[go: up one dir, main page]

WO2012011549A1 - P2x4 receptor antagonist - Google Patents

P2x4 receptor antagonist Download PDF

Info

Publication number
WO2012011549A1
WO2012011549A1 PCT/JP2011/066652 JP2011066652W WO2012011549A1 WO 2012011549 A1 WO2012011549 A1 WO 2012011549A1 JP 2011066652 W JP2011066652 W JP 2011066652W WO 2012011549 A1 WO2012011549 A1 WO 2012011549A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
carbon atoms
substituted
halogen
atoms
Prior art date
Application number
PCT/JP2011/066652
Other languages
French (fr)
Japanese (ja)
Inventor
佐久間詔悟
荒井勝彦
小林邦夫
渡邉義一
齊藤大祐
今井利安
井上和秀
Original Assignee
日本ケミファ株式会社
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 日本ケミファ株式会社 filed Critical 日本ケミファ株式会社
Publication of WO2012011549A1 publication Critical patent/WO2012011549A1/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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to diazepine derivatives having P2X 4 receptor antagonism.
  • ATP receptors are broadly classified into the P2X family of ion channel receptors and the P2Y family of G protein-coupled receptors.
  • P2X 1-7 the P2X family of ion channel receptors
  • P2Y 1, 2, 4, 6 the P2Y family of G protein-coupled receptors.
  • 11-14 subtypes have been reported.
  • P2X 4 receptor a subtype of P2X family (Genebank No.X87763) has been reported to be expressed widely in the central nervous system like.
  • Non-patent document 1 Non-patent document 2, Non-patent document 3, Non-patent document 4, Non-patent document 5
  • NSAIDs non-steroidal anti-inflammatory drugs
  • morphine morphine
  • Neuropathic pain is often caused by damage to the peripheral nerve or central nerve, and is caused by, for example, sequelae of surgery, cancer, spinal cord injury, herpes zoster, diabetic neuritis, trigeminal neuralgia, and the like.
  • Non-patent document 6 Non-patent document 7, Patent document 1
  • substances which inhibit the action of P2X 4 receptors is expected as a prophylactic agent or therapeutic agent for pain in nociceptive pain, inflammatory pain and neuropathic pain.
  • Patent Document 2 the following general formula (A),
  • R 1 is halogen
  • R 2 is hydrogen, halogen, nitro, cyano, C (O) —OR 3 , C (O) —NR 4 R 5 , SO 2 —OR 3 , SO 2 —NR 4 R 5 or R 1 is hydrogen and R 2 is halogen, nitro, cyano, C (O) —OR 3 , C (O) —NR 4 R 5 , SO 2 —OR 3 , SO 2 — NR 4 R 5
  • benzofuro diazepin-2-one derivative represented by the it reported that with a P2X 4 receptor antagonism have been made. Also it reported that with paroxetine also P2X 4 receptor antagonism is antidepressants have been made. (Non-patent document 8)
  • Patent Document 3 Naphtho [1,2-e] -1,4- diazepin-2-one derivatives represented in is found that with a P2X 4 receptor antagonism, has filed a patent application.
  • Patent Document 4 the following formula (C),
  • An object of the present invention is to provide a diazepine derivative represented by the following general formula with a P2X 4 receptor antagonism (I) or (II).
  • R 1 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or the number of carbon atoms substituted by 1 to 3 halogen atoms.
  • An alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, and an alkylamino group having 1 to 8 carbon atoms A dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and an alkylsulfonylamino group having 1 to 8 carbon atoms Group, carboxyl group, acyl group having 2 to 8 carbon atoms, alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), carbamoyl group, alkylthio group having 1 to 8 carbon atoms, alkyl group having 1 to 8 carbon atoms Luffy Nyl group, an
  • R 5 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms.
  • Z represents O or S;
  • X C
  • Y N and consists of a solid line and a wavy line
  • the double line represents a double bond.
  • a pharmacologically acceptable salt thereof is also provides the following general formula (II),
  • R 11 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or the number of carbon atoms substituted by 1 to 3 halogen atoms.
  • R 15 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms.
  • a pharmacologically acceptable salt thereof
  • the present invention relates to P2X 4 receptor antagonist containing the above-mentioned general formula (I) or the compound represented by (II) or a pharmacologically acceptable salt thereof as an active ingredient. Furthermore, the present invention relates to a preventive or therapeutic agent for neuropathic pain containing the compound represented by the above general formula (I) or (II) or a pharmacologically acceptable salt thereof as an active ingredient.
  • the alkyl group having 1 to 8 carbon atoms of R 1 , R 2 , R 3 , R 4 and R 5 includes a methyl group, an ethyl group, a propyl group, Examples include isopropyl group, butyl group, i-butyl group, t-butyl group, pentyl group, hexyl group and the like.
  • Examples of the alkenyl group having 2 to 8 carbon atoms of R 1 , R 2 and R 5 include an allyl group.
  • Examples of the alkyl group having 1 to 8 carbon atoms that is substituted with 1 to 3 halogen atoms of R 1 , R 2 , R 3 , R 4 and R 5 include 1 to 3 fluorine atoms, chlorine atoms or bromine atoms And a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, or a t-butyl group substituted by a halogen atom such as trifluoromethyl group, chloromethyl group, 2-chloroethyl group, 2- bromoethyl or 2-fluoroethyl group, and the like.
  • Examples of the alkyl group having 1 to 3 carbon atoms substituted by the phenyl group of R 2 , R 3 and R 4 include a benzyl group.
  • Examples of the alkoxy group having 1 to 8 carbon atoms of R 1 and R 5 include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, i-butoxy group, t-butoxy group, pentyloxy group or hexyloxy group Etc.
  • the alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms of R 1 and R 5 includes methoxy substituted with 1 to 3 halogen atoms such as fluorine atom, chlorine atom or bromine atom Group, ethoxy group, propoxy group, isopropoxy group, butoxy group or t-butoxy group, etc., preferably trifluoromethoxy group, chloromethoxy group, 2-chloroethoxy group, 2-bromoethoxy group or 2-fluoro group. An ethoxy group etc. are mentioned.
  • Examples of the halogen atom for R 1 , R 3 , R 4 and R 5 include a fluorine atom, a chlorine atom, or a bromine atom.
  • Examples of the alkylamino group having 1 to 8 carbon atoms of R 1 and R 5 include a methylamino group and an ethylamino group.
  • Examples of the alkylamino group having 1 to 5 carbon atoms substituted with 1 to 5 halogen atoms of R 5 include 2,2,2-trifluoroethylamino group and the like.
  • Examples of the dialkylamino group having 2 to 8 carbon atoms of R 1 and R 5 include a dimethylamino group and a diethylamino group.
  • Examples of the acylamino group having 2 to 8 carbon atoms of R 1 and R 5 include an acetylamino group.
  • Examples of the acylamino group having 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms of R 1 and R 5 include a trifluoromethylcarbonylamino group.
  • Examples of the alkylsulfonylamino group having 1 to 8 carbon atoms of R 1 and R 5 include a methylsulfonylamino group.
  • Examples of the alkoxycarbonyl group for R 1 and R 5 include a methoxycarbonyl group and an ethoxycarbonyl group.
  • Examples of the alkylthio group having 1 to 8 carbon atoms of R 1 and R 5 include a methylthio group.
  • Examples of the alkylsulfinyl group having 1 to 8 carbon atoms of R 1 and R 5 include a methylsulfinyl group.
  • Examples of the alkylsulfonyl group having 1 to 8 carbon atoms of R 1 and R 5 include a methylsulfonyl group.
  • preferred substituents are alkyl groups having 1 to 8 carbon atoms such as methyl group and ethyl group, and 1 to 3 halogen atoms such as trifluoromethyl group.
  • Examples thereof include an alkyl group having 1 to 8 carbon atoms substituted with an atom, a halogen atom such as a fluorine atom, and a cyano group.
  • preferred heterocyclic groups include a tetrazolyl group, a triazolyl group, a pyridyl group, an imidazolyl group, an oxazolyl group or a thiazolyl group.
  • preferred substituents are alkyl groups having 1 to 8 carbon atoms such as methyl group and ethyl group, and 1 to 3 halogen atoms such as trifluoromethyl group.
  • R 1 and R 5 may be the same or different from each other in the ring substituted by R 1 and R 5 .
  • examples of the substituent include an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, and 1 to 3 An alkyl group having 1 to 8 carbon atoms substituted with 1 halogen atom, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, an alkylamino group having 1 to 8 carbon atoms, and Examples of the dialkylamino group having 2 to 8 carbon atoms include those exemplified for R 1 to R 6 in the above general formula (I).
  • R 11 and R 15 in the general formula (II) may be present in the same manner or different from each other in the ring substituted by R 11 and R 15 .
  • R 1 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms C1-C8 alkoxy groups substituted with atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, C1-C8 alkylamino groups, C2-C8 dialkylamino groups, carbon
  • R 2 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, represented by the above formula (1) or the above general formula (I) Or a pharmacologically acceptable salt thereof.
  • R 3 and R 4 may be the same or different and each is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms Or (2) or a diazepine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof.
  • R 5 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms.
  • R 5 is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and substituted with 1 to 3 halogen atoms Substituted from an alkoxy group having 1 to 8 carbon atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, alkylamino group having 1 to 8 carbon atoms and dialkylamino group having 2 to 8 carbon atoms
  • R 5 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms.
  • a diazepine derivative represented by the above (1) to (3) or the above general formula (I) which is an alkoxy group having 1 to 8 carbon atoms or a hydroxyl group substituted by an atom, or a pharmaceutically acceptable salt thereof.
  • R 11 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms.
  • R 11 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms.
  • R 13 and R 14 may be the same or different and each is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms Or (9) or a diazepine derivative represented by the above general formula (II) or a pharmacologically acceptable salt thereof.
  • R 15 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms.
  • R 15 is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and substituted with 1 to 3 halogen atoms Substituted from an alkoxy group having 1 to 8 carbon atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, alkylamino group having 1 to 8 carbon atoms and dialkylamino group having 2 to 8 carbon atoms
  • R 15 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms.
  • a diazepine derivative represented by the above (8) to (10) or the above general formula (II) or a pharmacologically acceptable salt thereof which is an alkoxy group having 1 to 8 carbon atoms or a hydroxyl group substituted with an atom.
  • Examples of the pharmacologically acceptable salt of the compounds represented by the general formulas (I) and (II) include hydrochlorides and alkali metal salts such as sodium, potassium, and lithium.
  • the compound of the present invention may have optical isomers such as cis / trans isomers, optically active isomers, and racemates, all of which are included in the present invention.
  • the compound of the present invention represented by the general formula (c) is obtained by subjecting the compound represented by the general formula (a) and the compound represented by the general formula (b) to a ring-closing reaction in the presence of a solvent such as THF. Obtainable.
  • R represents a lower alkyl group and R 1 , R 2 , R 3 , R 4 , R 5 and
  • the compound represented by the general formula (f) is obtained by reacting the compound represented by the general formula (d) and the compound represented by the general formula (e) in a solvent such as chloroform in the presence of sodium bicarbonate. Can be obtained. Next, the compound represented by the general formula (f) is subjected to a cyclization reaction in a solvent such as THF in the presence of sodium hydride to obtain the compound represented by the general formula (g). Can do. (Synthesis method 3) In the general formula (I), R 2 is H, X is N, Y is C ⁇ O, Z is O, and a double line composed of a solid line and a wavy line represents a single bond.
  • R represents a lower alkyl group
  • the compound represented by the general formula (j) can be obtained by reacting the compound represented by the general formula (h) and the compound represented by the general formula (i) in the presence of a solvent such as chloroform. .
  • the compound represented by general formula (k) can be obtained by subjecting the obtained compound represented by general formula (j) to a reduction reaction in a solvent such as ethanol in the presence of a Pd catalyst.
  • the compound represented by the general formula (k) is subjected to a cyclization reaction in a solvent such as ethanol in the presence of sodium alkoxide to obtain the compound represented by the general formula (l). it can.
  • Synthesis method 4 In the general formula (I), X is C, Y is N, Z is O, and a double line consisting of a solid line and a wavy line represents a double bond.
  • R represents a lower alkyl group and R 1 , R 2 , R 3 , R 4 , R 5 and
  • the compound represented by the general formula (o) is obtained by subjecting the compound represented by the general formula (m) and the compound represented by the general formula (n) to a ring-closing reaction in the presence of a solvent such as pyridine.
  • a solvent such as pyridine.
  • R 5 is a tetrazolyl group.
  • the tetrazole compound represented by the general formula (q) is an azide compound such as tri-n-butyltin azide or sodium azide in the presence of a solvent such as toluene or DMF in the nitrile compound represented by the general formula (p). Can be obtained by reacting.
  • the tetrazole compound represented by the general formula (q) is reacted with an inorganic base such as sodium hydrogen carbonate or potassium hydrogen carbonate in the presence of a solvent such as water or ethanol.
  • an inorganic base such as sodium hydrogen carbonate or potassium hydrogen carbonate
  • the P2X 4 receptor antagonism of the compounds of the present invention was measured as follows.
  • the 1321N1 cells were stably expressing human P2X 4 receptor were seeded in 96-well plates, 37 ° C., was used for intracellular calcium measured 24 hours at 5% CO 2 conditions.
  • Fura-2 AM which is a calcium fluorescent indicator, was used.
  • Fura-2 AM dissolved in assay buffer was added to the cells, allowed to stand at room temperature for 45 minutes to be taken into the cells, and then the plate was subjected to fluorescence measurement.
  • Test substances were treated in cells 15 minutes before the addition of ATP, and the intracellular calcium influx response induced by the addition of ATP was measured over time using a microplate reader. The ratio of the respective fluorescence values at excitation light of 340 nm and 380 nm was used as an index of intracellular calcium change, and the inhibitory activity of the test substance was calculated by comparison with the absence of the test substance (control).
  • the present invention compounds as is apparent from Examples 16 and 17 showed a P2X 4 receptor antagonism excellent.
  • the general formula (I) or diazepine derivative or a pharmacologically acceptable salt thereof represented by the general formula (II) is nociceptive pain from having a P2X 4 receptor antagonism, inflammatory pain and nerve It is thought to be useful as a preventive or therapeutic agent for pain in pathogenic pain. That is, it is useful as a prophylactic or therapeutic agent for various cancer pains, pain associated with neuropathy of diabetes, pain associated with viral diseases such as herpes, osteoarthritis and the like.
  • the preventive or therapeutic agent of the present invention may be used in combination with other drugs as necessary, for example, opioid analgesics (morphine, fentanyl), sodium channel blockers (novocaine, lidocaine), NSAIDs (aspirin, ibuprofen) Etc. are used together.
  • opioid analgesics morphine, fentanyl
  • sodium channel blockers novocaine, lidocaine
  • NSAIDs aspirin, ibuprofen
  • the compound of the present invention can be administered to humans by an appropriate administration method such as oral administration or parenteral administration.
  • an appropriate administration method such as oral administration or parenteral administration.
  • it can be produced into a dosage form such as tablets, granules, powders, capsules, suspensions, injections, suppositories and the like by conventional methods in the technical field of formulation.
  • a dosage form such as tablets, granules, powders, capsules, suspensions, injections, suppositories and the like by conventional methods in the technical field of formulation.
  • usual excipients, disintegrants, binders, lubricants, pigments and the like are used.
  • lactose, D-mannitol, crystalline cellulose, glucose and the like are used, as the disintegrant, starch, carboxymethylcellulose calcium (CMC-Ca) and the like, as the lubricant, magnesium stearate,
  • binders include talc and the like, hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), and the like.
  • Solvents, stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives and the like are used for the preparation of injections.
  • the compound of the present invention which is an active ingredient in injections, is about 0.01 mg to 100 mg per day, and 1 mg to 2000 mg per day for oral administration.
  • this invention is not limited to these.
  • reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and washed with chloroform.
  • the aqueous layer was neutralized with 2M hydrochloric acid, extracted with chloroform, washed with purified water, and dried over anhydrous sodium sulfate.
  • the P2X 4 receptor antagonism of the compounds of the present invention was measured as follows.
  • the 1321N1 cells were stably expressing human P2X 4 receptor were seeded in 96-well plates, 37 ° C., it was used for intracellular calcium measured incubated for 24 hours under 5% CO 2.
  • Fura-2 AM which is a calcium fluorescent indicator
  • Fura-2 AM dissolved in assay buffer was added to the cells, allowed to stand at room temperature for 45 minutes to be taken into the cells, and then the plate was subjected to fluorescence measurement.
  • Test substances were treated in cells 15 minutes before the addition of ATP, and the intracellular calcium influx response induced by the addition of ATP was measured over time using a microplate reader.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Engineering & Computer Science (AREA)
  • Pain & Pain Management (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

A diazepine derivative represented by formula (II) (where R11 is a hydrogen atom or C1-8 alkyl group; R13 and R14 are hydrogen atoms or C1-8 alkyl groups etc.; R15 is a hydrogen atom, C1-8 alkyl group, C1-8 alkoxy group, C1-8 alkyl group substituted by 1 to 3 halogen atoms, hydroxyl group, or a heterocyclic group optionally having substituent groups etc.; and AA is a thiophene ring, pyridine ring, pyrimidine ring, quinoline ring, indole ring, indoline ring, or indazole ring etc.), or a pharmacologically acceptable salt thereof is used as a P2X4 receptor antagonist.

Description

Ｐ２Ｘ４受容体拮抗剤P2X4 receptor antagonist
　本発明はＰ２Ｘ４受容体拮抗作用を有するジアゼピン誘導体に関する。 The present invention relates to diazepine derivatives having P2X 4 receptor antagonism.
　ＡＴＰ受容体はイオンチャネル型受容体のＰ２ＸファミリーとＧ蛋白質共役型受容体のＰ２Ｙファミリーに大別され、現在までそれぞれ７種類（Ｐ２Ｘ１－７）、８種類（Ｐ２Ｙ１，２，４，６，１１－１４）のサブタイプが報告されている。
　Ｐ２ＸファミリーのサブタイプであるＰ２Ｘ４受容体（Ｇｅｎｅｂａｎｋ　Ｎｏ．Ｘ８７７６３）は、中枢神経系などで広く発現していることが報告されている。（非特許文献１、非特許文献２、非特許文献３、非特許文献４、非特許文献５）
　神経因性疼痛をはじめとする難治性疼痛は発症の仕組みが正確には解かっておらず、非ステロイド系抗炎症剤（ＮＳＡＩＤｓ）やモルヒネが効かない場合は治療法がない。よって、患者や周囲の人たちの心身への負担は非常に重い。神経因性疼痛は末梢神経あるいは中枢神経の損傷によるものが多く、例えば、手術の後遺症、がん、脊髄損傷、帯状疱疹、糖尿病性神経炎、三叉神経痛などによって引き起こされる。 ATP receptors are broadly classified into the P2X family of ion channel receptors and the P2Y family of G protein-coupled receptors. Up to now, there are 7 types (P2X 1-7 ) and 8 types (P2Y 1, 2, 4, 6 ). 11-14 ) subtypes have been reported.
P2X 4 receptor a subtype of P2X family (Genebank No.X87763) has been reported to be expressed widely in the central nervous system like. (Non-patent document 1, Non-patent document 2, Non-patent document 3, Non-patent document 4, Non-patent document 5)
The mechanism of onset of intractable pain, including neuropathic pain, is not exactly understood, and there is no cure if non-steroidal anti-inflammatory drugs (NSAIDs) or morphine do not work. Therefore, the burden on the mind and body of the patient and the surrounding people is very heavy. Neuropathic pain is often caused by damage to the peripheral nerve or central nerve, and is caused by, for example, sequelae of surgery, cancer, spinal cord injury, herpes zoster, diabetic neuritis, trigeminal neuralgia, and the like.
　最近、井上らは異痛症（アロディニア）を検出できる、脊髄神経を損傷した動物モデルを使い神経因性疼痛におけるＰ２Ｘ受容体の関与を検証した。そして、脊髄のミクログリア細胞において発現するＰ２Ｘ４受容体を介して神経傷害性の異常疼痛（特にアロディニア）が誘発されることを発表している。（非特許文献６、非特許文献７、特許文献１）
　従って、Ｐ２Ｘ４受容体の働きを阻害する物質は、侵害受容性疼痛、炎症性疼痛及び神経因性疼痛における痛みの予防剤あるいは治療剤として期待される。
特許文献２には、次の一般式（Ａ）、 Recently, Inoue et al. Examined the involvement of the P2X receptor in neuropathic pain using an animal model that damaged spinal nerves that could detect allodynia. Then, it has announced that through the P2X 4 receptor expressed in spinal cord microglial cells neuropathic abnormal pain (especially allodynia) is triggered. (Non-patent document 6, Non-patent document 7, Patent document 1)
Accordingly, substances which inhibit the action of P2X 4 receptors is expected as a prophylactic agent or therapeutic agent for pain in nociceptive pain, inflammatory pain and neuropathic pain.
In Patent Document 2, the following general formula (A),
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
（式中、Ｒ１がハロゲンで、かつＲ２が水素、ハロゲン、ニトロ、シアノ、Ｃ（Ｏ）－ＯＲ３，Ｃ（Ｏ）－ＮＲ４Ｒ５，ＳＯ２－ＯＲ３，ＳＯ２－ＮＲ４Ｒ５であるか又はＲ１が水素で、かつＲ２がハロゲン、ニトロ、シアノ、Ｃ（Ｏ）－ＯＲ３，Ｃ（Ｏ）－ＮＲ４Ｒ５，ＳＯ２－ＯＲ３，ＳＯ２－ＮＲ４Ｒ５である。）

で表されるベンゾフロ－１，４－ジアゼピン－２－オン誘導体が、Ｐ２Ｘ４受容体拮抗作用を有する旨の報告がなされている。
　また抗うつ剤であるパロキセチンもＰ２Ｘ４受容体拮抗作用を有する旨の報告がなされている。（非特許文献８） (Wherein R 1 is halogen, and R 2 is hydrogen, halogen, nitro, cyano, C (O) —OR 3 , C (O) —NR 4 R 5 , SO 2 —OR 3 , SO 2 —NR 4 R 5 or R 1 is hydrogen and R 2 is halogen, nitro, cyano, C (O) —OR 3 , C (O) —NR 4 R 5 , SO 2 —OR 3 , SO 2 — NR 4 R 5 )

In benzofuro diazepin-2-one derivative represented by the, it reported that with a P2X 4 receptor antagonism have been made.
Also it reported that with paroxetine also P2X 4 receptor antagonism is antidepressants have been made. (Non-patent document 8)
　一方、本発明者等も次の式（Ｂ）、 On the other hand, the inventors also have the following formula (B):
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
で表されるナフト［１，２－ｅ］－１，４－ジアゼピン－２－オン誘導体が、Ｐ２Ｘ４受容体拮抗作用を有する旨を見出し、特許出願している。（特許文献３）
　特許文献４には、次の式（Ｃ）、 Naphtho [1,2-e] -1,4- diazepin-2-one derivatives represented in is found that with a P2X 4 receptor antagonism, has filed a patent application. (Patent Document 3)
In Patent Document 4, the following formula (C),
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
で表されるナフト［１，２－ｂ］－１，４－ジアゼピン－４－オン誘導体が記載されている。
但し、特許文献４には、上記式（Ｃ）で表される化合物が写真用カプラーとして用いられる旨の記載はあるが、これらの薬物とＰ２Ｘ４受容体拮抗作用との関係を示唆する記載はない。 A naphtho [1,2-b] -1,4-diazepin-4-one derivative represented by the formula:
However, Patent Document 4, there is a description that used as a compound photographic coupler represented by the above formula (C), but description suggesting the relationship between these drugs and P2X 4 receptor antagonism Absent.
米国特許公開　２００５００７４８１９US Patent Publication 20050074819 ＷＯ　２００４／０８５４４０WO 2004/085440 ＷＯ　２００８／０２３８４７WO 2008/023847 特開平２－３０４４３７JP-A-2-304437
　本発明の目的はＰ２Ｘ４受容体拮抗作用を有する下記一般式（Ｉ）又は（ＩＩ）で表されるジアゼピン誘導体を提供することにある。 An object of the present invention is to provide a diazepine derivative represented by the following general formula with a P2X 4 receptor antagonism (I) or (II).
　即ち、本発明は、次の一般式（Ｉ）、 That is, the present invention includes the following general formula (I):
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
（式中、Ｒ１は水素原子、炭素数１～８のアルキル基、炭素数２～８のアルケニル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、炭素数２～８のアシルアミノ基、１～３個のハロゲン原子で置換された炭素数２～８のアシルアミノ基、炭素数１～８のアルキルスルホニルアミノ基、カルボキシル基、炭素数２～８のアシル基、アルコキシカルボニル基（アルコキシ部分の炭素数は１～８。）、カルバモイル基、炭素数１～８のアルキルチオ基、炭素数１～８のアルキルスルフィニル基、炭素数１～８のアルキルスルホニル基、又はスルファモイル基を表し、
　Ｒ２は水素原子、炭素数１～８のアルキル基、炭素数２～８のアルケニル基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基又はフェニル基で置換された炭素数１～３のアルキル基を表し、
　Ｒ３及びＲ４は同一又は異なっていてもよく水素原子、炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、又はフェニル基で置換された炭素数１～３のアルキル基を表し、
　Ｒ５は水素原子、炭素数１～８のアルキル基、炭素数２～８のアルケニル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、１～５個のハロゲン原子で置換された炭素数１～５のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、炭素数２～８のアシルアミノ基、１～３個のハロゲン原子で置換された炭素数２～８のアシルアミノ基、炭素数１～８のアルキルスルホニルアミノ基、カルボキシル基、炭素数２～８のアシル基、アルコキシカルボニル基（アルコキシ部分の炭素数は１～８。）、カルバモイル基、炭素数１～８のアルキルチオ基、炭素数１～８のアルキルスルフィニル基、炭素数１～８のアルキルスルホニル基、スルファモイル基、置換基を有していても良いフェニル基、又は置換基を有していても良い複素環基を表し、ＸはＣまたはＮを表し (Wherein R 1 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or the number of carbon atoms substituted by 1 to 3 halogen atoms. An alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, and an alkylamino group having 1 to 8 carbon atoms A dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and an alkylsulfonylamino group having 1 to 8 carbon atoms Group, carboxyl group, acyl group having 2 to 8 carbon atoms, alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), carbamoyl group, alkylthio group having 1 to 8 carbon atoms, alkyl group having 1 to 8 carbon atoms Luffy Nyl group, an alkylsulfonyl group having 1 to 8 carbon atoms, or a sulfamoyl group;
R 2 is substituted with a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or a phenyl group Represents an alkyl group having 1 to 3 carbon atoms,
R 3 and R 4 may be the same or different, and may be a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, or a hydroxyl group. , A nitro group, a cyano group, an amino group, or an alkyl group having 1 to 3 carbon atoms substituted with a phenyl group,
R 5 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms. An alkyl group, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, 1 to C1-C5 alkylamino group substituted with 5 halogen atoms, C2-C8 dialkylamino group, C2-C8 acylamino group, carbon substituted with 1-3 halogen atoms An acylamino group having 2 to 8 carbon atoms, an alkylsulfonylamino group having 1 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxy group has 1 to 8 carbon atoms), a carbamoyl group, Charcoal An alkylthio group having 1 to 8 carbon atoms, an alkylsulfinyl group having 1 to 8 carbon atoms, an alkylsulfonyl group having 1 to 8 carbon atoms, a sulfamoyl group, an optionally substituted phenyl group, or a substituent. And X represents C or N.
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
は、チオフェン環、ピリジン環、ピリミジン環、キノリン環、インドール環、インドリン環、ベンズイミダゾール環、インダゾール環、ベンズイソキサゾール環及びベンズトリアゾール環から選択される複素環を表し、そして、複素環の環を構成する炭素原子を介してＸと結合している。
ＺはＯ又はＳを表し、
　そして、ＸがＮの時、ＹはＣ＝Ｏ又はＣ＝Ｓで、かつ実線と波線からなる二重線は単結合を表し
　ＸがＣの時、ＹはＮで、かつ実線と波線からなる二重線は二重結合を表す。）
で表されるジアゼピン誘導体又はその薬理学的に許容される塩に関する。
　
　また本発明は、次の一般式（ＩＩ）、 Represents a heterocyclic ring selected from thiophene ring, pyridine ring, pyrimidine ring, quinoline ring, indole ring, indoline ring, benzimidazole ring, indazole ring, benzisoxazole ring and benztriazole ring, and It is bonded to X through a carbon atom constituting the ring.
Z represents O or S;
When X is N, Y is C = O or C = S, and a double line consisting of a solid line and a wavy line represents a single bond. When X is C, Y is N and consists of a solid line and a wavy line The double line represents a double bond. )
Or a pharmacologically acceptable salt thereof.

