WO2011070781A1 - Dérivé d'aminothiazine substitué - Google Patents

Dérivé d'aminothiazine substitué Download PDF

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WO2011070781A1
WO2011070781A1 PCT/JP2010/007153 JP2010007153W WO2011070781A1 WO 2011070781 A1 WO2011070781 A1 WO 2011070781A1 JP 2010007153 W JP2010007153 W JP 2010007153W WO 2011070781 A1 WO2011070781 A1 WO 2011070781A1
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substituted
unsubstituted
carbocyclic
heterocyclic
ring
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PCT/JP2010/007153
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Japanese (ja)
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阿南浩輔
多田幸男
堀章洋
桝井盛泰
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塩野義製薬株式会社
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Priority to US13/514,516 priority Critical patent/US20120245154A1/en
Priority to JP2011545088A priority patent/JPWO2011070781A1/ja
Priority to EP10835704.7A priority patent/EP2514747A4/fr
Publication of WO2011070781A1 publication Critical patent/WO2011070781A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
    • C07D279/06—1,3-Thiazines; Hydrogenated 1,3-thiazines not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to a compound having an amyloid ⁇ production inhibitory effect and useful as a therapeutic or prophylactic agent for diseases induced by production, secretion and / or deposition of amyloid ⁇ protein.
  • Alzheimer's disease In the brain of Alzheimer's disease patients, insoluble spots (senile plaques) in which a peptide consisting of about 40 amino acids called amyloid ⁇ protein accumulates outside the nerve cells are widely observed. It is thought that Alzheimer's disease develops when this senile plaque kills nerve cells, and amyloid ⁇ protein degradation accelerators, amyloid ⁇ vaccines, and the like have been studied as therapeutic agents for Alzheimer's disease.
  • Secretase is an enzyme that cleaves a protein called amyloid ⁇ precursor protein (APP) in cells to produce amyloid ⁇ protein.
  • the enzyme responsible for the N-terminal generation of amyloid ⁇ protein is called ⁇ -site APP-cleaving enzyme 1, BACE1, and inhibiting this enzyme suppresses amyloid ⁇ protein production and treats Alzheimer's disease Or it could be a prophylactic agent.
  • Patent Document 8 and Non-Patent Document 2 describe compounds having a structure similar to that of the present invention, but describe that they are useful as dyes and antibacterial agents, respectively.
  • Patent Documents 1 to 7, 9, 10 and Non-Patent Document 1 are known as BACE1 inhibitors, all of which have a structure different from that of the compound of the present invention.
  • a compound having an inhibitory action on amyloid ⁇ production particularly a BACE1 inhibitory action, and useful as a therapeutic or preventive agent for diseases induced by production, secretion or deposition of amyloid ⁇ protein.
  • the present invention provides the following items, for example.
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxy Carbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted carbocyclic group or substituted or unsubstituted heterocyclic group, R 2a and R 2b are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, or substituted or unsubstituted carbamoyl;
  • R 3a is halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy
  • Substituted or unsubstituted alkylthio substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxy Carbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, substituted or unsub
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyano, substituted or unsubstituted carbocyclic group or substituted or unsubstituted heterocyclic group.
  • R 2a and R 2b are each independently hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
  • R 3a is halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy
  • Substituted or unsubstituted alkylthio substituted or unsubstituted alkenylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyl Oxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubsti
  • ring A ′ and ring B are each independently a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring
  • L 1 and L 2 are each independently a single bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene or substituted or unsubstituted alkynylene
  • R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted acyl
  • R 9 is hydrogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl
  • composition according to item (10) or (11) which is a medicament for treating or preventing a disease induced by production, secretion or deposition of amyloid ⁇ protein.
  • a pharmaceutical composition comprising the compound according to any one of items (1), (1 ′) and (2) to (9), a pharmaceutically acceptable salt thereof, or a solvate thereof is prepared.
  • the compound of the present invention is useful as a therapeutic or prophylactic agent for diseases (such as Alzheimer's disease) induced by production, secretion or deposition of amyloid ⁇ protein.
  • halogen includes fluorine, chlorine, bromine and iodine.
  • alkyl refers to a linear or branched alkyl having 1 to 15 carbon atoms, such as 1 to 10 carbon atoms, such as 1 to 6 carbon atoms, such as 1 to 3 carbon atoms.
  • alkoxy “halogenoalkyl”, “hydroxyalkyl”, “halogenoalkoxy”, “hydroxyalkoxy”, “alkoxycarbonyl”, “halogenoalkoxycarbonyl”, “alkoxycarbonylalkyl”, “alkylamino”
  • Aminoalkyl “alkoxyalkoxy”, “alkoxyalkenyl”, “alkoxyalkenyloxy”, “alkoxycarbonylalkenyl”, “alkoxyalkynyl”, “alkoxycarbonylalkynyl”, “alkylcarbamoyl”, “hydroxyalkylcarbamoyl”, “Alkoxyimino", “alkylthio", “alkylsulfonyl”, “alkylsulfonylamino”, “alkylsulfonylalkylamino”, “alkylsulfonylimino”, “Alkylsulfinylamino”, “alkylsulfinyla
  • substituted or unsubstituted alkyl may be substituted with one or more groups selected from the substituent group ⁇ .
  • the substituent group ⁇ is halogen, hydroxy, alkoxy, halogenoalkoxy, hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, alkylamino, imino, hydroxyimino, alkoxyimino, alkylthio, Carbamoyl, alkylcarbamoyl, hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl, alkylsulfonylamino, alkylsulfonylalkylamino, alkylsulfonylimino, alkylsulfinylamino, alkylsulfinylalkylamino, alkylsulfinylimino, cyano, nitro, carbon Cyclic and heterocyclic groups (where each carbo,
  • substituted or unsubstituted alkoxy “substituted or unsubstituted alkoxycarbonyl”, “substituted or unsubstituted alkylthio”, “substituted or unsubstituted alkylsulfinyl”, “substituted or unsubstituted alkyl”
  • substituent for “sulfonyl” include one or more groups selected from the substituent group ⁇ .
  • halogenoalkyl examples include trifluoromethyl, fluoromethyl, trichloromethyl and the like.
  • halogenoalkoxy examples include trifluoromethoxy, fluoromethoxy, trichloromethoxy and the like.
  • alkylidene includes the above-mentioned divalent group of “alkyl” and includes, for example, methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene, hexylidene and the like.
  • alkenyl means 2 to 15 carbon atoms having one or more double bonds at any position, for example, 2 to 10 carbon atoms, for example, 2 to 6 carbon atoms, for example, 2 carbon atoms. Includes up to 4 linear or branched alkenyl.
  • alkynyl is a straight chain or branched chain having 2 to 10 carbon atoms, for example, 2 to 8 carbon atoms, for example 3 to 6 carbon atoms, having one or more triple bonds at any position.
  • alkynyl Specifically, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like are included. These may further have a double bond at an arbitrary position.
