MGluR5 modulators VI
The present invention is directed to novel compounds, to a process for their preparation, their use in therapy and pharmaceutical compositions comprising the novel compounds.
1 . A compound of formula (I)
wherein
R 1 is methyl, halogen or cyano;
R 2 is hydrogen or fluoro;
R 3 is hydrogen, fluoro or C 1 -C 3 alkyl;
R 4 is hydrogen or C 1 -C 3 alkyl;
X is
and Z is
R 5 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy; or C 1 -C 3 haloalkoxy;
R 6 is hydrogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 haloalkoxy;
R 7 is hydrogen, fluoro or C 1 -C 3 alkyl;
as well as pharmaceutically acceptable salts, hydrates, isoforms, tautomers and/or enantiomers thereof.
2 . A compound according to claim 1 , wherein R 1 is halogen or cyano.
3 . A compound according to claim 2 , wherein R 1 is chloro.
4 . A compound according to claim 2 , wherein R 1 is cyano.
5 . A compound according to claim 1 , wherein R 2 is hydrogen.
6 . A compound according to claim 1 , wherein R 3 is hydrogen or fluoro.
7 . A compound according to claim 1 , wherein R 4 is hydrogen or methyl.
8 . A compound according to claim 1 , wherein R 5 is hydrogen, C 1 -C 2 alkyl or C 1 -C 2 alkoxy.
9 . A compound according to claim 1 , wherein R 6 is hydrogen, C 1 -C 2 alkyl or C 1 -C 2 alkoxy.
10 . A compound according to claim 1 , wherein R 7 is C 1 -C 2 alkyl or C 1 -C 2 alkoxy.
11 . A compound selected from
8-{[5-(3-Chlorophenyl)isoxazol-3-yl]methyl}-3-pyridin-4-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine;
8-{[5-(3-Chlorophenyl)isoxazol-3-yl]methyl}-3-(2-methoxypyridin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrimidine; and
3-(3-{(R)-Methyl[3-(2-methoxypyridin-4-yl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrimidin-8(5H)-yl]methyl} isoxazol-5-yl)benzonitrile
as well as pharmaceutically acceptable salts, hydrates, isoforms, tautomers and/or enantiomers thereof.
12 . A compound according to claim 1 for use in therapy.
13 . A pharmaceutical composition comprising a compound according to claim 1 as an active ingredient, together with a pharmacologically and pharmaceutically acceptable carrier.
14 . Use of a compound according to claim 1 , or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for the inhibition of transient lower esophageal sphincter relaxations.
15 . Use of a compound according to claim 1 , or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for treatment or prevention of gastroesophageal reflux disease.
16 . Use of a compound according to claim 1 , or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for treatment or prevention of pain.
17 . Use of a compound according to claim 1 , or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for treatment or prevention of anxiety.
18 . Use of a compound according to claim 1 , or a pharmaceutically acceptable salt or an optical isomer thereof, for the manufacture of a medicament for treatment or prevention of irritable bowel syndrome (IBS).
19 . A method for the inhibition of transient lower esophageal sphincter relaxations whereby an effective amount of a compound according to claim 1 is administered to a subject in need of such inhibition.
20 . A method for the treatment or prevention of gastroesophageal reflux disease, whereby an effective amount of a compound according to claim 1 is administered to a subject in need of such treatment or prevention.
21 . A method for the treatment or prevention of pain, whereby an effective amount of a compound according to claim 1 is administered to a subject in need of such treatment or prevention.
22 . A method for the treatment or prevention of anxiety, whereby an effective amount of a compound according to claim 1 is administered to a subject in need of such treatment or prevention.
23 . A method for the treatment or prevention of irritable bowel syndrome (IBS), whereby an effective amount of a compound according to claim 1 is administered to a subject in need of such treatment or prevention.
24 . A combination comprising (i) at least one compound according to claim 1 and (ii) at least one acid secretion inhibiting agent.
25 . A combination according to claim 24 wherein the acid secretion inhibiting agent is selected from cimetidine, ranitidine, omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole or leminoprazole.
26 . A compound selected from
3-[3-(1-hydroxyethyl)isoxazol-5-yl]benzonitrile;
1-[5-(3-Iodo-phenyl)-isoxazol-3-yl]-ethanol;
3-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-5-(3-iodo-phenyl)-isoxazole;
3-{3-[1-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-isoxazol-5-yl}-benzonitrile; and
1-[5-(3-Cyanophenyl)isoxazol-3-yl]ethyl methanesulfonate.