The present invention also provides the following general formula (II),
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
（式中、Ｒ１１は水素原子、炭素数１～８のアルキル基、炭素数２～８のアルケニル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、炭素数２～８のアシルアミノ基、１～３個のハロゲン原子で置換された炭素数２～８のアシルアミノ基、炭素数１～８のアルキルスルホニルアミノ基、カルボキシル基、炭素数２～８のアシル基、アルコキシカルボニル基（アルコキシ部分の炭素数は１～８。）、カルバモイル基、炭素数１～８のアルキルチオ基、炭素数１～８のアルキルスルフィニル基、炭素数１～８のアルキルスルホニル基、又はスルファモイル基を表し、
　Ｒ１３及びＲ１４は同一又は異なっていてもよく水素原子、炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、又はフェニル基で置換された炭素数１～３のアルキル基を表し、
　Ｒ１５は水素原子、炭素数１～８のアルキル基、炭素数２～８のアルケニル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、１～５個のハロゲン原子で置換された炭素数１～５のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、炭素数２～８のアシルアミノ基、１～３個のハロゲン原子で置換された炭素数２～８のアシルアミノ基、炭素数１～８のアルキルスルホニルアミノ基、カルボキシル基、炭素数２～８のアシル基、アルコキシカルボニル基（アルコキシ部分の炭素数は１～８。）、カルバモイル基、炭素数１～８のアルキルチオ基、炭素数１～８のアルキルスルフィニル基、炭素数１～８のアルキルスルホニル基、スルファモイル基、置換基を有していても良いフェニル基、又は置換基を有していても良い複素環基を表し、
そして、 (Wherein R 11 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or the number of carbon atoms substituted by 1 to 3 halogen atoms. An alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, and an alkylamino group having 1 to 8 carbon atoms A dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and an alkylsulfonylamino group having 1 to 8 carbon atoms Group, carboxyl group, acyl group having 2 to 8 carbon atoms, alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), carbamoyl group, alkylthio group having 1 to 8 carbon atoms, alkylsulfur group having 1 to 8 carbon atoms An ynyl group, an alkylsulfonyl group having 1 to 8 carbon atoms, or a sulfamoyl group,
R 13 and R 14 may be the same or different, and may be a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, or a hydroxyl group. , A nitro group, a cyano group, an amino group, or an alkyl group having 1 to 3 carbon atoms substituted with a phenyl group,
R 15 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. An alkyl group, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, 1 to C1-C5 alkylamino group substituted with 5 halogen atoms, C2-C8 dialkylamino group, C2-C8 acylamino group, carbon substituted with 1-3 halogen atoms An acylamino group having 2 to 8 carbon atoms, an alkylsulfonylamino group having 1 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxy group has 1 to 8 carbon atoms), a carbamoyl group, Having an alkylthio group having 1 to 8 carbon atoms, an alkylsulfinyl group having 1 to 8 carbon atoms, an alkylsulfonyl group having 1 to 8 carbon atoms, a sulfamoyl group, an optionally substituted phenyl group, or a substituent Represents an optionally substituted heterocyclic group,
And
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
は、チオフェン環、ピリジン環、ピリミジン環、キノリン環、インドール環、インドリン環、ベンズイミダゾール環、インダゾール環、ベンズイソキサゾール環及びベンズトリアゾール環から選択される複素環を表し、そして、複素環の環を構成する炭素原子を介してＸと結合している。）

で表されるジアゼピン誘導体又はその薬理学的に許容される塩に関する。 Represents a heterocyclic ring selected from thiophene ring, pyridine ring, pyrimidine ring, quinoline ring, indole ring, indoline ring, benzimidazole ring, indazole ring, benzisoxazole ring and benztriazole ring, and It is bonded to X through a carbon atom constituting the ring. )

Or a pharmacologically acceptable salt thereof.
　また、本発明は上記一般式（Ｉ）又は（ＩＩ）で表される化合物又はその薬理学的に許容される塩を有効成分として含有するＰ２Ｘ４受容体拮抗剤に関する。
　さらにまた、本発明は上記一般式（Ｉ）又は（ＩＩ）で表される化合物又はその薬理学的に許容される塩を有効成分として含有する神経因性疼痛の予防又は治療剤に関する。 The present invention relates to P2X 4 receptor antagonist containing the above-mentioned general formula (I) or the compound represented by (II) or a pharmacologically acceptable salt thereof as an active ingredient.
Furthermore, the present invention relates to a preventive or therapeutic agent for neuropathic pain containing the compound represented by the above general formula (I) or (II) or a pharmacologically acceptable salt thereof as an active ingredient.
　次に本発明を詳細に説明する。
　上記一般式（Ｉ）で表される本発明化合物において、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５の炭素数１～８のアルキル基としては、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、ｉ－ブチル基、ｔ－ブチル基、ペンチル基又はヘキシル基等が挙げられる。
　Ｒ１、Ｒ２及びＲ５の炭素数２～８のアルケニル基としては、アリル基等が挙げられる。
　Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＲ５の１～３個のハロゲン原子で置換された炭素数１～８のアルキル基としては、１～３個のフッ素原子、塩素原子若しくは臭素原子等のハロゲン原子により置換されたメチル基、エチル基、プロピル基、イソプロピル基、ブチル基又はｔ－ブチル基等が挙げられ、好ましくはトリフルオロメチル基、クロロメチル基、２－クロロエチル基、２－ブロモエチル基又は２－フルオロエチル基等が挙げられる。
　Ｒ２、Ｒ３及びＲ４のフェニル基で置換された炭素数１～３のアルキル基としては、ベンジル基等が挙げられる。
　Ｒ１及びＲ５の炭素数１～８のアルコキシ基としては、メトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基、ｉ－ブトキシ基、ｔ－ブトキシ基、ペンチルオキシ基又はヘキシルオキシ基等が挙げられる。
　Ｒ１及びＲ５の１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基としては、１～３個のフッ素原子、塩素原子若しくは臭素原子等のハロゲン原子により置換されたメトキシ基、エトキシ基、プロポキシ基、イソプロポキシ基、ブトキシ基又はｔ－ブトキシ基等が挙げられ、好ましくはトリフルオロメトキシ基、クロロメトキシ基、２－クロロエトキシ基、２－ブロモエトキシ基又は２－フルオロエトキシ基等が挙げられる。
　Ｒ１、Ｒ３、Ｒ４及びＲ５のハロゲン原子としては、フッ素原子、塩素原子、又は臭素原子等が挙げられる。
　Ｒ１及びＲ５の炭素数１～８のアルキルアミノ基としては、メチルアミノ基、エチルアミノ基等が挙げられる。
　Ｒ５の１～５個のハロゲン原子で置換された炭素数１～５のアルキルアミノ基としては、２，２，２－トリフルオロエチルアミノ基等が挙げられる。
また、Ｒ１及びＲ５の炭素数２～８のジアルキルアミノ基としては、ジメチルアミノ基、ジエチルアミノ基等が挙げられる。
　Ｒ１及びＲ５の炭素数２～８のアシルアミノ基としては、アセチルアミノ基が挙げられる。
　Ｒ１及びＲ５の１～３個のハロゲン原子で置換された炭素数２～８のアシルアミノ基としては、トリフルオロメチルカルボニルアミノ基が挙げられる。
　Ｒ１及びＲ５の炭素数１～８のアルキルスルホニルアミノ基としては、メチルスルホニルアミノ基が挙げられる。
Ｒ１及びＲ５の炭素数２～８のアシル基としては、アセチル基が挙げられる。
　Ｒ１及びＲ５のアルコキシカルボニル基（アルコキシ部分の炭素数１～８）としては、メトキシカルボニル基、エトキシカルボニル基等が挙げられる。
　Ｒ１及びＲ５の炭素数１～８のアルキルチオ基としては、メチルチオ基が挙げられる。
　Ｒ１及びＲ５の炭素数１～８のアルキルスルフィニル基としては、メチルスルフィニル基が挙げられる。
　Ｒ１及びＲ５の炭素数１～８のアルキルスルホニル基としては、メチルスルホニル基が挙げられる。

　Ｒ５の置換基を有していても良いフェニル基において、好ましい置換基としては、メチル基、エチル基等の炭素数１～８のアルキル基、トリフルオロメチル基等の１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、フッ素原子等のハロゲン原子、シアノ基等が挙げられる。
　Ｒ５の置換基を有していても良い複素環基において、好ましい複素環基としては、テトラゾリル基、トリアゾリル基、ピリジル基、イミダゾリル基、オキサゾリル基又はチアゾリル基等が挙げられる。
　Ｒ５の置換基を有していても良い複素環において、好ましい置換基としては、メチル基、エチル基等の炭素数１～８のアルキル基、トリフルオロメチル基等の１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、フッ素原子等のハロゲン原子、シアノ基、オキソ等が挙げられる。

　上記一般式（Ｉ）中のＲ１及びＲ５は、Ｒ１、Ｒ５が置換している環に、同一又は異なったものが複数個存在していても良い。 Next, the present invention will be described in detail.
In the compound of the present invention represented by the above general formula (I), the alkyl group having 1 to 8 carbon atoms of R 1 , R 2 , R 3 , R 4 and R 5 includes a methyl group, an ethyl group, a propyl group, Examples include isopropyl group, butyl group, i-butyl group, t-butyl group, pentyl group, hexyl group and the like.
Examples of the alkenyl group having 2 to 8 carbon atoms of R 1 , R 2 and R 5 include an allyl group.
Examples of the alkyl group having 1 to 8 carbon atoms that is substituted with 1 to 3 halogen atoms of R 1 , R 2 , R 3 , R 4 and R 5 include 1 to 3 fluorine atoms, chlorine atoms or bromine atoms And a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, or a t-butyl group substituted by a halogen atom such as trifluoromethyl group, chloromethyl group, 2-chloroethyl group, 2- bromoethyl or 2-fluoroethyl group, and the like.
Examples of the alkyl group having 1 to 3 carbon atoms substituted by the phenyl group of R 2 , R 3 and R 4 include a benzyl group.
Examples of the alkoxy group having 1 to 8 carbon atoms of R 1 and R 5 include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, i-butoxy group, t-butoxy group, pentyloxy group or hexyloxy group Etc.
The alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms of R 1 and R 5 includes methoxy substituted with 1 to 3 halogen atoms such as fluorine atom, chlorine atom or bromine atom Group, ethoxy group, propoxy group, isopropoxy group, butoxy group or t-butoxy group, etc., preferably trifluoromethoxy group, chloromethoxy group, 2-chloroethoxy group, 2-bromoethoxy group or 2-fluoro group. An ethoxy group etc. are mentioned.
Examples of the halogen atom for R 1 , R 3 , R 4 and R 5 include a fluorine atom, a chlorine atom, or a bromine atom.
Examples of the alkylamino group having 1 to 8 carbon atoms of R 1 and R 5 include a methylamino group and an ethylamino group.
Examples of the alkylamino group having 1 to 5 carbon atoms substituted with 1 to 5 halogen atoms of R 5 include 2,2,2-trifluoroethylamino group and the like.
Examples of the dialkylamino group having 2 to 8 carbon atoms of R 1 and R 5 include a dimethylamino group and a diethylamino group.
Examples of the acylamino group having 2 to 8 carbon atoms of R 1 and R 5 include an acetylamino group.
Examples of the acylamino group having 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms of R 1 and R 5 include a trifluoromethylcarbonylamino group.
Examples of the alkylsulfonylamino group having 1 to 8 carbon atoms of R 1 and R 5 include a methylsulfonylamino group.
The acyl group R 1 and the number of carbon atoms of R 5 2 ~ 8, acetyl groups.
Examples of the alkoxycarbonyl group for R 1 and R 5 (the alkoxy group having 1 to 8 carbon atoms) include a methoxycarbonyl group and an ethoxycarbonyl group.
Examples of the alkylthio group having 1 to 8 carbon atoms of R 1 and R 5 include a methylthio group.
Examples of the alkylsulfinyl group having 1 to 8 carbon atoms of R 1 and R 5 include a methylsulfinyl group.
Examples of the alkylsulfonyl group having 1 to 8 carbon atoms of R 1 and R 5 include a methylsulfonyl group.

In the phenyl group which may have a substituent of R 5 , preferred substituents are alkyl groups having 1 to 8 carbon atoms such as methyl group and ethyl group, and 1 to 3 halogen atoms such as trifluoromethyl group. Examples thereof include an alkyl group having 1 to 8 carbon atoms substituted with an atom, a halogen atom such as a fluorine atom, and a cyano group.
In the heterocyclic group which may have a substituent of R 5 , preferred heterocyclic groups include a tetrazolyl group, a triazolyl group, a pyridyl group, an imidazolyl group, an oxazolyl group or a thiazolyl group.
In the heterocyclic ring optionally having R 5 substituent, preferred substituents are alkyl groups having 1 to 8 carbon atoms such as methyl group and ethyl group, and 1 to 3 halogen atoms such as trifluoromethyl group. Examples thereof include an alkyl group having 1 to 8 carbon atoms substituted with an atom, a halogen atom such as a fluorine atom, a cyano group, and oxo.

In the general formula (I), R 1 and R 5 may be the same or different from each other in the ring substituted by R 1 and R 5 .
上記で挙げた一般式（Ｉ）のＲ１、Ｒ３、Ｒ４及びＲ５における炭素数１～８のアルキル基、炭素数２～８のアルケニル基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、フェニル基で置換された炭素数１～３のアルキル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、炭素数１～８のアルキルアミノ基、炭素数１～８のジアルキルアミノ基、炭素数２～８のアシルアミノ基、１～３個のハロゲン原子で置換された炭素数２～８のアシルアミノ基、炭素数１～８のアルキルスルホニルアミノ基、炭素数２～８のアシル基、アルコキシカルボニル基（アルコキシ部分の炭素数１～８）、炭素数１～８のアルキルチオ基、炭素数１～８のアルキルスルフィニル基、炭素数１～８のアルキルスルホニル基、置換基を有していても良いフェニル基及び置換基を有していても良い複素環基等の例示は、上記一般式（ＩＩ）のＲ１１、Ｒ１３、Ｒ１４及びＲ１５についても同様なものが挙げられる。

　同じく一般式（ＩＩ）のＲ１５の置換基を有していても良い複素環基について、置換基として挙げられる炭素数１～８のアルキル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、炭素数１～８のアルキルアミノ基及び炭素数２～８のジアルキルアミノ基は、上記の一般式（Ｉ）のＲ１～Ｒ６で例示したものが挙げられる。 Substituted with an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, or 1 to 3 halogen atoms in R 1 , R 3 , R 4 and R 5 of the general formula (I) listed above. In addition, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 3 carbon atoms substituted with a phenyl group, an alkoxy group having 1 to 8 carbon atoms, and 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. An alkoxy group, a halogen atom, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 1 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, and a carbon number 2 substituted with 1 to 3 halogen atoms An acylamino group having 1 to 8 carbon atoms, an alkylsulfonylamino group having 1 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (1 to 8 carbon atoms in the alkoxy moiety), an alkylthio group having 1 to 8 carbon atoms, carbon Number 1-8 alkylsul Iniru group, an alkylsulfonyl group having 1 to 8 carbon atoms, exemplified of such heterocyclic group which may have a may have a substituent phenyl group and a substituted group, the general formula (II) R 11 , R 13 , R 14 and R 15 are the same.

Similarly, for the heterocyclic group which may have a substituent of R 15 in the general formula (II), examples of the substituent include an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, and 1 to 3 An alkyl group having 1 to 8 carbon atoms substituted with 1 halogen atom, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, an alkylamino group having 1 to 8 carbon atoms, and Examples of the dialkylamino group having 2 to 8 carbon atoms include those exemplified for R 1 to R 6 in the above general formula (I).
　また上記一般式（ＩＩ）中のＲ１１及びＲ１５は、Ｒ１１、Ｒ１５が置換している環に、同一又は異なったものが複数個存在していても良い。 In addition, R 11 and R 15 in the general formula (II) may be present in the same manner or different from each other in the ring substituted by R 11 and R 15 .
上記一般式（Ｉ）で表される本発明化合物としては、次に示す化合物が好ましい。
（１）
　Ｒ１が水素原子、炭素数１～８のアルキル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、炭素数２～８のアシルアミノ基又は１～３個のハロゲン原子で置換された炭素数２～８のアシルアミノ基である上記一般式（Ｉ）で表されるジアゼピン誘導体又はその薬理学的に許容される塩。
（２）
　Ｒ２が水素原子、炭素数１～８のアルキル基、又は１～３個のハロゲン原子で置換された炭素数１～８のアルキル基である上記（１）又は上記一般式（Ｉ）で表されるジアゼピン誘導体又はその薬理学的に許容される塩。
（３）
　Ｒ３及びＲ４が同一又は異なっていてもよく水素原子、炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基である上記（１）若しくは（２）又は上記一般式（Ｉ）で表されるジアゼピン誘導体又はその薬理学的に許容される塩。
（４）
　Ｒ５が水素原子、炭素数１～８のアルキル基、炭素数２～８のアルケニル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、又は置換基を有していても良い複素環基である上記（１）～（３）又は上記一般式（Ｉ）で表されるジアゼピン誘導体又はその薬理学的に許容される塩。
（５）
　Ｒ５が炭素数１～８のアルキル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基及び炭素数２～８のジアルキルアミノ基から選択される置換基を有していても良いテトラゾリル基、トリアゾリル基、イミダゾリル基、オキサゾリル基又はチアゾリル基である上記（１）～（３）又は上記一般式（Ｉ）で表されるジアゼピン誘導体又はその薬理学的に許容される塩。
（６）
　Ｒ５が水素原子、炭素数１～８のアルキル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基又はヒドロキシル基である上記（１）～（３）又は上記一般式（Ｉ）で表されるジアゼピン誘導体又はその薬理学的に許容される塩。
（７）
　ＺがＯである上記（１）～（６）又は上記一般式（Ｉ）で表されるジアゼピン誘導体又はその薬理学的に許容される塩。 As this invention compound represented by the said general formula (I), the compound shown next is preferable.
(1)
R 1 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms C1-C8 alkoxy groups substituted with atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, C1-C8 alkylamino groups, C2-C8 dialkylamino groups, carbon A diazepine derivative represented by the above general formula (I), which is an acylamino group having 2 to 8 carbon atoms or an acylamino group having 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or a pharmacologically acceptable salt thereof. salt.
(2)
R 2 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, represented by the above formula (1) or the above general formula (I) Or a pharmacologically acceptable salt thereof.
(3)
The above (1), wherein R 3 and R 4 may be the same or different and each is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms Or (2) or a diazepine derivative represented by the above general formula (I) or a pharmacologically acceptable salt thereof.
(4)
R 5 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. Alkyl group, alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, alkylamino group having 1 to 8 carbon atoms, carbon number A diazepine derivative represented by the above (1) to (3) or the above general formula (I) which is a dialkylamino group having 2 to 8 or a heterocyclic group which may have a substituent, or a pharmacologically thereof Acceptable salt.
(5)
R 5 is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and substituted with 1 to 3 halogen atoms Substituted from an alkoxy group having 1 to 8 carbon atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, alkylamino group having 1 to 8 carbon atoms and dialkylamino group having 2 to 8 carbon atoms A diazepine derivative represented by the above (1) to (3) or the above general formula (I), which is a tetrazolyl group, triazolyl group, imidazolyl group, oxazolyl group or thiazolyl group which may have a group, or a pharmacological thereof Acceptable salt.
(6)
R 5 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms. A diazepine derivative represented by the above (1) to (3) or the above general formula (I) which is an alkoxy group having 1 to 8 carbon atoms or a hydroxyl group substituted by an atom, or a pharmaceutically acceptable salt thereof.
(7)
A diazepine derivative represented by the above (1) to (6) or the above general formula (I), wherein Z is O, or a pharmacologically acceptable salt thereof.
上記一般式（ＩＩ）の本発明化合物としては、次に示す化合物が好ましい。
（８）
　Ｒ１１が水素原子、炭素数１～８のアルキル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、炭素数２～８のアシルアミノ基又は１～３個のハロゲン原子で置換された炭素数２～８のアシルアミノ基である上記一般式（ＩＩ）で表されるジアゼピン誘導体又はその薬理学的に許容される塩。
（９）
　Ｒ１１が水素原子、炭素数１～８のアルキル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基又はハロゲン原子である上記一般式（ＩＩ）で表されるジアゼピン誘導体又はその薬理学的に許容される塩。
（１０）
　Ｒ１３及びＲ１４が同一又は異なっていてもよく水素原子、炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基である上記（８）若しくは（９）又は上記一般式（ＩＩ）で表されるジアゼピン誘導体又はその薬理学的に許容される塩。
（１１）
　Ｒ１５が水素原子、炭素数１～８のアルキル基、炭素数２～８のアルケニル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、又は置換基を有していても良い複素環基である上記（８）～（１０）又は上記一般式（ＩＩ）で表されるジアゼピン誘導体又はその薬理学的に許容される塩。
（１２）
　Ｒ１５が炭素数１～８のアルキル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基及び炭素数２～８のジアルキルアミノ基から選択される置換基を有していても良いテトラゾリル基、トリアゾリル基、イミダゾリル基、オキサゾリル基又はチアゾリル基である上記（８）～（１０）又は上記一般式（ＩＩ）で表されるジアゼピン誘導体又はその薬理学的に許容される塩。
（１３）
　Ｒ１５が水素原子、炭素数１～８のアルキル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基又はヒドロキシル基である上記（８）～（１０）又は上記一般式（ＩＩ）で表されるジアゼピン誘導体又はその薬理学的に許容される塩。 As the compound of the present invention represented by the general formula (II), the following compounds are preferred.
(8)
R 11 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms. C1-C8 alkoxy groups substituted with atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, C1-C8 alkylamino groups, C2-C8 dialkylamino groups, carbon A diazepine derivative represented by the above general formula (II), which is an acylamino group having 2 to 8 carbon atoms or an acylamino group having 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or a pharmacologically acceptable salt thereof. salt.
(9)
R 11 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms. A diazepine derivative represented by the above general formula (II) or a pharmaceutically acceptable salt thereof, which is an alkoxy group having 1 to 8 carbon atoms substituted by an atom or a halogen atom.
(10)
The above (8), wherein R 13 and R 14 may be the same or different and each is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms Or (9) or a diazepine derivative represented by the above general formula (II) or a pharmacologically acceptable salt thereof.
(11)
R 15 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. Alkyl group, alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, alkylamino group having 1 to 8 carbon atoms, carbon number A diazepine derivative represented by the above (8) to (10) or the above general formula (II) which is a dialkylamino group having 2 to 8 or an optionally substituted heterocyclic group, or a pharmacologically thereof Acceptable salt.
(12)
R 15 is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and substituted with 1 to 3 halogen atoms Substituted from an alkoxy group having 1 to 8 carbon atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, alkylamino group having 1 to 8 carbon atoms and dialkylamino group having 2 to 8 carbon atoms A diazepine derivative represented by the above (8) to (10) or the above general formula (II), which is a tetrazolyl group, triazolyl group, imidazolyl group, oxazolyl group or thiazolyl group, which may have a group, or a pharmacological thereof Acceptable salt.
(13)
R 15 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and 1 to 3 halogen atoms. A diazepine derivative represented by the above (8) to (10) or the above general formula (II) or a pharmacologically acceptable salt thereof which is an alkoxy group having 1 to 8 carbon atoms or a hydroxyl group substituted with an atom.
　上記一般式（Ｉ）及び（ＩＩ）で表される化合物の薬理学的に許容される塩としては、塩酸塩や、ナトリム、カリウム、リチウム等のアルカリ金属塩が挙げられる。
　また本発明化合物には、シス・トランス異性体や光学活性体、ラセミ体等の光学異性体が存在する場合もあるが、何れも本発明に含まれる。 Examples of the pharmacologically acceptable salt of the compounds represented by the general formulas (I) and (II) include hydrochlorides and alkali metal salts such as sodium, potassium, and lithium.
The compound of the present invention may have optical isomers such as cis / trans isomers, optically active isomers, and racemates, all of which are included in the present invention.
　次に上記一般式（Ｉ）で表される本発明化合物の合成スキームを以下に示す。

（合成方法１）
　一般式（Ｉ）で、ＸがＮで、ＹがＣ＝Ｏで、ＺがＯで、実線と波線からなる二重線が単結合を表す場合。
Next, a synthesis scheme of the compound of the present invention represented by the above general formula (I) is shown below.