  • substituted or unsubstituted alkenyl “substituted or unsubstituted alkynyl”, “substituted or unsubstituted alkenyloxy”, “substituted or unsubstituted alkynyloxy”, “substituted or unsubstituted alkenyl” Thio, substituted or unsubstituted alkynylthio, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted Examples of the substituent of “alkynylsulfinyl”, “substituted or unsubstituted alkenylsulfonyl” and “substituted or unsubstituted alkynylsulfonyl” include
  • alkoxyalkenyl As used herein, “alkoxyalkenyl”, “alkoxycarbonylalkenyl”, “alkenyloxy”, “alkenyloxycarbonyl”, “alkoxyalkenyloxy”, “alkenylthio”, “alkenylsulfinyl”, “alkenylsulfonyl” and “alkenyl”
  • alkenyl part of “amino” is the same as the above “alkenyl”.
  • alkoxyalkynyl As used herein, “alkoxyalkynyl”, “alkoxycarbonylalkynyl”, “alkynyloxy”, “alkoxyalkynyloxy”, “alkynyloxycarbonyl”, “alkynylsulfinyl”, “alkynylsulfonyl”, “alkynylthio” and “alkynyl”
  • alkynyl part of “amino” is the same as the above “alkynyl”.
  • substituents of “substituted or unsubstituted amino”, “substituted or unsubstituted carbamoyl”, “substituted or unsubstituted thiocarbamoyl” and “substituted or unsubstituted sulfamoyl” include alkyl, acyl 1 to 2 groups selected from hydroxy, alkoxy, alkoxycarbonyl, carbocyclic group, heterocyclic group and the like.
  • acyl includes aliphatic acyl having 1 to 10 carbon atoms, carbocyclic carbonyl and heterocyclic carbonyl. Specifically, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioroyl, methacryloyl, crotonoyl, benzoyl, cyclohexanecarbonyl, pyridinecarbonyl, furancarbonyl, thiophenecarbonyl, benzothiazolecarbonyl, pyrazinecarbonyl, Examples include piperidine carbonyl and thiomorpholino.
  • acyl part of “acyloxy” and “acylamino” is the same as the above “acyl”.
  • examples of the substituent of “substituted or unsubstituted acyl” and “substituted or unsubstituted acyloxy” include one or more groups selected from the substituent group ⁇ .
  • the ring portion of carbocyclic carbonyl and heterocyclic carbonyl is substituted with one or more groups selected from alkyl, substituent group ⁇ , and alkyl substituted with one or more groups selected from substituent group ⁇ . It may be.
  • “carbocyclic group” includes cycloalkyl, cycloalkenyl, aryl, non-aromatic fused carbocyclic group and the like.
  • cycloalkyl is a carbocyclic group having 3 to 10, for example, 3 to 8, for example, 4 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Includes cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
  • cycloalkylalkyl In the present specification, “cycloalkylalkyl”, “cycloalkyloxy”, “cycloalkylalkoxy”, “cycloalkylthio”, “cycloalkylamino”, “cycloalkylalkylamino”, “cycloalkylsulfamoyl”, “ The cycloalkyl part of “cycloalkylsulfonyl”, “cycloalkylcarbamoyl”, “cycloalkylalkylcarbamoyl”, “cycloalkylalkoxycarbonyl” and “cycloalkyloxycarbonyl” is the same as the above “cycloalkyl”.
  • cycloalkenyl includes those having one or more double bonds at any position in the ring of the “cycloalkyl”, specifically, cyclopropenyl, cyclobutenyl, And cyclopentenyl, cyclohexenyl, cycloheptynyl, cyclooctynyl, cyclohexadienyl and the like.
  • aryl includes phenyl, naphthyl, anthryl, phenanthryl and the like, and particularly includes phenyl.
  • non-aromatic fused carbocyclic group means a non-aromatic group in which two or more cyclic groups selected from the above “cycloalkyl”, “cycloalkenyl” and “aryl” are condensed. Specific examples include indanyl, indenyl, tetrahydronaphthyl and fluorenyl.
  • “carbocycle”, “carbocycle oxy”, “carbocycle alkyl”, “carbocycle alkoxy”, “carbocycle alkoxycarbonyl”, “carbocycle thio”, “carbocycle amino”, “carbocycle” Carbocycles of alkylamino, carbocyclic carbonyl, carbocyclic sulfamoyl, carbocyclic sulfinyl, carbocyclic sulfonyl, carbocyclic carbamoyl, carbocyclic alkylcarbamoyl, and carbocyclic oxycarbonyl The moiety is the same as the “carbocyclic group”.
  • arylalkyl In the present specification, “arylalkyl”, “aryloxy”, “aryloxycarbonyl”, “arylalkoxycarbonyl”, “arylthio”, “arylamino”, “arylalkoxy”, “arylalkylamino”, “arylsulfonyl”
  • aryl part of “arylsulfamoyl”, “arylcarbamoyl” and “arylalkylcarbamoyl” is the same as the above “aryl”.
  • the “heterocyclic group” includes a heterocyclic group having one or more hetero atoms arbitrarily selected from O, S and N, specifically, pyrrolyl, imidazolyl, 5- to 6-membered heteroaryl such as pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl; Dioxanyl, thilanyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imida
  • heterocycle “heterocycle alkyl”, “heterocycle oxy”, “heterocycle thio”, “heterocycle carbonyl”, “heterocycle oxycarbonyl”, “heterocycle alkoxy”, “heterocycle” “Amino”, “heterocyclic sulfamoyl”, “heterocyclic sulfinyl”, “heterocyclic sulfonyl”, “heterocyclic carbamoyl”, “heterocyclic oxycarbonyl”, “heterocyclic alkylamino”, “heterocyclic alkoxycarbonyl” and “heterocyclic”
  • the heterocyclic moiety of “ring alkylcarbamoyl” is the same as the above “heterocyclic group”.
  • the bond of the above “heterocyclic group” may be located on any ring.
  • heteroaryl includes those of the above “heterocyclic group” which are aromatic cyclic groups. The same applies to the heteroaryl part of “heteroarylalkyl” and “heteroarylalkoxy”.
  • ring A includes, for example, a group represented by the following formula:
  • ring A ′ and ring B are each independently a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring
  • W 2 is O, S or NR 8
  • R 8 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsubstituted acyl;
  • R 9 is hydrogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl or substituted or unsub
  • L is each independently a single bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene or substituted or unsubstituted alkynylene, and ring T is substituted with a group selected from substituent group ⁇
  • substituents include, for example, halogen, hydroxy, alkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, carbamoyl, amino, cyano, alkylamino and / or alkylthio, etc.); Substituent group ⁇ , alkyl substituted with one or more groups selected from the group consisting of hydroxyimino and alkoxyimino (wherein the substituents include, for example, halogen, hydroxy, alkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, carbamoyl, amino, cyano, alkylamino and / or alkylthio, etc.); Substituent group ⁇ , alkyl substituted with one or more groups selected from the group consisting of hydroxyimino and alkoxyimino (wherein the substituents include, for example, halogen
  • substituted or unsubstituted carbocycle substituted or unsubstituted benzene
  • substituted or unsubstituted heterocycle substituted or unsubstituted pyridine
  • substituents of “substituted or unsubstituted pyrimidine” and “substituted or unsubstituted pyrazine” are substituted with one or more groups selected from halogen, cyano, hydroxy, nitro, carboxy, substituent group ⁇ , for example.
  • examples of the substituent other than —Z-ring B in the “substituted or unsubstituted carbocycle” or “substituted or unsubstituted heterocycle” in ring A include, for example, halogen, hydroxy, alkyl, alkenyl , Alkynyl, alkoxy, alkenyloxy, alkynyloxy, acyl, carboxy, alkoxycarbonyl, amino or cyano.
