Cyclopropyl piperidine glycine transporter inhibitors
View Patent ↗The present invention is directed to cyclopropyl piperidine compounds that inhibit the glycine transporter GlyT1 and which are useful in the treatment of neurological and psychiatric disorders associated with glycinergic or glutamatergic neuro-transmission dysfunction and diseases in which the glycine transporter GlyT1 is involved.
1. A compound of Formula I
wherein R 2 is selected from the group consisting of:
(1) phenyl, which is substituted with R 2a , R 2b and R 2c ,
(2) furanyl, which is substituted with R 2a , R 2b and R 2c ,
(3) cyclohexyl, which is unsubstituted or substituted with 1-6 halogen, hydroxy or —NH 2 ,
R 2a , R 2b and R 2c are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —C 1-6 alkyl,
(4) —CF 3 , and
(5) —NH 2 ;
R 3 is C 1-6 alkyl or cyclopropyl;
R 4 and R 5 are independently selected from the group consisting of:
(1) hydrogen, and
(2) C 1-6 alkyl, which is unsubstituted or substituted with halogen or hydroxyl, or R 4 and R 5 taken together form a C 3-6 cycloalkyl ring;
A is selected from the group consisting of:
(1) —O—, and
(2) —NH—;
m is zero, whereby R 2 is attached directly to the carbonyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 of the formula Id′:
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 wherein R 2 is phenyl or furanyl and R 2a , R 2b and R 2c are independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —C 1-6 alkyl,
(4) —CH 3 , and
(5) —NH 2 .
4. The compound of claim 3 wherein R 2 is phenyl and R 2a , R 2b and R 2c are independently selected from the group consisting of:
(1) hydrogen,
(2) fluoro,
(3) chloro,
(4) bromo,
(5) —CH 3 , and
(6) —NH 2 .
5. The compound of claim 4 wherein R 2 is selected from the group consisting of:
(1) 2,3-difluorophenyl,
(2) 2,4-difluorophenyl,
(3) 2,4-dichlorophenyl,
(4) 2-chloro-4-fluorophenyl,
(5) 2-chloro-6-fluorophenyl, and
(6) 2-chloro-4,6-difluorophenyl.
6. The compound of claim 1 wherein R 3 is C 1-6 alkyl.
7. The compound of claim 6 wherein R 3 is —CH 2 CH 3 .
8. The compound of claim 6 wherein R 3 is cyclopropyl.
9. The compound of claim 1 wherein R 4 is hydrogen and R 5 is hydrogen.
10. A compound which is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
11. A compound which is:
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and the compound of claim 1 or
a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and the compound of claim 11 or
a pharmaceutically acceptable salt thereof.