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US 9,801,878 B2Granted
Quinoline derivatives as PDE10A enzyme inhibitors
AssigneeH. Lundbeck A/S
InventorsJan Kehler, Jacob Nielsen, Ask Püschl, John Paul Kilburn, Morten Langgård
Life of this patent
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Abstract
The present invention provides quinoline derivatives of formula I that are PDE10A enzyme inhibitors, and as such are useful to treat neurodegenerative and psychiatric disorders. Especially, the invention provides compounds that are highly selective for PDE10A over other PDE subtypes. The present invention also provides pharmaceutical compositions comprising compounds of the invention and methods of treating disorders using the compounds of the invention.
Claims15
A method of treating an obsessive/compulsive disorder comprising administering a therapeutically effective amount of a compound of formula I to a patient in need thereof
- wherein R1, R2, R3, R4, R5 and R6 are substituents, that are individually or coordinately selected, wherein said individually selected substituents are selected from the group consisting of hydrogen, hydroxyl, cyano, C1-C6 alkyl;
- C1-C6 alkoxy, and halogen, and said coordinately selected substituents form methylenedioxy, diflouromethylenedioxy or ethylenedioxy;
- wherein -L- is a linker selected from —CH2—CH2— and —CH═CH—;
- wherein HET is selected from the group consisting of
- wherein one or more of the carbon-bound hydrogen in the HET optionally may be substituted with up to three substituents R7, R8 and R9 individually selected from C1-C6 alkyl;
- halogen;
- cyano, halo(C1-C6)alkyl;
- aryl, alkoxy and C1-C6 hydroxyalkyl;
- wherein * denotes the attachment point;
- and wherein said compound of formula I is not:
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)quinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl)quinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)quinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl)quinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-3-fluoroquinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-5,8-difluoroquinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-5,8-difluoroquinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-7,8-difluoroquinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-3-methylquinoline;
- 2-(2-([1,2,4]triazolo[1,5-a]pyridin-2-)ethyl)quinoline;
- 7,8-dichloro-2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)quinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)quinoline;
- or
- (Z)-2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-6,7-dihydroquinoline.
21 more elements
A method of treating non-insulin demanding diabetes mellitus comprising administering a therapeutically effective amount of a compound of formula I to a patient in need thereof
- wherein R1, R2, R3, R4, R5 and R6 are substituents, that are individually or coordinately selected, wherein said individually selected substituents are selected from the group consisting of hydrogen, hydroxyl, cyano, C1-C6 alkyl;
- C1-C6 alkoxy, and halogen, and said coordinately selected substituents form methylenedioxy, diflouromethylenedioxy or ethylenedioxy;
- wherein -L- is a linker selected from —CH2—CH2— and —CH═CH—;
- wherein HET is selected from the group consisting of
- wherein one or more of the carbon-bound hydrogen in the HET optionally may be substituted with up to three substituents R7, R8 and R9 individually selected from C1-C6 alkyl;
- halogen;
- cyano, halo(C1-C6)alkyl;
- aryl, alkoxy and C1-C6 hydroxyalkyl;
- wherein * denotes the attachment point;
- and wherein said compound of formula I is not:
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)quinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl)quinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)quinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl)quinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-3-fluoroquinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-5,8-difluoroquinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl) ethyl)-5,8-difluoroquinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-7,8-difluoroquinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-3-methylquinoline;
- 2-(2-([1,2,4]triazolo[1,5-a]pyridin-2-yl)ethyl)quinoline;
- 7,8-dichloro-2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)quinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)yinyl)quinoline;
- or
- (Z)-2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-6,7-dihydroquinoline.
21 more elements
A method of treating Attention Deficit/Hyperactivity Disorder comprising administering a therapeutically effective amount of a compound of formula I to a patient in need thereof
- wherein R1, R2, R3, R4, R5 and R6 are substituents, that are individually or coordinately selected, wherein said individually selected substituents are selected from the group consisting of hydrogen, hydroxyl, cyano, C1-C6 alkyl;
- C1-C6 alkoxy, and halogen, and said coordinately selected substituents form methylenedioxy, diflouromethylenedioxy or ethylenedioxy;
- wherein -L- is a linker selected from —CH2—CH2— and —CH═CH—;
- wherein HET is selected from the group consisting of
- wherein one or more of the carbon-bound hydrogen in the HET optionally may be substituted with up to three substituents R7, R8 and R9 individually selected from C1-C6 alkyl;
- halogen;
- cyano, halo(C1-C6)alkyl;
- aryl, alkoxy and C1-C6 hydroxyalkyl;
- wherein * denotes the attachment point;
- and wherein said compound of formula I is not:
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)quinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl)quinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)quinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)ethyl)quinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-3-fluoroquinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-5,8-difluoroquinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl) ethyl)-5,8-difluoroquinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-7,8-difluoroquinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)-3-methylquinoline;
- 2-(2-([1,2,4]triazolo[1,5-a]pyridin-2-yl)ethyl)quinoline;
- 7,8-dichloro-2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)ethyl)quinoline;
- 2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)quinoline;
- or
- (Z)-2-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-6,7-dihydroquinoline.
21 more elements
Dependencies are inferred from the claim text.