(Synthesis method 1)
In the general formula (I), X is N, Y is C = O, Z is O, and a double line composed of a solid line and a wavy line represents a single bond.
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
（式中、Ｒ１、Ｒ２、Ｒ２３、Ｒ３、Ｒ４、Ｒ５及び (Wherein R 1 , R 2 , R 23 , R 3 , R 4 , R 5 and
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
は、前記と同じ。）

　一般式（ｃ）で表される本発明化合物は、一般式（ａ）で表される化合物と一般式（ｂ）で表される化合物をＴＨＦ等の溶媒の存在下、閉環反応に付すことにより得ることができる。

（合成方法２）
一般式（Ｉ）で、ＸがＮで、ＹがＣ＝Ｏで、ＺがＯで、実線と波線からなる二重線が単結合を表す場合。 Is the same as above. )

The compound of the present invention represented by the general formula (c) is obtained by subjecting the compound represented by the general formula (a) and the compound represented by the general formula (b) to a ring-closing reaction in the presence of a solvent such as THF. Obtainable.

(Synthesis method 2)
In the general formula (I), X is N, Y is C = O, Z is O, and a double line composed of a solid line and a wavy line represents a single bond.
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
（式中、Ｒは低級アルキル基を表し、そしてＲ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及び (Wherein R represents a lower alkyl group and R 1 , R 2 , R 3 , R 4 , R 5 and
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
は、前記と同じ。）

　一般式（ｆ）で表される化合物は、一般式（ｄ）で表される化合物と一般式（ｅ）で表される化合物をクロロホルム等の溶媒中、炭酸水素ナトリウムの存在下、反応させることにより得ることができる。　次いで、得られた一般式（ｆ）で表される化合物をＴＨＦ等の溶媒中、水素化ナトリウムの存在下、閉環反応に付すことにより一般式（ｇ）で表される本発明化合物を得ることができる。

（合成方法３）
一般式（Ｉ）で、Ｒ２がＨで、ＸがＮで、ＹがＣ＝Ｏで、ＺがＯで、実線と波線からなる二重線が単結合を表す場合。 Is the same as above. )

The compound represented by the general formula (f) is obtained by reacting the compound represented by the general formula (d) and the compound represented by the general formula (e) in a solvent such as chloroform in the presence of sodium bicarbonate. Can be obtained. Next, the compound represented by the general formula (f) is subjected to a cyclization reaction in a solvent such as THF in the presence of sodium hydride to obtain the compound represented by the general formula (g). Can do.

(Synthesis method 3)
In the general formula (I), R 2 is H, X is N, Y is C═O, Z is O, and a double line composed of a solid line and a wavy line represents a single bond.
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
（式中、Ｒは低級アルキル基を表し、そしてＲ１、Ｒ３、Ｒ４、Ｒ５及び Wherein R represents a lower alkyl group, and R 1 , R 3 , R 4 , R 5 and
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
は、前記と同じ）

　一般式（ｊ）で表される化合物は、一般式（ｈ）で表される化合物と一般式（ｉ）で表される化合物をクロロホルム等の溶媒の存在下、反応させることにより得ることができる。　得られた一般式（ｊ）で表される化合物をエタノール等の溶媒中、Ｐｄ触媒の存在下、還元反応に付すことにより一般式（ｋ）で表される化合物を得ることができる。次いで、得られた一般式（ｋ）で表される化合物にエタノール等の溶媒中、ナトリウムアルコキシドの存在下、閉環反応に付すことにより一般式（ｌ）で表される本発明化合物を得ることができる。

（合成方法４）
一般式（Ｉ）で、ＸがＣで、ＹがＮで、ＺがＯで、実線と波線からなる二重線が２重結合を表す場合。 Is the same as above)

The compound represented by the general formula (j) can be obtained by reacting the compound represented by the general formula (h) and the compound represented by the general formula (i) in the presence of a solvent such as chloroform. . The compound represented by general formula (k) can be obtained by subjecting the obtained compound represented by general formula (j) to a reduction reaction in a solvent such as ethanol in the presence of a Pd catalyst. Next, the compound represented by the general formula (k) is subjected to a cyclization reaction in a solvent such as ethanol in the presence of sodium alkoxide to obtain the compound represented by the general formula (l). it can.

(Synthesis method 4)
In the general formula (I), X is C, Y is N, Z is O, and a double line consisting of a solid line and a wavy line represents a double bond.
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
（式中、Ｒは低級アルキル基を表し、そしてＲ１、Ｒ２、Ｒ３、Ｒ４、Ｒ５及び (Wherein R represents a lower alkyl group and R 1 , R 2 , R 3 , R 4 , R 5 and
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
は、前記と同じ。）

　一般式（ｏ）で表される化合物は、一般式（ｍ）で表される化合物と一般式（ｎ）で表される化合物をピリジン等の溶媒の存在下、閉環反応に付すことにより得ることができる

（合成方法５）
一般式（Ｉ）で、Ｒ５がテトラゾリル基の場合。 Is the same as above. )

The compound represented by the general formula (o) is obtained by subjecting the compound represented by the general formula (m) and the compound represented by the general formula (n) to a ring-closing reaction in the presence of a solvent such as pyridine. Can

(Synthesis method 5)
In the general formula (I), R 5 is a tetrazolyl group.
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４、Ｒ２５、Ｘ、Ｙ及び実線と波線からなる二重線
並びに (Wherein R 1 , R 2 , R 3 , R 4 , R 25 , X, Y and a double line consisting of a solid line and a wavy line, and
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
は、前記と同じ）

　一般式（ｑ）で表されるテトラゾール化合物は、一般式（ｐ）で表されるニトリル化合物に、トルエン、ＤＭＦ等の溶媒の存在下、トリ－ｎ－ブチルスズアジドあるいはアジ化ナトリム等のアジド化合物を反応させることにより得ることができる。
　一般式（ｒ）で表される金属塩は、一般式（ｑ）で表されるテトラゾール化合物に、水、エタノール等の溶媒の存在下、炭酸水素ナトリウムあるいは炭酸水素カリウム等の無機塩基を反応させることにより得ることができる Is the same as above)

The tetrazole compound represented by the general formula (q) is an azide compound such as tri-n-butyltin azide or sodium azide in the presence of a solvent such as toluene or DMF in the nitrile compound represented by the general formula (p). Can be obtained by reacting.
In the metal salt represented by the general formula (r), the tetrazole compound represented by the general formula (q) is reacted with an inorganic base such as sodium hydrogen carbonate or potassium hydrogen carbonate in the presence of a solvent such as water or ethanol. Can be obtained by
　上記一般式（Ｉ）及び（ＩＩ）で表されるその他の本発明化合物も上記の合成方法、後記の実施例の他、前記の特許文献及び公知文献等を参考にして製造することができる。

　斯くして得られた本発明の代表化合物例を以下に示す。
（代表化合物例１） Other compounds of the present invention represented by the above general formulas (I) and (II) can also be produced by referring to the above-mentioned synthesis method, the examples described later, the above-mentioned patent documents and publicly known documents and the like.

Examples of representative compounds of the present invention thus obtained are shown below.
(Representative compound example 1)
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＡは表１～３記載の通り） (Wherein R 1 , R 2 , R 3 , R 4 and A are as described in Tables 1 to 3)
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000023
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000024
Figure JPOXMLDOC01-appb-T000025
Figure JPOXMLDOC01-appb-T000025
（代表化合物例２） (Representative compound example 2)
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
（式中、Ｒ１、Ｒ２、Ｒ３、Ｒ４及びＡは表４～６記載の通り） (Wherein R 1 , R 2 , R 3 , R 4 and A are as described in Tables 4 to 6)
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000027
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000028
Figure JPOXMLDOC01-appb-T000029
Figure JPOXMLDOC01-appb-T000029
　次に本発明の薬理効果について述べる。
　本発明化合物のＰ２Ｘ４受容体拮抗作用を、以下のように測定した。
ヒトＰ２Ｘ４受容体を安定発現させた１３２１Ｎ１細胞を９６ウェルプレートに播種し、３７℃、５％ＣＯ２条件下で２４時間培養して細胞内カルシウム測定に使用した。細胞内カルシウムの測定にはカルシウム蛍光指示薬であるＦｕｒａ－２　ＡＭを用いた。アッセイバッファーに溶解させたＦｕｒａ－２　ＡＭを細胞に添加し、室温で45分間静置して細胞内に取り込ませた後、プレートを蛍光測定に供した。被験物質はＡＴＰ添加１５分前に細胞に処置し、ＡＴＰ添加によって誘発される細胞内カルシウム流入応答をマイクロプレートリーダーを用いて経時的に測定した。励起光３４０ｎｍと３８０ｎｍでのそれぞれの蛍光値の比を細胞内カルシウム変化の指標とし、被験物質非存在下（コントロール）との比較により被検物質の阻害活性を算出した。
Next, the pharmacological effect of the present invention will be described.
The P2X 4 receptor antagonism of the compounds of the present invention was measured as follows.
The 1321N1 cells were stably expressing human P2X 4 receptor were seeded in 96-well plates, 37 ° C., was used for intracellular calcium measured 24 hours at 5% CO 2 conditions. For measurement of intracellular calcium, Fura-2 AM, which is a calcium fluorescent indicator, was used. Fura-2 AM dissolved in assay buffer was added to the cells, allowed to stand at room temperature for 45 minutes to be taken into the cells, and then the plate was subjected to fluorescence measurement. Test substances were treated in cells 15 minutes before the addition of ATP, and the intracellular calcium influx response induced by the addition of ATP was measured over time using a microplate reader. The ratio of the respective fluorescence values at excitation light of 340 nm and 380 nm was used as an index of intracellular calcium change, and the inhibitory activity of the test substance was calculated by comparison with the absence of the test substance (control).
　実施例１６及び１７から明らかなように本発明化合物は優れたＰ２Ｘ４受容体拮抗作用を示した。（表７，８参照）
　従って、上記一般式（Ｉ）又は（ＩＩ）で表されるジアゼピン誘導体又はその薬理学的に許容される塩は、Ｐ２Ｘ４受容体拮抗作用を有することから侵害受容性疼痛、炎症性疼痛及び神経因性疼痛における痛みの予防又は治療剤として有用であると考えられる。即ち各種癌による痛み、糖尿病の神経障害に伴う痛み、ヘルペスなどのウイルス性疾患に伴う痛み、変形性関節症等の予防又は治療剤として有用である。また、本発明の予防又は治療剤は必要に応じて他の薬剤と併用されても良く、例えばオピオイド鎮痛薬(モルヒネ、フェンタニル)、ナトリウムチャネル遮断剤(ノボカイン、リドカイン)、ＮＳＡＩＤｓ (アスピリン、イブプロフェン)等との併用が挙げられる。また、癌性疼痛に使用するときは、化学療法剤等の抗ガン剤との併用が挙げられる。 The present invention compounds as is apparent from Examples 16 and 17 showed a P2X 4 receptor antagonism excellent. (See Tables 7 and 8)
Accordingly, the general formula (I) or diazepine derivative or a pharmacologically acceptable salt thereof represented by the general formula (II) is nociceptive pain from having a P2X 4 receptor antagonism, inflammatory pain and nerve It is thought to be useful as a preventive or therapeutic agent for pain in pathogenic pain. That is, it is useful as a prophylactic or therapeutic agent for various cancer pains, pain associated with neuropathy of diabetes, pain associated with viral diseases such as herpes, osteoarthritis and the like. In addition, the preventive or therapeutic agent of the present invention may be used in combination with other drugs as necessary, for example, opioid analgesics (morphine, fentanyl), sodium channel blockers (novocaine, lidocaine), NSAIDs (aspirin, ibuprofen) Etc. are used together. Moreover, when using for cancer pain, combined use with anticancer agents, such as a chemotherapeutic agent, is mentioned.
　本発明化合物は、ヒトに対して経口投与又は非経口投与のような適当な投与方法により投与することができる。
　製剤化するためには、製剤の技術分野における通常の方法で錠剤、顆粒剤、散剤、カプセル剤、懸濁剤、注射剤、坐薬等の剤型に製造することができる。
　これらの調製には、例えば錠剤の場合、通常の賦形剤、崩壊剤、結合剤、滑沢剤、色素などが用いられる。ここで、賦形剤としては、乳糖、Ｄ－マンニトール、結晶セルロース、ブドウ糖などが、崩壊剤としては、デンプン、カルボキシメチルセルロースカルシウム（ＣＭＣ－Ｃａ）などが、滑沢剤としては、ステアリン酸マグネシウム、タルクなどが、結合剤としては、ヒドロキシプロピルセルロース（ＨＰＣ）、ゼラチン、ポリビニルピロリドン（ＰＶＰ）などが挙げられる。注射剤の調整には溶剤、安定化剤、溶解補助剤、懸濁剤、乳化剤、無痛化剤、緩衝剤、保存剤などが用いられる。 The compound of the present invention can be administered to humans by an appropriate administration method such as oral administration or parenteral administration.
For formulation, it can be produced into a dosage form such as tablets, granules, powders, capsules, suspensions, injections, suppositories and the like by conventional methods in the technical field of formulation.
For these preparations, for example, in the case of tablets, usual excipients, disintegrants, binders, lubricants, pigments and the like are used. Here, as the excipient, lactose, D-mannitol, crystalline cellulose, glucose and the like are used, as the disintegrant, starch, carboxymethylcellulose calcium (CMC-Ca) and the like, as the lubricant, magnesium stearate, Examples of binders include talc and the like, hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), and the like. Solvents, stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives and the like are used for the preparation of injections.
　投与量は通常成人においては、注射剤で有効成分である本発明化合物を１日約０．０１ｍｇ～１００ｍｇ，経口投与で１日１ｍｇ～２０００ｍｇであるが、年齢、症状等により増減することができる。

　次に、実施例を挙げ本発明を更に詳細に説明するが、本発明はこれらに限定されるものではない。
In general, for adults, the compound of the present invention, which is an active ingredient in injections, is about 0.01 mg to 100 mg per day, and 1 mg to 2000 mg per day for oral administration. .

Next, although an Example is given and this invention is demonstrated further in detail, this invention is not limited to these.
５－（１Ｈ－インダゾール－４－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン

（１）４－ニトロ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール
　４－ニトロ－１Ｈ－インダゾール（１．４１ｇ，８．６４ｍｍｏｌ）を乾燥テトラヒドロフラン（８６ｍＬ）に溶解し、氷冷攪拌下６０％水素化ナトリウム（０．３８ｇ，９．５０ｍｍｏｌ）を加えた。続いて２－（クロロメトキシ）エチルトリメチルシラン（１．６２ｍＬ，９．５０ｍｍｏｌ）を滴下後、氷冷下で１時間さらに室温で１時間攪拌した。反応混合物を氷水に注ぎ、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下に溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／５）に処し、橙色結晶として表題化合物（１．３０ｇ、収率５１％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０６（９Ｈ，ｓ），０．８８（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．５６（２Ｈ，ｔ，Ｊ＝８Ｈｚ），５．８２（２Ｈ，ｓ），７．５６（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．９６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．１９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．６４（１Ｈ，ｓ）．

（２）４－アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール
　４－ニトロ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール（１．７７ｇ，５．１９ｍｍｏｌ）をエタノール（１８ｍＬ）に溶解し、酸化白金（９ｍｇ）を加え、水素雰囲気下、室温で８時間攪拌した。不溶物をろ別し、ろ液を減圧下に濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／２）に処し、褐色油状物として表題化合物を得た（１．２９ｇ、収率９４％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０７（９Ｈ，ｓ），０．８９（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．５５（２Ｈ，ｔ，Ｊ＝８Ｈｚ），４．１２（２Ｈ，ｂｒ　ｓ），５．６８（２Ｈ，ｓ），６．３９（１Ｈ，ｄ，Ｊ＝７Ｈｚ），６．９６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．２０（１Ｈ，ｄｄ，Ｊ＝７Ｈｚ，８Ｈｚ），７．９５（１Ｈ，ｓ）．

（３）４－（１－ニトロ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール
　４－アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール（０．８５ｇ，３．２３ｍｍｏｌ）、１－ニトロ－２－ナフチルトリフラート（１．５６ｇ，４．８５ｍｍｏｌ）、炭酸カリウム（０．４５ｇ，３．２３ｍｍｏｌ）、テトラキス（トリフェニルホスフィン）パラジウム（０．３７ｇ，０．３２ｍｍｏｌ）、トリフェニルホスフィン（０．１７ｇ，０．６５ｍｍｏｌ）、及び乾燥トルエン（２６ｍＬ）を混合し、窒素雰囲気下２３時間加熱還流した。放冷後、水及び酢酸エチルを加え、不溶物をろ別した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下に溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（クロロホルム）に処し、褐色油状物として表題化合物を得た（１．２０ｇ、収率８５％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０５（９Ｈ，ｓ），０．９１（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．５９（２Ｈ，ｔ，Ｊ＝８Ｈｚ），５．７７（２Ｈ，ｓ），７．１２（１Ｈ，ｄｄ，Ｊ＝１Ｈｚ，７Ｈｚ），７．３５（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．４－７．５（３Ｈ，ｍ，），７．６６（１Ｈ，ｄｄｄ，Ｊ＝１Ｈｚ，７Ｈｚ，８Ｈｚ），７．７－７．８（２Ｈ，ｍ），７．９３（１Ｈ，ｓ），８．５５（１Ｈ，ｄ，Ｊ＝９Ｈｚ），９．６７（１Ｈ，ｓ）．

（４）４－（１－アミノ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール
　４－（１－ニトロ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール（１．６９ｇ，３．８９ｍｍｏｌ）をテトラヒドロフラン（８．５ｍＬ）－メタノール（８．５ｍＬ）に溶解し、酸化白金（１７ｍｇ）を加え、水素雰囲気下、室温で５５時間攪拌した。不溶物をろ別し、ろ液を減圧下に濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３）に処し、褐色油状物として表題化合物を得た（１．１５ｇ、収率７３％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０５（９Ｈ，ｓ），０．９１（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．５８（２Ｈ，ｔ，Ｊ＝８Ｈｚ），４．４４（２Ｈ，ｂｒ　ｓ），５．７０（２Ｈ，ｓ），５．７５（１Ｈ，ｓ），６．２６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．２０（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．３－７．４（２Ｈ，ｍ），７．４－７．６（２Ｈ，ｍ，），７．８－７．９（３Ｈ，ｍ）．

（５）５－［１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール－４－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
　４－（１－アミノ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール（１．１５ｇ，２．８４ｍｍｏｌ）を乾燥テトラヒドロフラン（７５ｍＬ）に溶解し、氷冷攪拌下マロニルクロリド（０．３３ｍＬ，３．４ｍｍｏｌ）を加え、室温で３０分間、４０℃で３０分間、続いて６０℃で１時間半撹拌した。この反応混合物に氷冷攪拌下氷片および飽和の炭酸水素ナトリウム水を加え、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下に溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（メタノール／クロロホルム＝１／５０および酢酸エチル／ヘキサン＝２／１）に処し、黄褐色油状物として表題化合物を得た（０．３６ｇ、収率２７％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０７（９Ｈ，ｓ），０．８８（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．５６（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．７０（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），３．７５（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），５．７２（２Ｈ，ｓ），６．９７（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．１８（１Ｈ，ｂｒ　ｓ），７．４６（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．５１（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．５－７．６（２Ｈ，ｍ，），７．６８（１Ｈ，ｔ，Ｊ＝７Ｈｚ），７．８１（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．１９（１Ｈ，ｄ，Ｊ＝９Ｈｚ），９．３４（１Ｈ，ｂｒ　ｓ）．


（６）５－（１Ｈ－インダゾール－４－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
　５－［１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール－４－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン（３６０ｍｇ，０．７６ｍｍｏｌ）を乾燥ジクロロメタン（１１ｍＬ）に溶解し、トリフルオロ酢酸（５．５ｍＬ）を加え、室温で１６時間攪拌した。この反応混合物に氷片および飽和の炭酸水素ナトリウム水を加え、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下に溶媒留去して５－（１－ヒドロキシメチル－１Ｈ－インダゾール－４－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオンの粗体を得た。得られた粗体（２６０ｍｇ）を乾燥テトラヒドロフラン（１１ｍＬ）に溶解し、エチレンジアミン（０．５１ｍＬ，７．６ｍｍｏｌ）を加え、室温で１８時間攪拌した。減圧下に溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝４／１）に処し、淡褐色結晶を得、酢酸エチル－ヘキサンより再結晶して微紅色結晶として表題化合物を得た（１１０ｍｇ、収率４２％）。
　ＦＡＢ－ＭＳ（ｍ／ｚ）：３４３（ Ｍ＋１）
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：３．２２（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），３．８５（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），６．９７（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．１１（１Ｈ，ｂｒ　ｓ），７．４４（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．５４（１Ｈ，ｂｒ　ｓ），７．５－７．７（４Ｈ，ｍ），７．６９（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．９０（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．２８（１Ｈ，ｄ，Ｊ＝８Ｈｚ），１０．９８（１Ｈ，ｓ），１３．２８（１Ｈ，ｓ）．
 5- (1H-indazol-4-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione

(1) 4-Nitro-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indazole 4-nitro-1H-indazole (1.41 g, 8.64 mmol) was dissolved in dry tetrahydrofuran (86 mL) and ice-cooled. 60% sodium hydride (0.38 g, 9.50 mmol) was added with stirring. Subsequently, 2- (chloromethoxy) ethyltrimethylsilane (1.62 mL, 9.50 mmol) was added dropwise, and the mixture was stirred for 1 hour under ice cooling and further for 1 hour at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1/5) to give the title compound (1.30 g, yield 51%) as orange crystals.
1 H NMR (CDCl 3 , 400 MHz) δ: −0.06 (9H, s), 0.88 (2H, t, J = 8 Hz), 3.56 (2H, t, J = 8 Hz), 5.82 (2H, s), 7.56 (1H, t, J = 8 Hz), 7.96 (1H, d, J = 8 Hz), 8.19 (1H, d, J = 8 Hz), 8.64 (1H , S).

(2) 4-Amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indazole 4-nitro-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indazole (1.77 g, 5.19 mmol) Was dissolved in ethanol (18 mL), platinum oxide (9 mg) was added, and the mixture was stirred at room temperature for 8 hours in a hydrogen atmosphere. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1/2) to give the title compound as a brown oil (1.29 g, yield 94%).
1 H NMR (CDCl 3 , 400 MHz) δ: −0.07 (9H, s), 0.89 (2H, t, J = 8 Hz), 3.55 (2H, t, J = 8 Hz), 4.12 (2H, br s), 5.68 (2H, s), 6.39 (1H, d, J = 7 Hz), 6.96 (1H, d, J = 8 Hz), 7.20 (1H, dd, J = 7 Hz, 8 Hz), 7.95 (1H, s).

(3) 4- (1-Nitro-2-naphthyl) amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indazole 4-amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indazole (0.85 g, 3.23 mmol), 1-nitro-2-naphthyl triflate (1.56 g, 4.85 mmol), potassium carbonate (0.45 g, 3.23 mmol), tetrakis (triphenylphosphine) palladium (0.25 g). 37 g, 0.32 mmol), triphenylphosphine (0.17 g, 0.65 mmol), and dry toluene (26 mL) were mixed and heated to reflux under a nitrogen atmosphere for 23 hours. After allowing to cool, water and ethyl acetate were added, and the insoluble material was filtered off. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform) to obtain the title compound as a brown oil (1.20 g, yield 85%).
1 H NMR (CDCl 3 , 400 MHz) δ: −0.05 (9H, s), 0.91 (2H, t, J = 8 Hz), 3.59 (2H, t, J = 8 Hz), 5.77 (2H, s), 7.12 (1H, dd, J = 1 Hz, 7 Hz), 7.35 (1H, d, J = 9 Hz), 7.4-7.5 (3H, m,), 7. 66 (1H, ddd, J = 1 Hz, 7 Hz, 8 Hz), 7.7-7.8 (2H, m), 7.93 (1H, s), 8.55 (1H, d, J = 9 Hz), 9.67 (1H, s).

