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WO2018181986A1 - Adamantylmethylamine derivative and use of same as pharmaceutical - Google Patents

Adamantylmethylamine derivative and use of same as pharmaceutical Download PDF

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Publication number
WO2018181986A1
WO2018181986A1 PCT/JP2018/013853 JP2018013853W WO2018181986A1 WO 2018181986 A1 WO2018181986 A1 WO 2018181986A1 JP 2018013853 W JP2018013853 W JP 2018013853W WO 2018181986 A1 WO2018181986 A1 WO 2018181986A1
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WIPO (PCT)
Prior art keywords
alkyl
phenyl
optionally substituted
methyl
hydrogen atom
Prior art date
Application number
PCT/JP2018/013853
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French (fr)
Japanese (ja)
Inventor
茂樹 森口
浩司 福永
好治 岩渕
Original Assignee
国立大学法人東北大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from PCT/JP2017/013616 external-priority patent/WO2018179343A1/en
Application filed by 国立大学法人東北大学 filed Critical 国立大学法人東北大学
Publication of WO2018181986A1 publication Critical patent/WO2018181986A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
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    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
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    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
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    • C07C235/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C235/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07C271/14—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by halogen atoms or by nitro or nitroso groups
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    • C07C311/02—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
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Definitions

  • the present invention relates to an adamantylmethylamine derivative and a pharmaceutically acceptable salt thereof. Furthermore, the present invention relates to a pharmaceutical composition containing the compound, and a method for treating or preventing a disease using the compound.
  • K ATP channel An ATP-sensitive K + channel (K ATP channel) is an inwardly rectifying K + channel that links intracellular metabolic state and excitability of the cell membrane, sulfonylurea receptor (SUR) and membrane belonging to the ABC protein family. It is known to have a heterooctamer structure composed of two-pass type Kir6.1 and Kir6.2. The activity of KATP channels is controlled by various K + channel openers , inhibitors, or intracellular nucleotides. All of these have an action point in the SUR subunit, and it has been reported that the reaction differs depending on the SUR subtype (Non-patent Document 1).
  • adamantane having a cage structure Some derivatives of adamantane having a cage structure are used as pharmaceuticals, and amantadine is used as an antiviral drug and a Parkinson's disease therapeutic drug.
  • Memantine hydrochloride is also approved in Japan as a treatment for moderate and severe Alzheimer's dementia.
  • Memantine is a non-competitive NMDA receptor inhibitor, and its mechanism of action is reported to prevent neuronal cell death caused by excessive release of glutamate caused by ischemia (Non-patent Document 2).
  • Patent Documents 1 to 3 Several reports have been made on adamantane derivatives having pharmaceutical activity.
  • the present invention aims to provide a pharmaceutical composition for use in the treatment or prevention of a cognitive function disease or disorder.
  • a further object of the present invention is to provide a method for treating or preventing a cognitive function disease or disorder using a specific adamantane derivative.
  • the present invention aims to provide a pharmaceutical composition for use in the treatment or prevention of diabetes or diabetic complications. It is another object of the present invention to provide a method for treating or preventing diabetes or diabetic complications using a specific adamantane derivative.
  • K ATP-sensitive K + channel includes Kir6.1 and Kir6.2, and is known as an action point of antidiabetic drugs and the like.
  • the present invention is directed to providing a Kir6.1 channel inhibitor or a Kir6.2 channel inhibitor of KATP channels.
  • a further object of the present invention is to provide a pharmaceutical composition for use in the treatment or prevention of diseases involving the Kir6.1 channel or Kir6.2 channel of the KATP channel.
  • a further object of the present invention is to provide a method for treating or preventing a disease involving a Kir6.1 channel or Kir6.2 channel of a KATP channel using a specific adamantylmethylamine derivative.
  • the inventors of the present invention have made extensive studies in order to achieve the above-mentioned problems. As a result, Kiram 6.2 channel inhibitory activity, Kir6.1 channel inhibitory activity, therapeutic effects in cognitive function diseases or disorders, and blood glucose A value lowering effect was found and the present invention was completed.
  • the disclosure of this specification includes the inventions described in [1] to [17] below.
  • Q 1 , Q 2 , R 1 and R 4 each independently represent a hydrogen atom, a halogen atom, C 1-6 alkyl optionally substituted with one or more halogen atoms, amino, X 1 Selected from C 6-10 aryl, carboxy, —OR 7 , and —SR 8 optionally substituted by one or more substituents selected from;
  • R 2 is a hydrogen atom, phenylsulfonyl optionally substituted with one or more substituents selected from X 1 , (C 1-6 alkyl) sulfonyl optionally substituted with one or more halogen atoms, or -COYR 6 ;
  • Y is a direct bond, O, or NR 9 ;
  • R 3 is optionally substituted by one or more optionally substituted with a substituent C 3-8 cycloalkyl, one or more substituents selected from X 1 is selected from X 1 C 6- 10 aryl, 1 or more phenyl amino
  • Q 1 is a hydrogen atom, a halogen atom, C 1-6 alkyl optionally substituted with one or more halogen atoms, amino, or —OR 10 ;
  • R 10 is a hydrogen atom, C 1-6 alkyl optionally substituted with one or more halogen atoms, or (C 1-6 alkyl) carbonyl optionally substituted with one or more halogen atoms;
  • Q 2 is a hydrogen atom, C 1-6 alkyl, or C 1-6 alkoxy, wherein alkyl or alkoxy may be substituted with one or more halogen atoms;
  • R 1 is a hydrogen atom, C 1-6 alkyl, or C 1-6 alkoxy, where alkyl or alkoxy may be substituted with one or more halogen atoms;
  • R 2 is a hydrogen atom, phenylsulfonyl optionally substituted with one or more substituents selected from X 1 , (C 1-6 alkyl) s
  • Q 1 is a hydrogen atom, a halogen atom, or —OR 10 ;
  • R 10 is a hydrogen atom or (C 1-6 alkyl) carbonyl optionally substituted with one or more halogen atoms;
  • R 2 is a hydrogen atom, phenylsulfonyl optionally substituted with one or more substituents selected from X 1 , (C 1-6 alkyl) sulfonyl optionally substituted with one or more halogen atoms, or -COYR 6 ;
  • Y is a direct bond, O, or NR 9 ;
  • R 3 is one or more phenyl which is substituted by a substituent or one or more substituents the optionally substituted 5 or 6 membered heteroaryl selected from X 1, is selected from X 1 Is;
  • R 4 is a hydrogen atom, a halogen atom, —OR 7 , or —SR 8 ;
  • R 5 is a hydrogen
  • R 2 is phenylsulfonyl optionally substituted by one or more substituents selected from X 1 , (C 1-6 alkyl) sulfonyl optionally substituted by one or more halogen atoms, or The compound according to any one of [1] to [6], its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof, which is COR 6 .
  • a pharmaceutical composition comprising the compound according to any one of [1] to [11], an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
  • composition according to [12] for use in the treatment or prevention of a cognitive function disease or disorder.
  • the cognitive function disease or disorder is selected from Alzheimer's dementia, cerebrovascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease, psychiatric disorder, neurodegenerative disease, [13] ]
  • the pharmaceutical composition of description is selected from Alzheimer's dementia, cerebrovascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease, psychiatric disorder, neurodegenerative disease, [13] ]
  • the pharmaceutical composition of description is selected from Alzheimer's dementia, cerebrovascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease, psychiatric disorder, neurodegenerative disease, [13] ]
  • the pharmaceutical composition of description is selected from Alzheimer's dementia, cerebrovascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease, psychiatric disorder, neurodegenerative disease, [13] ]
  • the pharmaceutical composition of description is selected from Alzheimer's dementia, cerebrovascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease, psych
  • a Kir6.2 channel inhibitor comprising the compound according to any one of [1] to [11], an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
  • a Kir6.1 channel inhibitor comprising the compound according to any one of [1] to [11], an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
  • one of Q 1 and R 4 is a halogen atom, and the other is a hydrogen atom or a halogen atom;
  • R 2 is a hydrogen atom, phenylsulfonyl optionally substituted with one or more substituents selected from X 1 , (C 1-6 alkyl) sulfonyl optionally substituted with one or more halogen atoms, or -COYR 6 ;
  • Y is a direct bond, O, or NR 7 ;
  • R 6 is C 1-6 alkyl, C 1-6 alkoxy optionally substituted by one or more halogen atoms, phenyl optionally substituted by one or more substituents selected from X 1 , or
  • X is one or more substituents may 5 or 6 membered heteroaryl optionally substituted by is selected from 1, wherein C 1-6 alkyl may be optionally substituted by one or more halogen atoms, and / Or optionally substituted by one substituent selected
  • R 2 is phenylsulfonyl optionally substituted by one or more substituents selected from X 1 , (C 1-6 alkyl) sulfonyl optionally substituted by one or more halogen atoms Or a compound according to any one of [1] to [3] which is —COYR 6 ; an enantiomer thereof; a diastereomer thereof; or a pharmaceutically acceptable salt thereof.
  • [1-8] A pharmaceutical composition comprising the compound according to any one of [1] to [7], an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
  • composition according to [8] for use in the treatment or prevention of a cognitive function disease or disorder.
  • the cognitive function disease or disorder is selected from Alzheimer's dementia, cerebrovascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease, mental illness, neurodegenerative disease, [9] The pharmaceutical composition according to [9].
  • a Kir6.2 channel inhibitor comprising the compound according to any one of [1] to [7], an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
  • a Kir6.1 channel inhibitor comprising the compound according to any one of [1] to [7], an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
  • R 4 represents a hydrogen atom or a halogen atom
  • R 3 is one or more phenyl which is substituted by a substituent or one or more substituents the optionally substituted 5 or 6 membered heteroaryl selected from X 1, is selected from X 1 Is
  • Each X 1 is independently selected from C 1-6 alkyl, a halogen atom, C 1-6 alkoxy, nitro, and cyano] Or its enantiomer, diastereomer, or salt thereof.
  • the present invention provides a pharmaceutical composition for use in the treatment or prevention of a cognitive function disease or disorder.
  • the present invention provides a Kir6.1 channel inhibitor or Kir6.2 channel inhibitor of KATP channel.
  • FIG. 1 is a graph showing the enhancement of CaMKII activity by the compound of the present invention in Kir6.2 channel overexpressing cells (Neuro2A cells). All significant differences displayed are for the subject (C, no drug treatment group in Kir6.2 expressing cells). Regarding the display of the significant difference shown in the figure of the present application, ** or ++ indicates that the significant difference is P ⁇ 0.01, and + or * indicates P ⁇ 0.05.
  • FIG. 2a shows the result of confirming Kir6.2 channel expression in N2A cells by immunoblotting with respect to Kir6.2 channel overexpressing cells using anti-Kir6.2 channel antibody. Significant differences with respect to the drug-untreated group ( ⁇ ) are indicated by **.
  • FIG. 1 is a graph showing the enhancement of CaMKII activity by the compound of the present invention in Kir6.2 channel overexpressing cells (Neuro2A cells). All significant differences displayed are for the subject (C, no drug treatment group in Kir6.2 expressing cells). Regarding the display of the significant difference shown in the figure of the present application, ** or ++ indicates that the significant difference is
  • FIG. 2b is an assay result by a whole-cell patch-clamp method showing that TP-014 suppresses outward potassium current in Kir6.2 channel overexpressing cells. This result indicates that TP-014 inhibits Kir6.2 channel and attenuates potassium current.
  • FIG. 3a shows the results of an assay by a calcium imaging method showing that intracellular calcium concentration increases by administering TP-014 in Kir6.2 channel overexpressing cells. A time-dependent change in the amount of calcium in the concentration-dependent treatment with the compound of the present invention and memantine was measured over 4 minutes. This result indicates that TP-014 inhibits Kir6.2 channel and increases intracellular calcium concentration.
  • FIG. 3b shows the results of an assay by a calcium imaging method showing that intracellular calcium concentration is increased by administering TP-014 in Kir6.2 channel overexpressing cells.
  • FIG. 4a is a graph showing experimental results in which TP-014 was administered to Alzheimer's disease model mice (APP23 mice) (12 months old) for 2 months and a cognitive function improving effect was observed by the Y-maze method.
  • FIG. 4b is a graph showing the results of an experiment in which TP-014 was administered to Alzheimer's disease model mice (APP23 mice) (12 months old) for 2 months and the cognitive function improving effect was observed by the Y-maze method.
  • FIG. 4c is a graph showing experimental results in which TP-014 was administered to Alzheimer's disease model mice (APP23 mice) (12 months old) for 2 months and a cognitive function improving effect was observed by a novel object recognition test method.
  • the significant difference of Novel (new object) when compared with each Family (same object) is indicated by **.
  • FIG. 4d is a graph showing experimental results in which TP-014 was administered to Alzheimer's disease model mice (APP23 mice) (12 months old) for 2 months and a cognitive function improving effect was observed by the fear conditioning test method.
  • FIG. 4e shows the results of long-term potentiation (LTP), which is an indicator of memory formation, by administering TP-014 to Alzheimer's disease model mice (APP23 mice) (12 months old) for 2 months and using electrophysiological techniques.
  • FIG. 4f shows the results of studying the long-term potentiation phenomenon (LTP), which is an index of memory formation, by administering TP-014 to Alzheimer's disease model mice (APP23 mice) (12 months old) for 2 months and using electrophysiological techniques. Show.
  • FIG. 4e shows the results of long-term potentiation (LTP), which is an indicator of memory formation, by administering TP-014 to Alzheimer's disease model mice (APP23 mice) (12 months old) for 2 months and using electrophysiological techniques.
  • LTP long-term potentiation
  • FIG. 5a is a band (image) obtained when an immunoblot was run, showing the results of examining the phosphorylation of each protein using antibodies against CaMKII, CaMKIV, and ERK by immunoblotting.
  • FIG. 5b is an analysis result obtained by quantifying the signal intensity of the band obtained when the immunoblot of FIG. 5a is migrated.
  • FIG. 5c is a band (image) obtained when an immunoblot was run, showing the results of examining the phosphorylation of each protein using antibodies against CaMKII, CaMKIV, and ERK by immunoblotting.
  • FIG. 5d is an analysis result obtained by quantifying the signal intensity of the band obtained when the immunoblot of FIG. 5c is migrated.
  • Significant differences compared to WT ( ⁇ ) (drug-untreated group) are indicated by **, and significant differences compared to drug-untreated group ( ⁇ ) of APP23 mice are denoted by ++.
  • FIG. 6a is a graph showing the results of experiments in which TP-014 was administered to an olfactory bulb-excised mouse (OBX mouse), which is a neurodegenerative disease model mouse, for 2 months, and as a result, a cognitive function improving effect was observed by the Y-maze method.
  • FIG. 6b is a graph showing the results of experiments in which TP-014 was administered to an olfactory bulb-excised mouse (OBX mouse), which is a neurodegenerative disease model mouse, for 2 months, and as a result, a cognitive function improving effect was observed by the Y-maze method. .
  • FIG. 6c is a graph showing experimental results in which TP-014 was administered to an olfactory bulb-extracted mouse (OBX mouse), which is a neurodegenerative disease model mouse, for 2 months, and as a result, a cognitive function improving effect was observed by a novel object recognition test method. is there.
  • OBX mouse olfactory bulb-extracted mouse
  • the significant difference of Novel (new object) when compared with each Family (same object) is indicated by **.
  • FIG. 6d is a graph showing the results of experiments in which TP-014 was administered for 2 months to olfactory bulbectomized mice (OBX mice), which are neurodegenerative disease model mice, and the cognitive function improving effect was observed by the fear conditioning test method. . Significant differences compared to WT in Retension trials are indicated by **, and significant differences compared to OBX mouse are indicated by +.
  • Fig. 6e shows the results of long-term potentiation (LTP), which is an index of memory formation, by administering TP-014 to olfactory bulbectomized mice (OBX mice), which are neurodegenerative disease model mice, for 2 months. Indicates. Fig.
  • LTP long-term potentiation
  • FIG. 6f shows the results of studying the long-term potentiation phenomenon (LTP), which is an index of memory formation, by administering TP-014 to olfactory bulbectomized mice (OBX mice), which are neurodegenerative disease model mice, for 2 months.
  • Fig. 6g shows the result of studying the long potentiation phenomenon (LTP), an index of memory formation, by administering TP-014 to olfactory bulbectomized mice (OBX mice), which are neurodegenerative disease model mice, for 2 months.
  • Significant differences compared to sham are indicated by **, and significant differences compared to OBX mice are indicated by ++ or +.
  • FIG. 7 a is a band (image) obtained when an immunoblot is run, showing the results of examining the phosphorylation of each protein using antibodies against CaMKII, CaMKIV, and ERK by immunoblotting.
  • FIG. 7b shows the analysis result obtained by quantifying the signal intensity of the band obtained when the immunoblot of FIG. 7a was run.
  • FIG. 7c is a band (image) obtained when an immunoblot was run, showing the results of examining the phosphorylation of each protein using antibodies against CaMKII, CaMKIV, and ERK by immunoblotting.
  • FIG. 7d is an analysis result obtained by quantifying the signal intensity of the band obtained when the immunoblot of FIG. 7c is migrated.
  • FIG. 8a is a graph showing experimental results in which TP-014 was administered to Kir6.2 channel-deficient mice for 2 months and an effect of improving cognitive function was observed by the Y-maze method.
  • FIG. 8b is a graph showing the results of an experiment in which TP-014 was administered to Kir6.2 channel-deficient mice for 2 months and an effect of improving cognitive function was observed by the Y-maze method.
  • * or ** indicates the significant difference in memory learning accuracy for Kir6.2-deficient mice.
  • FIG. 8c is a graph showing experimental results in which TP-014 was administered to Kir6.2 channel-deficient mice for 2 months and a cognitive function improving effect was observed by a novel object recognition test method. The> significant difference of Novel (new object) compared to each family (same object) is indicated by **.
  • FIG. 8d is a graph showing the results of experiments in which TP-014 was administered to Kir6.2 channel-deficient mice for 2 months and a cognitive function improving effect was observed by the fear conditioning test method. Significant differences compared to WT in Retension trials are indicated by *.
  • FIG. 8e shows the results of studying the long-term potentiation phenomenon (LTP), which is an index of memory formation, by administering TP-014 to Kir6.2 channel-deficient mice for 2 months and electrophysiological techniques.
  • LTP long-term potentiation phenomenon
  • FIG. 8f shows the results of studying the long-term potentiation phenomenon (LTP), which is an index of memory formation, by administering TP-014 to Kir6.2 channel-deficient mice for 2 months and electrophysiological techniques.
  • FIG. 8g shows the results of studying the long-term potentiation phenomenon (LTP), which is an index of memory formation, by administering TP-014 to Kir6.2 channel-deficient mice for 2 months and using electrophysiological techniques. Significant differences compared to WT are indicated with ** or *.
  • FIG. 9a is a band (image) obtained when an immunoblot was run, showing the results of examining the phosphorylation of each protein using antibodies against CaMKII, CaMKIV, and ERK by immunoblotting.
  • FIG. 9a is a band (image) obtained when an immunoblot was run, showing the results of examining the phosphorylation of each protein using antibodies against CaMKII, CaMKIV, and ERK by immunoblotting.
  • FIG. 9b is an analysis result obtained by quantifying the signal intensity of a band obtained when the immunoblot of FIG. 9a is migrated.
  • Significant differences compared to WT (-) (no drug treatment group) are indicated by ** or *.
  • FIG. 10 shows the result of staining a slice of brain slice showing the effect of the compound of the present invention on A ⁇ aggregation in APP23 mice.
  • FIG. 11 a is a test result for confirming the effect of improving the depression-like symptoms of OBX mice of the compound of the present invention.
  • Significant differences compared to sham (control group) are indicated by **, and significant differences compared to OBX mice are indicated by +.
  • FIG. 11 shows test results for confirming the effect of improving the depression-like symptoms of OBX mice of the compound of the present invention. Significant differences compared to sham (control group) are indicated by **, and significant differences compared to OBX mice are indicated by +.
  • FIG. 12a is a test result for confirming that the compound of the present invention exhibits an effect of improving depression through the inhibitory action of Kir6.1 channel. Significant differences compared to WT (control group) are indicated by **.
  • FIG. 12 b is a test result for confirming that the compound of the present invention exhibits an effect of improving depression through the inhibitory action of Kir6.1 channel. Significant differences compared to WT (control group) are indicated by **.
  • FIG. 12a is a test result for confirming that the compound of the present invention exhibits an effect of improving depression through the inhibitory action of Kir6.1 channel.
  • FIG. 12 b is a test result for confirming that the compound of the present invention exhibits an effect of improving depression through the inhibitory action of Kir6.1 channel.
  • FIG. 13a is a test result for confirming that the compound of the present invention inhibits the Kir6.1 channel and exhibits a depression-improving effect through the activation of CaMKIV. Significant differences compared to WT (control group) are indicated by **.
  • FIG. 13 b is a test result for confirming that the compound of the present invention inhibits the Kir6.1 channel and exhibits a depression-improving effect through activation of CaMKIV. Significant differences compared to WT (control group) are indicated by **.
  • FIG. 14 shows test results for confirming that the compound of the present invention has a blood glucose level-lowering effect. Weeks indicate the age of chronic administration, and a significant difference compared with ob / ob (saline) for each week is indicated by *.
  • TP-014 is a diagram for explaining the working mechanism of TP-014.
  • the Kir6.2 channel localized in spine is inhibited, the intracellular potassium cannot be excreted due to the inhibition of Kir6.2 channel, and the cell membrane potential is depolarized. As a result, the cell is opened by opening the voltage-dependent calcium channel. It is considered that the effect of improving cognitive function was recognized by the acceleration of calcium influx from outside, the activation of CaMKII, and the activation of GluA1 (Ser-831) (AMPA receptor) downstream of CaMKII.
  • TP-014 also inhibits the Kir6.1 channel localized in the neuronal cell body, and calcium flows into the cell by the same mechanism.
  • FIG. 16 shows the structure of the plasmid vector: pcDNA3.1-Kir6.2.
  • FIG. 17-1 shows the sequence of plasmid vector: pcDNA3.1-Kir6.2.
  • FIG. 17-2 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.2.
  • FIG. 17-3 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.2.
  • FIG. 17-4 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.2.
  • FIG. 17-5 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.2.
  • FIG. 18a is a graph showing the enhancement of CaMKIV activity by the compound of the present invention in Kir6.1 channel overexpressing cells (Neuro2A cells). All significant differences shown are for the subject (C, no drug treatment group in Kir6.1 expressing cells).
  • FIG. 18a shows the result of confirming Kir6.1 channel expression in N2A cells by immunoblotting for Kir6.1 channel overexpressing cells using anti-Kir6.1 channel antibody.
  • FIG. 18 b shows the results of measuring potassium current excreted from the inside of the cell by the usual patch-clamp method using Kir6.1 channel overexpressing cells.
  • FIG. 19a shows the result of examining vulnerability to anxiety of a group of mice used in the test by the elevated plus maze method. Significant differences compared to WT (-) for the staying time of mice in the open arm are indicated by ** or *, and significant differences compared with WT (CORT) are indicated by ++.
  • FIG. 19b is a photograph showing the device used in the elevated plus maze method.
  • FIG. 19c shows a test result by a light-dark test method.
  • FIG. 19d is a photograph showing the apparatus used in the light / dark test method.
  • FIG. 19e shows the result of the marble cracking test method (Marble burying method).
  • Significant differences compared to WT (-) are indicated by ** and significant differences compared to WT (CORT) are indicated by +.
  • FIG. 19f is a photograph showing an apparatus used in the marble cracking test method.
  • FIG. 19g shows the test results by the open field method.
  • Significant differences compared to WT (-) are shown as **, and significant differences compared to WT (CORT) are shown as ++.
  • FIG. 19h is a photograph showing an apparatus used in the open field method.
  • FIG. 19i shows the test result by the fear-conditioning test method (fear-conditining method). Significant differences compared to WT (-) are indicated by ** or *, and significant differences compared to WT (CORT) are indicated by ++.
  • FIG. 20 shows the structure of the plasmid vector: pcDNA3.1-Kir6.1.
  • FIG. 21-1 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.1.
  • FIG. 21-2 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.1.
  • FIG. 21-3 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.1.
  • FIG. 21-4 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.1.
  • FIG. 21-5 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.1.
  • a cognitive function disease or disorder comprising a compound of formula (I), an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition is provided. That is, the compounds of the present invention include compounds represented by the following formulas (I) and (II).
  • the compounds of the present invention include compounds represented by the following formulas (Ia) and (IIa).
  • the compounds of the present invention include compounds represented by the following formulas (Ib) and (IIb).
  • C 1-6 alkyl means a linear, branched, cyclic or partially cyclic alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl. I-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, and 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, and the like, for example, C 1-4 alkyl And C 1-3 alkyl and the like are also included.
  • C 1-6 alkoxy means an alkyloxy group [—O— (C 1-6 alkyl)] having an alkyl group having 1 to 6 carbon atoms already defined as the alkyl moiety, , Methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1- Includes ethylpropoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy, etc. Examples thereof include C 1-4 alkoxy and C 1-3 alkoxy. In this specification, “C 1-4 alkoxy” includes, for example, C 1-3 alkoxy and the like.
  • C 2-6 alkenyloxy means an alkenyloxy group having a straight chain, branched chain, cyclic or partially cyclic alkenyl group having 2 to 6 carbon atoms [—O— (C 2 -6 alkenyl)], and the alkenyl group has one or more, preferably 1 to 3, more preferably one double bond.
  • Examples of C 2-6 alkenyloxy include vinyloxy, 2-propenyloxy, 1-propenyloxy, 1-methylvinyloxy, 3-butenyloxy, 2-butenyloxy, 1-butenyloxy and the like.
  • C 2-6 alkynyloxy refers to an alkynyloxy group having a straight chain, branched chain, cyclic or partially cyclic alkynyl group having 2 to 6 carbon atoms [—O— (C 2 -6 alkynyl)], and the alkynyl group has one or more, preferably 1 to 3, more preferably one triple bond.
  • Examples of C 2-6 alkynyloxy include ethynyloxy, 2-propynyloxy, 1-propynyloxy, 3-butynyloxy, 2-butynyloxy, 1-butynyloxy and the like.
  • (C 1-6 alkyl) sulfonyl means an alkylsulfonyl group having a C 1-6 alkyl group that has already been defined as an alkyl moiety, and includes, for example, methylsulfonyl, ethylsulfonyl, tert-butylsulfonyl. In addition, (C 1-3 alkyl) sulfonyl and the like are included.
  • (C 1-6 alkoxy) carbonyl means an alkoxycarbonyl group having a C 1-6 alkoxy group already defined as an alkoxy moiety, such as methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl.
  • (C 1-3 alkoxy) carbonyl and the like are included.
  • the “5- or 6-membered heteroaryl” is a 5-membered or 6-membered heteroaryl containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom. There is no particular limitation.
  • Examples include pyridyl, pyrimidyl, pyridazinyl, pyrazyl, furanyl (furyl), thiophenyl (thienyl), oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • Examples of “(C 1-6 alkyl) sulfonyl optionally substituted with one or more halogen atoms” in the present specification include trifluoromethylsulfonyl, difluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl And perfluoroethylsulfonyl.
  • the “(C 1-6 alkyl) carbonyl optionally substituted with one or more halogen atoms” means that the alkyl portion of the above-mentioned (C 1-6 alkyl) carbonyl is 1 or more, for example, 1 to 5 Means a group which may be substituted by 1 to 3, specifically, 1 to 3 halogen atoms, and the alkyl moiety may be unsubstituted. Examples thereof include trifluoroacetyl and pentafluoropropionyl.
  • C 1-6 alkyl optionally substituted with one or more halogen atoms means one or more, for example, 1 to 5, specifically 1 of the above C 1-6 alkyl group. This means a group which may be substituted by up to 3 halogen atoms, and alkyl may be unsubstituted. Examples thereof include trifluoromethyl, pentafluoroethyl, and 2,2,2-trifluoroethyl.
  • C 1-6 alkoxy optionally substituted with one or more halogen atoms means one or more, for example, 1 to 5, specifically 1 of the above C 1-6 alkoxy group. Means a group which may be substituted by ⁇ 3 halogen atoms, alkoxy may be unsubstituted. Examples thereof include trifluoromethoxy, pentafluoroethoxy, and 2,2,2-trifluoroethoxy.
  • C 3-8 cycloalkyl means a cyclic alkyl group having 3 to 8 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • one or more phenyl aminocarbonyl optionally substituted by a substituent selected from X 1 means one or more (e.g. 1-5 selected from X 1 to the phenyl moiety, specifically Specifically, it means a —CONHPh group which may have 1 to 3 substituents, and the phenyl moiety may be unsubstituted.
  • the “5- to 10-membered monocyclic or bicyclic heteroaryl optionally substituted by one or more substituents selected from X 1 ” is selected from a nitrogen atom, an oxygen atom and a sulfur atom Means an aromatic heterocyclic group containing one or more heteroatoms, and includes 5- or 6-membered monocyclic heteroaryl groups and 8- to 10-membered bicyclic heteroaryl groups.
  • the number of substituents selected from X 1 may be 1 or more, for example 1 to 5, specifically 1 to 3, more specifically 1 or may be unsubstituted.
  • Examples of 5- or 6-membered monocyclic heteroaryl groups include pyridyl, pyrimidyl, pyridazinyl, pyrazyl, furanyl (furyl), thiophenyl (thienyl), oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, Examples include triazolyl and tetrazolyl.
  • Examples of 8- to 10-membered bicyclic heteroaryl groups include benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzooxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, Quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridyl and the like can be mentioned.
  • the “5- to 10-membered monocyclic or bicyclic non-aromatic heterocyclyl optionally substituted by one or more substituents selected from X 1 ” means a nitrogen atom, an oxygen atom, and a sulfur atom.
  • the number of substituents selected from X 1 may be 1 or more, for example 1 to 5, specifically 1 to 3, more specifically 1 or may be unsubstituted.
  • bicyclic non-aromatic heterocyclyl may be an aromatic ring group if one ring is a non-aromatic ring group, such as 2,3-dihydroindolyl, 2, 3-dihydrobenzofuranyl, 1,2,3,4-tetrahydroquinolyl and the like are included.
  • C 1-3 alkylene means a divalent saturated hydrocarbon group having 1 to 3 carbon atoms, which may be linear or branched. Examples thereof include methylene, ethylene and propylene.
  • C 1-3 alkenylene means a divalent hydrocarbon group having 2 or 3 carbon atoms, has one double bond, and is branched even if it is a straight chain. You may have. Examples thereof include ethylene and propylene. Examples thereof include ethenylene and propenylene.
  • C 6-10 aryl means phenyl, 1-naphthyl, or 2-naphthyl. When it may be substituted with one or more substituents, the number of substituents may be, for example, 1 to 5, specifically 1 to 3, more specifically 1 and may be unsubstituted. It may be.
  • methylene contained in an adamantyl group means a CH 2 group corresponding to a bridging moiety linking the bridgehead methine having an adamantane structure.
  • the substituent is, for example, 1 to 5, specifically 1 to 3, More specifically, the number is 1 to 2, and one methylene group may have two substituents. Any enantiomers, diastereomers, and other isomers arising from the substitution are included within the scope of the present invention.
  • the alkyl or alkoxy may be substituted with one or more halogen atoms.
  • the present invention can be carried out using the solvate.
  • the compounds of the present invention can be appropriately implemented as a mixture, solution, crystal polymorph and the like.
  • the present invention relating to the compound represented by the above formula (I) includes various stereoisomers such as tautomers, geometric isomers and optical isomers, diastereomers, and mixtures thereof.
  • the compound represented by the formula (I) includes the compounds of the following formulas (I-1) to (I-8).
  • the compound represented by the formula (I) includes the compounds of the following formulas (Ia-1) to (Ia-8).
  • the present invention also includes compounds of the following formulas (Ib-1) to (Ib-8).
  • the compounds described in the examples of the present specification can be used, and more specifically, the following compounds can be used: 2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5S, 7S) -5-chloro-2-((R) -phenyl (2,2,2-trifluoroacetamido) methyl) adamantane-1- Il (TP-014); N-((R)-((1S, 2R, 3S, 5S, 7S) -5-chloro-1-hydroxyadamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide ( TP-048); 2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5R, 7S) -2-((R) -phenyl (2,2,2-trifluoroacetamido) methyl) adamantan-1-yl (TP -049); 2,2,2-trifluoroacetic acid (1S, 2R, 3S,
  • the “pharmaceutically acceptable salt” of the compound of formula (I) is not particularly limited as long as it is a salt that can be used as a pharmaceutical product.
  • Examples of the salt formed by the compound of the present invention with a base include salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine and ethanolamine.
  • the salt may be an acid addition salt.
  • the salt examples include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and other mineral acids; and formic acid, Examples include acid addition salts with organic acids such as acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid.
  • organic acids such as acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid.
  • the atoms (for example, hydrogen atom, carbon atom, oxygen atom, nitrogen atom, sulfur atom and the like) contained in the compound represented by the formula (I) are each an isotope atom other than the most naturally occurring isotope.
  • the isotope atom may be a radioisotope atom. That is, according to one aspect of the present invention, there is provided a compound of formula (I) as defined herein, or a salt thereof, labeled with an isotope atom.
  • labeling with an isotope atom may be, for example, labeling with a radioisotope ( 3 H, 14 C, 32 P, etc.). From the aspect of ease of preparation of the compound, 3 H Labeling is preferred.
  • a compound of formula (I), its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof is administered as a prodrug and converted to the active compound in vivo.
  • the treatment of cognitive dysfunction or disorder in the present invention includes treatment for Alzheimer's dementia, cerebrovascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease, psychiatric disorder, and neurodegenerative disease. It is.
  • the pharmaceutical composition of the present invention includes improvement of brain dysfunction, for example, improvement of cerebral dysfunction caused by cerebrovascular disorder, brain trauma, brain tumor, viral encephalitis, hypoxic encephalopathy, alcoholism and the like.
  • the present invention is particularly applicable to cognitive dysfunction such as memory impairment, attention disorder, performance dysfunction, and social behavior disorder.
  • Cognitive dysfunction includes, for example, neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, Pick's disease, and Huntington's disease), mental disorders (schizophrenia, bipolar disorder, depression, phobias, sleep disorders, drug addiction) And pervasive developmental disorders (such as autism, Asperger syndrome, mental retardation, hyperactivity disorder, tic disorder, etc.).
  • neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Pick's disease, and Huntington's disease
  • mental disorders schizophrenia, bipolar disorder, depression, phobias, sleep disorders, drug addiction
  • pervasive developmental disorders such as autism, Asperger syndrome, mental retardation, hyperactivity disorder, tic disorder, etc.
  • Diabetic complications in the present invention include hyperglycemia, diabetic coma, ketonic coma, non-ketonic hyperosmotic coma, lactic acidosis, hypoglycemic coma, acute infections, microangiopathy, diabetic retinopathy, Examples include diabetic nephropathy, diabetic neuropathy, macrovascular disorder, cerebrovascular disorder, ischemic heart disease, diabetic gangrene, hyperlipidemia, chronic infection, cholelithiasis, and cataract.
  • a compound of formula (I), an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof is used as a Kir6.2 channel inhibitor, or a Kir6.1 channel inhibitor.
  • a compound of formula (I), an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof is a disease associated with Kir6.2 channel, such as a cognitive function disease or disorder, hyperglycemia, diabetes, diabetes Can be used to treat or prevent sexual complications. It can be used to treat or prevent diseases associated with Kir6.1 channel, such as cognitive function diseases or disorders, hyperglycemia, diabetes, diabetic complications, mental disorders.
  • the pharmaceutical composition of the present invention can be used in various dosage forms such as tablets, capsules, powders, granules, pills, solutions, emulsions, suspensions, solutions, spirits, syrups for oral administration.
  • parenteral preparations include, for example, injections such as subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections; transdermal administration or patches , Ointments or lotions; sublingual and buccal patches for buccal administration; and aerosols for nasal administration, but not limited thereto.
  • injections such as subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections; transdermal administration or patches , Ointments or lotions; sublingual and buccal patches for buccal administration; and aerosols for nasal administration, but not limited thereto.
  • These preparations can be produced by known methods usually used in the preparation process.
  • the pharmaceutical composition may contain various commonly used components, such as one or more pharmaceutically acceptable excipients, disintegrants, diluents, lubricants, flavoring agents, and coloring agents. , Sweeteners, flavoring agents, suspending agents, wetting agents, emulsifying agents, dispersing agents, adjuvants, preservatives, buffering agents, binders, stabilizers, coating agents and the like.
  • the pharmaceutical composition of the present invention may be in a sustained or sustained release dosage form.
  • the dosage of the therapeutic agent, prophylactic agent, or pharmaceutical composition of the present invention can be appropriately selected depending on the administration route, the patient's body shape, age, physical condition, degree of disease, elapsed time after onset, etc.
  • the pharmaceutical composition may comprise a therapeutically effective amount and / or a prophylactically effective amount of a compound of formula (I) as described above.
  • the compound of the above formula (I) can generally be used at a dose of 1-1000 mg / day / adult or 0.01-20 mg / day / kg body weight.
  • the pharmaceutical composition may be administered in a single dose or multiple doses.
  • the content of the compound is, for example, 0.001 to 1000 mg, specifically 0.01 to 500 mg, particularly specifically, per unit dosage form. Is 0.005 to 100 mg.
  • the compound of the present invention is, for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof, specifically TP-014 or TP-048, or a pharmaceutically acceptable salt thereof, specifically TP-048. Or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention contains conventionally known colorants, preservatives, flavors, flavors, coating agents, antioxidants, vitamins, amino acids, peptides, proteins, and minerals (iron, zinc, magnesium). , Iodine, etc.).
  • the therapeutic agent or prophylactic agent of the present invention is in a form suitable for pharmaceutical compositions, functional foods, health foods, beverages, supplements, etc., such as granules (including dry syrup), capsules (soft capsules, hard capsules). , Prepared in the form of various solid preparations such as tablets (including chewables), powders (powder), pills, or liquid preparations for internal use (including liquids, suspensions, syrups) May be.
  • the therapeutic agent or prophylactic agent of the present invention can be used as it is as a pharmaceutical composition, functional food, health food, supplement or the like.
  • additives for formulation for example, excipients, lubricants, binders, disintegrants, fluidizers, dispersants, wetting agents, preservatives, thickeners, pH adjusters, colorants, Examples include flavoring agents, surfactants, and solubilizing agents.
  • thickeners such as pectin, xanthan gum, and guar gum, can be mix
  • thickeners such as pectin, xanthan gum, and guar gum
  • it can also be set as a coating tablet using a coating agent, or it can also be set as a paste-form glue. Furthermore, even if it is a case where it prepares in another form, what is necessary is just to follow the conventional method.
  • the compounds of the present invention include compounds represented by the following formulas (III) and (IV).
  • the present invention relating to the compound represented by the above formula (I) includes various stereoisomers such as tautomers, geometric isomers and optical isomers, diastereomers, and mixtures thereof.
  • the compound represented by the formula (I) includes compounds of the following formulas (IIIa) to (IIIh).
  • the compound is a compound represented by formula (IIIa).
  • LiAlH 4 (5 mg, 0.13 mmol) was added to a THF (1 mL) solution of the obtained azide compound (31.5 mg, 0.085 mmol) under ice cooling. After stirring at room temperature for 5 hours, aqueous ammonia was added to the reaction solution under ice cooling. The mixture was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure. Dichloromethane (1 mL) was added to the residue, and triethylamine (56 ⁇ L, 0.4 mmol) and trifluoroacetic anhydride (TFAA, 34 ⁇ L, 0.24 mmol) were added under ice cooling.
  • TFAA trifluoroacetic anhydride
  • LiAlH 4 (300 mg, 8.00 mmol) was added to a solution of the obtained azide compound (750 mg, 2.67 mmol) in THF (14 mL) under ice cooling. After stirring at the same temperature for 1 hour, aqueous ammonia was added to the reaction solution. The mixture was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure. After adding dichloromethane (15 mL) to the residue, triethylamine (2.2 mL, 16.0 mmol) and trifluoroacetic anhydride (TFAA, 1.2 mL, 8.0 mmol) were added under ice cooling.
  • TFAA trifluoroacetic anhydride
  • TP-014 84.7 mg, 0.175 mmol
  • THF 2 mL
  • 0.5 M NaOH aqueous solution 1 mL
  • saturated aqueous NH 4 Cl solution was added, and the mixture was extracted with ethyl acetate.
  • the obtained organic layer was washed with saturated brine and dried over MgSO 4 .
  • LiAlH 4 (8.0 mg, 0.21 mmol) was added to a solution of the obtained azide compound (39.6 mg, 0.111 mmol) in THF (1 mL) under ice cooling. After slowly warming to room temperature and stirring for 1 hour, the reaction solution was ice-cooled and LiAlH 4 (8.0 mg, 0.21 mmol) was added. After stirring at room temperature for 1 hour, aqueous ammonia was added to the reaction solution under ice cooling. Filtration through Celite (registered trademark), the filtrate was dried over Na 2 SO 4 , and the solvent was distilled off under reduced pressure.
  • LiAlH 4 (41 mg, 1.1 mmol) was added to a solution of the obtained azide compound (225 mg, 0.716 mmol) in THF (4 mL) under ice cooling. After stirring at the same temperature for 1 hour, aqueous ammonia was added to the reaction solution. The mixture was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure. Dichloromethane (4 mL) was added to the residue, and triethylamine (497 ⁇ L, 3.86 mmol) and trifluoroacetic anhydride (TFAA, 299 ⁇ L, 2.15 mmol) were added under ice cooling.
  • TFAA trifluoroacetic anhydride
  • Diisopropyl azodicarboxylate (DIAD) was added to a THF (5 mL) solution of the obtained alcohol (258 mg, 1.0 mmol), diphenyl phosphate azide (DPPA, 237 ⁇ L, 1.1 mmol) and triphenylphosphine (239 mg, 1.1 mmol). , 214 ⁇ L, 1.1 mmol) was added under ice cooling. The temperature was slowly raised to room temperature and the mixture was stirred for 5 hours, and then the solvent was distilled off under reduced pressure.
  • DPPA diphenyl phosphate azide
  • triphenylphosphine 239 mg, 1.1 mmol
  • pcDNA3.1-Kir6.2 was obtained from Dr. Toru Ishizuka, graduate School of Life Sciences, Tohoku University.
  • pcDNA3.1-Kir6.2 was prepared using GenElute HP Plasmid Maxiprep Kit (Sigma-Aldrich) according to the attached manual.
  • N2A cells Neuro2A cells
  • DMEM culture medium Gibco
  • Composition Add 50 ml of bovine serum to 450 ml of DMEM culture medium and add 100 units of penicillin / streptomycin
  • Opti-Mem Gibco
  • Opti-Mem with 1 ⁇ g / ml of Lipofectamine R2000
  • adjusted pcDNA3.1-Kir6.2 (1 ⁇ g / ⁇ l)
  • memantine manufactured by Sigma-Aldrich
  • DMEM culture solution
  • Kir6.2 channel over-expressing N2A cells were collected, and after adding SDS sample buffer to the cells and suspending them, the primary antibody was anti-phosphorylated CaMKII antibody (Fukunaga K et al., J. Biol Chem. 1992, 267, 22527-22533) was measured for the activation of CaMKII using an anti-rabbit IgG antibody (manufactured by SouthernBiotech) as the secondary antibody. According to the law). The result is shown in FIG.
  • FIG. 1 shows the activation of CaMKII when the test compound is added, with the result when the test compound is not added (control: c) being 100%.
  • Test Example 2 Using the Kir6.2 channel overexpressing cells obtained in Test Example 1, the potassium current excreted from the cells to the outside was measured by the usual patch-clamp method. The results are shown in FIG.
  • the ATP-sensitive potassium channel (Kir6.2 channel) is localized in the cell membrane of nerve cells, and when the channel is blocked and occluded, the threshold of the nerve cell membrane rises, and a situation similar to the transient action potential is generated.
  • the potassium current is discharged from the inside of the cell to the outside of the cell, and instead, the calcium current flows from the outside of the cell to the inside of the cell.
  • FIG. 3a shows the result of measuring the time-dependent change of calcium amount dependent on TP-014 concentration when treated with TP-014 (1 to 100 nM) and memantine (100 nM) over 4 minutes.
  • TP-014 has a stronger calcium concentration-increasing action than memantine, and treatment with TP-014 significantly increases the amount of calcium in the cell due to the inhibitory action of potassium excretion outside the cells confirmed in Test Example 2. Was confirmed.
  • FIG. Figures 4a-d show the results of behavioral analysis.
  • the Y-maze method is a method that allows a mouse to freely walk three arms for 8 minutes. If the arms are A, B, and C, respectively, the mouse in A enters the arm of B or C. If the mouse enters B, then the mouse enters C, and thus, ABC and The correct answer is entered. On the other hand, the case where it does not enter the new arm with ABA is regarded as an incorrect answer, the position of the arm moved by the mouse is recorded in the selected order, and the number of times the mouse has moved to each arm within the measurement time is counted. This is total arm entries. If the answer is correct (a combination of three consecutively different arms selected), count this number as the number of alternations (No. of alternation), and subtract 2 from the total arm entries for No. of alternation. The ratio to the number subtracted is expressed as an alternation (%) as an index of normal alternation behavior (correction rate of spatial working memory).
  • mice tend to like novelty, normal mice show a 70% accuracy rate, but APP23 mice drop to around 50%.
  • the attention function (cognitive function) is analyzed using this% as an index.
  • the new object recognition test method two blocks of the same shape are put in a mouse cage and let the mouse play (this is called a training trial for 10 minutes). After an hour, change one building block to another. Since normal mice are interested in new things, the time to play with other forms of building blocks increases. Alzheimer's disease mice do not recognize novelty and have memory impairment. A trap that allows you to search freely for another 5 minutes with one of the blocks in another block (this is called holding trial).
  • the number of times of contact with each of the two objects was measured, and the ratio ⁇ ⁇ (%) ⁇ of the number of times of contact with another building block compared to the total number of times of contact in the holding trial was calculated as the discriminant index (Discrimination index) .
  • the fear conditioning test is an analysis that takes advantage of the characteristics that mice prefer a darker place than a brighter place.
  • On the first day place the mouse in a bright place. Since the mouse prefers a dark place, it enters a dark place (dark room box), at which time an electrical stimulus is applied. The mouse returns to a surprisingly bright place and then does not return to a dark place.
  • place the mouse in a bright place (the same place as day 1) and measure whether the mouse is in a dark place for 5 minutes. If the mouse immediately goes into a dark place, the fear memory is reduced.
  • “Latency” is the number of seconds measured for the time it takes to enter the dark room when the mouse is placed in a bright place on the second day. APP23 mice enter a dark place immediately, so a decrease in fear memory was confirmed, but treatment with TP-014 for 2 months confirmed an improvement effect.
  • LTP long-term potentiation phenomenon
  • the hippocampus of the brain is important for memory.
  • Artificial cerebrospinal fluid (126 mM NaCl, 5 mM) is made by slicing the hippocampus into a slice (400 ⁇ m thick) and saturating the slice with 95% O 2 /5% CO 2 gas.
  • KCl, 26 mM NaHCO 3 1.3 mM MgSO 4 -7H 2 O, 1.26 mM KH 2 PO 4 , 2.4 mM CaCl 2 -2H 2 O, 10 mM glucose
  • Hippocampal slices were transferred to the measurement chamber and TP-014 was added to the artificial cerebrospinal fluid and perfused.
  • TP-014 was added to the artificial cerebrospinal fluid and perfused.
  • fEPSP post-synaptic collecting potential
  • the recorded waveform is shown in FIG. After that, 100Hz electrical stimulation is applied to cause depopulation in the hippocampus (in the hippocampus, memory is thought to be formed by depopulation).
  • the rate of increase in neuronal excitability was reduced in APP23 mice and improved in chronic treatment with TP-014, indicating an improvement in memory learning by improving LTP.
  • CaMKII, CaMKIV, and ERK are all molecules that are thought to be important for memory formation.
  • a decrease in phosphorylation of CaMKII was found in normal APP23 mice, and an increase in phosphorylation of CaMKII was found in APP23 mice treated with PT-014 chronically (treatment conditions are the same as in Test Example 4). It was. This result indicates that the activation of CaMKII is important for the memory improvement effect by PT-014 treatment in APP23 mice.
  • GluA1 (Ser-831), Synapsin I (Ser-603), and CREB (Ser-133), known as molecules whose activation is induced by CaMKII activation, are suspended after adding SDS sample buffer to hippocampal slices. This was examined by immunoblotting. All antibodies against each molecule were obtained from Millipore. The results are shown in FIGS. 5c and 5d. It shows that the activation of GluA1 (Ser-831) and CREB (Ser-133) is induced by the activation of CaMKII.
  • 5a and c are bands (images) obtained when the immunoblot is actually run, and FIGS. 5b and 5d are analysis results obtained by quantifying the signal intensity of the bands of FIGS. 5a and 5c.
  • OBX mouse olfactory bulb-extracted mouse
  • FIGS. 6a to 6g Cognitive impairment in OBX mice was significantly improved by chronic administration of TP-014 (2 weeks).
