WO2011071135A1 - Dérivé d'oxazine - Google Patents

Dérivé d'oxazine Download PDF

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Publication number
WO2011071135A1
WO2011071135A1 PCT/JP2010/072193 JP2010072193W WO2011071135A1 WO 2011071135 A1 WO2011071135 A1 WO 2011071135A1 JP 2010072193 W JP2010072193 W JP 2010072193W WO 2011071135 A1 WO2011071135 A1 WO 2011071135A1
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WIPO (PCT)
Prior art keywords
substituted
unsubstituted
carbocyclic
ring
heterocyclic
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PCT/JP2010/072193
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English (en)
Japanese (ja)
Inventor
桝井　盛泰
章洋 堀
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塩野義製薬株式会社
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=44145678&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2011071135(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to JP2011545253A priority Critical patent/JPWO2011071135A1/ja
Priority to UAA201208561A priority patent/UA110467C2/uk
Priority to RU2012129168/04A priority patent/RU2012129168A/ru
Priority to BR112012013854A priority patent/BR112012013854A2/pt
Priority to CA2783958A priority patent/CA2783958A1/fr
Priority to CN2010800648635A priority patent/CN102834384A/zh
Priority to AU2010328975A priority patent/AU2010328975B2/en
Application filed by 塩野義製薬株式会社 filed Critical 塩野義製薬株式会社
Priority to MX2012006491A priority patent/MX2012006491A/es
Priority to ES10836054T priority patent/ES2590038T5/es
Priority to US13/513,839 priority patent/US8999980B2/en
Priority to EP10836054.6A priority patent/EP2511268B2/fr
Publication of WO2011071135A1 publication Critical patent/WO2011071135A1/fr
Priority to ZA2012/03777A priority patent/ZA201203777B/en
Priority to US14/627,700 priority patent/US9290466B2/en
Priority to US15/041,683 priority patent/US9656974B2/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C07D265/08—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • 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
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—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 Documents 1 to 11 describe a compound having a structure similar to that of the present invention and describe that it can be a therapeutic agent for Alzheimer's disease or Alzheimer-related symptoms. Also have a skeleton different from the compound of the present invention. Non-Patent Document 1 describes a compound having a structure similar to that of the present invention, but does not suggest any pharmaceutical activity.
  • 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.
  • Ring A is a substituted carbocycle or a substituted or unsubstituted heterocycle
  • 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 unsubstitute
  • R za and R zb are each independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted Substituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, carboxy, substituted or unsubstituted Alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted
  • ring A ′ and ring B are each independently a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring
  • Z is -L 1 '-N (R 8) -L 2' - a
  • L 1 ′ and L 2 ′ are each independently a single bond, substituted or unsubstituted alkylene (wherein the substituent is halogen, alkoxy, halogenoalkoxy, hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, Acylamino, alkylamino, imino, hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl, hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfinyl, alky
  • 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,
  • ring A is Wherein ring A ′ and ring B are each independently a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring, Z is -L 1 -N (R 8 ) -L 2- , L 1 and L 2 are each independently a single bond, substituted or unsubstituted alkylene (wherein the substituents are halogen, alkoxy, halogenoalkoxy, hydroxyalkoxy, alkoxyalkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, amino, acylamino, Alkylamino, imino, hydroxyimino, alkoxyimino, alkylthio, carbamoyl, alkylcarbamoyl, hydroxyalkylcarbamoyl, sulfamoyl, alkylsulfamoyl, alkylsulfamoyl, alkyls
  • Ring A is a substituted carbocycle or a substituted or unsubstituted heterocycle
  • 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
  • ring A is Wherein ring A ′ and ring B are each independently a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring, Z is -L 1 -N (R 8 ) -L 2- , 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) A compound, Or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • Z is “—L 1 —N (R 8 ) -L 2 —”, “L 1 ” is bonded to ring B and “L 2
  • ring A ′ and ring B are each independently a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring
  • Z is —L 1 —C ( ⁇ O) N (R 8 ) —L 2 —, —L 1 —N (R 8 ) C ( ⁇ O) —L 2 — or —L 1 —N (R 8 ) —
  • L 2- 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) Or a pharmaceutically acceptable salt or solvate thereof according to item (1), (1-1) or
  • Z represents “—L 1 —C ( ⁇ O) N (R 8 ) —L 2 —, —L 1 —N (R 8 ) C ( ⁇ O) —L 2 — or —L 1 —N (R 8 ).
  • “-L 2 —” “L 1 ” is bonded to ring B, and “L 2 ” is bonded to ring A ′.
  • R za and R zb are each independently hydrogen, halogen or a substituted or unsubstituted alkyl, and R 4a and R 4b are each independently hydrogen or a substituted or unsubstituted alkyl, (1), (1-1), (1-2) or (2) compound or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • R 3a , R 3b , R 4a and R 4b have the same meanings as item (1)
  • a pharmaceutically acceptable salt or solvate thereof according to item (1), (1-1), (1-2) or (2).
