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WO2010090300A1 - Dérivés de diazépinedione - Google Patents

Dérivés de diazépinedione Download PDF

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Publication number
WO2010090300A1
WO2010090300A1 PCT/JP2010/051740 JP2010051740W WO2010090300A1 WO 2010090300 A1 WO2010090300 A1 WO 2010090300A1 JP 2010051740 W JP2010051740 W JP 2010051740W WO 2010090300 A1 WO2010090300 A1 WO 2010090300A1
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WO
WIPO (PCT)
Prior art keywords
group
carbon atoms
hydrogen atom
acceptable salt
alkyl group
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2010/051740
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English (en)
Japanese (ja)
Inventor
佐久間詔悟
遠藤剛
高橋俊弘
今井利安
津田誠
井上和秀
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Nippon Chemiphar Co Ltd
Original Assignee
Nippon Chemiphar Co Ltd
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Filing date
Publication date
Application filed by Nippon Chemiphar Co Ltd filed Critical Nippon Chemiphar Co Ltd
Publication of WO2010090300A1 publication Critical patent/WO2010090300A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
    • C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
    • C07D243/10—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to di-azepine-dione derivatives having a 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 1-7
  • P2Y 1, 2, 4, 6 the P2Y 1, 2, 4, 6
  • 11-14 subtypes have been reported.
  • the P2X 4 receptor (Genebank No. X87763), a subtype of the P2X family, has been reported to be widely expressed in the central nervous system and the like.
  • Non-Patent Document 1 Buell et al. (1996) EMBO J. 15: 55-62
  • Non-Patent Document 2 Seguela et al. (1996) J. Neurosci. 16: 448-455; (1995) FEBS Lett.
  • Non-patent document 4 Soto et al. (1996) Proc Natl. Acad.Sci.USA 93: 3684-3788; Non-patent document 5: Wang et al. (1996) Biochem.Res.Commun. 220: 196-202)
  • NSAIDs non-steroidal anti-inflammatory drugs
  • 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.
  • 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.
  • 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 (WO 2004/085440) includes the following general formula (A), (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 )
  • the present inventors also have the following general formula (B) (Wherein R 11 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms, and R 21 represents an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom having 1 to 3 carbon atoms) And represents an alkyl group having 1 to 8 carbon atoms or a hydroxyl group substituted with R 31 , and R 31 represents a hydrogen atom or a halogen atom.)
  • R 11 represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms
  • R 21 represents an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, or a halogen atom having 1 to 3 carbon atoms
  • R 31 represents a hydrogen atom or a halogen atom.
  • Patent Document 3 WO 2008/023847
  • Patent Document 4 JP-A-2-304437
  • Patent Document 4 JP-A-2-304437
  • Patent Document 4 there is a description that the compound represented by the above formula (C) is used as the photographic couplers, but no description suggesting the relationship between these drugs and P2X 4 receptor antagonism .
  • An object of the present invention is to provide a di-azepine-dione derivative represented by the following general formula with a P2X 4 receptor antagonism (I). That is, the present invention provides the following general formula (I), (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 alkyl group having 1 to 8 carbon atoms substituted with a halogen atom having 1 to 3 carbon atoms, or a phenyl group.
  • R 2 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 a halogen atom having 1 to 3 carbon atoms.
  • R 4 and R 5 may be the same or different and each represents 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 a pharmacologically acceptable salt thereof.
