WO2013089212A1 - Substituted triazine derivative and pharmaceutical composition containing same - Google Patents

Substituted triazine derivative and pharmaceutical composition containing same Download PDF

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Publication number
WO2013089212A1
WO2013089212A1 PCT/JP2012/082444 JP2012082444W WO2013089212A1 WO 2013089212 A1 WO2013089212 A1 WO 2013089212A1 JP 2012082444 W JP2012082444 W JP 2012082444W WO 2013089212 A1 WO2013089212 A1 WO 2013089212A1
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substituted
unsubstituted
alkyl
compound
alkenyl
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PCT/JP2012/082444
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French (fr)
Japanese (ja)
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浩幸 甲斐
康彦 藤井
透 堀口
健太郎 旭
中村 健一郎
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塩野義製薬株式会社
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Publication of WO2013089212A1 publication Critical patent/WO2013089212A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/10Drugs for disorders of the urinary system of the bladder
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D251/00Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/26Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hetero atoms directly attached to ring carbon atoms
    • C07D251/40Nitrogen atoms
    • C07D251/42One nitrogen atom
    • C07D251/46One nitrogen atom with oxygen or sulfur atoms attached to the two other ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/02Heterocyclic 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
    • C07D401/12Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic 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
    • C07D401/14Heterocyclic 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 three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic 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
    • C07D403/12Heterocyclic 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 linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic 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
    • C07D413/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D417/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to compounds useful for treating diseases or conditions involving P2X receptors, particularly P2X 3 and / or P2X 2/3 receptors, and pharmaceutical compositions containing such compounds.
  • Adenosine triphosphate is known as an intracellular energy source and phosphorylated substrate. On the other hand, it is also known to work as an extracellular information transmission substance. Furthermore, ATP is released to the outside of cells by various stimuli such as cell damage, inflammation, nociceptive stimulation, reduction of blood oxygen concentration, and released from the primary sensory nerve ending together with other neurotransmitters. It is known. ATP released to the outside of the cell performs various extracellular information transmission via the ATP receptor (Non-patent Documents 4 and 5).
  • ATP receptors are roughly classified into an ion channel type P2X family and a G protein coupled type P2Y family. Seven types of subtypes have been reported in the P2X receptor family, and function as non-selective cation channels by forming homotrimers or heterotrimers with other P2X subtypes (Non-patent Document 6). ).
  • Non-Patent Document 1 Non-Patent Document 1
  • A-317491 has the following formula:
  • Patent Document 1 Is a tri-substituted-N-[(1S) -1,2,3,4-tetrahydro-1-taphthalenyl] benzamide derivative (Patent Document 1), which antagonizes P2X 3 and P2X 2/3 receptors It has been reported that it showed activity and showed analgesic action in a rat neuropathic pain model and inflammatory pain model (Non-patent Document 7). This indicates that it pain via the P2X 3 or P2X 2/3 receptor is transmitted, and P2X 3 or P2X 2/3 compounds with receptor antagonistic activity are useful as analgesics . Patent Documents 2 to 7 also describe compounds exhibiting P2X 3 or P2X 2/3 receptor antagonism.
  • Non-patent Document 2 a compound having a P2X 3 receptor antagonistic action is used in the treatment of diseases associated with abnormal urination function. It also suggests that it is useful.
  • Patent Documents 2 to 7 describe compounds exhibiting P2X 3 or P2X 2/3 receptor antagonism.
  • Non-Patent Document 9 neuroepithelial bodies (NEB) of the lungs
  • Non-Patent Document 10 ATP-induced cough
  • P2X 3 receptors It has been suggested that it is involved in information transmission in the respiratory organs (Non-patent Document 11).
  • Patent Document WO2006 a compound called A-317491, known as a P2X 3 and P2X 2/3 receptor antagonist
  • P2X 3 and P2X 2/3 receptor antagonist have been reported to inhibit the activity of vagal afferent A fibers in lung diseases.
  • Patent Document WO2006 / 012639
  • biphenyl and phenyl-pyridine derivatives have been reported as P2X 3 and / or P2X 2/3 receptor antagonists, suggesting that they have an action to improve respiratory diseases in asthma and lung function models
  • Patent Documents 2 to 7 describe compounds exhibiting P2X 3 or P2X 2/3 receptor antagonism.
  • Patent Documents 8, 9, 10, 11 and 15 and Non-Patent Document 14 describe compounds having a structure similar to that of the compound of the present invention, but analgesic action and P2X 3 or P2X 2/3 receptor antagonistic action Is not described.
  • Non-Patent Document 8 describes a compound having a structure similar to that of the compound of the present invention and showing analgesic activity, but does not describe P2X 3 or P2X 2/3 receptor antagonism.
  • Patent Document 12 and Non-Patent Documents 12 and 13 describe compounds having a P2X 3 receptor antagonistic action, but differ in structure from the compounds of the present invention.
  • Patent Literature 13 and Patent Literature 14 describe compounds having a P2X 3 or P2X 2/3 receptor antagonistic activity having a triazine skeleton.
  • the present invention provides novel P2X 3 and / or P2X 2/3 receptor antagonistic compounds. Further, to provide a pharmaceutical composition having a P2X 3 and / or P2X 2/3 receptor antagonism.
  • the present inventors have found that a novel compound that specifically binds to the P2X 3 and / or P2X 2/3 receptor and exhibits antagonism, and P2X 3 and / or Alternatively, a novel compound that specifically binds to the P2X 2/3 receptor was found. Also found a pharmaceutical composition having P2X 3 and / or P2X 2/3 receptor antagonism.
