4-substituted-3-benzyloxy-bicyclo[3.1.0]hexane compounds as mGluR 2/3 antagonists
A mGlu2/3 receptor antagonist of the formula: its uses, and methods for its preparation are described.
1. A compound of the formula
where R 1 and R 2 are each independently hydrogen, C 1 -C 3 alkoxycarbonyloxymethyl, C 1 -C 3 alkylcarbonyloxymethyl, or C 3-6 cycloalkylcarbonyloxymethyl;
R 3 is independently at each occurance methyl, fluoro, or chloro;
R 4 is hydroxyl, methylcarbonylamino, hydroxymethylcarbonylamino, methoxycarbonylamino, imidazol-2-ylsulfanyl, thiazol-2-ylsulfanyl, 1,2,4-triazolylsulfanyl, 1-methyl-1,2,4-triazol-3-ylsulfanyl, or 1-methyl-1,2,4-triazol-5-ylsulfanyl; and
n is 1 of 2;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 where n is 2, both R 3 groups are chloro, and the chloro groups are at the phenyl 3- and 4-positions, or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 where R 1 and R 2 are each hydrogen, or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1 where R 1 and R 2 are both other than hydrogen, or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 where R 1 and R 2 are the same and are other than hydrogen, or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 5 where R 1 and R 2 are each isopropyloxycarbonyloxymethyl.
7. The compound according to claim 1 which is (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1 which is bis(isopropoxycarbonyloxymethyl) (1R,2S,3S,4R,5S,6R)-4-amino-3-[(3,4-dichlorophenyl)methoxy]-2-hydroxy-bicyclo[3.1.0]hexane-4,6-dicarboxylate or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound of the formula
where R 1 and R 2 are each independently hydrogen, C 1 -C 3 alkoxycarbonyloxymethyl, C 1 -C 3 alkylcarbonyloxymethyl, or C 3-6 cycloalkylcarbonyloxymethyl;
R 3 is independently at each occurrence methyl, fluoro, or chloro;
R 4 is hydroxyl, methylcarbonylamino, hydroxymethylcarbonylamino, methoxycarbonylamino, imidazol-2-ylsulfanyl, thiazol-2-ylsulfanyl, 1,2,4-triazolylsulfanyl, 1-methyl-1,2,4-triazol-3-ylsulfanyl, or 1-methyl-1,2,4-triazol-5-ylsulfanyl; and
n is 1 of 2;
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
10. A method for treating disorders of excessive sleepiness in a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
11. The method of claim 10 where the mammal is a human.
12. The pharmaceutical composition according to claim 9 wherein the compound is bis(isopropoxycarbonyloxymethyl) (1R,2S,3S,4R,5S,6R)-4-amino-3-[(3,4-dichlorophenyl)methoxy]-2-hydroxy-bicyclo[3.1.0]hexane-4,6-dicarboxylate or a pharmaceutically acceptable salt thereof.