(4) 4- (1-Amino-2-naphthyl) amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indazole 4- (1-nitro-2-naphthyl) amino-1- [2- ( Trimethylsilyl) ethoxymethyl] -1H-indazole (1.69 g, 3.89 mmol) was dissolved in tetrahydrofuran (8.5 mL) -methanol (8.5 mL), platinum oxide (17 mg) was added, and a hydrogen atmosphere at room temperature was added. Stir for 55 hours. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1/3) to give the title compound as a brown oil (1.15 g, yield 73%).
1 H NMR (CDCl 3 , 400 MHz) δ: −0.05 (9H, s), 0.91 (2H, t, J = 8 Hz), 3.58 (2H, t, J = 8 Hz), 4.44 (2H, br s), 5.70 (2H, s), 5.75 (1H, s), 6.26 (1H, d, J = 8 Hz), 7.01 (1H, d, J = 8 Hz) 7.20 (1H, t, J = 8 Hz), 7.3-7.4 (2H, m), 7.4-7.6 (2H, m,), 7.8-7.9 (3H , M).

(5) 5- [1- [2- (Trimethylsilyl) ethoxymethyl] -1H-indazol-4-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione 4- (1-amino-2-naphthyl) amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indazole (1.15 g, 2.84 mmol) was dissolved in dry tetrahydrofuran (75 mL). Then, malonyl chloride (0.33 mL, 3.4 mmol) was added with stirring under ice cooling, followed by stirring at room temperature for 30 minutes, at 40 ° C. for 30 minutes, and then at 60 ° C. for 1 hour and a half. To this reaction mixture, ice pieces and saturated aqueous sodium hydrogen carbonate were added with stirring under ice cooling, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (methanol / chloroform = 1/50 and ethyl acetate / hexane = 2/1) to give the title compound as a tan oil (0.36 g). Yield 27%).
1 H NMR (CDCl 3 , 400 MHz) δ: −0.07 (9H, s), 0.88 (2H, t, J = 8 Hz), 3.56 (2H, t, J = 8 Hz), 3.70 (1H, d, J = 12 Hz), 3.75 (1H, d, J = 12 Hz), 5.72 (2H, s), 6.97 (1H, d, J = 9 Hz), 7.18 (1H , Br s), 7.46 (1H, t, J = 8 Hz), 7.51 (1H, d, J = 9 Hz), 7.5-7.6 (2H, m,), 7.68 (1H) , T, J = 7 Hz), 7.81 (1H, d, J = 8 Hz), 8.19 (1H, d, J = 9 Hz), 9.34 (1H, brs).


(6) 5- (1H-indazol-4-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione 5- [1- [2- (Trimethylsilyl) ethoxymethyl] -1H-indazol-4-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione (360 mg, 0.76 mmol) Was dissolved in dry dichloromethane (11 mL), trifluoroacetic acid (5.5 mL) was added, and the mixture was stirred at room temperature for 16 hr. Ice pieces and saturated aqueous sodium hydrogen carbonate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and 5- (1-hydroxymethyl-1H-indazol-4-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -A crude dione was obtained. The obtained crude product (260 mg) was dissolved in dry tetrahydrofuran (11 mL), ethylenediamine (0.51 mL, 7.6 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 4/1) to obtain pale brown crystals. Recrystallization from ethyl acetate-hexane gave the title compound as slightly red crystals. Obtained (110 mg, 42% yield).
FAB-MS (m / z): 343 (M + 1)
1 H NMR (DMSO-d 6 , 400 MHz) δ: 3.22 (1H, d, J = 12 Hz), 3.85 (1H, d, J = 12 Hz), 6.97 (1H, d, J = 9 Hz) ), 7.11 (1 H, br s), 7.44 (1 H, t, J = 8 Hz), 7.54 (1 H, br s), 7.5-7.7 (4 H, m), 7. 69 (1 H, t, J = 8 Hz), 7.90 (1 H, d, J = 8 Hz), 8.28 (1 H, d, J = 8 Hz), 10.98 (1 H, s), 13.28 ( 1H, s).
５－（１Ｈ－インダゾール－６－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン

（１）６－ニトロ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール
　６－ニトロ－１Ｈ－インダゾールを用い、実施例１（１）と同様の方法で表題化合物を淡黄色油状物として得た（収率５３％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０６（９Ｈ，ｓ），０．９０（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．５７（２Ｈ，ｔ，Ｊ＝８Ｈｚ），５．８２（２Ｈ，ｓ），７．８７（１Ｈ，ｄ，Ｊ＝９Ｈｚ），８．０８（１Ｈ，ｄｄ，Ｊ＝１Ｈｚ，９Ｈｚ），８．１４（１Ｈ，ｓ），８．５５（１Ｈ，ｓ）．

（２）６－アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール
　６－ニトロ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール（１．９２ｇ，６．５４ｍｍｏｌ）に、エタノール（３０ｍＬ）、酢酸（３０ｍＬ）、水（１０ｍｌ）、鉄粉（２．１ｇ）を加え、６０℃で２時間４０分攪拌した。室温に戻し、シリカゲル（１０ｇ）を加え、減圧乾固した。酢酸エチル、飽和の炭酸水素ナトリウム水を加え、不溶物をろ過し、有機層を水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下に溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３）に処し、微赤色油状物として表題化合物を得た（１．６５ｇ、収率９５％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０６（９Ｈ，ｓ），０．８９（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．５４（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．８９（２Ｈ，ｂｒ　ｓ），５．６２（２Ｈ，ｓ），６．６０（１Ｈ，ｄｄ，Ｊ＝１Ｈｚ，９Ｈｚ），６．７２（１Ｈ，ｄ，Ｊ＝１Ｈｚ），７．４９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．８２（１Ｈ，ｓ）．

（３）６－（１－ニトロ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール
　６－アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾールを用い、実施例１（３）と同様の方法で表題化合物を黄色粉末として得た（収率８８％）。

１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０６（９Ｈ，ｓ），０．９０（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．５７（２Ｈ，ｔ，Ｊ＝８Ｈｚ），５．７１（２Ｈ，ｓ），７．１１（１Ｈ，ｄ，Ｊ＝７Ｈｚ），７．４－７．５（３Ｈ，ｍ），７．６５（１Ｈ，ｔ，Ｊ＝７Ｈｚ），７．７－７．８（３Ｈ，ｍ），８．０１（１Ｈ，ｓ），８．５３（１Ｈ，ｄ，Ｊ＝９Ｈｚ），９．５５（１Ｈ，ｓ）．

（４）６－（１－アミノ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール
　６－（１－ニトロ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾールを用い、実施例１（４）と同様の方法で表題化合物を淡褐色粉末として得た（収率９６％）。

１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．１０（９Ｈ，ｓ），０．８４（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．５１（２Ｈ，ｔ，Ｊ＝８Ｈｚ），４．４１（２Ｈ，ｂｒ　ｓ），５．４８（１Ｈ，ｓ），５．５３（２Ｈ，ｓ），６．６２（１Ｈ，ｓ），６．７１（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，９Ｈｚ），７．３２（２Ｈ，ｓ），７．４－７．６（３Ｈ，ｍ），７．８－７．９（３Ｈ，ｍ）．

（５）５－［１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール－６－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
　６－（１－アミノ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾールを用い、実施例１（５）と同様の方法で表題化合物を微褐色粉末として得た（収率　２５％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．１０（９Ｈ，ｓ），０．８５（２Ｈ，ｄｄ，Ｊ＝７Ｈｚ，Ｊ＝９Ｈｚ），３．５４（２Ｈ，ｄｄ，Ｊ＝７Ｈｚ，Ｊ＝９Ｈｚ），３．６５（２Ｈ，ｓ），５．６４（１Ｈ，ｄ，Ｊ＝１１Ｈｚ），５．７０（１Ｈ，ｄ，Ｊ＝１１Ｈｚ），７．０４（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．０９（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，９Ｈｚ），７．５１（１Ｈ，ｓ），７．５－７．７（２Ｈ，ｍ），７．７１（１Ｈ，ｔ，Ｊ＝７Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．８５（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０３（１Ｈ，ｓ），８．０８（１Ｈ，ｄ，Ｊ＝９Ｈｚ），８．２８（１Ｈ，ｂｒ　ｓ）．

（６）５－（１Ｈ－インダゾール－６－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
５－［１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インダゾール－６－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオンを用い、実施例１（６）と同様の方法で表題化合物を白色粉末として得た（収率７３％）。

　ＦＡＢ－ＭＳ（ｍ／ｚ）：　３４３（Ｍ＋１）
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：３．１８（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），３．７５（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），６．８６（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，９Ｈｚ），７．０２（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．４９（１Ｈ，ｓ），７．６０（１Ｈ，ｔ，Ｊ＝７Ｈｚ），７．６－７．７（２Ｈ，ｍ），７．７９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．９１（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．１２（１Ｈ，ｓ），８．２８（１Ｈ，ｄ，Ｊ＝９Ｈｚ），１０．９２（１Ｈ，ｓ），１３．１５（１Ｈ，ｓ）．

 5- (1H-indazol-6-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione

(1) 6-nitro-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indazole The title compound was converted to a pale yellow oil in the same manner as in Example 1 (1) using 6-nitro-1H-indazole. (Yield 53%).
1 H NMR (CDCl 3 , 400 MHz) δ: −0.06 (9H, s), 0.90 (2H, t, J = 8 Hz), 3.57 (2H, t, J = 8 Hz), 5.82 (2H, s), 7.87 (1H, d, J = 9 Hz), 8.08 (1H, dd, J = 1 Hz, 9 Hz), 8.14 (1H, s), 8.55 (1H, s ).

(2) 6-amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indazole 6-nitro-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indazole (1.92 g, 6.54 mmol) Ethanol (30 mL), acetic acid (30 mL), water (10 ml) and iron powder (2.1 g) were added to the mixture, and the mixture was stirred at 60 ° C. for 2 hours and 40 minutes. The temperature was returned to room temperature, silica gel (10 g) was added, and the mixture was dried under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added, insoluble matter was filtered off, and the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1/3) to give the title compound as a slightly red oil (1.65 g, yield 95%).
1 H NMR (CDCl 3 , 400 MHz) δ: −0.06 (9H, s), 0.89 (2H, t, J = 8 Hz), 3.54 (2H, t, J = 8 Hz), 3.89 (2H, brs), 5.62 (2H, s), 6.60 (1H, dd, J = 1 Hz, 9 Hz), 6.72 (1H, d, J = 1 Hz), 7.49 (1H, d, J = 8 Hz), 7.82 (1H, s).

(3) 6- (1-Nitro-2-naphthyl) amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indazole 6-amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indazole Was used to give the title compound as a yellow powder in the same manner as in Example 1 (3) (yield 88%).

1 H NMR (CDCl 3 , 400 MHz) δ: −0.06 (9H, s), 0.90 (2H, t, J = 8 Hz), 3.57 (2H, t, J = 8 Hz), 5.71 (2H, s), 7.11 (1H, d, J = 7 Hz), 7.4-7.5 (3H, m), 7.65 (1H, t, J = 7 Hz), 7.7-7 .8 (3H, m), 8.01 (1H, s), 8.53 (1H, d, J = 9 Hz), 9.55 (1H, s).

(4) 6- (1-Amino-2-naphthyl) amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indazole 6- (1-nitro-2-naphthyl) amino-1- [2- ( The title compound was obtained as a light brown powder in the same manner as in Example 1 (4) using (trimethylsilyl) ethoxymethyl] -1H-indazole (yield 96%).

1 H NMR (CDCl 3 , 400 MHz) δ: −0.10 (9H, s), 0.84 (2H, t, J = 8 Hz), 3.51 (2H, t, J = 8 Hz), 4.41 (2H, br s), 5.48 (1H, s), 5.53 (2H, s), 6.62 (1H, s), 6.71 (1H, dd, J = 2 Hz, 9 Hz), 7 .32 (2H, s), 7.4-7.6 (3H, m), 7.8-7.9 (3H, m).

(5) 5- [1- [2- (Trimethylsilyl) ethoxymethyl] -1H-indazol-6-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione 6- (1-amino-2-naphthyl) amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indazole was used to obtain the title compound in the same manner as in Example 1 (5). Obtained as a brown powder (yield 25%).
1 H NMR (CDCl 3 , 400 MHz) δ: −0.10 (9H, s), 0.85 (2H, dd, J = 7 Hz, J = 9 Hz), 3.54 (2H, dd, J = 7 Hz, J = 9 Hz), 3.65 (2H, s), 5.64 (1H, d, J = 11 Hz), 5.70 (1H, d, J = 11 Hz), 7.04 (1H, d, J = 9 Hz), 7.09 (1 H, dd, J = 2 Hz, 9 Hz), 7.51 (1 H, s), 7.5-7.7 (2 H, m), 7.71 (1 H, t, J = 7 Hz), 7.77 (1 H, d, J = 8 Hz), 7.85 (1 H, d, J = 8 Hz), 8.03 (1 H, s), 8.08 (1 H, d, J = 9 Hz) , 8.28 (1H, br s).

(6) 5- (1H-indazol-6-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione 5- [1- [2- (Trimethylsilyl) ethoxymethyl] -1H-indazol-6-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione was used in Example 1 ( The title compound was obtained as a white powder in the same manner as in 6) (yield 73%).

FAB-MS (m / z): 343 (M + 1)
1 H NMR (DMSO-d 6 , 400 MHz) δ: 3.18 (1H, d, J = 12 Hz), 3.75 (1H, d, J = 12 Hz), 6.86 (1H, dd, J = 2 Hz) , 9 Hz), 7.02 (1 H, d, J = 9 Hz), 7.49 (1 H, s), 7.60 (1 H, t, J = 7 Hz), 7.6-7.7 (2 H, m) ), 7.79 (1H, d, J = 8 Hz), 7.91 (1H, d, J = 8 Hz), 8.12 (1H, s), 8.28 (1H, d, J = 9 Hz), 10.92 (1H, s), 13.15 (1H, s).

５－（１Ｈ－ベンズイミダゾール－５－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン

（１）５－ニトロ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンズイミダゾール
５－ニトロ－１Ｈ－ベンズイミダゾールを用い、実施例１（１）と同様の方法で表題化合物を黄色粉末として得た（収率４２％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０４（９Ｈ，ｓ），０．９２（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．５４（２Ｈ，ｔ，Ｊ＝８Ｈｚ），５．５９（２Ｈ，ｓ），７．６２（１Ｈ，ｄ，Ｊ＝９Ｈｚ），８．１５（１Ｈ，ｓ），８．２９（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，９Ｈｚ），８．７４（１Ｈ，ｄ，Ｊ＝２Ｈｚ）．

（２）５－アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンズイミダゾール
５－ニトロ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンズイミダゾールを用い、実施例１（２）と同様の方法で表題化合物を褐色油状物として得た（収率８８％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０５（９Ｈ，ｓ），０．８９（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．４９（２Ｈ，ｔ，Ｊ＝８Ｈｚ），５．４６（２Ｈ，ｓ），６．７５（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ、９Ｈｚ），７．１０（１Ｈ，ｄ，Ｊ＝２Ｈｚ），７．３１（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．８４（１Ｈ，ｓ）．

（３）５－（１－ニトロ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンズイミダゾール
５－アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンズイミダゾールを用い、実施例１（３）と同様の方法で表題化合物を橙色粉末として得た（収率８８％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０２（９Ｈ，ｓ），０．９４（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．５６（２Ｈ，ｔ，Ｊ＝８Ｈｚ），５．５７（２Ｈ，ｓ），７．２－７．３（２Ｈ，ｍ），７．３７（１Ｈ，ｔ，Ｊ＝７Ｈｚ），７．５－７．７（４Ｈ，ｍ，），７．７６（１Ｈ，ｄ，Ｊ＝１Ｈｚ），８．０４（１Ｈ，ｓ），８．６６（１Ｈ，ｄ，Ｊ＝９Ｈｚ），９．９１（１Ｈ，ｓ）．

（４）５－（１－アミノ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンズイミダゾール
５－（１－ニトロ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンズイミダゾールを用い、実施例１（４）と同様の方法で表題化合物を紫色粉末として得た（収率７６％）。

１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０４（９Ｈ，ｓ），０．９０（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．５０（２Ｈ，ｔ，Ｊ＝８Ｈｚ），５．３１（１Ｈ，ｓ），５．４７（２Ｈ，ｓ），６．８３（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，９Ｈｚ），７．１２（１Ｈ，ｄ，Ｊ＝２Ｈｚ），７．３１（２Ｈ，ｓ），７．３６（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．４－７．５（２Ｈ，ｍ），７．８６（１Ｈ，ｓ），７．７－７．９（２Ｈ，ｍ）．

（５）５－［１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンズイミダゾール－５－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
　５－（１－アミノ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンズイミダゾールを用い、実施例１（５）と同様の方法で表題化合物を褐色粉末として得た（収率９％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０３（９Ｈ，ｓ），０．９２（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．５３（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．６５（２Ｈ，ｓ），５．５４（２Ｈ，ｓ），７．０５（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．２３（１Ｈ，ｄｄ，Ｊ＝１Ｈｚ，９Ｈｚ），７．５－７．６（３Ｈ，ｍ），７．６８（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７２（１Ｈ，ｄ，Ｊ＝１Ｈｚ），７．８３（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０３（１Ｈ，ｓ），８．１２（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．７２（１Ｈ，ｂｒ　ｓ）．

（６）５－（１Ｈ－ベンズイミダゾール－５－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
５－［１－［２－（トリメチルシリル）エトキシメチル］ベンズイミダゾール－５－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオンを用い、実施例１（６）と同様の方法で表題化合物を微褐色粉末として得た（収率８１％）。
ＦＡＢ－ＭＳ（ｍ／ｚ）：３４３（Ｍ＋１）
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：３．１７（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），３．７２（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），６．９－７．１（１Ｈ，ｍ），７．０３（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．４－７．７（５Ｈ，ｍ，），７．９０（１Ｈ，ｄ，Ｊ＝７Ｈｚ），８．２－８．３（２Ｈ，ｍ），１０．９０（１Ｈ，ｓ），１２．５４（１Ｈ，ｂｒ　ｓ）．
 5- (1H-benzimidazol-5-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione

(1) 5-Nitro-1- [2- (trimethylsilyl) ethoxymethyl] -1H-benzimidazole Using 5-nitro-1H-benzimidazole and the title compound as a yellow powder in the same manner as in Example 1 (1) (Yield 42%).
1 H NMR (CDCl 3 , 400 MHz) δ: −0.04 (9H, s), 0.92 (2H, t, J = 8 Hz), 3.54 (2H, t, J = 8 Hz), 5.59 (2H, s), 7.62 (1H, d, J = 9 Hz), 8.15 (1H, s), 8.29 (1H, dd, J = 2 Hz, 9 Hz), 8.74 (1H, d , J = 2 Hz).

(2) 5-amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-benzimidazole Example 1 (using 5-nitro-1- [2- (trimethylsilyl) ethoxymethyl] -1H-benzimidazole) In the same manner as in 2), the title compound was obtained as a brown oil (yield 88%).
1 H NMR (CDCl 3 , 400 MHz) δ: −0.05 (9H, s), 0.89 (2H, t, J = 8 Hz), 3.49 (2H, t, J = 8 Hz), 5.46 (2H, s), 6.75 (1H, dd, J = 2 Hz, 9 Hz), 7.10 (1H, d, J = 2 Hz), 7.31 (1H, d, J = 9 Hz), 7.84 (1H, s).

(3) 5- (1-Nitro-2-naphthyl) amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-benzimidazole 5-amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H- The title compound was obtained as an orange powder in the same manner as in Example 1 (3) using benzimidazole (yield 88%).
1 H NMR (CDCl 3 , 400 MHz) δ: −0.02 (9H, s), 0.94 (2H, t, J = 8 Hz), 3.56 (2H, t, J = 8 Hz), 5.57 (2H, s), 7.2-7.3 (2H, m), 7.37 (1H, t, J = 7 Hz), 7.5-7.7 (4H, m,), 7.76 ( 1H, d, J = 1 Hz), 8.04 (1 H, s), 8.66 (1 H, d, J = 9 Hz), 9.91 (1 H, s).

(4) 5- (1-Amino-2-naphthyl) amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-benzimidazole 5- (1-nitro-2-naphthyl) amino-1- [2- Using (trimethylsilyl) ethoxymethyl] -1H-benzimidazole, the title compound was obtained as a purple powder in the same manner as in Example 1 (4) (yield 76%).

1 H NMR (CDCl 3 , 400 MHz) δ: −0.04 (9H, s), 0.90 (2H, t, J = 8 Hz), 3.50 (2H, t, J = 8 Hz), 5.31 (1H, s), 5.47 (2H, s), 6.83 (1H, dd, J = 2 Hz, 9 Hz), 7.12 (1H, d, J = 2 Hz), 7.31 (2H, s) ), 7.36 (1H, d, J = 9 Hz), 7.4-7.5 (2H, m), 7.86 (1H, s), 7.7-7.9 (2H, m).

(5) 5- [1- [2- (Trimethylsilyl) ethoxymethyl] -1H-benzimidazol-5-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H , 5H) -dione 5- (1-amino-2-naphthyl) amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-benzimidazole and the title compound in the same manner as in Example 1 (5) Was obtained as a brown powder (9% yield).
1 H NMR (CDCl 3 , 400 MHz) δ: −0.03 (9H, s), 0.92 (2H, t, J = 8 Hz), 3.53 (2H, t, J = 8 Hz), 3.65 (2H, s), 5.54 (2H, s), 7.05 (1H, d, J = 9 Hz), 7.23 (1H, dd, J = 1 Hz, 9 Hz), 7.5-7.6 (3H, m), 7.68 (1H, t, J = 8 Hz), 7.72 (1H, d, J = 1 Hz), 7.83 (1H, d, J = 8 Hz), 8.03 (1H , S), 8.12 (1H, d, J = 8 Hz), 8.72 (1H, br s).

(6) 5- (1H-benzimidazol-5-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione 5- [1- [2 Using (-(trimethylsilyl) ethoxymethyl] benzimidazol-5-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione, Example 1 (6 ) To give the title compound as a pale brown powder (yield 81%).
FAB-MS (m / z): 343 (M + 1)
1 H NMR (DMSO-d 6 , 400 MHz) δ: 3.17 (1H, d, J = 12 Hz), 3.72 (1H, d, J = 12 Hz), 6.9-7.1 (1H, m ), 7.03 (1H, d, J = 9 Hz), 7.4-7.7 (5H, m,), 7.90 (1H, d, J = 7 Hz), 8.2-8.3 ( 2H, m), 10.90 (1H, s), 12.54 (1H, br s).
５－（１Ｈ－インドール－６－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン

（１）６－ニトロ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インドール
６－ニトロ－１Ｈ－インドールを用い、実施例１（１）と同様の方法で表題化合物を褐色粉末として得た（収率９５％）。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：－０．１２（９Ｈ，ｓ），０．８１（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．４６（２Ｈ，ｔ，Ｊ＝８Ｈｚ），５．７１（２Ｈ，ｓ），６．７０（１Ｈ，ｄ，Ｊ＝３Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．９０（１Ｈ，ｄ，Ｊ＝３Ｈｚ），７．９６（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，９Ｈｚ）８．５５（１Ｈ，ｄ，Ｊ＝２Ｈｚ）．

（２）６－アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インドール
６－ニトロ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インドール（５．５１ｇ，１８．８ｍｍｏｌ）を酢酸エチル（２００ｍＬ）に溶解し、１０％パラジウム－炭素（１．２５ｇ）を加え、水素雰囲気下、室温で３時間攪拌した。不溶物をろ別し、ろ液を減圧下に濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３）に処し、褐色粉末として表題化合物を得た（４．３５ｇ、収率８８％）。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：－０．０７（９Ｈ，ｓ），０．８１（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．４２（２Ｈ，ｔ，Ｊ＝８Ｈｚ），４．８０（２Ｈ，ｂｒ　ｓ），５．３３（２Ｈ，ｓ），６．２２（１Ｈ，ｄ，Ｊ＝３Ｈｚ），６．４４（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，８Ｈｚ），６．６４（１Ｈ，ｄ，Ｊ＝２Ｈｚ），７．０７（１Ｈ，ｄ，Ｊ＝３Ｈｚ），７．１８（１Ｈ，ｄ，Ｊ＝８Ｈｚ）．

（３）６－（１－ニトロ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インドール
６－アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インドールを用い、実施例１（３）と同様の方法で表題化合物を橙色粉末として得た（収率８８％）。

１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０６（９Ｈ，ｓ），０．８９（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．４９（２Ｈ，ｔ，Ｊ＝８Ｈｚ），５．４５（２Ｈ，ｓ），６．５６（１Ｈ，ｄ，Ｊ＝３Ｈｚ），７．０７（１Ｈ，ｄｄ，Ｊ＝１Ｈｚ，８Ｈｚ），７．２－７．３（２Ｈ，ｍ），７．３６（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．４１（１Ｈ，ｓ），７．６－７．７（４Ｈ，ｍ，），８．６９（１Ｈ，ｄ，Ｊ＝９Ｈｚ），１０．０２（１Ｈ，ｂｒ　ｓ）．

（４）６－（１－アミノ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インドール
６－（１－ニトロ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インドール（３．３０ｇ，７．６１ｍｍｏｌ）を酢酸エチル（８１ｍＬ）に溶解し、１０％パラジウム－炭素（５０７ｍｇ）を加え、水素雰囲気下、室温で１２時間攪拌した。不溶物をろ別し、ろ液を減圧下に濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／３）に処し、褐色粉末として表題化合物を得た（２．２９ｇ、収率７４％）。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：－０．１１（９Ｈ，ｓ），０．７８（２Ｈ，ｄｄ，Ｊ＝７Ｈｚ，Ｊ＝９Ｈｚ），３．３９（２Ｈ，ｄｄ，Ｊ＝７Ｈｚ，Ｊ＝９Ｈｚ），５．２８（２Ｈ，ｓ），５．３１（２Ｈ，ｓ），６．３１（１Ｈ，ｓ），６．６６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），６．７９（１Ｈ，ｓ），７．１－７．２（３Ｈ，ｍ），７．３－７．４（４Ｈ，ｍ，），７．７２（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０８（１Ｈ，ｄ，Ｊ＝８Ｈｚ）．

（５）５－［１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インドール－６－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
　６－（１－アミノ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インドールを用い、実施例１（５）と同様の方法で表題化合物を褐色粉末として得た（収率２５％）。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：－０．１６（９Ｈ，ｓ），０．７５（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．１７（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），３．４１（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．７２（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），５．４８（１Ｈ，ｄ，Ｊ＝１１Ｈｚ），５．５２（１Ｈ，ｄ，Ｊ＝１１Ｈｚ），６．５４（１Ｈ，ｄ，Ｊ＝３Ｈｚ），６．９２（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．０２（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．４３（１Ｈ，ｓ），７．５－７．７（５Ｈ，ｍ），７．８９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．２７（１Ｈ，ｄ，Ｊ＝９Ｈｚ），１０．８８（１Ｈ，ｂｒ　ｓ）．

（６）５－（１Ｈ－インドール－６－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
５－［１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－インドール－６－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン（４５５ｍｇ，０．９６ｍｍｏｌ）を１．０Ｍ　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（８．６ｍＬ）に溶解し、エチレンジアミン（５４９μＬ）を加え、１６時間加熱還流した。この反応混合物を放冷後、水を加え酢酸エチルで抽出し、酢酸エチル層を無水硫酸ナトリウムで乾燥後、減圧下に濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／２）に処し、褐色アモルファスとして表題化合物を得た（３６２ｍｇ、定量的収率）。

ＦＡＢ－ＭＳ（ｍ／ｚ）：３４２（Ｍ＋１）
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：３．１７（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），３．７１（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），６．４７（１Ｈ，ｓ），６．７８（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．０４（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．２９（１Ｈ，ｓ），７．４３（１Ｈ，ｔ，Ｊ＝３Ｈｚ），７．５－７．７（４Ｈ，ｍ），７．９０（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．２６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），１０．８９（１Ｈ，ｂｒ　ｓ），１１．１８（１Ｈ，ｂｒ　ｓ）．
 5- (1H-Indol-6-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione

(1) 6-nitro-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indole Using 6-nitro-1H-indole, the title compound is obtained as a brown powder in the same manner as in Example 1 (1). (Yield 95%).
1 H NMR (DMSO-d 6 , 400 MHz) δ: −0.12 (9H, s), 0.81 (2H, t, J = 8 Hz), 3.46 (2H, t, J = 8 Hz), 5 .71 (2H, s), 6.70 (1H, d, J = 3 Hz), 7.77 (1H, d, J = 9 Hz), 7.90 (1H, d, J = 3 Hz), 7.96 (1H, dd, J = 2 Hz, 9 Hz) 8.55 (1H, d, J = 2 Hz).