  • R 3a and R 4a have the same meanings as item (1), or a compound or a pharmaceutically acceptable salt thereof according to item (1), (1-1), (1-2) or (2) Salts or solvates thereof.
  • Y 1 and Y 2 are each independently —C (R 5 ) ⁇ or —N ⁇ , and Q is as defined in item (1).
  • Y 1 is —C (R 5 ) ⁇ or —N ⁇
  • Y 2 is —C (R 5 ) (R 6 ) —, —N (R 7 ) —, —S—, —SO -, -SO 2 -or -O-
  • Q and R 4c are as defined in item (1)), item (1), (1-1), (1-2) or (2)
  • Y 1 is —C (R 5 ) (R 6 ) —, —N (R 7 ) —, —S—, —SO—, —SO 2 — or —O—
  • Y 1 and Y 2 are each independently —C (R 5 ) (R 6 ) —, —N (R 7 ) —, —S—, —SO—, —SO 2 — or —
  • a method for inhibiting BACE1 activity which comprises administering a compound described in 1. or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • a method for treating or preventing Alzheimer's disease which comprises administering the compound described in 1) or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • 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.
  • the 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,
  • Substituents of “substituted or unsubstituted alkoxy”, “substituted or unsubstituted alkoxycarbonyl”, “substituted or unsubstituted alkylthio”, “substituted or unsubstituted alkylsulfonyl” and “substituted or unsubstituted alkylsulfinyl” Includes 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 is a straight chain having 2 to 15 carbon atoms, such as 2 to 10 carbon atoms, such as 2 to 6 carbon atoms, such as 2 to 4 carbon atoms, having one or more double bonds at any position. Or includes branched alkenyl.
  • alkenyl part of “alkenyloxy”, “alkenyloxycarbonyl”, “alkenylcarbonyl”, “alkoxyalkenyloxy”, “alkenylthio”, “alkenylamino”, “alkenylsulfonyl” and “alkenylsulfinyl” is the above “alkenyl”. It is the same.
  • Alkynyl includes straight-chain or branched alkynyl 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. . 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.
  • alkynyl part of “alkoxyalkynyl”, “alkynyloxy”, “alkynyloxycarbonyl”, “alkynylcarbonyl”, “alkoxyalkynyloxy”, “alkynylthio”, “alkynylsulfinyl”, “alkynylsulfonyl” and “alkynylamino” 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, hydroxy, alkoxy, Examples thereof include 1 to 2 groups selected from alkoxycarbonyl, carbocyclic group, heterocyclic group and the like.
  • “Acyl” includes formyl, alkylcarbonyl having 1 to 10 carbon atoms, alkenylcarbonyl having 2 to 10 carbon atoms, alkynylcarbonyl having 2 to 10 carbon atoms, carbocyclic carbonyl and heterocyclic carbonyl.
  • acyl part of “acyloxy” and “acylamino” is the same as the above “acyl”.
  • the substituent of “substituted or unsubstituted acyl” and “substituted or unsubstituted acyloxy” includes one or more groups selected from 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, cycloheptyl, cyclooctyl. , Cyclononyl, cyclodecyl and the like.
  • Cycloalkylalkyl “Cycloalkylalkyl”, “cycloalkyloxy”, “cycloalkylalkoxy”, “cycloalkylthio”, “cycloalkylamino”, “cycloalkylalkylamino”, “cycloalkylsulfamoyl”, “cycloalkylsulfonyl”,
  • the cycloalkyl part of “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, cyclopentenyl, cyclohexenyl, cyclo Examples include heptynyl, cyclooctynyl and cyclohexadienyl.
  • Aryl includes phenyl, naphthyl, anthryl, phenanthryl, and the like, and particularly includes phenyl.
  • non-aromatic fused carbocyclic group includes a non-aromatic group in which two or more cyclic groups selected from the above “cycloalkyl”, “cycloalkenyl” and “aryl” are condensed, and specifically Includes indanyl, indenyl, tetrahydronaphthyl, fluorenyl and the like.
  • the carbocyclic portion of the “non-aromatic carbocycle” is the same as the above “cycloalkyl”, “cycloalkenyl”, and “non-aromatic fused carbocyclic group”, and more specifically, cyclopropane, cyclobutane, cyclo Including pentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene and the like.
  • Carbocycle “carbocycle oxy”, “carbocycle alkyl”, “carbocycle alkoxy”, “carbocycle alkoxycarbonyl”, “carbocycle thio”, “carbocycle amino”, “carbocycle alkylamino”, “ Carbon of carbocyclic carbonyl, carbocyclic sulfamoyl, carbocyclic sulfonyl, carbocyclic carbamoyl, carbocyclic alkylcarbamoyl, carbocyclic oxycarbonyl, carbocyclic sulfinyl, carbocyclic sulfonyl
  • the ring portion is the same as the “carbocyclic group”.
