4-substituted-3-phenylsulfanylmethyl-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 5 alkylcarbonyloxymethyl, or C 3-6 cycloalkylcarbonyloxymethyl;
R 3 is independently at each occurrence methyl, fluoro, or chloro;
R 4 is hydroxyl, amino, methylcarbonylamino, or 1,2,4-triazolylthio; and
n is 1 or 2;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 where R 1 and R 2 are each hydrogen, or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 where R 1 and R 2 are both other than hydrogen, or a pharmaceutically acceptable salt thereof.
4. 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.
5. The compound according to claim 4 where R 1 and R 2 are each isopropyloxycarbonyloxymethyl, or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 1 where n is 2 and the R 3 groups are at the phenyl 3- and 4-positions, or a pharmaceutically acceptable salt thereof.
7. The compound according to claim 1 where R 3 is independently at each occurrence chloro or fluoro, or a pharmaceutically acceptable salt thereof.
8. The compound according to claim 1 which is (1S,2R,3S,4S,5R,6R)-2-amino-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid, or a pharmaceutically acceptable salt thereof.
9. The compound according to claim 1 which is bis({[(1-methylethoxy)carbonyl]oxy}methyl)(1S,2R,3S,4S,5R,6R)-2-amino-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate, or a pharmaceutically acceptable salt thereof.
10. The compound according to claim 1 which is (1S,2R,3S,4S,5R,6R)-2-amino-3-{[(3-chloro-4-fluorophenyl)sulfanyl]methyl}-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid, or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 1 which is bis({[(1-methylethoxy)carbonyl]oxy}methyl)(1S,2R,3S,4S,5R,6R)-2-amino-3-{[(3-chloro-4-fluorophenyl)sulfanyl]methyl}-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate, or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, in combination with at least one pharmaceutically acceptable carrier, excipient or diluent.
13. The pharmaceutical composition according to claim 12 , wherein the compound is (1S,2R,3S,4S,5R,6R)-2-amino-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid, or a pharmaceutically acceptable salt thereof.
14. The pharmaceutical composition according to claim 12 , wherein the compound is bis({[(1-methylethoxy)carbonyl]oxy}methyl)(1S,2R,3S,4S,5R,6R)-2-amino-3-{[(3,4-difluorophenyl)sulfanyl]methyl}-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate, or a pharmaceutically acceptable salt thereof.
15. The pharmaceutical composition according to claim 12 , wherein the compound is (1S,2R,3S,4S,5R,6R)-2-amino-3-{[(3-chloro-4-fluorophenyl)sulfanyl]methyl}-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid, or a pharmaceutically acceptable salt thereof.
16. The pharmaceutical composition according to claim 12 , wherein the compound is bis({[(1-methylethoxy)carbonyl]oxy}methyl)(1S,2R,3S,4S,5R,6R)-2-amino-3-{[(3-chloro-4-fluorophenyl)sulfanyl]methyl}-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate, or a pharmaceutically acceptable salt thereof.
17. A method for treating depressive disorders 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.
18. The method of claim 17 where the mammal is a human.
19. 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.
20. The method of claim 19 where the mammal is a human.
21. A method for treating depressive disorders 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, in simultaneous, separate or sequential combination with a serotonin reuptake inhibitor.
22. The method of claim 21 wherein the serotonin reuptake inhibitor is fluoxetine or citalopram.
23. The method of claim 21 wherein the mammal is a human.
24. The method of claim 22 wherein the mammal is a human.