  • OBX mice were prepared using 10-week-old DDY male mice (Nippon SLC, Hamamatsu, Japan). Olfactory bulbectomy was performed under conditions of anesthesia with sodium pentobarbital (50 mg / kg ip; Dainippon, Osaka, Japan). The mouse was fixed to a brain fixator, the skull on the olfactory bulb was drilled with a drill, and a hole with a diameter of 1 mm was made. The olfactory bulb was removed by suction with a suction pump so as not to damage the prefrontal cortex. In the Sham group, the same operation as in the OBX group was performed except for removal of the olfactory bulb by suction.
  • TP-014 is the Kir6.2 channel.
  • the analysis method is the same as in Test Examples 4-7. Kir6.2-deficient mice were obtained from Kobe University School of Medicine, Prof. Susumu Kiyono (Miki T et al., Proc. Natl. Acad. Sci. USA 1998, 95, 10402-10406).
  • TP-014 does not affect the activation of CaMKII, indicating that the site of action of TP-014 is the Kir6.2 channel.
  • OBX mice were used as depression model mice, and the effect of TP-014 to improve depression-like symptoms was confirmed. The results are shown in FIG. Although the cognitive function of OBX mice is also reduced, it was originally established as a depression model mouse.
  • the tail-suspension method (a) and the forced swim method (b) were analyzed as methods for measuring depression.
  • the tail-suspension method is a method in which the tail of the mouse is sandwiched and hung in the opposite direction. If the mouse is depressed, the immobility time becomes longer. A normal mouse moves even when it is suspended, so the immobility time is low.
  • the forced swim method fills the beaker with water and allows the mouse to swim in the beaker.
  • OBX mice Depressed mice do not swim and do not move (floating), and measure this time (immobility time (s)).
  • OBX mice showed an increase in immobility time in the tail-suspension method (a) and the forced swim method (b).
  • Immobility time improved with chronic administration of TP-014 (2 weeks, the method of administration is the same as the previous example).
  • a heterozygous mouse is a mouse in which the expression level of Kir6.1 channel is halved unlike a homozygous mouse (completely deficient mouse) (a homozygous mouse causes arrhythmia after birth and dies).
  • the results are shown in FIG. Kir6.1-deficient mice show increased depression-like symptoms, and this result indicates that Kir6.1 is an important molecule for depression.
  • TP-014 has an effect of improving depression through the inhibitory action of Kir6.1 channel.
  • Kir6.1-deficient mice were obtained from Professor Susumu Kiyono, Faculty of Medicine, Kobe University (Miki T et al., Nature Medicine 2002, 8, 466-472).
  • TP-014 The blood glucose level-lowering effect of TP-014 was confirmed by measuring glucose concentration in blood using an assay kit (manufactured by Technicon International co). The results are shown in FIG. Measurement was conducted for 4 weeks, and TP-014 (1 mg / kg) was chronically treated for 4 weeks. As a result, a significant decrease in blood glucose level was confirmed after the 3rd week. Tolbutamide was used as a control.
  • the Kir6.2 channel binds to SUR1 (urea receptor) on the cell membrane to form a channel, and the mechanism of action is thought to be due to the Kir6.2 channel inhibitory action. Tolbutamide binds to SUR1 and inhibits the Kir6.2 channel.
  • the obtained Kir6.1 channel overexpressing cells were used to measure the activation of CaMKIV.
  • the measurement method was the same immunoblotting method as in Test Example 1, and the primary antibody was an anti-phosphorylated CaMKIV antibody (Kasahara J et al ., J. Biol. Chem. 2001, 276, 44 24044-50) and anti-rabbit IgG antibody (manufactured by Southern Biotech) as the secondary antibody.
  • ATP-sensitive potassium channel (Kir6.1 channel) is localized in the cell membrane of nerve cells, and when the channel is blocked and occluded, the threshold value of the nerve cell membrane rises, and a transient action potential is generated.
  • the potassium current is discharged from the inside of the cell to the outside of the cell, and instead, the calcium current flows from the outside of the cell to the inside of the cell.
  • FIG. 18a shows an immunoblotting method using an anti-Kir6.1 channel antibody (prepared based on a conventional method) on a cell overexpressing Kir6.1 channel (according to the method described above) (except for the use of anti-Kir6.1 channel antibody).
  • ⁇ -tubulin anti- ⁇ -tubulin antibody was obtained from Sigma-Aldrich, other conditions are the same as for Kir6.1 detection).
  • arms that are crossroads are provided at high places, and each arm is either in a state where the bottom can be seen or in a closed state. Mice that are vulnerable to anxiety will stay longer in the closed arm, while mice that are resistant to anxiety will stay in the open arm.
  • FIG. 19a shows the staying time of the open arm on the vertical axis.
  • FIG. 19e shows the number of marbles buried on the vertical axis.
  • fear-conditioning test method frear-conditining method
  • the vertical axis of Fig. 19i indicates the immobility time of the mouse.
  • ** or ++ indicates that the significant difference is P ⁇ 0.01, and + or * indicates P ⁇ 0.05.

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Abstract

The present invention provides a pharmaceutical composition for treating or preventing cognitive function disease or disorder, the composition comprising a compound represented by formula (I), an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.

Description

アダマンチルメチルアミン誘導体およびその医薬としての使用Adamantylmethylamine derivatives and their use as pharmaceuticals
　本発明は、アダマンチルメチルアミン誘導体およびその医薬的に許容な塩に関する。さらに本発明は、該化合物を含有する医薬組成物、および該化合物を使用する疾患の治療方法または予防方法に関する。 The present invention relates to an adamantylmethylamine derivative and a pharmaceutically acceptable salt thereof. Furthermore, the present invention relates to a pharmaceutical composition containing the compound, and a method for treating or preventing a disease using the compound.
　ＡＴＰ感受性Ｋ＋チャネル（ＫＡＴＰチャネル）は，細胞内の代謝状態と細胞膜の興奮性を結びつけている内向き整流性Ｋ＋チャネルであり、ＡＢＣタンパクファミリーに属するスルフォニルウレア受容体（ＳＵＲ）と膜２回貫通型のＫｉｒ６．１およびＫｉｒ６．２からなる，異種八量体構造を有することが知られている。ＫＡＴＰチャネルは，種々のＫ＋チャネル開口薬，阻害薬，あるいは細胞内のヌクレオチドにより，その活性が制御される。これらは全てＳＵＲサブユニットに作用点をもっており，ＳＵＲのサブタイプにより反応が異なるとの報告がされている（非特許文献１）。 An ATP-sensitive K + channel (K ATP channel) is an inwardly rectifying K + channel that links intracellular metabolic state and excitability of the cell membrane, sulfonylurea receptor (SUR) and membrane belonging to the ABC protein family. It is known to have a heterooctamer structure composed of two-pass type Kir6.1 and Kir6.2. The activity of KATP channels is controlled by various K + channel openers , inhibitors, or intracellular nucleotides. All of these have an action point in the SUR subunit, and it has been reported that the reaction differs depending on the SUR subtype (Non-patent Document 1).
　かご型構造を有するアダマンタンの誘導体は医薬として利用されているものもあり、アマンタジンは抗ウイルス薬およびパーキンソン病治療薬として使用されている。塩酸メマンチンは中等度・重度アルツハイマー型認知症の治療薬として日本においても承認がされている。メマンチンは非競合的ＮＭＤＡ受容体阻害薬であり，虚血が引き起こすグルタミン酸過剰放出による神経細胞死を防ぐという作用機作が報告されている（非特許文献２）。 Some derivatives of adamantane having a cage structure are used as pharmaceuticals, and amantadine is used as an antiviral drug and a Parkinson's disease therapeutic drug. Memantine hydrochloride is also approved in Japan as a treatment for moderate and severe Alzheimer's dementia. Memantine is a non-competitive NMDA receptor inhibitor, and its mechanism of action is reported to prevent neuronal cell death caused by excessive release of glutamate caused by ischemia (Non-patent Document 2).
　医薬としての活性を有するアダマンタン誘導体についていくつかの報告がされている（特許文献１～３）。 Several reports have been made on adamantane derivatives having pharmaceutical activity (Patent Documents 1 to 3).
特表２０１１－５２９０５７号Special table 2011-529057 特開２０１０－５２２２０３号JP 2010-522203 A 特表２００９－５０８９５６号Special table 2009-508956
　アルツハイマー病などの認知機能疾患または障害に対しては十分な効果が得られる治療方法および予防方法が確立しているとは言えず、既存の薬剤とは作用機作が異なる新規な治療剤および予防剤が求められている。また糖尿病に対する新規な治療剤および予防剤も強く求められている。 It cannot be said that treatment and prevention methods that can provide sufficient effects on cognitive dysfunctions or disorders such as Alzheimer's disease have been established, and new treatments and prevention that have different mechanisms of action from existing drugs There is a need for agents. There is also a strong need for novel therapeutic and preventive agents for diabetes.
　一つの側面において、本発明は認知機能疾患または障害の治療または予防に用いるための医薬組成物の提供を目的とする。さらに本発明は特定のアダマンタン誘導体を用いた認知機能疾患または障害の治療方法または予防方法の提供を目的とする。 In one aspect, the present invention aims to provide a pharmaceutical composition for use in the treatment or prevention of a cognitive function disease or disorder. A further object of the present invention is to provide a method for treating or preventing a cognitive function disease or disorder using a specific adamantane derivative.
　一つの側面において、本発明は糖尿病または糖尿病合併症の治療または予防に用いるための医薬組成物の提供を目的とする。さらに本発明は特定のアダマンタン誘導体を用いた糖尿病または糖尿病合併症の治療方法または予防方法の提供を目的とする。 In one aspect, the present invention aims to provide a pharmaceutical composition for use in the treatment or prevention of diabetes or diabetic complications. It is another object of the present invention to provide a method for treating or preventing diabetes or diabetic complications using a specific adamantane derivative.
　ＡＴＰ感受性Ｋ＋チャネル（ＫＡＴＰチャネル）は，Ｋｉｒ６．１およびＫｉｒ６．２を含み、抗糖尿病薬などの作用点として知られている。 ATP-sensitive K + channel (K ATP channel) includes Kir6.1 and Kir6.2, and is known as an action point of antidiabetic drugs and the like.
　一つの側面において、本発明はＫＡＴＰチャネルのＫｉｒ６．１チャネル阻害薬またはＫｉｒ６．２チャネル阻害薬の提供を目的とする。さらに本発明は、ＫＡＴＰチャネルのＫｉｒ６．１チャネルまたはＫｉｒ６．２チャネルが関与する疾患の治療または予防に用いるための医薬組成物の提供を目的とする。さらに本発明は、特定のアダマンチルメチルアミン誘導体を用いたＫＡＴＰチャネルのＫｉｒ６．１チャネルまたはＫｉｒ６．２チャネルが関与する疾患の治療方法または予防方法の提供を目的とする。 In one aspect, the present invention is directed to providing a Kir6.1 channel inhibitor or a Kir6.2 channel inhibitor of KATP channels. A further object of the present invention is to provide a pharmaceutical composition for use in the treatment or prevention of diseases involving the Kir6.1 channel or Kir6.2 channel of the KATP channel. A further object of the present invention is to provide a method for treating or preventing a disease involving a Kir6.1 channel or Kir6.2 channel of a KATP channel using a specific adamantylmethylamine derivative.
　本発明者らは、上記課題を達成するために鋭意研究を進めたところ、アダマンチルメチルアミン誘導体にＫｉｒ６．２チャネル阻害活性、Ｋｉｒ６．１チャネル阻害活性、認知機能疾患または障害における治療効果、および血糖値低下作用を見いだし、本発明を完成させた。本明細書の開示は、以下の［１］～［１７］に記載の発明を包含する。 The inventors of the present invention have made extensive studies in order to achieve the above-mentioned problems. As a result, Kiram 6.2 channel inhibitory activity, Kir6.1 channel inhibitory activity, therapeutic effects in cognitive function diseases or disorders, and blood glucose A value lowering effect was found and the present invention was completed. The disclosure of this specification includes the inventions described in [1] to [17] below.
　式（Ｉ）： Formula (I):
Figure JPOXMLDOC01-appb-C000004
 ［式中、Ｑ１、Ｑ２、Ｒ１、およびＲ４は、それぞれ独立に、水素原子、ハロゲン原子、１以上のハロゲン原子で置換されていてもよいＣ１－６アルキル、アミノ、Ｘ１より選択される１以上の置換基により置換されていてもよいＣ６－１０アリール、カルボキシ、－ＯＲ７、および－ＳＲ８から選択され； 
　Ｒ２は、水素原子、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルスルホニル、１以上のハロゲン原子により置換されていてもよい（Ｃ１－６アルキル）スルホニル、または－ＣＯＹＲ６であり；
　Ｙは、直接結合、Ｏ、またはＮＲ９であり；
　Ｒ３は、Ｘ１より選択される１以上の置換基により置換されていてもよいＣ３－８シクロアルキル、Ｘ１より選択される１以上の置換基により置換されていてもよいＣ６－１０アリール、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルアミノカルボニル、Ｘ１より選択される１以上の置換基により置換されていてもよい５～１０員単環式または二環式ヘテロアリール、Ｘ１より選択される１以上の置換基により置換されていてもよい５～１０員単環式または二環式非芳香族ヘテロシクリル、または－Ｑ３－Ｒ１３であり；
　Ｑ３は、Ｃ１－３アルキレン、またはＣ２－３アルケニレンであり；
　Ｒ１３は、Ｘ１より選択される１以上の置換基により置換されていてもよいＣ６－１０アリールであり；
　Ｒ５は、水素原子、または１以上のハロゲン原子で置換されていてもよいＣ１－６アルキルであり；
　Ｒ６は、Ｃ１－６アルキル、Ｘ１より選択される１以上の置換基により置換されていてもよいＣ６－１０アリール、またはＸ１より選択される１以上の置換基により置換されていてもよい５又は６員環ヘテロアリールであり、ここでアルキルは１以上のハロゲン原子により置換されていてもよく、および／またはＸ２より選択される１つの置換基により置換されていてもよく；
　Ｒ７は、水素原子、１以上のハロゲン原子で置換されていてもよいＣ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、１以上のハロゲン原子で置換されていてもよい（Ｃ１－６アルキル）カルボニル、またはＸ１より選択される１以上の置換基により置換されていてもよいＣ６－１０アリールであり；
　Ｒ８は、水素原子、１以上のハロゲン原子で置換されていてもよいＣ１－６アルキル、またはＸ１より選択される１以上の置換基により置換されていてもよいＣ６－１０アリールであり；
　Ｒ９は、水素原子、または１以上のハロゲン原子で置換されていてもよいＣ１－６アルキルであり；
　Ｘ１は、それぞれ独立に、Ｃ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ、ヒドロキシ、ニトロ、およびシアノから選択され；
　Ｘ２は、Ｃ１－６アルコキシ、Ｃ２－６アルケニルオキシ、Ｃ２－６アルキニルオキシ、および－ＮＲ１１Ｒ１２から選択され；
　Ｒ１１は、水素原子、Ｃ１－６アルキル、（Ｃ１－６アルコキシ）カルボニル、またはアリール部分がＸ１より選択される１以上の置換基により置換されていてもよい［（Ｃ６－１０アリール）Ｃ１－３アルコキシ］カルボニルであり、ここでアルキルまたはアルコキシ部分は１以上のハロゲン原子により置換されていてもよく；
　Ｒ１２は、水素原子、または１以上のハロゲン原子で置換されていてもよいＣ１－６アルキルであり；
　ここで、アダマンチル基に含まれるメチレンは、Ｃ１－６アルキル、Ｃ１－６アルコキシ、およびヒドロキシから独立に選択される１以上の基により置換されていてもよく、ここでアルキルまたはアルコキシは、１以上のハロゲン原子で置換されていてもよい］
で表される化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。
Figure JPOXMLDOC01-appb-C000004
 [Wherein, Q 1 , Q 2 , R 1 and R 4 each independently represent a hydrogen atom, a halogen atom, C 1-6 alkyl optionally substituted with one or more halogen atoms, amino, X 1 Selected from C 6-10 aryl, carboxy, —OR 7 , and —SR 8 optionally substituted by one or more substituents selected from;
R 2 is a hydrogen atom, phenylsulfonyl optionally substituted with one or more substituents selected from X 1 , (C 1-6 alkyl) sulfonyl optionally substituted with one or more halogen atoms, or -COYR 6 ;
Y is a direct bond, O, or NR 9 ;
R 3 is optionally substituted by one or more optionally substituted with a substituent C 3-8 cycloalkyl, one or more substituents selected from X 1 is selected from X 1 C 6- 10 aryl, 1 or more phenyl aminocarbonyl optionally substituted by a substituent, one or more 10-membered to 5 may be substituted by a substituent monocyclic selected from X 1 is selected from X 1 Or a bicyclic heteroaryl, a 5- to 10-membered monocyclic or bicyclic non-aromatic heterocyclyl optionally substituted by one or more substituents selected from X 1 , or —Q 3 —R 13 ;
Q 3 is C 1-3 alkylene or C 2-3 alkenylene;
R 13 is C 6-10 aryl optionally substituted by one or more substituents selected from X 1 ;
R 5 is a hydrogen atom or C 1-6 alkyl optionally substituted with one or more halogen atoms;
R 6 is, C 1-6 alkyl, optionally substituted by one or more substituents selected from optionally substituted C 6-10 aryl or X 1, by one or more substituents selected from X 1 Optionally substituted 5- or 6-membered heteroaryl, wherein alkyl may be substituted by one or more halogen atoms and / or may be substituted by one substituent selected from X 2 ;
R 7 is a hydrogen atom, C 1-6 alkyl optionally substituted with one or more halogen atoms, C 1-6 alkoxy C 1-6 alkyl, optionally substituted with one or more halogen atoms (C 1-6 alkyl) carbonyl, or C 6-10 aryl optionally substituted by one or more substituents selected from X 1 ;
R 8 is a hydrogen atom, C 1-6 alkyl optionally substituted with one or more halogen atoms, or C 6-10 aryl optionally substituted with one or more substituents selected from X 1 Yes;
R 9 is a hydrogen atom or C 1-6 alkyl optionally substituted with one or more halogen atoms;
Each X 1 is independently selected from C 1-6 alkyl, a halogen atom, C 1-6 alkoxy, hydroxy, nitro, and cyano;
X 2 is selected from C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, and —NR 11 R 12 ;
In R 11 , a hydrogen atom, C 1-6 alkyl, (C 1-6 alkoxy) carbonyl, or an aryl moiety may be substituted with one or more substituents selected from X 1 [(C 6-10 Aryl) C 1-3 alkoxy] carbonyl, wherein the alkyl or alkoxy moiety may be substituted by one or more halogen atoms;
R 12 is a hydrogen atom, or C 1-6 alkyl optionally substituted with one or more halogen atoms;
Here, the methylene contained in the adamantyl group may be substituted with one or more groups independently selected from C 1-6 alkyl, C 1-6 alkoxy, and hydroxy, where alkyl or alkoxy is May be substituted with one or more halogen atoms]
Or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.
　［２］式（Ｉ）： [2] Formula (I):
Figure JPOXMLDOC01-appb-C000005
 ［式中、Ｑ１は、水素原子、ハロゲン原子、１以上のハロゲン原子で置換されていてもよいＣ１－６アルキル、アミノ、または－ＯＲ１０であり；
　Ｒ１０は、水素原子、１以上のハロゲン原子で置換されていてもよいＣ１－６アルキル、または１以上のハロゲン原子で置換されていてもよい（Ｃ１－６アルキル）カルボニルであり；
　Ｑ２は、水素原子、Ｃ１－６アルキル、またはＣ１－６アルコキシであり、ここでアルキルまたはアルコキシは、１以上のハロゲン原子で置換されていてもよく；
　Ｒ１は、水素原子、Ｃ１－６アルキル、またはＣ１－６アルコキシであり、ここでアルキルまたはアルコキシは、１以上のハロゲン原子で置換されていてもよく；
　Ｒ２は、水素原子、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルスルホニル、１以上のハロゲン原子により置換されていてもよい（Ｃ１－６アルキル）スルホニル、または－ＣＯＹＲ６であり；
　Ｙは、直接結合、Ｏ、またはＮＲ９であり；
　Ｒ３は、Ｃ３－８シクロアルキル、Ｘ１より選択される１以上の置換基により置換されていてもよいＣ６－１０アリール、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルアミノカルボニル、Ｘ１より選択される１以上の置換基により置換されていてもよい５－１０員単環式または二環式ヘテロアリール、または－Ｑ３－Ｒ１３であり；
　Ｑ３は、Ｃ１－３アルキレン、またはＣ２－３アルケニレンであり；
　Ｒ１３は、Ｘ１より選択される１以上の置換基により置換されていてもよいＣ６－１０アリールであり；
　Ｒ４は、水素原子、ハロゲン原子、１以上のハロゲン原子により置換されていてもよいＣ１－６アルキル、Ｘ３より選択される１以上の置換基により置換されていてもよいフェニル、カルボキシ、－ＯＲ７、または－ＳＲ８であり；
　Ｒ５は、水素原子、またはＣ１－６アルキルであり；
　Ｒ６は、Ｃ１－６アルキル、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニル、またはＸ１より選択される１以上の置換基により置換されていてもよい５又は６員環ヘテロアリールであり、ここでアルキルは１以上のハロゲン原子により置換されていてもよく、および／またはＸ２より選択される１つの置換基により置換されていてもよく；
　Ｒ７は、水素原子、１以上のハロゲン原子で置換されていてもよいＣ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、または１以上のハロゲン原子で置換されていてもよい（Ｃ１－６アルキル）カルボニルであり；
　Ｒ８は、Ｃ１－６アルキル、またはＸ１より選択される１以上の置換基により置換されていてもよいフェニルであり；
　Ｒ９は、水素原子、またはＣ１－６アルキルであり；
　Ｘ１は、それぞれ独立に、Ｃ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ、ニトロ、およびシアノから選択され；
　Ｘ２は、Ｃ１－６アルコキシ、Ｃ２－６アルケニルオキシ、Ｃ２－６アルキニルオキシ、および－ＮＲ１１Ｒ１２から選択され；
　Ｘ３は、それぞれ独立に、Ｃ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ、ヒドロキシ、ニトロ、およびシアノから選択され；
　Ｒ１１は、水素原子、Ｃ１－６アルキル、（Ｃ１－６アルコキシ）カルボニル、またはフェニル部分がＸ１より選択される１以上の置換基により置換されていてもよいベンジルオキシカルボニルであり；
　Ｒ１２は、水素原子、またはＣ１－６アルキルであり；
　ここで、アダマンチル基に含まれるメチレンは、Ｃ１－６アルキル、およびＣ１－６アルコキシから独立に選択される１以上の基により置換されていてもよく、ここでアルキルまたはアルコキシは、１以上のハロゲン原子で置換されていてもよい］
で表される、［１］に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。
Figure JPOXMLDOC01-appb-C000005
 [Wherein Q 1 is a hydrogen atom, a halogen atom, C 1-6 alkyl optionally substituted with one or more halogen atoms, amino, or —OR 10 ;
R 10 is a hydrogen atom, C 1-6 alkyl optionally substituted with one or more halogen atoms, or (C 1-6 alkyl) carbonyl optionally substituted with one or more halogen atoms;
Q 2 is a hydrogen atom, C 1-6 alkyl, or C 1-6 alkoxy, wherein alkyl or alkoxy may be substituted with one or more halogen atoms;
R 1 is a hydrogen atom, C 1-6 alkyl, or C 1-6 alkoxy, where alkyl or alkoxy may be substituted with one or more halogen atoms;
R 2 is a hydrogen atom, phenylsulfonyl optionally substituted with one or more substituents selected from X 1 , (C 1-6 alkyl) sulfonyl optionally substituted with one or more halogen atoms, or -COYR 6 ;
Y is a direct bond, O, or NR 9 ;
R 3 is optionally substituted by C 3-8 cycloalkyl, the one or more optionally substituted with a substituent C 6-10 aryl, one or more substituents selected from X 1 is selected from X 1 Optionally phenylaminocarbonyl, 5-10 membered monocyclic or bicyclic heteroaryl optionally substituted by one or more substituents selected from X 1 , or —Q 3 —R 13 ;
Q 3 is C 1-3 alkylene or C 2-3 alkenylene;
R 13 is C 6-10 aryl optionally substituted by one or more substituents selected from X 1 ;
R 4 is a hydrogen atom, a halogen atom, C 1-6 alkyl which may be substituted with one or more halogen atoms, phenyl, carboxy which may be substituted with one or more substituents selected from X 3 , -OR 7 or -SR 8 ;
R 5 is a hydrogen atom or C 1-6 alkyl;
R 6 is, C 1-6 alkyl, phenyl optionally substituted by one or more substituents selected from X 1 or may be X 1 is substituted by one or more substituents selected from, 5 Or a 6-membered heteroaryl, wherein alkyl may be substituted by one or more halogen atoms and / or may be substituted by one substituent selected from X 2 ;
R 7 is a hydrogen atom, C 1-6 alkyl optionally substituted with one or more halogen atoms, C 1-6 alkoxy C 1-6 alkyl, or optionally substituted with one or more halogen atoms ( C 1-6 alkyl) carbonyl;
R 8 is C 1-6 alkyl, or phenyl optionally substituted by one or more substituents selected from X 1 ;
R 9 is a hydrogen atom or C 1-6 alkyl;
Each X 1 is independently selected from C 1-6 alkyl, a halogen atom, C 1-6 alkoxy, nitro, and cyano;
X 2 is selected from C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, and —NR 11 R 12 ;
Each X 3 is independently selected from C 1-6 alkyl, a halogen atom, C 1-6 alkoxy, hydroxy, nitro, and cyano;
R 11 is a hydrogen atom, C 1-6 alkyl, (C 1-6 alkoxy) carbonyl, or benzyloxycarbonyl, wherein the phenyl moiety may be substituted with one or more substituents selected from X 1 ;
R 12 is a hydrogen atom or C 1-6 alkyl;
Here, methylene contained in the adamantyl group may be substituted with one or more groups independently selected from C 1-6 alkyl and C 1-6 alkoxy, wherein alkyl or alkoxy is one or more May be substituted with a halogen atom of
The compound according to [1], an enantiomer, a diastereomer thereof, or a pharmaceutically acceptable salt thereof represented by:
　［３］式（Ｉａ）： [3] Formula (Ia):
Figure JPOXMLDOC01-appb-C000006
 ［式中、Ｑ１は、水素原子、ハロゲン原子、または－ＯＲ１０であり；
　Ｒ１０は、水素原子、または１以上のハロゲン原子で置換されていてもよい（Ｃ１－６アルキル）カルボニルであり；
　Ｒ２は、水素原子、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルスルホニル、１以上のハロゲン原子により置換されていてもよい（Ｃ１－６アルキル）スルホニル、または－ＣＯＹＲ６であり；
　Ｙは、直接結合、Ｏ、またはＮＲ９であり；
　Ｒ３は、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニル、またはＸ１より選択される１以上の置換基により置換されていてもよい５又は６員環ヘテロアリールであり；
　Ｒ４は、水素原子、ハロゲン原子、－ＯＲ７、または－ＳＲ８であり；
　Ｒ５は、水素原子、またはＣ１－６アルキルであり；
　Ｒ６は、Ｃ１－６アルキル、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニル、またはＸ１より選択される１以上の置換基により置換されていてもよい５又は６員環ヘテロアリールであり、ここでＣ１－６アルキルは１以上のハロゲン原子により置換されていてもよく、および／またはＸ２より選択される１つの置換基により置換されていてもよく；
　Ｒ７は、水素原子、Ｃ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、または１以上のハロゲン原子で置換されていてもよい（Ｃ１－６アルキル）カルボニルであり；
　Ｒ８は、Ｃ１－６アルキル、またはＸ１より選択される１以上の置換基により置換されていてもよいフェニルであり；
　Ｒ９は、水素原子、またはＣ１－６アルキルであり；
　Ｘ１は、それぞれ独立に、Ｃ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ、ニトロ、およびシアノから選択され；
　Ｘ２は、Ｃ１－６アルコキシ、Ｃ２－６アルケニルオキシ、Ｃ２－６アルキニルオキシ、および－ＮＲ１１Ｒ１２から選択され；
　Ｒ１１は、水素原子、Ｃ１－６アルキル、（Ｃ１－６アルコキシ）カルボニル、またはフェニル部分がＸ１より選択される１以上の置換基により置換されていてもよいベンジルオキシカルボニルであり；
　Ｒ１２は、水素原子、またはＣ１－６アルキルである］
で表される、［１］または［２］に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。
Figure JPOXMLDOC01-appb-C000006
 [Wherein Q 1 is a hydrogen atom, a halogen atom, or —OR 10 ;
R 10 is a hydrogen atom or (C 1-6 alkyl) carbonyl optionally substituted with one or more halogen atoms;
R 2 is a hydrogen atom, phenylsulfonyl optionally substituted with one or more substituents selected from X 1 , (C 1-6 alkyl) sulfonyl optionally substituted with one or more halogen atoms, or -COYR 6 ;
Y is a direct bond, O, or NR 9 ;
R 3 is one or more phenyl which is substituted by a substituent or one or more substituents the optionally substituted 5 or 6 membered heteroaryl selected from X 1, is selected from X 1 Is;
R 4 is a hydrogen atom, a halogen atom, —OR 7 , or —SR 8 ;
R 5 is a hydrogen atom or C 1-6 alkyl;
R 6 is, C 1-6 alkyl, phenyl optionally substituted by one or more substituents selected from X 1 or may be X 1 is substituted by one or more substituents selected from, 5 Or a 6-membered heteroaryl, wherein C 1-6 alkyl may be substituted by one or more halogen atoms and / or may be substituted by one substituent selected from X 2 ;
R 7 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, or (C 1-6 alkyl) carbonyl optionally substituted with one or more halogen atoms;
R 8 is C 1-6 alkyl, or phenyl optionally substituted by one or more substituents selected from X 1 ;
R 9 is a hydrogen atom or C 1-6 alkyl;
Each X 1 is independently selected from C 1-6 alkyl, a halogen atom, C 1-6 alkoxy, nitro, and cyano;
X 2 is selected from C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, and —NR 11 R 12 ;
R 11 is a hydrogen atom, C 1-6 alkyl, (C 1-6 alkoxy) carbonyl, or benzyloxycarbonyl, wherein the phenyl moiety may be substituted with one or more substituents selected from X 1 ;
R 12 is a hydrogen atom or C 1-6 alkyl]
The compound according to [1] or [2], an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof represented by:
　［４］Ｑ１およびＲ４が、水素原子である、［１］～［３］のいずれかに記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 [4] The compound according to any of [1] to [3], wherein Q 1 and R 4 are a hydrogen atom, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
　［５］Ｑ１およびＲ４が、ハロゲン原子より選択される、［１］～［３］のいずれかに記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 [5] The compound according to any one of [1] to [3], Q 1 and R 4 selected from a halogen atom, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof.
　［６］Ｑ１およびＲ４が、塩素原子である、［１］～［３］、および［５］のいずれかに記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 [6] The compound according to any one of [1] to [3] and [5], wherein Q 1 and R 4 are a chlorine atom, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof .
　［７］Ｒ２が、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルスルホニル、１以上のハロゲン原子により置換されていてもよい（Ｃ１－６アルキル）スルホニル、または－ＣＯＲ６である、［１］～［６］のいずれかに記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 [7] R 2 is phenylsulfonyl optionally substituted by one or more substituents selected from X 1 , (C 1-6 alkyl) sulfonyl optionally substituted by one or more halogen atoms, or The compound according to any one of [1] to [6], its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof, which is COR 6 .
　［８］Ｒ２が、トリフルオロアセチルである、［１］～［７］のいずれかに記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 [8] The compound according to any one of [1] to [7], wherein R 2 is trifluoroacetyl, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof.
　［９］Ｒ３が、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルである、［１］～［８］のいずれかに記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 [9] The compound according to any one of [1] to [8], its enantiomer, its diastereomer, wherein R 3 is phenyl optionally substituted by one or more substituents selected from X 1 Or a pharmaceutically acceptable salt thereof.
　［１０］Ｒ５は、水素原子である、［１］～［９］のいずれかに記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 [10] The compound according to any one of [1] to [9], wherein R 5 is a hydrogen atom, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
　［１１］２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－５－クロロ－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセトアミド）メチル）アダマンタン－１－イル；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－５－クロロ－１－ヒドロキシアダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド；
　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｒ，７Ｓ）－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセタミド）メチル）アダマンタン－１－イル；
　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－５－（２－メトキシエトキシ）－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセタミド）メチル）アダマンタン－１－イル；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－５－クロロ－１－ヒドロキシアダマンタン－２－イル）（ピリジン－３－イル）メチル）－２，２，２－トリフルオロアセトアミド；
　２，２，２－トリフルオロ－Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｒ，７Ｓ）－１－ヒドロキシアダマンタン－２－イル）（フェニル）メチル）アセタミド；
　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－５－メトキシ－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセタミド）メチル）アダマンタン－１－イル；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド；
　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミン；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アセタミド；
　メチル　（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）カーバメート；
　１－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－３－フェニルウレア；
　ベンジル　（２－（（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アミノ）－２－オキソエチル）カーバメート；
　２－アミノ－Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アセタミド；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）メタンスルホンアミド；
　２－ブロモ－Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アセタミド；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－２－（プロパ－２－イン－１－イルオキシ）アセタミド；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－１，１，１－トリフルオロメタンスルホンアミド；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－２－ニトロベンゼンスルホンアミド；および
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－４－ニトロベンゼンスルホンアミド；
　Ｎ－（（Ｓ）－（（１Ｓ，３Ｓ，５Ｓ，７Ｓ）－アダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド；
　Ｎ－（（Ｒ）－（（１Ｒ，３Ｒ，５Ｒ，７Ｒ）－アダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド； 
　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセトアミド）メチル）－５－（フェニルチオ）アダマンタン－１－イル；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）ベンズアミド；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）ピコリンアミド；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）ベンゼンスルホンアミド；
　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－５－クロロ－２－（（Ｓ）－フェニル（２，２，２－トリフルオロアセタミド）メチル）アダマンタン－１－イル； 
　Ｎ－（（１Ｒ）－（（１Ｒ，２Ｓ，３Ｒ，５Ｒ，７Ｒ）－５－クロロ－１－ヒドロキシアダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド；
　２，２，２－トリフルオロ酢酸（１Ｒ，２Ｓ，３Ｒ，５Ｒ，７Ｒ）－５－クロロ－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセタミド）メチル）アダマンタン－１－イル；および
　（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－２－（（Ｒ）－アミノ（フェニル）メチル）－５－クロロアダマンタン－１－オール
から選択される、［１］に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 [11] 2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5S, 7S) -5-chloro-2-((R) -phenyl (2,2,2-trifluoroacetamido) methyl) adamantane -1-yl;
N-((R)-((1S, 2R, 3S, 5S, 7S) -5-chloro-1-hydroxyadamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide;
2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5R, 7S) -2-((R) -phenyl (2,2,2-trifluoroacetamido) methyl) adamantan-1-yl;
2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5S, 7R) -5- (2-methoxyethoxy) -2-((R) -phenyl (2,2,2-trifluoroacetamide) Methyl) adamantan-1-yl;
N-((R)-((1S, 2R, 3S, 5S, 7S) -5-chloro-1-hydroxyadamantan-2-yl) (pyridin-3-yl) methyl) -2,2,2-tri Fluoroacetamide;
2,2,2-trifluoro-N-((R)-((1S, 2R, 3S, 5R, 7S) -1-hydroxyadamantan-2-yl) (phenyl) methyl) acetamide;
2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5S, 7R) -5-methoxy-2-((R) -phenyl (2,2,2-trifluoroacetamide) methyl) adamantane-1 -Il;
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide;
(R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine;
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) acetamide;
Methyl ((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) carbamate;
1-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -3-phenylurea;
Benzyl (2-(((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) amino) -2-oxoethyl) carbamate;
2-amino-N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) acetamide;
N-((R)-((1S, 2R, 3S, 5S, 7S) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) methanesulfonamide;
2-bromo-N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) acetamide;
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -2- (prop-2-yn-1-yloxy) Acetamide;
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -1,1,1-trifluoromethanesulfonamide;
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -2-nitrobenzenesulfonamide; and N-((R) -((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -4-nitrobenzenesulfonamide;
N-((S)-((1S, 3S, 5S, 7S) -adamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide;
N-((R)-((1R, 3R, 5R, 7R) -adamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide;
2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5S, 7S) -2-((R) -phenyl (2,2,2-trifluoroacetamido) methyl) -5- (phenylthio) adamantane 1-yl;
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) benzamide;
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) picolinamide;
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) benzenesulfonamide;
2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5S, 7S) -5-chloro-2-((S) -phenyl (2,2,2-trifluoroacetamide) methyl) adamantane-1 -Il;
N-((1R)-((1R, 2S, 3R, 5R, 7R) -5-chloro-1-hydroxyadamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide;
2,2,2-trifluoroacetic acid (1R, 2S, 3R, 5R, 7R) -5-chloro-2-((R) -phenyl (2,2,2-trifluoroacetamide) methyl) adamantane-1 -Yl; and (1S, 2R, 3S, 5S, 7S) -2-((R) -amino (phenyl) methyl) -5-chloroadamantan-1-ol, the compound according to [1] , Its enantiomers, its diastereomers, or pharmaceutically acceptable salts thereof.
　［１２］［１］～［１１］のいずれかに記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩を含有する医薬組成物。 [12] A pharmaceutical composition comprising the compound according to any one of [1] to [11], an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
　［１３］認知機能疾患または障害の治療又は予防に用いるための、［１２］に記載の医薬組成物。 [13] The pharmaceutical composition according to [12] for use in the treatment or prevention of a cognitive function disease or disorder.
　［１４］認知機能疾患または障害が、アルツハイマー型認知症、脳血管性認知症、レビー小体型認知症、前頭側頭型認知症、パーキンソン病、精神疾患、神経変性疾患から選択される、［１３］に記載の医薬組成物。 [14] The cognitive function disease or disorder is selected from Alzheimer's dementia, cerebrovascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease, psychiatric disorder, neurodegenerative disease, [13] ] The pharmaceutical composition of description.
　［１５］糖尿病または糖尿病性合併症の治療又は予防に用いるための、［１２］に記載の医薬組成物。 [15] The pharmaceutical composition according to [12] for use in the treatment or prevention of diabetes or diabetic complications.
　［１６］［１］～［１１］のいずれかに記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩を含有する、Ｋｉｒ６．２チャネル阻害薬。 [16] A Kir6.2 channel inhibitor comprising the compound according to any one of [1] to [11], an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
　［１７］［１］～［１１］のいずれかに記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩を含有する、Ｋｉｒ６．１チャネル阻害薬。 [17] A Kir6.1 channel inhibitor comprising the compound according to any one of [1] to [11], an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
　さらに、本明細書の開示は、以下の［１－１］～［１－１４］に記載のアダマンタン誘導体に関する発明を包含する。 Furthermore, the disclosure of this specification includes inventions relating to adamantane derivatives described in [1-1] to [1-14] below.
　［１－１］式（Ｉｂ）： [1-1] Formula (Ib):
Figure JPOXMLDOC01-appb-C000007
 ［式中、Ｑ１およびＲ４のうちの一方はハロゲン原子であり、他方は水素原子、またはハロゲン原子であり；
　Ｒ２は、水素原子、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルスルホニル、１以上のハロゲン原子により置換されていてもよい（Ｃ１－６アルキル）スルホニル、または－ＣＯＹＲ６であり；
　Ｙは、直接結合、Ｏ、またはＮＲ７であり；
　Ｒ６は、Ｃ１－６アルキル、１以上のハロゲン原子により置換されていてもよいＣ１－６アルコキシ、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニル、またはＸ１より選択される１以上の置換基により置換されていてもよい５又は６員環ヘテロアリールであり、ここでＣ１－６アルキルは１以上のハロゲン原子により置換されていてもよく、および／またはＸ２より選択される１つの置換基により置換されていてもよく；
　Ｒ７は、水素原子、またはＣ１－６アルキルであり；
　Ｘは、Ｏ、またはＮＲ５であり；
　Ｒ３は、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニル、またはＸ１より選択される１以上の置換基により置換されていてもよい５又は６員環ヘテロアリールであり；
　Ｒ５は、水素原子、またはＣ１－６アルキルであり；
　Ｘ１は、それぞれ独立に、Ｃ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ、ニトロ、およびシアノから選択され；
　Ｘ２は、Ｃ１－６アルコキシ、Ｃ２－６アルケニルオキシ、Ｃ２－６アルキニルオキシ、および－ＮＲ１１Ｒ１２から選択され；
　Ｒ１１は、水素原子、Ｃ１－６アルキル、（Ｃ１－６アルコキシ）カルボニル、またはフェニル部分がＸ１より選択される１以上の置換基により置換されていてもよいベンジルオキシカルボニルであり；
　Ｒ１２は、水素原子、またはＣ１－６アルキルである］
で表される化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。
Figure JPOXMLDOC01-appb-C000007
 [Wherein, one of Q 1 and R 4 is a halogen atom, and the other is a hydrogen atom or a halogen atom;
R 2 is a hydrogen atom, phenylsulfonyl optionally substituted with one or more substituents selected from X 1 , (C 1-6 alkyl) sulfonyl optionally substituted with one or more halogen atoms, or -COYR 6 ;
Y is a direct bond, O, or NR 7 ;
R 6 is C 1-6 alkyl, C 1-6 alkoxy optionally substituted by one or more halogen atoms, phenyl optionally substituted by one or more substituents selected from X 1 , or X is one or more substituents may 5 or 6 membered heteroaryl optionally substituted by is selected from 1, wherein C 1-6 alkyl may be optionally substituted by one or more halogen atoms, and / Or optionally substituted by one substituent selected from X 2 ;
R 7 is a hydrogen atom or C 1-6 alkyl;
X is O or NR 5 ;
R 3 is one or more phenyl which is substituted by a substituent or one or more substituents the optionally substituted 5 or 6 membered heteroaryl selected from X 1, is selected from X 1 Is;
R 5 is a hydrogen atom or C 1-6 alkyl;
Each X 1 is independently selected from C 1-6 alkyl, a halogen atom, C 1-6 alkoxy, nitro, and cyano;
X 2 is selected from C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, and —NR 11 R 12 ;
R 11 is a hydrogen atom, C 1-6 alkyl, (C 1-6 alkoxy) carbonyl, or benzyloxycarbonyl, wherein the phenyl moiety may be substituted with one or more substituents selected from X 1 ;
R 12 is a hydrogen atom or C 1-6 alkyl]
Or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.
　［１－２］Ｑ１およびＲ４が、ハロゲン原子より選択される、［１］に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 [1-2] The compound according to [1], wherein Q 1 and R 4 are selected from a halogen atom, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
　［１－３］Ｑ１およびＲ４が、塩素原子である、［１］または［２］に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 [1-3] The compound according to [1] or [2], wherein Q 1 and R 4 are a chlorine atom, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
　［１－４］Ｒ２が、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルスルホニル、１以上のハロゲン原子により置換されていてもよい（Ｃ１－６アルキル）スルホニル、または－ＣＯＹＲ６である、［１］～［３］のいずれかに記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 [1-4] R 2 is phenylsulfonyl optionally substituted by one or more substituents selected from X 1 , (C 1-6 alkyl) sulfonyl optionally substituted by one or more halogen atoms Or a compound according to any one of [1] to [3] which is —COYR 6 ; an enantiomer thereof; a diastereomer thereof; or a pharmaceutically acceptable salt thereof.
　［１－５］Ｒ３が、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルである、［１］～［４］のいずれかに記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 [1-5] The compound according to any one of [1] to [4], wherein R 3 is phenyl optionally substituted by one or more substituents selected from X 1 , its enantiomer, Diastereomers, or pharmaceutically acceptable salts thereof.
　［１－６］Ｘが、ＮＨである、［１］～［５］のいずれかに記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 [1-6] The compound according to any one of [1] to [5], wherein X is NH, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof.
　［１－７］Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド；
　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミン；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アセタミド；
　メチル　（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）カーバメート；
　１－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－３－フェニルウレア；
　ベンジル　（２－（（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アミノ）－２－オキソエチル）カーバメート；
　２－アミノ－Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アセタミド；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）メタンスルホンアミド；
　２－ブロモ－Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アセタミド；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－２－（プロパ－２－イン－１－イルオキシ）アセタミド；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－１，１，１－トリフルオロメタンスルホンアミド；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－２－ニトロベンゼンスルホンアミド；および
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－４－ニトロベンゼンスルホンアミド
から選択される、［１］に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 [1-7] N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroa Cetamide;
(R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine;
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) acetamide;
Methyl ((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) carbamate;
1-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -3-phenylurea;
Benzyl (2-(((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) amino) -2-oxoethyl) carbamate;
2-amino-N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) acetamide;
N-((R)-((1S, 2R, 3S, 5S, 7S) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) methanesulfonamide;
2-bromo-N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) acetamide;
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -2- (prop-2-yn-1-yloxy) Acetamide;
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -1,1,1-trifluoromethanesulfonamide;
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -2-nitrobenzenesulfonamide; and N-((R) — ((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -4-nitrobenzenesulfonamide, the compound according to [1], An enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof.
　［１－８］［１］～［７］のいずれかに記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩を含有する医薬組成物。 [1-8] A pharmaceutical composition comprising the compound according to any one of [1] to [7], an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
　［１－９］認知機能疾患または障害の治療又は予防に用いるための、［８］に記載の医薬組成物。 [1-9] The pharmaceutical composition according to [8] for use in the treatment or prevention of a cognitive function disease or disorder.
　［１－１０］認知機能疾患または障害が、アルツハイマー型認知症、脳血管性認知症、レビー小体型認知症、前頭側頭型認知症、パーキンソン病、精神疾患、神経変性疾患から選択される、［９］に記載の医薬組成物。 [1-10] The cognitive function disease or disorder is selected from Alzheimer's dementia, cerebrovascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease, mental illness, neurodegenerative disease, [9] The pharmaceutical composition according to [9].
　［１－１１］糖尿病または糖尿病性合併症の治療又は予防に用いるための、［８］に記載の医薬組成物。 [1-11] The pharmaceutical composition according to [8] for use in the treatment or prevention of diabetes or diabetic complications.
　［１－１２］［１］～［７］のいずれかに記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩を含有する、Ｋｉｒ６．２チャネル阻害薬。 [1-12] A Kir6.2 channel inhibitor comprising the compound according to any one of [1] to [7], an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
　［１－１３］［１］～［７］のいずれかに記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩を含有する、Ｋｉｒ６．１チャネル阻害薬。 [1-13] A Kir6.1 channel inhibitor comprising the compound according to any one of [1] to [7], an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
　［１－１４］式（ＩＩＩ） [1-14] Formula (III)
Figure JPOXMLDOC01-appb-C000008
 ［式中、Ｒ４は、水素原子、またはハロゲン原子であり；
　Ｒ３は、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニル、またはＸ１より選択される１以上の置換基により置換されていてもよい５又は６員環ヘテロアリールであり；
　Ｘ１は、それぞれ独立に、Ｃ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ、ニトロ、およびシアノから選択される］
で表される化合物、そのエナンチオマー、そのジアステレオマー、またはその塩。
Figure JPOXMLDOC01-appb-C000008
 [Wherein, R 4 represents a hydrogen atom or a halogen atom;
R 3 is one or more phenyl which is substituted by a substituent or one or more substituents the optionally substituted 5 or 6 membered heteroaryl selected from X 1, is selected from X 1 Is;
Each X 1 is independently selected from C 1-6 alkyl, a halogen atom, C 1-6 alkoxy, nitro, and cyano]
Or its enantiomer, diastereomer, or salt thereof.
　一つの側面において、本発明により認知機能疾患または障害の治療または予防に用いるための医薬組成物の提供が提供される。別の側面において、本発明によりＫＡＴＰチャネルのＫｉｒ６．１チャネル阻害薬またはＫｉｒ６．２チャネル阻害薬が提供される。 In one aspect, the present invention provides a pharmaceutical composition for use in the treatment or prevention of a cognitive function disease or disorder. In another aspect, the present invention provides a Kir6.1 channel inhibitor or Kir6.2 channel inhibitor of KATP channel.
