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WO2011071057A1 - Composition pharmaceutique pour le traitement ou la prévention de la maladie d'alzheimer contenant un dérivé hétérocyclique contenant du soufre - Google Patents

Composition pharmaceutique pour le traitement ou la prévention de la maladie d'alzheimer contenant un dérivé hétérocyclique contenant du soufre Download PDF

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Publication number
WO2011071057A1
WO2011071057A1 PCT/JP2010/071957 JP2010071957W WO2011071057A1 WO 2011071057 A1 WO2011071057 A1 WO 2011071057A1 JP 2010071957 W JP2010071957 W JP 2010071957W WO 2011071057 A1 WO2011071057 A1 WO 2011071057A1
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Prior art keywords
substituent
optionally substituted
compound
optionally
lower alkyl
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English (en)
Japanese (ja)
Inventor
章洋 堀
秀爾 米澤
千明 藤越
彩枝 松本
雄二 郡山
達彦 上野
輝和 加藤
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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Priority to JP2011545220A priority Critical patent/JP5554346B2/ja
Publication of WO2011071057A1 publication Critical patent/WO2011071057A1/fr
Anticipated expiration legal-status Critical
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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
    • 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
    • A61K31/54—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 sulfur as the ring hetero atoms, e.g. sulthiame
    • 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
    • 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
    • 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
    • C07D417/10—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 carbon chain containing aromatic rings
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a pharmaceutical composition for treating or preventing a disease, particularly Alzheimer's disease, which has an amyloid ⁇ production inhibitory action and is induced by production, secretion and / or deposition of amyloid ⁇ protein.
  • amyloid ⁇ protein 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.
  • APP amyloid ⁇ precursor protein
  • BACE1 ⁇ -site APP-cleaving enzyme 1
  • Patent Document 1 describes a compound having a structure similar to that of the compound contained in the pharmaceutical composition of the present invention, and discloses that it has NO synthase inhibitory activity and is effective for dementia.
  • Patent Documents 2 to 5 Non-Patent Document 1, and Non-Patent Document 2 describe compounds similar in structure to the compounds contained in the pharmaceutical composition of the present invention, but each has a blood pressure-elevating agent, morphine-like analgesic agent, or It is described that it is useful as a tranquilizer, pharmaceutical intermediate, NPYY5 antagonist, analgesic and the like.
  • Patent Documents 6 to 29 and the like are known as ⁇ -secretase inhibitors, all of which have a skeleton different from the compound contained in the pharmaceutical composition of the present invention.
  • a compound having an action of inhibiting amyloid ⁇ production particularly an action of inhibiting ⁇ secretase, and useful as a therapeutic or preventive agent for diseases induced by production, secretion or deposition of amyloid ⁇ protein.
  • the present invention 1) The following formula (I): (In the formula, ring A is a carbocyclic group which may have a substituent or a heterocyclic group which may have a substituent, R 1 may have a lower alkyl optionally having a substituent, a lower alkenyl optionally having a substituent, a lower alkynyl optionally having a substituent, cyano, and optionally having a substituent.
  • R 2a and R 2b are each independently hydrogen, optionally substituted lower alkyl, or optionally substituted acyl
  • R 3a and R 3c are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower Alkynyl
  • acyl optionally having substituent, lower alkoxy optionally having substituent, aryl lower alkyl optionally having substituent, heteroaryl lower optionally having substituent Alkyl
  • aryl lower alkoxy optionally having substituent
  • heteroaryl lower alkoxy optionally having substituent
  • lower alkylthio optionally having substituent, carboxy, cyano, having substituent
  • R x is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group;
  • R 3a and R 3b are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower Alkynyl, acyl optionally having substituent, lower alkoxy optionally having substituent, aryl lower alkyl optionally having substituent, heteroaryl lower optionally having substituent Alkyl, aryl lower alkoxy optionally having substituent, heteroaryl lower alkoxy optionally having substituent, lower alkylthio optionally having substituent, carboxy, cyano, having substituent Optionally substituted lower alkoxycarbonyl, optionally substituted amino, optionally substituted carbamoyl, optionally substituted carbocyclic Or have a substituent is a heterocyclic radical, Ring A, R 2a and R 2b are as defined in 1).
  • R y is a halogeno lower alkyl
  • R 3a , R 3b , R 3c and R 3d are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, and optionally substituted.
  • a pharmaceutical composition for treating or preventing Alzheimer's disease comprising the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof:
  • R za and R zb are each independently hydrogen, halogen, optionally substituted lower alkyl, or R za and R zb together with the carbon atom to which they are attached. Form a carbocycle, Ring A, R 1 , R 2a and R 2b are as defined in 1), and R 3c and R 3d are as defined in 3).
  • a pharmaceutical composition for treating or preventing Alzheimer's disease comprising the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof or a solvate thereof: 5) The pharmaceutical composition for treating or preventing Alzheimer's disease according to 1), wherein R 3a and R 3c are both hydrogen, 6) The pharmaceutical composition for treating or preventing Alzheimer's disease according to any one of 1), 4) or 5), wherein R 1 is alkyl having 1 to 3 carbon atoms, 7) R x is a cycloalkyl which may have a substituent, a phenyl which may have a substituent, or a nitrogen-containing aromatic heterocyclic group which may have a substituent.
  • a pharmaceutical composition for treating or preventing Alzheimer's disease 8) The pharmaceutical composition for treating or preventing Alzheimer's disease according to 2) or 7), wherein R 3a and R 3b are both hydrogen, 9) The pharmaceutical composition for treating or preventing Alzheimer's disease according to 3), wherein R 3a , R 3b , R 3c and R 3d are all hydrogen, 10) The pharmaceutical composition for treating or preventing Alzheimer's disease according to any one of 1) to 9), wherein R 2a and R 2b are both hydrogen,
  • Ring A is (Wherein ring A ′ is a carbocyclic group or a heterocyclic group; G is Wherein R 5 is hydrogen, lower alkyl or acyl, R 6 is optionally substituted lower alkyl, optionally substituted lower alkenyl or optionally substituted lower alkynyl, W 1 is O or S; W 2 is O, S or NR 5 ; Ak is a lower alkylene which may have a substituent, a lower alkenylene which may have a substituent, or a lower alkynylene which may have a substituent, Ring B is a carbocyclic group which may have a substituent or a heterocyclic group which may have a substituent.
  • R 4 each independently represents halogen, hydroxy, mercapto, halogeno lower alkyl, lower alkyl, lower alkoxy, optionally substituted amino or lower alkylthio, and n is an integer of 0-2.
  • the pharmaceutical composition according to the present invention is useful as a therapeutic or prophylactic agent for diseases (such as Alzheimer's disease) induced by the production, secretion or deposition of amyloid ⁇ protein.
  • the pharmaceutical composition according to the present invention can be a pharmaceutical with reduced side effects because it contains a compound having an effect such as high inhibitory activity against BACE1 and high selectivity for other enzymes.
  • the pharmaceutical composition according to the present invention can be a pharmaceutical with a wider safety margin against side effects by using an optically active substance having appropriate stereochemistry as an active ingredient.
  • the pharmaceutical composition according to the present invention has high metabolic stability, high solubility, high oral absorption, good bioavailability (BA), good clearance, high brain transferability, It can be an excellent pharmaceutical because it contains a compound with advantages such as long half-life, high non-protein binding rate, low hERG channel inhibition, low CYP inhibition and / or negative in Ames test. .
  • halogen includes fluorine, chlorine, bromine and iodine.
  • the halogen part of “halogeno lower alkyl”, “halogeno lower alkoxy” and “halogeno lower alkoxycarbonyl” is the same as the above “halogen”.
  • “Lower alkyl” includes linear or branched alkyl having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 3 carbon atoms.
  • the substituent group ⁇ is halogen, hydroxy, lower alkoxy, halogeno lower alkoxy, hydroxy lower alkoxy, lower alkoxy lower alkoxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, amino, acylamino, lower alkylamino, imino, hydroxy Imino, lower alkoxyimino, lower alkylthio, carbamoyl, lower alkylcarbamoyl, hydroxy lower alkylcarbamoyl, sulfamoyl, lower alkylsulfamoyl, lower alkylsulfinyl, lower alkylsulfonylamino, lower alkylsulfonyl lower alkylamino, lower alkylsulfonylimino, lower Alkylsulfinylamino, lower alkylsulfinyl lower alkylamino, lower alkylsulfinylimino, Bruno
  • Substituents of “lower alkoxy optionally having substituent”, “lower alkoxycarbonyl optionally having substituent” and “lower alkylthio optionally having substituent” are the above substituents And one or more groups selected from the group ⁇ .
  • Preferable embodiments of “halogeno lower alkyl” include trifluoromethyl, fluoromethyl, trichloromethyl and the like.
  • “Lower alkylidene” includes the above-mentioned divalent group of “lower alkyl” and includes, for example, methylidene, ethylidene, propylidene, isopropylidene, butylidene, pentylidene, hexylidene and the like.
  • “Lower alkenyl” has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more double bonds at any position. Of linear or branched alkenyl.
  • “Lower alkynyl” is a straight chain or branched alkynyl having 2 to 10, preferably 2 to 8, and more preferably 3 to 6 carbon atoms having one or more triple bonds at any position. Include. 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.
  • Examples of the substituent of “lower alkenyl optionally having substituent (s)” and “lower alkynyl optionally having substituent (s)” include one or more groups selected from the above substituent group ⁇ . “Hydroxy lower alkenyl”, “lower alkoxy lower alkenyl”, “lower alkoxycarbonyl lower alkenyl”, “carbocyclic lower alkenyl”, “lower alkenyloxy”, “lower alkoxy lower alkenyloxy”, “lower alkenylthio” and “lower The lower alkenyl part of “alkenylamino” is the same as the above “lower alkenyl”.
  • “Hydroxy lower alkynyl”, “lower alkoxy lower alkynyl”, “lower alkoxycarbonyl lower alkynyl”, “carbocyclic lower alkynyl”, “lower alkynyloxy”, “lower alkoxy lower alkynyloxy”, “lower alkynylthio” and “lower The lower alkynyl part of “alkynylamino” is the same as the above “lower alkynyl”.
  • substituents of “optionally substituted amino” and “optionally substituted carbamoyl” include lower alkyl, acyl, hydroxy, lower alkoxy, lower alkoxycarbonyl, carbocyclic group and Examples thereof include 1 to 2 groups selected from a heterocyclic group and the like.
  • “Acyl” includes aliphatic acyl having 1 to 10 carbon atoms, carbocyclic carbonyl and heterocyclic carbonyl.
  • acyl 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.
  • the acyl moiety of “acylamino” and “acyloxy” is the same as described above.