  • Arylalkyl “aryloxy”, “aryloxycarbonyl”, “arylalkoxycarbonyl”, “arylthio”, “arylamino”, “arylalkoxy”, “arylalkylamino”, “arylsulfonyl”, “arylsulfur”
  • aryl moiety of “famoyl”, “arylcarbamoyl” and “arylalkylcarbamoyl” is the same as the above “aryl”.
  • Heterocyclic group includes a heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N, specifically pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl.
  • 5- to 6-membered heteroaryl such as, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc .; Dioxanyl, thilanyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholinoyl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl,
  • Heterocycle “heterocycle alkyl”, “heterocycle oxy”, “heterocycle thio”, “heterocycle carbonyl”, “heterocycle alkoxy”, “heterocycle amino”, “heterocycle sulfamoyl”, “heterocycle”
  • the heterocyclic moiety of “sulfonyl”, “heterocyclic carbamoyl”, “heterocyclic oxycarbonyl”, “heterocyclic alkylamino”, “heterocyclic alkoxycarbonyl”, “heterocyclic alkylcarbamoyl” and “heterocyclic sulfinyl” is also referred to as “heterocyclic”.
  • heterocyclic portion of the “non-aromatic heterocyclic ring” is the same as the heterocyclic portion of the above “non-aromatic heterocyclic group”, and more specifically, dioxane, thiirane, oxirane, oxetane, oxathiolane, azetidine, thiane.
  • the bond of the above “heterocyclic group” may be located on any ring.
  • Heteroaryl includes an aromatic cyclic group among the above “heterocyclic groups”.
  • examples of the ring A include groups represented by the following formulae.
  • 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 N (R 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
  • 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 ⁇
  • substituted carbocycle “substituted or unsubstituted carbocycle”, “substituted or unsubstituted heterocycle”, “substituted or unsubstituted benzene” in ring A, ring A ′ and ring B ”,“ Substituted or unsubstituted pyridine ”,“ substituted or unsubstituted pyrimidine ”and“ substituted or unsubstituted pyrazine ”
  • substituent group ⁇ for example, halogen, hydroxy, alkoxy, acyl, acyloxy, carboxy, alkoxycarbonyl, carbamoyl, amino, cyano, alkylamino and / or alkylthio, etc.
  • 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.
  • substituent other than “—Z-ring B” in “substituted or unsubstituted carbocycle” or “substituted or unsubstituted heterocycle” in ring A include, for example, halogen, alkyl, alkenyl, alkynyl, alkoxy, Alkenyloxy, alkynyloxy or cyano.
  • substituent of “substituted or unsubstituted carbocycle”, “substituted or unsubstituted benzene” or “substituted or unsubstituted heterocycle” in ring A ′ is, for example, halogen.
  • Substituted or unsubstituted carbocycle “substituted or unsubstituted heterocycle”, “substituted or unsubstituted pyridine”, “substituted or unsubstituted pyrimidine”, or “substituted or unsubstituted pyrazine” in ring B
  • substituents are halogen, alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy and cyano.
  • Alkylene includes linear or branched divalent carbon chains having 1 to 10 carbon atoms, such as 1 to 6 carbon atoms, such as 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 refers to a straight or branched divalent carbon chain having a double bond at any position and having 2 to 10, for example, 2 to 6, for example, 2 to 4 carbon atoms. Include. Specific examples include vinylene, propenylene, butenylene, butadienylene, methylpropenylene, pentenylene and hexenylene.
  • Alkynylene is a linear or branched carbon having 2 to 10 carbon atoms, for example 2 to 6 carbon atoms, which has a triple bond at an arbitrary position and may further have a double bond, for example, And a divalent carbon chain having 2 to 4 carbon atoms. Specific examples include ethynylene, propynylene, butynylene, pentynylene and hexynylene.
  • substituents selected from the substituent group ⁇ such as halogen, hydroxy Etc.
  • 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.
  • each symbol has the same meaning as item (1), and Q ′ is a substituted or unsubstituted carbocycle.
  • 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.
  • R za and R zb together with the carbon atom to which they are attached form a substituted or unsubstituted non-aromatic carbocycle or substituted or unsubstituted non-aromatic heterocycle
  • R 3a and R 3b together with the carbon atom to which they are attached form a substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle and “R 4a and R 4b are The case of forming a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring together with the carbon atoms to be bonded is
  • 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 compound represented by the formula (I) includes a pharmaceutically acceptable salt.
  • 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.
  • 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. Preferably It is.
  • Optical isomers of compounds of formula (I) can be obtained by known techniques such as chiral chromatography or formation of diastereomeric salts from optically active acids or bases.
  • one or more hydrogen, carbon or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon or other atoms.