図１は、Ｋｉｒ６．２チャネルの過剰発現細胞（Ｎｅｕｒｏ２Ａ細胞）において、本発明化合物によるＣａＭＫＩＩ活性の増強を示すグラフである。表示されている全ての有意差は対象（Ｃ、Ｋｉｒ６．２発現細胞において薬物無処置群）に対してのものである。本願の図に示される有意差の表示について、＊＊もしくは＋＋は有意差がＰ＜０．０１であることを示し、＋もしくは＊はＰ＜０．０５を示す。FIG. 1 is a graph showing the enhancement of CaMKII activity by the compound of the present invention in Kir6.2 channel overexpressing cells (Neuro2A cells). All significant differences displayed are for the subject (C, no drug treatment group in Kir6.2 expressing cells). Regarding the display of the significant difference shown in the figure of the present application, ** or ++ indicates that the significant difference is P <0.01, and + or * indicates P <0.05. 図２ａは、抗Ｋｉｒ６．２チャネル抗体を用いたＫｉｒ６．２チャネル過剰発現細胞に対する免疫ブロット法により、Ｎ２Ａ細胞におけるＫｉｒ６．２チャネル発現を確認した結果を示す。薬物無処置群（－）に対しての有意差を＊＊で示す。FIG. 2a shows the result of confirming Kir6.2 channel expression in N2A cells by immunoblotting with respect to Kir6.2 channel overexpressing cells using anti-Kir6.2 channel antibody. Significant differences with respect to the drug-untreated group (−) are indicated by **. 図２ｂは、Ｋｉｒ６．２チャネル過剰発現細胞において、ＴＰ－０１４が外向きカリウム電流を抑制することを示すｗｈｏｌｅ－ｃｅｌｌ　ｐａｔｃｈ－ｃｌａｍｐ法によるアッセイ結果である。この結果より、ＴＰ－０１４はＫｉｒ６．２チャネルを阻害し、カリウム電流を減弱することが示される。FIG. 2b is an assay result by a whole-cell patch-clamp method showing that TP-014 suppresses outward potassium current in Kir6.2 channel overexpressing cells. This result indicates that TP-014 inhibits Kir6.2 channel and attenuates potassium current. 図３ａは、Ｋｉｒ６．２チャネル過剰発現細胞において、ＴＰ－０１４を投与することにより細胞内のカルシウム濃度が上昇すること示すカルシウムイメージング法によるアッセイを行った結果である。本発明化合物およびメマンチンを処置した際の濃度依存的なカルシウム量の経時変化を４分間にわたって測定した。この結果より、ＴＰ－０１４がＫｉｒ６．２チャネルを阻害し、細胞内カルシウム濃度を上昇させることが示される。FIG. 3a shows the results of an assay by a calcium imaging method showing that intracellular calcium concentration increases by administering TP-014 in Kir6.2 channel overexpressing cells. A time-dependent change in the amount of calcium in the concentration-dependent treatment with the compound of the present invention and memantine was measured over 4 minutes. This result indicates that TP-014 inhibits Kir6.2 channel and increases intracellular calcium concentration. 図３ｂは、Ｋｉｒ６．２チャネル過剰発現細胞において、ＴＰ－０１４を投与することにより細胞内のカルシウム濃度を上昇すること示すカルシウムイメージング法によるアッセイの結果である。メマンチン、本発明化合物の処置から４分後のカルシウム量を測定した。Kir6.2発現細胞（Neuro2A細胞）において薬物無処置群（－）に対しての有意差が確認されている。この結果より、ＴＰ－０１４がＫｉｒ６．２チャネルを阻害し、細胞内カルシウム濃度を上昇させることが示される。FIG. 3b shows the results of an assay by a calcium imaging method showing that intracellular calcium concentration is increased by administering TP-014 in Kir6.2 channel overexpressing cells. The amount of calcium was measured 4 minutes after the treatment with memantine and the compound of the present invention. A significant difference was confirmed in Kir6.2 expressing cells (Neuro2A cells) with respect to the drug-untreated group (−). This result indicates that TP-014 inhibits Kir6.2 channel and increases intracellular calcium concentration. 図４ａは、アルツハイマー病モデルマウス（ＡＰＰ２３マウス）（１２ヶ月齢）にＴＰ－０１４を２ヶ月間投与し、Y-maze法により認知機能改善効果が認められた実験結果を示すグラフである。FIG. 4a is a graph showing experimental results in which TP-014 was administered to Alzheimer's disease model mice (APP23 mice) (12 months old) for 2 months and a cognitive function improving effect was observed by the Y-maze method. 図４ｂは、アルツハイマー病モデルマウス（ＡＰＰ２３マウス）（１２ヶ月齢）にＴＰ－０１４を２ヶ月間投与し、Y-maze法により認知機能改善効果が認められた実験結果を示すグラフである。APP23マウスに対する記憶学習の正解率（alteration）のWTとの比較における有意差を**で、APP23マウスの対照（無処置群）との比較における有意差を++でそれぞれ示す。FIG. 4b is a graph showing the results of an experiment in which TP-014 was administered to Alzheimer's disease model mice (APP23 mice) (12 months old) for 2 months and the cognitive function improving effect was observed by the Y-maze method. The significant difference in comparison with WT of the memory learning accuracy for APP23 mice is indicated by **, and the significant difference in comparison with APP23 mice control (no treatment group) is indicated by ++. 図４ｃは、アルツハイマー病モデルマウス（ＡＰＰ２３マウス）（１２ヶ月齢）にＴＰ－０１４を２ヶ月間投与し、新規物体認識試験法により認知機能改善効果が認められた実験結果を示すグラフである。それぞれのFamiliar（同じ物体）と比較した際のNovel（新規物体）の有意差を**で示す。FIG. 4c is a graph showing experimental results in which TP-014 was administered to Alzheimer's disease model mice (APP23 mice) (12 months old) for 2 months and a cognitive function improving effect was observed by a novel object recognition test method. The significant difference of Novel (new object) when compared with each Family (same object) is indicated by **. 図４ｄは、アルツハイマー病モデルマウス（ＡＰＰ２３マウス）（１２ヶ月齢）にＴＰ－０１４を２ヶ月間投与し、恐怖条件付け試験法により認知機能改善効果が認められた実験結果を示すグラフである。Retension trialsにおける WTと比較した有意差を**で示し、APP23マウスと比較した有意差を+で示す。FIG. 4d is a graph showing experimental results in which TP-014 was administered to Alzheimer's disease model mice (APP23 mice) (12 months old) for 2 months and a cognitive function improving effect was observed by the fear conditioning test method. Significant differences compared to WT in Retension trials are indicated by **, and significant differences compared to APP23 mice are indicated by +. 図４ｅは、アルツハイマー病モデルマウス（ＡＰＰ２３マウス）（１２ヶ月齢）にＴＰ－０１４を２ヶ月間投与し、電気生理学的手法により記憶形成の指標である長期増強現象（LTP）について検討した結果を示す。Fig. 4e shows the results of long-term potentiation (LTP), which is an indicator of memory formation, by administering TP-014 to Alzheimer's disease model mice (APP23 mice) (12 months old) for 2 months and using electrophysiological techniques. Show. 図４ｆは、アルツハイマー病モデルマウス（ＡＰＰ２３マウス）（１２ヶ月齢）にＴＰ－０１４を２ヶ月間投与し、電気生理学的手法により記憶形成の指標である長期増強現象（LTP）について検討した結果を示す。FIG. 4f shows the results of studying the long-term potentiation phenomenon (LTP), which is an index of memory formation, by administering TP-014 to Alzheimer's disease model mice (APP23 mice) (12 months old) for 2 months and using electrophysiological techniques. Show. 図４ｇは、アルツハイマー病モデルマウス（ＡＰＰ２３マウス）（１２ヶ月齢）にＴＰ－０１４を２ヶ月間投与し、電気生理学的手法により記憶形成の指標である長期増強現象（LTP）について検討した結果を示す。WTと比較した有意差を**で、APP23マウスと比較した有意差を++もしくは+で示す。FIG. 4g shows the results of studying the long-term potentiation phenomenon (LTP), which is an index of memory formation, by administering TP-014 to Alzheimer's disease model mice (APP23 mice) (12 months old) for 2 months and using electrophysiological techniques. Show. Significant differences compared to WT are indicated by **, and significant differences compared to APP23 mice are indicated by ++ or +. 図５ａは、免疫ブロット法によりCaMKII、CaMKIV、ERKに対する抗体を用いて各タンパク質のリン酸化について検討した結果を示す、免疫ブロットを泳動した際に得られるバンド（画像）である。FIG. 5a is a band (image) obtained when an immunoblot was run, showing the results of examining the phosphorylation of each protein using antibodies against CaMKII, CaMKIV, and ERK by immunoblotting. 図５ｂは、図５ａの免疫ブロットを泳動した際に得られるバンドのシグナル強度を定量化した解析結果である。WT（－）（薬物無処置群）と比較>した有意差を**にて、APP23マウスの薬物無処置群（－）と比較した有意差を+で示す。FIG. 5b is an analysis result obtained by quantifying the signal intensity of the band obtained when the immunoblot of FIG. 5a is migrated. Significant differences compared with WT (−) (drug-untreated group)> are indicated by **, and significant differences compared with drug-untreated group (−) of APP23 mice are represented by +. 図５ｃは、免疫ブロット法によりCaMKII、CaMKIV、ERKに対する抗体を用いて各タンパク質のリン酸化について検討した結果を示す、免疫ブロットを泳動した際に得られるバンド（画像）である。FIG. 5c is a band (image) obtained when an immunoblot was run, showing the results of examining the phosphorylation of each protein using antibodies against CaMKII, CaMKIV, and ERK by immunoblotting. 図５ｄは、図５ｃの免疫ブロットを泳動した際に得られるバンドのシグナル強度を定量化した解析結果である。WT（－）（薬物無処置群）と比較した有意差を**にて、APP23マウスの薬物無処置群（－）と比較した有意差を++で示す。FIG. 5d is an analysis result obtained by quantifying the signal intensity of the band obtained when the immunoblot of FIG. 5c is migrated. Significant differences compared to WT (−) (drug-untreated group) are indicated by **, and significant differences compared to drug-untreated group (−) of APP23 mice are denoted by ++. 図６ａは、神経変性疾患モデルマウスである嗅球摘出マウス（OBXマウス）にＴＰ－０１４を２ヶ月間投与した結果、Y-maze法により認知機能改善効果が認められた実験結果を示すグラフである。FIG. 6a is a graph showing the results of experiments in which TP-014 was administered to an olfactory bulb-excised mouse (OBX mouse), which is a neurodegenerative disease model mouse, for 2 months, and as a result, a cognitive function improving effect was observed by the Y-maze method. . 図６ｂは、神経変性疾患モデルマウスである嗅球摘出マウス（OBXマウス）にＴＰ－０１４を２ヶ月間投与した結果、Y-maze法により認知機能改善効果が認められた実験結果を示すグラフである。OBXマウスに対する記憶学習の正解率（alteration）の有意差を WTと比較して**で、OBXマウスのcontrol（無処置群）と比較して++で示す。FIG. 6b is a graph showing the results of experiments in which TP-014 was administered to an olfactory bulb-excised mouse (OBX mouse), which is a neurodegenerative disease model mouse, for 2 months, and as a result, a cognitive function improving effect was observed by the Y-maze method. . The significant difference in the accuracy of memory learning for OBX mice is indicated by ** compared with WT and by ++ compared with control of OBX mice (no treatment group). 図６ｃは、神経変性疾患モデルマウスである嗅球摘出マウス（OBXマウス）にＴＰ－０１４を２ヶ月間投与した結果、新規物体認識試験法により認知機能改善効果が認められた実験結果を示すグラフである。それぞれのFamiliar（同じ物体）と比較した際のNovel（新規物体）の有意差を**で示す。FIG. 6c is a graph showing experimental results in which TP-014 was administered to an olfactory bulb-extracted mouse (OBX mouse), which is a neurodegenerative disease model mouse, for 2 months, and as a result, a cognitive function improving effect was observed by a novel object recognition test method. is there. The significant difference of Novel (new object) when compared with each Family (same object) is indicated by **. 図６ｄは、神経変性疾患モデルマウスである嗅球摘出マウス（OBXマウス）にＴＰ－０１４を２ヶ月間投与した結果、恐怖条件付け試験法により認知機能改善効果が認められた実験結果を示すグラフである。Retension trialsにおける WTと比較した有意差を**で示し、OBXマ>ウスと比較した有意差を+で示す。FIG. 6d is a graph showing the results of experiments in which TP-014 was administered for 2 months to olfactory bulbectomized mice (OBX mice), which are neurodegenerative disease model mice, and the cognitive function improving effect was observed by the fear conditioning test method. . Significant differences compared to WT in Retension trials are indicated by **, and significant differences compared to OBX mouse are indicated by +. 図６ｅは、神経変性疾患モデルマウスである嗅球摘出マウス（OBXマウス）にＴＰ－０１４を２ヶ月間投与し、電気生理学的手法により記憶形成の指標である長期増強現象（LTP）について検討した結果を示す。Fig. 6e shows the results of long-term potentiation (LTP), which is an index of memory formation, by administering TP-014 to olfactory bulbectomized mice (OBX mice), which are neurodegenerative disease model mice, for 2 months. Indicates. 図６ｆは、神経変性疾患モデルマウスである嗅球摘出マウス（OBXマウス）にＴＰ－０１４を２ヶ月間投与し、電気生理学的手法により記憶形成の指標である長期増強現象（LTP）について検討した結果を示す。Fig. 6f shows the results of studying the long-term potentiation phenomenon (LTP), which is an index of memory formation, by administering TP-014 to olfactory bulbectomized mice (OBX mice), which are neurodegenerative disease model mice, for 2 months. Indicates. 図６ｇは、神経変性疾患モデルマウスである嗅球摘出マウス（OBXマウス）にＴＰ－０１４を２ヶ月間投与し、電気生理学的手法により記憶形成の指標である長増強現象（LTP）について検討した結果を示す。shamと比較した有意差を**で、OBXマウスと比較した有意差を++もしくは+で示す。Fig. 6g shows the result of studying the long potentiation phenomenon (LTP), an index of memory formation, by administering TP-014 to olfactory bulbectomized mice (OBX mice), which are neurodegenerative disease model mice, for 2 months. Indicates. Significant differences compared to sham are indicated by **, and significant differences compared to OBX mice are indicated by ++ or +. 図７ａは、免疫ブロット法によりCaMKII、CaMKIV、ERKに対する抗体を用いて各タンパク質のリン酸化について検討した結果を示す、免疫ブロットを泳動した際に得られるバンド（画像）である。FIG. 7 a is a band (image) obtained when an immunoblot is run, showing the results of examining the phosphorylation of each protein using antibodies against CaMKII, CaMKIV, and ERK by immunoblotting. 図７ｂは、図７ａの免疫ブロットを泳動した際に得られるバンドのシグナル強度を定量化した解析結果である。FIG. 7b shows the analysis result obtained by quantifying the signal intensity of the band obtained when the immunoblot of FIG. 7a was run. 図７ｃは、免疫ブロット法によりCaMKII、CaMKIV、ERKに対する抗体を用いて各タンパク質のリン酸化について検討した結果を示す、免疫ブロットを泳動した際に得られるバンド（画像）である。FIG. 7c is a band (image) obtained when an immunoblot was run, showing the results of examining the phosphorylation of each protein using antibodies against CaMKII, CaMKIV, and ERK by immunoblotting. 図７ｄは、図７ｃの免疫ブロットを泳動した際に得られるバンドのシグナル強度を定量化した解析結果である。WT（－）（薬物無処置群）と比較した有意差を**で、OBXマウスの薬物無処置群（－）と比較した有意差を++で示す。FIG. 7d is an analysis result obtained by quantifying the signal intensity of the band obtained when the immunoblot of FIG. 7c is migrated. Significant differences compared to WT (−) (drug-untreated group) are indicated by **, and significant differences compared to drug-untreated group (−) of OBX mice are denoted by ++. 図８ａは、Kir6.2チャネル欠損マウスにＴＰ－０１４を２ヶ月間投与し、Y-maze法により認知機能改善効果が認められた実験結果を示すグラフである。FIG. 8a is a graph showing experimental results in which TP-014 was administered to Kir6.2 channel-deficient mice for 2 months and an effect of improving cognitive function was observed by the Y-maze method. 図８ｂは、Kir6.2チャネル欠損マウスにＴＰ－０１４を２ヶ月間投与し、Y-maze法により認知機能改善効果が認められた実験結果を示すグラフである。Kir6.2欠損マウスに対する記憶学習の正解率（alteration）の有意差を WTと比較して*もしくは**を示す。FIG. 8b is a graph showing the results of an experiment in which TP-014 was administered to Kir6.2 channel-deficient mice for 2 months and an effect of improving cognitive function was observed by the Y-maze method. Compared with WT, * or ** indicates the significant difference in memory learning accuracy for Kir6.2-deficient mice. 図８ｃは、Kir6.2チャネル欠損マウスにＴＰ－０１４を２ヶ月間投与し、新規物体認識試験法により認知機能改善効果が認められた実験結果を示すグラフである。それぞれのFamiliar（同じ物体）と比較した際のNovel（新規物体）の>有意差を**で示す。FIG. 8c is a graph showing experimental results in which TP-014 was administered to Kir6.2 channel-deficient mice for 2 months and a cognitive function improving effect was observed by a novel object recognition test method. The> significant difference of Novel (new object) compared to each family (same object) is indicated by **. 図８ｄは、Kir6.2チャネル欠損マウスにＴＰ－０１４を２ヶ月間投与し、恐怖条件付け試験法により認知機能改善効果が認められた実験結果を示すグラフである。Retension trialsにおける WTと比較した有意差を*で示す。FIG. 8d is a graph showing the results of experiments in which TP-014 was administered to Kir6.2 channel-deficient mice for 2 months and a cognitive function improving effect was observed by the fear conditioning test method. Significant differences compared to WT in Retension trials are indicated by *. 図８ｅは、Kir6.2チャネル欠損マウスにＴＰ－０１４を２ヶ月間投与し、電気生理学的手法により記憶形成の指標である長期増強現象（LTP）について検討した結果を示す。FIG. 8e shows the results of studying the long-term potentiation phenomenon (LTP), which is an index of memory formation, by administering TP-014 to Kir6.2 channel-deficient mice for 2 months and electrophysiological techniques. 図８ｆは、Kir6.2チャネル欠損マウスにＴＰ－０１４を２ヶ月間投与し、電気生理学的手法により記憶形成の指標である長期増強現象（LTP）について検討した結果を示す。FIG. 8f shows the results of studying the long-term potentiation phenomenon (LTP), which is an index of memory formation, by administering TP-014 to Kir6.2 channel-deficient mice for 2 months and electrophysiological techniques. 図８ｇは、Kir6.2チャネル欠損マウスにＴＰ－０１４を２ヶ月間投与し、電気生理学的手法により記憶形成の指標である長期増強現象（LTP）について検討した結果を示す。WTと比較した有意差を**もしくは*で示す。FIG. 8g shows the results of studying the long-term potentiation phenomenon (LTP), which is an index of memory formation, by administering TP-014 to Kir6.2 channel-deficient mice for 2 months and using electrophysiological techniques. Significant differences compared to WT are indicated with ** or *. 図９ａは、免疫ブロット法によりCaMKII、CaMKIV、ERKに対する抗体を用いて各タンパク質のリン酸化について検討した結果を示す、免疫ブロットを泳動した際に得られるバンド（画像）である。FIG. 9a is a band (image) obtained when an immunoblot was run, showing the results of examining the phosphorylation of each protein using antibodies against CaMKII, CaMKIV, and ERK by immunoblotting. 図９ｂは、図９ａの免疫ブロットを泳動した際に得られるバンドのシグナル強度を定量化した解析結果である。WT（－）（薬物無処置群）と比較した有意差を**もしくは*にて示す。FIG. 9b is an analysis result obtained by quantifying the signal intensity of a band obtained when the immunoblot of FIG. 9a is migrated. Significant differences compared to WT (-) (no drug treatment group) are indicated by ** or *. 図１０は、APP23マウスでのAβの凝集に対する本発明化合物の効果を示す、脳スライス切片の染色結果である。FIG. 10 shows the result of staining a slice of brain slice showing the effect of the compound of the present invention on Aβ aggregation in APP23 mice. 図１１ａは、本発明化合物のOBXマウスのうつ様症状の改善効果を確認するための試験結果である。sham（対照群）と比較した有意差を**で、OBXマウスと比較した有意差を+で示す。FIG. 11 a is a test result for confirming the effect of improving the depression-like symptoms of OBX mice of the compound of the present invention. Significant differences compared to sham (control group) are indicated by **, and significant differences compared to OBX mice are indicated by +. 図１１は、本発明化合物のOBXマウスのうつ様症状の改善効果を確認するための試験結果である。sham（対照群）と比較した有意差を**で、OBXマウスと比較した有意差を+で示す。FIG. 11 shows test results for confirming the effect of improving the depression-like symptoms of OBX mice of the compound of the present invention. Significant differences compared to sham (control group) are indicated by **, and significant differences compared to OBX mice are indicated by +. 図１２ａは、本発明化合物がKir6.1チャネルの阻害作用を介してうつ改善効果を示すことを確認するための試験結果である。WT（対照群）と比較した有意差を**で示す。FIG. 12a is a test result for confirming that the compound of the present invention exhibits an effect of improving depression through the inhibitory action of Kir6.1 channel. Significant differences compared to WT (control group) are indicated by **. 図１２ｂは、本発明化合物がKir6.1チャネルの阻害作用を介してうつ改善効果を示すことを確認するための試験結果である。WT（対照群）と比較した有意差を**で示す。FIG. 12 b is a test result for confirming that the compound of the present invention exhibits an effect of improving depression through the inhibitory action of Kir6.1 channel. Significant differences compared to WT (control group) are indicated by **. 図１３ａは、本発明化合物がKir6.1チャネルを阻害し、CaMKIVの活性化を介してうつ改善効果を示すことを確認するための試験結果である。WT（対照群）と比較した有意差を**で示す。FIG. 13a is a test result for confirming that the compound of the present invention inhibits the Kir6.1 channel and exhibits a depression-improving effect through the activation of CaMKIV. Significant differences compared to WT (control group) are indicated by **. 図１３ｂは、本発明化合物がKir6.1チャネルを阻害し、CaMKIVの活性化を介してうつ改善効果を示すことを確認するための試験結果である。WT（対照群）と比較した有意差を**で示す。FIG. 13 b is a test result for confirming that the compound of the present invention inhibits the Kir6.1 channel and exhibits a depression-improving effect through activation of CaMKIV. Significant differences compared to WT (control group) are indicated by **. 図１４は、本発明化合物が血糖値低下作用を有することを確認するための試験結果である。weeksは慢性投与した週齢を示しており、それぞれの週のob/ob (saline）と比較した有意差を*で示す。FIG. 14 shows test results for confirming that the compound of the present invention has a blood glucose level-lowering effect. Weeks indicate the age of chronic administration, and a significant difference compared with ob / ob (saline) for each week is indicated by *. 図１５はTP-014の作用機作を説明する図である。スパインに局在するKir6.2チャネルを阻害されると、Kir6.2チャネルの阻害により細胞内のカリウムが排出できず、細胞膜電位が脱分極し、その結果、電位依存性カルシウムチャンネルの開口により細胞外からのカルシウム流入が促進し、CaMKIIの活性化を惹起し、CaMKIIの下流であるGluA1 (Ser-831)（AMPA受容体）が活性化することにより認知機能改善効果が認められたと考えられる。また、TP-014は神経細胞体に局在するKir6.1チャネルも同様に阻害し、同様のメカニズムにより細胞内にカルシウムを流入する。流入したカルシウムはCaMKIVを活性化し、CREB (Ser-133)の活性化を介して神経新生を介してうつ病改善効果を示すと考えられる。TP-014には、Kir6.2チャネル阻害作用による認知機能改善効果（アルツハイマー病の中核症状）とKir6.1チャネル阻害作用によるうつ病改善効果（アルツハイマー病の周辺症状）の両方の作用を持つ新しい認知機能改善薬である。FIG. 15 is a diagram for explaining the working mechanism of TP-014. When the Kir6.2 channel localized in spine is inhibited, the intracellular potassium cannot be excreted due to the inhibition of Kir6.2 channel, and the cell membrane potential is depolarized. As a result, the cell is opened by opening the voltage-dependent calcium channel. It is considered that the effect of improving cognitive function was recognized by the acceleration of calcium influx from outside, the activation of CaMKII, and the activation of GluA1 (Ser-831) (AMPA receptor) downstream of CaMKII. TP-014 also inhibits the Kir6.1 channel localized in the neuronal cell body, and calcium flows into the cell by the same mechanism. Inflowed calcium activates CaMKIV and is thought to show depression-improving effect via neurogenesis through activation of CREB (Ser-133). TP-014 has a new effect of improving cognitive function by inhibiting Kir6.2 channel (core symptoms of Alzheimer's disease) and improving depression by Kir6.1 channel inhibiting effect (peripheral symptoms of Alzheimer's disease) It is a cognitive improvement drug. 図１６はプラスミドベクター：pcDNA3.1-Kir6.2の構造を示す図である。FIG. 16 shows the structure of the plasmid vector: pcDNA3.1-Kir6.2. 図１７－１はプラスミドベクター：pcDNA3.1-Kir6.2の配列を示す図である。FIG. 17-1 shows the sequence of plasmid vector: pcDNA3.1-Kir6.2. 図１７－２はプラスミドベクター：pcDNA3.1-Kir6.2の配列を示す図である。FIG. 17-2 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.2. 図１７－３はプラスミドベクター：pcDNA3.1-Kir6.2の配列を示す図である。FIG. 17-3 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.2. 図１７－４はプラスミドベクター：pcDNA3.1-Kir6.2の配列を示す図である。FIG. 17-4 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.2. 図１７－５はプラスミドベクター：pcDNA3.1-Kir6.2の配列を示す図である。FIG. 17-5 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.2. 図１８ａは、Ｋｉｒ６．１チャネルの過剰発現細胞（Ｎｅｕｒｏ２Ａ細胞）において、本発明化合物によるＣａＭＫＩＶ活性の増強を示すグラフである。表示されている全ての有意差は対象（Ｃ、Ｋｉｒ６．１発現細胞において薬物無処置群）に対してのものである。FIG. 18a is a graph showing the enhancement of CaMKIV activity by the compound of the present invention in Kir6.1 channel overexpressing cells (Neuro2A cells). All significant differences shown are for the subject (C, no drug treatment group in Kir6.1 expressing cells). 図１８ａは、抗Kir6.1チャネル抗体を用いたKir6.1チャネル過剰発現細胞に対する免疫ブロット法により、N2A細胞におけるKir6.1チャネル発現を確認した結果を示す。薬物無処置群（－）に対しての有意差を**で示す。FIG. 18a shows the result of confirming Kir6.1 channel expression in N2A cells by immunoblotting for Kir6.1 channel overexpressing cells using anti-Kir6.1 channel antibody. Significant differences with respect to the drug-untreated group (-) are indicated by **. 図１８ｂは、Kir6.1チャネル過剰発現細胞を用いて、通常のPatch-clamp法により細胞内より細胞外へ排出されるカリウム電流を測定した結果を示す。FIG. 18 b shows the results of measuring potassium current excreted from the inside of the cell by the usual patch-clamp method using Kir6.1 channel overexpressing cells. 図１９ａは、高架式十字迷路法により、試験に用いたマウス群の不安に対する脆弱性を検討した結果を示す。open armにおけるマウスの滞在時間についてWT(-)と比較した有意差を**もしくは*で、WT (CORT）と比較した有意差を++で示す。FIG. 19a shows the result of examining vulnerability to anxiety of a group of mice used in the test by the elevated plus maze method. Significant differences compared to WT (-) for the staying time of mice in the open arm are indicated by ** or *, and significant differences compared with WT (CORT) are indicated by ++. 図１９ｂは高架式十字迷路法に用いた装置を示す写真である。FIG. 19b is a photograph showing the device used in the elevated plus maze method. 図１９ｃは、明暗試験法（light-dark 法）による試験結果を示す。WT(-)と比較した有意差を**で、WT (CORT）と比較した有意差を++で示す。FIG. 19c shows a test result by a light-dark test method. Significant differences compared to WT (-) are shown as **, and significant differences compared to WT (CORT) are shown as ++. 図１９ｄは明暗試験法に用いた装置を示す写真である。FIG. 19d is a photograph showing the apparatus used in the light / dark test method. 図１９ｅはビー玉かくし試験法（Marble burying法）による結果を示す。WT(-)と比較した有意差を**で、WT (CORT）と比較した有意差を+で示す。FIG. 19e shows the result of the marble cracking test method (Marble burying method). Significant differences compared to WT (-) are indicated by ** and significant differences compared to WT (CORT) are indicated by +. 図１９ｆはビー玉かくし試験法に用いた装置を示す写真である。FIG. 19f is a photograph showing an apparatus used in the marble cracking test method. 図１９ｇはオープンフィールド法（open field法）による試験結果を示す。WT(-)と比較した有意差を**で、WT (CORT）と比較した有意差を++で示す。FIG. 19g shows the test results by the open field method. Significant differences compared to WT (-) are shown as **, and significant differences compared to WT (CORT) are shown as ++. 図１９ｈはオープンフィールド法に用いた装置を示す写真である。FIG. 19h is a photograph showing an apparatus used in the open field method. 図１９ｉは、は恐怖条件付試験法（fear conditining法）による試験結果を示す。WT(-)と比較した有意差を**もしくは*で、WT (CORT）と比較した有意差を++で示す。FIG. 19i shows the test result by the fear-conditioning test method (fear-conditining method). Significant differences compared to WT (-) are indicated by ** or *, and significant differences compared to WT (CORT) are indicated by ++. 図２０はプラスミドベクター：pcDNA3.1-Kir6.1の構造を示す図である。FIG. 20 shows the structure of the plasmid vector: pcDNA3.1-Kir6.1. 図２１－１はプラスミドベクター：pcDNA3.1-Kir6.1の配列を示す図である。FIG. 21-1 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.1. 図２１－２はプラスミドベクター：pcDNA3.1-Kir6.1の配列を示す図である。FIG. 21-2 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.1. 図２１－３はプラスミドベクター：pcDNA3.1-Kir6.1の配列を示す図である。FIG. 21-3 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.1. 図２１－４はプラスミドベクター：pcDNA3.1-Kir6.1の配列を示す図である。FIG. 21-4 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.1. 図２１－５はプラスミドベクター：pcDNA3.1-Kir6.1の配列を示す図である。FIG. 21-5 shows the sequence of the plasmid vector: pcDNA3.1-Kir6.1.
　以下、本発明を更に具体的に説明する。 Hereinafter, the present invention will be described more specifically.
　本発明の１つの側面によれば、式（Ｉ）で表される化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩を含む、認知機能疾患または障害の治療または予防のための医薬組成物が提供される。すなわち、本発明の化合物は下記の式（Ｉ）および（ＩＩ）で表される化合物を包含する。 According to one aspect of the present invention, for the treatment or prevention of a cognitive function disease or disorder comprising a compound of formula (I), an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof A pharmaceutical composition is provided. That is, the compounds of the present invention include compounds represented by the following formulas (I) and (II).
Figure JPOXMLDOC01-appb-C000009
 　また、本発明の化合物は下記の式（Ｉａ）および（ＩＩａ）で表される化合物を包含する。
Figure JPOXMLDOC01-appb-C000009
 The compounds of the present invention include compounds represented by the following formulas (Ia) and (IIa).
Figure JPOXMLDOC01-appb-C000010
 　さらに、本発明の化合物は下記の式（Ｉｂ）および（ＩＩｂ）で表される化合物を包含する。
Figure JPOXMLDOC01-appb-C000010
 Furthermore, the compounds of the present invention include compounds represented by the following formulas (Ib) and (IIb).
Figure JPOXMLDOC01-appb-C000011
 　本明細書において「Ｃ１－６アルキル」とは、炭素数１～６の直鎖状、分岐鎖状、環状または部分的に環状のアルキル基を意味し、例えば、メチル、エチル、ｎ－プロピル、ｉ－プロピル、ｎ－ブチル、ｓ－ブチル、ｉ－ブチル、ｔ－ブチル、ｎ－ペンチル、３－メチルブチル、２－メチルブチル、１－メチルブチル、１－エチルプロピル、ｎ－ヘキシル、４－メチルペンチル、３－メチルペンチル、２－メチルペンチル、１－メチルペンチル、３－エチルブチル、および２－エチルブチル、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、およびシクロプロピルメチルなどが含まれ、例えば、Ｃ１－４アルキルおよびＣ１－３アルキルなども含まれる。
Figure JPOXMLDOC01-appb-C000011
 In the present specification, “C 1-6 alkyl” means a linear, branched, cyclic or partially cyclic alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl. I-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, 3-methylbutyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, n-hexyl, 4-methylpentyl , 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-ethylbutyl, and 2-ethylbutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, and the like, for example, C 1-4 alkyl And C 1-3 alkyl and the like are also included.
　本明細書において「Ｃ１－６アルコキシ」とは、アルキル部分として既に定義した炭素数１～６のアルキル基を有するアルキルオキシ基［－Ｏ－（Ｃ１－６アルキル）］を意味し、例えば、メトキシ、エトキシ、ｎ－プロポキシ、ｉ－プロポキシ、ｎ－ブトキシ、ｓ－ブトキシ、ｉ－ブトキシ、ｔ－ブトキシ、ｎ－ペントキシ、３－メチルブトキシ、２－メチルブトキシ、１－メチルブトキシ、１－エチルプロポキシ、ｎ－ヘキシルオキシ、４－メチルペントキシ、３－メチルペントキシ、２－メチルペントキシ、１－メチルペントキシ、３－エチルブトキシ、シクロペンチルオキシ、シクロヘキシルオキシ、シクロプロピルメチルオキシなどが含まれ、例えば、Ｃ１－４アルコキシおよびＣ１－３アルコキシなども含まれる。また、本明細書において「Ｃ１－４アルコキシ」には、例えばＣ１－３アルコキシなども含まれる。 In the present specification, “C 1-6 alkoxy” means an alkyloxy group [—O— (C 1-6 alkyl)] having an alkyl group having 1 to 6 carbon atoms already defined as the alkyl moiety, , Methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, i-butoxy, t-butoxy, n-pentoxy, 3-methylbutoxy, 2-methylbutoxy, 1-methylbutoxy, 1- Includes ethylpropoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, 3-ethylbutoxy, cyclopentyloxy, cyclohexyloxy, cyclopropylmethyloxy, etc. Examples thereof include C 1-4 alkoxy and C 1-3 alkoxy. In this specification, “C 1-4 alkoxy” includes, for example, C 1-3 alkoxy and the like.
　本明細書において「Ｃ２－６アルケニルオキシ」とは、炭素数２～６の直鎖状、分岐鎖状、環状または部分的に環状のアルケニル基を有するアルケニルオキシ基［－Ｏ－（Ｃ２－６アルケニル）］を意味し、アルケニル基は１以上、好ましくは１～３、さらに好ましくは１つの二重結合を有する。Ｃ２－６アルケニルオキシの例としては、ビニルオキシ、２－プロペニルオキシ、１－プロペニルオキシ、１－メチルビニルオキシ、３－ブテニルオキシ、２－ブテニルオキシ、および１－ブテニルオキシなどが含まれる。 In this specification, “C 2-6 alkenyloxy” means an alkenyloxy group having a straight chain, branched chain, cyclic or partially cyclic alkenyl group having 2 to 6 carbon atoms [—O— (C 2 -6 alkenyl)], and the alkenyl group has one or more, preferably 1 to 3, more preferably one double bond. Examples of C 2-6 alkenyloxy include vinyloxy, 2-propenyloxy, 1-propenyloxy, 1-methylvinyloxy, 3-butenyloxy, 2-butenyloxy, 1-butenyloxy and the like.
　本明細書において「Ｃ２－６アルキニルオキシ」とは、炭素数２～６の直鎖状、分岐鎖状、環状または部分的に環状のアルキニル基を有するアルキニルオキシ基［－Ｏ－（Ｃ２－６アルキニル）］を意味し、アルキニル基は１以上、好ましくは１～３、さらに好ましくは１つの三重結合を有する。Ｃ２－６アルキニルオキシの例としては、エチニルオキシ、２－プロピニルオキシ、１－プロピニルオキシ、３－ブチニルオキシ、２－ブチニルオキシ、および１－ブチニルオキシなどが含まれる。 In this specification, “C 2-6 alkynyloxy” refers to an alkynyloxy group having a straight chain, branched chain, cyclic or partially cyclic alkynyl group having 2 to 6 carbon atoms [—O— (C 2 -6 alkynyl)], and the alkynyl group has one or more, preferably 1 to 3, more preferably one triple bond. Examples of C 2-6 alkynyloxy include ethynyloxy, 2-propynyloxy, 1-propynyloxy, 3-butynyloxy, 2-butynyloxy, 1-butynyloxy and the like.
　本明細書において「（Ｃ１－６アルキル）スルホニル」とは、アルキル部分として既に定義したＣ１－６アルキル基を有するアルキルスルホニル基を意味し、例えばメチルスルホニル、エチルスルホニル、ｔｅｒｔ－ブチルスルホニルの他、（Ｃ１－３アルキル）スルホニルなどが含まれる。 As used herein, “(C 1-6 alkyl) sulfonyl” means an alkylsulfonyl group having a C 1-6 alkyl group that has already been defined as an alkyl moiety, and includes, for example, methylsulfonyl, ethylsulfonyl, tert-butylsulfonyl. In addition, (C 1-3 alkyl) sulfonyl and the like are included.
　本明細書において「（Ｃ１－６アルコキシ）カルボニル」とは、アルコキシ部分として既に定義したＣ１－６アルコキシ基を有するアルコキシカルボニル基を意味し、例えばメトキシカルボニル、エトキシカルボニル、ｔｅｒｔ－ブトキシカルボニルの他、（Ｃ１－３アルコキシ）カルボニルなどが含まれる。 As used herein, “(C 1-6 alkoxy) carbonyl” means an alkoxycarbonyl group having a C 1-6 alkoxy group already defined as an alkoxy moiety, such as methoxycarbonyl, ethoxycarbonyl, and tert-butoxycarbonyl. In addition, (C 1-3 alkoxy) carbonyl and the like are included.
　本明細書において「５又は６員環ヘテロアリール」とは、酸素原子、窒素原子、および硫黄原子から選択される１以上のヘテロ原子を含有する５員環または６員環のヘテロアリールであれば特に限定されない。その例には、ピリジル、ピリミジル、ピリダジニル、ピラジル、フラニル（フリル）、チオフェニル（チエニル）、オキサゾリル、イソキサゾリル、オキサジアゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、ピロリル、イミダゾリル、ピラゾリル、トリアゾリル、テトラゾリルなどが挙げられる。 In the present specification, the “5- or 6-membered heteroaryl” is a 5-membered or 6-membered heteroaryl containing one or more heteroatoms selected from an oxygen atom, a nitrogen atom, and a sulfur atom. There is no particular limitation. Examples include pyridyl, pyrimidyl, pyridazinyl, pyrazyl, furanyl (furyl), thiophenyl (thienyl), oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like.
　ハロゲン原子の例としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子などが挙げられる。 Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
　本明細書において「１以上のハロゲン原子で置換されていてもよい（Ｃ１－６アルキル）スルホニル」の例としては、トリフルオロメチルスルホニル、ジフルオロメチルスルホニル、２，２，２－トリフルオロエチルスルホニル、パーフルオロエチルスルホニルなどが挙げられる。 Examples of “(C 1-6 alkyl) sulfonyl optionally substituted with one or more halogen atoms” in the present specification include trifluoromethylsulfonyl, difluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl And perfluoroethylsulfonyl.
　本明細書において「１以上のハロゲン原子で置換されていてもよい（Ｃ１－６アルキル）カルボニル」とは、上述の（Ｃ１－６アルキル）カルボニルのアルキル部分が１以上、例えば１～５個の、具体的には１～３個のハロゲン原子により置換されていてもよい基を意味し、アルキル部分は無置換であってもよい。その例示として、トリフルオロアセチル、ペンタフルオロプロピオニルが挙げられる。 In the present specification, the “(C 1-6 alkyl) carbonyl optionally substituted with one or more halogen atoms” means that the alkyl portion of the above-mentioned (C 1-6 alkyl) carbonyl is 1 or more, for example, 1 to 5 Means a group which may be substituted by 1 to 3, specifically, 1 to 3 halogen atoms, and the alkyl moiety may be unsubstituted. Examples thereof include trifluoroacetyl and pentafluoropropionyl.
　本明細書において「１以上のハロゲン原子で置換されていてもよいＣ１－６アルキル」とは、上述のＣ１－６アルキル基が１以上、例えば１～５個の、具体的には１～３個のハロゲン原子により置換されていてもよい基を意味し、アルキルは無置換であってもよい。その例示として、トリフルオロメチル、ペンタフルオロエチル、２，２，２－トリフルオロエチルが挙げられる。 In the present specification, the “C 1-6 alkyl optionally substituted with one or more halogen atoms” means one or more, for example, 1 to 5, specifically 1 of the above C 1-6 alkyl group. This means a group which may be substituted by up to 3 halogen atoms, and alkyl may be unsubstituted. Examples thereof include trifluoromethyl, pentafluoroethyl, and 2,2,2-trifluoroethyl.
　本明細書において「１以上のハロゲン原子で置換されていてもよいＣ１－６アルコキシ」とは、上述のＣ１－６アルコキシ基が１以上、例えば１～５個の、具体的には１～３個のハロゲン原子により置換されていてもよい基を意味し、アルコキシは無置換であってもよい。その例示として、トリフルオロメトキシ、ペンタフルオロエトキシ、および２，２，２－トリフルオロエトキシが挙げられる。 In this specification, “C 1-6 alkoxy optionally substituted with one or more halogen atoms” means one or more, for example, 1 to 5, specifically 1 of the above C 1-6 alkoxy group. Means a group which may be substituted by ˜3 halogen atoms, alkoxy may be unsubstituted. Examples thereof include trifluoromethoxy, pentafluoroethoxy, and 2,2,2-trifluoroethoxy.
　本明細書において「Ｃ３－８シクロアルキル」とは、炭素数が３～８の環状アルキル基を意味する。その例示として、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、およびシクロオクチルが挙げられる。 As used herein, “C 3-8 cycloalkyl” means a cyclic alkyl group having 3 to 8 carbon atoms. Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
　本明細書において「Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルアミノカルボニル」とは、フェニル部分にＸ１より選択される１以上（例えば１～５個の、具体的には１～３個）の置換基を有してもよい、－ＣＯＮＨＰｈ基を意味し、フェニル部分は無置換であってもよい。 In the present specification, "one or more phenyl aminocarbonyl optionally substituted by a substituent selected from X 1" means one or more (e.g. 1-5 selected from X 1 to the phenyl moiety, specifically Specifically, it means a —CONHPh group which may have 1 to 3 substituents, and the phenyl moiety may be unsubstituted.
　本明細書において「Ｘ１より選択される１以上の置換基により置換されていてもよい５～１０員単環式または二環式ヘテロアリール」とは、窒素原子、酸素原子および硫黄原子から選択される１以上のヘテロ原子を含む芳香族ヘテロ環基を意味し、５または６員単環式ヘテロアリール基、および８～１０員環二環式ヘテロアリール基を包含する。Ｘ１より選択される置換基は１以上、例えば１～５個、具体的には１～３個、より具体的には１個であってもよく、無置換であってもよい。５または６員単環式ヘテロアリール基の例示として、ピリジル、ピリミジル、ピリダジニル、ピラジル、フラニル（フリル）、チオフェニル（チエニル）、オキサゾリル、イソキサゾリル、オキサジアゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、ピロリル、イミダゾリル、ピラゾリル、トリアゾリル、テトラゾリルなどが挙げられる。８～１０員二環式ヘテロアリール基の例示として、ベンゾフラニル、ベンゾチエニル、ベンゾチアジアゾリル、ベンゾチアゾリル、ベンゾオキサゾリル、ベンゾオキサジアゾリル、ベンゾイミダゾリル、インドリル、イソインドリル、インダゾリル、キノリル、イソキノリル、シンノリニル、キナゾリニル、キノキサリニル、ベンゾジオキソリル、インドリジニル、イミダゾピリジルなどが挙げられる。 In the present specification, the “5- to 10-membered monocyclic or bicyclic heteroaryl optionally substituted by one or more substituents selected from X 1 ” is selected from a nitrogen atom, an oxygen atom and a sulfur atom Means an aromatic heterocyclic group containing one or more heteroatoms, and includes 5- or 6-membered monocyclic heteroaryl groups and 8- to 10-membered bicyclic heteroaryl groups. The number of substituents selected from X 1 may be 1 or more, for example 1 to 5, specifically 1 to 3, more specifically 1 or may be unsubstituted. Examples of 5- or 6-membered monocyclic heteroaryl groups include pyridyl, pyrimidyl, pyridazinyl, pyrazyl, furanyl (furyl), thiophenyl (thienyl), oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyrrolyl, imidazolyl, pyrazolyl, Examples include triazolyl and tetrazolyl. Examples of 8- to 10-membered bicyclic heteroaryl groups include benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzooxadiazolyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, Quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl, imidazopyridyl and the like can be mentioned.
　本明細書において「Ｘ１より選択される１以上の置換基により置換されていてもよい５～１０員単環式または二環式非芳香族ヘテロシクリル」とは、窒素原子、酸素原子および硫黄原子から選択される１以上のヘテロ原子を含む非芳香族ヘテロ環基を意味し、５～１０員であれば、単環式ヘテロシクリル、または二環式ヘテロシクリルであってもよい。Ｘ１より選択される置換基は１以上、例えば１～５個、具体的には１～３個、より具体的には１個であってもよく、無置換であってもよい。その例示として、テトラヒドロフラニル、ピロリジニル、ピペリジニル、ピペラジニル、モルホリニルなどが挙げられる。また、二環式非芳香族ヘテロシクリルは、一方の環が非芳香族環基であれば、他方の環が芳香族環基であってもよく、例えば、２，３－ジヒドロインドリル、２，３－ジヒドロベンゾフラニル、１，２，３，４－テトラヒドロキノリルなどが含まれる。 In the present specification, the “5- to 10-membered monocyclic or bicyclic non-aromatic heterocyclyl optionally substituted by one or more substituents selected from X 1 ” means a nitrogen atom, an oxygen atom, and a sulfur atom. Means a non-aromatic heterocyclic group containing one or more heteroatoms selected from and may be monocyclic heterocyclyl or bicyclic heterocyclyl, provided that it is 5 to 10 members. The number of substituents selected from X 1 may be 1 or more, for example 1 to 5, specifically 1 to 3, more specifically 1 or may be unsubstituted. Examples thereof include tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and the like. The bicyclic non-aromatic heterocyclyl may be an aromatic ring group if one ring is a non-aromatic ring group, such as 2,3-dihydroindolyl, 2, 3-dihydrobenzofuranyl, 1,2,3,4-tetrahydroquinolyl and the like are included.
　本明細書において「Ｃ１－３アルキレン」とは、炭素数が１～３の２価の飽和炭化水素基を意味し、直鎖であっても、分枝を有していてもよい。その例示として、メチレン、エチレン、プロピレンが挙げられる。 In the present specification, “C 1-3 alkylene” means a divalent saturated hydrocarbon group having 1 to 3 carbon atoms, which may be linear or branched. Examples thereof include methylene, ethylene and propylene.
　本明細書において「Ｃ１－３アルケニレン」とは、炭素数が２または３の２価の炭化水素基を意味し、１つの二重結合を有し、直鎖であっても、分枝を有していてもよい。その例示として、エチレン、プロピレンが挙げられる。その例示として、エテニレン、プロペニレンが挙げられる。 In the present specification, “C 1-3 alkenylene” means a divalent hydrocarbon group having 2 or 3 carbon atoms, has one double bond, and is branched even if it is a straight chain. You may have. Examples thereof include ethylene and propylene. Examples thereof include ethenylene and propenylene.
　本明細書において「Ｃ６－１０アリール」とは、フェニル、１－ナフチル、または２－ナフチルを意味する。１以上の置換基により置換されていてもよい場合、置換基の数は、例えば１～５個、具体的には１～３個、より具体的には１個であってもよく、無置換であってもよい。 As used herein, “C 6-10 aryl” means phenyl, 1-naphthyl, or 2-naphthyl. When it may be substituted with one or more substituents, the number of substituents may be, for example, 1 to 5, specifically 1 to 3, more specifically 1 and may be unsubstituted. It may be.
　本明細書において「アダマンチル基に含まれるメチレン」とは、アダマンタン構造の橋頭位メチンを連結する橋掛部分に該当するＣＨ２基を意味する。該メチレンがＣ１－６アルキル、Ｃ１－６アルコキシ、およびヒドロキシから選択される１以上の基により置換される場合、置換基は、例えば１～５個、具体的には１～３個、より具体的には１～２個であり、１つのメチレン基が２つの置換基を有していてもよい。該置換に生じるいかなるエナンチオマー、ジアステレオマー、その他の異性体も本発明の範囲に含まれる。該アルキルまたはアルコキシは、１以上のハロゲン原子で置換されていてもよい。 In the present specification, “methylene contained in an adamantyl group” means a CH 2 group corresponding to a bridging moiety linking the bridgehead methine having an adamantane structure. When the methylene is substituted with one or more groups selected from C 1-6 alkyl, C 1-6 alkoxy, and hydroxy, the substituent is, for example, 1 to 5, specifically 1 to 3, More specifically, the number is 1 to 2, and one methylene group may have two substituents. Any enantiomers, diastereomers, and other isomers arising from the substitution are included within the scope of the present invention. The alkyl or alkoxy may be substituted with one or more halogen atoms.
　式：－ＣＯＹＲ６において、Ｙが直接結合の場合、該式は－ＣＯＲ６を表し、例えばアセチル、トリフルオロアセチル、ベンゾイルなどを包含する。 Formula: including in -COYR 6, when Y is a direct bond, the formula represents -COR 6, such as acetyl, trifluoroacetyl, benzoyl and the like.
　式（Ｉ）の化合物が水和物などの溶媒和物を形成する場合には、本発明は該溶媒和物を用いて実施することができる。さらに本発明の化合物は、混合物、溶液、結晶多形などとして適宜実施することができる。 When the compound of formula (I) forms a solvate such as a hydrate, the present invention can be carried out using the solvate. Furthermore, the compounds of the present invention can be appropriately implemented as a mixture, solution, crystal polymorph and the like.
　本明細書において１以上の置換基により置換されている場合、例えば、１～３個の置換基により置換されている。 In the present specification, when substituted with one or more substituents, for example, it is substituted with 1 to 3 substituents.
