Pyrido[4,3-b]indoles and methods of use
View Patent ↗This disclosure relates to new heterocyclic compounds that may be used to modulate a histamine receptor in an individual. Pyrido[4,3-b]indoles are described, as are pharmaceutical compositions comprising the compounds and methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.
1. A compound of the formula (Ii):
wherein:
R 1 is H, hydroxyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, C 1 -C 8 perhaloalkoxy, alkoxy, aryloxy, carboxyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R 1 and R 2a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 1 and R 10a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;
each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, nitro or R 2a and R 2b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 2a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;
each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, nitro, hydroxyl, alkoxy, substituted or unsubstituted amino, cycloalkyl, aryl, heteroaryl, heterocyclyl, acylamino, acyloxy or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 3a and R 10a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;
X 7 , is N or CR 4a ;
each R 4 and R 4a is independently H, hydroxyl, nitro, cyano, halo, C 1 -C 8 perhaloalkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 perhaloalkoxy, C 1 -C 8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, thiol, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
each R 8c ,R 8d ,R 8e and R 8f is independently H, hydroxyl, alkoxy, halo, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 2 -C 8 alkenyl, C 1 -C 8 perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or is taken together with a geminal R 8(c-f) to form a substituted or unsubstituted methylene moiety or a moiety of the formula —OCH 2 CH 2 O—, or is taken together with a geminal R 8(c-f) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety;
each R 10a and R 10b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, nitro, hydroxyl, alkoxy or R 10a and R 10b are taken together with the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or R 10a and R 1 are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety, or R 10a and R 3a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety; and
Q is substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy or acylamino;
provided that the compound conforms to one of provisions (i)-(iii): (i) R 1 and R 2a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety; (ii) R 1 and R 10a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety; and (iii) R 3a and R 10a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein X 7 , is CR 4a where R 4a is H, or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein R 8c and R 8d are both H, or a pharmaceutically acceptable salt thereof.
4. A compound, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
5. The compound of claim 1 , wherein R 1 and R 2a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety; or a pharmaceutically acceptable salt thereof.
6. The compound of claim 5 , wherein R 8c and R 8d are each H and at least one of R 8e and R 8f is an unsubstituted C 1 -C 8 alkyl or hydroxyl; or a pharmaceutically acceptable salt thereof.
7. The compound of claim 6 , wherein X 7 is CR 4a where R 4a is H and R 4 is H, halo or unsubstituted C 1 -C 8 alkyl; or a pharmaceutically acceptable salt thereof.
8. The compound of claim 7 , wherein Q is substituted or unsubstituted pyridyl; or a pharmaceutically acceptable salt thereof.
9. The compound of claim 5 , wherein each R 8c , R 8d , R 8e and R 8f is H; or a pharmaceutically acceptable salt thereof.
10. The compound of claim 9 , wherein Q is substituted or unsubstituted pyridyl; or a pharmaceutically acceptable salt thereof.
11. The compound of claim 1 , wherein the compound is of the formula (Ii-1):
wherein:
R 4 is halo or alkyl;
R 8e and R 8f are independently H, OH or CH 3 ; and
Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 11 , wherein X 7 is N, R 8e and R 8f are H, and Q is substituted or unsubstituted pyridyl; or a pharmaceutically acceptable salt thereof.
13. The compound of claim 11 , wherein X 7 is CR 4 where R 4 is H, R 8e is OH and R 8f is H or CH 3 , Q is substituted or unsubstituted pyridyl; or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 , wherein R 1 and R 2a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety,
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 , wherein X 7 is CR 4a where R 4a is H; or a pharmaceutically acceptable salt thereof.
16. The compound of claim 15 , wherein Q is substituted or unsubstituted pyridyl; or a pharmaceutically acceptable salt thereof.
17. The compound of claim 14 , wherein X 7 is N; or a pharmaceutically acceptable salt thereof.
18. The compound of claim 17 , wherein each R 8c , R 8d , R 8e and R 8f is H, and Q is substituted or unsubstituted pyridyl; or a pharmaceutically acceptable salt thereof.
19. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 10a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety.
21. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3a and R 10a are taken together to form a propylene (—CH 2 CH 2 CH 2 —) moiety or a butylene (—CH 2 CH 2 CH 2 CH 2 —) moiety.
22. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 10a and R 10b are taken together to form a moiety selected from the group consisting of the structures:
23. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 10a and R 10b are taken together to form a moiety selected from the group consisting of the structures:
24. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2a , R 2b , R 3a , R 3b , R 10a and R 10b are taken together to form a moiety selected from the group consisting of the structures:
25. A pharmaceutical composition comprising (a) a compound of claim 1 or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier.
26. A pharmaceutical composition comprising (a) a compound of claim 5 or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier.
27. A pharmaceutical composition comprising (a) a compound of claim 22 or a pharmaceutically acceptable salt thereof and (b) a pharmaceutically acceptable carrier.
28. A kit comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and instructions for use.
29. A kit comprising a compound of claim 5 or a pharmaceutically acceptable salt thereof and instructions for use.
30. A kit comprising a compound of claim 22 or a pharmaceutically acceptable salt thereof and instructions for use.