  • substituent of “substituted or unsubstituted carbocycle”, “substituted or unsubstituted benzene” or “substituted or unsubstituted heterocycle” in ring A ′ is, for example, halogen.
  • alkylene includes a linear or branched divalent carbon chain having 1 to 10, for example, 1 to 6, for example, 1 to 3 carbon atoms. Specific examples include methylene, dimethylene, trimethylene, tetramethylene, methyltrimethylene and the like.
  • alkylene part of “alkylenedioxy” is the same as the above “alkylene”.
  • alkenylene means a linear or branched carbon having 2 to 10 carbon atoms having a double bond at an arbitrary position, for example, 2 to 6 carbon atoms, such as 2 having 2 to 4 carbon atoms. Includes a valent carbon chain. Specific examples include vinylene, propenylene, butenylene, butadienylene, methylpropenylene, pentenylene and hexenylene.
  • alkynylene means a linear or branched carbon number of 2 to 10, for example, carbon number, which has a triple bond at an arbitrary position and may further have a double bond. It includes 2 to 6, for example, a divalent carbon chain having 2 to 4 carbon atoms. Specific examples include ethynylene, propynylene, butynylene, pentynylene and hexynylene.
  • substituents of “substituted or unsubstituted alkylene”, “substituted or unsubstituted alkenylene”, and “substituted or unsubstituted alkynylene” include substituents selected from the substituent group ⁇ . For example, halogen, hydroxy and the like.
  • Etc may be substituted at any position with one or more groups selected from the group consisting of alkyl substituted with one or more groups selected from substituent group ⁇ , unsubstituted alkyl, and substituent group ⁇ . Good.
  • Etc may be substituted at any position with one or more groups selected from the group consisting of alkyl substituted with one or more groups selected from substituent group ⁇ , unsubstituted alkyl, and substituent group ⁇ . Good.
  • the “solvate” includes, for example, solvates and hydrates with an organic solvent, and can be converted into solvates and hydrates by a known method.
  • Suitable solvates include solvates with acetone, 2-butanol, 2-propanol, ethanol, ethyl acetate, tetrahydrofuran, diethyl ether and the like.
  • non-toxic and water-soluble hydrates or solvates for example, ethanol and the like
  • it may be coordinated with any number of solvent molecules or water molecules.
  • the compounds represented by formula (I), formula (I ') and formula (Ia) to formula (In) include pharmaceutically acceptable salts.
  • alkali metals such as lithium, sodium or potassium
  • alkaline earth metals such as calcium
  • magnesium transition metals (such as zinc and iron), ammonium
  • salts with organic bases and amino acids or inorganic acids (such as hydrochloric acid and sulfuric acid) , Nitric acid, hydrobromic acid, phosphoric acid or hydroiodic acid) and organic acids (acetic acid, trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, And malic acid, benzoic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid and the like.
  • hydrochloric acid, phosphoric acid phosphoric
  • the compound represented by the formula (I) is not limited to a specific isomer, but all possible isomers (keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer) And rotational isomers) and racemates.
  • the compound represented by the formula (I) in which R 2a is hydrogen includes the following tautomers.
  • the compound represented by the formula (I) has an asymmetric carbon atom and includes any of the following optical isomers.
  • one or more hydrogen, carbon or other atoms of the compounds of formula (I), formula (I ′) and formula (Ia) to formula (In) are replaced with hydrogen, carbon or other isotopes of other atoms Can be done.
  • Compounds of formula (I), formula (I ′) and formula (Ia) to formula (In) are all radioactive of compounds of formula (I), formula (I ′) and formula (Ia) to formula (In) Includes a label.
  • Such “radiolabeled”, “radiolabeled” and the like of compounds of formula (I), formula (I ′) and formula (Ia) to formula (In) are each included in the present invention and are metabolized drugs. It is useful as a research and / or diagnostic tool in kinetic studies and binding assays. It is also useful as a pharmaceutical product.
  • isotopes that can be incorporated into the compounds of formula (I), formula (I ′) and formula (Ia) to formula (In) of the present invention include 2 H, 3 H, 11 C, 13 C, 14 Hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine, such as C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and 36 Cl Is included.
  • the radiolabeled compound of the present invention can be prepared by methods well known in the art.
  • a tritium labeled compound of formula (I) can be prepared by introducing tritium into a specific compound of formula (I) by, for example, catalytic dehalogenation reaction using tritium.
  • This method involves reacting a compound of formula (I) with a suitably halogen-substituted precursor and tritium gas in the presence of a suitable catalyst, for example Pd / C, in the presence or absence of a base.
  • a suitable catalyst for example Pd / C
  • the 14C-labeled compound can be prepared by using a raw material having 14C carbon.
  • the compounds of the present invention represented by the formulas (I), (I ′) and (Ia) to (In) are, for example, Patent Document 1 or Journal of Heterocyclic Chemistry, Vol. 14, 717. According to the method described in pages 723 to 723 (1977) or by the following method.
  • First step Enolate obtained by reacting with a target ester such as tert-butyl propionate in the presence of a base such as lithium diisopropylamide in a solvent such as toluene, dichloromethane or tetrahydrofuran, or in a mixed solvent thereof.
  • a titanium reagent such as chlorotitanium triisopropoxide and a compound a that can be prepared by a known method are added, and the temperature is ⁇ 80 ° C. to 30 ° C., preferably ⁇ 80 ° C. to 0 ° C., for 0.1 hour to 24
  • Compound b can be obtained by reacting for a period of time, preferably 0.1 to 12 hours.
  • Second Step Compound b is used in a solvent such as dioxane, methanol, dichloromethane, or a mixed solvent thereof in the presence of an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, preferably 0 ° C. to 80 ° C., preferably Can be obtained by reacting at 0 ° C. to 30 ° C. for 0.5 to 48 hours, preferably for 1 to 24 hours.
  • an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, preferably 0 ° C. to 80 ° C., preferably Can be obtained by reacting at 0 ° C. to 30 ° C. for 0.5 to 48 hours, preferably for 1 to 24 hours.
  • Third Step Compound c is added with a reducing agent such as borane, sodium borohydride, lithium aluminum hydride or the like in a solvent such as dioxane, tetrahydrofuran, toluene, or a mixed solvent thereof.
  • a reducing agent such as borane, sodium borohydride, lithium aluminum hydride or the like
  • a solvent such as dioxane, tetrahydrofuran, toluene, or a mixed solvent thereof.
  • the compound d can be obtained by reacting at ⁇ 20 ° C. to 30 ° C. for 0.5 to 48 hours, preferably for 1 to 12 hours.
  • Compound d is added with an oxidant such as 2-iodoxybenzoic acid in a solvent such as dimethyl sulfoxide or dichloromethane, and 0 ° C. to 80 ° C., preferably 10 ° C. to 40 ° C., for 0.5 to 48 hours.
  • compound e can be obtained by reacting for 1 to 12 hours.
  • the amine and / or aldehyde group of compound d and compound e is protected by the method described in Protective Groups in Organic Synthesis, Theodora W Greene (John Wiley & Sons), etc. as necessary. And can be deprotected in a timely manner.
  • the reaction is performed at 30 ° C. to 50 ° C., preferably ⁇ 10 ° C. to 25 ° C. for 0.1 hour to 12 hours, preferably 0.1 hour to 3 hours, followed by addition of concentrated sulfuric acid, concentrated nitric acid, etc.
