Treatment of cognitive and mood symptoms in neurodegenerative and neuropsychiatric disorders with Alpha5-containing GABA
Provided herein are alpha5-containing GABA A receptor agonists and pharmaceutical compositions and methods of treatment of cognitive and mood symptoms in neurodegenerative and neuropsychiatric disorders using them.
1. A compound according to any one of formulas (II) or (III):
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from the group consisting of N, C—F, C—Cl, C—Br, and C—NO 2 ;
R 1 is selected from the group consisting of —Br, C≡CH, -cyclopropyl, and bicycle[1.1.1]pentane
R 3 is —CH 3 ;
R 10 is selected from —H, C 1-6 alkyl, and cycloalkyl; and
R 11 is selected from C 1-6 alkyl and cycloalkyl;
with the proviso that the compound is not
2. A compound according to any one of formulas (V) or (VI):
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from the group consisting of N, C—H, C—F, C—Cl, C—Br, C—I, and C—NO 2 ;
R 1 is selected from the group consisting of —Br, —C≡CH, -cyclopropyl, and bicycle[1.1.1]pentane
R 3 is —CH 3 ; and
R 13 is selected from the group consisting of —H, —CD 3 , C 1-6 alkyl, and cycloalkyl.
3. The compound of claim 2 , wherein X is N.
4. The compound of claim 2 , wherein X is C—F.
5. The compound of claim 2 , wherein R 1 is Br.
6. The compound of claim 2 , wherein R 1 is —C≡CH.
7. The compound of claim 2 , wherein R 1 is cyclopropyl.
8. The compound of claim 2 , wherein R 13 is —CH 3 .
9. The compound of claim 2 , wherein R 13 is —CH 2 CH 3 .
10. The compound of claim 1 , wherein R 1 is —C≡CH.
11. The compound of claim 1 , wherein R 1 is cyclopropyl.
12. The compound of claim 1 , wherein X is N.
13. The compound of claim 1 , wherein X is C—F.
14. The compound of claim 1 , wherein X is C—Cl.
15. A compound according to any one of the formulas:
or a pharmaceutically acceptable salt thereof;
wherein
X is C—F, C—Cl, or N; and
R 4 is CH 3 and R 5 is H; or R 4 is H and R 5 is CH 3 .
16. A method of treating cognitive and/or mood symptoms, comprising administering a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
17. A method of treating cognitive and/or mood symptoms, comprising administering a compound according to claim 2 , or a pharmaceutically acceptable salt thereof, to a subject in need thereof.
18. The method of claim 16 , wherein the cognitive and/or mood symptoms result from depression and neurological disorders.
19. The method of claim 17 , wherein the cognitive and/or mood symptoms result from depression and neurological disorders.
20. A compound according to formula (IV):
or a pharmaceutically acceptable salt thereof, wherein:
X is selected from the group consisting of N, C—H, C—F, C—Cl, C—Br, C—I, and C—NO 2 ;
R 1 is selected from the group consisting of -cyclopropyl and bicycle[1.1.1]pentane
and
R 13 is selected from the group consisting of —H, —CD 3 , C 1-6 alkyl, and cycloalkyl.
21. The compound of claim 20 , or a pharmaceutically acceptable salt thereof, wherein R 1 is -cyclopropyl.
22. The compound of claim 21 , or a pharmaceutically acceptable salt thereof, wherein R 13 is C 1-6 alkyl.
23. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein:
the compound has formula
24. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 4 is CH 3 and R 5 is H.
25. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein:
the compound has formula
26. The compound of claim 25 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H and R 5 is CH 3 .
27. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein:
the compound has formula
28. The compound of claim 27 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H and R 5 is CH 3 .
29. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
the compound has formula (V);
X is selected from the group consisting of N, C—F, and C—Cl;
R 1 is —C≡CH; and
R 13 is selected from the group consisting of —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , and cycloalkyl.
30. The compound of claim 29 , or a pharmaceutically acceptable salt thereof, wherein R 13 is selected from the group consisting of —CH 3 , —CH 2 CH 3 , and —CH(CH 3 ) 2 .
31. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
the compound has formula (V);
X is selected from the group consisting of N, C—F, and C—Cl;
R 1 is cyclopropyl; and
R 13 is selected from the group consisting of —CH 3 , —CH 2 CH 3 , and —CH(CH 3 ) 2 .
32. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
the compound has formula (V);
X is selected from the group consisting of N, C—F, and C—Cl;
R 1 is —Br; and
R 13 is selected from the group consisting of —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , and cycloalkyl.
33. The compound of claim 32 , or a pharmaceutically acceptable salt thereof, wherein R 13 is selected from the group consisting of —CH 3 , —CH 2 CH 3 , and —CH(CH 3 ) 2 .
34. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein:
the compound has formula (VI);
X is selected from the group consisting of C—F and C—Cl;
R 1 is —C≡CH; and
R 13 is selected from the group consisting of —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , and cycloalkyl.
35. The compound of claim 34 , or a pharmaceutically acceptable salt thereof, wherein R 13 is selected from the group consisting of —CH 3 , —CH 2 CH 3 , and —CH(CH 3 ) 2 .
36. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein:
the compound has formula
37. The compound of claim 36 , or a pharmaceutically acceptable salt thereof, wherein R 4 is CH 3 and R 5 is H.
38. The compound of claim 37 , or a pharmaceutically acceptable salt thereof,
wherein the compound is
39. The compound of claim 36 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H and R 5 is CH 3 .
40. The compound of claim 39 , or a pharmaceutically acceptable salt thereof,
wherein the compound is
41. The compound of claim 39 , or a pharmaceutically acceptable salt thereof,
wherein the compound is
42. The compound of claim 2 , or a pharmaceutically acceptable salt thereof,
wherein the compound is
43. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein:
the compound has formula
44. The compound of claim 43 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H and R 5 is CH 3 .
45. The compound of claim 15 , or a pharmaceutically acceptable salt thereof, wherein:
the compound has formula
46. The compound of claim 45 , or a pharmaceutically acceptable salt thereof, wherein R 4 is H and R 5 is CH 3 .