(2) 6-amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indole 6-nitro-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indole (5.51 g, 18.8 mmol) Was dissolved in ethyl acetate (200 mL), 10% palladium-carbon (1.25 g) was added, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1/3) to give the title compound as a brown powder (4.35 g, yield 88%).
1 H NMR (DMSO-d 6 , 400 MHz) δ: −0.07 (9H, s), 0.81 (2H, t, J = 8 Hz), 3.42 (2H, t, J = 8 Hz), 4 .80 (2H, br s), 5.33 (2H, s), 6.22 (1 H, d, J = 3 Hz), 6.44 (1 H, dd, J = 2 Hz, 8 Hz), 6.64 ( 1H, d, J = 2 Hz), 7.07 (1H, d, J = 3 Hz), 7.18 (1H, d, J = 8 Hz).

(3) 6- (1-nitro-2-naphthyl) amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indole 6-amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indole In the same manner as in Example 1 (3), the title compound was obtained as an orange powder (yield 88%).

1 H NMR (CDCl 3 , 400 MHz) δ: −0.06 (9H, s), 0.89 (2H, t, J = 8 Hz), 3.49 (2H, t, J = 8 Hz), 5.45 (2H, s), 6.56 (1H, d, J = 3 Hz), 7.07 (1H, dd, J = 1 Hz, 8 Hz), 7.2-7.3 (2H, m), 7.36 (1H, t, J = 8 Hz), 7.41 (1H, s), 7.6-7.7 (4H, m,), 8.69 (1H, d, J = 9 Hz), 10.02 ( 1H, br s).

(4) 6- (1-Amino-2-naphthyl) amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indole 6- (1-nitro-2-naphthyl) amino-1- [2- ( Trimethylsilyl) ethoxymethyl] -1H-indole (3.30 g, 7.61 mmol) was dissolved in ethyl acetate (81 mL), 10% palladium-carbon (507 mg) was added, and the mixture was stirred at room temperature for 12 hours in a hydrogen atmosphere. Insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1/3) to give the title compound as a brown powder (2.29 g, yield 74%).
1 H NMR (DMSO-d 6 , 400 MHz) δ: −0.11 (9H, s), 0.78 (2H, dd, J = 7 Hz, J = 9 Hz), 3.39 (2H, dd, J = 7 Hz, J = 9 Hz), 5.28 (2H, s), 5.31 (2H, s), 6.31 (1 H, s), 6.66 (1 H, d, J = 8 Hz), 6.79 (1H, s), 7.1-7.2 (3H, m), 7.3-7.4 (4H, m,), 7.72 (1H, d, J = 8 Hz), 8.08 ( 1H, d, J = 8 Hz).

(5) 5- [1- [2- (Trimethylsilyl) ethoxymethyl] -1H-indol-6-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione 6- (1-amino-2-naphthyl) amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-indole was used to give the title compound in the same manner as in Example 1 (5). Obtained as a powder (25% yield).
1 H NMR (DMSO-d 6 , 400 MHz) δ: −0.16 (9H, s), 0.75 (2H, t, J = 8 Hz), 3.17 (1H, d, J = 12 Hz), 3 .41 (2H, t, J = 8 Hz), 3.72 (1H, d, J = 12 Hz), 5.48 (1H, d, J = 11 Hz), 5.52 (1H, d, J = 11 Hz) 6.54 (1H, d, J = 3 Hz), 6.92 (1H, d, J = 8 Hz), 7.02 (1H, d, J = 9 Hz), 7.43 (1H, s), 7 5-7.7 (5H, m), 7.89 (1H, d, J = 8 Hz), 8.27 (1H, d, J = 9 Hz), 10.88 (1H, br s).

(6) 5- (1H-Indol-6-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione 5- [1- [2- (Trimethylsilyl) ethoxymethyl] -1H-indol-6-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione (455 mg, 0.96 mmol) Was dissolved in 1.0 M tetrabutylammonium fluoride-tetrahydrofuran solution (8.6 mL), ethylenediamine (549 μL) was added, and the mixture was heated to reflux for 16 hours. The reaction mixture was allowed to cool, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1/2) to give the title compound as a brown amorphous (362 mg, quantitative yield).

FAB-MS (m / z): 342 (M + 1)
1 H NMR (DMSO-d 6 , 400 MHz) δ: 3.17 (1H, d, J = 12 Hz), 3.71 (1H, d, J = 12 Hz), 6.47 (1H, s), 6. 78 (1H, d, J = 8 Hz), 7.04 (1H, d, J = 9 Hz), 7.29 (1H, s), 7.43 (1H, t, J = 3 Hz), 7.5- 7.7 (4H, m), 7.90 (1 H, d, J = 8 Hz), 8.26 (1 H, d, J = 8 Hz), 10.89 (1 H, br s), 11.18 (1 H , Br s).
５－（１Ｈ－インドリン－６－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン　塩酸塩

（１）５－（１Ｈ－インドリン－６－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン

５－（１Ｈ－インドール－６－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン（１５０ｍｇ，０．４４ｍｍｏｌ）を酢酸（２．０ｍＬ）に懸濁し、氷冷後、シアノ水素化ホウ素ナトリウム（８３ｍｇ，１．３２ｍｍｏｌ）を加え、室温で２時間撹拌した。反応液に酢酸エチルを加え、１Ｍ　水酸化ナトリウム水溶液で洗浄し、酢酸エチル層を無水硫酸ナトリウムで乾燥後、減圧下に濃縮した。残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／１）に処し、褐色アモルファスとして表題化合物を得た（１２３ｍｇ、収率８１％）。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：２．９１（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．１０（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），３．４５（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．６３（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），５．６３（１Ｈ，ｓ），６．３－６．４（２Ｈ，ｍ），７．０－７．１（２Ｈ，ｍ），７．５－７．７（３Ｈ，ｍ），７．８９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．２１（１Ｈ，ｄ，Ｊ＝８Ｈｚ），１０．８３（１Ｈ，ｂｒ　ｓ）．

（２）５－（１Ｈ－インドリン－６－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン　塩酸塩
５－（１Ｈ－インドリン－６－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン（１２２ｍｇ，０．３６ｍｍｏｌ）をクロロホルム（３．０ｍＬ）／メタノール（３．０ｍＬ）に溶解し、氷冷後、２Ｍ　塩化水素－メタノール溶液（２．０ｍＬ）を加え、室温で１０分間撹拌した。反応液を減圧下に乾燥し、微褐色アモルファスとして表題化合物を得た（６１ｍｇ、収率４５％）。
ＦＡＢ－ＭＳ（ｍ／ｚ）：３４４（Ｍ＋１）
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：３．０－３．８（６Ｈ，ｍ），６．９－７．１（３Ｈ，ｍ），７．３７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．５－７．８（３Ｈ，ｍ），７．９２（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．２６（１Ｈ，ｄ，Ｊ＝９Ｈｚ），１０．９１（１Ｈ，ｂｒ　ｓ）．

 5- (1H-Indoline-6-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione hydrochloride

(1) 5- (1H-Indoline-6-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione

5- (1H-Indol-6-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione (150 mg, 0.44 mmol) was added to acetic acid (2 0 mL), and ice-cooled, sodium cyanoborohydride (83 mg, 1.32 mmol) was added, and the mixture was stirred at room temperature for 2 hr. Ethyl acetate was added to the reaction solution, washed with 1M aqueous sodium hydroxide solution, and the ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1/1) to give the title compound as a brown amorphous (123 mg, 81% yield).
1 H NMR (DMSO-d 6 , 400 MHz) δ: 2.91 (2H, t, J = 8 Hz), 3.10 (1H, d, J = 12 Hz), 3.45 (2H, t, J = 8 Hz) ), 3.63 (1H, d, J = 12 Hz), 5.63 (1H, s), 6.3-6.4 (2H, m), 7.0-7.1 (2H, m), 7.5-7.7 (3H, m), 7.89 (1H, d, J = 8 Hz), 8.21 (1H, d, J = 8 Hz), 10.83 (1H, br s).

(2) 5- (1H-Indoline-6-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione hydrochloride 5- (1H-Indoline) -6-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione (122 mg, 0.36 mmol) in chloroform (3.0 mL) / methanol ( 3.0 mL), and ice-cooled, 2M hydrogen chloride-methanol solution (2.0 mL) was added, and the mixture was stirred at room temperature for 10 min. The reaction was dried under reduced pressure to give the title compound as a slightly brown amorphous (61 mg, 45% yield).
FAB-MS (m / z): 344 (M + 1)
1 H NMR (DMSO-d 6 , 400 MHz) δ: 3.0-3.8 (6H, m), 6.9-7.1 (3H, m), 7.37 (1H, d, J = 8 Hz) ), 7.5-7.8 (3H, m), 7.92 (1H, d, J = 8 Hz), 8.26 (1H, d, J = 9 Hz), 10.91 (1H, br s) .

５－（１Ｈ－ベンゾトリアゾール－５－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン

（１）５－ニトロ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンゾトリアゾール
５－ニトロ－１Ｈ－ベンゾトリアゾールを用い、実施例１（１）と同様の方法で表題化合物を淡黄色油状物として得た（収率３６％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０２（９Ｈ，ｓ），０．９８（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．７８（２Ｈ，ｔ，Ｊ＝８Ｈｚ），６．０３（２Ｈ，ｓ），８．０５（１Ｈ，ｄ，Ｊ＝９Ｈｚ），８．２７（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，９Ｈｚ），８．９２（１Ｈ，ｄ，Ｊ＝２Ｈｚ）．

（２）５－アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンゾトリアゾール
５－ニトロ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンゾトリアゾールを用い、実施例１（２）と同様の方法で表題化合物を緑色油状物として得た（収率８４％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０４（９Ｈ，ｓ），０．９５（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．６９（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．８９（２Ｈ，ｂｒ　ｓ），５．８６（２Ｈ，ｓ），６．８－７．０（２Ｈ，ｍ），７．７０（１Ｈ，ｄ，Ｊ＝９Ｈｚ）．

（３）５－（１－ニトロ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンゾトリアゾール
５－アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンゾトリアゾールを用い、実施例１（３）と同様の方法で表題化合物を褐色油状物として得た（収率８８％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０１（９Ｈ，ｓ），０．９９（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．７６（２Ｈ，ｔ，Ｊ＝８Ｈｚ），５．９７（２Ｈ，ｓ），７．３１（１Ｈ，ｄｄ，Ｊ＝１Ｈｚ，９Ｈｚ），７．４－７．５（２Ｈ，ｍ），７．６５（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７－７．９（３Ｈ，ｍ），７．９５（１Ｈ，ｄ，Ｊ＝９Ｈｚ），８．５０（１Ｈ，ｄ，Ｊ＝９Ｈｚ），９．４５（１Ｈ，ｓ）．

（４）５－（１－アミノ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンゾトリアゾール
５－（１－ニトロ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンゾトリアゾールを用い、実施例１（４）と同様の方法で表題化合物を褐色粉末として得た（収率８６％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０４（９Ｈ，ｓ），０．９４（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．６８（２Ｈ，ｔ，Ｊ＝８Ｈｚ），４．４１（２Ｈ，ｂｒ　ｓ），５．５１（１Ｈ，ｓ），５．８４（２Ｈ，ｓ），６．７８（１Ｈ，ｄ，Ｊ＝２Ｈｚ），７．０３（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，Ｊ＝９Ｈｚ），７．２－７．４（２Ｈ，ｍ），７．４－７．６（２Ｈ，ｍ），７．７５（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．８－７．９（２Ｈ，ｍ）．

（５）５－［１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンゾトリアゾール－５－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
　５－（１－アミノ－２－ナフチル）アミノ－１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンゾトリアゾールを用い、実施例１（５）と同様の方法で表題化合物を褐色粉末として得た（収率５５％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：－０．０１（９Ｈ，ｓ），０．９７（２Ｈ，ｔ，Ｊ＝８Ｈｚ），３．６６（２Ｈ，ｓ），３．７３（２Ｈ，ｔ，Ｊ＝８Ｈｚ），５．９７（２Ｈ，ｓ），７．０５（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．２５（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，９Ｈｚ），７．５－７．７（２Ｈ，ｍ，），７．７１（１Ｈ，ｄｔ，Ｊ＝１Ｈｚ，Ｊ＝８Ｈｚ），７．８－７．９（２Ｈ，ｍ），７．９２（１Ｈ，ｄ，Ｊ＝１０Ｈｚ），８．１１（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．６１（１Ｈ，ｂｒ　ｓ）．


（６）５－（１Ｈ－ベンゾトリアゾール－５－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
５－［１－［２－（トリメチルシリル）エトキシメチル］－１Ｈ－ベンゾトリアゾール－５－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオンを用い、実施例１（６）と同様の方法で表題化合物を白色粉末として得た（収率４９％）。
ＦＡＢ－ＭＳ（ｍ／ｚ）：３４４（Ｍ＋１）
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：３．２０（１Ｈ，ｄ，Ｊ＝１１Ｈｚ），３．７６（１Ｈ，ｄ，Ｊ＝１１Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．１９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．６０（１Ｈ，ｔ，Ｊ＝７Ｈｚ），７．６－７．７（２Ｈ，ｍ），７．８－８．０（３Ｈ，ｍ），８．２９（１Ｈ，ｄ，Ｊ＝９Ｈｚ），１０．９４（１Ｈ，ｓ）．
 5- (1H-benzotriazol-5-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione

(1) 5-Nitro-1- [2- (trimethylsilyl) ethoxymethyl] -1H-benzotriazole Using 5-nitro-1H-benzotriazole in the same manner as in Example 1 (1), the title compound was pale yellow Obtained as an oil (yield 36%).
1 H NMR (CDCl 3 , 400 MHz) δ: −0.02 (9H, s), 0.98 (2H, t, J = 8 Hz), 3.78 (2H, t, J = 8 Hz), 6.03 (2H, s), 8.05 (1H, d, J = 9 Hz), 8.27 (1H, dd, J = 2 Hz, 9 Hz), 8.92 (1H, d, J = 2 Hz).

(2) 5-amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-benzotriazole Example 1 (using 5-nitro-1- [2- (trimethylsilyl) ethoxymethyl] -1H-benzotriazole The title compound was obtained as a green oil in the same manner as in 2) (yield 84%).
1 H NMR (CDCl 3 , 400 MHz) δ: −0.04 (9H, s), 0.95 (2H, t, J = 8 Hz), 3.69 (2H, t, J = 8 Hz), 3.89 (2H, brs), 5.86 (2H, s), 6.8-7.0 (2H, m), 7.70 (1H, d, J = 9 Hz).

(3) 5- (1-Nitro-2-naphthyl) amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-benzotriazole 5-amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H- The title compound was obtained as a brown oil in the same manner as in Example 1 (3) using benzotriazole (yield 88%).
1 H NMR (CDCl 3 , 400 MHz) δ: −0.01 (9H, s), 0.99 (2H, t, J = 8 Hz), 3.76 (2H, t, J = 8 Hz), 5.97 (2H, s), 7.31 (1H, dd, J = 1 Hz, 9 Hz), 7.4-7.5 (2H, m), 7.65 (1H, t, J = 8 Hz), 7.7 -7.9 (3H, m), 7.95 (1H, d, J = 9 Hz), 8.50 (1H, d, J = 9 Hz), 9.45 (1H, s).

(4) 5- (1-Amino-2-naphthyl) amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-benzotriazole 5- (1-nitro-2-naphthyl) amino-1- [2- Using (trimethylsilyl) ethoxymethyl] -1H-benzotriazole, the title compound was obtained as a brown powder in the same manner as in Example 1 (4) (yield 86%).
1 H NMR (CDCl 3 , 400 MHz) δ: −0.04 (9H, s), 0.94 (2H, t, J = 8 Hz), 3.68 (2H, t, J = 8 Hz), 4.41 (2H, br s), 5.51 (1H, s), 5.84 (2H, s), 6.78 (1H, d, J = 2 Hz), 7.03 (1H, dd, J = 2 Hz, J = 9 Hz), 7.2-7.4 (2H, m), 7.4-7.6 (2H, m), 7.75 (1H, d, J = 9 Hz), 7.8-7. 9 (2H, m).

(5) 5- [1- [2- (Trimethylsilyl) ethoxymethyl] -1H-benzotriazol-5-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H , 5H) -dione 5- (1-amino-2-naphthyl) amino-1- [2- (trimethylsilyl) ethoxymethyl] -1H-benzotriazole in the same manner as in Example 1 (5) Was obtained as a brown powder (55% yield).
1 H NMR (CDCl 3 , 400 MHz) δ: −0.01 (9H, s), 0.97 (2H, t, J = 8 Hz), 3.66 (2H, s), 3.73 (2H, t , J = 8 Hz), 5.97 (2H, s), 7.05 (1H, d, J = 9 Hz), 7.25 (1H, dd, J = 2 Hz, 9 Hz), 7.5-7.7 (2H, m,), 7.71 (1H, dt, J = 1 Hz, J = 8 Hz), 7.8-7.9 (2H, m), 7.92 (1H, d, J = 10 Hz), 8.11 (1H, d, J = 8 Hz), 8.61 (1H, br s).


(6) 5- (1H-benzotriazol-5-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione 5- [1- [2 Example using-(trimethylsilyl) ethoxymethyl] -1H-benzotriazol-5-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione The title compound was obtained as a white powder in the same manner as in 1 (6) (yield 49%).
FAB-MS (m / z): 344 (M + 1)
1 H NMR (DMSO-d 6 , 400 MHz) δ: 3.20 (1H, d, J = 11 Hz), 3.76 (1H, d, J = 11 Hz), 7.01 (1H, d, J = 9 Hz) ), 7.19 (1H, d, J = 8 Hz), 7.60 (1H, t, J = 7 Hz), 7.6-7.7 (2H, m), 7.8-8.0 (3H) M), 8.29 (1 H, d, J = 9 Hz), 10.94 (1 H, s).
５－（７－ヒドロキシキノリン－３－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン

（１）７－ベンジルオキシ－３－（１－ニトロ－２－ナフチル）アミノキノリン
３－アミノ－７－（ベンジルオキシ）キノリンを用い、実施例１（３）と同様の手法で黄色結晶である表題化合物を得た（収率６０％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：５．２４（２Ｈ，ｓ），７．２－７．７（９Ｈ，ｍ），７．７０（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．７４（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．７４（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．７９（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．９６（１Ｈ，ｄ，Ｊ＝２Ｈｚ），８．５６（１Ｈ，ｄ，Ｊ＝９Ｈｚ），８．８１（１Ｈ，ｄ，Ｊ＝２Ｈｚ），９．５６（１Ｈ，ｓ）．

（２）５－（７－ベンジルオキシキノリン－３－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
７－ベンジルオキシ－３－（１－ニトロ－２－ナフチル）アミノキノリン（７５０ｍｇ、１．７８ｍｍｏｌ）をエタノール（１５ｍＬ）に溶解した後、氷冷下で濃塩酸（１．９５ｍＬ）を加えた。続いて塩化スズ・二水和物（１．８０ｇ，８．００ｍｍｏｌ）のエタノール溶液（２ｍＬ）を滴下した後、室温に戻し一晩攪拌した。反応液を氷水に注いだ後、２Ｍ　水酸化ナトリウム水溶液を加え強塩基性とし更に酢酸エチルを加え一晩攪拌した。不溶物をろ別後、酢酸エチル層を分取した。酢酸エチル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。減圧下に溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝１／１）に処し、３－（１－アミノ－２－ナフチル）アミノ－７－ベンジルオキシキノリンを淡黄色結晶（４９０ｍｇ）として得た。得られた３－（１－アミノ－２－ナフチル）アミノ－７－ベンジルオキシキノリンは実施例１（５）と同様の手法を用いる事で微褐色結晶である表題化合物へと変換した（２工程収率１４％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：３．６８（２Ｈ，ｓ），５．２２（２Ｈ，ｓ），７．００（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．２－７．７（１０Ｈ，ｍ），７．８６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０４（１Ｈ，ｄ，Ｊ＝２Ｈｚ），８．０８（１Ｈ，ｄ，Ｊ＝２Ｈｚ），８．２５（１Ｈ，ｓ），８．５６（１Ｈ，ｄ，Ｊ＝９Ｈｚ），８．６６（１Ｈ，ｄ，Ｊ＝２Ｈｚ）．

（４）５－（７－ヒドロキシキノリン－３－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
５－（７－ベンジルオキシキノリン－３－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン（９０ｍｇ、０．１９６ｍｍｏｌ）をエタノール（９ｍＬ）に溶解し１０％パラジウム－炭素（１９ｍｇ）を加えた。水素雰囲気下、室温で７２時間攪拌した後、不溶物をろ別し、ろ液を減圧下に濃縮した。残留物をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１００／１）に処し、微黄白色結晶である表題化合物を得た（２５ｍｇ、収率３５％）。
ＦＡＢ－ＭＳ（ｍ／ｚ）：３７０（Ｍ＋１）
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：３．２２（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），３．８０（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），７．０４（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．１９（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，Ｊ＝９Ｈｚ），７．２９（１Ｈ，ｄ，Ｊ＝２Ｈｚ），７．５－７．７（３Ｈ，ｍ，），７．８３（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．９３（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０７（１Ｈ，ｄ，Ｊ＝２Ｈｚ），８．３０（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．６７（１Ｈ，ｄ，Ｊ＝２Ｈｚ），１０．３０（１Ｈ，ｂｒ　ｓ），１０．９０（１Ｈ，ｓ）．
 5- (7-Hydroxyquinolin-3-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione

(1) 7-benzyloxy-3- (1-nitro-2-naphthyl) aminoquinoline Using 3-amino-7- (benzyloxy) quinoline, yellow crystals are obtained in the same manner as in Example 1 (3). The title compound was obtained (yield 60%).
1 H NMR (CDCl 3 , 400 MHz) δ: 5.24 (2H, s), 7.2-7.7 (9H, m), 7.70 (1H, d, J = 9 Hz), 7.74 ( 1H, d, J = 9 Hz), 7.74 (1H, d, J = 9 Hz), 7.79 (1H, d, J = 9 Hz), 7.96 (1H, d, J = 2 Hz), 8. 56 (1H, d, J = 9 Hz), 8.81 (1H, d, J = 2 Hz), 9.56 (1H, s).