  • Compound (IIa) can be obtained by reacting at 0 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C., for 0.5 to 24 hours, preferably for 1 to 12 hours.
  • R 3a1 is halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, carboxy or substituted or Unsubstituted alkoxycarbonyl, and other symbols are as defined above)
  • a solvent such as toluene, dichloromethane, tetrahydrofuran, or a mixed solvent thereof
  • a base such as tert-butyllithium, sec-butyllithium, n-butyllithium and in the presence of an additive such as tetramethylethylenediamine
  • various electrophiles eg, alkyl halides, various aldehydes, etc.
  • the temperature is -80 ° C to 30 ° C, preferably
  • R 3a2 is substituted or unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, substituted or unsubstituted alkylthio, substituted or unsubstituted amino, substituted or unsubstituted carbocyclic group or substituted Or an unsubstituted heterocyclic group, wherein R 9 and R 10 are hydrogen or substituted or unsubstituted alkyl, or R 9 and R 10 are substituted together with the oxygen atom to which they are attached Or an unsubstituted ring, and other symbols are as defined above)
  • First step In the presence of a base such as tert-butyllithium, sec-butyllithium, n-butyllithium and the presence of an additive such as tetramethylethylenediamine in a solvent such as toluene, dichloromethane, tetrahydrofuran, or a mixed solvent thereof After reacting Compound (II) in the
  • Second Step Compound (III) is a commercially available product or a carbocyclic halide or heterocyclic halide which can be synthesized by a known method and a method analogous thereto, toluene, tetrahydrofuran, dimethylformamide, 1,2-dimethoxyethane , 1,4-dioxane, methanol, etc., in the presence of a base such as triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, trisdibenzylideneacetone dipalladium, palladium acetate, or palladium prepared in the system (0 ) And the like and triphenylphosphine, tritert-butylphosphine, dicyclohexylbiphenylphosphine, 9,9-dimethyl-4,5-bis (diphenylphosphino) xanthene (Xantphos), 2-dicyclohexylphosphino-2 ′, 4 ′
  • R 3a3 is cyano, or substituted or unsubstituted carbamoyl, and other symbols are as defined above
  • Each compound (Ia) can be variously derivatized by the methods described in the new experimental chemistry course (Maruzen, 1978, synthesis and reaction of organic compounds) and the like to obtain compound (Ic).
  • Step 1 Compound a, which can be prepared by a known method, is a target carbonyl compound such as cyclopentanone in a solvent such as toluene, dichloromethane or tetrahydrofuran, or in a mixed solvent thereof in the presence of a base such as lithium diisopropylamide.
  • a target carbonyl compound such as cyclopentanone in a solvent such as toluene, dichloromethane or tetrahydrofuran, or in a mixed solvent thereof in the presence of a base such as lithium diisopropylamide.
  • the compound is reacted at ⁇ 80 ° C. to 30 ° C., preferably ⁇ 80 ° C. to 0 ° C. for 0.1 hour to 24 hours, preferably 0.1 hour to 12 hours. h can be obtained.
  • Second Step Compound h is added at 0 ° C. to 80 ° C. in the presence of an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid in a solvent such as dioxane, methanol, dichloromethane or a mixed solvent thereof, preferably Can be obtained by reacting at 0 ° C. to 30 ° C. for 0.5 hour to 48 hours, preferably 1 hour to 24 hours.
  • an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid
  • a solvent such as dioxane, methanol, dichloromethane or a mixed solvent thereof
  • Second Step Compound i is added with a thiocyanate having a protecting group (for example, benzoyl isothiocyanate) prepared in a commercially available or known method in a solvent such as dioxane, tetrahydrofuran, toluene, acetone, or a mixed solvent thereof, and ⁇
  • the reaction is performed at 30 ° C. to 50 ° C., preferably ⁇ 10 ° C. to 25 ° C. for 0.1 hour to 12 hours, preferably 0.1 hour to 3 hours, followed by addition of concentrated sulfuric acid, concentrated nitric acid, etc.
  • Compound j can be obtained by reacting at 0 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C., for 0.5 to 24 hours, preferably for 1 to 12 hours.
  • the compound (Id) in which the broken line indicates the presence of a bond is obtained by the above-described method, and the compound (Id) in which the broken line indicates the absence of a bond can be produced by a method of hydrogenation under the usual conditions. .
  • Step 1 Compound a obtained by the same method as described above is used as a target for cyclopentanone or the like in a solvent such as toluene, dichloromethane or tetrahydrofuran, or in a mixed solvent thereof in the presence of a base such as lithium diisopropylamide.
  • a base such as lithium diisopropylamide.
  • the reaction is carried out at ⁇ 80 ° C. to 30 ° C., preferably ⁇ 80 ° C. to 0 ° C. for 0.1 hour to 24 hours, preferably 0.1 hour to 12 hours.
  • compound k can be obtained.
  • Second Step Compound k is added to a Grignard reagent such as methylmagnesium bromide prepared by a commercially available or known method in a solvent such as dioxane, tetrahydrofuran, ether, toluene or the like, or a mixed solvent thereof.
  • a Grignard reagent such as methylmagnesium bromide prepared by a commercially available or known method in a solvent such as dioxane, tetrahydrofuran, ether, toluene or the like, or a mixed solvent thereof.
  • an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid after reacting at -20 ° C, preferably -20 ° C to 30 ° C, for 0.5 hour to 48 hours, preferably 1 hour to 12 hours
  • Compound 1 can be obtained by reacting at 0 ° C. to 80 ° C., preferably 0 ° C. to 30 ° C., for
  • Third Step Compound l is added in a solvent such as dioxane, tetrahydrofuran, toluene, acetone or the like, or a mixed solvent thereof, and isothiocyanate having a protecting group (for example, benzoyl isothiocyanate) prepared by a commercially available or known method, The reaction is performed at 30 ° C. to 50 ° C., preferably ⁇ 10 ° C. to 25 ° C. for 0.1 hour to 12 hours, preferably 0.1 hour to 3 hours, followed by addition of concentrated sulfuric acid, concentrated nitric acid, etc.
  • Compound m can be obtained by reacting at 0 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C., for 0.5 to 24 hours, preferably for 1 to 12 hours.
  • Fourth step Add compound m in a solvent such as dichloromethane, tetrahydrofuran, toluene, etc., add oxalyl chloride, thionyl chloride and the like and a catalytic amount of N, N-dimethylformamide, or a chlorinating reagent such as 1-chloro-2-trimethylpropenylamine And reaction is carried out at 0 ° C. to 100 ° C., preferably 10 ° C. to 50 ° C. for 0.5 hour to 72 hours, preferably 0.5 hour to 6 hours, to obtain compound n.
  • a solvent such as dichloromethane, tetrahydrofuran, toluene, etc.
  • a phosphine ligand such as dicyclohexylbiphenylphosphine is added, and a reagent having a substituent corresponding to the target compound such as lithium hexamethyldisilazide and benzophenoneimine is added at ⁇ 10 ° C. to 30 ° C.
  • Compound (Ig) can be obtained by reacting at the reflux temperature of the solvent, preferably 50 to 100 ° C., for 0.5 to 48 hours, preferably 3 to 20 hours.
