Bridged heterocyclic compounds and methods of use
View Patent ↗This disclosure relates to new compounds that may be used to modulate a histamine receptor in an individual. Novel compounds are described, including new bridged heterocyclic [4,3-b]indole compounds. Pharmaceutical compositions are also provided. 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 method of treating a disorder in an individual in need thereof, wherein the disorder is schizophrenia, comprising administering to the individual an effective amount of a compound of the formula (A-2):
wherein:
R 1 is unsubstituted C 1 -C 8 alkyl;
each X 7 , X 8 , X 9 and X 10 is independently N or CR 4 ;
q is 0;
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, thiol, carbonylalkoxy, 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 and R 8f is independently H, hydroxyl, C 1 -C 8 alkyl, C 1 -C 8 perhaloalkyl, carboxy or carbonylalkoxy;
R 8e is independently hydroxyl, C 1 -C 8 alkyl, C 1 -C 8 perhaloalkyl, carboxy or carbonylalkoxy; and
Q is a 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, unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy or acylamino;
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein in the compound, or a pharmaceutically acceptable salt thereof, R 8c , R 8d , R 8e and R 8f are taken together with the carbon atoms to which they are attached form a moiety selected from the group consisting of:
3. The method of claim 1 , wherein the compound is selected from the group consisting of compounds 52, 53, 54 and 55:
Compound #
Structure
52
53
54
55
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the compound is selected from the group consisting of compounds 91, 98 and 99:
Compound #
Structure
91
98
99
or a pharmaceutically acceptable salt thereof.
5. The method of claim 1 , wherein the compound is selected from the group consisting of compounds 160 and 161:
Compound #
Structure
160
161
or a pharmaceutically acceptable salt thereof.
6. A method of treating a disorder in an individual in need thereof, wherein the disorder is schizophrenia, comprising administering to the individual an effective amount of a compound of the formula (A-2):
or a pharmaceutically acceptable salt thereof,
wherein each X 8 and X 9 is independently CR 4 where R 4 is H, halo or methyl; each X 7 and X 10 is CH; R 1 is methyl; q is 0 or 1; each R 8a and R 8b is H when present; each R 8c and R 8d is H; each R 8e and R 8f is independently H, hydroxy or methyl and Q is selected from the group consisting of:
7. The method of claim 6 , wherein the compound is selected from the group consisting of compounds 32, 34, 35, 37, 38, 57, 61, 62 and 71:
Compound #
Structure
32
34
35
37
38
57
61
62
71
or a pharmaceutically acceptable salt thereof.
8. The method of claim 6 , wherein the compound is selected from the group consisting of compounds 77, 79, 80, 86, 89, 90, 92, 94, 95, 96, 97 and 102:
Compound #
Structure
77
79
80
86
89
90
92
94
95
96
97
102
or a pharmaceutically acceptable salt thereof.
9. A method of treating a disorder in an individual in need thereof, wherein the disorder is schizophrenia, comprising administering to the individual an effective amount of a compound of the formula (F-1):
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, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy;
each R 2 and R 10 is independently H, hydroxyl, alkoxyl or substituted or unsubstituted C 1 -C 8 alkyl;
each R 3a and R 3b is independently H, substituted or unsubstituted C 1 -C 8 alkyl, halo, cyano, nitro, hydroxyl, alkoxy, amino, substituted amino, cycloalkyl, acylamino or acyloxy; or R 3a and R 3b are taken together to form a cycloalkyl or a carbonyl moiety;
p is 1 or 2;
each X 7 , X 8 , X 9 and X 10 is independently N or CR 4 ;
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, thiol, carbonylalkoxy, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;
R 11 and R 12 are independently H, C 1 -C 8 alkyl, C 1 -C 8 perhaloalkyl, carboxy, carbonylalkoxy, or taken together with the carbon atoms to which they are attached to form substituted or unsubstituted C 3 -C 8 cycloalkenyl or substituted or unsubstituted heterocyclyl moiety or are taken together to form a bond, thereby providing an acetylenyl moiety; indicates the presence of either an E or Z double bond configuration; and
Q is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or an unsubstituted heterocyclyl, unsubstituted amino, substituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy, aminocarbonylalkoxy, acylamino, carboxy, alkynyl or cyano;
or a pharmaceutically acceptable salt thereof.
10. The method of claim 9 , wherein in the compound, or a pharmaceutically acceptable salt thereof, R 1 is methyl; each R 2 , R 3a , R 3b and R 10 is H; p is 1; X 9 is CR 4 where R 4 is halo or methyl; each X 7 , X 8 and X 10 is CH; R 11 is H; R 12 is methyl and Q is substituted phenyl.
11. The method of claim 9 , wherein the compound is of the formula (F-2):
or a pharmaceutically acceptable salt thereof.
12. The method of claim 11 , wherein in the compound, or a pharmaceutically acceptable salt thereof, R 1 is methyl; each R 2 , R 3a , R 3b and R 10 is H; p is 1; X 9 is CR 4 where R 4 is halo or methyl; each X 7 , X 8 and X 10 is CH and Q is substituted pyridyl.
13. The method of claim 9 , wherein in the compound, or a pharmaceutically acceptable salt thereof, R 11 is H and Q is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
14. The method of claim 13 , wherein in the compound, or a pharmaceutically acceptable salt thereof, R 12 is H or methyl.
15. The method of claim 14 , wherein in the compound, or a pharmaceutically acceptable salt thereof, R1 is methyl, p is 1, and X9 is CR4 where R4 is halo or methyl.
16. The method of claim 9 , wherein the compound is selected from the group consisting of compounds 115, 116, 117, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136 and 137:
Compound #
Structure
115
116
117
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
or a pharmaceutically acceptable salt thereof.
17. The method of claim 9 , wherein the compound is selected from the group consisting of compounds 163 and 164:
Compound #
Structure
163
164
or a pharmaceutically acceptable salt thereof.
18. The method of claim 11 , wherein the compound is selected from the group consisting of compounds 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154 and 155:
Compound #
Structure
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
or a pharmaceutically acceptable salt thereof.
19. The method of claim 11 , wherein the compound is compound 165:
Compound #
Structure
165
or a pharmaceutically acceptable salt thereof.