2,6-disubstituted pyridine derivative
The present invention relates to a pyridine derivative of formula (1) wherein R 1 is optionally-substituted C 1-6 alkyl, optionally-substituted C 3-10 cycloalkyl, or optionally-substituted 5- to 10-membered saturated or partially-unsaturated heterocyclyl; R 2 is halogen atom, cyano, C 1-6 alkyl which may be optionally substituted with 1 to 3 the same or different halogen atoms, C 1-6 alkoxy which may be optionally substituted with 1 to 3 the same or different halogen atoms, or amino which may be optionally substituted with 1 to 2 the same or different C 1-6 alkyl; and the bind with broken line is single or double bond, or a pharmaceutically acceptable salt thereof, which is useful as a medicament for treating symptoms in anxiety-related disorder.
1. A compound of formula (1):
or a pharmaceutically acceptable salt thereof, wherein
R 1 is optionally-substituted C 1-6 alkyl, optionally-substituted C 3-10 cycloalkyl, or optionally-substituted 5- to 10-membered saturated or partially-unsaturated heterocyclyl group; and
R 2 is halogen atom, cyano, C 1-6 alkyl which may be optionally substituted with 1 to 3 the same or different halogen atoms, C 1-6 alkoxy which may be optionally substituted with 1 to 3 the same or different halogen atoms, or amino which may be optionally substituted with 1 or 2 the same or different C 1-6 alkyl groups.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein
R 1 is
(1) C 1-6 alkyl which may be optionally substituted with 1 to 3 the same or different substituents selected from the group consisting of halogen atom, hydroxy, C 3-7 cycloalkyl, and C 1-6 alkoxy,
(2) C 3-10 cycloalkyl which may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, cyano, C 1-6 alkyl which may be optionally substituted with 1 to 3 the same or different halogen atom or C 1-6 alkoxy, C 1-6 alkoxy which may be optionally substituted with 1 to 3 the same or different halogen atom or C 1-6 alkoxy, and amino which may be optionally substituted with 1 or 2 the same or different C 1-6 alkyl, or
(3) 5- to 10-membered saturated or partially-unsaturated heterocyclyl group which may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, hydroxy, cyano, C 1-6 alkyl which may be optionally substituted with 1 to 3 the same or different halogen atom or C 1-6 alkoxy, C 1-6 alkoxy which may be optionally substituted with 1 to 3 the same or different halogen atom or C 1-6 alkoxy, and amino which may be optionally substituted with 1 or 2 the same or different C 1-6 alkyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is
(1) C 3-7 cycloalkyl which may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, and C 1-6 alkyl which may be optionally substituted with 1 to 3 the same or different halogen atom or C 1-6 alkoxy, or
(2) 5- or 6-membered saturated or partially-unsaturated heterocyclyl group which may be optionally substituted with 1 to 4 the same or different substituents selected from the group consisting of halogen atom, and C 1-6 alkyl which may be optionally substituted with 1 to 3 the same or different halogen atom or C 1-6 alkoxy.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is C 3-7 cycloalkyl which may be optionally substituted with 1 to 4 fluorine atoms, or 5- or 6-membered saturated or partially-unsaturated heterocyclyl group which may be optionally substituted with 1 to 4 fluorine atoms.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is cyclohexyl which may be optionally substituted with 1 to 4 fluorine atoms, tetrahydropyranyl, tetrahydrofuryl, dihydropyranyl, or dihydrofuryl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is difluorocyclohexyl, or tetrahydropyranyl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is halogen atom, or C 1-6 alkyl which may be optionally substituted with 1 to 3 the same or different halogen atoms.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1-4 alkyl which may be optionally substituted with 1 to 3 fluorine atoms.
9. The compound of claim 1 , which is selected from the group consisting of:
4,4-difluoro-N-(2-{4-[6-(trifluoromethyl)pyridin-2-yl]piperidin-1-yl}ethyl)cyclohexane-carboxamide,
N-{2-[4-(6-methylpyridin-2-yl)piperidin-1-yl]ethyl}-tetrahydro-2H-pyran-4-carboxamide,
2,2-dimethyl-N-(2-{4-[6-(trifluoromethyl)pyridin-2-yl]piperidin-1-yl}ethyl)propanamide, and
N-(2-(4-[6-(trifluoromethyl)pyridin-2-yl]piperidin-1-yl)ethyl)-tetrahydro-2H-pyran-4-carboxamide,
or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 , which is 2,2-dimethyl-N-(2-{4-[6-(trifluoromethyl)pyridin-2-yl]piperidin-1-yl}ethyl)propanamide, or a pharmaceutically acceptable salt thereof.
11. A medicament comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient, additive and/or carrier.
12. A method for treating a disease or disorder selected from the group consisting of generalized anxiety disorder, major depression, obsessive-compulsive disorder, Parkinson's disease, and Rett syndrome, the method comprising administering a therapeutically effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof.
13. A medicament comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one other medicament selected from drugs classified as an antianxiety drug or an antidepressant drug.
14. The medicament of claim 13 , wherein the antianxiety drug is a selective serotonin reuptake inhibitor.
15. The medicament of claim 14 , wherein the selective serotonin reuptake inhibitor is at least one drug selected from the group consisting of sertraline, escitalopram, fluvoxamine, fuoxetine, paroxetine, clomipramine, and pharmaceutically acceptable salts thereof.
16. The medicament of claim 13 , wherein the antidepressant drug is a serotonin reuptake inhibitor.
17. The medicament of claim 16 , wherein the serotonin reuptake inhibitor is at least one drug selected from the group consisting of milnacipran, duloxetine, venlafaxine, amoxapine, clomipramine, nortriptyline, imipramine, vortioxetine, and pharmaceutically acceptable salts thereof.
18. The method of claim 12 , wherein the compound is 4,4-difluoro-N-(2-{4-[6-(trifluoromethyl)pyridin-2-yl]piperidin-1-yl-}ethyl)cyclohexane-carboxamide, or a pharmaceutically acceptable salt thereof.
19. The method of claim 12 , wherein the compound is N-{2-[4-(6-methylpyridin-2-yl)piperidin-1-yl]ethyl}-tetrahydro-2H-pyran-4-carboxamide, or a pharmaceutically acceptable salt thereof.
20. The method of claim 12 , wherein the compound is N-(2-{4-[6 -(trifluoromethyl)pyridin-2-yl]piperidin-1-yl }ethyl)-tetrahydro-2H-pyran-4-carboxamide, or a pharmaceutically acceptable salt thereof.
21. The method of claim 12 , wherein the disease or disorder is generalized anxiety disorder, major depression, or obsessive-compulsive disorder.
22. The method of claim 18 , wherein the disease or disorder is generalized anxiety disorder, major depression, or obsessive-compulsive disorder.
23. The method of claim 19 , wherein the disease or disorder is generalized anxiety disorder, major depression, or obsessive-compulsive disorder.
24. The method of claim 20 , wherein the disease or disorder is generalized anxiety disorder, major depression, or obsessive-compulsive disorder.