　上記式（Ｉ）で表される化合物に関する本発明には、互変異性体、幾何異性体、光学異性体などの各種の立体異性体、ジアステレオマー、およびそれらの混合物が含まれる。例えば、式（Ｉ）で表される化合物は、下記の式（Ｉ－１）～（Ｉ－８）の化合物を包含する。 The present invention relating to the compound represented by the above formula (I) includes various stereoisomers such as tautomers, geometric isomers and optical isomers, diastereomers, and mixtures thereof. For example, the compound represented by the formula (I) includes the compounds of the following formulas (I-1) to (I-8).
Figure JPOXMLDOC01-appb-C000012
 　また、式（Ｉ）で表される化合物は、下記の式（Ｉａ－１）～（Ｉａ－８）の化合物を包含する。
Figure JPOXMLDOC01-appb-C000012
 Further, the compound represented by the formula (I) includes the compounds of the following formulas (Ia-1) to (Ia-8).
Figure JPOXMLDOC01-appb-C000013
 　また、本発明は、下記の式（Ｉｂ－１）～（Ｉｂ－８）の化合物を包含する。
Figure JPOXMLDOC01-appb-C000013
 The present invention also includes compounds of the following formulas (Ib-1) to (Ib-8).
Figure JPOXMLDOC01-appb-C000014
 　本発明の化合物として、例えば本明細書実施例に記載の化合物を使用することができ、より具体的には以下の化合物を使用することができる：
　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－５－クロロ－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセトアミド）メチル）アダマンタン－１－イル（ＴＰ－０１４）；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－５－クロロ－１－ヒドロキシアダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド（ＴＰ－０４８）；
　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｒ，７Ｓ）－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセタミド）メチル）アダマンタン－１－イル（ＴＰ－０４９）；
　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－５－（２－メトキシエトキシ）－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセタミド）メチル）アダマンタン－１－イル（ＴＰ－０５０）；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－５－クロロ－１－ヒドロキシアダマンタン－２－イル）（ピリジン－３－イル）メチル）－２，２，２－トリフルオロアセトアミド（ＴＰ－０５１）；
　２，２，２－トリフルオロ－Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｒ，７Ｓ）－１－ヒドロキシアダマンタン－２－イル）（フェニル）メチル）アセタミド（ＴＰ－０５２）；
　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－５－メトキシ－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセタミド）メチル）アダマンタン－１－イル（ＴＰ－０５３）；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド（ＴＰ－０５４）；
　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミン塩酸塩（ＴＰ－０５５）；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アセタミド（ＴＰ－０５６）；
　メチル　（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）カーバメート（ＴＰ－０５７）；
　１－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－３－フェニルウレア（ＴＰ－０５８）；
　ベンジル　（２－（（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アミノ）－２－オキソエチル）カーバメート（ＴＰ－０５９）；
　２－アミノ－Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アセタミド（ＴＰ－０６０）；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）メタンスルホンアミド（ＴＰ－０６１）；
　２－ブロモ－Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アセタミド（ＴＰ－０６２）；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－２－（プロパ－２－イン－１－イルオキシ）アセタミド（ＴＰ－０６３）；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－１，１，１－トリフルオロメタンスルホンアミド（ＴＰ－０６４）；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－２－ニトロベンゼンスルホンアミド（ＴＰ－０６５）；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－４－ニトロベンゼンスルホンアミド（ＴＰ－０６６）；
　Ｎ－（（Ｓ）－（（１Ｓ，３Ｓ，５Ｓ，７Ｓ）－アダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド（ＴＰ－０６７）；
　Ｎ－（（Ｒ）－（（１Ｒ，３Ｒ，５Ｒ，７Ｒ）－アダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド（ＴＰ－０６８）；および
　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセトアミド）メチル）－５－（フェニルチオ）アダマンタン－１－イル（ＴＰ－０６９）；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）ベンズアミド（ＴＰ－０７０）；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）ピコリンアミド（ＴＰ－０７１）；
　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）ベンゼンスルホンアミド（ＴＰ－０７２）；
　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－５－クロロ－２－（（Ｓ）－フェニル（２，２，２－トリフルオロアセタミド）メチル）アダマンタン－１－イル（ＴＰ－０７３）； 
　Ｎ－（（１Ｒ）－（（１Ｒ，２Ｓ，３Ｒ，５Ｒ，７Ｒ）－５－クロロ－１－ヒドロキシアダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド（ＴＰ－０７４）；
　２，２，２－トリフルオロ酢酸（１Ｒ，２Ｓ，３Ｒ，５Ｒ，７Ｒ）－５－クロロ－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセタミド）メチル）アダマンタン－１－イル（ＴＰ－０７５）；および
　（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－２－（（Ｒ）－アミノ（フェニル）メチル）－５－クロロアダマンタン－１－オール（ＴＰ－０７６）。
Figure JPOXMLDOC01-appb-C000014
 As the compounds of the present invention, for example, the compounds described in the examples of the present specification can be used, and more specifically, the following compounds can be used:
2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5S, 7S) -5-chloro-2-((R) -phenyl (2,2,2-trifluoroacetamido) methyl) adamantane-1- Il (TP-014);
N-((R)-((1S, 2R, 3S, 5S, 7S) -5-chloro-1-hydroxyadamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide ( TP-048);
2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5R, 7S) -2-((R) -phenyl (2,2,2-trifluoroacetamido) methyl) adamantan-1-yl (TP -049);
2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5S, 7R) -5- (2-methoxyethoxy) -2-((R) -phenyl (2,2,2-trifluoroacetamide) Methyl) adamantan-1-yl (TP-050);
N-((R)-((1S, 2R, 3S, 5S, 7S) -5-chloro-1-hydroxyadamantan-2-yl) (pyridin-3-yl) methyl) -2,2,2-tri Fluoroacetamide (TP-051);
2,2,2-trifluoro-N-((R)-((1S, 2R, 3S, 5R, 7S) -1-hydroxyadamantan-2-yl) (phenyl) methyl) acetamide (TP-052);
2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5S, 7R) -5-methoxy-2-((R) -phenyl (2,2,2-trifluoroacetamide) methyl) adamantane-1 -Ile (TP-053);
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide (TP- 054);
(R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine hydrochloride (TP-055);
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) acetamide (TP-056);
Methyl ((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) carbamate (TP-057);
1-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -3-phenylurea (TP-058);
Benzyl (2-(((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) amino) -2-oxoethyl) carbamate (TP- 059);
2-Amino-N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) acetamide (TP-060);
N-((R)-((1S, 2R, 3S, 5S, 7S) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) methanesulfonamide (TP-061);
2-Bromo-N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) acetamide (TP-062);
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -2- (prop-2-yn-1-yloxy) Acetamide (TP-063);
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -1,1,1-trifluoromethanesulfonamide (TP- 064);
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -2-nitrobenzenesulfonamide (TP-065);
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -4-nitrobenzenesulfonamide (TP-066);
N-((S)-((1S, 3S, 5S, 7S) -adamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide (TP-067);
N-((R)-((1R, 3R, 5R, 7R) -adamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide (TP-068); and 2,2 , 2-trifluoroacetic acid (1S, 2R, 3S, 5S, 7S) -2-((R) -phenyl (2,2,2-trifluoroacetamido) methyl) -5- (phenylthio) adamantan-1-yl (TP-069);
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) benzamide (TP-070);
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) picolinamide (TP-071);
N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) benzenesulfonamide (TP-072);
2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5S, 7S) -5-chloro-2-((S) -phenyl (2,2,2-trifluoroacetamide) methyl) adamantane-1 -Ile (TP-073);
N-((1R)-((1R, 2S, 3R, 5R, 7R) -5-chloro-1-hydroxyadamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide ( TP-074);
2,2,2-trifluoroacetic acid (1R, 2S, 3R, 5R, 7R) -5-chloro-2-((R) -phenyl (2,2,2-trifluoroacetamide) methyl) adamantane-1 -Yl (TP-075); and (1S, 2R, 3S, 5S, 7S) -2-((R) -amino (phenyl) methyl) -5-chloroadamantan-1-ol (TP-076).
　式（Ｉ）の化合物の「医薬として許容な塩」とは、医薬品として使用可能な塩であれば特に限定されない。本発明化合物が塩基と形成する塩としては、ナトリウム、カリウム、マグネシウム、カルシウム、アルミニウムなどの無機塩基との塩；メチルアミン、エチルアミン、エタノールアミン等の有機塩基との塩などが挙げられる。当該塩は、酸付加塩であってもよく、かかる塩としては、具体的には、塩酸、臭化水素酸、ヨウ化水素酸、硫酸、硝酸、リン酸等の鉱酸；および、ギ酸、酢酸、プロピオン酸、シュウ酸、マロン酸、コハク酸、フマル酸、マレイン酸、乳酸、リンゴ酸、酒石酸、クエン酸、メタンスルホン酸、エタンスルホン酸などの有機酸との酸付加塩が挙げられる。 The “pharmaceutically acceptable salt” of the compound of formula (I) is not particularly limited as long as it is a salt that can be used as a pharmaceutical product. Examples of the salt formed by the compound of the present invention with a base include salts with inorganic bases such as sodium, potassium, magnesium, calcium and aluminum; salts with organic bases such as methylamine, ethylamine and ethanolamine. The salt may be an acid addition salt. Specific examples of the salt include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and other mineral acids; and formic acid, Examples include acid addition salts with organic acids such as acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid.
　式（Ｉ）で表される化合物に含まれる原子（例えば、水素原子、炭素原子、酸素原子、窒素原子、および硫黄原子など）は、それぞれの天然に最も多く存在する同位体以外の同位体原子であってもよく、当該同位体原子は放射性同位体原子であってもよい。すなわち、本発明の１つの側面によれば、同位体原子で標識化された本明細書で既に定義された式（Ｉ）の化合物、またはその塩が提供される。ここで、同位体原子による標識化は、例えば、放射性同位体による標識化（３Ｈ、１４Ｃ、３２Ｐなど）であってもよく、化合物の調製の容易さの側面からは、３Ｈによる標識化が好ましい。 The atoms (for example, hydrogen atom, carbon atom, oxygen atom, nitrogen atom, sulfur atom and the like) contained in the compound represented by the formula (I) are each an isotope atom other than the most naturally occurring isotope. The isotope atom may be a radioisotope atom. That is, according to one aspect of the present invention, there is provided a compound of formula (I) as defined herein, or a salt thereof, labeled with an isotope atom. Here, labeling with an isotope atom may be, for example, labeling with a radioisotope ( 3 H, 14 C, 32 P, etc.). From the aspect of ease of preparation of the compound, 3 H Labeling is preferred.
　本発明の１つの態様において、式（Ｉ）の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩は、プロドラッグとして投与され、生体内において活性化合物に変換される。 In one embodiment of the present invention, a compound of formula (I), its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof is administered as a prodrug and converted to the active compound in vivo.
　本発明における認知機能疾患または障害の治療には、アルツハイマー型認知症、脳血管性認知症、レビー小体型認知症、前頭側頭型認知症、パーキンソン病、精神疾患、神経変性疾患に対する処置が含まれる。また本発明における医薬組成物は、脳機能障害の改善、例えば、脳血管障害、脳外傷、脳腫瘍、ウイルス性脳炎、低酸素脳症、アルコール中毒などに起因する脳機能障害の改善が含まれる。本発明は特に、記憶障害、注意障害、遂行機能障害、社会的行動障害などの認知機能障害に適用することができる。認知機能障害には、例えば、神経変性疾患（アルツハイマー病、パーキンソン病、ピック病、およびハンチントン病など）、精神疾患（統合失調症、双極性障害、うつ病、恐怖症、睡眠障害、薬物依存症など）、広汎性発達障害（自閉症、アスペルガー症候群、精神遅滞、多動性障害、チック障害など）などが含まれる。 The treatment of cognitive dysfunction or disorder in the present invention includes treatment for Alzheimer's dementia, cerebrovascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease, psychiatric disorder, and neurodegenerative disease. It is. The pharmaceutical composition of the present invention includes improvement of brain dysfunction, for example, improvement of cerebral dysfunction caused by cerebrovascular disorder, brain trauma, brain tumor, viral encephalitis, hypoxic encephalopathy, alcoholism and the like. The present invention is particularly applicable to cognitive dysfunction such as memory impairment, attention disorder, performance dysfunction, and social behavior disorder. Cognitive dysfunction includes, for example, neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, Pick's disease, and Huntington's disease), mental disorders (schizophrenia, bipolar disorder, depression, phobias, sleep disorders, drug addiction) And pervasive developmental disorders (such as autism, Asperger syndrome, mental retardation, hyperactivity disorder, tic disorder, etc.).
　本発明における糖尿病合併症には、高血糖症、糖尿病性昏睡、ケトン性昏睡、非ケトン性高浸透圧性昏睡、乳酸アシドーシス、低血糖性昏睡、急性感染症、細小血管障害、糖尿病性網膜症、糖尿病性腎症、糖尿病性神経障害、大血管障害、脳血管障害、虚血性心疾患、糖尿病性壊疽、高脂血症、慢性感染症、胆石症、白内障などが含まれる。 Diabetic complications in the present invention include hyperglycemia, diabetic coma, ketonic coma, non-ketonic hyperosmotic coma, lactic acidosis, hypoglycemic coma, acute infections, microangiopathy, diabetic retinopathy, Examples include diabetic nephropathy, diabetic neuropathy, macrovascular disorder, cerebrovascular disorder, ischemic heart disease, diabetic gangrene, hyperlipidemia, chronic infection, cholelithiasis, and cataract.
　本発明の１つの態様において、式（Ｉ）の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩は、Ｋｉｒ６．２チャネル阻害薬、またはＫｉｒ６．１チャネル阻害薬として使用される。すなわち、式（Ｉ）の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩は、Ｋｉｒ６．２チャネルに関連する疾患、例えば、認知機能疾患または障害、高血糖症、糖尿病、糖尿病性合併症の治療または予防に使用することができる。Ｋｉｒ６．１チャネルに関連する疾患、例えば、認知機能疾患または障害、高血糖症、糖尿病、糖尿病性合併症、精神疾患の治療または予防に使用することができる。 In one embodiment of the invention, a compound of formula (I), an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof is used as a Kir6.2 channel inhibitor, or a Kir6.1 channel inhibitor. . That is, a compound of formula (I), an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof is a disease associated with Kir6.2 channel, such as a cognitive function disease or disorder, hyperglycemia, diabetes, diabetes Can be used to treat or prevent sexual complications. It can be used to treat or prevent diseases associated with Kir6.1 channel, such as cognitive function diseases or disorders, hyperglycemia, diabetes, diabetic complications, mental disorders.
　本発明の医薬組成物は、種々の剤形、例えば、経口投与のためには、錠剤、カプセル剤、散剤、顆粒剤、丸剤、液剤、乳剤、懸濁液、溶液剤、酒精剤、シロップ剤、エキス剤、エリキシル剤とすることができ、非経口剤としては、例えば、皮下注射剤、静脈内注射剤、筋肉内注射剤、腹腔内注射剤などの注射剤；経皮投与または貼付剤、軟膏またはローション；口腔内投与のための舌下剤、口腔貼付剤；ならびに経鼻投与のためのエアゾール剤とすることができるが、これらには限定されない。これらの製剤は、製剤工程において通常用いられる公知の方法により製造することができる。 The pharmaceutical composition of the present invention can be used in various dosage forms such as tablets, capsules, powders, granules, pills, solutions, emulsions, suspensions, solutions, spirits, syrups for oral administration. And parenteral preparations include, for example, injections such as subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections; transdermal administration or patches , Ointments or lotions; sublingual and buccal patches for buccal administration; and aerosols for nasal administration, but not limited thereto. These preparations can be produced by known methods usually used in the preparation process.
　当該医薬組成物は、一般に用いられる各種成分を含みうるものであり、例えば、１種以上の薬学的に許容され得る賦形剤、崩壊剤、希釈剤、滑沢剤、着香剤、着色剤、甘味剤、矯味剤、懸濁化剤、湿潤剤、乳化剤、分散剤、補助剤、防腐剤、緩衝剤、結合剤、安定剤、コーティング剤等を含みうる。また本発明の医薬組成物は、持続性または徐放性剤形であってもよい。 The pharmaceutical composition may contain various commonly used components, such as one or more pharmaceutically acceptable excipients, disintegrants, diluents, lubricants, flavoring agents, and coloring agents. , Sweeteners, flavoring agents, suspending agents, wetting agents, emulsifying agents, dispersing agents, adjuvants, preservatives, buffering agents, binders, stabilizers, coating agents and the like. The pharmaceutical composition of the present invention may be in a sustained or sustained release dosage form.
　本発明の治療剤、予防剤、または医薬組成物の投与量は、投与経路、患者の体型、年齢、体調、疾患の度合い、発症後の経過時間等により、適宜選択することができ、本発明の医薬組成物は、治療有効量および／または予防有効量の上記式（Ｉ）の化合物を含むことができる。本発明において上記式（Ｉ）の化合物は、一般に１～１０００ｍｇ／日／成人または０．０１～２０ｍｇ／日／ｋｇ体重の用量で使用されうる。当該医薬組成物の投与は、単回投与または複数回投与であってもよい。 The dosage of the therapeutic agent, prophylactic agent, or pharmaceutical composition of the present invention can be appropriately selected depending on the administration route, the patient's body shape, age, physical condition, degree of disease, elapsed time after onset, etc. The pharmaceutical composition may comprise a therapeutically effective amount and / or a prophylactically effective amount of a compound of formula (I) as described above. In the present invention, the compound of the above formula (I) can generally be used at a dose of 1-1000 mg / day / adult or 0.01-20 mg / day / kg body weight. The pharmaceutical composition may be administered in a single dose or multiple doses.
　本発明の化合物を含有する経口投与用の組成物において、該化合物の含有量は、単位剤形当たり、例えば、０．００１～１０００ｍｇ、具体的には、０．０１～５００ｍｇ、特に具体的には、０．００５～１００ｍｇである。ここで、本発明の化合物は、例えば式（Ｉ）の化合物または医薬として許容なその塩、具体的にはＴＰ－０１４もしくはＴＰ－０４８または医薬として許容なその塩，具体的にはＴＰ－０４８または医薬として許容なその塩である。 In the composition for oral administration containing the compound of the present invention, the content of the compound is, for example, 0.001 to 1000 mg, specifically 0.01 to 500 mg, particularly specifically, per unit dosage form. Is 0.005 to 100 mg. Here, the compound of the present invention is, for example, a compound of formula (I) or a pharmaceutically acceptable salt thereof, specifically TP-014 or TP-048, or a pharmaceutically acceptable salt thereof, specifically TP-048. Or a pharmaceutically acceptable salt thereof.
　本発明の医薬組成物は、必要に応じ、従来公知の着色剤、保存剤、香料、風味剤、コーティング剤、抗酸化剤、ビタミン、アミノ酸、ペプチド、タンパク質、およびミネラル分（鉄、亜鉛、マグネシム、ヨードなど）などの成分を含有していてもよい。本発明の治療剤または予防剤は、医薬組成物、機能性食品、健康食品、飲料、サプリメントなどに適した形態、例えば顆粒剤（ドライシロップを含む）、カプセル剤（軟カプセル剤、硬カプセル剤）、錠剤（チュアブル剤などを含む）、散剤（粉末剤）、丸剤などの各種の固形製剤、または内服用液剤（液剤、懸濁剤、シロップ剤を含む）などの液状製剤などの形態で調製してもよい。また、本発明の治療剤または予防剤は、そのまま、医薬組成物、機能性食品、健康食品、サプリメントなどとして使用することもできる。 If necessary, the pharmaceutical composition of the present invention contains conventionally known colorants, preservatives, flavors, flavors, coating agents, antioxidants, vitamins, amino acids, peptides, proteins, and minerals (iron, zinc, magnesium). , Iodine, etc.). The therapeutic agent or prophylactic agent of the present invention is in a form suitable for pharmaceutical compositions, functional foods, health foods, beverages, supplements, etc., such as granules (including dry syrup), capsules (soft capsules, hard capsules). , Prepared in the form of various solid preparations such as tablets (including chewables), powders (powder), pills, or liquid preparations for internal use (including liquids, suspensions, syrups) May be. In addition, the therapeutic agent or prophylactic agent of the present invention can be used as it is as a pharmaceutical composition, functional food, health food, supplement or the like.
　製剤化のための添加物としては、例えば、賦形剤、滑沢剤、結合剤、崩壊剤、流動化剤、分散剤、湿潤剤、防腐剤、粘稠剤、ｐＨ調整剤、着色剤、矯味矯臭剤、界面活性剤、溶解補助剤が挙げられる。また、液剤の形態にする場合は、ペクチン、キサンタンガム、グアガムなどの増粘剤を配合することができる。また、コーティング剤を用いてコーティング錠剤にしたり、ペースト状の膠剤とすることもできる。さらに、他の形態に調製する場合であっても、従来の方法に従えばよい。 As additives for formulation, for example, excipients, lubricants, binders, disintegrants, fluidizers, dispersants, wetting agents, preservatives, thickeners, pH adjusters, colorants, Examples include flavoring agents, surfactants, and solubilizing agents. Moreover, when making it into the form of a liquid agent, thickeners, such as pectin, xanthan gum, and guar gum, can be mix | blended. Moreover, it can also be set as a coating tablet using a coating agent, or it can also be set as a paste-form glue. Furthermore, even if it is a case where it prepares in another form, what is necessary is just to follow the conventional method.
　本発明の一つの側面において、式（Ｉ）の化合物などの合成に有用な合成中間体である、式（ＩＩＩ）で表される化合物、、そのエナンチオマー、そのジアステレオマー、またはその塩提が供される。すなわち、本発明の化合物は下記の式（ＩＩＩ）および（ＩＶ）で表される化合物を包含する。 In one aspect of the present invention, a compound represented by formula (III), an enantiomer thereof, a diastereomer thereof, or a salt thereof, which is a synthetic intermediate useful for the synthesis of a compound of formula (I) and the like. Provided. That is, the compounds of the present invention include compounds represented by the following formulas (III) and (IV).
Figure JPOXMLDOC01-appb-C000015
 　上記式（Ｉ）で表される化合物に関する本発明には、互変異性体、幾何異性体、光学異性体などの各種の立体異性体、ジアステレオマー、およびそれらの混合物が含まれる。例えば、式（Ｉ）で表される化合物は、下記の式（ＩＩＩａ）～（ＩＩＩｈ）の化合物を包含する。
Figure JPOXMLDOC01-appb-C000015
 The present invention relating to the compound represented by the above formula (I) includes various stereoisomers such as tautomers, geometric isomers and optical isomers, diastereomers, and mixtures thereof. For example, the compound represented by the formula (I) includes compounds of the following formulas (IIIa) to (IIIh).
Figure JPOXMLDOC01-appb-C000016
 　本発明の１つの態様において、Ｒ４がハロゲン原子であり、Ｒ３が置換されていてもよいフェニルである、式（ＩＩＩ）で表される化合物が提供される。好ましい態様において、当該化合物は式（ＩＩＩａ）で表される化合物である。
Figure JPOXMLDOC01-appb-C000016
 In one embodiment of the present invention, there is provided a compound of formula (III), wherein R 4 is a halogen atom and R 3 is optionally substituted phenyl. In a preferred embodiment, the compound is a compound represented by formula (IIIa).
　以下、実施例を示すことにより本発明をさらに詳細に説明するが、本発明はこれらの実施例に限定されるものではない。 Hereinafter, the present invention will be described in more detail by showing examples, but the present invention is not limited to these examples.
　［実施例１］ [Example 1]
Figure JPOXMLDOC01-appb-C000017
 　［第１工程］（１Ｓ，２Ｒ，５Ｒ）－２－（（Ｓ）－ヒドロキシ（フェニル）メチル）－７－メチレンビシクロ［３．３．１］ノナン－３－オンの調製
　ビス（（Ｓ）－１－フェニルエチル）アミン（１０．０ｍＬ，４４ｍｍｏｌ），塩化リチウム（３．４ｇ，８０ｍｍｏｌ）のＴＨＦ（１００ｍＬ）溶液にｎ－ブチルリチウムのヘキサン溶液（１．５６Ｍ，２８．２ｍＬ，４４ｍｍｏｌ）を氷冷下滴下した。同温にて３０分撹拌後，反応溶液を－７８℃まで冷却した。反応混合物に，７－メチレンビシクロ［３．３．１］ノナン－３－オン（６．００ｇ，４０ｍｍｏｌ）のＴＨＦ（６０ｍＬ）溶液をカニュレーションにより加えた。１時間撹拌後，ベンズアルデヒド（６．１ｍＬ，６０ｍｍｏｌ）のＴＨＦ（４０ｍＬ）溶液をカニュレーションにより加えた。２時間撹拌後，反応溶液に酢酸，飽和塩化アンモニウム水溶液を順次加え，ジエチルエーテルにて抽出した。得られた有機層を飽和食塩水で洗浄し，ＭｇＳＯ４で乾燥した。減圧下溶媒を留去し，残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝４：１）に付し，（１Ｓ，２Ｒ，５Ｒ）－２－（（Ｓ）－ヒドロキシ（フェニル）メチル）－７－メチレンビシクロ［３．３．１］ノナン－３－オン（８．３ｇ，８１％）を白色固体として得た。これをジエチルエーテルから再結晶を行うことで無色針状結晶を得た。
Figure JPOXMLDOC01-appb-C000017
 [Step 1] Preparation of (1S, 2R, 5R) -2-((S) -hydroxy (phenyl) methyl) -7-methylenebicyclo [3.3.1] nonan-3-one Bis ((S) A solution of n-butyllithium in hexane (1.56M, 28.2 mL, 44 mmol) was added to a THF (100 mL) solution of (-1-phenylethyl) amine (10.0 mL, 44 mmol) and lithium chloride (3.4 g, 80 mmol). The solution was added dropwise under ice cooling. After stirring at the same temperature for 30 minutes, the reaction solution was cooled to -78 ° C. To the reaction mixture was added cannula solution of 7-methylenebicyclo [3.3.1] nonan-3-one (6.00 g, 40 mmol) in THF (60 mL). After stirring for 1 hour, a solution of benzaldehyde (6.1 mL, 60 mmol) in THF (40 mL) was added by cannulation. After stirring for 2 hours, acetic acid and a saturated aqueous ammonium chloride solution were sequentially added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated brine and dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 4: 1) to give (1S, 2R, 5R) -2-((S) -hydroxy (phenyl) methyl)- 7-methylenebicyclo [3.3.1] nonan-3-one (8.3 g, 81%) was obtained as a white solid. This was recrystallized from diethyl ether to obtain colorless needle crystals.
　mp 122 ℃; [α]D 21= -17.9 (c = 0.32, CHCl3); 1H-NMR (400 MHz, CDCl3): δ7.38-7.25 (m, 5H), 4.79 (d, J = 1.8 Hz, 1H), 4.76 (d, J = 1.8 Hz, 1H), 4.71 (d, J = 6.8 Hz, 1H), 2.90 (s, 1H), 2.64 (dd, J = 15.7, 6.8 Hz, 1H), 2.48-2.18 (m, 6H), 2.01 (br d, J = 14.3 Hz, 1H); 13C-NMR (100 MHz, CDCl3): δ 211.0, 141.6, 128.8, 127.6, 114.8, 74.6, 62.7, 45.7, 42.2, 41.3, 32.4, 31.9, 28.4; IR (ニート, cm-1): 3390, 1711; MS (EI): m/z 256 (M+), 95 (100%); HRMS (EI): 計算値 C17H20O2 (M+) 256.1463, 実測値 256.1450。 mp 122 ° C; [α] D 21 = -17.9 (c = 0.32, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ7.38-7.25 (m, 5H), 4.79 (d, J = 1.8 Hz, 1H), 4.76 (d, J = 1.8 Hz, 1H), 4.71 (d, J = 6.8 Hz, 1H), 2.90 (s, 1H), 2.64 (dd, J = 15.7, 6.8 Hz, 1H) , 2.48-2.18 (m, 6H), 2.01 (br d, J = 14.3 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ 211.0, 141.6, 128.8, 127.6, 114.8, 74.6, 62.7, 45.7, 42.2, 41.3, 32.4, 31.9, 28.4; IR (Neat, cm -1 ): 3390, 1711; MS (EI): m / z 256 (M + ), 95 (100%); HRMS (EI): Calculated C 17 H 20 O 2 (M +) 256.1463, found 256.1450.
　［第２工程］（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－２－（（Ｒ）－アジド（フェニル）メチル）－５－クロロアダマンタン－１－オールの調製
　（１Ｓ，２Ｒ，５Ｒ）－２－（（Ｓ）－ヒドロキシ（フェニル）メチル）－７－メチレンビシクロ［３．３．１］ノナン－３－オン（１．００ｇ，３．９ｍｍｏｌ），ＤＰＰＡ（０．９３ｍＬ，４．３ｍｍｏｌ），トリフェニルホスフィン（１．１ｇ，４．３ｍｍｏｌ）のＴＨＦ（２０ｍＬ）溶液にＤＩＡＤ（０．８５ｍＬ，４．３ｍｍｏｌ）を氷冷下加えた。同温にて１時間撹拌後，減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝３０：１～８：１）に付し粗アジドを得た。 [Second Step] Preparation of (1S, 2R, 3S, 5S, 7S) -2-((R) -azido (phenyl) methyl) -5-chloroadamantan-1-ol (1S, 2R, 5R) -2 -((S) -hydroxy (phenyl) methyl) -7-methylenebicyclo [3.3.1] nonan-3-one (1.00 g, 3.9 mmol), DPPA (0.93 mL, 4.3 mmol), DIAD (0.85 mL, 4.3 mmol) was added to a solution of triphenylphosphine (1.1 g, 4.3 mmol) in THF (20 mL) under ice cooling. After stirring at the same temperature for 1 hour, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 30: 1 to 8: 1) to obtain a crude azide.
　得られた粗アジドにジクロロメタン（１８ｍＬ）を加え，氷冷下ＴｉＣｌ４（０．１２ｍＬ，１．１ｍｍｏｌ）を加えた。室温にて１時間撹拌後，飽和ＮａＨＣＯ３水溶液を氷冷下加えた。セライト（登録商標）で濾過を行い，濾液をジエチルエーテルにて抽出した。得られた有機層を食塩水で洗浄し，ＭｇＳＯ４で乾燥した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル＝８：１～４：１）に付し、（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－２－（（Ｒ）－アジド（フェニル）メチル）－５－クロロアダマンタン－１－オール（９６９．９ｍｇ，８３％）を無色個体として得た。 Dichloromethane (18 mL) was added to the resulting crude azide, and TiCl 4 (0.12 mL, 1.1 mmol) was added under ice cooling. After stirring at room temperature for 1 hour, saturated aqueous NaHCO 3 solution was added under ice cooling. The mixture was filtered through Celite (registered trademark), and the filtrate was extracted with diethyl ether. The obtained organic layer was washed with brine and dried over MgSO 4 . The residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 8: 1-4: 1) to give (1S, 2R, 3S, 5S, 7S) -2-((R) -azido (phenyl) methyl)- 5-Chloroadamantan-1-ol (969.9 mg, 83%) was obtained as a colorless solid.
　[α]D 27 = +154.2 (c = 0.99, CHCl3); 1H-NMR (400 MHz, CDCl3): δ7.42-7.24 (m, 5H), 4.76 (d, J = 9.5 Hz, 1H), 2.57 (s, 1H), 2.34 (s, 1H), 2.13-1.98 (m, 8H), 1.89 (d, J = 13.1 Hz, 1H), 1.45 (t, J = 14.3 Hz, 2H), 0.93 (s, 1H); 13C-NMR (100 MHz, CDCl3): δ139.7, 129.1, 128.6, 127.5, 71.8, 66.6, 65.5, 56.8, 53.2, 47.8, 46.5, 38.6, 33.5, 32.0, 28.8; IR (ニート, cm-1): 3418; MS (EI): m/z 275 (M+-N3), 104 (100%); HRMS (EI): 計算値 C17H20OCl (M+-N3) 275.1295, 実測値 275.1186。 [α] D 27 = +154.2 (c = 0.99, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ7.42-7.24 (m, 5H), 4.76 (d, J = 9.5 Hz, 1H ), 2.57 (s, 1H), 2.34 (s, 1H), 2.13-1.98 (m, 8H), 1.89 (d, J = 13.1 Hz, 1H), 1.45 (t, J = 14.3 Hz, 2H), 0.93 (s, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ139.7, 129.1, 128.6, 127.5, 71.8, 66.6, 65.5, 56.8, 53.2, 47.8, 46.5, 38.6, 33.5, 32.0, 28.8; IR (Neat, cm -1 ): 3418; MS (EI): m / z 275 (M + -N 3 ), 104 (100%); HRMS (EI): Calculated value C 17 H 20 OCl (M + - N 3 ) 275.1295, found 275.1186.
Figure JPOXMLDOC01-appb-C000018
 　［第３工程］Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミドの調製
　（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－２－（（Ｒ）－アジド（フェニル）メチル）－５－クロロアダマンタン－１－オール（２２９ｍｇ，０．７２１ｍｍｏｌ）のジクロロメタン（７ｍＬ）溶液にピリジン（０．１５ｍＬ，１．８ｍｍｏｌ）、塩化チオニル（０．１１ｍＬ，１．４ｍｍｏｌ）を氷冷下加えた。室温にて２時間攪拌後塩化チオニル（０．２２ｍＬ，２．９ｍｍｏｌ）を加えた。反応溶液を終夜加熱還流した後、氷冷下飽和ＮａＨＣＯ３水溶液を加え、ジクロロメタンで抽出した。得られた有機層をＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝１５：１）に付し、（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－２－（（Ｒ）－アジド（フェニル）メチル）－１，５－ジクロロアダマンタン（１５６ｍｇ，６４％）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000018
 [Third Step] N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroa Preparation of Cetamide (1S, 2R, 3S, 5S, 7S) -2-((R) -Azido (phenyl) methyl) -5-chloroadamantan-1-ol (229 mg, 0.721 mmol) in dichloromethane (7 mL) Pyridine (0.15 mL, 1.8 mmol) and thionyl chloride (0.11 mL, 1.4 mmol) were added to the solution under ice cooling. After stirring at room temperature for 2 hours, thionyl chloride (0.22 mL, 2.9 mmol) was added. The reaction solution was heated to reflux overnight, then a saturated aqueous NaHCO 3 solution was added under ice-cooling, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 15: 1) to give (1S, 2R, 3S, 5S, 7S) -2-((R) -azide (phenyl). ) Methyl) -1,5-dichloroadamantane (156 mg, 64%) was obtained as a colorless oil.
　得られたアジド化合物（１５６ｍｇ，０．４６３ｍｍｏｌ）のＴＨＦ（５ｍＬ）溶液にＬｉＡｌＨ４（２６ｍｇ，０．６９ｍｍｏｌ）を氷冷下加えた。同温度にて１時間攪拌後、反応溶液にアンモニア水を加え、セライト（商標登録）で濾過した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝１：１）に付し、（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミンを無色油状物として得た。 LiAlH 4 (26 mg, 0.69 mmol) was added to a solution of the obtained azide compound (156 mg, 0.463 mmol) in THF (5 mL) under ice cooling. After stirring at the same temperature for 1 hour, aqueous ammonia was added to the reaction solution, and the mixture was filtered through Celite (registered trademark). The residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 1: 1) to give (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl ) Methanamine was obtained as a colorless oil.
　得られたアミン（２３．５ｍｇ，０．０７５７ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液に、トリエチルアミン（４２μＬ，３．０３ｍｍｏｌ）、無水トリフルオロ酢酸（ＴＦＡＡ、２１μＬ，０．１５ｍｍｏｌ）を氷冷下加えた。室温で終夜攪拌後、飽和ＮａＨＣＯ３水溶液を氷冷下加え、ジクロロメタンで抽出した。得られた有機層をＮａ２ＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝１０：１）に付し、Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド（ＴＰ－０５４、３０．３ｍｇ，９８％）を白色固体として得た。 To a solution of the obtained amine (23.5 mg, 0.0757 mmol) in dichloromethane (1 mL), triethylamine (42 μL, 3.03 mmol) and trifluoroacetic anhydride (TFAA, 21 μL, 0.15 mmol) were added under ice cooling. After stirring at room temperature overnight, a saturated aqueous NaHCO 3 solution was added under ice-cooling, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over Na 2 SO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 10: 1) to give N-((R)-((1S, 2R, 3S, 5S, 7R) -1, 5-Dichloroadamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide (TP-054, 30.3 mg, 98%) was obtained as a white solid.
　[α]D 23 = +146.6 (c = 0.469, CHCl3); 1H-NMR (400 MHz, CDCl3): δ 7.39-7.26 (m, 5H), 6.49 (br d, J = 9.7 Hz, 1H), 5.52 (dd, J = 9.7, 8.9 Hz, 1H), 2.69 (br d, J = 8.9 Hz, 1H), 2.53-2.43 (m, 4H), 2.33 (br s, 1H), 2.24-2.15 (m, 2H), 2.09 (br s, 2H), 1.92 (br d, J = 13.0 Hz, 1H), 1.77 (br d, J = 13.5 Hz, 1H), 1.46 (br d, J = 12.1 Hz, 1H); 13C-NMR (100MHz, CDCl3): δ 156.0 (q, J = 37.1 Hz),141.6, 129.0, 128.2, 127.2, 115.8 (q, J = 288.4 Hz), 68.2, 65.3, 59.1, 54.1, 52.9, 47.5, 45.8, 40.8, 35.4, 32.7, 28.7; IR (ニート, cm-1):3308, 2944, 1696, 1552, 1206, 1183; MS (EI): m/z 405 (M+), 202 (100%); HRMS (EI): 計算値C19H20Cl2F3NO (M+) 405.0874, 実測値405.0864。 [α] D 23 = +146.6 (c = 0.469, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.39-7.26 (m, 5H), 6.49 (br d, J = 9.7 Hz, 1H ), 5.52 (dd, J = 9.7, 8.9 Hz, 1H), 2.69 (br d, J = 8.9 Hz, 1H), 2.53-2.43 (m, 4H), 2.33 (br s, 1H), 2.24-2.15 ( m, 2H), 2.09 (br s, 2H), 1.92 (br d, J = 13.0 Hz, 1H), 1.77 (br d, J = 13.5 Hz, 1H), 1.46 (br d, J = 12.1 Hz, 1H ); 13 C-NMR (100 MHz, CDCl 3 ): δ 156.0 (q, J = 37.1 Hz), 141.6, 129.0, 128.2, 127.2, 115.8 (q, J = 288.4 Hz), 68.2, 65.3, 59.1, 54.1, 52.9, 47.5, 45.8, 40.8, 35.4, 32.7, 28.7; IR (Neat, cm -1 ): 3308, 2944, 1696, 1552, 1206, 1183; MS (EI): m / z 405 (M + ), 202 (100%); HRMS (EI): Calculated C 19 H 20 Cl 2 F 3 NO (M + ) 405.0874, found 405.0864.
　［実施例２］ [Example 2]
Figure JPOXMLDOC01-appb-C000019
 　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミン（１９．６ｍｇ，０．０６３２ｍｍｏｌ）のメタノール（１ｍＬ）溶液に氷冷下クロロトリメチルシラン（ＴＭＳＣｌ、３０μＬ，０．２４ｍＬ）を加えた。同温度で３０分間攪拌後、減圧下溶媒を留去し、（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミン塩酸塩(ＴＰ－０５５、２０．１ｍｇ，９２％)を白色固体として得た。
Figure JPOXMLDOC01-appb-C000019
 (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine (19.6 mg, 0.0632 mmol) in methanol (1 mL) was cooled with ice. Lower chlorotrimethylsilane (TMSCl, 30 μL, 0.24 mL) was added. After stirring at the same temperature for 30 minutes, the solvent was distilled off under reduced pressure to give (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine hydrochloride (TP-055, 20.1 mg, 92%) was obtained as a white solid.
　[α]D 24 = +32.5 (c = 0.2775, MeOH); 1H-NMR (400 MHz, DMSO-d6): δ 8.33 (br, 3H),7.55 (d, J = 6.8 Hz, 1H), 7.38-7.32 (m, 3H), 4.73 (br d, J = 10.6 Hz, 1H), 3.16 (br s, 1 H), 2.80 (br d, J = 10.6 Hz, 1H), 2.54-2.44 (m, 2H), 2.34-2.14 (m, 4H), 2.06 (br s, 2H), 1.93. (br d, J = 14.0 Hz, 1H), 1.79 (br d, J = 13.0 Hz, 1H), 1.42 (br d, J =13.0 Hz, 1H); 13C-NMR (100MHz, DMSO-d6): a 139.8, 128.7, 128.4, 128.2, 68.8, 67.1, 58.4, 54.2, 51.1, 45.8, 44.9, 33.9, 32.7, 27.5; IR (ニート, cm-1):3299, 2937; HRMS (ESI): 計算値C17H22Cl2N (M+-Cl) 310.1129, 実測値310.1120。 [α] D 24 = +32.5 (c = 0.2775, MeOH); 1 H-NMR (400 MHz, DMSO-d 6 ): δ 8.33 (br, 3H), 7.55 (d, J = 6.8 Hz, 1H), 7.38-7.32 (m, 3H), 4.73 (br d, J = 10.6 Hz, 1H), 3.16 (br s, 1 H), 2.80 (br d, J = 10.6 Hz, 1H), 2.54-2.44 (m, 2H), 2.34-2.14 (m, 4H), 2.06 (br s, 2H), 1.93. (Br d, J = 14.0 Hz, 1H), 1.79 (br d, J = 13.0 Hz, 1H), 1.42 (br d, J = 13.0 Hz, 1H); 13 C-NMR (100 MHz, DMSO-d 6 ): a 139.8, 128.7, 128.4, 128.2, 68.8, 67.1, 58.4, 54.2, 51.1, 45.8, 44.9, 33.9, 32.7, 27.5; IR (neat, cm −1 ): 3299, 2937; HRMS (ESI): calculated C 17 H 22 Cl 2 N (M + —Cl) 310.1129, found 310.1120.
　［実施例３］ [Example 3]
Figure JPOXMLDOC01-appb-C000020
 　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミン（２３．６ｍｇ，０．０７６２ｍｍｏｌ）のジクロロメタン（２ｍＬ）溶液にトリエチルアミン（２１μＬ，０．１５ｍｍｏｌ）、無水酢酸（１１μＬ，０．１１ｍｍｏｌ）を氷冷下加えた。室温にて３０分間攪拌後、氷冷下飽和ＮａＨＣＯ３水溶液を加え、ジクロロメタンで抽出した。得られた有機層をＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝１：１）に付し、Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アセタミド（ＴＰ－０５６、１６．４ｍｇ，６１％）を白色固体として得た。
Figure JPOXMLDOC01-appb-C000020
 (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine (23.6 mg, 0.0762 mmol) in dichloromethane (2 mL) in triethylamine (2 mL) 21 μL, 0.15 mmol) and acetic anhydride (11 μL, 0.11 mmol) were added under ice cooling. After stirring at room temperature for 30 minutes, a saturated aqueous NaHCO 3 solution was added under ice cooling, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 1: 1) to give N-((R)-((1S, 2R, 3S, 5S, 7R) -1, 5-Dichloroadamantan-2-yl) (phenyl) methyl) acetamide (TP-056, 16.4 mg, 61%) was obtained as a white solid.
　[α]D 23 = +67.9 (c = 0.276, CHCl3);1H-NMR (400 MHz, CDCl3): δ 7.31 (m, 5H), 5.61-5.50 (m, 2H), 2.60-2.57 (m, 2H), 2.48-2.44 (m, 3H), 2.31 (br s, 1H), 2.23-2.14 (m, 2H), 2.08 (br s, 2H), 1.93-1.86 (m, 5H), 1.39 (br d, J = 13.5 Hz, 1H); 13C-NMR (100MHz, CDCl3): δ 168.6, 144.1, 128.7, 127.4, 127.3, 68.8, 66.0, 59.1, 53.1, 52.9, 47.7, 46.0, 40.8, 35.6, 32.9, 28.7, 23.7; IR (ニート, cm-1):3277, 2942, 1645, 1547; MS (EI): m/z 351 (M+), 148 (100%); HRMS (EI): 計算値C19H23Cl2NO (M+) 351.1157, 実測値351.1167。 [α] D 23 = +67.9 (c = 0.276, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.31 (m, 5H), 5.61-5.50 (m, 2H), 2.60-2.57 ( m, 2H), 2.48-2.44 (m, 3H), 2.31 (br s, 1H), 2.23-2.14 (m, 2H), 2.08 (br s, 2H), 1.93-1.86 (m, 5H), 1.39 ( br d, J = 13.5 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ 168.6, 144.1, 128.7, 127.4, 127.3, 68.8, 66.0, 59.1, 53.1, 52.9, 47.7, 46.0, 40.8, 35.6 , 32.9, 28.7, 23.7; IR (neat, cm -1 ): 3277, 2942, 1645, 1547; MS (EI): m / z 351 (M + ), 148 (100%); HRMS (EI): calculation The value C 19 H 23 Cl 2 NO ( M +) 351.1157, Found 351.1167.
　［実施例４］ [Example 4]
Figure JPOXMLDOC01-appb-C000021
 　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミン（４９．８ｍｇ，０．１６１ｍｍｏｌ）のＴＨＦ（２ｍＬ）溶液に２Ｍ　ＮａＯＨ水溶液（１ｍＬ）、クロロギ酸メチル（２５μＬ，０．３２ｍｍｏｌ）を氷冷下加えた。同温度にて１５分間攪拌後、反応溶液に蒸留水を加え、酢酸エチルで抽出した。得られた有機層を飽和食塩水で洗浄し、ＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝８：１～４：１）に付し、メチル　（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）カーバメート（ＴＰ－０５７、５４．４ｍｇ，９２％）を白色固体として得た。
Figure JPOXMLDOC01-appb-C000021
 (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine (49.8 mg, 0.161 mmol) in THF (2 mL) in 2 M NaOH Aqueous solution (1 mL) and methyl chloroformate (25 μL, 0.32 mmol) were added under ice cooling. After stirring at the same temperature for 15 minutes, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 8: 1-4: 1) to give methyl ((R)-((1S, 2R, 3S, 5S, 7R) -1,5-Dichloroadamantan-2-yl) (phenyl) methyl) carbamate (TP-057, 54.4 mg, 92%) was obtained as a white solid.
　[α]D 23 = +115.9 (c = 0.272, CHCl3);1H-NMR (400 MHz, CDCl3): δ 7.34-7.23 (m, 5H), 5.22 (dd, J = 9.7, 8.7 Hz, 1H), 4.91 (br d, J = 9.7 HZ, 1H), 3.63 (s, 3H), 2.58-2.45 (m, 5H), 2.34 (br s, 1H), 2.20-2.05 (m, 4H), 1.90 (br d, J = 11.6 Hz, 1H), 1.43 (br d, J = 13.5 Hz, 1H); 13C-NMR (100MHz, CDCl3): δ 156.2, 144.1, 128.7, 127.3, 126.9, 68.9, 66.0, 59.2, 55.3, 53.4, 52.3, 47.8, 46.0, 40.8, 35.1, 32.9, 29.0; IR (ニート, cm-1): 3327, 2943, 1692, 1537; MS (EI): m/z 367 (M+), 164 (100%); HRMS (EI): 計算値C19H23Cl2NO2(M+) 367.1106, 実測値367.1123。 [α] D 23 = +115.9 (c = 0.272, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.34-7.23 (m, 5H), 5.22 (dd, J = 9.7, 8.7 Hz, 1H), 4.91 (br d, J = 9.7 HZ, 1H), 3.63 (s, 3H), 2.58-2.45 (m, 5H), 2.34 (br s, 1H), 2.20-2.05 (m, 4H), 1.90 (br d, J = 11.6 Hz, 1H), 1.43 (br d, J = 13.5 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ 156.2, 144.1, 128.7, 127.3, 126.9, 68.9, 66.0 , 59.2, 55.3, 53.4, 52.3, 47.8, 46.0, 40.8, 35.1, 32.9, 29.0; IR (Neat, cm -1 ): 3327, 2943, 1692, 1537; MS (EI): m / z 367 (M + ), 164 (100%); HRMS (EI): Calculated C 19 H 23 Cl 2 NO 2 (M + ) 367.1106, found 367.1123.
　［実施例５］ [Example 5]
Figure JPOXMLDOC01-appb-C000022
 　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミン（５６．２ｍｇ，０．１８１ｍｍｏｌ）のジクロロメタン（２ｍＬ）溶液にイソシアン酸フェニル（２４μＬ，０．２２ｍｍｏｌ）を氷冷下加えた。同温度にて１５分間攪拌後、反応溶液に蒸留水を加え、ジクロロメタンで抽出した。得られた有機層をＭｇＳＯ４で乾燥し、減圧下溶媒を留去した。得られた白色固体をメタノール－クロロホルムから再結晶し、１－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－３－フェニルウレア（ＴＰ－０５８、６３．８ｍｇ，８２％）を無色結晶として得た。
Figure JPOXMLDOC01-appb-C000022
 Isocyanic acid to a solution of (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine (56.2 mg, 0.181 mmol) in dichloromethane (2 mL) Phenyl (24 μL, 0.22 mmol) was added under ice cooling. After stirring at the same temperature for 15 minutes, distilled water was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 and the solvent was distilled off under reduced pressure. The obtained white solid was recrystallized from methanol-chloroform to give 1-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -3-Phenylurea (TP-058, 63.8 mg, 82%) was obtained as colorless crystals.
