Blood-brain barrier disruption inhibitor
An object of the present invention is to provide a blood-brain barrier disruption inhibitor. The present invention provides a blood-brain barrier disruption inhibitor which comprises as an active ingredient a pyrazolone derivative represented by the following formula (I) or a physiologically acceptable salt thereof, or a hydrate thereof or a solvate thereof: wherein R 1 represents a hydrogen atom, an aryl group, an alkyl group, or an alkoxycarbonylalkyl group; R 2 represents a hydrogen atom, an aryloxy group, an arylmercapto group, an alkyl group or a hydroxyalkyl group; or R 1 and R 2 are combined with each other to represent an alkylene group; and R 3 represents a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, a benzyl group, a naphthyl group, a phenyl group, or a phenyl group substituted with 1 to 3 substituents selected from the group consisting of an alkyl group, an alkoxy group, a hydroxyalkyl group, an alkoxycarbonyl group, an alkylmercapto group, an alkylamino group, a dialkylamino group, a halogen atom, a trifluoromethyl group, a carboxyl group, a cyano group, a hydroxyl group, a nitro group, an amino group and an acetamide group.
1 . A blood-brain barrier disruption inhibitor which comprises as an active ingredient a pyrazolone derivative represented by the following formula (I) or a physiologically acceptable salt thereof, or a hydrate thereof or a solvate thereof:
wherein R 1 represents a hydrogen atom, an aryl group, a C 1-5 alkyl group, or a C 3-6 (total carbon number) alkoxycarbonylalkyl group; R 2 represents a hydrogen atom, an aryloxy group, an arylmercapto group, a C 1-5 alkyl group or a C 1-3 hydroxyalkyl group; or R 1 and R 2 are combined with each other to represent C 3-5 alkylene group; and R 3 represents a hydrogen atom, a C 1-5 alkyl group, a C 5-7 cycloalkyl group, a C 1-3 hydroxyalkyl group, a benzyl group, a naphthyl group, a phenyl group, or a phenyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of a C 1-5 alkyl group, a C 1-5 alkoxy group, a C 1-3 hydroxyalkyl group, a C 2-5 (total carbon number) alkoxycarbonyl group, a C 1-3 alkylmercapto group, a C 1-4 alkylamino group, a C 2-8 (total carbon number) dialkylamino group, a halogen atom, a trifluoromethyl group, a carboxyl group, a cyano group, a hydroxyl group, a nitro group, an amino group and an acetamide group.
2 . The blood-brain barrier disruption inhibitor according to claim 1 which has an action of inhibiting increases in permeability of the blood-brain barrier.
3 . The blood-brain barrier disruption inhibitor according to claim 1 which has an action of inhibiting increases in the amount of inflammatory cytokines in spinal fluid.
4 . The blood-brain barrier disruption inhibitor according to claim 1 wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one.
5 . A medicament for prevention and/or treatment of multiple sclerosis, meningitis, cerebritis or brain abscess, which comprises as an active ingredient a pyrazolone derivative represented by the above-described formula (I) or a physiologically acceptable salt thereof, or a hydrate thereof or a solvate thereof:
wherein R 1 represents a hydrogen atom, an aryl group, a C 1-5 alkyl group, or a C 3-6 (total carbon number) alkoxycarbonylalkyl group; R 2 represents a hydrogen atom, an aryloxy group, an arylmercapto group, a C 1-5 alkyl group or a C 1-3 hydroxyalkyl group; or R 1 and R 2 are combined with each other to represent C 3-5 alkylene group; and R 3 represents a hydrogen atom, a C 1-5 alkyl group, a C 5-7 cycloalkyl group, a C 1-3 hydroxyalkyl group, a benzyl group, a naphthyl group, a phenyl group, or a phenyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of a C 1-5 alkyl group, a C 1-5 alkoxy group, a C 1-3 hydroxyalkyl group, a C 2-5 (total carbon number) alkoxycarbonyl group, a C 1-3 alkylmercapto group, a C 1-4 alkylamino group, a C 2-8 (total carbon number) dialkylamino group, a halogen atom, a trifluoromethyl group, a carboxyl group, a cyano group, a hydroxyl group, a nitro group, an amino group and an acetamide group.
6 . The medicament according to claim 5 wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one.
7 . A method for inhibiting a blood-brain barrier disruption which comprises a step of administering to mammals such as a human, an effective amount of a pyrazolone derivative represented by the formula (I) or a physiologically acceptable salt thereof, or a hydrate thereof or a solvate thereof:
wherein R 1 represents a hydrogen atom, an aryl group, a C 1-5 alkyl group, or a C 3-6 (total carbon number) alkoxycarbonylalkyl group; R 2 represents a hydrogen atom, an aryloxy group, an arylmercapto group, a C 1-5 alkyl group or a C 1-3 hydroxyalkyl group; or R 1 and R 2 are combined with each other to represent C 3-5 alkylene group; and R 3 represents a hydrogen atom, a C 1-5 alkyl group, a C 5-7 cycloalkyl group, a C 1-3 hydroxyalkyl group, a benzyl group, a naphthyl group, a phenyl group, or a phenyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of a C 1-5 alkyl group, a C 1-5 alkoxy group, a C 1-3 hydroxyalkyl group, a C 2-5 (total carbon number) alkoxycarbonyl group, a C 1-3 alkylmercapto group, a C 1-4 alkylamino group, a C 2-8 (total carbon number) dialkylamino group, a halogen atom, a trifluoromethyl group, a carboxyl group, a cyano group, a hydroxyl group, a nitro group, an amino group and an acetamide group.
