Use of CRAC channel inhibitors for the treatment of stroke and traumatic brain injury
Described herein are methods of treatment of stroke and traumatic brain injury comprising administration of a CRAC channel inhibitor.
1. A method for treating stroke or traumatic brain injury in an individual in need thereof comprising administering to the individual a therapeutically effective amount of a compound having the structure of Formula (II):
wherein:
R′ 1 is
L 2 is —NH—C(═O)—, or —C(═O)NH—;
X is CR 3 or N;
Y is independently selected from CR 9 or N;
R 2 is C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 4 alkyleneC 2 -C 8 heterocycloalkyl, aryl, heteroaryl, fused aryl or fused heteroaryl; wherein C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 8 heterocycloalkyl, C 1 -C 4 alkyleneC 2 -C 8 heterocycloalkyl, aryl, heteroaryl, fused aryl or fused heteroaryl is optionally substituted with at least one R 3 ;
R 3 is independently selected from H, F, D, Cl, Br, I, —CN, —NO 2 , —OH, —CF 3 , —OCF 3 , —OR 5 , C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 haloalkyl, C 2 -C 5 heterocycloalkyl, optionally substituted aryl, optionally substituted O-aryl, optionally substituted heteroaryl,
n is an integer selected from 0-2;
R 9 is independently selected from H, D, halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR 5 , —OCF 3 , C 1 -C 6 carbonylalkyl, or —CF 3 ; or two R 9 attached to the same carbon atom form an oxetane ring;
R 10 is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR 5 , —OCF 3 , C 1 -C 6 carbonylalkyl, or —CF 3 ;
R 5 is independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, phenyl, and benzyl;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 wherein X is CH.
3. The method of claim 1 wherein R′ 1 is
and Y is CH.
4. The method of claim 3 wherein R 2 is phenyl substituted with at least one R 3 .
5. The method of claim 4 wherein at least one R 3 is selected from Cl, Br, F, I, CF 3 , C 1 -C 6 alkyl, or OC 1 -C 6 alkyl.
6. The method of claim 5 wherein at least one R 3 is selected from Cl, F, and CH 3 .
7. The method of claim 3 wherein R 2 is phenyl substituted with at least one F.
8. The method of claim 7 wherein at least one R 9 is a halogen.
9. The method of claim 1 wherein R′ 1 is
and n is 0.
10. The method of claim 9 wherein R 10 is a halogen or C 1 -C 6 alkyl.
11. The method of claim 10 wherein R 10 is Cl.
12. The method of claim 10 wherein R 10 is —CH 3 .
13. The method of claim 10 wherein R 10 is —CH 2 CH 3 .
14. The method of claim 1 wherein R 2 is phenyl substituted with two R 3 , wherein one R 3 is F and one R 3 is CH 3 .
15. The method of claim 1 wherein R 2 is phenyl substituted with two R 3 , wherein each R 3 is F.
16. The method of claim 1 wherein R 2 is phenyl substituted with three R 3 , wherein each R 3 is F.
17. The method of claim 1 wherein R 2 is heteroaryl substituted with at least one R 3 .
18. The method of claim 17 wherein heteroaryl is pyridyl.
19. The method of claim 17 wherein R 2 is heteroaryl substituted with at least one R 3 selected from Cl, Br, F, I, CF 3 , C 1 -C 6 alkyl, or OC 1 -C 6 alkyl.
20. The method of claim 1 wherein L 2 is —NH—C(═O)—.