3-azabicyclo[3.1.0]hexane derivative and use thereof for medical purpose
View Patent ↗The object of the present invention is to provide a compound having an antagonistic action against μ-opioid receptors, which causes less side effects and thus is highly safe. A compound represented by the general formula (I), or a pharmacologically acceptable salt thereof: wherein R 1 and R 2 are the same or different, and each represents a hydrogen atom or a halogen atom, provided that R 1 and R 2 are not simultaneously halogen atoms, R 3 represents a C 1 -C 3 alkyl group or a vinyl group, and R 4 represents the formula (II): wherein R 5 represents a hydroxy group or a C 1 -C 3 alkoxy group, and R 6 and R 7 are the same or different, and each represents a hydrogen atom or a halogen atom; or the formula (III): wherein Ring A represents a halogen atom(s)-substituted C 5 -C 7 cycloalkyl group which is optionally substituted by a C 1 -C 3 alkoxy group, or a halogen atom(s)-substituted 5- to 7-membered saturated heterocyclic group.
1. A compound represented by the general formula (I), or a pharmacologically acceptable salt thereof:
wherein
R 1 represents a hydrogen atom, and
R 2 represents a hydrogen atom or a halogen atom, and
R 3 represents a C 1 -C 3 alkyl group, and
R 4 represents the formula (II):
wherein R 5 represents a hydroxy group or a C 1 -C 3 alkoxy group, and R 6 and R 7 represent a hydrogen atom provided that R 5 represents a hydroxy group when R 2 represents a halogen atom, and R 5 represents a C 1 -C 3 alkoxy group when R 2 represents a hydrogen atom;
or the formula (III):
wherein Ring A represents a halogen atom(s)-substituted C 5 -C 7 cycloalkyl group which is optionally substituted by a C 1 -C 3 alkoxy group, or a halogen atom(s)-substituted 5- to 7-membered saturated heterocyclic group.
2. The compound or a pharmacologically acceptable salt thereof according to claim 1 , wherein R 3 is an ethyl group in the general formula (I).
3. The compound or a pharmacologically acceptable salt thereof according to claim 1 , wherein R 4 is the formula (II) in the general formula (I):
wherein R 5 represents a hydroxy group or a C 1 -C 3 alkoxy group, and R 6 and R 7 represent a hydrogen atom provided the R 5 represents a hydroxy group when R 2 represents a halogen atom, and R 5 represents a C 1 -C 3 alkoxy group when R 2 represents a hydrogen atom.
4. The compound or a pharmacologically acceptable salt thereof according to claim 1 , wherein R 2 is a hydrogen atom or a fluorine atom, and R 3 is an ethyl group in the general formula (I).
5. The compound or a pharmacologically acceptable salt thereof according to claim 1 , wherein R 4 is the formula (III):
wherein Ring A is a halogen atom(s)-substituted C 5 -C 7 cycloalkyl group which is optionally substituted by a C 1 -C 3 alkoxy group, or a halogen atom(s)-substituted 5- to 7-membered saturated heterocyclic group in the general formula (I).
6. The compound or a pharmacologically acceptable salt thereof according to claim 5 , wherein Ring A is a fluorine atom(s)-substituted cyclohexyl group which is optionally substituted by a C 1 -C 3 alkoxy group, or a fluorine atom(s)-substituted 5- to 6-membered nitrogen-containing saturated heterocyclic group in the formula (III).
7. The compound or a pharmacologically acceptable salt thereof according to claim 6 , wherein Ring A is any group selected from the following group:
in the formula (III).
8. The compound or a pharmacologically acceptable salt thereof according to claim 3 , wherein the compound is selected from the group consisting of:
N-(3-{(1R,5S,6r)-6-ethyl-3-[(2-hydroxy-2,3-dihydro-1H-inden-2-yl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl}-4-fluorophenyl)cyclopropanesulfonamide, and
N-(3-{(1R,5S,6r)-6-ethyl-3-[(2-methoxy-2,3-dihydro-1H-inden-2-yl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl}phenyl)cyclopropanesulfonamide.
9. The compound or a pharmacologically acceptable salt thereof according to claim 5 , wherein the compound is selected from the group consisting of:
N-(3-{(1R,5S,6r)-3-[3-(4,4-difluorocyclohexyl)propyl]-6-ethyl-3-azabicyclo[3.1.0]hexan-6-yl}phenyl)cyclopropanesulfonamide,
N-(3-{(1R,5S,6r)-3-[3-(4,4-difluorocyclohexyl)propyl]-6-ethyl-3-azabicyclo[3.1.0]hexan-6-yl}-4-fluorophenyl)cyclopropanesulfonamide,
N-(3-{(1R,5S,6r)-3-[3-(4,4-difluoro-1-methoxycyclohexyl)propyl]-6-ethyl-3-azabicyclo[3.1.0]hexan-6-yl}phenyl)cyclopropanesulfonamide,
N-(3-{(1R,5S,6r)-3-[3-(4,4-difluoropiperidin-1-yl)propyl]-6-ethyl-3-azabicyclo[3.1.0]hexan-6-yl}phenyl)cyclopropanesulfonamide,
N-(3-{(1R,5S,6r)-3-[3-(3,3-difluoropyrrolidin-1-yl)propyl]-6-ethyl-3-azabicyclo[3.1.0]hexan-6-yl}phenyl)cyclopropanesulfonamide,
N-(3-{(1R,5S,6r)-3-[3-(4,4-difluoropiperidin-1-yl)propyl]-6-ethyl-3-azabicyclo[3.1.0]hexan-6-yl}-4-fluorophenyl)cyclopropanesulfonamide, and
N-(3-{(1R,5S,6r)-3-[3-(3,3-difluoropiperidin-1-yl)propyl]-6-ethyl-3-azabicyclo[3.1.0]hexan-6-yl}phenyl)cyclopropanesulfonamide.
10. A medicament comprising the compound or a pharmacologically acceptable salt thereof according to claim 1 as an active ingredient.
11. A process for treating pruritus comprising administering the medicament according to claim 10 to a subject in need thereof.
12. The compound or a pharmacologically acceptable salt thereof according to claim 3 , wherein the compound is
N-(3-{(1R,5S,6r)-6-ethyl-3-[(2-hydroxy-2,3-dihydro-1H-inden-2-yl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl}-4-fluorophenyl)cyclopropanesulfonamide.
13. The compound or a pharmacologically acceptable salt thereof according to claim 3 , wherein the compound is
N-(3-{(1R,5S,6r)-6-ethyl-3-[(2-methoxy-2,3-dihydro-1H-inden-2-yl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl}phenyl)cyclopropanesulfonamide.
14. The compound or a pharmacologically acceptable salt thereof according to claim 5 , wherein the compound is
N-(3-{(1R,5S,6r)-3-[3-(4,4-difluorocyclohexyl)propyl]-6-ethyl-3-azabicyclo[3.1.0]hexan-6-yl}phenyl)cyclopropanesulfonamide.
15. The compound or a pharmacologically acceptable salt thereof according to claim 5 , wherein the compound is
N-(3-{(1R,5S,6r)-3-[3-(4,4-difluoro-1-methoxycyclohexyl)propyl]-6-ethyl-3-azabicyclo[3.1.0]hexan-6-yl}phenyl)cyclopropanesulfonamide.