3-cyano-4-(4-tetrahydropyran-phenyl)-pyridin-2-one derivatives
View Patent ↗The present invention relates to novel compounds, in particular novel pyridinone derivatives according to Formula (I) including any stereochemically isomeric form thereof, or a pharmaceutically acceptable salt thereof or a solvate thereof, wherein all radicals are defined in the application and claims. The compounds according to the invention are positive allosteric modulators of metabotropic glutamate 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 such 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 of formula
including any stereochemically isomeric form thereof, wherein
R 1 is C 4-6 alkyl, or C 1-3 alkyl substituted with C 3-7 cycloalkyl;
R 2 is hydrogen, halo or trifluoromethyl;
R 3 is hydrogen or C 1-4 alkyl substituted with hydroxyl;
X is O or NH;
n is an integer of value 1 or 2;
or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1 wherein R 1 is C 4-6 alkyl.
3. A compound as claimed in claim 2 wherein R 1 is 1-butyl or 3-methyl-1-butyl.
4. A compound as claimed in claim 1 wherein R 1 is C 1-3 alkyl substituted with C 3-7 cycloalkyl.
5. A compound as claimed in claim 4 wherein R 1 is cyclopropylmethyl or 2-(cyclopropyl)-1-ethyl.
6. A compound as claimed in claim 1 wherein R 2 is hydrogen or halo.
7. A compound as claimed in claim 1 wherein R 2 is trifluoromethyl.
8. A compound as claimed in claim 1 wherein R 3 is hydrogen.
9. A compound as claimed in claim 1 wherein R 3 is C 1-4 alkyl substituted with hydroxyl.
10. A compound as claimed in claim 9 wherein R 3 is CH 2 OH.
11. A compound as claimed in claim 1 wherein X is O or NH.
12. A compound as claimed in claim 1 wherein n is 1 or 2.
13. A compound as claimed in claim 1 wherein n is 1 and R 2 is other than hydrogen and said R 2 is placed in meta position compared to the pyridinone moiety.
14. A compound as claimed in claim 1 wherein R 1 is 1-butyl, methyl-1-butyl, cyclopropylmethyl or 2-(cyclopropyl)-1-ethyl; R 2 is hydrogen, fluoro, chloro or trifluoromethyl; R 3 is hydrogen; n is 1.
15. A compound as claimed in claim 1 wherein the compound is selected from
R 2
3-F
3-Cl
3-CF 3
3-Cl
3-Cl
3-Cl
3-CF 3
H
2-F
2-F
3-F
3-Cl
or a pharmaceutically acceptable salt thereof.
16. A compound as claimed in claim 1 wherein the compound is selected from
R 2
3-F
3-Cl
3-CF 3
3-Cl
3-Cl
3-Cl
3-CF 3
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in claim 1 and a pharmaceutically acceptable carrier or diluent.
18. A process for preparing a compound as claimed in claim 1 , comprising
a) reacting an intermediate of formula (II) wherein Y represents a halo or triflate, with an intermediate of formula (III) wherein R 4 and R 5 represent hydrogen or C 1-4 alkyl, or wherein R 4 and R 5 may be taken together to form the bivalent radical of formula —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, or —C(CH 3 ) 2 C(CH 3 ) 2 —, in a suitable reaction-inert solvent, in the presence of a suitable base and a suitable catalyst, under thermal conditions
with R 1 , R 2 , R 3 , X and n as defined in claim 1 ;
or, if desired, further converting compounds of formula (I) into each other following art-known transformations; or further, if desired, converting the compounds of formula (I), into a therapeutically active non-toxic acid addition salt by treatment with an acid, or conversely, converting the acid addition salt form into the free base by treatment with alkali; or, if desired, preparing stereochemically isomeric forms thereof.