
line does not represent a bond; or [0335] B-5) compounds of class B
or, whenever possible, any subgroup thereof as mentioned
hereinbefore as embodiment wherein R.sup.I- represents a 5-membered
monocyclic heterocycle containing at least 2 heteroatoms, in
particular pyrazolyl, triazolyl or oxadiazolyl; a 6-membered
monocyclic aromatic heterocycle, in particular pyrimidinyl; or a
5-membered aromatic heterocycle containing at least 2 heteroatoms
fused with a 5-membered heterocycle, in particular imidazopyrazolyl
or imidazothiazolyl; wherein each of said heterocycles may
optionally be substituted, preferably with one or two substituents.
Particular substituents of said heterocycles include oxo,
C.sub.1-6alkyl optionally substituted with aryl-C(.dbd.O)-- or
C.sub.1-4alkyloxycarbonyl; hydroxyC.sub.1-6alkyl optionally
substituted with aryl or aryl-C(.dbd.O)--; amino; mono- or
di(C.sub.1-6alkyl)amino; R.sup.5R.sup.4N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl-NR.sup.x--; aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
C.sub.3-6cycloalkyl; C.sub.3-6cycloalkylC.sub.1-4alkyl; aryl;
aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--;
aryl-C(.dbd.O)--C.sub.1-4alkyl; Het; HetC.sub.1-4alkyl; [0336]
Het-C(.dbd.O)--; Het-C(.dbd.O)--C.sub.1-4alkyl; Het-O--; more in
particular C.sub.1-6alkyl optionally substituted with
aryl-C(.dbd.O)-- or C.sub.1-4alkyloxycarbonyl;
hydroxyC.sub.1-6alkyl optionally substituted with aryl; mono- or
di(C.sub.1-6alkyl)amino; R.sup.5R.sup.4N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl-NR.sup.x--; Het-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; aryl; arylC.sub.1-4alkyl;
aryl-C(.dbd.O)--C.sub.1-4alkyl or Het; or [0337] B-6) compounds of
class B or, whenever possible, any subgroup thereof as mentioned
hereinbefore as embodiment wherein the compound of class B is a
compound of formula (I')
##STR00010##
[0337] wherein R.sup.3a and R.sup.3b each independently represent
hydrogen; hydroxyl; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with hydroxyl; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyloxy optionally substituted with C.sub.1-4alkyloxy;
C.sub.1-6alkylthio; polyhaloC.sub.1-6alkyloxy;
C.sub.1-6alkyloxycarbonyl; cyano; aminocarbonyl; mono- or
di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkylcarbonyl; nitro;
amino; mono- or di(C.sub.1-4alkyl)amino;
C.sub.1-4alkylcarbonylamino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; and
wherein R.sup.3c represents hydrogen; hydroxyl; carboxyl; halo;
C.sub.1-6alkyl; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy;
[0338] C.sub.1-6alkylthio; polyhalo-C.sub.1-6alkyloxy;
C.sub.1-6alkyloxycarbonyl wherein C.sub.1-6alkyl may optionally be
substituted with aryl; cyano; C.sub.1-6alkylcarbonyl; nitro; amino;
mono- or di(C.sub.1-4alkyl)amino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; R.sup.5R.sup.4N--C(.dbd.O)--;
R.sup.5R.sup.4N--C.sub.1-6alkyl; C.sub.3-6cyclo-alkyl; aryl;
aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--; Het;
HetC.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--. or [0339] B-7)
compounds of class B or, whenever possible, any subgroup thereof as
mentioned hereinbefore as embodiment wherein the compound of class
B is a compound of formula (I'')
##STR00011##
[0339] wherein R.sup.3a and R.sup.3b each independently represent
hydrogen; hydroxyl; carboxyl; halo; C.sub.1-6alkyl;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; and
wherein R.sup.3c represents hydrogen; hydroxyl; carboxyl; halo;
C.sub.1-6alkyl optionally substituted with hydroxyl;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyl-oxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; C.sub.1-4alkylcarbonyl-amino;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; R.sup.5R.sup.4N--C(.dbd.O)--;
R.sup.5R.sup.4N--C.sub.1-6alkyl; C.sub.3-6cycloalkyl; aryl;
aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--; Het;
HetC.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; or [0340] B-8)
compounds of class B or, whenever possible, any subgroup thereof as
mentioned hereinbefore as embodiment wherein the compound of
formula (I) is a compound of formula (I') or (I'') and wherein
R.sup.3a and R.sup.3b each independently represent halo,
polyhaloC.sub.1-6alkyl, C.sub.1-6alkyl or C.sub.1-6alkyloxy, in
particular both R.sup.3a and R.sup.3b represent halo, more in
particular both R.sup.3a and R.sup.3b represent chloro; or [0341]
B-9) compounds of class B or, whenever possible, any subgroup
thereof as mentioned hereinbefore as embodiment wherein the
compound of class B is a compound of formula (I') or (I'') and
wherein R.sup.3c represents hydrogen, hydroxyl, carboxyl; halo;
amino; mono- or di-(C.sub.1-4alkyl)amino; C.sub.1-6alkyl;
C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; C.sub.1-6alkylthio;
C.sub.1-4alkylcarbonylamino; R.sup.5R.sup.4N--C(.dbd.O)--;
R.sup.5R.sup.4N--C.sub.1-6alkyl; Het-C(.dbd.O)-- or
HetC.sub.1-4alkyl; or R.sup.3c represents hydrogen; or [0342] B-10)
compounds of class B or, whenever possible, any subgroup thereof as
mentioned hereinbefore as embodiment wherein p represents 2; or
[0343] B-11) compounds of class B or, whenever possible, any
subgroup thereof as mentioned hereinbefore as embodiment wherein Z
represents C.sub.1-6alkanediyl, in particular CH.sub.2 or
CH.sub.2--CH.sub.2; or [0344] B-12) compounds of class B or,
whenever possible, any subgroup thereof as mentioned hereinbefore
as embodiment wherein R.sup.1 represents hydrogen; or [0345] B-13)
compounds of class B or, whenever possible, any subgroup thereof as
mentioned hereinbefore as embodiment wherein R.sup.8 represents
hydrogen; or [0346] B-14) compounds of class B or, whenever
possible, any subgroup thereof as mentioned hereinbefore as
embodiment wherein R.sup.8 represents halo, C.sub.1-4alkyl or
C.sub.1-4alkyl substituted with hydroxyl; in particular R.sup.8
represents halo or C.sub.1-4alkyl; or [0347] B-15) compounds of
class B or, whenever possible, any subgroup thereof as mentioned
hereinbefore as embodiment wherein R.sup.3 represents
C.sub.3-6cycloalkyl, phenyl, naphtalenyl, 1,3-benzodioxolyl or a
6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein
said C.sub.3-6cyclo-alkyl, phenyl, naphtalenyl, 1,3-benzodioxolyl
or 6-membered aromatic heterocycle may optionally be substituted
with at least one substituent, in particular one or two
substituents, preferably each substituent independently selected
from hydroxyl; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with hydroxy; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyloxy; C.sub.1-6alkylthio; C.sub.1-6alkyloxycarbonyl;
amino; mono- or di(C.sub.1-4alkyl)amino;
C.sub.1-4alkylcarbonylamino; Het; HetC.sub.1-4alkyl; or [0348]
B-16) compounds of class B or any subgroup thereof as mentioned
hereinbefore as embodiment wherein one or more, preferably all, of
the following restrictions apply : [0349] a) X represents
--NR.sup.x--C(.dbd.O)--; or --Z--C(.dbd.O)--; [0350] b) the
compound of class B is a compound of formula (I''), in particular a
compound of formula (I'') wherein R.sup.3a and R.sup.3b represent
halo; more in particular chloro; and wherein R.sup.3C represents
hydrogen; [0351] c) A represents N; [0352] d) A represents CH;
[0353] e) the dotted line does not represent a bond; [0354] f) Z
represents C.sub.1-6alkanediyl; [0355] g) R.sup.1 represents a
5-membered monocyclic aromatic heterocycle containing at least 2
heteroatoms, in particular pyrazolyl or triazolyl; a 6-membered
monocyclic aromatic heterocycle; or a 5-membered aromatic
heterocycle containing at least 2 heteroatoms fused with a
5-membered heterocycle; each of said heterocycles optionally being
substituted, in particular substituted with oxo, C.sub.1-6alkyl
optionally substituted with aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl
optionally substituted with aryl; C.sub.3-6cycloalkyl-NR.sup.x--;
Het-NR.sup.x--; arylC.sub.1-4alkyl-NR.sup.x--; aryl;
arylC.sub.1-4alkyl. [0356] h) R.sup.x represents hydrogen;
[0357] or [0358] B-17) compounds of class B or any subgroup thereof
as mentioned hereinbefore as embodiment wherein one or more,
preferably all, of the following restrictions apply: [0359] a) A
represents CH or N; [0360] b) the dotted line does not represents a
bond in case A represents a carbon atom; [0361] c) X represents
--NR.sup.x--C(.dbd.O)--; --Z--C(.dbd.O)--;
--Z--NR.sup.x--C(.dbd.O)--; [0362] d) Z represents a bivalent
radical selected from C.sub.1-6alkanediyl; [0363] e) R.sup.x
represents hydrogen; [0364] f) R.sup.1 represents a 5-membered
monocyclic heterocycle containing at least 2 heteroatoms; a
6-membered aromatic monocyclic heterocycle; or a 5-membered
heterocycle containing at least 2 heteroatoms fused with a
5-membered heterocycle; wherein each of said heterocycles such as
for example pyrazolyl, triazolyl, oxadiazolyl, pyrimidinyl,
imidazopyrazolyl or imidazothienyl, may optionally be substituted
with at least one substituent, in particular one or two
substituents, each substituent independently being selected from
oxo; C.sub.1-6alkyl optionally substituted with
C.sub.1-4alkyloxycarbonyl; hydroxyC.sub.1-6alkyl optionally
substituted with aryl; mono- or di(C.sub.1-6alkyl)amino;
R.sup.5R.sup.4N--C.sub.1-6alkyl; Het-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; aryl; arylC.sub.1-4alkyl;
aryl-C(.dbd.O)--C.sub.1-4alkyl; Het; [0365] g) R.sup.3 represents
C.sub.3-6cycloalkyl, phenyl, naphtalenyl, 1,3-benzodioxolyl, or a
6-membered aromatic heterocycle containing 1 or 2 N atoms, wherein
said C.sub.3-6cyclo-alkyl, phenyl, naphtalenyl, 1,3-benzodioxolyl
or 6-membered aromatic heterocycle may optionally be substituted
with at least one substituent, in particular one or two
substituents, each substituent independently selected from
hydroxyl; carboxyl; halo; C.sub.1-6alkyl optionally substituted
with hydroxy; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy;
C.sub.1-6alkylthio; C.sub.1-6alkyloxycarbonyl; mono- or
di(C.sub.1-4alkyl)amino; C.sub.1-4alkyl-carbonylamino; Het;
HetC.sub.1-4alkyl; [0366] h) R.sup.4 represents hydrogen or
C.sub.1-4alkyl; [0367] i) R.sup.5 represents hydrogen or
C.sub.1-4alkyl; [0368] j) R.sup.8 represents hydrogen; [0369] k)
aryl represents phenyl or phenyl substituted with at least one
substituent, in particular one substituent, said substituent being
selected from halo; C.sub.1-6alkyl; C.sub.1-6alkyloxy; [0370] l)
Het represents a monocyclic non-aromatic or aromatic heterocycle
containing at least one heteroatom selected from O, S,
S(.dbd.O).sub.p or N; said monocyclic heterocycle optionally being
substituted with C.sub.1-6alkyloxycarbonyl; or [0371] B-18)
compounds of class B selected from
TABLE-US-00001 ##STR00012## [0371] A X R.sup.1 R.sup.q N
##STR00013## ##STR00014## H-- N ##STR00015## ##STR00016## H-- N
##STR00017## ##STR00018## H-- N ##STR00019## ##STR00020##
##STR00021## N ##STR00022## ##STR00023## ##STR00024## N
##STR00025## ##STR00026## HOCH.sub.2--
including any stereochemically isomeric form thereof; [0372] a
N-oxide thereof, a pharmaceutically acceptable salt thereof or a
solvate thereof.
[0373] The next embodiments of the present invention are those
combinations of a DGAT inhibitor, more in particular a DGAT1
inhibitor and a PPAR agonist, in particular a PPAR-.alpha. agonist,
more in particular a fibrate, even more in particular fenofibrate;
wherein the DGAT inhibitor is selected from compounds of Class C.
Preferred embodiments of compounds of class C are: [0374] C-1)
compounds of class C having the following formula (I)
##STR00027##
[0374] including any stereochemically isomeric form thereof,
wherein [0375] A represents CH or N; [0376] the dotted line
represents an optional bond in case A represents a carbon atom;
[0377] X represents --NR.sup.x--C(.dbd.O)--; --Z--C(.dbd.O)--;
--Z--NR.sup.x--C(.dbd.O)--; --C(.dbd.O)--Z--;
--NR.sup.x--C(.dbd.O)--Z--; C(.dbd.S)--; --NR.sup.x--C(.dbd.S)--;
--Z--C(.dbd.S)--; --Z--NR.sup.x--C(.dbd.S)--; --C(.dbd.S)--Z--;
--NR.sup.x--C(.dbd.S)--Z--; [0378] Z represents a bivalent radical
selected from C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or
C.sub.2-6alkynediyl; wherein each of said C.sub.1-6alkanediyl,
C.sub.2-6alkenediyl or C.sub.2-6alkynediyl may optionally be
substituted with hydroxyl; [0379] R.sup.x represents hydrogen or
C.sub.1-4alkyl; [0380] Y represents C(.dbd.O)--NR.sup.x-- or
--NR.sup.x--C(.dbd.O)--; [0381] R.sup.1 represents
C.sub.3-6cycloalkyl; aryl.sup.1 or Het.sup.1; [0382] R.sup.2
represents C.sub.3-6cycloalkyl, phenyl, naphtalenyl,
2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, wherein said
C.sub.3-6cycloalkyl, phenyl, naphtalenyl,
2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl may optionally be
substituted with at least one substituent, in particular one, two,
three, four or five substituents, each substituent independently
selected from hydroxyl; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with hydroxy; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl;
R.sup.4R.sup.3N--C(.dbd.O)--; R.sup.4R.sup.3N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl; C.sub.3-6cycloalkylC.sub.1-4alkyl;
C.sub.3-6cycloalkyl-C(.dbd.O)--; aryl; aryloxy; arylC.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--;
[0383] R.sup.3 represents hydrogen; C.sub.1-4alkyl optionally
substituted with hydroxyl or C.sub.1-4alkyloxy;
R.sup.6R.sup.5N--C.sub.1-4alkyl; C.sub.1-4alkyloxy; Het; aryl;
R.sup.6R.sup.5N--C(.dbd.O)--C.sub.1-4alkyl; [0384] R.sup.4
represents hydrogen or C.sub.1-4alkyl; [0385] R.sup.5 represents
hydrogen; C.sub.1-4alkyl; C.sub.1-4alkylcarbonyl; [0386] R.sup.6
represents hydrogen or C.sub.1-4alkyl; or [0387] R.sup.5 and
R.sup.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
selected from O, S, S(.dbd.O).sub.p or N; and which heterocycle may
optionally be substituted with C.sub.1-4alkyl; [0388] aryl
represents phenyl or phenyl substituted with at least one
substituent, in particular one, two, three, four or five
substituents, each substituent independently being selected from
hydroxyl; carboxyl; halo; C.sub.1-6alkyl optionally substituted
with C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; [0389]
aryl.sup.1 represents phenyl, naphthalenyl or fluorenyl; each of
said phenyl, naphthalenyl or fluorenyl optionally substituted with
at least one substituent, in particular one, two, three, four or
five substituents, each substituent independently being selected
from hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally
substituted with aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyloxy optionally substituted with C.sub.1-4alkyloxy;
C.sub.1-6alkylthio; polyhaloC.sub.1-6alkyloxy;
C.sub.1-6alkyloxy-carbonyl wherein C.sub.1-6alkyl may optionally be
substituted with aryl; cyano; aminocarbonyl; mono- or
di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkylcarbonyl; nitro;
amino; mono- or di(C.sub.1-6alkyl)amino;
C.sub.3-6cycloalkyl-NR.sup.x--; aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--; Het;
HetC.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; [0390] Het represents
a monocyclic non-aromatic or aromatic heterocycle containing at
least one heteroatom selected from O, S, S(.dbd.O).sub.p or N; or a
bicyclic or tricyclic non-aromatic or aromatic heterocycle
containing at least one heteroatom selected from O, S,
S(.dbd.O).sub.p or N; said monocyclic heterocycle or said bi- or
tricyclic heterocycle optionally being substituted with at least
one substituent, in particular one, two, three, four or five
substituents, each substituent independently being selected from
hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with C.sub.1-4alkyloxy, amino or mono- or
di(C.sub.1-4alkyl)amino; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyl-oxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; [0391]
Het.sup.1 represents a monocyclic non-aromatic or aromatic
heterocycle containing at least one heteroatom selected from O, S,
S(.dbd.O).sub.p or N; or a bicyclic or tricyclic non-aromatic or
aromatic heterocycle containing at least one heteroatom selected
from O, S, S(.dbd.O).sub.p or N; said monocyclic heterocycle or
said bi- or tricyclic heterocycle optionally being substituted with
at least one substituent, in particular one, two, three, four or
five substituents, each substituent independently being selected
from hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally
substituted with aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyloxy optionally substituted with C.sub.1-4alkyloxy;
C.sub.1-6alkylthio; [0392] polyhaloC.sub.1-6alkyloxy;
C.sub.1-6alkyloxy-carbonyl wherein C.sub.1-6alkyl may optionally be
substituted with aryl; cyano; aminocarbonyl; mono- or
di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkylcarbonyl; nitro;
amino; mono- or di(C.sub.1-6alkyl)amino;
C.sub.3-6cycloalkyl-NR.sup.x--; aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--; Het;
HetC.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; [0393] p represents 1
or 2; [0394] a N-oxide thereof, a pharmaceutically acceptable salt
thereof or a solvate thereof; or [0395] C-2) compounds of class C
or, whenever possible, any subgroup thereof as mentioned
hereinbefore as embodiment wherein X represents O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--; --Z--C(.dbd.O)--;
--Z--NR.sup.x--C(.dbd.O)--; --C(.dbd.O)--Z--;
--NR.sup.x--C(.dbd.O)--Z--; --NR.sup.x--C(.dbd.S)--; in particular
wherein X represents --NR.sup.x--C(.dbd.O)--; --Z--C(.dbd.O)--;
--Z--NR.sup.x--C(.dbd.O)--; --C(.dbd.O)--Z--;
--NR.sup.x--C(.dbd.O)--Z--; --NR.sup.x--C(.dbd.S)--; more in
particular wherein X represents --NR.sup.x--C(.dbd.O)--;
--Z--C(.dbd.O)--; --Z--NR.sup.x--C(.dbd.O)--; even more in
particular X represents --NR.sup.x--C(.dbd.O)-- or
--Z--NR.sup.x--C(.dbd.O)--; or X represents --NR.sup.x--C(.dbd.O)--
or --Z--C(.dbd.O)--. Or X represents O--C(.dbd.O)--;
--C(.dbd.O)--C(.dbd.O)--; --NR.sup.x--C(.dbd.O)--;
--Z--C(.dbd.O)--; --Z--NR.sup.x--C(.dbd.O)--; C(.dbd.S)--;
--NR.sup.x--C(.dbd.S)--; --Z--C(.dbd.S)--;
--Z--NR.sup.x--C(.dbd.S)--; or [0396] C-3) compounds of class C or,
whenever possible, any subgroup thereof as mentioned hereinbefore
as embodiment wherein A represents N; or [0397] C-4) compounds of
class C or, whenever possible, any subgroup thereof as mentioned
hereinbefore as embodiment wherein A represents CH, in particular
wherein A represents CH and the dotted line does not represent a
bond; or [0398] C-5) compounds of class C or, whenever possible,
any subgroup thereof as mentioned hereinbefore as embodiment
wherein R.sup.1 represents aryl.sup.1 or Het.sup.1; in particular
optionally substituted phenyl, optionally substituted fluorenyl or
an optionally substituted monocyclic non-aromatic or aromatic
heterocycle containing at least one heteroatom each independently
selected from O, S, S(.dbd.O).sub.p or N, in particular S or N;
more in particular phenyl or fluorenyl, said phenyl or fluorenyl
optionally substituted with one or two substituents, said
substituents independently selected from oxo, carboxyl, halo,
C.sub.1-6alkyl optionally substituted with carboxyl or
C.sub.1-4alkyloxycarbonyl, C.sub.1-6alkyloxy,
C.sub.1-6alkyloxycarbonyl, amino, aryl, Het or
polyhaloC.sub.1-6alkyl; or a 4-, 5-or 6-membered non-aromatic or
aromatic heterocycle, such as for example azetidinyl,
thiazolidinyl, thiazolyl, pyrrolidinyl, piperidinyl, said 5- or
6-membered heterocycle optionally substituted with one or two
substituents, said substituents independently selected from
hydroxyl, oxo, C.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl, aryl or
Het; or [0399] C-6) compounds of class C or, whenever possible, any
subgroup thereof as mentioned hereinbefore as embodiment wherein
R.sup.2 represents C.sub.3-6cycloalkyl, phenyl,
2,3-dihydro-1,4-benzodioxinyl or a 6-membered aromatic heterocycle
containing 1 or 2 N atoms such as for example pyridyl, wherein said
phenyl or heterocycle are optionally substituted with one to four
substituents, preferably each substituent independently selected
from halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy, C.sub.1-6alkylthio,
C.sub.1-6alkyloxycarbonyl, nitro, amino, mono- or
di(C.sub.1-4alkyl)amino, aryloxy, R.sup.4R.sup.3N--C.sub.1-6alkyl,
Het-C(.dbd.O)--C.sub.1-4alkyl; or [0400] C-7) compounds of class C
or, whenever possible, any subgroup thereof as mentioned
hereinbefore as embodiment wherein the compound of class C is a
compound of formula (I')
##STR00028##
[0400] wherein R.sup.3a and R.sup.3b each independently represent
hydrogen; hydroxyl; carboxyl; halo; C.sub.1-6alkyl;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; and
wherein R.sup.3c represents hydrogen; hydroxyl; carboxyl; halo;
C.sub.1-6alkyl; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl;
R.sup.4R.sup.3N--C(.dbd.O)--; R.sup.4R.sup.3N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl; aryl; aryloxy; arylC.sub.1-4alkyl;
aryl-C(.dbd.O)--C.sub.1-4alkyl; aryl-C(.dbd.O)--; Het;
HetC.sub.1-4alkyl; Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--;
Het-O--; or [0401] C-8) compounds of class C or, whenever possible,
any subgroup thereof as mentioned hereinbefore as embodiment
wherein the compound of class C is a compound of formula (I'')
##STR00029##
[0401] wherein R.sup.3a and R.sup.3b each independently represent
hydrogen; hydroxyl; carboxyl; halo; C.sub.1-6alkyl;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; and
wherein R.sup.3c represents hydrogen; hydroxyl; carboxyl; halo;
C.sub.1-6alkyl; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl;
R.sup.4R.sup.3N--C(.dbd.O)--; R.sup.4R.sup.3N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl; aryl; aryloxy; arylC.sub.1-4alkyl;
aryl-C(.dbd.O)--C.sub.1-4alkyl; aryl-C(.dbd.O)--; Het;