(2) 5- (7-Benzyloxyquinolin-3-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione 7-benzyloxy-3 -(1-Nitro-2-naphthyl) aminoquinoline (750 mg, 1.78 mmol) was dissolved in ethanol (15 mL), and concentrated hydrochloric acid (1.95 mL) was added under ice cooling. Subsequently, an ethanol solution (2 mL) of tin chloride dihydrate (1.80 g, 8.00 mmol) was added dropwise, and the mixture was returned to room temperature and stirred overnight. After pouring the reaction solution into ice water, 2M aqueous sodium hydroxide solution was added to make it strongly basic, and ethyl acetate was further added and stirred overnight. The insoluble material was filtered off, and the ethyl acetate layer was separated. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 1/1) to give 3- (1-amino-2-naphthyl) amino-7-benzyloxyquinoline as pale yellow crystals. (490 mg). The obtained 3- (1-amino-2-naphthyl) amino-7-benzyloxyquinoline was converted to the title compound as pale brown crystals using the same procedure as in Example 1 (5) (2 steps). Yield 14%).
1 H NMR (CDCl 3 , 400 MHz) δ: 3.68 (2H, s), 5.22 (2H, s), 7.00 (1H, d, J = 8 Hz), 7.2-7.7 ( 10H, m), 7.86 (1H, d, J = 8 Hz), 8.04 (1H, d, J = 2 Hz), 8.08 (1H, d, J = 2 Hz), 8.25 (1H, s), 8.56 (1H, d, J = 9 Hz), 8.66 (1H, d, J = 2 Hz).

(4) 5- (7-hydroxyquinolin-3-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione 5- (7-benzyloxy ) Quinolin-3-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione (90 mg, 0.196 mmol) was dissolved in ethanol (9 mL). % Palladium-carbon (19 mg) was added. After stirring at room temperature for 72 hours under a hydrogen atmosphere, insoluble matters were filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform / methanol = 100/1) to give the title compound as pale yellowish white crystals (25 mg, yield 35%).
FAB-MS (m / z): 370 (M + 1)
1 H NMR (DMSO-d 6 , 400 MHz) δ: 3.22 (1H, d, J = 12 Hz), 3.80 (1H, d, J = 12 Hz), 7.04 (1H, d, J = 9 Hz) ), 7.19 (1H, dd, J = 2 Hz, J = 9 Hz), 7.29 (1H, d, J = 2 Hz), 7.5-7.7 (3H, m,), 7.83 ( 1H, d, J = 9 Hz), 7.93 (1H, d, J = 8 Hz), 8.07 (1H, d, J = 2 Hz), 8.30 (1H, d, J = 8 Hz), 8. 67 (1H, d, J = 2 Hz), 10.30 (1 H, br s), 10.90 (1 H, s).
５－［２－（トリフルオロメチル）－１Ｈ－ベンズイミダゾール－５－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン

（１）５－（１－ニトロ－２－ナフチル）アミノ－２－（トリフルオロメチル）－１Ｈ－ベンズイミダゾール
５－アミノ－２－（トリフルオロメチル）－１Ｈ－ベンズイミダゾールを用い、実施例１（３）と同様の手法で黄色結晶である表題化合物を得た（収率１９％）。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：７．２９（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．３７（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．４６（１Ｈ，ｄｄ，Ｊ＝７Ｈｚ，８Ｈｚ），７．５３（１Ｈ，ｂｒ　ｓ），７．６６（１Ｈ，ｄｄ、Ｊ＝７Ｈｚ，９Ｈｚ），７．７４（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．９２（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．９８（１Ｈ，ｄ，Ｊ＝９Ｈｚ），８．０３（１Ｈ，ｄ，Ｊ＝９Ｈｚ），９．２９（１Ｈ，ｓ）．

（２）５－（１－アミノ－２－ナフチル）アミノ－２－（トリフルオロメチル）－１Ｈ－ベンズイミダゾール
５－（１－ニトロ－２－ナフチル）アミノ－２－（トリフルオロメチル）－１Ｈ－ベンズイミダゾール（０．３６ｇ，０．９７ｍｍｏｌ）をテトラヒドロフラン（９ｍＬ）－メタノール（９ｍＬ）に溶解し、含水５％パラジウム－炭素（０．０４ｇ）を加え、水素雰囲気下、室温で１５時間攪拌した。不溶物をろ別し、ろ液を減圧下に濃縮して、褐色アモルファスとして表題化合物を得た（０．３３ｇ、収率１００％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：４．４１（２Ｈ，ｂｒ　ｓ），５．５０（１Ｈ，ｓ），６．５４（１Ｈ，ｄ，Ｊ＝２Ｈｚ），６．９２（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，７Ｈｚ），７．２－７．４（２Ｈ，ｍ，），７．４－７．６（２Ｈ，ｍ），７．７１（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．８－７．９（２Ｈ，ｍ），９．２３（１Ｈ，ｓ）．

（３）５－［２－（トリフルオロメチル）－１Ｈ－ベンズイミダゾール－５－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
　５－（１－アミノ－２－ナフチル）アミノ－２－（トリフルオロメチル）－１Ｈ－ベンズイミダゾール）を用い実施例１（５）と同様の手法で微褐色アモルファスとして表題化合物を得た（収率１２％）。
ＦＡＢ－ＭＳ（ｍ／ｚ）：４１１（Ｍ＋１）
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：３．２０（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），３．７５（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），７．０２（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．１３（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．６０（１Ｈ，ｔ，Ｊ＝７Ｈｚ），７．６－７．７（３Ｈ，ｍ），７．７７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．９２（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．２８（１Ｈ，ｄ，Ｊ＝８Ｈｚ），１０．９３（１Ｈ，ｓ），１４．１６（１Ｈ，ｓ）．
 5- [2- (Trifluoromethyl) -1H-benzimidazol-5-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione

(1) Example 5 using 5- (1-nitro-2-naphthyl) amino-2- (trifluoromethyl) -1H-benzimidazole and 5-amino-2- (trifluoromethyl) -1H-benzimidazole The title compound as yellow crystals was obtained in the same manner as in (3) (yield 19%).
1 H NMR (DMSO-d 6 , 400 MHz) δ: 7.29 (1H, d, J = 9 Hz), 7.37 (1H, d, J = 9 Hz), 7.46 (1H, dd, J = 7 Hz) , 8 Hz), 7.53 (1 H, br s), 7.66 (1 H, dd, J = 7 Hz, 9 Hz), 7.74 (1 H, d, J = 9 Hz), 7.92 (1 H, d, J = 8 Hz), 7.98 (1H, d, J = 9 Hz), 8.03 (1H, d, J = 9 Hz), 9.29 (1H, s).

(2) 5- (1-Amino-2-naphthyl) amino-2- (trifluoromethyl) -1H-benzimidazole 5- (1-nitro-2-naphthyl) amino-2- (trifluoromethyl) -1H -Benzimidazole (0.36 g, 0.97 mmol) was dissolved in tetrahydrofuran (9 mL) -methanol (9 mL), water-containing 5% palladium-carbon (0.04 g) was added, and the mixture was stirred at room temperature for 15 hours in a hydrogen atmosphere. . The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound as a brown amorphous (0.33 g, yield 100%).
1 H NMR (CDCl 3 , 400 MHz) δ: 4.41 (2H, br s), 5.50 (1H, s), 6.54 (1H, d, J = 2 Hz), 6.92 (1H, dd , J = 2Hz, 7Hz), 7.2-7.4 (2H, m,), 7.4-7.6 (2H, m), 7.71 (1H, d, J = 8Hz), 7. 8-7.9 (2H, m), 9.23 (1H, s).

(3) 5- [2- (trifluoromethyl) -1H-benzimidazol-5-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H)- Using dione 5- (1-amino-2-naphthyl) amino-2- (trifluoromethyl) -1H-benzimidazole) in the same manner as in Example 1 (5), the title compound was obtained as a slightly brown amorphous substance ( Yield 12%).
FAB-MS (m / z): 411 (M + 1)
1 H NMR (DMSO-d 6 , 400 MHz) δ: 3.20 (1H, d, J = 12 Hz), 3.75 (1H, d, J = 12 Hz), 7.02 (1H, d, J = 9 Hz) ), 7.13 (1H, d, J = 9 Hz), 7.60 (1H, t, J = 7 Hz), 7.6-7.7 (3H, m), 7.77 (1H, d, J = 8 Hz), 7.92 (1 H, d, J = 8 Hz), 8.28 (1 H, d, J = 8 Hz), 10.93 (1 H, s), 14.16 (1 H, s).
５－（３－メチルベンズイソキサゾール－６－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン

（１）３－メチル－６－（１－ニトロ－２－ナフチル）アミノベンズイソキサゾール
６－アミノ－３－メチルベンズイソキサゾールを用い、実施例１（３）と同様の手法で表題化合物を得た（収率６０％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：２．５８（３Ｈ，ｓ），７．１６（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，Ｊ＝９Ｈｚ），７．１８（１Ｈ，ｄ，Ｊ＝２Ｈｚ），７．４－７．７（５Ｈ，ｍ），７．７７（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．８５（１Ｈ，ｄ，Ｊ＝９Ｈｚ），８．４０（１Ｈ，ｄ，Ｊ＝９Ｈｚ），９．１７（１Ｈ，ｓ）．

（２）３－メチル－６－（１－アミノ－２－ナフチル）アミノベンズイソキサゾール
３－メチル－６－（１－ニトロ－２－ナフチル）アミノベンズイソキサゾールを用い、実施例４（２）と同様の手法で、表題化合物を微褐色結晶として得た（収率７２％）。
　　　　　　　
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：２．４８（３Ｈ，ｓ），４．４０（２Ｈ，ｂｒｓ），５．６３（１Ｈ，ｂｒｓ），６．６３（１Ｈ，ｄ，Ｊ＝２Ｈｚ），６．７３（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，Ｊ＝９Ｈｚ），７．２７（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．３３（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．３９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．４－７．６（２Ｈ，ｍ），７．８－７．９（２Ｈ，ｍ）．

（３）５－（３－メチルベンズイソキサゾール－６－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
　
３－メチル－６－（１－アミノ－２－ナフチル）アミノ－３－メチルベンズイソキサゾールを用い、実施例１（５）と同様の手法で表題化合物を白色結晶として得た（収率２２％）。

ＦＡＢ－ＭＳ（ｍ／ｚ）：３５８（Ｍ＋１）
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：３．１２（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），３．６９（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），６．９０（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．０４（１Ｈ，ｄｄ，Ｊ＝１Ｈｚ，Ｊ＝９Ｈｚ），７．５２（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．５－７．６（２Ｈ，ｍ，），７．６７（１Ｈ，ｄ，Ｊ＝１Ｈｚ），７．８０（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．８４（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．２１（１Ｈ，ｄ，Ｊ＝８Ｈｚ），１０．８６（１Ｈ，ｓ）．
 5- (3-Methylbenzisoxazol-6-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione

(1) 3-methyl-6- (1-nitro-2-naphthyl) aminobenzisoxazole The title compound was prepared in the same manner as in Example 1 (3) using 6-amino-3-methylbenzisoxazole. (Yield 60%).
1 H NMR (CDCl 3 , 400 MHz) δ: 2.58 (3H, s), 7.16 (1H, dd, J = 2 Hz, J = 9 Hz), 7.18 (1H, d, J = 2 Hz), 7.4-7.7 (5H, m), 7.77 (1H, d, J = 9Hz), 7.85 (1H, d, J = 9Hz), 8.40 (1H, d, J = 9Hz) ), 9.17 (1H, s).

(2) 3-methyl-6- (1-amino-2-naphthyl) aminobenzisoxazole Example 4 (3-methyl-6- (1-nitro-2-naphthyl) aminobenzisoxazole was used. In the same manner as in 2), the title compound was obtained as pale brown crystals (yield 72%).

1 H NMR (CDCl 3 , 400 MHz) δ: 2.48 (3H, s), 4.40 (2H, brs), 5.63 (1H, brs), 6.63 (1H, d, J = 2 Hz) 6.73 (1H, dd, J = 2 Hz, J = 9 Hz), 7.27 (1H, d, J = 9 Hz), 7.33 (1H, d, J = 9 Hz), 7.39 (1H, d, J = 8 Hz), 7.4-7.6 (2H, m), 7.8-7.9 (2H, m).

(3) 5- (3-Methylbenzisoxazol-6-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione
The title compound was obtained as white crystals in the same manner as in Example 1 (5) using 3-methyl-6- (1-amino-2-naphthyl) amino-3-methylbenzisoxazole (yield 22 %).

FAB-MS (m / z): 358 (M + 1)
1 H NMR (DMSO-d 6 , 400 MHz) δ: 3.12 (1H, d, J = 12 Hz), 3.69 (1H, d, J = 12 Hz), 6.90 (1H, d, J = 9 Hz) ), 7.04 (1H, dd, J = 1 Hz, J = 9 Hz), 7.52 (1H, t, J = 8 Hz), 7.5-7.6 (2H, m,), 7.67 ( 1H, d, J = 1 Hz), 7.80 (1H, d, J = 8 Hz), 7.84 (1H, d, J = 8 Hz), 8.21 (1H, d, J = 8 Hz), 10. 86 (1H, s).
５－（ピリジン－３－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン

（１）３－（１－ニトロ－２－ナフチル）アミノピリジン
３－アミノピリジンを用い、実施例１（３）と同様の手法により、黄色結晶として表題化合物を得た（収率１２％）。
（２）３－（１－アミノ－２－ナフチル）アミノピリジン
３－（１－ニトロ－２－ナフチル）アミノピリジンを用い、実施例７（２）と同様の手法により淡黄色結晶として表題化合物を得た（収率９６％）。　　　　　　　　　　　
（３）３－［２－（ピリジン－３－イルアミノ）ナフタレン－１－イルアミノ］－３－オキソプロピオン酸　エチルエステル
　３－（１－アミノ－２－ナフチル）アミノピリジン（０．１７ｇ，０．７２ｍｍｏｌ）及び炭酸水素ナトリウム（０．１８ｇ，２．１６ｍｍｏｌ）をクロロホルム（７．２ｍＬ）に溶解した後、氷冷した。窒素雰囲気下でエチルマロニルクロライド（０．１１ｍＬ，０．８６ｍｍｏｌ）を滴下した後、室温に戻し３時間攪拌した。反応溶液に飽和の炭酸水素ナトリウム水を加え、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下に溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝５／１）に処し、黄色アモルファス（０．０４ｇ，収率１８％）として表題化合物を得た。
（４）５－（ピリジン－３－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
　３－［２－（ピリジン－３－イルアミノ）ナフタレン－１－イルアミノ］－３－オキソプロピオン酸　エチルエステル（０．０４ｇ，０．１１ｍｍｏｌ）を無水テトラヒドロフラン（２．２ｍＬ）に溶解した後、氷冷した。６０％水素化ナトリウム（０．０２ｇ，０．３６ｍｍｏｌ）を加えた後、室温で３時間攪拌した。飽和の炭酸水素ナトリウム水を加え、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下に溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝５／１）に処し、黄色結晶（０．０２ｇ，収率６６％）として表題化合物を得た。
ＦＡＢ－ＭＳ（ｍ／ｚ）：３０４（Ｍ＋１）．
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：３．６５（２Ｈ，ｓ），６．９５（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．３６（１Ｈ，ｄｄ，Ｊ＝５Ｈｚ，８Ｈｚ），７．５－７．８（４Ｈ，ｍ），７．８５（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．２４（１Ｈ，ｄ，Ｊ＝９Ｈｚ），８．５３（１Ｈ，ｄ，Ｊ＝２Ｈｚ），８．５６（１Ｈ，ｄ，Ｊ＝５Ｈｚ），９．７－１０．０（１Ｈ，ｂｒ　ｓ）．
ＩＲ（ＫＢｒ，ｃｍ－１）：３３０１，１６９５，１６６０，１５７５，１４７３，１４１７，１３６９，１３１３，１２８２，１１１０，９７５，８７３，８４２，８０４，７４８，７０７，５１４．
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　 5- (Pyridin-3-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione

(1) 3- (1-Nitro-2-naphthyl) aminopyridine Using 3-aminopyridine, the title compound was obtained as yellow crystals in the same manner as in Example 1 (3) (yield 12%).
(2) 3- (1-Amino-2-naphthyl) aminopyridine Using 3- (1-nitro-2-naphthyl) aminopyridine, the title compound was obtained as pale yellow crystals in the same manner as in Example 7 (2). Obtained (yield 96%).
(3) 3- [2- (Pyridin-3-ylamino) naphthalen-1-ylamino] -3- oxopropionic acid ethyl ester 3- (1-amino-2-naphthyl) aminopyridine (0.17 g, 0.72 mmol) ) And sodium hydrogen carbonate (0.18 g, 2.16 mmol) were dissolved in chloroform (7.2 mL) and then ice-cooled. Ethylmalonyl chloride (0.11 mL, 0.86 mmol) was added dropwise under a nitrogen atmosphere, and the mixture was returned to room temperature and stirred for 3 hours. To the reaction solution was added saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 5/1) to give the title compound as a yellow amorphous (0.04 g, yield 18%).
(4) 5- (Pyridin-3-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione 3- [2- (Pyridin-3- (Ilamino) naphthalen-1-ylamino] -3-oxopropionic acid ethyl ester (0.04 g, 0.11 mmol) was dissolved in anhydrous tetrahydrofuran (2.2 mL) and then ice-cooled. After adding 60% sodium hydride (0.02 g, 0.36 mmol), the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 5/1) to give the title compound as yellow crystals (0.02 g, yield 66%).
FAB-MS (m / z): 304 (M + 1).
1 H NMR (CDCl 3 , 400 MHz) δ: 3.65 (2H, s), 6.95 (1H, d, J = 9 Hz), 7.36 (1H, dd, J = 5 Hz, 8 Hz), 7. 5-7.8 (4H, m), 7.85 (1H, d, J = 8Hz), 8.24 (1H, d, J = 9Hz), 8.53 (1H, d, J = 2Hz), 8.56 (1H, d, J = 5 Hz), 9.7-10.0 (1H, br s).
IR (KBr, cm −1 ): 3301, 1695, 1660, 1575, 1473, 1417, 1369, 1313, 1282, 1110, 975, 873, 842, 804, 748, 707, 514.

５－（ピリミジン－２－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン

（１）２－（１－ニトロ－２－ナフチル）アミノピリミジン
２－アミノピリミジンを用い、実施例１（３）と同様の手法により、黄色結晶として表題化合物を得た（収率８１％）。
　　　　　　　　　　　　　　　　　　　　　　　　　　　
（２）２－（１－アミノ－２－ナフチル）アミノピリミジン
　２－（１－ニトロ－２－ナフチル）アミノピリミジンを用い、実施例４（２）と同様の手法により褐色油状物として表題化合物を得た（定量的収率）。
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
（３）５－（ピリミジン－２－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
　２－（１－アミノ－２－ナフチル）アミノピリミジンを用い、実施例１（５）と同様の手法により、微褐色結晶として表題化合物を得た（収率１２％）。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：３．５－３．８（２Ｈ，ｍ），６．９５（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．３３（１Ｈ，ｔ，Ｊ＝５Ｈｚ），７．５－７．８（３Ｈ，ｍ），７．８６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０４（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．１－８．２（１Ｈ，ｂｒ　ｓ），８．８１（２Ｈ，ｄ，Ｊ＝５Ｈｚ）．
ＦＡＢ－ＭＳ（ｍ／ｚ）：３０５（Ｍ＋１）
ＩＲ（ＫＢｒ，ｃｍ－１）：３４４２，３２０７，２９７９，２９３１，１６９７，１６６４，１５６７，１４７５，１４０７，１３７６，１３１３，１２４１，１０４３，８２１，７５４，６７３，５２０，４３０．
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　 5- (pyrimidin-2-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione

(1) 2- (1-Nitro-2-naphthyl) aminopyrimidine Using 2-aminopyrimidine, the title compound was obtained as yellow crystals in the same manner as in Example 1 (3) (yield 81%).

(2) 2- (1-Amino-2-naphthyl) aminopyrimidine Using 2- (1-nitro-2-naphthyl) aminopyrimidine, the title compound as a brown oil was obtained in the same manner as in Example 4 (2). Obtained (quantitative yield).

(3) 5- (pyrimidin-2-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione 2- (1-amino-2-naphthyl) ) Using aminopyrimidine, the title compound was obtained as fine brown crystals in the same manner as in Example 1 (5) (yield 12%).
1 H NMR (CDCl 3 , 400 MHz) δ: 3.5-3.8 (2H, m), 6.95 (1H, d, J = 9 Hz), 7.33 (1H, t, J = 5 Hz), 7.5-7.8 (3H, m), 7.86 (1H, d, J = 8 Hz), 8.04 (1H, d, J = 8 Hz), 8.1-8.2 (1H, br s), 8.81 (2H, d, J = 5 Hz).
FAB-MS (m / z): 305 (M + 1)
IR (KBr, cm −1 ): 3442, 3207, 2979, 2931, 1697, 1664, 1567, 1475, 1407, 1376, 1313, 1241, 1043, 821, 754, 673, 520, 430.

５－（５－メトキシピリジン－３－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン

（１）３－（１－ニトロ－２－ナフチル）アミノ－５－メトキシピリジン
２－アミノ－１－ニトロナフタレン（０．５０ｇ，２．６６ｍｍｏｌ）、炭酸セシウム（１．３０ｇ，４ｍｍｏｌ）、酢酸パラジウム（０．０６ｇ，０．２７ｍｍｏｌ）、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（０．３１ｇ，０．５３ｍｍｏｌ）および乾燥トルエン（１３ｍＬ）を混合し、窒素雰囲気下で４８時間加熱還流した。放冷後、水及び酢酸エチルを加え、不溶物を濾別した。酢酸エチル層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧下に溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／２）に処し、黄色結晶として表題化合物を得た（０．４８ｇ、収率６１％）。
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
（２）３－（１－アミノ－２－ナフチル）アミノ－５－メトキシピリジン
３－（１－ニトロ－２－ナフチル）アミノ－５－メトキシピリジンを用い、実施例４（２）と同様の手法により、微褐色油状物として表題化合物を得た（収率１２％）。
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
（３）３－［２－（５－メトキシピリジン－３－イルアミノ）ナフタレン－１－イルアミノ］－３－オキソプロピオン酸　エチルエステル
３－（１－アミノ－２－ナフチル）アミノ－５－メトキシピリジンを用い、実施例１０（３）と同様の手法により、淡黄色油状物として表題化合物を得た（収率２９％）。
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　
（４）５－（５－メトキシピリジン－３－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
３－［２－（５－メトキシピリジン－３－イルアミノ）ナフタレン－１－イルアミノ］－３－オキソプロピオン酸　エチルエステルを用い、実施例１０（４）と同様の手法により、褐色油状物として表題化合物を得た（収率５６％）。
ＦＡＢ－ＭＳ（ｍ／ｚ）：３３４（Ｍ＋１）
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：３．６４（２Ｈ，ｓ），３．８４（３Ｈ，ｓ），６．９９（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．２－７．３（１Ｈ，ｍ），７．５５－７．６５（２Ｈ，ｍ），７．７１（１Ｈ，ｔ，Ｊ＝７Ｈｚ），７．８６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．１－８．２（１Ｈ，ｍ），８．２２（１Ｈ，ｄ，Ｊ＝９Ｈｚ），８．２８（１Ｈ，ｄ，Ｊ＝２Ｈｚ），９．７８（１Ｈ，ｓ）．
　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　 5- (5-Methoxypyridin-3-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione

(1) 3- (1-Nitro-2-naphthyl) amino-5-methoxypyridine 2-amino-1-nitronaphthalene (0.50 g, 2.66 mmol), cesium carbonate (1.30 g, 4 mmol), palladium acetate (0.06 g, 0.27 mmol), 4,5-bis (diphenylphosphino) -9,9-dimethylxanthene (0.31 g, 0.53 mmol) and dry toluene (13 mL) were mixed under a nitrogen atmosphere. The mixture was heated to reflux for 48 hours. After allowing to cool, water and ethyl acetate were added, and the insoluble material was filtered off. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1/2) to give the title compound as yellow crystals (0.48 g, yield 61%).

(2) 3- (1-Amino-2-naphthyl) amino-5-methoxypyridine Using 3- (1-nitro-2-naphthyl) amino-5-methoxypyridine, the same procedure as in Example 4 (2) Gave the title compound as a pale brown oil (12% yield).

(3) 3- [2- (5-Methoxypyridin-3-ylamino) naphthalen-1-ylamino] -3-oxopropionic acid ethyl ester 3- (1-amino-2-naphthyl) amino-5-methoxypyridine And the title compound was obtained as a pale yellow oil in the same manner as in Example 10 (3) (yield 29%).

