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US 9,284,277 B2Granted
Benzazepines as serotonin 5-HT2C receptor ligands and uses thereof
AssigneeABT Holding Company
InventorsMike Robarge, John Harrington, David Gerrish, John Mecom
Life of this patent
Estimating the term…
Abstract
The present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents. More specifically, compounds of the present invention are benzazepine compounds. These compounds are serotonin receptor (5-HT2c) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT2c) is desired (e.g. addiction, anxiety, depression, obesity, and others).
Claims21
A compound of the formula
- where
- R1 is selected from the group consisting of H, alkyl, perhaloalkyl, alkanoyl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
- R2 and R3 are independently selected from the group consisting of H, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl, CN, OR8, NR8R9, SR8, OCOR10, CONR8R9, NR8COR10, NR8CO2R10, SO2NR8R9, SO2R10, NR8SO2R10, aryl, heteroaryl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
- R4 and R5 together with the atoms which they are attached form a 5- or 6-membered carbocycle ring, substituted with R14a and one or more of each of R11a, R11b, R12a, R12b, R13a, R13b, and R14b;
- R6a and R6b are independently selected from the group consisting of H, C1-8alkyl, OR8, and heteroaryl;
- or R6a and R6b taken together are —CH2CH2—;
- R7a and R7b are independently selected from the group consisting of H, C1-8alkyl, OR8, aryl, and heteroaryl;
- or R7a and R7b taken together are —CH2CH2—;
- R8 is selected from the group consisting of H, C1-8alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl, C1-8 alkyl-O—C1-8 alkyl, aryl, heteroaryl, C1-8 alkyl-O-aryl, C1-8 alkyl-O-heteroaryl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
- R9 is selected from the group consisting of H, C1-8alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl, C1-8 alkyl-O—C1-8 alkyl, aryl, heteroaryl, C1-8 alkyl-O-aryl, C1-8 alkyl-O-heteroaryl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
- R10 is selected from the group consisting of C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl, C1-8 alkyl-O—C1-8 alkyl, aryl, heteroaryl, C1-8 alkyl-O-aryl, C1-8 alkyl-O-heteroaryl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
- R11a and R11b are independently selected from the group consisting of H, halogen, C1-8 alkyl, perhaloalkyl, aryl, and heteroaryl;
- R12a and R12b are independently selected from the group consisting of H, halogen, C1-8 alkyl, perhalo alkyl, aryl, and heteroaryl
- R13a and R13b are independently selected from the group consisting of H, halogen, C1-8 alkyl, perhaloalkyl, aryl, and heteroaryl;
- R14a is selected from the group consisting of halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl, CN, OR8, NR8R9, SR8, OCOR10, OCONR8R9, CONR8R9, NR8COR10, NR8CO2R10, NR8SO2R10, aryl, heteroaryl, C1-8 alkylaryl, and C1-8 alkylheteroaryl,
- R14b is selected from the group consisting of H, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl, CN, OR8, NR8R9, SR8, OCOR10, OCONR8R9, CONR8R9, NR8COR10, NR8CO2R10, NR8SO2R10, aryl, heteroaryl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
- or an isomer or a pharmaceutically acceptable salt thereof.