HetC.sub.1-4alkyl; Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--;
Het-O--; or [0402] C-9) compounds of class C or any subgroup
thereof as mentioned hereinbefore as embodiment wherein the
compound of formula (I) is a compound of formula (I') or (I'') and
wherein R.sup.3a and R.sup.3b each independently represent halo,
C.sub.1-6alkyl or C.sub.1-6alkyloxy; in particular halo or
C.sub.1-6alkyl; more in particular both R.sup.1a and R.sup.3b
represent halo, more in particular both R.sup.3a and R.sup.3b
represent chloro; or [0403] C-10) compounds of class C or, whenever
possible, any subgroup thereof as mentioned hereinbefore as
embodiment wherein the compound of formula (I) is a compound of
formula (I') or (I'') and wherein R.sup.3c represents amino; mono-
or di(C.sub.1-4alkyl)amino; R.sup.4R.sup.3N--C(.dbd.O)--;
R.sup.4R.sup.3N--C.sub.1-6alkyl; Het-C(.dbd.O)-- or
HetC.sub.1-4alkyl; or R.sup.3c represents hydrogen; or [0404] C-11)
compounds of class C or, whenever possible, any subgroup thereof as
mentioned hereinbefore as embodiment wherein p represents 2; or
[0405] C-12) compounds of class C or, whenever possible, any
subgroup thereof as mentioned hereinbefore as embodiment wherein Z
represents C.sub.1-6alkanediyl or C.sub.2-6alkenediyl, in
particular C.sub.1-6alkanediyl, more in particular CH.sub.2--; or
[0406] C-13) compounds of class C or, whenever possible, any
subgroup thereof as mentioned hereinbefore as embodiment wherein
R.sup.x represents hydrogen; or [0407] C-14) compounds of class C
or, whenever possible, any subgroup thereof as mentioned
hereinbefore as embodiment wherein Y represents
NR.sup.x--C(.dbd.O)--; or [0408] C-15) compounds of class C or,
whenever possible, any subgroup thereof as mentioned hereinbefore
as embodiment wherein Y represents C(.dbd.O)--NR.sup.x--; or [0409]
C-16) compounds of class C or, whenever possible, any subgroup
thereof as mentioned hereinbefore as embodiment wherein R.sup.7
represents hydrogen; or [0410] C-17) compounds of class C or,
whenever possible, any subgroup thereof as mentioned hereinbefore
as embodiment wherein R.sup.7 represents halo, C.sub.1-4alkyl or
C.sub.1-4alkyl substituted with hydroxyl; in particular halo; or
[0411] C-18) compounds of class C or, whenever possible, any
subgroup thereof as mentioned hereinbefore as embodiment wherein
aryl represents phenyl or phenyl substituted with halo,
C.sub.1-6alkyl, polyhaloC.sub.1-6alkyl or
C.sub.1-6alkyloxycarbonyl; or [0412] C-19) compounds of class C or,
whenever possible, any subgroup thereof as mentioned hereinbefore
as embodiment wherein Het represents a monocyclic non-aromatic or
aromatic heterocycle containing at least one heteroatom each
independently selected from O, S, S(.dbd.O).sub.p or N; or a
bicyclic non-aromatic or aromatic heterocycle containing at least
one heteroatom each independently selected from O, S,
S(.dbd.O).sub.p or N, in particular N; said monocyclic heterocycle
or said bicyclic heterocycle optionally being substituted with one
or two substituents, each substituent independently being selected
from oxo; or C.sub.1-6alkyl; or [0413] C-20) compounds of class C
or, whenever possible, any subgroup thereof as mentioned
hereinbefore as embodiment wherein one or more, preferably all, of
the following restrictions apply: [0414] a) X represents
--NR.sup.x--C(.dbd.O)--; --Z--NR.sup.x--C(.dbd.O)--; or
--NR.sup.x--C(.dbd.S)--; [0415] b) R.sup.1 represents aryl.sup.1 or
Het.sup.1; [0416] c) R.sup.2 represents C.sub.3-6cycloalkyl, phenyl
or 2,3-dihydro-1,4-benzodioxinyl, wherein said phenyl is optionally
substituted with one to four substituents, each substituent
independently selected from halo, C.sub.1-6alkyl,
C.sub.1-6alkyloxy, C.sub.1-6alkylthio, C.sub.1-6alkyloxycarbonyl,
nitro, amino, mono- or di(C.sub.1-4alkyl)amino, aryloxy; [0417] d)
A represents N; [0418] e) A represents CH; [0419] f) Z represents
C.sub.1-6alkanediyl or C.sub.2-6alkenediyl; [0420] g) R.sup.x
represents hydrogen. [0421] h) aryl.sup.1 represents phenyl or
fluorenyl, said phenyl or fluorenyl optionally substituted with
halo, C.sub.1-6alkyl or polyhaloC.sub.1-6alkyl; [0422] i) Het.sup.1
represents a 4-, 5-or 6-membered non-aromatic or aromatic
heterocycle, such as for example azetidinyl, thiazolidinyl,
thiazolyl, pyrrolidinyl, piperidinyl, said 5- or 6-membered
heterocycle optionally substituted with hydroxyl, oxo,
C.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl, aryl or Het; [0423] j) Y
represents NR.sup.x--C(.dbd.O)--; [0424] k) R.sup.7 represents
hydrogen; or [0425] C-21) compounds of class C or, whenever
possible, any subgroup thereof as mentioned hereinbefore as
embodiment wherein one or more, preferably all, of the following
restrictions apply : [0426] a) A represents CH; [0427] b) A
represents N; [0428] c) the dotted line represents a bond in case A
represents a carbon atom; [0429] d) the dotted line doesn't
represents a bond in case A represents a carbon atom; [0430] e) X
represents O--C(.dbd.O)--; --NR.sup.x--C(.dbd.O)--;
--Z--C(.dbd.O)--; --Z--NR.sup.x--C(.dbd.O)--;
--NR.sup.x--C(.dbd.S)--; [0431] f) Z represents
C.sub.1-6alkanediyl; [0432] g) R.sup.x represents hydrogen; [0433]
h) Y represents C(.dbd.O)--NR.sup.x-- or --NR.sup.x--C(.dbd.O)--;
[0434] i) R.sup.1 represents aryl.sup.1 or Het.sup.1; [0435] j)
R.sup.2 represents C.sub.3-6cycloalkyl, phenyl,
2,3-dihydro-1,4-benzodioxinyl, or a 6-membered aromatic heterocycle
containing 1 or 2 N atoms, wherein said C.sub.3-6cycloalkyl,
phenyl, 2,3-dihydro-1,4-benzodioxinyl, or 6-membered aromatic
heterocycle containing 1 or 2 N atoms may optionally be substituted
with at least one substituent, in particular one to four
substituents, each substituent independently selected from halo;
C.sub.1-6alkyl; C.sub.1-6alkyloxy; C.sub.1-6alkylthio;
C.sub.1-6alkyloxycarbonyl; nitro; mono- or di(C.sub.1-4alkyl)amino;
R.sup.4R.sup.3N--C.sub.1-6alkyl; aryloxy;
Het-C(.dbd.O)--C.sub.1-4alkyl; [0436] k) R.sup.3 represents
C.sub.1-4alkyl; [0437] l) R.sup.4 represents C.sub.1-4alkyl; [0438]
m) R.sup.7 represents hydrogen or halo; [0439] n) aryl represents
phenyl or phenyl substituted with halo; C.sub.1-6alkyl;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxycarbonyl; [0440] o)
aryl.sup.1 represents phenyl or fluorenyl; each of said phenyl or
fluorenyl optionally substituted with one or two substituents, each
substituent independently being selected from oxo; carboxyl; halo;
C.sub.1-6alkyl optionally substituted with carboxyl or
C.sub.1-4alkyloxycarbonyl; C.sub.1-6alkyloxy;
C.sub.1-6alkyloxy-carbonyl; amino; aryl; Het; [0441] p) Het
represents a monocyclic non-aromatic or aromatic heterocycle
containing at least one heteroatom each independently selected from
O, S, S(.dbd.O).sub.p or N; or a bicyclic non-aromatic or aromatic
heterocycle containing at least one heteroatom each independently
selected from N; said monocyclic heterocycle or said bicyclic
heterocycle optionally being substituted with one or two
substituents, each substituent independently being selected from
oxo or C.sub.1-6alkyl; [0442] q) Het.sup.1 represents a monocyclic
non-aromatic or aromatic heterocycle containing at least one
heteroatom each independently selected from S or N; said monocyclic
heterocycle optionally being substituted with at least one
substituent, in particular one or two substituents, each
substituent independently being selected from hydroxyl; oxo;
C.sub.1-6alkyl; C.sub.1-6alkyloxy-carbonyl; aryl; Het; [0443] r) p
represents 2; or [0444] C-22)compounds of class C selected from
##STR00030##
[0444] including any stereochemically isomeric form thereof; [0445]
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a
solvate thereof; or [0446] C-23) compounds of formula (I), wherein
the compound is selected from [0447]
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[-
3-(1-pyrrolidinyl)phenyl]-benzamide (compound 151 Class C); [0448]
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazin-
yl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 152 Class C);
[0449]
4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-
-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 147 Class C);
[0450]
4-[4-[[2,6-dichloro-4-[(4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]ac-
etyl]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide
(compound 150 Class C); [0451]
4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-pi-
perazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound 149
Class C); [0452]
4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl-
]-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (compound
148 Class C); including any stereochemically isomeric form thereof;
[0453] a N-oxide thereof, a pharmaceutically acceptable salt
thereof or a solvate thereof; or [0454] C-24) compounds of class C
or, whenever possible, any subgroup thereof as mentioned
hereinbefore as embodiment wherein R.sup.2 represents hydrogen,
C.sub.1-6alkyl or C.sub.2-6alkenyl. [0455] The next embodiments of
the present invention are those combinations of a DGAT inhibitor,
more in particular a DGAT1 inhibitor and a PPAR agonist, in
particular a PPAR-.alpha. agonist, more in particular a fibrate,
even more in particular fenofibrate; wherein the DGAT inhibitor is
selected from compounds of Class D. Preferred embodiments of
compounds of class D are: [0456] D-1) compounds of class D having
the following formula (I)
##STR00031##
[0456] including any stereochemically isomeric form thereof,
wherein [0457] A represents CH or N; [0458] the dotted line
represents an optional bond in case A represents a carbon atom;
[0459] X represents C(.dbd.O)--; --NR.sup.x--C(.dbd.O)--;
--Z.sup.1--C(.dbd.O)--; --Z.sup.1--NR.sup.x--C(.dbd.O)--;
--C(.dbd.O)--Z.sup.1--; --NR.sup.x--C(.dbd.O)--Z.sup.1--;
--S(.dbd.O).sub.p--; C(.dbd.S)--; --NR.sup.x--C(.dbd.S)--;
--Z.sup.1--C(.dbd.S)--; --Z.sup.1--NR.sup.x--C(.dbd.S)--;
--C(.dbd.S)--Z.sup.1--; --NR.sup.x--C(.dbd.S)--Z.sup.1--; [0460]
Z.sup.1 represents a bivalent radical selected from
C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or C.sub.2-6alkynediyl;
wherein each of said C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or
C.sub.2-6alkynediyl may optionally be substituted with hydroxyl;
[0461] Y represents NR.sup.x--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z.sup.2--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--O--Z.sup.2--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z.sup.2--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z.sup.2--; --C(.dbd.O)--Z.sup.2--O--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--O--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--C(.dbd.O)--O--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--O--C(.dbd.O)--;
--C(.dbd.O)--NR.sup.x--O--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--C(.dbd.O)--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--C(.dbd.O)--O--; [0462]
Z.sup.2 represents a bivalent radical selected from
C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or C.sub.2-6alkynediyl;
wherein each of said C.sub.1-6alkanediyl, C.sub.2-6alkenediyl
or
[0463] C.sub.2-6alkynediyl may optionally be substituted with
C.sub.1-4alkyloxy, C.sub.1-4alkylthio, hydroxyl, cyano or aryl; and
wherein two hydrogen atoms attached to the same carbon atom in the
definition of Z.sup.2 may optionally be replaced by
C.sub.1-6alkanediyl; [0464] R.sup.x represents hydrogen or
C.sub.1-4alkyl; [0465] R.sup.y represents hydrogen; C.sub.1-4alkyl
optionally substituted with C.sub.3-6cycloalkyl or aryl or Het;
C.sub.2-4alkenyl; or S(.dbd.O).sub.p-aryl; [0466] R.sup.1
represents C.sub.1-12alkyl optionally substituted with cyano,
C.sub.1-4alkyloxy, C.sub.1-4alkyl-oxyC.sub.1-4alkyloxy,
C.sub.3-6cycloalkyl or aryl; C.sub.2-6alkenyl; C.sub.2-6alkynyl;
C.sub.3-6cycloalkyl; aryl.sup.1 ; aryl.sup.1C.sub.1-6alkyl;
Het.sup.1; or Het.sup.1C.sub.1-6alkyl; provided that when Y
represents --NR.sup.x--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--O--Z.sup.2--; or
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--; then R.sup.1 may also
represent hydrogen; [0467] R.sup.2 represents hydrogen,
C.sub.1-6alkyl, C.sub.2-6alkenyl or R.sup.3; [0468] R.sup.3
represents C.sub.3-6cycloalkyl, phenyl, naphtalenyl,
2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl, wherein said
C.sub.3-6cycloalkyl, phenyl, naphtalenyl,
2,3-dihydro-1,4-benzodioxinyl, 1,3-benzodioxolyl may optionally be
substituted with at least one substituent, in particular one, two,
three, four or five substituents, each substituent independently
selected from hydroxyl; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with hydroxy; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl;
R.sup.5R.sup.4N--C(.dbd.O)--; R.sup.5R.sup.4N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl; C.sub.3-6cycloalkylC.sub.1-4alkyl;
C.sub.3-6cycloalkyl-C(.dbd.O)--; aryl; aryloxy; arylC.sub.1-4alkyl;
aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--;
[0469] R.sup.4 represents hydrogen; C.sub.1-4alkyl optionally
substituted with hydroxyl or C.sub.1-4alkyloxy;
R.sup.7R.sup.6N--C.sub.1-4alkyl; C.sub.1-4alkyloxy; Het; aryl;
R.sup.7R.sup.6N--C(.dbd.O)--C.sub.1-4alkyl; [0470] R.sup.5
represents hydrogen or C.sub.1-4alkyl; [0471] R.sup.6 represents
hydrogen; C.sub.1-4alkyl; C.sub.1-4alkylcarbonyl; [0472] R.sup.7
represents hydrogen or C.sub.1-4alkyl; or [0473] R.sup.6 and
R.sup.7 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
selected from O, S, S(.dbd.O).sub.p or N; and which heterocycle may
optionally be substituted with C.sub.1-4alkyl; [0474] aryl
represents phenyl or phenyl substituted with at least one
substituent, in particular one, two, three, four or five
substituents, each substituent independently being selected from
hydroxyl; carboxyl; halo; C.sub.1-6alkyl optionally substituted
with C.sub.1-4alkyloxy, amino or mono- or di(C.sub.1-4alkyl)amino;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; [0475]
aryl.sup.1 represents phenyl, naphthalenyl or fluorenyl; each of
said phenyl, naphthalenyl or fluorenyl optionally substituted with
at least one substituent, in particular one, two, three, four or
five substituents, each substituent independently being selected
from hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally
substituted with aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyloxy optionally substituted with C.sub.1-4alkyloxy;
C.sub.1-6alkylthio; polyhaloC.sub.1-6alkyloxy;
C.sub.1-6alkyloxy-carbonyl wherein C.sub.1-6alkyl may optionally be
substituted with aryl; cyano; aminocarbonyl; mono- or
di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkylcarbonyl; nitro;
amino; mono- or di(C.sub.1-6alkyl)amino;
C.sub.3-6cycloalkyl-NR.sup.x--; aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--; Het;
HetC.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; [0476] Het represents
a monocyclic non-aromatic or aromatic heterocycle containing at
least one heteroatom selected from O, S, S(.dbd.O).sub.p or N; or a
bicyclic or tricyclic non-aromatic or aromatic heterocycle
containing at least one heteroatom selected from O, S,
S(.dbd.O).sub.p or N; said monocyclic heterocycle or said bi- or
tricyclic heterocycle optionally being substituted with at least
one substituent, in particular one, two, three, four or five
substituents, each substituent independently being selected from
hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with C.sub.1-4alkyloxy, amino or mono- or
di(C.sub.1-4alkyl)amino; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyl-oxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; [0477]
Het.sup.1 represents a monocyclic non-aromatic or aromatic
heterocycle containing at least one heteroatom selected from O, S,
S(.dbd.O).sub.p or N; or a bicyclic or tricyclic non-aromatic or
aromatic heterocycle containing at least one heteroatom selected
from O, S, S(.dbd.O).sub.p or N; said monocyclic heterocycle or
said bi- or tricyclic heterocycle optionally being substituted with
at least one substituent, in particular one, two, three, four or
five substituents, each substituent independently being selected
from hydroxyl; oxo; carboxyl; halo; C.sub.1-6alkyl optionally
substituted with aryl-C(.dbd.O)--; hydroxyC.sub.1-6alkyl optionally
substituted with aryl or aryl-C(.dbd.O)--; polyhaloC.sub.1-6alkyl;
C.sub.1-6alkyloxy optionally substituted with C.sub.1-4alkyloxy;
C.sub.1-6alkylthio; polyhaloC.sub.1-6alkyloxy;
C.sub.1-6alkyloxy-carbonyl wherein C.sub.1-6alkyl may optionally be
substituted with aryl; cyano; aminocarbonyl; mono- or
di(C.sub.1-4alkyl)aminocarbonyl; C.sub.1-6alkylcarbonyl; nitro;
amino; mono- or di(C.sub.1-6alkyl)amino;
C.sub.3-6cycloalkyl-NR.sup.x--; aryl-NR.sup.x--; Het-NR.sup.x--;
C.sub.3-6cycloalkylC.sub.1-4alkyl-NR.sup.x--;
arylC.sub.1-4alkyl-NR.sup.x--; HetC.sub.1-4alkyl-NR.sup.x--;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.3-6cycloalkylC.sub.1-4alkyl; C.sub.3-6cycloalkyl-C(.dbd.O)--;
aryl; aryloxy; arylC.sub.1-4alkyl; aryl-C(.dbd.O)--; Het;
HetC.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; [0478] p represents 1
or 2; [0479] a N-oxide thereof, a pharmaceutically acceptable salt
thereof or a solvate thereof; or [0480] D-2) compounds of class D
or any subgroup thereof as mentioned hereinbefore as embodiment
wherein X represents C(.dbd.O)--C(.dbd.O)--; O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--; --Z.sup.1--C(.dbd.O)--;
--Z.sup.1--NR.sup.x--C(.dbd.O)--; --C(.dbd.O)--Z.sup.1--;
--NR.sup.x--C(.dbd.O)--Z.sup.1--; --S(.dbd.O).sub.p--;
--NR.sup.x--C(.dbd.S)--; in particular X represents
--NR.sup.x--C(.dbd.O)--; --Z.sup.1--C(.dbd.O)--;
--Z.sup.1--NR.sup.x--C(.dbd.O)--; --C(.dbd.O)--Z.sup.1--;
--NR.sup.x--C(.dbd.O)--Z.sup.1--; --S(.dbd.O).sub.p--;
--NR.sup.x--C(.dbd.S)--; more in particular X represents
--NR.sup.x--C(.dbd.O)--; --Z.sup.1--C(.dbd.O)--;
--C(.dbd.O)--Z.sup.1--; --Z.sup.1--NR.sup.x--C(.dbd.O)--;
--NR.sup.x--C(.dbd.S)-- or --S(.dbd.O).sub.p--; even more in
particular X represents --NR.sup.x--C(.dbd.O)-- or
--Z.sup.1--NR.sup.x--C(.dbd.O)--; even more in particular
--NR.sup.x--C(.dbd.O)--; or [0481] D-3) compounds of class D or any
subgroup thereof as mentioned hereinbefore as embodiment wherein A
represents N; or [0482] D-4) compounds of class D or any subgroup
thereof as mentioned hereinbefore as embodiment wherein A
represents CH, in particular wherein A represents CH and the dotted
line does not represent a bond; or [0483] D-5) compounds of class D
or any subgroup thereof as mentioned hereinbefore as embodiment
wherein R.sup.1 represents [0484] C.sub.3-6cycloalkyl; adamantanyl;
aryls; aryl.sup.1C.sub.1-6alkyl; Het.sup.1; or
Het.sup.1C.sub.1-6alkyl;aryl.sup.1; in particular
aryl.sup.1C.sub.1-6alkyl; Het.sup.1; or Het.sup.1C.sub.1-6alkyl;
more in particular aryls; aryl.sup.1C.sub.1-6alkyl; Het.sup.1; or
Het.sup.1C.sub.1-6alkyl, wherein said aryl.sup.1 or Het.sup.1
represent phenyl, naphthalenyl, morpholinyl, piperidinyl,
piperazinyl, pyrrolidinyl, furanyl, imidazolyl, thienyl, pyridyl;
each of said cycles representing aryl.sup.1 or Het.sup.1 being
optionally substituted with one or two substituents; in particular
with aryl, C.sub.1-6alkyl, arylC.sub.1-4alkyl, hydroxyl, halo,
polyhaloC.sub.1-6alkyl, C.sub.1-6alkyloxy, nitro,
C.sub.1-6alkyloxycarbonyl, --S(.dbd.O).sub.2--C.sub.1-4alkyl; more
in particular with aryl, C.sub.1-6alkyl, arylC.sub.1-4alkyl, halo,
C.sub.1-6alkyloxy, C.sub.1-6alkyloxycarbonyl,
--S(.dbd.O).sub.2--C.sub.1-4alkyl. More in particular R.sup.1
represents aryl.sup.1 wherein aryl.sup.1 represents preferably
optionally substituted phenyl. Even more in particular R.sup.1
represents phenyl substituted with C.sub.1-6alkyloxy, e.g. methoxy;
or [0485] D-6) compounds of class D or any subgroup thereof as
mentioned hereinbefore as embodiment wherein R.sup.1 represents
[0486] C.sub.1-12alkyl optionally substituted with cyano,
C.sub.1-4alkyloxy, C.sub.1-4alkyl-oxyC.sub.1-4alkyloxy,
C.sub.3-6cycloalkyl or aryl; C.sub.2-6alkenyl; C.sub.2-6alkynyl;
provided that when Y represents --NR.sup.x--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--O--Z.sup.2--; or
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--; then [0487] R.sup.1 may
also represent hydrogen; or [0488] D-7) compounds of class D or any
subgroup thereof as mentioned hereinbefore as embodiment wherein
R.sup.2 represents C.sub.1-12alkyl; in particular C.sub.1-6alkyl;
or [0489] D-8) compounds of class D or any subgroup thereof as
mentioned hereinbefore as embodiment wherein R.sup.2 represents
C.sub.1-6alkyl or R.sup.3; in particular wherein R.sup.2 represents
R.sup.3 and said R.sup.3 represents phenyl, naphthalenyl,
2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle
containing 1 or 2 N atoms, each of said cycles, in particular
phenyl, being optionally substituted with one to five substituents,
said substituents being in particular halo, C.sub.1-6alkyl
optionally substituted with hydroxy, polyhaloC.sub.1-6alkyl,
C.sub.1-6alkylthio, polyhaloC.sub.1-6alkyloxy, carboxyl, hydroxyl,
C.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxy,
C.sub.1-6alkyloxycarbonyl, nitro, R.sup.5R.sup.4N--C(.dbd.O)--,
R.sup.5R.sup.4N--C.sub.1-6alkyl, HetC.sub.1-4alkyl,
Het-C(.dbd.O)--C.sub.1-4allkyl, Het-C(.dbd.O)--; said substituents
being more in particular halo, C.sub.1-6alkyl optionally
substituted with hydroxy, polyhaloC.sub.1-6alkyl,
polyhaloC.sub.1-6alkyloxy, carboxyl, hydroxyl,
C.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxy, C.sub.1-6alkylthio,
C.sub.1-6alkyloxycarbonyl, nitro, R.sup.5R.sup.4N--C.sub.1-6alkyl,
HetC.sub.1-4alkyl; more in particular wherein R.sup.2 represents
phenyl substituted with one, two or three substituents, preferably
three substituents, each substituent being selected from halo, e.g.