  • the present invention relates to P2X 4 receptor antagonist containing acceptable salt compound represented by or its pharmacologically by the general formula (I) as an active ingredient. Furthermore, this invention relates to the preventive or therapeutic agent of neuropathic pain which contains the compound represented with the said general formula (I), or its pharmacologically acceptable salt 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 include an allyl group.
  • Examples of the alkoxy group having 1 to 8 carbon atoms of R 2 and R 3 include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, i-butoxy group, t-butoxy group, pentyloxy group or hexyloxy group Etc.
  • Examples of the halogen atom for R 2 and R 3 include a fluorine atom, a chlorine atom, or a bromine atom.
  • 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, bromine atoms, etc.
  • 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 preferably trifluoromethyl group, chloromethyl group, 2-chloroethyl group, 2-bromoethyl. Group or 2-fluoroethyl group.
  • Examples of the alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms of R 2 and R 3 include a methyl group substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom or a bromine atom , Ethyl group, propyl group, isopropyl group, butyl group or t-butyl group, preferably trifluoromethoxy group, chloromethoxy group, 2-chloroethoxy group, 2-bromoethoxy group or 2-fluoroethoxy group Etc.
  • Examples of the acyl group for R 2 and R 3 include an acetyl group.
  • Examples of the alkoxycarbonyl group for R 2 and R 3 include a methoxycarbonyl group and an ethoxycarbonyl group.
  • Examples of the alkyl group having 1 to 3 carbon atoms substituted by the phenyl group of R 1 include a benzyl group.
  • Examples of the alkylamino group having 1 to 8 carbon atoms of R 2 include a methylamino group and an ethylamino group.
  • examples of the dialkylamino group having 1 to 8 carbon atoms of R 2 include a dimethylamino group and a diethylamino group.
  • Examples of the acylamino group having 2 to 8 carbon atoms for R 2 include an acetylamino group. Examples of the acylamino group having 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms of R 2 include a trifluoromethylcarbonylamino group. Examples of the alkylsulfonylamino group having 1 to 8 carbon atoms of R 2 include a methylsulfonylamino group. Examples of the alkylthio group having 1 to 8 carbon atoms of R 2 include a methylthio group. Examples of the alkylsulfinyl group having 1 to 8 carbon atoms of R 2 include a methylsulfinyl group.
  • alkylsulfonyl group having 1 to 8 carbon atoms of R 2 examples include a methylsulfonyl group.
  • R 2 and R 3 may be present in the same or different benzene rings substituted by R 2 and R 3 .
  • the compound of the present invention represented by the general formula (I) the following compounds are preferred.
  • R 4 and R 5 are both hydrogen atoms.
  • R 3 is a hydrogen atom
  • examples of the pharmacologically acceptable salt of the compound represented by the general formula (I) include hydrochloride and the like when R 2 and R 3 are amino groups.
  • alkali metal salts such as sodium, potassium and lithium are exemplified.
  • 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 represented by the general formula (d) is obtained by converting the compound represented by the general formula (c) into iron, stannous chloride, zinc, or palladium in a solvent that does not participate in the reaction such as THF, methanol, chloroform, and acetic acid. -It can be obtained by reduction by catalytic addition using carbon or the like as a catalyst.
  • the compound of the present invention represented by the general formula (f) is a compound represented by the general formula (d) and the general formula (d) in a solvent such as toluene and THF in the presence or absence of a base. It can be obtained by reacting the compound represented by e).
  • this invention compound represented by the said general formula (I) can also be manufactured with reference to the said patent document and well-known literature other than the Example of a postscript.