  • a catalytic reduction catalyst such as 10% palladium / carbon or the like is added to compound (Ih) in a solvent such as tetrahydrofuran, ethyl acetate, methanol, etc., and the reaction is performed under a hydrogen atmosphere of normal pressure to 5 atmospheres, preferably normal pressure to 2 atmospheres. Or 0.5 to 48 hours, preferably 6 to 20 hours at 50 ° C. to 120 ° C., preferably 6 to 20 hours, or by the method described in Comprehensive Organic Transformations, Richard C. Larock (Mcgraw-Hill) Compound (Ii) can be obtained.
  • a solvent such as tetrahydrofuran, ethyl acetate, methanol, etc.
  • R p is an amino protecting group, and other symbols are as defined above
  • the amino group-protected compound (Ij) can be deprotected by the method described in Protective Groups in Organic Synthesis, Theodora W Greene (John Wiley & Sons), etc. to obtain a compound represented by the formula (Ig).
  • the amino protecting group may be any substituent that can be deprotected by the method described in Protective Groups in Organic Synthesis, Theodora W Greene (John Wiley & Sons), etc., for example, alkoxycarbonyl, alkenyloxycarbonyl, trialkylsilyl, acyl, Examples include methanesulfonyl, trifluoroethanesulfonyl, toluenesulfonyl and the like.
  • compound (Ig) Dimethylformamide, tetrahydrofuran, dichloromethane, and other solvents, dicyclohexylcarbodiimide, A carboxylic acid having a substituent corresponding to the target compound such as benzoic acid and 2-pyridinecarboxylic acid in the presence of a dehydrating condensing agent such as benzyldiimidazole and dicyclohexylcarbodiimide-N-hydroxybenzotriazole, and ⁇ 80 ° C. to 100 ° C.
  • Compound (Ik) can be obtained by reacting at ⁇ 20 ° C. to 40 ° C. for 0.1 hour to 24 hours, preferably 1 hour to 12 hours.
  • Method A Condensation under acidic conditions A commercially available or aryl halide or heteroaryl halide and compound that can be synthesized by a known method (Tetrahedron, 2009, 65, 757-764) or a method analogous thereto (Ig) in a solvent such as methanol, ethanol, isopropyl alcohol, butanol, isobutanol, sec-butanol, acetic acid, water, or a mixed solvent thereof, hydrogen chloride, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethane An acid such as sulfonic acid or perchloric acid is added and reacted at 0 ° C. to the reflux temperature of the solvent, preferably 20 ° C. to 140 ° C., for 0.1 hour to 120 hours, preferably 0.5 hour to 72 hours.
  • a compound represented by the general formula (Il) can be obtained.
  • Method B Condensation under basic conditions A commercially available product or an aryl halide or heteroaryl halide which can be synthesized by a known method (Tetrahedron, 2009, 65, 757-764) or a method analogous thereto Compound (Ig) in a solvent such as toluene, tetrahydrofuran, dimethylformamide, 1,2-dimethoxyethane, 1,4-dioxane, methanol and the like, triethylamine, sodium carbonate, potassium carbonate, cesium carbonate, sodium methoxide, potassium tert-butoxide N-butyllithium, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide and the like in the presence of a base at 0 ° C. to the reflux temperature of the solvent, preferably 20 ° C. to 140 ° C. .5 hours to 100 hours, good Details, to obtain
  • trisdibenzylideneacetone dipalladium, palladium acetate, palladium (0), etc. prepared in the system and triphenylphosphine, tritert-butylphosphine, dicyclohexylbiphenylphosphine, 9,9-dimethyl-4,5-bis (Diphenylphosphino) xanthene (Xantphos), 2-dicyclohexylphosphino-2 ′, 4 ′, 6′-triisopropylbiphenyl (X-Phos), 2-dicyclohexylphosphino-2 ′, 6′-diisopropoxy 1
  • the reaction may be carried out by adding a phosphine ligand such as 1,1'-biphenyl (Ruphos).
  • reaction is carried out at 0 ° C. to 150 ° C., preferably 10 ° C. to 100 ° C. for 0.5 hours to 72 hours, preferably 1 hour to 24 hours under microwave irradiation or non-irradiation.
  • a compound represented by (Il) can be obtained.
  • a compound having a protected carboxy group is obtained by the above method 1), and the substituent R 3a is introduced by the methods 2) to 4) to obtain (Ia), (Ib) or (Ic).
  • the compound (Id) or (Ie) having a protected carboxy is obtained by the method of 5) or 6) described above.
  • the compound thus obtained is deprotected by the method described in Protective Groups in Organic Synthesis, Theodora W Greene (John Wiley & Sons), etc. to obtain a compound (Im) having a carboxy group.
  • a solvent such as dimethylformamide, tetrahydrofuran, dichloromethane, etc.
  • a dehydration condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, dicyclohexylcarbodiimide-N-hydroxybenzotriazole, a primary amine or a secondary amine having a substituent corresponding to the target compound.
  • the above compounds b, h, and k are, for example, (1) T. Fujisawa et al., Tetrahedron Lett., 37, 3881-3884 (1996), (2) D. H. Hua et al, Sulfur Reports, vol. 21 , Pp. 211-239 (1999) (3) Y. Koriyama et al., Tetrahedron, 58, 9621-9628 (2002), (4) T. Vilavan et al, Cuuent Organic Chemistry, 9, 1315-1392 (2005) ), Patent Document 1, Patent Document 2, Patent Document 3, and the like.
  • the optically active compound (I) is an optically active raw material, an asymmetric synthesis is carried out at an appropriate stage to obtain an optically active intermediate, or an intermediate or final product of each racemate is processed at an appropriate stage. It can be manufactured by optically dividing with Optical resolution methods include separation of optical isomers using an optically active column, kinetic optical resolution using enzymatic reactions, etc., diastereomers by salt formation using chiral acids and chiral bases. There are crystallization division, preferential crystallization method and the like.
  • R 1 includes substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyano, substituted or unsubstituted carbocyclic group, or substituted or unsubstituted heterocyclic group.
  • R 1 is, for example, unsubstituted alkyl having 1 to 3 carbon atoms.
  • R 2a and R 2b each independently include hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted acyl.
  • R 2a and R 2b are, for example, both hydrogen.
  • R 3a includes halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxy, substituted or Unsubstituted carbocyclic oxy, substituted or unsubstituted heterocyclic oxy, substituted or unsubstituted alkylthio, carboxy, cyano, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted Or an unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group, and R 4a includes hydrogen or a substituted or unsubstituted alkyl.
  • R 3a is, for example, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, carboxy, cyano, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted A carbocyclic group or a substituted or unsubstituted heterocyclic group, and R 4a is, for example, hydrogen.
  • R 3a is, for example, substituted or unsubstituted alkyl, cyano, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted carbamoyl or a substituted or unsubstituted heterocyclic group, and R 4a is, for example, hydrogen is there.
  • Ring A, ring A ′ and ring B each independently include a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle.
  • Ring A or ring A ′ is, for example, substituted or unsubstituted benzene or substituted or unsubstituted pyridine. Preferred is benzene substituted with halogen.
  • Ring B is, for example, substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, or substituted or unsubstituted pyrazine.
  • the substituent is one or more groups selected from the group consisting of halogen, cyano, alkyl and alkoxy.
  • L 1 is bonded to ring B
  • L 2 is bonded to ring A ′.
