Alkynyl derivatives as modulators of metatropic glutamate receptors
The present invention relates to novel compounds of formula (I) wherein W, n, X and W′ are defined in the description; invention compounds are modulators of metabotropic glutamate receptors-subtype 5 (“mGluR5”) which are useful for the treatment of central nervous system disorders as well as other disorders modulated by mGluR5 receptors.
1. A compound represented by the formula II-A2-a2:
or a pharmaceutically acceptable salt or hydrate thereof; wherein
R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylhalo and C 0 -C 6 -alkyl-NR 5 R 6 substituents;
R 5 and R 6 are each independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylhalo, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 6 -alkyl, heteroaryl, C 1 -C 6 -alkyl-heteroaryl, and aryl;
G q groups are each independently selected from the group consisting of hydrogen, halogen, CN, an optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylhalo, O—C 0 -C 6 -alkyl, O—C 0 -C 6 -alkylaryl, heteroaryl and aryl;
q is an integer from 1 to 5; and
any N may be an N-oxide.
2. A compound represented by the formula II
or a pharmaceutically acceptable salt or hydrate thereof;
wherein
W is a heteroaryl selected from:
R 1 , R 2 , R 3 and R 4 are each independently selected from the group consisting of hydrogen, halogen, an optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylhalo, aryl, C 0 -C 6 -alkyl-OR 5 , C 0 -C 6 -alkyl-NR 5 R 6 , C 0 -C 6 -alkyl-NR 5 C(═O)—R 6 and C 0 -C 6 -alkyl-NR 5 S(═O) 2 —R 6 substituents;
R 5 and R 6 are each independently selected from the group consisting of hydrogen, an optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylhalo, C 3 -C 7 -cycloalkyl, C 3 -C 7 -cycloalkyl-C 1 -C 6 -alkyl, heteroaryl, C 1 -C 6 -alkyl-heteroaryl, and aryl;
X is an optionally substituted C 1 -alkyl;
W′ is
G q groups are each independently selected from the group consisting of hydrogen, halogen, nitro, optionally substituted C 1 -C 6 -alkyl, C 1 -C 6 -alkylhalo, C 0 -C 6 -alkyl-OR 7 , O—C 0 -C 6 -alkylaryl, heteroaryl, aryl, C 0 -C 6 -alkyl-NR 7 R 8 and C 0 -C 6 -alkyl-NR 7 —S(═O) 2 R 8 substituents;
q is an integer from 1 to 5;
R 7 and R 8 are each independently selected from hydrogen, an optionally substituted C 1 -C 6 -alkyl, or C 1 -C 6 -alkylhalo; and
any N may be an N-oxide.
3. A compound selected from the group consisting of:
2-(4-(Pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine;
8-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine;
5-Methyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine;
5-Phenyl-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine;
2-(4-(2-Methylthiazol-4-yl)but-3-ynyl)imidazo[1,2-a]pyridine;
6-Fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine;
2-(4-(5-Fluoropyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine;
8-Chloro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine;
8-Chloro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine;
6-fluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine;
6-fluoro-2-(4-(2-(fluoromethyl)thiazol-4-yl)but-3-ynyl)-imidazo[1,2-a]pyridine;
8-bromo-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine;
8-(benzyloxy)-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine;
2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)-8-phenyl-imidazo[1,2-a]pyridine;
6,8-difluoro-2-(4-(pyridin-2-yl)but-3-ynyl)-imidazo[1,2-a]pyridine; and
6,8-Difluoro-2-(4-(6-(fluoromethyl)pyridin-2-yl)but-3-ynyl)H-imidazo[1,2-a]pyridine;
or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1 , which can exist as optical isomers, wherein said compound is either the racemic mixture or one or both of the individual optical isomers.
5. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier and/or excipient.
6. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 2 and a pharmaceutically acceptable carrier and/or excipient.
7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 3 and a pharmaceutically acceptable carrier and/or excipient.
8. A method for treating Parkinson's disease, the method comprising administering to a mammalian patient in need of such treatment an effective amount of a compound according to claim 1 .