  • Examples of the compound of the present invention thus obtained are shown in Tables 1 to 10.
  • the P2X 4 receptor antagonism of the compounds of the present invention was measured as follows.
  • ATP receptor human P2X 4
  • Fura-2 AM which is a calcium fluorescent indicator, was dissolved in an extracellular solution for calcium imaging, treated on the seeded cells, and allowed to stand at room temperature for 45 minutes to incorporate fura-2 AM into the cells.
  • a microplate reader Fluostar optima BMG Labtech
  • the light emitted from the xenon lamp is transmitted through each of the 340nm and 380nm filters to observe the fluorescence F 340 and F 380 of 510nm emanating upon irradiating the cells, intracellular calcium changes in ratio value F 340 / F 380 It was an indicator of change.
  • the measurement was performed by adding each well to an ATP final concentration of 1 ⁇ M and observing the ATP-induced Ca 2+ response over time.
  • the inhibitory activity of the test substance was measured by pretreating the test substance with ATP for 15 minutes, and was calculated by comparison with the case in the absence of the test substance.
  • the present invention compounds as is apparent from Example 6 showed a P2X 4 receptor antagonism excellent.
  • salts-diazepine-dione derivative or a pharmacologically acceptable represented by the general formula (I) nociceptive pain from having a P2X 4 receptor antagonism, inflammatory pain and neuropathic It is considered useful as an agent for preventing or treating pain in 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
  • Etc. are used together.
  • anticancer agents such as a chemotherapeutic agent
  • the compound of the present invention can be administered to humans by an appropriate administration method such as oral administration or parenteral administration.
  • it can be produced into a dosage form such as a tablet, granule, powder, capsule, suspension, injection, suppository and the like by a conventional method in the technical field of formulation.
  • excipients for example, in the case of tablets, usual excipients, disintegrants, binders, lubricants, pigments and the like are used.
  • excipient lactose, D-mannitol, crystalline cellulose, glucose and the like
  • disintegrant starch, carboxymethylcellulose calcium (CMC-Ca), etc.
  • lubricant magnesium stearate
  • binders include talc and the like, and 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 dose is usually about 0.01 mg to 100 mg of the compound of the present invention, which is an active ingredient in injections, and 1 mg to 2000 mg per day by oral administration in adults, but may be increased or decreased depending on age, symptoms, etc. .
  • an Example is given and this invention is demonstrated further in detail, this invention is not limited to these.
  • the P2X 4 receptor antagonism of the compounds of the present invention was measured as follows.
  • ATP receptor human P2X 4
  • Fura-2 AM which is a calcium fluorescent indicator, was dissolved in an extracellular solution for calcium imaging, treated on the seeded cells, and allowed to stand at room temperature for 45 minutes to incorporate fura-2 AM into the cells.
  • a microplate reader Fluostar optima BMG Labtech
  • the light emitted from the xenon lamp is transmitted through each of the 340nm and 380nm filters to observe the fluorescence F 340 and F 380 of 510nm emanating upon irradiating the cells, intracellular calcium changes in ratio value F 340 / F 380 It was an indicator of change.
  • the measurement was performed by adding each well to an ATP final concentration of 1 ⁇ M and observing the ATP-induced Ca 2+ response over time.
  • the inhibitory activity of the test substance was measured by pretreating the test substance with ATP for 15 minutes, and was calculated by comparison with the case in the absence of the test substance. (Test results)
  • compounds of Table 11 described it was found to have excellent P2X 4 receptor antagonism.

