Derivatives of 5-pyridinyl-1-azabicyclo[3.2.1]octane, preparation method thereof and use of same in therapeutics
View Patent ↗The invention relates to compounds having general formula (I), wherein R is as defined herein. The invention also relates to acid addition salt, a hydrate or a solvate of compounds of formula (I). The invention further relates to the method of preparing said compounds and to the use of same in therapeutics.
1. A method of treating a disorder associated with dysfunction of the nicotinic receptors, comprising administering to a patient in need of said treatment a therapeutically effective amount of a compound of formula (I):
in which:
R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl and tetrazolyl, said group optionally substituted with one or more groups chosen from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, amino, (C 1 -C 6 )alkylamino and di(C 1 -C 6 )alkylamino group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond;
or a pharmaceutically acceptable salt thereof;
wherein the disorder is selected from the group consisting of executive function disorders associated with Alzheimer's disease and schizophrenia.
2. The method according to claim 1 , wherein for the compound of formula (I):
R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl and tetrazolyl, said group optionally substituted with one or more (C 1 -C 6 )alkyl group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.
3. The method according to claim 1 , wherein for the compound of formula (I):
R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl and tetrazolyl, said group optionally substituted with one or more groups chosen from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, amino, (C 1 -C 6 )alkylamino and di(C 1 -C 6 )alkylamino group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.
4. The method according to claim 1 , wherein for the compound of formula (I):
R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl and tetrazolyl, said group optionally substituted with one or more (C 1 -C 6 )alkyl group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.
5. The method according to claim 1 , wherein for the compound of formula (I):
R represents a pyrazolyl group optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, amino, (C 1 -C 6 )alkylamino or di(C 1 -C 6 )alkylamino group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.
6. The method according to claim 1 , wherein for the compound of formula (I):
R represents a pyrazolyl group optionally substituted with one or more (C 1 -C 6 )alkyl group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.
7. The method according to claim 1 , wherein for the compound of formula (I):
R represents a pyrazolyl group optionally substituted with one or more (C 1 -C 6 )alkyl groups; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single bond.
8. The method according to claim 1 , wherein the compound is selected from the group consisting of:
5-[2-(1-methyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]oct-3-ene;
5-[2-(1-methyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]-oct-3-ene;
5-[2-(1H-imidazol-1-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]oct-3-ene
5-[2-(1H-imidazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]oct-3-ene
5-[2-(1H-imidazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(1H-imidazol-1-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(1H-imidazol-2-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1H-1,2,4-triazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1,3-oxazol-2-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(thiazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(pyrazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(2-methylthiazol-5-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(tetrazol-5-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1-isobutyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane; and
5-[2-(1-n-propyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
or a pharmaceutically acceptable salt thereof.
9. A method of inhibiting a nicotinic receptor, comprising administering to a patient in need of said inhibition a therapeutically effective amount of a compound of formula (I):
in which:
R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl and tetrazolyl, said group optionally substituted with one or more groups chosen from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, amino, (C 1 -C 6 )alkylamino and di(C 1 -C 6 )alkylamino group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond;
or a pharmaceutically acceptable salt thereof.
10. The method according to claim 9 , wherein for the compound of formula (I):
R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl and tetrazolyl, said group optionally substituted with one or more (C 1 -C 6 )alkyl group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.
11. The method according to claim 9 , wherein for the compound of formula (I):
R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl and tetrazolyl, said group optionally substituted with one or more groups chosen from halogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, amino, (C 1 -C 6 )alkylamino and di(C 1 -C 6 )alkylamino group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.
12. The method according to claim 9 , wherein for the compound of formula (I):
R represents a group chosen from pyrazolyl, imidazolyl, triazolyl, oxazolyl, oxadiazolyl, thiazolyl and tetrazolyl, said group optionally substituted with one or more (C 1 -C 6 )alkyl group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.
13. The method according to claim 9 , wherein for the compound of formula (I):
R represents a pyrazolyl group optionally substituted with one or more (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, trifluoromethoxy, trifluoromethyl, nitro, cyano, hydroxyl, amino, (C 1 -C 6 )alkylamino or di(C 1 -C 6 )alkylamino group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.
14. The method according to claim 9 , wherein for the compound of formula (I):
R represents a pyrazolyl group optionally substituted with one or more (C 1 -C 6 )alkyl group; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single or a double bond.
15. The method according to claim 9 , wherein for the compound of formula (I):
R represents a pyrazolyl group optionally substituted with one or more (C 1 -C 6 )alkyl groups; and wherein
the carbon-carbon bond between positions 3 and 4 of the azabicyclooctane ring is a single bond.
16. The method according to claim 9 , wherein the compound is selected from the group consisting of:
5-[2-(1-methyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]oct-3-ene;
5-[2-(1-methyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]-oct-3-ene;
5-[2-(1H-imidazol-1-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]oct-3-ene
5-[2-(1H-imidazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]oct-3-ene
5-[2-(1H-imidazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(1H-imidazol-1-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(1H-imidazol-2-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(3,5-dimethyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1H-1,2,4-triazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(5-methyl-1,2,4-oxadiazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1,3-oxazol-2-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(thiazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(pyrazol-3-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(2-methylthiazol-5-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane
5-[2-(tetrazol-5-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
5-[2-(1-isobutyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane; and
5-[2-(1-n-propyl-1H-pyrazol-4-yl)pyrid-5-yl]-1-azabicyclo[3.2.1]octane;
or a pharmaceutically acceptable salt thereof.