chloro, or HetC.sub.1-4alkyl, e.g. pyrrolidinylmethyl; or [0490]
D-9) compounds of class D or any subgroup thereof as mentioned
hereinbefore as embodiment wherein the compound of class D is a
compound of formula (I')
##STR00032##
[0490] wherein R.sup.3a and R.sup.3b each independently represent
hydrogen; hydroxyl; carboxyl; halo; C.sub.1-6alkyl;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; and
wherein R.sup.3c represents hydrogen; hydroxyl; carboxyl; halo;
C.sub.1-6alkyl; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl;
R.sup.5R.sup.4N--C(.dbd.O)--; R.sup.5R.sup.4N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl; aryl; aryloxy; arylC.sub.1-4alkyl;
aryl-C(.dbd.O)--C.sub.1-4alkyl; aryl-C(.dbd.O)--; Het;
HetC.sub.1-4alkyl; Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--;
Het-O--; or [0491] D-10) compounds of class D or any subgroup
thereof as mentioned hereinbefore as embodiment wherein the
compound of class D is a compound of formula (I'')
##STR00033##
[0491] wherein R.sup.3a and R.sup.3b each independently represent
hydrogen; hydroxyl; carboxyl; halo; C.sub.1-6alkyl;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy optionally substituted
with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhaloC.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl; cyano;
aminocarbonyl; mono- or di(C.sub.1-4alkyl)aminocarbonyl;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl; and
wherein R.sup.3c represents hydrogen; hydroxyl; carboxyl; halo;
C.sub.1-6alkyl; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy
optionally substituted with C.sub.1-4alkyloxy; C.sub.1-6alkylthio;
polyhalo-C.sub.1-6alkyloxy; C.sub.1-6alkyloxycarbonyl wherein
C.sub.1-6alkyl may optionally be substituted with aryl; cyano;
C.sub.1-6alkylcarbonyl; nitro; amino; mono- or
di(C.sub.1-4alkyl)amino; --S(.dbd.O).sub.p--C.sub.1-4alkyl;
R.sup.5R.sup.4N--C(.dbd.O)--; R.sup.5R.sup.4N--C.sub.1-6alkyl;
C.sub.3-6cycloalkyl; aryl; aryloxy; aryl-C(.dbd.O)--C.sub.1-4alkyl;
arylC.sub.1-4alkyl; aryl-C(.dbd.O)--; Het; HetC.sub.1-4alkyl;
Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--; Het-O--; or [0492]
D-11) compounds of class D or any subgroup thereof as mentioned
hereinbefore as embodiment wherein the compound of class D is a
compound of formula (I') or (I'') and wherein R.sup.3a and R.sup.3b
each independently represent halo, C.sub.1-6alkyl or
C.sub.1-6alkyloxy; in particular halo or C.sub.1-6alkyl; more in
particular both R.sup.1a and R.sup.3b represent halo, more in
particular both R.sup.3a and R.sup.3b represent chloro; or [0493]
D-12) compounds of class D or any subgroup thereof as mentioned
hereinbefore as embodiment wherein the compound of formula (I) is a
compound of formula (I') or (I'') and wherein R.sup.3c represents
amino; mono- or di(C.sub.1-4alkyl)amino;
R.sup.5R.sup.4N--C(.dbd.O)--; R.sup.5R.sup.4N--C.sub.1-6alkyl;
Het-C(.dbd.O)--; Het-C(.dbd.O)--C.sub.1-4alkyl or
HetC.sub.1-4alkyl; or R.sup.3c represents hydrogen; more in
particular wherein R.sup.3c represents amino; mono- or
di(C.sub.1-4alkyl)amino; R.sup.5R.sup.4N--C(.dbd.O)--;
R.sup.5R.sup.4N--C.sub.1-6alkyl; Het-C(.dbd.O)-- or
HetC.sub.1-4alkyl; or R.sup.3c represents hydrogen; even more in
particular wherein R.sup.3c represents HetC.sub.1-4alkyl, e.g.
pyrrolidinylmethyl; or D-13) compounds of class D or any subgroup
thereof as mentioned hereinbefore as embodiment wherein p
represents 2; or [0494] D-14) compounds of class D or any subgroup
thereof as mentioned hereinbefore as embodiment wherein Y
represents --NR.sup.x--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z.sup.2--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--O--Z.sup.2--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--O--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--C(.dbd.O)--O--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--O--C(.dbd.O)--;
--C(.dbd.O)--NR.sup.x--O--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--C(.dbd.O)--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--C(.dbd.O)--O--; or
wherein Y represents NR.sup.x--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z.sup.2--; or wherein Y represents
NR.sup.x--C(.dbd.O)--Z.sup.2-- or
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y; or wherein Y represents
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--O-- or
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--O--. More in particular
Y represents --NR.sup.x--C(.dbd.O)--Z.sup.2--; or [0495] D-15)
compounds of class D or any subgroup thereof as mentioned
hereinbefore as embodiment wherein Y represents
NR.sup.x--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z.sup.2--; --C(.dbd.O)--NR.sup.x--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--O--; or [0496] D-16) compounds of
class D or any subgroup thereof as mentioned hereinbefore as
embodiment wherein Z.sup.2 represents C.sub.1-6alkanediyl or
C.sub.2-6alkenediyl; in particular C.sub.1-6alkanediyl; more in
particular methylene; or [0497] D-17) compounds of class D or any
subgroup thereof as mentioned hereinbefore as embodiment wherein
Z.sup.1 represents C.sub.1-6alkanediyl, optionally substituted with
hydroxyl or amino, or wherein two hydrogen atoms attached to the
same carbon atom in C.sub.1-6alkanediyl may optionally be replaced
by C.sub.1-6alkanediyl; in particular wherein Z.sup.1 represents
C.sub.1-6alkanediyl; or [0498] D-18) compounds of class D or any
subgroup thereof as mentioned hereinbefore as embodiment wherein
R.sup.x represents hydrogen; or [0499] D-19) compounds of class D
or any subgroup thereof as mentioned hereinbefore as embodiment
wherein R.sup.y represents hydrogen or C.sub.1-4alkyl or
C.sub.2-4alkenyl or S(.dbd.O).sub.p-aryl; or [0500] D-20) compounds
of class D or any subgroup thereof as mentioned hereinbefore as
embodiment wherein R.sup.8 represents hydrogen; or [0501] D-21)
compounds of class D or any subgroup thereof as mentioned
hereinbefore as embodiment wherein R.sup.8 represents halo,
C.sub.1-4alkyl or C.sub.1-4alkyl substituted with hydroxyl; or
[0502] D-22) compounds of class D or any subgroup thereof as
mentioned hereinbefore as embodiment wherein aryl represents phenyl
or phenyl substituted with one or two substituents, preferably each
substituent independently selected from halo, C.sub.1-6alkyl,
polyhaloC.sub.1-6alkyl, C.sub.1-6alkyloxy,
C.sub.1-6alkyloxycarbonyl or nitro; or [0503] D-23) compounds of
class D or any subgroup thereof as mentioned hereinbefore as
embodiment wherein Het.sup.1 represents a monocyclic non-aromatic
or aromatic heterocycle or a bicyclic non-aromatic heterocycle,
each of said cycles may optionally be substituted. In particular
Het.sup.1 represents morpholinyl, pyrrolidinyl, piperazinyl,
homopiperazinyl, piperidinyl, furanyl, imidazolyl, thienyl,
pyridyl, 1,3-benzodioxolyl, tetrahydropyranyl, each of said
heterocycles optionally being substituted with one or two
substituents, preferably each substituent independently being
selected from halo, C.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl,
--S(.dbd.O).sub.p--C.sub.1-4alkyl, aryl, arylC.sub.1-4alkyl,
polyhaloC.sub.1-6alkyl, C.sub.1-6alkyloxy, nitro; more preferably
each substituent independently being selected from halo,
C.sub.1-6alkyl, C.sub.1-6alkyloxycarbonyl,
--S(.dbd.O).sub.p--C.sub.1-4alkyl, aryl, arylC.sub.1-4alkyl; or
[0504] D-24) compounds of class D or any subgroup thereof as
mentioned hereinbefore as embodiment wherein aryl.sup.1 represents
phenyl, naphthalenyl or phenyl substituted with one or two
substituents, preferably each substituent independently being
selected from hydroxyl, halo, C.sub.1-6alkyl, C.sub.1-6alkyloxy,
C.sub.1-6alkyloxycarbonyl or Het; or D-25) compounds of class D or
any subgroup thereof as mentioned hereinbefore as embodiment
wherein Het is a monocyclic non-aromatic or aromatic heterocycle,
each of said heterocycles may optionally be substituted. In
particular, Het is piperidinyl, pyrrolidinyl, piperazinyl, pyridyl,
morpholinyl, each of said heterocycles optionally being substituted
with one substituent, preferably the substituent is selected from
C.sub.1-6alkyl, C.sub.1-6alkyl substituted with C.sub.1-4alkyloxy,
--S(.dbd.O).sub.p--C.sub.1-4alkyl, C.sub.1-6alkylcarbonyl; or
[0505] D-26) compounds of class D or any subgroup thereof as
mentioned hereinbefore as embodiment wherein one or more,
preferably all, of the following restrictions apply: [0506] a) X
represents --NR.sup.x--C(.dbd.O)--; --Z'-C(.dbd.O)--;
--Z.sup.1--NR.sup.x--C(.dbd.O)--; --C(.dbd.O)--Z'--; --S(.dbd.O)p-;
--NR.sup.x--C(.dbd.S)--; [0507] b) R.sup.2 represents
C.sub.1-6alkyl or R.sup.3, with R.sup.3 representing phenyl,
naphthalenyl or 1,3-benzodioxolyl, each of said cycles being
optionally substituted with one to five substituents, said
substituents being in particular halo, C.sub.1-6alkyl optionally
substituted with hydroxy, polyhaloC.sub.1-6alkyl,
polyhaloC.sub.1-6alkyloxy, carboxyl, hydroxyl,
C.sub.1-6alkylcarbonyl, C.sub.1-6alkyloxy, C.sub.1-6alkylthio,
C.sub.1-6alkyloxycarbonyl, nitro, R.sup.5R.sup.4N--C.sub.1-6alkyl,
HetC.sub.1-4alkyl. [0508] c) A represents N; [0509] d) A represents
CH; [0510] e) Y represents NR.sup.x--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z.sup.2--; [0511] f) Z.sup.1 represents
C.sub.1-6alkanediyl optionally substituted with hydroxy; [0512] g)
R.sup.y represents hydrogen; C.sub.1-4alkyl optionally substituted
with C.sub.3-6cycloalkyl or aryl; C.sub.2-4alkenyl; or
S(.dbd.O).sub.p-aryl; [0513] h) aryl.sup.1 represents phenyl, said
phenyl optionally substituted with C.sub.1-6alkyl, halo,
polyhaloC.sub.1-6alkyl, C.sub.1-6alkyloxy, nitro,
C.sub.1-6alkyloxycarbonyl; [0514] i) Het.sup.1 represents a 5-or
6-membered non-aromatic or aromatic heterocycle, such as for
example morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl,
furanyl, imidazolyl, thienyl, pyridyl, said 5- or 6-membered
heterocycle optionally substituted with aryl, C.sub.1-6alkyl,
arylC.sub.1-6alkyl, halo, polyhaloC.sub.1-6alkyl,
C.sub.1-6alkyloxycarbonyl, --S(.dbd.O)2-C.sub.1-4alkyl; or [0515]
D-27) compounds of class D having the following formula
##STR00034##
[0515] wherein one or more, preferably all, of the following
restrictions apply : [0516] a) A represents CH or N; [0517] b) X
represents --O--C(.dbd.O)--; --C(.dbd.O)--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--; --Z'-C(.dbd.O)--;
--Z.sup.1--NR.sup.x--C(.dbd.O)--; --C(.dbd.O)--Z'--;
--S(.dbd.O).sub.p--; --NR.sup.x--C(.dbd.S)--; [0518] c) Z.sup.1
represents C.sub.1-6alkanediyl; wherein said C.sub.1-6alkanediyl
may optionally be substituted with hydroxyl or amino; and wherein
two hydrogen atoms attached to the same carbon atom in
C.sub.1-6alkanediyl may optionally be replaced by
C.sub.1-6alkanediyl; [0519] d) Y represents
NR.sup.x--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--O--C(.dbd.O)--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--O--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--NR.sup.y--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z.sup.2--; --C(.dbd.O)--NR.sup.x--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--O--; [0520] e) Z.sup.2 represents a
bivalent radical selected from C.sub.1-6alkanediyl,
C.sub.2-6alkenediyl or C.sub.2-6alkynediyl; wherein each of said
C.sub.1-6alkanediyl, C.sub.2-6alkenediyl or C.sub.2-6alkynediyl may
optionally be substituted with C.sub.1-4alkyloxy,
C.sub.1-4alkylthio, hydroxyl, cyano or aryl; and wherein two
hydrogen atoms attached to the same carbon atom in the definition
of Z.sup.2 may optionally be replaced by C.sub.1-6alkanediyl;
[0521] f) R.sup.x represents hydrogen or C.sub.1-4alkyl; [0522] g)
R.sup.y represents hydrogen; C.sub.1-4alkyl; C.sub.2-4alkenyl; or
S(.dbd.O).sub.p-aryl; [0523] h) R.sup.1 represents C.sub.1-12alkyl
optionally substituted with cyano, C.sub.1-4alkyloxy,
C.sub.1-4alkyl-oxyC.sub.1-4alkyloxy, C.sub.3-6cycloalkyl or aryl;
C.sub.2-6alkenyl; C.sub.2-6alkynyl; C.sub.3-6cycloalkyl;
adamantanyl; aryl.sup.1; Het.sup.1; or Het.sup.1C.sub.1-6alkyl;
provided that when Y represents --NR.sup.x--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y;
--NR.sup.x--C(.dbd.O)--Z.sup.2--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--Z.sup.2--;
--NR.sup.x--C(.dbd.O)--Z.sup.2--NR.sup.y--C(.dbd.O)--NR.sup.y--;
--C(.dbd.O)--NR.sup.x--Z.sup.2--;
--C(.dbd.O)--NR.sup.x--O--Z.sup.2--; or
--C(.dbd.O)--NR.sup.x--Z.sup.2--NR.sup.y--; then R.sup.1 may also
represent hydrogen; [0524] i) R.sup.2 represents C.sub.1-12alkyl or
R.sup.3; [0525] j) R.sup.3 represents phenyl, naphtalenyl,
2,3-dihydrobenzofuranyl or a 6-membered aromatic heterocycle
containing 1 or 2 N atoms, wherein said phenyl, naphtalenyl,
2,3-dihydrobenzofuranyl or 6-membered aromatic heterocycle
containing 1 or 2 N atoms may optionally be substituted with at
least one substituent, in particular one, two, three, four or five
substituents, each substituent independently selected from
hydroxyl; carboxyl; halo; C.sub.1-6alkyl optionally substituted
with hydroxy; polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy;
C.sub.1-6alkylthio; polyhalo-C.sub.1-6alkyloxy;
C.sub.1-6alkyloxycarbonyl; C.sub.1-6alkylcarbonyl; nitro;
R.sup.5R.sup.4N--C(.dbd.O)--; R.sup.5R.sup.4N--C.sub.1-6alkyl;
HetC.sub.1-4alkyl; Het-C(.dbd.O)--C.sub.1-4alkyl; Het-C(.dbd.O)--;
[0526] k) R.sup.4 represents hydrogen; C.sub.1-4alkyl optionally
substituted with hydroxyl or C.sub.1-4alkyloxy;
R.sup.7R.sup.6N--C.sub.1-4alkyl; Het-C.sub.1-4alkyl;
R.sup.7R.sup.6N--C(.dbd.O)--C.sub.1-4alkyl; [0527] l) R.sup.5
represents hydrogen or C.sub.1-4alkyl; [0528] m) R.sup.6 represents
C.sub.1-4alkyl or C.sub.1-4alkylcarbonyl; [0529] n) R.sup.7
represents hydrogen or C.sub.1-4alkyl; or [0530] o) R.sup.6 and
R.sup.7 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 O or N; [0531] p) R.sup.8 represents
hydrogen, halo, C.sub.1-4alkyl substituted with hydroxyl; [0532] q)
aryl represents phenyl or phenyl substituted with at least one
substituent, in particular one or two substituents, each
substituent independently being selected from halo; C.sub.1-6alkyl;
polyhaloC.sub.1-6alkyl; C.sub.1-6alkyloxy; nitro; [0533] r)
aryl.sup.1 represents phenyl or naphthalenyl; wherein phenyl may
optionally be substituted with one or two substituents, each
substituent independently being selected from hydroxyl; halo;
C.sub.1-6alkyl; C.sub.1-6alkyloxy; C.sub.1-6alkyloxy-carbonyl or
Het; [0534] s) Het represents a monocyclic non-aromatic or aromatic
heterocycle containing at least one heteroatom each independently
selected from O, S, S(.dbd.O).sub.p or N, in particular N; said
monocyclic heterocycle optionally being substituted with one
substituent, said substituent being selected from C.sub.1-6alkyl
optionally substituted with C.sub.1-4alkyloxy;
C.sub.1-6alkylcarbonyl or --S(.dbd.O).sub.p--C.sub.1-4alkyl; [0535]
t) Het.sup.1 represents a monocyclic non-aromatic or aromatic
heterocycle containing at least one heteroatom each independently
selected from O, S, S(.dbd.O).sub.p or N, in particular N, O or S;
or a bicyclic non-aromatic heterocycle containing at least one
heteroatom each independently selected from O, S, S(.dbd.O).sub.p
or N, in particular O; said monocyclic heterocycle or said bicyclic
heterocycle optionally being substituted with one or two
substituents, each substituent independently being selected from
halo; C.sub.1-6alkyl; C.sub.1-6alkyloxy-carbonyl;
--S(.dbd.O).sub.p--C.sub.1-4alkyl; aryl; or arylC.sub.1-4alkyl;
[0536] u) p represents 2; or [0537] D-28) compounds of class D
selected from
##STR00035## ##STR00036##
[0537] including any stereochemically isomeric form thereof; [0538]
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a
solvate thereof or [0539] D-29) compounds of class D selected
from
##STR00037##
[0539] including any stereochemically isomeric form thereof; [0540]
a N-oxide thereof, a pharmaceutically acceptable salt thereof or a
solvate thereof or [0541] D-30) compounds of class D selected from:
[0542]
N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]p-
henyl]-4-methoxy-benzeneacetamide (compound 355 Class D); [0543]
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-N-[-
[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound 354 Class D);
[0544]
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-piperazin-
yl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound 356
Class D); [0545]
4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piper-
azinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 358
Class D); [0546]
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazin-
yl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 353 Class
D); [0547]
4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-pi-
perazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 357
Class D); [0548]
4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-pip-
erazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 360
Class D); [0549]
4-[4-[[2,6-dichloro-4-[(4-ethyl-1-piperazinyl)methyl]phenyl]acetyl]-1-pip-
erazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound
359 Class D); [0550]
4-[4-[[2,6-dichloro-4-[(4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]ac-
etyl]-1-piperazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide
(compound 364 Class D); [0551]
4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-pi-
perazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound
361 Class D); [0552]
4-[4-[[2,6-dichloro-4-[(4-(methylsulfonyl)-1-piperazinyl]methyl]phenyl]ac-
etyl]-1-piperazinyl]-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide
(compound 363 Class D); [0553]
4-[4-[[4-[(4-acetyl-1-piperazinyl)methyl]-2,6-dichlorophenyl]acetyl]-1-pi-
perazinyl]-N-[(3,5-dimethoxyphenyl)methyl]-benzamide (compound 362
Class D); [0554]
N-[4-[4-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]hydroxyacetyl]-1-pipera-
zinyliphenyl]-4-methoxy-benzeneacetamide (compound 352 Class D);
[0555]
N-[4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazin-
yl]phenyl]-4-methoxy-benzeneacetamide (compound 351 Class D);
[0556]
4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-
-N-[[3-(1-pyrrolidinyl)phenyl]methyl]-benzamide (compound 267 Class
D); [0557] including any stereochemically isomeric form thereof;
[0558] a N-oxide thereof, a pharmaceutically acceptable salt
thereof or a solvate thereof.