8 . The method according to claim 7 wherein the blood-brain barrier disruption is inhibited by inhibiting increases in permeability of the blood-brain barrier.
9 . The method according to claim 7 wherein the blood-brain barrier disruption is inhibited by inhibiting increases in the amount of inflammatory cytokines in spinal fluid.
10 . The method according to claim 7 wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one.
11 . A method for preventing and/or treating multiple sclerosis, meningitis, cerebritis or brain abscess which comprises a step of administering to mammals such as a human, an effective amount of a pyrazolone derivative represented by the formula (I) or a physiologically acceptable salt thereof, or a hydrate thereof or a solvate thereof:
wherein R 1 represents a hydrogen atom, an aryl group, a C 1-5 alkyl group, or a C 3-6 (total carbon number) alkoxycarbonylalkyl group; R 2 represents a hydrogen atom, an aryloxy group, an arylmercapto group, a C 1-5 alkyl group or a C 1-3 hydroxyalkyl group; or R 1 and R 2 are combined with each other to represent C 3-5 alkylene group; and R 3 represents a hydrogen atom, a C 1-5 alkyl group, a C 5-7 cycloalkyl group, a C 1-3 hydroxyalkyl group, a benzyl group, a naphthyl group, a phenyl group, or a phenyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of a C 1-5 alkyl group, a C 1-5 alkoxy group, a C 1-3 hydroxyalkyl group, a C 2-5 (total carbon number) alkoxycarbonyl group, a C 1-3 alkylmercapto group, a C 1-4 alkylamino group, a C 2-8 (total carbon number) dialkylamino group, a halogen atom, a trifluoromethyl group, a carboxyl group, a cyano group, a hydroxyl group, a nitro group, an amino group and an acetamide group.
12 . The method according to claim 11 wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one.
13 . Use of a pyrazolone derivative represented by formula (I) or a physiologically acceptable salt thereof, or a hydrate thereof or a solvate thereof, for the production of a blood-brain barrier disruption inhibitor;
wherein R 1 represents a hydrogen atom, an aryl group, a C 1-5 alkyl group, or a C 3-6 (total carbon number) alkoxycarbonylalkyl group; R 2 represents a hydrogen atom, an aryloxy group, an arylmercapto group, a C 1-5 alkyl group or a C 1-3 hydroxyalkyl group; or R 1 and R 2 are combined with each other to represent C 3-5 alkylene group; and R 3 represents a hydrogen atom, a C 1-5 alkyl group, a C 5-7 cycloalkyl group, a C 1-3 hydroxyalkyl group, a benzyl group, a naphthyl group, a phenyl group, or a phenyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of a C 1- 5 alkyl group, a C 1-5 alkoxy group, a C 1-3 hydroxyalkyl group, a C 2-5 (total carbon number) alkoxycarbonyl group, a C 1-3 alkylmercapto group, a C 1-4 alkylamino group, a C 2-8 (total carbon number) dialkylamino group, a halogen atom, a trifluoromethyl group, a carboxyl group, a cyano group, a hydroxyl group, a nitro group, an amino group and an acetamide group.
14 . The use according to claim 13 wherein the blood-brain barrier disruption inhibitor has an action of inhibiting increases in permeability of the blood-brain barrier.
15 . The use according to claim 13 wherein the blood-brain barrier disruption inhibitor has an action of inhibiting increases in the amount of inflammatory cytokines in spinal fluid.
16 . The use according to claim 13 wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one.
17 . Use of a pyrazolone derivative represented by formula (I) or a physiologically acceptable salt thereof, or a hydrate thereof or a solvate thereof, for the production of a medicament for prevention and/or treatment of multiple sclerosis, meningitis, cerebritis or brain abscess:
wherein R 1 represents a hydrogen atom, an aryl group, a C 1-5 alkyl group, or a C 3-6 (total carbon number) alkoxycarbonylalkyl group; R 2 represents a hydrogen atom, an aryloxy group, an arylmercapto group, a C 1-5 alkyl group or a C 1-3 hydroxyalkyl group; or R 1 and R 2 are combined with each other to represent C 3-5 alkylene group; and R 3 represents a hydrogen atom, a C 1-5 alkyl group, a C 5-7 cycloalkyl group, a C 1-3 hydroxyalkyl group, a benzyl group, a naphthyl group, a phenyl group, or a phenyl group substituted with the same or different 1 to 3 substituents selected from the group consisting of a C 1-5 alkyl group, a C 1-5 alkoxy group, a C 1-3 hydroxyalkyl group, a C 2-5 (total carbon number) alkoxycarbonyl group, a C 1-3 alkylmercapto group, a C 1-4 alkylamino group, a C 2-8 (total carbon number) dialkylamino group, a halogen atom, a trifluoromethyl group, a carboxyl group, a cyano group, a hydroxyl group, a nitro group, an amino group and an acetamide group.
18 . The use according to claim 17 wherein the pyrazolone derivative represented by the formula (I) is 3-methyl-1-phenyl-2-pyrazolin-5-one.
19 . The blood-brain barrier disruption inhibitor according to claim 2 which has an action of inhibiting increases in the amount of inflammatory cytokines in spinal fluid.
20 . The method according to claim 8 wherein the blood-brain barrier disruption is inhibited by inhibiting increases in the amount of inflammatory cytokines in spinal fluid.