  • substituent of “acyl optionally having substituent (s)” include one or more groups selected from substituent group ⁇ .
  • the ring portion of carbocyclic carbonyl and heterocyclic carbonyl is represented by one or more groups selected from lower alkyl substituted with one or more groups selected from lower alkyl, substituent group ⁇ , and substituent group ⁇ . May be substituted.
  • the “carbocyclic group” includes cycloalkyl, cycloalkenyl, aryl, non-aromatic fused carbocyclic group and the like.
  • “Cycloalkyl” is a carbocyclic group having 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 4 to 8 carbon atoms.
  • Cycloalkyl lower alkyl "cycloalkyloxy”, “cycloalkyl lower alkoxy”, “cycloalkylthio", “cycloalkylamino”, “cycloalkyl lower alkylamino”, “cycloalkylsulfamoyl”, “cycloalkyl
  • the cycloalkyl part of “sulfonyl”, “cycloalkylcarbamoyl”, “cycloalkyl lower alkylcarbamoyl”, “cycloalkyl lower alkoxycarbonyl” and “cycloalkyloxycarbonyl” is the same as the above “cycloalkyl”.
  • Cycloalkenyl includes those having one or more double bonds at any position in the cycloalkyl ring, specifically, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclo Examples include heptynyl, cyclooctynyl and cyclohexadienyl.
  • Aryl includes phenyl, naphthyl, anthryl, phenanthryl and the like, with phenyl being particularly preferred.
  • 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. “To form a carbocycle together with carbon atoms to be bonded” means that two substituents are combined to form the above “cycloalkyl” or “cycloalkenyl”.
  • Carbocyclic oxy “Carbocyclic lower alkyl”, “Carbocyclic lower alkenyl”, “Carbocyclic lower alkynyl”, “Carbocyclic lower alkoxy”, “Carbocyclic lower alkoxycarbonyl”, “Carbocyclic thio”, “Carbon “Ring amino”, “carbocyclic lower alkylamino”, “carbocyclic carbonyl”, “carbocyclic sulfamoyl”, “carbocyclic sulfonyl”, “carbocyclic carbamoyl", “carbocyclic lower alkyl carbamoyl” and “carbocyclic oxycarbonyl”
  • the carbocyclic moiety is the same as the “carbocyclic group”.
  • Aryl lower alkyl “aryloxy”, “aryloxycarbonyl”, “aryloxycarbonyloxy”, “aryl lower alkoxycarbonyl”, “arylthio”, “arylamino”, “aryl lower alkoxy”, “aryl lower alkyl”
  • the aryl part of “amino”, “arylsulfonyl”, “arylsulfonyloxy”, “arylsulfinyl”, “arylsulfamoyl”, “arylcarbamoyl” and “arylloweralkylcarbamoyl” 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,
  • Heterocyclic lower alkyl "heterocyclic oxy”, “heterocyclic thio", "heterocyclic carbonyl”, “heterocyclic lower alkoxy”, “heterocyclic amino”, “heterocyclic carbonylamino”, “heterocyclic sulfamoyl” , “Heterocyclic sulfonyl”, “heterocyclic carbamoyl”, “heterocyclic oxycarbonyl”, “heterocyclic lower alkylamino”, “heterocyclic lower alkoxycarbonyl” and “heterocyclic lower alkylcarbamoyl” are also referred to as " The same as “heterocyclic group”.
  • the “nitrogen-containing aromatic heterocyclic group” is a group containing at least one nitrogen among the above “heterocyclic groups”, for example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 5- to 6-membered heteroaryl such as triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, etc .; , Quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, Ndoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazo
  • the bond of the above “heterocyclic group” and “nitrogen-containing aromatic heterocyclic group” may be located on any ring.
  • the “nitrogen-containing aromatic heteromonocyclic group” means a monocyclic group among the above-mentioned “nitrogen-containing aromatic heterocyclic groups”.
  • Examples include 5- to 6-membered heteroaryl such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
  • the bond of the above “nitrogen-containing aromatic heteromonocyclic group” may be located on any carbon atom.
  • the “heteroaryl” includes those that are aromatic cyclic groups among the above “heterocyclic groups”. The same applies to the heteroaryl part of “heteroaryl lower alkyl” and “heteroaryl lower alkoxy”.
  • Substituent group ⁇ (preferably halogen, hydroxy, acyl, acyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, amino, cyano, lower alkylamino and / or lower alkylthio, etc.), Substituent group ⁇ , lower alkyl optionally substituted with one or more groups selected from the group consisting of hydroxyimino and lower alkoxyimino (wherein the substituent is preferably halogen, hydroxy, lower alkoxy and / or lower Alkoxycarbonyl), An amino lower alkyl substituted with one or more groups selected from the substituent group ⁇ (wherein the substituent is preferably acyl, lower alkyl and / or lower alkoxy, etc.), Hydroxyimino lower alkyl, Lower alkoxyimino lower alkyl, Lower alkoxyimino lower alky
  • Lower alkynyloxy optionally substituted with one or more groups selected from substituent group ⁇ (preferably halogen and / or hydroxy etc. as a substituent), Lower alkoxy lower alkynyloxy optionally substituted with one or more groups selected from substituent group ⁇ , Lower alkylthio optionally substituted with one or more groups selected from substituent group ⁇ , Lower alkenylthio optionally substituted with one or more groups selected from substituent group ⁇ , Lower alkynylthio optionally substituted with one or more groups selected from substituent group ⁇ , Lower alkylamino substituted with one or more groups selected from substituent group ⁇ , Lower alkenylamino substituted with one or more groups selected from substituent group ⁇ , Lower alkynylamino substituted with one or more groups selected from substituent group ⁇ , Aminooxy optionally substituted with one or more groups selected from substituent group ⁇ and lower alkylidene, Acyl substituted with one or more groups selected from the substituent group ⁇
  • a carbocyclic group (for example, cycloalkyl, aryl, etc.) that may be substituted with one or more groups selected from the group consisting of substituent group ⁇ , azide, lower alkyl and halogeno lower alkyl, A heterocyclic group which may be substituted with one or more groups selected from the group consisting of the substituent group ⁇ , azide, lower alkyl and halogeno lower alkyl, A carbocyclic lower alkyl optionally substituted with one or more groups selected from the group consisting of the substituent group ⁇ , azide, lower alkyl and halogeno lower alkyl (eg, cycloalkyl lower alkyl, aryl lower alkyl, etc.), Heterocyclic lower alkyl optionally substituted with one or more groups selected from the group consisting of substituent group ⁇ , azide, lower alkyl and halogeno lower alkyl, Substituent group ⁇ , azido, carbocyclic oxy optionally substitute
  • Heterocyclic lower alkoxy optionally substituted with one or more groups selected from the group consisting of the substituent group ⁇ , azide, lower alkyl and halogeno lower alkyl, Substituent group ⁇ , azido, carbocyclic lower alkoxycarbonyl (eg, cycloalkyl lower alkoxycarbonyl, aryl lower alkoxycarbonyl, etc.) optionally substituted with one or more groups selected from the group consisting of azide, lower alkyl and halogeno lower alkyl , Heterocyclic group lower alkoxycarbonyl optionally substituted with one or more groups selected from the group consisting of substituent group ⁇ , azide, lower alkyl and halogeno lower alkyl, Substituent group ⁇ , azido, carbocyclic thio (eg, cycloalkylthio, arylthio etc.) optionally substituted with one or more groups selected from the group consisting of lower alkyl and
  • a carbocyclic sulfamoyl group (eg, cycloalkylsulfamoyl, arylsulfamoyl etc.) optionally substituted with one or more groups selected from the group consisting of the substituent group ⁇ , azide, lower alkyl and halogeno lower alkyl, Heterocyclic sulfamoyl optionally substituted with one or more groups selected from the group consisting of the substituent group ⁇ , azide, lower alkyl and halogeno lower alkyl, A carbocyclic sulfonyl optionally substituted with one or more groups selected from the group consisting of the substituent group ⁇ , azide, lower alkyl and halogeno lower alkyl (for example, cycloalkylsulfonyl, arylsulfonyl, etc.), Heterocyclic sulfonyl optionally substituted with one or more groups selected from the group consisting of substituent group ⁇ , azi
  • ring A has the substituents shown below:
  • Ak 1 , Ak 2 and Ak 3 each independently have a single bond, a lower alkylene which may have a substituent, a lower alkenylene which may have a substituent or a substituent. And may be lower alkynylene, Ak 4 is lower alkylene which may have a substituent, lower alkenylene which may have a substituent or lower alkynylene which may have a substituent, W 1 and W 3 are each independently O or S; Each W 2 is independently O, S or NR 5 ; R 5 and R 6 are each independently hydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbocyclic lower alkyl, lower alkenyl, hydroxy lower alkenyl, lower alkoxy lower alkenyl, lower alkoxycarbonyl Lower alkenyl, carbocyclic lower alkenyl, lower alkynyl, hydroxy lower alkynyl, lower alkoxy lower alkenyl Lower
  • substituent of “group” include one or more groups selected from the group consisting of lower alkyl optionally substituted with one or more groups selected from substituent group ⁇ and substituent group ⁇ .
  • substituent group include one or more groups selected from the group consisting of lower alkyl optionally substituted with one or more groups selected from substituent group ⁇ and substituent group ⁇ .
  • R 4 halogen, lower alkyl, halogeno lower alkyl, lower alkoxy, halogeno lower alkoxy are preferable.
  • the “lower alkylene” includes a linear or branched divalent carbon chain having 1 to 10, preferably 1 to 6, and more preferably 1 to 3 carbon atoms. Specific examples include methylene, dimethylene, trimethylene, tetramethylene, methyltrimethylene and the like.
  • the lower alkylene part of “lower alkylenedioxy” is the same as the above “lower alkylene”.
  • “Lower alkenylene” is a divalent carbon having 2 to 10 carbon atoms, preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having a double bond at any position. Includes chains.
  • “Lower alkynylene” is a straight chain or branched chain having 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, which has a triple bond at an arbitrary position and may further have a double bond. More preferably, it includes a divalent carbon chain having 2 to 4 carbon atoms. Specific examples include ethynylene, propynylene, butynylene, pentynylene and hexynylene.
  • R 3a and R 3c may be combined to form a ring” means the following formula (I ′′) (In the formula, ring C is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, and other symbols are as defined in formula (I). .) Preferred examples of ring C include benzene, pyridine, pyrimidine, cyclohexene, tetrahydropyridine, dihydropyran and the like.
  • the “solvate” includes, for example, solvates with organic solvents, hydrates and the like, 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
  • 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.
  • hydrochloric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like are preferable.
