[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2018230528A1 - Novel nitrocatechol derivative - Google Patents

Novel nitrocatechol derivative Download PDF

Info

Publication number
WO2018230528A1
WO2018230528A1 PCT/JP2018/022310 JP2018022310W WO2018230528A1 WO 2018230528 A1 WO2018230528 A1 WO 2018230528A1 JP 2018022310 W JP2018022310 W JP 2018022310W WO 2018230528 A1 WO2018230528 A1 WO 2018230528A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
optionally substituted
title compound
fluoro
added
Prior art date
Application number
PCT/JP2018/022310
Other languages
French (fr)
Japanese (ja)
Inventor
宏茂 加藤
勗 井上
幸帆 永山
竜光 徳山
精一 小橋
松本　浩二
拓司 細谷
Original Assignee
株式会社富士薬品
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 株式会社富士薬品 filed Critical 株式会社富士薬品
Publication of WO2018230528A1 publication Critical patent/WO2018230528A1/en

Links

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C07D249/06—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles with aryl radicals directly attached to ring atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/08—1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/08—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing alicyclic rings

Definitions

  • the present invention relates to a novel nitrocatechol derivative or salt thereof having a catechol-O-methyltransferase (COMT) inhibitory action and a dopa decarboxylase (DDC) inhibitory action, and a pharmaceutical composition containing them.
  • a catechol-O-methyltransferase (COMT) inhibitory action and a dopa decarboxylase (DDC) inhibitory action
  • DDC dopa decarboxylase
  • Parkinson's disease is caused by the degeneration of dopaminergic nerves in the substantia nigra of the brain and the ventral tegmental area. It is a progressive neurodegenerative disease characterized by movement disorders due to muscle stiffness.
  • Surgical treatment includes, for example, deep brain electrical stimulation therapy by stereotaxic brain surgery, but it requires electrode mounting to the brain and implantation of a chest stimulation device. Risk of cerebral hemorrhage is great.
  • pharmacotherapy includes adenosine A2a receptor antagonists as new mechanism drugs. Even today, dopamine replacement therapy with L-dopa is most effective. Treatment. L-dopa is a precursor of dopamine and is metabolized by dopamine and exerts its action after moving into the brain. However, L-dopa is rapidly metabolized by peripheral COMT and DDC upon entering the body and has a short blood half-life. Therefore, each inhibitor is administered at the same time, and L-dopa is reduced to half in blood. Prolonging the period and increasing the amount of L-dopa transferred into the brain and the amount of dopamine produced in the brain are effective means for improving motor symptoms (Non-patent Document 1).
  • Non-Patent Document 3 Patent Documents 1 to 7
  • entacapone (E) -2-cyano-N, N-diethyl-3- (3,4-Dihydroxy-5-nitrophenyl) acrylamide) has been used in many patients, but has a problem that its action is weak and lacks durability (Non-patent Document 4).
  • tolcapone (3,4-dihydroxy-4'-methyl-5-nitrobenzophenone) has been reported to have impaired liver function (Non-patent Document 5).
  • Non-Patent Document 6 opicapon (5- [3- (2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,2], a more potent and long-lasting COMT inhibitor. 4] oxadiazol-5-yl] -3-nitrobenzene-1,2-diol) (Non-Patent Document 6).
  • JP 2008-308495 A Special table 2009-533423
  • Special table 2009-544571 JP 2011-21010 A JP 2011-021009 A JP 2012-51884 A Japanese Patent Publication No. 7-42254
  • a pharmaceutical compound having two actions of COMT inhibition and DDC inhibition can facilitate the regulation of L-dopa by expressing both actions simultaneously, and also improves patient convenience and compliance. Therefore, development of a novel dual inhibitor is desired.
  • An object of the present invention is to provide a novel nitrocatechol derivative having a COMT inhibitory action and a DDC inhibitory action or a salt thereof, and a pharmaceutical composition containing them.
  • the present invention provides the following inventions [1] to [11].
  • R 1 and R 2 are each independently a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 1 -C 6 alkylcarbonyl group, or optionally substituted.
  • R 3 represents a hydrogen atom, a halogen atom, a haloalkyl group, a cyano group, or a carboxy group
  • R 4 represents a hydrogen atom, a halogen atom, an optionally substituted C 1 -C 6 alkyl group, a haloalkyl group, a cyano group, a carboxy group, an aminocarbonyl group, or an optionally substituted C 1 -C 6 alkylsulfanyl.
  • haloalkylsulfanyl group optionally substituted arylsulfanyl group, optionally substituted C 1 -C 6 alkoxy group, optionally substituted aryloxy group, optionally substituted heteroaryloxy group , optionally substituted C 1 -C 6 alkoxycarbonyl group, an optionally substituted C 1 -C 6 alkylcarbonyl group, an optionally substituted arylcarbonyl group, heteroaryl carbonyl which may be substituted Group, optionally substituted C 1 -C 6 alkylsulfonyl group, optionally substituted C 1 -C 6 alkylsulfinyl group, optionally substituted arylsulfonyl group, optionally substituted heteroarylsulfonyl group, optionally substituted arylsulfinyl group, optionally substituted heteroaryl A sulfinyl group, an optionally substituted C 1 -C 6 alkylaminocarbonyl group, an optionally substitute
  • R 11 represents a hydrogen atom, an optionally substituted C 1 -C 6 alkylcarbonyl group, an optionally substituted C 1 -C 6 alkoxycarbonyl group, or an optionally substituted C 1 -C 6 alkyl
  • X, Y, and Z each represents a single bond, a carbon atom, an oxygen atom, a nitrogen atom, or a sulfur atom
  • ----- represents a single bond or a double bond
  • Q 1 to Q 6 are each independently a carbon atom (each carbon atom is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 1 -C 6 alkylthio group) May have a C 1 -C 6 alkoxy group which may be substituted, a halogen atom, a nitro group, a trifluoromethyl group, a cyano group, or a carboxy group, or a carbon atom or A ring may be
  • R 12 represents a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, a carboxy group, an optionally substituted C 1 -C 6 alkoxycarbonyl group, an optionally substituted aminocarbonyl group, or Represents a cyano group;
  • R 13 and R 14 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group), or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are hydrogen atoms.
  • R 11 is a hydrogen atom and n is a number from 1 to 3.
  • Q 1 to Q 6 each represent a carbon atom (each carbon atom may have any substituent of a hydrogen atom, a halogen atom, a trifluoromethyl group, or a cyano group); n is 1 to 3, the compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof.
  • the structure of the ZYX moiety is a single bond, a C 1 -C 3 linear or branched alkylene group, a C 2 -C 3 linear alkenylene group, an oxymethyl group, a thiomethyl group,
  • Pharmaceutically acceptable salt [7]
  • a pharmaceutical composition comprising the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.
  • the novel nitrocatechol compound or a salt thereof of the present invention has high safety, has an excellent COMT inhibitory action and DDC inhibitory action, and is useful for the treatment of Parkinson's disease.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • C 1 -C 6 alkyl group means a saturated hydrocarbon chain that may be linear, branched, cyclic, or a combination thereof. Examples thereof include a linear or branched C 1 -C 6 alkyl group and a C 3 -C 6 cycloalkyl group. Specific examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, n-pentyl group, n-hexyl group, and cyclopropyl group. , Cyclobutyl group, cyclopentyl group, cyclohexyl group and the like.
  • Haloalkyl group means a C 1 -C 6 alkyl group substituted with 1 to 3 of the same or different halogen atoms, and includes, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, trifluoro An ethyl group etc. are mentioned.
  • C 1 -C 6 alkylsulfanyl group examples include methylsulfanyl group, ethylsulfanyl group, n-propylsulfanyl group, isopropylsulfanyl group, cyclopropylsulfanyl group, cyclopentylsulfanyl group and the like.
  • haloalkylsulfanyl group examples include a trifluoromethylsulfanyl group.
  • arylsulfanyl group examples include a phenylsulfanyl group and a naphthylsulfanyl group.
  • C 1 -C 6 alkoxy group examples include methoxy group, ethoxy group, isopropoxy group, t-butoxy group, cyclopropoxy group, cyclobutyloxy group, cyclopentyloxy group and the like.
  • aryloxy group examples include a phenoxy group and a naphthyloxy group.
  • heteroaryloxy group examples include a pyridyloxy group and a thiophenoxy group.
  • C 1 -C 6 alkoxycarbonyl group examples include a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, and the like.
  • C 1 -C 6 alkylcarbonyl group examples include a methylcarbonyl group, an ethylcarbonyl group, an isobutylcarbonyl group, a cyclopropylcarbonyl group, a cyclohexylcarbonyl group, and the like.
  • arylcarbonyl group examples include a phenylcarbonyl group.
  • heteroarylcarbonyl group examples include pyridinylcarbonyl group, thienylcarbonyl group, thiazolocarbonyl group and the like.
  • C 1 -C 6 alkylsulfonyl group examples include a methanesulfonyl group, an isopropylsulfonyl group, a cyclopentylsulfonyl group, and the like.
  • arylsulfonyl group examples include a phenylsulfonyl group.
  • heteroarylsulfonyl group is a monocyclic or bicyclic heterocycle containing 1 to 5 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. It has a sulfonyl group having a ring, and examples thereof include a pyridylsulfonyl group and a thienylsulfonyl group.
  • C 1 -C 6 alkylsulfinyl group examples include a methylsulfinyl group, an isopropylsulfinyl group, a cyclopentylsulfinyl group, and the like.
  • arylsulfinyl group examples include a phenylsulfinyl group.
  • heteroarylsulfinyl group is a monocyclic or bicyclic heterocycle containing 1 to 5 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. It has a sulfinyl group having a ring, and examples thereof include a pyridylsulfinyl group and a thienylsulfinyl group.
  • C 1 -C 6 alkylaminocarbonyl group examples include a methylaminocarbonyl group, an ethylaminocarbonyl group, a cyclopropylaminocarbonyl group, a cyclohexylaminocarbonyl group, and the like.
  • Examples of the “aminosulfonyl group” include a methylaminosulfonyl group.
  • Heterocycloalkylcarbonyl group refers to a carbonyl compound having a 4- to 7-membered saturated heterocyclic ring containing a nitrogen atom, an oxygen atom or a sulfur atom in the ring and bonded via a carbon atom.
  • tetrahydrofuryl Examples include carbonyl group, tetrahydrothienylcarbonyl group, pyrrolidinylcarbonyl group, piperidinylcarbonyl group, morpholinylcarbonyl group and the like.
  • Heterocycle is a 5- or 6-membered saturated or unsaturated heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in the ring.
  • Ring heterocycles include pyrrolidine, pyrrole, pyrroline, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, triazole, triazoline, tetrazole, furan, dihydrofuran, dioxolane, thiophene, dihydrothiophene, thiazole, thiadiazole, isothiazole, isothiazoline, oxazole , Isoxazole, oxadiazole, dihydroisoxazole, diazoline, oxadiazoline, isoxazoline, dioxazoline and the like, and examples of the 6-membered heterocyclic ring include piperidine, pyridine, pyridazine, pyr
  • R 1 and R 2 are preferably a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkylcarbonyl group, a C 1 -C 6 alkoxycarbonyl group, or a C 1 -C 6 alkylaminocarbonyl group, An atom, a C 1 -C 6 alkylcarbonyl group, a C 1 -C 6 alkoxycarbonyl group or a C 1 -C 6 alkylaminocarbonyl group is more preferred, and a hydrogen atom is more preferred.
  • R 3 is preferably a hydrogen atom, a halogen atom, a haloalkyl group, a cyano group or a carboxy group, more preferably a hydrogen atom or a halogen atom.
  • R 4 includes a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a haloalkyl group, a cyano group, a carboxy group, an aminocarbonyl group, a C 1 -C 6 alkylsulfanyl group, a haloalkylsulfanyl group, an arylsulfanyl group, C 1 -C 6 alkoxy group, aryloxy group, heteroaryloxy group, C 1 -C 6 alkoxycarbonyl group, C 1 -C 6 alkylcarbonyl group, arylcarbonyl group, heteroarylcarbonyl group, C 1 -C 6 alkyl Sulfonyl group, C 1 -C 6 alkylsulfinyl group, arylsulfonyl group, heteroarylsulfonyl group, arylsulfinyl group, heteroarylsulfinyl group, C 1 -C
  • R 4 is further a hydrogen atom, a halogen atom, an optionally substituted C 1 -C 6 alkyl group, a haloalkyl group, a cyano group, a carboxy group, an aminocarbonyl group, or a C 1 -C 6 alkylsulfanyl.
  • the structure of the ZYX moiety includes a single bond, a C 1 -C 3 linear or branched alkylene group, a C 2 -C 3 linear alkenylene group, an oxymethyl group, a thiomethyl group, a methyloxy group
  • a group selected from a C 2 -C 3 linear alkenylene group, an oxymethyl group, a thiomethyl group, a methyloxy group, a methylthio group, and a C 1 -C 3 haloalkylene group is more preferable.
  • benzene As the structure represented by Q 1 to Q 6 , benzene, cyclohexane, thiophene, pyridazine, benzothiophene, benzimidazoline, and benzoxazole are preferable, and benzene is particularly preferable.
  • Q 1 to Q 6 represents a benzene ring
  • Q 1 -Q 6 is a carbon atom.
  • a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkylthio group, a C 1 -C 6 alkoxy group, a halogen atom Nitro group, trifluoromethyl group, cyano group, carboxy group may be substituted, preferably hydrogen atom, halogen atom, trifluoromethyl group or cyano group may be substituted, more preferably hydrogen atom or A halogen atom may be substituted.
  • R 11 is preferably a hydrogen atom, a C 1 -C 6 alkylcarbonyl group, a C 1 -C 6 alkoxycarbonyl group, or a C 1 -C 6 alkylaminocarbonyl group, and more preferably a hydrogen atom.
  • N is preferably 1 to 3.
  • the ring A which may be substituted includes the following A-1 to A-15
  • R 12 represents a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, a carboxy group, an optionally substituted C 1 -C 6 alkoxycarbonyl group, an optionally substituted aminocarbonyl group, or Represents a cyano group
  • R 13 represents a hydrogen atom or a heterocyclic ring selected from a C 1 -C 6 alkyl group.
  • ring A includes triazole (A-6, A-7, A-8), tetrazole (A-3), oxozal (A-2, A-5, A-11), oxadiazole (A-1 A-15), dihydroisoxazole (A-9), thiazole (A-4), and thiadiazole (A-10) (wherein R 12 and R 13 are the same as those described above).
  • Ring A is a ring represented by A-1 to A-15;
  • R 1 and R 2 are a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkylcarbonyl group, a C 1 -C 6 alkoxycarbonyl group, or a C 1 -C 6 alkylaminocarbonyl group;
  • R 3 is a hydrogen atom, a halogen atom, a haloalkyl group, a cyano group, or a carboxy group;
  • R 4 is a hydrogen atom, halogen atom, C 1 -C 6 alkyl group, haloalkyl group, cyano group, carboxy group, aminocarbonyl group, C 1 -C 6 alkylsulfanyl group, haloalkylsulfanyl group, arylsulfanyl group, C 1 —C 6 alkoxy group, aryloxy group,
  • Ring A is a ring represented by A-1 to A-15;
  • R 1 and R 2 are hydrogen atoms;
  • R 3 is a hydrogen atom or a halogen atom;
  • R 4 is a hydrogen atom, halogen atom, C 1 -C 6 alkyl group, haloalkyl group, cyano group, carboxy group, aminocarbonyl group, C 1 -C 6 alkylsulfanyl group, haloalkylsulfanyl group, arylsulfanyl group, C 1 —C 6 alkoxy group, aryloxy group, heteroaryloxy group, C 1 -C 6 alkoxycarbonyl group, C 1 -C 6 alkylcarbonyl group, arylcarbonyl group, heteroarylcarbonyl group, C 1 -C 6 alkylsulfonyl Group, C 1 -C 6 alkylsulfinyl group, arylsulfonyl group, heteroarylsul
  • a preferred embodiment of the general formula (1) is a compound comprising a combination of each of the above-mentioned preferred groups.
  • the compounds described in the examples, their pharmaceutically acceptable salts, or their hydrates, or solvents Japanese products are listed.
  • the compound of the present invention represented by the general formula (1) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a geometric isomer or tautomer based on a double bond depending on the type of substituent.
  • optical isomers and diastereomers may exist due to the presence of an asymmetric carbon atom.
  • all these isolated isomers or mixtures thereof are included.
  • the salt of the compound of the present invention is a pharmaceutically acceptable salt of the compound of the general formula (1), and can be produced by treating the compound of the general formula (1) with a desired base in a solvent.
  • Examples of such salt forms include lithium salts, potassium salts, sodium salts and the like, with sodium salts being preferred.
  • the compounds of the present invention also include compounds labeled with various radioactive or non-radioactive isotopes.
  • the compound of the present invention represented by the general formula (1) may exist as an isomer, for example, a geometric isomer, an optical isomer, or a diastereoisomer may exist. In the present invention, all of these isomers isolated, arbitrary mixtures, racemates and the like are included.
  • the compound of the present invention represented by the general formula (1) or a pharmaceutically acceptable salt thereof is also included in the scope of the present invention as a prodrug as its equivalent compound.
  • a “prodrug” is a compound that is converted into a compound of the general formula (1) by a metabolic mechanism in vivo, that is, in vivo, enzymatically oxidized, reduced, hydrolyzed, or hydrolyzed by stomach acid, etc. What changes into the compound of general formula (1).
  • a prodrug of the compound of the general formula (1) a compound in which a phosphate group or a hydroxyl group is modified with an acyl group or an alkyl group, for example, an acetylated, pivaloylated or pivaloyloxymethylated compound, etc. Can be mentioned. These compounds can be synthesized from the compound of the general formula (1) by a known method. These prodrugs change to compounds of the general formula (1) under the conditions described in, for example, “The Organic chemistry of drug design and drug action (second edition)” chapter 8, p497-557. There may be.
  • the production method of the compound of the present invention is not particularly limited, but can be produced, for example, according to the following steps.
  • compounds labeled with various radioactive or non-radioactive isotopes included in the present invention can also be produced in the same manner as in the following production method using isotope-substituted raw materials.
  • R 2 is a methyl group, benzyl group, etc.
  • R 11 is a hydroxyl-protecting group such as methoxymethyl group, methyl group, etc., and the other symbols are as defined above
  • Compound (3) can be produced by reacting compound (2) with lithium chloride in N, N-dimethylformamide, N-methylpyrrolidone or N-methylmorpholine solvent under heating conditions. it can.
  • Second step Compound (4) is treated with aluminum bromide in the presence of a base in the presence of a base at room temperature or under heating, or by treatment with hydrobromic acid in an acetic acid solvent or without a solvent.
  • the solvent include 1,2-dichloroethane, pyridine and the like.
  • the base include triethylamine, diisopropylethylamine, pyridine and the like.
  • Compound (1) is produced by treating compound (4) with hydrochloric acid, boron tribromide or hydrobromic acid solution in a dichloromethane solvent or without solvent under room temperature to warming conditions. Can do.
  • the carboxylic acid intermediate (7) is converted into a base by using thionyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, oxalyl chloride or the like in an organic solvent at room temperature to warming condition.
  • a mixed acid anhydride can be produced using ethyl chloroformate, isobutyl chloroformate or the like.
  • the acid chloride and mixed acid anhydride are used in the sixth step as the acylating agent (8).
  • the solvent include dichloromethane, tetrahydrofuran, ethyl acetate and the like.
  • the base include triethylamine, diisopropylethylamine, morpholine and the like.
  • Step 5 Compound (6) is obtained by reacting cyano compound (5) with hydroxyamine in a solvent under room temperature to warming conditions.
  • the solvent include methanol, ethanol, tetrahydrofuran and the like, preferably ethanol.
  • Step 6 The acylating agent (8) obtained in Step 4 and the compound (6) obtained in Step 5 are reacted in a solvent in the presence of a base at ⁇ 20 ° C. to warming conditions.
  • a solvent include dichloromethane, ethyl acetate, tetrahydrafuran, N, N-dimethylformamide
  • examples of the base include triethylamine, diisopropylethylamine, diazabicycloundecene, and the like.
  • Step 7 Compound (2-A-1) can be produced by adding the catalyst obtained in Step 6 to a catalyst in a solvent and reacting under room temperature to warming conditions.
  • the solvent include N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran and the like.
  • the catalyst include p-toluenesulfonic acid, camphorsulfonic acid, tetrabutylammonium fluoride and the like.
  • the compound (7) in which R 1 or R 2 is substituted it can be produced according to, for example, a method described in JP-A-2011-148882, JP-A-2012-51884, or a modification thereof.
  • the production method of the compound of the present invention can also be produced by desorption of a suitable protecting group when it has a functional group at the raw material or intermediate stage.
  • suitable protecting group examples include amino groups, hydroxy groups, carboxy groups, etc.
  • the types of protective groups and desorption methods are described in, for example, “Protective Groups in Organic Synthesis (Fourth Edition)” (by Greene, Wuts). The method etc. are mentioned.
  • the compound of the general formula (1) synthesized as described above is in the free state or as a salt thereof, which is a normal chemical operation such as extraction, concentration, distillation, crystallization, filtration, recrystallization, various chromatography, etc. Can be isolated and purified. Moreover, when it contains an optical isomer, a stereoisomer, and a position isomer, each can be isolated by a fractional recrystallization method, a chiral column method, a diastereomer method, etc.
  • the compound of the present invention Since the compound of the present invention has an excellent COMT and DDC inhibitory action, it is useful as a therapeutic or prophylactic agent for Parkinson's disease, and is preferably used in combination with L-dopa. Further, the compound of the present invention and L-dopa may be used in combination with an aromatic L-amino acid decarboxylase inhibitor. Examples of the aromatic L-amino acid decarboxylase inhibitor that can be used in combination with the present invention include carbidopa and benserazide. Examples of the COMT inhibitor that can be used in combination with the present invention include entacapone, tolcapone, and opikapon.
  • the compound of the present invention is also useful as a therapeutic or prophylactic agent for other than Parkinson's disease, such as depression, Lewy body dementia, juvenile dementia, Alzheimer's dementia, and schizophrenia.
  • the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof may be used as it is, but a pharmaceutical containing a pharmaceutically acceptable carrier, for example, one or more of pharmaceutical additives. It may be used as a composition.
  • the pharmaceutical composition may be used in any dosage form, such as tablets, pills, capsules, powders, fine granules, granules, solutions, suspensions, syrups, injections, external preparations, suppositories, etc. As applicable.
  • the type of pharmaceutical additive used in the pharmaceutical composition comprising the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the Pharmaceutical Additives Dictionary (2007) Yakuho Nippo) base, excipient, lubricant, coating agent, sugar coating, wetting agent, binder, disintegrant, solvent, solubilizer, solubilizer, solubilizer, suspending agent, Dispersants, emulsifiers, surfactants, isotonic agents, buffers, pH adjusters, soothing agents, preservatives, preservatives, stabilizers, antioxidants, colorants, sweeteners, etc. alone or in appropriate combination Can be used.
  • the compound of the present invention can be used in combination with other therapeutic agents or preventive agents for diseases for which the compound of the present invention is considered effective.
  • the combined use means simultaneous administration, administration separately individually or at a desired time interval.
  • the simultaneous administration preparation may be a combination preparation or a kit preparation.
  • the single dose of the compound of the present invention or a salt thereof is about 1 to 100 mg / kg per body weight, and this is administered once a day or 1 to 3 times a week.
  • the appropriate dose is about 0.1 to 10 mg / kg per body weight, and is administered once a day or once to several times a month.
  • the dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
  • MOM methoxymethyl group
  • Bn benzyl group
  • Ph phenyl group
  • PMB paramethoxybenzyl group
  • Ac acetyl group
  • MS indicates mass spectrometry, and uses an instrument whose ionization method is ESI (electrospray ionization method)
  • ESI electrospray ionization method
  • the solvent was distilled off under reduced pressure, citric acid aqueous solution and ethyl acetate (60.0 mL) were added to the residue, the insoluble material was removed, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (11.2 g).
  • Methyl 2,2-difluoro-2- ⁇ [4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl ⁇ acetate prepared in Reference Example 4 was added dropwise with 2M ammonia ethanol solution (5.0 mL) under ice cooling, Stir at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (400 mg).
  • Example 29 5- ⁇ 3- [3- (3,4-dihydroxyphenyl) propyl] -1,2,4-oxadiazol-5-yl ⁇ -3-nitrobenzene-1,2-diol 4- ( Using 3,4-dimethoxyphenyl) butanenitrile, the title compound was obtained in the same manner as in Reference Examples 12, 13, and Examples 1 and 2.
  • Example 38 3- ⁇ 2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] ethyl ⁇ benzo [b] thiophene-5,6 -Diol
  • Example 43 4- ⁇ 2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] ethyl ⁇ -3-methylbenzene-1,2 -Diol
  • Example 49 3- [5- (3,4-Dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] -1- (3-hydroxythiophen-2-yl) propane -1-On
  • Example 68 4- [5- (3,4-Dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] -3-fluorobenzene-1,2-diol
  • Example 70 5- [3- (2,4-difluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
  • Example 72 5- ⁇ 3- [2- (2,4-difluoro-5-hydroxyphenyl) ethyl)]-1,2,4-oxadiazol-5-yl ⁇ -3-nitrobenzene-1,2 -Diol
  • Example 80 3-chloro-4- ⁇ 3- [2- (4-fluoro-3-hydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl ⁇ -6-nitrobenzene-1, 2-diol
  • Example 81 4- ⁇ 2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] ethyl ⁇ -3-fluorobenzene-1,2 -Diol
  • Example 90 4-( ⁇ [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] methyl ⁇ sulfanyl) -2-hydroxybenzonitrile
  • Example 100 4-chloro-5- [3- (3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
  • Example 104 6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -2,3-dihydroxy-4-nitrobenzonitrile
  • Example 105 6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrobenzoic acid
  • Example 94 6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrobenzonitrile prepared in Example 94 was carried out In the same manner as in Example 5, the title compound (yield 4%) was obtained.
  • Example 110 5-( ⁇ 3-[(4-fluoro-3-hydroxyphenyl) methyl] amino ⁇ -1,2,4-oxadiazol-5-yl) -3-nitrobenzene-1,2-diol
  • Example 112 5- ⁇ 3-[(1R * , 2R * )-2- (4-fluoro-3-hydroxyphenyl) cyclopropyl] -1,2,4-oxadiazol-5-yl ⁇ -3 -Nitro-4- (trifluoromethyl) benzene-1,2-diol
  • Example 113 4-chloro-5- ⁇ 3- [3- (4-fluoro-3-hydroxyphenyl) propyl] -1,2,4-oxadiazol-5-yl ⁇ -3-nitrobenzene-1, 2-diol
  • Example 114 4-chloro-5- ⁇ 3-[(1R * , 2R * )-2- (4-fluoro-3-hydroxyphenyl) cyclopropyl] -1,2,4-oxadiazole-5 Il ⁇ -3-nitrobenzene-1,2-diol
  • Example 122 5- (3- ⁇ difluoro [(4-fluoro-3-hydroxyphenyl) sulfanyl] methyl ⁇ -1,2,4-oxadiazol-5-yl) -4- (methylsulfanyl) -3 -Nitrobenzene-1,2-diol
  • Example 126 cyclohexyl ⁇ 6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrophenyl ⁇ methanone
  • Example 128 4- ⁇ 5- [4,5-dihydroxy-3-nitro-2- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-3-yl ⁇ -2-hydroxybenzonitrile
  • Example 130 4- (cyclopentylsulfanyl) -5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2- Diol
  • Example 132 4- (cyclopentylsulfonyl) -5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2- Diol
  • Example 130 The intermediate of Example 130, 5- [2- (cyclopentylsulfanyl) -4,5-dimethoxy-3-nitrophenyl] -3- (4-fluoro-3-methoxyphenyl) -1,2,4-oxa Diazole was oxidized with 3-chloroperbenzoic acid to give 5- [2- (cyclopentylsulfonyl) -4,5-dimethoxy-3-nitrophenyl] -3- (4-fluoro-3-methoxyphenyl) -1, The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2, using 2,4-oxadiazole.
  • Example 135 3-nitro-4- (trifluoromethyl) -5- [3- (3,4,5-trifluorophenyl) -1,2,4-oxadiazol-5-yl] benzene-1 , 2-diol
  • Example 138 5- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -4-[(propan-2-yl) oxy] -3- Nitrobenzene-1,2-diol
  • Example 140 [6- (3- ⁇ difluoro [(4-fluoro-3-hydroxyphenyl) sulfanyl] methyl ⁇ -1,2,4-oxadiazol-5-yl) -3,4-dihydroxy-2 -Nitrophenyl] (phenyl) methanone
  • Example 142 5- (3- ⁇ difluoro [(4-fluoro-3-hydroxyphenyl) sulfanyl] methyl ⁇ -1,2,4-oxadiazol-5-yl) -3-nitrobenzene-1,2- Diol
  • Example 143 4-chloro-5- (3- ⁇ difluoro [(4-fluoro-3-hydroxyphenyl) sulfanyl] methyl ⁇ -1,2,4-oxadiazol-5-yl) -3-nitrobenzene- 1,2-diol
  • Example 145 4-cyclopentyl-5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
  • Example 146 5- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -4-[(propan-2-yl) sulfonyl] -3- Nitrobenzene-1,2-diol
  • Example 148 5- (3- ⁇ difluoro-[(4-fluoro-3-hydroxyphenyl) sulfanyl] methyl ⁇ -1,2,4-oxadiazol-5-yl) -3-nitro-4- [ (Trifluoromethyl) sulfanyl] benzene-1,2-diol
  • Reference Example 12 was prepared using 2- ⁇ [4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl ⁇ -2-methylpropanenitrile and 3,4-dimethoxy-5-nitrobenzoyl chloride prepared in the same manner as Reference Example 6. 13, In the same manner as in Example 3, the title compound (yield 3%) was obtained.
  • Example 151 1 Benzyl 3- (3,4-dihydroxy-5-nitrophenyl) -5-methyl-4,5-dihydroisoxazole-5-carboxylate
  • Example 152 3- (3,4-dihydroxy-5-nitrophenyl) -5-methyl-4,5-dihydroisoxazole-5-carboxylic acid
  • Example 159 4- [3- (3,4-dihydroxy-5-nitrophenyl) -5-methyl-4,5-dihydroisoxazol-5-yl] benzoic acid
  • Example 163 4- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-thiadiazol-3-yl] benzoic acid
  • Example 165 t-butyl 2- [2- (3,4-dihydroxy-5-nitrophenyl) -4-phenylthiazole-5-carbonyl] hydrazine-1-carboxylate
  • Example 172 4- [5- (3,4-dihydroxy-5-nitrophenyl) -1H-1,2,4-triazol-3-yl] pyridine-2-carbonitrile
  • Example 176 5- ⁇ 3- [3,5-bis (trifluoromethyl) phenyl] -1H-1,2,4-triazol-5-yl ⁇ -3-nitrobenzene-1,2-diol
  • Example 180 3- [3- (3,4-dihydroxy-5-nitrophenyl) -1-methyl-1H-1,2,4-triazol-5-yl] benzonitrile
  • Example 207 4-chloro-5- [4- (4-fluoro-3-hydroxyphenyl) -1H-1,2,3-triazol-1-yl] -3-nitrobenzene-1,2-diol
  • Example 212 6- (3- ⁇ difluoro [(4-fluoro-3 -hydroxyphenyl) thio] methyl ⁇ -1,2,4-oxadiazol-5-yl) -3,4-dihydroxy-2- Nitrobenzonitrile
  • Example 213 6- (3- ⁇ difluoro [(4-fluoro-3- hydroxyphenyl) thio] methyl ⁇ -1,2,4-oxadiazol-5-yl) -3,4-dihydroxy-2- Nitrobenzamide
  • (+)-10-Camphorsulfonic acid (69 mg) was added to a solution of (b) in N, N-dimethylformamide (5.0 mL), and the mixture was stirred at 100 ° C. for 63 hours.
  • Potassium carbonate (1.66 g) and chloromethyl methyl ether (0.68 mL) were added at room temperature, and the mixture was stirred at 40 ° C. for 4 hours.
  • Example 214 1- ⁇ 6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrophenyl ⁇ - 2-Methylpropan-1-one
  • Example 215 6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-N-isobutyl-2-nitrobenzamide
  • Example 216 ⁇ 6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrophenyl ⁇ (4- Methoxyphenyl) methanone
  • Example 217 4- ⁇ 6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrobenzoyl ⁇ benzoate acid
  • Example 220 ⁇ 6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrophenyl ⁇ (thiophene- 2-yl) methanone
  • Example 224 ⁇ 6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrophenyl ⁇ (thiophene- 3-yl) methanone
  • Example 229 ⁇ 6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxazol-5-yl] -3,4-dihydroxy-2-nitrophenyl ⁇ (morpholino) methanone
  • Example 232 Acetic acid 5- [5- (5-acetoxy-2-benzoyl-4-hydroxy-3-nitrophenyl) -1,2,4-oxadiazol-3-yl] -2-fluorophenyl ester
  • Example 233 ⁇ 6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrophenyl ⁇ (piperidine- 1-yl) methanone
  • Rat liver COMT and DDC inhibition test (enzyme preparation method): The liver of a rat exsanguinated under isoflurane anesthesia was excised, and the ice-cold homogenate buffer (containing 0.135 mol / L KCl) was 4 times the liver weight. 10 mmol / L sodium phosphate buffer (pH 8.0) was added and homogenized. After the homogenate solution was centrifuged (20000 ⁇ g, 4 ° C., 10 minutes), the supernatant was collected and centrifuged again (20000 ⁇ g, 4 ° C., 30 minutes) to obtain the final supernatant. 400 ⁇ L of the obtained supernatant was added to a gel filtration column, and about 800 ⁇ L of the eluate was used as an enzyme solution.
  • Test Example 1 Measurement of rat COMT inhibitory action: In each well of a 96-well plate, 91 ⁇ L of 10 mmol / L sodium phosphate buffer (pH 7.8), 2 ⁇ L of 500 mmol / L MgCl 2 , 2 ⁇ L of 200 ⁇ mol / L Esculetin, 2 ⁇ L of 30 mmol / L AdoMet and 1 ⁇ L of each test substance solution were added and mixed. As the blank, a 30 mmol / L AdoMet non-added sample was used.
  • Test Example 2 (Measurement of rat DDC inhibitory action): 186 ⁇ L of 30 mmol / L potassium phosphate buffer (pH 6.8), 2 ⁇ L of 100 mmol / L L-Dopa, 2 ⁇ L of 7 mmol / L pyridoxal phosphate and each test substance solution 2 ⁇ L was added and mixed. 8 ⁇ L of the prepared enzyme solution was added and incubated (37 ° C., 15 minutes). A sample of 0 minute incubation was used for Blank. Thereafter, it was boiled at 100 ° C. for 3 minutes, cooled on ice for 2 minutes, and then centrifuged (4 ° C., 10000 rpm, 10 minutes).
  • the supernatant was recovered, diluted with 400 ⁇ L of distilled water, added to the Amberlite CG50 (NH 4 + ) column, and washed twice with 0.3 mL and 1.5 mL of distilled water. Thereafter, dopamine was eluted with 1.2 mL of 2N acetic acid, the absorbance (wavelength 279 nm) was measured with a spectrophotometer, and this value was defined as the enzyme activity. IC 50 values indicate concentrations that inhibit enzyme activity by 50%. As comparative examples, tolcapone and entacapone were similarly tested.
  • Rat mitochondrial toxicity test (method for preparing rat heart mitochondrial solution): The heart of a rat that had been exsanguinated under isoflurane anesthesia was removed, and the ice-cooled homogenate buffer (210 mmol / L mannitol, 70 mmol) was 8 times the heart weight. / L sucrose, 5 mmol / L HEPES, 1 mmol / L EGTA buffer, pH 7.2) was added and homogenized. After the homogenate solution was centrifuged (500 ⁇ g, 4 ° C., 10 minutes), the supernatant was collected and centrifuged again (10000 ⁇ g, 4 ° C., 10 minutes).
  • the resulting precipitate was suspended in 8 times the amount of homogenate buffer, and then centrifuged (10000 ⁇ g, 4 ° C., 10 minutes). After repeating the same operation once, the obtained precipitate was suspended in 0.25 mL of a homogenate buffer per 1 g of heart weight to obtain a mitochondrial solution.
  • Test Example 3 Measurement of Rat Heart Mitochondrial Inhibitory Action: Using an oxygen consumption measurement system (NeoFox, FOL / C1T500P, Intech), mitochondrial oxygen consumption at 30 ° C. was measured. Reaction solution (220 mmol / L mannitol, 70 mmol / L sucrose, 2 mmol / L HEPES, 1 mmol / L EGTA, 10 mmol / L potassium dihydrogen phosphate, 5 mmol / L magnesium chloride, pH 7.2) in the measurement chamber was added to each test substance solution, 5.2 ⁇ L, and a mitochondrial solution was added to 15 ⁇ L.
  • Reaction solution (220 mmol / L mannitol, 70 mmol / L sucrose, 2 mmol / L HEPES, 1 mmol / L EGTA, 10 mmol / L potassium dihydrogen phosphate, 5 mmol / L magnesium chloride, pH 7.2
  • Table 27 shows the results of Test Example 3.
  • Formulation example 1 (tablet): In Example 53, granules are prepared by wet granulation using crystalline cellulose, D-mannitol, hydroxypropylcellulose, and carmellose sodium as additives, and magnesium stearate is added, followed by a conventional method. Manufactured by.
  • Example 53 D-mannitol and sodium citrate are used as additives, dissolved in purified water, and an injection is prepared by a conventional method.
  • the compound of the present invention has a COMT inhibitory action and a DDC inhibitory action and is useful for the treatment of Parkinson's disease.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Provided are a novel nitrocatechol derivative having COMT inhibitory effect and DDC inhibitory effect or a salt thereof and a medicinal composition comprising the same. A compound represented by general formula (1) or a pharmaceutically acceptable salt thereof, and a medicinal composition comprising the same.