　[α]D 23 = +91.8 (c = 0.351, MeOH); 1H-NMR (400 MHz, CD3OD): δ 7.88 (s, 1H), 7.35-7.28 (m, 6H), 7.22-7.18 (m, 3H), 6.94 (t, J = 7.2 HZ, 1H), 5.40 (d, J = 7.2 Hz, 1H), 2.65-2.60 (m, 2H), 2.52-2.40 (m, 3H), 2.30 (br s, 1H), 2.10 (br s, 2H), 2.08 (br s, 2 H), 2.00 (br d, J = 13.5 Hz, 1H), 1.89 (br d, J = 13.0 Hz, 1H), 1.45 (br d, J = 13.5 Hz, 1H); 13C-NMR (100MHz, CD3OD): δ 156.9, 146.4, 140.8, 129.8, 129.5, 128.3, 127.9, 123.5, 120.1, 70.5, 67.3, 60.6, 54.9, 54.5, 49.6, 48.9, 47.2, 42.0, 36.5, 34.5, 29.8; IR (ニート, cm-1): 3310, 2941, 1642, 1154, 748; MS (EI): m/z 428 (M+), 132 (100%); HRMS (EI): 計算値C24H26Cl2N2O (M+) 428.1422, 実測値428.1416。 [α] D 23 = +91.8 (c = 0.351, MeOH); 1 H-NMR (400 MHz, CD 3 OD): δ 7.88 (s, 1H), 7.35-7.28 (m, 6H), 7.22-7.18 ( m, 3H), 6.94 (t, J = 7.2 HZ, 1H), 5.40 (d, J = 7.2 Hz, 1H), 2.65-2.60 (m, 2H), 2.52-2.40 (m, 3H), 2.30 (br s, 1H), 2.10 (br s, 2H), 2.08 (br s, 2 H), 2.00 (br d, J = 13.5 Hz, 1H), 1.89 (br d, J = 13.0 Hz, 1H), 1.45 ( br d, J = 13.5 Hz, 1H); 13 C-NMR (100 MHz, CD 3 OD): δ 156.9, 146.4, 140.8, 129.8, 129.5, 128.3, 127.9, 123.5, 120.1, 70.5, 67.3, 60.6, 54.9, 54.5, 49.6, 48.9, 47.2, 42.0, 36.5, 34.5, 29.8; IR (Neat, cm -1 ): 3310, 2941, 1642, 1154, 748; MS (EI): m / z 428 (M + ), 132 (100%); HRMS (EI): Calculated C 24 H 26 Cl 2 N 2 O (M + ) 428.1422, found 428.1416.
　［実施例６］ [Example 6]
Figure JPOXMLDOC01-appb-C000023
 　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミン（４９．１ｍｇ，０．１５８ｍｍｏｌ）のジクロロメタン（２ｍＬ）溶液にベンシルオキシカルボニルグリシン（F.-T. Tsai et al. J. Am. Chem. Soc. 2016, 138, 4626. の方法で調製）（５０ｍｇ，０．２４ｍｍｏｌ），Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド（ＤＣＣ，４９ｍｇ，０．２４ｍｍｏｌ），Ｎ，Ｎ－ジメチル－４－アミノピリジン（ＤＭＡＰ，２ｍｇ，０．０２ｍｍｏｌ）を氷冷下加えた。室温にて１５分間攪拌後、反応溶液に蒸留水を加え、ジエチルエーテルで抽出した。得られた有機層を飽和食塩水で洗浄し、ＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝２：１）に付し、ベンジル　（２－（（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アミノ）－２－オキソエチル）カーバメート（ＴＰ－０５９、５５．１１ｍｇ，６９％）を白色固体として得た。
Figure JPOXMLDOC01-appb-C000023
 (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine (49.1 mg, 0.158 mmol) in dichloromethane (2 mL) in benzyl Oxycarbonylglycine (prepared by the method of F.-T. Tsai et al. J. Am. Chem. Soc. 2016, 138, 4626.) (50 mg, 0.24 mmol), N, N′-dicyclohexylcarbodiimide (DCC, 49 mg, 0.24 mmol), N, N-dimethyl-4-aminopyridine (DMAP, 2 mg, 0.02 mmol) was added under ice cooling. After stirring at room temperature for 15 minutes, distilled water was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated brine and dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 2: 1) to give benzyl (2-(((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) amino) -2-oxoethyl) carbamate (TP-059, 55.11 mg, 69%) was obtained as a white solid.
　[α]D 25 = +73.1 (c = 0.621, CHCl3); 1H-NMR (400 MHz, CDCl3): δ 7.36-7.23 (m, 10H),6.52 (br, 1H), 5.52 (dd, J = 9.8, 8.8 Hz, 1H), 5.36 (br, 1H), 5.10 (s, 2H), 3.78 (dd, J = 16.3, 5.9 Hz, 1H), 3.70 (dd, J = 16.3, 5.9 Hz, 1H), 2.54-2.46 (m, 4H), 2.37 (br s, 1H), 2.15-2.05 (m, 4H), 1.88-1.78 (m, 2H), 1.31 (m, 1H); 13C-NMR (100MHz, CDCl3): δ 167.7, 156.8, 143.5, 136.0, 128.64, 128.61, 128.4, 128.0, 127.4, 127.2, 68.8, 67.3, 65.9, 59.1, 53.3, 52.9, 47.7, 45.9, 45.1, 40.8, 35.1, 32.8, 28.8; IR (ニート, cm-1): 3306, 2938, 1712, 1655, 1528, 1262; MS (EI): m/z 392 (M+-C7H8O), 189 (100%); HRMS (EI): 計算値C20H22Cl2N2O2(M+-C7H8O) 392.1058, 実測値392.1043。 [α] D 25 = +73.1 (c = 0.621, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.36-7.23 (m, 10H), 6.52 (br, 1H), 5.52 (dd, J = 9.8, 8.8 Hz, 1H), 5.36 (br, 1H), 5.10 (s, 2H), 3.78 (dd, J = 16.3, 5.9 Hz, 1H), 3.70 (dd, J = 16.3, 5.9 Hz, 1H ), 2.54-2.46 (m, 4H), 2.37 (br s, 1H), 2.15-2.05 (m, 4H), 1.88-1.78 (m, 2H), 1.31 (m, 1H); 13 C-NMR (100 MHz , CDCl 3 ): δ 167.7, 156.8, 143.5, 136.0, 128.64, 128.61, 128.4, 128.0, 127.4, 127.2, 68.8, 67.3, 65.9, 59.1, 53.3, 52.9, 47.7, 45.9, 45.1, 40.8, 35.1, 32.8, 28.8; IR (Neat, cm -1 ): 3306, 2938, 1712, 1655, 1528, 1262; MS (EI): m / z 392 (M + -C 7 H 8 O), 189 (100%); HRMS (EI): calculated C 20 H 22 Cl 2 N 2 O 2 (M + -C 7 H 8 O) 392.1058, Found 392.1043.
　２－アミノ－Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アセタミド（ＴＰ－０５９、８２．８ｍｇ，０．１６５ｍｍｏｌ）のメタノール（１．５ｍＬ）溶液にクロロトリメチルシラン（１０４μＬ，０．８３ｍｍｏｌ），１０％パラジウム炭素（１０ｍｇ）を加えた。水素雰囲気下室温にて終夜攪拌後、反応溶液をセライト（商標登録）で濾過を行い、減圧下溶媒を留去することでＴＰ－０６０（７０．６ｍｇ，定量的）を黄色固体として得た。 2-Amino-N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) acetamide (TP-059, 82.8 mg, To a solution of 0.165 mmol) in methanol (1.5 mL) was added chlorotrimethylsilane (104 μL, 0.83 mmol) and 10% palladium on carbon (10 mg). After stirring overnight at room temperature under a hydrogen atmosphere, the reaction solution was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure to obtain TP-060 (70.6 mg, quantitative) as a yellow solid.
　[α]D 25 = +79.5 (c = 0.824, CHCl3); 1H-NMR (400 MHz, DMSO-d6): δ 9.13 (br 1H), 8.12 (br, 2H), 7.38 (d, J = 7.2 Hz, 2H), 7.26 (dd, J = 7.2, 7.0 Hz, 2H), 7.18 (t, J = 7.0 Hz, 1H), 5.35 (m, 1H), 3.56 (br d, J = 15.0 Hz, 1H), 3.46 (br d, J = 15.0 Hz, 1H), 2.70-2.59 (m, 2H), 2.43-2.37 (m, 2H), 2.24 (br s, 1H), 2.14 (br s, 2H), 2.05 (br s, 2H), 1.86 (br d, J = 12.1 Hz, 1H), 1.73-1.70 (m, 2H), 1.35 (br d, J = 13.0 Hz, 1H); 13C-NMR (100MHz, DMSO-d6): δ 164.4, 144.1, 128.0, 127.8, 126.7, 70.4, 67.7, 58.4, 52.3, 52.2, 46.6, 45.2, 40.2, 34.6, 32.6, 28.0; IR (ニート, cm-1):3210, 2937, 1684, 1558; HRMS (ESI): 計算値C19H25Cl2N2O (M+-Cl) 367.1338, 実測値367.1331。 [α] D 25 = +79.5 (c = 0.824, CHCl 3 ); 1 H-NMR (400 MHz, DMSO-d 6 ): δ 9.13 (br 1H), 8.12 (br, 2H), 7.38 (d, J = 7.2 Hz, 2H), 7.26 (dd, J = 7.2, 7.0 Hz, 2H), 7.18 (t, J = 7.0 Hz, 1H), 5.35 (m, 1H), 3.56 (br d, J = 15.0 Hz, 1H), 3.46 (br d, J = 15.0 Hz, 1H), 2.70-2.59 (m, 2H), 2.43-2.37 (m, 2H), 2.24 (br s, 1H), 2.14 (br s, 2H), 2.05 (br s, 2H), 1.86 (br d, J = 12.1 Hz, 1H), 1.73-1.70 (m, 2H), 1.35 (br d, J = 13.0 Hz, 1H); 13 C-NMR (100MHz, DMSO-d 6 ): δ 164.4, 144.1, 128.0, 127.8, 126.7, 70.4, 67.7, 58.4, 52.3, 52.2, 46.6, 45.2, 40.2, 34.6, 32.6, 28.0; IR (neat, cm -1 ): 3210, 2937, 1684, 1558; HRMS (ESI): Calculated C 19 H 25 Cl 2 N 2 O (M + -Cl) 367.1338, found 367.1331.
　［実施例７］ [Example 7]
Figure JPOXMLDOC01-appb-C000024
 　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミン（３５．２ｍｇ，０．１１４ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液に塩化メタンスルホニル（１０．５μＬ，０．１４ｍｍｏｌ），トリエチルアミン（２４μＬ，０．１７ｍｍｏｌ）を氷冷下加えた。同温度にて３０分間攪拌後、反応溶液に飽和ＮａＨＣＯ３溶液を加え、ジクロロメタンで抽出した。得られた有機層をＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝２：１）に付し、Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）メタンスルホンアミド（ＴＰ－０６１、３５．８ｍｇ，８１％）を白色固体として得た。
Figure JPOXMLDOC01-appb-C000024
 (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine (35.2 mg, 0.114 mmol) in dichloromethane (1 mL) in methane chloride Sulfonyl (10.5 μL, 0.14 mmol) and triethylamine (24 μL, 0.17 mmol) were added under ice cooling. After stirring at the same temperature for 30 minutes, a saturated NaHCO 3 solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 2: 1) to give N-((R)-((1S, 2R, 3S, 5S, 7S) -1, 5-Dichloroadamantan-2-yl) (phenyl) methyl) methanesulfonamide (TP-061, 35.8 mg, 81%) was obtained as a white solid.
　[α]D 25 = +47.7 (c = 0.380, CHCl3); 1H-NMR (400 MHz, CDCl3): δ 7.39-7.28 (m, 5H), 4.88 (m, 2H), 2.67 (br s, 1H), 2.58 (br d, J = 12.6 Hz, 1H), 2.47-2.37 (m, 7H), 2.21-2.06 (m, 5H), 1.90 (br d, J = 13.0 Hz, 1H), 1.46 (br d, J = 14.0 Hz, 1H); 13C-NMR (100MHz, CDCl3): δ 143.0, 129.0, 128.0, 127.2, 69.0, 65.8, 59.3, 58.4, 54.5, 47.7, 45.9, 41.7, 40.7, 34.7, 32.9, 28.5; IR (ニート, cm-1): 3263, 2941, 1456, 1319, 1157; HRMS (ESI): 計算値C18H23Cl2NNaO2S (M++Na) 410.0724, 実測値410.0719。 [α] D 25 = +47.7 (c = 0.380, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.39-7.28 (m, 5H), 4.88 (m, 2H), 2.67 (br s , 1H), 2.58 (br d, J = 12.6 Hz, 1H), 2.47-2.37 (m, 7H), 2.21-2.06 (m, 5H), 1.90 (br d, J = 13.0 Hz, 1H), 1.46 ( br d, J = 14.0 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ 143.0, 129.0, 128.0, 127.2, 69.0, 65.8, 59.3, 58.4, 54.5, 47.7, 45.9, 41.7, 40.7, 34.7 , 32.9, 28.5; IR (neat, cm -1 ): 3263, 2941, 1456, 1319, 1157; HRMS (ESI): calculated C 18 H 23 Cl 2 NNaO 2 S (M + + Na) 410.0724, measured 410.0719.
　［実施例８］ [Example 8]
Figure JPOXMLDOC01-appb-C000025
 　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミン（５１．４ｍｇ，０．１６６ｍｍｏｌ）のジクロロメタン（２ｍＬ）溶液にブロモ酢酸（２７ｍｇ，０．２０ｍｍｏｌ），Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド（ＤＣＣ，４１ｍｇ，０．２０ｍｍｏｌ），Ｎ，Ｎ－ジメチル－４－アミノピリジン（ＤＭＡＰ，２ｍｇ，０．０２ｍｍｏｌ）を氷冷下加えた。室温にて終夜攪拌後、反応溶液に蒸留水を加え、ジエチルエーテルで抽出した。得られた有機層を飽和食塩水で洗浄し、ＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝４：１～２：１）に付し、２－ブロモ－Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アセタミド（ＴＰ－０６２、６４．３ｍｇ，９０％）を白色固体として得た。
Figure JPOXMLDOC01-appb-C000025
 To a solution of (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine (51.4 mg, 0.166 mmol) in dichloromethane (2 mL) (27 mg, 0.20 mmol), N, N′-dicyclohexylcarbodiimide (DCC, 41 mg, 0.20 mmol), N, N-dimethyl-4-aminopyridine (DMAP, 2 mg, 0.02 mmol) were added under ice cooling. . After stirring at room temperature overnight, distilled water was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated brine and dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 4: 1 to 2: 1) to give 2-bromo-N-((R)-((1S, 2R, 3S , 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) acetamide (TP-062, 64.3 mg, 90%) was obtained as a white solid.
　[α]D 28 = +84.9 (c = 0.256, CHCl3); 1H-NMR (400 MHz, CDCl3): δ 7.36-7.27 (m, 5H), 6.82 (br d, J = 9.3 Hz, 1H), 5.53 (dd, J = 9.3, 9.3 Hz, 1H), 3.87 (d, J = 13.7 Hz, 1H), 3.81 (d, J = 13.7 Hz, 1H), 2.62-2.33 (m, 5H), 2.21 (br s, 1H), 2.18-2.08 (m, 4H), 1.90 (br d, J = 12.7 Hz, 1H), 1.84 (br d, J = 13.7 Hz, 1H), 1.45 (br d, J = 13.7 Hz, 1H); 13C-NMR (100MHz, CDCl3): δ 163.8, 142.9, 128.8, 127.6, 127.1, 68.7, 65.7, 59.1, 53.7, 53.3, 47.8, 45.9, 40.8, 35.1, 32.7, 29.6, 29.0; IR (ニート, cm-1): 3276, 2942, 1647; MS (EI): m/z 350 (M+-Br), 226 (100%); HRMS (EI): 計算値C19H22Cl2NO (M+-Br) 350.1078, 実測値350.1075。 [α] D 28 = +84.9 (c = 0.256, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.36-7.27 (m, 5H), 6.82 (br d, J = 9.3 Hz, 1H ), 5.53 (dd, J = 9.3, 9.3 Hz, 1H), 3.87 (d, J = 13.7 Hz, 1H), 3.81 (d, J = 13.7 Hz, 1H), 2.62-2.33 (m, 5H), 2.21 (br s, 1H), 2.18-2.08 (m, 4H), 1.90 (br d, J = 12.7 Hz, 1H), 1.84 (br d, J = 13.7 Hz, 1H), 1.45 (br d, J = 13.7 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ 163.8, 142.9, 128.8, 127.6, 127.1, 68.7, 65.7, 59.1, 53.7, 53.3, 47.8, 45.9, 40.8, 35.1, 32.7, 29.6, 29.0 IR (Neat, cm -1 ): 3276, 2942, 1647; MS (EI): m / z 350 (M + -Br), 226 (100%); HRMS (EI): Calculated C 19 H 22 Cl 2 NO (M + -Br) 350.1078, found 350.1075.
　［実施例９］ [Example 9]
Figure JPOXMLDOC01-appb-C000026
 　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミン（２１．０ｍｇ，０．０６７８ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液に２－（２－プロピニルオキシ）酢酸（X. Zhang et al. Green Chem. 2011, 13, 397.の方法で調製）（１５ｍｇ，０．１３ｍｍｏｌ），Ｎ，Ｎ’－ジシクロヘキセイルカルボジイミド（ＤＣＣ，２０ｍｇ，０．０９７ｍｍｏｌ），Ｎ，Ｎ－ジメチル－４－アミノピリジン（ＤＭＡＰ，１ｍｇ，０．００８ｍｍｏｌ）を氷冷下加えた。室温にて６時間攪拌後、反応溶液に蒸留水を加え、ジエチルエーテルで抽出した。得られた有機層を飽和食塩水で洗浄し、ＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝４：１～２：１）に付し、Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－２－（プロパ－２－イン－１－イルオキシ）アセタミド（ＴＰ－０６３、１９．２５ｍｇ，７０％）を白色固体として得た。
Figure JPOXMLDOC01-appb-C000026
 To a solution of (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine (21.0 mg, 0.0678 mmol) in dichloromethane (1 mL) was added 2- (2-propynyloxy) acetic acid (prepared by the method of X. Zhang et al. Green Chem. 2011, 13, 397) (15 mg, 0.13 mmol), N, N′-dicyclohexylcarbodiimide (DCC, 20 mg, 0.097 mmol), N, N-dimethyl-4-aminopyridine (DMAP, 1 mg, 0.008 mmol) was added under ice cooling. After stirring at room temperature for 6 hours, distilled water was added to the reaction solution, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated brine and dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 4: 1 to 2: 1) to give N-((R)-((1S, 2R, 3S, 5S, 7R ) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -2- (prop-2-yn-1-yloxy) acetamide (TP-063, 19.25 mg, 70%) as a white solid It was.
　[α]D 20 = +96.2 (c = 0.283, CHCl3);1H-NMR (400 MHz, CDCl3): δ 7.33-7.25 (m, 5H), 6.75 (br d, J = 10.1 Hz, 1H), 5.60 (dd, J = 10.1, 8.7 Hz, 1H), 4.16 (s, 2H), 4.08 (d, J = 14.8 Hz, 1H), 3.93 (d, J = 14.8 Hz, 1H), 2.62-2.57 (m, 2H), 2.53-20.45 (m, 3H), 2.38 (m, 1H), 2.33 (br s, 1H), 2.17-2.08 (m, 4H), 1.91-1.88 (m, 2H), 1.41 (br d, J = 13.5 Hz, 1H); 13C-NMR (100MHz, CDCl3): δ 167.5, 143.5, 128.7, 127.4, 127.3, 78.0, 75.9, 69.1, 68.7, 65.9, 59.2, 58.7, 53.3, 52.2, 47.8, 46.0, 40.8, 35.2, 32.9, 28.9; IR (ニート, cm-1): 3295, 2938, 1658, 1528, 1107; MS (EI): m/z 404 (M+-H), 202 (100%); HRMS (EI): 計算値C22H24Cl2NO2(M+-H) 404.1184, 実測値404.1201.
　［実施例１０］ [α] D 20 = +96.2 (c = 0.283, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.33-7.25 (m, 5H), 6.75 (br d, J = 10.1 Hz, 1H ), 5.60 (dd, J = 10.1, 8.7 Hz, 1H), 4.16 (s, 2H), 4.08 (d, J = 14.8 Hz, 1H), 3.93 (d, J = 14.8 Hz, 1H), 2.62-2.57 (m, 2H), 2.53-20.45 (m, 3H), 2.38 (m, 1H), 2.33 (br s, 1H), 2.17-2.08 (m, 4H), 1.91-1.88 (m, 2H), 1.41 ( br d, J = 13.5 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ 167.5, 143.5, 128.7, 127.4, 127.3, 78.0, 75.9, 69.1, 68.7, 65.9, 59.2, 58.7, 53.3, 52.2 , 47.8, 46.0, 40.8, 35.2, 32.9, 28.9; IR (Neat, cm -1 ): 3295, 2938, 1658, 1528, 1107; MS (EI): m / z 404 (M + -H), 202 ( 100%); HRMS (EI): calculated C 22 H 24 Cl 2 NO 2 (M + -H) 404.1184, found 404.1201.
[Example 10]
Figure JPOXMLDOC01-appb-C000027
 　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミン（２４．２ｍｇ，０．０７８１ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液に２，６－ルチジン（２７μＬ，０．２３ｍｍｏｌ）、トリフルオロメタンスルホン酸無水物（１５．７μＬ，０．０９４ｍｍｏｌ）を－７８℃で加えた。同温度にて１０分間攪拌後、反応溶液に飽和ＮａＨＣＯ３水溶液を加え、ジクロロメタンで抽出した。得られた有機層をＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝１５：１～８：１）に付し、Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－１，１，１－トリフルオロメタンスルホンアミド（ＴＰ－０６４、２７．８ｍｇ，８１％）を白色固体として得た。
Figure JPOXMLDOC01-appb-C000027
 (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine (24.2 mg, 0.0781 mmol) in a dichloromethane (1 mL) solution with 2, 6-Lutidine (27 μL, 0.23 mmol) and trifluoromethanesulfonic anhydride (15.7 μL, 0.094 mmol) were added at −78 ° C. After stirring at the same temperature for 10 minutes, a saturated aqueous NaHCO 3 solution was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 15: 1-8: 1) to give N-((R)-((1S, 2R, 3S, 5S, 7R ) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -1,1,1-trifluoromethanesulfonamide (TP-064, 27.8 mg, 81%) was obtained as a white solid.
　[α]D 29 = +54.1 (c = 0.494, CHCl3); 1H-NMR (400 MHz, CDCl3): δ 7.37-7.25 (m, 5H), 5.42 (br s, 1H), 5.01 (br s, 1H), 2.61 (br s, 1H), 2.48-2.44 (m, 4H), 2.36 (br s, 1H), 2.23-2.03 (m, 5H), 1.90 (br d, J = 12.7 Hz, 1H), 1.50 (br d, J = 13.7 Hz, 1H); 13C-NMR (100MHz, CDCl3): δ 141.2, 128.8, 128.4, 127.0, 120.0 (q, J = 321.7 Hz), 68.6, 65.3, 60.4, 59.3, 55.0, 47.7, 45.8, 40.5, 34.9, 32.7, 28.5; IR (ニート, cm-1): 3263, 2950, 1457, 1364, 1196; MS (EI): m/z 441 (M+), 238 (100%); HRMS (EI): 計算値C18H20Cl2F3NO2S (M+) 441.0544, 実測値441.0521。 [α] D 29 = +54.1 (c = 0.494, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.37-7.25 (m, 5H), 5.42 (br s, 1H), 5.01 (br s, 1H), 2.61 (br s, 1H), 2.48-2.44 (m, 4H), 2.36 (br s, 1H), 2.23-2.03 (m, 5H), 1.90 (br d, J = 12.7 Hz, 1H ), 1.50 (br d, J = 13.7 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ 141.2, 128.8, 128.4, 127.0, 120.0 (q, J = 321.7 Hz), 68.6, 65.3, 60.4 , 59.3, 55.0, 47.7, 45.8, 40.5, 34.9, 32.7, 28.5; IR (Neat, cm -1 ): 3263, 2950, 1457, 1364, 1196; MS (EI): m / z 441 (M + ), 238 (100%); HRMS (EI): Calculated C 18 H 20 Cl 2 F 3 NO 2 S (M + ) 441.0544, found 441.0521.
　［実施例１１］ [Example 11]
Figure JPOXMLDOC01-appb-C000028
 　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミン（２６．１ｍｇ，０．０８４１ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液にピリジン（１４μＬ，０．１９ｍｍｏｌ）、２－ニトロベンゼンスルホニルクロリド（２２ｍｇ，０．１０ｍｍｏｌ）を氷冷下加えた。同温度にて３時間攪拌後、反応溶液に蒸留水を加え、ジクロロメタンで抽出した。得られた有機層をＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝８：１～４：１）に付し、Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－２－ニトロベンゼンスルホンアミド（ＴＰ－０６５、１７．１ｍｇ，４１％）を白色固体として得た。
Figure JPOXMLDOC01-appb-C000028
 (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine (26.1 mg, 0.0841 mmol) in dichloromethane (1 mL) in pyridine (1 mL) 14 μL, 0.19 mmol) and 2-nitrobenzenesulfonyl chloride (22 mg, 0.10 mmol) were added under ice cooling. After stirring at the same temperature for 3 hours, distilled water was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 8: 1-4: 1) to give N-((R)-((1S, 2R, 3S, 5S, 7R ) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -2-nitrobenzenesulfonamide (TP-065, 17.1 mg, 41%) was obtained as a white solid.
　[α]D 29 = +202.4 (c = 0.290, CHCl3); 1H-NMR (400 MHz, CDCl3): δ 7.80 (d, J = 7.8 Hz, 1H)), 7.61 (d, J = 7.3 Hz, 1H), 7.51-7.44 (m, 2H), 7.00-6.93 (m, 5H), 5.99 (br d, J =10.4 Hz, 1H), 4.97 (dd, J = 10.4, 7.8 Hz, 1H), 2.78 (br s, 1H), 2.49 (br d, J = 12.2 Hz, 1H), 2.46-2.41 (m, 4H), 2.22-2.10 (m, 5H), 1.91 (br d, J = 12.1 Hz, 1H), 1.55 (br d, J = 13.2 Hz, 1H); 13C-NMR (100MHz, CDCl3): δ 146.7, 140.8, 134.5, 132.9, 132.7, 131.0, 128.1, 127.4, 127.2, 125.2, 69.0, 656.8, 59.5, 54.5, 47.6, 46.0, 40.8, 34.7, 32.9, 38.7; IR (ニート, cm-1): 3223, 2940, 1537, 1168; HRMS (ESI): 計算値C23H24Cl2N2NaO4S (M++Na) 517.0732, 実測値517.0721。 [α] D 29 = +202.4 (c = 0.290, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.80 (d, J = 7.8 Hz, 1H)), 7.61 (d, J = 7.3 Hz, 1H), 7.51-7.44 (m, 2H), 7.00-6.93 (m, 5H), 5.99 (br d, J = 10.4 Hz, 1H), 4.97 (dd, J = 10.4, 7.8 Hz, 1H), 2.78 (br s, 1H), 2.49 (br d, J = 12.2 Hz, 1H), 2.46-2.41 (m, 4H), 2.22-2.10 (m, 5H), 1.91 (br d, J = 12.1 Hz, 1H ), 1.55 (br d, J = 13.2 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ 146.7, 140.8, 134.5, 132.9, 132.7, 131.0, 128.1, 127.4, 127.2, 125.2, 69.0, 656.8 , 59.5, 54.5, 47.6, 46.0, 40.8, 34.7, 32.9, 38.7; IR (Neat, cm -1 ): 3223, 2940, 1537, 1168; HRMS (ESI): Calculated value C 23 H 24 Cl 2 N 2 NaO 4 S (M ++ Na) 517.0732, found 517.0721.
　［実施例１２］ [Example 12]
Figure JPOXMLDOC01-appb-C000029
 　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミン（１１．７ｍｇ，０．０３６３ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液にピリジン（６．０μＬ，０．０７３ｍｍｏｌ）、４－ニトロベンゼンスルホニルクロリド（１０ｍｇ，０．０４４ｍｍｏｌ）を氷冷下加えた。同温度にて２時間攪拌後、反応溶液に蒸留水を加え、ジクロロメタンで抽出した。得られた有機層をＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝８：１～４：１）に付し、Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－４－ニトロベンゼンスルホンアミド（ＴＰ－０６６、１１．３ｍｇ，６３％）を白色固体として得た。
Figure JPOXMLDOC01-appb-C000029
 (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine (11.7 mg, 0.0363 mmol) in dichloromethane (1 mL) in pyridine (1 mL) 6.0 μL, 0.073 mmol) and 4-nitrobenzenesulfonyl chloride (10 mg, 0.044 mmol) were added under ice cooling. After stirring at the same temperature for 2 hours, distilled water was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 8: 1-4: 1) to give N-((R)-((1S, 2R, 3S, 5S, 7R ) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -4-nitrobenzenesulfonamide (TP-066, 11.3 mg, 63%) was obtained as a white solid.
　[α]D 29 = +21.4 (c = 0.253, CHCl3);1H-NMR (400 MHz, CDCl3): δ 7.98 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.03-6.97 (m, 3H), 6.86 (d, J = 7.3 Hz, 1H), 5.17 (m, 1H), 4.79 (dd, J = 9.8, 85.3 Hz, 1H), 2.70 (br s, 1H), 2.52 (br d, J = 12.7 HZ, 1H), 2.45-2.39 (m, 4H), 2.20-2.09 (m, 5H), 1.90 (br d, J = 12.2 Hz, 1H), 1.52 (br d, J = 13.2 Hz, 1H); 13C-NMR (100MHz, CDCl3): δ 149.5, 145.8, 141.5, 128.4, 128.2, 127.6, 126.9, 123.7, 68.9, 65.5, 59.2, 58.8, 54.7, 47.7, 45.9, 40.7, 34.8, 32.8, 28.6; IR (ニート, cm-1): 3279, 2939, 1159; HRMS (ESI): 計算値C23H24Cl2N2NaO4S (M++Na) 517.0732, 実測値517.0728。 [α] D 29 = +21.4 (c = 0.253, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.98 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.5 Hz , 2H), 7.03-6.97 (m, 3H), 6.86 (d, J = 7.3 Hz, 1H), 5.17 (m, 1H), 4.79 (dd, J = 9.8, 85.3 Hz, 1H), 2.70 (br s , 1H), 2.52 (br d, J = 12.7 HZ, 1H), 2.45-2.39 (m, 4H), 2.20-2.09 (m, 5H), 1.90 (br d, J = 12.2 Hz, 1H), 1.52 ( br d, J = 13.2 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ 149.5, 145.8, 141.5, 128.4, 128.2, 127.6, 126.9, 123.7, 68.9, 65.5, 59.2, 58.8, 54.7, 47.7 , 45.9, 40.7, 34.8, 32.8, 28.6; IR (Neat, cm -1 ): 3279, 2939, 1159; HRMS (ESI): Calculated C 23 H 24 Cl 2 N 2 NaO 4 S (M + + Na) 517.0732, found 517.0728.
　［実施例１３］ [Example 13]
Figure JPOXMLDOC01-appb-C000030
 　２－アダマンチル（フェニル）メタノール（N. Arunkumar et al. J. Org. Chem. 2002, 67, 8339. 記載の方法で調製、９４４ｍｇ，３．９０ｍｍｏｌ），ジフェニルリン酸アジド（ＤＰＰＡ、９２１μＬ，４．２９ｍｍｏｌ），トリフェニルホスフィン（１．１２ｇ，４．２９ｍｍｏｌ）のＴＨＦ（２０ｍＬ）溶液にジイソプロピルアゾジカルボキシレート（ＤＩＡＤ、８４１μＬ，４．２９ｍｍｏｌ）を氷冷下加えた。室温で２時間撹拌後，減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝１５：１）に付し粗アジドを得た。得られた粗アジドのＴＨＦ（２０ｍＬ）溶液にＬｉＡｌＨ４（２２２ｍｇ，５．８４ｍｍｏｌ）を氷冷下加えた。室温までゆっくりと昇温し終夜撹拌後，氷冷下反応溶液にアンモニア水を加えた。セライト（登録商標）で濾過を行い，減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（クロロホルム～クロロホルム－メタノール＝１０：１）に付し粗アミンを得た。得られた粗アミンのジクロロメタン（１５ｍＬ）溶液に，トリエチルアミン（１．０ｍＬ，７．８ｍｍｏｌ），無水トリフルオロ酢酸（ＴＦＡＡ、０．８３ｍＬ，５．８ｍｍｏｌ）を氷冷下加えた。同温度で１０分間撹拌後，飽和ＮａＨＣＯ３水溶液を加え，ジクロロメタンにて抽出した。得られた有機層をＭｇＳＯ４で乾燥した。減圧下溶媒を留去し，残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル＝１５：１）に付し、Ｎ－（２－アダマンチル（フェニル）メチル）２，２，２－トリフルオロアセトアミド（３７９ｍｇ，２９％）を得た。この一部を分取ＨＰＬＣ（ＣＨＩＲＡＬＣＥＬ　ＯＤ）に付し、Ｎ－（（Ｓ）－（（１Ｓ，３Ｓ，５Ｓ，７Ｓ）－アダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド（ＴＰ－０６７）、Ｎ－（（Ｒ）－（（１Ｒ，３Ｒ，５Ｒ，７Ｒ）－アダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド（ＴＰ－０６８）を得た。
Figure JPOXMLDOC01-appb-C000030
 2-adamantyl (phenyl) methanol (prepared by the method described in N. Arunkumar et al. J. Org. Chem. 2002, 67, 8339., 944 mg, 3.90 mmol), diphenyl phosphate azide (DPPA, 921 μL, 4. 29 mmol), triphenylphosphine (1.12 g, 4.29 mmol) in THF (20 mL) was added diisopropyl azodicarboxylate (DIAD, 841 μL, 4.29 mmol) under ice cooling. After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 15: 1) to obtain a crude azide. LiAlH 4 (222 mg, 5.84 mmol) was added to a solution of the obtained crude azide in THF (20 mL) under ice cooling. After slowly warming to room temperature and stirring overnight, aqueous ammonia was added to the reaction solution under ice cooling. The mixture was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform to chloroform-methanol = 10: 1) to obtain a crude amine. To a solution of the obtained crude amine in dichloromethane (15 mL), triethylamine (1.0 mL, 7.8 mmol) and trifluoroacetic anhydride (TFAA, 0.83 mL, 5.8 mmol) were added under ice cooling. After stirring at the same temperature for 10 minutes, a saturated aqueous NaHCO 3 solution was added, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 15: 1) to give N- (2-adamantyl (phenyl) methyl) 2,2,2-trifluoroacetamide (379 mg). 29%). A part of this was subjected to preparative HPLC (CHIRALCEL OD), and N-((S)-((1S, 3S, 5S, 7S) -adamantan-2-yl) (phenyl) methyl) -2,2,2 -Trifluoroacetamide (TP-067), N-((R)-((1R, 3R, 5R, 7R) -adamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroaceta Mid (TP-068) was obtained.
　1H-NMR (400 MHz, CDCl3): δ 7.38-7.29 (m, 5H), 6.36 (br d, J = 8.9 Hz, 1H), 5.30 (dd, J = 11.4 Hz, 8.9 Hz, 1H), 2.12-1.90 (m, 7H), 1.77-1.72 (m, 4H), 1.69-1.58 (m, 2H), 1.44 (br d, J = 11.1 Hz, 1H), 1.34 (br s, 1H); 13C-NMR (100MHz, CDCl3): δ156.4 (q, J = 36.6 Hz), 139.7, 129.0, 128.1, 127.0, 115.9 (q, J = 288.4 Hz), 55.0, 49.0, 38.8, 38.7, 37.9, 31.6, 31.4, 28.9, 28.7, 27.7, 27.4; IR (ニート, cm-1): 3295, 2911, 1695, 1557, 1186; MS (EI): m/z 337 (M+), 135 (100%); HRMS (EI): 計算値C19H22F3NO (M+) 337.1653, 実測値337.1662。 1 H-NMR (400 MHz, CDCl 3 ): δ 7.38-7.29 (m, 5H), 6.36 (br d, J = 8.9 Hz, 1H), 5.30 (dd, J = 11.4 Hz, 8.9 Hz, 1H), 2.12-1.90 (m, 7H), 1.77-1.72 (m, 4H), 1.69-1.58 (m, 2H), 1.44 (br d, J = 11.1 Hz, 1H), 1.34 (br s, 1H); 13 C -NMR (100MHz, CDCl 3 ): δ156.4 (q, J = 36.6 Hz), 139.7, 129.0, 128.1, 127.0, 115.9 (q, J = 288.4 Hz), 55.0, 49.0, 38.8, 38.7, 37.9, 31.6 , 31.4, 28.9, 28.7, 27.7, 27.4; IR (neat, cm -1 ): 3295, 2911, 1695, 1557, 1186; MS (EI): m / z 337 (M + ), 135 (100%); HRMS (EI): calcd C 19 H 22 F 3 NO (M + ) 337.1653, found 337.1662.
　［実施例１４］ [Example 14]
Figure JPOXMLDOC01-appb-C000031
 　（１Ｓ，２Ｒ，５Ｒ）－２－（（Ｒ）－アジド（フェニル）メチル）－７－メチレンビシクロ［３．３．１．］ノナン－３－オン（８８．１ｍｇ，０．３１５ｍｍｏｌ）のジクロロメタン（３ｍＬ）溶液に、チオフェノール（９７μＬ，０．９５ｍｍｏｌ），トリフルオロメタンスルホン酸スカンジウム（８ｍｇ，０．０１６ｍｍｏｌ）を氷冷下加えた。室温にて２４時間攪拌後、飽和ＮａＨＣＯ３水溶液を氷冷下加えジクロロメタンにて抽出した。得られた有機層をＭｇＳＯ４で乾燥し、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝１：１０～１：４）に付し、（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－２－（（Ｒ）－アジド（フェニル）メチル）－５－（フェニルチオ）アダマンタン－１－オール（５０．７ｍｇ，４１％）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000031
 (1S, 2R, 5R) -2-((R) -Azido (phenyl) methyl) -7-methylenebicyclo [3.3.1. ] To a solution of nonan-3-one (88.1 mg, 0.315 mmol) in dichloromethane (3 mL), thiophenol (97 μL, 0.95 mmol) and scandium trifluoromethanesulfonate (8 mg, 0.016 mmol) were added under ice cooling. It was. After stirring at room temperature for 24 hours, a saturated aqueous NaHCO 3 solution was added under ice cooling, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 1: 10-1: 4) to give (1S, 2R, 3S, 5S, 7S) -2-((R) -azido (phenyl) methyl)- 5- (Phenylthio) adamantan-1-ol (50.7 mg, 41%) was obtained as a colorless oil.
　得られたアジド化合物（３１．５ｍｇ，０．０８５ｍｍｏｌ）のＴＨＦ（１ｍＬ）溶液にＬｉＡｌＨ４（５ｍｇ，０．１３ｍｍｏｌ）を氷冷下加えた。室温で５時間攪拌後、反応溶液にアンモニア水を氷冷下加えた。セライト（商標登録）で濾過を行い、減圧下溶媒を留去した。残渣にジクロロメタン（１ｍＬ）を加え、トリエチルアミン（５６μＬ，０．４ｍｍｏｌ）、無水トリフルオロ酢酸（ＴＦＡＡ、３４μＬ，０．２４ｍｍｏｌ）を氷冷下加えた。同温度で４０分間攪拌後、飽和ＮａＨＣＯ３水溶液を氷冷下加え、ジクロロメタンで抽出した。得られた有機層をＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル＝１：１０）に付し、ＴＰ－０６９（２３．６ｍｇ，５２％）を白色個体として得た。 LiAlH 4 (5 mg, 0.13 mmol) was added to a THF (1 mL) solution of the obtained azide compound (31.5 mg, 0.085 mmol) under ice cooling. After stirring at room temperature for 5 hours, aqueous ammonia was added to the reaction solution under ice cooling. The mixture was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure. Dichloromethane (1 mL) was added to the residue, and triethylamine (56 μL, 0.4 mmol) and trifluoroacetic anhydride (TFAA, 34 μL, 0.24 mmol) were added under ice cooling. After stirring at the same temperature for 40 minutes, a saturated aqueous NaHCO 3 solution was added under ice-cooling, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 1: 10) to obtain TP-069 (23.6 mg, 52%) as a white solid.
　[α]D 23 = +50.1 (c = 0.357, CHCl3); 1H-NMR (400 MHz, CDCl3): δ 7.48-7.46 (m, 2H), 7.45-7.28 (m, 6H), 7.23-7.22 (m, 2H), 6.34 (br d, J = 9.5 Hz, 1H), 5.42 (dd, J = 11.0, 9.5 Hz, 1H), 3.08 (br d, J = 11.0 Hz, 1H), 2.68 (br d, J = 11.7 Hz, 1H), 2.37-2.36 (m, 3H), 1.96-1.79 (m, 7H), 1.36 (br d, J = 12.2 Hz, 1H); 13C-NMR (100 MHz, CDCl3): δ 156.0 (q, J = 37.1 HZ), 154.9 (q, J = 42.1 Hz), 139.3, 137.7, 129.3, 129.2, 129.1, 128.7, 128.6, 127.0, 116.3 (q, J = 288.9 Hz), 115.7 (q, J = 288.1 Hz), 87.2, 53.4, 48.4, 48.1, 46.8, 43.1, 42.1, 36.0, 33.8, 31.0, 29.0; IR (ニート, cm-1): 3302, 2933, 1776, 1697, 1552, 1222, 1172, 1148; MS (EI): m/z 557 (M+), 202 (100%); HRMS (EI): 計算値C27H25F6NO3S (M+) 557.1459, 実測値557.1461.
　［実施例１５］ [α] D 23 = +50.1 (c = 0.357, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.48-7.46 (m, 2H), 7.45-7.28 (m, 6H), 7.23- 7.22 (m, 2H), 6.34 (br d, J = 9.5 Hz, 1H), 5.42 (dd, J = 11.0, 9.5 Hz, 1H), 3.08 (br d, J = 11.0 Hz, 1H), 2.68 (br d, J = 11.7 Hz, 1H), 2.37-2.36 (m, 3H), 1.96-1.79 (m, 7H), 1.36 (br d, J = 12.2 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ 156.0 (q, J = 37.1 HZ), 154.9 (q, J = 42.1 Hz), 139.3, 137.7, 129.3, 129.2, 129.1, 128.7, 128.6, 127.0, 116.3 (q, J = 288.9 Hz), 115.7 (q, J = 288.1 Hz), 87.2, 53.4, 48.4, 48.1, 46.8, 43.1, 42.1, 36.0, 33.8, 31.0, 29.0; IR (neat, cm -1 ): 3302, 2933, 1776, 1697, 1552 , 1222, 1172, 1148; MS (EI): m / z 557 (M + ), 202 (100%); HRMS (EI): calculated C 27 H 25 F 6 NO 3 S (M + ) 557.1459, measured Value 557.1461.
[Example 15]
Figure JPOXMLDOC01-appb-C000032
 　（１Ｒ，２Ｓ，５Ｓ）－２－（（Ｒ）－ヒドロキシ（フェニル）メチル）－７－メチレンビシクロ［３．３．１］ノナン－３－オン（J. Am.Chem.Soc. 2014, 136, 17591-17600に記載の方法により調製、７５０ｍｇ，２．９ｍｍｏｌ）、ジフェニルリン酸アジド（ＤＰＰＡ、８２０μＬ，３．８１ｍｍｏｌ）、トリフェニルホスフィン（１．２０ｇ，４．４ｍｍｏｌ）のＴＨＦ（１５ｍＬ）溶液にジイソプロピルアゾジカルボキシレート（ＤＩＡＤ、２．２ｍＬ，４．４ｍｍｏｌ）を氷冷下加えた。同温度で１時間撹拌後，減圧下溶媒を留去した。残渣にジクロロメタン（１５ｍＬ）を加え，氷冷下ＴｉＣｌ４（８２０μＬ，２．３ｍｍｏｌ）を加えた。室温にて４時間撹拌後、飽和ＮａＨＣＯ３水溶液を氷冷下加えた．セライト（登録商標）で濾過を行い、濾液をジエチルエーテルにて抽出した。得られた有機層を飽和食塩水で洗浄し、ＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル＝１０：１）に付し、白色固体として（１Ｒ，２Ｓ，３Ｒ，５Ｒ，７Ｒ）－２－（（Ｓ）－アジド（フェニル）メチル）－５－クロロアダマンタン－１－オール（７５６ｍｇ，９２％）を得た。
Figure JPOXMLDOC01-appb-C000032
 (1R, 2S, 5S) -2-((R) -Hydroxy (phenyl) methyl) -7-methylenebicyclo [3.3.1] nonan-3-one (J. Am. Chem. Soc. 2014, 136 , 17591-17600, 750 mg, 2.9 mmol), diphenyl phosphate azide (DPPA, 820 μL, 3.81 mmol), triphenylphosphine (1.20 g, 4.4 mmol) in THF (15 mL) Diisopropyl azodicarboxylate (DIAD, 2.2 mL, 4.4 mmol) was added to the solution under ice cooling. After stirring at the same temperature for 1 hour, the solvent was distilled off under reduced pressure. Dichloromethane (15 mL) was added to the residue, and TiCl 4 (820 μL, 2.3 mmol) was added under ice cooling. After stirring at room temperature for 4 hours, a saturated aqueous NaHCO 3 solution was added under ice cooling. Filtration through Celite (registered trademark) and the filtrate was extracted with diethyl ether. The obtained organic layer was washed with saturated brine and dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 10: 1) to give (1R, 2S, 3R, 5R, 7R) -2-((S)- Azido (phenyl) methyl) -5-chloroadamantan-1-ol (756 mg, 92%) was obtained.
　得られたアジド化合物（７５０ｍｇ，２．６７ｍｍｌ）のＴＨＦ（１４ｍＬ）溶液にＬｉＡｌＨ４（３００ｍｇ，８．００ｍｍｏｌ）を氷冷下加えた。同温度で１時間撹拌後、反応溶液にアンモニア水を加えた。セライト（登録商標）で濾過を行い，減圧下溶媒を留去した。残渣にジクロロメタン（１５ｍＬ）を加えた後、トリエチルアミン（２．２ｍＬ，１６．０ｍｍｏｌ），無水トリフルオロ酢酸（ＴＦＡＡ、１．２ｍＬ，８．０ｍｍｏｌ）を氷冷下加えた。室温にて終夜撹拌後，飽和ＮａＨＣＯ３水溶液を加え，ジクロロメタンにて抽出した。得られた有機層をＭｇＳＯ４で乾燥した。減圧下溶媒を留去し，残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル＝１５：１）に付し、ＴＰ－０１３を（８７１ｍｇ，５６％）を白色固体として得た。 LiAlH 4 (300 mg, 8.00 mmol) was added to a solution of the obtained azide compound (750 mg, 2.67 mmol) in THF (14 mL) under ice cooling. After stirring at the same temperature for 1 hour, aqueous ammonia was added to the reaction solution. The mixture was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure. After adding dichloromethane (15 mL) to the residue, triethylamine (2.2 mL, 16.0 mmol) and trifluoroacetic anhydride (TFAA, 1.2 mL, 8.0 mmol) were added under ice cooling. After stirring at room temperature overnight, saturated aqueous NaHCO 3 solution was added, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 15: 1) to obtain TP-013 (871 mg, 56%) as a white solid.
　mp 83-85℃ (無色針状結晶, n-ヘキサン-Et2O); [α]D 31 = -84.1 (c = 1.08, CHCl3); 1H-NMR (400 MHz, CDCl3): δ 7.35-7.27 (m, 5H), 6.63 (d, J = 11.1 Hz, 1H), 5.44 (t, J = 10.4 Hz, 1H), 3.26 (d, J = 11.1 Hz, 1H), 2.99 (d, J = 11.1 Hz, 1H), 2.45-2.41 (m, 3H), 2.26-2.13 (m, 5H), 1.96 (br d, J = 12.4 Hz, 2H), 1.47 (br d, J = 14.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3): δ 156.2 (q, J = 37.4 Hz), 154.9 (q, J = 42.3 Hz), 139.1, 129.2, 128.7, 127.1, 115.8 (q, J = 288.1 Hz), 113.3 (q, J = 287.3 Hz), 86.6, 65.1, 53.4, 50.2, 48.0, 46.9, 46.1, 35.6, 34.6, 31.7, 28.5; IR (ニート, cm-1): 3296, 2945, 1775, 1698; MS (EI): m/z 483 (M+), 202 (100%); HRMS (EI): 計算値 C21H20ClF6NO3(M+) 483.1036, 実測値483.1046。 mp 83-85 ℃ (colorless needle crystal, n-hexane-Et 2 O); [α] D 31 = -84.1 (c = 1.08, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.35-7.27 (m, 5H), 6.63 (d, J = 11.1 Hz, 1H), 5.44 (t, J = 10.4 Hz, 1H), 3.26 (d, J = 11.1 Hz, 1H), 2.99 (d, J = 11.1 Hz, 1H), 2.45-2.41 (m, 3H), 2.26-2.13 (m, 5H), 1.96 (br d, J = 12.4 Hz, 2H), 1.47 (br d, J = 14.0 Hz, 1H) ; 13 C-NMR (100 MHz, CDCl 3 ): δ 156.2 (q, J = 37.4 Hz), 154.9 (q, J = 42.3 Hz), 139.1, 129.2, 128.7, 127.1, 115.8 (q, J = 288.1 Hz ), 113.3 (q, J = 287.3 Hz), 86.6, 65.1, 53.4, 50.2, 48.0, 46.9, 46.1, 35.6, 34.6, 31.7, 28.5; IR (neat, cm -1 ): 3296, 2945, 1775, 1698 MS (EI): m / z 483 (M + ), 202 (100%); HRMS (EI): calculated C 21 H 20 ClF 6 NO 3 (M + ) 483.1036, found 483.1046.
