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 (I):
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 3a are taken together to form an ethylene (—CH 2 CH 2 —) moiety or a propylene (—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 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;
each X 7 , X 8 and X 10 is CH;
X 9 is CR 4 ;
m and q are independently 0 or 1;
n is 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 , R 8d , R 8e and R 8f , 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-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(a-f) and the carbon to which they are attached to form a carbonyl moiety or a cycloalkyl moiety, or is taken together with a vicinal R 8(a-f) and the carbon atoms to which they are attached to form a substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl, or substituted or unsubstituted heterocyclyl moiety, or is taken together with a vicinal R 8(a-f) to form a bond provided that when an R 8(a-f) is taken together with a vicinal R 8(a-f) to form a bond, the geminal R 8(a-f) is other than hydroxyl;
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; 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) and (ii): (i) 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; and (ii) R 2a and R 3a are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety;
and provided that:
(A) when R 2a and R 3a are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety, X 7 -X 10 is CR 4 , each R 2b , R 3b , R 10a and R 10b are H, then (1) at least one of R 8e and R 8f is other than H; and/or (2) Q is other than a substituted aryl or substituted heteroaryl; and
(B) when 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, X 7 -X 10 is CR 4 , each R 2a , R 2b , R 3b , R 10a and R 10b are H, then (1) at least one of R 8(a-f) is hydroxyl, C 1 -C 8 alkyl or alkoxy; and/or (2) Q is other than a substituted aryl or substituted heteroaryl.
2. The compound of claim 1 , or a salt thereof, wherein 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 and each R 2a , R 2b , R 3b , R 10a and R 10b is H.
3. The compound of claim 2 , or a salt thereof, wherein at least one of R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is hydroxyl, alkoxy, or substituted or unsubstituted C 1 -C 8 alkyl.
4. The compound of claim 2 , or a salt thereof, wherein Q is unsubstituted aryl, unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl, or substituted or unsubstituted heterocyclyl.
5. The compound of claim 2 , or a salt thereof, wherein Q is substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, aminocarbonylalkoxy, cyano, alkynyl or acylamino.
6. The compound of claim 1 , or a salt thereof, wherein R 2a and R 3a are taken together to form a methylene (—CH 2 —) moiety or an ethylene (—CH 2 CH 2 —) moiety and each R 2b , R 3b , R 10a and R 10b is H.
7. The compound of claim 6 , or a salt thereof, wherein at least one of R 8e and R 8f is hydroxyl, alkoxy, substituted or unsubstituted C 1 -C 8 alkyl.
8. The compound of claim 6 , or a salt thereof, wherein Q is unsubstituted aryl, unsubstituted heteroaryl, substituted or unsubstituted C 3 -C 8 cycloalkyl, substituted or unsubstituted C 3 -C 8 cycloalkenyl, or substituted or unsubstituted heterocyclyl.
9. The compound of claim 6 , or a salt thereof, wherein Q is substituted or unsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl, carbonylalkoxy, aminocarbonylalkoxy, cyano, alkynyl or acylamino.
10. The compound of claim 1 , or a salt thereof, wherein R 4 is halo, substituted or unsubstituted C 1 -C 8 alkyl, or C 1 -C 8 perhaloalkyl.
11. The compound of claim 1 , or a salt thereof, wherein q is 0 and m is 1.
12. The compound of claim 11 , or a salt thereof, wherein at least one of R 8c , R 8d , R 8e and R 8f is hydroxyl, alkoxy, or substituted or unsubstituted C 1 -C 8 alkyl.
13. The compound of claim 12 , or a salt thereof, wherein each R 8c and R 8d is H, R 8e is OH or CH 3 , and R 8f is H or CH 3 .
14. The compound of claim 1 , or a salt thereof, wherein Q is aminoacyl.
15. The compound of claim 14 , or a salt thereof, wherein Q is aminoacyl of the formula —NR a C(O)R b where each R a is H or alkyl and R b is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl and substituted heterocyclyl.
16. The compound of claim 15 , wherein R a is H.
17. The compound of claim 16 , wherein R b is unsubstituted or substituted heteroaryl.
18. A pharmaceutical composition comprising (a) a compound of claim 1 or a salt thereof and (b) a pharmaceutically acceptable carrier.
19. A kit comprising a compound of claim 1 or a salt thereof and instructions for use.
20. The compound of claim 1 , or a salt thereof, wherein the compound is selected from the group consisting of Compound Nos. 7, 8, 9, 10, 22, 23, 24 and 25
Compound No.
Structure
7
8
9
10
22
23
24
25