  • Compounds of formula (I) include all radiolabeled forms of compounds of formula (I). Such “radiolabeled”, “radiolabeled” and the like of the compounds of formula (I) are each encompassed by the present invention and are useful as research and / or diagnostic tools in metabolic pharmacokinetic studies and binding assays. . It is also useful as a pharmaceutical product.
  • Examples of isotopes that can be incorporated into the compounds of formula (I) of the present invention are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, respectively.
  • 35 S, 18 F, 123 I and 36 Cl include hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine.
  • 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) and (Ia) to (If) can be produced by the following method. In the following steps, when there are substituents that interfere with the reaction (for example, hydroxy, mercapto, amino, formyl, carbonyl, carboxyl, etc.), Protective Groups in Organic Synthesis, Theodora W Greene (John Wiley & Sons ) Or the like, and the protecting group may be removed at a desired stage.
  • substituents that interfere with the reaction for example, hydroxy, mercapto, amino, formyl, carbonyl, carboxyl, etc.
  • Protective Groups in Organic Synthesis for example, hydroxy, mercapto, amino, formyl, carbonyl, carboxyl, etc.
  • Theodora W Greene John Wiley & Sons
  • the protecting group may be removed at a desired stage.
  • First step In an enolate obtained by reacting a target ester such as ethyl 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 is added, and a compound a that can be prepared by a known method is added, and then at ⁇ 80 ° C. to 30 ° C., preferably at ⁇ 80 ° C. to 0 ° C., for 0.1 to 24 hours, Preferably, compound b can be obtained by reacting for 0.1 to 12 hours.
  • a target ester such as ethyl propionate
  • a base such as lithium diisopropylamide
  • a solvent such as toluene, dichloromethane or tetrahydrofuran, or in a mixed solvent thereof
  • Second Step Compound b is converted into a Grignard reagent such as methylmagnesium bromide prepared in a solvent such as dioxane, tetrahydrofuran, ether, toluene or the like, or a mixed solvent thereof by a commercially available method, or borane or sodium borohydride. Then, a reducing agent such as lithium aluminum hydride is added and reacted at ⁇ 80 ° C. to 80 ° C., preferably ⁇ 20 ° C. to 30 ° C. for 0.5 hour to 48 hours, preferably 1 hour to 12 hours. c can be obtained.
  • a reducing agent such as lithium aluminum hydride
  • Third Step Compound c is subjected to 0 to 80 ° C. in the presence of an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or trifluoroacetic acid in a solvent such as dioxane, methanol or dichloromethane or in a mixed solvent thereof.
  • an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or trifluoroacetic acid
  • a solvent such as dioxane, methanol or dichloromethane or in a mixed solvent thereof.
  • Compound d is added with an isothiocyanate having a protecting group (for example, benzoyl isothiocyanate) prepared by a commercially available or known method in a solvent such as dioxane, tetrahydrofuran, toluene, acetone, or a mixed solvent thereof.
  • Compound e can be obtained by reacting at ⁇ 30 ° C. to 50 ° C., preferably ⁇ 10 ° C. to 25 ° C., for 0.1 to 12 hours, preferably for 0.1 to 3 hours.
  • First step In a solvent such as toluene, dichloromethane, tetrahydrofuran or the like, or a mixed solvent thereof, a compound a that can be prepared by a known method is added to a Grignard reagent such as allylmagnesium bromide, and -80 ° C to 30 ° C, preferably Compound f can be obtained by reacting at -80 ° C. to 0 ° C. for 0.1 to 24 hours, preferably 0.1 to 12 hours.
  • a Grignard reagent such as allylmagnesium bromide
  • Compound g can be obtained by reacting at 0 ° C. to 80 ° C., preferably 0 ° C. to 30 ° C., for 0.5 to 48 hours, preferably for 1 to 24 hours.
  • Third Step Compound g is added with an isocyanate having a protective group (for example, benzoyl isocyanate) prepared in a solvent such as dichloromethane, dioxane, tetrahydrofuran, toluene, acetone or the like, or a mixed solvent thereof by a commercially available or known method, and- Compound h can be obtained by reacting 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.
  • a protective group for example, benzoyl isocyanate
  • Compound h is added with a halogenium cation source such as iodine, bromine, N-bromosuccinimide (NBS) in a solvent such as dichloromethane, and -20 ° C to 40 ° C, preferably 0 ° C to 20 ° C.
  • a base such as pyrrolidine, piperidine, piperazine, morpholine is added, and 20 ° C to 100 ° C, preferably 40 ° C to 80 ° C.
  • Compound (Ib) can be obtained by reacting for 1 to 24 hours, preferably 1 to 12 hours.
