3-substituted sulfonyl piperidine derivative
AssigneeMsd K.K.
InventorsTsuyoshi Nagase, Takahide Sasaki, Toshiyuki Takahashi
Life of this patent
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Abstract
[Problem] There is provided a compound useful as a preventive or remedy for cardiovascular disease, neurologic disease, metabolic disease, reproductive disease, and digestive disease. [Means for Resolution] A compound or a pharmaceutically acceptable salt thereof represented by the following Formula (I) wherein Z represents wherein n1, n2, and n3 are 0, 1, or 2, respectively; R1 represents C1-6 alkyl, C3-8 cycloalkyl, or the like; R2 represents aryl or heteroaryl; R3 represents a hydrogen atom, C1-6 alkyl, or the like; and M1, M2, M3, and M4 independently represent a hydrogen atom, C1-6 alkyl, or the like, or M1, together with M2, M3, or M4, forms —CH2— or the like.
Claims15
1-17. (canceled)
A compound represented by the following Formula (I) or a pharmaceutically acceptable salt thereof;
- wherein,
- Z is selected from the group consisting of the following Formulae (II-1), (II-2), and (II-3)
- where n1, n2, and n3 are 0, 1, or 2, respectively
- wherein,
- R1 represents C1-6 alkyl, C3-8 cycloalkyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aryl, or heteroaryl are unsubstituted or substituted with a substituent selected from the group consisting of:
- hydroxy, cyano, carboxyl, sulfo, halogen, C1-6 alkyl, halo C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, halo C1-6 alkoxy, amino, wherein the amino is unsubstituted or substituted with 1 to 2 C1-6 alkyls, aryls, or heteroaryls, carbamoyl, wherein the carbamoyl is unsubstituted or substituted with 1 to 2 C1-6 alkyls, aryls, or heteroaryls, sulfanyl, wherein the sulfanyl is unsubstituted or substituted with one C1-6 alkyl, aryl, or heteroaryl, C1-6 alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, C1-6 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, wherein the sulfamoyl is unsubstituted or substituted with 1 to 2 C1-6 alkyls, aryls, or heteroaryls, C1-6 alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, C1-6 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C1-6 alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoylamino, wherein the carbamoylamino is unsubstituted or substituted with 1 to 2 C1-6 alkyls, aryls, or heteroaryls, C1-6 alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, C1-6 alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aryl, heteroaryl, aralkyl, heteroaralkyl, aralkyloxy, and heteroaralkyloxy;
- R2 represents phenyl or heteroaryl, wherein the phenyl or heteroaryl may be substituted with a substituent selected from the group consisting of:
- hydroxy, cyano, carboxyl, sulfo, halogen, C1-6 alkyl, halo C1-6 alkyl, C3-8 cycloalkyl, C1-6 alkoxy, halo C1-6 alkoxy, amino, wherein the amino is unsubstituted or substituted with 1 to 2 C1-6 alkyls, aryls, or heteroaryls, carbamoyl, wherein the carbamoyl is unsubstituted or substituted with 1 to 2 C1-6 alkyls, aryls, or heteroaryls, sulfanyl, wherein the sulfanyl is unsubstituted or substituted with one C1-6 alkyl, aryl, or heteroaryl, C1-6 alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, C1-6 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, sulfamoyl, wherein the sulfamoyl is unsubstituted or substituted with 1 to 2 C1-6 alkyls, aryls, or heteroaryls, C1-6 alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, C1-6 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C1-6 alkoxycarbonyl, aryloxycarbonyl, heteroaryloxycarbonyl, carbamoylamino, wherein the carbamoylamino is unsubstituted or substituted with 1 to 2 C1-6 alkyls, aryls, or heteroaryls, C1-6 alkoxycarbonylamino, aryloxycarbonylamino, heteroaryloxycarbonylamino, C1-6 alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, aryl, wherein the aryl is unsubstituted or substituted with C1-6 alkoxy, heteroaryl, aryloxy, heteroaryloxy, aralkyl, heteroaralkyl, aralkyloxy, and heteroaralkyloxy;
- R3 represents a hydrogen atom, C1-6 alkyl, C3-8 cycloalkyl, aralkyl, heteroaralkyl, aryl, or heteroaryl, wherein the alkyl, cycloalkyl, aralkyl, heteroaralkyl, aryl, or heteroaryl is unsubstituted or substituted with a substituent selected from the group consisting of halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy, and halo C1-6 alkoxy;
- and
- M1, M2, M3, and M4, wherein M1, together with M2, M3 or M4, forms —CH2— or —CH2—CH2—, or M4, together with M2, forms —CH2— or —CH2—CH2—, provided that any two of M1, M2, M3, and M4 together form —CH2— or —CH2—CH2— when R3 is a hydrogen atom.