  • L 1 and L 2 each independently include a single bond, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene.
  • Z is, for example, —L 1 —C ( ⁇ O) N (R 8 ) —L 2 —, —L 1 —N (R 8 ) C ( ⁇ O) — or —N (R 8 ) —L 2 —.
  • L 1 and L 2 are single bonds).
  • “L 1 ” is bonded to ring B
  • “L 2 ” is bonded to ring A ′.
  • Z is, for example, —L 1 —C ( ⁇ O) N (R 8 ) —L 2 — (L 1 and L 2 are a single bond) or —N (R 8 ) —.
  • L 1 is bonded to ring B
  • L 2 is bonded to ring A ′.
  • R 8 includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl.
  • R 8 is, for example, hydrogen.
  • R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted Examples include alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted carbocyclic group or substituted or unsubstituted heterocyclic group .
  • R 2a and R 2b each independently include hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, substituted or unsubstituted alkoxycarbonyl, or substituted or unsubstituted carbamoyl.
  • R 3a Halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or Unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted Or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, substituted or
  • R 4a Hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, Substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl Substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino
  • Ring Q includes a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle.
  • R 3b and R 4b are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano Nitro, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubsti
  • the broken line a and the broken line b each independently indicate the presence or absence of a bond, If dashed line a indicates the presence of a bond, R 3b is not present, When the broken line b indicates the presence of a bond, R 4b is not present.
  • Y 3 and Y 4 are each independently —C (R 5 ) (R 6 ) —, —N (R 7 ) —, —S—, —SO—, —SO 2 — or —O—. It is done.
  • R 5 and R 6 are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano , Nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, substituted
  • R 7 is hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Substituted alkynyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl Substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl
  • Ring A includes a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle. However, the following compounds are excluded
  • R 1 is substituted or unsubstituted alkyl, R 2a and R 2b are both hydrogen,
  • R 3a is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, cyano, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted (Thiocarbamoyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted heterocyclic group)
  • Ring A is a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • R 1 is unsubstituted alkyl having 1 to 3 carbon atoms; R 2a and R 2b are both hydrogen,
  • R 3a is substituted or unsubstituted alkyl (wherein the substituent is one or more groups selected from the group consisting of halogen and hydroxy), cyano, alkoxycarbonyl, substituted or unsubstituted carbamoyl (wherein the substituent is alkyl and One or more groups selected from the group consisting of alkoxyalkyl) or heterocyclic groups)
  • Ring A is
  • Ring A ′ is a substituted or unsubstituted carbocycle
  • Ring B is a substituted or unsubstituted heterocycle
  • R 8 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl), or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Ring A ′ is a benzene ring optionally substituted with halogen
  • Ring B is substituted or unsubstituted pyridine or substituted or unsubstituted pyrazine (wherein each substituent is one or more groups selected from the group consisting of halogen, cyano, alkyl, and alkoxy)
  • R 8 is hydrogen
  • R b1 and R b2 are each independently hydrogen, chloro, fluoro, methoxy, butynyloxy, cyano, amino or carbamoyl.
  • (vii) A compound in which the combination of ring B, R b1 and R b2 (B, R b1 , R b2 ) is as follows.
  • ring B (B3, hydrogen, hydrogen) (hereinafter, ring B is b60), (B3, hydrogen, chloro) (hereinafter, ring B is b61), (B3, hydrogen, fluoro) (hereinafter, ring B is b62), (B3, hydrogen, methoxy) (hereinafter, ring B is b63), (B3, hydrogen, butynyloxy) (hereinafter, ring B is b64), (B3, hydrogen, cyano) (hereinafter, ring B is b65), (B3, hydrogen, amino) (hereinafter, ring B is b66), (B3, hydrogen, carbamoyl) (hereinafter, ring B is assumed to be b67), (B3, chloro, hydrogen) (hereinafter, ring B is b68), (B3, chloro, chloro) (hereinafter, ring B is b69), (B3, chloro, fluoro) (hereinafter, ring B is b70), (B3, chloro,
  • a compound in which the combination of ring B and R b1 (B, R b1 ) is as follows.
  • R 2a and R 2b are hydrogen, R 1 is methyl,
  • a combination of ring A and ring B is as follows. (r1, A1, b1), (r1, A1, b2), (r1, A1, b3), (r1, A1, b4), (r1, A1, b5), (r1, A1, b6), (r1 , A1, b7), (r1, A1, b8), (r1, A1, b9), (r1, A1, b10), (r1, A1, b11), (r1, A1, b12), (r1, A1 , b13), (r1, A1, b14), (r1, A1, b15), (r1, A1, b16), (r1, A1, b17), (r1, A1, b18), (r1, A1, b19 ), (r1, A1, b20), (r1, A1, b21), (r1, A1, b22), (r1, A1, b23), (r1, A1, b24), (r1, A1, b25), (r1, A1, b20), (
  • the compound of the present invention is useful for diseases induced by production, secretion or deposition of amyloid ⁇ protein.
  • diseases induced by production, secretion or deposition of amyloid ⁇ protein For example, Alzheimer type dementia (Alzheimer's disease, Alzheimer type senile dementia etc.), Down's syndrome, memory disorder, prion disease (Kreuz's disease) Felt-Jakob disease, etc.), mild cognitive impairment (MCI), Dutch hereditary amyloid cerebral hemorrhage, cerebral amyloid angiopathy, other degenerative dementia, mixed vascular dementia, dementia associated with Parkinson's disease, progression Treatment and / or prevention of dementia associated with supranuclear paralysis, dementia associated with corticobasal degeneration, diffuse Lewy body Alzheimer's disease, age-related macular degeneration, Parkinson's disease, amyloid angiopathy, etc. It is effective for improvement.
  • Alzheimer type dementia Alzheimer's disease, Alzheimer type senile dementia etc.
  • treatment of Alzheimer's disease includes prevention of the severity of MCI and prevention of the onset of familial Alzheimer's disease.
  • the term “pharmaceutical composition for treating Alzheimer's disease” includes a pharmaceutical composition for preventing the onset of MCI, a pharmaceutical composition for preventing the onset of familial Alzheimer's disease, and the like.
  • the compound of the present invention has high inhibitory activity against BACE1 and / or high selectivity to other enzymes, and therefore can be a pharmaceutical with reduced side effects. Furthermore, since it has a high inhibitory effect on amyloid ⁇ production in cell systems, and particularly has a high inhibitory effect on amyloid ⁇ production in the brain, it can be an excellent pharmaceutical product. Moreover, it can become a pharmaceutical with a wider safety margin with respect to a side effect by setting it as the optically active substance which has appropriate stereochemistry.
  • the compound of the present invention has high metabolic stability, high solubility, high oral absorption, good bioavailability, good clearance, high brain transferability, long half-life, non-protein binding rate It also has advantages such as high HERG channel inhibition, low CYP inhibition, low CYP MBI (mechanism-based inhibition) and / or negative Ames test.
  • the compound of the present invention When the compound of the present invention is administered, it may be used in combination with other drugs (for example, other Alzheimer's disease therapeutic agents or preventive agents such as acetylcholinesterase).
  • other drugs for example, other Alzheimer's disease therapeutic agents or preventive agents such as acetylcholinesterase.
  • antidementia drugs such as donepezil hydrochloride, tacrine, galantamine, rivastigmine, zanapezil, memantine, and vinpocetine.