  • First step In an enolate obtained by reacting with a target carbonyl compound such as diethyl ketone in the presence of a base such as lithium diisopropylamide in a solvent such as toluene, dichloromethane, tetrahydrofuran, or a mixed solvent thereof, A titanium reagent such as chlorotitanium triisopropoxide is added, and a compound a that can be prepared by a known method is added, and the temperature is ⁇ 80 ° C. to 30 ° C., preferably ⁇ 80 ° C. to 0 ° C.
  • compound i can be obtained by reacting for 0.1 to 12 hours.
  • Second Step Compound i is subjected to 0 to 80 ° C. in the presence of an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or trifluoroacetic acid in a solvent such as dioxane, methanol or 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 or trifluoroacetic acid
  • a solvent such as dioxane, methanol or dichloromethane or a mixed solvent thereof
  • Third Step Compound j is added with an isocyanate having a protective group (for example, benzoyl isocyanate) prepared in a solvent such as dioxane, tetrahydrofuran, toluene, acetone or the like, or a mixed solvent thereof by a commercially available or known method, and -30
  • the compound k can be obtained by reacting at a temperature of from 50 ° C. to 50 ° C., preferably from ⁇ 10 ° C. to 25 ° C. for 0.1 hour to 12 hours, preferably 0.1 hour to 3 hours.
  • Step 1 Compound a which can be prepared by a known method is a target carbonyl compound such as cyclopentanone 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 target carbonyl compound such as cyclopentanone
  • a base such as lithium diisopropylamide
  • a solvent such as toluene, dichloromethane or tetrahydrofuran, or in a mixed solvent thereof.
  • 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.
  • l can be obtained.
  • Second Step Compound 1 is dissolved 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 1 to 24 hours.
  • 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 1 to 24 hours.
  • Third Step Compound m is added with a protecting group (for example, benzoyl isocyanate) having a protective group prepared by a commercially available or known method in a solvent such as dioxane, tetrahydrofuran, toluene, acetone or the like, or a mixed solvent thereof.
  • the reaction is carried out at -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 (Id) can be obtained by reacting at -100 ° C, preferably 0 ° C-60 ° C, for 0.5-24 hours, preferably 1-12 hours.
  • 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.
  • n can be obtained.
  • Second Step Compound n is added with 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 o can be obtained by reacting at 0 ° C. to 80 ° C., preferably 0 ° C. to 30 ° C., for
  • Third Step Compound o is added with a protecting group (for example, benzoyl isocyanate) having a protective group prepared by a commercially available or known method in a solvent such as dioxane, tetrahydrofuran, toluene, acetone or the like, or a mixed solvent thereof.
  • the reaction is carried out at -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 p can be obtained by reacting at -100 ° C., preferably 0 ° C.-60 ° C., for 0.5-24 hours, preferably 1-12 hours.
  • Compound p is chlorinated in a solvent such as dichloromethane, tetrahydrofuran, toluene, etc. by adding oxalyl chloride, thionyl chloride, etc. and a catalytic amount of N, N-dimethylformamide, or 1-chloro-2-trimethylpropenylamine, etc.
  • Compound (Ie) can be obtained by adding a reagent and reacting 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. .
  • First step In a solvent such as toluene, diethyl ether, tetrahydrofuran or the like, or in a mixed solvent thereof, Grignard reagent such as phenyl magnesium bromide having a hydroxyl group which may be protected at the ortho position, or protected at the ortho position
  • Grignard reagent such as phenyl magnesium bromide having a hydroxyl group which may be protected at the ortho position, or protected at the ortho position
  • Compound a which can be prepared by a known method, is added to a lithium reagent such as pyridyllithium having a good hydroxyl group, and the temperature is ⁇ 80 ° C. to 30 ° C., preferably ⁇ 80 ° C. to 0 ° C. for 0.1 hour to 24 hours, preferably
  • the compound q can be obtained by reacting for 0.1 to 12 hours and then removing the protecting group of the hydroxyl group by a known method.
  • Second Step Compound q is dissolved in a solvent such as dioxane, methanol, dichloromethane or the like, 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.
  • a solvent such as dioxane, methanol, dichloromethane or the like, 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.
  • an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, preferably 0 ° C. to 80 ° C.
  • Compound r is added with an isothiocyanate having a protecting group (for example, benzoyl isothiocyanate) prepared in a solvent such as dioxane, tetrahydrofuran, toluene, acetone or the like, or a mixed solvent thereof, commercially or by a known method, Compound s can be obtained by reacting at ⁇ 30 ° C. to 50 ° C., preferably ⁇ 10 ° C. to 25 ° C., for 0.1 to 12 hours, preferably for 0.1 to 3 hours.
  • a protecting group for example, benzoyl isothiocyanate
  • 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.
  • Ring A includes a substituted carbocycle or a substituted or unsubstituted heterocycle.
  • 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 N (R 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
  • 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 ⁇
  • substituent group ⁇ The other symbols are as defined above)
  • 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 includes hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl.
  • R 8 includes hydrogen
  • Ring A ′ and ring B each independently include a substituted or unsubstituted carbocycle or a substituted or unsubstituted heterocycle.
