1,3-disubstituted-4-phenyl-1H-pyridin-2-ones
The present invention relates to novel compounds, in particular novel pyridinone derivatives according to Formula (I) wherein all radicals are as defined in the application and claims. The compounds according to the invention are positive allosteric modulators of metabotropic receptors—subtype 2 (“mGluR2”) which are useful for the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which the mGluR2 subtype of metabotropic receptors is involved. In particular, such diseases are central nervous system disorders selected from the group of anxiety, schizophrenia, migraine, depression, and epilepsy. The invention is also directed to pharmaceutical compositions and processes to prepare such compounds and compositions, as well as to the use of such compounds for the prevention and treatment of such diseases in which mGluR2 is involved.
1. A compound having the formula (I)
or a stereochemically isomeric form thereof, wherein
R 1 is C 1-6 alkyl; or C 1-3 alkyl substituted with C 3-7 cycloalkyl, phenyl, or phenyl substituted with halo, trifluoromethyl or trifluoromethoxy;
R 2 is halo, trifluoromethyl, C 1-3 alkyl or cyclopropyl;
R 3 is hydrogen, halo or trifluoromethyl;
R 4 is hydrogen, C 1-3 alkyl, C 1-3 alkyloxy, hydroxyC 1-3 alkyl or tetrahydropyran-2-yloxy C 1-3 alkyl;
n is 1 or 2;
X is a covalent bond, O or NR 5 ;
R 5 is hydrogen, C 1-3 alkyl or hydroxyC 2-3 alkyl;
Y is O or CR 6 (OH);
R 6 is hydrogen or C 1-3 alkyl; or
R 4 and R 6 form a radical —CH 2 —CH 2 —;or
a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 wherein
R 1 is 1-butyl, 2-methyl-1-propyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)- 1-ethyl;
R 2 is halo;
R 3 is hydrogen, chloro or trifluoromethyl;
R 4 is hydrogen or hydroxymethyl;
N is 2;
X is a covalent bond, O or NR 5 ;
R 5 is hydrogen;
Y is O or CR 6 (OH);
R 6 is hydrogen or methyl;
or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 wherein
R 1 is 1-butyl, 3-methyl-1-butyl, (cyclopropyl)methyl or 2-(cyclopropyl)-1-ethyl;
R 2 is chloro;
R 3 is hydrogen or chloro;
R 4 is hydrogen or hydroxymethyl;
n is 2;
X is a covalent bond, O or NR 5 ;
R 5 is hydrogen;
Y is O or CR 6 (OH);
R 6 is hydrogen or methyl;
or a pharmaceutically acceptable salt thereof.
4. A compound wherein said compound is trifluoro-methanesulfonic acid 1-butyl-3-chloro-2-oxo-1,2-dihydropyridin-4-yl ester.
5. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.