  • the compounds according to the present invention are not limited to specific isomers, but all possible isomers (keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers and rotational isomers). Etc.) and racemates.
  • the compound represented by the formula (I) in which R 2a is hydrogen includes the following tautomers. Similar tautomers are also included in the compounds represented by formulas (II), (III) and (IV).
  • the compound according to the present invention has an asymmetric carbon atom and includes optical isomers.
  • the compound represented by the formula (I) includes any of the following optical isomers. Preferably It is.
  • optical isomers are included in the compounds represented by the formulas (II), (III) and (IV).
  • the optical isomers of the compounds according to the invention can be obtained by known techniques such as chiral chromatography or the formation of diastereomeric salts from optically active acids or bases.
  • one or more hydrogen, carbon or other atoms of the compounds according to the present invention may be replaced with isotopes of hydrogen, carbon or other atoms.
  • Compounds of formula (I) include all radiolabeled compounds of the compounds according to the invention. Such “radiolabeled”, “radiolabeled” and the like of the compounds according to the present invention 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.
  • isotopes examples include 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, respectively. Hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, iodine and chlorine are included, such as 18 F, 123 I and 36 Cl.
  • the radiolabeled compound of the present invention can be prepared by methods well known in the art. For example, a tritium-labeled compound of the compound according to the present invention can be prepared by introducing tritium into a specific compound of the compound according to the present invention, for example, by a catalytic dehalogenation reaction using tritium.
  • This method involves reacting a tritium gas with a suitably halogen-substituted precursor of a compound according to the invention 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
  • Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987).
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • the compound according to the present invention represented by the formula (I), (II), (III) or (IV) should be produced, for example, according to the method described in Patent Document 15 or Non-Patent Document 1, or by the following method. Can do. In all of 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) and the like, and the protecting group may be removed at a desired stage. Moreover, about all the said processes, the order of the process to implement can be changed suitably, and each intermediate body may be isolated and used for the following process.
  • 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,
  • the compound represented by formula (I) can be produced, for example, according to the synthesis method of compound v or compound ab shown below.
  • R 2a is hydrogen, optionally substituted lower alkyl, or optionally substituted acyl
  • R 3c each independently represents hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, substituent Lower alkoxy, which may have a substituent, aralkyl which may have a substituent, heteroarylalkyl which may have a substituent, aralkyloxy which may have a substituent, Optionally substituted heteroarylalkyloxy, optionally substituted lower alkylthio, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, substituent A carbamoyl which may have, a carbocyclic group which may have a substituent or a heterocyclic group which may have a substituent.
  • First step Enolate obtained by reacting with a target ester such as t-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 is added, and a compound p that can be prepared by a known method is added, and the temperature is ⁇ 80 ° C. to 30 ° C., preferably ⁇ 80 ° C.
  • Compound q can be obtained diastereoselectively by reacting for a period of time, preferably 0.1 to 12 hours.
  • 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.
  • an acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid, preferably 0 ° C. to 80 ° C.
  • Second Step Add a reducing agent such as borane, sodium hydride, lithium aluminum hydride to the compound r in a solvent such as dioxane, tetrahydrofuran, toluene, or a mixed solvent thereof, and -80 ° C to 80 ° C, preferably Compound s can be obtained by reacting at ⁇ 20 ° C. to 30 ° C. for 0.5 to 48 hours, preferably for 1 to 12 hours.
  • a reducing agent such as borane, sodium hydride, lithium aluminum hydride
  • the compound s is added with an oxidizing agent such as 2-iodoxybenzoic acid in a solvent such as dimethyl sulfoxide or dichloromethane, and 0 to 80 ° C., preferably 10 to 40 ° C., for 0.5 to 48 hours.
  • compound u can be obtained by reacting for 1 to 12 hours.
  • the amine and / or aldehyde groups of compound s and compound u are protected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), etc. as necessary. And can be deprotected in a timely manner.
  • isothiocyanate for example, benzoyl isothiocyanate
  • a solvent such as dioxane, tetrahydrofuran, toluene, acetone, or a mixed solvent thereof
  • 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 v 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 3a is each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, substituent Lower alkoxy, which may have a substituent, aralkyl which may have a substituent, heteroarylalkyl which may have a substituent, aralkyloxy which may have a substituent, Optionally substituted heteroarylalkyloxy, optionally substituted lower alkylthio, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, substituent A carbamoyl which may have a carbocyclic group which may have a substituent or a heterocyclic group which may have a substituent, Other symbols are as defined above. )
  • Second Step Conditions for Swern Oxidation Reaction Using Oxalyl Chloride-Dimethyl Sulfoxide in a Solvent such as Toluene, Dichloromethane, Tetrahydrofuran, etc. Or an alcohol group oxidizing agent such as 2-iodoxybenzoic acid is added, and the reaction is carried out at 0 ° C. to 80 ° C., preferably 10 ° C. to 40 ° C., for 0.5 hour to 48 hours, preferably 1 hour to 12 hours. Compound x can be obtained.
  • Second Step The compound x corresponds to a target product such as methylmagnesium bromide at ⁇ 80 ° C. to 50 ° C., preferably ⁇ 20 ° C. to 20 ° C.
  • Compound y can be obtained by adding a Grignard reagent and reacting for 0.2 to 48 hours, preferably 1 to 24 hours. In the reaction, the yield can be improved by adding titanium tetrachloride.
  • Compound y is added with an oxidant of an alcohol group such as oxalyl chloride-dimethyl sulfoxide or 2-iodoxybenzoic acid in a solvent such as dimethyl sulfoxide, and at 0 ° C. to 80 ° C., preferably 10 ° C. to 40 ° C.
  • Compound aa can be obtained by reacting for 0.5 to 48 hours, preferably 1 to 6 hours.
  • isothiocyanate having a protecting group (for example, benzoyl isothiocyanate) prepared by a commercially available or known method is added, 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 ab can be obtained by reacting at 0 ° C. to 100 ° C., preferably 0 ° C. to 60 ° C., for 0.5 to 12 hours, preferably for 1 to 6 hours.
  • R x is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group
  • R 2a and R 2b are each independently hydrogen, optionally substituted lower alkyl, or optionally substituted acyl
  • R 3a and R 3b are each independently hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl.
  • L is a leaving group such as halogen or a lower alkylsulfonyloxy group, Other symbols are as defined above. )
  • Step 1 Compound a, which can be prepared commercially or by a known method, is present in a solvent such as toluene, dichloromethane or tetrahydrofuran, or in a mixed solvent thereof in the presence of a base such as pyridine, triethylamine, diisopropylethylamine or 4-dimethylaminopyridine.
  • a base such as pyridine, triethylamine, diisopropylethylamine or 4-dimethylaminopyridine.
  • N O-dimethylhydroxylamine hydrochloride or a free form thereof at ⁇ 40 ° C. to 60 ° C., preferably ⁇ 20 ° C. to 30 ° C., for 0.1 hour to 24 hours, preferably 0.3 hour to 6 hours.
  • Compound b can be obtained by reaction.
  • Compound b corresponds to a target product such as cyclohexylmagnesium bromide in a solvent such as ether or tetrahydrofuran or a mixed solvent thereof at ⁇ 80 ° C. to 50 ° C., preferably ⁇ 20 ° C. to 20 ° C.
  • Compound c can be obtained by adding a Grignard reagent and reacting for 0.2 to 48 hours, preferably 1 to 24 hours.
  • the first step may not be performed.
  • a solvent such as ether, tetrahydrofuran, dioxane, or a mixed solvent thereof, commercially available or R 3a R 3b CHPPh 3 L that can be synthesized by a known method (for example, methyltriphenylphosphonium iodide, etc.)
  • a compound c dissolved in a solvent such as ether, tetrahydrofuran or dioxane is prepared by adding a strong base such as an alkyl metal reagent such as butyl lithium to prepare a Wittig reagent corresponding to the target product, preferably -40 ° C to 60 ° C, preferably Compound d can be obtained by adding ⁇ 20 ° C. to 30 ° C.
  • Step d is reacted for 1 hour to 72 hours, preferably 6 hours to 48 hours by adding thiophosgene, iodine or thiocyanate in a solvent such as toluene, dichloromethane, tetrahydrofuran, water, or a mixed solvent thereof.
  • a solvent such as toluene, dichloromethane, tetrahydrofuran, water, or a mixed solvent thereof.
  • a fifth step in which an appropriate amount of phase transfer catalyst (for example, tetra-n-butylammonium chloride, tetramethylammonium bromide, etc.) can be added and reacted.
  • phase transfer catalyst for example, tetra-n-butylammonium chloride, tetramethylammonium bromide, etc.
  • Compound e is toluene, dichloromethane, tetrahydrofuran, etc.
  • R 2a R 2b -amine is added and reacted at 0 ° C. to 120 ° C., preferably 20 ° C. to 80 ° C. for 1 hour to 72 hours, preferably 6 hours to 48 hours.
  • Compound f can be obtained.
  • First Step Compound g that can be prepared commercially or by a known method is prepared in a solvent such as toluene, dichloromethane, tetrahydrofuran, or a mixed solvent thereof in the presence of a base such as diisopropylethylamine, triethylamine, trimethylamine, etc.
  • compound i can be obtained.
  • Third step According to the method described in Chem. Lett., 3, 373-376 (1990), compound i is dissolved in a solvent such as methanol, ethanol, isopropyl alcohol, water, potassium hydroxide, sodium hydroxide, hydroxide.
  • Compound j can be obtained by reacting at 20 ° C. to 100 ° C., preferably 50 ° C. to 100 ° C. for 0.5 hours to 24 hours, preferably 1 hour to 12 hours in the presence of a base such as lithium. .
  • Fourth Step 2-Chloroacetonitrile and concentrated sulfuric acid are added to Compound j in the presence of carboxylic acid such as acetic acid, formic acid, trifluoroacetic acid, and the like, and added at ⁇ 20 ° C. to 100 ° C., preferably 0 ° C. to 40 ° C., 0.2
  • carboxylic acid such as acetic acid, formic acid, trifluoroacetic acid, and the like
  • Compound k can be obtained by reacting for a period of time to 24 hours, preferably 1 hour to 12 hours.
  • Fifth Step Acetic acid and thiourea are added to compound k in a solvent such as methanol, ethanol, isopropyl alcohol and the like, and the temperature is ⁇ 20 ° C. to 100 ° C., preferably 0 ° C.
  • Compound 1 can be obtained by reacting for 1 to 12 hours.
  • the fourth and fifth steps can be performed according to the method described in Synthesis, 12, 1709-1712 (2000).
  • Compound m can be obtained by reacting for 0.2 hour to 24 hours, preferably 1 hour to 12 hours.
