Metabotropic glutamate receptor-5 modulators
View Patent ↗Phenyl compounds substituted at the 1-position with a fused bicyclo moeity formed from a five-membered heterocycle fused to a six-membered carbocycle, to a six-membered aryl, or to a six-membered hetaryl, and further optionally substituted at the 3,4 positions, are mGluR5 modulators useful in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, and panic, as well as in the treatment of pain and other diseases.
1. A compound represented by Formula (I):
or a pharmaceutically acceptable salt thereof, wherein
X is N or NR 4 when Y is O, and X is O when Y is N or NR 4 ;
Y is O when X is N or NR 4 , and Y is N or NR 4 when X is O;
one of Z 1 , Z 2 , Z 3 or Z 4 is N, or NH;
R 1 is optionally substituted with 1–5 substituents; wherein each substituent is independently halogen, —OH, —CN, —C 1-6 alkyl, —C 1-4 alkoxyl, —N(C 0-4 alkyl)(C 0-4 alkyl), —C 0-4 alkyl-C(O)—O—C 0-4 alkyl, —C 0-4 alkyl-morpholinyl, or —C 0-4 alkyl-benzoxazolyl;
R 2 is hydrogen, halogen, —OH, —CN, —N(C 0-4 alkyl)(C 0-4 alkyl), —NO 2 ; or —C 1-6 alkyl, —C 1-4 alkoxyl, —C 0-4 alkyl-phenyl, or —C 1-4 alkoxy-phenyl group, wherein any of the groups is optionally substituted with 1–3 independently halogen, —OH, —CN, or —C 1-4 alkoxyl substituents;
R 3 is hydrogen or —C 1-4 alkoxyl;
R 4 is —C 0-4 alkyl; and
R 5 is H, halogen, or —C 1-4 alkyl.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Z 1 is N;
X is N; and
Y is O.
3. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is —C 0-4 alkyl-pyridyl optionally substituted with 1–5 substituents; wherein each substituent is independently halogen, —OH, —CN, —C 1-6 alkyl, —C 1-4 alkoxyl, —N(C 0-4 alkyl)(C 0-4 alkyl), —C 0-4 alkyl-C(O)—O—C 0-4 alkyl, —C 0-4 alkyl-morpholinyl, or —C 0-4 alkyl-benzoxazolyl.
4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Z 2 or Z 3 is N;
X is N; and
Y is O.
5. The compound according to claim 1 represented by
or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1 represented by
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
8. A method of treatment of pain comprising the step of administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
9. A method of treatment of a pain disorder wherein said pain disorder is acute pain, persistent pain, chronic pain, inflammatory pain, or neuropathic pain, comprising the step of administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
10. A method of treatment of neuropathic pain comprising the step of administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.
11. A method of treatment of inflammatory pain comprising the step of administering a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof.