1,4-disubstituted 3-cyano-pyridone derivatives and their use as positive mGluR2-receptor modulators
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 or halo;
A is pyridinyl substituted with one or two substituents, each substituent independently selected from halo or C 1-4 alkyl;
n is an integer of value 1 or 2;
or a pharmaceutically acceptable salt thereof;
provided that if R 2 is 2-fluoro then A is not 3-pyridinyl substituted with one or two substituents, each substituent independently selected from halo or C 1-4 alkyl,
provided that a compound is not
- - - -R 1
R 2
- - - -A
H
H
H
H
2. A compound as claimed in claim 1 wherein A is pyridinyl substituted with one substituent, wherein said substituent is halo or C 1-4 alkyl.
3. A compound as claimed in claim 1 wherein R 1 is C 4-6 alkyl.
4. A compound as claimed in claim 3 wherein R 1 is 1-butyl or 3-methyl-1-butyl.
5. A compound as claimed in claim 1 wherein R 1 is C 1-3 alkyl substituted with C 3-7 cycloalkyl.
6. A compound as claimed in claim 5 wherein R 1 is cyclopropylmethyl or 2-(cyclopropyl)-1-ethyl.
7. A compound as claimed in claim 1 wherein R 2 is hydrogen or fluoro.
8. A compound as claimed in claim 1 wherein R 2 is halo.
9. A compound as claimed in claim 8 wherein R 2 is fluoro.
10. A compound as claimed in claim 1 wherein n is 1 or 2 and R 2 is halo.
11. A compound as claimed in claim 1 wherein the pyridinyl ring represented by A is substituted with one substituent selected from chloro or methyl.
12. A compound as claimed in claim 1 wherein the pyridinyl ring represented by A is substituted with two substituents, each substituent independently being selected from chloro or methyl.
13. A compound as claimed in claim 1 wherein R 1 is 1-butyl, 3-methyl-1-butyl, cyclopropylmethyl or 2-(cyclopropyl)-1-ethyl; R 2 is hydrogen or fluoro; n is 1 or 2; A is pyridinyl substituted with one or two substituents, each substituent independently being selected from methyl or chloro.
14. A compound as claimed in claim 1 wherein the compound is selected from
- - - -R 1
R 2
- - - -A
2-F
3-F
3-F
2-F
3-F
2-F
3-F
2-F
3-F
2-F
3-F
3-F
2-F
3-F
3,5-diF
H
or a pharmaceutically acceptable salt thereof or a solvate thereof.
15. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in claim 1 and a pharmaceutically acceptable carrier or diluent.
16. A process for preparing a compound as claimed in claim 1 , comprising reacting an intermediate of formula (II) wherein Y represents a group suitable for Pd mediated coupling with boronic acids or boronic esters, with an intermediate of formula (III) wherein R 3 and R 4 represent hydrogen or C 1-4 alkyl; or wherein R 3 and R 4 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 , A 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.