  • the compound of the present invention When the compound of the present invention is administered to humans, it can be administered orally as powders, granules, tablets, capsules, pills, liquids, etc. or parenterally as injections, suppositories, transdermal absorption agents, inhalants, etc. Can be administered.
  • excipients, binders, wetting agents, disintegrants, lubricants and other pharmaceutical additives suitable for the dosage form may be mixed with an effective amount of the present compound as necessary to obtain a pharmaceutical preparation. it can.
  • the dose varies depending on the disease state, administration route, patient age, or body weight, but when administered orally to an adult, it is usually 0.1 ⁇ g to 1 g / day, preferably 0.01 to 200 mg / day. In the case of parenteral administration, it is usually 1 ⁇ g to 10 g / day, preferably 0.1 to 2 g / day.
  • Second Step Compound (11) (90 mg) and 2-bromopyridine (25 mg) obtained in the first step were dissolved in a mixed solvent of dimethylformamide (2.7 ml) and water (0.3 ml). Potassium carbonate (66.2 mg) and [1,1-bis (di-tert-butylphosphino) ferrocene] dichloropalladium (10 mg) were added, and the mixture was stirred at room temperature for 5 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • Second Step Compound (14) (55 mg) obtained in the first step was dissolved in a mixed solvent of acetonitrile (3 ml) and water (0.3 ml), aminooxysulfonic acid (17.37 mg) was added, and For 1 hour.
  • the reaction solution was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution and water were added to the resulting residue, and the precipitated solid was collected by filtration with a Kiriyama funnel.
  • Thionyl chloride (1 ml) was added to the obtained solid (40 mg) at 0 ° C., and the mixture was warmed to room temperature and stirred for 3 hours.
  • the reaction solution was poured into ice water and basified with a saturated aqueous sodium hydrogen carbonate solution.
  • Step 3 Methanol (5.6 ml) was added to the compound (28a, 564 mg) and compound (28b, 150 mg) to dissolve, and the mixture was stirred at room temperature, followed by addition of hydrochloric acid-methanol solution (5-10%) (9.4 ml) and stirring. .
  • reaction mixture was poured into ice and ethyl acetate (80 ml), and extracted by adding saturated aqueous sodium hydrogen carbonate solution (30 ml). The organic layer was washed once with saturated brine (30 ml), dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (560 mg) was subjected to silica gel column chromatography to obtain compound (29) (462 mg, 90%).
  • Step 4 Compound (29) (462 mg) was dissolved in tetrahydrofuran (11.6 ml), and benzoyl isothiocyanate (0.233 ml) was added with stirring under ice-cooling in a nitrogen stream. After 1 hour, stirring was performed at room temperature. It was. After 1 hour, the reaction solution was distilled off under reduced pressure.
  • Step 6 Tetrahydrofuran (8.6 ml) was added to and suspended in compound (31) (171 mg) and diN, N-dimethylaminopyridine (61 mg), and di-tert-butyl-dicarbonate ( 0.134 ml) was added at once and stirred as it was.
  • Step 1 Compound (14) (80 mg) is dissolved in methanol (2 ml), 1M sodium methoxide (NaOMe) in methanol (0.722 ml) and TOSMIC (40.3 mg) are added in that order and stirred at room temperature for 1 hour. did. A saturated aqueous sodium hydrogen carbonate (NaHCO 3 ) solution was added to the reaction solution, and the precipitated solid was collected by filtration with a Kiriyama funnel to obtain compound (41) (84 mg).
  • NaOMe 1M sodium methoxide
  • TOSMIC 40.3 mg
  • RT represents the retention time (minutes).
  • the substrate peptide was synthesized by reacting biotin-XSEVNLDAEFRHDSGC (Peptide Institute) with cryptate TBPCOOH mono SMP (CIS bio international).
  • the final concentration of substrate peptide is 18 nmol / L
  • the final concentration of recombinant human BACE1 is 7.4 nmol / L
  • the reaction buffer is sodium acetate buffer (50 mmol / L sodium acetate pH 5.0, 0.008% Triton X-100). Using.
  • the enzyme activity was determined from the count rate at each measurement wavelength (10000 ⁇ count 665 / count 620), and the dose (IC 50 ) that inhibits the enzyme activity by 50% was calculated.
  • Compound I-8 had an IC 50 value of 0.012 ⁇ mol / L.
  • compounds I-1 to 7, 9 to 21, 53 to 58, 60, 61, and 63 had IC 50 values of 1 ⁇ mol / L or less.
  • Neuroblastoma SH-SY5Y cells (SH / APPwt) overexpressing human wild-type ⁇ APP were adjusted to 8 ⁇ 105 cells / mL and plated on 96-well culture plates (Falcon) at 150 ⁇ l per well. The cells were cultured at 37 ° C. in a 5% carbon dioxide incubator for 2 hours. Thereafter, a solution in which a test compound (DMSO: dimethyl sulfoxide solution) was added and suspended in advance to be a 2 ⁇ l / 50 ⁇ l medium was added to the cell solution.
  • DMSO dimethyl sulfoxide solution
  • the final DMSO concentration was 1%, and the cell culture solution was 200 ⁇ l. After 24 hours of incubation from the addition of the test compound, 100 ⁇ l of the culture supernatant was collected and the amount of A ⁇ contained therein was measured.
  • the amount of A ⁇ was measured by culturing 10 ⁇ l of homogeneous time-resolved fluorescence (HTRF) measurement reagent (Amyloid ⁇ 1-40 peptide; IBA Molecular Holding, SA) on a 384 well half area plate (black plate; manufactured by Coaster). 10 ⁇ l of the supernatant was added, mixed, and left at 4 ° C. overnight protected from light. Thereafter, the fluorescence intensity (excitation wavelength: 337 nm, measurement wavelengths: 620 nm and 665 nm) was measured using a Wallac 1420 multilabel counter (Perkin Elmer life sciences).
  • HTRF time-resolved fluorescence
  • the amount of A ⁇ was determined from the count rate of each measurement wavelength (10000 ⁇ count 665 / count 620), and the dose that inhibits A ⁇ production by 50% (IC50) was calculated from at least 6 different doses.
  • Compound I-8 had an IC 50 value of 0.002 ⁇ mol / L.
  • Compounds I-1 to 7, 9 to 21, and 53 to 63 had IC 50 values of 5 ⁇ mol / L or less.
  • Test Example 3 Rat brain ⁇ -amyloid reducing action
  • the test compound is suspended in 0.5% methylcellulose, prepared to a final concentration of 2 mg / mL, and orally administered to male Crj: SD rats (7-9 weeks old) to 10 mg / kg. .
  • the base control group is administered with 0.5% methylcellulose alone, and 3 to 8 animals are administered in each group.
  • the brain is removed, the cerebral hemisphere is isolated, weighed, and then immediately frozen in liquid nitrogen and stored at ⁇ 80 ° C. until the date of extraction.
  • the frozen cerebral hemisphere was transferred to a Teflon (registered trademark) homogenizer under ice-cooling, and an extraction buffer (1% CHAPS ( ⁇ 3-[(3-chloroamidopropyl) dimethylammonio] -1-propane) having a volume 5 times its weight was used. Sulfonate ⁇ ), 20 mmol / L Tris-HCl (pH 8.0), 150 mmol / L NaCl and Complete (Roche) protease inhibitor) are added, and the mixture is repeatedly homogenized for 2 minutes to solubilize. The suspension is transferred to a centrifuge tube and left on ice for 3 hours or more, and then centrifuged at 100,000 ⁇ g, 4 ° C.