Description

新規ニトロカテコール誘導体New nitrocatechol derivatives
　本発明は、カテコール－Ｏ－メチルトランスフェラーゼ（ＣＯＭＴ）阻害作用およびドパデカルボキシラーゼ（ＤＤＣ）阻害作用を有する新規ニトロカテコール誘導体又はその塩、およびこれらを含有する医薬組成物に関する。 The present invention relates to a novel nitrocatechol derivative or salt thereof having a catechol-O-methyltransferase (COMT) inhibitory action and a dopa decarboxylase (DDC) inhibitory action, and a pharmaceutical composition containing them.
　パーキンソン病は、脳の黒質緻密部、腹側被蓋野にあるドパミン作動性神経の変性に伴い、神経伝達物質であるドパミンの減少により、無動・寡動、安静時振戦、姿勢反射障害、筋固縮による運動障害を特徴とする進行性の神経変性疾患である。 Parkinson's disease is caused by the degeneration of dopaminergic nerves in the substantia nigra of the brain and the ventral tegmental area. It is a progressive neurodegenerative disease characterized by movement disorders due to muscle stiffness.
　近年、日本においては高齢化に伴い１０万人に１００～１５０人、欧米においても１５０～２００人と有病率は増加傾向にある。発症は中高齢に多く、高齢になるほど発病率が増加傾向にある。また、若年性パーキンソン病と呼ばれる４０歳以下で発症する例もあり、この中には遺伝子異常が明らかにされた症例もある。 In recent years, the prevalence rate has been increasing in Japan with 100-150 people per 100,000 people and 150-200 people in Europe and America with the aging of the population. The onset is common in middle-aged and older people, and the incidence tends to increase with increasing age. In addition, there is a case called juvenile Parkinson's disease that develops at the age of 40 years or younger.
　パーキンソン病の治療には、外科的療法と薬物療法がある。外科的治療としては、例えば定位脳手術による深部脳電気刺激療法があるが、脳への電極装着と胸部刺激装置の埋め込みを必要とし、高齢者には負担が大きく、機器の高磁場による影響、脳内出血等のリスクが大きい。 There are two types of treatment for Parkinson's disease: surgical therapy and drug therapy. Surgical treatment includes, for example, deep brain electrical stimulation therapy by stereotaxic brain surgery, but it requires electrode mounting to the brain and implantation of a chest stimulation device. Risk of cerebral hemorrhage is great.
　薬物療法としては、ドパミン受容体刺激薬やモノアミン酸化酵素Ｂ阻害薬の他、新しい機序の薬としてアデノシンＡ２ａ受容体拮抗薬などがあるが、現在でもＬ－ドパによるドパミン補充療法が最も効果的な治療法である。Ｌ－ドパはドパミンの前駆物質であり、脳内へ移行した後、ドパミンに代謝され作用を発揮する。しかしながら、Ｌ－ドパは体内に入ると速やかに末梢のＣＯＭＴおよびＤＤＣにより代謝され、血中半減期が短い欠点があるため、それぞれの阻害薬を同時に投与し、Ｌ－ドパの血中半減期を延長させ、Ｌ－ドパの脳内への移行量および脳内でのドパミン生成量を増大させることが運動症状改善の有効な手段となる（非特許文献１）。 In addition to dopamine receptor stimulants and monoamine oxidase B inhibitors, pharmacotherapy includes adenosine A2a receptor antagonists as new mechanism drugs. Even today, dopamine replacement therapy with L-dopa is most effective. Treatment. L-dopa is a precursor of dopamine and is metabolized by dopamine and exerts its action after moving into the brain. However, L-dopa is rapidly metabolized by peripheral COMT and DDC upon entering the body and has a short blood half-life. Therefore, each inhibitor is administered at the same time, and L-dopa is reduced to half in blood. Prolonging the period and increasing the amount of L-dopa transferred into the brain and the amount of dopamine produced in the brain are effective means for improving motor symptoms (Non-patent Document 1).
　ＤＤＣ阻害薬としては、カルビドパ（（－）－Ｌ－α－ヒドラジノ－アルファ－メチル－β－（３，４－ジヒドロキシベンゼン）プロピオン酸一水和物）があり、合剤としてＬ－ドパと併用されるが、病気の進行にともない効果持続時間が短縮し、ウェアリングオフ現象と呼ばれる運動症状の日内変動がみられるようになる。そのため、さらにＣＯＭＴ阻害薬を併用して血中Ｌ－ドパ濃度を上昇させることで症状の改善を図る必要がある（非特許文献２）。 As a DDC inhibitor, there is carbidopa ((−)-L-α-hydrazino-alpha-methyl-β- (3,4-dihydroxybenzene) propionic acid monohydrate). Although it is used in combination, the duration of the effect is shortened as the disease progresses, and diurnal movements of the motor symptoms called wear-off phenomenon are observed. For this reason, it is necessary to further improve symptoms by increasing the L-DOPA concentration in the blood in combination with a COMT inhibitor (Non-patent Document 2).
　ＣＯＭＴ阻害薬としては、カテコール系化合物が多く開発されているが（例えば、非特許文献３、特許文献１～７）、中でもエンタカポン（（Ｅ）－２－シアノ－Ｎ，Ｎ－ジエチル－３－（３，４－ジヒドロキシ－５－ニトロフェニル）アクリルアミド）が多くの患者に使用されているが、作用が弱く、持続性に欠ける問題点を有している（非特許文献４）。また、トルカポン（３，４－ジヒドロキシ－４’－メチル－５－ニトロベンゾフェノン）は肝機能障害が報告されている（非特許文献５）。更に近年、より強力で持続的なＣＯＭＴ阻害薬であるオピカポン（５－［３－（２，５－ジクロロ－４，６－ジメチル－１－オキシ－ピリジン－３－イル）－［１，２，４］オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール）が開発された（非特許文献６）。 As COMT inhibitors, many catechol compounds have been developed (for example, Non-Patent Document 3, Patent Documents 1 to 7), and among them, entacapone ((E) -2-cyano-N, N-diethyl-3- (3,4-Dihydroxy-5-nitrophenyl) acrylamide) has been used in many patients, but has a problem that its action is weak and lacks durability (Non-patent Document 4). In addition, tolcapone (3,4-dihydroxy-4'-methyl-5-nitrobenzophenone) has been reported to have impaired liver function (Non-patent Document 5). More recently, opicapon (5- [3- (2,5-dichloro-4,6-dimethyl-1-oxy-pyridin-3-yl)-[1,2,2], a more potent and long-lasting COMT inhibitor. 4] oxadiazol-5-yl] -3-nitrobenzene-1,2-diol) (Non-Patent Document 6).
特開２００８－３０８４９５号公報JP 2008-308495 A 特表２００９－５３３４２３号公報Special table 2009-533423 特表２００９－５４４５７１号公報Special table 2009-544571 特開２０１１－２１０１０号公報JP 2011-21010 A 特開２０１１－０２１００９号公報JP 2011-021009 A 特開２０１２－５１８８４号公報JP 2012-51884 A 特公平７－４２２５４号公報Japanese Patent Publication No. 7-42254
　しかしながら、ＣＯＭＴ阻害薬とＤＤＣ阻害薬が併用される場合は、それぞれの薬において作用の発現時間や持続性が異なるため、血中Ｌ－ドパ濃度の調節が困難であり、期待されたほどの効果が得られなかったり、効きすぎることによりジスキネジアなどの副作用が発現するといった問題が生じる。 However, when a COMT inhibitor and a DDC inhibitor are used in combination, since the onset time and the duration of action of each drug are different, it is difficult to adjust the blood L-dopa concentration, and as expected There are problems that side effects such as dyskinesia appear due to inefficiency or excessive effect.
　したがって、ＣＯＭＴ阻害とＤＤＣ阻害の二つの作用を有する医薬化合物であれば、両作用を同時に発現することによりＬ－ドパの調節が容易になると考えられ、また、患者の利便性と服薬コンプライアンス面からも、新規なデュアル阻害薬の開発が望まれている。 Therefore, it is considered that a pharmaceutical compound having two actions of COMT inhibition and DDC inhibition can facilitate the regulation of L-dopa by expressing both actions simultaneously, and also improves patient convenience and compliance. Therefore, development of a novel dual inhibitor is desired.
　本発明の課題は、ＣＯＭＴ阻害作用およびＤＤＣ阻害作用を有する新規ニトロカテコール誘導体又はその塩、及びそれらを含有する医薬組成物を提供することにある。 An object of the present invention is to provide a novel nitrocatechol derivative having a COMT inhibitory action and a DDC inhibitory action or a salt thereof, and a pharmaceutical composition containing them.
　本発明者らは上記課題を解決するため鋭意検討した結果、式（１）で表されるＣＯＭＴおよびＤＤＣのデュアル阻害作用を有する、新規ニトロカテコール誘導体を見出すに至った。 As a result of intensive studies to solve the above problems, the present inventors have found a novel nitrocatechol derivative having a dual inhibitory action of COMT and DDC represented by the formula (1).
　すなわち、本発明は、次の発明〔１〕～〔１１〕を提供するものである。 That is, the present invention provides the following inventions [1] to [11].
〔１〕下記一般式（１）で表される化合物又はその医薬上許容される塩。 [1] A compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000003
Figure JPOXMLDOC01-appb-C000003
［式中、
Ｒ１及びＲ２は、それぞれ独立して、水素原子、置換されていてもよいＣ1－Ｃ6アルキル基、置換されていてもよいＣ１－Ｃ６アルキルカルボニル基、置換されていてもよいＣ１－Ｃ６アルコキシカルボニル基、又は置換されていてもよいＣ１－Ｃ６アルキルアミノカルボニル基を示し；
Ｒ３は、水素原子、ハロゲン原子、ハロアルキル基、シアノ基、又はカルボキシ基を示し；
Ｒ４は、水素原子、ハロゲン原子、置換されていてもよいＣ１－Ｃ６アルキル基、ハロアルキル基、シアノ基、カルボキシ基、アミノカルボニル基、置換されていてもよいＣ１－Ｃ６アルキルスルファニル基、ハロアルキルスルファニル基、置換されていてもよいアリールスルファニル基、置換されていてもよいＣ１－Ｃ６アルコキシ基、置換されていてもよいアリールオキシ基、置換されていてもよいヘテロアリールオキシ基、置換されていてもよいＣ１－Ｃ６アルコキシカルボニル基、置換されていてもよいＣ１－Ｃ６アルキルカルボニル基、置換されていてもよいアリールカルボニル基、置換されていてもよいヘテロアリールカルボニル基、置換されていてもよいＣ１－Ｃ６のアルキルスルホニル基、置換されていてもよいＣ１－Ｃ６のアルキルスルフィニル基、置換されていてもよいアリールスルホニル基、置換されていてもよいヘテロアリールスルホニル基、置換されていてもよいアリールスルフィニル基、置換されていてもよいヘテロアリールスルフィニル基、置換されていてもよいＣ１－Ｃ６のアルキルアミノカルボニル基、置換されていてもよいアミノスルホニル基、置換されていてもよいヘテロシクロアルキルカルボニル基、置換されていてもよいベンゾフラン、置換されていてもよい２，３－ジヒドロフラン、クロマン環、置換されていてもよい２－クロマノン環、置換されていてもよい３－クロマノン環、置換されていてもよい４－クロマノン環、置換されていてもよいクマリン環、置換されていてもよいクロモン環、置換されていてもよい２－クマラノン環、置換されていてもよいインデン環、置換されていてもよいインデノン環、又は置換されていてもよいフタリド環を示し；
Ｒ５～Ｒ１０は、それぞれ独立して水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、シアノ基、隣接するお互いでカルボニル基を形成し、又は隣接するお互いでシクロアルキル基を形成してもよく；
Ｒ１１は、水素原子、置換されていてもよいＣ１－Ｃ６アルキルカルボニル基、置換されていてもよいＣ１－Ｃ６アルコキシカルボニル基、又は置換されていてもよいＣ１－Ｃ６アルキルアミノカルボニル基を示し；
Ｘ、Ｙ、Ｚは、それぞれ単結合、炭素原子、酸素原子、窒素原子、又は硫黄原子を示し；
-----は、単結合または二重結合を示し；
Ｑ１～Ｑ６は、それぞれ独立して炭素原子（各々の炭素原子は、水素原子、置換されていてもよいＣ１－Ｃ６アルキル基、置換されていてもよいＣ１－Ｃ６アルキルチオ基、置換されていてもよいＣ１－Ｃ６アルコキシ基、ハロゲン原子、ニトロ基、トリフルオロメチル基、シアノ基、若しくはカルボキシ基のいずれかの置換基を有していてもよく、又は炭素原子もしくはヘテロ原子を介して環を形成していてもよい）、窒素原子、隣接するお互いで環を形成してもよく、又はＱ２とＱ３は一緒で硫黄原子、又は酸素原子を示し；
ｎは、０～３を示し（但し、Ｑ２～Ｑ６のうち１つが窒素原子で残りが炭素原子の場合は、ｎは１～３を示す）；
環Ａは、置換されていてもよい３～６員の複素環を示す。］
〔２〕置換されていてもよい環Ａが、 [Where:
R 1 and R 2 are each independently a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 1 -C 6 alkylcarbonyl group, or optionally substituted. Represents a C 1 -C 6 alkoxycarbonyl group or an optionally substituted C 1 -C 6 alkylaminocarbonyl group;
R 3 represents a hydrogen atom, a halogen atom, a haloalkyl group, a cyano group, or a carboxy group;
R 4 represents a hydrogen atom, a halogen atom, an optionally substituted C 1 -C 6 alkyl group, a haloalkyl group, a cyano group, a carboxy group, an aminocarbonyl group, or an optionally substituted C 1 -C 6 alkylsulfanyl. Group, haloalkylsulfanyl group, optionally substituted arylsulfanyl group, optionally substituted C 1 -C 6 alkoxy group, optionally substituted aryloxy group, optionally substituted heteroaryloxy group , optionally substituted C 1 -C 6 alkoxycarbonyl group, an optionally substituted C 1 -C 6 alkylcarbonyl group, an optionally substituted arylcarbonyl group, heteroaryl carbonyl which may be substituted Group, optionally substituted C 1 -C 6 alkylsulfonyl group, optionally substituted C 1 -C 6 alkylsulfinyl group, optionally substituted arylsulfonyl group, optionally substituted heteroarylsulfonyl group, optionally substituted arylsulfinyl group, optionally substituted heteroaryl A sulfinyl group, an optionally substituted C 1 -C 6 alkylaminocarbonyl group, an optionally substituted aminosulfonyl group, an optionally substituted heterocycloalkylcarbonyl group, an optionally substituted benzofuran, Optionally substituted 2,3-dihydrofuran, chroman ring, optionally substituted 2-chromanone ring, optionally substituted 3-chromanone ring, optionally substituted 4-chromanone ring, substituted Coumarin ring optionally substituted, chromone ring optionally substituted, optionally substituted 2-coumaranone ring, shows good indene ring optionally substituted, may be substituted indenone ring, or an optionally phthalide ring optionally substituted;
R 5 to R 10 are each independently a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a cyano group, an adjacent carbonyl group, or an adjacent cycloalkyl group. Well;
R 11 represents a hydrogen atom, an optionally substituted C 1 -C 6 alkylcarbonyl group, an optionally substituted C 1 -C 6 alkoxycarbonyl group, or an optionally substituted C 1 -C 6 alkyl Represents an aminocarbonyl group;
X, Y, and Z each represents a single bond, a carbon atom, an oxygen atom, a nitrogen atom, or a sulfur atom;
----- represents a single bond or a double bond;
Q 1 to Q 6 are each independently a carbon atom (each carbon atom is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 1 -C 6 alkylthio group) May have a C 1 -C 6 alkoxy group which may be substituted, a halogen atom, a nitro group, a trifluoromethyl group, a cyano group, or a carboxy group, or a carbon atom or A ring may be formed through a hetero atom), a nitrogen atom, an adjacent ring may be formed with each other, or Q 2 and Q 3 together represent a sulfur atom or an oxygen atom;
n represents 0 to 3 (provided that when one of Q 2 to Q 6 is a nitrogen atom and the remaining is a carbon atom, n represents 1 to 3);
Ring A represents a 3-6 membered heterocyclic ring which may be substituted. ]
[2] An optionally substituted ring A is
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
（式中、
Ｒ１２は、水素原子、置換されていてもよいＣ１－Ｃ６アルキル基、カルボキシ基、置換されていてもよいＣ１－Ｃ６アルコキシカルボニル基、置換されていてもよいアミノカルボニル基、又はシアノ基を示し；
Ｒ１３およびＲ１4はそれぞれ独立して 、水素原子、又はＣ１－Ｃ６アルキル基を示す）である、〔１〕記載の化合物又はその医薬上許容される塩。
〔３〕Ｒ１およびＲ２が、水素原子である、〔１〕又は〔２〕記載の化合物又はその医薬上許容される塩。
〔４〕Ｒ１１が水素原子であり、ｎが１～３の数である〔１〕～〔３〕のいずれかに記載の化合物又はその医薬上許容される塩。
〔５〕Ｑ１～Ｑ６が、炭素原子（各々の炭素原子は、水素原子、ハロゲン原子、トリフルオロメチル基又はシアノ基のいずれかの置換基を有していてもよい）を示し；
ｎは、１～３を示す〔１〕～〔４〕のいずれかに記載の化合物又はその医薬上許容される塩。
〔６〕Ｚ－Ｙ－Ｘ部分の構造が、単結合、Ｃ1－Ｃ3の直鎖又は分岐鎖のアルキレン基、Ｃ2－Ｃ3の直鎖のアルケニレン基、オキシメチル基、チオメチル基、メチルオキシ基、メチルチオ基、Ｃ1－Ｃ3のハロアルキレン基、アミド基、シクロプロピル基、及びアミノメチル基から選ばれる基を示す〔１〕～〔５〕のいずれかに記載の化合物又はその医薬上許容される塩。
〔７〕〔１〕～〔６〕のいずれかに記載の化合物又はその医薬上許容される塩を含有する医薬組成物。
〔８〕パーキンソン病治療用医薬組成物である〔７〕記載の医薬組成物。
〔９〕パーキンソン病の治療に用いるための〔１〕～〔６〕のいずれかに記載の化合物又はその医薬上許容される塩。
〔10〕パーキンソン病治療用医薬組成物製造のための、〔１〕～〔６〕のいずれかに記載の化合物又はその医薬上許容される塩の使用。
〔11〕〔１〕～〔６〕のいずれかに記載の化合物又はその医薬上許容される塩の有効量を投与することを特徴とするパーキンソン病の治療法。 (Where
R 12 represents a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, a carboxy group, an optionally substituted C 1 -C 6 alkoxycarbonyl group, an optionally substituted aminocarbonyl group, or Represents a cyano group;
R 13 and R 14 each independently represent a hydrogen atom or a C 1 -C 6 alkyl group), or a pharmaceutically acceptable salt thereof.
[3] The compound according to [1] or [2] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are hydrogen atoms.
[4] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [3], wherein R 11 is a hydrogen atom and n is a number from 1 to 3.
[5] Q 1 to Q 6 each represent a carbon atom (each carbon atom may have any substituent of a hydrogen atom, a halogen atom, a trifluoromethyl group, or a cyano group);
n is 1 to 3, the compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof.
[6] The structure of the ZYX moiety is a single bond, a C 1 -C 3 linear or branched alkylene group, a C 2 -C 3 linear alkenylene group, an oxymethyl group, a thiomethyl group, The compound according to any one of [1] to [5] or a compound thereof, which represents a group selected from a methyloxy group, a methylthio group, a C 1 -C 3 haloalkylene group, an amide group, a cyclopropyl group, and an aminomethyl group Pharmaceutically acceptable salt.
[7] A pharmaceutical composition comprising the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.
[8] The pharmaceutical composition according to [7], which is a pharmaceutical composition for treating Parkinson's disease.
[9] The compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof for use in the treatment of Parkinson's disease.
[10] Use of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating Parkinson's disease.
[11] A method for treating Parkinson's disease, comprising administering an effective amount of the compound according to any one of [1] to [6] or a pharmaceutically acceptable salt thereof.
　本発明の新規ニトロカテコール化合物又はその塩は、安全性が高く、優れたＣＯＭＴ阻害作用およびＤＤＣ阻害作用を有し、パーキンソン病の治療に有用である。 The novel nitrocatechol compound or a salt thereof of the present invention has high safety, has an excellent COMT inhibitory action and DDC inhibitory action, and is useful for the treatment of Parkinson's disease.
　以下、本発明を具体的に説明する。 Hereinafter, the present invention will be specifically described.
　本明細書記載の「置換されていてもよい」とは、無置換、若しくは置換基を１～５個有していることを意味し、複数個の置換基を有する場合、それらの置換基は同一であっても、互いに異なっていてもよい。 The term “which may be substituted” in the present specification means unsubstituted or having 1 to 5 substituents, and when having a plurality of substituents, these substituents are They may be the same or different from each other.
　本明細書中の「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。 In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
　「Ｃ１－Ｃ６アルキル基」とは、直鎖状、分岐鎖状、環状、又はそれらの組み合わせのいずれであってもよい飽和炭化水素鎖を意味する。例えば、直鎖又は分岐鎖のＣ1－Ｃ6アルキル基、Ｃ3－Ｃ6のシクロアルキル基が挙げられる。具体例としては、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓ－ブチル基、ｔ－ブチル基、ｎ－ペンチル基、ｎ－ヘキシル基、シクロプロピル基、シクロブチル基、シクロペンチル基、シクロヘキシル基等が挙げられる。 “C 1 -C 6 alkyl group” means a saturated hydrocarbon chain that may be linear, branched, cyclic, or a combination thereof. Examples thereof include a linear or branched C 1 -C 6 alkyl group and a C 3 -C 6 cycloalkyl group. Specific examples include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, s-butyl group, t-butyl group, n-pentyl group, n-hexyl group, and cyclopropyl group. , Cyclobutyl group, cyclopentyl group, cyclohexyl group and the like.
　「ハロアルキル基」とは、１～３個の同種または異種のハロゲン原子で置換されたＣ1－Ｃ6アルキル基を意味し、例えば、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、トリフルオロエチル基などが挙げられる。 “Haloalkyl group” means a C 1 -C 6 alkyl group substituted with 1 to 3 of the same or different halogen atoms, and includes, for example, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, trifluoro An ethyl group etc. are mentioned.
　「Ｃ１－Ｃ６アルキルスルファニル基」としては、例えば、メチルスルファニル基、エチルスルファニル基、ｎ－プロピルスルファニル基、イソプロピルスルファニル基、シクロプロピルスルファニル基、シクロペンチルスルファニル基等が挙げられる。 Examples of the “C 1 -C 6 alkylsulfanyl group” include methylsulfanyl group, ethylsulfanyl group, n-propylsulfanyl group, isopropylsulfanyl group, cyclopropylsulfanyl group, cyclopentylsulfanyl group and the like.
　「ハロアルキルスルファニル基」としては、例えば、トリフルオロメチルスルファニル基等が挙げられる。 Examples of the “haloalkylsulfanyl group” include a trifluoromethylsulfanyl group.
　「アリールスルファニル基」としては、例えば、フェニルスルファニル基、ナフチルスルファニル基等が挙げられる。 Examples of the “arylsulfanyl group” include a phenylsulfanyl group and a naphthylsulfanyl group.
　「Ｃ１－Ｃ６アルコキシ基」としては、例えば、メトキシ基、エトキシ基、イソプロポキシ基、ｔ－ブトキシ基、シクロプロポキシ基、シクロブチルオキシ基、シクロペンチルオキシ基等が挙げられる。 Examples of the “C 1 -C 6 alkoxy group” include methoxy group, ethoxy group, isopropoxy group, t-butoxy group, cyclopropoxy group, cyclobutyloxy group, cyclopentyloxy group and the like.
　「アリールオキシ基」としては、例えば、フェノキシ基、ナフチルオキシ基等が挙げられる。「ヘテロアリールオキシ基」としては、例えば、ピリジルオキシ基、チオフェンオキシ基等が挙げられる。 Examples of the “aryloxy group” include a phenoxy group and a naphthyloxy group. Examples of the “heteroaryloxy group” include a pyridyloxy group and a thiophenoxy group.
　「Ｃ１－Ｃ６のアルコキシカルボニル基」としては、例えば、メトキシカルボニル基、エトキシカルボニル基、ｔ－ブトキシカルボニル基等が挙げられる。 Examples of the “C 1 -C 6 alkoxycarbonyl group” include a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycarbonyl group, and the like.
　「Ｃ１－Ｃ６のアルキルカルボニル基」としては、例えば、メチルカルボニル基、エチルカルボニル基、イソブチルカルボニル基、シクロプロピルカルボニル基、シクロヘキシルカルボニル基等が挙げられる。 Examples of the “C 1 -C 6 alkylcarbonyl group” include a methylcarbonyl group, an ethylcarbonyl group, an isobutylcarbonyl group, a cyclopropylcarbonyl group, a cyclohexylcarbonyl group, and the like.
　「アリールカルボニル基」とは、例えば、フェニルカルボニル基等が挙げられる。「ヘテロアリールカルボニル基」としては、ピリジニルカルボニル基、チエニルカルボニル基、チアゾロカルボニル基等が挙げられる。 Examples of the “arylcarbonyl group” include a phenylcarbonyl group. Examples of the “heteroarylcarbonyl group” include pyridinylcarbonyl group, thienylcarbonyl group, thiazolocarbonyl group and the like.
　「Ｃ１－Ｃ６アルキルスルホニル基」としては、例えば、メタンスルホニル基、イソプロピルスルホニル基、シクロペンチルスルホニル基等が挙げられる。 Examples of the “C 1 -C 6 alkylsulfonyl group” include a methanesulfonyl group, an isopropylsulfonyl group, a cyclopentylsulfonyl group, and the like.
　「アリールスルホニル基」としては、例えば、フェニルスルホニル基等が挙げられる。 Examples of the “arylsulfonyl group” include a phenylsulfonyl group.
　「ヘテロアリールスルホニル基」としては、１～５個の炭素原子ならびに酸素原子、窒素原子及び硫黄原子からなる群から選択される１～４個のヘテロ原子を含有する単環あるいは二環式の複素環を有するスルホニル基を有し、例えば、ピリジルスルホニル基、チエニルスルホニル基等が挙げられる。 The “heteroarylsulfonyl group” is a monocyclic or bicyclic heterocycle containing 1 to 5 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. It has a sulfonyl group having a ring, and examples thereof include a pyridylsulfonyl group and a thienylsulfonyl group.
　「Ｃ１－Ｃ６アルキルスルフィニル基」としては、例えば、メチルスルフィニル基、イソプロピルスルフィニル基、シクロペンチルスルフィニル基等が挙げられる。 Examples of the “C 1 -C 6 alkylsulfinyl group” include a methylsulfinyl group, an isopropylsulfinyl group, a cyclopentylsulfinyl group, and the like.
　「アリールスルフィニル基」としては、例えば、フェニルスルフィニル基が挙げられる。 Examples of the “arylsulfinyl group” include a phenylsulfinyl group.
　「ヘテロアリールスルフィニル基」としては、１～５個の炭素原子ならびに酸素原子、窒素原子及び硫黄原子からなる群から選択される１～４個のヘテロ原子を含有する単環あるいは二環式の複素環を有するスルフィニル基を有し、例えば、ピリジルスルフィニル基、チエニルスルフィニル基が挙げられる。 The “heteroarylsulfinyl group” is a monocyclic or bicyclic heterocycle containing 1 to 5 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms. It has a sulfinyl group having a ring, and examples thereof include a pyridylsulfinyl group and a thienylsulfinyl group.
　「Ｃ１－Ｃ６アルキルアミノカルボニル基」としては、例えば、メチルアミノカルボニル基、エチルアミノカルボニル基、シクロプロピルアミノカルボニル基、シクロヘキシルアミノカルボニル基等が挙げられる。 Examples of the “C 1 -C 6 alkylaminocarbonyl group” include a methylaminocarbonyl group, an ethylaminocarbonyl group, a cyclopropylaminocarbonyl group, a cyclohexylaminocarbonyl group, and the like.
　「アミノスルホニル基」としては、例えば、メチルアミノスルホニル基等が挙げられる。 Examples of the “aminosulfonyl group” include a methylaminosulfonyl group.
　「ヘテロシクロアルキルカルボニル基」としては環内に窒素原子、酸素原子、硫黄原子を含有し炭素原子を介して結合する４～７員環の飽和複素環を有するカルボニル化合物を表し、例えば、テトラヒドロフリルカルボニル基、テトラヒドロチエニルカルボニル基、ピロリジニルカルボニル基、ピペリジニルカルボニル基、モルホリニルカルボニル基等が挙げられる。 “Heterocycloalkylcarbonyl group” refers to a carbonyl compound having a 4- to 7-membered saturated heterocyclic ring containing a nitrogen atom, an oxygen atom or a sulfur atom in the ring and bonded via a carbon atom. For example, tetrahydrofuryl Examples include carbonyl group, tetrahydrothienylcarbonyl group, pyrrolidinylcarbonyl group, piperidinylcarbonyl group, morpholinylcarbonyl group and the like.
　「複素環」とは、窒素原子、酸素原子及び硫黄原子から選ばれるヘテロ原子を１～４個環内に含む、５又は６員環の飽和複素環又は不飽和複素環であり、例えば５員環複素環としては、ピロリジン、ピロール、ピロリン、ピラゾール、ピラゾリン、ピラゾリジン、イミダゾール、イミダゾリン、トリアゾール、トリアゾリン、テトラゾール、フラン、ジヒドロフラン、ジオキソラン、チオフェン、ジヒドロチオフェン、チアゾール、チアジアゾール、イソチアゾール、イソチアゾリン、オキサゾール、イソオキサゾール、オキサジアゾール、ジヒドロイソキサゾール、ジアゾリン、オキサジアゾリン、イソオキサゾリン、ジオキサゾリン等が挙げられ、６員環複素環としては、ピペリジン、ピリジン、ピリダジン、ピリミジン、テトラヒドロピラン、１，４－ジオキサン、モルホリン、チオモルホリン、ジチアン等が挙げられる。又、これら複素環内のヘテロ原子の位置および置換されていてもよい複素環の置換基の位置は、化学的に許容される位置ならば特に限定されるものではない。 “Heterocycle” is a 5- or 6-membered saturated or unsaturated heterocycle containing 1 to 4 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom in the ring. Ring heterocycles include pyrrolidine, pyrrole, pyrroline, pyrazole, pyrazoline, pyrazolidine, imidazole, imidazoline, triazole, triazoline, tetrazole, furan, dihydrofuran, dioxolane, thiophene, dihydrothiophene, thiazole, thiadiazole, isothiazole, isothiazoline, oxazole , Isoxazole, oxadiazole, dihydroisoxazole, diazoline, oxadiazoline, isoxazoline, dioxazoline and the like, and examples of the 6-membered heterocyclic ring include piperidine, pyridine, pyridazine, pyrimidine, tetrahydride Pyran, 1,4-dioxane, morpholine, thiomorpholine, dithiane and the like. Moreover, the position of the hetero atom in these heterocyclic rings and the position of the substituent of the heterocyclic ring which may be substituted are not particularly limited as long as they are chemically acceptable positions.
　Ｒ1及びＲ2としては、水素原子、Ｃ1－Ｃ6アルキル基、Ｃ1－Ｃ6アルキルカルボニル基、Ｃ1－Ｃ6アルコキシカルボニル基、Ｃ1－Ｃ6アルキルアミノカルボニル基が好ましく、水素原子、Ｃ1－Ｃ6アルキルカルボニル基、Ｃ1－Ｃ6アルコキシカルボニル基又はＣ1－Ｃ6アルキルアミノカルボニル基がより好ましく、水素原子がさらに好ましい。 R 1 and R 2 are preferably a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkylcarbonyl group, a C 1 -C 6 alkoxycarbonyl group, or a C 1 -C 6 alkylaminocarbonyl group, An atom, a C 1 -C 6 alkylcarbonyl group, a C 1 -C 6 alkoxycarbonyl group or a C 1 -C 6 alkylaminocarbonyl group is more preferred, and a hydrogen atom is more preferred.
　Ｒ3としては、水素原子、ハロゲン原子、ハロアルキル基、シアノ基、カルボキシ基が好ましく、水素原子、ハロゲン原子がより好ましい。 R 3 is preferably a hydrogen atom, a halogen atom, a haloalkyl group, a cyano group or a carboxy group, more preferably a hydrogen atom or a halogen atom.
　Ｒ４としては、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、ハロアルキル基、シアノ基、カルボキシ基、アミノカルボニル基、Ｃ１－Ｃ６アルキルスルファニル基、ハロアルキルスルファニル基、アリールスルファニル基、Ｃ１－Ｃ６アルコキシ基、アリールオキシ基、ヘテロアリールオキシ基、Ｃ１－Ｃ６アルコキシカルボニル基、Ｃ１－Ｃ６アルキルカルボニル基、アリールカルボニル基、ヘテロアリールカルボニル基、Ｃ１－Ｃ６のアルキルスルホニル基、Ｃ１－Ｃ６のアルキルスルフィニル基、アリールスルホニル基、ヘテロアリールスルホニル基、アリールスルフィニル基、ヘテロアリールスルフィニル基、Ｃ１－Ｃ６のアルキルアミノカルボニル基、アミノスルホニル基、ヘテロシクロアルキルカルボニル基、ベンゾフラン、２，３－ジヒドロフラン、クロマン環、２－クロマノン環、３－クロマノン環、４－クロマノン環、クマリン環、クロモン環、２－クマラノン環、インデン環、インデノン環、又はフタリド環が好ましい。
　このうち、Ｒ4としては、さらに、水素原子、ハロゲン原子、置換されていてもよいＣ１－Ｃ６アルキル基、ハロアルキル基、シアノ基、カルボキシ基、アミノカルボニル基、Ｃ１－Ｃ６アルキルスルファニル基、ハロアルキルスルファニル基、アリールスルファニル基、Ｃ１－Ｃ６アルコキシ基、アリールオキシ基、ヘテロアリールオキシ基、Ｃ１－Ｃ６アルコキシカルボニル基、Ｃ１－Ｃ６アルキルカルボニル基、アリールカルボニル基、ヘテロアリールカルボニル基、Ｃ１－Ｃ６のアルキルスルホニル基、Ｃ１－Ｃ６のアルキルスルフィニル基、アリールスルホニル基、ヘテロアリールスルホニル基、アリールスルフィニル基、ヘテロアリールスルフィニル基、Ｃ１－Ｃ６のアルキルアミノカルボニル基、アミノスルホニル基、ヘテロシクロアルキルカルボニル基又はフタリド環が好ましい。 R 4 includes a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a haloalkyl group, a cyano group, a carboxy group, an aminocarbonyl group, a C 1 -C 6 alkylsulfanyl group, a haloalkylsulfanyl group, an arylsulfanyl group, C 1 -C 6 alkoxy group, aryloxy group, heteroaryloxy group, C 1 -C 6 alkoxycarbonyl group, C 1 -C 6 alkylcarbonyl group, arylcarbonyl group, heteroarylcarbonyl group, C 1 -C 6 alkyl Sulfonyl group, C 1 -C 6 alkylsulfinyl group, arylsulfonyl group, heteroarylsulfonyl group, arylsulfinyl group, heteroarylsulfinyl group, C 1 -C 6 alkylaminocarbonyl group, aminosulfonyl group, heterocycloalkylcarbohydrate D Group, benzofuran, 2,3-dihydrofuran, chroman ring, 2-chromanone ring, 3-chromanone ring, 4-chromanone ring, coumarin ring, chromone ring, 2-coumaranone ring, indene ring, indenone ring, or phthalide ring Is preferred.
Among these, R 4 is further a hydrogen atom, a halogen atom, an optionally substituted C 1 -C 6 alkyl group, a haloalkyl group, a cyano group, a carboxy group, an aminocarbonyl group, or a C 1 -C 6 alkylsulfanyl. Group, haloalkylsulfanyl group, arylsulfanyl group, C 1 -C 6 alkoxy group, aryloxy group, heteroaryloxy group, C 1 -C 6 alkoxycarbonyl group, C 1 -C 6 alkylcarbonyl group, arylcarbonyl group, hetero Arylcarbonyl group, C 1 -C 6 alkylsulfonyl group, C 1 -C 6 alkylsulfinyl group, arylsulfonyl group, heteroarylsulfonyl group, arylsulfinyl group, heteroarylsulfinyl group, C 1 -C 6 alkylamino Carbonyl group, aminosulfur Group, a heterocycloalkyl carbonyl or phthalide ring.
　Ｚ－Ｙ－Ｘ部分の構造としては、単結合、Ｃ1－Ｃ3の直鎖又は分岐鎖のアルキレン基、Ｃ2－Ｃ3の直鎖のアルケニレン基、オキシメチル基、チオメチル基、メチルオキシ基、メチルチオ基、Ｃ1－Ｃ3のハロアルキレン基、アミド基、シクロプロピル基、及びアミノメチル基から選ばれる基が好ましく、単結合、Ｃ1－Ｃ3の直鎖又は分岐鎖アルキレン基、Ｃ2－Ｃ3の直鎖のアルケニレン基、オキシメチル基、チオメチル基、メチルオキシ基、メチルチオ基、及びＣ1－Ｃ3のハロアルキレン基から選ばれる基がより好ましい。 The structure of the ZYX moiety includes a single bond, a C 1 -C 3 linear or branched alkylene group, a C 2 -C 3 linear alkenylene group, an oxymethyl group, a thiomethyl group, a methyloxy group A group selected from a group, a methylthio group, a C 1 -C 3 haloalkylene group, an amide group, a cyclopropyl group, and an aminomethyl group, preferably a single bond, a C 1 -C 3 linear or branched alkylene group, A group selected from a C 2 -C 3 linear alkenylene group, an oxymethyl group, a thiomethyl group, a methyloxy group, a methylthio group, and a C 1 -C 3 haloalkylene group is more preferable.
　Ｑ1～Ｑ6で示される構造としては、ベンゼン、シクロヘキサン、チオフェン、ピリダジン、ベンゾチオフェン、ベンゾイミダゾリン、ベンゾオキサゾール が好ましく、ベンゼンが特に好ましい。ここで、Ｑ1～Ｑ6で示される構造がベンゼン環を示すとき、Ｑ1－Ｑ6は炭素原子である。 As the structure represented by Q 1 to Q 6 , benzene, cyclohexane, thiophene, pyridazine, benzothiophene, benzimidazoline, and benzoxazole are preferable, and benzene is particularly preferable. Here, when the structure represented by Q 1 to Q 6 represents a benzene ring, Q 1 -Q 6 is a carbon atom.
　Ｑ1～Ｑ6で示される構造の環を構成する炭素原子上には、水素原子、Ｃ1－Ｃ6アルキル基、Ｃ1－Ｃ6アルキルチオ基、Ｃ1－Ｃ6アルコキシ基、ハロゲン原子、ニトロ基、トリフルオロメチル基、シアノ基、カルボキシ基が置換していてもよく、好ましくは水素原子、ハロゲン原子、トリフルオロメチル基又はシアノ基が置換していてもよく、さらに好ましくは水素原子又はハロゲン原子が置換していてもよい。 On the carbon atoms constituting the ring of the structure represented by Q 1 to Q 6 , a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkylthio group, a C 1 -C 6 alkoxy group, a halogen atom, Nitro group, trifluoromethyl group, cyano group, carboxy group may be substituted, preferably hydrogen atom, halogen atom, trifluoromethyl group or cyano group may be substituted, more preferably hydrogen atom or A halogen atom may be substituted.
　Ｒ11としては、水素原子、Ｃ1－Ｃ6アルキルカルボニル基、Ｃ1－Ｃ6アルコキシカルボニル基、Ｃ1－Ｃ6アルキルアミノカルボニル基が好ましく、水素原子がさらに好ましい。また、ｎは１～３が好ましい。 R 11 is preferably a hydrogen atom, a C 1 -C 6 alkylcarbonyl group, a C 1 -C 6 alkoxycarbonyl group, or a C 1 -C 6 alkylaminocarbonyl group, and more preferably a hydrogen atom. N is preferably 1 to 3.
　（Ｒ11Ｏ）が置換したＱ1～Ｑ6で示される構造の好ましい例を以下に示す。 Preferred examples of the structure represented by Q 1 to Q 6 substituted with (R 11 O) are shown below.
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
　置換されていてもよい環Ａとしては、次のＡ－１～Ａ－１５ The ring A which may be substituted includes the following A-1 to A-15
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
（式中、
Ｒ１２は、水素原子、置換されていてもよいＣ１－Ｃ６アルキル基、カルボキシ基、置換されていてもよいＣ１－Ｃ６アルコキシカルボニル基、置換されていてもよいアミノカルボニル基、又はシアノ基を示し；
Ｒ１３は、水素原子、又はＣ１－Ｃ６アルキル基を示す）から選ばれる複素環が好ましい。 (Where
R 12 represents a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, a carboxy group, an optionally substituted C 1 -C 6 alkoxycarbonyl group, an optionally substituted aminocarbonyl group, or Represents a cyano group;
R 13 represents a hydrogen atom or a heterocyclic ring selected from a C 1 -C 6 alkyl group.
　さらに環Ａとしては、トリアゾール（Ａ－６、Ａ－７、Ａ－８）、テトラゾール（Ａ－３）、オキソザール（Ａ－２、Ａ－５、Ａ－１１）、オキサジアゾール（Ａ－１、Ａ－１５）、ジヒドロイソオキサゾール（Ａ－９）、チアゾール（Ａ－４）、チアジアゾール（Ａ－１０）（Ｒ12、Ｒ13は前記と同じ）がより好ましい。 Further, ring A includes triazole (A-6, A-7, A-8), tetrazole (A-3), oxozal (A-2, A-5, A-11), oxadiazole (A-1 A-15), dihydroisoxazole (A-9), thiazole (A-4), and thiadiazole (A-10) (wherein R 12 and R 13 are the same as those described above).
　本発明化合物の好ましい態様は次のとおりである。
（ａ）環Ａが前記Ａ－１～Ａ－１５で表される環であり；
　Ｒ1及びＲ2が、水素原子、Ｃ1－Ｃ6アルキル基、Ｃ1－Ｃ6アルキルカルボニル基、Ｃ1－Ｃ6アルコキシカルボニル基、又はＣ1－Ｃ6アルキルアミノカルボニル基であり；
　Ｒ3が、水素原子、ハロゲン原子、ハロアルキル基、シアノ基、又はカルボキシ基であり；
　Ｒ４が、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、ハロアルキル基、シアノ基、カルボキシ基、アミノカルボニル基、Ｃ１－Ｃ６アルキルスルファニル基、ハロアルキルスルファニル基、アリールスルファニル基、Ｃ１－Ｃ６アルコキシ基、アリールオキシ基、ヘテロアリールオキシ基、Ｃ１－Ｃ６アルコキシカルボニル基、Ｃ１－Ｃ６アルキルカルボニル基、アリールカルボニル基、ヘテロアリールカルボニル基、Ｃ１－Ｃ６のアルキルスルホニル基、Ｃ１－Ｃ６のアルキルスルフィニル基、アリールスルホニル基、ヘテロアリールスルホニル基、アリールスルフィニル基、ヘテロアリールスルフィニル基、Ｃ１－Ｃ６のアルキルアミノカルボニル基、アミノスルホニル基、ヘテロシクロアルキルカルボニル基、ベンゾフラン、２，３－ジヒドロフラン、クロマン環、２－クロマノン環、３－クロマノン環、４－クロマノン環、クマリン環、クロモン環、２－クマラノン環、インデン環、インデノン環、又はフタリド環であり；
　Ｚ－Ｙ－Ｘ部分の構造が、単結合、Ｃ1－Ｃ3の直鎖又は分岐鎖のアルキレン基、Ｃ2－Ｃ3の直鎖のアルケニレン基、オキシメチル基、チオメチル基、メチルオキシ基、メチルチオ基、Ｃ1－Ｃ3のハロアルキレン基、アミド基、シクロプロピル基、及びアミノメチル基から選ばれる基であり；
　Ｑ1～Ｑ6で示される構造が、ベンゼン、シクロヘキサン、チオフェン、フラン、ピリダジン、ベンゾチオフェン、ベンゾイミダゾリン、又はベンゾオキサゾールであり；
　Ｑ1～Ｑ6で示される構造の環を構成する炭素原子上には、水素原子、Ｃ1－Ｃ6アルキル基、Ｃ1－Ｃ6アルキルチオ基、Ｃ1－Ｃ6アルコキシ基、ハロゲン原子、ニトロ基、トリフルオロメチル基、シアノ基、カルボキシ基が置換していてもよく；
　Ｒ11が、水素原子、Ｃ1－Ｃ6アルキルカルボニル基、Ｃ1－Ｃ6アルコキシカルボニル基、又はＣ1－Ｃ6アルキルアミノカルボニル基であり；
　ｎが１～３である化合物又はその産業上許容される塩。 Preferred embodiments of the compound of the present invention are as follows.
(A) Ring A is a ring represented by A-1 to A-15;
R 1 and R 2 are a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkylcarbonyl group, a C 1 -C 6 alkoxycarbonyl group, or a C 1 -C 6 alkylaminocarbonyl group;
R 3 is a hydrogen atom, a halogen atom, a haloalkyl group, a cyano group, or a carboxy group;
R 4 is a hydrogen atom, halogen atom, C 1 -C 6 alkyl group, haloalkyl group, cyano group, carboxy group, aminocarbonyl group, C 1 -C 6 alkylsulfanyl group, haloalkylsulfanyl group, arylsulfanyl group, C 1 —C 6 alkoxy group, aryloxy group, heteroaryloxy group, C 1 -C 6 alkoxycarbonyl group, C 1 -C 6 alkylcarbonyl group, arylcarbonyl group, heteroarylcarbonyl group, C 1 -C 6 alkylsulfonyl Group, C 1 -C 6 alkylsulfinyl group, arylsulfonyl group, heteroarylsulfonyl group, arylsulfinyl group, heteroarylsulfinyl group, C 1 -C 6 alkylaminocarbonyl group, aminosulfonyl group, heterocycloalkylcarbonyl group , Benzofuran, 2,3-dihydrofuran, chroman ring, 2-chromanone ring, 3-chromanone ring, 4-chromanone ring, coumarin ring, chromone ring, 2-coumaranone ring, indene ring, indenone ring, or phthalide ring;
The structure of the Z—Y—X moiety is a single bond, a C 1 -C 3 linear or branched alkylene group, a C 2 -C 3 linear alkenylene group, an oxymethyl group, a thiomethyl group, a methyloxy group , A methylthio group, a C 1 -C 3 haloalkylene group, an amide group, a cyclopropyl group, and an aminomethyl group;
The structure represented by Q 1 to Q 6 is benzene, cyclohexane, thiophene, furan, pyridazine, benzothiophene, benzimidazoline, or benzoxazole;
On the carbon atoms constituting the ring of the structure represented by Q 1 to Q 6 , a hydrogen atom, a C 1 -C 6 alkyl group, a C 1 -C 6 alkylthio group, a C 1 -C 6 alkoxy group, a halogen atom, A nitro group, a trifluoromethyl group, a cyano group or a carboxy group may be substituted;
R 11 is a hydrogen atom, a C 1 -C 6 alkylcarbonyl group, a C 1 -C 6 alkoxycarbonyl group, or a C 1 -C 6 alkylaminocarbonyl group;
a compound wherein n is 1 to 3, or an industrially acceptable salt thereof;
（ｂ）環Ａが前記Ａ－１～Ａ－１５で表される環であり；
　Ｒ1及びＲ2が水素原子であり；
　Ｒ3が水素原子又はハロゲン原子であり；
　Ｒ4が、水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、ハロアルキル基、シアノ基、カルボキシ基、アミノカルボニル基、Ｃ１－Ｃ６アルキルスルファニル基、ハロアルキルスルファニル基、アリールスルファニル基、Ｃ１－Ｃ６アルコキシ基、アリールオキシ基、ヘテロアリールオキシ基、Ｃ１－Ｃ６アルコキシカルボニル基、Ｃ１－Ｃ６アルキルカルボニル基、アリールカルボニル基、ヘテロアリールカルボニル基、Ｃ１－Ｃ６のアルキルスルホニル基、Ｃ１－Ｃ６のアルキルスルフィニル基、アリールスルホニル基、ヘテロアリールスルホニル基、アリールスルフィニル基、ヘテロアリールスルフィニル基、Ｃ１－Ｃ６のアルキルアミノカルボニル基、アミノスルホニル基、ヘテロシクロアルキルカルボニル基、又はフタリド環であり；
　Ｚ－Ｙ－Ｘ部分の構造が、単結合、Ｃ1－Ｃ3の直鎖又は分岐鎖のアルキレン基、Ｃ2－Ｃ3の直鎖のアルケニレン基、オキシメチル基、チオメチル基、メチルオキシ基、メチルチオ基、及びＣ1－Ｃ3のハロアルキレン基から選ばれる基であり；
　Ｑ1～Ｑ6で示される構造が、ベンゼンであり；Ｑ1～Ｑ6で示される環を構成する炭素原子上には水素原子又はハロゲン原子が置換していてもよく；
　Ｒ11が水素原子であり、ｎが１～３である化合物又はその医薬上許容される塩。 (B) Ring A is a ring represented by A-1 to A-15;
R 1 and R 2 are hydrogen atoms;
R 3 is a hydrogen atom or a halogen atom;
R 4 is a hydrogen atom, halogen atom, C 1 -C 6 alkyl group, haloalkyl group, cyano group, carboxy group, aminocarbonyl group, C 1 -C 6 alkylsulfanyl group, haloalkylsulfanyl group, arylsulfanyl group, C 1 —C 6 alkoxy group, aryloxy group, heteroaryloxy group, C 1 -C 6 alkoxycarbonyl group, C 1 -C 6 alkylcarbonyl group, arylcarbonyl group, heteroarylcarbonyl group, C 1 -C 6 alkylsulfonyl Group, C 1 -C 6 alkylsulfinyl group, arylsulfonyl group, heteroarylsulfonyl group, arylsulfinyl group, heteroarylsulfinyl group, C 1 -C 6 alkylaminocarbonyl group, aminosulfonyl group, heterocycloalkylcarbonyl group , Is an phthalide ring;
The structure of the Z—Y—X moiety is a single bond, a C 1 -C 3 linear or branched alkylene group, a C 2 -C 3 linear alkenylene group, an oxymethyl group, a thiomethyl group, a methyloxy group , A methylthio group, and a C 1 -C 3 haloalkylene group;
Q 1 ~ structure represented by Q 6 are located in benzene; on carbon atoms constituting the ring represented by Q 1 ~ Q 6 may be substituted is hydrogen atom or a halogen atom;
A compound or a pharmaceutically acceptable salt thereof, wherein R 11 is a hydrogen atom and n is 1 to 3.
　一般式（１）の好ましい態様としては、上記記載の各好ましい基の組み合わせからなる化合物であるが、例えば、実施例記載の化合物、それら医薬上許容される塩、又はそれら水和物、若しくは溶媒和物などが挙げられる。 A preferred embodiment of the general formula (1) is a compound comprising a combination of each of the above-mentioned preferred groups. For example, the compounds described in the examples, their pharmaceutically acceptable salts, or their hydrates, or solvents Japanese products are listed.
　一般式（１）で表される、本発明の化合物又はその医薬上許容される塩、水和物、溶媒和物は、置換基の種類により二重結合に基づく幾何異性体や互変異性体が存在する場合、あるいは不斉炭素原子の存在により光学異性体やジアステレオマーが存在しうる場合がある。本発明においては、これら異性体を単離したもの、あるいは混合物すべて包含する。 The compound of the present invention represented by the general formula (1) or a pharmaceutically acceptable salt, hydrate, or solvate thereof is a geometric isomer or tautomer based on a double bond depending on the type of substituent. In some cases, optical isomers and diastereomers may exist due to the presence of an asymmetric carbon atom. In the present invention, all these isolated isomers or mixtures thereof are included.
　本発明の化合物の塩とは、一般式（１）の化合物の薬学上許容される塩であり、一般式（１）の化合物を溶媒中、所望の塩基と処理することにより製造することができる。このような塩の形態としては、リチウム塩、カリウム塩、ナトリウム塩等が挙げられ、好ましくはナトリウム塩である。また、本発明の化合物は、種々の放射性又は非放射性同位体でラベルされた化合物も含む。 The salt of the compound of the present invention is a pharmaceutically acceptable salt of the compound of the general formula (1), and can be produced by treating the compound of the general formula (1) with a desired base in a solvent. . Examples of such salt forms include lithium salts, potassium salts, sodium salts and the like, with sodium salts being preferred. The compounds of the present invention also include compounds labeled with various radioactive or non-radioactive isotopes.
　一般式（１）で表される本発明の化合物は、異性体として存在する場合があり、例えば幾何異性体、光学異性体又はジアステレオ異性体が存在する場合がある。本発明においては、これら異性体の単離したもの、任意の混合物、ラセミ体等はすべて包含する。 The compound of the present invention represented by the general formula (1) may exist as an isomer, for example, a geometric isomer, an optical isomer, or a diastereoisomer may exist. In the present invention, all of these isomers isolated, arbitrary mixtures, racemates and the like are included.
　一般式（１）で表される本発明の化合物、又はその薬学上許容される塩は、その均等化合物としてプロドラッグも本発明の請求範囲に包含される。「プロドラッグ」とは、生体内の代謝機構により一般式（１）の化合物に変換される化合物、すなわち生体内において酵素的に酸化、還元、加水分解、あるいは胃酸等により加水分解等を起こし、一般式（１）の化合物に変化するものをいう。一般式（１）の化合物のプロドラッグとしては、リン酸基、水酸基がアシル基、アルキル基等に修飾された化合物、例えば、アセチル化、ピバロイル化、ピバロイルオキシメチル化された化合物等が挙げられる。これらの化合物は、公知の方法によって一般式（１）の化合物から合成することができる。またこれらのプロドラッグは、例えば「Ｔｈｅ　Ｏｒｇａｎｉｃ　ｃｈｅｍｉｓｔｒｙ　ｏｆ　ｄｒｕｇ　ｄｅｓｉｇｎ　ａｎｄ　ｄｒｕｇ　ａｃｔｉｏｎ（ｓｅｃｏｎｄ　ｅｄｉｔｉｏｎ）」ｃｈａｐｔｅｒ　８　ｐ４９７－５５７に記載されているような条件で、一般式（１）の化合物に変化するものであってもよい。 The compound of the present invention represented by the general formula (1) or a pharmaceutically acceptable salt thereof is also included in the scope of the present invention as a prodrug as its equivalent compound. A “prodrug” is a compound that is converted into a compound of the general formula (1) by a metabolic mechanism in vivo, that is, in vivo, enzymatically oxidized, reduced, hydrolyzed, or hydrolyzed by stomach acid, etc. What changes into the compound of general formula (1). As a prodrug of the compound of the general formula (1), a compound in which a phosphate group or a hydroxyl group is modified with an acyl group or an alkyl group, for example, an acetylated, pivaloylated or pivaloyloxymethylated compound, etc. Can be mentioned. These compounds can be synthesized from the compound of the general formula (1) by a known method. These prodrugs change to compounds of the general formula (1) under the conditions described in, for example, “The Organic chemistry of drug design and drug action (second edition)” chapter 8, p497-557. There may be.
　本発明化合物の製造方法は特に限定されないが、例えば下記の工程に従って製造することができる。また、本発明に包含される種々の放射性または非放射性同位体でラベル化された化合物についても、同位体置換原料により、下記製造方法と同様に製造できる。 The production method of the compound of the present invention is not particularly limited, but can be produced, for example, according to the following steps. In addition, compounds labeled with various radioactive or non-radioactive isotopes included in the present invention can also be produced in the same manner as in the following production method using isotope-substituted raw materials.
　以下、新規ニトロカテコール化合物の代表的な製造方法について説明する。 Hereinafter, representative methods for producing novel nitrocatechol compounds will be described.
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
（式中、Ｒ2はメチル基、ベンジル基等、Ｒ11はメトキシメチル基、メチル基等の水酸基の保護基であり、他の記号は前記と同義である） (Wherein R 2 is a methyl group, benzyl group, etc., R 11 is a hydroxyl-protecting group such as methoxymethyl group, methyl group, etc., and the other symbols are as defined above)
　第１工程：化合物（２）を加温条件下、Ｎ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン中あるいはＮ－メチルモルホリン溶媒中、塩化リチウムと反応させることにより化合物（３）を製造することができる。 First step: Compound (3) can be produced by reacting compound (2) with lithium chloride in N, N-dimethylformamide, N-methylpyrrolidone or N-methylmorpholine solvent under heating conditions. it can.
　第２工程：化合物（３）を室温乃至加温条件下、溶媒中、塩基存在下、塩化アルミニウムで処理、あるいは、酢酸溶媒中あるいは無溶媒で、臭化水素酸で処理することにより化合物（４）を製造することができる。溶媒としては１，２－ジクロロエタン、ピリジン等が挙げられる。塩基としてはトリエチルアミン、ジイソプロピルエチルアミン、ピリジン等が挙げられる。 Second step: Compound (4) is treated with aluminum bromide in the presence of a base in the presence of a base at room temperature or under heating, or by treatment with hydrobromic acid in an acetic acid solvent or without a solvent. ) Can be manufactured. Examples of the solvent include 1,2-dichloroethane, pyridine and the like. Examples of the base include triethylamine, diisopropylethylamine, pyridine and the like.
　第３工程：化合物（４）を室温乃至加温条件下、ジクロロメタン溶媒中、あるいは無溶媒で、塩酸、三臭化ホウ素、臭化水素酸溶液で処理することにより化合物（１）を製造することができる。 Third step: Compound (1) is produced by treating compound (4) with hydrochloric acid, boron tribromide or hydrobromic acid solution in a dichloromethane solvent or without solvent under room temperature to warming conditions. Can do.
　環Ａが１，２，４－オキサジアゾール環の場合、第１工程で使用される化合物（２－Ａ－１）は、以下のような通常の反応操作を行い、下記の反応式のとおり製造することができる。 When ring A is a 1,2,4-oxadiazole ring, the compound (2-A-1) used in the first step is subjected to the following ordinary reaction procedure, as shown in the following reaction formula: Can be manufactured.
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
　第４工程：カルボン酸中間体（７）を有機溶媒中、室温乃至加温条件下、塩化チオニル、五塩化リン、三塩化リン、オキシ塩化リン、塩化オキザリル等を用いて酸塩化物を、塩基存在下、クロロギ酸エチル、クロロギ酸イソブチル等を用いて混合酸無水物を製造することができる。酸塩化物、混合酸無水物はアシル化剤（８）として第６工程に用いる。溶媒としては、ジクロロメタン、テトラヒドロフラン、酢酸エチル等が挙げられる。塩基としては、トリエチルアミン、ジイソプロピルエチルアミン、モルホリン等が挙げられる。 Fourth step: The carboxylic acid intermediate (7) is converted into a base by using thionyl chloride, phosphorus pentachloride, phosphorus trichloride, phosphorus oxychloride, oxalyl chloride or the like in an organic solvent at room temperature to warming condition. In the presence, a mixed acid anhydride can be produced using ethyl chloroformate, isobutyl chloroformate or the like. The acid chloride and mixed acid anhydride are used in the sixth step as the acylating agent (8). Examples of the solvent include dichloromethane, tetrahydrofuran, ethyl acetate and the like. Examples of the base include triethylamine, diisopropylethylamine, morpholine and the like.
　第５工程：室温乃至加温条件下，シアノ体（５）を溶媒中、ヒドロキシアミンを反応させることにより、化合物（６）とする。溶媒としては、メタノール、エタノール、テトラヒドロフラン等が挙げられ、好ましくはエタノールである。 Step 5: Compound (6) is obtained by reacting cyano compound (5) with hydroxyamine in a solvent under room temperature to warming conditions. Examples of the solvent include methanol, ethanol, tetrahydrofuran and the like, preferably ethanol.
　第６工程：第４工程より得られたアシル化剤（８）と第５工程で得られた化合物（６）を溶媒中、塩基存在下、－２０℃乃至加温条件下反応させる。溶媒としては、ジクロロメタン、酢酸エチル、テトラヒドラフラン、Ｎ，Ｎ－ジメチルホルムアミド等が挙げられ、塩基としては、トリエチルアミン、ジイソプロピルエチルアミン、ジアザビシクロウンデセン等が上げられる。 Step 6: The acylating agent (8) obtained in Step 4 and the compound (6) obtained in Step 5 are reacted in a solvent in the presence of a base at −20 ° C. to warming conditions. Examples of the solvent include dichloromethane, ethyl acetate, tetrahydrafuran, N, N-dimethylformamide, and examples of the base include triethylamine, diisopropylethylamine, diazabicycloundecene, and the like.
　第７工程：第６工程より得られた化合物を、溶媒中、触媒を添加し、室温乃至加温条件下反応することにより化合物（２－Ａ－１）を製造することができる。溶媒としては、例えばＮ，Ｎ－ジメチルホルムアミド、Ｎ－メチルピロリドン、テトラヒドロフラン等が挙げられる。触媒としては、例えばｐ－トルエンスルホン酸、カンファースルホン酸、若しくはテトラブチルアンモニウムフルオリド等が挙げられる。 Step 7: Compound (2-A-1) can be produced by adding the catalyst obtained in Step 6 to a catalyst in a solvent and reacting under room temperature to warming conditions. Examples of the solvent include N, N-dimethylformamide, N-methylpyrrolidone, tetrahydrofuran and the like. Examples of the catalyst include p-toluenesulfonic acid, camphorsulfonic acid, tetrabutylammonium fluoride and the like.
　上記に示したスキームは、本発明の化合物を製造するための方法の例示であり、様々な改変が可能である。 The scheme shown above is an example of a method for producing the compound of the present invention, and various modifications are possible.
　Ｒ１またはＲ２が置換された化合物（７）の製造としては、例えば特開２０１１－１４８７８２、特開２０１２－５１８８４等の方法に準じ、若しくは改変し、製造することができる。 As the production of the compound (7) in which R 1 or R 2 is substituted, it can be produced according to, for example, a method described in JP-A-2011-148882, JP-A-2012-51884, or a modification thereof.
　本発明化合物の製造方法は、原料若しくは中間体の段階で官能基を有する場合、適当な保護基の脱着により製造することもできる。このような官能基としてはアミノ基、ヒドロキシ基、カルボキシ基等が挙げられ、保護基の種類、脱着方法としては、例えば「Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ　（Ｆｏｕｒｔｈ　Ｅｄｉｔｉｏｎ）」（Ｇｒｅｅｎｅ，　Ｗｕｔｓ著）に記載の方法等が挙げられる。 The production method of the compound of the present invention can also be produced by desorption of a suitable protecting group when it has a functional group at the raw material or intermediate stage. Examples of such functional groups include amino groups, hydroxy groups, carboxy groups, etc. The types of protective groups and desorption methods are described in, for example, “Protective Groups in Organic Synthesis (Fourth Edition)” (by Greene, Wuts). The method etc. are mentioned.
　上記のように合成された一般式（１）の化合物は、遊離のまま、あるいはその塩として、通常の化学操作である抽出、濃縮、留去、結晶化、濾過、再結晶、各種クロマトグラフィー等により単離、精製することができる。又、光学異性体、立体異性体、位置異性体を含有する場合は、分別再結晶法、キラルカラム法、ジアステレオマー法等により、それぞれを単離できる。 The compound of the general formula (1) synthesized as described above is in the free state or as a salt thereof, which is a normal chemical operation such as extraction, concentration, distillation, crystallization, filtration, recrystallization, various chromatography, etc. Can be isolated and purified. Moreover, when it contains an optical isomer, a stereoisomer, and a position isomer, each can be isolated by a fractional recrystallization method, a chiral column method, a diastereomer method, etc.
　本発明の化合物は、優れたＣＯＭＴおよびＤＤＣ阻害作用を有することから、パーキンソン病の治療または予防薬として有用であり、好適にはＬ－ドパと組み合わせて使用される。また、本発明の化合物およびＬ－ドパと、芳香族Ｌ－アミノ酸デカルボキシラーゼ阻害剤とを組み合わせて使用してもよい。本発明と組み合わせて使用できる芳香族Ｌ－アミノ酸デカルボキシラーゼ阻害剤としては、例えば、カルビドパ、ベンセラジドなどが挙げられる。また、本発明と組み合わせて使用できるＣＯＭＴ阻害剤としては、エンタカポン、トルカポン、オピカポンが挙げられる。 Since the compound of the present invention has an excellent COMT and DDC inhibitory action, it is useful as a therapeutic or prophylactic agent for Parkinson's disease, and is preferably used in combination with L-dopa. Further, the compound of the present invention and L-dopa may be used in combination with an aromatic L-amino acid decarboxylase inhibitor. Examples of the aromatic L-amino acid decarboxylase inhibitor that can be used in combination with the present invention include carbidopa and benserazide. Examples of the COMT inhibitor that can be used in combination with the present invention include entacapone, tolcapone, and opikapon.
　本発明の化合物はパーキンソン病以外の、例えば、うつ病、レビー小体型認知症、若年性認知症、アルツハイマー型認知症、統合失調症の治療または予防薬としても有用である。 The compound of the present invention is also useful as a therapeutic or prophylactic agent for other than Parkinson's disease, such as depression, Lewy body dementia, juvenile dementia, Alzheimer's dementia, and schizophrenia.
　一般式（１）で表される化合物又はその薬学上許容される塩は、そのまま用いても良いが、薬学上許容される担体、例えば製剤用添加物の１種又は２種以上を含有する医薬組成物として使用しても良い。該医薬組成物は、如何なる剤形で用いても良く、錠剤、丸剤、カプセル剤、散剤、細粒剤、顆粒剤、液剤、懸濁剤、シロップ剤、注射剤、外用剤、坐剤等として適用できる。 The compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof may be used as it is, but a pharmaceutical containing a pharmaceutically acceptable carrier, for example, one or more of pharmaceutical additives. It may be used as a composition. The pharmaceutical composition may be used in any dosage form, such as tablets, pills, capsules, powders, fine granules, granules, solutions, suspensions, syrups, injections, external preparations, suppositories, etc. As applicable.
　一般式（１）で表される化合物又はその薬学上許容される塩を有効成分として含んでなる医薬組成物に用いられる製剤用添加物の種類は特に限定されないが、例えば医薬品添加物辞典（２００７　薬事日報社）記載の基剤、賦形剤、滑沢剤、コーティング剤、糖衣剤、湿潤剤、結合剤、崩壊剤、溶剤、可溶化剤、溶解剤、溶解補助剤、懸濁化剤、分散剤、乳化剤、界面活性剤、等張化剤、緩衝剤、ｐＨ調節剤、無痛化剤、防腐剤、保存剤、安定化剤、抗酸化剤、着色剤、甘味剤等単独で又は適宜組み合わせて用いることができる。 There are no particular limitations on the type of pharmaceutical additive used in the pharmaceutical composition comprising the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. For example, the Pharmaceutical Additives Dictionary (2007) Yakuho Nippo) base, excipient, lubricant, coating agent, sugar coating, wetting agent, binder, disintegrant, solvent, solubilizer, solubilizer, solubilizer, suspending agent, Dispersants, emulsifiers, surfactants, isotonic agents, buffers, pH adjusters, soothing agents, preservatives, preservatives, stabilizers, antioxidants, colorants, sweeteners, etc. alone or in appropriate combination Can be used.
　本発明の化合物は、本発明化合物が有効性を示すと考えられる疾患の他の治療剤、又は予防剤と併用することができる。当該併用とは、同時投与、又は個別に連続して、若しくは所望の時間間隔をおいて投与することを意味する。同時投与製剤は、配合剤、キット製剤であってもよい。 The compound of the present invention can be used in combination with other therapeutic agents or preventive agents for diseases for which the compound of the present invention is considered effective. The combined use means simultaneous administration, administration separately individually or at a desired time interval. The simultaneous administration preparation may be a combination preparation or a kit preparation.
　通常経口投与の場合、本発明化合物又はその塩の１回投与量は、体重あたり約１～１００ｍｇ／ｋｇ程度であり、これを１日１回であるいは週１乃至３回投与する。静脈内投与される場合は、１回の投与量は、体重当たり約０．１～１０ｍｇ／ｋｇが適当で、１日１回あるいは月１回～数回投与する。投与量は症状、年令、性別等を考慮して個々の場合に応じて適宜決定される。 Usually, in the case of oral administration, the single dose of the compound of the present invention or a salt thereof is about 1 to 100 mg / kg per body weight, and this is administered once a day or 1 to 3 times a week. When administered intravenously, the appropriate dose is about 0.1 to 10 mg / kg per body weight, and is administered once a day or once to several times a month. The dose is appropriately determined according to individual cases in consideration of symptoms, age, sex, and the like.
　以下、実施例を挙げて本発明を具体的に説明するが、本発明は下記実施例により限定されることはない。 Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to the following examples.
　実施例における略号の意味は下記のとおりである。
１Ｈ－ＮＭＲ：プロトン核磁気共鳴スペクトル、ＣＤＣｌ３：重水素クロロホルム、ＤＭＳＯ－ｄ６：重水素ジメチルスルホキシド、Ｄ２Ｏ：重水、Ｈｚ：ヘルツ、Ｊ：カップリング定数、ｍ：マルチプレット、ｓｅｐｔ：セプテット、ｑｕｉｎｔ：クインテット、ｑ：クワルテット、ｄｔ：ダブルトリプレット、ｄｄ：ダブルダブレット、ｄｄｄ：ダブルダブルダブレット、ｔ：トリプレット、ｄ：ダブレット、ｓ：シングレット、ｂｒ：ブロード、Ｍ：モル濃度。
ＭＯＭ：メトキシメチル基、Ｂｎ：ベンジル基、Ｐｈ：フェニル基、ＰＭＢ：パラメトキシベンジル基、Ａｃ：アセチル基、ＭＳは質量分析を示し、イオン化法がＥＳＩ（エレクトロスプレーイオン化法）である機器を使用し、実施例化合物を０．１％ギ酸水溶液－アセトニトリルに溶解して測定した。 The meanings of the abbreviations in the examples are as follows.
1 H-NMR: proton nuclear magnetic resonance spectrum, CDCl 3 : deuterium chloroform, DMSO-d 6 : deuterium dimethyl sulfoxide, D 2 O: heavy water, Hz: hertz, J: coupling constant, m: multiplet, sept : Septet, quintet, q: quartet, dt: double triplet, dd: double doublet, ddd: double doublet, t: triplet, d: doublet, s: singlet, br: broad, M: molar concentration.
MOM: methoxymethyl group, Bn: benzyl group, Ph: phenyl group, PMB: paramethoxybenzyl group, Ac: acetyl group, MS indicates mass spectrometry, and uses an instrument whose ionization method is ESI (electrospray ionization method) The Example compounds were dissolved in 0.1% aqueous formic acid-acetonitrile and measured.
参考例１：（Ｅ）－３－［３，４－ビス（メトキシメトキシ）フェニル］アクリロニトリル Reference Example 1: (E) -3- [3,4-bis (methoxymethoxy) phenyl] acrylonitrile
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
　シアノメチルホスホン酸ジエチル（１．８５ｍＬ）のテトラヒドロフラン（２０．０ｍＬ）溶液に、氷冷下、６０％水素化ナトリウム（４８０ｍｇ）を加え、室温で１０分間撹拌した。氷冷下、３，４－ビス（メトキシメトキシ）ベンズアルデヒド（２．２６ｇ）のテトラヒドロフラン（５．０ｍＬ）溶液を滴下し、室温で２時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（２．４３ｇ）を得た。
1H-NMR(CDCl3)δ:3.50(3H,s),3.52(3H,s),5.24(2H,s),5.26(2H,s),5.73(1H,d,J=16.4Hz),7.05(1H,dd,J=2.4,8.8Hz),7.16(1H,d,J=8.0Hz),7.22-7.33(2H,m). To a solution of diethyl cyanomethylphosphonate (1.85 mL) in tetrahydrofuran (20.0 mL) was added 60% sodium hydride (480 mg) under ice cooling, and the mixture was stirred at room temperature for 10 min. Under ice cooling, a solution of 3,4-bis (methoxymethoxy) benzaldehyde (2.26 g) in tetrahydrofuran (5.0 mL) was added dropwise, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (2.43 g).
1 H-NMR (CDCl 3 ) δ: 3.50 (3H, s), 3.52 (3H, s), 5.24 (2H, s), 5.26 (2H, s), 5.73 (1H, d, J = 16.4Hz), 7.05 (1H, dd, J = 2.4,8.8Hz), 7.16 (1H, d, J = 8.0Hz), 7.22-7.33 (2H, m).
参考例２：３－［３，４－ビス（メトキシメトキシ）フェニル］プロパンニトリル Reference Example 2: 3- [3,4-Bis (methoxymethoxy) phenyl] propanenitrile
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
　参考例１で製造した（Ｅ）－３－［３，４－ビス（メトキシメトキシ）フェニル］アクリロニトリル（６２４ｍｇ）のテトラヒドロフラン（５．０ｍＬ）に溶液に、５％パラジウム活性炭（６０ｍｇ）を加え、水素雰囲気下、室温で５時間撹拌した。不溶物を除去後、溶媒を減圧留去し、表題化合物（２５０ｍｇ）を得た。
1H-NMR(CDCl3)δ:2.60(2H,t,J=10.8Hz),2.90(2H,dd,J=10.8,11.2Hz),3.52(3H,s),3.53(3H,s),5.22(2H,s),5.24(2H,s),6.83(1H,dd,J=3.2,12.0Hz),7.04(1H,d,J=3.2Hz),7.12(1H,d,J=12.8Hz). To a solution of (E) -3- [3,4-bis (methoxymethoxy) phenyl] acrylonitrile (624 mg) prepared in Reference Example 1 in tetrahydrofuran (5.0 mL) was added 5% palladium activated carbon (60 mg), and hydrogen was added. Stir for 5 hours at room temperature under atmosphere. The insoluble material was removed, and the solvent was evaporated under reduced pressure to give the title compound (250 mg).
1 H-NMR (CDCl 3 ) δ: 2.60 (2H, t, J = 10.8Hz), 2.90 (2H, dd, J = 10.8, 11.2Hz), 3.52 (3H, s), 3.53 (3H, s), 5.22 (2H, s), 5.24 (2H, s), 6.83 (1H, dd, J = 3.2,12.0Hz), 7.04 (1H, d, J = 3.2Hz), 7.12 (1H, d, J = 12.8Hz ).
参考例３：３－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝プロピオン酸２－エチルへキシル Reference Example 3: 2-{[4-Fluoro-3- (methoxymethoxy) phenyl] sulfanyl} propionic acid 2-ethylhexyl
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
　４－ブロモ－１－フルオロ－２－（メトキシメトキシ）ベンゼン（７．９７ｇ）の１，４－ジオキサン（５０ｍＬ）溶液に、トリス（ジベンジリデンアセトン）ジパラジウム（６７６ｍｇ）、４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテン（１．４６ｇ）を３－スルファニルプロピオン酸２－エチルヘキシル（７．０５ｇ）を加え、窒素雰囲気下、１０５℃で１１時間撹拌した。溶媒を減圧留去し、残渣にクエン酸水溶液、酢酸エチル（６０．０ｍＬ）を加え、不溶物を除去後、有機層を水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、表題化合物（１１．２ｇ）を得た。