The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is C1-6 alkyl, C3-8 cycloalkyl, aryl, or heteroaryl, and wherein the C1-6 alkyl, the C3-8 cycloalkyl, the aryl, and the heteroaryl are each unsubstituted or substituted with a substituent selected from the group consisting of halogen, C1-6 alkyl, and C1-6 alkoxy.
The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R1 is one of propyl, isopropyl, butyl, isobutyl, cyclopropyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, pyrazin-2-yl, pyridazin-3-yl, 2-thienyl, 3-thienyl, 1-methyl-1H-imidazol-4-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 1,3-thiazol-2-yl, 1,3-oxazol-2-yl, and 1,3,4-thiadiazol-2-yl.
The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R2 is phenyl or heteroaryl, and wherein the phenyl and the heteroaryl are each unsubstituted or substituted with a substituent selected from the group consisting of halogen, C1-6 alkyl, halo C1-6 alkyl, C1-6 alkoxy, C3-6 cycloalkyl, aryl, aralkyl, and aralkyloxy.
The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein R2 is one of phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2-isopropoxyphenyl, 3-isopropoxyphenyl, 4-isopropoxyphenyl, 2-benzylphenyl, 3-benzylphenyl, 4-benzylphenyl, 2-benzyloxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl, 5-isopropoxyphenylpyridin-2-yl, 6-isopropoxyphenylpyridin-3-yl, 5-isopropoxypyrimidin-2-yl, 3-methoxypyridin-2-yl, 3-cyclopropyl-1H-pyrazol-5-yl, and 5-isopropoxy-1H-pyrazol-3-yl.
The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein Z is of the Formula (II-1), and wherein n1 is 0.
A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein Z is of the Formula (II-2), and wherein n2 is 1.
The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein M1, together with M3, forms —CH2— or —CH2—CH2—, and M2 and M4 independently represent a hydrogen atom, or C1-6 alkyl unsubstituted or substituted with halogen.
The compound or the pharmaceutically acceptable salt thereof according to claim 9, wherein M1, together with M3, forms —CH2—CH2—, and M2 and M4 each represent a hydrogen atom.
The compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein M1, together with M2, forms —CH2— or —CH2—CH2—, and M3 and M4 independently represent a hydrogen atom, or C1-6 alkyl optionally substituted with halogen.
The compound or the pharmaceutically acceptable salt thereof according to claim 11, wherein M1, together with M2, forms —CH2—CH2—, and M3 and M4 each represent a hydrogen atom.
A compound or the pharmaceutically acceptable salt thereof selected from the group consisting of:
- (1R**,4S**,6R**)-N-(4-isopropoxyphenyl)-2-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-2-azabicyclo[2.2.2]octane-6-carboxamide;
- (1S**,4R**,6S**)-N-(4-isopropoxyphenyl)-2-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-2-azabicyclo[2.2.2]octane-6-carboxamide;
- (1R*,4S*,6R*)-2-(butylsulfonyl)-N-(3-cyclopropyl-1H-pyrazol-5-yl)-2-azabicyclo[2.2.2]octane-6-carboxamide;
- (1R*,4S*,6R*)-N-(5-isopropoxypyridin-2-yl)-2-(pyridin-2-ylsulfonyl)-2-azabicyclo[2.2.2]octane-6-carboxamide;
- (1R**,4S**,6R**)-N-(5-isopropoxypyridin-2-yl)-2-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-2-azabicyclo[2.2.2]octane-6-carboxamide;
- (1R*,4S*,6R*)-N-(4-isopropoxyphenyl)-2-(phenylsulfonyl)-2-azabicyclo[2.2.2]octane-6-carboxamide;
- (1R*,4S*,6R*)-N-(5-Isopropoxypyridin-2-yl)-2-(phenylsulfonyl)-2-azabicyclo[2.2.2]octane-6-carboxamide;
- (1S**,4R**,6S**)-N-(5-isopropoxypyridin-2-yl)-2-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-2-azabicyclo[2.2.2]octane-6-carboxamide;
- and
- (1R*,4S*,6R*)-N-(5-isopropoxy-1H-pyrazol-3-yl)-2-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-2-azabicyclo[2.2.2]octane-6-carboxamide.
A pharmaceutical composition, which comprises the compound or the pharmaceutically acceptable salt thereof of any one of claim 1.
A method for treating diabetes mellitus, obesity, or non-alcoholic fatty liver, comprising administering to a subject a compound or the pharmaceutically acceptable salt thereof of claim 1.
Dependencies are inferred from the claim text.