  • Ring A ′ is, for example, substituted or unsubstituted benzene
  • ring B is substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine, or substituted or unsubstituted pyrazine.
  • 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 1 is, for example, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, cyano, substituted or unsubstituted carbocyclic group or substituted or unsubstituted heterocyclic group. Can be mentioned.
  • R 1 is, for example, unsubstituted alkyl having 1 to 3 carbon atoms.
  • 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 2a and R 2b are hydrogen.
  • R za and R zb are each independently hydrogen, halogen, 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 Carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl
  • R za and R zb each independently include, for example, hydrogen, halogen, substituted or unsubstituted alkyl, or R za and R zb are Together with the carbon atoms to which it is attached, it forms a substituted or unsubstituted carbocycle.
  • R za and R zb each independently include, for example, hydrogen, halogen, or substituted or unsubstituted alkyl.
  • R 3a and R 3b 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,
  • R 3a and R 3b are each independently, for example, 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 alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, Carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substituted or
  • substituent (rb) is a group in which R 3a is, for example, alkyl, R 3b is, for example, hydrogen, and broken line a indicates the absence of a bond.
  • R 3a and R 3b are both hydrogen and the broken line a indicates the absence of a bond.
  • R 3a is, for example, hydrogen and the broken line a indicates the presence of a bond.
  • R 3a is, for example, alkyl and the broken line a indicates the presence of a bond.
  • R 3c is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted amino, substituted or unsubstituted Substituted carbamoyl, substituted or unsubstituted thiocarbamoyl, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted carbocyclic group, substituted or unsubstituted carbocyclic oxycarbonyl A substituted or unsubstituted heterocyclic group, a substituted or unsubstituted heterocyclic oxycarbonyl, and when broken line b indicates the presence of a bond, R 3c is absent.
  • substituent (rc) is a group in which R 3c is, for example, hydrogen and the broken line b indicates the absence of a bond.
  • R 3c is, for example, hydrogen
  • R 3c does not exist
  • a group in which the broken line b indicates the presence of a bond can be mentioned.
  • R 4a , R 4b and R 4c 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,
  • R 4a , R 4b and R 4c are each independently, for example, hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted Or an unsubstituted alkenyl or a substituted or unsubstituted alkynyl, where R 4b is absent when the dashed line a indicates the presence of a bond, and R 4c is absent when the dashed line c indicates the presence of a bond.
  • R 4a and R 4b include, for example, a group in which both are hydrogen.
  • One embodiment of the substituent (rb) is a group in which R 4a and R 4b are both hydrogen and the broken line a indicates the absence of a bond.
  • R 4a is, for example, hydrogen, and a group in which the broken line a indicates the presence of a bond is exemplified.
  • R 4c is, for example, hydrogen, and a group in which the broken line c indicates the absence of a bond can be mentioned.
  • One embodiment of the substituent (rc) includes a group in which R 4c is not present, for example, and the broken line c indicates the presence of a bond.
  • the ring Q includes a substituted or unsubstituted carbocyclic ring or a substituted or unsubstituted heterocyclic ring.
  • Y 1 and Y 2 are each independently —C (R 5 ) (R 6 ) —, —C (R 5 ) ⁇ , —N (R 7 ) —, —N ⁇ , —S—, —SO—, —SO 2 — or —O— can be mentioned.
  • Y 1 and Y 2 are each independently, for example, —C (R 5 ) (R 6 ) — or —C (R 5 ) ⁇ .
  • Y 3 and Y 4 are each independently —C (R 5 ) (R 6 ) —, —N (R 7 ) —, —S—, —SO—, —SO 2 — or —O— may be mentioned.
  • Y 3 and Y 4 are each independently, for example, —C (R 5 ) (R 6 ) —.
  • R 5 and R 6 are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted Substituted 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
  • R 5 and R 6 are each independently, for example, 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 alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, Cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted thiocarbamoyl, substitute
  • R 5 and R 6 are each independently, for example, hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted Or unsubstituted acyl, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted amino, or substituted or unsubstituted carbamoyl.
  • 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 alkynyloxy, substituted or unsubstituted acyl, substituted or unsubstituted acyloxy, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted Substituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted substituted or unsubstituted alkenyl
  • R 7 is for example 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 acyl, cyano, nitro, carboxy, substituted or unsubstituted alkoxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkylsulfinyl Substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl, substituted or unsubstituted carbamoyl, substituted or
  • R 7 is for example hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted acyl, cyano, carboxy, substituted or unsubstituted Examples include alkoxycarbonyl or substituted or unsubstituted carbamoyl.