  • An isothiocyanate having a protecting group (for example, benzoyl isothiocyanate) prepared by commercially available or known methods is added to compound m in a solvent such as dichloromethane, tetrahydrofuran, toluene, or a mixed solvent, and -30 ° C to 50 ° C is added.
  • Compound n can be obtained by reacting at 0 ° C., preferably ⁇ 10 ° C. to 25 ° C., for 0.5 to 24 hours, preferably 0.5 to 12 hours.
  • Compound n is added to a solvent such as dichloromethane, tetrahydrofuran, toluene, oxalyl chloride, thionyl chloride and the like and a catalytic amount of N, N, -dimethylformamide, or chloro such as 1-chloro-2-trimethylpropenylamine.
  • Compound o can be obtained by adding a oxidant and reacting at 0 ° C. to 100 ° C., preferably 20 ° C. to 50 ° C., for 0.5 hour to 72 hours, preferably 0.5 hour to 12 hours.
  • the compound j can also be synthesized by the following method. (Wherein P c is a protecting group for carboxylic acid, and other symbols are as defined above.)
  • First Step A compound ca that can be prepared commercially or by a known method is dissolved in a solvent such as toluene, dichloromethane, tetrahydrofuran, or a mixed solvent thereof, and a corresponding Grignard reagent such as Rx magnesium bromide is ⁇ 80 ° C. to 30 ° C., preferably Compound cb can be obtained by reacting at ⁇ 40 ° C. to 10 ° C. for 0.1 to 24 hours, preferably 0.1 to 12 hours.
  • Second Step A compound j can be obtained by subjecting the protecting group P c of the carboxylic acid to a deprotection reaction by an ordinary method.
  • C Production of compound represented by formula (III)
  • the compound represented by formula (III) can be produced, for example, according to the synthesis method of compound ai or compound al shown below.
  • C-1) Synthesis of compound ai Wherein R 11 is an optionally substituted aryl, R y is a halogeno lower alkyl; R 3d has hydrogen, halogen, hydroxy, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted acyl, and optionally substituted.
  • Lower alkoxy which may have, aralkyl which may have a substituent, heteroarylalkyl which may have a substituent, aralkyloxy which may have a substituent, which may have a substituent Good heteroarylalkyloxy, optionally substituted lower alkylthio, carboxy, optionally substituted lower alkoxycarbonyl, optionally substituted amino, substituted An optionally substituted carbamoyl, an optionally substituted carbocyclic group or an optionally substituted heterocyclic group, Other symbols are as defined above. )
  • a solvent ac such as dioxane, tetrahydrofuran, toluene, or a mixed solvent thereof, which is commercially available or can be prepared by a known method
  • dehydration is performed at 50 ° C. to 200 ° C., preferably 80 ° C. to 150 ° C. for 1 hour to 48 hours, preferably 2 hours to 24 hours.
  • Compound ad can be obtained by reacting under conditions.
  • Second Step Compound ad is added in a solvent such as ether or tetrahydrofuran, or a mixed solvent thereof, to a vinyl lithium reagent corresponding to the desired product at ⁇ 80 ° C. to 50 ° C., preferably ⁇ 80 ° C. to 0 ° C.
  • the compound ae can be obtained by reacting for 0.2 to 24 hours, preferably 0.5 to 12 hours.
  • the vinyl lithium reagent can be prepared by adding an alkyl lithium reagent such as butyl lithium to the target tetravinyltin.
  • Third Step Compound ae is added with a borane reagent in a solvent such as dioxane, tetrahydrofuran or the like, or a mixed solvent thereof, and 0 ° C to 60 ° C, preferably 20 ° C to 50 ° C, for 0.2 hours to 12 hours, Preferably, the compound af can be obtained by reacting for 0.5 to 6 hours, adding alkaline water such as aqueous sodium hydroxide and hydrogen peroxide solution, and reacting for 0.5 to 12 hours. .
  • Fourth Step Compound af is added to a palladium catalyst such as Pd (OH) 2 , Pd—C, etc.
  • Compound ag can be obtained by reacting at ⁇ 60 ° C., preferably 20 ° C. to 50 ° C. for 1 hour to 24 hours, preferably 1 hour to 12 hours.
  • Fifth Step Compound is added in a solvent such as dioxane, tetrahydrofuran, toluene, acetone or the like, or a mixed solvent thereof, isothiocyanate having a protecting group (for example, benzoyl isothiocyanate) prepared by a commercially available or known method, ⁇ Compound ah can be obtained by reacting at 30 ° C.
  • Compound ah is chlorinated in a solvent such as dichloromethane, tetrahydrofuran or toluene with oxalyl chloride, thionyl chloride or the like and a catalytic amount of N, N-dimethylformamide added, or 1-chloro-2-trimethylpropenylamine or the like.
  • Compound ai 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, dichloromethane, tetrahydrofuran, or a mixed solvent thereof, in the presence of a base such as lithium diisopropylamide or potassium hexamethyldisilazide, the corresponding phenyl alkyl ketone (for example, acetophenone) is Compound p that can be prepared by a known method is added to the enolate obtained by the reaction, and the mixture is -80 ° C to 30 ° C, preferably -80 ° C to 0 ° C, for 0.1 hour to 24 hours, preferably 0. Compound aj can be obtained stereoselectively by reacting for 1 to 12 hours.
  • a base such as lithium diisopropylamide or potassium hexamethyldisilazide
  • Second Step To the compound aj obtained in the first step, hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like are added, and 0 ° C. to 60 ° C., preferably 0 ° C. to 30 ° C., for 0.1 hour to 24 hours, Preferably, compound ak can be obtained by reacting for 0.5 to 12 hours.
  • Compound (IV) can be produced, for example, according to the synthesis method of compound ao, compound be or compound bh shown below.
  • D-1) Synthesis of compound ao (Wherein R za and R zb each independently represents a lower alkyl optionally having substituent (s), or together with the carbon atom to which they are bonded, forms a carbocycle; Other symbols are as defined above. )
  • Second Step To the compound am obtained in the first step, hydrochloric acid, hydrobromic acid, trifluoroacetic acid and the like are added, and 0 ° C. to 60 ° C., preferably 0 ° C. to 30 ° C., for 0.1 hour to 24 hours, Preferably, compound an can be obtained by reacting for 0.5 to 12 hours.
  • Third Step Add an isothiocyanate having a protecting group (for example, benzoyl isothiocyanate) prepared by commercially available or known methods in a solvent such as dioxane, tetrahydrofuran, toluene, acetone, or a mixed solvent thereof, and- The reaction is carried out at 30 ° C.
  • a protecting group for example, benzoyl isothiocyanate
  • Compound ao can be obtained by adding nitric acid or the like and reacting at ⁇ 30 ° C. to 70 ° C., preferably ⁇ 20 ° C. to 50 ° C. for 1 hour to 12 hours, preferably 1 hour to 6 hours.
  • Second Step A hydrogen chloride solution is added to the compound ba obtained in the first step in a solvent such as methanol, ethanol, water or a mixed solvent thereof, and the temperature is ⁇ 20 ° C. to 80 ° C., preferably 0 ° C. to 30 ° C.
  • the compound bb can be obtained by reacting for 0.1 to 24 hours, preferably 0.1 to 12 hours.
  • Third step Compound bb is added in a solvent such as dichloromethane, dioxane, tetrahydrofuran, toluene, acetone, or a mixed solvent thereof, or an isothiocyanate having a protective group prepared by a commercially available or known method (for example, benzoyl isothiocyanate) is added.
  • Compound bc can be obtained by reacting at ⁇ 30 ° C. to 70 ° C., preferably ⁇ 20 ° C. to 50 ° C. for 0.1 hour to 12 hours, preferably 0.1 hour to 6 hours.
  • Compound bc is added with a halogen cation source such as iodine, bromine or NBS in a solvent such as dichloromethane, and is ⁇ 20 ° C. to 40 ° C., preferably 0 ° C. to 20 ° C. for 0.1 hour to 12 hours.
  • a halogen cation source such as iodine, bromine or NBS
  • a solvent such as dichloromethane
  • the compound bd can be obtained by reacting for 0.1 to 6 hours.
  • the compound bd is added with a base such as pyrrolidine, piperidine, piperazine, morpholine in a solvent such as dioxane, tetrahydrofuran, toluene or the like, or a mixed solvent thereof, and 20 ° C-100 ° C, preferably 40 ° C-80 ° C.
  • the compound bd can be obtained by reacting for 0.1 to 24 hours, preferably 1 to 12 hours.
  • Step 1 Compound bf is prepared by adding ethyl acrylate and a Grubbs reagent to compound bb in which an amino group is protected with a protecting group in a solvent such as toluene, dichloromethane, tetrahydrofuran or the like, or a mixed solvent thereof, and subjecting it to an olefin metathesis reaction. Can be obtained.
  • the reaction temperature is ⁇ 20 ° C. to 60 ° C., preferably 0 ° C. to 30 ° C.
  • the reaction time is 0.5 hour to 24 hours, preferably 1 hour to 12 hours.
  • Second step Compound bf is added with an isothiocyanate (for example, benzoyl isothiocyanate) having a protective group prepared by a commercially available or known method in a solvent such as dichloromethane, dioxane, tetrahydrofuran, toluene, acetone, or a mixed solvent thereof.
  • Compound bg can be obtained by reacting at ⁇ 30 ° C. to 70 ° C., preferably ⁇ 20 ° C. to 50 ° C. for 0.1 hour to 12 hours, preferably 0.1 hour to 6 hours.
  • the compound bg is subjected to a reduction reaction by adding diisobutylaluminum hydride, lithium aluminum hydride, sodium hydride, etc. in a solvent such as dioxane, tetrahydrofuran, toluene, or a mixed solvent thereof.
  • Compound bh can be obtained by reacting at 0 ° C., preferably ⁇ 80 ° C. to ⁇ 20 ° C., for 0.1 hour to 12 hours, preferably 0.1 hour to 3 hours.
  • the compound bh can be further converted by subjecting it to an appropriate reaction.
  • Compound af-1 can be obtained by reacting at -100 ° C. for 0.5 to 48 hours, preferably 3 to 20 hours.
  • the amino protecting group may be any substituent that can be deprotected by the method described in Protective Groups in Organic Synthesis, Theodora W Green (John Wiley & Sons), etc., for example, lower alkoxycarbonyl, lower alkenyloxycarbonyl, trialkylsilyl, Examples include acyl, methanesulfonyl, trifluoroethanesulfonyl, toluenesulfonyl and the like.
  • the compounds v, ab, al, ao, be and bh 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) or (4) T. Vilavan et al, Cuuent Organic Chemistry, 9, It can be produced according to the method described in 1315-1392 (2005), or by optical resolution of each intermediate and final product, or by the following method.