1H-NMR(CDCl3):δ:0.85-0.92(6H,m),1.25-1.40(8H,m),2.60(2H,t,J=7.2Hz),3.11(2H,t,J=7.2Hz),3.52(3H,s),4.01(2H,dd,J=5.6,2.6Hz),5.20(2H,s),7.00-7.30(2H,m),7.25(1H,dd,J=7.6,1.6Hz). To a solution of 4-bromo-1-fluoro-2- (methoxymethoxy) benzene (7.97 g) in 1,4-dioxane (50 mL) was added tris (dibenzylideneacetone) dipalladium (676 mg), 4,5-bis ( Diphenylphosphino) -9,9-dimethylxanthene (1.46 g) was added to 2-ethylhexyl 3-sulfanylpropionate (7.05 g), and the mixture was stirred at 105 ° C. for 11 hours under a nitrogen atmosphere. The solvent was distilled off under reduced pressure, citric acid aqueous solution and ethyl acetate (60.0 mL) were added to the residue, the insoluble material was removed, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (11.2 g).
1 H-NMR (CDCl 3 ): δ: 0.85-0.92 (6H, m), 1.25-1.40 (8H, m), 2.60 (2H, t, J = 7.2Hz), 3.11 (2H, t, J = 7.2 Hz), 3.52 (3H, s), 4.01 (2H, dd, J = 5.6, 2.6Hz), 5.20 (2H, s), 7.00-7.30 (2H, m), 7.25 (1H, dd, J = 7.6, 1.6Hz).
参考例４：２，２－ジフルオロ－２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝酢酸メチル Reference Example 4: Methyl 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} acetate
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
　参考例３で製造した３－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝プロピオン酸２－エチルへキシル（１．００ｇ）のテトラヒドロフラン（３．０ｍＬ）溶液を氷冷し、窒素雰囲気下、１Ｍカリウム　ｔｅｒｔ－ブトキシドテトラヒドロフラン溶液（３．０ｍＬ）を滴下し、室温で２．５時間撹拌後、５０℃で２０分間撹拌した。氷冷下、ブロモジフロロ酢酸メチル（５２１ｍｇ）のテトラヒドロフラン（１．０ｍＬ）溶液を滴下し、室温で１．５時間撹拌した。溶媒を減圧留去し、表題化合物を得た。
1H-NMR(CDCl3)δ:3.53(3H,s),3.85(3H,s),5.22(2H,s),7.12(1H,dd,J=10.8,8.4Hz),7.24(1H,ddd,J=8.4,4.4,2.4Hz),7.46(1H,dd,J=8.4,2.4Hz). A solution of 2-ethylhexyl 3-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} propionate (1.00 g) produced in Reference Example 3 in tetrahydrofuran (3.0 mL) was ice-cooled and nitrogen was added. Under atmosphere, 1M potassium tert-butoxide tetrahydrofuran solution (3.0 mL) was added dropwise, and the mixture was stirred at room temperature for 2.5 hours and then at 50 ° C. for 20 minutes. Under ice cooling, a solution of methyl bromodifluoroacetate (521 mg) in tetrahydrofuran (1.0 mL) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure to obtain the title compound.
1 H-NMR (CDCl 3 ) δ: 3.53 (3H, s), 3.85 (3H, s), 5.22 (2H, s), 7.12 (1H, dd, J = 10.8, 8.4 Hz), 7.24 (1H, ddd , J = 8.4, 4.4, 2.4Hz), 7.46 (1H, dd, J = 8.4, 2.4Hz).
参考例５：２，２－ジフルオロ－２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝アセタミド Reference Example 5: 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} acetamide
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
　参考例４で製造した２，２－ジフルオロ－２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝酢酸メチル、氷冷下、２Ｍアンモニアエタノール溶液（５．０ｍＬ）を滴下し、室温で３０分間撹拌した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（４００ｍｇ）を得た。
1H-NMR(CDCl3)δ:3.52(3H,s),5.23(2H,s),7.12(1H,dd,J=10.4,8.8Hz),7.28(1H,ddd,J=8.8,4.4,2.4Hz),7.50(1H,dd,J=8.8,2.4Hz). Methyl 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} acetate prepared in Reference Example 4 was added dropwise with 2M ammonia ethanol solution (5.0 mL) under ice cooling, Stir at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (400 mg).
1 H-NMR (CDCl 3 ) δ: 3.52 (3H, s), 5.23 (2H, s), 7.12 (1H, dd, J = 10.4, 8.8Hz), 7.28 (1H, ddd, J = 8.8, 4.4, 2.4Hz), 7.50 (1H, dd, J = 8.8,2.4Hz).
参考例６：２，２－ジフルオロ－２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝アセトニトリル Reference Example 6: 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} acetonitrile
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　参考例５で製造した２，２－ジフルオロ－２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝アセタミド（２．２０ｇ）のピリジン（２２．０ｍＬ）溶液に、氷冷下、トリフルオロメタンスルホン酸無水物（４．４０ｇ）を滴下し、室温で１０時間撹拌した。溶媒を減圧留去し、残渣にクエン酸水溶液を加え、酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（２．１０ｇ）を得た。
1H-NMR(CDCl3)δ:3.53(3H,s),5.25(2H,s),7.19(1H,dd,J=10.4,8.4Hz),7.33(1H,ddd,J=8.4,4.4,2.0Hz),7.56(1H,dd,J=8.4,2.0Hz). To a solution of 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} acetamide (2.20 g) prepared in Reference Example 5 in pyridine (22.0 mL) under ice-cooling, Trifluoromethanesulfonic anhydride (4.40 g) was added dropwise and stirred at room temperature for 10 hours. The solvent was distilled off under reduced pressure, an aqueous citric acid solution was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (2.10 g).
1 H-NMR (CDCl 3 ) δ: 3.53 (3H, s), 5.25 (2H, s), 7.19 (1H, dd, J = 10.4, 8.4 Hz), 7.33 (1H, ddd, J = 8.4, 4.4, 2.0Hz), 7.56 (1H, dd, J = 8.4,2.0Hz).
参考例７：２，２－ジフルオロ－２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝－Ｎ－ヒドロキシアセトイミダミド Reference Example 7: 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} -N-hydroxyacetimidamide
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　参考例６で製造した２，２－ジフルオロ－２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝アセトニトリル（２．１０ｇ）のエタノール（２１．０ｍＬ）溶液に、氷浴下、５０％ヒドロキシルアミンエタノール溶液を（８．０ｍＬ）滴下し、室温で４０分間撹拌した。溶媒を減圧留去し、表題化合物（２．４５ｇ）を得た。
1H-NMR(CDCl3)δ:3.52(3H,s),5.22(2H,s),7.11(1H,dd,J=10.8,8.8Hz),7.27(1H,ddd,J=8.8,4.4,2.0Hz),7.56(1H,dd,J=8.8,2.0Hz). To a solution of 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} acetonitrile (2.10 g) prepared in Reference Example 6 in ethanol (21.0 mL), in an ice bath, A 50% hydroxylamine ethanol solution (8.0 mL) was added dropwise, and the mixture was stirred at room temperature for 40 minutes. The solvent was distilled off under reduced pressure to obtain the title compound (2.45 g).
1 H-NMR (CDCl 3 ) δ: 3.52 (3H, s), 5.22 (2H, s), 7.11 (1H, dd, J = 10.8, 8.8Hz), 7.27 (1H, ddd, J = 8.8, 4.4, 2.0Hz), 7.56 (1H, dd, J = 8.8,2.0Hz).
参考例８：［４－フルオロ－３－（メトキシメトキシ）フェニル］メタンチオール Reference Example 8: [4-Fluoro-3- (methoxymethoxy) phenyl] methanethiol
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
　４－（クロロメチル）－１－フルオロ－２－（メトキシメトキシ）ベンゼン（１．６２ｇ）のＮ，Ｎ－ジメチルホルムアミド（９．０ｍＬ）溶液を氷冷し、窒素雰囲気下、チオ酢酸カリウム（９９６ｍｇ）を加え、室温で１時間撹拌した。反応液を氷冷し、水酸化リチウム（８１９ｍｇ）、メタノール（３．０ｍＬ）、水（１．５ｍＬ）を加え、室温で４５分間撹拌した。反応液にクエン酸水溶液を加え、酢酸エチルで抽出し、飽和食塩水洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、表題化合物（１．６０ｇ）を得た。 A solution of 4- (chloromethyl) -1-fluoro-2- (methoxymethoxy) benzene (1.62 g) in N, N-dimethylformamide (9.0 mL) was ice-cooled, and potassium thioacetate (996 mg) was added under a nitrogen atmosphere. ) And stirred at room temperature for 1 hour. The reaction mixture was ice-cooled, lithium hydroxide (819 mg), methanol (3.0 mL) and water (1.5 mL) were added, and the mixture was stirred at room temperature for 45 min. To the reaction solution was added an aqueous citric acid solution, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.60 g).
参考例９：２，２－ジフルオロ－２－（｛［４－フルオロ－３－（メトキシメトキシ）フェニル］メチル｝スルファニル）アセタミド Reference Example 9: 2,2-difluoro-2-({[4-fluoro-3- (methoxymethoxy) phenyl] methyl} sulfanyl) acetamide
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　参考例８で製造した［４－フルオロ－３－（メトキシメトキシ）フェニル］メタンチオール（１．６０ｇ）のテトラヒドロフラン（１６．０ｍＬ）溶液を氷冷し、窒素雰囲気下、ブロモジフロロ酢酸メチル（１．６０ｇ）、ジアザビシクロウンデセン（１．４４ｇ）を加え、室温で１時間撹拌した。溶媒を減圧留去し、クエン酸水溶液を加えて酢酸エチルで抽出し、飽和食塩水洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去して得られた残渣を氷冷し、４％アンモニアメタノール溶液（３０．０ｍＬ）を加え、室温で２時間撹拌した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（１．８５ｇ）を得た。 A solution of [4-fluoro-3- (methoxymethoxy) phenyl] methanethiol (1.60 g) prepared in Reference Example 8 in tetrahydrofuran (16.0 mL) was ice-cooled and methyl bromodifluoroacetate (1.60 g) under a nitrogen atmosphere. ) And diazabicycloundecene (1.44 g) were added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, an aqueous citric acid solution was added, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by distilling off the solvent under reduced pressure was ice-cooled, 4% ammonia methanol solution (30.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.85 g).
参考例１０：２，２－ジフルオロ－２－（｛［４－フルオロ－３－（メトキシメトキシ）フェニル］メチル｝スルファニル）アセトニトリル Reference Example 10: 2,2-difluoro-2-({[4-fluoro-3- (methoxymethoxy) phenyl] methyl} sulfanyl) acetonitrile
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　参考例９で製造した２，２－ジフルオロ－２－（｛［４－フルオロ－３－（メトキシメトキシ）フェニル］メチル｝スルファニル）アセタミド（１．６０ｇ）のピリジン（７．０ｍＬ）溶液に、氷冷下、トリフルオロメタンスルホン酸無水物（１．９０ｇ）を滴下し、室温で３時間撹拌した。溶媒を減圧留去し、クエン酸水溶液を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（０．７５ｇ）を得た。 To a solution of 2,2-difluoro-2-({[4-fluoro-3- (methoxymethoxy) phenyl] methyl} sulfanyl) acetamide (1.60 g) prepared in Reference Example 9 in pyridine (7.0 mL), ice Under cooling, trifluoromethanesulfonic anhydride (1.90 g) was added dropwise and stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, an aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (0.75 g).
参考例１１：２，２－ジフルオロ－２－（｛［４－フルオロ－３－（メトキシメトキシ）フェニル］メチル｝スルファニル）－Ｎ－ヒドロキシアセトイミダミド Reference Example 11: 2,2-difluoro-2-({[4-fluoro-3- (methoxymethoxy) phenyl] methyl} sulfanyl) -N-hydroxyacetimidamide
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
　参考例１０で製造した２，２－ジフルオロ－２－（｛［４－フルオロ－３－（メトキシメトキシ）フェニル］メチル｝スルファニル）アセトニトリル（０．７５ｇ）のエタノール（７．０ｍＬ）溶液に、氷冷下、５０％ヒドロキシルアミンエタノール溶液（０．２０ｍＬ）を加え、室温で１時間撹拌した。溶媒を減圧留去し、表題化合物（０．８４ｇ）を得た。
1H-NMR(CDCl3)δ:3.52(3Hs),4.04(2H,s),5.17(2H,s),4.90(2H,bs),6.94(1H,ddd,J=84,4,4,2.4Hz),7.01(1H,dd,J=10.8,8.4Hz),7.19(1H,dd,J=8.4,2.4Hz). To a solution of 2,2-difluoro-2-({[4-fluoro-3- (methoxymethoxy) phenyl] methyl} sulfanyl) acetonitrile (0.75 g) prepared in Reference Example 10 in ethanol (7.0 mL), ice Under cooling, 50% hydroxylamine ethanol solution (0.20 mL) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure to obtain the title compound (0.84 g).
1 H-NMR (CDCl 3 ) δ: 3.52 (3Hs), 4.04 (2H, s), 5.17 (2H, s), 4.90 (2H, bs), 6.94 (1H, ddd, J = 84, 4, 4, 2.4Hz), 7.01 (1H, dd, J = 10.8,8.4Hz), 7.19 (1H, dd, J = 8.4,2.4Hz).
参考例１２：５－（３，４－ジメトキシ－５－ニトロフェニル）－３－［（３－メトキシフェニル）メチル］－１，２，４－オキサジアゾール Reference Example 12: 5- (3,4-dimethoxy-5-nitrophenyl) -3-[(3-methoxyphenyl) methyl] -1,2,4-oxadiazole
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
　（ａ）：２－（３－メトキシフェニル）アセトニトリル（５８８ｍｇ）のエタノール（１０．０ｍＬ）溶液に、５０％ヒドロキシアミン水溶液（２．０ｍＬ）を加え、８０℃で６時間撹拌後、溶媒を減圧留去した。
　（ｂ）：（ａ）にＮ，Ｎ－ジメチルホルムアミド（６．０ｍＬ）、３，４－ジメトキシ－５－ニトロベンゾイルクロライド（７３６ｍｇ）、ジイソプロピルエチルアミン（０．６０ｍＬ）を加え、室温で１５時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去した。
　（ｃ）：（ｂ）にＮ，Ｎ－ジメチルホルムアミド（６．０ｍＬ）、カンファースルホン酸（３５０ｍｇ）を加え、１００℃で２時間撹拌した。水を加えて析出した結晶をろ取し、表題化合物（５２４ｍｇ）を得た。
1H-NMR(CDCl3)δ:3.79(3H,s),4.00(3H,s),4.05(3H,s),4.10(2H,s),6.72-6.84(3H,m),7.26(1H,dd,J=6.4,9.2Hz),7.76(1H,d,J=2.0Hz),7.80(1H,d,J=2.0Hz). (A): To a solution of 2- (3-methoxyphenyl) acetonitrile (588 mg) in ethanol (10.0 mL) was added 50% aqueous hydroxyamine solution (2.0 mL), and the mixture was stirred at 80 ° C. for 6 hours. Distilled off.
(B): N, N-dimethylformamide (6.0 mL), 3,4-dimethoxy-5-nitrobenzoyl chloride (736 mg) and diisopropylethylamine (0.60 mL) are added to (a) and stirred at room temperature for 15 hours. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure.
(C): N, N-dimethylformamide (6.0 mL) and camphorsulfonic acid (350 mg) were added to (b), and the mixture was stirred at 100 ° C. for 2 hours. Water was added and the precipitated crystals were collected by filtration to give the title compound (524 mg).
1 H-NMR (CDCl 3 ) δ: 3.79 (3H, s), 4.00 (3H, s), 4.05 (3H, s), 4.10 (2H, s), 6.72-6.84 (3H, m), 7.26 (1H , dd, J = 6.4,9.2Hz), 7.76 (1H, d, J = 2.0Hz), 7.80 (1H, d, J = 2.0Hz).
参考例１３：２－メトキシ－４－｛３－［（３－メトキシフェニル）メチル］－１，２，４－オキサジアゾール－５－イル｝－６－ニトロフェノール Reference Example 13: 2-methoxy-4- {3-[(3-methoxyphenyl) methyl] -1,2,4-oxadiazol-5-yl} -6-nitrophenol
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
　参考例１２で製造した５－（３，４－ジメトキシ－５－ニトロフェニル）－３－［（３－メトキシフェニル）メチル］－１，２，４－オキサジアゾール（５２４ｍｇ）のＮ－メチルモルホリン（５．０ｍＬ）溶液に、塩化リチウム（２４５ｍｇ）を加え、１３０℃で３時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、表題化合物（４５０ｍｇ）を得た。
1H-NMR(CDCl3)δ:3.70(3H,s),3.95(3H,s),4.09(2H,s),6.74-6.91(3H,m),7.22(1H,dd,J=7.6,8.0Hz),8.09(1H,d,J=2.0Hz),8.84(1H,s). 5- (3,4-Dimethoxy-5-nitrophenyl) -3-[(3-methoxyphenyl) methyl] -1,2,4-oxadiazole (524 mg) of N-methylmorpholine prepared in Reference Example 12 (5.0 mL) To the solution was added lithium chloride (245 mg), and the mixture was stirred at 130 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (450 mg).
1 H-NMR (CDCl 3 ) δ: 3.70 (3H, s), 3.95 (3H, s), 4.09 (2H, s), 6.74-6.91 (3H, m), 7.22 (1H, dd, J = 7.6, 8.0Hz), 8.09 (1H, d, J = 2.0Hz), 8.84 (1H, s).
実施例１：５－｛３－［（３－メトキシフェニル）メチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 1: 5- {3-[(3-methoxyphenyl) methyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　参考例１３で製造した２－メトキシ－４－｛３－［（３－メトキシフェニル）メチル］－１，２，４－オキサジアゾール－５－イル｝－６－ニトロフェノール（４５０ｍｇ）の１，２－ジクロロエタン（５．０ｍＬ）溶液に、ピリジン（０．５４ｍＬ）、塩化アルミニウム（３７２ｍｇ）を加え、５５℃で５時間撹拌した。反応液に１Ｍ塩酸水を加え、室温で３０分間撹拌後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をジエチルエーテル：ｎ－ヘキサン（１０：１）で洗浄し、表題化合物（２９５ｍｇ）を得た。 1,2-methoxy-4- {3-[(3-methoxyphenyl) methyl] -1,2,4-oxadiazol-5-yl} -6-nitrophenol (450 mg) prepared in Reference Example 13 Pyridine (0.54 mL) and aluminum chloride (372 mg) were added to a 2-dichloroethane (5.0 mL) solution, and the mixture was stirred at 55 ° C. for 5 hours. 1M aqueous hydrochloric acid was added to the reaction mixture, and the mixture was stirred at room temperature for 30 min and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with diethyl ether: n-hexane (10: 1) to obtain the title compound (295 mg).
実施例２：５－｛３－［（３－ヒドロキシフェニル）メチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 2: 5- {3-[(3-hydroxyphenyl) methyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　実施例１で製造した５－｛３－［（３－メトキシフェニル）メチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール（２７５ｍｇ）のジクロロメタン（５．０ｍＬ）溶液に、１Ｍ三臭化ホウ素ジクロロメタン溶液（２．４ｍＬ）を加え、室温で１５時間撹拌した。反応液に１Ｍ塩酸水を加え、室温で３０分間撹拌し、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をＯＤＳフラッシュカラムで精製し、表題化合物（８０ｍｇ）を得た。 5- {3-[(3-methoxyphenyl) methyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol (275 mg) of dichloromethane prepared in Example 1 To the (5.0 mL) solution, 1M boron tribromide dichloromethane solution (2.4 mL) was added and stirred at room temperature for 15 hours. 1M aqueous hydrochloric acid was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by ODS flash column to obtain the title compound (80 mg).
参考例１４：４－（ベンジルオキシ）－５－メトキシ－２－（トリフルオロメチル）安息香酸メチル Reference Example 14: Methyl 4- (benzyloxy) -5-methoxy-2- (trifluoromethyl) benzoate
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
　４－（ベンジルオキシ）－２－ヨード－５－メトキシ安息香酸メチル（３．００ｇ）のＮ，Ｎ－ジメチルホルムアミド（１０．０ｍＬ）溶液に、２，２－ジフルオロ－２－（フルオロスルホニル）酢酸メチル（７．２ｇ）、ヨウ化銅（Ｉ）（１．７２ｇ）を加え、１００℃で２０時間撹拌した。反応液に酢酸エチルを加え、不溶物除去し、水を加え酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（１．０２ｇ）を得た。
1H-NMR(CDCl3)δ:3.90(3H,s),3.94(3H,s),5.21(2H,s),7.18-7.50(7H,m). To a solution of methyl 4- (benzyloxy) -2-iodo-5-methoxybenzoate (3.00 g) in N, N-dimethylformamide (10.0 mL), 2,2-difluoro-2- (fluorosulfonyl) acetic acid Methyl (7.2 g) and copper (I) iodide (1.72 g) were added, and the mixture was stirred at 100 ° C. for 20 hours. Ethyl acetate was added to the reaction solution to remove insolubles, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (1.02 g).
1 H-NMR (CDCl 3 ) δ: 3.90 (3H, s), 3.94 (3H, s), 5.21 (2H, s), 7.18-7.50 (7H, m).
参考例１５：４－（ベンジルオキシ）－５－メトキシ－２－（トリフルオロメチル）安息香酸 Reference Example 15: 4- (Benzyloxy) -5-methoxy-2- (trifluoromethyl) benzoic acid
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
　参考例１４で製造した４－（ベンジルオキシ）－５－メトキシ－２－（トリフルオロメチル）安息香酸メチル（１．０２ｇ）をテトラヒドロフラン：メタノール：水（１：２：１）（２０ｍＬ）に溶解し、水酸化リチウム一水和物（５０４ｍｇ）を加え、室温で１５時間撹拌した。反応液に１Ｍ塩酸水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、表題化合物（１．０１ｇ）を得た。
1H-NMR(CDCl3)δ:3.96(3H,s),5.21(2H,s),7.28(1H,s),7.29-7.46(5H,m),7.51(1H,s). Methyl 4- (benzyloxy) -5-methoxy-2- (trifluoromethyl) benzoate (1.02 g) prepared in Reference Example 14 was dissolved in tetrahydrofuran: methanol: water (1: 2: 1) (20 mL). Lithium hydroxide monohydrate (504 mg) was added, and the mixture was stirred at room temperature for 15 hours. 1M aqueous hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (1.01 g).
1 H-NMR (CDCl 3 ) δ: 3.96 (3H, s), 5.21 (2H, s), 7.28 (1H, s), 7.29-7.46 (5H, m), 7.51 (1H, s).
参考例１６：４－｛３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール－５－イル｝－２－メトキシ－５－（トリフルオロメチル）フェノール Reference Example 16: 4- {3- [4-Fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -2-methoxy-5- (trifluoromethyl) phenol
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
　（ａ）：参考例１５で製造した４－（ベンジルオキシ）－５－メトキシ－２－（トリフルオロメチル）安息香酸（４４０ｍｇ）をトルエン：テトラヒドロフラン（４：１）（５．０ｍＬ）に溶解し、塩化チオニル（０．５０ｍＬ）を加え、６５℃で５時間撹拌した。溶媒を減圧留去し、トルエン共沸した。
　（ｂ）：（ａ）にＮ，Ｎ－ジメチルホルムアミド（５．０ｍＬ）、ジイソプロピルエチルアミン（０．３０ｍＬ）、４－フルオロ－Ｎ－ヒドロキシ－３－（メトキシメトキシ）ベンズイミダミド（５３５ｍｇ）を加え、室温で１５時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。
　（ｃ）：（ｂ）にテトラヒドロフラン（１５．０ｍＬ）、１Ｍテトラブチルアンモニウムフロリドテトラヒドロフラン溶液（３．０ｍＬ）を加え、室温で１５時間撹拌した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製した。
　（ｄ）：（ｃ）にＮ，Ｎ－ジメチルホルムアミド（５．０ｍＬ）、酢酸（１．０ｍＬ）、５％パラジウム活性炭（６００ｍｇ）を加え、水素雰囲気下、室温で５時間撹拌した。不溶物除去後、溶媒を減圧留去し、表題化合物（２００ｍｇ）を得た。
1H-NMR(CDCl3)δ:3.55(3H,s),4.05(3H,s),5.30(2H,s),7.17-7.22(1H,m),7.41(1H,s),7.55(1H,s),7.80-7.91(1H,m),8.02-8.12(1H,m). (A): 4- (Benzyloxy) -5-methoxy-2- (trifluoromethyl) benzoic acid (440 mg) prepared in Reference Example 15 was dissolved in toluene: tetrahydrofuran (4: 1) (5.0 mL). , Thionyl chloride (0.50 mL) was added, and the mixture was stirred at 65 ° C. for 5 hours. The solvent was distilled off under reduced pressure and azeotroped with toluene.
(B): N, N-dimethylformamide (5.0 mL), diisopropylethylamine (0.30 mL), 4-fluoro-N-hydroxy-3- (methoxymethoxy) benzimidamide (535 mg) was added to (a) at room temperature. For 15 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(C): Tetrahydrofuran (15.0 mL) and 1M tetrabutylammonium fluoride tetrahydrofuran solution (3.0 mL) were added to (b) and stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
(D): N, N-dimethylformamide (5.0 mL), acetic acid (1.0 mL), and 5% palladium activated carbon (600 mg) were added to (c), and the mixture was stirred at room temperature for 5 hours in a hydrogen atmosphere. After removing insolubles, the solvent was distilled off under reduced pressure to obtain the title compound (200 mg).
1 H-NMR (CDCl 3 ) δ: 3.55 (3H, s), 4.05 (3H, s), 5.30 (2H, s), 7.17-7.22 (1H, m), 7.41 (1H, s), 7.55 (1H , s), 7.80-7.91 (1H, m), 8.02-8.12 (1H, m).
参考例１７：４－｛３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサゾール－５－イル｝－６－メトキシ－２－ニトロ－３－（トリフルオロメチル）フェノール Reference Example 17: 4- {3- [4-Fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxazol-5-yl} -6-methoxy-2-nitro-3- (trifluoromethyl ) Phenol
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
　参考例１６で製造した４－｛３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール－５－イル｝－２－メトキシ－５－（トリフルオロメチル）フェノール（２００ｍｇ）を酢酸（２．０ｍＬ）に溶解し、水冷下、６０％硝酸（４０μＬ）を加え、室温で１．５時間撹拌した。水を加え、析出した結晶をろ取し、表題化合物（１７０ｍｇ）を得た。
1H-NMR(CDCl3)δ:3.55(3H,s),4.10(3H,s),5.30(2H,s),7.15-7.32(1H,m),7.43(1H,s), 7.72-7.86(1H,m),7.94-8.08(1H,m). 4- {3- [4-Fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -2-methoxy-5- (trifluoromethyl) prepared in Reference Example 16 ) Phenol (200 mg) was dissolved in acetic acid (2.0 mL), 60% nitric acid (40 μL) was added under water cooling, and the mixture was stirred at room temperature for 1.5 hours. Water was added, and the precipitated crystals were collected by filtration to give the title compound (170 mg).
1 H-NMR (CDCl 3 ) δ: 3.55 (3H, s), 4.10 (3H, s), 5.30 (2H, s), 7.15-7.32 (1H, m), 7.43 (1H, s), 7.72-7.86 (1H, m), 7.94-8.08 (1H, m).
実施例３：５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロ－４－（トリフルオロメチル）ベンゼン－１，２－ジオール Example 3: 5- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitro-4- (trifluoromethyl) benzene-1, 2-diol
　（ａ）：参考例１７で製造した４－｛３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサゾール－５－イル｝－６－メトキシ－２－ニトロ－３－（トリフルオロメチル）フェノール（１７０ｍｇ）の１，２－ジクロロエタン（５．０ｍＬ）溶液に、ピリジン（０．５４ｍＬ）、塩化アルミニウム（３７２ｍｇ）を加え、５５℃で５時間撹拌した。１Ｍ塩酸水を加えて３０分撹拌後、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去して、析出した結晶をジエチルエーテル：ｎ－ヘキサン（１０：１）で洗浄した。
　（ｂ）：（ａ）に４Ｍ塩酸１，４－ジオキサン溶液（５．０ｍＬ）を加え、室温で１６時間撹拌した。溶媒を減圧留去し、水を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、溶媒を減圧留去し、表題化合物（１００ｍｇ）を得た。 (A): 4- {3- [4-Fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxazol-5-yl} -6-methoxy-2-nitro- prepared in Reference Example 17 Pyridine (0.54 mL) and aluminum chloride (372 mg) were added to a solution of 3- (trifluoromethyl) phenol (170 mg) in 1,2-dichloroethane (5.0 mL), and the mixture was stirred at 55 ° C. for 5 hours. 1M aqueous hydrochloric acid was added and the mixture was stirred for 30 minutes and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with diethyl ether: n-hexane (10: 1).
(B): 4M hydrochloric acid 1,4-dioxane solution (5.0 mL) was added to (a), and the mixture was stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated under reduced pressure to give the title compound (100 mg).
参考例１８：５－（ベンジルオキシ）－４－メトキシ－２－｛３－［３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール－５－イル｝ベンゾニトリル Reference Example 18: 5- (Benzyloxy) -4-methoxy-2- {3- [3- (methoxymethoxy) phenyl] -1,2,4-oxadiazol-5-yl} benzonitrile
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
　（ａ）：５－（ベンジルオキシ）－２－ホルミル－４－メトキシベンゾニトリルより、参考例２３と同様に合成した４－（ベンジルオキシ）－２－シアノ－５－メトキシ安息香酸（５６６ｍｇ）の酢酸エチル（１０．０ｍＬ）溶液に、Ｎ－ヒドロキシ－３－（メトキシメトキシ）ベンズイミダミド（４９０ｍｇ）、トリエチルアミン（０．８３ｍＬ）、５０％２，４，６－トリプロピル－１，３，５，２，４，６－トリオキサトリホスホリナン－２，４，６－トリオキシド酢酸エチル溶液（１．８０ｍＬ）を加え、室温で１９時間撹拌した。反応液に酢酸エチルを加え、水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。
　（ｂ）：（ａ）にテトラヒドロフラン（２０．０ｍＬ）、１Ｍテトラブチルアンモニウムフロリドテトラヒドロフラン溶液（４．０ｍＬ）を加え、室温で１５時間撹拌した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（２２０ｍｇ）を得た。
1H-NMR(CDCl3)δ:3.50(3H,s),4.05(3H,s),5.24(2H,s),5.25(2H,s),7.17-7.22(1H,m),7.29(1H,s),7.31-7.48(6H,m),7.72(1H,s),7.81-7.89(2H,m). (A): 4- (benzyloxy) -2-cyano-5-methoxybenzoic acid (566 mg) synthesized in the same manner as in Reference Example 23 from 5- (benzyloxy) -2-formyl-4-methoxybenzonitrile To an ethyl acetate (10.0 mL) solution, N-hydroxy-3- (methoxymethoxy) benzimidamide (490 mg), triethylamine (0.83 mL), 50% 2,4,6-tripropyl-1,3,5,2 , 4,6-Trioxatriphosphorinane-2,4,6-trioxide ethyl acetate solution (1.80 mL) was added, and the mixture was stirred at room temperature for 19 hours. Ethyl acetate was added to the reaction mixture, washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(B): Tetrahydrofuran (20.0 mL) and 1M tetrabutylammonium fluoride tetrahydrofuran solution (4.0 mL) were added to (a) and stirred at room temperature for 15 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (220 mg).
1 H-NMR (CDCl 3 ) δ: 3.50 (3H, s), 4.05 (3H, s), 5.24 (2H, s), 5.25 (2H, s), 7.17-7.22 (1H, m), 7.29 (1H , s), 7.31-7.48 (6H, m), 7.72 (1H, s), 7.81-7.89 (2H, m).
参考例１９：５－ヒドロキシ－４－メトキシ－２－｛３－［３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール－５－イル｝ベンゾニトリル Reference Example 19: 5-hydroxy-4-methoxy-2- {3- [3- (methoxymethoxy) phenyl] -1,2,4-oxadiazol-5-yl} benzonitrile
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
　参考例１８で製造した５－（ベンジルオキシ）－４－メトキシ－２－｛３－［３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール－５－イル｝ベンゾニトリル（２２０ｍｇ）をメタノール：テトラヒドロフラン（２：３）（５ｍＬ）に溶解し、５％パラジウム活性炭（６００ｍｇ）を加え、水素雰囲気下、室温で１時間撹拌した。不溶物を除去し、酢酸エチルを加え、水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、表題化合物（１７８ｍｇ）を得た。
1H-NMR(CDCl3)δ:3.50(3H,s),4.09(3H,s),5.25(2H,s),7.16-7.23(1H,m),7.38(1H,s),7.42(1H,dd,J=8.0,8.4Hz),7.72(1H,d,0.8Hz),7.81-7.87(2H,m). 5- (Benzyloxy) -4-methoxy-2- {3- [3- (methoxymethoxy) phenyl] -1,2,4-oxadiazol-5-yl} benzonitrile (220 mg) prepared in Reference Example 18 ) Was dissolved in methanol: tetrahydrofuran (2: 3) (5 mL), 5% palladium activated carbon (600 mg) was added, and the mixture was stirred at room temperature for 1 hour in a hydrogen atmosphere. Insoluble matter was removed, ethyl acetate was added, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (178 mg).
1 H-NMR (CDCl 3 ) δ: 3.50 (3H, s), 4.09 (3H, s), 5.25 (2H, s), 7.16-7.23 (1H, m), 7.38 (1H, s), 7.42 (1H , dd, J = 8.0,8.4Hz), 7.72 (1H, d, 0.8Hz), 7.81-7.87 (2H, m).
実施例４：３，４－ジヒドロキシ－６－［３－（３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－２－ニトロベンゾニトリル Example 4: 3,4-dihydroxy-6- [3- (3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -2-nitrobenzonitrile
　参考例１９で製造した５－ヒドロキシ－４－メトキシ－２－｛３－［３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール－５－イル｝ベンゾニトリル（１７８ｍｇ）から実施例３と同様に製造し、表題化合物（１１０ｍｇ）を得た。 Performed from 5-hydroxy-4-methoxy-2- {3- [3- (methoxymethoxy) phenyl] -1,2,4-oxadiazol-5-yl} benzonitrile (178 mg) prepared in Reference Example 19 Prepared in the same manner as in Example 3 to obtain the title compound (110 mg).
実施例５：３，４－ジヒドロキシ－６－［３－（３－ヒドロキシフェニル）－１，２，４－オキサジアゾロ－５－イル］－２－ニトロ安息香酸 Example 5: 3,4-Dihydroxy-6- [3- (3-hydroxyphenyl) -1,2,4-oxadiazolo-5-yl] -2-nitrobenzoic acid
　実施例４で製造した３，４－ジヒドロキシ－６－［３－（３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－２－ニトロベンゾニトリル（９０ｍｇ）のエタノール（２．０ｍＬ）溶液に、４Ｍ水酸化ナトリウム水溶液（１．０ｍＬ）を加え、８０℃で１５時間撹拌した。４Ｍ塩酸水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、得られた残渣をＯＤＳフラッシュカラムで精製し、表題化合物（１０ｍｇ）を得た。 3,4-Dihydroxy-6- [3- (3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -2-nitrobenzonitrile (90 mg) prepared in Example 4 in ethanol ( 2.0 mL) solution was added 4M aqueous sodium hydroxide solution (1.0 mL) and stirred at 80 ° C. for 15 hours. 4M aqueous hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified with an ODS flash column to obtain the title compound (10 mg).
参考例２０：２－［４－フルオロ－３－（メトキシメトキシ）フェノキシ］アセトニトリル Reference Example 20: 2- [4-Fluoro-3- (methoxymethoxy) phenoxy] acetonitrile
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
　４－フルオロ－３－（メトキシメトキシ）フェノール（１３０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３．０ｍＬ）溶液に、氷冷下、６０％水素化ナトリウム（４５ｍｇ）を加え、１０分撹拌した。ブロモアセトニトリル（１３７ｍｇ）を加え、室温で４時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、表題化合物（１４８ｍｇ）を得た。
1H-NMR(CDCl3)δ:3.51(3H,s),4.72(2H,s),5.21(2H,s),6.51-6.62(1H,m),6.86-6.92(1H,m),7.01-7.12(1H,m). To a solution of 4-fluoro-3- (methoxymethoxy) phenol (130 mg) in N, N-dimethylformamide (3.0 mL) was added 60% sodium hydride (45 mg) under ice cooling, and the mixture was stirred for 10 minutes. Bromoacetonitrile (137 mg) was added and stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (148 mg).
1 H-NMR (CDCl 3 ) δ: 3.51 (3H, s), 4.72 (2H, s), 5.21 (2H, s), 6.51-6.62 (1H, m), 6.86-6.92 (1H, m), 7.01 -7.12 (1H, m).
参考例２１：５－［４－（ベンジルオキシ）－２－ヨード－５－メトキシフェニル］－３－［４－フルオロ－３－（メトキシフェニル）］－１，２，４－オキサジアゾール Reference Example 21: 5- [4- (benzyloxy) -2-iodo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxyphenyl)]-1,2,4-oxadiazole
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
　４－（ベンジルオキシ）－５－メトキシ－２－ヨード安息香酸（７６６ｍｇ）及び４－フルオロ－Ｎ－ヒドロキシ－３－メトキシベンズイミダミド（５５２ｍｇ）を用いて参考例１２と同様に製造し、表題化合物（３８０ｍｇ）を得た。
1H-NMR(CDCl3)δ:3.95(3H,s),3.99(2H,s),5.19(2H,s),7.16-7.24(1H,m),7.32-7.58(5H,m),7.53(2H,d,J=4.0Hz),7.72-7.84(2H,m). Prepared in the same manner as in Reference Example 12 using 4- (benzyloxy) -5-methoxy-2-iodobenzoic acid (766 mg) and 4-fluoro-N-hydroxy-3-methoxybenzimidamide (552 mg). Compound (380 mg) was obtained.
1 H-NMR (CDCl 3 ) δ: 3.95 (3H, s), 3.99 (2H, s), 5.19 (2H, s), 7.16-7.24 (1H, m), 7.32-7.58 (5H, m), 7.53 (2H, d, J = 4.0Hz), 7.72-7.84 (2H, m).
参考例２２：５－［４－（ベンジルオキシ）－５－メトキシ－２－フェノキシフェニル］－３－（４－フルオロ－３－メトキシフェニル）－１，２，４－オキサジアゾール Reference Example 22: 5- [4- (benzyloxy) -5-methoxy-2-phenoxyphenyl] -3- (4-fluoro-3-methoxyphenyl) -1,2,4-oxadiazole
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
　参考例２１で製造した５－［４－（ベンジルオキシ）－２－ヨード－５－メトキシフェニル］－３－［４－フルオロ－３－（メトキシフェニル）］－１，２，４－オキサジアゾール（５３２ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５．０ｍＬ）溶液に、ヨウ化銅（Ｉ）（２１４ｍｇ）、１，１０－フェナントロリン（２０５ｍｇ）、炭酸セシウム（５１３ｍｇ）、フェノール（１４１ｍｇ）を加え、１１０℃で３時間撹拌した。反応液に酢酸エチルを加え、不溶物をろ去し、水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（３００ｍｇ）を得た。
1H-NMR(CDCl3)δ:3.94(3H,s),4.01(3H,s),5.11(2H,s),6.67(1H,s)6.84-6.95(1H,m),7.28-7.34(5H,m),7.62-7.72(3H,m). 5- [4- (Benzyloxy) -2-iodo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxyphenyl)]-1,2,4-oxadiazole prepared in Reference Example 21 To a solution of (532 mg) in N, N-dimethylformamide (5.0 mL), copper (I) iodide (214 mg), 1,10-phenanthroline (205 mg), cesium carbonate (513 mg) and phenol (141 mg) were added. Stir at 110 ° C. for 3 hours. Ethyl acetate was added to the reaction solution, the insoluble material was removed by filtration, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (300 mg).
1 H-NMR (CDCl 3 ) δ: 3.94 (3H, s), 4.01 (3H, s), 5.11 (2H, s), 6.67 (1H, s) 6.84-6.95 (1H, m), 7.28-7.34 ( 5H, m), 7.62-7.72 (3H, m).
参考例２３：２－クロロ－３，４－ジメトキシ－５－ニトロ安息香酸 Reference Example 23: 2-Chloro-3,4-dimethoxy-5-nitrobenzoic acid
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
　２－クロロ－３，４－ジメトキシ－５－ニトロベンズアルデヒド（２．８０ｇ）をテトラヒドロフラン：水（１：１）（４８ｍＬ）に溶解し、氷冷下、２－メチル－２－ブテン（２．１ｍＬ）、亜塩素酸ナトリウム（１．３５ｇ）、クエン酸（１．６０ｇ）、を加え、室温で３０分間撹拌した。１０％亜硝酸ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をクロロホルム／ｎ－ヘキサンで洗浄し、表題化合物（１．９０ｇ）を得た。
1H-NMR(DMSO-d6)δ:3.90(3H,s),4.01(3H,s),8.12(2H,s) 2-Chloro-3,4-dimethoxy-5-nitrobenzaldehyde (2.80 g) was dissolved in tetrahydrofuran: water (1: 1) (48 mL), and 2-methyl-2-butene (2.1 mL) was cooled with ice. ), Sodium chlorite (1.35 g) and citric acid (1.60 g) were added, and the mixture was stirred at room temperature for 30 minutes. A 10% aqueous sodium nitrite solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with chloroform / n-hexane to obtain the title compound (1.90 g).
1 H-NMR (DMSO-d 6 ) δ: 3.90 (3H, s), 4.01 (3H, s), 8.12 (2H, s)
参考例２４：２－クロロ－４，５－ジメトキシ－３－ニトロ安息香酸
Figure JPOXMLDOC01-appb-C000032
 Reference Example 24: 2-chloro-4,5-dimethoxy-3-nitrobenzoic acid
Figure JPOXMLDOC01-appb-C000032
　４－（ベンジルオキシ）－３－メトキシ安息香酸エチル（５．９０ｇ）のＮ，Ｎ－ジメチルホルムアミド（１００ｍＬ）溶液に、Ｎ－クロロコハク酸イミド（４．４３ｇ）を加え、７０℃で７時間撹拌した。反応液に水を加え、ジエチルエーテルで抽出し、有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、４－（ベンジルオキシ）－２－クロロ－５－メトキシ安息香酸エチル（６．１６ｇ）を得た。これを参考例１９、参考例１７、参考例４８、実施例５に従い、表題化合物を得た。
1H-NMR(CDCl3)δ:3.96(3H,s),4.02(3H,s),7.68(1H,s). To a solution of ethyl 4- (benzyloxy) -3-methoxybenzoate (5.90 g) in N, N-dimethylformamide (100 mL) was added N-chlorosuccinimide (4.43 g), and the mixture was stirred at 70 ° C. for 7 hours. did. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain ethyl 4- (benzyloxy) -2-chloro-5-methoxybenzoate (6.16 g). The title compound was obtained according to Reference Example 19, Reference Example 17, Reference Example 48, and Example 5.
1 H-NMR (CDCl 3 ) δ: 3.96 (3H, s), 4.02 (3H, s), 7.68 (1H, s).
参考例２５：４，５－ジメトキシ－３－ニトロ－２－（フェニルスルファニル）安息香酸 Reference Example 25: 4,5-dimethoxy-3-nitro-2- (phenylsulfanyl) benzoic acid
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
　（ａ）：４－（ベンジルオキシ）－２－ヨード－５－メトキシ安息香酸メチル（７３５ｍｇ）を１，４－ジオキサン（６．０ｍＬ）に溶解し、ジイソプロピルエチルアミン（０．６３ｍＬ）、ベンゼンチオール（０．２５ｍＬ）、トリス（ジベンジリデンアセトン）ジパラジウム（６３ｍｇ）、４，５－ビス（ジフェニルホスフィノ）－９，９－ジメチルキサンテン（８１ｍｇ）、ヒドロキシメタンスルフィン酸ナトリウム二水和物（２８７ｍｇ）を加え、１００℃で２６時間撹拌した。この反応液に酢酸エチルを加え、不溶物を除去し、濾液を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し、４－（ベンジルオキシ）－５－メトキシ－２－（フェニルスルファニル）安息香酸メチル（４８８ｍｇ）を得た。
　（ｂ）：（ａ）にジクロロメタン（５．０ｍＬ）、四塩化チタン（０．１８ｍＬ）を加え、室温で１時間撹拌した。反応液に１０％塩酸水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し、４－ヒドロキシ－５－メトキシ－２－（フェニルスルファニル）安息香酸メチル（０．３０ｇ）を得た。これを参考例１７、４８、実施例５に従い、表題化合物を得た。
1H-NMR(CDCl3)δ:3.99(3H,s),4.01(3H,s),7.15-7.26(5H,m),7.63(1H,s). (A): Methyl 4- (benzyloxy) -2-iodo-5-methoxybenzoate (735 mg) was dissolved in 1,4-dioxane (6.0 mL), diisopropylethylamine (0.63 mL), benzenethiol ( 0.25 mL), tris (dibenzylideneacetone) dipalladium (63 mg), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (81 mg), sodium hydroxymethanesulfinate dihydrate (287 mg) And stirred at 100 ° C. for 26 hours. Ethyl acetate was added to the reaction solution to remove insoluble matters, and the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl 4- (benzyloxy) -5-methoxy-2- (phenylsulfanyl) benzoate (488 mg).
(B): Dichloromethane (5.0 mL) and titanium tetrachloride (0.18 mL) were added to (a) and stirred at room temperature for 1 hour. 10% aqueous hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl 4-hydroxy-5-methoxy-2- (phenylsulfanyl) benzoate (0.30 g). The title compound was obtained according to Reference Examples 17 and 48 and Example 5.
1 H-NMR (CDCl 3 ) δ: 3.99 (3H, s), 4.01 (3H, s), 7.15-7.26 (5H, m), 7.63 (1H, s).
参考例２６：４，５－ジメトキシ－３－ニトロ－２－（フェニルスルホニル）安息香酸 Reference Example 26: 4,5-dimethoxy-3-nitro-2- (phenylsulfonyl) benzoic acid
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
　４－（ベンジルオキシ）－５－メトキシ－２－（フェニルスルファニル）安息香酸メチル（２．０３ｇ）の酢酸エチル（３０．０ｍＬ）溶液に、ｍ－クロロ過安息香酸（２．８３ｇ）を加え、室温で１時間撹拌した。氷冷下、反応液に炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出し、有機層を水酸化ナトリウム水溶液、水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。残渣にｎ－ヘキサン：酢酸エチル（１：１）を加えて析出した結晶をろ取した。ろ液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィーで精製後、結晶と合わせて、４－（ベンジルオキシ）－５－メトキシ－２－フェニルスルホニル安息香酸メチル（１．４３ｇ）を得た。これを参考例２５と同様にして表題化合物を得た。
1H-NMR(DMSO-d6)δ:3.85(3H,s),4.02(3H,s),7.54(1H,s),7.67(2H,dt,J=1.6Hz,7.2Hz),7.75(1H,tt,J=1.6Hz,7.2Hz),7.99(2H,dd,J=1.6Hz,7.2Hz). To a solution of methyl 4- (benzyloxy) -5-methoxy-2- (phenylsulfanyl) benzoate (2.03 g) in ethyl acetate (30.0 mL) was added m-chloroperbenzoic acid (2.83 g), Stir at room temperature for 1 hour. Under ice-cooling, an aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous sodium hydroxide solution, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. . N-Hexane: ethyl acetate (1: 1) was added to the residue, and the precipitated crystals were collected by filtration. The filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, and combined with the crystals to give methyl 4- (benzyloxy) -5-methoxy-2-phenylsulfonylbenzoate (1.43 g). The title compound was obtained in the same manner as in Reference Example 25.
1 H-NMR (DMSO-d 6 ) δ: 3.85 (3H, s), 4.02 (3H, s), 7.54 (1H, s), 7.67 (2H, dt, J = 1.6 Hz, 7.2 Hz), 7.75 ( 1H, tt, J = 1.6Hz, 7.2Hz), 7.99 (2H, dd, J = 1.6Hz, 7.2Hz).
参考例２７：４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）安息香酸 Reference Example 27: 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
　（ａ）：４－アセトキシ－２－ヨード－５－メトキシ安息香酸エチル（１．２２ｇ）のＮ，Ｎ－ジメチルホルムアミド（２０．０ｍＬ）溶液に、ヨウ化銅（Ｉ）（９５４ｍｇ）、２，２－ジフルオロ－２－（フルオロスルホニル）酢酸メチル（１．３０ｍＬ）を加え、８０℃で５時間撹拌した。反応液に水を加え、不溶物を除去後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、４－アセトキシ－５－メトキシ－２－（トリフルオロメチル）安息香酸エチル（１．３７ｇ）を得た。
　（ｂ）：（ａ）にエタノール（１５．０ｍＬ）に溶解し、炭酸カリウム（１．８６ｇ）を加えて室温で８時間撹拌した。反応液に１Ｍ塩酸水を加え、酢酸エチルで抽出し、水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、４－ヒドロキシ－５－メトキシ－２－（トリフルオロメチル）安息香酸エチル（１．０７ｇ）を得た。
　（ｃ）：（ｂ）に酢酸（５．０ｍＬ）、６０％硝酸（０．４０ｍＬ）を加え、室温で５分間撹拌した。水を加え、析出した結晶をろ取した。
　（ｄ）：（ｃ）にテトラヒドロフラン（１０．０ｍＬ）、メタノール（０．２０ｍＬ）、トリフェニルホスフィン（１．５５ｇ）、ジイソプロピルアゾジカルボキシレート（１．００ｍＬ）を加え、室温で１時間撹拌した。酢酸エチルを加え、有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。
　（ｅ）：（ｄ）により得られた残渣にメタノール（１０．０ｍＬ）、テトラヒドロフラン（１０．０ｍＬ）、２Ｍ水酸化ナトリウム水溶液（２０．０ｍＬ）を加え、室温で４．５時間撹拌した。反応液に１Ｍ塩酸水を加え、酢酸エチルで抽出後、飽和炭酸水素ナトリウム水で抽出した。水層に１Ｍ塩酸水を加え、析出した結晶をろ取した。結晶を水で３回洗浄し、表題化合物（５９５ｍｇ）を得た。
1H-NMR(DMSO-d6)δ:3.91(3H,s),4.03(3H,s),7.61(1H,s),14.26(1H,brs). (A): To a solution of ethyl 4-acetoxy-2-iodo-5-methoxybenzoate (1.22 g) in N, N-dimethylformamide (20.0 mL), copper (I) iodide (954 mg), 2, 2-Difluoro-2- (fluorosulfonyl) methyl acetate (1.30 mL) was added, and the mixture was stirred at 80 ° C. for 5 hours. Water was added to the reaction solution to remove insoluble matters, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain ethyl 4-acetoxy-5-methoxy-2- (trifluoromethyl) benzoate (1.37 g).
(B): Dissolved in (a) in ethanol (15.0 mL), added potassium carbonate (1.86 g), and stirred at room temperature for 8 hours. 1M aqueous hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain ethyl 4-hydroxy-5-methoxy-2- (trifluoromethyl) benzoate (1.07 g).
(C) Acetic acid (5.0 mL) and 60% nitric acid (0.40 mL) were added to (b) and stirred at room temperature for 5 minutes. Water was added and the precipitated crystals were collected by filtration.
(D): Tetrahydrofuran (10.0 mL), methanol (0.20 mL), triphenylphosphine (1.55 g) and diisopropyl azodicarboxylate (1.00 mL) were added to (c) and stirred at room temperature for 1 hour. . Ethyl acetate was added, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(E): Methanol (10.0 mL), tetrahydrofuran (10.0 mL), and 2M aqueous sodium hydroxide solution (20.0 mL) were added to the residue obtained in (d), and the mixture was stirred at room temperature for 4.5 hours. 1M aqueous hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate and extracted with saturated aqueous sodium hydrogen carbonate. 1M aqueous hydrochloric acid was added to the aqueous layer, and the precipitated crystals were collected by filtration. The crystals were washed 3 times with water to give the title compound (595 mg).
1 H-NMR (DMSO-d 6 ) δ: 3.91 (3H, s), 4.03 (3H, s), 7.61 (1H, s), 14.26 (1H, brs).
参考例２８：４，５－ジメトキシ－２－（メチルスルファニル）－３－ニトロ安息香酸 Reference Example 28: 4,5-dimethoxy-2- (methylsulfanyl) -3-nitrobenzoic acid
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
　２－フルオロ－４，５－ジメトキシ－３－ニトロ安息香酸メチル（０．６０ｇ）のＮ，Ｎ－ジメチルホルムアミド（４．０ｍＬ）溶液に、ナトリウムチオメトキシド（０．１２ｇ）を加え、室温で１．５時間撹拌した。反応液に１Ｍ塩酸水を加え、酢酸エチルで抽出し、水、飽和食塩水で洗浄後、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し、４，５－ジメトキシ－２－メチルチオ－３－ニトロ安息香酸メチルを得た。この化合物を実施例５に従い、表題化合物（０．３８ｇ）を得た。
1H-NMR(CDCl3)δ:2.47(3H,s),3.98(3H,s),3.99(3H,s),7.77(1H,s). Sodium thiomethoxide (0.12 g) was added to a solution of methyl 2-fluoro-4,5-dimethoxy-3-nitrobenzoate (0.60 g) in N, N-dimethylformamide (4.0 mL) at room temperature. Stir for 1.5 hours. 1M aqueous hydrochloric acid was added to the reaction mixture, the mixture was extracted with ethyl acetate, washed with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl 4,5-dimethoxy-2-methylthio-3-nitrobenzoate. This compound was obtained according to Example 5 to give the title compound (0.38 g).
1 H-NMR (CDCl 3 ) δ: 2.47 (3H, s), 3.98 (3H, s), 3.99 (3H, s), 7.77 (1H, s).
参考例２９：３－［４－（ベンジルオキシ）－３－メトキシ－５－ニトロフェニル］－５－メチル－５－フェニル－４，５－ジヒドロイソキサゾール Reference Example 29: 3- [4- (benzyloxy) -3-methoxy-5-nitrophenyl] -5-methyl-5-phenyl-4,5-dihydroisoxazole
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
　（ａ）：４－（ベンジルオキシ）－３－メトキシ－５－ニトロベンズアルデヒドオキシム（５００ｍｇ）のジクロロメタン（５．０ｍＬ）溶液に、Ｎ－クロロコハク酸イミド（２４０ｍｇ）を加え、室温で３０分撹拌した。反応液に水（６．０ｍＬ）を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。
　（ｂ）：（ａ）にジクロロメタン（５．０ｍＬ）、１－メチルスチレン（０．２８ｍＬ）、トリエチルアミン（１．５０ｍＬ）を加え、室温で１時間撹拌した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（４４７ｍｇ）を得た。
1H-NMR(CDCl3)δ:1.82(3H,s),3.44(1H,d,J=16.5Hz),3.53(1H,d,J=16.5Hz),3.98(3H,s),5.20(2H,s),7.25-7.58(11H,m),7.69(1H,d,J=1.9Hz). (A): N-chlorosuccinimide (240 mg) was added to a solution of 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime (500 mg) in dichloromethane (5.0 mL) and stirred at room temperature for 30 minutes. . Water (6.0 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(B): Dichloromethane (5.0 mL), 1-methylstyrene (0.28 mL) and triethylamine (1.50 mL) were added to (a), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (447 mg).
1 H-NMR (CDCl 3 ) δ: 1.82 (3H, s), 3.44 (1H, d, J = 16.5Hz), 3.53 (1H, d, J = 16.5Hz), 3.98 (3H, s), 5.20 ( 2H, s), 7.25-7.58 (11H, m), 7.69 (1H, d, J = 1.9Hz).
参考例３０：３，４－ジメトキシ－５－ニトロベンズアミド Reference Example 30: 3,4-dimethoxy-5-nitrobenzamide
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
　３，４－ジメトキシ－５－ニトロ安息香酸（０．５０ｇ）の酢酸エチル（５．０ｍＬ）溶液に塩化チオニル（０．６０ｍＬ）を加え、１時間還流した。溶媒を減圧留去し、トルエン共沸後、氷冷下、２Ｍアンモニアメタノール溶液（２０．０ｍＬ）を滴下し、室温で３時間撹拌した。溶媒を減圧留去し、、残渣に水を加え、析出した結晶をろ過し、表題化合物（０．４５ｇ）を得た。
1H-NMR(CDCl3)δ:3.99(3H,s),4.04(3H,s),7.68(1H,d,J=2Hz),7.71(1H,d,J=2Hz). To a solution of 3,4-dimethoxy-5-nitrobenzoic acid (0.50 g) in ethyl acetate (5.0 mL) was added thionyl chloride (0.60 mL), and the mixture was refluxed for 1 hour. The solvent was distilled off under reduced pressure, toluene was azeotroped, 2M ammonia methanol solution (20.0 mL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, water was added to the residue, and the precipitated crystals were filtered to obtain the title compound (0.45 g).
1 H-NMR (CDCl 3 ) δ: 3.99 (3H, s), 4.04 (3H, s), 7.68 (1H, d, J = 2Hz), 7.71 (1H, d, J = 2Hz).
参考例３１：３，４－ジメトトキシ－５－ニトロベンゾチオアミド Reference Example 31: 3,4-Dimethoxy-5-nitrobenzothioamide
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
　３，４－ジメトキシ－５－ニトロべンズアミド（０．４５ｇ）のトルエン（１０．０ｍＬ）溶液に、２，４－ビス（４－メトキシフェニル）－１，３－ジチア－２，４－ジホスフェタン－２，４－ジスルフィド（ローソン試薬）（０．８９ｇ）を加え、８０℃で２時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（０．５３ｇ）を得た。
1H-NMR(CDCl3)δ:3.99(3H,s),4.03(3H,s),7.68(1H,d,J=2Hz),7.85(1H,d,J=2Hz). To a solution of 3,4-dimethoxy-5-nitrobenzamide (0.45 g) in toluene (10.0 mL), 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane- 2,4-Disulfide (Lawson reagent) (0.89 g) was added, and the mixture was stirred at 80 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.53 g).
1 H-NMR (CDCl 3 ) δ: 3.99 (3H, s), 4.03 (3H, s), 7.68 (1H, d, J = 2Hz), 7.85 (1H, d, J = 2Hz).
参考例３２：２－（３，４－ジメトキシ－５－ニトロフェニル）－４－フェニルチアゾール－５－カルボニトリル Reference Example 32: 2- (3,4-dimethoxy-5-nitrophenyl) -4-phenylthiazole-5-carbonitrile
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
　（ａ）：Ｎ，Ｎ－ジメチルベンズアミドジメチルアセタール（１．３０ｇ）と３，４－ジメトキシ－５－ニトロべンゾチオアミド（０．４０ｇ）を混合し、６０℃で１時間撹拌した。反応液に水を加え酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。
　溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、Ｎ－［（ジメチルアミノ）（フェニル）メチレン］－３，４－ジメトキシ－５－ニトロベンゾチオアミドを得た。
　（ｂ）：（ａ）で製造したＮ－［（ジメチルアミノ）（フェニル）メチレン］－３，４－ジメトキシ－５－ニトロベンゾチオアミドのアセトン（５．０ｍＬ）溶液に、ブロモアセトニトリル（０．１３ｇ）を加え、室温で２４時間で撹拌した。溶媒を減圧留去し、残渣に酢酸（５．０ｍＬ）を加え、１時間還流した。この反応液に水を加え、析出した結晶をろ取し、ジイソプロピルエーテルで洗浄後、表題化合物（０．１９ｇ）を得た。
1H-NMR(CDCl)δ:4.06(6H,s),7.51-7.58(3H,m),7.77(1H,d,J=2Hz),7.95(1H,d,J=2Hz), 8.15-8.24(2H,m). (A): N, N-dimethylbenzamide dimethylacetal (1.30 g) and 3,4-dimethoxy-5-nitrobenzothioamide (0.40 g) were mixed and stirred at 60 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain N-[(dimethylamino) (phenyl) methylene] -3,4-dimethoxy-5-nitrobenzothioamide.
(B): To a solution of N-[(dimethylamino) (phenyl) methylene] -3,4-dimethoxy-5-nitrobenzothioamide prepared in (a) in acetone (5.0 mL), bromoacetonitrile (0.13 g ) And stirred at room temperature for 24 hours. The solvent was distilled off under reduced pressure, acetic acid (5.0 mL) was added to the residue, and the mixture was refluxed for 1 hour. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration and washed with diisopropyl ether to give the title compound (0.19 g).
1 H-NMR (CDCl) δ: 4.06 (6H, s), 7.51-7.58 (3H, m), 7.77 (1H, d, J = 2Hz), 7.95 (1H, d, J = 2Hz), 8.15-8.24 (2H, m).
参考例３３：５－（３，４－ジメトキシ－５－ニトロフェニル）－３－フェニル－１，２，４－チアジアゾール Reference Example 33: 5- (3,4-dimethoxy-5-nitrophenyl) -3-phenyl-1,2,4-thiadiazole
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
　Ｎ－［（ジメチルアミノ）（フェニル）メチレン］－３，４－ジメトキシ－５－ニトロベンゾチオアミド（０．３４ｇ）のメタノール（４．０ｍＬ）溶液に、ピリジン（０．１３ｇ）、ヒドロキシアミン－Ｏ－スルホン酸（０．１４ｇ）を加え、室温で１時間撹拌した。反応液に１０％塩酸水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をジイソプロピルエーテルで洗浄し、表題化合物（０．１５ｇ）を得た。
1H-NMR(CDCl3)δ:4.08(6H,s),7.49-7.56(3H,m),7.79(1H,d,J=2Hz),7.98(1H,d,J=2Hz),8.34-8.43(2H,m). To a solution of N-[(dimethylamino) (phenyl) methylene] -3,4-dimethoxy-5-nitrobenzothioamide (0.34 g) in methanol (4.0 mL), pyridine (0.13 g), hydroxyamine-O -Sulfonic acid (0.14 g) was added and stirred at room temperature for 1 hour. 10% aqueous hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether to give the title compound (0.15 g).
1 H-NMR (CDCl 3 ) δ: 4.08 (6H, s), 7.49-7.56 (3H, m), 7.79 (1H, d, J = 2Hz), 7.98 (1H, d, J = 2Hz), 8.34 8.43 (2H, m).
参考例３４：（Ｅ）－１－［４－（ベンジルオキシ）－３－メトキシ－５－ニトロフェニル］－３－フェニルプロパ－２－エン－１－オン Reference Example 34: (E) -1- [4- (Benzyloxy) -3-methoxy-5-nitrophenyl] -3-phenylprop-2-en-1-one
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
　ベンズアルデヒド（０．４１ｍＬ）のメタノール（５．０ｍＬ）溶液に、ピペリジン（０．３８ｍＬ）を加え、６０℃で１時間撹拌し、１－［４－（ベンジルオキシ）－３－メトキシ－５－ニトロフェニル］エタン－１－オン（６０２ｍｇ）を加え、１５時間撹拌した。この反応液にクエン酸水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（６００ｍｇ）を得た。
1H-NMR(CDCl3)δ:4.05(3H,s),5.29(2H,s),7.28-7.56(9H,m),7.62-7.78(2H,m),7.80-7.95(2H,m),8.00(1H,d,J=1.9Hz). Piperidine (0.38 mL) was added to a solution of benzaldehyde (0.41 mL) in methanol (5.0 mL), stirred at 60 ° C. for 1 hour, and 1- [4- (benzyloxy) -3-methoxy-5-nitro. Phenyl] ethane-1-one (602 mg) was added and stirred for 15 hours. To this reaction solution was added citric acid water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (600 mg).
1 H-NMR (CDCl 3 ) δ: 4.05 (3H, s), 5.29 (2H, s), 7.28-7.56 (9H, m), 7.62-7.78 (2H, m), 7.80-7.95 (2H, m) , 8.00 (1H, d, J = 1.9Hz).
参考例３５：３－［４－（ベンジルオキシ）－３－メトキシ－５－ニトロフェニル］－５－フェニル－１Ｈ－ピラゾール Reference Example 35: 3- [4- (Benzyloxy) -3-methoxy-5-nitrophenyl] -5-phenyl-1H-pyrazole
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
　参考例３４で製造した（Ｅ）－１－［４－（ベンジルオキシ）－３－メトキシ－５－ニトロフェニル］－３－フェニルプロパ－２－エン－１－オン（１００ｍｇ）の１，４－ジオキサン（２．０ｍＬ）溶液に、ヒドラジン一水和物（２０μＬ）を加え、室温で２時間撹拌した。反応液に２，３－ジクロロ－５，６－ジシアノ－１，４－ベンゾキノン（１００ｍｇ）を加え、１時間撹拌した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（３１ｍｇ）を得た。
1H-NMR(CDCl3)δ:3.99(3H,s),5.21(2H,s),6.84(1H,s),7.28-7.62(8H,m),7.66-7.72(3H,m),7.72(1H,d,J=1.9Hz). (E) -1- [4- (Benzyloxy) -3-methoxy-5-nitrophenyl] -3-phenylprop-2-en-1-one (100 mg) of 1,4- Hydrazine monohydrate (20 μL) was added to the dioxane (2.0 mL) solution, and the mixture was stirred at room temperature for 2 hours. 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (100 mg) was added to the reaction solution and stirred for 1 hour. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (31 mg).
1 H-NMR (CDCl 3 ) δ: 3.99 (3H, s), 5.21 (2H, s), 6.84 (1H, s), 7.28-7.62 (8H, m), 7.66-7.72 (3H, m), 7.72 (1H, d, J = 1.9Hz).
　参考例３６：３，４－ジメトキシ－５－ニトロ－Ｎ－（２－オキソ－２－フェニルエチル）ベンズアミド Reference Example 36: 3,4-Dimethoxy-5-nitro-N- (2-oxo-2-phenylethyl) benzamide
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
　３，４－ジメトキシ－５－ニトロ安息香酸（３４０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（３．０ｍＬ）溶液に、２－アミノ－１－フェニルエタン－１－オン（４００ｍｇ）、１－ヒドロキシベンゾトリアゾール（２４５ｍｇ）、トリエチルアミン（０．２５ｍＬ）、１－エチル－３－（３－ジメチルアミノプロピル）カルボジイミド塩酸塩（３５２ｍｇ）を加え、室温で１５時間撹拌した。反応液に水（６．０ｍＬ）、飽和炭酸水素ナトリウム水溶液（３．０ｍＬ）を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、表題化合物（５１０ｍｇ）を得た。
1H-NMR(CDCl3)δ:4.00(3H,s),4.04(3H,s),4.95(2H,d,J=4.3Hz),7.39-7.73(4H,m),7.80(1H,d,J=2.4Hz),8.00-8.13(2H,m),9.09(1H,s). To a solution of 3,4-dimethoxy-5-nitrobenzoic acid (340 mg) in N, N-dimethylformamide (3.0 mL), 2-amino-1-phenylethane-1-one (400 mg), 1-hydroxybenzotriazole (245 mg), triethylamine (0.25 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (352 mg) were added, and the mixture was stirred at room temperature for 15 hours. Water (6.0 mL) and saturated aqueous sodium hydrogen carbonate solution (3.0 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (510 mg).
1 H-NMR (CDCl 3 ) δ: 4.00 (3H, s), 4.04 (3H, s), 4.95 (2H, d, J = 4.3 Hz), 7.39-7.73 (4H, m), 7.80 (1H, d , J = 2.4Hz), 8.00-8.13 (2H, m), 9.09 (1H, s).
参考例３７：２－（３，４－ジメトキシ－５－ニトロフェ二ル）－４－フェニル－１Ｈ－イミダゾール Reference Example 37: 2- (3,4-Dimethoxy-5-nitrophenyl) -4-phenyl-1H-imidazole
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
　参考例３６で製造した３，４－ジメトキシ－５－ニトロ－Ｎ－（２－オキソ－２－フェニルエチル）ベンズアミド（５００ｍｇ）の酢酸（５．０ｍＬ）溶液に、酢酸アンモニウム（２８０ｍｇ）を加え、１１０℃で５時間撹拌した。反応液に１Ｍ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（２５３ｍｇ）を得た。
1H-NMR(CDCl3)δ:4.00(3H,s),4.02(3H,s),7.22-7.49(5H,m),7.66(1H,d,J=1.9Hz),7.62-7.89(1H,m),7.85(1H,d,J=1.9Hz). To a solution of 3,4-dimethoxy-5-nitro-N- (2-oxo-2-phenylethyl) benzamide (500 mg) prepared in Reference Example 36 in acetic acid (5.0 mL), ammonium acetate (280 mg) was added, Stir at 110 ° C. for 5 hours. To the reaction solution was added 1M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (253 mg).
1 H-NMR (CDCl 3 ) δ: 4.00 (3H, s), 4.02 (3H, s), 7.22-7.49 (5H, m), 7.66 (1H, d, J = 1.9Hz), 7.62-7.89 (1H , m), 7.85 (1H, d, J = 1.9Hz).
参考例３８：２－（３，４－ジメトキシ－５－ニトロフェ二ル）－５－フェニル－１，３－オキサゾール Reference Example 38: 2- (3,4-dimethoxy-5-nitrophenyl) -5-phenyl-1,3-oxazole
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
　参考例３７で製造した２－（３，４－ジメトキシ－５－ニトロフェ二ル）－４－フェニル－１Ｈ－イミダゾール（３５０ｍｇ）に、濃硫酸（３．０ｍＬ）を加え、８０℃で３時間撹拌した。反応液に１Ｍ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（２５３ｍｇ）を得た。
1H-NMR(CDCl3)δ:4.04(3H,s),4.05(3,s),7.32-7.53(4H,m),7.73(1H,d,J=7.0Hz),7.83(1H,d,J=1.6Hz),8.05(1H,d,J=1.9Hz). Concentrated sulfuric acid (3.0 mL) was added to 2- (3,4-dimethoxy-5-nitrophenyl) -4-phenyl-1H-imidazole (350 mg) prepared in Reference Example 37 and stirred at 80 ° C. for 3 hours. did. To the reaction solution was added 1M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (253 mg).
1 H-NMR (CDCl 3 ) δ: 4.04 (3H, s), 4.05 (3, s), 7.32-7.53 (4H, m), 7.73 (1H, d, J = 7.0 Hz), 7.83 (1H, d , J = 1.6Hz), 8.05 (1H, d, J = 1.9Hz).
参考例３９：５－［４－（４－ヒドロキシフェニル）チアゾール－２－イル］－３－ニトロベンゼン－１，２－ジオール Reference Example 39: 5- [4- (4-hydroxyphenyl) thiazol-2-yl] -3-nitrobenzene-1,2-diol
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
　（ａ）：３，４－ジメトキシ－５－ニトロベンゾチオアミド（２００ｍｇ）のメタノール（１．０ｍＬ）溶液に、１－［４－（ベンジルオキシ）フェニル］－２－ブロモエタン－１－オン（２５０ｍｇ）を加え、１２０℃で１５時間撹拌し、溶媒を減圧留去した。
　（ｂ）：（ａ）で得られた残渣にＮ－メチルモルホリン（５．０ｍＬ）、塩化リチウム（１２０ｍｇ）を加え、１３０℃で５時間撹拌した。反応液に１０％塩酸水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。
　（ｃ）：（ｂ）で得られた残渣に１，２－ジクロロエタン（５．０ｍＬ）、ピリジン（０．４３ｍＬ）、塩化アルミニウム（２８７ｍｇ）を加え、５０℃で１５時間撹拌した。１Ｍ塩酸水を加えて３０分撹拌後、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。
　（ｄ）：（ｃ）にトリフルオロ酢酸（２．０ｍＬ）、チオアニソール（０．０３ｍＬ）を加え、７０℃で１５時間撹拌した。溶媒を減圧留去して、得られた残渣をＯＤＳフラッシュカラムにて精製し、表題化合物（５０ｍｇ）を得た。
1H-NMR(DMSO-d6)δ:6.79-6.94(2H,m),7.58-7.88(4H,m),8.11(1H,s). (A): To a solution of 3,4-dimethoxy-5-nitrobenzothioamide (200 mg) in methanol (1.0 mL), 1- [4- (benzyloxy) phenyl] -2-bromoethane-1-one (250 mg) And stirred at 120 ° C. for 15 hours, and the solvent was distilled off under reduced pressure.
(B): N-methylmorpholine (5.0 mL) and lithium chloride (120 mg) were added to the residue obtained in (a), and the mixture was stirred at 130 ° C. for 5 hours. A 10% aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(C): 1,2-Dichloroethane (5.0 mL), pyridine (0.43 mL) and aluminum chloride (287 mg) were added to the residue obtained in (b), and the mixture was stirred at 50 ° C. for 15 hours. 1M aqueous hydrochloric acid was added, and the mixture was stirred for 30 min and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(D): Trifluoroacetic acid (2.0 mL) and thioanisole (0.03 mL) were added to (c), and the mixture was stirred at 70 ° C. for 15 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified with an ODS flash column to obtain the title compound (50 mg).
1 H-NMR (DMSO-d 6 ) δ: 6.79-6.94 (2H, m), 7.58-7.88 (4H, m), 8.11 (1H, s).
参考例４０：４－［５－（３，４－ジメトキシ－５－ニトロフェニル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリダジン Reference Example 40: 4- [5- (3,4-dimethoxy-5-nitrophenyl) -1H-1,2,4-triazol-3-yl] pyridazine
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
　エチル３，４－ジメトキシ－５－ニトロベンズイミデート（２２５ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５．０ｍＬ）溶液に、ピリダジン－４－カルボヒドラジド塩酸塩（１４６ｍｇ）を加え、１００℃で１５時間撹拌した。反応液に水を加え、析出した結晶をろ取し、水（５．０ｍＬ）で３回、酢酸エチル（５．０ｍＬ）で洗浄し、表題化合物（１９７ｍｇ）を得た。
1H-NMR(DMSO-d6)δ:3.96(3H,s),4.04(3H,s),8.01(1H,d,J=2.8Hz),8.12(1H,d,J=2.4Hz),8.22(1H,dd,J=3.6,8.0Hz),9.40(1H,d,J=8.0Hz),9.83(1H,s) To a solution of ethyl 3,4-dimethoxy-5-nitrobenzimidate (225 mg) in N, N-dimethylformamide (5.0 mL) was added pyridazine-4-carbohydrazide hydrochloride (146 mg), and the mixture was stirred at 100 ° C. for 15 hours. Stir. Water was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water (5.0 mL) three times and ethyl acetate (5.0 mL) to obtain the title compound (197 mg).
1 H-NMR (DMSO-d 6 ) δ: 3.96 (3H, s), 4.04 (3H, s), 8.01 (1H, d, J = 2.8Hz), 8.12 (1H, d, J = 2.4Hz), 8.22 (1H, dd, J = 3.6,8.0Hz), 9.40 (1H, d, J = 8.0Hz), 9.83 (1H, s)
参考例４１：２－（３，４－ジメトキシ－５－ニトロフェニル）－５－［２－（３，４－ジメトキシフェニル）エチル］－１，３，４－オキサジアゾール Reference Example 41: 2- (3,4-dimethoxy-5-nitrophenyl) -5- [2- (3,4-dimethoxyphenyl) ethyl] -1,3,4-oxadiazole
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
　（ａ）：３，４－ジメトキシ－５－ニトロ安息香酸（２２５ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５．０ｍＬ）溶液に、３－（３，４－ジメトキシフェニル）プロピルカルボヒドラジド塩酸塩（１０８ｍｇ）、トリエチルアミン（０．７ｍＬ）、５０％プロピルホスホン酸無水物酢酸エチル溶液（０．６０ｍＬ）を加え、室温で１．５時間撹拌した。反応液にクエン酸水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製した。
　（ｂ）：トリフェニルホスフィンオキシド（４２５ｍｇ）をジクロロメタン（１０ｍＬ）に溶解し、氷冷下トリフルオロメタンスルホン酸無水物（０．１３ｍＬ）を加え、５分撹拌した。この溶液に、（ａ）で得られた残渣を加え、室温で２時間撹拌した。反応液に水を加え、クロロホルムで抽出し、有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をＮＨシリカゲルカラムクロマトグラフィーで精製し、表題化合物（６６ｍｇ）を得た。
1H-NMR(CDCl3)δ:3.13(2H,t,J=6.8Hz),3.21-3.28(2H,m),3.87(3H,s),4.02(3H,s),4.06(3H,s),6.74-6.84(3H,m),7.79(1H,d,J=2.0Hz),7.90(1H,d,J=2.0Hz). (A): To a solution of 3,4-dimethoxy-5-nitrobenzoic acid (225 mg) in N, N-dimethylformamide (5.0 mL), 3- (3,4-dimethoxyphenyl) propylcarbohydrazide hydrochloride (108 mg ), Triethylamine (0.7 mL) and 50% propylphosphonic anhydride ethyl acetate solution (0.60 mL) were added, and the mixture was stirred at room temperature for 1.5 hours. Citric acid water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography.
(B): Triphenylphosphine oxide (425 mg) was dissolved in dichloromethane (10 mL), trifluoromethanesulfonic anhydride (0.13 mL) was added under ice cooling, and the mixture was stirred for 5 minutes. To this solution, the residue obtained in (a) was added and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by NH silica gel column chromatography to obtain the title compound (66 mg).
1 H-NMR (CDCl 3 ) δ: 3.13 (2H, t, J = 6.8Hz), 3.21-3.28 (2H, m), 3.87 (3H, s), 4.02 (3H, s), 4.06 (3H, s ), 6.74-6.84 (3H, m), 7.79 (1H, d, J = 2.0Hz), 7.90 (1H, d, J = 2.0Hz).
参考例４２：５－エチニル－１，２－ジメトキシ－３－ニトロベンゼン Reference Example 42: 5-ethynyl-1,2-dimethoxy-3-nitrobenzene