　［実施例１６］ [Example 16]
Figure JPOXMLDOC01-appb-C000033
 　ビス（（Ｓ）－１－フェニルエチル）アミン（１０．０ｍＬ，４４ｍｍｏｌ）、塩化リチウム（３．４ｇ，８０ｍｍｏｌ）のＴＨＦ（１００ｍＬ）溶液にｎ－ブチルリチウムのヘキサン溶液（１．５６Ｍ，２８．２ｍＬ，４４ｍｍｏｌ）を氷冷下滴下した。同温度で３０分撹拌後、反応溶液を－７８℃まで冷却した。反応混合物に、７－メチレンビシクロ［３．３．１］ノナン－３－オン（６．００ｇ，４０ｍｍｏｌ）のＴＨＦ（６０ｍＬ）溶液をカニュレーションにより加えた。１時間撹拌後、ベンズアルデヒド（６．１ｍＬ，６０ｍｍｏｌ）のＴＨＦ（４０ｍＬ）溶液をカニュレーションにより加えた。２時間撹拌後、反応溶液に酢酸，飽和塩化アンモニウム水溶液を順次加え、ジエチルエーテルにて抽出した。得られた有機層を飽和食塩水で洗浄し、ＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝４：１）に付し、（１Ｓ，２Ｒ，５Ｒ）－２－（（Ｓ）－ヒドロキシ（フェニル）メチル）－７－メチレンビシクロ［３．３．１］ノナン－３－オン（８．３ｇ，８１％）を白色固体として得た。これをジエチルエーテルから再結晶を行うことで無色針状結晶を得た。
Figure JPOXMLDOC01-appb-C000033
 Bis ((S) -1-phenylethyl) amine (10.0 mL, 44 mmol), lithium chloride (3.4 g, 80 mmol) in THF (100 mL) solution in n-butyllithium in hexane (1.56 M, 28. 2 mL, 44 mmol) was added dropwise under ice cooling. After stirring at the same temperature for 30 minutes, the reaction solution was cooled to −78 ° C. To the reaction mixture, a solution of 7-methylenebicyclo [3.3.1] nonan-3-one (6.00 g, 40 mmol) in THF (60 mL) was added by cannulation. After stirring for 1 hour, a solution of benzaldehyde (6.1 mL, 60 mmol) in THF (40 mL) was added by cannulation. After stirring for 2 hours, acetic acid and a saturated aqueous solution of ammonium chloride were sequentially added to the reaction solution, followed by extraction with diethyl ether. The obtained organic layer was washed with saturated brine and dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 4: 1) to give (1S, 2R, 5R) -2-((S) -hydroxy (phenyl) methyl)- 7-methylenebicyclo [3.3.1] nonan-3-one (8.3 g, 81%) was obtained as a white solid. This was recrystallized from diethyl ether to obtain colorless needle crystals.
　mp 122 ℃; [α]D 21= -17.9 (c = 0.32, CHCl3); 1H-NMR (400 MHz, CDCl3): δ7.38-7.25 (m, 5H), 4.79 (d, J = 1.8 Hz, 1H), 4.76 (d, J = 1.8 Hz, 1H), 4.71 (d, J = 6.8 Hz, 1H), 2.90 (s, 1H), 2.64 (dd, J = 15.7, 6.8 Hz, 1H), 2.48-2.18 (m, 6H), 2.01 (br d, J = 14.3 Hz, 1H); 13C-NMR (100 MHz, CDCl3): δ 211.0, 141.6, 128.8, 127.6, 114.8, 74.6, 62.7, 45.7, 42.2, 41.3, 32.4, 31.9, 28.4; IR (ニート, cm-1): 3390, 1711; MS (EI): m/z 256 (M+), 95 (100%); HRMS (EI): 計算値 C17H20O2 (M+) 256.1463, 実測値 256.1450。 mp 122 ° C; [α] D 21 = -17.9 (c = 0.32, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ7.38-7.25 (m, 5H), 4.79 (d, J = 1.8 Hz, 1H), 4.76 (d, J = 1.8 Hz, 1H), 4.71 (d, J = 6.8 Hz, 1H), 2.90 (s, 1H), 2.64 (dd, J = 15.7, 6.8 Hz, 1H) , 2.48-2.18 (m, 6H), 2.01 (br d, J = 14.3 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ 211.0, 141.6, 128.8, 127.6, 114.8, 74.6, 62.7, 45.7, 42.2, 41.3, 32.4, 31.9, 28.4; IR (Neat, cm -1 ): 3390, 1711; MS (EI): m / z 256 (M + ), 95 (100%); HRMS (EI): Calculated C 17 H 20 O 2 (M +) 256.1463, found 256.1450.
　（１Ｓ，２Ｒ，５Ｒ）－２－（（Ｓ）－ヒドロキシ（フェニル）メチル）－７－メチレンビシクロ［３．３．１］ノナン－３－オン（２．００ｇ，７．５ｍｍｏｌ）、ＤＰＰＡ（２．３ｍＬ，１１ｍｍｏｌ）、トリフェニルホスフィン（３．０ｇ，１１ｍｍｏｌ）のＴＨＦ（３８ｍＬ）溶液にＤＩＡＤ（２．２ｍＬ，１１ｍｍｏｌ）を氷冷下加えた。同温度で１時間撹拌後、減圧下溶媒を留去した。残渣にジクロロメタン（３８ｍＬ）を加え、氷冷下ＴｉＣｌ４（０．８ｍＬ，７．５ｍｍｏｌ）を加えた。室温にて４時間撹拌後、飽和ＮａＨＣＯ３水溶液を氷冷下加えた。セライト（登録商標）で濾過を行い、濾液をジエチルエーテルにて抽出した。得られた有機層を飽和食塩水で洗浄し、ＭｇＳＯ４で乾燥した。減圧下溶媒を留去し，残渣にテトラヒドロピラン（ＴＨＰ、４０ｍＬ）を加えた。これにＬｉＡｌＨ４（４３０ｍｇ，１１ｍｍｏｌ）を氷冷下加えた。同温度で３０分撹拌後、反応溶液にアンモニア水を加えた。セライト（登録商標）濾過を行い，減圧下溶媒を留去した。残渣にジクロロメタン（４０ｍＬ）を加えた後，トリエチルアミン（６．３ｍＬ，４５ｍｍｏｌ）、ＴＦＡＡ（３．２ｍＬ，２３ｍｍｏｌ）を氷冷下加えた。室温にて終夜撹拌後、飽和ＮａＨＣＯ３水溶液を加え、ジクロロメタンにて抽出した。得られた有機層をＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル＝１５：１）に付し，粗生成物を白色固体として得た。これをジエチルエーテル－ヘキサンから再結晶し、ＴＰ－０１４（１．２７ｇ，３５％）を白色固体として得た。 (1S, 2R, 5R) -2-((S) -Hydroxy (phenyl) methyl) -7-methylenebicyclo [3.3.1] nonan-3-one (2.00 g, 7.5 mmol), DPPA ( DIAD (2.2 mL, 11 mmol) was added to a THF (38 mL) solution of 2.3 mL, 11 mmol) and triphenylphosphine (3.0 g, 11 mmol) under ice cooling. After stirring at the same temperature for 1 hour, the solvent was distilled off under reduced pressure. Dichloromethane (38 mL) was added to the residue, and TiCl 4 (0.8 mL, 7.5 mmol) was added under ice cooling. After stirring for 4 hours at room temperature, saturated aqueous NaHCO 3 was added under ice-cooling. Filtration through Celite (registered trademark) and the filtrate was extracted with diethyl ether. The obtained organic layer was washed with saturated brine and dried over MgSO 4 . The solvent was distilled off under reduced pressure, and tetrahydropyran (THP, 40 mL) was added to the residue. To this, LiAlH 4 (430 mg, 11 mmol) was added under ice cooling. After stirring for 30 minutes at the same temperature, aqueous ammonia was added to the reaction solution. Celite (trademark) filtration was performed and the solvent was distilled off under reduced pressure. Dichloromethane (40 mL) was added to the residue, and then triethylamine (6.3 mL, 45 mmol) and TFAA (3.2 mL, 23 mmol) were added under ice cooling. After stirring at room temperature overnight, saturated aqueous NaHCO 3 solution was added, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 15: 1) to obtain a crude product as a white solid. This was recrystallized from diethyl ether-hexane to obtain TP-014 (1.27 g, 35%) as a white solid.
　mp 89 ℃; [α]D 21 = +89.1 (c = 0.31, CHCl3); 1H-NMR (400 MHz, CDCl3): δ 7.35-7.27 (m, 5H), 6.63 (d, J = 11.1 Hz, 1H), 5.44 (t, J = 10.4 Hz, 1H), 3.26 (d, J = 11.1 Hz, 1H), 2.99 (d, J = 11.1 Hz, 1H), 2.45-2.41 (m, 3H), 2.26-2.13 (m, 5H), 1.96 (br d, J = 12.4 Hz, 2H), 1.47 (br d, J = 14.0 Hz, 1H); 13C-NMR (100 MHz, CDCl3): δ 156.2 (q, J = 37.4 Hz), 154.9 (q, J = 42.3 Hz), 139.1, 129.2, 128.7, 127.1, 115.8 (q, J = 288.1 Hz), 113.3 (q, J = 287.3 Hz), 86.6, 65.1, 53.4, 50.2, 48.0, 46.9, 46.1, 35.6, 34.6, 31.7, 28.5; IR (ニート, cm-1): 3296, 2945, 1775, 1698; MS (EI): m/z 483 (M+), 202 (100%); HRMS (EI): 計算値 for C21H20ClF6NO3(M+) 483.1036, 実測値 483.1046; 元素分析: 計算値 C21H20ClF6NO3: C, 52.13; H, 4.17; N, 2.89. 実測値 C, 52.27; H, 4.18; N, 2.88。 mp 89 ° C; [α] D 21 = +89.1 (c = 0.31, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.35-7.27 (m, 5H), 6.63 (d, J = 11.1 Hz, 1H), 5.44 (t, J = 10.4 Hz, 1H), 3.26 (d, J = 11.1 Hz, 1H), 2.99 (d, J = 11.1 Hz, 1H), 2.45-2.41 (m, 3H), 2.26-2.13 (m, 5H), 1.96 (br d, J = 12.4 Hz, 2H), 1.47 (br d, J = 14.0 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ 156.2 ( q, J = 37.4 Hz), 154.9 (q, J = 42.3 Hz), 139.1, 129.2, 128.7, 127.1, 115.8 (q, J = 288.1 Hz), 113.3 (q, J = 287.3 Hz), 86.6, 65.1, 53.4, 50.2, 48.0, 46.9, 46.1, 35.6, 34.6, 31.7, 28.5; IR (Neat, cm -1 ): 3296, 2945, 1775, 1698; MS (EI): m / z 483 (M + ), 202 (100%); HRMS (EI): Calculated for C 21 H 20 ClF 6 NO 3 (M + ) 483.1036, Found 483.1046; Elemental Analysis: Calculated C 21 H 20 ClF 6 NO 3 : C, 52.13; H 4.17; N, 2.89. Found C, 52.27; H, 4.18; N, 2.88.
　［実施例１７］ [Example 17]
Figure JPOXMLDOC01-appb-C000034
 　ＴＰ－０１４（８４．７ｍｇ，０．１７５ｍｍｏｌ）のＴＨＦ（２ｍＬ）溶液に０．５Ｍ　ＮａＯＨ水溶液（１ｍＬ）を氷冷下加えた。同温度で１５分間攪拌後、飽和ＮＨ４Ｃｌ水溶液を加え酢酸エチルにて抽出した。得られた有機層を飽和食塩水で洗浄し、ＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝８：１～４：１）に付し、ＴＰ－０４８（６５．５ｍｇ，９６％）を白色個体として得た。
Figure JPOXMLDOC01-appb-C000034
 To a solution of TP-014 (84.7 mg, 0.175 mmol) in THF (2 mL) was added 0.5 M NaOH aqueous solution (1 mL) under ice cooling. After stirring at the same temperature for 15 minutes, saturated aqueous NH 4 Cl solution was added, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 8: 1-4: 1) to obtain TP-048 (65.5 mg, 96%) as a white solid.
　[α]D 26 = +109.2 (c = 0.772, CHCl3); 1H-NMR (400 MHz, CDCl3): δ 7.41-7.32 (m, 5H), 6.98 (br, 1H), 5.34 (t, J = 9.7 Hz, 1H), 2.36-2.29 (m, 3H), 2.19-2.00 (m, 7H), 1.77 (br d, J = 11.6 Hz, 1H), 1.41-1.33 (m, 2H); 13C-NMR (100 MHz, CDCl3): δ 156.2 (q, J = 37.1), 140.5, 129.4, 128.6, 127.4, 115.8 (q, J = 288.1 Hz), 72.3, 66.1, 56.7, 54.2, 52.4, 47.7, 46.3, 38.6, 34.4, 31.8, 28.8; IR (ニート, cm-1): 3553, 3297, 2940, 1698, 1552, 1208, 1183, 1165; MS (EI): m/z 387 (M+), 202 (100%); HRMS (EI):計算値C19H21ClF3NO2(M+) 387.1213, 実測値387.1196。 [α] D 26 = +109.2 (c = 0.772, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.41-7.32 (m, 5H), 6.98 (br, 1H), 5.34 (t, J = 9.7 Hz, 1H), 2.36-2.29 (m, 3H), 2.19-2.00 (m, 7H), 1.77 (br d, J = 11.6 Hz, 1H), 1.41-1.33 (m, 2H); 13 C -NMR (100 MHz, CDCl 3 ): δ 156.2 (q, J = 37.1), 140.5, 129.4, 128.6, 127.4, 115.8 (q, J = 288.1 Hz), 72.3, 66.1, 56.7, 54.2, 52.4, 47.7, 46.3, 38.6, 34.4, 31.8, 28.8; IR (Neat, cm -1 ): 3553, 3297, 2940, 1698, 1552, 1208, 1183, 1165; MS (EI): m / z 387 (M + ), 202 (100%); HRMS (EI): calculated C 19 H 21 ClF 3 NO 2 (M + ) 387.1213, found 387.1196.
　［実施例１８］ [Example 18]
Figure JPOXMLDOC01-appb-C000035
 　ＴＰ－０１４（３０．０ｍｇ，０．０６２ｍｍｏｌ）のトルエン（２ｍＬ）溶液にトリス（トリメチルシリル）シラン（２９μＬ, ０．０９５ｍｍｏｌ）、アゾビスイソブチロニトリル（ＡＩＢＮ、２．０ｍｇ，０．０１２ｍｍｏｌ）を室温にて加えた。終夜加熱還流後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝１５：１）に付し、ＴＰ－０４９（２３．０ｍｇ，８３％）を白色個体として得た。
Figure JPOXMLDOC01-appb-C000035
 Tris (trimethylsilyl) silane (29 μL, 0.095 mmol) and azobisisobutyronitrile (AIBN, 2.0 mg, 0.012 mmol) were added to a solution of TP-014 (30.0 mg, 0.062 mmol) in toluene (2 mL). Added at room temperature. After heating and refluxing overnight, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 15: 1) to obtain TP-049 (23.0 mg, 83%) as a white solid.
　[α]D 29 = +106.4 (c = 0.385, CHCl3); 1H-NMR (400 MHz, CDCl3): δ 7.33-7.27 (m, 5H), 6.31 (br d, J = 10.1 Hz, 1H), 5.50 (dd, J = 10.9, 10.1 Hz, 1H), 3.20 (br d, J = 10.9 Hz, 1H), 2.60 (br d, J = 11.6 Hz, 1H), 2.45 (br d, J = 12.1 Hz, 1H), 2.28-2.27 (m, 3H), 2.04-1.80 (m, 6H), 1.72 (br s, 2H); 13C-NMR (100 MHz, CDCl3): δ 156.0 (q, J = 37.1 Hz), 155.1 (q, J = 41.8 Hz), 139.8, 129.0, 128.4, 127.2, 115.8 (q, J = 288.1 Hz), 113.5 (q, J = 287.3 Hz), 87.5, 53.6, 49.4, 41.3, 37.2, 36.1, 33.0, 30.6, 30.4, 30.2; IR (ニート, cm-1): 3335, 2927, 1775, 1700, 1556, 1218, 1169; MS (EI): m/z 449 (M+), 202 (100%); HRMS (EI): 計算値C21H21F3NO3 (M+) 449.1426, 実測値449.1447。 [α] D 29 = +106.4 (c = 0.385, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.33-7.27 (m, 5H), 6.31 (br d, J = 10.1 Hz, 1H ), 5.50 (dd, J = 10.9, 10.1 Hz, 1H), 3.20 (br d, J = 10.9 Hz, 1H), 2.60 (br d, J = 11.6 Hz, 1H), 2.45 (br d, J = 12.1 Hz, 1H), 2.28-2.27 (m, 3H), 2.04-1.80 (m, 6H), 1.72 (br s, 2H); 13 C-NMR (100 MHz, CDCl 3 ): δ 156.0 (q, J = 37.1 Hz), 155.1 (q, J = 41.8 Hz), 139.8, 129.0, 128.4, 127.2, 115.8 (q, J = 288.1 Hz), 113.5 (q, J = 287.3 Hz), 87.5, 53.6, 49.4, 41.3, 37.2, 36.1, 33.0, 30.6, 30.4, 30.2; IR (Neat, cm -1 ): 3335, 2927, 1775, 1700, 1556, 1218, 1169; MS (EI): m / z 449 (M + ), 202 (100%); HRMS (EI): Calculated C 21 H 21 F 3 NO 3 (M + ) 449.1426, found 449.1447.
　ＴＰ－０４９（６１．５ｍｇ，０．１３７ｍｍｏｌ）のＴＨＦ（１．４ｍＬ）溶液にＮａＯＨ水溶液（０．５Ｍ、０．５ｍＬ）を氷冷下加えた。同温度で５分間攪拌後、反応溶液に２Ｍ塩酸を加え酢酸エチルにて抽出した。得られた有機層を飽和食塩水で洗浄し、ＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝４：１～２：１）に付し、ＴＰ－０５２（４９．４ｍｇ，ｑｕａｎｔ．）を白色個体として得た。 To a solution of TP-049 (61.5 mg, 0.137 mmol) in THF (1.4 mL) was added NaOH aqueous solution (0.5 M, 0.5 mL) under ice cooling. After stirring at the same temperature for 5 minutes, 2M hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 4: 1 to 2: 1) to obtain TP-052 (49.4 mg, quant.) As a white solid.
　TP-052：[α]D 14 = +130.7 (c = 0.243, CHCl3); 1H-NMR (400 MHz, CDCl3): δ 7.39-7.31 (m, 5H), 6.77 (br d, J = 8.9 Hz, 1H), 5.40 (dd, J = 9.7, 8.9 Hz, 1H), 2.32 (br d, J = 9.7 Hz, 1H), 2.31-2.07 (m, 4H), 1.85-1.79 (m, 2H), 1.72-1.57 (m, 5H), 1.52-1.44 (m, 2H), 1.29 (br, 1H); 13C-NMR (100 MHz, CDCl3): δ 156.1 (q, 37.1 Hz), 140.7, 129.4, 128.5, 127.5, 115.9 (q, 288 Hz), 77.2, 54.3, 53.0, 50.5, 48.5, 41.4, 39.6, 39.4, 33.2, 30.6, 29.6; IR (ニート, cm-1): 3566, 3291, 2919, 1698, 1183; MS (EI): m/z 353 (M+), 151 (100%); HRMS (EI): 計算値C19H22F3NO2(M+) 353.1603, 実測値353.1604。 TP-052: [α] D 14 = +130.7 (c = 0.243, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.39-7.31 (m, 5H), 6.77 (br d, J = 8.9 Hz, 1H), 5.40 (dd, J = 9.7, 8.9 Hz, 1H), 2.32 (br d, J = 9.7 Hz, 1H), 2.31-2.07 (m, 4H), 1.85-1.79 (m, 2H) , 1.72-1.57 (m, 5H), 1.52-1.44 (m, 2H), 1.29 (br, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ 156.1 (q, 37.1 Hz), 140.7, 129.4 , 128.5, 127.5, 115.9 (q, 288 Hz), 77.2, 54.3, 53.0, 50.5, 48.5, 41.4, 39.6, 39.4, 33.2, 30.6, 29.6; IR (neat, cm -1 ): 3566, 3291, 2919, 1698, 1183; MS (EI): m / z 353 (M + ), 151 (100%); HRMS (EI): calculated C 19 H 22 F 3 NO 2 (M + ) 353.1603, found 353.1604.
　［実施例１９］ [Example 19]
Figure JPOXMLDOC01-appb-C000036
 　（１Ｓ，２Ｒ，５Ｒ）－２－（Ｒ－アジド（フェニル）メチル）－７－メチレンビシクロ［３．３．１．］ノナン‐３－オン（５７．４ｍｇ，０．２０４ｍｍｏｌ）のジクロロメタン（２ｍＬ）溶液に、氷冷下２－メトキシエタノール（７８μＬ，１．０ｍｍｏｌ）、トリフルオロメタンスルホン酸スカンジウム（５．０ｍｇ，０．０１ｍｍｏｌ）を順次加えた。室温にて２日間攪拌後、飽和ＮａＨＣＯ３水溶液を氷冷下加えジクロロメタンにて抽出した。得られた有機層をＭｇＳＯ４で乾燥し減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝１：２～１：１）に付し、（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－２－（（Ｒ）－アジド（フェニル）メチル）－５－（２－メトキシエトキシ）アダマンタン‐１－オール（４１．２ｍｇ，５６％）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000036
 (1S, 2R, 5R) -2- (R-azido (phenyl) methyl) -7-methylenebicyclo [3.3.1. ] To a solution of nonan-3-one (57.4 mg, 0.204 mmol) in dichloromethane (2 mL) under ice cooling, 2-methoxyethanol (78 μL, 1.0 mmol), scandium trifluoromethanesulfonate (5.0 mg, 0. 01 mmol) was added sequentially. After stirring at room temperature for 2 days, a saturated aqueous NaHCO 3 solution was added under ice cooling, and the mixture was extracted with dichloromethane. The resulting organic layer was distilled off dried solvent under reduced pressure over MgSO 4. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 1: 2 to 1: 1) to give (1S, 2R, 3S, 5S, 7S) -2-((R) -azido (phenyl) methyl)- 5- (2-methoxyethoxy) adamantan-1-ol (41.2 mg, 56%) was obtained as a colorless oil.
　得られたアジド化合物（３９．６ｍｇ，０．１１１ｍｍｏｌ）のＴＨＦ（１　ｍＬ）溶液にＬｉＡｌＨ４（８．０ｍｇ，０．２１ｍｍｏｌ）を氷冷下加えた。室温までゆっくりと昇温し１時間攪拌後、反応溶液を氷冷しＬｉＡｌＨ４（８．０ｍｇ，０．２１ｍｍｏｌ）を加えた。室温にて１時間攪拌後、氷冷下反応溶液にアンモニア水を加えた。セライト（商標登録）で濾過を行い、濾液をＮａ２ＳＯ４で乾燥し減圧下溶媒を留去した。残渣にジクロロメタン（１ｍＬ）を加え、トリエチルアミン（７７μＬ，０．５６ｍｍｏｌ）、無水トリフルオロ酢酸（ＴＦＡＡ、４７μＬ，０．３３ｍｍｏｌ）を氷冷下加えた。室温にて５時間攪拌後、飽和ＮａＨＣＯ３水溶液を氷冷下加え、ジクロロメタンで抽出した。得られた有機層をＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝１：４～１：２）に付し、ＴＰ－０５０（３１．６ｍｇ，５４％）を無色油状物として得た。 LiAlH 4 (8.0 mg, 0.21 mmol) was added to a solution of the obtained azide compound (39.6 mg, 0.111 mmol) in THF (1 mL) under ice cooling. After slowly warming to room temperature and stirring for 1 hour, the reaction solution was ice-cooled and LiAlH 4 (8.0 mg, 0.21 mmol) was added. After stirring at room temperature for 1 hour, aqueous ammonia was added to the reaction solution under ice cooling. Filtration through Celite (registered trademark), the filtrate was dried over Na 2 SO 4 , and the solvent was distilled off under reduced pressure. Dichloromethane (1 mL) was added to the residue, and triethylamine (77 μL, 0.56 mmol) and trifluoroacetic anhydride (TFAA, 47 μL, 0.33 mmol) were added under ice cooling. After stirring at room temperature for 5 hours, a saturated aqueous NaHCO 3 solution was added under ice-cooling, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 . The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 1: 4 to 1: 2) to give TP-050 (31.6 mg, 54%) as a colorless oil. .
　[α]D 25 = +72.1 (c = 0.965, CHCl3); 1H-NMR (400 MHz, CDCl3):δ 7.34-7.23 (m, 5H), 6.33 (br d, J = 9.9 Hz, 1H), 5.44 (dd, J = 10.9, 9.9 Hz, 1H), 3.59-3.56 (m, 2H), 3.51-3.48 (m, 2H), 3.37 (s, 3H), 3.17 (br d, J = 10.9 Hz, 1H), 2.65 (br d, J = 10.6 Hz, 1H), 2.43-2.37 (m, 3H), 1.95-1.81 (m, 7H), 1.38 (br d, J = 11.6 Hz, 1H); 13C-NMR (100 MHz, CDCl3):δ 156.1 (q, J = 37.4 Hz), 154.9 (q, J = 42.1 Hz), 139.4, 129.1, 128.5, 127.2, 115.8 (q, J = 288.1 Hz), 113.4 (q, J = 287.3 Hz), 87.6, 73.7, 72.3, 60.2, 59.1, 53.5, 48.5, 45.0, 41.1, 39.9, 36.3, 30.5, 29.2; IR (ニート, cm-1): 3303, 2936, 1775, 1698, 1554, 1221, 1172; MS (EI): m/z 523 (M+), 202 (100%); HRMS (EI): 計算値 C24H27F6NO5 (M+) 523.1793, 実測値523.1797。 [α] D 25 = +72.1 (c = 0.965, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.34-7.23 (m, 5H), 6.33 (br d, J = 9.9 Hz, 1H ), 5.44 (dd, J = 10.9, 9.9 Hz, 1H), 3.59-3.56 (m, 2H), 3.51-3.48 (m, 2H), 3.37 (s, 3H), 3.17 (br d, J = 10.9 Hz , 1H), 2.65 (br d, J = 10.6 Hz, 1H), 2.43-2.37 (m, 3H), 1.95-1.81 (m, 7H), 1.38 (br d, J = 11.6 Hz, 1H); 13 C -NMR (100 MHz, CDCl 3 ): δ 156.1 (q, J = 37.4 Hz), 154.9 (q, J = 42.1 Hz), 139.4, 129.1, 128.5, 127.2, 115.8 (q, J = 288.1 Hz), 113.4 (q, J = 287.3 Hz), 87.6, 73.7, 72.3, 60.2, 59.1, 53.5, 48.5, 45.0, 41.1, 39.9, 36.3, 30.5, 29.2; IR (neat, cm -1 ): 3303, 2936, 1775, 1698, 1554, 1221, 1172; MS (EI): m / z 523 (M + ), 202 (100%); HRMS (EI): calculated C 24 H 27 F 6 NO 5 (M + ) 523.1793, measured Value 523.1797.
　［実施例２０］ [Example 20]
Figure JPOXMLDOC01-appb-C000037
 　（１Ｓ，２Ｒ，５Ｒ）－２－（Ｒ－アジド（フェニル）メチル）－７－メチレンビシクロ［３．３．１．］ノナン‐３－オン（２３８ｍｇ，０．８４８ｍｍｏｌ）のメタノール（８．５ｍＬ）溶液に、トリフルオロメタンスルホン酸スカンジウム（２０ｍｇ，０．０４ｍｍｏｌ）を氷冷下加えた。室温にて１８時間攪拌後、飽和ＮａＨＣＯ３水溶液を氷冷下加え酢酸エチルにて抽出した。得られた有機層を飽和食塩水で洗浄し、ＭｇＳＯ４で乾燥後減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝１：４～１：２）に付し、（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－２－（（Ｒ）－アジド（フェニル）メチル）－５－メトキシアダマンタン‐１－オール（２２５ｍｇ，８５％）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000037
 (1S, 2R, 5R) -2- (R-azido (phenyl) methyl) -7-methylenebicyclo [3.3.1. To a solution of nonan-3-one (238 mg, 0.848 mmol) in methanol (8.5 mL), scandium trifluoromethanesulfonate (20 mg, 0.04 mmol) was added under ice cooling. After stirring at room temperature for 18 hours, a saturated aqueous NaHCO 3 solution was added under ice cooling, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over MgSO 4 , and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 1: 4 to 1: 2) to give (1S, 2R, 3S, 5S, 7S) -2-((R) -azido (phenyl) methyl)- 5-Methoxyadamantan-1-ol (225 mg, 85%) was obtained as a colorless oil.
　得られたアジド化合物（２２５ｍｇ，０．７１６ｍｍｏｌ）のＴＨＦ（４ｍＬ）溶液にＬｉＡｌＨ４（４１ｍｇ，１．１ｍｍｏｌ）を氷冷下加えた。同温で１時間攪拌後、反応溶液にアンモニア水を加えた。セライト（商標登録）で濾過を行い、減圧下溶媒を留去した。残渣にジクロロメタン（４ｍＬ）を加え、トリエチルアミン（４９７μＬ，３．８６ｍｍｏｌ）、無水トリフルオロ酢酸（ＴＦＡＡ、２９９μＬ，２．１５ｍｍｏｌ）を氷冷下加えた。室温にて４０時間攪拌後、飽和ＮａＨＣＯ３水溶液を氷冷下加え、ジクロロメタンで抽出した。得られた有機層をＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝１：８～１：２）に付し、ＴＰ－０５３（２６２ｍｇ，７５％）を白色個体として得た。 LiAlH 4 (41 mg, 1.1 mmol) was added to a solution of the obtained azide compound (225 mg, 0.716 mmol) in THF (4 mL) under ice cooling. After stirring at the same temperature for 1 hour, aqueous ammonia was added to the reaction solution. The mixture was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure. Dichloromethane (4 mL) was added to the residue, and triethylamine (497 μL, 3.86 mmol) and trifluoroacetic anhydride (TFAA, 299 μL, 2.15 mmol) were added under ice cooling. After stirring at room temperature for 40 hours, a saturated aqueous NaHCO 3 solution was added under ice-cooling, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 1: 8 to 1: 2) to obtain TP-053 (262 mg, 75%) as a white solid.
　[α]D 14 = +97.2 (c = 0.179, CHCl3); 1H-NMR (400 MHz, CDCl3):δ 7.33 (m, 5H), 6.35 (br d, J = 9.9 Hz, 1H), 5.45 (dd, J = 10.6, 9.9 Hz, 1H), 3.25 (s, 3H), 3.17 (br d, J = 10.6 Hz, 1H), 2.61 (br d J = 10.6 Hz, 1H), 2.45-2.37 (m, 3H), 1.97-1.73 (m, 7H), 1.39 (br d, J = 13.5 Hz, 1H); 13C-NMR (100 MHz, CDCl3): δ 156.0 (q, J = 37.4 Hz), 155.0 (q, J = 41.8 Hz), 139.4, 129.1, 128.6, 127.1, 115.8 (q, 288.1 Hz), 113.4 (q, 287.0 Hz), 87.7, 75.5, 53.5, 48.7, 48.6, 44.5, 40.8, 39.5, 36.3, 33.3, 30.4, 29.3; IR (ニート, cm-1): 3299, 2941, 1776, 1697, 1221, 1172; MS (EI): m/z 479 (M+), 202 (100%); HRMS (EI): 計算値C22H23F6NO4(M+) 479.1531, 実測値479.1486。 [α] D 14 = +97.2 (c = 0.179, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 7.33 (m, 5H), 6.35 (br d, J = 9.9 Hz, 1H), 5.45 (dd, J = 10.6, 9.9 Hz, 1H), 3.25 (s, 3H), 3.17 (br d, J = 10.6 Hz, 1H), 2.61 (br d J = 10.6 Hz, 1H), 2.45-2.37 ( m, 3H), 1.97-1.73 (m, 7H), 1.39 (br d, J = 13.5 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ 156.0 (q, J = 37.4 Hz), 155.0 (q, J = 41.8 Hz), 139.4, 129.1, 128.6, 127.1, 115.8 (q, 288.1 Hz), 113.4 (q, 287.0 Hz), 87.7, 75.5, 53.5, 48.7, 48.6, 44.5, 40.8, 39.5, 36.3, 33.3, 30.4, 29.3; IR (Neat, cm -1 ): 3299, 2941, 1776, 1697, 1221, 1172; MS (EI): m / z 479 (M + ), 202 (100%); HRMS (EI): Calculated C 22 H 23 F 6 NO 4 (M + ) 479.1531, found 479.1486.
　［実施例２１］ [Example 21]
Figure JPOXMLDOC01-appb-C000038
 　ビス（（Ｓ）－１－フェニルエチル）アミン（２．５ｍＬ，１１ｍｍｏｌ）、塩化リチウム（８５０ｍｇ，２０ｍｍｏｌ）のＴＨＦ（２５ｍＬ）溶液にｎ－ブチルリチウムのヘキサン溶液（１．５６Ｍ，７．１ｍＬ，１１ｍｍｏｌ）を氷冷下滴下した。同温度で３０分撹拌後、反応溶液を－７８℃まで冷却した。反応混合物に、７－メチレンビシクロ［３．３．１］ノナン－３－オン（１．５２ｇ，１０ｍｍｏｌ）のＴＨＦ（１５ｍＬ）溶液をカニュレーションにより加えた。３０分撹拌後、ニコチンアルデヒド（１．１ｍＬ，１２ｍｍｏｌ）のＴＨＦ（１０ｍＬ）溶液をカニュレーションにより加えた。４０分撹拌後、反応溶液に酢酸、飽和塩化アンモニウム水溶液を順次加え、酢酸エチルにて抽出した。得られた有機層を飽和食塩水で洗浄し、Ｋ２ＣＯ３で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐アセトン＝３：２～１：２）に付し、（１Ｓ，２Ｒ，５Ｒ）－２－（（Ｓ）－ヒドロキシ（ピリジン－３－イル）メチル）－７－メチレンビシクロ［３．３．１］ノナン－３－オン（２．７ｇ，８１％）を白色固体として得た。これを酢酸エチルから再結晶を行うことで無色結晶（９９％ｅｅ）を得た。
Figure JPOXMLDOC01-appb-C000038
 A solution of bis ((S) -1-phenylethyl) amine (2.5 mL, 11 mmol) and lithium chloride (850 mg, 20 mmol) in THF (25 mL) in a hexane solution of n-butyllithium (1.56 M, 7.1 mL, 11 mmol) was added dropwise under ice cooling. After stirring at the same temperature for 30 minutes, the reaction solution was cooled to −78 ° C. To the reaction mixture, 7-methylenebicyclo [3.3.1] nonan-3-one (1.52 g, 10 mmol) in THF (15 mL) was added by cannulation. After stirring for 30 minutes, a solution of nicotinaldehyde (1.1 mL, 12 mmol) in THF (10 mL) was added by cannulation. After stirring for 40 minutes, acetic acid and a saturated aqueous ammonium chloride solution were sequentially added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over K 2 CO 3 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-acetone = 3: 2 to 1: 2) to give (1S, 2R, 5R) -2-((S) -hydroxy (pyridine- 3-yl) methyl) -7-methylenebicyclo [3.3.1] nonan-3-one (2.7 g, 81%) was obtained as a white solid. This was recrystallized from ethyl acetate to obtain colorless crystals (99% ee).
　得られたアルコール（２５８ｍｇ，１．０ｍｍｏｌ）、ジフェニルリン酸アジド（ＤＰＰＡ、２３７μＬ，１．１ｍｍｏｌ）、トリフェニルホスフィン（２３９ｍｇ，１．１ｍｍｏｌ）のＴＨＦ（５ｍＬ）溶液にジイソプロピルアゾジカルボキシレート（ＤＩＡＤ、２１４μＬ，１．１ｍｍｏｌ）を氷冷下加えた。室温までゆっくりと昇温し５時間撹拌後、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝４：１～２：１）に付し、（１Ｓ，２Ｒ，５Ｒ）－２－（（Ｒ）－アジド（ピリジン－３－イル）メチル）－７－メチレンビシクロ［３．３．１］ノナン－３－オン（１８７ｍｇ，６６％）を無色油状物として得た。 Diisopropyl azodicarboxylate (DIAD) was added to a THF (5 mL) solution of the obtained alcohol (258 mg, 1.0 mmol), diphenyl phosphate azide (DPPA, 237 μL, 1.1 mmol) and triphenylphosphine (239 mg, 1.1 mmol). , 214 μL, 1.1 mmol) was added under ice cooling. The temperature was slowly raised to room temperature and the mixture was stirred for 5 hours, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 4: 1 to 2: 1) to give (1S, 2R, 5R) -2-((R) -azido (pyridin-3-yl) methyl)- 7-methylenebicyclo [3.3.1] nonan-3-one (187 mg, 66%) was obtained as a colorless oil.
　得られたアジド化合物（１８７ｍｇ，０．６６ｍｍｏｌ）のジクロロメタン（７ｍＬ）溶液に氷冷下ＴｉＣｌ４（３００μＬ，０．２７ｍｍｏｌ）を加えた。室温にて３時間撹拌後，飽和ＮａＨＣＯ３水溶液を氷冷下加えジエチルエーテルにて抽出した。得られた有機層を飽和食塩水で洗浄し，ＭｇＳＯ４で乾燥した。減圧下溶媒を留去し，得られた個体を冷ジエチルエーテルで洗浄し（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－２－（（Ｒ）－アジド（ピリジン－３－イル）メチル）－５－クロロアダマンタン－１－オール（９８．５ｍｇ，９２％）を得た。 TiCl 4 (300 μL, 0.27 mmol) was added to a solution of the obtained azide compound (187 mg, 0.66 mmol) in dichloromethane (7 mL) under ice cooling. After stirring at room temperature for 3 hours, a saturated aqueous NaHCO 3 solution was added under ice cooling, and the mixture was extracted with diethyl ether. The obtained organic layer was washed with saturated brine and dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the resulting solid was washed with cold diethyl ether (1S, 2R, 3S, 5S, 7S) -2-((R) -azido (pyridin-3-yl) methyl) -5 -Chloroadamantan-1-ol (98.5 mg, 92%) was obtained.
　得られた化合物（７５．４ｍｇ，０．２５７ｍｍｏｌ）のＴＨＦ（２ｍＬ）溶液に、ＬｉＡｌＨ４（２３ｍｇ，０．６１ｍｍｏｌ）を氷冷下加えた。同温度で１時間攪拌後、反応溶液にアンモニア水を氷冷下加えた。セライト（商標登録）で濾過を行い、減圧下溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー（ＣＨＣｌ３－メタノール＝１：０～４：１）に付し、粗アミンを得た。 LiAlH 4 (23 mg, 0.61 mmol) was added to a solution of the obtained compound (75.4 mg, 0.257 mmol) in THF (2 mL) under ice cooling. After stirring at the same temperature for 1 hour, aqueous ammonia was added to the reaction solution under ice cooling. The mixture was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (CHCl 3 -methanol = 1: 0 to 4: 1) to obtain a crude amine.
　得られた粗アミンにジクロロメタン（２ ｍＬ）を加えた後、トリエチルアミン（１７８μＬ，１．２８ｍｍｏｌ）、無水トリフルオロ酢酸（ＴＦＡＡ、１０７μＬ，０．７６ｍｍｏｌ）を氷冷下加えた。室温まで昇温し４時間攪拌後、飽和ＮａＨＣＯ３水溶液を氷冷下加え、ジクロロメタンで抽出した。得られた有機層をＮａ２ＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル＝２：１～１：４）に付し、ＴＰ－０５１（４８．８ｍｇ，４９％）を白色個体として得た。 Dichloromethane (2 mL) was added to the resulting crude amine, and then triethylamine (178 μL, 1.28 mmol) and trifluoroacetic anhydride (TFAA, 107 μL, 0.76 mmol) were added under ice cooling. After warming to room temperature and stirring for 4 hours, a saturated aqueous NaHCO 3 solution was added under ice-cooling, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over Na 2 SO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 2: 1 to 1: 4) to obtain TP-051 (48.8 mg, 49%) as a white solid.
　[α]D 20 = +53.9 (c = 0.379, CHCl3);1H-NMR (400 MHz, CDCl3): δ 8.57 (d, J = 1.0 Hz, 1H), 8.50 (dd, J = 4.9, 1.5 Hz, 1H), 7.72 (br d, J = 7.8 Hz, 1H), 7.41 (br d, J =9.8 Hz, 1H), 7.32 (dd, J = 7.8, 4.9 Hz, 1H), 5.35 (dd, J = 9.8, 9.3 Hz, 1H), 2.40-2.38 (m, 2H), 2.29 (br s, 1H), 2.22-1.99 (m, 7H), 1.75 (br, 1H), 1.68 (br d, J = 13.7 Hz, 1H), 1.48 (br d, J = 13.2 Hz, 1H), 1.42 (br d, J = 13.2 Hz, 1H); 13C-NMR (100MHz, CDCl3): δ156.4 (q, J = 37.1 Hz), 148.2, 147.7, 138.3, 136.5, 124.0, 115.8 (q, J = 287.8 Hz), 71.9, 66.1, 57.3, 52.6, 51.7, 47.6, 46.3, 38.3, 34.3, 31.6, 28.6; IR (ニート, cm-1): 3292, 2938, 1700, 1558, 1212, 1184, 1161, 759; MS (EI): m/z 388 (M+), 203 (100%); HRMS (EI): 計算値C18H20ClF3N2O2(M+) 388.1165, 実測値388.1177。 [α] D 20 = +53.9 (c = 0.379, CHCl 3 ); 1 H-NMR (400 MHz, CDCl 3 ): δ 8.57 (d, J = 1.0 Hz, 1H), 8.50 (dd, J = 4.9, 1.5 Hz, 1H), 7.72 (br d, J = 7.8 Hz, 1H), 7.41 (br d, J = 9.8 Hz, 1H), 7.32 (dd, J = 7.8, 4.9 Hz, 1H), 5.35 (dd, J = 9.8, 9.3 Hz, 1H), 2.40-2.38 (m, 2H), 2.29 (br s, 1H), 2.22-1.99 (m, 7H), 1.75 (br, 1H), 1.68 (br d, J = 13.7 Hz, 1H), 1.48 (br d, J = 13.2 Hz, 1H), 1.42 (br d, J = 13.2 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ156.4 (q, J = 37.1 Hz), 148.2, 147.7, 138.3, 136.5, 124.0, 115.8 (q, J = 287.8 Hz), 71.9, 66.1, 57.3, 52.6, 51.7, 47.6, 46.3, 38.3, 34.3, 31.6, 28.6; IR (Neat , cm -1 ): 3292, 2938, 1700, 1558, 1212, 1184, 1161, 759; MS (EI): m / z 388 (M + ), 203 (100%); HRMS (EI): calculated C 18 H 20 ClF 3 N 2 O 2 (M + ) 388.1165, found 388.1177.
　［実施例２２］ [Example 22]
Figure JPOXMLDOC01-appb-C000039
 　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－ニル）（フェニル）メタンアミン（２５．０ｍｇ，０．０８０６ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液に、トリエチルアミン（１７μＬ，０．１３ｍｍｏｌ），ＤＭＡＰ（１ｍｇ），塩化ベンゾイル（１１μＬ，０．０９７ｍｍｏｌ）を氷冷下加えた。２０分撹拌後、反応液に飽和ＮａＨＣＯ３水溶液を氷冷下加え、ジクロロメタンにて抽出した。得られた有機層をＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝４：１）に付し、ＴＰ－０７０（２８．０ｍｇ，８４％）を黄色固体として得た。
Figure JPOXMLDOC01-appb-C000039
 To a solution of (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine (25.0 mg, 0.0806 mmol) in dichloromethane (1 mL) was added triethylamine. (17 μL, 0.13 mmol), DMAP (1 mg), and benzoyl chloride (11 μL, 0.097 mmol) were added under ice cooling. After stirring for 20 minutes, a saturated aqueous NaHCO 3 solution was added to the reaction solution under ice-cooling, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 4: 1) to obtain TP-070 (28.0 mg, 84%) as a yellow solid.
　1H-NMR (400 MHz, CDCl3): δ7.69 (d，J = 7.7 Hz，2H)，7.49-7.25 (m，8H)，6.34 (d，J = 9.5 Hz，1H)，5.77 (dd，J = 9.5, 9.0 Hz，1H)，2.73 (d，J = 9.0 Hz，1H)，2.65 (d，J =13.0 Hz，1H)，2.59 (s，1H)，2.51 (m，2H)，2.32 (s，1H)，2.20 (s，2H)，2.08 (s，2H)，1.99 (d，J = 13.5 Hz，1H)，1.91 (d，J =14.0 Hz，1H)，1.39 (br d，J = 13.5 Hz，1H); 13C-NMR (100 MHz, CDCl3): δ166.1，143.9，134.4，131.7，128.8，128.6，127.5，127.3，126.8，69.0，66.0，59.2，53.44，53.39，47.8，46.0，40.9，35.8，32.9，28.8; IR (ニート, cm-1):3583，3290，2940，2092，1631，1536; MS (EI): m/z 413 (M+), 210 (100%), HRMS (EI): 計算値 C24H25Cl2NO (M+) 413.1313, 実測値 413.1314。 1 H-NMR (400 MHz, CDCl 3 ): δ7.69 (d, J = 7.7 Hz, 2H), 7.49-7.25 (m, 8H), 6.34 (d, J = 9.5 Hz, 1H), 5.77 (dd , J = 9.5, 9.0 Hz, 1H), 2.73 (d, J = 9.0 Hz, 1H), 2.65 (d, J = 13.0 Hz, 1H), 2.59 (s, 1H), 2.51 (m, 2H), 2.32 (s, 1H), 2.20 (s, 2H), 2.08 (s, 2H), 1.99 (d, J = 13.5 Hz, 1H), 1.91 (d, J = 14.0 Hz, 1H), 1.39 (br d, J = 13.5 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ 166.1, 143.9, 134.4, 131.7, 128.8, 128.6, 127.5, 127.3, 126.8, 69.0, 66.0, 59.2, 53.44, 53.39, 47.8 , 46.0, 40.9, 35.8, 32.9, 28.8; IR (neat, cm -1 ): 3583, 3290, 2940, 2092, 1631, 1536; MS (EI): m / z 413 (M + ), 210 (100% ), HRMS (EI): calculated C 24 H 25 Cl 2 NO (M +) 413.1313, found 413.1314.
　［実施例２３］ [Example 23]
Figure JPOXMLDOC01-appb-C000040
 　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－ニル）（フェニル）メタンアミン（２９．６ｍｇ，０．０９５５ｍｍｏｌ）のジクロロメタン（１ｍＬ）溶液に、ピコリン酸（１８ｍｇ，０．１４ｍｍｏｌ）、ＤＣＣ（３０ｍｇ，０．１４ｍｍｏｌ）、ＤＭＡＰ（１ｍｇ，１０ｍｏｌ％）を氷冷下加えた。氷冷下で１時間撹拌後、反応液に水を加え、ジクロロメタンにて抽出した。得られた有機層をＭｇＳＯ４で乾燥後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝２：１）に付し、ＴＰ－０７１（２９．８ｍｇ，７５％）を黄色油状物として得た。
Figure JPOXMLDOC01-appb-C000040
 To a solution of (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine (29.6 mg, 0.0955 mmol) in dichloromethane (1 mL) was added picoline. Acid (18 mg, 0.14 mmol), DCC (30 mg, 0.14 mmol) and DMAP (1 mg, 10 mol%) were added under ice cooling. After stirring for 1 hour under ice cooling, water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 , the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 2: 1), and TP-071 (29.8 mg, 75% ) Was obtained as a yellow oil.
