WO2018181986A1 - Dérivé d'adamantylméthylamine et son utilisation en tant que produit pharmaceutique - Google Patents

Dérivé d'adamantylméthylamine et son utilisation en tant que produit pharmaceutique Download PDF

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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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alkyl
phenyl
optionally substituted
methyl
hydrogen atom
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PCT/JP2018/013853
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Japanese (ja)
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茂樹 森口
浩司 福永
好治 岩渕
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国立大学法人東北大学
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Priority claimed from PCT/JP2017/013616 external-priority patent/WO2018179343A1/fr
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Publication of WO2018181986A1 publication Critical patent/WO2018181986A1/fr

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    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
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    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
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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

La présente invention concerne une composition pharmaceutique pour traiter ou prévenir une maladie ou un trouble de la fonction cognitive, la composition comprenant un composé représenté par la formule (I), un énantiomère, un diastéréoisomère, ou un sel pharmaceutiquement acceptable de celui-ci.
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