  • 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.
  • Formula (I ′) 1) a compound in which ring A ′ is phenyl or a nitrogen-containing aromatic heterocyclic group (hereinafter referred to as a compound in which ring A ′ is A′1), A compound wherein ring A ′ is phenyl, pyridyl, indolyl, benzisoxazolyl, benzopyrazolyl or benzofuryl, benzothienyl, benzodioxolyl, or dihydrobenzodioxolanyl (hereinafter, ring A ′ is A′2) Compound), A compound in which ring A ′ is phenyl (hereinafter referred to as a compound in which ring A ′ is A′3), A compound in which ring A ′ is pyridyl (hereinafter referred to as a compound in which ring A ′ is A′4), 2) R 1 compounds is
  • R 4 is R4-1 Compound
  • R 4 is R4-2
  • G is the above (ii), (iv), (v), (x), (xiii) or (xiv)
  • G is G1
  • G is the above (ii ′), (ii ′′), (iv ′), (v ′), (x ′), (xiii ′) or (xiv ′)
  • G is G2
  • G is the above (ii ′), (ii ′′), (iv ′), (v ′), (x ′), (xiii ′) or (xiv ′)
  • G is G2
  • G is the above (ii ′), (ii ′′), (iv ′),
  • Mayoxazolyl which may have a substituent, benzothiazolyl which may have a substituent, thiazopyridyl which may have a substituent, quinolyl which may have a substituent, Good isoquinolyl or optionally substituted naphthyridinyl, optionally substituted quinazolinyl or optionally substituted pyridopyrimidinyl (wherein the substituent is the substituent group ⁇ And a compound having 1 to 3 groups selected from the group consisting of lower alkyl optionally substituted with one or more groups selected from substituent group ⁇ (hereinafter, G is G4) ), G is the above (ii ′), R 5 is hydrogen or lower alkyl, W 1 is O, and ring B may have an optionally substituted pyridyl or optionally substituted.
  • a combination of ring A ′, R 1 , R 2a and R 2b , R 3a and R 3c , n and R 4 , G is as follows: (A'1, R1-1, R2-1, R3-1, R4-1, G1), (A'1, R1-1, R2-1, R3-1, R4-1, G2), (A '1, R1-1, R2-1, R3-1, R4-1, G3), (A'1, R1-1, R2-1, R3-1, R4-1, G4), (A'1 , R1-1, R2-1, R3-1, R4-1, G5), (A'1, R1-1, R2-1, R3-1, R4-2, G1), (A'1, R1 -1, R2-1, R3-1, R4-2, G2), (A'1, R1-1, R2-1, R3-1, R4-2, G3), (A'1, R1-1 , R2-1, R3-1, R4-2, G4),
  • R x is have good carbocyclic group or a substituted group which may have a substituent is also optionally heterocyclic group compound (hereinafter, R x is a compound which is Rx-1) , R x represents phenyl optionally having substituent, pyridyl optionally having substituent, pyrazinyl optionally having substituent, thiazolyl optionally having substituent, and substituent.
  • R x is Rx-2 And a compound that is A compound in which R x is cyclohexyl, pyrrolinyl, morpholinyl, piperidyl, piperazinyl (hereinafter referred to as a compound in which R x is Rx-3), 3) A compound in which R 2a and R 2b are each independently hydrogen, lower alkyl or acyl (hereinafter referred to as a compound in which R 2a and R 2b are R2-1), A compound in which R 2a and R 2b are both hydrogen (hereinafter referred to as a compound in which R 2a and R 2b are both hydrogen (hereinafter referred to as a compound in which R 2a and R 2b are both hydrogen (hereinafter referred to as a compound in which R 2a and R 2b are both hydrogen (hereinafter referred to as a compound in which R 2a and R 2b are both hydrogen (hereinafter referred to as a compound in which R 2a and R 2b are both hydrogen (her
  • R 4 is R4-1 And a compound in which n is 0 to 2 and each R 4 is independently a halogen (hereinafter referred to as a compound in which R 4 is R4-2), 6) A compound in which G is the above (ii), (iv), (v), (x), (xiii) or (xiv) (hereinafter referred to as a compound in which G is G1), A compound in which G is the above (ii ′), (ii ′′), (iv ′), (v ′), (x ′), (xiii ′) or (xiv ′) (hereinafter, a compound in which G is G2) And) G is the above (ii ′), (ii ′′), (iv ′), (
  • Mayoxazolyl which may have a substituent, benzothiazolyl which may have a substituent, thiazopyridyl which may have a substituent, quinolyl which may have a substituent, Good isoquinolyl or optionally substituted naphthyridinyl, optionally substituted quinazolinyl or optionally substituted pyridopyrimidinyl (wherein the substituent is the substituent group ⁇ And a compound having 1 to 3 groups selected from the group consisting of lower alkyl optionally substituted with one or more groups selected from substituent group ⁇ (hereinafter, G is G4) ), G is the above (ii ′), R 5 is hydrogen or lower alkyl, W 1 is O, and ring B may have an optionally substituted pyridyl or optionally substituted.
  • a compound in which the combination of ring A ′, R x , R 2a and R 2b , R 3a and R 3b , n and R 4 , G in formula (II ′) is as follows: (A'1, Rx-1, R2-1, R3-1, R4-1, G1), (A'1, Rx-1, R2-1, R3-1, R4-1, G2), (A '1, Rx-1, R2-1, R3-1, R4-1, G3), (A'1, Rx-1, R2-1, R3-1, R4-1, G4), (A'1 , Rx-1, R2-1, R3-1, R4-1, G5), (A'1, Rx-1, R2-1, R3-1, R4-2, G1), (A'1, Rx -1, R2-1, R3-1, R4-2, G2), (A'1, Rx-1, R2-1, R3-1, R4-2, G3), (A'1, Rx-1 , R2-1, R3-1, R4
  • R y is lower alkyl substituted by halogen
  • R y is a compound which is Ry-1
  • a compound in which R y is trifluoromethyl hereinafter referred to as a compound in which R y is Ry-2
  • a compound in which R 2a and R 2b are each independently hydrogen, lower alkyl or acyl hereinafter referred to as a compound in which R 2a and R 2b are R2-1
  • a compound in which R 2a and R 2b are both hydrogen (hereinafter referred to as a compound in which R 2a and R 2b are R2-2)
  • R 3a , R 3b , R 3c and R 3d are each independently hydrogen, halogen, hydroxy, lower alkyl or amino
  • R 3a , R 3b , R 3c and R 3d are R3-1)
  • R 4 is R4-1 And a compound in which n is 0 to 2 and each R 4 is independently a halogen (hereinafter referred to as a compound in which R 4 is R4-2), 6) A compound in which G is the above (ii), (iv), (v), (x), (xiii) or (xiv) (hereinafter referred to as a compound in which G is G1), A compound in which G is the above (ii ′), (ii ′′), (iv ′), (v ′), (x ′), (xiii ′) or (xiv ′) (hereinafter, a compound in which G is G2) And) G is the above (ii ′), (ii ′′), (iv ′), (
  • a compound in which the combination of ring A ′, R y , R 2a and R 2b , R 3a , R 3b , R 3c and R 3d , n and R 4 , G is as follows: (A'1, Ry-1, R2-1, R3-1, R4-1, G1), (A'1, Ry-1, R2-1, R3-1, R4-1, G2), (A '1, Ry-1, R2-1, R3-1, R4-1, G3), (A'1, Ry-1, R2-1, R3-1, R4-1, G4), (A'1 , Ry-1, R2-1, R3-1, R4-1, G5), (A'1, Ry-1, R2-1, R3-1, R4-2, G1), (A'1, Ry -1, R2-1, R3-1, R4-2, G2), (A'1, Ry-1, R2-1, R3-1, R4-2, G3), (A'1, Ry-1 , R2-1, R3-1, R4-2, G4), (A
  • R za and R zb are each independently hydrogen, halogen, or optionally substituted lower alkyl, 1) A compound in which ring A ′ is phenyl or a nitrogen-containing aromatic heterocyclic group (hereinafter referred to as a compound in which ring A ′ is A′1), A compound in which ring A ′ is phenyl, pyridyl, indolyl, benzisoxazolyl, benzopyrazolyl or benzofuryl, benzothienyl, benzodioxolyl, dihydrobenzodioxolanyl (hereinafter, a compound in which ring A ′ is A′2) And) A compound in which ring A ′ is phenyl (hereinafter referred to as a compound in which ring A ′ is A′3), A compound in which ring A ′ is pyridyl (hereinafter referred to as a compound in which ring A ′),
  • R 1 compounds is lower alkyl which may have a substituent (hereinafter, R 1 is a compound which is R1-1), A compound in which R 1 is methyl (hereinafter referred to as a compound in which R 1 is R1-2), 3) A compound in which R 2a and R 2b are each independently hydrogen, lower alkyl or acyl (hereinafter referred to as a compound in which R 2a and R 2b are R2-1), A compound in which R 2a and R 2b are both hydrogen (hereinafter referred to as a compound in which R 2a and R 2b are R2-2), 4) A compound in which R 3c and R 3d are each independently hydrogen, halogen, hydroxy, lower alkyl or amino (hereinafter referred to as a compound in which R 3c and R 3d are R3-1), Compound R 3c and R 3d are the same substituent selected from halogen or lower alkyl (hereinafter, R 3c and R 3d are the compounds which are R3-2), A compound in which R 3
  • R 4 is R4-1 And a compound in which n is 0 to 2 and each R 4 is independently a halogen (hereinafter referred to as a compound in which R 4 is R4-2), 6) A compound in which G is the above (ii), (iv), (v), (x), (xiii) or (xiv) (hereinafter referred to as a compound in which G is G1), A compound in which G is the above (ii ′), (ii ′′), (iv ′), (v ′), (x ′), (xiii ′) or (xiv ′) (hereinafter, a compound in which G is G2) And) G is the above (ii ′), (ii ′′), (iv ′), (
  • Mayoxazolyl which may have a substituent, benzothiazolyl which may have a substituent, thiazopyridyl which may have a substituent, quinolyl which may have a substituent, Good isoquinolyl or optionally substituted naphthyridinyl, optionally substituted quinazolinyl or optionally substituted pyridopyrimidinyl (wherein the substituent is the substituent group ⁇ And a compound having 1 to 3 groups selected from the group consisting of lower alkyl optionally substituted with one or more groups selected from substituent group ⁇ (hereinafter, G is G4) ), G is the above (ii ′), R 5 is hydrogen or lower alkyl, W 1 is O, and ring B may have an optionally substituted pyridyl or optionally substituted.