　1H-NMR (400 MHz, CDCl3): δ 8.52 (d，J = 4.3 Hz，1H)，8.46 (d，J = 10.6 Hz，1H)，8.17 (d，J = 8.0 Hz，1H)，7.82 (ddd，J = 8.0, 7.7, 1.4 Hz, 1H)，7.44-7.39(m，3H)，7.33(dd，J = 7.7, 7.5 Hz，2H)，7.23 (t，J = 7.5 Hz, 1H)，5.79 (dd，J = 10.6, 7.7 Hz, 1H)，2.71 (d，J = 7.7 Hz，1H)，2.66(br d，J = 13.0 Hz，1H)，2.57-2.48 (m，3H)，2.34 (s，1H)，2.17 (m，2H)，2.08 (m，2H)，2.01 (br d，J = 13.5 Hz，1H)，1.91 (br d，J = 13.0 Hz，1H)，1.81 (br d，J = 13.5 Hz，1H); 13C-NMR (100 MHz, CDCl3): δ162.8，149.6，148.1，143.7，137.4，128.7，127.24，127.20，126.3，122.5，69.0，66.1，59.3，53.7，52.8，47.9，46.1，40.9，35.1，32.9，29.1; IR (ニート, cm-1): 3583，3369，2939，2092，1673，1513; MS (EI): m/z 414 (M+), 211(100%); HRMS (EI): 計算値 C23H24Cl2N2O (M+) 414.1266, 実測値 414.1279。 1 H-NMR (400 MHz, CDCl 3 ): δ 8.52 (d, J = 4.3 Hz, 1H), 8.46 (d, J = 10.6 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 7.82 (ddd, J = 8.0, 7.7, 1.4 Hz, 1H), 7.44-7.39 (m, 3H), 7.33 (dd, J = 7.7, 7.5 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1H), 5.79 (dd, J = 10.6, 7.7 Hz, 1H), 2.71 (d, J = 7.7 Hz, 1H), 2.66 (br d, J = 13.0 Hz, 1H), 2.57-2.48 (m, 3H), 2.34 ( s, 1H), 2.17 (m, 2H), 2.08 (m, 2H), 2.01 (br d, J = 13.5 Hz, 1H), 1.91 (br d, J = 13.0 Hz, 1H), 1.81 (br d, J = 13.5 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ 162.8, 149.6, 148.1, 143.7, 137.4, 128.7, 127.24, 127.20, 126.3, 122.5, 69.0, 66.1, 59.3, 53.7, 52.8, 47.9, 46.1, 40.9, 35.1, 32.9, 29.1; IR (neat, cm -1 ): 3583, 3369, 2939, 2092, 1673, 1513; MS (EI): m / z 414 (M + ), 211 (100%); HRMS (EI ): calculated C 23 H 24 Cl 2 N 2 O (M +) 414.1266, Found 414.1279.
　［実施例２４］ [Example 24]
Figure JPOXMLDOC01-appb-C000041
 　(Ｒ)－((１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ)－１，５－ジクロロアダマンタン－２－ニル)(フェニル)メタンアミン(１８．８ｍｇ，０．０６０４ｍｍｏｌ)のジクロロメタン(１ｍL)溶液に、ピリジン(１０μL，０．１２ｍｍｏｌ)、ベンゼンスルホニルクロリド(１２μL，０．０９１ｍｍｏｌ)を氷冷下加えた。２．５時間撹拌後、反応液に水を加え、ジクロロメタンにて抽出した。得られた有機層をＭｇＳＯ４で乾燥後、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン‐酢酸エチル＝８：１）に付し、ＴＰ－０７２(１１．１ｍｇ,４１％)を黄色油状物として得た。
Figure JPOXMLDOC01-appb-C000041
 To a solution of (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine (18.8 mg, 0.0604 mmol) in dichloromethane (1 mL) was added pyridine. (10 μL, 0.12 mmol) and benzenesulfonyl chloride (12 μL, 0.091 mmol) were added under ice cooling. After stirring for 2.5 hours, water was added to the reaction solution, and the mixture was extracted with dichloromethane. The obtained organic layer was dried over MgSO 4 , the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 8: 1), and TP-072 (11.1 mg, 41% ) Was obtained as a yellow oil.
　1H-NMR (400 MHz, CDCl3): δ7.49(d，J = 7.2 Hz，2H)，7.36(t，J = 7.5 Hz，1H)，7.20(t，J = 7.7 Hz，2H)，7.02-6.98(m，3H)，6.84-6.82(dd，J = 1.4, 1.9 Hz，2H)，4.76-4.71(m，1H)，2.70(s，1H)，2.55(d，J = 13.5 Hz，1H)，2.43(s，2H)，2.37(s，2H)，2.28(d，J = 13.5 Hz，1H)，2.19(d，J = 12.6 Hz，1H)，2.10(s，3H)，1.86(d，J = 12.6 Hz，1H)，1.48(d，J = 14.0 Hz，1H)，1.25(s，1H); 13C-NMR (100 MHz, CDCl3): δ142.3，140.1，132.2，128.7，128.3，127.1，127.0，126.4，69.4，65.9，59.3，58.4，55.0，47.9，46.0，40.6，34.8，33.0，28.6; IR (ニート, cm-1): 3583，3276，2938，1589，1454; MS (EI): m/z 246 (M+- C10H12Cl2), 246(100%); HRMS (EI): 計算値 C13H12NO2S (M+- C10H12Cl2) 246.0589, 実測値 246.0591。 1 H-NMR (400 MHz, CDCl 3 ): δ 7.49 (d, J = 7.2 Hz, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.20 (t, J = 7.7 Hz, 2H), 7.02-6.98 (m, 3H), 6.84-6.82 (dd, J = 1.4, 1.9 Hz, 2H), 4.76-4.71 (m, 1H), 2.70 (s, 1H), 2.55 (d, J = 13.5 Hz, 1H), 2.43 (s, 2H), 2.37 (s, 2H), 2.28 (d, J = 13.5 Hz, 1H), 2.19 (d, J = 12.6 Hz, 1H), 2.10 (s, 3H), 1.86 ( d, J = 12.6 Hz, 1H), 1.48 (d, J = 14.0 Hz, 1H), 1.25 (s, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ142.3, 140.1, 132.2, 128.7 , 128.3, 127.1, 127.0, 126.4, 69.4, 65.9, 59.3, 58.4, 55.0, 47.9, 46.0, 40.6, 34.8, 33.0, 28.6; IR (neat, cm -1 ): 3583, 3276, 2938, 1589, 1454; MS (EI): m / z 246 (M + -C 10 H 12 Cl 2 ), 246 (100%); HRMS (EI): calculated value C 13 H 12 NO 2 S (M + -C 10 H 12 Cl 2 ) 246.0589, measured value 246.0591.
　［実施例２５］ [Example 25]
Figure JPOXMLDOC01-appb-C000042
 　（１Ｒ，２Ｓ，５Ｓ）－２－（（Ｓ）－アジド（フェニル）メチル）－７－メチレンビシクロ［３．３．１］ノナン－３－オン（４１８ｍｇ，１．４８ｍｍｏｌ）のジクロロメタン（８ｍＬ）溶液に四塩化チタン（０．１０ｍＬ，０．８９ｍｍｏｌ）を‐３０℃下で加えた。同温度下で１時間撹拌後、反応液をジエチルエーテルで希釈した。水を加え反応を停止後、ジエチルエーテルにて抽出した。得られた有機層を飽和食塩水で洗浄し、ＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル＝１０：１）に付し、（１Ｒ，２Ｓ，３Ｒ，５Ｒ，７Ｒ）－２－（（Ｒ）－アジド（フェニル）メチル）－５－クロロアダマンタン－１－オール（４４６ｍｇ，９５％）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000042
 (1R, 2S, 5S) -2-((S) -Azido (phenyl) methyl) -7-methylenebicyclo [3.3.1] nonan-3-one (418 mg, 1.48 mmol) in dichloromethane (8 mL) To the solution was added titanium tetrachloride (0.10 mL, 0.89 mmol) at −30 ° C. After stirring at the same temperature for 1 hour, the reaction solution was diluted with diethyl ether. Water was added to stop the reaction, followed by extraction with diethyl ether. The obtained organic layer was washed with saturated brine and dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 10: 1) to give (1R, 2S, 3R, 5R, 7R) -2-((R) -azide (phenyl). ) Methyl) -5-chloroadamantan-1-ol (446 mg, 95%) was obtained as a colorless oil.
　得られたアルコール（７２．１ｍｇ，０．２２７ｍｍｏｌ）のメタノール（１ｍＬ）溶液に１０％パラジウム炭素（７ｍｇ）を加えた。水素雰囲気下室温にて終夜攪拌後、反応溶液をセライト（商標登録）で濾過し、減圧下溶媒を留去した。残渣にジクロロメタン（１ｍＬ）を加え、氷冷下トリエチルアミン（１５７μＬ，１．１４ｍｍｏｌ），ＴＦＡＡ（９６μＬ，０．６８ｍｍｏｌ）を順次加えた。氷冷下１０分撹拌後、飽和ＮａＨＣＯ３水溶液を加え、ジクロロメタンにて抽出を行い、ＭｇＳＯ４で乾燥した。減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（ヘキサン－酢酸エチル＝１０：１）に付し、ＴＰ－０７４（２０．１ｍｇ，１８％）、及びＴＰ－０７５（１２．７ｍｇ，１２％）をそれぞれ無色固体として得た。 To a solution of the obtained alcohol (72.1 mg, 0.227 mmol) in methanol (1 mL) was added 10% palladium carbon (7 mg). After stirring overnight at room temperature under a hydrogen atmosphere, the reaction solution was filtered through Celite (registered trademark), and the solvent was distilled off under reduced pressure. Dichloromethane (1 mL) was added to the residue, and triethylamine (157 μL, 1.14 mmol) and TFAA (96 μL, 0.68 mmol) were sequentially added under ice cooling. After stirring for 10 minutes under ice-cooling, a saturated aqueous NaHCO 3 solution was added, extracted with dichloromethane, and dried over MgSO 4 . The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane-ethyl acetate = 10: 1) to give TP-074 (20.1 mg, 18%) and TP-075 (12.7 mg, 12). %) As a colorless solid.
　また、同様の手法を用いて（１Ｓ，２Ｒ，５Ｒ）－２－（（Ｒ）－アジド（フェニル）メチル）－７－メチレンビシクロ［３．３．１］ノナン－３－オンからＴＰ－０７３を合成した。
・ＴＰ－０７４
　1H-NMR (400 MHz, CDCl3): δ8.94 (s，1H)，7.37-7.27 (m，5H)，4.90-4.86 (m，1H)，2.36 (s，1H)，2.26-2.20 (m，2H)，2.11-2.05 (m，3H)，2.02 (s，3H)，1.98-1.94 (m，1H)，1.87-1.83 (m，2H)，1.72 (s，1H)，1.54 (d，J = 12.1 Hz，1H)，1.32 (d，J = 13.5 Hz，1H) ; 13C-NMR (100 MHz, CDCl3): δ156.6 (q，J = 36.1 Hz)，140.5，128.8，127.9，127.0，115.8 (q, 287.5 Hz), 74.1，65.7，57.4，56.3，51.3，47.1，46.3，38.7，33.3，32.0，28.7; IR (ニート, cm-1): 3584，3256，2938，1711，1543; MS (EI): m/z 387 (M+), 202(100%)。
・ＴＰ－０７５
　1H-NMR (400 MHz, CDCl3): δ7.35-7.27 (m，5H)，6.63 (d，J = 10.1 Hz，1H)，5.44(dd，J = 10.6Hz, 10.1 Hz，1H)，3.26(d，J = 11.1 Hz，1H)，2.99 (d，J = 11.1 Hz，1H)，2.45-2.41(m，3H)，2.26-2.13(m，5H)，1.96(br d，J = 12.4 Hz，2H)，1.47(br d，J = 14.0 Hz，1H); 13C-NMR (100 MHz, CDCl3): δ156.2 (q，37.4 Hz)，154.9 (q，42.3 Hz)，139.1，129.2，128.7，127.1，115.8 (q，288.1 Hz)，113.3 (q，287.3 Hz)，86.6，65.1，53.4，50.2，48.0，46.9，46.1，35.6，34.6，31.7，28.5; IR (ニート, cm-1): 3296，2945，1775，1698，1172; MS (EI): m/z 483 (M+), 202(100%); HRMS (EI): 計算値 C21H20ClF6NO3(M+)， 483.1036, 実測値483.1046。 In addition, using the same method, (1S, 2R, 5R) -2-((R) -azido (phenyl) methyl) -7-methylenebicyclo [3.3.1] nonan-3-one is converted to TP-073. Was synthesized.
・ TP-074
1 H-NMR (400 MHz, CDCl 3 ): δ8.94 (s, 1H), 7.37-7.27 (m, 5H), 4.90-4.86 (m, 1H), 2.36 (s, 1H), 2.26-2.20 ( m, 2H), 2.11-2.05 (m, 3H), 2.02 (s, 3H), 1.98-1.94 (m, 1H), 1.87-1.83 (m, 2H), 1.72 (s, 1H), 1.54 (d, J = 12.1 Hz, 1H), 1.32 (d, J = 13.5 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ156.6 (q, J = 36.1 Hz), 140.5, 128.8, 127.9, 127.0, 115.8 (q, 287.5 Hz), 74.1, 65.7, 57.4, 56.3, 51.3, 47.1, 46.3, 38.7, 33.3, 32.0, 28.7; IR (neat, cm -1 ): 3584, 3256, 2938, 1711, 1543 MS (EI): m / z 387 (M + ), 202 (100%).
・ TP-075
1 H-NMR (400 MHz, CDCl 3 ): δ7.35-7.27 (m, 5H), 6.63 (d, J = 10.1 Hz, 1H), 5.44 (dd, J = 10.6 Hz, 10.1 Hz, 1H), 3.26 (d, J = 11.1 Hz, 1H), 2.99 (d, J = 11.1 Hz, 1H), 2.45-2.41 (m, 3H), 2.26-2.13 (m, 5H), 1.96 (br d, J = 12.4 Hz, 2H), 1.47 (br d, J = 14.0 Hz, 1H); 13 C-NMR (100 MHz, CDCl 3 ): δ156.2 (q, 37.4 Hz), 154.9 (q, 42.3 Hz), 139.1, 129.2,128.7,127.1,115.8 (q, 288.1 Hz), 113.3 (q, 287.3 Hz), 86.6,65.1,53.4,50.2,48.0,46.9,46.1,35.6,34.6,31.7,28.5; IR ( neat, cm - 1 ): 3296, 2945, 1775, 1698, 1172; MS (EI): m / z 483 (M + ), 202 (100%); HRMS (EI): calculated C 21 H 20 ClF 6 NO 3 (M + ), 483.1036, found 483.1046.
　［実施例２６］ [Example 26]
Figure JPOXMLDOC01-appb-C000043
 　（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－２－（（Ｒ）－アジド（フェニル）メチル）－５－クロロアダマンタン(１５６ｍｇ，０．４９ｍｍｏｌ)のＴＨＦ(５ｍＬ)溶液に、水素化アルミニウムリチウム(２６ｍｇ，０．７４ｍｍｏｌ)を氷冷下加えた。同温度で１時間撹拌後、２８％アンモニア水を加え反応を停止後、反応溶液をセライト（商標登録）で濾過を行い、減圧下溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（クロロホルム‐メタノール＝１０：１）に付し、ＴＰ－０７６ （７５ｍｇ，５２％）を無色油状物として得た。
Figure JPOXMLDOC01-appb-C000043
 To a solution of (1S, 2R, 3S, 5S, 7S) -2-((R) -azido (phenyl) methyl) -5-chloroadamantane (156 mg, 0.49 mmol) in THF (5 mL) was added lithium aluminum hydride ( 26 mg, 0.74 mmol) was added under ice cooling. After stirring at the same temperature for 1 hour, 28% aqueous ammonia was added to stop the reaction, the reaction solution was filtered through Celite (registered trademark), the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform-methanol). = 10: 1) to give TP-076 (75 mg, 52%) as a colorless oil.
　1H-NMR (400 MHz, CDCl3): δ7.38-7.35(m，5H)，4.13(d，J=10.1Hz，1H)，2.66(brs，1H)，2.30(brs，1H)，2.21-1.98(m，8H)，1.80(brd，J=13.0Hz，1H)，1.60-1.46(m, 3H), 1.44(brd，J=13.5Hz，2H) ; IR (ニート, cm-1): 3581, 3300, 3359，2935，2861，1600，1492，1453; MS (EI): m/z 291 (M+), 106(100%); HRMS (ESI): 計算値 C17H23NOCl (M++H)， 292.1459, 実測値 292.1463。 1 H-NMR (400 MHz, CDCl 3 ): δ 7.38-7.35 (m, 5H), 4.13 (d, J = 10.1Hz, 1H), 2.66 (brs, 1H), 2.30 (brs, 1H), 2.21 -1.98 (m, 8H), 1.80 (brd, J = 13.0Hz, 1H), 1.60-1.46 (m, 3H), 1.44 (brd, J = 13.5Hz, 2H); IR (neat, cm -1 ): 3581, 3300, 3359, 2935, 2861, 1600, 1492, 1453; MS (EI): m / z 291 (M + ), 106 (100%); HRMS (ESI): calculated value C 17 H 23 NOCl (M + + H), 292.1459, found 292.1463.
　ＴＰ－０７６（６２ｍｇ，０．２１ｍｍｏｌ）のメタノール（２．６ｍＬ）溶液に、クロロトリメチルシラン（３２．６μL，０．７４ｍｍｏｌ）を室温で加えた。同温度で１時間撹拌後、減圧下溶媒を留去し、（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－５－クロロ―１―ヒドロキシアダマンタン－２－ニル）（フェニル）メタン塩化アンモニウム塩（２７ｍｇ，３９％）を白色固体として得た。 Chlorotrimethylsilane (32.6 μL, 0.74 mmol) was added to a solution of TP-076 (62 mg, 0.21 mmol) in methanol (2.6 mL) at room temperature. After stirring at the same temperature for 1 hour, the solvent was distilled off under reduced pressure, and (R)-((1S, 2R, 3S, 5S, 7S) -5-chloro-1-hydroxyadamantan-2-yl) (phenyl) methane Ammonium chloride salt (27 mg, 39%) was obtained as a white solid.
　[α]D 24 = +18.4 (c = 0.50, MeOH); 1H-NMR (400 MHz, CD3COCD3): δ8.80(brs，2H)，7.65(d，J=6.8Hz，2H)，7.34-7.27(m，3H)，4.67(d，J=9.7Hz，1H), 3.14 (brs, 1H), 3.00-2.70(m，3H)，2.23-1.88(m，8H)，1.48-1.35(m，2H) ; 13C-NMR (100 MHz, CD3COCD3): 140.4，129.7，129.1，128.9，72.2，68.2，66.1，58.2，52.2，48.4，47.3，38.7，34.5，32.8，29.8; IR (ニート, cm-1): 3583，3294，2933，2864; HRMS (EI): 計算値 C17H23Cl2NO (M+-NH4Cl)，274.1124 , 実測値 274.1153。 [α] D 24 = +18.4 (c = 0.50, MeOH); 1 H-NMR (400 MHz, CD 3 COCD 3 ): δ8.80 (brs, 2H), 7.65 (d, J = 6.8Hz, 2H) , 7.34-7.27 (m, 3H), 4.67 (d, J = 9.7Hz, 1H), 3.14 (brs, 1H), 3.00-2.70 (m, 3H), 2.23-1.88 (m, 8H), 1.48-1.35 (m, 2H); 13 C-NMR (100 MHz, CD 3 COCD 3 ): 140.4, 129.7, 129.1, 128.9, 72.2, 68.2, 66.1, 58.2, 52.2, 48.4, 47.3, 38.7, 34.5, 32.8, 29.8; IR (neat, cm -1 ): 3583, 3294, 2933, 2864; HRMS (EI): calculated C 17 H 23 Cl 2 NO (M + -NH 4 Cl), 274.1124, found 274.1153.
　［試験例１］
　Kir6.2チャネルのcDNAが挿入されたプラスミドベクター：pcDNA3.1-Kir6.2は東北大学大学院生命科学研究科、石塚徹博士より入手した。pcDNA3.1-Kir6.2をGenElute HP Plasmid Maxiprep Kit (Sigma-Aldrich社製)を用い付属のマニュアルにしたがい調製した。DMEM培養液（Gibco）に培養しているNeuro2A細胞（N2A細胞、医薬基盤研究所）の培養液（組成：DMEM培養液450mlに50mlの牛血清を加え、ペニシリン・ストレプトマイシンを100 Unit）を、上記調整したpcDNA3.1-Kir6.2（1μg/μl）を加えたOpti-Mem（Gibco）（Lipofectamine R2000を1ug/1mlで加える）に交換し、5時間培養することにより、Kir6.2チャネルを過剰発現させたN2A細胞を得た。再びDMEM培養液に交換後、2日間培養した。その後、メマンチン（Sigma-Aldrich社製）、および本発明化合物（各群について、n=4）を培養液（DMEM、Gibco）に対し10nMの濃度となるように添加後、1時間静置した。静置後、Kir6.2チャネル過剰発現N2A細胞を回収し、同細胞にSDSサンプルバッファーを加え懸濁後、免疫ブロット法により一次抗体に抗リン酸化CaMKII抗体（Fukunaga K et al., J. Biol. Chem. 1992, 267, 22527-22533）を、2次抗体に抗ウサギIgG抗体（SouthernBiotech社製）を用いてCaMKIIの活性化について測定した（前記した抗体の使用以外の条件は通常の免疫ブロット法にしたがった）。その結果を図１に示す。 [Test Example 1]
The plasmid vector with the cDNA of Kir6.2 channel: pcDNA3.1-Kir6.2 was obtained from Dr. Toru Ishizuka, Graduate School of Life Sciences, Tohoku University. pcDNA3.1-Kir6.2 was prepared using GenElute HP Plasmid Maxiprep Kit (Sigma-Aldrich) according to the attached manual. The culture solution of Neuro2A cells (N2A cells, National Institute for Pharmaceutical Sciences) cultured in DMEM culture medium (Gibco) (Composition: Add 50 ml of bovine serum to 450 ml of DMEM culture medium and add 100 units of penicillin / streptomycin) Replace with Opti-Mem (Gibco) (with 1 μg / ml of Lipofectamine R2000) supplemented with adjusted pcDNA3.1-Kir6.2 (1 μg / μl), and incubate for 5 hours. Expressed N2A cells were obtained. After exchanging with DMEM culture medium again, the cells were cultured for 2 days. Thereafter, memantine (manufactured by Sigma-Aldrich) and the compound of the present invention (n = 4 for each group) were added to the culture solution (DMEM, Gibco) to a concentration of 10 nM, and then allowed to stand for 1 hour. After resting, Kir6.2 channel over-expressing N2A cells were collected, and after adding SDS sample buffer to the cells and suspending them, the primary antibody was anti-phosphorylated CaMKII antibody (Fukunaga K et al., J. Biol Chem. 1992, 267, 22527-22533) was measured for the activation of CaMKII using an anti-rabbit IgG antibody (manufactured by SouthernBiotech) as the secondary antibody. According to the law). The result is shown in FIG.
　図１において、試験化合物を添加しなかった場合（対照：ｃ）の結果を１００％として、試験化合物を添加した場合のCaMKIIの活性化が示されている。 FIG. 1 shows the activation of CaMKII when the test compound is added, with the result when the test compound is not added (control: c) being 100%.
　［試験例２］
　試験例１で得られたKir6.2チャネル過剰発現細胞を用いて、通常のPatch-clamp法により細胞内より細胞外へ排出されるカリウム電流を測定した。結果を図２に示す。ATP感受性カリウムチャネル（Kir6.2チャネル）は、神経細胞の細胞膜に局在し、チャネルが阻害され閉塞すると神経細胞膜の閾値が上昇し、一過性の活動電位が発生するのと類似した状況を作り、細胞内より細胞外へカリウム電流が排出され、その代わりに細胞外より細胞内へカルシウム電流が流入する。図２aは、抗Kir6.2チャネル抗体（常法に基づき作成）を用いたKir6.2チャネル過剰発現細胞（上述の方法による）に対する免疫ブロット法（抗Kir6.2チャネル抗体の使用以外の条件は試験例１の条件と同様、n=5）により、N2A細胞でKir6.2チャネルが過剰発現していることを確認した（上は免疫ブロット法による染色像、下は同染色像のバンドシグナル強度を量的に表現したもの）。ハウスキーピング遺伝子であるβチューブリンに変動はみられなかった（抗βチューブリン抗体はSigma-Aldrichから入手し、他の条件はKir6.2の検出に同じ）。図２bは、TP-014を電気生理学実験用緩衝液中の濃度で10nMになるように添加した電気生理学実験用緩衝液中でKir6.2チャネル過剰発現細胞に静置すると、神経細胞の膜電位をプラス側へ変化させる際に流れる外向きに流れるカリウム電流が抑制されることを確認した結果である（各群n=5）。この結果は、TP-014はKir6.2チャネルを阻害し、細胞内より細胞外へ排出されるカリウム電流を阻害したことを示している。 [Test Example 2]
Using the Kir6.2 channel overexpressing cells obtained in Test Example 1, the potassium current excreted from the cells to the outside was measured by the usual patch-clamp method. The results are shown in FIG. The ATP-sensitive potassium channel (Kir6.2 channel) is localized in the cell membrane of nerve cells, and when the channel is blocked and occluded, the threshold of the nerve cell membrane rises, and a situation similar to the transient action potential is generated. The potassium current is discharged from the inside of the cell to the outside of the cell, and instead, the calcium current flows from the outside of the cell to the inside of the cell. Fig. 2a shows the immunoblotting method using the anti-Kir6.2 channel antibody (prepared based on the conventional method) on the cells overexpressing Kir6.2 channel (according to the method described above). Similar to the conditions in Test Example 1, n = 5) confirmed that the Kir6.2 channel was overexpressed in N2A cells (the upper is a stained image by immunoblotting, the lower is the band signal intensity of the stained image) Quantitative expression). There was no change in the housekeeping gene β-tubulin (anti-β-tubulin antibody was obtained from Sigma-Aldrich, other conditions are the same as for Kir6.2 detection). Fig. 2b shows the neuronal membrane potential when resting on Kir6.2 channel-overexpressing cells in electrophysiological laboratory buffer supplemented with TP-014 to a concentration of 10 nM in electrophysiological laboratory buffer. It is the result of having confirmed that the potassium current which flows outward when changing to the plus side is suppressed (each group n = 5). This result shows that TP-014 inhibited the Kir6.2 channel and the potassium current excreted from the inside of the cell to the outside of the cell.
　［試験例３］
　試験例１と同様のKir6.2チャネル過剰発現細胞を用いて、TP-014処置による細胞外より細胞内へ流入するカルシウム量をカルシウムイメージング法により測定した。結果を図３に示す。カルシウムイメージング法は、培養した神経細胞にカルシウム蛍光色素（Fura2、同仁化学研究所製）を培養液中に4μMとなるように調整して処置し、カルシウム量を蛍光の強さで測定する方法である。イメージング装置（SUTTER INSTRUMENT 社製、LAMBDA10-2）を用い、同装置のマニュアルに従いイメージングを行った。図３aは、TP-014（1～100nM）およびメマンチン（100nM）を処置した際のTP-014濃度依存的なカルシウム量の経時変化を4分間にわたって測定した結果である。図３bは、メマンチン（100nM）、TP-014（1-100nM）処置から4分後のカルシウム量を測定した結果である（各群n=5）。TP-014はメマンチンより強力なカルシウム濃度増加作用を有しており、TP-014処置により、試験例２で確認された細胞外へのカリウム排出阻害作用による細胞内でのカルシウム量の有意な増加が確認された。 [Test Example 3]
Using the same Kir6.2 channel overexpressing cells as in Test Example 1, the amount of calcium flowing into the cells from outside the cells treated with TP-014 was measured by the calcium imaging method. The results are shown in FIG. In the calcium imaging method, cultured neurons are treated with calcium fluorescent dye (Fura2, manufactured by Dojindo Laboratories) adjusted to 4 μM in the culture solution, and the amount of calcium is measured by the intensity of fluorescence. is there. Imaging was performed using an imaging device (SUTTER INSTRUMENT, LAMBDA10-2) according to the manual of the device. FIG. 3a shows the result of measuring the time-dependent change of calcium amount dependent on TP-014 concentration when treated with TP-014 (1 to 100 nM) and memantine (100 nM) over 4 minutes. FIG. 3b shows the results of measuring the amount of calcium 4 minutes after treatment with memantine (100 nM) and TP-014 (1-100 nM) (each group n = 5). TP-014 has a stronger calcium concentration-increasing action than memantine, and treatment with TP-014 significantly increases the amount of calcium in the cell due to the inhibitory action of potassium excretion outside the cells confirmed in Test Example 2. Was confirmed.
　［試験例４］
　アルツハイマー病モデルマウス（APP23マウス、Sturchler-Pierrat et al., Proc. Natl. Acad. Sci. U.S.A. 1997, 94, 13287-13292）（12ヶ月齢）にTP-014（1mg/kg）を1日1回、２ヶ月間慢性処置（経口投与）した結果、有意な認知機能改善効果が確認された。結果を図４に示す。図４a-dは、行動解析の結果を示す。図４aおよび図４bは、通常のY-maze法により、野生型マウス（C57BL/6J、日本SLC）およびAPP23マウス（各n=5）の注意機能を検討した結果を示し、TP-014処置により有意な注意機能の改善効果が認められた。Y-maze法は、8分間マウスに３つのアームを自由に歩かせる方法である。アームをそれぞれＡ、Ｂ、ＣとするとＡにいるマウスはＢもしくはＣのアームに入り、仮にＢにマウスが入ったとすると、次にマウスはＣに入り、このように、Ａ－Ｂ－Ｃと入った場合を正解とする。一方、Ａ－Ｂ－Ａと新規のアームに入らない場合を不正解とし、マウスが移動したアームの位置を選択した順に記録し、マウスが測定時間内に各アームに移動した回数をカウントし、これを total arm entries とする。さらにこの中で正解だった場合（連続して異なる三つのアームを選択した組み合わせ）をカウントし、この数を交替行動回数 (No. of alternation) とし、No. of alternation の total arm entries から 2 を引いた数に対する割合を、正常の交替行動の指標 (空間作業記憶の正解率) としてalternation (%) で表す。 [Test Example 4]
Alzheimer's disease model mice (APP23 mice, Sturchler-Pierrat et al., Proc. Natl. Acad. Sci. USA 1997, 94, 13287-13292) (12 months old) TP-014 (1 mg / kg) per day As a result of chronic treatment (oral administration) for 2 months, a significant cognitive improvement effect was confirmed. The results are shown in FIG. Figures 4a-d show the results of behavioral analysis. 4a and 4b show the results of examining the attention function of wild-type mice (C57BL / 6J, Japan SLC) and APP23 mice (each n = 5) by the usual Y-maze method, and by TP-014 treatment. A significant improvement in attention function was observed. The Y-maze method is a method that allows a mouse to freely walk three arms for 8 minutes. If the arms are A, B, and C, respectively, the mouse in A enters the arm of B or C. If the mouse enters B, then the mouse enters C, and thus, ABC and The correct answer is entered. On the other hand, the case where it does not enter the new arm with ABA is regarded as an incorrect answer, the position of the arm moved by the mouse is recorded in the selected order, and the number of times the mouse has moved to each arm within the measurement time is counted. This is total arm entries. If the answer is correct (a combination of three consecutively different arms selected), count this number as the number of alternations (No. of alternation), and subtract 2 from the total arm entries for No. of alternation. The ratio to the number subtracted is expressed as an alternation (%) as an index of normal alternation behavior (correction rate of spatial working memory).
　マウスは新規性を好む傾向があり、通常のマウスでは70%の正解率を示すが、APP23マウスは50%程度に低下する。この%を指標として注意機能（認知機能）を解析する。 Mice tend to like novelty, normal mice show a 70% accuracy rate, but APP23 mice drop to around 50%. The attention function (cognitive function) is analyzed using this% as an index.
　図４cは通常の新規物体認識試験法による新規の物に対する記憶を、野生型マウス、App23マウスともn=5で、測定した結果を示す。新規物体認識試験法は同じ形の積み木を２つマウスケージに入れ、マウスに遊ばせる（10分間、これを訓練試行という）。その1時間後、片方の積み木を別の形のものに変える。通常のマウスは新規の物に興味を示すので、別の形の積み木と遊ぶ時間は増加する。アルツハイマー病マウスは新規物を認識しておらず、記憶障害がみられる。片方を別の積み木にした状態でさらに5分間自由に探索させる (これを保持試行という)。訓練試行及び保持試行では、2つのオブジェクトに対するそれぞれの接触回数を測定し、保持試行における総接触回数に対する入れ替えた別の積み木への接触回数の割合 (%) を判別指数 (Discrimination index) として算出した。 Fig. 4c shows the result of measuring the memory of a new object by a normal new object recognition test method with n = 5 for both wild type and App23 mice. In the new object recognition test method, two blocks of the same shape are put in a mouse cage and let the mouse play (this is called a training trial for 10 minutes). After an hour, change one building block to another. Since normal mice are interested in new things, the time to play with other forms of building blocks increases. Alzheimer's disease mice do not recognize novelty and have memory impairment. A trap that allows you to search freely for another 5 minutes with one of the blocks in another block (this is called holding trial). In the training trial and the holding trial, the number of times of contact with each of the two objects was measured, and the ratio 回 数 (%) の of the number of times of contact with another building block compared to the total number of times of contact in the holding trial was calculated as the discriminant index (Discrimination index) .
　図４dは、通常の恐怖条件付け試験法により恐怖記憶を測定（各n=5）した結果を示す。恐怖条件付け試験法は、マウスが明るい場所より暗い場所を好む特徴を利用した解析で、1日目にマウスを明るい場所に置く。マウスは暗い場所を好むので、暗い場所（暗室ボックス）に入るが、その時に電気刺激を与える。マウスは驚き明るい場所に戻り、その後、暗い場所には戻らない。2日目にマウスを明るい場所（1日目と同じ場所）に置き、マウスが暗い場所にはいるかどうかを5分間測定する。仮に、マウスがすぐに暗い場所に入れば恐怖記憶が低下していることになる。「Latency」は2日目に明るい場所にマウスを置いた際、暗室へ入るまでの時間を測定した秒数である。APP23マウスは暗い場所にすぐに入るので恐怖記憶の低下が確認されるが、TP-014を2ヶ月間処置すると改善効果が確認された。 FIG. 4d shows the result of measuring fear memory (each n = 5) by the usual fear conditioning test method. The fear conditioning test is an analysis that takes advantage of the characteristics that mice prefer a darker place than a brighter place. On the first day, place the mouse in a bright place. Since the mouse prefers a dark place, it enters a dark place (dark room box), at which time an electrical stimulus is applied. The mouse returns to a surprisingly bright place and then does not return to a dark place. On day 2, place the mouse in a bright place (the same place as day 1) and measure whether the mouse is in a dark place for 5 minutes. If the mouse immediately goes into a dark place, the fear memory is reduced. "Latency" is the number of seconds measured for the time it takes to enter the dark room when the mouse is placed in a bright place on the second day. APP23 mice enter a dark place immediately, so a decrease in fear memory was confirmed, but treatment with TP-014 for 2 months confirmed an improvement effect.
　図４e～図４gは電気生理学的手法により記憶形成の指標である長期増強現象（LTP）について検討した結果を示す。脳の海馬は記憶に重要であり、海馬をスライス状（400マイクロメートル厚）にし、同スライスを95% O2/5% CO2ガスで飽和させた人工脳脊髄液 (126 mM NaCl, 5 mM KCl, 26 mM NaHCO3, 1.3 mM MgSO4-7H2O, 1.26 mM KH2PO4, 2.4 mM CaCl2-2H2O, 10 mM グルコース) 中において、34 ℃で2時間回復させた。海馬スライスを測定チャンバーに移し、TP-014を人工脳脊髄液に添加して、灌流適用した。電気刺激による神経細胞の活動を記録と、シナプス後集合電位（fEPSP）の測定を行い、LTPの改善の程度を評価した。記録した波形を、図４eに示す。その後、100Hzの電気刺激を加え海馬に過疎的な変化を生じさせる（海馬では過疎的変化により記憶が形成されると考えられている）。神経細胞の興奮性の上昇率が、APP23マウスでは低下し、TP-014慢性処置では改善することが確認され、LTPの改善による記憶学習の改善効果を示している。 4e to 4g show the results of studying the long-term potentiation phenomenon (LTP), which is an index of memory formation, by electrophysiological techniques. The hippocampus of the brain is important for memory. Artificial cerebrospinal fluid (126 mM NaCl, 5 mM) is made by slicing the hippocampus into a slice (400 μm thick) and saturating the slice with 95% O 2 /5% CO 2 gas. (KCl, 26 mM NaHCO 3 , 1.3 mM MgSO 4 -7H 2 O, 1.26 mM KH 2 PO 4 , 2.4 mM CaCl 2 -2H 2 O, 10 mM glucose) at 34 ° C. for 2 hours. Hippocampal slices were transferred to the measurement chamber and TP-014 was added to the artificial cerebrospinal fluid and perfused. We recorded neuronal activity by electrical stimulation and measured post-synaptic collecting potential (fEPSP) to evaluate the degree of improvement of LTP. The recorded waveform is shown in FIG. After that, 100Hz electrical stimulation is applied to cause depopulation in the hippocampus (in the hippocampus, memory is thought to be formed by depopulation). The rate of increase in neuronal excitability was reduced in APP23 mice and improved in chronic treatment with TP-014, indicating an improvement in memory learning by improving LTP.
　［試験例５］
　APP23マウスの海馬を摘出し、海馬切片にSDSサンプルバッファーを加え懸濁後、免疫ブロット法によりCaMKII、CaMKIV、ERKに対する抗体（CaMKII：Fukunaga et al., J. Biol. Chem. 1992, 267, 22527-22533、CaMKIV：Kasahara et al., J. Biol. Chem.2001, 276, 24044-24050、ERK：Sigma-Aldrich社製）を用いて各タンパク質のリン酸化について検討した。結果を図５aおよび図５b に示す。CaMKII、CaMKIV、ERK はいずれも記憶形成に重要であると考えられている分子である。その結果、通常のAPP23マウスではCaMKIIのリン酸化の低下が見出され、PT-014慢性処置（処置条件は試験例４の場合と同じ）のAPP23マウスではCaMKIIのリン酸化の亢進が見出された。この結果より、CaMKIIの活性化がAPP23マウスにおけるPT-014処置による記憶改善効果に重要であることが示されている。 [Test Example 5]
The hippocampus of APP23 mice was excised, SDS sample buffer was added to the hippocampal slice, suspended, and antibodies against CaMKII, CaMKIV and ERK (CaMKII: Fukunaga et al., J. Biol. Chem. 1992, 267, 22527) by immunoblotting. -22533, CaMKIV: Kasahara et al., J. Biol. Chem. 2001, 276, 24044-24050, ERK (manufactured by Sigma-Aldrich)), phosphorylation of each protein was examined. The results are shown in FIGS. 5a and 5b. CaMKII, CaMKIV, and ERK are all molecules that are thought to be important for memory formation. As a result, a decrease in phosphorylation of CaMKII was found in normal APP23 mice, and an increase in phosphorylation of CaMKII was found in APP23 mice treated with PT-014 chronically (treatment conditions are the same as in Test Example 4). It was. This result indicates that the activation of CaMKII is important for the memory improvement effect by PT-014 treatment in APP23 mice.
　CaMKIIの活性化により活性化が誘導される分子として知られる、GluA1 (Ser-831)、Synapsin I (Ser-603)、CREB (Ser-133)について、海馬切片にSDSサンプルバッファーを加え懸濁後、免疫ブロット法により検討した。各分子に対する抗体はすべてMilipore社から入手した。結果を図５cおよび図５d に示す。GluA1 (Ser-831)およびCREB (Ser-133)の活性化がCaMKIIの活性化により誘導されていることを示している。図５aおよび図cは、実際に免疫ブロットを泳動した際に得られるバンド（画像）、図５bおよび図５dは図５aおよび図５cのバンドのシグナル強度を定量化しての解析結果である。 GluA1 (Ser-831), Synapsin I (Ser-603), and CREB (Ser-133), known as molecules whose activation is induced by CaMKII activation, are suspended after adding SDS sample buffer to hippocampal slices. This was examined by immunoblotting. All antibodies against each molecule were obtained from Millipore. The results are shown in FIGS. 5c and 5d. It shows that the activation of GluA1 (Ser-831) and CREB (Ser-133) is induced by the activation of CaMKII. 5a and c are bands (images) obtained when the immunoblot is actually run, and FIGS. 5b and 5d are analysis results obtained by quantifying the signal intensity of the bands of FIGS. 5a and 5c.
　［試験例６］
　図４と同様な実験を神経変性疾患モデルマウスである嗅球摘出マウス（OBXマウス）において確認した。結果を図６a～図６gに示す。OBXマウスにおける認知機能障害は、TP-014の慢性投与（2週間）により有意に改善した。OBXマウスは、10週齢のDDY 雄性マウス(Nippon SLC, Hamamatsu, Japan)を用いて作製した。嗅球摘出手術は、ペントバルビタールナトリウム(50mg/kg i.p.; Dainippon, Osaka, Japan) で麻酔した条件で施行した。マウスを脳固定器に固定し、嗅球上の頭蓋骨をドリルで穿孔し、直径1mmの穴をあけた。嗅球を、吸引ポンプにて前頭前皮質を傷つけないように吸引除去した。Sham 群では、嗅球の吸引除去を除いて OBX 群と同一の操作を行った。 [Test Example 6]
An experiment similar to FIG. 4 was confirmed in an olfactory bulb-extracted mouse (OBX mouse) which is a neurodegenerative disease model mouse. The results are shown in FIGS. 6a to 6g. Cognitive impairment in OBX mice was significantly improved by chronic administration of TP-014 (2 weeks). OBX mice were prepared using 10-week-old DDY male mice (Nippon SLC, Hamamatsu, Japan). Olfactory bulbectomy was performed under conditions of anesthesia with sodium pentobarbital (50 mg / kg ip; Dainippon, Osaka, Japan). The mouse was fixed to a brain fixator, the skull on the olfactory bulb was drilled with a drill, and a hole with a diameter of 1 mm was made. The olfactory bulb was removed by suction with a suction pump so as not to damage the prefrontal cortex. In the Sham group, the same operation as in the OBX group was performed except for removal of the olfactory bulb by suction.
　［試験例７］
　図５と同様に、OBXマウスにおける認知機能障害の細胞内メカニズムについて検討した。その結果を図７a～図７dに示す。記憶形成に重要な部位である海馬ではCaMKIIとCaMKIVの活性化が重要であることが明らかになった。また、CaMKIIとCaMKIVの活性化の下流分子であるGluA1 (Ser-831), CREB (Ser-133)の活性化も同様に重要であることが確認された。GluA1 (Ser-831), CREB (Ser-133)に対する抗体はいずれもMilipore社から入手した。図４～７の結果より、TP-014の認知機能改善効果には、CaMKIIとCaMKIVの活性亢進が重要であることが明らかとなった。CaMKIVの遺伝子を欠損したマウスでは、認知機能障害は認められないことから、認知機能改善効果にはCaMKIIが重要だと考えられる。 [Test Example 7]
Similar to FIG. 5, the intracellular mechanism of cognitive impairment in OBX mice was examined. The results are shown in FIGS. 7a to 7d. It was revealed that activation of CaMKII and CaMKIV is important in the hippocampus, which is an important site for memory formation. It was also confirmed that activation of GluA1 (Ser-831) and CREB (Ser-133), which are downstream molecules of the activation of CaMKII and CaMKIV, is also important. Antibodies against GluA1 (Ser-831) and CREB (Ser-133) were both obtained from Millipore. From the results of FIGS. 4 to 7, it became clear that the enhancement of the activities of CaMKII and CaMKIV is important for the improvement of cognitive function of TP-014. In mice lacking the CaMKIV gene, cognitive dysfunction is not observed, so CaMKII is thought to be important for improving cognitive function.
　［試験例８］
　TP-014の作用がKir6.2チャネル阻害作用であることを確認するために、Kir6.2チャネル欠損マウスを用いてTP-014の作用部位の同定を図４と同様の行動実験（図８aおよび図８b：Y-mazeテスト、図８c：新規物体認識試験法、図８ｄ：恐怖条件付け試験法、図８e～図８g：LTP改善評価、各群ともn=5）行った。結果を図８に示す。Kir6.2欠損マウスでは認知機能障害を誘発していることが確認された。この結果は、Kir6.2チャネルが記憶形成に重要であることを示す。また、Kir6.2欠損マウスの記憶障害およびLTPの減弱は、TP-014慢性処置（2ヶ月）では改善しないことが明らかとなった。この結果は、TP-014の作用部位がKir6.2チャネルであることを示している。解析手法は、試験例４～７と同様である。なお、Kir6.2欠損マウスは神戸大学医学部、清野進教授より入手した（Miki T et al., Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 10402-10406）。 [Test Example 8]
In order to confirm that the action of TP-014 is a Kir6.2 channel inhibitory action, the action site of TP-014 was identified using a Kir6.2 channel-deficient mouse in the same behavioral experiment as in FIG. Fig. 8b: Y-maze test, Fig. 8c: New object recognition test method, Fig. 8d: Fear conditioning test method, Fig. 8e to Fig. 8g: LTP improvement evaluation, n = 5 for each group. The results are shown in FIG. Kir6.2-deficient mice were confirmed to induce cognitive impairment. This result indicates that the Kir6.2 channel is important for memory formation. Moreover, it became clear that memory impairment and LTP attenuation in Kir6.2-deficient mice were not improved by chronic treatment with TP-014 (2 months). This result indicates that the site of action of TP-014 is the Kir6.2 channel. The analysis method is the same as in Test Examples 4-7. Kir6.2-deficient mice were obtained from Kobe University School of Medicine, Prof. Susumu Kiyono (Miki T et al., Proc. Natl. Acad. Sci. USA 1998, 95, 10402-10406).
　［試験例９］
　図４～７と同様の手法でCaMKIIの活性化、およびCaMKIIの活性化により活性化が誘導される分子として知られるGluA1 (Ser-831)について海馬切片にSDSサンプルバッファーを加え懸濁後に免疫ブロット法を行い、Kir6.2欠損マウスにおける認知機能障害の細胞内メカニズムについて検討した。結果を図９に示す（図９a：免疫ブロット法によるバンド像、図９b：バンドのシグナル強度の定量化結果）。Kir6.2欠損マウスの海馬では、CaMKIIの活性化は亢進しており、TP-014の慢性処置においても影響は認められなかった。Kir6.2チャネルの欠損により細胞内外におけるカルシウムの恒常性（バランス）に異常が認められ、CaMKIIのリン酸化が亢進した。TP-014はCaMKIIの活性化に影響を与えず、TP-014の作用部位がKir6.2チャネルであることを示す。 [Test Example 9]
Activated CaMKII in the same manner as in Figs. 4-7, and GluA1 (Ser-831), known as a molecule whose activation is induced by CaMKII activation, added SDS sample buffer to hippocampal slices and suspended immunoblots We investigated the intracellular mechanism of cognitive impairment in Kir6.2-deficient mice. The results are shown in FIG. 9 (FIG. 9a: band image by immunoblotting, FIG. 9b: quantification result of band signal intensity). In the hippocampus of Kir6.2-deficient mice, the activation of CaMKII was increased, and no effect was observed in chronic treatment with TP-014. Abnormality in calcium homeostasis (balance) was observed due to the loss of Kir6.2 channel, and phosphorylation of CaMKII was enhanced. TP-014 does not affect the activation of CaMKII, indicating that the site of action of TP-014 is the Kir6.2 channel.
　［試験例１０］
　アルツハイマー病の原因に関するamyloid-β（Aβ）仮説は、今なお重視されている。Aβの凝集がAPP23マウス（14ヶ月齢）で起こることを免疫染色法により確認している。脳を50マイクロメートルのスライス切片を作成し、WTは野生型（対照マウス）、APP23マウスそれぞれの場合について、6E10（Aβの抗体、abcam社製）およびThioflavinで染色した結果（凝集体を評価する指標）を図１０に示す。それ以外の条件は通常の免疫染色法に従った。APP23マウスにおいてはAβの凝集が促進していることが明らかになり、特に、大脳皮質（PFC）で多く認められた。一方、海馬（CA1）ではほとんど認められなかった。TP-014慢性処置によりAβの凝集は抑制されていた。この結果は、TP-014には、Aβの凝集抑制効果があることを示す。 [Test Example 10]
The amyloid-β (Aβ) hypothesis regarding the cause of Alzheimer's disease remains important. It has been confirmed by immunostaining that Aβ aggregation occurs in APP23 mice (14 months old). The brain was sliced into 50-micrometer slices, and WT was stained with 6E10 (Aβ antibody, abcam) and Thioflavin for wild-type (control mice) and APP23 mice (assessed aggregates) The index) is shown in FIG. Other conditions followed normal immunostaining. In APP23 mice, it was revealed that aggregation of Aβ was promoted, especially in the cerebral cortex (PFC). On the other hand, it was hardly observed in the hippocampus (CA1). Aβ aggregation was suppressed by chronic treatment with TP-014. This result indicates that TP-014 has an effect of suppressing aggregation of Aβ.