14 more elements
A compound selected from the group consisting of:
- 1-Methyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1-Ethyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1-Cyclopropyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1-Propyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 4-Chloro-1-ethyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1-Ethyl-4-iodo-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1-Ethyl-4-fluoro-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1-Phenyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 4-Chloro-1-phenyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1-Pyridin-3-yl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 4-Fluoro-1-pyridin-3-yl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1,1-Dimethyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 2,2-Difluoro-1-phenyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 2,2-Difluoro-1-o-tolyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 2,2-Difluoro-1-m-tolyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 2,2-Difluoro-1-p-tolyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 2,2-Difluoro-1-(3-trifluoromethyl-phenyl)-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 2,2-Difluoro-1-(3-trifluoromethoxy-phenyl)-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 2,2-Difluoro-1-(4-fluoro-phenyl)-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 2,2-Difluoro-1-(3-fluoro-phenyl)-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1-Cyclopropyl-2,2-difluoro-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1-(3-Chloro-phenyl)-2,2-difluoro-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1-(4-Chloro-phenyl)-2,2-difluoro-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 2,2-Difluoro-1-(2-methoxy-phenyl)-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 2,2-Difluoro-1-(3-methoxy-phenyl)-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 2,2-Difluoro-1-(4-methoxy-phenyl)-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 2,2-Difluoro-1-pyridin-3-yl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 2,2-Difluoro-1-pyridin-4-yl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 4-Chloro-2,2-difluoro-1-pyridin-3-yl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1-Ethyl-2,2-difluoro-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 2,2-Difluoro-1-methyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1-Benzyl-2,2-difluoro-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 2,2-Difluoro-1,1-dimethyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1,1-Dimethyl-4-phenyl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1-Ethyl-1,2,7,8,9,10-hexahydro-6H-3-oxa-8-aza-cyclohepta[e]indene;
- 1-Ethyl-2,3,8,9,10,11-hexahydro-1H,7H-4-oxa-9-aza-cyclohepta[a]naphthalene;
- 2,2-Difluoro-1-methoxy-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1-Phenyl-7,8,9,10-tetrahydro-6H-3-oxa-8-aza-cyclohepta[e]indene;
- 1-Thiazol-2-yl-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 1-Ethoxy-2,2-difluoro-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- 2,2-Difluoro-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene;
- and
- 1-Methoxy-1,2,3,6,7,8,9,10-octahydro-8-aza-cyclohepta[e]indene.
40 more elements
A compound of the formula
- where
- X is S, SO2 or O;
- R1 is selected from the group consisting of H, alkyl, perhaloalkyl, alkanoyl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
- R2 and R3 are independently selected from the group consisting of H, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl, CN, OR8, NR8R9, SR8, OCOR10, CONR8R9, NR8COR10, NR8CO2R10, SO2NR8R9, SO2R10, NR8SO2R10, aryl, heteroaryl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
- R8 is selected from the group consisting of H, C1-8alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl, C1-8 alkyl-O—C1-8 alkyl, aryl, heteroaryl, C1-8 alkyl-O-aryl, C1-8 alkyl-O-heteroaryl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
- R9 is selected from the group consisting of H, C1-8alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl, C1-8 alkyl-O—C1-8 alkyl, aryl, heteroaryl, C1-8 alkyl-O-aryl, C1-8 alkyl-O-heteroaryl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
- R10 is selected from the group consisting of C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl, C1-8 alkyl-O—C1-8 alkyl, aryl, heteroaryl, C1-8 alkyl-O-aryl, C1-8 alkyl-O-heteroaryl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
- R12a and R12b are independently selected from the group consisting of H, halogen, C1-8 alkyl, perhalo alkyl, aryl, and heteroaryl;
- R13a and R13b are independently selected from the group consisting of H, halogen, C1-8 alkyl, perhaloalkyl, aryl, and heteroaryl;
- R14a is selected from the group consisting of halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl, CN, OR8, NR8R9, SR8, OCOR10, OCONR8R9, CONR8R9, NR8COR10, NR8CO2R10, NR8SO2R10, aryl, heteroaryl, C1-8 alkylaryl, and C1-8 alkylheteroaryl;
- R14b is selected from the group consisting of H, halogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, perhaloalkyl, CN, OR8, NR8R9, SR8, OCOR10, OCONR8R9, CONR8R9, NR8COR10, NR8CO2R10, NR8SO2R10, aryl, heteroaryl, C1-8 alkylaryl, and C1-8 alkylheteroaryl,
- provided that when the is a double bond, then R12b and R14b are not present,
- or an isomer or a pharmaceutically acceptable salt thereof.
10 more elements
Dependencies are inferred from the claim text.