(4) 5- (5-Methoxypyridin-3-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione 3- [2- (5 -Methoxypyridin-3-ylamino) naphthalen-1-ylamino] -3-oxopropionic acid ethyl ester was used to give the title compound as a brown oil in the same manner as in Example 10 (4) (yield 56 %).
FAB-MS (m / z): 334 (M + 1)
1 H NMR (CDCl 3 , 400 MHz) δ: 3.64 (2H, s), 3.84 (3H, s), 6.99 (1H, d, J = 9 Hz), 7.2-7.3 ( 1H, m), 7.55-7.65 (2H, m), 7.71 (1H, t, J = 7 Hz), 7.86 (1H, d, J = 8 Hz), 8.1-8. 2 (1H, m), 8.22 (1 H, d, J = 9 Hz), 8.28 (1 H, d, J = 2 Hz), 9.78 (1 H, s).
５－（５－ヒドロキシピリジン－３－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン

５－（５－メトキシピリジン－３－イル）－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン（０．１５ｇ，０．４４ｍｍｏｌ）を乾燥ジクロロメタン（４．４ｍＬ）に溶解し氷冷した。窒素雰囲気下、１．０Ｍ　三臭化ホウ素／ジクロロメタン溶液（１．３２ｍＬ，１．３２ｍｍｏｌ）を滴下し、室温で１６時間攪拌した。反応溶液に２５％アンモニア水溶液を加えた後、飽和の塩化アンモニウム水溶液を加えｐＨを６とし水層をクロロホルムで抽出した。クロロホルム層を飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した後、減圧下に溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝４／１）に処し、淡黄色結晶として表題化合物を得た（０．０３ｇ、収率２３％）。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：３．１６（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），３．７３（１Ｈ，ｄ，Ｊ＝１２Ｈｚ），７．０１（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．０５－７．１５（１Ｈ，ｍ），７．５－７．８（３Ｈ，ｍ），７．８６（１Ｈ，ｓ），７．９３（１Ｈ，ｄ，Ｊ＝７Ｈｚ），８．０－８．１（１Ｈ，ｍ），８．２５（１Ｈ，ｄ，Ｊ＝８Ｈｚ），１０．２３（１Ｈ，ｓ），１０．９１（１Ｈ，ｓ）．
ＦＡＢ－ＭＳ（ｍ／ｚ）：３２０（Ｍ＋１）
ＩＲ（ＫＢｒ，ｃｍ－１）：３１４９，２９２９，２３６０，１６９８，１６４４，１５９４，１４１９，１３８４，１３１９，１２９２，１２４７，１１８０，１１５７，９７０，８７１，８０６，７４８，７０２，５６６．
 5- (5-Hydroxypyridin-3-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione

5- (5-methoxypyridin-3-yl) -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione (0.15 g, 0.44 mmol) Dissolved in dry dichloromethane (4.4 mL) and cooled on ice. Under a nitrogen atmosphere, 1.0 M boron tribromide / dichloromethane solution (1.32 mL, 1.32 mmol) was added dropwise, and the mixture was stirred at room temperature for 16 hours. A 25% aqueous ammonia solution was added to the reaction solution, a saturated aqueous ammonium chloride solution was added to adjust the pH to 6, and the aqueous layer was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 4/1) to give pale yellow crystals. The title compound was obtained (0.03 g, 23% yield).
1 H NMR (DMSO-d 6 , 400 MHz) δ: 3.16 (1H, d, J = 12 Hz), 3.73 (1H, d, J = 12 Hz), 7.01 (1H, d, J = 9 Hz) ), 7.05-7.15 (1H, m), 7.5-7.8 (3H, m), 7.86 (1H, s), 7.93 (1H, d, J = 7 Hz), 8.0-8.1 (1H, m), 8.25 (1 H, d, J = 8 Hz), 10.23 (1 H, s), 10.91 (1 H, s).
FAB-MS (m / z): 320 (M + 1)
IR (KBr, cm −1 ): 3149, 2929, 2360, 1698, 1644, 1594, 1419, 1384, 1319, 1292, 1247, 1180, 1157, 970, 871, 806, 748, 702, 566.
５－［５－（１Ｈ－テトラゾール－５－イル）チオフェン－２－イル］－１，３－ジヒドロナフト［１，２－ｅ］－１，４－ジアゼピン－２－オン　ナトリウム塩

（１）５－［ヒドロキシ（１－ニトロ－２－ナフチル）メチル］チオフェン－２－カルボニトリル
ビス（２－ジメチルアミノエチル）エーテル（１．２０ｍＬ，６．３８ｍｍｏｌ）の乾燥テトラヒドロフラン（２５ｍＬ）溶液に窒素雰囲気下、２Ｍ　イソプロピルマグネシウムクロリド／テトラヒドロフラン溶液を室温で滴下し、２０分間撹拌した。続いて５－ブロモチオフェン－２－カルボニトリル（１．００ｇ，５．３２ｍｍｏｌ）を加え３０分間撹拌した。さらに氷冷下１－ニトロ－２－ナフトアルデヒドを加え室温で１時間撹拌した。この反応混合物に１Ｍ　塩酸を注ぎ酢酸エチルで抽出した。有機層を水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下に溶媒留去し、残留物をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝３／１）に処し、橙緑色結晶として表題化合物（１．０６ｇ，収率６５％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：２．９２（１Ｈ，ｄ，Ｊ＝４Ｈｚ），６．２９（１Ｈ，ｄ，Ｊ＝４Ｈｚ），６．９０（１Ｈ，ｄ，Ｊ＝４Ｈｚ），７．４６（１Ｈ，ｄ，Ｊ＝４Ｈｚ），７．６－７．７（３Ｈ，ｍ），７．８０（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．９２（１Ｈ，ｄ，Ｊ＝７Ｈｚ），８．０２（１Ｈ，ｄ，Ｊ＝９Ｈｚ）．

（２）５－（１－ニトロ－２－ナフトイル）チオフェン－２－カルボニトリル
５－［ヒドロキシ（１－ニトロ－２－ナフチル）メチル］チオフェン－２－カルボニトリル（１．０６ｇ，３．４１ｍｍｏｌ）を乾燥ジクロロメタン（１０ｍＬ）に溶解し、シリカゲル（５ｇ）を加えた。さらにジクロム酸ピリジ二ウム（１．９２ｇ，５．１２ｍｍｏｌ）を加え１８時間撹拌した。得られた反応混合物をセライトろ過し、ろ物をクロロホルムで洗浄した。ろ液を減圧下に溶媒留去し、得られた粗体を酢酸エチルで再結晶しヘキサンで洗浄後、乾燥して淡黄色結晶として表題化合物（８２５ｍｇ，収率７８％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：７．４２（１Ｈ，ｄ，Ｊ＝４Ｈｚ），７．６０（１Ｈ，ｄ，Ｊ＝４Ｈｚ），７．６３（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．７－７．９（２Ｈ，ｍ），８．０４（１Ｈ，ｄｄ，Ｊ＝２Ｈｚ，８Ｈｚ），８．１８（２Ｈ，ｄ，Ｊ＝８Ｈｚ）．

（３）５－（１－アミノ－２－ナフトイル）チオフェン－２－カルボニトリル
　５－（１－ニトロ－２－ナフトイル）チオフェン－２－カルボニトリル（８２５ｍｇ，２．６８ｍｍｏｌ）を酢酸（１５ｍＬ）、エタノール（１５ｍＬ）および水（１．５ｍＬ）に６５℃で加熱溶解した。室温まで放冷後、鉄粉（８６７ｍｇ，１５．５ｍｍｏｌ）を加え、再度６５℃で１時間撹拌した。放冷後、シリカゲル（５ｇ）を加えセライトろ過し、ろ物を酢酸エチルで洗浄した。得られたろ液を減圧下に溶媒留去した後、残渣を酢酸エチルに溶解し飽和の炭酸水素ナトリウム水および飽和食塩水で洗浄、無水硫酸ナトリウムで乾燥した。減圧下に溶媒留去し、橙色粉末として表題化合物（７４５ｍｇ，収率１００％）を得た。
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：７．０８（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．４２（２Ｈ，ｂｒ　ｓ），７．５－７．６（２Ｈ，ｍ），７．６－７．７（２Ｈ，ｍ），７．７２（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．７７（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．９６（１Ｈ，ｄ，Ｊ＝８Ｈｚ）．

（４）５－（５－シアノチオフェン－２－イル）－１，３－ジヒドロナフト［１，２－ｅ］－１，４－ジアゼピン－２－オン
　５－（１－アミノ－２－ナフトイル）チオフェン－２－カルボニトリル（６９５ｍｇ，２．５０ｍｍｏｌ）をピリジン（３０ｍＬ）に溶解し、グリシンエチルエステル塩酸塩（５２３ｍｇ，３．７５ｍｍｏｌ）を加え、窒素雰囲気下、４２時間加熱還流した。放冷後、減圧下に溶媒を留去し残渣をクロロホルムに溶解した。不溶物をろ別したのち、ろ液を飽和の炭酸水素ナトリウム水で洗浄し無水硫酸ナトリウムで乾燥した。減圧下に濃縮した残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝２／３）に処し、粗体として褐色油状物を得た。酢酸エチル（１０ｍＬ）－メタノール（３ｍＬ）より結晶化させ、表題化合物（２９３ｍｇ，収率３７％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：３．８６（１Ｈ，ｄ，Ｊ＝１０Ｈｚ），４．５３（１Ｈ，ｄ，Ｊ＝１０Ｈｚ），７．２８（１Ｈ，ｄ，Ｊ＝４Ｈｚ），７．６－７．８（３Ｈ，ｍ），７．８３（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．９５（１Ｈ，ｄ，Ｊ＝４Ｈｚ），８．０５（１Ｈ，ｄ，Ｊ＝７Ｈｚ），８．３６（１Ｈ，ｄ，Ｊ＝９Ｈｚ），１０．９３（１Ｈ，ｓ）．

（５）５－［５－（１Ｈ－テトラゾール－５－イル）チオフェン－２－イル］－１，３－ジヒドロナフト［１，２－ｅ］－１，４－ジアゼピン－２－オン
　５－（５－シアノチオフェン－２－イル）－１，３－ジヒドロナフト［１，２－ｅ］－１，４－ジアゼピン－２－オン（１５０ｍｇ，０．４７３ｍｍｏｌ）の無水トルエン（２ｍＬ）－無水ＤＭＦ（０．７ｍＬ）溶液に、トリ－ｎ－ブチルスズアジド（２６１μＬ，０．９４６ｍｍｏｌ）を加え、１１０℃で６時間撹拌した。放冷後、反応混合物を飽和の炭酸水素ナトリウム水に注いでクロロホルムで洗浄した。水層に２Ｍ塩酸を加え中和後、クロロホルムで抽出し、精製水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧下に溶媒を留去し、残留物をクロマトグラフィー（クロロホルム／メタノール＝９５／５）に処し、酢酸エチル－メタノールより再結晶し、微褐色結晶として表題化合物（６２ｍｇ，収率３６％）を得た。
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：３．８４（１Ｈ，ｄ，Ｊ＝１０Ｈｚ），４．５０（１Ｈ，ｄ，Ｊ＝１０Ｈｚ），７．２１（１Ｈ，ｄ，Ｊ＝４Ｈｚ），７．６１（１Ｈ，ｄ，Ｊ＝４Ｈｚ），７．６－７．８（３Ｈ，ｍ，），７．８４（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．０－８．１（１Ｈ，ｍ），８．３６（１Ｈ，ｄ，Ｊ＝９Ｈｚ），１０．８４（１Ｈ，ｂｒ　ｓ）．

（６）５－［５－（１Ｈ－テトラゾール－５－イル）チオフェン－２－イル］－１，３－ジヒドロナフト［１，２－ｅ］－１，４－ジアゼピン－２－オン　ナトリウム塩
　５－［５－（１Ｈ－テトラゾール－５－イル）チオフェン－２－イル］－１，３－ジヒドロナフト［１，２－ｅ］－１，４－ジアゼピン－２－オン（６２ｍｇ，０．１７２ｍｍｏｌ）のエタノール（２ｍＬ）および水（１ｍL）溶液に、炭酸水素ナトリウム（１４．５ｍｇ，０．１７２ｍｍｏｌ）を加え、室温で２０分間撹拌した。減圧下に濃縮後、残留物を減圧乾固し、微褐色粉末として表題化合物（６４ｍｇ、収率９７％）を得た。
ＦＡＢ－ＭＳ（ｍ／ｚ）：３８３（Ｍ＋１）
１Ｈ　ＮＭＲ（ＤＭＳＯ－ｄ６，４００ＭＨｚ）δ：３．７７（１Ｈ，ｄ，Ｊ＝１０Ｈｚ），４．４６（１Ｈ，ｄ，Ｊ＝１０Ｈｚ），７．０７（１Ｈ，ｄ，Ｊ＝３Ｈｚ），７．３７（１Ｈ，ｄ，Ｊ＝３Ｈｚ），７．６－７．９（４Ｈ，ｍ），８．０３（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．３６（１Ｈ，ｄ，Ｊ＝８Ｈｚ），１０．７８（１Ｈ，ｓ）．
 5- [5- (1H-tetrazol-5-yl) thiophen-2-yl] -1,3-dihydronaphtho [1,2-e] -1,4-diazepin-2-one sodium salt

(1) 5- [Hydroxy (1-nitro-2-naphthyl) methyl] thiophene-2-carbonitrile Bis (2-dimethylaminoethyl) ether (1.20 mL, 6.38 mmol) in dry tetrahydrofuran ( In a nitrogen atmosphere, 2M isopropylmagnesium chloride / tetrahydrofuran solution was added dropwise to the solution at room temperature and stirred for 20 minutes. Subsequently, 5-bromothiophene-2-carbonitrile (1.00 g, 5.32 mmol) was added and stirred for 30 minutes. Further, 1-nitro-2-naphthaldehyde was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. And extracted with ethyl acetate poured 1M hydrochloric acid to the reaction mixture. The organic layer was washed with water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 3/1) to give the title compound (1.06 g, yield 65%) as orange-green crystals.
1 H NMR (CDCl 3 , 400 MHz) δ: 2.92 (1H, d, J = 4 Hz), 6.29 (1H, d, J = 4 Hz), 6.90 (1H, d, J = 4 Hz), 7.46 (1H, d, J = 4Hz), 7.6-7.7 (3H, m), 7.80 (1H, d, J = 8Hz), 7.92 (1H, d, J = 7Hz) ), 8.02 (1H, d, J = 9Hz).

(2) 5- (1-Nitro-2-naphthoyl) thiophene-2-carbonitrile 5- [hydroxy (1-nitro-2-naphthyl) methyl] thiophene-2-carbonitrile (1.06 g, 3.41 mmol) Was dissolved in dry dichloromethane (10 mL) and silica gel (5 g) was added. Further, pyridinium dichromate (1.92 g, 5.12 mmol) was added and stirred for 18 hours. The resulting reaction mixture was filtered through Celite, and the filtrate was washed with chloroform. The filtrate was evaporated under reduced pressure, and the resulting crude product was recrystallized from ethyl acetate, washed with hexane, and dried to give the title compound (825 mg, yield 78%) as pale yellow crystals.
1 H NMR (CDCl 3 , 400 MHz) δ: 7.42 (1H, d, J = 4 Hz), 7.60 (1H, d, J = 4 Hz), 7.63 (1H, d, J = 9 Hz), 7.7-7.9 (2H, m), 8.04 (1H, dd, J = 2 Hz, 8 Hz), 8.18 (2H, d, J = 8 Hz).

(3) 5- (1-amino-2-naphthoyl) thiophene-2-carbonitrile 5- (1-nitro-2-naphthoyl) thiophene-2-carbonitrile (825 mg, 2.68 mmol) in acetic acid (15 mL), It was heated and dissolved at 65 ° C. in ethanol (15 mL) and water (1.5 mL). After allowing to cool to room temperature, iron powder (867 mg, 15.5 mmol) was added, and the mixture was again stirred at 65 ° C. for 1 hour. After allowing to cool, silica gel (5 g) was added and the mixture was filtered through Celite, and the residue was washed with ethyl acetate. After the obtained filtrate was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (745 mg, yield 100%) as an orange powder.
1 H NMR (CDCl 3 , 400 MHz) δ: 7.08 (1H, d, J = 9 Hz), 7.42 (2H, br s), 7.5-7.6 (2H, m), 7.6 -7.7 (2H, m), 7.72 (1H, d, J = 9Hz), 7.77 (1H, d, J = 8Hz), 7.96 (1H, d, J = 8Hz).

(4) 5- (5-Cyanothiophen-2-yl) -1,3-dihydronaphtho [1,2-e] -1,4-diazepin-2-one 5- (1-amino-2-naphthoyl) Thiophene-2-carbonitrile (695 mg, 2.50 mmol) was dissolved in pyridine (30 mL), glycine ethyl ester hydrochloride (523 mg, 3.75 mmol) was added, and the mixture was heated to reflux for 42 hours under a nitrogen atmosphere. After cooling, the residue was evaporated under reduced pressure and dissolved in chloroform. The insoluble material was filtered off, and the filtrate was washed with saturated aqueous sodium hydrogen carbonate and dried over anhydrous sodium sulfate. The residue concentrated under reduced pressure was subjected to silica gel column chromatography (ethyl acetate / hexane = 2/3) to give a brown oil as a crude product. Crystallization from ethyl acetate (10 mL) -methanol (3 mL) gave the title compound (293 mg, yield 37%).
1 H NMR (DMSO-d 6 , 400 MHz) δ: 3.86 (1H, d, J = 10 Hz), 4.53 (1H, d, J = 10 Hz), 7.28 (1H, d, J = 4 Hz) ), 7.6-7.8 (3H, m), 7.83 (1H, d, J = 9 Hz), 7.95 (1H, d, J = 4 Hz), 8.05 (1H, d, J = 7 Hz), 8.36 (1 H, d, J = 9 Hz), 10.93 (1 H, s).

(5) 5- [5- (1H-tetrazol-5-yl) thiophen-2-yl] -1,3-dihydronaphtho [1,2-e] -1,4-diazepin-2-one 5- ( 5-cyanothiophen-2-yl) -1,3-dihydronaphtho [1,2-e] -1,4-diazepin-2-one (150 mg, 0.473 mmol) in anhydrous toluene (2 mL) -anhydrous DMF ( To the solution, tri-n-butyltin azide (261 μL, 0.946 mmol) was added and stirred at 110 ° C. for 6 hours. After allowing to cool, the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and washed with chloroform. The aqueous layer was neutralized with 2M hydrochloric acid, extracted with chloroform, washed with purified water, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to chromatography (chloroform / methanol = 95/5) and recrystallized from ethyl acetate-methanol to give the title compound (62 mg, yield 36%) as fine brown crystals. Obtained.
1 H NMR (DMSO-d 6 , 400 MHz) δ: 3.84 (1H, d, J = 10 Hz), 4.50 (1H, d, J = 10 Hz), 7.21 (1H, d, J = 4 Hz) ), 7.61 (1H, d, J = 4 Hz), 7.6-7.8 (3H, m,), 7.84 (1H, d, J = 8 Hz), 8.0-8.1 ( 1H, m), 8.36 (1 H, d, J = 9 Hz), 10.84 (1 H, br s).

(6) 5- [5- (1H-tetrazol-5-yl) thiophen-2-yl] -1,3-dihydronaphtho [1,2-e] -1,4-diazepin-2-one sodium salt 5 -[5- (1H-tetrazol-5-yl) thiophen-2-yl] -1,3-dihydronaphtho [1,2-e] -1,4-diazepin-2-one (62 mg, 0.172 mmol) Sodium bicarbonate (14.5 mg, 0.172 mmol) was added to an ethanol (2 mL) and water (1 mL) solution, and the mixture was stirred at room temperature for 20 minutes. After concentration under reduced pressure, the residue was evaporated to dryness to give the title compound (64 mg, 97% yield) as a fine brown powder.
FAB-MS (m / z): 383 (M + 1)
1 H NMR (DMSO-d 6 , 400 MHz) δ: 3.77 (1H, d, J = 10 Hz), 4.46 (1H, d, J = 10 Hz), 7.07 (1H, d, J = 3 Hz) ), 7.37 (1H, d, J = 3 Hz), 7.6-7.9 (4H, m), 8.03 (1H, d, J = 8 Hz), 8.36 (1H, d, J = 8Hz), 10.78 (1H, s).
５－［１－メチル－２－（トリフルオロメチル）－１Ｈ－ベンズイミダゾール－６－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
（実施例１５のＡ）及び５－［１－メチル－２－（トリフルオロメチル）－１Ｈ－ベンズイミダゾール－５－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン（実施例１５のＢ）
　実施例８で得た５－［２－（トリフルオロメチル）－１Ｈ－ベンズイミダゾール－５－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン（１４ｍｇ，３４μｍｏｌ）をエタノール（２．８ｍＬ）に溶解し、炭酸水素ナトリウム（２．９ｍｇ，３４μｍｏｌ）の水溶液（０．３ｍＬ）に加えた。この混合溶液を減圧下濃縮し、真空乾燥して白色結晶を得た。この　ナトリウム塩（３４μｍｏｌ）を乾燥ジメチルホルムアミド（０．３ｍＬ）に溶解し、ヨウ化メチル（２１μＬ，０．３４ｍｍｏｌ）を加え、室温で４日間攪拌後、ヨウ化メチル（４２μＬ，０．６８ｍｍｏｌ）を加え、５０℃で一晩攪拌した。この反応混合物に冷水、及び２Ｍ塩酸を加え、酢酸エチルで抽出した。酢酸エチル層を飽和食塩水で洗い、無水硫酸ナトリウムで乾燥した。溶媒を減圧下留去し、残留物をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１／１－２／１）に処し、５－［１－メチル－２－（トリフルオロメチル）－１Ｈ－ベンズイミダゾール－６－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン （４ｍｇ、収率２６％）、及び ５－［１－メチル－２－（トリフルオロメチル）－１Ｈ－ベンズイミダゾール－５－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン（３ｍｇ、収率２１％）を得た。
５－［１－メチル－２－（トリフルオロメチル）－１Ｈ－ベンズイミダゾール－６－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：３．６５（２Ｈ，ｓ），３．８８（３Ｈ，ｓ），７．０１（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．１９（１Ｈ，ｄ，Ｊ＝８Ｈｚ），７．４３（１Ｈ，ｓ），７．５－７．７（２Ｈ，ｍ，），７．７３（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．８－７．９（２Ｈ，ｍ），８．１１（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．５６（１Ｈ，ｓ）．
５－［１－メチル－２－（トリフルオロメチル）－１Ｈ－ベンズイミダゾール－５－イル］－１Ｈ－ナフト［１，２－ｂ］［１，４］ジアゼピン－２，４（３Ｈ，５Ｈ）－ジオン
１Ｈ　ＮＭＲ（ＣＤＣｌ３，４００ＭＨｚ）δ：３．６５（２Ｈ，ｓ），３．９５（３Ｈ，ｓ），７．００（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．３１（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．４５（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．５４（１Ｈ，ｄ，Ｊ＝９Ｈｚ），７．６０（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．７１（１Ｈ，ｔ，Ｊ＝８Ｈｚ），７．８０（１Ｈ，ｓ），７．８３（１Ｈ，ｄ，Ｊ＝８Ｈｚ），８．１２（１Ｈ，ｄ，Ｊ＝９Ｈｚ），８．６７（１Ｈ，ｓ）．
 5- [1-Methyl-2- (trifluoromethyl) -1H-benzimidazol-6-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -Dione (A in Example 15) and 5- [1-methyl-2- (trifluoromethyl) -1H-benzimidazol-5-yl] -1H-naphtho [1,2-b] [1,4] Diazepine-2,4 (3H, 5H) -dione (Example 15B)
5- [2- (Trifluoromethyl) -1H-benzimidazol-5-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, obtained in Example 8) 5H) -dione (14 mg, 34 μmol) was dissolved in ethanol (2.8 mL) and added to an aqueous solution (0.3 mL) of sodium bicarbonate (2.9 mg, 34 μmol). The mixed solution was concentrated under reduced pressure and dried under vacuum to obtain white crystals. This sodium salt (34 μmol) was dissolved in dry dimethylformamide (0.3 mL), methyl iodide (21 μL, 0.34 mmol) was added, and after stirring at room temperature for 4 days, methyl iodide (42 μL, 0.68 mmol) was added. In addition, the mixture was stirred at 50 ° C. overnight. Cold water and 2M hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (ethyl acetate / hexane = 1 / 1-2 / 1) to give 5- [1-methyl-2- (trifluoromethyl) -1H-benzen. Imidazol-6-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione (4 mg, 26% yield), and 5- [1-methyl -2- (Trifluoromethyl) -1H-benzimidazol-5-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -dione (3 mg, yield) 21%) was obtained.
5- [1-Methyl-2- (trifluoromethyl) -1H-benzimidazol-6-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -Zeon
1 H NMR (CDCl 3 , 400 MHz) δ: 3.65 (2H, s), 3.88 (3H, s), 7.01 (1H, d, J = 9 Hz), 7.19 (1H, d, J = 8 Hz), 7.43 (1H, s), 7.5-7.7 (2H, m,), 7.73 (1H, t, J = 8 Hz), 7.8-7.9 (2H) M), 8.11 (1H, d, J = 8 Hz), 8.56 (1H, s).
5- [1-Methyl-2- (trifluoromethyl) -1H-benzimidazol-5-yl] -1H-naphtho [1,2-b] [1,4] diazepine-2,4 (3H, 5H) -Zeon
1 H NMR (CDCl 3 , 400 MHz) δ: 3.65 (2H, s), 3.95 (3H, s), 7.00 (1H, d, J = 9 Hz), 7.31 (1H, d, J = 9 Hz), 7.45 (1H, d, J = 9 Hz), 7.54 (1H, d, J = 9 Hz), 7.60 (1H, t, J = 8 Hz), 7.71 (1H, t, J = 8 Hz), 7.80 (1H, s), 7.83 (1H, d, J = 8 Hz), 8.12 (1H, d, J = 9 Hz), 8.67 (1H, s) .
（試験方法）
本発明化合物のＰ２Ｘ４受容体拮抗作用を、以下のように測定した。
ヒトＰ２Ｘ４受容体を安定発現させた１３２１Ｎ１細胞を９６ウェルプレートに播種し、３７℃、５％ＣＯ２条件下で２４時間培養して細胞内カルシウム測定に使用した。細胞内カルシウムの測定にはカルシウム蛍光指示薬であるＦｕｒａ－２　ＡＭを用いた。アッセイバッファーに溶解させたＦｕｒａ－２　ＡＭを細胞に添加し、室温で45分間静置して細胞内に取り込ませた後、プレートを蛍光測定に供した。被験物質はＡＴＰ添加１５分前に細胞に処置し、ＡＴＰ添加によって誘発される細胞内カルシウム流入応答をマイクロプレートリーダーを用いて経時的に測定した。励起光３４０ｎｍと３８０ｎｍでのそれぞれの蛍光値の比を細胞内カルシウム変化の指標とし、被験物質非存在下（コントロール）との比較により被検物質の阻害活性を算出した。

試験結果を表７に記載する。
（試験結果） (Test method)
The P2X 4 receptor antagonism of the compounds of the present invention was measured as follows.
The 1321N1 cells were stably expressing human P2X 4 receptor were seeded in 96-well plates, 37 ° C., it was used for intracellular calcium measured incubated for 24 hours under 5% CO 2. For measurement of intracellular calcium, Fura-2 AM, which is a calcium fluorescent indicator, was used. Fura-2 AM dissolved in assay buffer was added to the cells, allowed to stand at room temperature for 45 minutes to be taken into the cells, and then the plate was subjected to fluorescence measurement. Test substances were treated in cells 15 minutes before the addition of ATP, and the intracellular calcium influx response induced by the addition of ATP was measured over time using a microplate reader. The ratio of the respective fluorescence values at excitation light of 340 nm and 380 nm was used as an index of intracellular calcium change, and the inhibitory activity of the test substance was calculated by comparison with the absence of the test substance (control).

