Tetracyclic compounds
View Patent ↗This disclosure relates to new tetracyclic compounds that may be used to modulate a histamine receptor in an individual. The compounds in one embodiment are tetracyclic [4,3-b]indoles. Pharmaceutical compositions comprising the compounds are also provided, as are 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 (E):
or a salt thereof, wherein:
R 1 is H, hydroxyl, nitro, cyano, halo, 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, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
wherein acyl is selected from the group consisting of H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and substituted heterocyclic-C(O)—;
wherein sulfonylamino is selected from the group consisting of —SO 2 NH 2 —SO 2 NR-alkyl, —SO 2 NR-substituted alkyl, —SO 2 NR-alkenyl, —SO 2 NR-substituted alkenyl, —SO 2 NR-alkynyl, —SO 2 NR-substituted alkynyl, —SO 2 NR-aryl, —SO 2 NR-substituted aryl, —SO 2 NR-heteroaryl, —SO 2 NR-substituted heteroaryl, —SO 2 NR-heterocyclic, and —SO 2 NR-substituted heterocyclic, where R is H or alkyl, or —SO 2 NR 2 , wherein the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring;
wherein sulfonyl is selected from the group consisting of —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -alkynyl, —SO 2 -substituted alkynyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, and —SO 2 -substituted heterocyclic;
each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R 2a and R 2b are taken together with the carbon to which they are attached to form a carbonyl moiety or R 2a and R 2b are taken together with the carbon to which they are attached to form a cycloalkyl moiety;
each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety or R 3a and R 3b are taken together with the carbon to which they are attached to form a cycloalkyl moiety;
X 7 , X 8 , X 9 and X 10 are taken together to provide an aromatic moiety selected from the group consisting of:
m and q are independently 0 or 1;
each R 4 , where present, is independently hydroxyl, nitro, cyano, halo, C 1 -C 8 perhaloalkyl, carboxy, 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;
wherein acyl is selected from the group consisting of H—C(O)—, alkyl-C(O)—, substituted alkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—, aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—, heterocyclic-C(O)—, and substituted heterocyclic-C(O)—;
wherein sulfonylamino is selected from the group consisting of —SO 2 NH 2 —SO 2 NR-alkyl, —SO 2 NR-substituted alkyl, —SO 2 NR-alkenyl, —SO 2 NR-substituted alkenyl, —SO 2 NR-alkynyl, —SO 2 NR-substituted alkynyl, —SO 2 NR-aryl, —SO 2 NR-substituted aryl, —SO 2 NR-heteroaryl, —SO 2 NR-substituted heteroaryl, —SO 2 NR-heterocyclic, and —SO 2 NR-substituted heterocyclic, where R is H or alkyl, or —SO 2 NR 2 , wherein the two R groups are taken together and with the nitrogen atom to which they are attached to form a heterocyclic or substituted heterocyclic ring;
wherein sulfonyl is selected from the group consisting of —SO 2 -alkyl, —SO 2 -substituted alkyl, —SO 2 -alkenyl, —SO 2 -substituted alkenyl, —SO 2 -alkynyl, —SO 2 -substituted alkynyl, —SO 2 -aryl, —SO 2 -substituted aryl, —SO 2 -heteroaryl, —SO 2 -substituted heteroaryl, —SO 2 -heterocyclic, and —SO 2 -substituted heterocyclic;
each R 8a , R 8b , R 8c , R 8d , R 8e and R 8f , where present, is independently H, hydroxyl, C 1 -C 8 alkyl, carboxy, carbonylalkoxy or is taken together with the carbon to which it is attached and a geminal R 8 to form a cycloalkyl moiety or a carbonyl moiety;
each R 10a and R 10b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R 10a and R 10b are taken together with the carbon to which they are attached to form a carbonyl moiety or R 10a and R 10b are taken together with the carbon to which they are attached to form a cycloalkyl moiety; and
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
2. The compound of claim 1 , or a salt thereof, wherein X 7 , X 8 , X 9 and X 10 are taken together to provide an aromatic moiety selected from the group consisting of:
3. The compound of claim 1 , or a salt thereof, wherein at least one of R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is hydroxyl, C 1 -C 8 alkyl, carboxy, carbonylalkoxy, or is taken together with the carbon to which it is attached and a geminal R 8(a-f) to form a cycloalkyl moiety or a carbonyl moiety.
4. The compound of claim 1 , or a salt thereof, wherein each R 8a , R 8b , R 8c , R 8d , R 8e and R 8f , where present, is H.
5. The compound of claim 1 , or a salt thereof, wherein at least one of R 8c , R 8d , R 8e and R 8f , where present, is other than H.
6. The compound of claim 1 , or a salt thereof, wherein at least one of R 8e and R 8f is other than H.
7. The compound of claim 6 , or a salt thereof, wherein the compound has at least one R 4 , and wherein each R 4 is independently substituted or unsubstituted C 1 -C 8 alkyl, perhaloalkyl or halo.
8. The compound of claim 7 , or a salt thereof, wherein each R 4 is independently methyl, CH 2 F, CHF 2 , CF 3 , chloro or fluoro.
9. The compound of claim 1 , or a salt thereof, wherein at least one of R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is substituted or unsubstituted C 1 -C 8 alkyl.
10. The compound of claim 1 , or a salt thereof, wherein at least one of R 8a , R 8b , R 8c , R 8d , R 8e and R 8f is methyl.
11. The compound of claim 1 , or a salt thereof, wherein —R 8c R 8d —R 8e R 8f — and the carbons to which they are attached are taken together to form a moiety selected from the group consisting of —CH 2 —C(H)(CH 3 )—, —C(H)(CH 3 )—CH 2 —, —CH 2 —C(CH 3 )(CH 3 )—, —C(CH 2 CH 2 )—CH 2 - and —CH 2 —C(CH 2 CH 2 )—.