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
　（ａ）：３，４－ジヒドロキシ－５－ニトロベンズアルデヒド（５．４７ｇ）のＮ，Ｎ－ジメチルホルムアミド（５５．０ｍＬ）溶液に、炭酸カリウム（６，４０ｇ）、ジメチル硫酸（２．２ｍＬ）を加え、６０℃で撹拌後、反応液に６０％水素化ナトリウム（８８ｍｇ）を加え、６時間撹拌した。析出した結晶をろ取した。
　（ｂ）：（ａ）に、テトラヒドロフラン（１１．０ｍＬ）、トリフェニルホスフィン（１．７０ｇ）、メタノール（０．３３ｍＬ）、アゾジカルボン酸ジイソプロピル（１．２７ｍＬ）を加え、１５時間撹拌した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィーで精製した。
　（ｃ）：（ｂ）にメタノール（１３．０ｍＬ）、炭酸カリウム（６３４ｍｇ）、１－ジアゾアセトニルホスホン酸ジメチル（８８４ｍｇ）を加え，室温で３時間撹拌した。反応液に酢酸エチルを加え、有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、表題化合物（８５０ｍｇ）を得た。
1H-NMR(CDCl3)δ:3.13(1H,s),3.93(3H,s),3.99(1H,s),7.18(1H,d,J=1.9Hz),7.47(1H,d,J=1.9Hz) (A): To a solution of 3,4-dihydroxy-5-nitrobenzaldehyde (5.47 g) in N, N-dimethylformamide (55.0 mL), potassium carbonate (6,40 g) and dimethyl sulfate (2.2 mL) were added. After stirring at 60 ° C., 60% sodium hydride (88 mg) was added to the reaction mixture, and the mixture was stirred for 6 hr. The precipitated crystals were collected by filtration.
(B): Tetrahydrofuran (11.0 mL), triphenylphosphine (1.70 g), methanol (0.33 mL) and diisopropyl azodicarboxylate (1.27 mL) were added to (a) and stirred for 15 hours. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography.
(C): Methanol (13.0 mL), potassium carbonate (634 mg), and dimethyl 1-diazoacetonylphosphonate (884 mg) were added to (b), and the mixture was stirred at room temperature for 3 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (850 mg).
1 H-NMR (CDCl 3 ) δ: 3.13 (1H, s), 3.93 (3H, s), 3.99 (1H, s), 7.18 (1H, d, J = 1.9Hz), 7.47 (1H, d, J = 1.9Hz)
参考例４３：４－（３，４－ジメトキシ－５－ニトロフェニル）－１－（４－フルオロ－３－メトキシフェニル）－１Ｈ－１，２，３－トリアゾール Reference Example 43: 4- (3,4-dimethoxy-5-nitrophenyl) -1- (4-fluoro-3-methoxyphenyl) -1H-1,2,3-triazole
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
　４－フルオロ－３－メトキシフェニルボロン酸（４００ｍｇ）のメタノール（１０．０ｍＬ）溶液に、アジ化ナトリウム（１６３ｍｇ）、酢酸銅（２２ｍｇ）を加え、６０℃で１時間撹拌した。反応液に参考例４２で製造した５－エチニル－１，２－ジメトキシ－３－ニトロベンゼン（４９７ｍｇ）のアセトニトリル（１０．０ｍＬ）溶液とヨウ化銅（Ｉ）（１７ｍｇ）を加え、８５℃で１時間撹拌した。反応液に塩酸水を加え、析出した結晶をろ取し、表題化合物（４１０ｍｇ）を得た。
1H-NMR(DMSO-d6)δ:3.92(3H,s),3.99(3H,s),4.03(3H,s),7.47-7.56(2H,m),7.73(1H,dd,J=2.0Hz,8.4Hz),7.89(1H,d,J=1.6Hz),7.94(1H,d,J=1.6Hz),9.45(1H,s). To a solution of 4-fluoro-3-methoxyphenylboronic acid (400 mg) in methanol (10.0 mL) were added sodium azide (163 mg) and copper acetate (22 mg), and the mixture was stirred at 60 ° C. for 1 hour. To the reaction solution was added a solution of 5-ethynyl-1,2-dimethoxy-3-nitrobenzene (497 mg) prepared in Reference Example 42 in acetonitrile (10.0 mL) and copper (I) iodide (17 mg), and 1 Stir for hours. Hydrochloric acid was added to the reaction mixture, and the precipitated crystals were collected by filtration to give the title compound (410 mg).
1 H-NMR (DMSO-d 6 ) δ: 3.92 (3H, s), 3.99 (3H, s), 4.03 (3H, s), 7.47-7.56 (2H, m), 7.73 (1H, dd, J = 2.0Hz, 8.4Hz), 7.89 (1H, d, J = 1.6Hz), 7.94 (1H, d, J = 1.6Hz), 9.45 (1H, s).
参考例４４：３－（４－ヒドロキシ－３－メトキシフェニル）エチニルベンゾニトリル Reference Example 44: 3- (4-hydroxy-3-methoxyphenyl) ethynylbenzonitrile
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
　２－メトキシ－４－［（トリメチルシリル）エチニル］フェノール（８００ｍｇ）のトリエチルアミン（４．０ｍＬ）溶液に、３－ヨードベンゾニトリル（９１６ｍｇ）、１Ｍテトラブチルアンモニウムフルオリドテトラヒドロフラン溶液（４．４ｍＬ），ヨウ化銅（６．９ｍｇ）、テトラキス（トリフェニルホスフィン）パラジウム（４２ｍｇ）を加え、５０℃で１５時間撹拌した。反応液に１Ｍ塩酸水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（５５１ｍｇ）を得た。 To a solution of 2-methoxy-4-[(trimethylsilyl) ethynyl] phenol (800 mg) in triethylamine (4.0 mL), 3-iodobenzonitrile (916 mg), 1M tetrabutylammonium fluoride tetrahydrofuran solution (4.4 mL), iodine Copper chloride (6.9 mg) and tetrakis (triphenylphosphine) palladium (42 mg) were added, and the mixture was stirred at 50 ° C. for 15 hours. 1M aqueous hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain the title compound (551 mg).
参考例４５：３－［４－（４－ヒドロキシ－３－メトキシフェニル）－４，５－ジヒドロ－１Ｈ－１，２，３－トリアゾール－５－イル］ベンゾニトリル Reference Example 45: 3- [4- (4-Hydroxy-3-methoxyphenyl) -4,5-dihydro-1H-1,2,3-triazol-5-yl] benzonitrile
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
　参考例４４で製造した３－（４－ヒドロキシ－３－メトキシフェニル）エチニルベンゾニトリル（４９１ｍｇ）のジメチルスルホキシド（５．０ｍＬ）溶液に、アジ化ナトリウム（２５６ｍｇ）を加え、９５℃で撹拌した。反応液に酢酸エチルを加え、飽和クエン酸水、水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を減圧留去し、表題化合物（５６５ｍｇ）を得た。
1H-NMR(DMSO-d6)δ:1H-NMR(CDCl3-d6)δ:4.00(3H,s),6.19(1H,brs),7.06(1H,d,J=7.8Hz),7.31-7.43(4H,m),7.44-7.56(2H,m). Sodium azide (256 mg) was added to a solution of 3- (4-hydroxy-3-methoxyphenyl) ethynylbenzonitrile (491 mg) prepared in Reference Example 44 in dimethyl sulfoxide (5.0 mL), and the mixture was stirred at 95 ° C. Ethyl acetate was added to the reaction mixture, washed with saturated aqueous citric acid, water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (565 mg).
1 H-NMR (DMSO-d 6 ) δ: 1 H-NMR (CDCl 3 -d 6 ) δ: 4.00 (3H, s), 6.19 (1H, brs), 7.06 (1H, d, J = 7.8 Hz) , 7.31-7.43 (4H, m), 7.44-7.56 (2H, m).
参考例４６：３－［４－（４－ヒドロキシ－３－メトキシ－５－ニトロフェニル）－１Ｈ－１，２，３－トリアゾール－５－イル］ベンゾニトリル Reference Example 46: 3- [4- (4-Hydroxy-3-methoxy-5-nitrophenyl) -1H-1,2,3-triazol-5-yl] benzonitrile
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
　参考例４５で製造した３－［４－（４－ヒドロキシ－３－メトキシフェニル）－４，５－ジヒドロ－１Ｈ－１，２，３－トリアゾール－５－イル］ベンゾニトリル（５６５ｍｇ）の酢酸（２．８ｍＬ）溶液に、氷冷下、６０％硝酸（８１μＬ）を滴下し、室温で１時間撹拌した。氷水に反応液を加え、クロロホルムで抽出した。有機層を水及び飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣を酢酸エチルで洗浄し、表題化合物（４６５ｍｇ）を得た。 3- [4- (4-Hydroxy-3-methoxyphenyl) -4,5-dihydro-1H-1,2,3-triazol-5-yl] benzonitrile (565 mg) of acetic acid (565 mg) prepared in Reference Example 45 (2.8 mL) To the solution, 60% nitric acid (81 μL) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to ice water and extracted with chloroform. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate to obtain the title compound (465 mg).
参考例４７：４－ヒドロキシ－３－メトキシ－５－ニトロベンゾニトリルの合成 Reference Example 47: Synthesis of 4-hydroxy-3-methoxy-5-nitrobenzonitrile
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
　４－ヒドロキシ－３－メトキシベンゾニトリル（１０．０ｇ）の酢酸（３５．０ｍＬ）酢酸溶液に、氷冷下、６０％硝酸（３．１ｍＬ）を加え、１時間撹拌した。反応液にｎ－ヘキサンを加え、析出した結晶をろ取し、表題化合物（７．８ｇ）を得た。 To a solution of 4-hydroxy-3-methoxybenzonitrile (10.0 g) in acetic acid (35.0 mL) in acetic acid, 60% nitric acid (3.1 mL) was added under ice cooling, and the mixture was stirred for 1 hour. N-Hexane was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain the title compound (7.8 g).
参考例４８：３，４－ジヒドロキシ－５－ニトロベンゾニトリルの合成 Reference Example 48: Synthesis of 3,4-dihydroxy-5-nitrobenzonitrile
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
　参考例４７で製造した４－ヒドロキシ－３－メトキシ－５－ニトロベンゾニトリル（６．１０ｇ）のテトラヒドロフラン（６０．０ｍＬ）溶液に、メタノール（１．９ｍＬ）、トリフェニルホスフィン（９．７０ｇ）およびアゾジカルボン酸ジイソプロピル（７．３ｍＬ）を加え、１５時間撹拌した。反応液に酢酸エチルを加え、水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣を酢酸エチル／ｎ－ヘキサンで洗浄し、表題化合物を含む粗生成物（５．４０ｇ）を得た。 To a solution of 4-hydroxy-3-methoxy-5-nitrobenzonitrile (6.10 g) prepared in Reference Example 47 in tetrahydrofuran (60.0 mL), methanol (1.9 mL), triphenylphosphine (9.70 g) and Diisopropyl azodicarboxylate (7.3 mL) was added and stirred for 15 hours. Ethyl acetate was added to the reaction mixture, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was washed with ethyl acetate / n-hexane to obtain a crude product (5.40 g) containing the title compound.
参考例４９：５－（３，４－ジメトキシ－５－ニトロフェニル）－２Ｈ－テトラゾール Reference Example 49: 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
　参考例４８で製造した３，４－ジヒドロキシ－５－ニトロベンゾニトリル（４．８０ｇ）のＮ，Ｎ－ジメチルホルムアミド（２４．０ｍＬ）溶液に、アジ化ナトリウム（２．３０ｇ）、水（２４．０ｍＬ）、臭化亜鉛（５．７０ｇ）を加え、１２０℃で２時間撹拌した。反応液に２Ｍ塩酸水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣を２－プロパノール／ｎ－ヘキサンで洗浄し、表題化合物（２．３０ｇ）を得た。 To a solution of 3,4-dihydroxy-5-nitrobenzonitrile (4.80 g) prepared in Reference Example 48 in N, N-dimethylformamide (24.0 mL), sodium azide (2.30 g) and water (24.24 g) were added. 0 mL) and zinc bromide (5.70 g) were added, and the mixture was stirred at 120 ° C. for 2 hours. 2M aqueous hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with 2-propanol / n-hexane to obtain the title compound (2.30 g).
参考例５０：２－ベンジル－５－（３，４－ジメトキシ－５－ニトロフェニル）－２Ｈ－テトラゾール Reference Example 50: 2-benzyl-5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
　参考例４９で製造した５－（３，４－ジメトキシ－５－ニトロフェニル）－２Ｈ－テトラゾール（５００ｍｇ）のアセトン（５．０ｍＬ）溶液に，炭酸カリウム（８２８ｍｇ）、ベンジルブロミド（０．２６ｍＬ）を加え、６０℃で１５時間撹拌した。反応液に１Ｍ塩酸水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（５０７ｍｇ）を得た。
1H-NMR(CDCl3)δ:4.01(3H,s),4.03(3H,s),5.81(2H,s),7.34-7.47(5H,m),7.88(1H,d,J=1.9Hz),8.10(1H,d,J=1.9Hz). To a solution of 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole (500 mg) prepared in Reference Example 49 in acetone (5.0 mL), potassium carbonate (828 mg), benzyl bromide (0.26 mL) And stirred at 60 ° C. for 15 hours. 1M aqueous hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (507 mg).
1 H-NMR (CDCl 3 ) δ: 4.01 (3H, s), 4.03 (3H, s), 5.81 (2H, s), 7.34-7.47 (5H, m), 7.88 (1H, d, J = 1.9Hz ), 8.10 (1H, d, J = 1.9Hz).
参考例５１：５－（３，４－ジメトキシ－５－ニトロフェニル）－２－フェニル－２Ｈ－テトラゾール Reference Example 51: 5- (3,4-dimethoxy-5-nitrophenyl) -2-phenyl-2H-tetrazole
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
　参考例４９で製造した５－（３，４－ジメトキシ－５－ニトロフェニル）－２Ｈ－テトラゾール（２１２ｍｇ）のジメチルスルホキシド（４．０ｍＬ）溶液に、フェニルボロン酸（２０５ｍｇ）、ヨウ化銅（Ｉ）（８．０ｍｇ）を加え、酸素雰囲気下、１００℃で１．５時間撹拌した。反応液に１Ｍ塩酸水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去し、表題化合物を含む粗生成物（２２０ｍｇ）を得た。
1H-NMR(CDCl3)δ:4.07(6H,s),7.51-7.64(3Hm),8.00(1H,d,J=1.9Hz),8.19-8.24(3H,m). To a solution of 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole (212 mg) prepared in Reference Example 49 in dimethyl sulfoxide (4.0 mL), phenylboronic acid (205 mg), copper iodide (I ) (8.0 mg) was added, and the mixture was stirred at 100 ° C. for 1.5 hours under an oxygen atmosphere. 1M aqueous hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product (220 mg) containing the title compound.
1 H-NMR (CDCl 3 ) δ: 4.07 (6H, s), 7.51-7.64 (3Hm), 8.00 (1H, d, J = 1.9Hz), 8.19-8.24 (3H, m).
参考例５２：４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）アニリン Reference Example 52: 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) aniline
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
　（ａ）：４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）安息香酸（１．００ｇ）のトルエン（１０．０ｍＬ）溶液に、ジフェニルリン酸アジド（１．２０ｇ）、ジイソプロピルエチルアミン（１．８ｍＬ）、ｔ－ブタノール（１．３ｍＬ）を加え、６０℃で１４時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥後、溶媒を減圧留去した。
　（ｂ）：（ａ）で得られた残渣に４Ｍ塩酸酢酸エチル溶液（１２．０ｍＬ）、４Ｍ塩酸１，４－ジオキサン溶液（６０．０ｍＬ）を加え、室温で３時間撹拌した。溶媒を減圧留去し，残渣にクロロホルム（５．０ｍＬ）を加え、不溶物をろ去後，溶媒を減圧留去し、表題化合物（０．９２ｇ）を得た。 (A): To a solution of 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid (1.00 g) in toluene (10.0 mL), diphenylphosphoric acid azide (1.20 g), diisopropylethylamine (1.8 mL) and t-butanol (1.3 mL) were added, and the mixture was stirred at 60 ° C. for 14 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(B): 4M hydrochloric acid ethyl acetate solution (12.0 mL) and 4M hydrochloric acid 1,4-dioxane solution (60.0 mL) were added to the residue obtained in (a), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, chloroform (5.0 mL) was added to the residue, insoluble material was removed by filtration, and the solvent was distilled off under reduced pressure to obtain the title compound (0.92 g).
参考例５３：１－アジド－４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）ベンゼン Reference Example 53: 1-azido-4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzene
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
　参考例５２で製造した４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）アニリン（０．５０ｇ）のジメチルスルホキシド（８．０ｍＬ）溶液に、２Ｍ塩酸水（２．０ｍＬ）を加え、氷冷下、硝酸ナトリウム（０．２０ｇ）の水（０．５ｍＬ）溶液を滴下し、１５分間撹拌した。アジ化ナトリウム（０．２０ｇ）の水（０．５ｍＬ）溶液を氷冷下滴下した。反応液に水を加え、酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去して、表題化合物（０．９０ｇ）を得た。 To a solution of 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) aniline (0.50 g) prepared in Reference Example 52 in dimethyl sulfoxide (8.0 mL) was added 2M aqueous hydrochloric acid (2.0 mL). Under ice cooling, a solution of sodium nitrate (0.20 g) in water (0.5 mL) was added dropwise and stirred for 15 minutes. A solution of sodium azide (0.20 g) in water (0.5 mL) was added dropwise under ice cooling. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.90 g).
参考例５４：１－［４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）フェニル］－４－（４－フルオロ－３－メトキシフェニル）－１Ｈ－１，２，３－トリアゾール Reference Example 54: 1- [4,5-dimethoxy-3-nitro-2- (trifluoromethyl) phenyl] -4- (4-fluoro-3-methoxyphenyl) -1H-1,2,3-triazole
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
　参考例５３で製造した１－アジド－４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）ベンゼン（０．８０ｇ）のｔ－ブタノール（４０．０ｍＬ）溶液に、水（１５．０ｍＬ）、４－エチニル－１－フルオロ－２－メトキシベンゼン（０．４０ｇ）、ヨウ化銅（Ｉ）（１４９ｍｇ）、トリス［（１－ベンジル－１Ｈ－１，２，３－トリアゾール－イル）メチル］アミン（１３８ｍｇ）を加え、１５時間還流した。不溶物を除去し、濾液を減圧留去した。残渣に水を加え、酢酸エチルで抽出し、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（０．３７ｇ）を得た。 To a solution of 1-azido-4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzene (0.80 g) prepared in Reference Example 53 in t-butanol (40.0 mL) was added water (15.0 mL). ), 4-ethynyl-1-fluoro-2-methoxybenzene (0.40 g), copper (I) iodide (149 mg), tris [(1-benzyl-1H-1,2,3-triazol-yl) methyl ] Amine (138 mg) was added and refluxed for 15 hours. Insoluble matter was removed, and the filtrate was distilled off under reduced pressure. Water was added to the residue, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (0.37 g).
実施例６：４－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］安息香酸 Example 6: 4- [5- (3,4-Dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] benzoic acid
　４－シアノ安息香酸メチルを用いて参考例１２，１３及び実施例３と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3 using methyl 4-cyanobenzoate.
実施例７：５－［３－（フェニルメチル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 7: 5- [3- (Phenylmethyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　２－フェニルアセトニトリルを用いて参考例１２，１３及び実施例１と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1 using 2-phenylacetonitrile.
実施例８：３－ニトロ－５－［３－（１－フェニルエチル）－１，２，４－オキサゾール－５－イル］ベンゼン－１，２－ジオール Example 8: 3-nitro-5- [3- (1-phenylethyl) -1,2,4-oxazol-5-yl] benzene-1,2-diol
　２－フェニルプロピオニトリルを用いて参考例１２，１３及び実施例１と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1 using 2-phenylpropionitrile.
実施例９：３－ニトロ－５－［３－（１－フェニルプロピル）－１，２，４－オキサジアゾール－５－イル］ベンゼン－１，２－ジオール Example 9: 3-Nitro-5- [3- (1-phenylpropyl) -1,2,4-oxadiazol-5-yl] benzene-1,2-diol
　２－フェニルブタンニトリルを用いて参考例１２、１３及び実施例１と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1 using 2-phenylbutanenitrile.
実施例１０：３－ニトロ－５－［３－（２－フェニルエチル）－１，２，４－オキサゾール－５－イル］ベンゼン－１，２－ジオール Example 10: 3-nitro-5- [3- (2-phenylethyl) -1,2,4-oxazol-5-yl] benzene-1,2-diol
　３－フェニルプロピオニトリルを用いて参考例１２，１３及び実施例１と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1 using 3-phenylpropionitrile.
実施例１１：５－［３－（２－シクロヘキシルエチル）－１，２，４－オキサゾール－５－イル］ベンゼン－１，２－ジオール Example 11: 5- [3- (2-Cyclohexylethyl) -1,2,4-oxazol-5-yl] benzene-1,2-diol
　３－シクロヘキシルプロピオニトリルを用いて参考例１２、１３及び実施例１と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1 using 3-cyclohexylpropionitrile.
実施例１２：５－［３－（２，３－ジメチルフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 12: 5- [3- (2,3-dimethylphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　２，３－ジメチルベンゾニトリルを用いて参考例１２、１３及び実施例１と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1 using 2,3-dimethylbenzonitrile.
実施例１３：３－ニトロ－５－［３－（２，３，４，５－テトラフルオロフェニル）－１，２，４－オキサゾール－５－イル］ベンゼン－１，２－ジオール Example 13: 3-nitro-5- [3- (2,3,4,5-tetrafluorophenyl) -1,2,4-oxazol-5-yl] benzene-1,2-diol
　２，３，４，５－テトラフルオロベンゾニトリルを用いて参考例１２、１３及び実施例１と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1 using 2,3,4,5-tetrafluorobenzonitrile.
実施例１４：３－［５－（３，４－ヒドロキシ－５－ニトロフェノール）－１，２，４－オキサジアゾール－３－イル］安息香酸 Example 14: 3- [5- (3,4-Hydroxy-5-nitrophenol) -1,2,4-oxadiazol-3-yl] benzoic acid
３－シアノ安息香酸を用い、参考例１２、１３及び実施例３と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3 using 3-cyanobenzoic acid.
　実施例１５：５－｛３－［２－（４－ヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 15: 5- {3- [2- (4-hydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　３－（４－メトキシフェニル）プロパンニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物を得た。 Using 3- (4-methoxyphenyl) propanenitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.
実施例１６：５－｛３－［２－（３－ヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 16: 5- {3- [2- (3-hydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　３－（３－メトキシフェニル）プロパンニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物を得た。 Using 3- (3-methoxyphenyl) propanenitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.
実施例１７：５－｛３－［２－（３，４－ジヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 17: 5- {3- [2- (3,4-dihydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　３－（３，４－ジメトキシフェニル）プロパンニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物を得た。 Using 3- (3,4-dimethoxyphenyl) propanenitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.
実施例１８：５－｛３－［２－（２，３－ジヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 18: 5- {3- [2- (2,3-dihydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　３－（２，３－ジメトキシフェニル）プロパンニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率２３％）を得た。 Using 3- (2,3-dimethoxyphenyl) propanenitrile, the title compound (23% yield) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例１９：５－｛３－［（４－ヒドロキシフェニル）メチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 19: 5- {3-[(4-hydroxyphenyl) methyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　２－（４－メトキシフェニル）アセトニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率２％）を得た。 Using 2- (4-methoxyphenyl) acetonitrile, the title compound (yield 2%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例２０：５－［３－（３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 20: 5- [3- (3-Hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　３－メトキシベンゾニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物を得た。 Using 3-methoxybenzonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.
実施例２１：５－｛２－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］エチル｝ベンゼン－１，２，３－トリオール Example 21: 5- {2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] ethyl} benzene-1,2,3-triol
　３－（２，３，４－トリメトキシフェニル）プロパンニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率１９％）を得た。 Using 3- (2,3,4-trimethoxyphenyl) propanenitrile, the title compound (yield 19%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.
実施例２２：４－ブロモ－５－｛２－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］エチル｝ベンゼン－１，２，３－トリオール Example 22: 4-Bromo-5- {2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] ethyl} benzene-1,2 , 3-triol
　実施例２１の副生成物として、表題化合物（収率２１％）を得た。 As a by-product of Example 21, the title compound (yield 21%) was obtained.
実施例２３：５－｛［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］メチル｝ベンゼン－１，２，３－トリオール Example 23: 5-{[5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] methyl} benzene-1,2,3-triol
　２－（３，４，５－トリメトキシフェニル）アセトニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率３８％）を得た。 Using 2- (3,4,5-trimethoxyphenyl) acetonitrile, the title compound (yield 38%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例２４：５－｛３－［２－（３，５－ジヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 24: 5- {3- [2- (3,5-dihydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　３－［３，５－ビス（メトキシエトキシ）フェニル］プロパンニトリルを用い、参考例１２、１３及び実施例３と同様にして表題化合物（収率３％）を得た。 Using 3- [3,5-bis (methoxyethoxy) phenyl] propanenitrile, the title compound (yield 3%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.
実施例２５：５－｛３－［３－（３－ヒドロキシフェニル）プロピル］－１，２，４－オキサジアゾール－５－イル］｝－３－ニトロベンゼン－１，２－ジオール Example 25: 5- {3- [3- (3-hydroxyphenyl) propyl] -1,2,4-oxadiazol-5-yl]}-3-nitrobenzene-1,2-diol
　４－（３－メトキシフェニル）ブタンニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物を得た。 Using 4- (3-methoxyphenyl) butanenitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.
実施例２６：５－｛３－［２－（２，５－ジヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 26: 5- {3- [2- (2,5-dihydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　３－［２，５－ビス（メトキシメトキシ）フェニル］プロパンニトリルを用い、参考例１２、１３及び実施例３と同様にして表題化合物（収率１１％）を得た。 Using 3- [2,5-bis (methoxymethoxy) phenyl] propanenitrile, the title compound (yield 11%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.
実施例２７：５－｛［（２－ヒドロキシフェニル）メチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 27: 5-{[(2-hydroxyphenyl) methyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　２－（３－メトキシフェニル）アセトニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率２％）を得た。 Using 2- (3-methoxyphenyl) acetonitrile, the title compound (yield 2%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例２８：５－｛３－［３－（４－ヒドロキシフェニル）プロピル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 28: 5- {3- [3- (4-hydroxyphenyl) propyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　４－（４－メトキシフェニル）ブタンニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率４８％）を得た。 4- (4-Methoxyphenyl) butanenitrile was used in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2, to give the title compound (yield 48%).
実施例２９：５－｛３－［３－（３，４－ジヒドロキシフェニル）プロピル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール
　４－（３，４－ジメトキシフェニル）ブタンニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物を得た。 Example 29: 5- {3- [3- (3,4-dihydroxyphenyl) propyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol 4- ( Using 3,4-dimethoxyphenyl) butanenitrile, the title compound was obtained in the same manner as in Reference Examples 12, 13, and Examples 1 and 2.
実施例３０：５－｛［３－（３，４－ジメトキシフェニル）メチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 30: 5-{[3- (3,4-dimethoxyphenyl) methyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　２－（３，４－ジメトキシフェニル）アセトニトリルを用い、参考例１２、１３、実施例１と同様にして表題化合物を得た。 Using 2- (3,4-dimethoxyphenyl) acetonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1.
実施例３１：５－｛３－［（３，４－ジヒドロキシフェニル）メチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 31: 5- {3-[(3,4-dihydroxyphenyl) methyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　５－｛３－［（３，４－ジメトキシフェニル）メチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオールを用い、実施例２と同様にして表題化合物を得た。 5- {3-[(3,4-dimethoxyphenyl) methyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol was used in the same manner as in Example 2. To give the title compound.
実施例３２：５－｛３－［２－（２，４－ジヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 32: 5- {3- [2- (2,4-dihydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　３－（２，４－ジメトキシフェニル）プロピオニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率２１％）を得た。 Using 3- (2,4-dimethoxyphenyl) propionitrile, the title compound (yield 21%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例３３：５－｛３－［（４－ブロモ－３－ヒドロキシフェニル）メチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 33: 5- {3-[(4-Bromo-3-hydroxyphenyl) methyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　実施例２の副生成物として表題化合物を得た。 The title compound was obtained as a byproduct of Example 2.
実施例３４：５－｛３－［３－（２－ヒドロキシフェニル）プロピル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 34: 5- {3- [3- (2-hydroxyphenyl) propyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　４－（２－メトキシフェニル）ブタンニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率２２％）を得た。 Using 4- (2-methoxyphenyl) butanenitrile, the title compound (yield 22%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例３５：５－［３－（３，４－ジヒドロキシフェ二ル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 35: 5- [3- (3,4-dihydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　３，４－ジメトキシベンゾニトリルを用いて、参考例１２、１３、実施例１、２と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2, using 3,4-dimethoxybenzonitrile.
実施例３６：５－｛３－［２－（２－ヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 36: 5- {3- [2- (2-hydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　３－（２－メトキシフェニル）プロパンニトリルを用いて、参考例１２、１３、実施例１、２と同様にして表題化合物（収率７％）を得た。 Using 3- (2-methoxyphenyl) propanenitrile, the title compound (yield 7%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例３７：５－｛３－［（２，３－ジヒドロキシフェニル）メチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 37: 5- {3-[(2,3-dihydroxyphenyl) methyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　２－［２，３－ビス（メトキシメトキシ）フェニル］アセトニトリルを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率４８％）を得た。 Using 2- [2,3-bis (methoxymethoxy) phenyl] acetonitrile, the title compound (yield 48%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.
実施例３８：３－｛２－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］エチル｝ベンゾ［ｂ］チオフェン－５，６－ジオール Example 38: 3- {2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] ethyl} benzo [b] thiophene-5,6 -Diol
　３－（５，６－ジメトキシベンゾ［ｂ］チオフェン－３－イル）プロパンニトリルを用いて、参考例１２、１３、実施例１、２と同様にして表題化合物（収率２７％）を得た。 Using 3- (5,6-dimethoxybenzo [b] thiophen-3-yl) propanenitrile, the title compound (yield 27%) was obtained in the same manner as in Reference Examples 12, 13, and Examples 1 and 2. .
実施例３９：５－［３－（２，３－ジヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 39: 5- [3- (2,3-dihydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　２，３－ビス（メトキシメトキシ）ベンゾニトリルを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率３％）を得た。 Using 2,3-bis (methoxymethoxy) benzonitrile, the title compound (yield 3%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3.
実施例４０：４－｛２－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］エチル｝ベンゼン－１，２，３－トリオール Example 40 4- {2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] ethyl} benzene-1,2,3-triol
　３－［２，３，４－トリス（メトキシメトキシ）フェニル］プロパンニトリルを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率６１％）を得た。　 Using 3- [2,3,4-tris (methoxymethoxy) phenyl] propanenitrile, the title compound (61% yield) was obtained in the same manner as in Reference Examples 12, 13, and Example 3. *
実施例４１：５－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］－１，３－ジヒドロ－２Ｈ－ベンゾ［ｄ］イミダゾール－２－オン Example 41: 5- [5- (3,4-Dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] -1,3-dihydro-2H-benzo [d] imidazole -2-On
　２－オキソ－２，３－ジヒドロ－１Ｈ－ベンゾ［ｄ］イミダゾール－５－カルボニトリルを用い、参考例１２、１３、実施例１と同様にして表題化合物（収率５８％）を得た。 Using 2-oxo-2,3-dihydro-1H-benzo [d] imidazole-5-carbonitrile, the title compound (yield 58%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 1.
実施例４２：３－クロロ－４－｛２－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］エチル｝ベンゼン－１，２－ジオール Example 42 3-chloro-4- {2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] ethyl} benzene-1,2 -Diol
　３－（２－クロロ－３，４－ジメトキシフェニル）プロパンニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率４％）を得た。 Using 3- (2-chloro-3,4-dimethoxyphenyl) propanenitrile, the title compound (yield 4%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例４３：４－｛２－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］エチル｝－３－メチルベンゼン－１，２－ジオール Example 43: 4- {2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -3-methylbenzene-1,2 -Diol
　３－［３，４－ビス（メトキシメトキシ）－２－メチルフェニル］プロパンニトリルを用い、参考例１２、１３、実施３と同様にして表題化合物（３４％）を得た。 Using 3- [3,4-bis (methoxymethoxy) -2-methylphenyl] propanenitrile, the title compound (34%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3.
実施例４４：５－｛３－［２－（２，６－ジメトキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 44: 5- {3- [2- (2,6-dimethoxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　３－（２，６－ジメトキシフェニル）プロパンニトリルを用いて、参考例１２、１３、実施例１と同様にして表題化合物（収率８３％）を得た。 Using 3- (2,6-dimethoxyphenyl) propanenitrile, the title compound (yield 83%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 1.
実施例４５：５－｛３－［２－（２，６－ジヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 45: 5- {3- [2- (2,6-dihydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　５－｛３－［２－（２，６－ジメトキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオールを用いて、実施例２と同様にして表題化合物（収率４４％）を得た。 Example 2 using 5- {3- [2- (2,6-dimethoxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol To give the title compound (44% yield).
実施例４６：５－［３－（４－ヒドロキシ－３－メトキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 46: 5- [3- (4-Hydroxy-3-methoxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　３－メトキシ－４－（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物を得た。 Using 3-methoxy-4- (methoxymethoxy) benzonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.
実施例４７：（Ｅ）－５－｛３－［２－（３，４－ジヒドロキシフェニル）エテン－１－イル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 47: (E) -5- {3- [2- (3,4-dihydroxyphenyl) ethen-1-yl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene- 1,2-diol
　（Ｅ）－３－［３，４－ビス（メトキシメトキシ）フェニル］アクリロニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物を得た。 (E) -3- [3,4-Bis (methoxymethoxy) phenyl] acrylonitrile was used in the same manner as in Reference Examples 12 and 13 and Example 3 to obtain the title compound.
実施例４８：５－｛３－［２－（３－フルオロ－２－ヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 48: 5- {3- [2- (3-Fluoro-2-hydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　３－［３－フルオロ－２－（メトキシメトキシ）フェニル］プロパンニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率４１％）を得た。 Using 3- [3-fluoro-2- (methoxymethoxy) phenyl] propanenitrile, the title compound (yield 41%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.
実施例４９：３－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］－１－（３－ヒドロキシチオフェン－２－イル）プロパン－１－オン Example 49: 3- [5- (3,4-Dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] -1- (3-hydroxythiophen-2-yl) propane -1-On
　４－（３－メトキシチオフェン－２－イル）－４－オキソブタンニトリルを用いて、参考例１２、１３、実施例１、２と同様にして表題化合物（収率５２％）を得た。 Using 4- (3-methoxythiophen-2-yl) -4-oxobutanenitrile, the title compound (yield 52%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例５０：５－｛３－［２－（３，４－ジヒドロキシ－５－メチルフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 50: 5- {3- [2- (3,4-dihydroxy-5-methylphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2- Diol
　３－［３，４－ビス（メトキシメトキシ）－５－メチルフェニル］プロパンニトリルを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率５％）を得た。 Using 3- [3,4-bis (methoxymethoxy) -5-methylphenyl] propanenitrile, the title compound (yield 5%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3.
実施例５１：５－｛３－［２－（３－ブロモ－２，６－ジヒドロフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 51: 5- {3- [2- (3-bromo-2,6-dihydrophenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2- Diol
　実施例４５の副生成物として、表題化合物（収率１７％）を得た。 The title compound (yield 17%) was obtained as a byproduct of Example 45.
実施例５２：５－［３－（２－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 52: 5- [3- (2-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　２－（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率１４％）を得た。 Using 2- (methoxymethoxy) benzonitrile, the title compound (yield 14%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.
実施例５３：５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 53: 5- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物を得た。 Using 4-fluoro-3- (methoxymethoxy) benzonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.
実施例５４：５－［３－（３－ヒドロキシ－４－メチルフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 54: 5- [3- (3-hydroxy-4-methylphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　３－（メトキシメトキシ）－４－メチルベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物を得た。 Using 3- (methoxymethoxy) -4-methylbenzonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.
実施例５５：５－［３－（２，６－ジヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 55: 5- [3- (2,6-dihydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　２，６－ビス（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率２１％）を得た。 Using 2,6-bis (methoxymethoxy) benzonitrile, the title compound (yield 21%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.
実施例５６：５－｛３－［２－（４－クロロ－２，３－ジヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 56: 5- {3- [2- (4-chloro-2,3-dihydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2- Diol
　３－（４－クロロ－２，３－ジメトキシフェニル）プロパンニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率４３％）を得た。 Using 3- (4-chloro-2,3-dimethoxyphenyl) propanenitrile, the title compound (43% yield) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例５７：５－｛３－［２－（２－フルオロ－３－ヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 57: 5- {3- [2- (2-fluoro-3-hydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　３－（２－フルオロ－３－メトキシフェニル）プロパンニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率６０％）を得た。 Using 3- (2-fluoro-3-methoxyphenyl) propanenitrile, the title compound (yield 60%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例５８：５－｛３－［２－（４－フルオロ－３－ヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 58: 5- {3- [2- (4-Fluoro-3-hydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　３－（４－フルオロ－３－メトキシフェニル）プロパンニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率５２％）を得た。 Using 3- (4-fluoro-3-methoxyphenyl) propanenitrile, the title compound (yield 52%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例５９：５－［３－（３－ヒドロキシ－４－メトキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 59: 5- [3- (3-hydroxy-4-methoxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　４－メトキシ－３－（メトキシメトキシ）ベンゾニトリルを用いて、参考例１２、１３、実施例３と同様にして表題化合物を得た。 Using 4-methoxy-3- (methoxymethoxy) benzonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.
実施例６０：５－［３－（２－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 60: 5- [3- (2-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　２－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物を得た。 Using 2-fluoro-3- (methoxymethoxy) benzonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.
実施例６１：３－ニトロ－５－｛３－［２－（２，４，５－トリフルオロ－３－ヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝ベンゼン－１，２－ジオール Example 61: 3-nitro-5- {3- [2- (2,4,5-trifluoro-3-hydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} benzene- 1,2-diol
　３－（２，４，５－トリフルオロ－３－メトキシフェニル）プロパンニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率４５％）を得た。 Using 3- (2,4,5-trifluoro-3-methoxyphenyl) propanenitrile, the title compound (yield 45%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.
実施例６２：５－｛３－［２－（３－フルオロ－４－ヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼンー１，２－ジオール Example 62: 5- {3- [2- (3-Fluoro-4-hydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　３－（３－フルオロ－４－メトキシフェニル）プロパンニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（５７％）を得た。 Using 3- (3-fluoro-4-methoxyphenyl) propanenitrile, the title compound (57%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例６３：５－［３－（４－クロロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 63: 5- [3- (4-Chloro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　４－クロロ－３－（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物を得た。 Using 4-chloro-3- (methoxymethoxy) benzonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.
実施例６４：５－［３－（４－フルオロ－３－メトキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 64: 5- [3- (4-Fluoro-3-methoxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　４－フルオロ－３－メトキシベンゾニトリルを用い、参考例１２、１３、実施例１と同様にして表題化合物を得た。 Using 4-fluoro-3-methoxybenzonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 1.
実施例６５：５－［３－（２，４－ジフルオロ－５－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 65: 5- [3- (2,4-difluoro-5-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　２，４－ジフルオロ－５－（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物を得た。 Using 2,4-difluoro-5- (methoxymethoxy) benzonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.
実施例６６：３－クロロ－４－［３－（３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－６－ニトロベンゼン－１，２－ジオール Example 66: 3-chloro-4- [3- (3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -6-nitrobenzene-1,2-diol
　３－（メトキシメトキシ）ベンゾニトリルと２－クロロ－３，４－ジメトキシ－５－ニトロベンゾイルクロリドを用いて、参考例１２、１３、実施例３と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Examples 12, 13, and Example 3 using 3- (methoxymethoxy) benzonitrile and 2-chloro-3,4-dimethoxy-5-nitrobenzoyl chloride.
実施例６７：４－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］－２－ヒドロキシベンゾニトリル Example 67: 4- [5- (3,4-Dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] -2-hydroxybenzonitrile
　（ａ）：４－ヨード－３－メトキシベンゾニトリルを用いて、参考例１２と同様にして５－（３，４－ジメトキシ－５－ニトロフェニル）－３－（４－ヨード－３－メトキシフェニル）－１，２，４－オキサジアゾールを得た。
　（ｂ）：（ａ）とシアン化銅（Ｉ）を反応させ、４－［５－（３，４－ジメトキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］－２－メトキシベンゾニトリルとし、参考例１３、実施例１、２と同様にして表題化合物（収率７％）を得た。 (A): 5- (3,4-dimethoxy-5-nitrophenyl) -3- (4-iodo-3-methoxyphenyl) using 4-iodo-3-methoxybenzonitrile in the same manner as in Reference Example 12. ) -1,2,4-oxadiazole was obtained.
(B): (a) is reacted with copper (I) cyanide to give 4- [5- (3,4-dimethoxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] The title compound (yield 7%) was obtained in the same manner as in Reference Example 13 and Examples 1 and 2, using -2-methoxybenzonitrile.
実施例６８：４－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］－３－フルオロベンゼン－１，２－ジオール Example 68: 4- [5- (3,4-Dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] -3-fluorobenzene-1,2-diol
　２－フルオロ－３，４－ジメトキシベンゾニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率１５％）を得た。 Using 2-fluoro-3,4-dimethoxybenzonitrile, the title compound (yield 15%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例６９：５－｛３－［２－（４－ヒドロキシベンゾ［ｄ］オキサゾール－７－イル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 69: 5- {3- [2- (4-hydroxybenzo [d] oxazol-7-yl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1, 2-diol
　３－［４－（メトキシメトキシ）ベンゾ［ｄ］オキサゾール－７－イル］プロパンニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（８％）を得た。 Using 3- [4- (methoxymethoxy) benzo [d] oxazol-7-yl] propanenitrile, the title compound (8%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3.
実施例７０：５－［３－（２，４－ジフルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 70: 5- [3- (2,4-difluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　２，４－ジフルオロ－３－（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率２３％）を得た。 Using 2,4-difluoro-3- (methoxymethoxy) benzonitrile, the title compound (23% yield) was obtained in the same manner as in Reference Examples 12, 13, and Example 3.
実施例７１：５－｛［３－（４－フルオロ－３－ヒドロキシフェニル）メチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 71: 5-{[3- (4-fluoro-3-hydroxyphenyl) methyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　２－［４－フルオロ－３－（メトキシメトキシ）フェニル］アセトニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率３９％）を得た。 Using 2- [4-fluoro-3- (methoxymethoxy) phenyl] acetonitrile, the title compound (yield 39%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3.
実施例７２：５－｛３－［２－（２，４－ジフルオロ－５－ヒドロキシフェニル）エチル）］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 72: 5- {3- [2- (2,4-difluoro-5-hydroxyphenyl) ethyl)]-1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2 -Diol
　３－［２，４－ジフルオロ－５－（メトキシメトキシ）フェニル］プロパンニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物を得た。 Using 3- [2,4-difluoro-5- (methoxymethoxy) phenyl] propanenitrile, the title compound was obtained in the same manner as in Reference Examples 12, 13, and Example 3.
実施例７３：５－（｛３－［（３，４－ジヒドロキシフェニル）スルファニル］メチル｝－１，２，４－オキサジアゾール－５－イル）－３－ニトロベンゼン－１，２－ジオール Example 73: 5-({3-[(3,4-dihydroxyphenyl) sulfanyl] methyl} -1,2,4-oxadiazol-5-yl) -3-nitrobenzene-1,2-diol
　２－［（３，４－ジメトキシフェニル）スルファニル］アセトニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率１９％）を得た。 Using 2-[(3,4-dimethoxyphenyl) sulfanyl] acetonitrile, the title compound (yield 19%) was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2.
実施例７４：５－｛３－［３－（４－フルオロ－３－ヒドロキシフェニル）プロピル］－１，２，４－オキサゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 74: 5- {3- [3- (4-fluoro-3-hydroxyphenyl) propyl] -1,2,4-oxazol-5-yl} -3-nitrobenzene-1,2-diol
　４－［４－フルオロ－３－（メトキシメトキシ）フェニル］ブタンニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率２８％）を得た。 Using 4- [4-fluoro-3- (methoxymethoxy) phenyl] butanenitrile, the title compound (yield 28%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.
実施例７５：５－［３－（２－フルオロ－５－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 75: 5- [3- (2-Fluoro-5-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　２－フルオロ－５－メトキシベンゾニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率４０％）を得た。 Using 2-fluoro-5-methoxybenzonitrile, the title compound (yield 40%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例７６：５－［３－（２－クロロ－５－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 76: 5- [3- (2-Chloro-5-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　２－クロロ－５－メトキシベンゾニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率１２％）を得た。 Using 2-chloro-5-methoxybenzonitrile, the title compound (yield 12%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例７７：５－［３－（３，４－ジフルオロ－５－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 77: 5- [3- (3,4-difluoro-5-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　３，４－ジフルオロ－５－（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率３６％）を得た。 Using 3,4-difluoro-5- (methoxymethoxy) benzonitrile, the title compound (yield 36%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3.
実施例７８：５－［３－（４－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 78: 5- [3- (4-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　４－メトキシベンゾニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率１３％）を得た。 Using 4-methoxybenzonitrile, the title compound (yield 13%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例７９：５－［３－（４－フルオロ－２，３－ジヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 79: 5- [3- (4-Fluoro-2,3-dihydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　４－フルオロ－２，３－ジメトキシベンゾニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率１６％）を得た。 Using 4-fluoro-2,3-dimethoxybenzonitrile, the title compound (yield 16%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例８０：３－クロロ－４－｛３－［２－（４－フルオロ－３－ヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－６－ニトロベンゼン－１，２－ジオール Example 80: 3-chloro-4- {3- [2- (4-fluoro-3-hydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -6-nitrobenzene-1, 2-diol
　３－［４－フルオロ－３－（メトキシメトキシ）フェニル］プロパンニトリルと２－クロロ－３，４－ジメトキシ－５－ニトロベンゾイルクロリドを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率９％）を得た。 Using 3- [4-fluoro-3- (methoxymethoxy) phenyl] propanenitrile and 2-chloro-3,4-dimethoxy-5-nitrobenzoyl chloride in the same manner as in Reference Examples 12, 13, and Example 3, A compound (yield 9%) was obtained.
実施例８１：４－｛２－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］エチル｝－３－フルオロベンゼン－１，２－ジオール Example 81: 4- {2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] ethyl} -3-fluorobenzene-1,2 -Diol
　３－（２－フルオロ－３，４－ジメトキシフェニル）プロパンニトリルを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率７％）を得た。 Using 3- (2-fluoro-3,4-dimethoxyphenyl) propanenitrile, the title compound (yield 7%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例８２：３－クロロ－４－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－６－ニトロベンゼン－１，２－ジオール Example 82: 3-chloro-4- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -6-nitrobenzene-1,2-diol
　４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルと２－クロロ－３，４－ジメトキシ－５－ニトロベンゾイルクロリドを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率１７％）を得た。 Using 4-fluoro-3- (methoxymethoxy) benzonitrile and 2-chloro-3,4-dimethoxy-5-nitrobenzoyl chloride in the same manner as in Reference Examples 12, 13, and Example 3, the title compound (yield 17 %).
実施例８３：３－クロロ－４－｛３－［２－（２，４－ジフルオロ－５－ヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－６－ニトロベンゼン－１，２－ジオール Example 83 3-chloro-4- {3- [2- (2,4-difluoro-5-hydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -6-nitrobenzene- 1,2-diol
　３－［２，４－ジフルオロ－５－（メトキシメトキシ）フェニル］プロパンニトリルと２－クロロ－３，４－ジメトキシ－５－ニトロベンゾイルクロリドを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率３１％）を得た。 Using 3- [2,4-difluoro-5- (methoxymethoxy) phenyl] propanenitrile and 2-chloro-3,4-dimethoxy-5-nitrobenzoyl chloride in the same manner as in Reference Examples 12, 13, and Example 3. To give the title compound (yield 31%).
実施例８４：５－（｛３－［（４－フルオロ－３－ヒドロキシフェニル）スルファニル］メチル｝－１，２，４－オキサジアゾール－５－イル）－３－ニトロベンゼン－１，２－ジオール Example 84: 5-({3-[(4-fluoro-3-hydroxyphenyl) sulfanyl] methyl} -1,2,4-oxadiazol-5-yl) -3-nitrobenzene-1,2-diol
　２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝アセトニトリルを用いて、参考例１２、１３、実施例３と同様にして表題化合物を得た。 Using 2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} acetonitrile, the title compound was obtained in the same manner as in Reference Examples 12 and 13 and Example 3.
実施例８５：２，３－ジヒドロキシ－６－［３－（３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－４－ニトロベンゾニトリル Example 85: 2,3-dihydroxy-6- [3- (3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -4-nitrobenzonitrile
　２－（メトキシメトキシ）ベンゾニトリルと２－シアノ－３，４－ジメトキシ－５－ニトロベンゾイルクロリドを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率３０％）を得た。 Using 2- (methoxymethoxy) benzonitrile and 2-cyano-3,4-dimethoxy-5-nitrobenzoyl chloride, the title compound (yield 30%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3. It was.
実施例８６：５－｛３－［（１Ｒ＊，２Ｒ＊）－２－（２，４－ジフルオロ－５－ヒドロキシフェニル）シクロプロピル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 86: 5- {3-[(1R * , 2R * )-2- (2,4-difluoro-5-hydroxyphenyl) cyclopropyl] -1,2,4-oxadiazol-5-yl} -3-Nitrobenzene-1,2-diol
　（１Ｒ＊，２Ｒ＊）－２－［２，４－ジフルオロ－５－（メトキシメトキシ）フェニル］シクロプロパン－１－カルボニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率５９％）を得た。 (1R * , 2R * )-2- [2,4-Difluoro-5- (methoxymethoxy) phenyl] cyclopropane-1-carbonitrile was used in the same manner as in Reference Examples 12, 13, and Example 3 to give the title compound. (Yield 59%) was obtained.
実施例８７：５－｛３－［（１Ｒ＊，２Ｓ＊）－２－（２，４－ジフルオロ－５－ヒドロキシフェニル）シクロプロピル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 87: 5- {3-[(1R * , 2S * )-2- (2,4-difluoro-5-hydroxyphenyl) cyclopropyl] -1,2,4-oxadiazol-5-yl} -3-Nitrobenzene-1,2-diol
　（１Ｒ＊，２Ｓ＊）－２－［２，４－ジフルオロ－５－（メトキシメトキシ）フェニル］シクロプロパン－１－カルボニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率４１％）を得た。 (1R * , 2S * )-2- [2,4-Difluoro-5- (methoxymethoxy) phenyl] cyclopropane-1-carbonitrile was used in the same manner as in Reference Examples 12, 13, and Example 3 to give the title compound. (Yield 41%) was obtained.
実施例８８：５－［３－（５－ヒドロキシピリジン－３－イル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 88: 5- [3- (5-hydroxypyridin-3-yl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　３－シアノ－５－（メトキシメトキシ）ピリジンを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率８％）を得た。 Using 3-cyano-5- (methoxymethoxy) pyridine, the title compound (yield 8%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3.
実施例８９：５－［３－（４－ヒドロキシピリジン－２－イル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 89: 5- [3- (4-hydroxypyridin-2-yl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　２－シアノ－４－メトキシピリジンを用い、参考例１２、１３、実施例１、２と同様にして表題化合物（収率１７％）を得た。 Using 2-cyano-4-methoxypyridine, the title compound (yield 17%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例９０：４－（｛［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］メチル｝スルファニル）－２－ヒドロキシベンゾニトリル Example 90: 4-({[5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] methyl} sulfanyl) -2-hydroxybenzonitrile
　４－（シアノメチル）スルファニル－２－（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率１１％）を得た。 Using 4- (cyanomethyl) sulfanyl-2- (methoxymethoxy) benzonitrile, the title compound (yield 11%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3.
実施例９１：５－（３－｛［（４－フルオロ－３－ヒドロキシフェニル）スルホニル］メチル｝－１，２，４－オキサジアゾール－５－イル）－３－ニトロベンゼン－１，２－ジオール Example 91: 5- (3-{[(4-Fluoro-3-hydroxyphenyl) sulfonyl] methyl} -1,2,4-oxadiazol-5-yl) -3-nitrobenzene-1,2-diol
　２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルホニル｝アセトニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率１１％）を得た。 Using 2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfonyl} acetonitrile, the title compound (yield 11%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3.
実施例９２：５－［３－（６－ヒドロキシピリジン－２－イル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 92: 5- [3- (6-Hydroxypyridin-2-yl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　２－シアノ－６－メトキシピリジンを用い、参考例１２、１３、実施例１，２と同様にして表題化合物（収率４１％）を得た。 Using 2-cyano-6-methoxypyridine, the title compound (yield 41%) was obtained in the same manner as in Reference Examples 12 and 13, and Examples 1 and 2.
実施例９３：４－フルオロ－５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 93: 4-fluoro-5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　２－フルオロ－４，５－ジメトキシ－３－ニトロベンゾイルクロリドと４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率２８％）を得た。 Using 2-fluoro-4,5-dimethoxy-3-nitrobenzoyl chloride and 4-fluoro-3- (methoxymethoxy) benzonitrile in the same manner as in Reference Examples 12, 13, and Example 3, the title compound (yield) 28%).
実施例９４：６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロベンゾニトリル Example 94: 6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrobenzonitrile
　２－シアノ－４，５－ジメトキシ－３－ニトロベンゾイルクロリドと４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率１４％）を得た。 Using 2-cyano-4,5-dimethoxy-3-nitrobenzoyl chloride and 4-fluoro-3- (methoxymethoxy) benzonitrile in the same manner as in Reference Examples 12, 13, and Example 3, the title compound (yield) 14%).
実施例９５：３－クロロ－４－（３－｛［（４－フルオロ－３－ヒドロキシフェニル）スルファニル］メチル｝－１，２，４－オキサジアゾール－５－イル）－６－ニトロベンゼン－１，２－ジオール Example 95: 3-chloro-4- (3-{[(4-fluoro-3-hydroxyphenyl) sulfanyl] methyl} -1,2,4-oxadiazol-5-yl) -6-nitrobenzene-1 , 2-diol
　２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝アセトニトリルと２－クロロ－３，４－ジメトキシ－５－ニトロベンゾイルクロリドを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率３５％）を得た。 2-{[4-Fluoro-3- (methoxymethoxy) phenyl] sulfanyl} acetonitrile and 2-chloro-3,4-dimethoxy-5-nitrobenzoyl chloride were used in the same manner as in Reference Examples 12, 13, and Example 3. To give the title compound (yield 35%).
実施例９６：４－クロロ－５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 96 4-chloro-5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　参考例２４で製造した２－クロロ－４，５－ジメトキシ－３－ニトロ安息香酸を塩化チオニルで２－クロロ－４，５－ジメトキシ－３－ニトロベンゾイルクロリドとした後、２－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率６０％）を得た。 2-Chloro-4,5-dimethoxy-3-nitrobenzoic acid prepared in Reference Example 24 was converted to 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, and then 2-fluoro-3- The title compound (yield 60%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3 using (methoxymethoxy) benzonitrile.
実施例９７：３－クロロ－４－｛３－［（１Ｒ＊，２Ｒ＊）－２－（４－フルオロ－３－ヒドロキシフェニル）シクロプロピル］－１，２，４－オキサジアゾール－５－イル｝－６－ニトロベンゼン－１，２－ジオール Example 97: 3-chloro-4- {3-[(1R * , 2R * )-2- (4-fluoro-3-hydroxyphenyl) cyclopropyl] -1,2,4-oxadiazole-5 Il} -6-nitrobenzene-1,2-diol
　（１Ｒ＊，２Ｒ＊）－２－［４－フルオロ－３－（メトキシメトキシ）フェニル］シクロプロパン－１－カルボニトリルと２－クロロ－３，４－ジメトキシ－５－ニトロベンゾイルクロリドを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率９％）を得た。 (1R * , 2R * )-2- [4-Fluoro-3- (methoxymethoxy) phenyl] cyclopropane-1-carbonitrile and 2-chloro-3,4-dimethoxy-5-nitrobenzoyl chloride The title compound (yield 9%) was obtained in the same manner as in Examples 12, 13 and Example 3.
実施例９８：４－クロロ－５－｛３－［（３－ヒドロキシフェニル）メチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 98: 4-chloro-5- {3-[(3-hydroxyphenyl) methyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2-diol
　２－［３－（メトキシメトキシ）フェニル］アセトニトリルと２－クロロ－４，５－ジメトキシ－３－ニトロベンゾイルクロリドを用いて、参考例１２、１３、実施例３と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Examples 12, 13 and Example 3 using 2- [3- (methoxymethoxy) phenyl] acetonitrile and 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride. .
実施例９９：４－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－６－ニトロ－３－（トリフルオロメチル）ベンゼン－１，２－ジオール Example 99: 4- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -6-nitro-3- (trifluoromethyl) benzene-1, 2-diol
　３，４－ジメトキシ－５－ニトロ－２－（トリフルオロメチル）ベンゾイルクロリドと４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率１７％）を得た。 Using 3,4-dimethoxy-5-nitro-2- (trifluoromethyl) benzoyl chloride and 4-fluoro-3- (methoxymethoxy) benzonitrile in the same manner as in Reference Examples 12, 13, and Example 3, A compound (yield 17%) was obtained.
実施例１００：４－クロロ－５－［３－（３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 100: 4-chloro-5- [3- (3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　２－［３－（メトキシメトキシ）フェニル］アセトニトリルと２－クロロ－４，５－ジメトキシ－３－ニトロベンゾイルクロリドを用いて、参考例１２、１３、実施例３と同様にして表題化合物（７２％）を得た。 Using 2- [3- (methoxymethoxy) phenyl] acetonitrile and 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride in the same manner as in Reference Examples 12, 13, and Example 3, the title compound (72% )
実施例１０１：３－クロロ－４－（｛３－［ジフルオロ－（４－フルオロ－３－ヒドロキシフェニル）スルファニル］メチル｝－１，２，４－オキサジアゾール－５－イル）－６－ニトロベンゼン－１，２－ジオール Example 101: 3-chloro-4-({3- [difluoro- (4-fluoro-3-hydroxyphenyl) sulfanyl] methyl} -1,2,4-oxadiazol-5-yl) -6-nitrobenzene -1,2-diol
　参考例７で製造した２，２－ジフルオロ－２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝－Ｎ－ヒドロキシアセトイミダミドと２－クロロ－３，４－ジメトキシ－５－ニトロベンゾイルクロリドを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率３８％）を得た。 2,2-Difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} -N-hydroxyacetimidamide prepared in Reference Example 7 and 2-chloro-3,4-dimethoxy-5- The title compound (38% yield) was obtained in the same manner as in Reference Examples 12, 13, and Example 3 using nitrobenzoyl chloride.
実施例１０２：５－［３－（３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロ－４－（トリフルオロメチル）ベンゼン－１，２－ジオール Example 102: 5- [3- (3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitro-4- (trifluoromethyl) benzene-1,2-diol
　参考例１５で製造した４－（ベンジルオキシ）－５－メトキシ－２－（トリフルオロメチル）安息香酸と３－（メトキシメトキシ）ベンゾニトリルを用い、参考例１６、１７、実施例３と同様にして表題化合物を得た。 Using 4- (benzyloxy) -5-methoxy-2- (trifluoromethyl) benzoic acid and 3- (methoxymethoxy) benzonitrile prepared in Reference Example 15 in the same manner as Reference Examples 16, 17, and Example 3. To give the title compound.
実施例１０３：４－［５－（２－クロロ－３，４－ジヒドロキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］－２－ヒドロキシベンゾニトリル Example 103: 4- [5- (2-Chloro-3,4-dihydroxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] -2-hydroxybenzonitrile
　（ａ）：４－ヨード－３－メトキシベンゾニトリルと２－クロロ－３，４－ジメトキシ－５－ニトロベンゾイルクロリドを用いて、参考例１２と同様にして５－（２－クロロ－３，４－ジメトキシ－５－ニトロフェニル）－３－（４－ヨード－３－メトキシフェニル）－１，２，４－オキサジアゾールを得た。