  • a compound in which the combination of ring A ′, R 1 , R 2a and R 2b , R 3c and R 3d , n and R 4 , G is as follows: (A'1, R1-1, R2-1, R3-1, R4-1, G1), (A'1, R1-1, R2-1, R3-1, R4-1, G2), (A '1, R1-1, R2-1, R3-1, R4-1, G3), (A'1, R1-1, R2-1, R3-1, R4-1, G4), (A'1 , R1-1, R2-1, R3-1, R4-1, G5), (A'1, R1-1, R2-1, R3-1, R4-2, G1), (A'1, R1 -1, R2-1, R3-1, R4-2, G2), (A'1, R1-1, R2-1, R3-1, R4-2, G3), (A'1, R1-1 , R2-1, R3-1, R4-2, G4), (A'1,
  • the compound contained in the pharmaceutical composition 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 Disorders, prion diseases (such as Creutzfeldt-Jakob disease), mild cognitive impairment (MCI), Dutch hereditary amyloid cerebral hemorrhage, cerebral amyloid angiopathy, other degenerative dementia, mixed vascular degeneration, Parkinson's disease Treatment of concomitant dementia, dementia associated with progressive supranuclear palsy, 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 also includes prevention of the severity of mild cognitive impairment (MCI) and prevention of the development of familial Alzheimer's disease.
  • pharmaceutical composition for the treatment of Alzheimer's disease includes a pharmaceutical composition for preventing the severity of mild cognitive impairment (MCI) and a pharmaceutical composition for preventing the onset of familial Alzheimer's disease. .
  • the compound contained in the pharmaceutical composition of the present invention has high inhibitory activity on ⁇ -secretase 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 according to the present invention has high metabolic stability, high solubility, high oral absorption, good bioavailability, good clearance, high brain transferability, long half-life, non-protein It also has advantages such as high binding rate, low hERG channel inhibition, low CYP inhibition, low CYP MBI (Mechanism Based Inhibition), and / or negative Ames test.
  • the pharmaceutical composition of the present invention When the pharmaceutical composition 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 pharmaceutical composition of the present invention When the pharmaceutical composition of the present invention is administered to humans, it can be administered orally as powders, granules, tablets, capsules, pills, liquids, etc. or non-injectables, suppositories, transdermal absorption agents, inhalants It can be administered orally.
  • excipients, binders, wetting agents, disintegrants, lubricants and the like suitable for the dosage form may be mixed with an effective amount of this 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 is usually 0.1 ⁇ g to 1 g / day, preferably 0.01 to 200 mg / day when orally administered to an adult. In the case of parenteral administration, it is usually 1 ⁇ g to 10 g / day, preferably 0.1 to 2 g / day.
  • LC / MS data of the compound contained in the pharmaceutical composition of the present invention was measured under any of the following conditions (Methods A and B), and indicated a retention time and [M + H] + .
  • Methodhod A Column: Waters XBridge C18 5 ⁇ m Size: 4.6x50mm Flow rate: 3 mL / min Column oven: 50 ° C UV detection wavelength: PDA (254 nm) A linear gradient of 10% -100% solvent (0.1% formic acid-containing acetonitrile solution) was performed for 3 minutes, and 100% solvent (0.1% formic acid-containing acetonitrile solution) was maintained for 0.5 minutes.
  • reaction solvent was extracted with ethyl acetate and washed with an aqueous sodium thiosulfate solution and distilled water. The separated organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Dichloromethane and diisopropyl ether were added to the residue, and the precipitated solid was collected by filtration to obtain compound (12) (532 mg).
  • Step 6 To a solution of the compound (27) (3.77 g) obtained in Step 5 in methanol (60 ml), methyl orthoformate (38 ⁇ l) and p-toluenesulfonic acid monohydrate (66 mg) were added. The mixture was stirred for 30 minutes under heating and reflux. The solvent was distilled off under reduced pressure and diluted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Compound (28) (3.55 g) as a crude product.
  • Step 9 Compound (48) (50 mg) is dissolved in methanol (0.5 ml), 20% Pd (OH) 2 (28 mg: 50% wet) is added, and the mixture is stirred for 8 hours under a hydrogen stream, and then filtered through Celite. The filtrate obtained in 1 was evaporated under reduced pressure to obtain a crude product (49) (33 mg).
  • Step 12 Compound (51) (80 mg) was dissolved in dichloromethane (2 ml), and 1-chloro-2-trimethylpropenylamine (0.043 ml) was added under a nitrogen stream. After stirring at room temperature for 1 hour, an aqueous sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate, washed with water and washed with brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel thin layer chromatography to obtain compound (52) (58 mg).
  • Second Step 4 mol / L hydrochloric acid / dioxane solution (1.8 ml) and methanol (45 ⁇ l) were added to a mixture (380 mg) of the compound (55) obtained in the first step, and the mixture was stirred at room temperature for 1.5 hours. Diethyl ether and water were added, the aqueous layer was made alkaline with 28% aqueous ammonia, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain Compound (56) (181 mg).
  • Second Step A 4 mol / L hydrochloric acid / dioxane solution (1.65 ml) and methanol (40 ⁇ l) were added to the compound (60) (307 mg) obtained in the first step, and the mixture was stirred at room temperature for 1 hour. Diethyl ether and water were added, the aqueous layer was made alkaline with 28% aqueous ammonia, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain compound (61) (209 mg).
  • Step 1 Compound (71) (8.00 g) is dissolved in methylene chloride (20 ml), ethyl acrylate (40 ml) and second-generation Grubbs catalyst (0.412 g) are added, and the mixture is stirred for 2 hours at room temperature under a nitrogen atmosphere. Stir. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain compound (72) (8.34 g).
  • reaction mixture was diluted with ethyl acetate and water, sodium sulfite was added, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate.
  • the organic layer was dried over anhydrous sodium sulfate and filtered, then the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain compound (74) (0.939 g).
  • Step 4 Compound (74) (0.700 mg) is dissolved in toluene (2.5 ml), keeping the internal temperature at -50 ° C or lower, 1 mol / L diisobutylaluminum hydride toluene solution is added dropwise over 5 minutes, acetone-dry The mixture was further stirred for 30 minutes under cooling with an ice bath. After quenching with methanol, the mixture was warmed to room temperature and filtered, and then the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography to obtain compound (75) (0.183 g).
  • Step 1 Compound (77) (500 mg) is dissolved in dimethylacetamide (7.5 ml), potassium carbonate (440 mg) and 1H-1,2,4-triazole (200 mg) are added, and the mixture is irradiated under microwave irradiation. Stir at 0 ° C. for 10 minutes. Water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropyl alcohol to obtain Compound (78) (451 mg).
  • n 1 or 2
  • compound (89) (10.0 g) was dissolved in acetonitrile (200 ml), and benzyl 2-bromoethyl ether (9.5 ml) and potassium carbonate (11.3 g) were added. Stir for hours.
  • Second Step Compound (103) (1.05 g) is dissolved in ethanol (3 ml), acetamidine hydrochloride (500 mg) is added, and the mixture is heated to reflux for 7 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with ethyl acetate.
  • Step 3 Compound (104) (2.15 g) is added to a pyridine (20 ml) solution, selenium dioxide (4.01 g) is added, and the mixture is stirred at 80 ° C. for 4 hours. The mixture was allowed to stand overnight at room temperature, insoluble matters were removed by filtration, and then the solvent was distilled off under reduced pressure.
  • Step 5 A solution of the compound (112) obtained in Step 4 in tetrahydrofuran (10 ml) was added dropwise with 1 mol / L borane / tetrahydrofuran solution (66.0 ml) under ice-cooling and stirred at room temperature for 3 hours. It was. The reaction solution was poured onto ice and acidified with concentrated hydrochloric acid, and then stirred at room temperature for 15 minutes. A 4 mol / L aqueous sodium hydroxide solution was added to make the mixture basic, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain the compound (113) as a crude product.
  • the sixth step compound (123) (146 mg) was dissolved in tetrahydrofuran (1.5 mL), Boc 2 O (298 mg) was added, and the mixture was stirred at room temperature for about 1 hr. After adding water, the mixture was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The obtained residue was purified by chromatography to give compound (124) (174 mg).
  • the crude product of the eighth step (125) (24 mg) was dissolved in chloroform (0.5 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 3 hr.
  • the reaction solution was concentrated, neutralized with aqueous sodium carbonate solution, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate.
  • the obtained residue was purified by chromatography and then washed with isopropyl ether to obtain Compound (203) (3.5 mg).
  • Second step compound (127) (100 mg), 2-fluoropyridine-3-boronic acid (40.7 mg), Pd (PPh 3 ) 4 (25.7 mg) and sodium carbonate (47.1 mg) in DME (2 mL) and Water (0.5 mL) was added, and the mixture was stirred overnight at 50 ° C., then warmed to 70 ° C., and stirred for about 7.5 hours. After allowing to cool to room temperature, 2 mol / L hydrochloric acid was added and stirred overnight, trifluoroacetic acid was added, and the mixture was stirred for 9 hours. A saturated aqueous sodium carbonate solution was added, and the mixture was extracted with ethyl acetate, washed with brine, and dried over sodium sulfate.
  • Step 3 Butyllithium (2.73 mol / L: 0.914 mL) was dissolved in toluene (5 mL) and hexane (3 mL), and the crude product (130) (500 mg) at -78 ° C in toluene (1 mL) The solution was added dropwise. After stirring for 45 minutes, dry ice was slowly added. After stirring for 40 minutes, the temperature was raised to room temperature. After adding ether, the precipitated solid was collected by filtration to obtain a crude product (131) (461 mg). The fourth step crude product (131) (361 mg) was dissolved in methanol (8 mL), thionyl chloride (0.218 mL) was added, and the mixture was heated to reflux for about 2 hours.
  • the sixth step compound (133) 64 mg was dissolved in tetrahydrofuran (1 mL), 1 mol / L aqueous sodium hydroxide solution (0.391 mL) was added at 0 ° C., and the mixture was stirred at room temperature for 2.5 hr. The solution was concentrated, 2 mol / L hydrochloric acid (0.195 mL) was added at 0 ° C., and the resulting solid was collected by filtration to obtain a crude product (134) (47 mg).
  • the seventh step crude product (134) 47 mg was dissolved in DMF (1 mL), oxalyl chloride (0.066 mL) was added at 0 ° C., and the mixture was stirred for 2 hr.
  • the second step compound (137) (7.57 g) was dissolved in 22 ml of ethanol, 2 mol / L hydrochloric acid / ethanol solution (22 ml) was added, and the mixture was stirred at room temperature for 30 minutes. After diluting with water and washing with hexane-diethyl ether (1: 1), the aqueous layer was basified with potassium carbonate, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was distilled off under reduced pressure to obtain Compound (138). The whole amount was used for the next reaction without purification.