  • Ring A ′ is a substituted or unsubstituted carbocycle (the substituent is, for example, a halogen)
  • Ring B is substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine or substituted or unsubstituted pyrazine (the substituent is, for example, halogen, hydroxy, alkoxy, amino or cyano);
  • R 1 is substituted or unsubstituted alkyl (more specifically, R 1 is unsubstituted alkyl);
  • R 8 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl (more specifically, R 8 is hydrogen);
  • R za and R zb are each independently hydrogen or substituted or unsubstituted alkyl (more specifically, R za and R zb are both hydrogen)) Is mentioned.
  • Ring A ′ is a substituted or unsubstituted carbocycle (substituent is, for example, halogen) or substituted or unsubstituted thiophene (substituent is, for example, halogen);
  • Ring B is substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine or substituted or unsubstituted pyrazine (the substituent is, for example, halogen, hydroxy, alkyl, halogenoalkyl, alkynyl, alkoxy, halogenoalkoxy, amino or cyano )
  • R 1 is substituted or unsubstituted alkyl (more specifically, R 1 is unsubstituted alkyl);
  • R 8 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl (more specifically, R 8 is hydrogen)
  • Ring A ′ is a substituted or unsubstituted carbocycle (the substituent is, for example, a halogen)
  • Ring B is substituted or unsubstituted pyridine, substituted or unsubstituted pyrimidine or substituted or unsubstituted pyrazine (the substituent is, for example, halogen, hydroxy, alkyl, halogenoalkyl, alkoxy, halogenoalkoxy, amino or cyano).
  • R 1 is substituted or unsubstituted alkyl (more specifically, R 1 is unsubstituted alkyl);
  • R 3 is hydrogen or substituted or unsubstituted alkyl (more specifically, R 3 is unsubstituted alkyl);
  • R 8 is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted acyl (more specifically, R 8 is hydrogen)) Is mentioned.
  • Ring A is A compound,
  • Ring B is Wherein R b1 and R b2 are each independently hydrogen, chloro, fluoro, methoxy, butynyloxy, cyano, amino or carbamoyl.
  • R b1 and R b2 are each independently hydrogen, chloro, fluoro, methoxy, butynyloxy, cyano, amino or carbamoyl.
  • a compound, A compound in which the combination of ring B, R b1 and R b2 (B, R b1 , R b2 ) is as follows.
  • ring B (B1, hydrogen, hydrogen) (hereinafter, ring B is b1), (B1, hydrogen, chloro) (hereinafter, ring B is b2), (B1, hydrogen, fluoro) (hereinafter, ring B is b3), (B1, hydrogen, methoxy) (hereinafter, ring B is b4), (B1, hydrogen, butynyloxy) (hereinafter, ring B is b5), (B1, hydrogen, cyano) (hereinafter, ring B is b6), (B1, hydrogen, amino) (hereinafter, ring B is b7), (B1, hydrogen, carbamoyl) (hereinafter, ring B is b8), (B1, chloro, hydrogen) (hereinafter, ring B is b9), (B1, chloro, chloro) (hereinafter, ring B is b10), (B1, chloro, fluoro) (hereinafter, ring B is b11), (B1, chloro, methoxy
  • 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.
  • a combination of ring A and ring B (r, A, 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, A1, b9
  • 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.
  • treatment of Alzheimer's disease includes prevention of MCI severity and prevention of familial Alzheimer's disease.
  • pharmaceutical composition for treating Alzheimer's disease includes a pharmaceutical composition for preventing MCI from becoming severe, 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 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 treatment or prevention agents such as acetylcholinesterase).
  • other drugs for example, other Alzheimer's disease treatment or prevention 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.
  • compound (9) (3.00 g) prepared by the method described in WO2009 / 151098 was dissolved in tetrahydrofuran (30 ml) and cooled in a dry ice-acetone bath.
  • 2-Methylallyl magnesium chloride (0.5 mol / L THF solution, 85.0 ml) was added dropwise at -78 ° C, and the mixture was stirred at -78 ° C for 2 hours.
  • a saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate, and washed successively with water and saturated brine.
  • N, N-Diisopropylethylamine (2.42 ml) and methyl iodide (1.97 g) were added to a solution of the sixth step compound (15) (4.61 g) in acetonitrile (20 ml), and the mixture was stirred at room temperature for 24 hours.
  • the solvent was distilled off under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed successively with 1 mol / L hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous magnesium sulfate.
  • the solvent was distilled off under reduced pressure to obtain Compound (16) (4.36 g).
  • Example 4 Synthesis of Compound (I-55) First Step Compound (20) (30 g) was dissolved in chloroform (60 ml), trimethylaluminum (33.3 g) and bromine (12.9 ml) were added at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Thereafter, the temperature was raised to 50 ° C. and the mixture was stirred for 2 hours, then trimethylaluminum (16.0 g) was added, and the mixture was stirred for 1 hour. The temperature of the reaction solution was returned to room temperature, sodium acetate was added, and the mixture was filtered through Celite. This was extracted with chloroform and dried over sodium sulfate.