　（ｂ）：（ａ）にシアン化銅（Ｉ）を反応させ、４－［５－（２－クロロ－３，４－ジメトキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］－２－メトキシベンゾニトリルとし、参考例１３、実施例１、２と同様にして表題化合物を得た。 (A): 5- (2-chloro-3,4) in the same manner as in Reference Example 12 using 4-iodo-3-methoxybenzonitrile and 2-chloro-3,4-dimethoxy-5-nitrobenzoyl chloride. -Dimethoxy-5-nitrophenyl) -3- (4-iodo-3-methoxyphenyl) -1,2,4-oxadiazole was obtained.
(B): (a) is reacted with copper (I) cyanide to give 4- [5- (2-chloro-3,4-dimethoxy-5-nitrophenyl) -1,2,4-oxadiazole- 3-yl] -2-methoxybenzonitrile was used, and the title compound was obtained in the same manner as in Reference Example 13 and Examples 1 and 2.
実施例１０４：６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－２，３－ジヒドロキシ－４－ニトロベンゾニトリル Example 104: 6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -2,3-dihydroxy-4-nitrobenzonitrile
　２－シアノ－３，４－ジメトキシ－５－ニトロベンゾイルクロリドと４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率２６％）を得た。 Using 2-cyano-3,4-dimethoxy-5-nitrobenzoyl chloride and 4-fluoro-3- (methoxymethoxy) benzonitrile in the same manner as in Reference Examples 12, 13, and Example 3, the title compound (yield) 26%).
実施例１０５：６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロ安息香酸 Example 105: 6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrobenzoic acid
　実施例９４で製造した６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロベンゾニトリルを実施例５と同様にして表題化合物（収率４％）を得た。 6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrobenzonitrile prepared in Example 94 was carried out In the same manner as in Example 5, the title compound (yield 4%) was obtained.
実施例１０６：３－フルオロ－４－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－６－ニトロベンゼン－１，２－ジオール Example 106: 3-fluoro-4- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -6-nitrobenzene-1,2-diol
　２－フルオロ－３，４－ジヒドロキシ－５－ニトロベンゾイルクロリドと４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率３８％）を得た。 Using 2-fluoro-3,4-dihydroxy-5-nitrobenzoyl chloride and 4-fluoro-3- (methoxymethoxy) benzonitrile in the same manner as in Reference Examples 12, 13, and Example 3, the title compound (yield) 38%).
実施例１０７：６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－２，３－ジヒドロキシ－４－ニトロ安息香酸 Example 107: 6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -2,3-dihydroxy-4-nitrobenzoic acid
　実施例１０４で製造した６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－２，３－ジヒドロキシ－４－ニトロベンゾニトリルを実施例５と同様にして表題化合物（収率２％）を得た。 6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -2,3-dihydroxy-4-nitrobenzonitrile prepared in Example 104 was carried out In the same manner as in Example 5, the title compound (yield 2%) was obtained.
実施例１０８：５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロ－４－（フェニルスルファニル）ベンゼン－１，２－ジオール Example 108: 5- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitro-4- (phenylsulfanyl) benzene-1,2 -Diol
　参考例２５で製造した４，５－ジメトキシ－３－ニトロ－２－（フェニルスルファニル）安息香酸を塩化チオニルで４，５－ジメトキシ－３－ニトロ－２－（フェニルスルファニル）ベンゾイルクロリドとした後、４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率５８％）を得た。 After 4,5-dimethoxy-3-nitro-2- (phenylsulfanyl) benzoic acid produced in Reference Example 25 was converted to 4,5-dimethoxy-3-nitro-2- (phenylsulfanyl) benzoyl chloride with thionyl chloride, The title compound (yield 58%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3 using 4-fluoro-3- (methoxymethoxy) benzonitrile.
実施例１０９：５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロ－４－（フェニルスルホニル）ベンゼン－１，２－ジオール Example 109: 5- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitro-4- (phenylsulfonyl) benzene-1,2 -Diol
　参考例２６で製造した４，５－ジメトキシ－３－ニトロ－２－（フェニルスルホニル）安息香酸を塩化チオニルで４，５－ジメトキシ－３－ニトロ－２－（フェニルスルホニル）ベンゾイルクロリドとした後、４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率２６％）を得た。 4,5-Dimethoxy-3-nitro-2- (phenylsulfonyl) benzoic acid prepared in Reference Example 26 was converted to 4,5-dimethoxy-3-nitro-2- (phenylsulfonyl) benzoyl chloride with thionyl chloride. The title compound (yield 26%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3 using 4-fluoro-3- (methoxymethoxy) benzonitrile.
実施例１１０：５－（｛３－［（４－フルオロ－３－ヒドロキシフェニル）メチル］アミノ｝－１，２，４－オキサジアゾール－５－イル）－３－ニトロベンゼン－１，２－ジオール Example 110: 5-({3-[(4-fluoro-3-hydroxyphenyl) methyl] amino} -1,2,4-oxadiazol-5-yl) -3-nitrobenzene-1,2-diol
　（ａ）：４，５－ジメトキシ－５－ニトロベンゾイルクロリドと１－ｔｅｒｔ－ブトキシカルボニル－グアニジンをピリジン中で反応させ、Ｎ，Ｎ－（ｔｅｒｔ－ブトキシカルバミドリル）－３，４－ジメトキシ－５－ニトロベンズアミドを得た。
　（ｂ）：（ａ）とヨードベンゼンジアセタートをＮ，Ｎ－ジメチルホルムアミド溶液中で反応させ、ｔｅｒｔ－ブチル［５－（３，４－ジメトキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］カルバメートを得た。
　（ｃ）：（ｂ）のジクロロメタン溶液にトリフルオロ酢酸を反応させ、３－アミノ－５－（３，４－ジメトキシ－５－ニトロフェニル）－１，２，４－オキサジアゾールを得た。
　（ｄ）：（ｃ）のテトラヒドロフラン溶液に、リチウムビス（トリメチルシリル）アミド、トリフルオロ酢酸無水物を反応させ、Ｎ－［５－（３，４－ジメトキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］－２，２，２－トリフルオロアセトアミドを得た。
　（ｅ）：（ｄ）のテトラヒドロフラン溶液に［４－フルオロ－３－（メトキシメトキシ）フェニル］メタノール、トリフェニルホスフィン、アゾジカルボン酸ビス（２－メトキシエチル）を反応させ、Ｎ－［５－（３，４－ジメトキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］－２，２，２－トリフルオロ－Ｎ－［４－フルオロ－３－（メトキシメトキシ）ベンジル］アセトアミドを得た。これを、参考例１３、実施例３と同様にして表題化合物（収率０．５％）を得た。 (A): 4,5-dimethoxy-5-nitrobenzoyl chloride and 1-tert-butoxycarbonyl-guanidine are reacted in pyridine, and N, N- (tert-butoxycarbamidolyl) -3,4-dimethoxy-5 -Nitrobenzamide was obtained.
(B): (a) is reacted with iodobenzene diacetate in an N, N-dimethylformamide solution to give tert-butyl [5- (3,4-dimethoxy-5-nitrophenyl) -1,2,4 -Oxadiazol-3-yl] carbamate was obtained.
(C): Trichloroacetic acid was reacted with the dichloromethane solution of (b) to obtain 3-amino-5- (3,4-dimethoxy-5-nitrophenyl) -1,2,4-oxadiazole.
(D): Lithium bis (trimethylsilyl) amide and trifluoroacetic anhydride are reacted with a tetrahydrofuran solution of (c) to give N- [5- (3,4-dimethoxy-5-nitrophenyl) -1,2, 4-Oxadiazol-3-yl] -2,2,2-trifluoroacetamide was obtained.
(E): [4-fluoro-3- (methoxymethoxy) phenyl] methanol, triphenylphosphine, azodicarboxylate bis (2-methoxyethyl) was reacted with the tetrahydrofuran solution of (d), and N- [5- ( 3,4-dimethoxy-5-nitrophenyl) -1,2,4-oxadiazol-3-yl] -2,2,2-trifluoro-N- [4-fluoro-3- (methoxymethoxy) benzyl Acetamide was obtained. The title compound (yield 0.5%) was obtained in the same manner as in Reference Example 13 and Example 3.
実施例１１１：３－クロロ－４－｛３－［３－ヒドロキシ－４－（トリフルオロメチル）フェニル］－１，２，４－オキサジアゾール－５－イル｝－６－ニトロベンゼン－１，２－ジオール Example 111: 3-chloro-4- {3- [3-hydroxy-4- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-5-yl} -6-nitrobenzene-1,2 -Diol
　３－（メトキシメトキシ）－４－（トリフルオロメチル）ベンゾニトリルとと２－クロロ－３，４－ジメトキシ－５－ニトロベンゾイルクロリドを用いて、参考例１２、１３、実施例３と同様にして表題化合物を得た。 In the same manner as in Reference Examples 12, 13, and Example 3 using 3- (methoxymethoxy) -4- (trifluoromethyl) benzonitrile and 2-chloro-3,4-dimethoxy-5-nitrobenzoyl chloride The title compound was obtained.
実施例１１２：５－｛３－［（１Ｒ＊，２Ｒ＊）－２－（４－フルオロ－３－ヒドロキシフェニル）シクロプロピル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロ－４－（トリフルオロメチル）ベンゼン－１，２－ジオール Example 112: 5- {3-[(1R * , 2R * )-2- (4-fluoro-3-hydroxyphenyl) cyclopropyl] -1,2,4-oxadiazol-5-yl} -3 -Nitro-4- (trifluoromethyl) benzene-1,2-diol
　参考例２７で製造した４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）安息香酸を塩化チオニルで４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）ベンゾイルクロリドとした後、（１Ｒ＊，２Ｒ＊）－２－［４－フルオロ－３－（メトキシメトキシ）フェニル］シクロプロパン－１－カルボニトリルを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率１７％）を得た。 4,5-Dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid prepared in Reference Example 27 was converted to 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoyl chloride with thionyl chloride. Thereafter, (1R * , 2R * )-2- [4-fluoro-3- (methoxymethoxy) phenyl] cyclopropane-1-carbonitrile was used in the same manner as in Reference Examples 12 and 13 and Example 3. A compound (yield 17%) was obtained.
実施例１１３：４－クロロ－５－｛３－［３－（４－フルオロ－３－ヒドロキシフェニル）プロピル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 113: 4-chloro-5- {3- [3- (4-fluoro-3-hydroxyphenyl) propyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1, 2-diol
　参考例２３で製造した２－クロロ－４，５－ジメトキシ－３－ニトロ安息香酸を塩化チオニルで２－クロロ－４，５－ジメトキシ－３－ニトロベンゾイルクロリドとした後、４－［４－フルオロ－３－（メトキシメトキシ）フェニル］ブタンニトリルを用いて参考例１２、１３、実施例３と同様にして表題化合物を得た。 2-Chloro-4,5-dimethoxy-3-nitrobenzoic acid prepared in Reference Example 23 was converted to 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, and then 4- [4-fluoro The title compound was obtained in the same manner as in Reference Examples 12, 13, and Example 3 using -3- (methoxymethoxy) phenyl] butanenitrile.
実施例１１４：４－クロロ－５－｛３－［（１Ｒ＊，２Ｒ＊）－２－（４－フルオロ－３－ヒドロキシフェニル）シクロプロピル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 114: 4-chloro-5- {3-[(1R * , 2R * )-2- (4-fluoro-3-hydroxyphenyl) cyclopropyl] -1,2,4-oxadiazole-5 Il} -3-nitrobenzene-1,2-diol
　参考例２４で製造した２－クロロ－４，５－ジメトキシ－３－ニトロ安息香酸を塩化チオニルで２－クロロ－４，５－ジメトキシ－３－ニトロベンゾイルクロリドとした後、（１Ｒ＊，２Ｒ＊）－２－［４－フルオロ－３－（メトキシメトキシ）フェニル］シクロプロパン－１－カルボニトリルを用いて、参考例１２、１３、実施例３と同様にして表題化合物（６２％）を得た。 2-Chloro-4,5-dimethoxy-3-nitrobenzoic acid produced in Reference Example 24 was converted to 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, and then (1R * , 2R * ) -2- [4-Fluoro-3- (methoxymethoxy) phenyl] cyclopropane-1-carbonitrile was used in the same manner as in Reference Examples 12, 13, and Example 3 to obtain the title compound (62%). .
実施例１１５：５－｛３－［２－（４－フルオロ－３－ヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロ－４－（トリフルオロメチル）ベンゼン－１，２－ジオール Example 115: 5- {3- [2- (4-fluoro-3-hydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitro-4- (trifluoromethyl ) Benzene-1,2-diol
　参考例２７で製造した４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）安息香酸を塩化チオニルで４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）ベンゾイルクロリドとした後、３－［４－フルオロ－３－（メトキシメトキシ）フェニル］プロパンニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率１４％）を得た。 4,5-Dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid prepared in Reference Example 27 was converted to 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoyl chloride with thionyl chloride. Thereafter, 3- [4-fluoro-3- (methoxymethoxy) phenyl] propanenitrile was used in the same manner as in Reference Examples 12, 13, and Example 3 to obtain the title compound (yield 14%).
実施例１１６：（Ｅ）－４－クロロ－５－｛３－［（４－フルオロ－３－ヒドロキシフェニル）エテン－２－イル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 116: (E) -4-chloro-5- {3-[(4-fluoro-3-hydroxyphenyl) ethen-2-yl] -1,2,4-oxadiazol-5-yl}- 3-Nitrobenzene-1,2-diol
　参考例２４で製造した２－クロロ－４，５－ジメトキシ－３－ニトロ安息香酸を塩化チオニルで２－クロロ－４，５－ジメトキシ－３－ニトロベンゾイルクロリドとした後、（Ｅ）－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］アクリロニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率１５％）を得た。 After 2-chloro-4,5-dimethoxy-3-nitrobenzoic acid prepared in Reference Example 24 was converted to 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, (E) -3- [4-Fluoro-3- (methoxymethoxy) phenyl] acrylonitrile was used in the same manner as in Reference Examples 12, 13 and Example 3 to obtain the title compound (yield 15%).
実施例１１７：（Ｅ）－５－｛［３－（４－フルオロ－３－ヒドロキシフェニル）エテン－２－イル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロ－４－（トリフルオロメチル）ベンゼン－１，２－ジオール Example 117: (E) -5-{[3- (4-fluoro-3-hydroxyphenyl) ethen-2-yl] -1,2,4-oxadiazol-5-yl} -3-nitro- 4- (Trifluoromethyl) benzene-1,2-diol
　参考例２７で製造した４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）安息香酸を塩化チオニルで４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）ベンゾイルクロリドとした後、（Ｅ）－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］アクリロニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物を得た。 4,5-Dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid prepared in Reference Example 27 was converted to 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoyl chloride with thionyl chloride. Thereafter, the title compound was obtained in the same manner as in Reference Examples 12, 13, and Example 3 using (E) -3- [4-fluoro-3- (methoxymethoxy) phenyl] acrylonitrile.
実施例１１８：５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロ－４－フェノキシベンゼン－１，２－ジオール Example 118: 5- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitro-4-phenoxybenzene-1,2-diol
　参考例２２で製造した５－［４－（ベンジルオキシ）－５－メトキシ－２－フェノキシフェニル］－３－（４－フルオロ－３－メトキシフェニル）－１，２，４－オキサジアゾールを参考例１９と同様にした後、参考例１７、実施例３と同様にして表題化合物を得た。 Reference was made to 5- [4- (benzyloxy) -5-methoxy-2-phenoxyphenyl] -3- (4-fluoro-3-methoxyphenyl) -1,2,4-oxadiazole prepared in Reference Example 22 After the same procedure as in Example 19, the title compound was obtained in the same manner as in Reference Example 17 and Example 3.
実施例１１９：４－クロロ－５－｛３－［（４－フルオロ－３－ヒドロキシフェノキシ）メチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 119: 4-chloro-5- {3-[(4-fluoro-3-hydroxyphenoxy) methyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene-1,2- Diol
　参考例２４で製造した２－クロロ－４，５－ジメトキシ－３－ニトロ安息香酸を塩化チオニルで２－クロロ－４，５－ジメトキシ－３－ニトロベンゾイルクロリドとした後、参考例２０で得た２－［４－フルオロ－３－（メトキシメトキシ）フェノキシ］アセトニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物を得た。 The 2-chloro-4,5-dimethoxy-3-nitrobenzoic acid produced in Reference Example 24 was converted to 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride and then obtained in Reference Example 20. The title compound was obtained in the same manner as in Reference Examples 12, 13, and Example 3 using 2- [4-fluoro-3- (methoxymethoxy) phenoxy] acetonitrile.
実施例１２０：５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－４－（メチルスルファニル）－３－ニトロベンゼン－１，２－ジオール Example 120: 5- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -4- (methylsulfanyl) -3-nitrobenzene-1,2- Diol
　参考例２８で製造した４，５－ジメトキシ－２－（メチルスルファニル）－３－ニトロ安息香酸を塩化チオニルで４，５－ジメトキシ－２－（メチルスルファニル）－３－ニトロベンゾイルクロリドとした後、４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率７５％）を得た。 4,5-Dimethoxy-2- (methylsulfanyl) -3-nitrobenzoic acid produced in Reference Example 28 was converted to 4,5-dimethoxy-2- (methylsulfanyl) -3-nitrobenzoyl chloride with thionyl chloride, Using 4-fluoro-3- (methoxymethoxy) benzonitrile, the title compound (yield 75%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3.
実施例１２１：５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－４－（メチルスルホニル）－３－ニトロベンゼン－１，２－ジオール Example 121: 5- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -4- (methylsulfonyl) -3-nitrobenzene-1,2- Diol
　（ａ）：５－［４，５－ジメトキシ－２－（メチルスルファニル）－３－ニトロフェニル］－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール（０．２６ｇ）の酢酸エチル（５．０ｍＬ）溶液に、３－クロロ過安息香酸（３００ｍｇ）を加え、室温で１８時間撹拌した。反応液に１Ｍ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、５－［４，５－ジメトキシ－２－（メチルスルホニル）－３－ニトロフェニル］－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール（０．２１ｇ）を得た。
　（ｂ）：（ａ）を参考例１３、実施例３と同様にして表題化合物（６３％）を得た。 (A): 5- [4,5-Dimethoxy-2- (methylsulfanyl) -3-nitrophenyl] -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxadi 3-Chloroperbenzoic acid (300 mg) was added to a solution of azole (0.26 g) in ethyl acetate (5.0 mL), and the mixture was stirred at room temperature for 18 hours. To the reaction solution was added 1M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to give 5- [4,5-dimethoxy-2- (methylsulfonyl) -3-nitrophenyl] -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4. -Oxadiazole (0.21 g) was obtained.
(B): The title compound (63%) was obtained in the same manner as in Reference Example 13 and Example 3 in (a).
実施例１２２：５－（３－｛ジフルオロ［（４－フルオロ－３－ヒドロキシフェニル）スルファニル］メチル｝－１，２，４－オキサジアゾール－５－イル）－４－（メチルスルファニル）－３－ニトロベンゼン－１，２－ジオール Example 122: 5- (3- {difluoro [(4-fluoro-3-hydroxyphenyl) sulfanyl] methyl} -1,2,4-oxadiazol-5-yl) -4- (methylsulfanyl) -3 -Nitrobenzene-1,2-diol
　参考例２８で製造した４，５－ジメトキシ－２－（メチルスルファニル）－３－ニトロ安息香酸を塩化チオニルで４，５－ジメトキシ－２－（メチルスルファニル）－３－ニトロベンゾイルクロリドとした後、参考例７で得た２，２－ジフルオロ－２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝－Ｎ－ヒドロキシアセトイミダミドを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率１７％）を得た。 4,5-Dimethoxy-2- (methylsulfanyl) -3-nitrobenzoic acid produced in Reference Example 28 was converted to 4,5-dimethoxy-2- (methylsulfanyl) -3-nitrobenzoyl chloride with thionyl chloride, Using 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} -N-hydroxyacetimidamide obtained in Reference Example 7, Reference Examples 12 and 13, Example 3 and In the same manner, the title compound (yield 17%) was obtained.
実施例１２３：５－（３，４－ジヒドロキシ－５－ニトロフェニル）－Ｎ－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－３－カルボキサミド Example 123: 5- (3,4-dihydroxy-5-nitrophenyl) -N- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-3-carboxamide
　（ａ）：シアノギ酸メチルを用いて、参考例１２と同様にして５－（３，４－ジメトキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－カルボン酸メチルを得た。
　（ｂ）：（ａ）を参考例２７（ｅ）と同様にして、５－（３，４－ジメトキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－カルボン酸を得た。
　（ｃ）：（ｂ）にオキザリルクロリドを反応させ、５－（３，４－ジメトキシ－５－ニトロフェニル）－１，２，４－オキサジアゾール－３－ベンゾイルクロリドを得た。
　（ｄ）（ｃ）に４－フルオロ－３－（メトキシメトキシ）アニリンを反応させ、５－（３，４－ジメトキシ－５－ニトロフェニル）－Ｎ－［４－フルオロ－３－（メトキシメトキシ）フェニル］１，２，４－オキサジアゾール－３－カルボキサミドとし、参考例１３、実施例３と同様にして表題化合物（収率２８％）を得た。 (A): Methyl 5- (3,4-dimethoxy-5-nitrophenyl) -1,2,4-oxadiazole-3-carboxylate was obtained in the same manner as in Reference Example 12 using methyl cyanoformate. It was.
(B): 5- (3,4-Dimethoxy-5-nitrophenyl) -1,2,4-oxadiazole-3-carboxylic acid is obtained by treating (a) in the same manner as in Reference Example 27 (e). It was.
(C): Oxalyl chloride was reacted with (b) to obtain 5- (3,4-dimethoxy-5-nitrophenyl) -1,2,4-oxadiazol-3-benzoyl chloride.
(D) (c) is reacted with 4-fluoro-3- (methoxymethoxy) aniline to give 5- (3,4-dimethoxy-5-nitrophenyl) -N- [4-fluoro-3- (methoxymethoxy) Phenyl] 1,2,4-oxadiazole-3-carboxamide was used in the same manner as in Reference Example 13 and Example 3 to obtain the title compound (yield 28%).
実施例１２４：５－［３－（４－フルオロ－２，３－ジヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロ－４－（トリフルオロメチル）ベンゼン－１，２－ジオール Example 124: 5- [3- (4-fluoro-2,3-dihydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitro-4- (trifluoromethyl) benzene- 1,2-diol
　参考例２７で製造した４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）安息香酸を塩化チオニルで４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）ベンゾイルクロリドとした後、４－フルオロ－２，３－ビス（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率２６％）を得た。 4,5-Dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid prepared in Reference Example 27 was converted to 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoyl chloride with thionyl chloride. Thereafter, 4-fluoro-2,3-bis (methoxymethoxy) benzonitrile was used and the title compound (yield 26%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3.
実施例１２５：５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－４－ヨード－３－ニトロベンゼン－１，２－ジオール Example 125: 5- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -4-iodo-3-nitrobenzene-1,2-diol
　２－ヨード－４，５－ジメトキシ－３－ニトロ安息香酸をを塩化チオニルで２－ヨード－４，５－ジメトキシ－３－ニトロベンゾイルクロリドとした後、４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率３１％）を得た。 After 2-iodo-4,5-dimethoxy-3-nitrobenzoic acid is converted to 2-iodo-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, 4-fluoro-3- (methoxymethoxy) benzo The title compound (yield 31%) was obtained in the same manner as in Reference Examples 12, 13 and Example 3 using nitrile.
実施例１２６：シクロヘキシル｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロフェニル｝メタノン Example 126: cyclohexyl {6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrophenyl} methanone
　（ａ）：特開２０１１－１４８７８２に記載の方法に従い、４－（ベンジルオキシ）－２－（シクロヘキサンカルボニル）－５－メトキシ安息香酸メチルを合成し、参考例１９、１７、２７（ｅ）と同様の操作を行い、２－（シクロヘキシルカルボニル）－４，５－ジメトキシ－３－ニトロ安息香酸を得た。
　（ｂ）：（ａ）を塩化チオニルで２－（シクロヘキシルカルボニル）－４，５－ジメトキシ－３－ニトロベンゾイルクロリドとした後、４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率３３％）を得た。 (A): Methyl 4- (benzyloxy) -2- (cyclohexanecarbonyl) -5-methoxybenzoate was synthesized according to the method described in JP2011-148882A, and Reference Examples 19, 17, 27 (e) and The same operation was performed to obtain 2- (cyclohexylcarbonyl) -4,5-dimethoxy-3-nitrobenzoic acid.
(B): (a) was converted to 2- (cyclohexylcarbonyl) -4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, and then 4-fluoro-3- (methoxymethoxy) benzonitrile was used as a reference example. 12, 13 In the same manner as in Example 3, the title compound (yield 33%) was obtained.
実施例１２７：２，２，２－トリフルオロ－１－｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロフェニル｝エタン－１－オン Example 127: 2,2,2-trifluoro-1- {6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4 -Dihydroxy-2-nitrophenyl} ethane-1-one
　（ａ）：特開２０１１－１４８７８２に記載の方法に従い、４－（ベンジルオキシ）－５－メトキシ－２－（２，２，２－トリフルオロアセチル）安息香酸エチルを合成し、参考例１９、１７、２７（ｅ）と同様にして、４，５－ジメトキシ－３－ニトロ－２－（２，２，２－トリフルオロアセチル）安息香酸を得た。
　（ｂ）：（ａ）を塩化チオニルで４，５－ジメトキシ－３－ニトロ－２－（２，２，２－トリフルオロアセチル）ベンゾイルクロリドとした後、４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルとし、参考例１２、１３、実施例３と同様にして表題化合物（収率２０％）を得た。 (A): Ethyl 4- (benzyloxy) -5-methoxy-2- (2,2,2-trifluoroacetyl) benzoate was synthesized according to the method described in JP2011-148882A, Reference Example 19, In the same manner as in 17 and 27 (e), 4,5-dimethoxy-3-nitro-2- (2,2,2-trifluoroacetyl) benzoic acid was obtained.
(B): (a) is converted to 4,5-dimethoxy-3-nitro-2- (2,2,2-trifluoroacetyl) benzoyl chloride with thionyl chloride, and then 4-fluoro-3- (methoxymethoxy). Benzonitrile was used, and the title compound (yield 20%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3.
実施例１２８：４－｛５－［４，５－ジヒドロキシ－３－ニトロ－２－（トリフルオロメチル）フェニル］－１，２，４－オキサジアゾール－３－イル｝－２－ヒドロキシベンゾニトリル Example 128: 4- {5- [4,5-dihydroxy-3-nitro-2- (trifluoromethyl) phenyl] -1,2,4-oxadiazol-3-yl} -2-hydroxybenzonitrile
　（ａ）：参考例２７で製造した４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）安息香酸を塩化チオニルで４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）ベンゾイルクロライドとした
　（ｂ）：（ａ）と４－ヨード－３－（メトキシメトキシ）ベンゾニトリルを用いて、参考例１２と同様に５－［４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）フェニル］－３－（４－ヨード－３－メトキシフェニル）－１，２，４－オキサジアゾールを得た。
　（ｃ）：（ｂ）とシアン化銅（Ｉ）の反応で得られた４－｛５－［４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）フェニル］－１，２，４－オキサジアゾール－３－イル｝－２－（メトキシメトキシ）ベンゾニトリルを参考例１３、実施例１、２と同様にして表題化合物（収率１１％）を得た。 (A): 4,5-Dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid prepared in Reference Example 27 was converted to 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) with thionyl chloride. Using benzoyl chloride (b): 5- [4,5-dimethoxy-3-nitro-2-(()) and 4-iodo-3- (methoxymethoxy) benzonitrile as in Reference Example 12 Trifluoromethyl) phenyl] -3- (4-iodo-3-methoxyphenyl) -1,2,4-oxadiazole was obtained.
(C): 4- {5- [4,5-dimethoxy-3-nitro-2- (trifluoromethyl) phenyl] -1,2, obtained by reaction of (b) with copper (I) cyanide 4-oxadiazol-3-yl} -2- (methoxymethoxy) benzonitrile was used in the same manner as in Reference Example 13 and Examples 1 and 2 to obtain the title compound (yield 11%).
実施例１２９：５－（３，４－ジヒドロキシ－５－ニトロフェニル）－Ｎ－エチル－Ｎ－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－３－カルボキサミド Example 129: 5- (3,4-dihydroxy-5-nitrophenyl) -N-ethyl-N- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazole-3-carboxamide
　（ａ）：実施例１２３で製造した５－（３，４－ジメトキシ－５－ニトロフェニル）－Ｎ－［（４－フルオロ－３－メトキシメトキシ）フェニル］１，２，４－オキサジアゾール－３－カルボキサミドに水素化ナトリウムとヨウ化エチルを作用させ、５－（３，４－ジメトキシ－５－ニトロフェニル）－Ｎ－エチル－Ｎ－［（４－フルオロ－３－メトキシメトキシ）フェニル］１，２，４－オキサジアゾール－３－カルボキサミドをとし、参考例１２、１３、実施例３と同様にして表題化合物（収率１３％）を得た。 (A): 5- (3,4-Dimethoxy-5-nitrophenyl) -N-[(4-fluoro-3-methoxymethoxy) phenyl] 1,2,4-oxadiazole prepared in Example 123 3-Carboxamide is reacted with sodium hydride and ethyl iodide to give 5- (3,4-dimethoxy-5-nitrophenyl) -N-ethyl-N-[(4-fluoro-3-methoxymethoxy) phenyl] 1 , 2,4-oxadiazole-3-carboxamide, and the title compound (yield 13%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3.
実施例１３０：４－（シクロペンチルスルファニル）－５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 130: 4- (cyclopentylsulfanyl) -5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2- Diol
　５－［４－（ベンジルオキシ）－２－ヨード－５－メトキシフェニル］－３，４－フルオロ－３－（メトキシフェニル－１，２，４－オキサジアゾールとシクロペンチルチオールを用い、参考例２２と同様に５－［４－（ベンジルオキシ）－２－（シクロペンチルスルファニル）－５－メトキシフェニル］－３－（４－フルオロ－３－メトキシフェニル）－１，２，４－オキサジアゾールとし、参考例１９，１７、実施例１，２と同様にして表題化合物を得た。 Reference Example 22 using 5- [4- (benzyloxy) -2-iodo-5-methoxyphenyl] -3,4-fluoro-3- (methoxyphenyl-1,2,4-oxadiazole and cyclopentylthiol In the same manner as 5- [4- (benzyloxy) -2- (cyclopentylsulfanyl) -5-methoxyphenyl] -3- (4-fluoro-3-methoxyphenyl) -1,2,4-oxadiazole, The title compound was obtained in the same manner as in Reference Examples 19 and 17 and Examples 1 and 2.
実施例１３１：４－クロロ－５－［３－（３，４－ジフルオロフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 131: 4-chloro-5- [3- (3,4-difluorophenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　参考例２４で製造した２－クロロ－４，５－ジメトキシ－３－ニトロ安息香酸を塩化チオニルで２－クロロ－４，５－ジメトキシ－３－ニトロベンゾイルクロリドとした後、３，４－ジフルオロベンゾニトリルを用いて、参考例１２、１３、実施例１と同様にして表題化合物を得た。 2-Chloro-4,5-dimethoxy-3-nitrobenzoic acid prepared in Reference Example 24 was converted to 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, and then 3,4-difluorobenzo The title compound was obtained in the same manner as in Reference Examples 12, 13, and Example 1 using nitrile.
実施例１３２：４－（シクロペンチルスルホニル）－５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 132: 4- (cyclopentylsulfonyl) -5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2- Diol
　実施例１３０の中間体である５－［２－（シクロペンチルスルファニル）－４，５－ジメトキシ－３－ニトロフェニル］－３－（４－フルオロ－３－メトキシフェニル）－１，２，４－オキサジアゾールを３－クロロ過安息香酸で酸化し、５－［２－（シクロペンチルスルホニル）－４，５－ジメトキシ－３－ニトロフェニル］－３－（４－フルオロ－３－メトキシフェニル）－１，２，４－オキサジアゾールとし、参考例１２、１３、実施例１、２と同様にして表題化合物を得た。 The intermediate of Example 130, 5- [2- (cyclopentylsulfanyl) -4,5-dimethoxy-3-nitrophenyl] -3- (4-fluoro-3-methoxyphenyl) -1,2,4-oxa Diazole was oxidized with 3-chloroperbenzoic acid to give 5- [2- (cyclopentylsulfonyl) -4,5-dimethoxy-3-nitrophenyl] -3- (4-fluoro-3-methoxyphenyl) -1, The title compound was obtained in the same manner as in Reference Examples 12 and 13 and Examples 1 and 2, using 2,4-oxadiazole.
実施例１３３：３－ニトロ－５－［３－（２，３，４，５－テトラフルオロフェニル）－１，２，４－オキサジアゾール－５－イル］－４－（トリフルオロメチル）ベンゼン－１，２－ジオール Example 133: 3-nitro-5- [3- (2,3,4,5-tetrafluorophenyl) -1,2,4-oxadiazol-5-yl] -4- (trifluoromethyl) benzene -1,2-diol
　参考例２７で製造した４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）安息香酸を塩化チオニルで４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）ベンゾイルクロリドとした後、２，３，４，５－テトラフルオロベンゾニトリルを用いて、参考例１２、１３、実施例１と同様にして表題化合物（収率７％）を得た。 4,5-Dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid prepared in Reference Example 27 was converted to 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoyl chloride with thionyl chloride. Thereafter, the title compound (yield 7%) was obtained in the same manner as in Reference Examples 12, 13, and Example 1 using 2,3,4,5-tetrafluorobenzonitrile.
実施例１３４：５－［３－（４－フルオロフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロ－４－（トリフルオロメチル）ベンゼン－１，２－ジオール Example 134: 5- [3- (4-fluorophenyl) -1,2,4-oxadiazol-5-yl] -3-nitro-4- (trifluoromethyl) benzene-1,2-diol
　参考例２７で製造した４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）安息香酸を塩化チオニルで４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）ベンゾイルクロリドとした後、４－フルオロベンゾニトリルを用いて、参考例１２、１３、実施例１と同様にして表題化合物（収率７％）を得た。 4,5-Dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid prepared in Reference Example 27 was converted to 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoyl chloride with thionyl chloride. Thereafter, the title compound (yield 7%) was obtained in the same manner as in Reference Examples 12 and 13 and Example 1 using 4-fluorobenzonitrile.
実施例１３５：３－ニトロ－４－（トリフルオロメチル）－５－［３－（３，４，５－トリフルオロフェニル）－１，２，４－オキサジアゾール－５－イル］ベンゼン－１，２－ジオール Example 135: 3-nitro-4- (trifluoromethyl) -5- [3- (3,4,5-trifluorophenyl) -1,2,4-oxadiazol-5-yl] benzene-1 , 2-diol
　参考例２７で製造した４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）安息香酸を塩化チオニルで４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）ベンゾイルクロリドとした後、３，４，５－トリフルオロベンゾニトリルを用いて、参考例１２、１３、実施例１と同様にして表題化合物（収率２１％）を得た。 4,5-Dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid prepared in Reference Example 27 was converted to 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoyl chloride with thionyl chloride. Thereafter, the title compound (yield 21%) was obtained in the same manner as in Reference Examples 12, 13 and Example 1 using 3,4,5-trifluorobenzonitrile.
実施例１３６：５－｛［３－ジフルオロ（４－フルオロ－３－ヒドロキシフェニルスルファニル）メチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロ－４－（フェニルスルホニル）ベンゼン－１，２－ジオール Example 136: 5-{[3-difluoro (4-fluoro-3-hydroxyphenylsulfanyl) methyl] -1,2,4-oxadiazol-5-yl} -3-nitro-4- (phenylsulfonyl) Benzene-1,2-diol
　参考例２６で製造した、４，５－ジメトキシ－３－ニトロ－２－（フェニルスルホニル）安息香酸を塩化チオニルで４，５－ジメトキシ－３－ニトロ－２－（フェニルスルホニル）ベンゾイルクロリドとした後、参考例７で製造した２，２－ジフルオロ－２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝－Ｎ－ヒドロキシアセトイミダミドを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率４０％）を得た。 After 4,5-dimethoxy-3-nitro-2- (phenylsulfonyl) benzoic acid prepared in Reference Example 26 was converted to 4,5-dimethoxy-3-nitro-2- (phenylsulfonyl) benzoyl chloride with thionyl chloride. 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} -N-hydroxyacetimidamide prepared in Reference Example 7 and Reference Examples 12, 13, and Examples The title compound (yield 40%) was obtained in the same manner as in 3.
実施例１３７：｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロフェニル｝（フェニル）メタノン Example 137: {6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrophenyl} (phenyl) Methanon
　（ａ）：特開２０１１－１４８７８２に記載の方法に従い、２－ベンゾイル－４－（ベンジルオキシ）－５－メトキシ安息香酸エチルを合成し、参考例１９、１７，２７と同様の反応を行った後、アルカリ加水分解を行い、２－ベンゾイル－４，５－ジメトキシ－３－ニトロ安息香酸を得た。
　（ｂ）：（ａ）を塩化チオニルで２－ベンゾイル－４，５－ジメトキシ－３－ニトロベンゾイルクロリドとし、４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率７０％）を得た。 (A): Ethyl 2-benzoyl-4- (benzyloxy) -5-methoxybenzoate was synthesized according to the method described in Japanese Patent Application Laid-Open No. 2011-148782, and the same reactions as in Reference Examples 19, 17, and 27 were performed. Thereafter, alkali hydrolysis was performed to obtain 2-benzoyl-4,5-dimethoxy-3-nitrobenzoic acid.
(B): Reference examples 12, 13 were carried out using 4-fluoro-3- (methoxymethoxy) benzonitrile in which (a) was converted to 2-benzoyl-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride. In the same manner as in Example 3, the title compound (yield 70%) was obtained.
実施例１３８：５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－４－［（プロパン－２－イル）オキシ］－３－ニトロベンゼン－１，２－ジオール Example 138: 5- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -4-[(propan-2-yl) oxy] -3- Nitrobenzene-1,2-diol
　実施例９３で製造した３－フルオロ－４－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－６－メトキシ－２－ニトロフェノールに水素化ナトリウム及び２－プロパノールを反応させ、４－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－［（プロパン－２－イル）オキシ］－６－メトキシ－２－ニトロフェノールとし、実施例１と同様にして表題化合物（収率１１％）を得た。 To 3-fluoro-4- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -6-methoxy-2-nitrophenol prepared in Example 93 Sodium hydride and 2-propanol are reacted to give 4- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-[(propane-2- Yl) oxy] -6-methoxy-2-nitrophenol and the title compound (yield 11%) was obtained in the same manner as in Example 1.
実施例１３９：４－ブロモ－５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 139: 4-bromo-5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　２－ブロモ－４，５－ジメトキシ－３－ニトロ安息香酸を塩化チオニルで２－ブロモ－４，５－ジメトキシ－３－ニトロベンゾイルクロライドとした後、４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率４２％）を得た。 2-Bromo-4,5-dimethoxy-3-nitrobenzoic acid is converted to 2-bromo-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, and then 4-fluoro-3- (methoxymethoxy) benzonitrile. The title compound (yield 42%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3.
実施例１４０：［６－（３－｛ジフルオロ［（４－フルオロ－３－ヒドロキシフェニル）スルファニル］メチル｝－１，２，４－オキサジアゾール－５－イル）－３，４－ジヒドロキシ－２－ニトロフェニル］（フェニル）メタノン Example 140: [6- (3- {difluoro [(4-fluoro-3-hydroxyphenyl) sulfanyl] methyl} -1,2,4-oxadiazol-5-yl) -3,4-dihydroxy-2 -Nitrophenyl] (phenyl) methanone
　実施例１３７の中間体である２－ベンゾイル－４，５－ジメトキシ－３－ニトロベンゾイルクロリドと参考例７で製造した２，２－ジフルオロ－２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝－Ｎ－ヒドロキシアセトイミダミドを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率４０％）を得た。 2-benzoyl-4,5-dimethoxy-3-nitrobenzoyl chloride, which is an intermediate of Example 137, and 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) prepared in Reference Example 7 Phenyl] sulfanyl} -N-hydroxyacetimidamide was used in the same manner as in Reference Examples 12, 13, and Example 3 to obtain the title compound (yield 40%).
実施例１４１：５－｛３－［１，１－ジフルオロ－２－（４－フルオロ－３－ヒドロキシフェニル）エチル］－１，２，４－オキサジアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 141: 5- {3- [1,1-difluoro-2- (4-fluoro-3-hydroxyphenyl) ethyl] -1,2,4-oxadiazol-5-yl} -3-nitrobenzene- 1,2-diol
　２，２－ジフルオロ－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］プロパンニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率５７％）を得た。 The title compound (yield 57%) was obtained in the same manner as in Reference Examples 12, 13, and Example 3 using 2,2-difluoro-3- [4-fluoro-3- (methoxymethoxy) phenyl] propanenitrile. .
実施例１４２：５－（３－｛ジフルオロ［（４－フルオロ－３－ヒドロキシフェニル）スルファニル］メチル｝－１，２，４－オキサジアゾール－５－イル）－３－ニトロベンゼン－１，２－ジオール Example 142: 5- (3- {difluoro [(4-fluoro-3-hydroxyphenyl) sulfanyl] methyl} -1,2,4-oxadiazol-5-yl) -3-nitrobenzene-1,2- Diol
　参考例７で製造した２，２－ジフルオロ－２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝－Ｎ－ヒドロキシアセトイミダミドを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率３９％）を得た。 Using 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} -N-hydroxyacetimidamide prepared in Reference Example 7, Reference Examples 12, 13, and Example 3 To give the title compound (yield 39%).
実施例１４３：４－クロロ－５－（３－｛ジフルオロ［（４－フルオロ－３－ヒドロキシフェニル）スルファニル］メチル｝－１，２，４－オキサジアゾール－５－イル）－３－ニトロベンゼン－１，２－ジオール Example 143: 4-chloro-5- (3- {difluoro [(4-fluoro-3-hydroxyphenyl) sulfanyl] methyl} -1,2,4-oxadiazol-5-yl) -3-nitrobenzene- 1,2-diol
　参考例２４で製造した２－クロロ－４，５－ジメトキシ－３－ニトロ安息香酸を塩化チオニルで２－クロロ－４，５－ジメトキシ－３－ニトロベンゾイルクロライドとした後、参考例７で製造した２，２－ジフルオロ－２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝－Ｎ－ヒドロキシアセトイミダミドを用いて、参考例１２、１３、実施例３と同様にして表題化合物（収率２５％）を得た。 The 2-chloro-4,5-dimethoxy-3-nitrobenzoic acid prepared in Reference Example 24 was converted to 2-chloro-4,5-dimethoxy-3-nitrobenzoyl chloride with thionyl chloride, and then prepared in Reference Example 7. Using 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} -N-hydroxyacetimidamide in the same manner as in Reference Examples 12, 13, and Example 3, the title compound (Yield 25%) was obtained.
実施例１４４：４－ブトキシ－５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 144: 4-Butoxy-5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　実施例９４の中間体である３－フルオロ－４－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－６－メトキシ－２－ニトロフェノールに水素化ナトリウム及びブタノールを反応させ、３－ブトキシ－４－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－６－メトキシ－２－ニトロフェノールとし、実施例１と同様にして表題化合物（収率２１％）を得た。 The intermediate of Example 94, 3-fluoro-4- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -6-methoxy-2-nitro Phenol is reacted with sodium hydride and butanol to give 3-butoxy-4- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -6-methoxy- 2-Nitrophenol was used, and the title compound (yield 21%) was obtained in the same manner as in Example 1.
実施例１４５：４－シクロペンチル－５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 145: 4-cyclopentyl-5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2-diol
　（ａ）：２－ヨード－５－メトキシ－４－（メトキシメトキシ）安息香酸エチルに１－シクロペンテニルボロン酸、テトラキス（トリフェニルホスフィン）パラジウム、炭酸セシウムを加え、１，４－ジオキサン及び水を溶媒として、１００℃で１５時間撹拌し、２－（シクロペンテン－１－イル）－５－メトキシ－４－（メトキシメトキシ）安息香酸エチルを得た。
　（ｂ）：（ａ）を接触還元した後に、参考例２７と同様に、２－シクロペンチル－４，５－ジメトキシ－３－ニトロ安息香酸を得た。
　（ｃ）：（ｂ）を塩化チオニルで酸クロリドとした後、４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率４６％）を得た。 (A): 1-cyclopentenylboronic acid, tetrakis (triphenylphosphine) palladium, cesium carbonate are added to ethyl 2-iodo-5-methoxy-4- (methoxymethoxy) benzoate, and 1,4-dioxane and water are added. The mixture was stirred at 100 ° C. for 15 hours as a solvent to obtain ethyl 2- (cyclopenten-1-yl) -5-methoxy-4- (methoxymethoxy) benzoate.
(B): After catalytic reduction of (a), 2-cyclopentyl-4,5-dimethoxy-3-nitrobenzoic acid was obtained in the same manner as in Reference Example 27.
(C): (b) was converted to acid chloride with thionyl chloride, and then 4-fluoro-3- (methoxymethoxy) benzonitrile was used in the same manner as in Reference Examples 12, 13, and Example 3 (yield) 46%).
実施例１４６：５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－４－［（プロパン－２－イル）スルホニル］－３－ニトロベンゼン－１，２－ジオール Example 146: 5- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -4-[(propan-2-yl) sulfonyl] -3- Nitrobenzene-1,2-diol
　参考例２６と同様に、２－［（プロパン－２－イル）スルホニル］－４，５－ジメトキシ－３－ニトロ安息香酸を合成し、塩化チオニルで２－［（プロパン－２－イル）スルホニル］－４，５－ジメトキシ－３－ニトロベンゾイルクロリドとした後、４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率２１％）を得た。 Similarly to Reference Example 26, 2-[(propan-2-yl) sulfonyl] -4,5-dimethoxy-3-nitrobenzoic acid was synthesized and 2-[(propan-2-yl) sulfonyl] with thionyl chloride. After preparing -4,5-dimethoxy-3-nitrobenzoyl chloride, 4-fluoro-3- (methoxymethoxy) benzonitrile was used in the same manner as in Reference Examples 12, 13, and Example 3 (yield 21 %).
実施例１４７：４－（シクロペンチルオキシ）－５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 147: 4- (cyclopentyloxy) -5- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3-nitrobenzene-1,2- Diol
　実施例９３の中間体である３－フルオロ－４－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－６－メトキシ－２－ニトロフェノールに水素化ナトリウム及びシクロペンタノールを反応させ、実施例１と同様にして表題化合物（収率２７％）を得た。 3-Fluoro-4- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -6-methoxy-2-nitro, an intermediate of Example 93 Phenol was reacted with sodium hydride and cyclopentanol to obtain the title compound (yield 27%) in the same manner as in Example 1.
実施例１４８：５－（３－｛ジフルオロ－［（４－フルオロ－３－ヒドロキシフェニル）スルファニル］メチル｝－１，２，４－オキサジアゾール－５－イル）－３－ニトロ－４－［（トリフルオロメチル）スルファニル］ベンゼン－１，２－ジオール Example 148: 5- (3- {difluoro-[(4-fluoro-3-hydroxyphenyl) sulfanyl] methyl} -1,2,4-oxadiazol-5-yl) -3-nitro-4- [ (Trifluoromethyl) sulfanyl] benzene-1,2-diol
　４，５－ジメトキシ－３－ニトロ－２－［（トリフルオロメチル）スルファニル］安息香酸と参考例７で製造した２，２－ジフルオロ－２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝－Ｎ－ヒドロキシアセトイミダミドを用いて、参考例１２、１３、実施例３と同様にして表題化合物（２０％）を得た。 4,2-Dimethoxy-3-nitro-2-[(trifluoromethyl) sulfanyl] benzoic acid and 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] prepared in Reference Example 7 ] Sulfanyl} -N-hydroxyacetimidamide was used to give the title compound (20%) in the same manner as in Reference Examples 12, 13, and Example 3.
実施例１４９：５－（３－｛２－［（４－フルオロ－３－ヒドロキシフェニル）スルファニル］プロパン－２－イル｝－１，２，４－オキサジアゾール－５－イル）－３－ニトロベンゼン－１，２－ジオール Example 149: 5- (3- {2-[(4-fluoro-3-hydroxyphenyl) sulfanyl] propan-2-yl} -1,2,4-oxadiazol-5-yl) -3-nitrobenzene -1,2-diol
　参考例６と同様に製造した２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝－２－メチルプロパンニトリルと３，４－ジメトキシ－５－ニトロベンゾイルクロリドを用い、参考例１２、１３、実施例３と同様にして表題化合物（収率３％）を得た。 Reference Example 12 was prepared using 2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} -2-methylpropanenitrile and 3,4-dimethoxy-5-nitrobenzoyl chloride prepared in the same manner as Reference Example 6. 13, In the same manner as in Example 3, the title compound (yield 3%) was obtained.
実施例１５０：５－（５－メチル－５－フェニル－４，５－ジヒドロイソオキサゾール－３－イル）－３－ニトロベンゼン－１，２－ジオール Example 150: 5- (5-methyl-5-phenyl-4,5-dihydroisoxazol-3-yl) -3-nitrobenzene-1,2-diol
　参考例２９で製造した３－［４－（ベンジルオキシ）－３－メトキシ－５－ニトロフェニル］－５－メチル―５－フェニル－４，５－ジヒドロイソキサゾールを用いて、参考例１３、実施例１と同様にして表題化合物を得た。 Using 3- [4- (benzyloxy) -3-methoxy-5-nitrophenyl] -5-methyl-5-phenyl-4,5-dihydroisoxazole prepared in Reference Example 29, Reference Example 13, The title compound was obtained in the same manner as in Example 1.
実施例１５１：３－（３，４－ジヒドロキシ－５－ニトロフェニル）－５－メチル－４，５－ジヒドロイソオキサゾール－５－カルボン酸ベンジル Example 151 1: Benzyl 3- (3,4-dihydroxy-5-nitrophenyl) -5-methyl-4,5-dihydroisoxazole-5-carboxylate
　４－（ベンジルオキシ）－３－メトキシ－５－ニトロベンズアルデヒドオキシムとベンジルメタクリレートを用いて、参考例２９、１３、実施例１と同様にして表題化合物を得た。 Using 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime and benzyl methacrylate, the title compound was obtained in the same manner as in Reference Examples 29 and 13 and Example 1.
実施例１５２：３－（３，４－ジヒドロキシ－５－ニトロフェニル）－５－メチル－４，５－ジヒドロイソオキサゾール－５－カルボン酸 Example 152: 3- (3,4-dihydroxy-5-nitrophenyl) -5-methyl-4,5-dihydroisoxazole-5-carboxylic acid
　４－（ベンジルオキシ）－３－メトキシ－５－ニトロベンズアルデヒドオキシムとメタクリル酸を用いて、参考例２９、１３、実施例１、５と同様にして表題化合物を得た。 Using 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime and methacrylic acid, the title compound was obtained in the same manner as in Reference Examples 29 and 13, and Examples 1 and 5.
実施例１５３：５－（５－エチル－５－フェニル－４，５－ジヒドロイソオキサゾール－３－イル）－３－ニトロベンゼン－１，２－ジオール Example 153: 5- (5-ethyl-5-phenyl-4,5-dihydroisoxazol-3-yl) -3-nitrobenzene-1,2-diol
　４－（ベンジルオキシ）－３－メトキシ－５－ニトロベンズアルデヒドオキシムと１－エチルスチレンを用いて、参考例２９、１３、実施例１と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Examples 29 and 13, and Example 1 using 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime and 1-ethylstyrene.
実施例１５４：５－［５－（４－クロロフェニル）－４，５－ジヒドロイソオキサゾール－３－イル］－３－ニトロベンゼン－１，２－ジオール Example 154: 5- [5- (4-chlorophenyl) -4,5-dihydroisoxazol-3-yl] -3-nitrobenzene-1,2-diol
　４－（ベンジルオキシ）－３－メトキシ－５－ニトロベンズアルデヒドオキシムと１－クロロ－４－ビニルベンゼンを用いて、参考例２９、１３、実施例１と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Examples 29 and 13 and Example 1 using 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime and 1-chloro-4-vinylbenzene.
実施例１５５：５－［５－（４－メトキシフェニル）－５－メチル－４，５－ジヒドロイソオキサゾール－３－イル］－３－ニトロベンゼン－１，２－ジオール Example 155: 5- [5- (4-methoxyphenyl) -5-methyl-4,5-dihydroisoxazol-3-yl] -3-nitrobenzene-1,2-diol
　４－（ベンジルオキシ）－３－メトキシ－５－ニトロベンズアルデヒドオキシムと１－メトキシ－４－（プロパ－１－エン－２－イル）ベンゼンを用いて、参考例２９、１３、実施例１と同様にして表題化合物を得た。 Same as Reference Examples 29 and 13 and Example 1 using 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime and 1-methoxy-4- (prop-1-en-2-yl) benzene To give the title compound.
実施例１５６：３－ニトロ－５－（５－フェニル－４，５－ジヒドロイソオキサゾール）ベンゼン－１，２－ジオール Example 156: 3-nitro-5- (5-phenyl-4,5-dihydroisoxazole) benzene-1,2-diol
　４－（ベンジルオキシ）－３－メトキシ－５－ニトロベンズアルデヒドオキシムとスチレンを用いて、参考例２９、１３、実施例１と同様にして表題化合物を得た。 Using 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime and styrene, the title compound was obtained in the same manner as in Reference Examples 29 and 13 and Example 1.
実施例１５７：５－（５－ベンジル－４，５－ジヒドロイソオキサゾール－３－イル）－３－ニトロベンゼン－１，２－ジオール Example 157: 5- (5-benzyl-4,5-dihydroisoxazol-3-yl) -3-nitrobenzene-1,2-diol
　４－（ベンジルオキシ）－３－メトキシ－５－ニトロベンズアルデヒドオキシムとアリルベンゼンを用いて、参考例２９、１３、実施例１と同様にして表題化合物を得た。 Using 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime and allylbenzene, the title compound was obtained in the same manner as in Reference Examples 29 and 13 and Example 1.
実施例１５８：５－｛５－［４－（ヒドロキシメチル）フェニル］－５－メチル－４，５－ジヒドロイソオキサゾール－３－イル｝－３－ニトロベンゼン－１，２－ジオール Example 158: 5- {5- [4- (hydroxymethyl) phenyl] -5-methyl-4,5-dihydroisoxazol-3-yl} -3-nitrobenzene-1,2-diol
　［４－（プロパ－１－エン－２－イル）フェニル］メタノールを用いて、参考例２９、１３、実施例１と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Examples 29 and 13 and Example 1 using [4- (prop-1-en-2-yl) phenyl] methanol.
実施例１５９：４－［３－（３，４－ジヒドロキシ－５－ニトロフェニル）－５－メチル－４，５－ジヒドロイソオキサゾール－５－イル］安息香酸 Example 159: 4- [3- (3,4-dihydroxy-5-nitrophenyl) -5-methyl-4,5-dihydroisoxazol-5-yl] benzoic acid
　４－（ベンジルオキシ）－３－メトキシ－５－ニトロベンズアルデヒドオキシムと４－（プロパ－１－エン－２－イル）安息香酸メチルを用いて、参考例２９、１３、実施例１、５と同様にして表題化合物を得た。 Same as Reference Examples 29 and 13 and Examples 1 and 5 using 4- (benzyloxy) -3-methoxy-5-nitrobenzaldehyde oxime and methyl 4- (prop-1-en-2-yl) benzoate To give the title compound.
実施例１６０：２－（３，４－ジヒドロキシ－５－ニトロフェニル）－４－フェニルチアゾール－５－カルボニトリル Example 160: 2- (3,4-dihydroxy-5-nitrophenyl) -4-phenylthiazole-5-carbonitrile
　参考例３２で製造した２－（３，４－ジメトキシ－５－ニトロフェニル）－４－フェニルチアゾール－５－カルボニトリル用いて、参考例１３、実施例１と同様にして表題化合物（収率７２％）を得た。 Using 2- (3,4-dimethoxy-5-nitrophenyl) -4-phenylthiazole-5-carbonitrile prepared in Reference Example 32 in the same manner as in Reference Example 13 and Example 1, the title compound (yield 72% %).
実施例１６１：３－ニトロ－５－（３－フェニル－１，２，４－チアジアゾール－５－イル）ベンゼン－１，２－ジオール Example 161: 3-nitro-5- (3-phenyl-1,2,4-thiadiazol-5-yl) benzene-1,2-diol
　参考例３３で製造した５－（３，４－ジメトキシ－５－ニトロフェニル）－３－フェニル－１，２，４－チアジアゾールを用いて、参考例１３、実施例１と同様にして表題化合物（収率５１％）を得た。 Using 5- (3,4-dimethoxy-5-nitrophenyl) -3-phenyl-1,2,4-thiadiazole prepared in Reference Example 33 in the same manner as in Reference Example 13 and Example 1, the title compound ( Yield 51%).
実施例１６２：２－（３，４－ジヒドロキシ－５－ニトロフェニル）－４－フェニルチアゾール－５－カルボン酸 Example 162: 2- (3,4-dihydroxy-5-nitrophenyl) -4-phenylthiazole-5-carboxylic acid
　Ｎ，Ｎ－ジメチルベンズアミドジメチルアセタールを用いて、参考例３２、１３、実施例１、５と同様にして表題化合物（収率８９％）を得た。 Using N, N-dimethylbenzamide dimethyl acetal, the title compound (yield 89%) was obtained in the same manner as in Reference Examples 32 and 13, and Examples 1 and 5.
実施例１６３：４－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，２，４－チアジアゾール－３－イル］安息香酸 Example 163: 4- [5- (3,4-dihydroxy-5-nitrophenyl) -1,2,4-thiadiazol-3-yl] benzoic acid
　４－（Ｎ’－（３，４－ジメトキシ－５－ニトロフェニルカルボニルチオイル）－Ｎ，Ｎ－ジメチルカルボアミドイル）安息香酸メチルを用いて、参考例３３、１３、実施例１、５と同様にして表題化合物（収率１２％）を得た。 Reference Examples 33 and 13, Examples 1, 5 and 4- (N ′-(3,4-dimethoxy-5-nitrophenylcarbonylthioyl) -N, N-dimethylcarboamidoyl) benzoate methyl Similarly, the title compound (yield 12%) was obtained.
実施例１６４：２－（３，４－ジヒドロキシ－５－ニトロフェニル）－４－［（３－ヒドロキシベンジル）オキシ］チアゾール－５－カルボン酸メチル Example 164: Methyl 2- (3,4-dihydroxy-5-nitrophenyl) -4-[(3-hydroxybenzyl) oxy] thiazole-5-carboxylate
実施例１６５：２－［２－（３，４－ジヒドロキシ－５－ニトロフェニル）－４－フェニルチアゾール－５－カルボニル］ヒドラジン－１－カルボン酸ｔ－ブチル Example 165: t-butyl 2- [2- (3,4-dihydroxy-5-nitrophenyl) -4-phenylthiazole-5-carbonyl] hydrazine-1-carboxylate
実施例１６６：２－（３，４－ジヒドロキシ－５－ニトロフェニル）－４－フェニルチアゾール－５－カルボヒドラジド塩酸塩 Example 166: 2- (3,4-dihydroxy-5-nitrophenyl) -4-phenylthiazole-5-carbohydrazide hydrochloride
実施例１６７：３－ニトロ－５－（５－フェニルチアゾール－２－イル）ベンゼン－１，２－ジオール Example 167: 3-nitro-5- (5-phenylthiazol-2-yl) benzene-1,2-diol
　参考例３５で製造した３－［４－（ベンジルオキシ）－３－メトキシ－５－ニトロフェニル］－５－フェニル－１Ｈ－チアゾールを用いて、参考例１３、実施例１と同様にして表題化合物を得た。 The title compound was prepared in the same manner as in Reference Example 13 and Example 1 using 3- [4- (benzyloxy) -3-methoxy-5-nitrophenyl] -5-phenyl-1H-thiazole prepared in Reference Example 35. Got.
実施例１６８：３－ニトロ－５－（３－フェニル－１Ｈ－ピラゾール－５－イル）ベンゼン－１，２－ジオール Example 168: 3-nitro-5- (3-phenyl-1H-pyrazol-5-yl) benzene-1,2-diol
　１－［４－（ベンジルオキシ）－３－メトキシ－５－ニトロフェニル］エタン－１－オンを用いて、参考例３４、３５、１３、実施例１と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Examples 34, 35 and 13, and Example 1 using 1- [4- (benzyloxy) -3-methoxy-5-nitrophenyl] ethane-1-one.
実施例１６９：３－ニトロ－５－（４－フェニル－１Ｈ－イミダゾール－２－イル）ベンゼン－１，２－ジオール Example 169: 3-nitro-5- (4-phenyl-1H-imidazol-2-yl) benzene-1,2-diol
　参考例３７で製造した２－（３，４－ジメトキシ－５－ニトロフェ二ル）－４－フェニル－１Ｈ－イミダゾールを用いて、参考例１３、実施例１と同様にして表題化合物を得た。 The title compound was obtained in the same manner as in Reference Example 13 and Example 1 using 2- (3,4-dimethoxy-5-nitrophenyl) -4-phenyl-1H-imidazole produced in Reference Example 37.
実施例１７０：３－ニトロ－５－（４－フェニルオキサゾール－２－イル）ベンゼン－１，２－ジオール Example 170: 3-nitro-5- (4-phenyloxazol-2-yl) benzene-1,2-diol
　参考例３８で製造した２－（３，４－ジメトキシ－５－ニトロフェ二ル）－５－フェニル－１，３－オキサゾールを用いて、参考例１３、実施例１と同様にして表題化合物を得た。 Using 2- (3,4-dimethoxy-5-nitrophenyl) -5-phenyl-1,3-oxazole prepared in Reference Example 38, the title compound was obtained in the same manner as in Reference Example 13 and Example 1. It was.
実施例１７１：３－ニトロ－５－［３－（ピリダジン－４－イル）－１Ｈ－１，２，４－トリアゾール－５－イル］ベンゼン－１，２－ジオール Example 171: 3-nitro-5- [3- (pyridazin-4-yl) -1H-1,2,4-triazol-5-yl] benzene-1,2-diol
　参考例４０で製造した４－［５－（３，４－ジメトキシ－５－ニトロフェニル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリダジンを用いて、参考例１３、実施例１と同様にして表題化合物（収率１２％）を得た。 Using 4- [5- (3,4-dimethoxy-5-nitrophenyl) -1H-1,2,4-triazol-3-yl] pyridazine prepared in Reference Example 40, Reference Example 13 and Example 1 To give the title compound (yield 12%).
実施例１７２：４－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１Ｈ－１，２，４－トリアゾール－３－イル］ピリジン－２－カルボニトリル Example 172: 4- [5- (3,4-dihydroxy-5-nitrophenyl) -1H-1,2,4-triazol-3-yl] pyridine-2-carbonitrile
　２－シアノピリジン－４－カルボヒドラジド塩酸塩とエチル３，４－ジメトキシ－５－ニトロベンズイミデートを用いて、参考例４０、１３、実施例１と同様にして表題化合物（収率４０％）を得た。 Using 2-cyanopyridine-4-carbohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzimidate in the same manner as in Reference Examples 40 and 13 and Example 1, the title compound (yield 40%) Got.
実施例１７３：３－ニトロ－５－（３－フェニル－１Ｈ－１，２，４－トリアゾール－５－イル）ベンゼン－１，２－ジオール Example 173: 3-nitro-5- (3-phenyl-1H-1,2,4-triazol-5-yl) benzene-1,2-diol
　ベンゾヒドラジド塩酸塩とエチル３，４－ジメトキシ－５－ニトロベンズイミデートを用いて、参考例４０、１３、実施例１と同様にして表題化合物（収率３８％）を得た。 Using the benzohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzimidate, the title compound (yield 38%) was obtained in the same manner as in Reference Examples 40 and 13 and Example 1.
実施例１７４：３－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１Ｈ－１，２，４－トリアゾール－３－イル］ベンゾニトリル Example 174: 3- [5- (3,4-dihydroxy-5-nitrophenyl) -1H-1,2,4-triazol-3-yl] benzonitrile
　３－シアノベンゾヒドラジド塩酸塩とエチル３，４－ジメトキシ－５－ニトロベンズイミデートを用いて、参考例４０、１３、実施例１と同様にして表題化合物（収率６５％）を得た。 Using 3-cyanobenzohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzimidate, the title compound (yield 65%) was obtained in the same manner as in Reference Examples 40 and 13 and Example 1.
実施例１７５：５－［３－（２－クロロピリジン－４－イル）－１Ｈ－１，２，４－トリアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 175: 5- [3- (2-chloropyridin-4-yl) -1H-1,2,4-triazol-5-yl] -3-nitrobenzene-1,2-diol
　２－クロロピリジン－４－カルボヒドラジド塩酸塩とエチル３，４－ジメトキシ－５－ニトロベンズイミデートを用いて、参考例４０、１３、実施例１と同様にして表題化合物（収率４８％）を得た。 Using 2-chloropyridine-4-carbohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzimidate in the same manner as in Reference Examples 40 and 13 and Example 1, the title compound (yield 48%) Got.
実施例１７６：５－｛３－［３，５－ビス（トリフルオロメチル）フェニル］－１Ｈ－１，２，４－トリアゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 176: 5- {3- [3,5-bis (trifluoromethyl) phenyl] -1H-1,2,4-triazol-5-yl} -3-nitrobenzene-1,2-diol
　３，５－ビス（トリフルオロメチル）ベンゾヒドラジド塩酸塩とエチル３，４－ジメトキシ－５－ニトロベンズイミデートを用いて、参考例４０、１３、実施例１と同様にして表題化合物（収率３８％）を得た。 Using 3,5-bis (trifluoromethyl) benzohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzimidate in the same manner as in Reference Examples 40, 13, and Example 1, the title compound (yield) 38%).
実施例１７７：３－ニトロ－５－｛３－［４－（トリフルオロメチル）フェニル］－１Ｈ－１，２，４－トリアゾール－５－イル｝ベンゼン－１，２－ジオール Example 177: 3-nitro-5- {3- [4- (trifluoromethyl) phenyl] -1H-1,2,4-triazol-5-yl} benzene-1,2-diol
　４－（トリフルオロメチル）ベンゾヒドラジド塩酸塩とエチル３，４－ジメトキシ－５－ニトロベンズイミデートを用いて、参考例４０、１３、実施例１と同様にして表題化合物（収率９％）を得た。 Using 4- (trifluoromethyl) benzohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzimidate in the same manner as in Reference Examples 40 and 13 and Example 1, the title compound (yield 9%) Got.
実施例１７８：５－［３－（２，５－ジクロロチオフェン－３－イル）－１Ｈ－１，２，４－トリアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 178: 5- [3- (2,5-dichlorothiophen-3-yl) -1H-1,2,4-triazol-5-yl] -3-nitrobenzene-1,2-diol
　２，５－ジクロロチオフェン－３－カルボヒドラジド塩酸塩とエチル３，４－ジメトキシ－５－ニトロベンズイミデートを用いて、参考例４０、１３、実施例１と同様にして表題化合物（収率１３％）を得た。 Using 2,5-dichlorothiophene-3-carbohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzimidate in the same manner as in Reference Examples 40, 13, and Example 1, the title compound (yield 13 %).
実施例１７９：５－［３－（４－フルオロ－３－ヒドロキシフェニル）－１Ｈ－１，２，４－トリアゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 179: 5- [3- (4-Fluoro-3-hydroxyphenyl) -1H-1,2,4-triazol-5-yl] -3-nitrobenzene-1,2-diol
　４－フルオロ－３－メトキシベンゾヒドラジド塩酸塩とエチル３，４－ジメトキシ－５－ニトロベンズイミデートを用いて、参考例４０、１３、実施例１、２と同様にして表題化合物（収率１０％）を得た。 Using 4-fluoro-3-methoxybenzohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzimidate in the same manner as in Reference Examples 40 and 13, and Examples 1 and 2, the title compound (yield 10 %).
実施例１８０：３－［３－（３，４－ジヒドロキシ－５－ニトロフェニル）－１－メチル－１Ｈ－１，２，４－トリアゾール－５－イル］ベンゾニトリル Example 180: 3- [3- (3,4-dihydroxy-5-nitrophenyl) -1-methyl-1H-1,2,4-triazol-5-yl] benzonitrile
　（ａ）：３，４－ビス（３，３－ジメトキシプロポキシ）－５－ニトロベンゾニトリル（３００ｍｇ）のメタノール（３．０ｍＬ）溶液に、ナトリウムエトキシド（４２ｍｇ）を加え、室温で１０分撹拌した。反応液に３－シアノ－Ｎ－メチルベンゾヒドラジド（１６４ｍｇ）を加え、６０℃にて１５時間撹拌した。クエン酸水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をカラムクロマトグラフィーで精製した。
　（ｂ）：（ａ）のアセトン（２．０ｍＬ）溶液に、水（１．０ｍＬ）、ｐ－トルエンスルホン酸一水和物（３０ｍｇ）を加え、６０℃で１５時間撹拌した。溶媒を減圧留去し、クエン酸水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、表題化合物（収率２７％）を得た。 (A): Sodium ethoxide (42 mg) was added to a methanol (3.0 mL) solution of 3,4-bis (3,3-dimethoxypropoxy) -5-nitrobenzonitrile (300 mg), and the mixture was stirred at room temperature for 10 minutes. did. 3-Cyano-N-methylbenzohydrazide (164 mg) was added to the reaction mixture, and the mixture was stirred at 60 ° C. for 15 hr. Citric acid water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography.
(B): Water (1.0 mL) and p-toluenesulfonic acid monohydrate (30 mg) were added to a solution of (a) in acetone (2.0 mL), and the mixture was stirred at 60 ° C. for 15 hours. The solvent was distilled off under reduced pressure, aqueous citric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (yield 27%).
実施例１８１：５－（１－メチル－３－フェニル－１Ｈ－１，２，４－トリアゾール－５－イル）－３－ニトロベンゼン－１，２－ジオール Example 181 5- (1-methyl-3-phenyl-1H-1,2,4-triazol-5-yl) -3-nitrobenzene-1,2-diol
　３，４－ビス（３，３－ジメトキシプロポキシ）－Ｎ’－メチル－５－ニトロベンゾヒドラジド（２８０ｍｇ）のＮ，Ｎ－ジメチルホルムアミド（５．０ｍＬ）溶液に、メチルベンズイミドチオエートヨウ化水素酸塩（４１７ｍｇ）を加え、１２０℃で３時間撹拌した。反応液に水を加え、酢酸エチルで抽出し、水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。溶媒を減圧留去し、残渣をカラムクロマトグラフィーで精製した。ジイソプロピルエーテル（５．０ｍＬ）を加えてスラリー洗浄し、表題化合物（収率６％）を得た。 To a solution of 3,4-bis (3,3-dimethoxypropoxy) -N′-methyl-5-nitrobenzohydrazide (280 mg) in N, N-dimethylformamide (5.0 mL) was added methylbenzimidethioate hydrogen iodide. The acid salt (417 mg) was added and stirred at 120 ° C. for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography. Diisopropyl ether (5.0 mL) was added and the slurry was washed to obtain the title compound (yield 6%).
実施例１８２：５－［５－（４－クロロフェニル）－１，３，４－オキサジアゾール－２－イル］－３－ニトロベンゼン－１，２－ジオール Example 182: 5- [5- (4-chlorophenyl) -1,3,4-oxadiazol-2-yl] -3-nitrobenzene-1,2-diol
