Substituted xanthines and methods of use thereof
Compounds, compositions and methods are described for inhibiting the TRPC5 ion channel and disorders related to TRPC5.
1. A method of therapeutically treating anxiety in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of Formula III:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is C 1 -C 6 alkoxy or C 6 -C 10 aryloxy substituted with 1-3 R 6 ;
R 3 is C 1 -C 6 heteroalkyl or C 2 -C 6 hydroxyalkyl;
R 4 is C 1 -C 6 alkyl;
R 6 is independently C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or C 1 -C 6 alkoxy;
each R a is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halo;
n is 1 or 2; and
m is 1, 2, or 3.
2. The method of claim 1 , wherein R 2 is C 6 -C 10 aryloxy.
3. The method of claim 1 , wherein R 3 is C 2 -C 6 hydroxyalkyl.
4. The method of claim 1 , wherein R 3 is hydroxypropyl.
5. The method of claim 1 , wherein R 2 is C 6 -C 10 aryloxy, and R 6 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 1 -C 6 -haloalkoxy.
6. The method of claim 1 , wherein R 2 is C 6 -C 10 aryloxy and R 6 is independently C 1 -C 6 haloalkyl or C 1 -C 6 -haloalkoxy.
7. The method of claim 1 , wherein R 2 is C 6 -C 10 aryloxy and R 6 is —CF 3 or —OCF 3 .
8. A compound of Formula III:
or a pharmaceutically acceptable salt thereof, wherein:
R 2 is C 1 -C 6 alkoxy or C 6 -C 10 aryloxy substituted with 1-3 R 6 ;
R 3 is C 1 -C 6 heteroalkyl or C 2 -C 6 hydroxyalkyl;
R 4 is C 1 -C 6 alkyl;
R 6 is independently C 1 -C 6 alkyl, halo, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, or C 1 -C 6 alkoxy;
each R a is C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or halo;
n is 1 or 2; and
m is 1, 2, or 3.
9. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydroxypropyl.
10. The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein each R a is independently chloro, fluoro, or methyl.
11. A compound selected from the group consisting of:
12. A compound having the structure:
or a pharmaceutically acceptable salt thereof.
13. A compound having the structure:
or a pharmaceutically acceptable salt thereof.
14. A compound having the structure:
or a pharmaceutically acceptable salt thereof.
15. A compound having the structure:
or a pharmaceutically acceptable salt thereof.
16. A compound having the structure:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 1 , wherein each R a is independently chloro, fluoro, or methyl.
18. The method of claim 1 , wherein the compound of Formula (III) is:
or a pharmaceutically acceptable salt thereof.
19. The method of claim 1 , wherein the compound of Formula (III) is:
or a pharmaceutically acceptable salt thereof.
20. The method of claim 1 , wherein the compound of Formula (III) is:
or a pharmaceutically acceptable salt thereof.
21. The method of claim 1 , wherein the compound of Formula (III) is:
or a pharmaceutically acceptable salt thereof.