  • RT retention time (minutes)
  • D deuterium
  • 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-1 IC 50 value 0.0473 ⁇ mol / L
  • Compound I-2 IC 50 value 0.027 ⁇ mol / L
  • Compound I-6 IC 50 value 0.054 ⁇ mol / L
  • Compound I-53 IC 50 value 0.046 ⁇ mol / L
  • Compound I-54 IC 50 value 0.097 ⁇ mol / L
  • Compounds I-3, 4, 5, 7 to 11, 52, and 55 to 60 also had an IC 50 value of 30 ⁇ 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-1 IC 50 value 0.0155 ⁇ mol / L
  • 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) ).
  • 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 ( ⁇ ).
  • Compound I-52 ( ⁇ )
  • 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.
  • Compound I-53 5 types> 20 ⁇ M
  • Test Example 6 FAT test Inoculate 20 ⁇ L of Salmonella typhimurium TA98 strain and 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 8 Metabolic stability test
  • the target compound is allowed to react for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism in the liver.
  • the absolute value of the maximum tail current is 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. Further, the inhibition rate with respect to the maximum tail current before application of the test substance is calculated, and compared with the medium application group (0.1% dimethyl sulfoxide solution), the influence of the test substance on I Kr is evaluated.
  • 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 was carried out from the tail vein using a syringe with an injection needle.
  • Evaluation item Blood was collected over time, and the plasma drug concentration was measured using LC / MS / MS.
  • Compound I-53 80.4%
  • Rats are intravenously administered at a dose of 0.5 mg / mL / kg, and after 30 minutes, they are exsanguinated by whole blood collection from the lower aorta under isoflurane anesthesia. The brain is then removed and 20-25% homogenate is prepared with distilled water. On the other hand, the obtained blood is made into plasma after centrifugation. Thereafter, control plasma is added to the brain sample and control brain is added to the plasma sample at a ratio of 1: 1, and each sample is measured using LC / MS / MS. The obtained area ratio (brain / plasma) at the time of measurement is defined as the brain Kp value.
  • 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.

Abstract

La présente invention concerne un composé, ou similaire, servant d'agent prophylactique ou thérapeutique contre des pathologies induites par la production, la sécrétion et/ou le dépôt de la protéine β-amyloïde. La présente invention concerne spécifiquement un composé de formule (I), l'un de ses sels de qualité pharmaceutique ou un solvate du composé ou du sel. (Dans la formule, R1, R2a, R2b, R3, R4a, R4b, le cycle A et le segment interrompu sont tels que définis dans la description.)
PCT/JP2010/072193 2009-12-11 2010-12-10 Dérivé d'oxazine WO2011071135A1 (fr)

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EP10836054.6A EP2511268B2 (fr) 2009-12-11 2010-12-10 Dérivé d'oxazine
AU2010328975A AU2010328975B2 (en) 2009-12-11 2010-12-10 Oxazine derivative
RU2012129168/04A RU2012129168A (ru) 2009-12-11 2010-12-10 Производные оксазина
BR112012013854A BR112012013854A2 (pt) 2009-12-11 2010-12-10 derivados de oxazina.
MX2012006491A MX2012006491A (es) 2009-12-11 2010-12-10 Derivados de oxazina.
CN2010800648635A CN102834384A (zh) 2009-12-11 2010-12-10 *嗪衍生物
UAA201208561A UA110467C2 (uk) 2009-12-11 2010-12-10 Похідні оксазину
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CA2783958A CA2783958A1 (fr) 2009-12-11 2010-12-10 Derive d'oxazine
ES10836054T ES2590038T5 (es) 2009-12-11 2010-12-10 Derivado de oxazina
US13/513,839 US8999980B2 (en) 2009-12-11 2010-12-10 Oxazine derivatives
ZA2012/03777A ZA201203777B (en) 2009-12-11 2012-05-23 Oxazine derivative
US14/627,700 US9290466B2 (en) 2009-12-11 2015-02-20 Oxazine derivatives
US15/041,683 US9656974B2 (en) 2009-12-11 2016-02-11 Oxazine derivatives

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US8703785B2 (en) 2008-10-22 2014-04-22 Shionogi & Co., Ltd. 2-aminopyrimidin-4-one and 2-aminopyridine derivatives both having BACE1-inhibiting activity
JP2014510769A (ja) * 2011-04-11 2014-05-01 エフ．ホフマン−ラ ロシュ アーゲー Ｂａｃｅ１及び／又はｂａｃｅ２阻害剤としての１，３−オキサジン
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WO2014134341A1 (fr) 2013-03-01 2014-09-04 Amgen Inc. Composés perfluorés 5,6-dihydro-4h-1,3-oxazine-2-amine substitués en tant qu'inhibiteurs de la bêta-sécrétase et procédés d'utilisation correspondants
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