　４－クロロベンゾヒドラジド塩酸塩とエチル３，４－ジメトキシ－５－ニトロ安息香酸を用いて、参考例４１、１３、実施例１と同様にして表題化合物（収率２８％）を得た。 Using 4-chlorobenzohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzoic acid, the title compound (yield 28%) was obtained in the same manner as in Reference Examples 41 and 13 and Example 1.
実施例１８３：３－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，３，４－オキサジアゾール－２－イル］ベンゾニトリル Example 183: 3- [5- (3,4-dihydroxy-5-nitrophenyl) -1,3,4-oxadiazol-2-yl] benzonitrile
　３－シアノベンゾヒドラジド塩酸塩とエチル３，４－ジメトキシ－５－ニトロ安息香酸を用いて、参考例４１、１３、実施例１と同様にして表題化合物（収率６％）を得た。 The title compound (yield 6%) was obtained in the same manner as in Reference Examples 41 and 13 and Example 1 using 3-cyanobenzohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzoic acid.
実施例１８４：３－シクロヘキシル－２－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－１，３，４－オキサジアゾール－２－イル］プロパンニトリル Example 184: 3-cyclohexyl-2- [5- (3,4-dihydroxy-5-nitrophenyl) -1,3,4-oxadiazol-2-yl] propanenitrile
　２－シアノ－３－シクロヘキシルプロパンカルボヒドラジド塩酸塩とエチル３，４－ジメトキシ－５－ニトロ安息香酸を用いて、参考例４１、１３、実施例１と同様にして表題化合物（収率４％）を得た。 Using 2-cyano-3-cyclohexylpropanecarbohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzoic acid in the same manner as in Reference Examples 41 and 13 and Example 1, the title compound (yield 4%) Got.
実施例１８５：５－（５－｛［（３，４－ジヒドロキシフェニル）メチル］スルファニル｝－１，３，４－オキサジアゾール－２－イル）－３－ニトロベンゼン－１，２－ジオール Example 185: 5- (5-{[(3,4-dihydroxyphenyl) methyl] sulfanyl} -1,3,4-oxadiazol-2-yl) -3-nitrobenzene-1,2-diol
　（ａ）：３，４－ジメトキシベンゾイルクロライドにヒドラジン一水和物を反応させ、３、４－ジメトキシ－５－ニトロベンゾヒドラジドを得た。
　（ｂ）：（ａ）に二硫化炭素、水酸化リチウム、エタノールを反応させた後に、４－（２－ブロモエチル）－１，２－ジメトキシベンゼンを反応させ、参考例１３、実施例１と同様にして表題化合物を得た。 (A): 3,4-Dimethoxybenzoyl chloride was reacted with hydrazine monohydrate to obtain 3,4-dimethoxy-5-nitrobenzohydrazide.
(B): (a) is reacted with carbon disulfide, lithium hydroxide, and ethanol, and then reacted with 4- (2-bromoethyl) -1,2-dimethoxybenzene, as in Reference Example 13 and Example 1. To give the title compound.
実施例１８６：５－［５－（４－フルオロ－３－ヒドロキシフェニル）－１，３，４－オキサジアゾール－２－イル］－３－ニトロベンゼン－１，２－ジオール Example 186: 5- [5- (4-Fluoro-3-hydroxyphenyl) -1,3,4-oxadiazol-2-yl] -3-nitrobenzene-1,2-diol
　４－フルオロ－３－メトキシベンゾヒドラジド塩酸塩とエチル３，４－ジメトキシ－５－ニトロ安息香酸を用いて、参考例４１、１３、実施例１、２と同様にして表題化合物（収率１６％）を得た。 Using 4-fluoro-3-methoxybenzohydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzoic acid in the same manner as in Reference Examples 41 and 13, and Examples 1 and 2, the title compound (yield 16% )
実施例１８７：５－｛５－［２－（３，４－ジヒドロキシフェニル）エチル］－１，３，４－オキサジアゾール－２－イル｝－３－ニトロベンゼン－１，２－ジオール Example 187: 5- {5- [2- (3,4-dihydroxyphenyl) ethyl] -1,3,4-oxadiazol-2-yl} -3-nitrobenzene-1,2-diol
　３－（３，４－ジメトキシフェニルエチル）プロパンヒドラジド塩酸塩とエチル３，４－ジメトキシ－５－ニトロ安息香酸を用いて、参考例４１、１３、実施例１、２と同様にして表題化合物（収率５％）を得た。 Using 3- (3,4-dimethoxyphenylethyl) propanehydrazide hydrochloride and ethyl 3,4-dimethoxy-5-nitrobenzoic acid in the same manner as in Reference Examples 41 and 13 and Examples 1 and 2, the title compound ( Yield 5%).
実施例１８８：３－［４－（３，４－ジヒドロキシ－５－ニトロフェニル）－１Ｈ－１，２，３－トリアゾール－５－イル］ベンゾニトリル Example 188: 3- [4- (3,4-dihydroxy-5-nitrophenyl) -1H-1,2,3-triazol-5-yl] benzonitrile
　参考例４６で製造した３－［４－（４－ヒドロキシ－３－メトキシ－５－ニトロフェニル）－１Ｈ－１，２，３－トリアゾール－５－イル］ベンゾニトリルを用いて、実施例１と同様にして表題化合物（収率１１％）を得た。 Using 3- [4- (4-hydroxy-3-methoxy-5-nitrophenyl) -1H-1,2,3-triazol-5-yl] benzonitrile prepared in Reference Example 46, Example 1 and Similarly, the title compound (yield 11%) was obtained.
実施例１８９：５－（１－ベンジル－１Ｈ－１，２，３－トリアゾール－４－イル）－３－ニトロベンゼン－１，２－ジオール Example 189: 5- (1-benzyl-1H-1,2,3-triazol-4-yl) -3-nitrobenzene-1,2-diol
　ベンジルボロン酸を用いて、参考例４３、１３、実施例１と同様にして表題化合物（収率１７％）を得た。 The title compound (17% yield) was obtained in the same manner as in Reference Examples 43 and 13 and Example 1 using benzylboronic acid.
実施例１９０：５－｛１－［２－（２－ブロモ－４，５－ジヒドロキシフェニル）エチル］－１Ｈ－１，２，３－トリアゾール－４－イル｝－３－ニトロベンゼン－１，２－ジオール Example 190: 5- {1- [2- (2-bromo-4,5-dihydroxyphenyl) ethyl] -1H-1,2,3-triazol-4-yl} -3-nitrobenzene-1,2- Diol
　実施例１９１の副生成物（収率１６％）として得た。 Obtained as a by-product of Example 191 (yield 16%).
実施例１９１：５－｛１－［２－（３，４－ジヒドロキシフェニル）エチル］－１Ｈ－１，２，３－トリアゾール－４－イル｝－３－ニトロベンゼン－１，２－ジオール Example 191: 5- {1- [2- (3,4-dihydroxyphenyl) ethyl] -1H-1,2,3-triazol-4-yl} -3-nitrobenzene-1,2-diol
　２－（３，４－ジメトキシフェニル）エチルアジドと５－エチニル－１，２－ジメトキシ－３－ニトロベンゼンを用いて、参考例５４、参考例１３、実施例１、２と同様にして表題化合物（収率２３％）を得た。 Using 2- (3,4-dimethoxyphenyl) ethyl azide and 5-ethynyl-1,2-dimethoxy-3-nitrobenzene in the same manner as in Reference Example 54, Reference Example 13, and Examples 1 and 2, 23%) was obtained.
実施例１９２：５－［１－（４－フルオロ－３－ヒドロキシフェニル）－１Ｈ－１，２，３－トリアゾール－４－イル］－３－ニトロベンゼン－１，２－ジオール Example 192: 5- [1- (4-Fluoro-3-hydroxyphenyl) -1H-1,2,3-triazol-4-yl] -3-nitrobenzene-1,2-diol
　４－フルオロ－３－メトキシフェニルボロン酸を用いて、参考例４３、１３、実施例１、２と同様にし表題化合物（収率６％）を得た。 Using 4-fluoro-3-methoxyphenylboronic acid, the title compound (yield 6%) was obtained in the same manner as Reference Examples 43 and 13 and Examples 1 and 2.
実施例１９３：４－クロロ－５－［１－（４－フルオロ－３－ヒドロキシフェニル）－１Ｈ－１，２，３－トリアゾール－４－イル］－３－ニトロベンゼン－１，２－ジオール Example 193: 4-chloro-5- [1- (4-fluoro-3-hydroxyphenyl) -1H-1,2,3-triazol-4-yl] -3-nitrobenzene-1,2-diol
　４－フルオロ－３－メトキシフェニルボロン酸と２－クロロ－４，５－ジメトキシ３－ニトロベンズアルデヒドを用いて、参考例４２、４３、１３、実施例１、２と同様にして表題化合物（収率１５％）を得た。 Using 4-fluoro-3-methoxyphenylboronic acid and 2-chloro-4,5-dimethoxy-3-nitrobenzaldehyde in the same manner as in Reference Examples 42, 43 and 13, and Examples 1 and 2, the title compound (yield) 15%).
実施例１９４：５－［１－（４－フルオロ－３－ヒドロキシフェニル）－１Ｈ－１，２，３－トリアゾール－４－イル］－３－ニトロ－４－（トリフルオロメチル）ベンゼン－１，２－ジオール Example 194: 5- [1- (4-fluoro-3-hydroxyphenyl) -1H-1,2,3-triazol-4-yl] -3-nitro-4- (trifluoromethyl) benzene-1, 2-diol
　４－フルオロ－３－メトキシフェニルボロン酸と２－トリフルオロメチル－４，５－ジメトキシ３－ニトロベンズアルデヒドを用いて、参考例４２、４３，１３、実施例１、２と同様にして表題化合物（収率１９％）を得た。 Using 4-fluoro-3-methoxyphenylboronic acid and 2-trifluoromethyl-4,5-dimethoxy-3-nitrobenzaldehyde in the same manner as in Reference Examples 42, 43 and 13, and Examples 1 and 2, the title compound ( Yield 19%).
実施例１９５：３，５－ジクロロ－４－［１－（４－フルオロ－３－ヒドロキシフェニル）－１Ｈ－１，２，３－トリアゾール－４－イル］－６－ニトロベンゼン－１，２－ジオール Example 195: 3,5-dichloro-4- [1- (4-fluoro-3-hydroxyphenyl) -1H-1,2,3-triazol-4-yl] -6-nitrobenzene-1,2-diol
　４－フルオロ－３－メトキシフェニルボロン酸と２，６－ジクロロ－４，５－ジメトキシ３－ニトロベンズアルデヒドを用いて、参考例４２、４３、１３、実施例１、２と同様にして表題化合物（収率２％）を得た。 Using 4-fluoro-3-methoxyphenylboronic acid and 2,6-dichloro-4,5-dimethoxy-3-nitrobenzaldehyde in the same manner as in Reference Examples 42, 43, 13 and Examples 1 and 2, the title compound ( Yield 2%).
実施例１９６：３－ニトロ－５－［２－（２－フェニルプロパン－２－イル）－２Ｈ－テトラゾール－５－イル］ベンゼン－１，２－ジオール Example 196: 3-nitro-5- [2- (2-phenylpropan-2-yl) -2H-tetrazol-5-yl] benzene-1,2-diol
　（ａ）：参考例４９で製造した５－（３，４－ジメトキシ－５－ニトロフェニル）－２Ｈ－テトラゾール（５００ｍｇ）のアセトン（５．０ｍＬ）溶液に、トリフルオロ酢酸（９１４ｍｇ）および２－フェニル－１－プロペン（０．５２ｍＬ）を加え、室温で４時間撹拌した。反応液に１Ｍ水酸化ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧蒸留した。
　（ｂ）：（ａ）にＮ，Ｎ－ジメチルホルムアミド（３．８ｍＬ）、塩化リチウム（１６９ｍｇ）を加え、１２０℃で２時間撹拌後、室温で１５時間撹拌した。反応液に２Ｍ塩酸水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥後、溶媒を減圧蒸留し、残渣に２－プロパノールおよびｎ－ヘキサンを加え、析出した結晶（２４３ｍｇ）をろ取した。
　（ｃ）：（ｂ）にピリジン（２．４ｍＬ）、塩化アルミニウム（２７２ｍｇ）を加え、室温で６時間撹拌した。反応液に２Ｍ塩酸を加え，酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、溶媒を減圧蒸留した。残渣に、２－プロパノールおよびｎ－ヘキサンを加え、析出した結晶をろ取し、表題化合物（２２１ｍｇ）を得た。 (A): To a solution of 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole (500 mg) prepared in Reference Example 49 in acetone (5.0 mL), trifluoroacetic acid (914 mg) and 2- Phenyl-1-propene (0.52 mL) was added and stirred at room temperature for 4 hours. To the reaction solution was added 1M aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled under reduced pressure.
(B): N, N-dimethylformamide (3.8 mL) and lithium chloride (169 mg) were added to (a), and the mixture was stirred at 120 ° C. for 2 hours and then at room temperature for 15 hours. 2M aqueous hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled under reduced pressure, 2-propanol and n-hexane were added to the residue, and the precipitated crystals (243 mg) were collected by filtration.
(C): Pyridine (2.4 mL) and aluminum chloride (272 mg) were added to (b) and stirred at room temperature for 6 hours. 2M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled under reduced pressure. To the residue were added 2-propanol and n-hexane, and the precipitated crystals were collected by filtration to give the title compound (221 mg).
実施例１９７：３－ニトロ－５－｛［２－（ピリジン－４－イル）メチル］－２Ｈ－テトラゾール－５－イル｝ベンゼン－１，２－ジオール Example 197: 3-nitro-5-{[2- (pyridin-4-yl) methyl] -2H-tetrazol-5-yl} benzene-1,2-diol
　（４－ブロモメチル）ピリジンと参考例４９で得た５－（３，４－ジメトキシ－５－ニトロフェニル）－２Ｈ－テトラゾールを用いて、参考例５０、１３、実施例１と同様にして表題化合物（収率４％）を得た。 The title compound was obtained in the same manner as in Reference Examples 50 and 13 and Example 1 using (4-bromomethyl) pyridine and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole obtained in Reference Example 49. (Yield 4%) was obtained.
実施例１９８：３－ニトロ－５－｛２－［２－（ピペリジン－１－イル）エチル］－２Ｈ－テトラゾール－５－イル｝ベンゼン－１，２－ジオール Example 198: 3-nitro-5- {2- [2- (piperidin-1-yl) ethyl] -2H-tetrazol-5-yl} benzene-1,2-diol
　１－（２－ブロモエチル）ピペリジンと参考例４９で得た５－（３，４－ジメトキシ－５－ニトロフェニル）－２Ｈ－テトラゾールを用いて、参考例５０、１３、実施例１と同様にして表題化合物を得た。 Using 1- (2-bromoethyl) piperidine and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole obtained in Reference Example 49, in the same manner as Reference Examples 50 and 13 and Example 1. The title compound was obtained.
実施例１９９：５－｛２－［（３，５－ジメトキシフェニル）メチル］－２Ｈ－テトラゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 199: 5- {2-[(3,5-dimethoxyphenyl) methyl] -2H-tetrazol-5-yl} -3-nitrobenzene-1,2-diol
　１－クロロメチル－（３，５－ジメトキシ）ベンゼンと参考例４９で得た５－（３，４－ジメトキシ－５－ニトロフェニル）－２Ｈ－テトラゾールを用いて、参考例５０、１３、実施例１と同様にして表題化合物（収率３４％）を得た。 Reference Examples 50, 13 and Examples using 1-chloromethyl- (3,5-dimethoxy) benzene and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole obtained in Reference Example 49 The title compound (yield 34%) was obtained in the same manner as in 1.
実施例２００：３－ニトロ－５－（２－フェニル－２Ｈ－テトラゾール－５－イル）ベンゼン－１，２－ジオール Example 200: 3-nitro-5- (2-phenyl-2H-tetrazol-5-yl) benzene-1,2-diol
　参考例５１で製造した５－（３，４－ジメトキシ－５－ニトロフェニル）－２－フェニル－２Ｈ－テトラゾールを、参考例１３、実施例１と同様にして表題化合物（収率３４％）を得た。 5- (3,4-Dimethoxy-5-nitrophenyl) -2-phenyl-2H-tetrazole prepared in Reference Example 51 was prepared in the same manner as Reference Example 13 and Example 1 to give the title compound (yield 34%) Obtained.
実施例２０１：５－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－２Ｈ－テトラゾール－２－イル］－２－フルオロ安息香酸メチル Example 201: Methyl 5- [5- (3,4-dihydroxy-5-nitrophenyl) -2H-tetrazol-2-yl] -2-fluorobenzoate
　４－フルオロ－３－（メトキシカルボニル）フェニルボロン酸と参考例４９で得た５－（３，４－ジメトキシ－５－ニトロフェニル）－２Ｈ－テトラゾールを用いて、参考例５１、１３、実施例１と同様にして表題化合物（収率３４％）を得た。 Reference Examples 51, 13 and Examples using 4-fluoro-3- (methoxycarbonyl) phenylboronic acid and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole obtained in Reference Example 49 The title compound (yield 34%) was obtained in the same manner as in 1.
実施例２０２：５－［５－（３，４－ジヒドロキシ－５－ニトロフェニル）－２Ｈ－テトラゾール－２－イル］－２－フルオロ安息香酸 Example 202: 5- [5- (3,4-Dihydroxy-5-nitrophenyl) -2H-tetrazol-2-yl] -2-fluorobenzoic acid
　４－フルオロ－３－（メトキシカルボニル）フェニルボロン酸と参考例４９で製造した５－（３，４－ジメトキシ－５－ニトロフェニル）－２Ｈ－テトラゾールを用いて、参考例５１、１３、実施例１、５と同様にして表題化合物（１７％）を得た。 Reference Examples 51, 13 and Examples using 4-fluoro-3- (methoxycarbonyl) phenylboronic acid and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole prepared in Reference Example 49 1 and 5 gave the title compound (17%).
実施例２０３：５－［２－（４－ヒドロキシフェニル）－２Ｈ－テトラゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 203: 5- [2- (4-hydroxyphenyl) -2H-tetrazol-5-yl] -3-nitrobenzene-1,2-diol
　４－メトキシフェニルボロン酸と参考例４９で製造した５－（３，４－ジメトキシ－５－ニトロフェニル）－２Ｈ－テトラゾールを用いて、参考例５１、１３、実施例１、２と同様にして表題化合物（収率３％）を得た。 Using 4-methoxyphenylboronic acid and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole prepared in Reference Example 49, in the same manner as Reference Examples 51 and 13 and Examples 1 and 2. The title compound (yield 3%) was obtained.
実施例２０４：５－［２－（３－ヒドロキシフェニル）－２Ｈ－テトラゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 204: 5- [2- (3-hydroxyphenyl) -2H-tetrazol-5-yl] -3-nitrobenzene-1,2-diol
　３－メトキシフェニルボロン酸と参考例４９で製造した５－（３，４－ジメトキシ－５－ニトロフェニル）－２Ｈ－テトラゾールを用いて、参考例５１、１３、実施例１、２と同様にして表題化合物（収率２％）を得た。 Using 3-methoxyphenylboronic acid and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole prepared in Reference Example 49, in the same manner as Reference Examples 51 and 13 and Examples 1 and 2. The title compound (yield 2%) was obtained.
実施例２０５：５－｛２－［３，４－（メチレンジオキシ）フェニル］－２Ｈ－テトラゾール－５－イル｝－３－ニトロベンゼン－１，２－ジオール Example 205: 5- {2- [3,4- (methylenedioxy) phenyl] -2H-tetrazol-5-yl} -3-nitrobenzene-1,2-diol
　３，４－（メチレンジオキシ）フェニルボロン酸と参考例４９で製造した５－（３，４－ジメトキシ－５－ニトロフェニル）－２Ｈ－テトラゾールを用いて、参考例５１、１３、実施例１と同様にして表題化合物（収率４％）を得た。 Reference Examples 51 and 13, Example 1 using 3,4- (methylenedioxy) phenylboronic acid and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole prepared in Reference Example 49 To give the title compound (yield 4%).
実施例２０６：５－［２－（３，４－ジヒドロキシフェニル）－２Ｈ－テトラゾール－５－イル］－３－ニトロベンゼン－１，２－ジオール Example 206: 5- [2- (3,4-dihydroxyphenyl) -2H-tetrazol-5-yl] -3-nitrobenzene-1,2-diol
　３，４－（メチレンジオキシ）フェニルボロン酸と参考例４９で製造した５－（３，４－ジメトキシ－５－ニトロフェニル）－２Ｈ－テトラゾールを用いて、参考例１、５１、１３、実施例１、２と同様にして表題化合物（収率４％）を得た。 Using Reference Examples 1, 51, 13 and 3,4- (methylenedioxy) phenylboronic acid and 5- (3,4-dimethoxy-5-nitrophenyl) -2H-tetrazole prepared in Reference Example 49 The title compound (yield 4%) was obtained in the same manner as in Examples 1 and 2.
実施例２０７：４－クロロ－５－［４－（４－フルオロ－３－ヒドロキシフェニル）－１Ｈ－１，２，３－トリアゾール－１－イル］－３－ニトロベンゼン－１，２－ジオール Example 207: 4-chloro-5- [4- (4-fluoro-3-hydroxyphenyl) -1H-1,2,3-triazol-1-yl] -3-nitrobenzene-1,2-diol
　４－エチニル－１－フルオロ－２－メトキシベンゼンと４，５－ジメトキシ－３－ニトロ－２－クロロ安息香酸を用いて、参考例５２，５３、５４、１３、実施例３と同様にして表題化合物（収率２２％）を得た。 Using 4-ethynyl-1-fluoro-2-methoxybenzene and 4,5-dimethoxy-3-nitro-2-chlorobenzoic acid in the same manner as in Reference Examples 52, 53, 54, 13 and Example 3, A compound (yield 22%) was obtained.
実施例２０８：５－［４－（４－フルオロ－３－ヒドロフェニル）－１Ｈ－１，２，３－トリアゾール－１－イル］－３－ニトロ－４－（トリフルオロメチル）ベンゼン－１，２－ジオール Example 208: 5- [4- (4-Fluoro-3-hydrophenyl) -1H-1,2,3-triazol-1-yl] -3-nitro-4- (trifluoromethyl) benzene-1, 2-diol
　４－エチニル－１－フルオロ－２－メトキシベンゼンと４，５－ジメトキシ－３－ニトロ－２－（トリフルオロメチル）安息香酸を用いて、参考例５２，５３、５４、１３、実施例１、２と同様にして表題化合物（収率１３％）を得た。 Using 4-ethynyl-1-fluoro-2-methoxybenzene and 4,5-dimethoxy-3-nitro-2- (trifluoromethyl) benzoic acid, Reference Examples 52, 53, 54 and 13, Example 1, In the same manner as in Example 2, the title compound (yield 13%) was obtained.
実施例２０９：３－｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロフェニル｝イソベンゾフラン－１（３Ｈ）－オン Example 209: 3- {6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrophenyl} iso Benzofuran-1 (3H) -one
　（ａ）：参考例２１で製造した５－［４－（ベンジルオキシ）－２－ヨード－５－メトキシフェニル］－３－［４－フルオロ－３－（メトキシフェニル）］－１，２，４－オキサジアゾールにｎ－ブチルリチウム、Ｎ，Ｎ－ジメチルホルムアミドを反応させ、５－（ベンジルオキシ）－２－｛３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール－５－イル｝－４－メトキシベンズアルデヒドを得た。
　（ｂ）：（ａ）に２－（メトキシカルボニル）フェニルマグネシウムヨージドを反応させ、３－［５－（ベンジルオキシ）－２－｛（３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール－５－イル｝－４－メトキシフェニル］イソベンゾフラン－１（３Ｈ）－オンを得た。
　（ｃ）：（ｂ）を用いて、参考例１９、１７、実施例３と同様にして表題化合物を得た。 (A): 5- [4- (Benzyloxy) -2-iodo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxyphenyl)]-1,2,4 prepared in Reference Example 21 -Oxadiazole is reacted with n-butyllithium and N, N-dimethylformamide to give 5- (benzyloxy) -2- {3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2, 4-Oxadiazol-5-yl} -4-methoxybenzaldehyde was obtained.
(B): (a) is reacted with 2- (methoxycarbonyl) phenylmagnesium iodide to give 3- [5- (benzyloxy) -2-{(3- [4-fluoro-3- (methoxymethoxy) phenyl ] -1,2,4-oxadiazol-5-yl} -4-methoxyphenyl] isobenzofuran-1 (3H) -one was obtained.
(C): The title compound was obtained in the same manner as in Reference Examples 19 and 17 and Example 3 using (b).
実施例２１０：５－（３－｛ジフロロ［（４－フルオロ－３－ヒドロキシベンジル）チオ］メチル｝－１，２，４－オキサジアゾール－５－イル）－３－ニトロベンゼン－１，２－ジオール Example 210: 5- (3- {difluoro [(4-fluoro-3-hydroxybenzyl) thio] methyl} -1,2,4-oxadiazol-5-yl) -3-nitrobenzene-1,2- Diol
　参考例１１で製造した２，２－ジフルオロ－２－（｛［４－フルオロ－３－（メトキシメトキシ）フェニル］メチル｝スルファニル）－Ｎ－ヒドロキシアセトイミダミドと３，４－ジメトキシ－５－ニトロベンゾイルクロリドを用い、参考例１２（ｂ）、（ｃ）、１３、実施例１と同様にして表題化合物を得た。 2,2-Difluoro-2-({[4-fluoro-3- (methoxymethoxy) phenyl] methyl} sulfanyl) -N-hydroxyacetimidamide and 3,4-dimethoxy-5-nitro prepared in Reference Example 11 The title compound was obtained in the same manner as in Reference Examples 12 (b), (c), 13 and Example 1 using benzoyl chloride.
実施例２１１：
５－（３－｛ジフロロ［（４－フルオロ－３－ヒドロキシフェニル）チオ］メチル｝－１，２，４－オキサジアゾール－５－イル）－４－メトキシ－３－ニトロベンゼン－１，２－ジオール  Example 211:
5- (3- {Difluoro [(4-fluoro-3-hydroxyphenyl) thio] methyl} -1,2,4-oxadiazol-5-yl) -4-methoxy-3-nitrobenzene-1,2- Diol
　２－フルオロ－４，５－ジメトキシ－３－ニトロベンゾイルクロリドと参考例１１で製造した２，２－ジフルオロ－２－（｛［４－フルオロ－３－（メトキシメトキシ）フェニル］メチル｝スルファニル）－Ｎ－ヒドロキシアセトイミダミドを参考例１２、１３と同様にして、６－（３－｛ジフロロ［（３－フルオロ－４－メトキシメトキシフェニル）チオ］メチル｝－１，２，４－オキサジアゾール－５－イル）－２－ヒドロキシ－３－メトキシ－６－フルオロニトロベンゼンを得た後、ナトリウムメトキシド及びメタノールを加え、５０℃で１８時間撹拌し、６－（３－｛ジフロロ［４－フルオロ－３ －メトキシメトキシフェニル）チオ］メチル｝－１，２，４－オキサジアゾール－５－イル）－２，５－ジメトキシ－６－ニトロフェノールを得た。この化合物を実施例３と同様にして表題化合物を得た。 2-Fluoro-4,5-dimethoxy-3-nitrobenzoyl chloride and 2,2-difluoro-2-({[4-fluoro-3- (methoxymethoxy) phenyl] methyl} sulfanyl)-prepared in Reference Example 11- N-hydroxyacetimidamide was treated in the same manner as in Reference Examples 12 and 13, and 6- (3- {difluoro [(3-fluoro-4-methoxymethoxyphenyl) thio] methyl} -1,2,4-oxadiazole was used. After obtaining -5-yl) -2-hydroxy-3-methoxy-6-fluoronitrobenzene, sodium methoxide and methanol were added and stirred at 50 ° C. for 18 hours to give 6- (3- {difluoro [4-fluoro -3 -methoxymethoxyphenyl) thio] methyl} -1,2,4-oxadiazol-5-yl) -2,5-dimethoxy-6-nitroph It was obtained Nord. This compound was obtained in the same manner as in Example 3 to obtain the title compound.
実施例２１２：６－（３－｛ジフロロ［（４－フルオロ－３ －ヒドロキシフェニル）チオ］メチル｝－１，２，４－オキサジアゾール－５－イル）－３，４－ジヒドロキシ－２－ニトロベンゾニトリル Example 212: 6- (3- {difluoro [(4-fluoro-3 -hydroxyphenyl) thio] methyl} -1,2,4-oxadiazol-5-yl) -3,4-dihydroxy-2- Nitrobenzonitrile
　２－シアノ－４，５－ジメトキシ－３－ニトロベンゾイルクロリドと参考例７で製造した２，２－ジフルオロ－２－｛［４－フルオロ－３－（メトキシメトキシ）フェニル］スルファニル｝－Ｎ－ヒドロキシアセトイミダミドを用いて、参考例１２、１３、実施例３と同様にして表題化合物を得た。 2-Cyano-4,5-dimethoxy-3-nitrobenzoyl chloride and 2,2-difluoro-2-{[4-fluoro-3- (methoxymethoxy) phenyl] sulfanyl} -N-hydroxy prepared in Reference Example 7 The title compound was obtained in the same manner as in Reference Examples 12, 13, and Example 3 using acetimidamide.
実施例２１３：６－（３－｛ジフロロ［（４－フルオロ－３－ ヒドロキシフェニル）チオ］メチル｝－１，２，４－オキサジアゾール－５－イル）－３，４－ジヒドロキシ－２－ニトロベンズアミド Example 213: 6- (3- {difluoro [(4-fluoro-3- hydroxyphenyl) thio] methyl} -1,2,4-oxadiazol-5-yl) -3,4-dihydroxy-2- Nitrobenzamide
　実施例２１２で得た、６－（３－｛ジフロロ［（４－フルオロ－３－ヒ ドロキシフェニル）チオ］メチル｝－１，２，４－オキサジアゾール－５－イル）－３，４－ジヒドロキシ－２－ニトロベンゾニトリル１１０ｍｇ、ジエチルヒドロキシアミン７５ｍｇ、酢酸銅１９５ｍｇ、水３ｍｌ及びＴＨＦ１ｍｌの混合物を室温下１８時間撹拌した。反応液にクエン酸水溶液を加え、酢酸エチルで抽出した。有機層を水及び飽和食塩水で洗浄後、無水硫酸　ナトリウムで脱水後、減圧下溶媒を留去し表題化合物を得た。 6- (3- {Difluoro [(4-fluoro-3-hydroxyphenyl) thio] methyl} -1,2,4-oxadiazol-5-yl) -3,4 obtained in Example 212 A mixture of 110 mg of dihydroxy-2-nitrobenzonitrile, 75 mg of diethylhydroxyamine, 195 mg of copper acetate, 3 ml of water and 1 ml of THF was stirred at room temperature for 18 hours. To the reaction solution was added an aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dehydrated over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound.
参考例５５：５－［４－（ベンジルオキシ）－２－ブロモ－５－メトキシフェニル］－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール Reference Example 55: 5- [4- (benzyloxy) -2-bromo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxadiazole
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
　（ａ）：４－（ベンジルオキシ）－２－ブロモ－５－メトキシ安息香酸（１．００ｇ）のジクロロメタン（１０．０ｍＬ）溶液に、Ｎ，Ｎ－ジメチルホルムアミド（１０μＬ）、塩化チオニル（０．３８ｍＬ）を加え、室温で１時間撹拌した。溶媒を減圧留去し、トルエン共沸した。
　（ｂ）：（ａ）のジクロロメタン（１０．０ｍＬ）溶液に、トリエチルアミン（０．４２ｍＬ）、４－フルオロ－Ｎ－ヒドロキシ－３－（メトキシメトキシ）ベンズイミダミド（７６２ｍｇ）を加え、室温で４０分間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、１Ｍ塩酸水、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。
　（ｃ）：（ｂ）のＮ，Ｎ－ジメチルホルムアミド（５．０ｍＬ）溶液に、（＋）－１０－カンファースルホン酸（６９ｍｇ）を加え、１００℃で６３時間撹拌した。炭酸カリウム（１．６６ｇ）、クロロメチルメチルエーテル（０．６８ｍＬ）を室温で加え、４０℃で４時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、１Ｍ塩酸水、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去し、表題化合物（１．４５ｇ）を得た。
1H-NMR(DMSO-d6)δ:3.46(3H,s),3.88(3H,s),5.26(2H,s),5.38(2H,s),7.33-7.53(6H,m),7.56(1H,s),7.63(1H,s),7.78(1H,ddd,J=8.8,4.4,2.0Hz),7.93(1H,dd,J=8.4,2.0Hz). (A): To a solution of 4- (benzyloxy) -2-bromo-5-methoxybenzoic acid (1.00 g) in dichloromethane (10.0 mL), N, N-dimethylformamide (10 μL), thionyl chloride (0. 38 mL) and stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure and azeotroped with toluene.
(B): Triethylamine (0.42 mL) and 4-fluoro-N-hydroxy-3- (methoxymethoxy) benzimidamide (762 mg) were added to a solution of (a) in dichloromethane (10.0 mL), and the mixture was stirred at room temperature for 40 minutes. did. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 1M aqueous hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(C): (+)-10-Camphorsulfonic acid (69 mg) was added to a solution of (b) in N, N-dimethylformamide (5.0 mL), and the mixture was stirred at 100 ° C. for 63 hours. Potassium carbonate (1.66 g) and chloromethyl methyl ether (0.68 mL) were added at room temperature, and the mixture was stirred at 40 ° C. for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, 1M aqueous hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.45 g).
1 H-NMR (DMSO-d 6 ) δ: 3.46 (3H, s), 3.88 (3H, s), 5.26 (2H, s), 5.38 (2H, s), 7.33-7.53 (6H, m), 7.56 (1H, s), 7.63 (1H, s), 7.78 (1H, ddd, J = 8.8,4.4,2.0Hz), 7.93 (1H, dd, J = 8.4,2.0Hz).
参考例５６：５－［４－（ベンジルオキシ）－２－ヨード－５－メトキシフェニル］－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール Reference Example 56: 5- [4- (benzyloxy) -2-iodo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxadiazole
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
　４－（ベンジルオキシ）－２－ヨード－５－メトキシ安息香酸（３．００ｇ）から参考例５５と同様に製造し、表題化合物（３．５４ｇ）を得た。
1H-NMR(DMSO-d6)δ:3.46(3H,s),3.85(3H,s),5.24(2H,s),5.38(2H,s),7.34-7.53(6H,m),7.55(1H,s),7.71(1H,s),7.78(1H,ddd,J=8.8,4.4,2.0Hz),7.93(1H,dd,J=8.4,2.0Hz). Prepared from 4- (benzyloxy) -2-iodo-5-methoxybenzoic acid (3.00 g) in the same manner as in Reference Example 55 to give the title compound (3.54 g).
1 H-NMR (DMSO-d 6 ) δ: 3.46 (3H, s), 3.85 (3H, s), 5.24 (2H, s), 5.38 (2H, s), 7.34-7.53 (6H, m), 7.55 (1H, s), 7.71 (1H, s), 7.78 (1H, ddd, J = 8.8,4.4,2.0Hz), 7.93 (1H, dd, J = 8.4,2.0Hz).
参考例５７：５－｛［２－ヨード－５－メトキシ－４－（４－メトキシベンジル）オキシ］フェニル｝－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール Reference Example 57: 5-{[2-iodo-5-methoxy-4- (4-methoxybenzyl) oxy] phenyl} -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4 -Oxadiazole
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
　（ａ）２－ヨード－５－メトキシ－４－［（４－メトキシベンジル）オキシ］安息香酸（１．９０ｇ）のテトラヒドロフラン（４０．０ｍＬ）溶液に、トリエチルアミン（０．６８ｍＬ）、クロロギ酸エチル（０．４３ｍＬ）を加え、室温で１０分間撹拌した。不溶物を除去し、溶媒を減圧留去した。
　（ｂ）：（ａ）のジクロロメタン（２０．０ｍＬ）溶液に、トリエチルアミン（０．４２ｍＬ）、４－フルオロ－Ｎ－ヒドロキシ－３－（メトキシメトキシ）ベンズイミダミド（１．１４ｇ）を加え、室温で１時間撹拌した。溶媒を留去し、水、酢酸エチルを加え、析出した固体をろ取した。ろ液を分液し、有機層を飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去して得られた残渣と固体を合わせた。
　（ｃ）：（ｂ）にＮ，Ｎ－ジメチルホルムアミド（２０．０ｍＬ）、（＋）－１０－カンファースルホン酸（５２ｍｇ）を加え、１００℃で１９時間撹拌した。炭酸カリウム（２．４５ｇ）、クロロメチルメチルエーテル（１．０１ｍＬ）を室温で加え、５０℃で２時間撹拌した。反応液に水（１５０ｍＬ）を加え、析出した固体をろ取し、水（１０．０ｍＬ）で２回、エタノール（２．０ｍＬ）で洗浄し、表題化合物（２．１０ｇ）を得た。
1H-NMR(DMSO-d6)δ:3.46(3H,s),3.77(3H,s),3.83(3H,s),5.15(2H,s),5.37(2H,s),6.98(2H,dd,J=8.8Hz),7.40(2H,dd,J=8.8Hz),7.50(1H,dd,J=11.2,8.8Hz),7.53(1H,s),7.71(1H,s),7.77(1H,ddd,J=8.8,4.4,2.0Hz),7.93(1H,dd,J=8.4,2.0Hz). (A) To a solution of 2-iodo-5-methoxy-4-[(4-methoxybenzyl) oxy] benzoic acid (1.90 g) in tetrahydrofuran (40.0 mL) was added triethylamine (0.68 mL) and ethyl chloroformate ( 0.43 mL) was added and stirred at room temperature for 10 minutes. Insoluble materials were removed, and the solvent was distilled off under reduced pressure.
(B): To a solution of (a) in dichloromethane (20.0 mL), triethylamine (0.42 mL) and 4-fluoro-N-hydroxy-3- (methoxymethoxy) benzimidamide (1.14 g) were added, and 1 at room temperature was added. Stir for hours. The solvent was distilled off, water and ethyl acetate were added, and the precipitated solid was collected by filtration. The filtrate was separated, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to combine the resulting residue and solid.
(C): N, N-dimethylformamide (20.0 mL) and (+)-10-camphorsulfonic acid (52 mg) were added to (b), and the mixture was stirred at 100 ° C. for 19 hours. Potassium carbonate (2.45 g) and chloromethyl methyl ether (1.01 mL) were added at room temperature, and the mixture was stirred at 50 ° C. for 2 hours. Water (150 mL) was added to the reaction mixture, and the precipitated solid was collected by filtration and washed twice with water (10.0 mL) and ethanol (2.0 mL) to give the title compound (2.10 g).
1 H-NMR (DMSO-d 6 ) δ: 3.46 (3H, s), 3.77 (3H, s), 3.83 (3H, s), 5.15 (2H, s), 5.37 (2H, s), 6.98 (2H , dd, J = 8.8Hz), 7.40 (2H, dd, J = 8.8Hz), 7.50 (1H, dd, J = 11.2,8.8Hz), 7.53 (1H, s), 7.71 (1H, s), 7.77 (1H, ddd, J = 8.8,4.4,2.0Hz), 7.93 (1H, dd, J = 8.4,2.0Hz).
実施例２１４：１－｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロフェニル｝－２－メチルプロパン－１－オン Example 214: 1- {6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrophenyl}- 2-Methylpropan-1-one
　（ａ）実施例２０９（ａ）で製造した５－（ベンジルオキシ）－２－｛３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール－５－イル｝－４－メトキシベンズアルデヒド（３９３ｍｇ）のテトラヒドロフラン（２０．０ｍＬ）溶液に、アルゴン雰囲気下イソプロピルマグネシウムクロリド・塩化リチウム錯体のテトラヒドロフラン溶液（１４％、２．６ｍＬ）を－１０℃で加え、０℃で２．５時間撹拌した。反応液に５％塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィ（ヘキサン：酢酸エチル＝３：１）で精製した。
　（ｂ）：（ａ）のジメチルスルホキシド（３．０ｍＬ）溶液に、トリエチルアミン（４０１μＬ）、三酸化硫黄・ピリジン錯体（４１５ｍｇ）を加え、室温で１９時間撹拌した。反応液に５％クエン酸水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィ（ヘキサン：酢酸エチル＝４：１）で精製した。
　（ｃ）：（ｂ）を参考例１９、１７、実施例３と同様にして、表題化合物（収率１１％）を得た。 (A) 5- (Benzyloxy) -2- {3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxadiazole-5-prepared in Example 209 (a) A solution of isopropylmagnesium chloride / lithium chloride complex in tetrahydrofuran (14%, 2.6 mL) at −10 ° C. was added to a solution of yl} -4-methoxybenzaldehyde (393 mg) in tetrahydrofuran (20.0 mL) at −10 ° C. For 2.5 hours. To the reaction solution was added 5% aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1).
(B): Triethylamine (401 μL) and sulfur trioxide / pyridine complex (415 mg) were added to a solution of (a) in dimethyl sulfoxide (3.0 mL), and the mixture was stirred at room temperature for 19 hours. To the reaction solution was added 5% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1).
(C): The title compound (yield 11%) was obtained by treating (b) in the same manner as in Reference Examples 19, 17 and Example 3.
実施例２１５：６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－Ｎ－イソブチル－２－ニトロベンズアミド Example 215: 6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-N-isobutyl-2-nitrobenzamide
　（ａ）：実施例２０９（ａ）で製造した５－（ベンジルオキシ）－２－｛３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール－５－イル｝－４－メトキシベンズアルデヒド（２１９ｍｇ）のアセトニトリル（３．０ｍＬ）溶液に、５％クエン酸水溶液（３．０ｍＬ）、２－メチル－２－ブタン（０．６７ｍＬ）、亜塩素酸ナトリウム（１２８ｍｇ）を加え、室温で２３時間撹拌した。反応液に５％クエン酸水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。
　（ｂ）：（ａ）のテトラヒドロフラン（５．０ｍＬ）溶液に、トリエチルアミン（１１９μＬ）、クロロギ酸イソブチル（１０４μＬ）を０℃で加え、室温で２時間撹拌した。反応液にイソブチルアミン（１７１μＬ）を加え、室温で１９時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去後、残渣をメタノールで洗浄した。
　（ｃ）：（ｂ）を参考例１９、１７、実施例３と同様にして、表題化合物（収率２４％）を得た。 (A): 5- (Benzyloxy) -2- {3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxadiazole-5 prepared in Example 209 (a) -Il} -4-methoxybenzaldehyde (219 mg) in acetonitrile (3.0 mL) was added to a 5% aqueous citric acid solution (3.0 mL), 2-methyl-2-butane (0.67 mL), sodium chlorite ( 128 mg), and the mixture was stirred at room temperature for 23 hours. To the reaction solution was added 5% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(B): To a tetrahydrofuran (5.0 mL) solution of (a), triethylamine (119 μL) and isobutyl chloroformate (104 μL) were added at 0 ° C., and the mixture was stirred at room temperature for 2 hours. Isobutylamine (171 μL) was added to the reaction solution, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was washed with methanol.
(C): The title compound (yield 24%) was obtained by treating (b) in the same manner as in Reference Examples 19, 17 and Example 3.
実施例２１６：｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロフェニル｝（４－メトキシフェニル）メタノン Example 216: {6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrophenyl} (4- Methoxyphenyl) methanone
　（ａ）：参考例５５で製造した５－［４－（ベンジルオキシ）－２－ブロモ－５－メトキシフェニル］－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール（２３７ｍｇ）のテトラヒドロフラン（８．０ｍＬ）溶液に、アルゴン雰囲気下、ｎ－ブチルリチウムのヘキサン溶液（２．６５Ｍ、０．１８ｍＬ）を－７０℃で加え３０分間撹拌後、４－メトキシベンズアルデヒド（０．１６ｍＬ）を同温で加え、室温で２．５時間撹拌した。反応液に５％クエン酸水溶液を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。
　（ｂ）：（ａ）のクロロホルム（８．０ｍＬ）溶液に、二酸化マンガン（３．０２ｇ）を加え、６０℃で１７時間撹拌した。さらに、二酸化マンガン（２．２８ｇ）を加え、６０℃で２０時間撹拌した。反応液をセライトろ過し、溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィ（ヘキサン：酢酸エチル＝３：１）で精製した。
　（ｃ）：（ｂ）を用いて、参考例１９、１７、実施例３と同様にして、表題化合物（収率３０％）を得た。 (A): 5- [4- (Benzyloxy) -2-bromo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2, prepared in Reference Example 55 To a solution of 4-oxadiazole (237 mg) in tetrahydrofuran (8.0 mL) was added an n-butyllithium hexane solution (2.65 M, 0.18 mL) at −70 ° C. under an argon atmosphere, and the mixture was stirred for 30 minutes. -Methoxybenzaldehyde (0.16 mL) was added at the same temperature, and the mixture was stirred at room temperature for 2.5 hours. To the reaction solution was added 5% aqueous citric acid solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure.
(B): To a solution of (a) in chloroform (8.0 mL), manganese dioxide (3.02 g) was added and stirred at 60 ° C. for 17 hours. Further, manganese dioxide (2.28 g) was added and stirred at 60 ° C. for 20 hours. The reaction solution was filtered through Celite, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1).
(C): The title compound (yield 30%) was obtained in the same manner as in Reference Examples 19 and 17 and Example 3 using (b).
実施例２１７：４－｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロベンゾイル｝安息香酸 Example 217: 4- {6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrobenzoyl} benzoate acid
（ａ）：参考例５５で製造した５－［４－（ベンジルオキシ）－２－ブロモ－５－メトキシフェニル］－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール（５０２ｍｇ）、４－（１，３－ジオキソラン－２－イル）ベンズアルデヒド（５２０ｍｇ）を用いて、実施例２１６（ａ）、（ｂ）と同様にした。
　（ｂ）：（ａ）をアセトン（４．０ｍＬ）及び水（４．０ｍＬ）に溶解し、ｐ－トルエンスルホン酸・一水和物（１５３ｍｇ）を加え、室温で１９時間撹拌した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィ（ヘキサン：酢酸エチル＝４：１）で精製した。
　（ｃ）：（ｂ）を用いて、実施例２１６（ａ）と同様にした後、テトラヒドロフラン（４．０ｍＬ）及びメタノール（１．０ｍＬ）に溶解し、トリメチルシリルジアゾメタンのジエチルエーテル溶液（２．０Ｍ、０．１６ｍＬ）を加え、室温で３．５時間撹拌した。反応液に酢酸を数滴加え、室温下３０分撹拌した。溶媒を減圧留去し、残渣をシリカゲルカラムクロマトグラフィ（ヘキサン：酢酸エチル＝３：１）で精製した。
　（ｄ）：（ｃ）を参考例１９、１７、実施例３と同様にした。
　（ｅ）：（ｄ）をテトラヒドロフラン（１．０ｍＬ）及びメタノール（１．０ｍＬ）、水（１．０ｍＬ）に溶解し、水酸化リチウム（３３ｍｇ）を加え、室温で２１時間撹拌した。反応液に１Ｍ塩酸を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去して、表題化合物（収率９％）を得た。 (A): 5- [4- (Benzyloxy) -2-bromo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2, prepared in Reference Example 55 The same procedure as in Examples 216 (a) and (b) was performed using 4-oxadiazole (502 mg) and 4- (1,3-dioxolan-2-yl) benzaldehyde (520 mg).
(B): (a) was dissolved in acetone (4.0 mL) and water (4.0 mL), p-toluenesulfonic acid monohydrate (153 mg) was added, and the mixture was stirred at room temperature for 19 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1).
(C): After using (b) in the same manner as in Example 216 (a), it was dissolved in tetrahydrofuran (4.0 mL) and methanol (1.0 mL), and trimethylsilyldiazomethane in diethyl ether (2.0 M 0.16 mL), and the mixture was stirred at room temperature for 3.5 hours. A few drops of acetic acid was added to the reaction solution, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 1).
(D): (c) was made the same as Reference Examples 19 and 17 and Example 3.
(E): (d) was dissolved in tetrahydrofuran (1.0 mL), methanol (1.0 mL) and water (1.0 mL), lithium hydroxide (33 mg) was added, and the mixture was stirred at room temperature for 21 hours. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (yield 9%).
実施例２１８：Ｎ，Ｎ－ジエチル－６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロベンズアミド Example 218: N, N-diethyl-6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitro Benzamide
　実施例２１５（ｂ）のイソブチルアミンの代わりにジエチルアミンを用いて、実施例２１５と同様にして表題化合物（収率３９％）を得た。 The title compound (yield 39%) was obtained in the same manner as in Example 215 using diethylamine instead of isobutylamine in Example 215 (b).
実施例２１９：４－｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロベンゾイル｝ベンゾニトリル Example 219: 4- {6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrobenzoyl} benzo Nitrile
　参考例５５で製造した５－［４－（ベンジルオキシ）－２－ブロモ－５－メトキシフェニル］－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール（３０４ｍｇ）及び４－ブロモベンゾニトリル（３５０ｍｇ）を用いて、実施例２１５（ａ）、２１７（ｂ）、参考例１９、１７、実施例３と同様にして、表題化合物（収率２２％）を得た。 5- [4- (Benzyloxy) -2-bromo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxadi prepared in Reference Example 55 Using azole (304 mg) and 4-bromobenzonitrile (350 mg) in the same manner as in Examples 215 (a), 217 (b), Reference Examples 19, 17, and Example 3, the title compound (yield 22% )
実施例２２０：｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロフェニル｝（チオフェン－２－イル）メタノン Example 220: {6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrophenyl} (thiophene- 2-yl) methanone
　（ａ）：参考例５６で製造した５－［４－（ベンジルオキシ）－２－ヨード－５－メトキシフェニル］－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール（５０３ｍｇ）及び２－チオフェンアルデヒド（０．２４ｍＬ）を用いて、実施例２１５（ａ）、２１７（ｂ）と同様にした。
　（ｂ）：（ａ）を酢酸エチル（２０．０ｍＬ）、テトラヒドロフラン（２０．０ｍＬ）、メタノール（８．０ｍＬ）に溶解し、２０％水酸化パラジウム（２．０３ｇ）を加え、水素雰囲気下、室温で３時間撹拌した。反応液をセライトろ過し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィ（ヘキサン：酢酸エチル＝３：２）で精製した。
　（ｃ）：（ｂ）を参考例１７、実施例３と同様にして、表題化合物（収率１０％）を得た。 (A): 5- [4- (Benzyloxy) -2-iodo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2, prepared in Reference Example 56 As in Examples 215 (a) and 217 (b), 4-oxadiazole (503 mg) and 2-thiophenaldehyde (0.24 mL) were used.
(B): (a) was dissolved in ethyl acetate (20.0 mL), tetrahydrofuran (20.0 mL), methanol (8.0 mL), 20% palladium hydroxide (2.03 g) was added, and under a hydrogen atmosphere, Stir at room temperature for 3 hours. The reaction solution was filtered through Celite, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2).
(C): The title compound (yield 10%) was obtained by treating (b) in the same manner as in Reference Example 17 and Example 3.
実施例２２１：４－ベンゾイル－５－［４－（４－フルオロ－３－ヒドロキシフェニル）－１Ｈ－１，２，３－トリアゾール－１－イル］－３－ニトロベンゼン－１，２－ジオール Example 221: 4-benzoyl-5- [4- (4-fluoro-3-hydroxyphenyl) -1H-1,2,3-triazol-1-yl] -3-nitrobenzene-1,2-diol
　実施例１３７の中間体である２－ベンゾイル－４，５－ジメトキシ－３－ニトロ安息香酸および４－エチニル－１－フルオロ－２－（メトキシメトキシ）ベンゼンを用いて、参考例５２、５３、５４、１３、実施例３と同様にして表題化合物（収率３０％）を得た。 By using 2-benzoyl-4,5-dimethoxy-3-nitrobenzoic acid and 4-ethynyl-1-fluoro-2- (methoxymethoxy) benzene as intermediates of Example 137, Reference Examples 52, 53, 54 13, In the same manner as in Example 3, the title compound (yield 30%) was obtained.
実施例２２２：５－（５－｛ジフルオロ［（４－フルオロ－３－ヒドロキシフェニル）スルファニル］メチル｝１，３，４－オキサジアゾール－２－イル）－３－ニトロベンゼン－１，２－ジオール Example 222: 5- (5- {difluoro [(4-fluoro-3-hydroxyphenyl) sulfanyl] methyl} 1,3,4-oxadiazol-2-yl) -3-nitrobenzene-1,2-diol
（ａ）：参考例１０で製造した２，２－ジフルオロ－２－（｛［４－フルオロ－３－（メトキシメトキシ）フェニル］メチル｝スルファニル）アセトニトリル（０．４１ｇ）のメタノール（４．０ｍＬ）溶液に、５Ｍナトリウムメトキシドのメタノール溶液（０．３ｍＬ）を加え、室温で１時間撹拌した。反応液に３，４－ジメトキシ－５－ニトロベンゾヒドラジド塩酸塩を加え、６０℃で３時間撹拌した。溶媒を減圧留去し、残渣に水を加え、結晶をろ取し、Ｎ’－｛２，２－ジフルオロ－２－［（４－フルオロ－３－ヒドロキシフェニル）スルファニル］－１－イミノエチル｝－３，４－ジメトキシ－５－ニトロベンゾヒドラジン（０．９０ｇ）を得た。
　（ｂ）：（ａ）にトルエン（２０ｍＬ）、トシル酸１水和物（８９ｍｇ）を加え、ディーン・スターク装置にて水を除去しながら８時間加熱還流した。反応液に水を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、溶媒を減圧蒸留した。残渣をシリカゲルカラムクロマトグラフィーで精製し、５－（｛［５－（３，４－ジメトキシ－５－ニトロフェニル）－１，３，４－オキサジアゾール－２－イル］ジフルオロメチル｝スルファニル）－２－フルオロフェノール（１６０ｍｇ）を得た。
　（ｃ）：（ｂ）を用いて参考例１３、実施例３と同様にして表題化合物を得た。 (A): 2,2-difluoro-2-({[4-fluoro-3- (methoxymethoxy) phenyl] methyl} sulfanyl) acetonitrile (0.41 g) prepared in Reference Example 10 in methanol (4.0 mL) To the solution was added 5M sodium methoxide in methanol (0.3 mL) and stirred at room temperature for 1 hour. 3,4-Dimethoxy-5-nitrobenzohydrazide hydrochloride was added to the reaction solution, and the mixture was stirred at 60 ° C. for 3 hours. The solvent was distilled off under reduced pressure, water was added to the residue, the crystals were collected by filtration, and N ′-{2,2-difluoro-2-[(4-fluoro-3-hydroxyphenyl) sulfanyl] -1-iminoethyl}- 3,4-Dimethoxy-5-nitrobenzohydrazine (0.90 g) was obtained.
(B): Toluene (20 mL) and tosylic acid monohydrate (89 mg) were added to (a), and the mixture was heated to reflux for 8 hours while removing water with a Dean-Stark apparatus. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled under reduced pressure. The residue was purified by silica gel column chromatography, and 5-({[5- (3,4-dimethoxy-5-nitrophenyl) -1,3,4-oxadiazol-2-yl] difluoromethyl} sulfanyl)- 2-Fluorophenol (160 mg) was obtained.
(C): The title compound was obtained in the same manner as in Reference Example 13 and Example 3 using (b).
実施例２２３：３－｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロベンゾイル｝ベンゾニトリル Example 223: 3- {6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrobenzoyl} benzo Nitrile
　参考例５６で製造した５－［４－（ベンジルオキシ）－２－ヨード－５－メトキシフェニル］－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール（７３１ｍｇ），３－シアノベンズアルデヒド（３９３ｍｇ）から実施例２１５（ａ）、２１７（ｂ）、（ｃ）と同様にして、表題化合物（１２５ｍｇ）を得た。 5- [4- (Benzyloxy) -2-iodo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxadi prepared in Reference Example 56 The title compound (125 mg) was obtained from azole (731 mg) and 3-cyanobenzaldehyde (393 mg) in the same manner as in Examples 215 (a), 217 (b) and (c).
実施例２２４：｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロフェニル｝（チオフェン－３－イル）メタノン Example 224: {6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrophenyl} (thiophene- 3-yl) methanone
　参考例５７で製造した５－｛［２－ヨード－５－メトキシ－４－（４－メトキシベンジル）オキシ］フェニル｝－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール（５９２ｍｇ）、３－シアノベンズアルデヒド（３４２ｍｇ）から実施例２１５（ａ）、２１７（ｂ）、（ｃ）と同様にして、表題化合物（１１５ｍｇ）を得た。 5-{[2-Iodo-5-methoxy-4- (4-methoxybenzyl) oxy] phenyl} -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2, prepared in Reference Example 57 , 4-oxadiazole (592 mg) and 3-cyanobenzaldehyde (342 mg) were obtained in the same manner as in Examples 215 (a), 217 (b) and (c) to give the title compound (115 mg).
実施例２２５：３，５－ジクロロ－４－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサゾール－５－イル］－６－ニトロベンゼン－１，２－ジオール Example 225: 3,5-dichloro-4- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxazol-5-yl] -6-nitrobenzene-1,2-diol
　４－フルオロ－３－（メトキシメトキシ）ベンゾニトリルと２，６－ジクロロ－３，４－ジメトキシ－５－ニトロベンゼンクロリドを用い参考例１２、１３、実施例３と同様にして表題化合物（収率６％）を得た。 Using 4-fluoro-3- (methoxymethoxy) benzonitrile and 2,6-dichloro-3,4-dimethoxy-5-nitrobenzene chloride in the same manner as in Reference Examples 12, 13, and Example 3, the title compound (yield 6 %).
実施例２２６：｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサゾール－５－イル］－３，４－ジヒドロキシ－５－ニトロフェニル｝（チアゾリ－２－イル）メタノン Example 226: {6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxazol-5-yl] -3,4-dihydroxy-5-nitrophenyl} (thiazoly-2- Il) Methanone
　参考例５５で得られた５－［４－（ベンジルオキシ）－２－ブロモ－５－メトキシフェニル］－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾールと２－ブロモチアゾールから実施例２１５（ａ）、２１７（ｂ）、参考例１９、１７、実施例３と同様に製造し、表題化合物（収率１４％）を得た。 5- [4- (Benzyloxy) -2-bromo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxa obtained in Reference Example 55 The title compound (yield 14%) was obtained from diazole and 2-bromothiazole in the same manner as in Examples 215 (a), 217 (b), Reference Examples 19, 17, and Example 3.
実施例２２７：｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロフェニル｝（２－メトキシフェニル）メタノン Example 227: {6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxazol-5-yl] -3,4-dihydroxy-2-nitrophenyl} (2-methoxyphenyl ) Methanone
　参考例５５で得られた５－［４－（ベンジルオキシ）－２－ブロモ－５－メトキシフェニル］－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾールと２－メトキシベンズアルデヒドから実施例２１７（ａ）、２１５（ｂ）、参考例１９、１７、実施例３と同様に製造し、表題化合物（収率１４％）を得た。 5- [4- (Benzyloxy) -2-bromo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxa obtained in Reference Example 55 The title compound (yield 14%) was obtained from diazole and 2-methoxybenzaldehyde in the same manner as in Examples 217 (a), 215 (b), Reference Examples 19, 17, and Example 3.
実施例２２８：｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロフェニル｝（３－メトキシフェニル）メタノン Example 228: {6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxazol-5-yl] -3,4-dihydroxy-2-nitrophenyl} (3-methoxyphenyl ) Methanone
　参考例５６で得られた５－［４－（ベンジルオキシ）－２－ヨード－５－メトキシフェニル］－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾールと３－メトキシベンズアルデヒドから実施例２１５（ａ）、２１７（ｂ）、参考例１９、１７、実施例３と同様に製造し、表題化合物（収率１４％）を得た。 5- [4- (Benzyloxy) -2-iodo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxa obtained in Reference Example 56 The title compound (yield 14%) was obtained from diazole and 3-methoxybenzaldehyde in the same manner as in Examples 215 (a), 217 (b), Reference Examples 19, 17, and Example 3.
実施例２２９：｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロフェニル｝（モルフォリノ）メタノン Example 229: {6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxazol-5-yl] -3,4-dihydroxy-2-nitrophenyl} (morpholino) methanone
　３－ベンジルオキシ－６－｛３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾール－５－イル｝－４－メトキシ－２－ニトロベンズアルデヒドとモルフォリンから実施例２１６、参考例１９、１７、実施例３と同様に製造し、表題化合物（４１％）を得た。 3-Benzyloxy-6- {3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxadiazol-5-yl} -4-methoxy-2-nitrobenzaldehyde and morpholine To 216, Reference Examples 19 and 17, and Example 3 to obtain the title compound (41%).
実施例２３０：｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロフェニル｝（４－フルオロフェニル）メタノン Example 230: {6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxazol-5-yl] -3,4-dihydroxy-2-nitrophenyl} (4-fluorophenyl ) Methanone
　参考例５６で得られた５－［４－（ベンジルオキシ）－２－ヨード－５－メトキシフェニル］－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾールと４－フルオロベンズアルデヒドから実施例２１５（ａ）、２１５（ｂ）、参考例１９、１７、実施例３と同様に製造し、表題化合物（収率１７％）を得た。 5- [4- (Benzyloxy) -2-iodo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxa obtained in Reference Example 56 The title compound (yield 17%) was obtained from diazole and 4-fluorobenzaldehyde in the same manner as in Examples 215 (a), 215 (b), Reference Examples 19, 17, and Example 3.
実施例２３１：｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロフェニル｝（２－フルオロフェニル）メタノン Example 231: {6- [3- (4-fluoro-3-hydroxyphenyl) -1,2,4-oxazol-5-yl] -3,4-dihydroxy-2-nitrophenyl} (2-fluorophenyl ) Methanone
　参考例５６で得られた５－［４－（ベンジルオキシ）－２－ヨード－５－メトキシフェニル］－３－［４－フルオロ－３－（メトキシメトキシ）フェニル］－１，２，４－オキサジアゾールと２－フルオロベンズアルデヒドから実施例２１５（ａ）、２１５（ｂ）、参考例１９、１７、実施例３と同様に製造し、表題化合物（収率２４％）を得た。 5- [4- (Benzyloxy) -2-iodo-5-methoxyphenyl] -3- [4-fluoro-3- (methoxymethoxy) phenyl] -1,2,4-oxa obtained in Reference Example 56 Prepared from diazole and 2-fluorobenzaldehyde in the same manner as in Examples 215 (a), 215 (b), Reference Examples 19, 17, and Example 3 to obtain the title compound (yield 24%).
実施例２３２：酢酸５－［５－（５－アセトキシ－２－ベンゾイル－４－ヒドロキシ－３－ニトロフェニル）－１，２，４－オキサジアゾール－３－イル］－２－フルオロフェニルエステル Example 232: Acetic acid 5- [5- (5-acetoxy-2-benzoyl-4-hydroxy-3-nitrophenyl) -1,2,4-oxadiazol-3-yl] -2-fluorophenyl ester
　実施例１３７で製造した｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロフェニル｝（フェニル）メタノン（１２１ｍｇ）をジクロロメタン（３．０ｍＬ）に溶解し、ピリジン（２２３μＬ）、無水酢酸（１３１μＬ）、Ｎ，Ｎ－ジメチル－４－アミノピリジン（２０ｍｇ）を加え、室温で１８時間撹拌した。反応液に１Ｍ塩酸を加え、酢酸エチルで抽出した。有機層を水、飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残渣をシリカゲルカラムクロマトグラフィ（酢酸エチル：メタノール＝１００：１）で精製して、表題化合物（収率２４％）を得た。 {6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrophenyl prepared in Example 137} ( Phenyl) methanone (121 mg) was dissolved in dichloromethane (3.0 mL), pyridine (223 μL), acetic anhydride (131 μL) and N, N-dimethyl-4-aminopyridine (20 mg) were added, and the mixture was stirred at room temperature for 18 hours. . 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: methanol = 100: 1) to obtain the title compound (yield 24%).
実施例２３３：｛６－［３－（４－フルオロ－３－ヒドロキシフェニル）－１，２，４－オキサジアゾール－５－イル］－３，４－ジヒドロキシ－２－ニトロフェニル｝（ピペリジン－１－イル）メタノン Example 233: {6- [3- (4-Fluoro-3-hydroxyphenyl) -1,2,4-oxadiazol-5-yl] -3,4-dihydroxy-2-nitrophenyl} (piperidine- 1-yl) methanone
　実施例２１５（ｂ）のイソブチルアミンの代わりにピペリジンを用いて、実施例２１５と同様にして表題化合物（収率２８％）を得た。 The title compound (yield 28%) was obtained in the same manner as in Example 215 using piperidine instead of isobutylamine in Example 215 (b).
　以下に実施例化学構造と機器データを示す。 The chemical structure and instrument data of the examples are shown below.
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000066
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000067
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000073
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000074
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000077
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000078
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000079
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000080
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000081
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000082
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000083
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000084
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000085
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000086
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000087
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000088
Figure JPOXMLDOC01-appb-T000089
Figure JPOXMLDOC01-appb-T000089
　ラット肝ＣＯＭＴ及びＤＤＣ阻害試験（酵素調製方法）：イソフルラン麻酔下で放血致死させたラットの肝臓を摘出し、肝重量に対し４倍量の氷冷したホモジネート緩衝液（０．１３５ｍｏｌ／Ｌ　ＫＣｌ含有１０ｍｍｍｏｌ／Ｌリン酸ナトリウム緩衝液、ｐＨ８．０）を加え、ホモジナイズした。ホモジネート溶液を遠心分離（２００００×ｇ、４℃、１０分間）後、上清を回収し、再度、遠心分離（２００００×ｇ、４℃、３０分間）して最終の上清を得た。得られた上清４００μＬをゲル濾過カラムに添加し、溶出液約８００μＬを酵素溶液とした。 Rat liver COMT and DDC inhibition test (enzyme preparation method): The liver of a rat exsanguinated under isoflurane anesthesia was excised, and the ice-cold homogenate buffer (containing 0.135 mol / L KCl) was 4 times the liver weight. 10 mmol / L sodium phosphate buffer (pH 8.0) was added and homogenized. After the homogenate solution was centrifuged (20000 × g, 4 ° C., 10 minutes), the supernatant was collected and centrifuged again (20000 × g, 4 ° C., 30 minutes) to obtain the final supernatant. 400 μL of the obtained supernatant was added to a gel filtration column, and about 800 μL of the eluate was used as an enzyme solution.
　試験例１（ラットＣＯＭＴ阻害作用の測定）：９６ウェルプレートの各ウェルに１０ｍｍｏｌ／Ｌリン酸ナトリウム緩衝液（ｐＨ７．８）を９１μＬ、５００ｍｍｏｌ／Ｌ　ＭｇＣｌ２を２μＬ、２００μｍｏｌ／Ｌ　Ｅｓｃｕｌｅｔｉｎを２μＬ、３０ｍｍｏｌ／Ｌ　ＡｄｏＭｅｔを２μＬ及び各被験物質溶液を１μＬ加え混合した。Ｂｌａｎｋには３０ｍｍｏｌ／Ｌ　ＡｄｏＭｅｔ未添加試料を用いた。調製した酵素溶液を２μＬ添加し、マイクロプレートリーダーにて蛍光強度（励起波長３９０ｎｍ、蛍光波長４６５ｎｍ、３７℃、６０分間）を測定した。ＣＯＭＴ活性は蛍光強度増加反応の定常状態における１秒あたりの増加量として算出した。ＩＣ５０値は、酵素活性を５０％阻害する濃度を示す。 Test Example 1 (Measurement of rat COMT inhibitory action): In each well of a 96-well plate, 91 μL of 10 mmol / L sodium phosphate buffer (pH 7.8), 2 μL of 500 mmol / L MgCl 2 , 2 μL of 200 μmol / L Esculetin, 2 μL of 30 mmol / L AdoMet and 1 μL of each test substance solution were added and mixed. As the blank, a 30 mmol / L AdoMet non-added sample was used. 2 μL of the prepared enzyme solution was added, and fluorescence intensity (excitation wavelength: 390 nm, fluorescence wavelength: 465 nm, 37 ° C., 60 minutes) was measured with a microplate reader. The COMT activity was calculated as the amount of increase per second in the steady state of the fluorescence intensity increasing reaction. IC 50 values indicate concentrations that inhibit enzyme activity by 50%.
　試験例２（ラットＤＤＣ阻害作用の測定）：３０ｍｍｏｌ／Ｌリン酸カリウム緩衝液（ｐＨ６．８）を１８６μＬ、１００ｍｍｏｌ／Ｌ　Ｌ－Ｄｏｐａを２μＬ、７ｍｍｏｌ／Ｌ　ピリドキサールリン酸を２μＬ及び各被験物質溶液を２μＬを加え混合した。調製した酵素溶液を８μＬ添加し、インキュベート（３７℃、１５分間）した。Ｂｌａｎｋにはインキュベート０分の試料を用いた。その後、１００℃で３分間煮沸し、氷上で２分間冷却後、遠心分離（４℃、１００００ｒｐｍ、１０分間）した。上清を回収し、蒸留水を４００μＬ加え希釈後、Ａｍｂｅｒｌｉｔｅ　ＣＧ５０（ＮＨ４ ＋）カラムに全量添加し、蒸留水０．３ｍＬ及び１．５ｍＬで二回洗浄した。その後、２Ｎ酢酸１．２ｍＬでドパミンを溶出させ、分光光度計により吸光度（波長２７９ｎｍ）を測定し、この値を酵素活性とした。ＩＣ５０値は、酵素活性を５０％阻害する濃度を示す。比較例として、トルカポンおよびエンタカポンを同様に試験した。 Test Example 2 (Measurement of rat DDC inhibitory action): 186 μL of 30 mmol / L potassium phosphate buffer (pH 6.8), 2 μL of 100 mmol / L L-Dopa, 2 μL of 7 mmol / L pyridoxal phosphate and each test substance solution 2 μL was added and mixed. 8 μL of the prepared enzyme solution was added and incubated (37 ° C., 15 minutes). A sample of 0 minute incubation was used for Blank. Thereafter, it was boiled at 100 ° C. for 3 minutes, cooled on ice for 2 minutes, and then centrifuged (4 ° C., 10000 rpm, 10 minutes). The supernatant was recovered, diluted with 400 μL of distilled water, added to the Amberlite CG50 (NH 4 + ) column, and washed twice with 0.3 mL and 1.5 mL of distilled water. Thereafter, dopamine was eluted with 1.2 mL of 2N acetic acid, the absorbance (wavelength 279 nm) was measured with a spectrophotometer, and this value was defined as the enzyme activity. IC 50 values indicate concentrations that inhibit enzyme activity by 50%. As comparative examples, tolcapone and entacapone were similarly tested.
　試験例１および試験例２の結果を表２５、表２６に示す。 Results of Test Example 1 and Test Example 2 are shown in Table 25 and Table 26.
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000090
Figure JPOXMLDOC01-appb-T000091
Figure JPOXMLDOC01-appb-T000091
　ラットミトコンドリア毒性試験（ラット心ミトコンドリア溶液の調製方法）：イソフルラン麻酔下で放血致死させたラットの心臓を摘出し、心臓重量に対し８倍量の氷冷したホモジネート緩衝液（２１０ｍｍｏｌ／Ｌ　マンニトール、７０ｍｍｏｌ／Ｌ　スクロース、５ｍｍｏｌ／Ｌ　ＨＥＰＥＳ、１ｍｍｏｌ／Ｌ　ＥＧＴＡからなる緩衝液、ｐＨ７．２）を加え、ホモジナイズした。ホモジネート溶液を遠心分離（５００×ｇ、４℃、１０分間）後、上清を回収し、再度、遠心分離（１００００×ｇ、４℃、１０分間）した。得られた沈殿を８倍量のホモジネート緩衝液で懸濁した後、遠心分離（１００００×ｇ、４℃、１０分間）した。同様な操作を１回繰り返した後、得られた沈殿を心臓重量１ｇ当たり０．２５ｍＬのホモジネート緩衝液で懸濁し、ミトコンドリア溶液とした。 Rat mitochondrial toxicity test (method for preparing rat heart mitochondrial solution): The heart of a rat that had been exsanguinated under isoflurane anesthesia was removed, and the ice-cooled homogenate buffer (210 mmol / L mannitol, 70 mmol) was 8 times the heart weight. / L sucrose, 5 mmol / L HEPES, 1 mmol / L EGTA buffer, pH 7.2) was added and homogenized. After the homogenate solution was centrifuged (500 × g, 4 ° C., 10 minutes), the supernatant was collected and centrifuged again (10000 × g, 4 ° C., 10 minutes). The resulting precipitate was suspended in 8 times the amount of homogenate buffer, and then centrifuged (10000 × g, 4 ° C., 10 minutes). After repeating the same operation once, the obtained precipitate was suspended in 0.25 mL of a homogenate buffer per 1 g of heart weight to obtain a mitochondrial solution.
　試験例３（ラット心ミトコンドリア阻害作用の測定）：酸素消費測定システム（ＮｅｏＦｏｘ、ＦＯＬ／Ｃ１Ｔ５００Ｐ、Ｉｎｓｔｅｃｈ社）を用いて、３０℃におけるミトコンドリアの酸素消費量を測定した。測定チャンバー内に反応液（２２０ｍｍｏｌ／Ｌ　マンニトール、７０ｍｍｏｌ／Ｌ　スクロース、２ｍｍｏｌ／Ｌ　ＨＥＰＥＳ、１ｍｍｏｌ／Ｌ　ＥＧＴＡ、１０ｍｍｏｌ／Ｌ　リン酸二水素カリウム、５ｍｍｏｌ／Ｌ　塩化マグネシウムからなる緩衝液、ｐＨ７．２）を４８５μＬ、各被験物質溶液を５．２μＬ、ミトコンドリア溶液を１５μＬを加え混合した。チャンバーを密閉した後、１分間温度平衡化した。７５０ｍｍｏｌ／Ｌ　Ｌ－リンゴ酸ナトリウム及び７５０ｍｍｏｌ／Ｌ　ピルビン酸ナトリウムからなる基質溶液を６．７μＬ添加し、１分間の酸素消費量を測定した（Ｓｔａｔｅ　４）。続けて５０ｍｍｏｌ／Ｌ　ＡＤＰを６．７μＬ添加し、１分間の酸素消費量を測定した（Ｓｔａｔｅ　３）。各被験物質添加による測定結果から呼吸調節率（Ｓｔａｔｅ　３／Ｓｔａｔｅ　４）を計算し、コントロール（被験物質添加なし）に対する低下率を求める。尚、ＩＣ５０値は、呼吸調節率を５０％低下させる濃度を示す。 Test Example 3 (Measurement of Rat Heart Mitochondrial Inhibitory Action): Using an oxygen consumption measurement system (NeoFox, FOL / C1T500P, Intech), mitochondrial oxygen consumption at 30 ° C. was measured. Reaction solution (220 mmol / L mannitol, 70 mmol / L sucrose, 2 mmol / L HEPES, 1 mmol / L EGTA, 10 mmol / L potassium dihydrogen phosphate, 5 mmol / L magnesium chloride, pH 7.2) in the measurement chamber Was added to each test substance solution, 5.2 μL, and a mitochondrial solution was added to 15 μL. After the chamber was sealed, the temperature was equilibrated for 1 minute. 6.7 μL of a substrate solution consisting of 750 mmol / L L-sodium malate and 750 mmol / L sodium pyruvate was added, and the oxygen consumption for 1 minute was measured (State 4). Subsequently, 6.7 μL of 50 mmol / L ADP was added, and the oxygen consumption for 1 minute was measured (State 3). The respiratory regulation rate (State 3 / State 4) is calculated from the measurement results obtained by adding each test substance, and the reduction rate relative to the control (no test substance added) is obtained. Incidentally, IC 50 value indicates the concentration that reduces the respiratory control ratio of 50%.
　試験例３の結果を表２７に示す。 Table 27 shows the results of Test Example 3.
Figure JPOXMLDOC01-appb-T000092
Figure JPOXMLDOC01-appb-T000092
　製剤例１（錠剤）：実施例５３に、添加剤として結晶セルロース、Ｄ－マンニトール、ヒドロキシプロピルセルロース、カルメロースナトリウムを用い、湿式造粒法により顆粒を製し、ステアリン酸マグネシウムを加えて常法により製造する。 Formulation example 1 (tablet): In Example 53, granules are prepared by wet granulation using crystalline cellulose, D-mannitol, hydroxypropylcellulose, and carmellose sodium as additives, and magnesium stearate is added, followed by a conventional method. Manufactured by.
　製剤例２（注射剤）：実施例５３に、添加剤としてＤ－マンニトール、クエン酸ナトリウムを用い、精製水に溶解し、常法により注射剤を製造する。 Formulation Example 2 (Injection): In Example 53, D-mannitol and sodium citrate are used as additives, dissolved in purified water, and an injection is prepared by a conventional method.
　本発明の化合物は、ＣＯＭＴ阻害作用およびＤＤＣ阻害作用を有し、パーキンソン病の治療に有用である。
  The compound of the present invention has a COMT inhibitory action and a DDC inhibitory action and is useful for the treatment of Parkinson's disease.