　［試験例１１］
　うつ病モデルマウスとしてOBXマウスを使用し、TP-014のうつ様症状の改善効果を確認した。結果を図１１に示す。OBXマウスは認知機能の低下も認められるが、もともとはうつ病モデルマウスとして確立したマウスであり、うつ病の測定法として、tail-suspension法（a）とforced swim法（b）を解析した。tail-suspension法はマウスの尻尾を挟み、逆向きに吊り下げる方法で、吊り下げられたマウスはうつ病であれば無動時間（immobility time）が長くなる。通常のマウスは吊り下げられても動くので無動時間は低い。forced swim法はビーカーに水を張りマウスをビーカーの中で泳がせる。うつ病のマウスは泳がず動かず（浮いた状況）、この動かない時間（無動時間、immmobility time(s) ）を測定する。OBXマウスはtail-suspension法（a）とforced swim法（b）における無動時間の増加が認められた。TP-014の慢性投与（2週間、投与方法は前例に同じ）で無動時間は改善した。この結果より、TP-014はOBXマウスのうつ様症状の改善効果があることが明らかになった（各群ともn=5）。 [Test Example 11]
OBX mice were used as depression model mice, and the effect of TP-014 to improve depression-like symptoms was confirmed. The results are shown in FIG. Although the cognitive function of OBX mice is also reduced, it was originally established as a depression model mouse. The tail-suspension method (a) and the forced swim method (b) were analyzed as methods for measuring depression. The tail-suspension method is a method in which the tail of the mouse is sandwiched and hung in the opposite direction. If the mouse is depressed, the immobility time becomes longer. A normal mouse moves even when it is suspended, so the immobility time is low. The forced swim method fills the beaker with water and allows the mouse to swim in the beaker. Depressed mice do not swim and do not move (floating), and measure this time (immobility time (s)). OBX mice showed an increase in immobility time in the tail-suspension method (a) and the forced swim method (b). Immobility time improved with chronic administration of TP-014 (2 weeks, the method of administration is the same as the previous example). These results revealed that TP-014 has an effect of improving depression-like symptoms in OBX mice (n = 5 in each group).
　［試験例１２］
　マウスは、Kir6.1欠損マウス（ヘテロ型、各群n=5）を用いて、図１１と同様の手法によりtail-suspension法（a）とforced swim法（b）における無動時間を測定した。ヘテロ型マウスはホモ型（完全な欠損マウス）と異なりKir6.1チャネルの発現量が半分になっているマウスである（ホモ型はすると生後に不整脈を起こし死亡する）。結果を図１２に示す。Kir6.1欠損マウスはうつ様症状の亢進を示し、この結果からKir6.1がうつ病に重要な分子であることがわかる。また、TP-014の慢性処置は効果を示さず、TP-014はKir6.1チャネルの阻害作用を介してうつ改善効果を示すことが確認された。Kir6.1欠損マウスは神戸大学医学部、清野進教授より入手した（Miki T et al., Nature Medicine 2002, 8, 466-472）。 [Test Example 12]
The mice were measured for immobility time in tail-suspension method (a) and forced swim method (b) using Kir6.1-deficient mice (heterotype, each group n = 5) in the same manner as in FIG. . A heterozygous mouse is a mouse in which the expression level of Kir6.1 channel is halved unlike a homozygous mouse (completely deficient mouse) (a homozygous mouse causes arrhythmia after birth and dies). The results are shown in FIG. Kir6.1-deficient mice show increased depression-like symptoms, and this result indicates that Kir6.1 is an important molecule for depression. In addition, it was confirmed that chronic treatment with TP-014 has no effect, and TP-014 has an effect of improving depression through the inhibitory action of Kir6.1 channel. Kir6.1-deficient mice were obtained from Professor Susumu Kiyono, Faculty of Medicine, Kobe University (Miki T et al., Nature Medicine 2002, 8, 466-472).
　［試験例１３］
　図１２と同様にKir6.1チャネルにより誘導されるCaMKIVについてCaMKIV欠損マウス（各群n=5*）を用いて解析した。結果を図１３に示す。CaMKIV欠損マウスでも同様にうつ様症状の亢進が確認され、この結果からCaMKIVもうつ病の発症機序に重要であることがわかる。TP-014は、CaMKIVのうつ症状（無動時間の亢進）に効果を示さなかった。TP-014は、Kir6.1チャネルを阻害し、CaMKIVの活性化を介してうつ病の改善効果を示すことが明らかとなった。CaMKIV欠損マウスは北里大学医学部、坂上洋行教授より入手した（Takao K et al., PLoS One 2010, 5, e9460）。 [Test Example 13]
Similarly to FIG. 12, CaMKIV induced by Kir6.1 channel was analyzed using CaMKIV-deficient mice (each group n = 5 *). The results are shown in FIG. CaMKIV-deficient mice were also found to have increased depression-like symptoms, and these results indicate that they are important for the pathogenesis of CaMKIV depression. TP-014 had no effect on CaMKIV depressive symptoms (increased immobility time). It was revealed that TP-014 inhibits the Kir6.1 channel and has an effect of improving depression through the activation of CaMKIV. CaMKIV-deficient mice were obtained from Prof. Hiroyuki Sakagami, Kitasato University School of Medicine (Takao K et al., PLoS One 2010, 5, e9460).
　［試験例１４］
　TP-014の血糖値の低下作用をassay kit（Technicon International co社製）を使用して血液中のglucose濃度を測定して確認した。結果を図１４に示す。測定は4週間行い、TP-014（1mg/kg）を4週間慢性処置した結果、3週目以降において有意な血糖値の低下が確認されました。対照としてtolbutamideを使用した。Kir6.2チャネルは細胞膜上でSUR1（尿素受容体）と結合し、チャネルを形成しており、作用機序は、Kir6.2チャネル阻害作用によるものと考えられる。TolbutamideはSUR1に結合し、Kir6.2チャネルを阻害する。 [Test Example 14]
The blood glucose level-lowering effect of TP-014 was confirmed by measuring glucose concentration in blood using an assay kit (manufactured by Technicon International co). The results are shown in FIG. Measurement was conducted for 4 weeks, and TP-014 (1 mg / kg) was chronically treated for 4 weeks. As a result, a significant decrease in blood glucose level was confirmed after the 3rd week. Tolbutamide was used as a control. The Kir6.2 channel binds to SUR1 (urea receptor) on the cell membrane to form a channel, and the mechanism of action is thought to be due to the Kir6.2 channel inhibitory action. Tolbutamide binds to SUR1 and inhibits the Kir6.2 channel.
　［試験例１５］
　Kir6.1チャネルのcDNAが挿入されたプラスミドベクター：pcDNA3.1-Kir6.1は東北大学大学院生命科学研究科、石塚徹博士より入手した。当該プラスミドベクターを用いた以外は、試験例１のKir6.2チャネル過剰発現N2A細胞の調製と同じ手法により、Kir6.1チャネルを過剰発現させたN2A細胞を得た。 [Test Example 15]
The plasmid vector inserted with Kir6.1 channel cDNA: pcDNA3.1-Kir6.1 was obtained from Tohoku University Graduate School of Life Sciences, Dr. Toru Ishizuka. N2A cells overexpressing the Kir6.1 channel were obtained by the same method as the preparation of Kir6.2 channel overexpressing N2A cells in Test Example 1 except that the plasmid vector was used.
　得られたKir6.1チャネル過剰発現細胞を用いて、CaMKIVの活性化について測定した、測定手法は試験例１と同様の免疫ブロット法であり、一次抗体に抗リン酸化CaMKIV抗体（Kasahara J et al., J. Biol. Chem.2001, 276, 24044-50）を、2次抗体に抗ウサギIgG抗体（SouthernBiotech社製）を用いた。 The obtained Kir6.1 channel overexpressing cells were used to measure the activation of CaMKIV. The measurement method was the same immunoblotting method as in Test Example 1, and the primary antibody was an anti-phosphorylated CaMKIV antibody (Kasahara J et al ., J. Biol. Chem. 2001, 276, 44 24044-50) and anti-rabbit IgG antibody (manufactured by Southern Biotech) as the secondary antibody.
　さらに、得られたKir6.1チャネル過剰発現細胞を用いて、通常のPatch-clamp法により細胞内より細胞外へ排出されるカリウム電流を測定した。結果を図１８に示す。ATP感受性カリウムチャネル（Kir6.1チャネル）は、神経細胞の細胞膜に局在し、チャネルが阻害され閉塞すると神経細胞膜の閾値が上昇し、一過性の活動電位が発生するのと類似した状況を作り、細胞内より細胞外へカリウム電流が排出され、その代わりに細胞外より細胞内へカルシウム電流が流入する。図１８aは、抗Kir6.1チャネル抗体（常法に基づき作成）を用いたKir6.1チャネル過剰発現細胞（上述の方法による）に対する免疫ブロット法（抗Kir6.1チャネル抗体の使用以外の条件は試験例１の条件と同様、n=5）により、N2A細胞でKir6.1チャネルが過剰発現していることを確認した（上は免疫ブロット法による染色像、下は同染色像のバンドシグナル強度を量的に表現したもの）。ハウスキーピング遺伝子であるβチューブリンに変動はみられなかった（抗βチューブリン抗体はSigma-Aldrichから入手し、他の条件はKir6.1の検出に同じ）。図１８ｂは、TP-014を電気生理学実験用緩衝液中の濃度で10nMになるように添加した電気生理学実験用緩衝液中でKir6.2チャネル過剰発現細胞に静置すると、神経細胞の膜電位をプラス側へ変化させる際に流れる外向きに流れるカリウム電流が抑制されることを確認した結果である（各群n=5）。この結果は、TP-014はKir6.1チャネルを阻害し、細胞内より細胞外へ排出されるカリウム電流を阻害したことを示している。 Furthermore, using the obtained Kir6.1 channel overexpressing cells, the potassium current discharged from the inside of the cell to the outside of the cell was measured by the usual patch-clamp method. The results are shown in FIG. ATP-sensitive potassium channel (Kir6.1 channel) is localized in the cell membrane of nerve cells, and when the channel is blocked and occluded, the threshold value of the nerve cell membrane rises, and a transient action potential is generated. The potassium current is discharged from the inside of the cell to the outside of the cell, and instead, the calcium current flows from the outside of the cell to the inside of the cell. FIG. 18a shows an immunoblotting method using an anti-Kir6.1 channel antibody (prepared based on a conventional method) on a cell overexpressing Kir6.1 channel (according to the method described above) (except for the use of anti-Kir6.1 channel antibody). As in Test Example 1, n = 5) confirmed that the Kir6.1 channel was overexpressed in N2A cells (upper stained image by immunoblotting, lower band signal intensity of the same stained image) Quantitative expression). There was no change in the housekeeping gene β-tubulin (anti-β-tubulin antibody was obtained from Sigma-Aldrich, other conditions are the same as for Kir6.1 detection). FIG. 18 b shows that when resting on Kir6.2 channel overexpressing cells in an electrophysiological laboratory buffer supplemented with TP-014 to a concentration of 10 nM in the electrophysiological laboratory buffer, the membrane potential of the neuronal cell It is the result of having confirmed that the potassium current which flows outward when changing to the plus side is suppressed (each group n = 5). This result indicates that TP-014 inhibited the Kir6.1 channel and the potassium current excreted from the inside of the cell to the outside of the cell.
　［試験例１６］
　不安様症状を示す疾患モデルマウスとしてコルチコステロンを投与した野生型マウス（C57BL/6J、日本SLC、２ヶ月齢、5mg/kgで1日1回の投与を2週間）およびコルチコステロンを投与したKir6.1欠損マウスを用いて不安関連行動に関する５つの行動試験を行った。なお、Kir6.1欠損マウスは神戸大学医学部、清野進教授より入手した（Miki T et al., Nature Mededicine2002, 8, 466-472）。 [Test Example 16]
Wild-type mice (C57BL / 6J, Japan SLC, 2 months old, 5 mg / kg administered once a day for 2 weeks) administered corticosterone as a disease model mouse showing anxiety-like symptoms and corticosterone Five behavioral tests on anxiety-related behaviors were conducted using Kir6.1-deficient mice. Kir6.1-deficient mice were obtained from Kobe University School of Medicine and Prof. Susumu Kiyono (Miki T et al., Nature Mededicine 2002, 8, 466-472).
　コルチコステロン投与野生型マウス、およびコルチコステロン投与Kir6.1欠損マウスにTP-014（1mg/kg）を1日1回、２週間慢性処置（経口投与）した結果、有意な不安症状亢進の改善効果が確認された。結果を図１９に示す。 Corticosterone-treated wild-type mice and corticosterone-treated Kir6.1-deficient mice were treated with TP-014 (1 mg / kg) once a day for 2 weeks, resulting in significant anxiety symptoms. The improvement effect was confirmed. The results are shown in FIG.
　図１９aは、高架式十字迷路法（elevated-plus maze法、図１９b）により、各群（各n=5）の不安に対する脆弱性を検討した結果を示す。ここで使用する装置では高い場所に十字路となったアームが設けられており、各アームは下が見える状態か、閉ざされた状態のいずれかとなっている。不安に対して脆弱なマウスは閉ざされたアーム（close arm）に長く留まる、不安に対して抵抗性を有するマウスは下が見えるアーム（open arm）に留まる。図１９aは縦軸にopen armの滞在時間を示す。 Fig. 19a shows the results of examining the vulnerability to anxiety of each group (each n = 5) by the elevated plus maze method (elevated plus maze method, Fig. 19b). In the apparatus used here, arms that are crossroads are provided at high places, and each arm is either in a state where the bottom can be seen or in a closed state. Mice that are vulnerable to anxiety will stay longer in the closed arm, while mice that are resistant to anxiety will stay in the open arm. FIG. 19a shows the staying time of the open arm on the vertical axis.
　図１９cは、明暗試験法（light-dark 法、図１９d）による試験結果を示す（各群n=5）。黒い箱の中（暗い場所）に入れたマウスが、光に対して不安を感じた結果、外（明るい場所）へ出て来るまでに要する時間を測定した。図１９cは縦軸に外へ出るまでの時間（entory of open compartment）を示す。 FIG. 19c shows the test results by the light-dark test method (light-dark test method, FIG. 19d) (each group n = 5). As a result of feeling anxious about the light in the black box (dark place), the time required for the mouse to come out (light place) was measured. FIG. 19c shows the time (entory of open compartment) until going out on the vertical axis.
　図１９eはビー玉かくし試験法（Marble burying法、図１９f）による結果を示す（各群n=5）。マウスをいれたケージに床敷チップをしき、その上にビー玉を２０個マウスから見えるように置く。マウスを30分間自由に探索させ、床敷チップの中に埋めて隠すビー玉の数を測定する。マウスは光る物体を苦手とするため、不安に対して強いマウスが多くのビー玉に接触する。図１９eは縦軸に埋められたビー玉の数を示す。 FIG. 19e shows the result of the marble cracking test method (Marble-burying method, FIG. 19f) (each group n = 5). Place a floor chip in the cage containing the mouse and place 20 marbles on it so that it can be seen by the mouse. Allow the mouse to explore freely for 30 minutes and measure the number of marbles buried and hidden in the floor chip. Since mice are not good at shining objects, mice that are strong against anxiety come in contact with many marbles. FIG. 19e shows the number of marbles buried on the vertical axis.
　図１９gは、オープンフィールド法（open field法、図１９h）による試験結果を示す（各群n=5）。四角い箱の中に入れたマウスに30分間箱内を探索させる。一般的にマウスは不安が強く、箱の隅に沿ってを歩く習性を持つが、不安に強いマウスは箱の中心部分を通る割合が多くなることを指標とする。図１９gは箱の中心部分に留まる時間を示す。 FIG. 19g shows the test results by the open field method (open field method, FIG. 19h) (each group n = 5). Let the mouse in the box search for 30 minutes. In general, mice have strong anxiety and have a habit of walking along the corners of the box, but mice that are strong in anxiety use the ratio of passing through the center of the box as an index. FIG. 19g shows the time spent in the center of the box.
　図１９iは、は、恐怖条件付試験法（fear conditining法）による試験結果を示す（各群n=5）。明暗試験法の試験装置を使用し、マウスを暗い場所に入れ、30秒間に渡り音（高音）を鳴らし、その後、電気刺激を3秒与える。音の後に電気刺激を3回繰り返し、マウスに音がなると電気刺激を受けることを認識させる。翌日、5分間音を鳴らし続ける際に恐怖不安を感じたマウスの無動時間（immobility time）を測定する。図１９iの縦軸はマウスの無動時間を示す。 FIG. 19i shows the test results by the fear-conditioning test method (fear-conditining method) (each group n = 5). Using a light / dark test method, place the mouse in a dark place, play a high tone for 30 seconds, and then apply electrical stimulation for 3 seconds. Repeat the electrical stimulation three times after the sound, and let the mouse recognize that it receives the electrical stimulation when it makes a sound. The next day, measure the immobility time of mice that felt fearful when they continued to sound for 5 minutes. The vertical axis of Fig. 19i indicates the immobility time of the mouse.
　上記の全ての試験結果においてTP-014の慢性投与（２週間）が不安様症状亢進を改善することが確認された。またKir6.1欠損マウスもコルチコステロンの投与により不安様症状を示すが、TP-014の投与による改善効果は認められなかった。この結果より、本発明化合物の不安様症状亢進の改善効果はKir6.1を介することが確認された。 In all the above test results, it was confirmed that chronic administration of TP-014 (2 weeks) improved anxiety-like symptoms. Kir6.1-deficient mice also showed anxiety-like symptoms by administration of corticosterone, but no improvement effect was observed by administration of TP-014. From this result, it was confirmed that the improvement effect of anxiety-like symptom enhancement of the compound of the present invention is mediated by Kir6.1.
　なお、本願の図に示される有意差の表示について、＊＊もしくは＋＋は有意差がＰ＜０．０１であることを示し、＋もしくは＊はＰ＜０．０５を示す。 In the display of the significant difference shown in the figure of the present application, ** or ++ indicates that the significant difference is P <0.01, and + or * indicates P <0.05.

Claims (17)

  1. 　式（Ｉ）：
    ［式中、Ｑ１、Ｑ２、Ｒ１、およびＲ４は、それぞれ独立に、水素原子、ハロゲン原子、１以上のハロゲン原子で置換されていてもよいＣ１－６アルキル、アミノ、Ｘ１より選択される１以上の置換基により置換されていてもよいＣ６－１０アリール、カルボキシ、－ＯＲ７、および－ＳＲ８から選択され；
    　Ｒ２は、水素原子、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルスルホニル、１以上のハロゲン原子により置換されていてもよい（Ｃ１－６アルキル）スルホニル、または－ＣＯＹＲ６であり；
    　Ｙは、直接結合、Ｏ、またはＮＲ９であり；
    　Ｒ３は、Ｘ１より選択される１以上の置換基により置換されていてもよいＣ３－８シクロアルキル、Ｘ１より選択される１以上の置換基により置換されていてもよいＣ６－１０アリール、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルアミノカルボニル、Ｘ１より選択される１以上の置換基により置換されていてもよい５～１０員単環式または二環式ヘテロアリール、Ｘ１より選択される１以上の置換基により置換されていてもよい５～１０員単環式または二環式非芳香族ヘテロシクリル、または－Ｑ３－Ｒ１３であり；
    　Ｑ３は、Ｃ１－３アルキレン、またはＣ２－３アルケニレンであり；
    　Ｒ１３は、Ｘ１より選択される１以上の置換基により置換されていてもよいＣ６－１０アリールであり；
    　Ｒ５は、水素原子、または１以上のハロゲン原子で置換されていてもよいＣ１－６アルキルであり；
    　Ｒ６は、Ｃ１－６アルキル、Ｘ１より選択される１以上の置換基により置換されていてもよいＣ６－１０アリール、またはＸ１より選択される１以上の置換基により置換されていてもよい５又は６員環ヘテロアリールであり、ここでアルキルは１以上のハロゲン原子により置換されていてもよく、および／またはＸ２より選択される１つの置換基により置換されていてもよく；
    　Ｒ７は、水素原子、１以上のハロゲン原子で置換されていてもよいＣ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、１以上のハロゲン原子で置換されていてもよい（Ｃ１－６アルキル）カルボニル、またはＸ１より選択される１以上の置換基により置換されていてもよいＣ６－１０アリールであり；
    　Ｒ８は、水素原子、１以上のハロゲン原子で置換されていてもよいＣ１－６アルキル、またはＸ１より選択される１以上の置換基により置換されていてもよいＣ６－１０アリールであり；
    　Ｒ９は、水素原子、または１以上のハロゲン原子で置換されていてもよいＣ１－６アルキルであり；
    　Ｘ１は、それぞれ独立に、Ｃ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ、ヒドロキシ、ニトロ、およびシアノから選択され；
    　Ｘ２は、Ｃ１－６アルコキシ、Ｃ２－６アルケニルオキシ、Ｃ２－６アルキニルオキシ、および－ＮＲ１１Ｒ１２から選択され；
    　Ｒ１１は、水素原子、Ｃ１－６アルキル、（Ｃ１－６アルコキシ）カルボニル、またはアリール部分がＸ１より選択される１以上の置換基により置換されていてもよい［（Ｃ６－１０アリール）Ｃ１－３アルコキシ］カルボニルであり、ここでアルキルまたはアルコキシ部分は１以上のハロゲン原子により置換されていてもよく；
    　Ｒ１２は、水素原子、または１以上のハロゲン原子で置換されていてもよいＣ１－６アルキルであり；
    　ここで、アダマンチル基に含まれるメチレンは、Ｃ１－６アルキル、Ｃ１－６アルコキシ、およびヒドロキシから独立に選択される１以上の基により置換されていてもよく、ここでアルキルまたはアルコキシは、１以上のハロゲン原子で置換されていてもよく、
    　前記単環式または二環式非芳香族ヘテロシクリルのメチレン部分はオキソにより置換されていてもよい］
    で表される化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。     Formula (I):
    [Wherein, Q 1 , Q 2 , R 1 and R 4 each independently represent a hydrogen atom, a halogen atom, C 1-6 alkyl optionally substituted with one or more halogen atoms, amino, X 1 Selected from C 6-10 aryl, carboxy, —OR 7 , and —SR 8 optionally substituted by one or more substituents selected from;
    R 2 is a hydrogen atom, phenylsulfonyl optionally substituted with one or more substituents selected from X 1 , (C 1-6 alkyl) sulfonyl optionally substituted with one or more halogen atoms, or -COYR 6 ;
    Y is a direct bond, O, or NR 9 ;
    R 3 is optionally substituted by one or more optionally substituted with a substituent C 3-8 cycloalkyl, one or more substituents selected from X 1 is selected from X 1 C 6- 10 aryl, 1 or more phenyl aminocarbonyl optionally substituted by a substituent, one or more 10-membered to 5 may be substituted by a substituent monocyclic selected from X 1 is selected from X 1 Or a bicyclic heteroaryl, a 5- to 10-membered monocyclic or bicyclic non-aromatic heterocyclyl optionally substituted by one or more substituents selected from X 1 , or —Q 3 —R 13 ;
    Q 3 is C 1-3 alkylene or C 2-3 alkenylene;
    R 13 is C 6-10 aryl optionally substituted by one or more substituents selected from X 1 ;
    R 5 is a hydrogen atom or C 1-6 alkyl optionally substituted with one or more halogen atoms;
    R 6 is, C 1-6 alkyl, optionally substituted by one or more substituents selected from optionally substituted C 6-10 aryl or X 1, by one or more substituents selected from X 1 Optionally substituted 5- or 6-membered heteroaryl, wherein alkyl may be substituted by one or more halogen atoms and / or may be substituted by one substituent selected from X 2 ;
    R 7 is a hydrogen atom, C 1-6 alkyl optionally substituted with one or more halogen atoms, C 1-6 alkoxy C 1-6 alkyl, optionally substituted with one or more halogen atoms (C 1-6 alkyl) carbonyl, or C 6-10 aryl optionally substituted by one or more substituents selected from X 1 ;
    R 8 is a hydrogen atom, C 1-6 alkyl optionally substituted with one or more halogen atoms, or C 6-10 aryl optionally substituted with one or more substituents selected from X 1 Yes;
    R 9 is a hydrogen atom or C 1-6 alkyl optionally substituted with one or more halogen atoms;
    Each X 1 is independently selected from C 1-6 alkyl, a halogen atom, C 1-6 alkoxy, hydroxy, nitro, and cyano;
    X 2 is selected from C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, and —NR 11 R 12 ;
    In R 11 , a hydrogen atom, C 1-6 alkyl, (C 1-6 alkoxy) carbonyl, or an aryl moiety may be substituted with one or more substituents selected from X 1 [(C 6-10 Aryl) C 1-3 alkoxy] carbonyl, wherein the alkyl or alkoxy moiety may be substituted by one or more halogen atoms;
    R 12 is a hydrogen atom, or C 1-6 alkyl optionally substituted with one or more halogen atoms;
    Here, the methylene contained in the adamantyl group may be substituted with one or more groups independently selected from C 1-6 alkyl, C 1-6 alkoxy, and hydroxy, where alkyl or alkoxy is Optionally substituted with one or more halogen atoms,
    The methylene moiety of the monocyclic or bicyclic non-aromatic heterocyclyl may be substituted by oxo]
    Or an enantiomer, diastereomer, or pharmaceutically acceptable salt thereof.
  2. 　式（Ｉ）：
    Figure JPOXMLDOC01-appb-C000002
     ［式中、Ｑ１は、水素原子、ハロゲン原子、１以上のハロゲン原子で置換されていてもよいＣ１－６アルキル、アミノ、または－ＯＲ１０であり；
    　Ｒ１０は、水素原子、１以上のハロゲン原子で置換されていてもよいＣ１－６アルキル、または１以上のハロゲン原子で置換されていてもよい（Ｃ１－６アルキル）カルボニルであり；
    　Ｑ２は、水素原子、Ｃ１－６アルキル、またはＣ１－６アルコキシであり、ここでアルキルまたはアルコキシは、１以上のハロゲン原子で置換されていてもよく；
    　Ｒ１は、水素原子、Ｃ１－６アルキル、またはＣ１－６アルコキシであり、ここでアルキルまたはアルコキシは、１以上のハロゲン原子で置換されていてもよく；
    　Ｒ２は、水素原子、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルスルホニル、１以上のハロゲン原子により置換されていてもよい（Ｃ１－６アルキル）スルホニル、または－ＣＯＹＲ６であり；
    　Ｙは、直接結合、Ｏ、またはＮＲ９であり；
    　Ｒ３は、Ｃ３－８シクロアルキル、Ｘ１より選択される１以上の置換基により置換されていてもよいＣ６－１０アリール、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルアミノカルボニル、Ｘ１より選択される１以上の置換基により置換されていてもよい５～１０員単環式または二環式ヘテロアリール、または－Ｑ３－Ｒ１３であり；
    　Ｑ３は、Ｃ１－３アルキレン、またはＣ２－３アルケニレンであり；
    　Ｒ１３は、Ｘ１より選択される１以上の置換基により置換されていてもよいＣ６－１０アリールであり；
    　Ｒ４は、水素原子、ハロゲン原子、１以上のハロゲン原子により置換されていてもよいＣ１－６アルキル、Ｘ３より選択される１以上の置換基により置換されていてもよいフェニル、カルボキシ、－ＯＲ７、または－ＳＲ８であり；
    　Ｒ５は、水素原子、またはＣ１－６アルキルであり；
    　Ｒ６は、Ｃ１－６アルキル、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニル、またはＸ１より選択される１以上の置換基により置換されていてもよい５又は６員環ヘテロアリールであり、ここでアルキルは１以上のハロゲン原子により置換されていてもよく、および／またはＸ２より選択される１つの置換基により置換されていてもよく；
    　Ｒ７は、水素原子、１以上のハロゲン原子で置換されていてもよいＣ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、または１以上のハロゲン原子で置換されていてもよい（Ｃ１－６アルキル）カルボニルであり；
    　Ｒ８は、Ｃ１－６アルキル、またはＸ１より選択される１以上の置換基により置換されていてもよいフェニルであり；
    　Ｒ９は、水素原子、またはＣ１－６アルキルであり；
    　Ｘ１は、それぞれ独立に、Ｃ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ、ニトロ、およびシアノから選択され；
    　Ｘ２は、Ｃ１－６アルコキシ、Ｃ２－６アルケニルオキシ、Ｃ２－６アルキニルオキシ、および－ＮＲ１１Ｒ１２から選択され；
    　Ｘ３は、それぞれ独立に、Ｃ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ、ヒドロキシ、ニトロ、およびシアノから選択され；
    　Ｒ１１は、水素原子、Ｃ１－６アルキル、（Ｃ１－６アルコキシ）カルボニル、またはフェニル部分がＸ１より選択される１以上の置換基により置換されていてもよいベンジルオキシカルボニルであり；
    　Ｒ１２は、水素原子、またはＣ１－６アルキルであり；
    　ここで、アダマンチル基に含まれるメチレンは、Ｃ１－６アルキル、およびＣ１－６アルコキシから独立に選択される１以上の基により置換されていてもよく、ここでアルキルまたはアルコキシは、１以上のハロゲン原子で置換されていてもよい］
    で表される、請求項１に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。     Formula (I):
    Figure JPOXMLDOC01-appb-C000002
     [Wherein Q 1 is a hydrogen atom, a halogen atom, C 1-6 alkyl optionally substituted with one or more halogen atoms, amino, or —OR 10 ;
    R 10 is a hydrogen atom, C 1-6 alkyl optionally substituted with one or more halogen atoms, or (C 1-6 alkyl) carbonyl optionally substituted with one or more halogen atoms;
    Q 2 is a hydrogen atom, C 1-6 alkyl, or C 1-6 alkoxy, wherein alkyl or alkoxy may be substituted with one or more halogen atoms;
    R 1 is a hydrogen atom, C 1-6 alkyl, or C 1-6 alkoxy, where alkyl or alkoxy may be substituted with one or more halogen atoms;
    R 2 is a hydrogen atom, phenylsulfonyl optionally substituted with one or more substituents selected from X 1 , (C 1-6 alkyl) sulfonyl optionally substituted with one or more halogen atoms, or -COYR 6 ;
    Y is a direct bond, O, or NR 9 ;
    R 3 is optionally substituted by C 3-8 cycloalkyl, the one or more optionally substituted with a substituent C 6-10 aryl, one or more substituents selected from X 1 is selected from X 1 Optionally phenylaminocarbonyl, 5- to 10-membered monocyclic or bicyclic heteroaryl optionally substituted by one or more substituents selected from X 1 , or —Q 3 —R 13 ;
    Q 3 is C 1-3 alkylene or C 2-3 alkenylene;
    R 13 is C 6-10 aryl optionally substituted by one or more substituents selected from X 1 ;
    R 4 is a hydrogen atom, a halogen atom, C 1-6 alkyl which may be substituted with one or more halogen atoms, phenyl, carboxy which may be substituted with one or more substituents selected from X 3 , -OR 7 or -SR 8 ;
    R 5 is a hydrogen atom or C 1-6 alkyl;
    R 6 is, C 1-6 alkyl, phenyl optionally substituted by one or more substituents selected from X 1 or may be X 1 is substituted by one or more substituents selected from, 5 Or a 6-membered heteroaryl, wherein alkyl may be substituted by one or more halogen atoms and / or may be substituted by one substituent selected from X 2 ;
    R 7 is a hydrogen atom, C 1-6 alkyl optionally substituted with one or more halogen atoms, C 1-6 alkoxy C 1-6 alkyl, or optionally substituted with one or more halogen atoms ( C 1-6 alkyl) carbonyl;
    R 8 is C 1-6 alkyl, or phenyl optionally substituted by one or more substituents selected from X 1 ;
    R 9 is a hydrogen atom or C 1-6 alkyl;
    Each X 1 is independently selected from C 1-6 alkyl, a halogen atom, C 1-6 alkoxy, nitro, and cyano;
    X 2 is selected from C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, and —NR 11 R 12 ;
    Each X 3 is independently selected from C 1-6 alkyl, a halogen atom, C 1-6 alkoxy, hydroxy, nitro, and cyano;
    R 11 is a hydrogen atom, C 1-6 alkyl, (C 1-6 alkoxy) carbonyl, or benzyloxycarbonyl, wherein the phenyl moiety may be substituted with one or more substituents selected from X 1 ;
    R 12 is a hydrogen atom or C 1-6 alkyl;
    Here, methylene contained in the adamantyl group may be substituted with one or more groups independently selected from C 1-6 alkyl and C 1-6 alkoxy, wherein alkyl or alkoxy is one or more May be substituted with a halogen atom of
    The compound according to claim 1, which is represented by the formula: embedded image thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
  3. 　式（Ｉａ）：
    Figure JPOXMLDOC01-appb-C000003
     ［式中、Ｑ１は、水素原子、ハロゲン原子、または－ＯＲ１０であり；
    　Ｒ１０は、水素原子、または１以上のハロゲン原子で置換されていてもよい（Ｃ１－６アルキル）カルボニルであり；
    　Ｒ２は、水素原子、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルスルホニル、１以上のハロゲン原子により置換されていてもよい（Ｃ１－６アルキル）スルホニル、または－ＣＯＹＲ６であり；
    　Ｙは、直接結合、Ｏ、またはＮＲ９であり；
    　Ｒ３は、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニル、またはＸ１より選択される１以上の置換基により置換されていてもよい５又は６員環ヘテロアリールであり；
    　Ｒ４は、水素原子、ハロゲン原子、－ＯＲ７、または－ＳＲ８であり；
    　Ｒ５は、水素原子、またはＣ１－６アルキルであり；
    　Ｒ６は、Ｃ１－６アルキル、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニル、またはＸ１より選択される１以上の置換基により置換されていてもよい５又は６員環ヘテロアリールであり、ここでＣ１－６アルキルは１以上のハロゲン原子により置換されていてもよく、および／またはＸ２より選択される１つの置換基により置換されていてもよく；
    　Ｒ７は、水素原子、Ｃ１－６アルキル、Ｃ１－６アルコキシＣ１－６アルキル、または１以上のハロゲン原子で置換されていてもよい（Ｃ１－６アルキル）カルボニルであり；
    　Ｒ８は、Ｃ１－６アルキル、またはＸ１より選択される１以上の置換基により置換されていてもよいフェニルであり；
    　Ｒ９は、水素原子、またはＣ１－６アルキルであり；
    　Ｘ１は、それぞれ独立に、Ｃ１－６アルキル、ハロゲン原子、Ｃ１－６アルコキシ、ニトロ、およびシアノから選択され；
    　Ｘ２は、Ｃ１－６アルコキシ、Ｃ２－６アルケニルオキシ、Ｃ２－６アルキニルオキシ、および－ＮＲ１１Ｒ１２から選択され；
    　Ｒ１１は、水素原子、Ｃ１－６アルキル、（Ｃ１－６アルコキシ）カルボニル、またはフェニル部分がＸ１より選択される１以上の置換基により置換されていてもよいベンジルオキシカルボニルであり；
    　Ｒ１２は、水素原子、またはＣ１－６アルキルである］
    で表される、請求項１または２に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。     Formula (Ia):
    Figure JPOXMLDOC01-appb-C000003
     [Wherein Q 1 is a hydrogen atom, a halogen atom, or —OR 10 ;
    R 10 is a hydrogen atom or (C 1-6 alkyl) carbonyl optionally substituted with one or more halogen atoms;
    R 2 is a hydrogen atom, phenylsulfonyl optionally substituted with one or more substituents selected from X 1 , (C 1-6 alkyl) sulfonyl optionally substituted with one or more halogen atoms, or -COYR 6 ;
    Y is a direct bond, O, or NR 9 ;
    R 3 is one or more phenyl which is substituted by a substituent or one or more substituents the optionally substituted 5 or 6 membered heteroaryl selected from X 1, is selected from X 1 Is;
    R 4 is a hydrogen atom, a halogen atom, —OR 7 , or —SR 8 ;
    R 5 is a hydrogen atom or C 1-6 alkyl;
    R 6 is, C 1-6 alkyl, phenyl optionally substituted by one or more substituents selected from X 1 or may be X 1 is substituted by one or more substituents selected from, 5 Or a 6-membered heteroaryl, wherein C 1-6 alkyl may be substituted by one or more halogen atoms and / or may be substituted by one substituent selected from X 2 ;
    R 7 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy C 1-6 alkyl, or (C 1-6 alkyl) carbonyl optionally substituted with one or more halogen atoms;
    R 8 is C 1-6 alkyl, or phenyl optionally substituted by one or more substituents selected from X 1 ;
    R 9 is a hydrogen atom or C 1-6 alkyl;
    Each X 1 is independently selected from C 1-6 alkyl, a halogen atom, C 1-6 alkoxy, nitro, and cyano;
    X 2 is selected from C 1-6 alkoxy, C 2-6 alkenyloxy, C 2-6 alkynyloxy, and —NR 11 R 12 ;
    R 11 is a hydrogen atom, C 1-6 alkyl, (C 1-6 alkoxy) carbonyl, or benzyloxycarbonyl, wherein the phenyl moiety may be substituted with one or more substituents selected from X 1 ;
    R 12 is a hydrogen atom or C 1-6 alkyl]
    The compound of Claim 1 or 2 represented by these, its enantiomer, its diastereomer, or its pharmaceutically acceptable salt.
  4. 　Ｑ１およびＲ４が、水素原子である、請求項１～３のいずれか１項に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 The compound according to any one of claims 1 to 3, wherein Q 1 and R 4 are a hydrogen atom, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
  5. 　Ｑ１およびＲ４が、ハロゲン原子より選択される、請求項１～３のいずれか１項に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 The compound, enantiomer, diastereomer thereof, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein Q 1 and R 4 are selected from halogen atoms.
  6. 　Ｑ１およびＲ４が、塩素原子である、請求項１～３、および５のいずれか１項に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 The compound according to any one of claims 1 to 3, and 5, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof, wherein Q 1 and R 4 are a chlorine atom.
  7. 　Ｒ２が、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルスルホニル、１以上のハロゲン原子により置換されていてもよい（Ｃ１－６アルキル）スルホニル、または－ＣＯＲ６である、請求項１～６のいずれか１項に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 R 2 is phenylsulfonyl optionally substituted with one or more substituents selected from X 1 , (C 1-6 alkyl) sulfonyl optionally substituted with one or more halogen atoms, or —COR 6 The compound according to any one of claims 1 to 6, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof.
  8. 　Ｒ２が、トリフルオロアセチルである、請求項１～７のいずれか１項に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 The compound according to any one of claims 1 to 7, R 2 is trifluoroacetyl, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
  9. 　Ｒ３が、Ｘ１より選択される１以上の置換基により置換されていてもよいフェニルである、請求項１～８のいずれか１項に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 The compound according to any one of claims 1 to 8, its enantiomer, its diastereomer, or R 3 , which is phenyl optionally substituted by one or more substituents selected from X 1 A pharmaceutically acceptable salt thereof.
  10. 　Ｒ５は、水素原子である、請求項１～９のいずれか１項に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。 The compound according to any one of claims 1 to 9, R 5 is a hydrogen atom, an enantiomer thereof, a diastereomer thereof, or a pharmaceutically acceptable salt thereof.
  11. 　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－５－クロロ－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセトアミド）メチル）アダマンタン－１－イル；
    　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－５－クロロ－１－ヒドロキシアダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド；
    　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｒ，７Ｓ）－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセタミド）メチル）アダマンタン－１－イル；
    　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－５－（２－メトキシエトキシ）－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセタミド）メチル）アダマンタン－１－イル；
    　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－５－クロロ－１－ヒドロキシアダマンタン－２－イル）（ピリジン－３－イル）メチル）－２，２，２－トリフルオロアセトアミド；
    　２，２，２－トリフルオロ－Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｒ，７Ｓ）－１－ヒドロキシアダマンタン－２－イル）（フェニル）メチル）アセタミド；
    　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－５－メトキシ－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセタミド）メチル）アダマンタン－１－イル；
    　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド；
    　（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メタンアミン；
    　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アセタミド；
    　メチル　（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）カーバメート；
    　１－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－３－フェニルウレア；
    　ベンジル　（２－（（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アミノ）－２－オキソエチル）カーバメート；
    　２－アミノ－Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アセタミド；
    　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）メタンスルホンアミド；
    　２－ブロモ－Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）アセタミド；
    　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－２－（プロパ－２－イン－１－イルオキシ）アセタミド；
    　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－１，１，１－トリフルオロメタンスルホンアミド；
    　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－２－ニトロベンゼンスルホンアミド；および
    　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）－４－ニトロベンゼンスルホンアミド；
    　Ｎ－（（Ｓ）－（（１Ｓ，３Ｓ，５Ｓ，７Ｓ）－アダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド；
    　Ｎ－（（Ｒ）－（（１Ｒ，３Ｒ，５Ｒ，７Ｒ）－アダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド；および
    　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセトアミド）メチル）－５－（フェニルチオ）アダマンタン－１－イル；
    　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）ベンズアミド；
    　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）ピコリンアミド；
    　Ｎ－（（Ｒ）－（（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｒ）－１，５－ジクロロアダマンタン－２－イル）（フェニル）メチル）ベンゼンスルホンアミド；
    　２，２，２－トリフルオロ酢酸（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－５－クロロ－２－（（Ｓ）－フェニル（２，２，２－トリフルオロアセタミド）メチル）アダマンタン－１－イル； 
    　Ｎ－（（１Ｒ）－（（１Ｒ，２Ｓ，３Ｒ，５Ｒ，７Ｒ）－５－クロロ－１－ヒドロキシアダマンタン－２－イル）（フェニル）メチル）－２，２，２－トリフルオロアセタミド；
    　２，２，２－トリフルオロ酢酸（１Ｒ，２Ｓ，３Ｒ，５Ｒ，７Ｒ）－５－クロロ－２－（（Ｒ）－フェニル（２，２，２－トリフルオロアセタミド）メチル）アダマンタン－１－イル；および
    　（１Ｓ，２Ｒ，３Ｓ，５Ｓ，７Ｓ）－２－（（Ｒ）－アミノ（フェニル）メチル）－５－クロロアダマンタン－１－オール
    から選択される、請求項１に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩。     2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5S, 7S) -5-chloro-2-((R) -phenyl (2,2,2-trifluoroacetamido) methyl) adamantane-1- Ill;
    N-((R)-((1S, 2R, 3S, 5S, 7S) -5-chloro-1-hydroxyadamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide;
    2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5R, 7S) -2-((R) -phenyl (2,2,2-trifluoroacetamido) methyl) adamantan-1-yl;
    2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5S, 7R) -5- (2-methoxyethoxy) -2-((R) -phenyl (2,2,2-trifluoroacetamide) Methyl) adamantan-1-yl;
    N-((R)-((1S, 2R, 3S, 5S, 7S) -5-chloro-1-hydroxyadamantan-2-yl) (pyridin-3-yl) methyl) -2,2,2-tri Fluoroacetamide;
    2,2,2-trifluoro-N-((R)-((1S, 2R, 3S, 5R, 7S) -1-hydroxyadamantan-2-yl) (phenyl) methyl) acetamide;
    2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5S, 7R) -5-methoxy-2-((R) -phenyl (2,2,2-trifluoroacetamide) methyl) adamantane-1 -Il;
    N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide;
    (R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methanamine;
    N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) acetamide;
    Methyl ((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) carbamate;
    1-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -3-phenylurea;
    Benzyl (2-(((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) amino) -2-oxoethyl) carbamate;
    2-amino-N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) acetamide;
    N-((R)-((1S, 2R, 3S, 5S, 7S) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) methanesulfonamide;
    2-bromo-N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) acetamide;
    N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -2- (prop-2-yn-1-yloxy) Acetamide;
    N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -1,1,1-trifluoromethanesulfonamide;
    N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -2-nitrobenzenesulfonamide; and N-((R) -((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) -4-nitrobenzenesulfonamide;
    N-((S)-((1S, 3S, 5S, 7S) -adamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide;
    N-((R)-((1R, 3R, 5R, 7R) -adamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide; and 2,2,2-trifluoro Acetic acid (1S, 2R, 3S, 5S, 7S) -2-((R) -phenyl (2,2,2-trifluoroacetamido) methyl) -5- (phenylthio) adamantan-1-yl;
    N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) benzamide;
    N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) picolinamide;
    N-((R)-((1S, 2R, 3S, 5S, 7R) -1,5-dichloroadamantan-2-yl) (phenyl) methyl) benzenesulfonamide;
    2,2,2-trifluoroacetic acid (1S, 2R, 3S, 5S, 7S) -5-chloro-2-((S) -phenyl (2,2,2-trifluoroacetamide) methyl) adamantane-1 -Il;
    N-((1R)-((1R, 2S, 3R, 5R, 7R) -5-chloro-1-hydroxyadamantan-2-yl) (phenyl) methyl) -2,2,2-trifluoroacetamide;
    2,2,2-trifluoroacetic acid (1R, 2S, 3R, 5R, 7R) -5-chloro-2-((R) -phenyl (2,2,2-trifluoroacetamide) methyl) adamantane-1 The compound of claim 1, selected from: -yl; and (1S, 2R, 3S, 5S, 7S) -2-((R) -amino (phenyl) methyl) -5-chloroadamantan-1-ol , Its enantiomers, its diastereomers, or pharmaceutically acceptable salts thereof.
  12. 　請求項１～１１のいずれか１項に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 11, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof.
  13. 　認知機能疾患または障害の治療又は予防に用いるための、請求項１２に記載の医薬組成物。 The pharmaceutical composition according to claim 12, for use in the treatment or prevention of a cognitive function disease or disorder.
  14. 　認知機能疾患または障害が、アルツハイマー型認知症、脳血管性認知症、レビー小体型認知症、前頭側頭型認知症、パーキンソン病、精神疾患、神経変性疾患から選択される、請求項１３に記載の医薬組成物。 The cognitive function disease or disorder is selected from Alzheimer's dementia, cerebrovascular dementia, Lewy body dementia, frontotemporal dementia, Parkinson's disease, psychiatric disorder, neurodegenerative disease. Pharmaceutical composition.
  15. 　糖尿病または糖尿病性合併症の治療又は予防に用いるための、請求項１２に記載の医薬組成物。 The pharmaceutical composition according to claim 12, for use in the treatment or prevention of diabetes or diabetic complications.
  16. 　請求項１～１１のいずれか１項に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩を含有する、Ｋｉｒ６．２チャネル阻害薬。 A Kir6.2 channel inhibitor comprising the compound according to any one of claims 1 to 11, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof.
  17. 　請求項１～１１のいずれか１項に記載の化合物、そのエナンチオマー、そのジアステレオマー、または医薬として許容なその塩を含有する、Ｋｉｒ６．１チャネル阻害薬。
          A Kir6.1 channel inhibitor comprising the compound according to any one of claims 1 to 11, its enantiomer, its diastereomer, or a pharmaceutically acceptable salt thereof.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3663279A4 (en) * 2017-08-02 2022-07-06 Tohoku University Adamantylmethylamine derivative and use thereof as pharmaceutical

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008525425A (en) * 2004-12-22 2008-07-17 ニューロケム （インターナショナル） リミテッド Methods and compositions for treating amyloid-related diseases
JP2010519304A (en) * 2007-02-26 2010-06-03 ヴァイティー ファーマシューティカルズ，インコーポレイテッド Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1
WO2017131097A1 (en) * 2016-01-26 2017-08-03 国立大学法人東北大学 Adamantane derivative and use thereof
CN107556244A (en) * 2016-07-01 2018-01-09 上海迪诺医药科技有限公司 And cycle compound, its pharmaceutical composition and application

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008525425A (en) * 2004-12-22 2008-07-17 ニューロケム （インターナショナル） リミテッド Methods and compositions for treating amyloid-related diseases
JP2010519304A (en) * 2007-02-26 2010-06-03 ヴァイティー ファーマシューティカルズ，インコーポレイテッド Cyclic urea and carbamate inhibitors of 11β-hydroxysteroid dehydrogenase 1
WO2017131097A1 (en) * 2016-01-26 2017-08-03 国立大学法人東北大学 Adamantane derivative and use thereof
CN107556244A (en) * 2016-07-01 2018-01-09 上海迪诺医药科技有限公司 And cycle compound, its pharmaceutical composition and application

Non-Patent Citations (11)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY [online] 2015, retrieved from STN Database accession no. RN1782740-93-5 *
DATABASE REGISTRY 2016, retrieved from STN Database accession no. RN1974817-09-8 *
DATABASE REGISTRY 2016, retrieved from STN Database accession no. RN1975313-60-0 *
DATABASE REGISTRY 2016, retrieved from STN Database accession no. RN1976903-74-8 *
DATABASE REGISTRY 2016, retrieved from STN Database accession no. RN1979117-44-6 *
DATABASE REGISTRY 2016, retrieved from STN Database accession no. RN1980645-09-7 *
DATABASE REGISTRY 2016, retrieved from STN Database accession no. RN1981386-54-2 *
DATABASE REGISTRY 4 June 2018 (2018-06-04), retrieved from STN Database accession no. RN1974644-59-1 *
LACHENICHT, S. ET AL.: "Synthesis of Modified 4H-1,2,4-Benzothiadiazine-1,1-dioxides and Determination of their Affinity and Selectivity for Different Types of KATP Channels", CHEMMEDCHEM, vol. 4, no. 11, 2009, pages 1850 - 1858, XP055553106, DOI: doi:10.1002/cmdc.200900261 *
MORIGUCHI, S. ET AL.: "Blockade of the KATP channel Kir6. 2 by memantine represents a novel mechanism relevant to Alzheimer's disease therapy", MOLECULAR PSYCHIATRY, vol. 23, no. 2, 2016, pages 211 - 221, XP055553101 *
TERAMOTO, N.: "Pharmacological Profile of U-37883A, a Channel Blocker of Smooth Muscle-Type ATP-Sensitive K+ Channels", CARDIOVASCULAR DRUG REVIEWS, vol. 24, no. 1, 2006, pages 25 - 32, XP055553127, DOI: doi:10.1111/j.1527-3466.2006.00025.x *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3663279A4 (en) * 2017-08-02 2022-07-06 Tohoku University Adamantylmethylamine derivative and use thereof as pharmaceutical
US11608313B2 (en) 2017-08-02 2023-03-21 Tohoku University Adamantylmethylamine derivative and use thereof as pharmaceutical

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