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WO2012011549A1 - Antagoniste du récepteur p2x4 - Google Patents

Antagoniste du récepteur p2x4 Download PDF

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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
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group
carbon atoms
substituted
halogen
atoms
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English (en)
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
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Nippon Chemiphar Co Ltd
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Nippon Chemiphar Co Ltd
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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.

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Abstract

La présente invention concerne un dérivé de diazépine qui est représenté par la formule (II), ou l'un de ses sels pharmacologiquement admis, ce dérivé ou ce sel convenant comme antagoniste du récepteur P2X4. Dans cette formule (II), R11 est atome d'hydrogène ou groupe alkyle en C1-8; R13 et R14 sont atomes d'hydrogène ou groupes alkyle en C1-8, etc.; R15 est atome d'hydrogène, groupe alkyle en C1-8, groupe alcoxy en C1-8, groupe alkyle en C1-8 substitué par 1 à 3 atomes halogènes, groupe hydroxyle, ou groupe hétérocyclique éventuellement porteur de groupes substituants, etc.; enfin, AA est noyau thiophène, noyau pyridine, noyau pyrimidine, noyau quinoléine, noyau indole, noyau indoléine, ou noyau indazole, etc.
PCT/JP2011/066652 2010-07-23 2011-07-22 Antagoniste du récepteur p2x4 Ceased WO2012011549A1 (fr)

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JP2010165607A JP2013209292A (ja) 2010-07-23 2010-07-23 Ｐ２ｘ４受容体拮抗剤
JP2010-165607 2010-07-23

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013105608A1 (fr) * 2012-01-13 2013-07-18 日本ケミファ株式会社 Antagoniste des récepteurs p2x4
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
EP3132803A3 (fr) * 2010-11-05 2017-04-26 Kyushu University Agent préventif ou thérapeutique de la douleur associée au zona en phase aiguë
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

Citations (3)

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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
WO2003082832A2 (fr) * 2002-03-28 2003-10-09 Wisys Technology Foundation, Inc. Agents anxiolytiques a effets sedatifs et ataxiques reduits
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
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