Claims (9)

  1. 　下記一般式（１）で表される化合物又はその医薬上許容される塩。
    Figure JPOXMLDOC01-appb-C000001
     ［式中、
    Ｒ１及びＲ２は、それぞれ独立して、水素原子、置換されていてもよいＣ1－Ｃ6アルキル基、置換されていてもよいＣ１－Ｃ６アルキルカルボニル基、置換されていてもよいＣ１－Ｃ６アルコキシカルボニル基、又は置換されていてもよいＣ１－Ｃ６アルキルアミノカルボニル基を示し；
    Ｒ３は、水素原子、ハロゲン原子、ハロアルキル基、シアノ基、又はカルボキシ基を示し；
    Ｒ４は、水素原子、ハロゲン原子、置換されていてもよいＣ１－Ｃ６アルキル基、ハロアルキル基、シアノ基、カルボキシ基、アミノカルボニル基、置換されていてもよいＣ１－Ｃ６アルキルスルファニル基、ハロアルキルスルファニル基、置換されていてもよいアリールスルファニル基、置換されていてもよいＣ１－Ｃ６アルコキシ基、置換されていてもよいアリールオキシ基、置換されていてもよいヘテロアリールオキシ基、置換されていてもよいＣ１－Ｃ６アルコキシカルボニル基、置換されていてもよいＣ１－Ｃ６アルキルカルボニル基、置換されていてもよいアリールカルボニル基、置換されていてもよいヘテロアリールカルボニル基、置換されていてもよいＣ１－Ｃ６のアルキルスルホニル基、置換されていてもよいＣ１－Ｃ６のアルキルスルフィニル基、置換されていてもよいアリールスルホニル基、置換されていてもよいヘテロアリールスルホニル基、置換されていてもよいアリールスルフィニル基、置換されていてもよいヘテロアリールスルフィニル基、置換されていてもよいＣ１－Ｃ６のアルキルアミノカルボニル基、置換されていてもよいアミノスルホニル基、置換されていてもよいヘテロシクロアルキルカルボニル基、置換されていてもよいベンゾフラン、置換されていてもよい２，３－ジヒドロフラン、クロマン環、置換されていてもよい２－クロマノン環、置換されていてもよい３－クロマノン環、置換されていてもよい４－クロマノン環、置換されていてもよいクマリン環、置換されていてもよいクロモン環、置換されていてもよい２－クマラノン環、置換されていてもよいインデン環、置換されていてもよいインデノン環、又は置換されていてもよいフタリド環を示し；
    Ｒ５～Ｒ１０は、それぞれ独立して水素原子、ハロゲン原子、Ｃ１－Ｃ６アルキル基、シアノ基、隣接するお互いでカルボニル基を形成し、又は隣接するお互いでシクロアルキル基を形成してもよく；
    Ｒ１１は、水素原子、置換されていてもよいＣ１－Ｃ６アルキルカルボニル基、置換されていてもよいＣ１－Ｃ６アルコキシカルボニル基、又は置換されていてもよいＣ１－Ｃ６アルキルアミノカルボニル基を示し；
    Ｘ、Ｙ、Ｚは、それぞれ単結合、炭素原子、酸素原子、窒素原子、又は硫黄原子を示し；
    ----は、単結合または二重結合を示し；
    Ｑ１～Ｑ６は、それぞれ独立して炭素原子（各々の炭素原子は、水素原子、置換されていてもよいＣ１－Ｃ６アルキル基、置換されていてもよいＣ１－Ｃ６アルキルチオ基、置換されていてもよいＣ１－Ｃ６アルコキシ基、ハロゲン原子、ニトロ基、トリフルオロメチル基、シアノ基、若しくはカルボキシ基のいずれかの置換基を有していてもよく、又は炭素原子もしくはヘテロ原子を介して環を形成していてもよい）、窒素原子、隣接するお互いで環を形成してもよく、又はＱ２とＱ３は一緒で硫黄原子、又は酸素原子を示し；
    ｎは、０～３を示し（但し、Ｑ２～Ｑ６のうち１つが窒素原子で残りが炭素原子の場合は、ｎは１～３を示す）；
    環Ａは、置換されていてもよい３～６員の複素環を示す。］     A compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.
    Figure JPOXMLDOC01-appb-C000001
     [Where:
    R 1 and R 2 are each independently a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 1 -C 6 alkylcarbonyl group, or optionally substituted. Represents a C 1 -C 6 alkoxycarbonyl group or an optionally substituted C 1 -C 6 alkylaminocarbonyl group;
    R 3 represents a hydrogen atom, a halogen atom, a haloalkyl group, a cyano group, or a carboxy group;
    R 4 represents a hydrogen atom, a halogen atom, an optionally substituted C 1 -C 6 alkyl group, a haloalkyl group, a cyano group, a carboxy group, an aminocarbonyl group, or an optionally substituted C 1 -C 6 alkylsulfanyl. Group, haloalkylsulfanyl group, optionally substituted arylsulfanyl group, optionally substituted C 1 -C 6 alkoxy group, optionally substituted aryloxy group, optionally substituted heteroaryloxy group , optionally substituted C 1 -C 6 alkoxycarbonyl group, an optionally substituted C 1 -C 6 alkylcarbonyl group, an optionally substituted arylcarbonyl group, heteroaryl carbonyl which may be substituted Group, optionally substituted C 1 -C 6 alkylsulfonyl group, optionally substituted C 1 -C 6 alkylsulfinyl group, optionally substituted arylsulfonyl group, optionally substituted heteroarylsulfonyl group, optionally substituted arylsulfinyl group, optionally substituted heteroaryl A sulfinyl group, an optionally substituted C 1 -C 6 alkylaminocarbonyl group, an optionally substituted aminosulfonyl group, an optionally substituted heterocycloalkylcarbonyl group, an optionally substituted benzofuran, Optionally substituted 2,3-dihydrofuran, chroman ring, optionally substituted 2-chromanone ring, optionally substituted 3-chromanone ring, optionally substituted 4-chromanone ring, substituted Coumarin ring optionally substituted, chromone ring optionally substituted, optionally substituted 2-coumaranone ring, shows good indene ring optionally substituted, may be substituted indenone ring, or an optionally phthalide ring optionally substituted;
    R 5 to R 10 are each independently a hydrogen atom, a halogen atom, a C 1 -C 6 alkyl group, a cyano group, an adjacent carbonyl group, or an adjacent cycloalkyl group. Well;
    R 11 represents a hydrogen atom, an optionally substituted C 1 -C 6 alkylcarbonyl group, an optionally substituted C 1 -C 6 alkoxycarbonyl group, or an optionally substituted C 1 -C 6 alkyl Represents an aminocarbonyl group;
    X, Y, and Z each represents a single bond, a carbon atom, an oxygen atom, a nitrogen atom, or a sulfur atom;
    ---- represents a single bond or a double bond;
    Q 1 to Q 6 are each independently a carbon atom (each carbon atom is a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, an optionally substituted C 1 -C 6 alkylthio group) May have a C 1 -C 6 alkoxy group which may be substituted, a halogen atom, a nitro group, a trifluoromethyl group, a cyano group, or a carboxy group, or a carbon atom or A ring may be formed through a hetero atom), a nitrogen atom, an adjacent ring may be formed with each other, or Q 2 and Q 3 together represent a sulfur atom or an oxygen atom;
    n represents 0 to 3 (provided that when one of Q 2 to Q 6 is a nitrogen atom and the remaining is a carbon atom, n represents 1 to 3);
    Ring A represents a 3-6 membered heterocyclic ring which may be substituted. ]
  2. 　置換されていてもよい環Ａが、
    Figure JPOXMLDOC01-appb-C000002
     （式中、
    Ｒ１２は、水素原子、置換されていてもよいＣ１－Ｃ６アルキル基、カルボキシ基、置換されていてもよいＣ１－Ｃ６アルコキシカルボニル基、置換されていてもよいアミノカルボニル基、又はシアノ基を示し；
    Ｒ１３およびＲ１4はそれぞれ独立して、水素原子、又はＣ１－Ｃ６アルキル基を示す）である、請求項１記載の化合物、又はその医薬上許容される塩。      Ring A which may be substituted is
    Figure JPOXMLDOC01-appb-C000002
     (Where
    R 12 represents a hydrogen atom, an optionally substituted C 1 -C 6 alkyl group, a carboxy group, an optionally substituted C 1 -C 6 alkoxycarbonyl group, an optionally substituted aminocarbonyl group, or Represents a cyano group;
    The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 13 and R 14 each independently represents a hydrogen atom or a C 1 -C 6 alkyl group.
  3. 　Ｒ１およびＲ２が、水素原子である、請求項１記載の化合物又はその医薬上許容される塩。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are hydrogen atoms.
  4. 　Ｒ１１が水素原子であり、ｎが１～３の数である請求項１記載の化合物又はその医薬上許容される塩。 The compound according to claim 1, wherein R 11 is a hydrogen atom, and n is a number from 1 to 3, or a pharmaceutically acceptable salt thereof.
  5. 　Ｑ１～Ｑ６が、炭素原子（各々の炭素原子は、水素原子、ハロゲン原子、トリフルオロメチル基又はシアノ基のいずれかの置換基を有していてもよい）を示し；
    ｎは、１～３を示す請求項１記載の化合物又はその医薬上許容される塩。     Q 1 to Q 6 each represent a carbon atom (each carbon atom may have any substituent of a hydrogen atom, a halogen atom, a trifluoromethyl group, or a cyano group);
    2. The compound according to claim 1, wherein n is 1 to 3, or a pharmaceutically acceptable salt thereof.
  6. 　Ｚ－Ｙ－Ｘ部分の構造が、単結合、Ｃ1－Ｃ3の直鎖又は分岐鎖のアルキレン基、Ｃ2－Ｃ3の直鎖のアルケニレン基、オキシメチル基、チオメチル基、メチルオキシ基、メチルチオ基、Ｃ1－Ｃ3のハロアルキレン基、アミド基、シクロプロピル基、及びアミノメチル基から選ばれる基を示す請求項１記載の化合物又はその医薬上許容される塩。 The structure of the Z—Y—X moiety is a single bond, a C 1 -C 3 linear or branched alkylene group, a C 2 -C 3 linear alkenylene group, an oxymethyl group, a thiomethyl group, a methyloxy group The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which represents a group selected from a methylthio group, a C 1 -C 3 haloalkylene group, an amide group, a cyclopropyl group, and an aminomethyl group.
  7. 　請求項１～６のいずれか１項記載の化合物又はその医薬上許容される塩を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.
  8. 　パーキンソン病治療用医薬組成物である請求項７記載の医薬組成物。 The pharmaceutical composition according to claim 7, which is a pharmaceutical composition for treating Parkinson's disease.
  9. 　パーキンソン病治療用医薬組成物製造のための、請求項１～６のいずれか１項記載の化合物又はその医薬上許容される塩の使用。
          Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical composition for treating Parkinson's disease.
PCT/JP2018/022310 2017-06-13 2018-06-12 Novel nitrocatechol derivative WO2018230528A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2017132272A JP2020158391A (en) 2017-06-13 2017-06-13 Novel nitrocatechol derivative
JP2017-132272 2017-06-13

