Pyrido[3,4-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 method of treating a psychotic disorder in an individual comprising administering to an individual in need thereof an effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H or substituted or unsubstituted C 1 -C 8 alkyl, 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, 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, or R 3a and R 3b are taken together with the carbon atom 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 , wherein at most one of X 7 , X 8 , X 9 and X 10 is N;
m is 1 and q is 0;
n is 1;
each R 4 is independently H, halo, C 1 -C 8 perhaloalkyl, or substituted or unsubstituted C 1 -C 8 alkyl;
each R 8c , R 8d , R 8e and R 8f is independently H, hydroxyl, or substituted or unsubstituted C 1 -C 8 alkyl, or is taken together with a geminal R 8(c-f) and the carbon atom to which they are attached to form a carbonyl moiety;
each R 10a and R 10b is independently H, 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;
Q is substituted or unsubstituted aryl;
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;
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 8(c-f) is hydroxyl or C 1 -C 8 alkyl, and/or (2) Q is other than a substituted aryl; 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(c-f) is hydroxyl or C 1 -C 8 alkyl, and/or (2) Q is other than a substituted aryl.
2. A method of treating a psychotic disorder in an individual comprising administering to an individual in need thereof an effective amount of a compound of formula (A):
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H or substituted or unsubstituted C 1 -C 8 alkyl, 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, 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, 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 , wherein at most one of X 7 , X 8 , X 9 and) X 10 is N;
m, and q are 0;
each R 4 is independently H, halo, C 1 -C 8 perhaloalkyl, or substituted or unsubstituted C 1 -C 8 alkyl;
each R 10a and R 10b is independently H, 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, or substituted or unsubstituted C 1 -C 8 alkyl, and the
bond indicates the presence of either an E or Z double bond configuration; and
Q is substituted or unsubstituted aryl;
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.
3. The method of claim 2 , wherein the compound, or a pharmaceutically acceptable salt thereof, has one of X 7 , X 8 , X 9 and X 10 is N.
4. The method of claim 3 , wherein the compound, or a pharmaceutically acceptable salt thereof, has X 7 , X 8 , X 9 and X 10 taken together to form an aromatic moiety of the structure:
5. The method of claim 2 , wherein the compound, or a pharmaceutically acceptable salt thereof, has each X 7 , X 8 , X 9 and X 10 is CR 4 .
6. The method of claim 2 , wherein the compound, or a pharmaceutically acceptable salt thereof, has each R 4 is independently H, halo, or unsubstituted C 1 -C 8 alkyl.
7. The method of claim 2 , wherein the compound, or a pharmaceutically acceptable salt thereof, has at least one of R 11 and R 12 is other than H.
8. The method of claim 7 , wherein the compound, or a pharmaceutically acceptable salt thereof, has R 11 is H and R 12 is unsubstituted C 1 -C 8 alkyl.
9. The method of claim 2 , wherein the compound, or a pharmaceutically acceptable salt thereof, has Q is substituted aryl.
10. The method of claim 2 , wherein the compound is of formula (B):
or a pharmaceutically acceptable salt thereof, wherein:
R 2b is H;
each R 3a and R 3b is H;
p is 1 or 2; and
each R 10a and R 10b is H.
11. The method of claim 10 , wherein the compound, or a pharmaceutically acceptable salt thereof, has p is 1.
12. The method of claim 10 , wherein the compound, or a pharmaceutically acceptable salt thereof, has each X 7 , X 8 , X 9 and X 10 is CR 4 .
13. The method of claim 12 , wherein the compound, or a pharmaceutically acceptable salt thereof, has each R 4 is independently H, halo, or unsubstituted C 1 -C 8 alkyl.
14. The method of claim 13 , wherein the compound, or a pharmaceutically acceptable salt thereof, has R 11 is H and R 12 is unsubstituted C 1 -C 8 alkyl.
15. The method of claim 14 , wherein the compound, or a pharmaceutically acceptable salt thereof, has Q is substituted.
16. The method of claim 2 , wherein the compound is selected from the group consisting of Compound Nos. 3, 4, 5, 6, 9, 20, 21, 23, and 30, or a pharmaceutically acceptable salt thereof:
Compound No.
Structure
3
4
5
6
9
20
21
23
30
17. The method of claim 2 , wherein the compound is selected from the group consisting of Compound Nos. 3, 4, 5, and 6, or a pharmaceutically acceptable salt thereof:
Compound No.
Structure
3
4
5
6
18. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has 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:
19. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has 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:
20. The method of claim 1 , wherein the compound, or a pharmaceutically acceptable salt thereof, has 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:
21. The method of claim 1 , wherein the compound is selected from the group consisting of Compound Nos. 1, 2, 7, 8, 12, 13, 17, 22, 24, and 27, or a pharmaceutically acceptable salt thereof:
22. The method of claim 1 , wherein the psychotic disorder is schizophrenia.
23. The method of claim 2 , wherein the psychotic disorder is schizophrenia.