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

Abstract

La présente invention concerne des dérivés de diazépinedione, qui sont représentés par la formule générale (I), ou certains de leurs sels pharmaceutiquement admis. Ces dérivés et sels conviennent comme antagonistes du récepteur P2X4. Dans la formule générale (I), R1 est atome d'hydrogène, groupe alkyle en C1-C8, ou analogue. R2 est atome d'hydrogène, groupe alkyle en C1-C8, groupe alcoxy en C1-C8, groupe alkyle en C1-C8, mono-, di-, ou tri-halogéné, atome d'halogène, groupe hydroxyle, groupe nitro, groupe amino, groupe carboxyle, groupe cyano, ou analogue. R3 est atome d'hydrogène, groupe alkyle en C1-C8, ou analogue. Enfin, R4 et R5, qui peuvent être identiques ou différents, sont chacun atome d'hydrogène, groupe alkyle en C1-C8, ou analogue.
PCT/JP2010/051740 2009-02-03 2010-02-02 Dérivés de diazépinedione Ceased WO2010090300A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2009-022242 2009-02-03
JP2009022242A JP2012087053A (ja) 2009-02-03 2009-02-03 ジアゼピンジオン誘導体

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012008478A1 (fr) * 2010-07-13 2012-01-19 日本ケミファ株式会社 Antagoniste des récepteurs p2x4
WO2012014910A1 (fr) * 2010-07-29 2012-02-02 日本ケミファ株式会社 Antagoniste du récepteur p2x4
WO2012060397A1 (fr) 2010-11-05 2012-05-10 国立大学法人九州大学 Agent préventif ou thérapeutique de la douleur associée au zona en phase aiguë
WO2013105608A1 (fr) 2012-01-13 2013-07-18 日本ケミファ株式会社 Antagoniste des récepteurs p2x4
JPWO2012161301A1 (ja) * 2011-05-25 2014-07-31 国立大学法人九州大学 ギラン・バレー症候群に伴う神経因性疼痛の予防又は治療剤
WO2015005467A1 (fr) 2013-07-12 2015-01-15 日本ケミファ株式会社 Antagoniste des récepteurs p2x4
WO2015005468A1 (fr) 2013-07-12 2015-01-15 日本ケミファ株式会社 Antagoniste des récepteurs p2x4
WO2017188365A1 (fr) * 2016-04-28 2017-11-02 日本ケミファ株式会社 Méthode pour le traitement de la sclérose en plaques
CN107400090A (zh) * 2017-09-11 2017-11-28 华润赛科药业有限责任公司 一种苯并咪唑衍生物的合成方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051274A2 (fr) * 2001-12-14 2003-06-26 Astrazeneca Ab Derives de la benzodiazepine, leur preparation et leur utilisation
WO2007072974A1 (fr) * 2005-12-19 2007-06-28 Nippon Chemiphar Co., Ltd. Antagoniste du recepteur p2x4
WO2008023847A1 (fr) * 2006-08-25 2008-02-28 Nippon Chemiphar Co., Ltd. Antagoniste du récepteur p2x4

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003051274A2 (fr) * 2001-12-14 2003-06-26 Astrazeneca Ab Derives de la benzodiazepine, leur preparation et leur utilisation
WO2007072974A1 (fr) * 2005-12-19 2007-06-28 Nippon Chemiphar Co., Ltd. Antagoniste du recepteur p2x4
WO2008023847A1 (fr) * 2006-08-25 2008-02-28 Nippon Chemiphar Co., Ltd. Antagoniste du récepteur p2x4