Publications (1)

Publication Number Publication Date
WO2018230528A1 true WO2018230528A1 (en) 2018-12-20

Family

ID=64659166

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2018/022310 WO2018230528A1 (en) 2017-06-13 2018-06-12 Novel nitrocatechol derivative

Country Status (4)

Country Link
JP (1) JP2020158391A (en)
AR (1) AR112139A1 (en)
TW (1) TW201902882A (en)
WO (1) WO2018230528A1 (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111909110A (en) * 2020-08-31 2020-11-10 浙江工业大学 Preparation method of 2, 4-disubstituted thiazole compound
CN114044774A (en) * 2021-12-06 2022-02-15 北京超维知药科技有限公司 EGFR inhibitor and preparation method and application thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111548319B (en) * 2019-02-11 2024-03-08 沈阳化工大学 1, 1-dicyanooxime ether compound and application thereof

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62240649A (en) * 1986-03-11 1987-10-21 エフ・ホフマン―ラ　ロシユ　アーゲー Catechol derivative
JP2008308493A (en) * 2007-05-17 2008-12-25 Kissei Pharmaceut Co Ltd New catechol derivative, pharmaceutical composition containing the same and use thereof
JP2009544571A (en) * 2005-07-26 2009-12-17 バイアル−ポルテラ アンド シーエー，エス．エー． COMT inhibitor
JP2011021009A (en) * 2009-06-18 2011-02-03 Kissei Pharmaceutical Co Ltd Method for producing nitrocatechol derivative, and intermediate for producing the same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS62240649A (en) * 1986-03-11 1987-10-21 エフ・ホフマン―ラ　ロシユ　アーゲー Catechol derivative
JP2009544571A (en) * 2005-07-26 2009-12-17 バイアル−ポルテラ アンド シーエー，エス．エー． COMT inhibitor
JP2008308493A (en) * 2007-05-17 2008-12-25 Kissei Pharmaceut Co Ltd New catechol derivative, pharmaceutical composition containing the same and use thereof
JP2011021009A (en) * 2009-06-18 2011-02-03 Kissei Pharmaceutical Co Ltd Method for producing nitrocatechol derivative, and intermediate for producing the same

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE Database REGISTRY [o] 1 November 2012 (2012-11-01), retrieved from STN Database accession no. 1402714- 31-1 *
EGOROV, M. ET AL.: "A concise formation of N- substituted 3, 4-diarylpyrroles - synthesis and cytotoxic activity", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 12, no. 9, 2014, pages 1518 - 1524, XP055204836 *
KISS, L. E. ET AL.: "Discovery of a Long-Acting, Peripherally Selective Inhibitor of Catechol-0- methyltransferase", JOURNAL OF MEDICINAL CHEMISTRY, vol. 53, no. 8, 24 March 2010 (2010-03-24), pages 3396 - 3411, XP055563225, Retrieved from the Internet <URL:doi:10.1021/jm1001524> *
SCHOBERT, R. ET AL.: "4-(3-Halo/amino-4, 5- dimethoxyphenyl)-5-aryloxazoles and -N- methylimidazoles That Are Cytotoxic against Combretastatin A Resistant Tumor Cells and Vascular Disrupting in a Cisplatin Resistant Germ Cell Tumor Model", JOURNAL OF MEDICINAL CHEMISTRY, vol. 53, no. 18, 23 August 2010 (2010-08-23), pages 6595 - 6602, XP055147808 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111909110A (en) * 2020-08-31 2020-11-10 浙江工业大学 Preparation method of 2, 4-disubstituted thiazole compound
CN114044774A (en) * 2021-12-06 2022-02-15 北京超维知药科技有限公司 EGFR inhibitor and preparation method and application thereof
CN114044774B (en) * 2021-12-06 2024-04-09 光武惠文生物科技(北京)有限公司 EGFR inhibitor and preparation method and application thereof

Also Published As

Publication number Publication date
AR112139A1 (en) 2019-09-25
JP2020158391A (en) 2020-10-01
TW201902882A (en) 2019-01-16

Similar Documents

Publication Publication Date Title
US8664401B2 (en) N-linked hydroxamic acid derivatives useful as antibacterial agents
US20230113085A1 (en) Novel small molecule inhibitors of tead transcription factors
US20100144733A1 (en) Compounds, compositions and methods comprising heteroaromatic derivatives
JP2013047189A (en) Novel parabanic acid derivative, and medicine containing the same as effective component
US9365551B2 (en) 2-(benzyloxy) benzamides as LRRK2 kinase inhibitors
US20090318429A1 (en) Compounds, Compositions and Methods Comprising Heteroaromatic Derivatives
TWI583670B (en) Partially saturated nitrogenous heterocyclic compounds
US11911372B2 (en) Compounds
JP2005508962A (en) 2&#39;-Methyl-5- (1,3,4-oxadiazol-2-yl) -1,1&#39;-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors
US11634391B2 (en) Compounds which are inhibitors of Notum
WO2018230528A1 (en) Novel nitrocatechol derivative
JP7408819B2 (en) Isoindoline derivatives and pharmaceutical compositions and uses thereof
JP2008308495A (en) New catechol derivative, medicinal composition containing the same and its use
CN109843879A (en) Benzothiazole derivant as DYRK1 inhibitor
JP2018522068A (en) Anti-tumor compounds targeting IDH2 mutations and methods of use thereof
RU2809680C1 (en) Isoindoline derivative, its pharmaceutical composition and use
US20170298081A1 (en) Condensed heterocyclic compound
JP2017516803A (en) Benzenesulfonamides useful as sodium channel inhibitors

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: JP

122 Ep: pct application non-entry in european phase

Ref document number: 18817428

Country of ref document: EP

Kind code of ref document: A1