12. The compound of claim 1 , or a salt thereof, wherein q is 0, and m is 1.
13. The compound of claim 1 , or a salt thereof, wherein the compound has at least one R 4 , and wherein each R 4 is independently hydroxyl, 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, thiol, carbonylalkoxy, thioalkyl, alkylsulfonylamino or acyl.
14. The compound of claim 1 , or a salt thereof, wherein the compound has at least one R 4 , and wherein each R 4 is independently nitro, cyano, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, or carbonylalkylenealkoxy.
15. The compound of claim 1 , or a salt thereof, wherein the compound has at least one R 4 , wherein each R 4 is independently substituted or unsubstituted C 1 -C 8 alkyl, perhaloalkyl or halo.
16. The compound of claim 15 , or a salt thereof, wherein each R 4 is independently methyl, CH 2 F, CHF 2 , CF 3 , chloro or fluoro.
17. The compound of claim 1 , or a salt thereof, wherein each R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is independently H, unsubstituted or substituted C 1 -C 8 alkyl, or halo.
18. The compound of claim 17 , or a salt thereof, wherein each R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is H.
19. The compound of claim 1 , or a salt thereof, wherein Q is a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
20. The compound of claim 19 , or a salt thereof, wherein Q is selected from the group consisting of:
wherein each R 9 , where present, is independently halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, substituted or unsubstituted heterocyclyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino.
21. The compound of claim 1 , or a salt thereof, wherein Q is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
22. The compound of claim 21 , or a salt thereof, wherein Q is selected from the group consisting of:
wherein each R 9 , where present, is independently halo, cyano, nitro, perhaloalkyl, perhaloalkoxy, substituted or unsubstituted C 1 -C 8 alkyl, substituted or unsubstituted C 2 -C 8 alkenyl, substituted or unsubstituted C 2 -C 8 alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted or unsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl, aminoacyl or aminocarbonylamino.
23. The compound of claim 1 , or a salt thereof, wherein:
R 1 is methyl or ethyl;
each R 8C , R 8d , R 8e and R 8f , where present, is independently H or C 1 -C 8 alkyl;
X 7 is CR 4 where R 4 is H;
X 8 and X 10 are independently CR 4 where R 4 is H or halo;
X 9 is CR 4 where R 4 is halo, methyl, CH 2 F, CHF 2 , CF 3 , or ethyl; and
Q is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl.
24. The compound of claim 23 , or a salt thereof, wherein q is 0 and m is 1.
25. The compound of claim 24 , or a salt thereof, wherein each R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is H.
26. The compound of claim 1 , or a salt thereof, wherein:
R 1 is unsubstituted C 1 -C 8 alkyl;
each of R 2a , R 2b , R 3a , R 3b , R 10a and R 10b is H; and
each R 8a , R 8b , R 8C , R 8d , R 8e and R 8f is independently H, hydroxyl, C 1 -C 8 alkyl, carboxy, carbonylalkoxy, or is taken together with the carbon to which it is attached and a geminal R 8(a-f) to form a cycloalkyl moiety or a carbonyl moiety.
27. The compound of claim 26 , or a salt thereof, wherein q is 0 and m is 1.
28. The compound of claim 27 , or a salt thereof, wherein —R 8c R 8d —R 8e R 8f — and the carbons to which they are attached are taken together to form a moiety selected from the group consisting of —CH 2 —C(H)(CH 3 )—, —C(H)(CH 3 )—CH 2 —, —CH 2 —C(CH 3 )(CH 3 )—, —C(CH 2 CH 2 )—CH 2 - and —CH 2 —C(CH 2 CH 2 )—.
29. The compound of claim 26 , or a salt thereof, wherein Q is a substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
30. The compound of claim 1 , or a salt thereof, wherein:
R 1 is H, hydroxyl, nitro, cyano, halo, 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, thiol, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
each R 2a and R 2b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, hydroxyl, alkoxy, cyano, nitro or R 2a and R 2b are taken together with the carbon to which they are attached to form a carbonyl moiety;
each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, nitro or R 3a and R 3b are taken together with the carbon to which they are attached to form a carbonyl moiety;
X 7 , X 8 , X 9 and X 10 are taken together to provide an aromatic moiety selected from the group consisting of:
m and q are independently 0 or 1;
each R 4 , where present, is independently 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, 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 8 , where present, is independently H, hydroxyl, C 1 -C 8 alkyl, carboxy, carbonylalkoxy or is taken together with the carbon to which it is attached and a geminal R 8 to form a cycloalkyl moiety or a carbonyl moiety;
each R 10a and R 10b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, hydroxyl, alkoxy, or R 10a and R 10b are taken together with the carbon to which they are attached to form a carbonyl moiety; and
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted or unsubstituted heterocyclyl.
31. The compound of claim 1 , or a salt thereof, wherein the compound is selected from the group consisting of:
Compound
No.
Structure
11
12
14
15
168
169
170
175
176
177
178
181
182
183
185
210
213
214
259H
260H
261H
273H
276H
291
346
347
348
353
355
482
484
541
544
546
547
548
32. A pharmaceutical composition comprising a compound according to claim 1 , or a salt thereof, and a pharmaceutically acceptable carrier.
33. A kit comprising a compound according to claim 1 , or a salt thereof, and instructions for use.
34. A pharmaceutical composition comprising a compound according to claim 26 , or a salt thereof, and a pharmaceutically acceptable carrier.
35. A kit comprising a compound according to claim 26 , or a salt thereof, and instructions for use.