Cited By (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103080094B (zh) * 2010-07-13 2015-06-24 日本化学医药株式会社 P2x4受体拮抗剂
CN103080094A (zh) * 2010-07-13 2013-05-01 日本化学医药株式会社 P2x4受体拮抗剂
WO2012008478A1 (fr) * 2010-07-13 2012-01-19 日本ケミファ株式会社 Antagoniste des récepteurs p2x4
WO2012014910A1 (fr) * 2010-07-29 2012-02-02 日本ケミファ株式会社 Antagoniste du récepteur p2x4
WO2012060397A1 (fr) 2010-11-05 2012-05-10 国立大学法人九州大学 Agent préventif ou thérapeutique de la douleur associée au zona en phase aiguë
EP2636414A4 (fr) * 2010-11-05 2014-04-02 Univ Kyushu Agent préventif ou thérapeutique de la douleur associée au zona en phase aiguë
EP3132803A3 (fr) * 2010-11-05 2017-04-26 Kyushu University Agent préventif ou thérapeutique de la douleur associée au zona en phase aiguë
EP3132803A2 (fr) 2010-11-05 2017-02-22 Kyushu University Agent préventif ou thérapeutique de la douleur associée au zona en phase aiguë
JPWO2012161301A1 (ja) * 2011-05-25 2014-07-31 国立大学法人九州大学 ギラン・バレー症候群に伴う神経因性疼痛の予防又は治療剤
US20190046539A1 (en) * 2011-05-25 2019-02-14 Kyushu University Prophylactic or therapeutic agent for neuropathic pain associated with guillain-barre syndrome
JP2017119702A (ja) * 2011-05-25 2017-07-06 国立大学法人九州大学 ギラン・バレー症候群に伴う神経因性疼痛の予防又は治療剤
US20170065608A1 (en) * 2011-05-25 2017-03-09 Kyushu University Prophylactic or therapeutic agent for neuropathic pain associated with guillain-barre syndrome
CN110483423A (zh) * 2012-01-13 2019-11-22 日本化学药品株式会社 P2x4受体拮抗剂
CN111333588A (zh) * 2012-01-13 2020-06-26 日本化学药品株式会社 P2x4受体拮抗剂
US9382236B2 (en) 2012-01-13 2016-07-05 Nippon Chemiphar Co., Ltd P2X4 receptor antagonist
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JPWO2013105608A1 (ja) * 2012-01-13 2015-05-11 日本ケミファ株式会社 Ｐ２ｘ４受容体拮抗剤
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KR20140116926A (ko) 2012-01-13 2014-10-06 닛뽕 케미파 가부시키가이샤 P2x4 수용체 길항제
AU2013208536B2 (en) * 2012-01-13 2017-07-20 Nippon Chemiphar Co., Ltd. P2X4 receptor antagonist
WO2013105608A1 (fr) 2012-01-13 2013-07-18 日本ケミファ株式会社 Antagoniste des récepteurs p2x4
US10633349B2 (en) 2012-01-13 2020-04-28 Nippon Chemiphar Co., Ltd P2X4 receptor antagonist
CN104066724B (zh) * 2012-01-13 2020-04-17 日本化学药品株式会社 P2x4受体拮抗剂
US9969700B2 (en) 2012-01-13 2018-05-15 Nippon Chemiphar Co., Ltd. P2X4 receptor antagonist
KR20200032762A (ko) 2012-01-13 2020-03-26 닛뽕 케미파 가부시키가이샤 P2x4 수용체 길항제
CN108863959A (zh) * 2012-01-13 2018-11-23 日本化学药品株式会社 P2x4受体拮抗剂
EP2803662A4 (fr) * 2012-01-13 2015-06-03 Nippon Chemiphar Co Antagoniste des récepteurs p2x4
CN104066724A (zh) * 2012-01-13 2014-09-24 日本化学药品株式会社 P2x4受体拮抗剂
US10150744B2 (en) 2013-07-12 2018-12-11 Nippon Chemiphar Co., Ltd P2X4 receptor antagonist
WO2015005467A1 (fr) 2013-07-12 2015-01-15 日本ケミファ株式会社 Antagoniste des récepteurs p2x4
EP3564217A1 (fr) * 2013-07-12 2019-11-06 Nippon Chemiphar Co., Ltd. Antagoniste des récepteurs p2x4
US10472333B2 (en) 2013-07-12 2019-11-12 Nippon Chemiphar Co., Ltd. P2X4 receptor antagonist
EP3020707A4 (fr) * 2013-07-12 2016-12-07 Nippon Chemiphar Co Antagoniste des récepteurs p2x4
WO2015005468A1 (fr) 2013-07-12 2015-01-15 日本ケミファ株式会社 Antagoniste des récepteurs p2x4
JP2018172431A (ja) * 2013-07-12 2018-11-08 日本ケミファ株式会社 Ｐ２ｘ４受容体拮抗剤
US9873683B2 (en) 2013-07-12 2018-01-23 Nippon Chemiphar Co., Ltd P2X4 receptor antagonist
WO2017188365A1 (fr) * 2016-04-28 2017-11-02 日本ケミファ株式会社 Méthode pour le traitement de la sclérose en plaques
JPWO2017188365A1 (ja) * 2016-04-28 2019-04-04 日本ケミファ株式会社 多発性硬化症の治療のための医薬
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US11918589B2 (en) 2016-04-28 2024-03-05 Nippon Chemiphar Co., Ltd. Medicament for treatment of multiple sclerosis
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CN107400090A (zh) * 2017-09-11 2017-11-28 华润赛科药业有限责任公司 一种苯并咪唑衍生物的合成方法
CN107400090B (zh) * 2017-09-11 2020-02-07 华润赛科药业有限责任公司 一种苯并咪唑衍生物的合成方法

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