  • ⁇ -amyloid 40 manufactured by Wako Pure Chemical Industries, Ltd., product number 294-62501.
  • the ELISA measurement is performed according to the attached instructions.
  • the decreasing effect is calculated as the ratio of the base control group of each test to ⁇ -amyloid 40 in the brain.
  • the CYP3A4 fluorescent MBI test is a test for examining the enhancement of CYP3A4 inhibition of a compound by metabolic reaction, and 7-benzyloxytrifluoromethylcoumarin (7-BFC) is debenzylated by CYP3A4 enzyme using E. coli-expressed CYP3A4 as an enzyme.
  • the reaction for producing a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (HFC) was performed as an index.
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), Pre-reaction 62.5 pmol / mL, reaction 6.25 pmol / mL (10-fold dilution); test drug concentration, 0.625, 1.25, 2.5, 5, 10, 20 ⁇ mol / L (6 points) ).
  • NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer.
  • the control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution added was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model. The case where the difference in IC 50 values was 5 ⁇ M or more was designated as (+), and the case where it was 3 ⁇ M or less was designated as ( ⁇ ). (result) Compound I-20: ( ⁇ ).
  • Test Example 5 CYP inhibition test
  • CYP1A2 O-deethylation of 7-ethoxyresorufin
  • methyl tolbutamide as a typical substrate metabolic reaction of the major human CYP5 species (CYP1A2, 2C9, 2C19, 2D6, 3A4) -Index of hydroxylation (CYP2C9), mephenytoin 4'-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadine hydroxylation (CYP3A4).
  • the degree of inhibition by the test compound was evaluated.
  • reaction conditions are as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsomes 0.2 mg protein / mL; test drug concentration 1, 5, 10, 20 ⁇ mol / L (4 points) ).
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the supernatant of the centrifugation was collected with a fluorescent multilabel counter
  • tolbutamide hydroxide CYP2C9 metabolite
  • mephenytoin 4 ′ hydroxide CYP2C19 metabolite
  • Dextrorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • the control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration of the test drug solution was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model. (result) Compound I-2: 5 species> 21 ⁇ M.
  • Test Example 6 FAT test Inoculate 20 ⁇ L of Salmonella typhimurium TA98 strain, TA100 strain in a cryopreserved 10 mL liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and incubate at 37 ° C for 10 hours before shaking.
  • TA98 strain 9 mL of the bacterial solution is centrifuged (2000 ⁇ g, 10 minutes) to remove the culture solution, and 9 mL of Micro F buffer solution (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g /) L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L), and 110 mL of Exposure Add to medium (BioF: 8 ⁇ g / mL, histidine: 0.2 ⁇ g / mL, glucose: MicroF buffer solution containing 8 mg / mL), TA100 strain to 3.16 mL bacterial solution added to 120 mL of Exposure medium and test bacterial solution To prepare.
  • Micro F buffer solution K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g /) L, (NH
  • Test substance DMSO solution (maximum dose 50 mg / mL to 8-fold dilution at 2-fold common ratio), DMSO as negative control, 50 ⁇ g / mL 4-nitroquinoline for TA98 strain under non-metabolic activation conditions as positive control -1-oxide DMSO solution, for TA100 strain, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution, for metabolic activation conditions, for TA98 strain 40 ⁇ g / mL 2-aminoanthracene DMSO solution and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and test bacterial solution 588 ⁇ L (under metabolic activation conditions, test bacterial solution 498 ⁇ L and S9 mix 90 ⁇ L) and incubate at 37 ° C for 90 minutes with shaking.
  • Test Example 7 Solubility test
  • Test Example 8 Metabolic stability test
  • the target compound was allowed to react for a certain period of time, and the residual rate was calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism in the liver.
  • Human liver microsomes 0.5 mg protein / mL in 0.2 mL buffer (50 mmol / L tris-HCl pH 7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) in the presence of 1 mmol / L NADPH
  • the reaction was carried out at 0 ° C. for 0 minutes or 30 minutes (oxidative reaction).
  • test compound I-19 96.4%.
  • the absolute value of the maximum tail current was measured from the obtained I Kr using the analysis software (DataXpress ver. 1, Molecular Devices Corporation) based on the current value at the holding membrane potential. Furthermore, the inhibition rate with respect to the maximum tail current before application of the test substance was calculated, and compared with the medium application group (0.1% dimethyl sulfoxide solution), the influence of the test substance on I Kr was evaluated. (result) Compound I-14: 3.8%.
  • Test Example 10 Powder solubility test
  • JP-1 solution 2.0 g sodium chloride, 7.0 mL hydrochloric acid to add 1000 mL
  • JP-2 solution 500 mL pH 6.8 phosphate buffer, 500 mL water
  • TCA sodium taurocholate
  • JP-2 solution water was added to TCA 1.08 g to make 100 mL
  • 200 ⁇ L each was added.
  • If dissolved after adding the test solution add bulk powder as appropriate. Seal and shake at 37 ° C for 1 hour. Filter, add 100 ⁇ L of methanol to 100 ⁇ L of each filtrate and dilute 2 times. Change the dilution factor as necessary. Check for bubbles and precipitates, seal and shake. Quantify using HPLC with the absolute calibration curve method.
  • Intravenous administration is performed from the tail vein using a syringe with an injection needle.
  • Evaluation items Blood is collected over time, and the drug concentration in plasma is measured using LC / MS / MS.
  • Rats were intravenously administered at a dose of 0.5 mg / mL / kg, and 30 minutes later, they were exsanguinated by whole blood sampling from the lower aorta under isoflurane anesthesia. Thereafter, the brain was removed and 20-25% homogenate was prepared with distilled water. On the other hand, the obtained blood was made into plasma after centrifugation. Thereafter, control plasma was added to the brain sample, and control brain was added to the plasma sample at a ratio of 1: 1, and each sample was measured using LC / MS / MS. The obtained area ratio (brain / plasma) at the time of measurement was defined as the brain Kp value. (result) Compound I-54: 2.5.
  • Formulation Example 1 A granule containing the following ingredients is produced.
  • Formulation Example 2 A capsule filling granule containing the following ingredients is produced.
  • Formulation Example 3 A tablet containing the following ingredients is produced.
  • Formulation Example 4 The following ingredients are heated and mixed and then sterilized to give an injection.
  • the compound of the present invention can be a useful drug as a therapeutic or prophylactic agent for diseases induced by production, secretion and / or deposition of amyloid ⁇ protein.

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Abstract

La présente invention concerne un agent thérapeutique ou prophylactique contre les maladies induites par la production, la sécrétion et/ou le dépôt de la protéine β-amyloïde. L'invention concerne spécifiquement un composé représenté par la formule (I) (où R1, R2a, R2b, R3, R4a, R4b, l'anneau A et la ligne en pointillés sont tels que définis dans la description), un sel pharmaceutiquement acceptable du composé, ou un solvat du composé ou du sel pharmaceutiquement acceptable.
PCT/JP2010/007153 2009-12-09 2010-12-08 Dérivé d'aminothiazine substitué WO2011070781A1 (fr)

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