3,3-difluoropiperidine carbamate heterocyclic compounds as NR2B NMDA receptor antagonists
Disclosed are chemical entities of Formula (I), wherein R 1 and Z are defined herein, as NR2B subtype selective receptor antagonists. Also disclosed are pharmaceutical compositions comprising a chemical entity of Formula (I), and methods of treating various diseases and disorders associated with NR2B antagonism, e.g., diseases and disorders of the CNS, such as depression, by administering a chemical entity of Formula (I).
1. A method of treating a disease or disorder responsive to NR2B antagonism, wherein the disease or disorder is depression, in a subject in need of such treatment, comprising administering an effective amount of a chemical entity which is a compound of formula:
wherein:
R 5 is selected from the group consisting of —H, —CH 3 , —F, —Cl, —CH 2 CH 3 , —CF 2 H, —CH 2 F, —CF 3 , —CF 2 CH 3 , —CH 2 CF 3 , cyclopropyl, —OCF 3 , —OCF 2 H, —SCH 3 , —SO 2 CH 3 , and ethynyl;
R 6 is selected from the group consisting of —H and —F;
R 7 is selected from the group consisting of —H, —F, —Cl, and —CH 3 ; and
Z is
2. The method of claim 1 , wherein the chemical entity is selected from the group consisting of:
TABLE 1.E1
compound
Z
R 5
R 6
R 7
E1-22.1
Z22
H
H
H
E1-22.2
Z22
CH 3
H
H
E1-22.3
Z22
Cl
H
H
E1-22.4
Z22
F
H
H
E1-22.5
Z22
CH 2 CH 3
H
H
E1-22.6
Z22
CF 2 H
H
H
E1-22.7
Z22
CH 2 F
H
H
E1-22.8
Z22
CF 3
H
H
E1-22.9
Z22
CF 2 CH 3
H
H
E1-22.10
Z22
CH 2 CF 3
H
H
E1-22.11
Z22
cyclopropyl
H
H
E1-22.12
Z22
OCF 3
H
H
E1-22.13
Z22
OCF 2 H
H
H
E1-22.14
Z22
Cl
H
F
E1-22.15
Z22
CH 3
H
F
E1-22.16
Z22
CH 3
F
H
E1-22.17
Z22
Cl
F
H
E1-22.18
Z22
F
F
H
E1-22.19
Z22
F
H
F
E1-22.20
Z22
F
H
Cl
E1-22.21
Z22
F
H
CH 3
E1-22.22
Z22
Cl
H
CH 3
E1-22.23
Z22
SCH 3
H
H
E1-22.24
Z22
SO 2 CH 3
H
H
E1-22.25
Z22
ethynyl
H
H
3. The method of claim 1 , wherein R 5 is —H, R 6 is —H, and R 7 is —H.
4. The method of claim 1 , wherein R 5 is —CH 3 , R 6 is —H, and R 7 is —H.
5. The method of claim 1 , wherein R 5 is —Cl, R 6 is —H, and R 7 is —H.
6. The method of claim 1 , wherein R 5 is —F, R 6 is —H, and R 7 is —H.
7. The method of claim 1 , wherein R 5 is —CH 2 CH 3 , R 6 is —H, and R 7 is —H.
8. The method of claim 1 , wherein R 5 is —CF 2 H, R 6 is —H, and R 7 is —H.
9. The method of claim 1 , wherein R 5 is —CH 2 F, R 6 is —H, and R 7 is —H.
10. The method of claim 1 , wherein R 5 is —CF 3 , R 6 is —H, and R 7 is —H.
11. The method of claim 1 , wherein R 5 is —CF 2 CH 3 , R 6 is —H, and R 7 is —H.
12. The method of claim 1 , wherein R 5 is —CH 2 CF 3 , R 6 is —H, and R 7 is —H.
13. The method of claim 1 , wherein R 5 is cyclopropyl, R 6 is —H, and R 7 is —H.
14. The method of claim 1 , wherein R 5 is —OCF 3 , R 6 is —H, and R 7 is —H.
15. The method of claim 1 , wherein R 5 is —OCF 2 H, R 6 is —H, and R 7 is —H.
16. The method of claim 1 , wherein R 5 is —Cl, R 6 is —H, and R 7 is —F.
17. The method of claim 1 , wherein R 5 is —CH 3 , R 6 is —H, and R 7 is —F.
18. The method of claim 1 , wherein R 5 is —CH 3 , R 6 is —F, and R 7 is —H.
19. The method of claim 1 , wherein R 5 is —Cl, R 6 is —F, and R 7 is —H.
20. The method of claim 1 , wherein R 5 is —F, R 6 is —F, and R 7 is —H.
21. The method of claim 1 , wherein R 5 is —F, R 6 is —H, and R 7 is —F.
22. The method of claim 1 , wherein R 5 is —F, R 6 is —H, and R 7 is —Cl.
23. The method of claim 1 , wherein R 5 is —F, R 6 is —H, and R 7 is —CH 3 .
24. The method of claim 1 , wherein R 5 is —Cl, R 6 is —H, and R 7 is —CH 3 .
25. The method of claim 1 , wherein R 5 is —SCH 3 , R 6 is —H, and R 7 is —H.
26. The method of claim 1 , wherein R 5 is —SO 2 CH 3 , R 6 is —H, and R 7 is —H.
27. The method of claim 1 , wherein R 5 is ethynyl, R 6 is —H, and R 7 is —H.