  • the third step compound (138) was dissolved in methylene chloride (30 ml), benzoyl isothiocyanate (2.05 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 30 minutes, and then the solvent was distilled off under reduced pressure. Compound (139) was obtained. The whole amount was used for the next reaction without purification. Concentrated sulfuric acid (30 ml) previously ice-cooled was added to the fourth step compound (139), dissolved gradually, stirred at 15 ° C. for 40 minutes, and further concentrated sulfuric acid (10 ml) previously ice-cooled was added. Stir for 20 minutes.
  • reaction solution was transferred to ice water, neutralized with potassium carbonate, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain compound (140) (2.86 g).
  • the fifth step compound (140) (296.6 g) was dissolved in toluene (3 ml), and 1 mol / L diisobutylaluminum hydride / toluene solution (3.31 ml) was added dropwise at -78 ° C over 5 minutes. After stirring at temperature for 1 hour, the mixture was stirred for 1 hour under ice cooling. A 20 w / w% aqueous potassium potassium tartrate solution (10 ml) -ethyl acetate (10 ml) was added, the mixture was stirred at room temperature for 30 minutes, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate.
  • Step 7 Compound (142) (94 mg) was dissolved in tetrahydrofuran (2 ml), t-butyl dicarbonate (209 mg) was added, and the mixture was stirred at 60 ° C. for 2 hours. The solvent was evaporated under reduced pressure, The residue was subjected to column chromatography to obtain compound (143) (111 mg).
  • the eighth step compound (143) (110 mg) was dissolved in methylene chloride (2 ml), manganese dioxide (510 mg) was added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered through celite, and the filtrate was evaporated under reduced pressure to give compound (144). The whole amount was used for the next reaction without purification. After dissolving the 9th step compound (144) in methylene chloride (2 ml), N, N-diethylaminosulfur trifluoride (88 ul) was added under ice-cooling, and at the same temperature for 1 hour at 50 ° C. The mixture was stirred for 3 hours at 65 ° C. for 3 hours.
  • Test Example 1 Rat Brain ⁇ -Amyloid Reduction Action Test compounds were suspended in 0.5% methylcellulose and prepared to a final concentration of 2 mg / mL. For male Crj: SD rats (7-9 weeks old) It was orally administered at 10 mg / kg. The vehicle control group was administered with 0.5% methylcellulose alone, and the administration test was performed with 3 to 8 animals in each group. Three hours after administration, the brain was removed, and the cerebral hemisphere was isolated and 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-Cholamidopropyl) dimethylammonio] -1-propanesulfonate ⁇ ), 20% by weight), 20 mM Tris-HCl (pH 8.0), 150 mM NaCl, complete (produced by Roche) protease inhibitor) was added, and the mixture was homogenized for 2 minutes by repeated vertical movement and solubilized. The suspension was transferred to a tube for centrifugation and left on ice for 3 hours or more, and then centrifuged at 100,000 ⁇ g, 4 ° C. for 20 minutes.
  • an extraction buffer 1% CHAPS ( ⁇ 3-[(3-Cholamidopropyl) dimethylammonio] -1-propanesulfonate ⁇
  • 20 mM Tris-HCl pH 8.0
  • 150 mM NaCl complete (produced by Roche
  • ⁇ -amyloid 40 manufactured by Immunobiological Research Institute: product number 27730 or Wako Pure Chemical Industries: product number 294-62501.
  • ELISA measurement was performed according to the attached instruction. The decreasing action was calculated as the ratio (inhibition rate) to ⁇ -amyloid 40 in the brain of the vehicle control group of each test.
  • CYP3A4 Fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of a compound by a metabolic reaction.
  • the reaction was debenzylated with an enzyme to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (HFC) as an indicator.
  • the 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) ).
  • Enzyme and test drug solution are added to K-Pi buffer (pH 7.4) as a pre-reaction solution in a 96-well plate with the above pre-reaction composition, and the substrate and K-Pi buffer are added to another 96-well plate. A part of the solution was transferred so as to be diluted by 1/10, and the reaction using NADPH as a coenzyme was started as an indicator (no pre-reaction).
  • Test Example 3 CYP Inhibition Test Using a commercially available pooled human liver microsome, O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) ( CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4'-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadine hydroxylation (CYP3A4) The degree to which the metabolite production was inhibited by the test compound was evaluated.
  • CYP1A2, 2C9, 2C19, 2D6, 3A4 O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6,
  • 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 microsome 0.2 mg protein / mL; test drug concentration, 1, 5, 10, 20 ⁇ mol / L (4 point).
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the supernatant of the centrifugation was collected with a fluorescent multi-label 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 35: 5 types> 20 ⁇ M Compound 63: 5 types> 20 ⁇ M Compound 68: 5 types> 20 ⁇ M Compound 104: 5 types> 20 ⁇ M Compound 106: 5 types> 20 ⁇ M
  • Test Example 4 Solubility Test Addition (2%) of 2-fold dilution series (12 points) of 10 mM DMSO solution of the test compound to the media (JP-I, JP-II), and turbidity after 4 hours (crystallization information) ), The solubility was evaluated in three stages (High;> 40 ⁇ M, Medium; 3 to 40 ⁇ M, Low; ⁇ 3 ⁇ M). (result) Compound 2: High (JP-I) Compound 9: High (JP-I) Compound 23: High (JP-I) Compound 32: High (JP-I) Compound 60: High (JP-I) Compound 70: High (JP-I)
  • Test Example 5 Metabolic stability test Using commercially available pooled human liver microsomes, the test compound was reacted 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 microsome 0.5 mg protein / mL containing 0.2 mL buffer solution (50 mmol / L tris-HCl pH7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) at 37 ° C. in the presence of 1 mmol / L NADPH , Reacted for 0 or 30 minutes (oxidative reaction).
  • Test Example 6 hERG test Using HEK293 cells expressing human ether-a-go-go related gene (hERG) channels to play an important role in the ventricular repolarization process for the purpose of risk assessment of ECG QT interval prolongation The effect on delayed rectifier K + current (I Kr ) was investigated. Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.), hold the cells at a membrane potential of -80 mV using the whole cell patch clamp method, and then apply a +50 mV depolarization stimulus for 2 seconds. I Kr evoked when a 50 mV repolarization stimulus was applied for 2 seconds was recorded.
  • PatchXpress 7000A Axon Instruments Inc.
  • Test example 7 FAT test 20 ⁇ L of Salmonella typhimurium TA98, TA100 strain cryopreserved was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutrient broth No. 2) and shaken at 37 ° C. for 10 hours. Pre-culture.
  • 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 against TA98 strain 40 ⁇ g / mL 2-aminoanthracene DMSO solution and for TA100 strain, 20 ⁇ g / mL 2-aminoanthracene DMSO solution each 12 ⁇ L and test bacterial solution 588 ⁇ L (under metabolic activation conditions, test bacterial solution 498 ⁇ L and S9 mix 90 ⁇ L of the mixture), and cultured with shaking at 37 ° C.
  • 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.
  • Test Example 9 Brain Transfer Test Rats are intravenously administered at a dose of 0.5 mg / mL / kg, and 30 minutes later, 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.
  • Ingredient Compound represented by formula (I) 10 mg Lactose 700 mg Corn starch 274 mg HPC-L 16 mg 1000 mg
  • the compound of formula (I) and lactose are passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed in a V-type mixer.
  • HPC-L low-viscosity hydroxypropylcellulose
  • aqueous solution to the powder mixture, knead, granulate (extruded granulation pore size 0.5-1mm), and dry.
  • the obtained dried granules are combed with a vibrating sieve (12/60 mesh) to obtain granules.
  • Formulation Example 2 A capsule filling granule containing the following ingredients is produced.
  • Ingredient Compound represented by formula (I) 15 mg Lactose 90 mg Corn starch 42 mg HPC-L 3 mg 150 mg
  • the compound of formula (I), lactose is passed through a 60 mesh sieve. Pass cornstarch through a 120 mesh sieve. These are mixed, and the HPC-L solution is added to the mixed powder to knead, granulate and dry. After sizing the obtained dry granules, 150 mg thereof is filled into No. 4 hard gelatin capsules.
  • Formulation Example 3 A tablet containing the following ingredients is produced.
  • Ingredient Compound represented by formula (I) 10 mg Lactose 90 mg Microcrystalline cellulose 30 mg CMC-Na 15 mg Magnesium stearate 5 mg 150 mg
  • the compound of formula (I), lactose, microcrystalline cellulose and CMC-Na (carboxymethylcellulose sodium salt) are passed through a 60 mesh sieve and mixed.
  • the mixed powder is mixed with magnesium stearate to obtain a mixed powder for tableting. This mixed powder is directly hit to obtain a 150 mg tablet.
  • the pharmaceutical composition according to the present invention can be a medicament useful as a therapeutic or preventive agent for diseases induced by production, secretion and / or deposition of amyloid ⁇ protein, particularly Alzheimer's disease.

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Abstract

La présente invention a pour objet une composition pharmaceutique pour le traitement ou la prévention de la maladie d'Alzheimer. La présente invention concerne spécifiquement une composition pharmaceutique contenant un composé représenté par la formule (I) (dans laquelle le cycle A représente un groupe carbocyclique qui peut avoir un substituant, ou un groupe hétérocyclique qui peut avoir un substituant ; R1 représente un groupe alkyle inférieur qui peut avoir un substituant, ou analogue ; R2a et R2b représentent indépendamment un atome d'hydrogène, un groupe alkyle inférieur qui peut avoir un substituant, ou analogue ; et R3a et R3c représentent indépendamment un atome d'hydrogène, un atome d'halogène, un groupe hydroxy, un groupe alkyle inférieur qui peut avoir un substituant, ou analogue), un sel pharmaceutiquement acceptable du composé, ou un solvate du composé ou du sel pharmaceutiquement acceptable.