[0559] In an embodiment, the present invention also relates to a
combination of
##STR00038##
including any stereochemically isomeric form thereof; [0560] a
N-oxide thereof, a pharmaceutically acceptable salt thereof or a
solvate thereof; and fenofibrate.
[0561] In an embodiment, the present invention also relates to a
combination of
4-[4-[[2,6-dichloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-1-piperazinyl]-
-N-[(3,5-dimethoxyphenyl) methyl]-benzamide (compound 358 Class D),
including any stereochemically isomeric form thereof, a N-oxide
thereof, a pharmaceutically acceptable salt thereof or a solvate
thereof;
and fenofibrate.
General Preparation
[0562] I) Class A compounds [0563] The general preparation of the
compounds of Class A is described in WO2008/148851, the content of
which is enclosed by reference in the present application. [0564]
II) Class B compounds [0565] The general preparation of the
compounds of Class B is described in WO2008/148840, the content of
which is enclosed by reference in the present application. [0566]
III) Class C compounds [0567] The general preparation of the
compounds of Class C is described in WO2008/148849, the content of
which is enclosed by reference in the present application. [0568]
IV) Class D compounds [0569] The general preparation of the
compounds of Class D is described in WO2008/148868, the content of
which is enclosed by reference in the present application. [0570]
In addition to the general procedures described in WO2008/148868,
intermediates of Class D of formula (XI) can also be prepared from
an intermediate of formula (LXIV) in the presence of an acid such
as, for example, an HCl solution. The reaction may be performed in
the presence of a suitable solvent such as, for example, dioxane.
Intermediates of formula (LXIV) wherein R.sup.2 contains
Het-C.sub.1-4alkyl as substituent (Het is defined as a saturated
N-containing heterocycle such as, for example, pyrrollidinyl) and
wherein Xi is a direct bond, said intermediates being represented
by formula (LXIV-a) can be prepared by reacting an intermediate of
formula (LXV) in het presence of a saturated N-containing
heterocycle such as, for example, pyrrolidine, and water.
Intermediates of formula (LXV) can be prepared by reacting an
intermediate of formula (LXII) wherein R.sup.2 contains
Het-C.sub.1-4alkyl as substituent, hereby named (LXII-a), in the
presence of tetrabromomethane and a catalyst such as, for example,
triphenylphosphine.
[0571] This reaction can be performed in a suitable solvent such
as, for example, DCM.
##STR00039##
Pharmacological Part
[0572] As already indicated above, the present invention relates to
the use of a drug combination comprising a DGAT inhibitor and a
PPAR agonist or a prodrug thereof, as a medicament.
[0573] In particular, the present invention relates to the use of a
drug combination comprising a DGAT inhibitor and a PPAR-.alpha.
agonist or a prodrug thereof, as a medicament.
[0574] In particular, the present invention relates to the use of a
drug combination comprising a DGAT1 inhibitor and a PPAR-.alpha.
agonist or a prodrug thereof, as a medicament.
[0575] In particular, the combinations according to the present
invention are suitable for reducing food intake, for reducing
weight, for suppressing appetite, for inducing satiety; or for the
treatment or prevention, in particular treatment, of metabolic
disorders, such as obesity and/or obesity related disorders
(including, but not limited to, peripheral vascular disease,
cardiac failure, myocardial ischaemia, cerebral ischaemia, cardiac
myopathies), diabetes, in particular type II diabetes mellitus,
and/or complications arising therefrom (such as retinopathy,
neuropathy, nephropathy), syndrome X, insulin resistance, impaired
glucose tolerance, conditions of impaired fasting glucose,
hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia,
pancreatitis, hypercholesterolemia, hyperlipidemia, dyslipidemia,
mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver
disease, fatty liver, increased mesenteric fat, non-alcoholic
steatohepatitis, liver fibrosis, metabolic acidosis, ketosis,
dysmetabolic syndrome; dermatological conditions such as acne,
psoriasis; cardiovascular diseases, such as atherosclerosis,
arteriosclerosis, acute heart failure, congestive heart failure,
coronary artery disease, cardiomyopathy, myocardial infarction,
angina pectoris, hypertension, hypotension, stroke, ischemia,
ischemic reperfusion injury, aneurysm, restenosis or vascular
stenosis; alzheimer's disease; neoplastic diseases, such as solid
tumors, skin cancer, melanoma, lymphoma or endothelial cancers,
e.g., breast cancer, lung cancer, colorectal cancer, stomach
cancer, other cancers of the gastrointestinal tract (e.g.,
esophageal cancer or pancreatic cancer), prostate cancer, kidney
cancer, liver cancer, bladder cancer, cervical cancer, uterine
cancer, testicular cancer or ovarian cancer.
[0576] In an embodiment, the combinations according to the present
invention are suitable for reducing food intake, for reducing
weight, for suppressing appetite, for inducing satiety; or for the
treatment or prevention, in particular treatment, of metabolic
disorders, such as obesity and/or obesity related disorders
(including, but not limited to, peripheral vascular disease,
cardiac failure, myocardial ischaemia, cerebral ischaemia, cardiac
myopathies), diabetes, in particular type II diabetes mellitus,
and/or complications arising therefrom (such as retinopathy,
neuropathy, nephropathy), syndrome X, insulin resistance, impaired
glucose tolerance, conditions of impaired fasting glucose,
hypoglycemia, hyperglycemia, hyperuricemia, hyperinsulinemia,
pancreatitis, hypercholesterolemia, hyperlipidemia, dyslipidemia,
mixed dyslipidemia, hypertriglyceridemia, nonalcoholic fatty liver
disease, fatty liver, increased mesenteric fat, non-alcoholic
steatohepatitis, liver fibrosis, metabolic acidosis, ketosis,
dysmetabolic syndrome; dermatological conditions such as acne,
psoriasis; cardiovascular diseases, such as atherosclerosis,
arteriosclerosis, acute heart failure, congestive heart failure,
coronary artery disease, cardiomyopathy, myocardial infarction,
angina pectoris, hypertension, hypotension, stroke, ischemia,
ischemic reperfusion injury, aneurysm, restenosis or vascular
stenosis.
[0577] In an embodiment, the combinations according to the present
invention are suitable for for reducing food intake, for reducing
weight, for suppressing appetite, for inducing satiety; or for the
treatment or prevention, in particular treatment, of obesity and/or
obesity related disorders, hypercholesterolemia, hyperlipidemia,
dyslipidemia, mixed dyslipidemia, hypertriglyceridemia, fatty
liver, nonalcoholic fatty liver disease, liver fibrosis,
non-alcoholic steatohepatitis or diabetes.
[0578] In an embodiment, the combinations according to the present
invention are suitable for reducing food intake, for reducing
weight, for suppressing appetite, for inducing satiety; for the
treatment or prevention of obesity and/or obesity related
disorders, obesity or cardiovascular diseases.
[0579] In an embodiment, said obesity related disorder is selected
from peripheral vascular disease, cardiac failure, myocardial
ischaemia, cerebral ischaemia or cardiac myopathies.
[0580] In an embodiment, the combinations according to the present
invention are suitable for reducing food intake and/or for reducing
weight.
[0581] In an embodiment, the combinations according to the present
invention are suitable for reducing food intake.
[0582] In an embodiment, the combinations according to the present
invention are suitable for the treatment of said diseases or
conditions.
[0583] In an embodiment, the combinations according to the present
invention are suitable for use in the treatment or prevention, in
particular treatment, of said diseases or conditions.
[0584] In an embodiment, the combinations according to the present
invention are suitable for the manufacture of a medicament; in
particular a medicament for the treatment or prevention, in
particular the treatment, of the diseases or conditions mentioned
hereinbefore.
[0585] The present invention also relates to a product containing
a) a DGAT inhibitor, in particular a DGAT1 inhibitor, more in
particular a compound of Class A, Class B, Class C or Class D, and
(b) an agonist of peroxisome proliferators-activator receptor or a
prodrug thereof such as for example fenofibrate, as a combined
preparation for simultaneous, separate or sequential use in the
treatment of a disease which can benefit from an elevated level of
GLP-1 or DGAT inhibition, such as for example diabetes, in
particular type II diabetes mellitus, obesity, for suppressing
appetite, inducing satiety or for reducing food intake.
[0586] In view of the utility of the combinations of the present
invention, there is provided a method of treating warm-blooded
animals, including humans, suffering from or a method of preventing
warm-blooded animals, including humans, to suffer from any one of
the diseases or conditions mentioned hereinbefore.
[0587] Said methods comprise the administration, i.e. the systemic
or topical administration, preferably oral administration, of an
effective amount of an above mentioned combination to warm-blooded
animals, including humans.
[0588] Those of skill in the treatment of such diseases could
determine the effective therapeutic daily amount from the test
results presented hereinafter. An effective therapeutic daily
amount of a combination of PPAR agonist (or prodrug thereof)/DGAT
inhibitor would be from about 0.01 mg/kg to 250 mg/kg body weight,
preferably from 0.01 mg/kg to 50 mg/kg body weight, more preferably
from about 0.01 mg/kg to about 10 mg/kg, even more preferably from
about 0.05 mg/kg to about 1 mg/kg body weight. The amount of a
compound according to the present invention, also referred to here
as the active ingredient, which is required to achieve a
therapeutically effect will of course, vary on case-by-case basis,
for example with the particular compound, the route of
administration, the age and condition of the recipient, and the
particular disorder or disease being treated.
[0589] A method of treatment may also include administering the
active ingredient on a regimen of between one and four intakes per
day. In these methods of treatment the compounds according to the
invention are preferably formulated prior to administration. As
described herein below, suitable pharmaceutical formulations are
prepared by known procedures using well known and readily available
ingredients.
[0590] In an embodiment, the present invention also relates to
pharmaceutical compositions comprising a pharmaceutically
acceptable carrier, and as active ingredient a therapeutically
effective amount of the combinations mentioned hereinbefore or
hereinafter.
[0591] The combinations of the present invention may be formulated
into various pharmaceutical forms for administration purposes. As
appropriate compositions there may be cited all compositions
usually employed for systemically administering drugs. To prepare
the pharmaceutical compositions of this invention, an effective
amount of the particular combination, as the active ingredient, is
combined in intimate admixture with a pharmaceutically acceptable
carrier, which carrier may take a wide variety of forms depending
on the form of preparation desired for administration. These
pharmaceutical compositions are desirable in unitary dosage form
suitable, particularly, for administration orally, rectally,
percutaneously, or by parenteral injection. For example, in
preparing the compositions in oral dosage form, any of the usual
pharmaceutical media may be employed such as, for example, water,
glycols, oils, alcohols and the like in the case of oral liquid
preparations such as suspensions, syrups, elixirs, emulsions and
solutions; or solid carriers such as starches, sugars, kaolin,
diluents, lubricants, binders, disintegrating agents and the like
in the case of powders, pills, capsules, and tablets. Because of
their ease in administration, tablets and capsules represent the
most advantageous oral dosage unit forms, in which case solid
pharmaceutical carriers are obviously employed. For parenteral
compositions, the carrier will usually comprise sterile water, at
least in large part, though other ingredients, for example, to aid
solubility, may be included. Injectable solutions, for example, may
be prepared in which the carrier comprises saline solution, glucose
solution or a mixture of saline and glucose solution. Injectable
suspensions may also be prepared in which case appropriate liquid
carriers, suspending agents and the like may be employed. Also
included are solid form preparations, which are intended to be
converted, shortly before use, to liquid form preparations. In the
compositions suitable for percutaneous administration, the carrier
optionally comprises a penetration enhancing agent and/or a
suitable wetting agent, optionally combined with suitable additives
of any nature in minor proportions, which additives do not
introduce a significant deleterious effect on the skin. Said
additives may facilitate the administration to the skin and/or may
be helpful for preparing the desired compositions. These
compositions may be administered in various ways, e.g., as a
transdermal patch, as a spot-on, as an ointment.
[0592] The combinations of the present invention may also be
administered via inhalation or insufflation by means of methods and
formulations employed in the art for administration via this way.
Thus, in general the compounds of the present invention may be
administered to the lungs in the form of a solution, a suspension
or a dry powder. Any system developed for the delivery of
solutions, suspensions or dry powders via oral or nasal inhalation
or insufflation are suitable for the administration of the present
compounds.
[0593] The combinations of the present invention may also be
topically administered in the form of drops, in particular eye
drops. Said eye drops may be in the form of a solution or a
suspension. Any system developed for the delivery of solutions or
suspensions as eye drops are suitable for the administration of the
present compounds.
[0594] It is especially advantageous to formulate the
aforementioned pharmaceutical compositions in unit dosage form for
ease of administration and uniformity of dosage. Unit dosage form
as used herein refers to physically discrete units suitable as
unitary dosages, each unit containing a predetermined quantity of
active ingredient calculated to produce the desired therapeutic
effect in association with the required pharmaceutical carrier.
Examples of such unit dosage forms are tablets (including scored or
coated tablets), capsules, pills, powder packets, wafers,
suppositories, injectable solutions or suspensions and the like,
and segregated multiples thereof.
[0595] The exact dosage and frequency of administration depends on
the particular combination of the present invention used, the
particular condition being treated, the severity of the condition
being treated, the age, weight, sex, extent of disorder and general
physical condition of the particular patient as well as other
medication the individual may be taking, as is well known to those
skilled in the art. Furthermore, it is evident that said effective
daily amount may be lowered or increased depending on the response
of the treated subject and/or depending on the evaluation of the
physician prescribing the combinations of the instant
invention.
[0596] Depending on the mode of administration, the pharmaceutical
composition will preferably comprise from 0.05 to 99% by weight,
more preferably from 0.1 to 70% by weight, even more preferably
from 0.1 to 50% by weight of the combination of PPAR agonist/DGAT
inhibitor, and, from 1 to 99.95% by weight, more preferably from 30
to 99.9% by weight, even more preferably from 50 to 99.9% by weight
of a pharmaceutically acceptable carrier, all percentages being
based on the total weight of the composition.
[0597] In all previous embodiments, the different drugs of a
combination or product may be combined in a single preparation
together with pharmaceutically acceptable carriers or they may be
present in a separate preparation together with pharmaceutically
acceptable carriers.
[0598] As already indicated above, the present invention also
relates to the use of the novel DGAT inhibitors of group Q, in
particular DGAT1 inhibitors of group Q, to elevate levels of one or
more satiety hormones, in particular GLP-1 levels. The present
invention also relates to the use of a DGAT inhibitor of group Q,
in particular a novel DGAT1 inhibitor of group Q, for the
manufacture of a medicament for the prevention or the treatment, in
particular for the treatment, of a disease which can benefit from
an elevated level of one or more satiety hormones, in particular a
disease which can benefit from an elevated GLP-1 level. In
particular, GLP-1 levels are elevated in plasma or in portal blood,
more in particular in plasma. By elevated GLP-1 levels, e.g.
elevated GLP-1 plasma level or an elevated GLP-1 level in portal
blood, it is meant that the GLP-1 level of a subject having taken a
DGAT1 inhibitor is elevated or increased compared to the subject
under the same conditions but not having taken the DGAT1 inhibitor.
In particular GLP-1 levels are elevated in fasting conditions or
postprandial, more in particular postprandial.
