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 (A):
or a salt thereof, 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 3a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—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, or R 2a and R 3a are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—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 or 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 1 are taken together to form ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety, or R 3a and R 2a are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) 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;
each X 7 , X 8 , X 9 and X 10 is independently N or CR 4 ;
m, and q are independently 0 or 1;
each R 4 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 8a , R 8b , R 8c and R 8d , where present, 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, carboxyl, carbonylalkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or is taken together with a geminal R 8(a-d) 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(a-d) 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;
each R 11 and R 12 is independently H, halo, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, carboxy, or carbonylalkoxy and the bond indicates the presence of either an E or Z double bond configuration, or R 11 and R 12 are taken together to form a bond or are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C 3-8 cycloalkenyl or substituted or unsubstituted heterocyclyl 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, aminocarbonylalkoxy, cyano, alkynyl or acylamino;
provided that the compound conforms to one of provisions (i)-(v): (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 3a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—CH 2 CH 2 CH 2 —) moiety; (iii) 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; (iv) R 2a and R 3a are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety; and (v) 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.
2. The compound of claim 1 , or a salt thereof, wherein m is 0.
3. The compound of claim 2 , or a salt thereof, wherein q is 0.
4. The compound of claim 1 , or a salt thereof, wherein each X 7 , X 8 , X 9 and X 10 is CR 4 .
5. The compound of claim 4 , or a salt thereof, wherein each R 4 is independently H, hydroxyl, halo, C 1 -C 8 perhaloalkyl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, C 1 -C 8 perhaloalkoxy, C 1 -C 8 alkoxy, aryloxy, carboxyl, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl.
6. The compound of claim 5 , or a salt thereof, wherein each R 4 is independently H, halo, substituted or unsubstituted C 1 -C 8 alkyl, or C 1 -C 8 perhaloalkyl.
7. The compound of claim 1 , or a salt thereof, wherein at least one of X 7 , X 8 , X 9 and X 10 is N.
8. The compound of claim 7 , or a salt thereof, wherein X 7 is N and X 9 is CR 4 .
9. The compound of claim 8 , or a salt thereof, wherein R 4 is halo, substituted or unsubstituted C 1 -C 8 alkyl, or C 1 -C 8 perhaloalkyl.
10. The compound of claim 1 , or a salt thereof, wherein each m and q is 0 and at least one of R 11 and R 12 is other than H.
11. The compound of claim 10 , or a salt thereof, wherein R 11 is H and R 12 is substituted or unsubstituted C 1 -C 8 alkyl, or substituted or unsubstituted C 3 -C 8 cycloalkyl.
12. The compound of claim 1 , or a salt thereof, wherein each m and q is 0 and R 11 and R 12 are taken together to form a bond.
13. The compound of claim 1 , or a salt thereof, wherein 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, or substituted or unsubstituted heterocyclyl.
14. The compound of claim 1 , or a salt thereof, wherein Q is substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, aminocarbonylalkoxy, cyano, alkynyl or acylamino.
15. The compound of claim 1 , wherein the compound is of the formula (B):
or a salt thereof, wherein:
R 2b is H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, hydroxyl, alkoxy, or nitro;
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 or 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;
each X 7 , X 8 , X 9 and X 10 is independently N or CR 4 ;
m and q are independently 0 or 1;
p is 1 or 2;
each R 4 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 8a , R 8b , R 8c and R 8d 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(a-d) 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(a-d) 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;
each R 11 and R 12 is independently H, halo, alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 3 -C 8 cycloalkyl, carboxy, or carbonylalkoxy and the bond indicates the presence of either an E or Z double bond configuration, or R 11 and R 12 are taken together to form a bond or are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C 3-8 cycloalkenyl or substituted or unsubstituted heterocyclyl 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, aminocarbonylalkoxy, cyano, alkynyl or acylamino.
16. The compound of claim 15 , or a salt thereof, wherein p is 1.
17. The compound of claim 15 , or a salt thereof, wherein each X 7 , X 8 , X 9 and X 10 is CR 4 .
18. The compound of claim 15 , or a salt thereof, wherein X 7 is N and X 9 is CR 4 .
19. The compound of claim 18 , or a salt thereof, wherein each X 8 and X 10 is CH.
20. The compound of claim 17 , or a salt thereof, wherein each R 4 is independently H, halo, substituted or unsubstituted C 1 -C 8 alkyl, or C 1 -C 8 perhaloalkyl.
21. The compound of claim 20 , or a salt thereof, wherein each R 2b , R 3a , R 3b , R 10a and R 10b is H.
22. The compound of claim 21 , or a salt thereof, wherein each m and q is 0 and at least one of R 11 and R 12 is other than H.
23. The compound of claim 22 , or a salt thereof, wherein R 11 is H and R 12 is substituted or unsubstituted C 1 -C 8 alkyl.
24. The compound of claim 23 , or a salt thereof, wherein Q is substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
25. The compound of claim 24 , or a salt thereof, wherein Q is substituted or unsubstituted pyridyl.
26. A pharmaceutical composition comprising (a) a compound of claim 1 or a salt thereof and (b) a pharmaceutically acceptable carrier.
27. A kit comprising a compound of claim 1 or a salt thereof and instructions for use in the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder or a neuronal disorder.
28. The compound of claim 1 , or a salt thereof, wherein the compound is selected from the group consisting of Compound Nos. 3, 4, 5, 6, 9, 10, 14, 16, 18, 20, 21, 23, 25, 28, 30 and 32:
Compound No.
Structure
3
4
5
6
9
10
14
16
18
20
21
23
25
28
30
32