The test results are listed in Table 7.
(Test results)
Figure JPOXMLDOC01-appb-T000030
Figure JPOXMLDOC01-appb-T000030
表７記載のとおり実施例記載の本発明化合物は、優れたＰ２Ｘ４受容体拮抗作用を有することが判明した。 Table 7 compounds of the invention as described in Examples described, were found to have excellent P2X 4 receptor antagonism.
実施例１６と同様な方法で、実施例１５記載の本発明化合物のＰ２Ｘ４受容体拮抗作用を測定し、その結果を表８に示す。 In the same manner as in Example 16, to measure the P2X 4 receptor antagonism of the present invention the compound of Example 15, the results are shown in Table 8.
Figure JPOXMLDOC01-appb-T000031
Figure JPOXMLDOC01-appb-T000031
表８記載のとおり実施例記載の本発明化合物は、優れたＰ２Ｘ４受容体拮抗作用を有することが判明した。 Table 8 compound of the invention as described in Examples described, were found to have excellent P2X 4 receptor antagonism.

Claims (17)

  1. 　次の一般式（Ｉ）、
    Figure JPOXMLDOC01-appb-C000001
    （式中、Ｒ１は水素原子、炭素数１～８のアルキル基、炭素数２～８のアルケニル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、 １～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、炭素数２～８のアシルアミノ基、 １～３個のハロゲン原子で置換された炭素数２～８のアシルアミノ基、炭素数１～８のアルキルスルホニルアミノ基、カルボキシル基、炭素数２～８のアシル基、アルコキシカルボニル基（アルコキシ部分の炭素数は１～８。）、カルバモイル基、炭素数１～８のアルキルチオ基、炭素数１～８のアルキルスルフィニル基、炭素数１～８のアルキルスルホニル基、又はスルファモイル基を表し、
    　Ｒ２は水素原子、炭素数１～８のアルキル基、炭素数２～８のアルケニル基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基又はフェニル基で置換された炭素数１～３のアルキル基を表し、
    　Ｒ３及びＲ４は同一又は異なっていてもよく水素原子、炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、又はフェニル基で置換された炭素数１～３のアルキル基を表し、
    　Ｒ５は水素原子、炭素数１～８のアルキル基、炭素数２～８のアルケニル基、炭素数１～８のアルコキシ基、 １～３個のハロゲン原子で置換された炭素数１～８のアルキル基、１～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、１～５個のハロゲン原子で置換された炭素数１～５のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、炭素数２～８のアシルアミノ基、１～３個のハロゲン原子で置換された炭素数２～８のアシルアミノ基、炭素数１～８のアルキルスルホニルアミノ基、カルボキシル基、炭素数２～８のアシル基、アルコキシカルボニル基（アルコキシ部分の炭素数は１～８。）、カルバモイル基、炭素数１～８のアルキルチオ基、炭素数１～８のアルキルスルフィニル基、炭素数１～８のアルキルスルホニル基、スルファモイル基、置換基を有していても良いフェニル基、又は置換基を有していても良い複素環基を表し、ＸはＣまたはＮを表し
    Figure JPOXMLDOC01-appb-C000002
    は、チオフェン環、ピリジン環、ピリミジン環、キノリン環、インドール環、インドリン環、ベンズイミダゾール環、インダゾール環、ベンズイソキサゾール環及びベンズトリアゾール環から選択される複素環を表し、そして、複素環の環を構成する炭素原子を介してＸと結合している。
    ＺはＯ又はＳを表し、
    　そして、ＸがＮの時、ＹはＣ＝Ｏ又はＣ＝Ｓで、かつ実線と波線からなる二重線は単結合を表し
    　ＸがＣの時、ＹはＮで、かつ実線と波線からなる二重線は二重結合を表す。）
    　で表されるジアゼピン誘導体又はその薬理学的に許容される塩。     The following general formula (I),
    Figure JPOXMLDOC01-appb-C000001
    (Wherein R 1 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or the number of carbon atoms substituted by 1 to 3 halogen atoms. An alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms Group, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and an alkylsulfonylamino group having 1 to 8 carbon atoms Group, carboxyl group, acyl group having 2 to 8 carbon atoms, alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), carbamoyl group, alkylthio group having 1 to 8 carbon atoms, alkylsulfur group having 1 to 8 carbon atoms Group, an alkylsulfonyl group having 1 to 8 carbon atoms, or a sulfamoyl group,
    R 2 is substituted with a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or a phenyl group Represents an alkyl group having 1 to 3 carbon atoms,
    R 3 and R 4 may be the same or different, and may be a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, or a hydroxyl group. , A nitro group, a cyano group, an amino group, or an alkyl group having 1 to 3 carbon atoms substituted with a phenyl group,
    R 5 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. An alkyl group, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, 1 to C1-C5 alkylamino group substituted with 5 halogen atoms, C2-C8 dialkylamino group, C2-C8 acylamino group, carbon substituted with 1-3 halogen atoms An acylamino group having 2 to 8 carbon atoms, an alkylsulfonylamino group having 1 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxy group has 1 to 8 carbon atoms), a carbamoyl group, An alkylthio group having 1 to 8 carbon atoms, an alkylsulfinyl group having 1 to 8 carbon atoms, an alkylsulfonyl group having 1 to 8 carbon atoms, a sulfamoyl group, an optionally substituted phenyl group, or a substituent. And X represents C or N.
    Figure JPOXMLDOC01-appb-C000002
    Represents a heterocyclic ring selected from thiophene ring, pyridine ring, pyrimidine ring, quinoline ring, indole ring, indoline ring, benzimidazole ring, indazole ring, benzisoxazole ring and benztriazole ring, and It is bonded to X through a carbon atom constituting the ring.
    Z represents O or S;
    When X is N, Y is C = O or C = S, and a double line consisting of a solid line and a wavy line represents a single bond. When X is C, Y is N and consists of a solid line and a wavy line The double line represents a double bond. )
    Or a pharmacologically acceptable salt thereof.
  2. 　Ｒ１が水素原子、炭素数１～８のアルキル基、炭素数１～８のアルコキシ基、１～３個のハロゲン原子で置換された炭素数１～８のアルキル基、 １～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、炭素数２～８のアシルアミノ基又は １～３個のハロゲン原子で置換された炭素数２～８のアシルアミノ基である請求項１記載のジアゼピン誘導体又はその薬理学的に許容される塩。 R 1 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, 1 to 3 halogen atoms C1-C8 alkoxy groups substituted with atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, C1-C8 alkylamino groups, C2-C8 dialkylamino groups, carbon The diazepine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is an acylamino group having 2 to 8 carbon atoms or an acylamino group having 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms.
  3. 　Ｒ２が水素原子、炭素数１～８のアルキル基、又は １～３個のハロゲン原子で置換された炭素数１～８のアルキル基である請求項１又は２の何れかの項に記載のジアゼピン誘導体又はその薬理学的に許容される塩。 The R 2 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. A diazepine derivative or a pharmacologically acceptable salt thereof.
  4. 　Ｒ３及びＲ４が同一又は異なっていてもよく水素原子、炭素数１～８のアルキル基、 １～３個のハロゲン原子で置換された炭素数１～８のアルキル基である請求項１～３の何れかの項に記載のジアゼピン誘導体又はその薬理学的に許容される塩。 R 3 and R 4 may be the same or different and are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. 4. The diazepine derivative or a pharmacologically acceptable salt thereof according to any one of items 3.
  5. 　Ｒ５が水素原子、炭素数１～８のアルキル基、炭素数２～８のアルケニル基、炭素数１～８のアルコキシ基、 １～３個のハロゲン原子で置換された炭素数１～８のアルキル基、 １～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、又は置換基を有していても良い複素環基である請求項１～４の何れかの項に記載のジアゼピン誘導体又はその薬理学的に許容される塩。 R 5 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. Alkyl group, alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, alkylamino group having 1 to 8 carbon atoms, carbon number The diazepine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is a dialkylamino group having 2 to 8 or a heterocyclic group which may have a substituent.
  6. 　Ｒ５が炭素数１～８のアルキル基、炭素数１～８のアルコキシ基、 １～３個のハロゲン原子で置換された炭素数１～８のアルキル基、 １～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基及び炭素数２～８のジアルキルアミノ基から選択される置換基を有していても良いテトラゾリル基、トリアゾリル基、イミダゾリル基、オキサゾリル基又はチアゾリル基である請求項１～４の何れかの項に記載のジアゼピン誘導体又はその薬理学的に許容される塩。 R 5 is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and substituted with 1 to 3 halogen atoms Substituted selected from alkoxy groups having 1 to 8 carbon atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, alkylamino groups having 1 to 8 carbon atoms and dialkylamino groups having 2 to 8 carbon atoms The diazepine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 4, which is a tetrazolyl group, triazolyl group, imidazolyl group, oxazolyl group or thiazolyl group which may have a group.
  7. 　Ｒ５が水素原子、炭素数１～８のアルキル基、炭素数１～８のアルコキシ基、 １～３個のハロゲン原子で置換された炭素数１～８のアルキル基、 １～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基又はヒドロキシル基である請求項１～４の何れかの項に記載のジアゼピン誘導体又はその薬理学的に許容される塩。 R 5 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or 1 to 3 halogen atoms. The diazepine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is an alkoxy group having 1 to 8 carbon atoms or a hydroxyl group substituted with an atom.
  8. 　ＺがＯである請求項１～７記載のジアゼピン誘導体又はその薬理学的に許容される塩。 The diazepine derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein Z is O.
  9. 　次の一般式（ＩＩ）、
    Figure JPOXMLDOC01-appb-C000003
    （式中、Ｒ１１は水素原子、炭素数１～８のアルキル基、炭素数２～８のアルケニル基、炭素数１～８のアルコキシ基、 １～３個のハロゲン原子で置換された炭素数１～８のアルキル基、 １～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、炭素数２～８のアシルアミノ基、 １～３個のハロゲン原子で置換された炭素数２～８のアシルアミノ基、炭素数１～８のアルキルスルホニルアミノ基、カルボキシル基、炭素数２～８のアシル基、アルコキシカルボニル基（アルコキシ部分の炭素数は１～８。）、カルバモイル基、炭素数１～８のアルキルチオ基、炭素数１～８のアルキルスルフィニル基、炭素数１～８のアルキルスルホニル基、又はスルファモイル基を表し、
    　Ｒ１３及びＲ１４は同一又は異なっていてもよく水素原子、炭素数１～８のアルキル基、 １～３個のハロゲン原子で置換された炭素数１～８のアルキル基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、又はフェニル基で置換された炭素数１～３のアルキル基を表し、
    　Ｒ１５は水素原子、炭素数１～８のアルキル基、炭素数２～８のアルケニル基、炭素数１～８のアルコキシ基、 １～３個のハロゲン原子で置換された炭素数１～８のアルキル基、 １～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、１～５個のハロゲン原子で置換された炭素数１～５のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、炭素数２～８のアシルアミノ基、 １～３個のハロゲン原子で置換された炭素数２～８のアシルアミノ基、炭素数１～８のアルキルスルホニルアミノ基、カルボキシル基、炭素数２～８のアシル基、アルコキシカルボニル基（アルコキシ部分の炭素数は１～８。）、カルバモイル基、炭素数１～８のアルキルチオ基、炭素数１～８のアルキルスルフィニル基、炭素数１～８のアルキルスルホニル基、スルファモイル基、置換基を有していても良いフェニル基、又は置換基を有していても良い複素環基を表し、
    そして、
    Figure JPOXMLDOC01-appb-C000004
    は、チオフェン環、ピリジン環、ピリミジン環、キノリン環、インドール環、インドリン環、ベンズイミダゾール環、インダゾール環、ベンズイソキサゾール環及びベンズトリアゾール環から選択される複素環を表し、そして、複素環の環を構成する炭素原子を介してＸと結合している。）

    　で表されるジアゼピン誘導体又はその薬理学的に許容される塩。     The following general formula (II),
    Figure JPOXMLDOC01-appb-C000003
    (Wherein R 11 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or the number of carbon atoms substituted by 1 to 3 halogen atoms. An alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms Group, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and an alkylsulfonylamino group having 1 to 8 carbon atoms Group, carboxyl group, acyl group having 2 to 8 carbon atoms, alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), carbamoyl group, alkylthio group having 1 to 8 carbon atoms, alkylsulfur group having 1 to 8 carbon atoms Represents a finyl group, an alkylsulfonyl group having 1 to 8 carbon atoms, or a sulfamoyl group,
    R 13 and R 14 may be the same or different, and may be a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, or a hydroxyl group. , A nitro group, a cyano group, an amino group, or an alkyl group having 1 to 3 carbon atoms substituted with a phenyl group,
    R 15 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. An alkyl group, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, 1 to An alkylamino group having 1 to 5 carbon atoms substituted with 5 halogen atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, and a carbon substituted with 1 to 3 halogen atoms An acylamino group having 2 to 8 carbon atoms, an alkylsulfonylamino group having 1 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the carbon number of the alkoxy moiety is 1 to 8), a carbamoyl group An alkylthio group having 1 to 8 carbon atoms, an alkylsulfinyl group having 1 to 8 carbon atoms, an alkylsulfonyl group having 1 to 8 carbon atoms, a sulfamoyl group, an optionally substituted phenyl group, or a substituent. Represents an optionally substituted heterocyclic group,
    And
    Figure JPOXMLDOC01-appb-C000004
    Represents a heterocyclic ring selected from thiophene ring, pyridine ring, pyrimidine ring, quinoline ring, indole ring, indoline ring, benzimidazole ring, indazole ring, benzisoxazole ring and benztriazole ring, and It is bonded to X through a carbon atom constituting the ring. )

    Or a pharmacologically acceptable salt thereof.
  10. 　Ｒ１１が水素原子、炭素数１～８のアルキル基、炭素数１～８のアルコキシ基、 １～３個のハロゲン原子で置換された炭素数１～８のアルキル基、 １～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、炭素数２～８のアシルアミノ基又は １～３個のハロゲン原子で置換された炭素数２～８のアシルアミノ基である請求項９記載のジアゼピン誘導体又はその薬理学的に許容される塩。 R 11 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, 1 to 3 halogen atoms C1-C8 alkoxy groups substituted with atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, C1-C8 alkylamino groups, C2-C8 dialkylamino groups, carbon The diazepine derivative or a pharmacologically acceptable salt thereof according to claim 9, which is an acylamino group having 2 to 8 carbon atoms or an acylamino group having 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms.
  11. 　Ｒ１１が水素原子、炭素数１～８のアルキル基、炭素数１～８のアルコキシ基、 １～３個のハロゲン原子で置換された炭素数１～８のアルキル基、 １～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基又はハロゲン原子である請求項９記載のジアゼピン誘導体又はその薬理学的に許容される塩。 R 11 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, 1 to 3 halogen atoms The diazepine derivative or a pharmaceutically acceptable salt thereof according to claim 9, which is an alkoxy group having 1 to 8 carbon atoms substituted by an atom or a halogen atom.
  12. 　Ｒ１３及びＲ１４が同一又は異なっていてもよく水素原子、炭素数１～８のアルキル基、 １～３個のハロゲン原子で置換された炭素数１～８のアルキル基である請求項９～１１の何れかの項に記載のジアゼピン誘導体又はその薬理学的に許容される塩。 R 13 and R 14 may be the same or different and each is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. 12. The diazepine derivative or a pharmacologically acceptable salt thereof according to any one of items 11.
  13. 　Ｒ１５が水素原子、炭素数１～８のアルキル基、炭素数２～８のアルケニル基、炭素数１～８のアルコキシ基、 １～３個のハロゲン原子で置換された炭素数１～８のアルキル基、 １～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基、炭素数２～８のジアルキルアミノ基、又は置換基を有していても良い複素環基である請求項９～１２の何れかの項に記載のジアゼピン誘導体又はその薬理学的に許容される塩。 R 15 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. Alkyl group, alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, alkylamino group having 1 to 8 carbon atoms, carbon number The diazepine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 12, which is a dialkylamino group of 2 to 8 or a heterocyclic group which may have a substituent.
  14. 　Ｒ１５が炭素数１～８のアルキル基、炭素数１～８のアルコキシ基、 １～３個のハロゲン原子で置換された炭素数１～８のアルキル基、 １～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基、ハロゲン原子、ヒドロキシル基、ニトロ基、シアノ基、アミノ基、炭素数１～８のアルキルアミノ基及び炭素数２～８のジアルキルアミノ基から選択される置換基を有していても良いテトラゾリル基、トリアゾリル基、イミダゾリル基、オキサゾリル基又はチアゾリル基である請求項９～１２の何れかの項に記載のジアゼピン誘導体又はその薬理学的に許容される塩。 R 15 is an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and substituted with 1 to 3 halogen atoms Substituted from an alkoxy group having 1 to 8 carbon atoms, halogen atom, hydroxyl group, nitro group, cyano group, amino group, alkylamino group having 1 to 8 carbon atoms and dialkylamino group having 2 to 8 carbon atoms The diazepine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 12, which is a tetrazolyl group, a triazolyl group, an imidazolyl group, an oxazolyl group or a thiazolyl group, which may have a group.
  15. 　Ｒ１５が水素原子、炭素数１～８のアルキル基、炭素数１～８のアルコキシ基、 １～３個のハロゲン原子で置換された炭素数１～８のアルキル基、 １～３個のハロゲン原子で置換された炭素数１～８のアルコキシ基又はヒドロキシル基である請求項９～１２の何れかの項に記載のジアゼピン誘導体又はその薬理学的に許容される塩。 R 15 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or 1 to 3 halogen atoms. The diazepine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 9 to 12, which is an alkoxy group having 1 to 8 carbon atoms or a hydroxyl group substituted with an atom.
  16. 　請求項１～１５の何れかの項に記載のジアゼピン誘導体又はその薬理学的に許容される塩を有効成分として含有するＰ２Ｘ４受容体拮抗剤。 Diazepine derivatives or P2X 4 receptor antagonist containing a pharmacologically acceptable salt thereof as an active ingredient according to any one of claims 1 to 15.
  17. 　請求項１～１５の何れかの項に記載のジアゼピン誘導体又はその薬理学的に許容される塩を有効成分として含有する神経因性疼痛の予防又は治療剤。 A preventive or therapeutic agent for neuropathic pain comprising the diazepine derivative or a pharmacologically acceptable salt thereof according to any one of claims 1 to 15 as an active ingredient.
PCT/JP2011/066652 2010-07-23 2011-07-22 P2x4 receptor antagonist WO2012011549A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2010165607A JP2013209292A (en) 2010-07-23 2010-07-23 P2x4 receptor antagonist
JP2010-165607 2010-07-23

Publications (1)

Publication Number Publication Date
WO2012011549A1 true WO2012011549A1 (en) 2012-01-26

Family

ID=45496967

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2011/066652 WO2012011549A1 (en) 2010-07-23 2011-07-22 P2x4 receptor antagonist

Country Status (2)

Country Link
JP (1) JP2013209292A (en)
WO (1) WO2012011549A1 (en)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013105608A1 (en) * 2012-01-13 2013-07-18 日本ケミファ株式会社 P2x4 receptor antagonist
WO2015005468A1 (en) 2013-07-12 2015-01-15 日本ケミファ株式会社 P2x4 receptor antagonist
WO2015005467A1 (en) 2013-07-12 2015-01-15 日本ケミファ株式会社 P2x4 receptor antagonist
EP3132803A3 (en) * 2010-11-05 2017-04-26 Kyushu University Preventive or therapeutic agent for pain associated with herpes zoster in acute phase
WO2017188365A1 (en) * 2016-04-28 2017-11-02 日本ケミファ株式会社 Medicine for treating multiple sclerosis

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051274A2 (en) * 2001-12-14 2003-06-26 Astrazeneca Ab Benzodiazepine derivatives, preparation thereof and use thereof
WO2003082832A2 (en) * 2002-03-28 2003-10-09 Wisys Technology Foundation, Inc. Anxiolytic agents with reduced sedative and ataxic effects
WO2008023847A1 (en) * 2006-08-25 2008-02-28 Nippon Chemiphar Co., Ltd. P2x4 receptor antagonist

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051274A2 (en) * 2001-12-14 2003-06-26 Astrazeneca Ab Benzodiazepine derivatives, preparation thereof and use thereof
WO2003082832A2 (en) * 2002-03-28 2003-10-09 Wisys Technology Foundation, Inc. Anxiolytic agents with reduced sedative and ataxic effects
WO2008023847A1 (en) * 2006-08-25 2008-02-28 Nippon Chemiphar Co., Ltd. P2x4 receptor antagonist

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
QI HUANG ET AL.: "Benzo-fused Benzodiazepines Employed as Topological Probes for the Study of Benzodiazepine Receptor Subtypes", MED. CHEM. RES., vol. 6, no. 6, 1996, pages 384 - 391, XP009013214 *

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3132803A3 (en) * 2010-11-05 2017-04-26 Kyushu University Preventive or therapeutic agent for pain associated with herpes zoster in acute phase
US9969700B2 (en) 2012-01-13 2018-05-15 Nippon Chemiphar Co., Ltd. P2X4 receptor antagonist
CN104066724A (en) * 2012-01-13 2014-09-24 日本化学药品株式会社 P2X4 receptor antagonist
US12116351B2 (en) 2012-01-13 2024-10-15 Nippon Chemiphar Co., Ltd P2X4 receptor antagonist
US11434207B2 (en) 2012-01-13 2022-09-06 Nippon Chemiphar Co., Ltd P2X4 receptor antagonist
EP2803662A4 (en) * 2012-01-13 2015-06-03 Nippon Chemiphar Co ANTAGONIST OF P2X4 RECEPTORS
US9382236B2 (en) 2012-01-13 2016-07-05 Nippon Chemiphar Co., Ltd P2X4 receptor antagonist
WO2013105608A1 (en) * 2012-01-13 2013-07-18 日本ケミファ株式会社 P2x4 receptor antagonist
US10633349B2 (en) 2012-01-13 2020-04-28 Nippon Chemiphar Co., Ltd P2X4 receptor antagonist
CN104066724B (en) * 2012-01-13 2020-04-17 日本化学药品株式会社 P2X4 receptor antagonists
JPWO2015005467A1 (en) * 2013-07-12 2017-03-02 日本ケミファ株式会社 P2X4 receptor antagonist
JPWO2015005468A1 (en) * 2013-07-12 2017-03-02 日本ケミファ株式会社 P2X4 receptor antagonist
JP2018172431A (en) * 2013-07-12 2018-11-08 日本ケミファ株式会社 P2X4 receptor antagonist
US10150744B2 (en) 2013-07-12 2018-12-11 Nippon Chemiphar Co., Ltd P2X4 receptor antagonist
US9873683B2 (en) 2013-07-12 2018-01-23 Nippon Chemiphar Co., Ltd P2X4 receptor antagonist
WO2015005468A1 (en) 2013-07-12 2015-01-15 日本ケミファ株式会社 P2x4 receptor antagonist
EP3564217A1 (en) * 2013-07-12 2019-11-06 Nippon Chemiphar Co., Ltd. P2x4 receptor antagonist
US10472333B2 (en) 2013-07-12 2019-11-12 Nippon Chemiphar Co., Ltd. P2X4 receptor antagonist
WO2015005467A1 (en) 2013-07-12 2015-01-15 日本ケミファ株式会社 P2x4 receptor antagonist
CN109414503A (en) * 2016-04-28 2019-03-01 日本化学药品株式会社 The pharmaceuticals for the treatment of for multiple sclerosis
JP7116679B2 (en) 2016-04-28 2022-08-10 日本ケミファ株式会社 Medicine for the treatment of multiple sclerosis
WO2017188365A1 (en) * 2016-04-28 2017-11-02 日本ケミファ株式会社 Medicine for treating multiple sclerosis
US11918589B2 (en) 2016-04-28 2024-03-05 Nippon Chemiphar Co., Ltd. Medicament for treatment of multiple sclerosis
JPWO2017188365A1 (en) * 2016-04-28 2019-04-04 日本ケミファ株式会社 Medicinal agents for the treatment of multiple sclerosis

Also Published As

Publication number Publication date
JP2013209292A (en) 2013-10-10

Similar Documents

Publication Publication Date Title
US12077521B2 (en) Pyrazole derivatives as MALT1 inhibitors
KR101890441B1 (en) P2x4 receptor antagonist
AU2014288115C1 (en) P2X4 receptor antagonist
JP5592278B2 (en) Diazepinedione derivatives
KR101890442B1 (en) P2x4 receptor antagonist
WO2015005468A1 (en) P2x4 receptor antagonist
KR20140116926A (en) P2X4 receptor antagonist
CN103201270B (en) P2x4 receptor antagonist
CZ20012551A3 (en) Triazole compounds and use thereof
CN107922350B (en) Novel benzimidazole compounds and their medicinal uses
WO2012011549A1 (en) P2x4 receptor antagonist
JP2022163241A (en) P2X4 receptor antagonist
US20070049582A1 (en) Substituted-3-indolyl-4-piperidino-alkyl heterocycles for the treatment of depression

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11809719

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11809719

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: JP