[0599] Therapeutic uses for a compound which elevates GLP-1 level
include, but are not limited to, improving learning, enhancing
neuro-protection, and/or alleviating a symptom of a disease or
disorder of the central nervous system, e.g., through modulation of
neurogenesis, and e.g., Parkinson's Disease, Alzheimer's Disease,
Huntington's Disease, ALS, stroke, hemorrhage, cerebrovascular
accident, ADD, and neuropsychiatric syndromes; converting liver
stem/progenitor cells into functional pancreatic cells; preventing
beta-cell deterioration and stimulation of beta-cell proliferation;
treating pancreatitis; treating obesity; suppressing appetite and
inducing satiety; treating irritable bowel syndrome or inflammatory
bowel disease such as Crohn's disease and ulcerative colitis;
reducing the morbidity and/or mortality associated with myocardial
infarction and stroke; treating acute coronary syndrome
characterized by an absence of Q-wave myocardial infarction;
attenuating post-surgical catabolic changes; treating hibernating
myocardium or diabetic cardiomyopathy; suppressing plasma blood
levels of norepinepherine; increasing urinary sodium excretion,
decreasing urinary potassium concentration; treating conditions or
disorders associated with toxic hypervolemia, e.g., renal failure,
congestive heart failure, nephrotic syndrome, cirrhosis, pulmonary
edema, and hypertension; inducing an inotropic response and
increasing cardiac contractility; treating polycystic ovary
syndrome; treating respiratory distress; improving nutrition via a
non-alimentary route, i.e., via intravenous, subcutaneous,
intramuscular, peritoneal, or other injection or infusion; treating
nephropathy; treating left ventricular systolic dysfunction, e.g.,
with abnormal left ventricular ejection fraction; inhibiting
antro-duodenal motility, e.g., for the treatment or prevention of
gastrointestinal disorders such as diarrhea, postoperative dumping
syndrome and irritable bowel syndrome, and as premedication in
endoscopic procedures; treating critical illness polyneuropathy
(CIPN) and systemic inflammatory response syndrome (SIRS);
modulating triglyceride levels and treating dyslipidemia; treating
organ tissue injury (e.g. brain tissue injury) caused by
reperfusion of blood flow following ischemia; improving the
function of ischemic and reperfused brain tissue; treating coronary
heart disease risk factor (CHDRF) syndrome.
[0600] Further diseases which can benefit from an elevated GLP-1
level, include, but are not limited to, ischemic myocardial
stunning; ishemic/reperfusion injury; acute myocardial infarction;
left ventricular dysfunction; vascular disease; neuropathy,
including periphere sensoric neuropathy associated with type II
diabetes; bone-related disorders, including osteoporosis, obesity,
diabetes. Because of the effect on GLP-1, the DGAT inhibitors of
group Q can also be used to provide cardioprotection.
[0601] References supporting the above indications include
Experimental Neurology, Vol. 203(2), pp 293-301 (2007); U.S. Pat.
No. 7,186,683; J. Pharm. Exp. Ther. vol. 312, No. 1, pp 303-308
(2005); Diabetes, vol. 54, pp 146-151 (2005); US2007/0021339, which
are incorporated herein by reference.
[0602] In view of the DGAT inhibitory activity, in particular the
DGAT1 inhibitory activity, the present novel compounds of group Q
can be used as a medicament. In particular, the present invention
relates to a compound of group Q for use as a medicament, in
particular for use as a medicament for the prevention or the
treatment of a disease which can benefit from an elevated GLP-1
level. In particular, the present invention also relates to the use
of a compound of group Q for the manufacture of a medicament for
the prevention or the treatment of a disease which can benefit from
an elevated GLP-1 level, such as the diseases and disorders
mentioned above.
[0603] In view of the DGAT inhibitory activity of the compounds of
group Q, there is provided a method of treating a warm-blooded
mammal, including a human, suffering from or a method of preventing
a warm-blooded mammal, including a human, to suffer from a disease
which can benefit from an elevated level of GLP-1, in particular a
method of treating a warm-blooded mammal, including a human,
suffering from a disease which can benefit from an elevated level
of GLP-1. Said methods comprise the administration of an effective
amount of a compound of group Q to a warm-blooded mammal, including
a human.
[0604] In view of the DGAT inhibitory activity, in particular the
DGAT1 inhibitory activity, the present invention also relates to a
compound of group Q for use as a medicament, in particular for use
as a medicament for the prevention or the treatment of a diseases
which can benefit from inhibition of DGAT, in particular DGAT1.
[0605] The invention also relates to a compound of group Q for the
prevention or the treatment of a disease or disorder which can
benefit from inhibition of DGAT, in particular DGAT1. Diseases or
disorders which can benefit from inhibition of DGAT, in particular
DGAT1 include, but are not limited to metabolic disorders, such as
obesity and/or obesity related disorders (including peripheral
vascular disease, cardiac failure, myocardial ischaemia, cerebral
ischaemia, cardiac myopathies), diabetes, in particular type II
diabetes mellitus, and/or complications arising therefrom (such as
retinopathy, neuropathy, nephropathy), syndrome X, insulin
resistance, impaired glucose tolerance, conditions of impaired
fasting glucose, hypoglycemia, hyperglycemia, hyperuricemia,
hyperinsulinemia, pancreatitis, hypercholesterolemia,
hyperlipidemia, dyslipidemia, mixed dyslipidemia,
hypertriglyceridemia, nonalcoholic fatty liver disease, fatty
liver, increased mesenteric fat, non-alcoholic steatohepatitis,
liver fibrosis, metabolic acidosis, ketosis, dysmetabolic syndrome;
dermatological conditions such as acne, psoriasis; cardiovascular
diseases, such as atherosclerosis, arteriosclerosis, acute heart
failure, congestive heart failure, coronary artery disease,
cardiomyopathy, myocardial infarction, angina pectoris,
hypertension, hypotension, stroke, ischemia, ischemic reperfusion
injury, aneurysm, restenosis or vascular stenosis; neoplastic
diseases, such as solid tumors, skin cancer, melanoma, lymphoma or
endothelial cancers, e.g., breast cancer, lung cancer, colorectal
cancer, stomach cancer, other cancers of the gastrointestinal tract
(e.g., esophageal cancer and pancreatic cancer), prostate cancer,
kidney cancer, liver cancer, bladder cancer, cervical cancer,
uterine cancer, testicular cancer or ovarian cancer; or other
diseases and conditions that are sensitive or responsive to
modulation, in particular inhibition, of DGAT function, in
particular DGAT1 function.
[0606] Particular diseases or disorders which can benefit from
inhibition of DGAT, in particular DGAT1, are selected from obesity,
hypercholesterolemia, hyperlipidemia, dyslipidemia, mixed
dyslipidemia, hypertriglyceridemia, fatty liver, nonalcoholic fatty
liver disease, liver fibrosis, non-alcoholic steatohepatitis or
diabetes, in particular type II diabetes.
[0607] The invention also relates to a compound of group Q for use
in the prevention or the treatment, in particular for use in the
treatment, of a disease or disorder which can benefit from
inhibition of DGAT, in particular DGAT1.
[0608] In an embodiment the invention also relates to the use of a
compound of group Q for the manufacture of a medicament for
treating or preventing the above mentioned diseases or
conditions.
[0609] In view of the DGAT inhibitory activity of the compounds of
group Q, there is provided a method of treating a warm-blooded
mammal, including a human, suffering from or a method of preventing
a warm-blooded mammal, including a human, to suffer from a disease
which can benefit from inhibition of DGAT, in particular a method
of treating a warm-blooded mammal, including a human, suffering
from a disease which can benefit from inhibition of DGAT. Said
methods comprise the administration of an effective amount of a
compound of group Q to a warm-blooded mammal, including a
human.
[0610] In an embodiment, the present invention also relates to
pharmaceutical compositions comprising a pharmaceutically
acceptable carrier, and as active ingredient a therapeutically
effective amount of a compound of group Q.
[0611] The present invention also provides compositions for
preventing or treating a disease which can benefit from an elevated
GLP-1 level or which can benefit from inhibition of DGAT, in
particular DGAT1, in particular for treating a disease which can
benefit from elevated GLP-1 levels or which can benefit from
inhibition of DGAT, in particular DGAT1. Said compositions comprise
a therapeutically effective amount of a compound of group Q and a
pharmaceutically acceptable carrier.
[0612] The novel compounds of group Q of the present invention may
be formulated into various pharmaceutical forms for administration
purposes. As appropriate compositions there may be cited all
compositions usually employed for systemically administering drugs.
To prepare the pharmaceutical compositions of this invention, an
effective amount of the particular compound, optionally in salt
form, as the active ingredient is combined in intimate admixture
with a pharmaceutically acceptable carrier, which carrier may take
a wide variety of forms depending on the form of preparation
desired for administration. These pharmaceutical compositions are
desirable in unitary dosage form suitable, particularly, for
administration orally, rectally, percutaneously, or by parenteral
injection. For example, in preparing the compositions in oral
dosage form, any of the usual pharmaceutical media may be employed
such as, for example, water, glycols, oils, alcohols and the like
in the case of oral liquid preparations such as suspensions,
syrups, elixirs, emulsions and solutions; or solid carriers such as
starches, sugars, kaolin, diluents, lubricants, binders,
disintegrating agents and the like in the case of powders, pills,
capsules, and tablets. Because of their ease in administration,
tablets and capsules represent the most advantageous oral dosage
unit forms, in which case solid pharmaceutical carriers are
obviously employed. For parenteral compositions, the carrier will
usually comprise sterile water, at least in large part, though
other ingredients, for example, to aid solubility, may be included.
Injectable solutions, for example, may be prepared in which the
carrier comprises saline solution, glucose solution or a mixture of
saline and glucose solution. Injectable suspensions may also be
prepared in which case appropriate liquid carriers, suspending
agents and the like may be employed. Also included are solid form
preparations, which are intended to be converted, shortly before
use, to liquid form preparations. In the compositions suitable for
percutaneous administration, the carrier optionally comprises a
penetration enhancing agent and/or a suitable wetting agent,
optionally combined with suitable additives of any nature in minor
proportions, which additives do not introduce a significant
deleterious effect on the skin. Said additives may facilitate the
administration to the skin and/or may be helpful for preparing the
desired compositions. These compositions may be administered in
various ways, e.g., as a transdermal patch, as a spot-on, as an
ointment.
[0613] The compounds of group Q of the present invention may also
be administered via inhalation or insufflation by means of methods
and formulations employed in the art for administration via this
way. Thus, in general the compounds of the present invention may be
administered to the lungs in the form of a solution, a suspension
or a dry powder. Any system developed for the delivery of
solutions, suspensions or dry powders via oral or nasal inhalation
or insufflation are suitable for the administration of the present
compounds.
[0614] The compounds of the present invention may also be topically
administered in the form of drops, in particular eye drops. Said
eye drops may be in the form of a solution or a suspension. Any
system developed for the delivery of solutions or suspensions as
eye drops are suitable for the administration of the present
compounds.
[0615] It is especially advantageous to formulate the
aforementioned pharmaceutical compositions in unit dosage form for
ease of administration and uniformity of dosage. Unit dosage form
as used herein refers to physically discrete units suitable as
unitary dosages, each unit containing a predetermined quantity of
active ingredient calculated to produce the desired therapeutic
effect in association with the required pharmaceutical carrier.
Examples of such unit dosage forms are tablets (including scored or
coated tablets), capsules, pills, powder packets, wafers,
suppositories, injectable solutions or suspensions and the like,
and segregated multiples thereof.
[0616] The exact dosage and frequency of administration depends on
the particular compound of group Q used, the particular condition
being treated, the severity of the condition being treated, the
age, weight, sex, extent of disorder and general physical condition
of the particular patient as well as other medication the
individual may be taking, as is well known to those skilled in the
art. Furthermore, it is evident that said effective daily amount
may be lowered or increased depending on the response of the
treated subject and/or depending on the evaluation of the physician
prescribing the compounds of the instant invention.
[0617] Depending on the mode of administration, the pharmaceutical
composition will preferably comprise from 0.05 to 99% by weight,
more preferably from 0.1 to 70% by weight, even more preferably
from 0.1 to 50% by weight of the compound of group Q, and, from 1
to 99.95% by weight, more preferably from 30 to 99.9% by weight,
even more preferably from 50 to 99.9% by weight of a
pharmaceutically acceptable carrier, all percentages being based on
the total weight of the composition.
[0618] The following examples are intended to illustrate the
present invention.
Experimental Part
[0619] Hereinafter, the term `THF` means tetrahydrofuran,
`Et.sub.2O` means diethyl ether, `CH.sub.3OH` means methanol,
`EtOAc` means ethyl acetate, `NaHCO.sub.3` means carbonic acid
monosodium salt, `CH.sub.2Cl.sub.2` or `DCM` means dichloromethane,
`CH.sub.3CN` means acetonitrile, `EtOH` means ethanol, `HBTU` means
1-[bis(di-methylamino)methylene]-1H-benzo-triazoliumhexafluorophosphate(1-
)-3-oxide, `DMF` means N,N-dimethyl-formamide, `DIPEA` means
N-ethyl-N-(1-methylethyl)-2-propanamine, `HOBt` or `HOBT` means
1-hydroxy-1H-benzotriazole, `EDCI` means
N-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine
monohydrochloride, `DMSO` means dimethylsulfoxide, `m.p.` means
melting point, `MeOH` means methanol, `Et.sub.3N` means
triethylamine, `eq.` means equivalent, `r.m.` means reaction
mixture, `r.t.` means room temperature, `h` means hour(s), `min`
means minute(s), and `TFA` means trifluoroacetic acid.
[0620] Experimental Procedures for the Class A Compounds
[0621] The experimental procedures for the preparation of the
compounds of Class A, are described in WO2008/148851, the content
of which is enclosed by reference in the present application.
[0622] Experimental Procedures for the Class B Compounds
[0623] The experimental procedures for the preparation of the
compounds of Class B, are described in WO2008/148840, the content
of which is enclosed by reference in the present application.
[0624] Experimental Procedures for the Class C Compounds
[0625] The experimental procedures for the preparation of the
compounds of Class C, are described in WO2008/148849, the content
of which is enclosed by reference in the present application.
[0626] In addition, some typical examples of Class C compounds are
described below.
[0627] Intermediates (Class C)
Preparation of
4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide and
4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide.HCl.
##STR00040##
[0629] Pd/C 10% (1 g) was suspended in MeOH (150 ml) under N.sub.2
flow.
4-[4-(phenylmethyl)-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide
(5.62 g, 0.0126 mol; prepared according to the teachings described
in WO2008/148849) was added and the r.m. was stirred at 50.degree.
C. under H.sub.2 atmosphere until 1 eq. of H.sub.2 was absorbed.
The catalyst was filtered off over diatomaceous earth
(Dicalite.RTM.). The solvent was evaporated and co-evaporated with
toluene. The residue was stirred in Et.sub.2O and filtered off. The
product was dried (50.degree. C., 18 h, in vacuo). Yield: 4.23 g of
4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide (96%).
[0630] 4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide
.HCl was prepared in analogy to the free base form. For the
preparation of the hydrochloric acid salt,
4-[4-[[[3-(1-pyrrolidinyl)phenyl]amino]carbonyl]phenyl]-1-piperazinecarbo-
xylic acid, 1,1-dimethylethyl ester (the tert-butoxy variant of
4-[4-(phenylmethyl)-1-piperazinyl]-N-[3-(1-pyrrolidinyl)phenyl]-benzamide-
) was deprotected with a HCl solution in dioxane.
Preparation of 1-1(4-bromo-3-chlorophenyl)methyl]-pyrrolidine
##STR00041##
[0632] A solution of 1-bromo-2-chloro-4-(chloromethyl)-benzene
(25.2 g, 105.03 mmol) and Et.sub.3N (16.1 ml, 115.53 mmol) in THF
(150 ml) was stirred at r.t. Pyrrolidine (8.2 g, 115.53 mmol) was
added dropwise. The r.m. was stirred overnight at r.t. and was then
concentrated in vacuo. The residue was taken up into water and
extracted with CH.sub.2Cl.sub.2 (3.times.100 ml). The combined
organic layer was washed with saturated NaHCO.sub.3 and brine, and
was then dried (MgSO.sub.4), filtered and the solvent was
evaporated in vacuo. Yield: 25.8 g of
1-[(4-bromo-3-chlorophenyl)methyl]-pyrrolidine (90% yield, crude
product; used in next reaction step, without further
purification).
Preparation of 2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde
##STR00042##
[0634] Reaction under N.sub.2 atmosphere. A solution of
1-[(4-bromo-3-chlorophenyl)methyl]-pyrrolidine (25.8 g, 93.96 mmol)
in THF (200 ml) was stirred at -78.degree. C. for 15 min. A 2.5 M
n-BuLi solution in hexane was added to the mixture over a period of
15 min. After 30 min, a solution of DMF (7.3 ml, 93.96 mmol) in THF
(50 ml) was added dropwise to the mixture. The reaction temperature
was allowed to rise to r.t. slowly, and the mixture was stirred
overnight. The reaction was quenched by the addition of water at
0.degree. C. The mixture was extracted with EtOAc (3.times.150 ml).
The combined organic layer was washed with brine, dried
(MgSO.sub.4), filtered and the solvent was evaporated in vacuo.
[0635] Yield: 20.3 g of
2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde (97%, crude Yield:).
The crude product was used for next step directly without further
purification.
Preparation of
2-chloro-.alpha.-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetonitrile
##STR00043##
[0637] Trimethylsilanecarbonitrile (10 ml, 76.6 mmol) and
ZnBr.sub.2 (0.5 g) were added to a solution of
2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde (9.8 g, 43.8 mmol)
in DCM (100 ml). The r.m. was stirred for 5 h at r.t. Then, the
mixture was heated to 50.degree. C. and stirred overnight.
2-chloro-.alpha.-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetonitrile
was used as a crude in the next reaction step.
Preparation of
2-chloro-.alpha.-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetic
acid (TFA-salt)
##STR00044##
[0639] A mixture of
2-chloro-.alpha.-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetonitrile
(10.9 g, 43.8 mmol) in concentrated HCl (50 ml) was stirred and
refluxed for 24 h. The mixture was cooled and the solvent was
evaporated. The crude product was purified by preparative HPLC
(Synergi: 250.times.20 mm; Mobile Phase: 0-30% CH.sub.3CN in
H.sub.2O (0.1% TFA); Flow
[0640] Rate: 80 ml/min; Finished Time: 30 min). The desired
fraction was collected and the organic phase was evaporated to give
a yellow oil. Yield: 6.2 g of
2-chloro-.alpha.-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetic
acid (TFA-salt), used as such in the next reaction step (52.5%;
TFA-salt).
[0641] Final Compounds (Class C)
[0642] Preparation of Compound 152
##STR00045##
[0643] A mixture of
2-chloro-.alpha.-hydroxy-4-(1-pyrrolidinylmethyl)-benzeneacetic
acid (1.1 g, 2.87 mmol),
4-(1-piperazinyl)-N-[3-(1-pyrrolidinyl)phenyl]-benzamide .HCl (1.1
g, 2.87 mmol), EDCI (0.55 g, 2.87 mmol), HOBT (0.39 g, 2.87 mmol)
and Et.sub.3N (1.6 ml, 11.48 mmol) in DCM (50 ml) was stirred
overnight at r.t. Water was added to the mixture, and the organic
layer was separated. The aqueous layer was extracted with DCM
(3.times.30 ml).
[0644] The combined organic layer was washed with brine, dried
(MgSO.sub.4), filtered and the solvent was evaporated in vacuo. The
residue was purified by flash column chromatography over silica gel
(eluent: DCM/MeOH 30/1). The product fractions were collected and
the solvent was evaporated. Yield: 0.8 g of crude compound 152
(purity 82% on LCMS). The crude compound 152 was purified by
neutral high performance liquid chromatography (Column: Daisopak
250.times.20 mm; Mobile Phase: 80-100% CH.sub.3CN in water; Flow
Rate: 14 ml/min; Finished Time: 15 min). The desired fraction was
collected and evaporated in vacuo. Yield: 0.4 g of compound 152
(23%).
[0645] Compound 151 was prepared by analogy to compound 152, but
2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (for which the
synthesis protocol is described in detail in the experimental
procedures for the Class D compounds) was used as starting
material.
[0646] Compounds 147, 148, 149 and 150 were also prepared by
analogy to compound 152, starting from the appropriate starting
materials.
[0647] Experimental Procedures for the Class D Compounds
[0648] The experimental procedures for the preparation of the
compounds of Class D, are described in WO2008/148868, the content
of which is enclosed by reference in the present application.
[0649] In addition, some typical examples of Class D compounds are
described below.