PCT/JP2010/071957 2009-12-09 2010-12-08 Composition pharmaceutique pour le traitement ou la prévention de la maladie d'alzheimer contenant un dérivé hétérocyclique contenant du soufre Ceased WO2011071057A1 (fr)

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WO2012057248A1 (fr) 2010-10-29 2012-05-03 塩野義製薬株式会社 Dérivé de naphtyridine
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WO2012147762A1 (fr) 2011-04-26 2012-11-01 塩野義製薬株式会社 Dérivé de pyridine et inhibiteur de bace-1 le contenant
WO2012147763A1 (fr) 2011-04-26 2012-11-01 塩野義製薬株式会社 Dérivé d'oxazine et inhibiteur de bace 1 le contenant
WO2013013614A1 (fr) * 2011-07-28 2013-01-31 南京英派药业有限公司 4-(3-hétéroarylarylamino)quinazoline et 1-(3-hétéroarylarylamino)isoquinoline utilisées en tant qu'inhibiteurs de la voie hedgehog et leur utilisation
US8557826B2 (en) 2009-10-08 2013-10-15 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions, and their use
US8563543B2 (en) 2009-10-08 2013-10-22 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use
US8569310B2 (en) 2009-10-08 2013-10-29 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions and their use
US8637504B2 (en) 2008-06-13 2014-01-28 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
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WO2014059185A1 (fr) 2012-10-12 2014-04-17 Amgen Inc. Composés amino-dihydrothiazine et amino-dioxydo dihydrothiazine en tant qu'antagonistes de bêta-sécrétase et procédés d'utilisation
US8703785B2 (en) 2008-10-22 2014-04-22 Shionogi & Co., Ltd. 2-aminopyrimidin-4-one and 2-aminopyridine derivatives both having BACE1-inhibiting activity
US8729071B2 (en) 2009-10-08 2014-05-20 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
WO2014078314A1 (fr) 2012-11-15 2014-05-22 Amgen Inc. Composés d'amino-oxazine et d'amino-dihydrothiazine jouant le rôle de modulateurs de bêta-sécrétase et procédés d'utilisation
JP2014526534A (ja) * 2011-09-21 2014-10-06 エフ．ホフマン−ラ ロシュ アーゲー ＢＡＣＥ１阻害剤としてのＮ−（３−（２−アミノ−６，６−ジフルオロ−４，４ａ，５，６，７，７ａ−ヘキサヒドロ−シクロペンタ［ｅ］［１，３］オキサジン−４−イル）−フェニル）−アミド
US8999980B2 (en) 2009-12-11 2015-04-07 Shionogi & Co., Ltd. Oxazine derivatives
US9145426B2 (en) 2011-04-07 2015-09-29 Merck Sharp & Dohme Corp. Pyrrolidine-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
WO2015156421A1 (fr) 2014-04-11 2015-10-15 Shionogi & Co., Ltd. Dérivés de dihydrothiazine et de dihydrooxazine présentant une activité inhibitrice de bace1
US9181236B2 (en) 2011-08-22 2015-11-10 Merck Sharp & Dohme Corp. 2-spiro-substituted iminothiazines and their mono-and dioxides as bace inhibitors, compositions and their use
US9221839B2 (en) 2011-04-07 2015-12-29 Merck Sharp & Dohme Corp. C5-C6 oxacyclic-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9296734B2 (en) 2013-03-01 2016-03-29 Amgen Inc. Perfluorinated 5,6-dihydro-4H-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
US9522923B2 (en) 2015-02-23 2016-12-20 Eli Lilly And Company Selective BACE1 inhibitors
US9540359B2 (en) 2012-10-24 2017-01-10 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
US9550762B2 (en) 2014-08-08 2017-01-24 Amgen, Inc. Cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
US9611261B2 (en) 2013-03-08 2017-04-04 Amgen Inc. Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
WO2017061534A1 (fr) 2015-10-08 2017-04-13 Shionogi & Co., Ltd. Dérivés de dihydrothiazine
WO2017081615A1 (fr) 2015-11-09 2017-05-18 Wockhardt Limited 7-oxo-6-(sulfooxy)-1,6-diazabicyclo[3.2.1] octane contenant des composés et leur utilisation dans le traitement d'infections bactériennes
CN106795093A (zh) * 2014-10-14 2017-05-31 先正达参股股份有限公司 用于制备1‑(3,5‑二氯苯基)‑2,2,2‑三氟乙酮及其衍生物的方法
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US9029358B2 (en) 2005-10-25 2015-05-12 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
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US8633188B2 (en) 2005-10-25 2014-01-21 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives
US8168630B2 (en) 2007-04-24 2012-05-01 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group
US8653067B2 (en) 2007-04-24 2014-02-18 Shionogi & Co., Ltd. Pharmaceutical composition for treating Alzheimer's disease
US8895548B2 (en) 2007-04-24 2014-11-25 Shionogi & Co., Ltd. Pharmaceutical composition for treating alzheimer's disease
US8884062B2 (en) 2007-04-24 2014-11-11 Shionogi & Co., Ltd. Aminodihydrothiazine derivatives substituted with a cyclic group
US9273053B2 (en) 2008-06-13 2016-03-01 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having Beta secretase inhibitory activity
US9650371B2 (en) 2008-06-13 2017-05-16 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
US8637504B2 (en) 2008-06-13 2014-01-28 Shionogi & Co., Ltd. Sulfur-containing heterocyclic derivative having beta secretase inhibitory activity
US8703785B2 (en) 2008-10-22 2014-04-22 Shionogi & Co., Ltd. 2-aminopyrimidin-4-one and 2-aminopyridine derivatives both having BACE1-inhibiting activity
US9428475B2 (en) 2009-10-08 2016-08-30 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US8557826B2 (en) 2009-10-08 2013-10-15 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions, and their use
US9475785B2 (en) 2009-10-08 2016-10-25 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
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US8729071B2 (en) 2009-10-08 2014-05-20 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions and their use
US8569310B2 (en) 2009-10-08 2013-10-29 Merck Sharp & Dohme Corp. Pentafluorosulfur imino heterocyclic compounds as BACE-1 inhibitors, compositions and their use
US9029362B2 (en) 2009-10-08 2015-05-12 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as brace inhibitors, compositions, and their use
US8940748B2 (en) 2009-10-08 2015-01-27 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US8563543B2 (en) 2009-10-08 2013-10-22 Merck Sharp & Dohme Corp. Iminothiadiazine dioxide compounds as bace inhibitors, compositions, and their use
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US8999980B2 (en) 2009-12-11 2015-04-07 Shionogi & Co., Ltd. Oxazine derivatives
US8927721B2 (en) 2010-10-29 2015-01-06 Shionogi & Co., Ltd. Naphthyridine derivative
US9018219B2 (en) 2010-10-29 2015-04-28 Shionogi & Co., Ltd. Fused aminodihydropyrimidine derivative
WO2012057248A1 (fr) 2010-10-29 2012-05-03 塩野義製薬株式会社 Dérivé de naphtyridine
WO2012057247A1 (fr) 2010-10-29 2012-05-03 塩野義製薬株式会社 Dérivé d'aminodihydropyrimidine fusionnée
US9221839B2 (en) 2011-04-07 2015-12-29 Merck Sharp & Dohme Corp. C5-C6 oxacyclic-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
US9145426B2 (en) 2011-04-07 2015-09-29 Merck Sharp & Dohme Corp. Pyrrolidine-fused thiadiazine dioxide compounds as BACE inhibitors, compositions, and their use
CN103649082A (zh) * 2011-04-26 2014-03-19 盐野义制药株式会社 吡啶衍生物和含有该吡啶衍生物的bace1抑制剂
WO2012147762A1 (fr) 2011-04-26 2012-11-01 塩野義製薬株式会社 Dérivé de pyridine et inhibiteur de bace-1 le contenant
US8883779B2 (en) 2011-04-26 2014-11-11 Shinogi & Co., Ltd. Oxazine derivatives and a pharmaceutical composition for inhibiting BACE1 containing them
WO2012147763A1 (fr) 2011-04-26 2012-11-01 塩野義製薬株式会社 Dérivé d'oxazine et inhibiteur de bace 1 le contenant
WO2013013614A1 (fr) * 2011-07-28 2013-01-31 南京英派药业有限公司 4-(3-hétéroarylarylamino)quinazoline et 1-(3-hétéroarylarylamino)isoquinoline utilisées en tant qu'inhibiteurs de la voie hedgehog et leur utilisation
US9181236B2 (en) 2011-08-22 2015-11-10 Merck Sharp & Dohme Corp. 2-spiro-substituted iminothiazines and their mono-and dioxides as bace inhibitors, compositions and their use
JP2014526534A (ja) * 2011-09-21 2014-10-06 エフ．ホフマン−ラ ロシュ アーゲー ＢＡＣＥ１阻害剤としてのＮ−（３−（２−アミノ−６，６−ジフルオロ−４，４ａ，５，６，７，７ａ−ヘキサヒドロ−シクロペンタ［ｅ］［１，３］オキサジン−４−イル）−フェニル）−アミド
US9556135B2 (en) 2012-10-12 2017-01-31 Amgen, Inc. Amino-dihydrothiazine and amino-dioxido dihydrothiazine compounds as beta-secretase antagonists and methods of use
WO2014059185A1 (fr) 2012-10-12 2014-04-17 Amgen Inc. Composés amino-dihydrothiazine et amino-dioxydo dihydrothiazine en tant qu'antagonistes de bêta-sécrétase et procédés d'utilisation
US9540359B2 (en) 2012-10-24 2017-01-10 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
US9758513B2 (en) 2012-10-24 2017-09-12 Shionogi & Co., Ltd. Dihydrooxazine or oxazepine derivatives having BACE1 inhibitory activity
WO2014078314A1 (fr) 2012-11-15 2014-05-22 Amgen Inc. Composés d'amino-oxazine et d'amino-dihydrothiazine jouant le rôle de modulateurs de bêta-sécrétase et procédés d'utilisation
JP2016511258A (ja) * 2013-03-01 2016-04-14 アムジエン・インコーポレーテツド ベータ−セクレターゼ阻害剤としてのパーフルオロ化５，６−ジヒドロ−４ｈ−１，３−オキサジン−２−アミン化合物および使用方法
US9296734B2 (en) 2013-03-01 2016-03-29 Amgen Inc. Perfluorinated 5,6-dihydro-4H-1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
US9611261B2 (en) 2013-03-08 2017-04-04 Amgen Inc. Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
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WO2015156421A1 (fr) 2014-04-11 2015-10-15 Shionogi & Co., Ltd. Dérivés de dihydrothiazine et de dihydrooxazine présentant une activité inhibitrice de bace1
US9550762B2 (en) 2014-08-08 2017-01-24 Amgen, Inc. Cyclopropyl fused thiazin-2-amine compounds as beta-secretase inhibitors and methods of use
CN106795093B (zh) * 2014-10-14 2019-05-28 先正达参股股份有限公司 用于制备1-(3,5-二氯苯基)-2,2,2-三氟乙酮及其衍生物的方法
CN106795093A (zh) * 2014-10-14 2017-05-31 先正达参股股份有限公司 用于制备1‑(3,5‑二氯苯基)‑2,2,2‑三氟乙酮及其衍生物的方法
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