[0650] Intermediates (Class D)
Preparation of
1-[[3-chloro-4-(2,2-dibromoethenyl)phenyl]methyl]-pyrrolidine
##STR00046##
[0652] A mixture of 2-chloro-4-(1-pyrrolidinylmethyl)-benzaldehyde
(prepared according to the teachings in WO2008/148868) (10.0 g,
44.70 mmol) and tetrabromomethane (22.2 g, 67.05 mmol) in DCM (300
ml) was stirred at 0.degree. C. A solution of triphenylphosphine
(35.2 g, 134.10 mmol) in DCM (500 ml) was added. The mixture was
stirred for 30 min at 0.degree. C. The mixture was concentrated in
vacuo. The residue was taken up into CHC13, and the precipitate was
filtered off. The filtrate was concentrated in vacuo. The residue
(crude
1-[[3-chloro-4-(2,2-dibromoethenyl)phenyl[methyl]-pyrrolidine) was
used as such in the next reaction step.
Preparation of
1-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-pyrrolidine
##STR00047##
[0654] A mixture of pyrrolidine (150 ml) and water (15 ml) was
stirred at r.t.
1-[[3-chloro-4-(2,2-dibromoethenyl)phenyl[methyl[-pyrrolidine
(crude, max. 44.70 mmol) was added to the mixture and subsequently,
the mixture was stirred overnight at r.t. The solvent was
evaporated, yielding
1-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-pyrrolidine as
a crude that was used as such in the next reaction step.
Preparation of 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic
acid
##STR00048##
[0656] A solution of
1-[[2-chloro-4-(1-pyrrolidinylmethyl)phenyl]acetyl]-pyrrolidine
(crude, max. 44.70 mmol) in dioxane (100 ml) was stirred at r.t. A
6 M HCl solution was added.
[0657] The mixture was stirred and refluxed for 3 days. The mixture
was concentrated in vacuo. The residue was taken up in water and
the mixture was brought to pH 10 with a 4 N NaOH solution. The
solution was washed with diethyl ether (3.times.40 ml). The aqueous
layer was acidified to pH 3 with a 6 N HCl solution. The mixture
was concentrated in vacuo. The residue was purified by neutral high
performance liquid chromatography (Column: Lana 300.times.50 mm, 10
.mu.m; Mobile Phase: 0-20% CH.sub.3CN in water; Flow Rate: 80
ml/min; Finished Time: 25 min). The desired fraction was collected
and evaporated in vacuo. Yield: 2.8 g of
2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid (25% yield
over last 3 steps).
[0658] 2,6-Dichloro-4-(1-pyrrolidinylmethyl)-benzeneacetyl chloride
.HCl was prepared by analogy to
2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid by using the
appropriate reaction conditions well known to those skilled in the
art.
[0659] 2,6-Dichloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid
.HCl was prepared by analogy to
2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid by using the
appropriate reaction conditions well known to those skilled in the
art.
Preparation of
4-[4-[[[(3,5-dimethoxyphenyl)methyl]amino]carbonyl]phenyl]-1-piperazineca-
rboxylic acid, 1,1-dimethylethyl ester
##STR00049##
[0661] A mixture of 3,5-dimethoxybenzenemethanamine (3.34 g, 20
mmol), 4-(4-carboxyphenyl)-1-piperazinecarboxylic acid,
1-(1,1-dimethylethyl) ester (6.13 g, 20 mmol), EDCI (4.2 g, 22
mmol), HOBT (2.97 g, 22 mmol), N(CH.sub.2CH.sub.3).sub.3 (12 ml)
and DCM (80 ml) was stirred overnight at r.t. The solvent was
evaporated. The residue was purified by column chromatography
(eluent: petroleum ether/EtOAc 2/1). The desired fractions were
collected and the solvent was evaporated. Yield: 5.3 g of
4-[4-[[[(3,5-dimethoxyphenyl)methyl]amino]carbonyl]phenyl]-1-piperazineca-
rboxylic acid, 1,1-dimethylethyl ester (58.24% yield).
Preparation of
N-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide
(HCl-salt)
##STR00050##
[0663]
4-[4-[[[(3,5-dimethoxyphenyl)methyl]amino]carbonyl]phenyl]-1-pipera-
zinecarboxylic acid, 1,1-dimethylethyl ester (5.2 g, 11.4 mmol) was
dissolved in HCl/dioxane (100 ml) and the reaction solution was
stirred overnight. The solvent was evaporated. The solid residue
was washed with petroleum ether and dried. Yield: 4.2 g of
N-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide
(HCl-salt) as a crude (97.7%). 1 g of the crude product was
purified by preparative HPLC (YMC: 250.times.80 mm; Mobile Phase:
10-35% CH.sub.3CN % in H.sub.2O (0.1% TFA); Finished Time: 25 min).
The desired fractions were collected and solvent was evaporated.
The residue was neutralized with an aqueous NaHCO.sub.3 solution
and extracted with EtOAc. The separated organic layer was washed
with brine, dried (Na.sub.2SO.sub.4), filtered and the solvent was
evaporated to yield a white solid. Yield: 0.4 g of
N-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide
(HCl-salt).
[0664] Final Compounds (Class D)
[0665] Preparation of Compound 353
##STR00051##
[0666] A mixture of 2-chloro-4-(1-pyrrolidinylmethyl)-benzeneacetic
acid (0.94 g, 3.70 mmol) and
N-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide
(HCl-salt) (1.5 g, 3.83 mmol) in DCM (20 ml) was stirred at r.t.
Et.sub.3N (1.3 ml, 9.58 mmol) was added to the mixture. Then EDCI
(0.73 g, 3.83 mmol) and HOBT (0.52 g, 3.83 mmol) were added to the
mixture. The mixture was stirred overnight at r.t. The mixture was
washed with water, dried (MgSO.sub.4), filtered and the solvent was
evaporated in vacuo. The residue was purified by flash column
chromatography over silica gel (eluent: CH.sub.2Cl.sub.2/CH.sub.3OH
20/1). The product fractions were collected and the solvent was
evaporated. Yield: 0.78 g of compound 353 (36%).
[0667] Preparation of compound 358
##STR00052##
[0668] A mixture of
2,6-dichloro-4-(1-pyrrolidinylmethyl)-benzeneacetyl chloride .HCl
and 2,6-dichloro-4-(1-pyrrolidinylmethyl)-benzeneacetic acid .HCl
(1.29 g of the mixture) was added portionwise to a stirring mixture
of N-[(3,5-dimethoxyphenyl)methyl]-4-(1-piperazinyl)-benzamide .HCl
(1.406 g, 0.00358 mol) and NaHCO.sub.3 (0.993 g, 0.0118 mol) in
CH.sub.3CN (60 ml; dried on molecular sieves). The r.m. was stirred
under N.sub.2 atmosphere for 4 h. Subsequently, Et.sub.3N (1 ml)
and HBTU (1.358 g, 0.00358 mol) were added and the r.m. was stirred
at r.t. for 65 h. Then, the mixture was poured into stirring
H.sub.2O (300 ml) and this aqueous mixture was stirred for 20 min.
The product was filtered off and washed with H.sub.2O (3.times.).
The product was stirred in boiling 2-propanol (70 ml), filtered off
hot, and the filtrate was left standing for 3 h (crystallization
started after 5 min). The product was filtered off, washed with
2-propanol (3.times.), and dried (50.degree. C., in vacuo) to yield
1.12 g of compound 358 (50%). An additional amount of compound 358
(0.481 g) was obtained by evaporation of the filtrate and
purification of the residue by HPLC. The desired fractions were
evaporated and crystallized from boiling 2-propanol again.
[0669] Compounds 354, 355, 359, 360, 361, 362, 363 and 364 from
Class D were prepared by analogy to compound 353, starting from the
appropriate starting materials.
[0670] Compounds 356 and 357 from Class D were prepared by analogy
to compounds 152 from Class C, starting from the appropriate
starting materials.
[0671] The tables below list compounds of class A, class B, class C
or class D. The novel compounds of group Q (compounds 147 till 152
from Class C and compounds 353 till 364 from Class D) are enclosed
in class C and class D.
[0672] Table for the Class A compounds
TABLE-US-00002 TABLE A1 ##STR00053## Compound 8 ##STR00054##
Compound 10 ##STR00055## Compound 11 ##STR00056## Compound 12
##STR00057## Compound 13 ##STR00058## Compound 14 ##STR00059##
Compound 15 ##STR00060## Compound 16 ##STR00061## Compound 17
##STR00062## Compound 18 ##STR00063## Compound 19
[0673] Tables for the Class B compounds
TABLE-US-00003 TABLE B1 ##STR00064## Co. No. A X R.sup.1 R.sup.q 1
N ##STR00065## ##STR00066## H-- 2 N ##STR00067## ##STR00068## H-- 3
N ##STR00069## ##STR00070## H-- 4 N ##STR00071## ##STR00072## H-- 5
N ##STR00073## ##STR00074## H-- 6 N ##STR00075## ##STR00076## H-- 7
CH ##STR00077## ##STR00078## H-- 8 N ##STR00079## ##STR00080## H--
9 N ##STR00081## ##STR00082## H-- 10 N ##STR00083## ##STR00084##
H-- 11 N ##STR00085## ##STR00086## H-- 12 N ##STR00087##
##STR00088## H-- 13 N ##STR00089## ##STR00090## H-- 14 N
##STR00091## ##STR00092## H-- 15 N ##STR00093## ##STR00094## H-- 16
N ##STR00095## ##STR00096## H-- 17 N ##STR00097## ##STR00098## H--
18 N ##STR00099## ##STR00100## H-- 19 N ##STR00101## ##STR00102##
H-- 20 N ##STR00103## ##STR00104## H-- 21 N ##STR00105##
##STR00106## H-- 22 N ##STR00107## ##STR00108## H-- 23 N
##STR00109## ##STR00110## H-- 24 N ##STR00111## ##STR00112## H-- 25
N ##STR00113## ##STR00114## H-- 26 N ##STR00115## ##STR00116## H--
27 N ##STR00117## ##STR00118## H-- 28 N ##STR00119## ##STR00120##
H-- 29 N ##STR00121## ##STR00122## H-- 30 N ##STR00123##
##STR00124## H-- 31 N ##STR00125## ##STR00126## H-- 32 N
##STR00127## ##STR00128## H-- 33 N ##STR00129## ##STR00130## H-- 34
N ##STR00131## ##STR00132## H-- 35 N ##STR00133## ##STR00134## H--
36 N ##STR00135## ##STR00136## H-- 37 N ##STR00137## ##STR00138##
H-- 38 N ##STR00139## ##STR00140## H-- 39 N ##STR00141##
##STR00142## H-- 40 N ##STR00143## ##STR00144## H-- 41 N
##STR00145## ##STR00146## H-- 42 N ##STR00147## ##STR00148## H-- 43
N ##STR00149## ##STR00150## H-- 44 CH ##STR00151## ##STR00152## H--
45 N ##STR00153## ##STR00154## H-- 46 CH ##STR00155## ##STR00156##
H-- 47 N ##STR00157## ##STR00158## H-- 48 CH ##STR00159##
##STR00160## H-- 49 N ##STR00161## ##STR00162## H-- 50 CH
##STR00163## ##STR00164## H-- 51 N ##STR00165## ##STR00166## H-- 52
N ##STR00167## ##STR00168## H-- 53 N ##STR00169## ##STR00170##
##STR00171## 54 N ##STR00172## ##STR00173## ##STR00174## 55 N
##STR00175## ##STR00176## ##STR00177## 56 N ##STR00178##
##STR00179## ##STR00180## 57 N ##STR00181## ##STR00182##
HOCH.sub.2-- 58 N ##STR00183## ##STR00184## ##STR00185## 59 N
##STR00186## ##STR00187## HOCH.sub.2-- 60 N ##STR00188##
##STR00189## ##STR00190## 61 N ##STR00191## ##STR00192## HO-- 62 N
##STR00193## ##STR00194## HO-- 63 N ##STR00195## ##STR00196##
##STR00197## 64 N ##STR00198## ##STR00199## ##STR00200## 65 N
##STR00201## ##STR00202## ##STR00203##
TABLE-US-00004 TABLE B2 ##STR00204## Co. No. X R.sup.1 R.sup.2 Salt
66 ##STR00205## ##STR00206## ##STR00207## 67 ##STR00208##
##STR00209## ##STR00210## 68 ##STR00211## ##STR00212## ##STR00213##
69 ##STR00214## ##STR00215## ##STR00216## 70 ##STR00217##
##STR00218## ##STR00219## 71 ##STR00220## ##STR00221## ##STR00222##
72 ##STR00223## ##STR00224## ##STR00225## 73 ##STR00226##
##STR00227## ##STR00228## 74 ##STR00229## ##STR00230## ##STR00231##
75 ##STR00232## ##STR00233## ##STR00234## 76 ##STR00235##
##STR00236## ##STR00237## 77 ##STR00238## ##STR00239## ##STR00240##
78 ##STR00241## ##STR00242## ##STR00243## 79 ##STR00244##
##STR00245## ##STR00246## 80 ##STR00247## ##STR00248## ##STR00249##
81 ##STR00250## ##STR00251## ##STR00252## 82 ##STR00253##
##STR00254## ##STR00255## 83 ##STR00256## ##STR00257## ##STR00258##
84 ##STR00259## ##STR00260## ##STR00261## 85 ##STR00262##
##STR00263## ##STR00264## 86 ##STR00265## ##STR00266## ##STR00267##
87 ##STR00268## ##STR00269## ##STR00270## 88 ##STR00271##
##STR00272## ##STR00273## 89 ##STR00274## ##STR00275## ##STR00276##
90 ##STR00277## ##STR00278## ##STR00279## 91 ##STR00280##
##STR00281## ##STR00282## 92 ##STR00283## ##STR00284## ##STR00285##
93 ##STR00286## ##STR00287## ##STR00288## 94 ##STR00289##
##STR00290## ##STR00291## 95 ##STR00292## ##STR00293## ##STR00294##
96 ##STR00295## ##STR00296## ##STR00297## 97 ##STR00298##
##STR00299## ##STR00300## 98 ##STR00301## ##STR00302## ##STR00303##
99 ##STR00304## ##STR00305## ##STR00306## 100 ##STR00307##
##STR00308## ##STR00309## 101 ##STR00310## ##STR00311##
##STR00312## 102 ##STR00313## ##STR00314## ##STR00315## 103
##STR00316## ##STR00317## ##STR00318## 104 ##STR00319##
##STR00320## ##STR00321## 105 ##STR00322## ##STR00323##
##STR00324## 106 ##STR00325## ##STR00326## ##STR00327## 107
##STR00328## ##STR00329## ##STR00330## 108 ##STR00331##
##STR00332## ##STR00333## 109 ##STR00334## ##STR00335##
##STR00336## 110 ##STR00337## ##STR00338## ##STR00339## 111
##STR00340## ##STR00341## ##STR00342## 112 ##STR00343##
##STR00344## ##STR00345## 113 ##STR00346## ##STR00347##
##STR00348## 114 ##STR00349## ##STR00350## ##STR00351## 115
##STR00352## ##STR00353## ##STR00354## trifluoroacetate salt 116
##STR00355## ##STR00356## ##STR00357## 117 ##STR00358##
##STR00359## ##STR00360##
[0674] Tables for the Class C compounds
TABLE-US-00005 TABLE C1 ##STR00361## Comp. no. R.sup.1a R.sup.1b
R.sup.1c 125 H ##STR00362## H 12 H ##STR00363## H 13 H ##STR00364##
H 4 ##STR00365## H H 14 H ##STR00366## H 15 H H ##STR00367## 16 H
##STR00368## H 17 H ##STR00369## H 18 ##STR00370## H H 19 H H
##STR00371## 20 H ##STR00372## H 21 H H ##STR00373## 22
##STR00374## H H 23 H ##STR00375## H 24 H H ##STR00376## 25 H H
##STR00377## 26 ##STR00378## H H 27 H H ##STR00379## 28 H
##STR00380## H 29 H H ##STR00381## 30 H H ##STR00382## 31 H
##STR00383## H 32 ##STR00384## H H 33 H H ##STR00385## 34
##STR00386## H H 35 ##STR00387## H H 36 H ##STR00388## H 127 H
##STR00389## H 37 H ##STR00390## H 38 H H ##STR00391## 39
##STR00392## H H 40 H ##STR00393## H 41 H ##STR00394## H 42
##STR00395## H H 43 H ##STR00396## H 44 H H ##STR00397## 45
##STR00398## H H 126 H H ##STR00399##
TABLE-US-00006 TABLE C2 ##STR00400## Comp. no. A R.sup.1 Salt 46 CH
##STR00401## tri- fluoro- acetate 47 CH ##STR00402## tri- fluoro-
acetate 48 CH ##STR00403## tri- fluoro- acetate 10 CH ##STR00404##
tri- fluoro- acetate 49 CH ##STR00405## tri- fluoro- acetate 1 CH
##STR00406## 50 CH ##STR00407## 51 CH ##STR00408## 52 CH
##STR00409## 3 CH ##STR00410## 53 CH ##STR00411## 54 CH
##STR00412## 55 CH ##STR00413## 56 CH ##STR00414## 57 CH
##STR00415## 58 CH ##STR00416## 59 CH ##STR00417## 60 CH
##STR00418## 61 CH ##STR00419## 62 CH ##STR00420## 63 CH
##STR00421## 64 CH ##STR00422## 11 N ##STR00423## 2 N ##STR00424##
65 N ##STR00425## 66 N ##STR00426## 67 N ##STR00427##
TABLE-US-00007 TABLE C3 ##STR00428## Co. no. X R.sup.2 6 --C.dbd.O
##STR00429## 68 --NH--C.dbd.S ##STR00430## 8 --NH--C.dbd.S
##STR00431## 69 --NH--C.dbd.O (CH.sub.3).sub.3--C-- 5 --NH--C.dbd.O
##STR00432## 70 --NH--C.dbd.O ##STR00433## 71 --NH--C.dbd.O
##STR00434## 72 --NH--C.dbd.O ##STR00435## 73 --NH--C.dbd.O
##STR00436## 74 --NH--C.dbd.O ##STR00437## 75 --NH--C.dbd.O
##STR00438## 76 --NH--C.dbd.O ##STR00439## 77 --NH--C.dbd.O
##STR00440## 78 --NH--C.dbd.O ##STR00441## 79 --NH--C.dbd.O
##STR00442## 80 --NH--C.dbd.O ##STR00443## 81 --NH--C.dbd.O
##STR00444## 82 --NH--C.dbd.O ##STR00445## 83 --NH--C.dbd.O
##STR00446## 84 --NH--C.dbd.O ##STR00447## 85 --NH--C.dbd.O
##STR00448## 86 --NH--C.dbd.O ##STR00449## 87 --NH--C.dbd.O
##STR00450## 88 --NH--C.dbd.O ##STR00451## 89 --NH--C.dbd.O
##STR00452## 90 --NH--C.dbd.O ##STR00453## 91 --NH--C.dbd.O
##STR00454## 92 --NH--C.dbd.O ##STR00455## 93 --NH--C.dbd.O
##STR00456## 94 --NH--C.dbd.O ##STR00457## 9 --NH--C.dbd.O
##STR00458## 95 --NH--C.dbd.O ##STR00459## 96 --NH--C.dbd.O
##STR00460## 97 --NH--C.dbd.O ##STR00461## 98 --NH--C.dbd.O
##STR00462## 99 --NH--C.dbd.O ##STR00463## 100 --NH--C.dbd.O
##STR00464## 101 --NH--C.dbd.O ##STR00465## 102 --NH--C.dbd.O
##STR00466## 103 --NH--C.dbd.O ##STR00467## 104 --NH--C.dbd.O
##STR00468## 105 --NH--C.dbd.O ##STR00469## 106 --NH--C.dbd.O
##STR00470##
TABLE-US-00008 TABLE C4 ##STR00471## Co. no. R.sup.2 107
CH.sub.2.dbd.CH--CH.sub.2-- 7 ##STR00472## 108 ##STR00473## 109
##STR00474## 110 ##STR00475## 111 ##STR00476## 128 ##STR00477## 112
##STR00478## 113 ##STR00479## 114 ##STR00480## 115 ##STR00481## 116
##STR00482## 117 ##STR00483## 118 ##STR00484##
TABLE-US-00009 TABLE C5 ##STR00485## Co. no. R.sup.2 119
CH.sub.3--CH.sub.2--CH.sub.2-- 120 ##STR00486## 121 ##STR00487##
122 ##STR00488## 123 ##STR00489## 124 ##STR00490##
TABLE-US-00010 TABLE C6 ##STR00491## Comp. no. X R.sup.2 R.sup.1a
R.sup.1a' R.sup.1b R.sup.1c R.sup.7 131 --CH.sub.2--C.dbd.O
##STR00492## H H ##STR00493## H H 134 --CH.sub.2--C.dbd.O
##STR00494## Cl Cl H H H 135 --CH.sub.2--NH--C.dbd.O ##STR00495##
Cl Cl H H H 133 --NH--C.dbd.O ##STR00496## H H H --OCH.sub.3 F 130
NH C.dbd.O ##STR00497## H H ##STR00498## H H 147
--CH.sub.2--C.dbd.O ##STR00499## H H ##STR00500## H H 148
--CH.sub.2--C.dbd.O ##STR00501## H H ##STR00502## H H 149
--CH.sub.2--C.dbd.O ##STR00503## H H ##STR00504## H H 150
--CH.sub.2--C.dbd.O ##STR00505## H H ##STR00506## H H 151
--CH.sub.2--C.dbd.O ##STR00507## H H ##STR00508## H H 152
--CH(OH)--C.dbd.O ##STR00509## H H ##STR00510## H H 129 --NH--C
.dbd.O ##STR00511## H H ##STR00512## H H 132 --CH.sub.2--C.dbd.O
##STR00513## H H ##STR00514## H H
TABLE-US-00011 TABLE C7 ##STR00515## Comp. no. X R.sup.2 R.sup.1a
R.sup.1b R.sup.1c 144 --NH--C.dbd.O ##STR00516## ##STR00517## H H
142 --CH.sub.2--C.dbd.O ##STR00518## H Br H 141 --CH.sub.2--C.dbd.O
##STR00519## H H --(CH.sub.2).sub.3CH.sub.3 139 --O--C.dbd.O
##STR00520## H ##STR00521## H 137 --NH--C.dbd.O ##STR00522## H
##STR00523## H 146 --CH.sub.2--C.dbd.O ##STR00524## H ##STR00525##
H 145 --CH.sub.2--C.dbd.O ##STR00526## H ##STR00527## H 140
--NH--C.dbd.O ##STR00528## H ##STR00529## H 143 --NH--C.dbd.O
##STR00530## H ##STR00531## H 138 --NH--C.dbd.O ##STR00532## H
##STR00533## H 136 --NH--C.dbd.O ##STR00534## H ##STR00535## H
[0675] Tables for the Class D compounds
TABLE-US-00012 TABLE D1 ##STR00536## Co. No. 33 ##STR00537## Co.
No. 34 ##STR00538## Co. No. 18 ##STR00539## Co. No. 35 ##STR00540##
Co. No. 36 ##STR00541## Co. No. 37 ##STR00542## Co. No. 17
##STR00543## Co. No. 38 ##STR00544## Co. No. 39 ##STR00545## Co.
No. 40 ##STR00546## Co. No. 41 ##STR00547## Co. No. 42 ##STR00548##
Co. No. 43 ##STR00549## Co. No. 44 ##STR00550## Co. No. 45
##STR00551## Co. No. 2 ##STR00552## Co. No. 10 ##STR00553## Co. No.
46 ##STR00554## Co. No. 12 ##STR00555## Co. No. 47 ##STR00556## Co.
No. 48 ##STR00557## Co. No. 49 ##STR00558## Co. No. 50 ##STR00559##
Co. No. 51 ##STR00560## Co. No. 13 ##STR00561## Co. No. 24
##STR00562## Co. No. 52 ##STR00563## Co. No. 53 ##STR00564## Co.
No. 19 ##STR00565## Co. No. 54 ##STR00566## Co. No. 27 ##STR00567##
Co. No. 55 ##STR00568## Co. No. 56 ##STR00569## Co. No. 57
##STR00570## Co. No. 189 ##STR00571## Co. No. 8 ##STR00572## Co.
No. 3 ##STR00573## Co. No. 29 ##STR00574## Co. No. 58 ##STR00575##
Co. No. 28 ##STR00576## Co. No. 59 ##STR00577## Co. No. 60
##STR00578## Co. No. 61 ##STR00579## Co. No. 62 ##STR00580## Co.
No. 63 ##STR00581## Co. No. 64 ##STR00582## Co. No. 11 ##STR00583##
Co. No. 65 ##STR00584## Co. No. 66 ##STR00585## Co. No. 67
##STR00586## Co. No. 68 ##STR00587## Co. No. 71 ##STR00588## Co.
No. 70 ##STR00589## Co. No. 73 ##STR00590## Co. No. 72 ##STR00591##
Co. No. 75 ##STR00592## Co. No. 74 ##STR00593## Co. No. 77
##STR00594## Co. No. 76 ##STR00595## Co. No. 79 ##STR00596## Co.
No. 78 ##STR00597## Co. No. 81 ##STR00598## Co. No. 80 ##STR00599##
Co. No. 83 ##STR00600## Co. No. 82 ##STR00601## Co. No. 85
##STR00602## Co. No. 84 ##STR00603## Co. No. 87 ##STR00604## Co.
No. 86 ##STR00605## Co. No. 89 ##STR00606## Co. No. 88 ##STR00607##
Co. No. 91 ##STR00608## Co. No. 90 ##STR00609## Co. No. 93
##STR00610## Co. No. 92 ##STR00611## Co. No. 95 ##STR00612## Co.
No. 94 ##STR00613## Co. No. 97 ##STR00614## Co. No. 96 ##STR00615##
Co. No. 99 ##STR00616## Co. No. 98 ##STR00617## Co. No. 101
##STR00618## Co. No. 100 ##STR00619## Co. No. 103 ##STR00620## Co.
No. 102 ##STR00621## Co. No. 105 ##STR00622## Co. No. 104
##STR00623## Co. No. 107 ##STR00624## Co. No. 106 ##STR00625## Co.
No. 109 ##STR00626## Co. No. 108 ##STR00627## Co. No. 111
##STR00628## Co. No. 110 ##STR00629## Co. No. 113 ##STR00630## Co.
No. 112 ##STR00631## Co. No. 115 ##STR00632## Co. No. 114
##STR00633## Co. No. 117 ##STR00634## Co. No. 116 ##STR00635## Co.
No. 119 ##STR00636## Co. No. 118 ##STR00637## Co. No. 121
##STR00638## Co. No. 120 ##STR00639## Co. No. 20 ##STR00640## Co.
No. 122 ##STR00641## Co. No. 124 ##STR00642## Co. No. 123
##STR00643## Co. No. 126 ##STR00644## Co. No. 125 ##STR00645## Co.
No. 128 ##STR00646## Co. No. 127 ##STR00647## Co. No. 130
##STR00648## Co. No. 129 ##STR00649## Co. No. 132 ##STR00650## Co.
No. 131 ##STR00651## Co. No. 134 ##STR00652## Co. No. 133
##STR00653## Co. No. 136 ##STR00654## Co. No. 135 ##STR00655## Co.
No. 138 ##STR00656## Co. No. 137 ##STR00657## Co. No. 140
##STR00658## Co. No. 139 ##STR00659## Co. No. 142
##STR00660## Co. No. 141 ##STR00661## Co. No. 144 ##STR00662## Co.
No. 143 ##STR00663## Co. No. 1 ##STR00664## Co. No. 145
##STR00665## Co. No. 147 ##STR00666## Co. No. 146 ##STR00667## Co.
No. 149 ##STR00668## Co. No. 148 ##STR00669## Co. No. 151
##STR00670## Co. No. 150 ##STR00671## Co. No. 153 ##STR00672## Co.
No. 152 ##STR00673## Co. No. 155 ##STR00674## Co. No. 154
##STR00675## Co. No. 157 ##STR00676## Co. No. 156 ##STR00677## Co.
No. 159 ##STR00678## Co. No. 158 ##STR00679## Co. No. 161
##STR00680## Co. No. 160 ##STR00681## Co. No. 162 ##STR00682## Co.
No. 23 ##STR00683## Co. No. 164 ##STR00684## Co. No. 163
##STR00685## Co. No. 14 ##STR00686## Co. No. 165 ##STR00687## Co.
No. 167 ##STR00688## Co. No. 166 ##STR00689## Co. No. 169
##STR00690## Co. No. 168 ##STR00691## Co. No. 171 ##STR00692## Co.
No. 170 ##STR00693## Co. No. 4 ##STR00694## Co. No. 172
##STR00695## Co. No. 174 ##STR00696## Co. No. 173 ##STR00697## Co.
No. 175 ##STR00698## Co. No. 32 ##STR00699## Co. No. 177
##STR00700## Co. No. 176 ##STR00701## Co. No. 179 ##STR00702## Co.
No. 178 ##STR00703## Co. No. 180 ##STR00704## Co. No. 26
##STR00705## Co. No. 182 ##STR00706## Co. No. 181 ##STR00707## Co.
No. 7 ##STR00708## Co. No. 22 ##STR00709## Co. No. 185 ##STR00710##
Co. No. 183 ##STR00711## Co. No. 31 ##STR00712## Co. No. 184
##STR00713## Co. No. 186 ##STR00714## Co. No. 16 ##STR00715## Co.
No. 187 ##STR00716## Co. No. 30 ##STR00717## Co. No. 188
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S*relative stereochemistry
[0676] Analytical Part
[0677] Analytical Data for the Compounds of Group Q (Compounds
147-152 from Class C and Compounds 353-364 from Class D):
[0678] LCMS
[0679] For (LC)MS-characterization of the compounds of the present
invention, the following methods were used.
[0680] General Procedure A
[0681] The LCMS analyses for a number of compounds were done at the
Surveyor MSQ.TM. (Thermo Finnigan, USA) comprising a photo diode
array detector (PDA; 190-800 nm) and a column as specified in the
respective methods below. Flow from the column was split to a MS
spectrometer. The MS detector was configured with APCI (atmospheric
pressure chemical ionization, + or - ions). Mass spectra were
acquired by scanning from 45 to 1000 (of atomic mass unit) in 0.3
seconds. Typical APCI conditions use a corona discharge current of
10 .mu.A and a cone voltage of 30 V. The APCI probe temperature was
640.degree. C. Nitrogen was used as the nebulizer gas. Data
acquisition was performed with an Xcalibur.TM. data system.
[0682] General Procedure B
[0683] The HPLC measurement was performed using an Agilent 1100
module comprising a pump, a diode-array detector (DAD) (wavelength
used 220 nm), a column heater and a column as specified in the
respective methods below. Flow from the column was split to a
Agilent MSD Series G1946C and G1956A. MS detector was configured
with API-ES (atmospheric pressure electrospray ionization). Mass
spectra were acquired by scanning from 100 to 1000. The capillary
needle voltage was 2500 V for positive ionization mode and 3000 V
for negative ionization mode. Fragmentation voltage was 50 V.
Drying gas temperature was maintained at 350.degree. C. at a flow
of 10 l/min.
[0684] Method 1
[0685] In addition to general procedure A: Reversed phase HPLC was
carried out on a Waters XTerra MS C18 column (3.5 .mu.m,
2.1.times.30 mm) with a flow rate of 1.0 ml/min. Two mobile phases
(mobile phase A: 0.1% aqueous solution of formic acid; mobile phase
B: CH.sub.3CN) were used. First, 100% A was hold for 0.1 minutes
(min). Then a gradient was applied to 5% A and 95 B in 3 min and
hold for 0.8 min. The injection volume was 1 .mu.l. The column was
at room temperature.
[0686] Method 2
[0687] In addition to general procedure B: Reversed phase HPLC was
carried out on a YMC-Pack ODS-AQ, 50.times.2.0 mm 5 .mu.m column
with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase A:
water with 0.1% TFA; mobile phase B: CH.sub.3CN with 0.05% TFA)
were used. First, 90% A and 10% B was hold for 0.8 min. Then a
gradient was applied to 20% A and 80% B in 3.7 min and hold for 3
min. Typical injection volumes of 2.mu.l were used. Oven
temperature was 50.degree. C. (MS polarity: positive)
[0688] Method 3
[0689] In addition to general procedure B: Reversed phase HPLC was
carried out on an Ultimate XB-C18, 50.times.2.1 mm 5 .mu.m column
with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase C:
10 mmol/L NH.sub.4HCO.sub.3; mobile phase D: CH.sub.3CN) were used.
First, 90% C and 10% D was hold for 0.8 min. Then a gradient was
applied to 20% C and 80% D in 3.7 min and hold for 3 min. Typical
injection volumes of 2.mu.l were used. Oven temperature was
50.degree. C. (MS polarity: positive)
[0690] Method 4
[0691] In addition to general procedure B: Reversed phase HPLC was
carried out on an Ultimate XB-C18, 50.times.2.1 mm 5 .mu.m column
with a flow rate of 0.8 ml/min. Two mobile phases (mobile phase C:
10 mmol/L NH.sub.4HCO.sub.3; mobile phase D: CH.sub.3CN) were used.
First, 100% C was hold for 1 min. Then a gradient was applied to
40% C and 60% D in 4 min and hold for 2.5 min. Typical injection
volumes of 2 .mu.l were used. Oven temperature was 50.degree. C.
(MS polarity: positive)
[0692] Melting Points
[0693] For a number of compounds (147-150 of Class C; 358-364 of
Class D), m.p. were determined by using a Gallenkamp apparatus from
Sanyo Gallenkamp.
[0694] For a number of compounds (151-152 of Class C; 353-357 of
Class D), m.p. were determined with a WRS-2A melting point
apparatus that was purchased from Shanghai Precision and Scientific
Instrument Co. Ltd. Melting points were measured with a linear
heating up rate of 0.2-5.0.degree. C./min. The reported values are
melt ranges. The maximum temperature was 300.degree. C.
TABLE-US-00013 TABLE Y (LC) MS analytical data and m.p. - R.sub.t
means retention time (in minutes); [MH].sup.+ means the protonated
mass of the compound (free base); Method refers to the method used
for (LC) MS; `dec.` means decomposition. Comp. Nr. R.sub.t
[MH].sup.+ Method m.p. (.degree. C.) 147 - Class C 1.62 620 1
262-263 148 - Class C 1.60 663 1 180-182 149 - Class C 1.63 677 1
250-252 150 - Class C 1.68 713 1 240-242 151 - Class C 3.41 586 2
224.1-225.4 152 - Class C 4.84 602 3 138.7-140.9 353 - Class D 3.49
591 2 126.6-128.1 354 - Class D 3.23 600 2 206.3-209.4 355 - Class
D 3.42 561 2 153.3-155.2 356 - Class D 3.10 616 2 134.4-137.0 357 -
Class D 5.65 607 4 dec. at 124.8 358 - Class D 1.57 625 1 199-200
359 - Class D 1.61 677 1 240-241 360 - Class D 1.52 668 1 159-160
361 - Class D 1.53 691 1 164-166 362 - Class D 1.51 682 1 123-126
363 - Class D 1.61 727 1 241-243 364 - Class D 1.56 718 1
152-154
[0695] Analytical data for the other Class A, Class B, Class C and
Class D compounds are listed in WO2008/148851, WO2008/148840,
WO2008/148849 and WO2008/148868, the contents of which are enclosed
by reference in the present application.
[0696] Pharmacological Example
[0697] All mpk (mg/kg/day) values mentioned in the measurements
described below, were estimated based on average food intake and
average body weight.
[0698] A) Measurement of Inhibition of DGAT1 Activity by the
Compounds of Class A, Class B, Class C and Class D
[0699] The inhibiting activity of compounds of Class A, Class B,
Class C and Class D on DGAT1 activity was screened in a single well
procedure assay using DGAT1 comprising membrane preparations and
DGAT1 substrate comprising micelles and determining formed
radio-active triacylglycerol coming in close proximity of a
flashplate surface by radioluminescence.
[0700] Said assay is described in full detail in WO2006/067071, the
content of which is incorporated herein by reference.
[0701] By DGAT1 activity is meant the transfer of coenzyme A
activated fatty acids to the 3-position of 1,2-diacylglycerols,
thus forming a triglyceride molecule, by enzyme DGAT1.
[0702] Step 1 Of the Assay: Expression of DGAT1
[0703] human DGAT1 (NM012079.2) was cloned into the pFastBac
vector, containing translation start, a FLAG-tag at the N-terminus
as described in literature and a viral Kozak sequence (AAX)
preceding the ATG to improve expression in insect cells. Expression
was done as described in literature (Cases, S., Smith, S. J.,
Zheng, Y., Myers H. M., Lear, S. R., Sande, E., Novak, S., Collins,
C., Welch, C. B., Lusis, A. J., Erickson, S. K. and Farese, R. V.
(1998) Proc. Natl. Acad. Sci. USA 95, 13018-13023.) using SF9
cells.
[0704] Step 2 of the Assay: Preparation of DGAT1 Membranes
[0705] 72 h transfected SF9 cells were collected by centrifugation
(13000 rpm-15 min-4.degree. C.) and lysed in 2.times.500 ml
lysisbuffer (0.1M Sucrose, 50 mM KCl, 40 mM KH.sub.2PO.sub.4, 30 mM
EDTA pH 7.2. Cells were homogenized by cell disruptor. After
centrifugation 1380 rpm-15 min-4.degree. C. (SN discarded), pellet
was resuspended in 500 ml lysisbuffer and total cell membranes
collected by ultracentrifugation at 34000 rpm (100 000 g) for 60
min (4.degree. C.). The collected membranes were resuspended in
lysis buffer, divided in aliquots and stored with 10% glycerol at
-80.degree. C. until use.
[0706] Step 3 OF THE ASSAY: Preparation of DGAT Substrate
Comprising Micelles
[0707] Materials [0708] a) 1,2-dioleoyl-sn-glycerol, 10 mg/ml
(1,2-diacylglycerol (DAG)) Dissolve in acetonitrile; evaporate the
acetonitrile solution under nitrogen and reconstitute in chloroform
at a final concentration of 10 mg/ml. [0709] b)
L-.alpha.-phosphatidylcholine, 1 mg/ml (phosphatidylcholine (PC))
Dissolve in chloroform at a final concentration of 1 mg/ml and
store at 4.degree. C. [0710] c) L-.alpha.-phosphatidyl-L-serine, 1
mg/ml (phophatidylserine (PS))
[0711] Dissolve in chloroform at a final concentration of 1 mg/ml
and store at 4.degree. C.
[0712] Method
[0713] Add 1 ml dioleoyl-sn-glycerol (10 mg/ml) to 10 ml of
L-.alpha.-phosphatidylcholine (1 mg/ml) and 10 ml of
L-.alpha.-phosphatidyl-L-serine (1 mg/ml) in a thick glass
recipient. Evaporate under nitrogen and put on ice for 15 min.
Reconstitute in 10 ml Tris/HCl (10 mM, pH 7.4) by sonication on
ice. The sonification process includes sonification cycles of 10
seconds in the sonification bath followed by 10 seconds cool down
on ice and repeating this sonification cycle till a homogeneous
solution is obtained (takes about 15 min). The thus obtained
micelles are stored at -20.degree. C. till later use and contain
DAG at a final concentration of 1.61 mM.
[0714] Step 4 of the Assay: DGAT FlashPlate.TM. Assay
[0715] Materials
[0716] a) Assaybuffer [0717] 50 mM Tris-HCl (pH 7.4), 150 mM MgCl,
1 mM EDTA, 0.2% BSA.
[0718] b) N-ethylmaleimide, 5M [0719] Dissolve 5 g into a final
volume of 8 ml DMSO 100% and store at -20.degree. C. in aliquots
till later use.
[0720] c) Substrate mix (for 1 384 well plate=3840 .mu.l)
[0721] 612 .mu.l micelles stock (51 .mu.M final)
[0722] 16.6 .mu.l oleoylCoA 9.7 mM
[0723] 23 .mu.l [.sup.3H]-oleoylCoA (49 Ci/mmol, 500 .mu.Ci/ml)
[0724] 3188.4 .mu.l Tris pH 7.4, 10 mM
[0725] d) Enzyme mix (for 1 384 well plate=3520 .mu.l) (5 .mu.g/ml)
[0726] Add 11.73 .mu.l of DGAT membrane stock (1500 pg/ml stock) to
3508 .mu.l assay buffer.
[0727] e) Stop mix (for 1 384 well plate=7.68 ml) (250 mM) [0728]
Add 384 .mu.l of N-ethylmaleimide (5M) to 3.456 ml DMSO 100%, and
further dilute 3.84 ml of said solution with 3.84 ml DMSO 10%.
[0729] Method
[0730] DGAT activity in membrane preparations was assayed in 50 mM
Tris-HCl (pH 7.4), 150 mM MgCl.sub.2, 1 mM EDTA and 0.2% BSA,
containing 50 .mu.M DAG, 32 .mu.g/ml PC/PS and 8.4 .mu.M
[.sup.3H]-oleoylCoA (at a specific activity of 30 nCi/well) in a
final volume of 50 .mu.l in 384-well format using the red shifted
Basic Image FlashPlatel.TM. (Perkin Elmer Cat.No. SMP400).
[0731] In detail, 10 .mu.l enzyme mix and 10 .mu.l substrate mix
were added to 30 .mu.l of assay buffer, optionally in the presence
of 1 .mu.l DMSO (blank and controls) or 1 .mu.l of the compound to
be tested. This r.m. was incubated for 120 min at 37.degree. C. and
the enzymatic reaction stopped by adding 20 .mu.l of the stop mix.
The plates were sealed and the vesicles allowed to settle overnight
at room temperature. Plates were centrifuged for 5 min at 1500 rpm
and measured in Leadseeker.
[0732] Experiments with different concentrations of the test
compound were performed and curves were calculated and drawn based
on % CTRL.sub.min (% of normalized control). % CTRL.sub.min was
calculated according to equation 1,
% CTRL.sub.min=(sample-LC)/(HC-LC) Equation 1:
where HC (high control) refers to the median of radioluminescence
value measured in the wells with enzyme and substrate but without
test compound, LC (low control) refers to median background
radioluminescence value measured in the wells with substrate
without enzyme and without test compound, and sample refers to the
radioluminescence value measured in the wells with substrate,
enzyme and test compound at a particular concentration.
[0733] The calculated % CTRL.sub.min values form a sigmoidal dose
response descending curve and from this curve pIC.sub.50 values
were calculated (-logIC.sub.50 where IC.sub.50 represents the
concentration at which the test compound gives 50% inhibition of
DGAT1 activity).
[0734] All the tested compounds of Class A, C and D showed
pIC.sub.50 values between 5 and 9.
[0735] All the tested compounds of Class B showed pIC.sub.50 values
between 5 and 8.5.
[0736] In order to determine selectivity of the present compounds
for DGAT1 compared to DGAT2, the inhibiting activity of the
compounds on DGAT2 was also determined in the above assay, slightly
modified to obtain optimal assay conditions for DGAT2. The tested
compounds did not show inhibiting activity for DGAT2 (Human DGAT2
(NM032564) was cloned and expressed as described in J. Biolog.
Chem. 276(42), pp 38870-38876 (2001)).
[0737] For a selected number of compounds, the pIC50 values are
shown in Table E.
TABLE-US-00014 TABLE E pIC.sub.50 values Co. Nr. pIC.sub.50 151 -
6.50 Class C 152 - 7.45 Class C 147 - 7.41 Class C 148 - 8.04 Class
C 149 - 8.21 Class C 150 - 8.22 Class C 353 - 6.59 Class D 354 -
6.19 Class D 355 - 6.04 Class D 356 - 7.13 Class D 357 - 7.26 Class
D 358 - 7.59 Class D 359 - 7.55 Class D 360 - 8.12 Class D 361 -
7.87 Class D 362 - 8.04 Class D 363 - 7.94 Class D 364 - 8.24 Class
D 352 - 6.45 Class D 351 - 6.62 Class D 267 - 6.97 Class D
[0738] Pharmacological data for the other Class A, Class B, Class C
and Class D compounds are listed in WO2008/148851, WO2008/148840,
WO2008/148849 and WO2008/148868, the contents of which are enclosed
by reference in the present application.
[0739] B) In Vivo Study for Effect of Test Compound on GLP-1 Plasma
Levels
[0740] Elevation of GLP-1 plasma levels by a DGAT inhibitor can be
studied as follows:
[0741] Dogs are deprived from food for a period of 22 h. At time 0,
animals are given a liquid meal, containing 18% fat (w/w), by
gavage with a stomach tube. The test compound is given orally
together with the meal. Afterwards, a postprandial plasma profile
is determined for GLP-1. Therefore, blood is collected at
predetermined time intervals in ice-cooled Vacutainers EDTA-plasma
tubes and GLP-1 levels are measured in the samples taken at 0 h
(just before the meal) and at 0.5, 1, 2, 4, 6, 8 and 24 h after
dosing. Six dogs (3 males and 3 females) are included per dosage
group and the plasma GLP-1 profile is compared with their own GLP-1
profile previously determined in the same conditions but without
administration of the test compound. GLP-1 determinations in plasma
are performed with a Glucagon-like peptide-1 (active) ELISA kit
96-well plate of LINCO Research.
[0742] C) Food Intake/Body Weight Effect of DGAT/Fenofibrate
Combination
[0743] General Procedure
[0744] Male C57BL/6 mice were housed in individually ventilated
cages under controlled temperature (21.degree. C.), humidity
(45-65%) and light (12 h-12 h reverse light/dark cycle; Lights
on--6 PM-6 AM). Mice were set on 60 kcal % fat energy diet until
their average body weight was over 45 grams, at which time they
were switched to a 45 kcal % fat diet.
[0745] For the purpose of Tests A, B and C, the mice were moved
into modified type-2 cages with: doublewide food cup, wire grids
and a tissue for bedding for several months before experiment to
adapt to new housing/feeding conditions. Food (Research diets 45
kcal % diet D12451--see Scheme A) was provided in powdered form in
a food hopper located off the front of the cage. Mice had been used
to test several compounds for effects on food intake before being
used in the current experiment, but had a wash-out period of at
least one month before starting the current experiments.
TABLE-US-00015 Scheme A: Composition of control diet (high-fat) and
premix (used for adding drug) Control Diet Added during D12451
Premix diet preparation Ingredient g/kg diet D04071407px g/kg diet
Casein, 80 Mesh 233.1 233.1 L-Cystine 3.5 3.5 Corn Starch 84.8 84.8
Maltodextrin 10 3.5 3.5 Sucrose 201.4 201.4 Cellulose 58.3 58.3
Soybean Oil 29.1 29.1 Lard 206.8 104.9 102 Mineral Mix S10026 11.7
11.7 DiCalcium Phosphate 15.1 15.1 Calcium Carbonate 6.4 6.4
Potassium Citrate, 1 H20 19.2 19.2 Vitamin Mix 11.7 11.7 Choline
Bitartrate 2.3 2.3 FD&C Red Dye #40 0.1
[0746] Compound 223 of Class D (Tests A and B) or compound 358
(Test C) of Class D, and/or fenofibrate (also called `F` in the
continuation of the pharmacological examples) were brought to a
fine emulsion by stirring in the appropriate amount of soybean oil
for 1 day. This was then mixed with the diet premix (Scheme A). The
diet premix was formulated to contain none of the necessary soybean
oil, and only half the final amount of lard. The soybean oil, and
the rest of the lard was added in-house during diet preparation.
After the soybean oil/drug was mixed with the premix for 15 min,
the remainder of the lard was added to complete the diet. Diet was
provided in powder form.
[0747] The mice were weighted the day before trial onset. For
treatment allocation, mice were ranked according to body weight and
randomly assigned to treatments within repetitions/blocks (40 mice,
4 treatments, 10 repetitions/block, unless otherwise mentioned).
The food intake the day before trial onset was also measured.
[0748] At trial onset, mice's food (diet D12451) was replaced with
the `inhouse` diet made from premix D04071407px and added oil/lard,
fenofibrate and/or the DGAT inhibitor. In tests A and B compound
223 of Class D (also called `D` in the continuation of the
pharmacological examples) was used:
##STR00898##
[0749] Food cups were filled and weighted daily during the
experiment. Body weight was recorded every 2nd or 3rd day.
[0750] Food Intake and Body Weight data were analyzed using General
Linear Models procedures appropriate for a 2.times.2 factorial
design with blocking and repeated measures. Means comparisons were
done using Duncan's Multiple Range test (SAS For Windows, Version
8.02; SAS.RTM., Cary, N.C.). Results were expressed as means.+-.SEM
(standard error of the mean).
[0751] Test A
[0752] In test A, the efficacy of the treatment in DIO C57BL/6 mice
with only fenofibrate and only a DGAT inhibitor (compound 223 from
Class D) was compared with the combined treatment with both D and
fenofibrate.
[0753] For the purpose of test A, the mice were assigned to one of
the following treatments:
[0754] 45 kcal % fat diet (Control)
[0755] 45 kcal % fat diet+0.05% fenofibrate (F)
[0756] 45 kcal % fat diet+0.04% compound 223 from Class D (D)
[0757] 45 kcal % fat diet+0.04% compound 223 from Class D+0.05%
fenofibrate (D+F)
[0758] The results of test A are shown in Figures A1 and A2.
[0759] In figure A1 it can be seen that except for 1 or 2 days out
of the 12 day trial, food intake of mice fed with the compound 223
of Class D (D) or fenofibrate-containing (F) diet was not
significantly less than control mice. In contrast, food intake of
mice fed with the compound 223 of Class D and
fenofibrate-containing (D+F) diet was significantly less
(P<0.05) on 9 out of 12 days. The cumulative food intake of the
compound 223 of Class D group (D) and the fenofibrate group (F) was
not significantly less than the control group when compared by
Duncans Multiple Range test (3.2% and 7.5% respectively); whereas
food intake of the group with the compound 223 of Class D and
fenofibrate-containing (D+F) diet was significantly less (23%) than
all other groups (P<0.05). When cumulative intake was analysed
as a 2.times.2 factorial design, there was a significant DGAT
effect and fenofibrate effect (P<0.005), but there was also a
significant DGAT (compound 223 from Class D) x fenofibrate
interaction, indicating that the combined effect was larger than
the main effect of either alone (P<0.05) (synergistic
effect).
[0760] The average daily drug intake of mice fed with the compound
223 of Class D or fenofibrate-containing diet was 23.5 and 29 mpk/d
respectively. The average daily drug intake of mice fed the
compound 223 of Class D and fenofibrate-combination diet was 43.2
mg/kg/day.
[0761] In figure A2 it can be seen that by day 2, body weight loss
of mice fed with the compound 223 of Class D and
fenofibrate-containing diet was significantly greater than control
mice (P<0.05). By day 4, body weight change of all drug treated
mice was significantly different than controls. Mice fed with the
compound 223 of Class D or fenofibrate-containing diet lost from
1-2 grams during the trial, whereas controls gained 0.6 grams. In
contrast, mice fed with the compound 223 of Class D and
fenofibrate-combination diet (D+F) significantly lost more weight
than mice fed with either drug alone, indicating a synergistic
effect of the 2 compounds on weight loss. When day 12 weight loss
was analysed by a 2.times.2 factorial design, the main effect of
DGAT and fenofibrate were both significant (P<0.001), but DGAT x
fenofibrate interaction was also significant (type 3 SS,
P<0.05). This test supports the increased effect on weight loss
of the combination diet when compared with single treatment.
[0762] At the end of test A, blood was collected under isoflurane
anesthesia for serum biochemistry determinations. There was no
indication of enhanced liver enzymes with the combination diet.
Blood glucose and serum triglyceride levels were consistently lower
in the (D+F) diet group than the control group.
[0763] Test B
[0764] In test B, the efficacy of the treatment in DIO C57BL/6 mice
with the fenofibrate/compound 223 from Class D combination was
compared at different doses. In test A, fenofibrate and compound
223 of Class D were included at 0.05 and 0.04% of the diet (w/w)
respectively. In test B, fenofibrate (F)/compound 223 of Class D
(D) was included at 3 lower doses 0.05F/0.02D, 0.025F/0.02D and
0.0125F/0.01D.
[0765] For the purpose of test B, the mice were assigned to one of
the following treatments:
[0766] 45 kcal % fat diet (Control)
[0767] 45 kcal % fat diet+0.02% D+0.05% F (0.05F/0.02D)
[0768] 45 kcal % fat diet+0.02% D+0.025% F (0.025F/0.02D)
[0769] 45 kcal % fat diet+0.01% D+0.0125% F (0.0125F/0.01D)
[0770] The results of test B are shown in Figures B1, B2 and
B3.
[0771] The average daily drug intake of F/D was 26.0/10.4,
13.2/10.6 and 6.6/5.3 mpk/d respectively for mice fed with the
high, medium and low concentration diets. In Figure B1, it can be
seen that the baseline food intake (i.e. day 0) of mice fed the
0.0125/0.01 was significantly lower than for other groups. During
the first day of exposure to the drug-containing diets, all
treatment groups ate significantly less than controls. (2.6 vs. 3.7
g for treated vs. controls respectively). Treated mice ate
significantly (P<0.05 or less) less than controls on all trial
days except days 9, 14 and 15.
[0772] In FIG. B2, it can be seen that body weight change of mice
fed with F/D-containing diets was significantly different from
control mice by the 2.sup.nd day of the trial (all P<0.001).
Body weight changed significantly over time (time effect,
P<0.001), and was significantly influenced by treatment
(time.times.treatment interaction (P<0.05).
[0773] In figure B3, food intake of all treatment groups on day 1
is shown. All groups ate about 30% less than controls regardless of
dietary D/F combination.
[0774] It can be concluded that compound 223 of Class D in
combination with fenofibrate, reduced food intake in diet-induced
obese mice for almost 2 weeks. This reduction in food intake was
accompanied with a significant weight change when compared to
controls. Control mice gained almost 2 grams during the first 5
days of the experiment. It appeared that mice had lost some weight
during adaptation to the feeding cages. Although they regained most
of this weight prior to the trial, some control mice clearly still
regained weight during the first week of the experiment. This was
not the case for mice treated with the combination of compound 223
of Class D and fenofibrate, even when the 2 were combined in the
diet at 0.01 and 0.0125 w/w respectively. These results suggest
that fenofibrates may reduce the efficacious dose of a DGAT
inhibitor and prolong the time a DGAT inhibitor will reduce food
intake.
[0775] Test C
[0776] In test C, the efficacies of the treatments in DIO C57BL/6
mice with only fenofibrate and only a DGAT inhibitor (compound 358
from Class D) were compared with the combined treatment with both
compound 358 of Class D and fenofibrate.
[0777] For the purpose of test C, the 32 DIO mice (n=8/group,
average starting weight
[0778] 46.5 g) were assigned to one of the following
treatments:
[0779] 45 kcal % fat diet (Control)
[0780] 45 kcal % fat diet+0.05% fenofibrate (F)
[0781] 45 kcal % fat diet+0.04% compound 358 from Class D
[0782] 45 kcal % fat diet+0.04% compound 358 from Class D+0.05%
fenofibrate (F)
[0783] The results of test C are shown in Figures C1 and C2.
[0784] In figure C1 it can be seen that food intake of mice fed
with a diet containing only compound 358 of Class D or a diet only
containing fenofibrate, was not significantly less than control
mice. Food intake of mice fed with the compound 358 of Class
D+fenofibrate-containing diet was only significantly less
(P<0.05) from controls on days 1 to 3, due to an increase in
food intake above baseline levels in control mice rather than a
decrease in intake of compound 358+fenofibrate-treated mice. The
21-day cumulative food intake of all drug-treated mice turned out
not to be significantly less than the control group, although there
was a tendency for mice fed compound 358 of Class D and
fenofibrate-containing diet to eat less.
[0785] The average daily drug intake of mice fed with the compound
358 of Class D or fenofibrate-containing diet was 27 and 34 mpk/d
respectively. The average daily drug intake of mice fed the
compound 358 of Class D and fenofibrate-combination diet was 58
mg/kg/day.
[0786] When analysed as a 2.times.2 factorial experiment (figure
C2), both DGAT and fenofibrate treated mice gained less weight than
controls (21 days body weight change, both main effects P<0.05).
The combination of the 2 treatments resulted in a weight loss
corresponding to the additive effect of both (interaction
P>0.05, no synergistic effect).
[0787] D) Short-Term Food Intake Effect of DGAT/Fenofibrate
Combination in Lean C57BL/6 Mice.
[0788] In Test A and Test B, it was demonstrated that DGAT
inhibition (compound 223 of Class D, also called 13') in
combination with fenofibrate (F) significantly reduced food intake
and body weight of diet-induced obese mice fed a high-fat diet to a
greater degree than when either compound was administered alone. To
further evaluate the mechanism of action of this food intake
reduction, it was evaluated whether combined treatment with a DGAT
inhibitor (compound 223 of Class D) and fenofibrate reduce food
intake in mice fed with a low-fat diet.
[0789] For the experiment, animals were moved into modified type-2
cages as described before. Once in the feeding cages, mice were
adapted to a 10 kcal % fat diet for 1 week before trial 1 was
started.
[0790] For the purpose of this test, the mice were assigned to one
of the following treatments:
[0791] Low Fat Diets (Trial 1; figure D1):
[0792] 10 kcal % fat diet (Control)
[0793] 10 kcal % fat diet+0.01% D+0.0125% F (0.01% D/0.0125% F)
[0794] 10 kcal % fat diet+0.04% D+0.05% F (0.04% D/0.05% F)
[0795] High Fat Diet (Trial 2; figure D2)
[0796] 45 kcal % fat diet (Control)
[0797] 45 kcal % fat diet+0.01% D+0.0125% F (0.01% D/0.0125% F)
[0798] 45 kcal % fat diet+0.02% D+0.05% F (0.02% D/0.05% F)
[0799] Compound 223 of Class D (D) and fenofibrate (F) were brought
to a fine emulsion by stirring in the appropriate amount of soybean
oil for 1 day. This was then mixed with the diet premix. After the
soybean oil/drug was mixed with the premix for 15 min, the
necessary amount of the lard was added to complete the diet. Diet
was provided in powder form.
[0800] Mice's `baseline` (BL) food intake was measured for 1 day
before both Trial 1 (low-fat diet) and 2 (high-fat diet). For
treatment allocation, mice were ranked according to their pretrial
food intake and randomly assigned to treatments within
repetitions/block (30 mice, 3 treatments, 8-9 repetitions/block).
Several mice had low or high food intakes and were not included in
the experiment.
[0801] Food intake data were analysed using General Linear Models
procedures appropriate for a randomized complete block design.
Means comparisons were done using Duncan's Multiple Range test (SAS
For Windows, Version 8.02; SAS.RTM., Cary, NC). Results are
expressed as means .+-.SEM.
[0802] Trial 1: Food Intake of Lean Mice Fed a Low-Fat Diet
[0803] Mice were given 1 week to adapt to the food intake cages and
a low-fat powdered diet (Research Diets D12450B-10 kcal % fat).
After 1 day of baseline food intake measurement, mice's food was
replaced by the same 10 kcal % fat diet containing 0/0, 0.01/0.0125
or 0.04/0.05 w/w D/F. The food cups were filled and weight daily
during the 3-day experiment.
[0804] In figure D1 (Trial 1), it can be seen that food intake of
mice fed the diet containing a 0.01/0.0125% D/F was not reduced at
any time during the 3-day trial, whereas mice fed the diet
containing 0.04/0.05% D/F reduced their food intake by 9% on day 1,
but ate similar amounts as controls thereafter.
[0805] The average daily drug intake of F/D was 71/57 or 17/14
mpk/d respectively for mice fed the high, and low concentration
diets.
[0806] Trial 2: Food Intake of Lean Mice Fed a High-Fat Diet
[0807] At the termination of trial 1, mice were switched to a
high-fat diet (D12451-45 k cal % fat) and allowed to adapt for 3
days. Once adapted, food intake was recorded for 1 day to establish
a baseline food intake (for treatment allotment). The following
day, mice were switched to the same 45 kcal % fat diet containing
0/0, 0.01/0.0125 or 0.02/0.05% w/w D/F (Figure D2).
[0808] In Figure D2, it is shown that food intake of mice fed the
diets containing a 0.01/0.0125% and 0.02/0.05% D/F was
significantly reduced compared to controls, especially on day 1.
Thereafter lean mice adapted more quickly than was generally been
observed with obese mice. By day 2, mice were eating 90% of control
values.
[0809] The average daily drug intake of F/D was 44/18 or 10.8/8.6
mpk/d respectively for mice fed the high, and low concentration
diets.
[0810] It can be seen from figure D3 that food intake during the
first 24 h of exposure to the drug-supplemented diet (0.01% D/
0.0125% F) was significantly reduced in mice fed a high-fat diet
(24% below control levels), but not in mice fed a low-fat diet (4%
below control levels). These results clearly indicate that a
certain amount of dietary fat is necessary for the feeding
suppressive effects of D/F.
[0811] E) Composition Examples
[0812] "Active ingredient" (a.i.) as used throughout these examples
relates to, unless otherwise is indicated,
[0813] a) a combination of a DGAT inhibitor and a PPAR agonist or a
prodrug thereof; in particular to any one of the exemplified DGAT
inhibitors combined with a fibrate; or
[0814] b) a compound of group Q.
[0815] Typical examples of recipes for the formulation of the
invention are as follows:
[0816] 1. Tablets
TABLE-US-00016 Active ingredient 5 to 100 mg Di-calcium phosphate
20 mg Lactose 30 mg Talcum 10 mg Magnesium stearate 5 mg Potato
starch ad 200 mg
[0817] In addition to tablets wherein both the DGAT inhibitor and
the PPAR agonist are comprised together in 1 tablet, the DGAT
inhibitor and the PPAR agonist may also be present in separate
tablets. In that case, the active ingredient will be the DGAT
inhibitor for one tablet and the PPAR agonist for the second
tablet.
[0818] 2. Suspension
[0819] An aqueous suspension is prepared for oral administration so
that each milliliter contains 1 to 5 mg of active ingredient, 50 mg
of sodium carboxymethyl cellulose, 1 mg of sodium benzoate, 500 mg
of sorbitol and water ad 1 ml.
[0820] 3. Injectable
[0821] A parenteral composition is prepared by stirring 1.5%
(weight/volume) of active ingredient in 0.9% NaCl solution.
[0822] 4. Ointment
TABLE-US-00017 Active ingredient 5 to 1000 mg Stearyl alcohol 3 g
Lanoline 5 g White petroleum 15 g Water ad 100 g
* * * * *