  • the pharmaceutical compositions encompassed by the compounds or the present invention included in the present invention, P2X 3 receptor inhibiting activity, a rat serum albumin (hereinafter, RSA) good results in P2X 3 receptor inhibitory activity and the like in the presence of Indicated.
  • the compound included in the present invention or the pharmaceutical composition included in the present invention is a CYP enzyme inhibition confirmation test, FAT test, solubility confirmation test, metabolic stability confirmation test, hERG inhibitory activity confirmation test, bioavailability confirmation. Good results were also shown in tests and / or protein binding confirmation tests.
  • the present invention relates to the following (1) to (37).
  • R a and R b are both a hydrogen atom or together, oxo, thioxo or ⁇ N—R x ;
  • R d and R e are both hydrogen atoms or together, oxo, thioxo or ⁇ N—R y ;
  • R x and R y are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Alkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
  • R c is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted
  • R 11c is — (C (R 11c ) (R 11d )) m′-CN
  • R 11c each independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl
  • R 11d is each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl
  • R 11c and R 11d bonded to the same carbon atom are A substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted or unsubstituted non-aromatic heterocycle
  • m ′ is an integer of 1 to 4
  • R c is substituted with 3 to 5 hydroxy groups, and substituent group ⁇ (substituent group ⁇ : halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubsti
  • R c is substituted with 3 to 5 hydroxy groups, and substituent group A (substituent group A: halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubent group A
  • R 9 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, Any of (1) to (3) and (3 ′) above, which is substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkenyl Or a pharmaceutically acceptable salt thereof. (5) formula:
  • —X— and —L— are as defined above (1); R 9 is halogen or substituted or unsubstituted alkyl; Y 1 , Y 2 and Y 3 are each independently CH or N; provided that Y 1 , Y 2 and Y 3 are not simultaneously N), and the compound according to any one of (1) to (3), (3 ′) and (4) above Or a pharmaceutically acceptable salt thereof.
  • Ring B is thiazole, isothiazole, oxazole, isoxazole, pyrazole, imidazole, triazole, furan, thiophene, thiadiazole, oxadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine or benzoxazole.
  • Ring B is thiazole, isothiazole, oxazole, isoxazole, pyrazole, imidazole, triazole, furan, thiophene, thiadiazole, oxadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine or benzoxazole.
  • Ring (B) is thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyrazine or pyridazine, (1) to (3), (3 ′) and (4) to (8) Or a pharmaceutically acceptable salt thereof.
  • s ′ is 1 or 2, and at least one R 9 ′ is hydroxy, carboxy, cyano, substituted alkyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl or
  • the compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), (3 ′) and (4) to (9), which is substituted sulfinyl.
  • R 11a independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl
  • R 11b is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl
  • R 11a and R 11b bonded to the same carbon atom are A substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted or unsubstituted non-aromatic heterocycle
  • m is an integer of 2 to 4, and the compound or a pharmaceutically acceptable salt thereof according to any one of (1) or (4) to (13) above.
  • R c is — (C (R 11a ) (R 11b )) m—OH
  • R 11a represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl
  • R 11b is — (C (R 12a ) (R 12b )) u—OH
  • R 12a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Or substituted or unsubstituted alkynyl
  • each R 12b independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl
  • u is an integer of 0 to 2 )
  • m is an integer of 2 to 4, and the compound or pharmaceutically acceptable salt thereof according to any
  • R c is of the formula:
  • a substituted or unsubstituted cycloalkane a substituted or unsubstituted cycloalkene, or a substituted or unsubstituted non-aromatic heterocycle
  • t ′ is an integer of 1 to 4
  • R 15a ′ and R 15b ′ each independently represent a hydrogen atom, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted (1) or (4) to (13) or a pharmaceutically acceptable salt thereof, which is substituted sulfamoyl, substituted or unsubstituted acyl, substituted sulfonyl or substituted sulfinyl).
  • R c is of the formula:
  • R a and R b are both a hydrogen atom or together, oxo, thioxo or ⁇ N—R x ;
  • R d and R e are both hydrogen atoms or together, oxo, thioxo or ⁇ N—R y ;
  • R x and R y are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Alkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
  • R c is substituted with 3 to 5 hydroxy groups, and further substituted group ⁇ (substituent group ⁇ : halogen, cyano,
  • R a and R b are both a hydrogen atom or together, oxo, thioxo or ⁇ N—R x ;
  • R d and R e are both hydrogen atoms or together, oxo, thioxo or ⁇ N—R y ;
  • R x and R y are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Alkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
  • R c is substituted with 3 to 5 hydroxy groups, and further substituted group A (substituent group A: halogen, cyano, substituted
  • R a and R b together are oxo
  • R d and R e together are oxo
  • R c is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group
  • n is 1,
  • R 4a and R 4b are both hydrogen atoms
  • -X- is -N (H)-
  • -L- is -O-
  • Ring D is benzene
  • Ring B is pyridine or thiazole
  • s ′ is an integer from 1 to 3
  • at least one R 9 ′ is carboxy or alkyloxycarbonyl, and the other symbols are as defined in (1) above, or Its pharmaceutically acceptable salt.
  • R a and R b together are oxo, R d and R e together are oxo, R c is alkyl; n is 1, R 4a and R 4b are both hydrogen atoms, -X- is -N (H)-; Ring D is benzene, s is an integer of 1 to 3,
  • n 1, R 4a and R 4b are both hydrogen atoms, R 2 is substituted or unsubstituted cycloalkyl, -X- is -N (H)-; -L- is -O-, Ring D is benzene,
  • R a and R b are together oxo, and R d and R e are together oxo, (1) to (3), (3 ′), (4) to (19 ), (19 ′) and (20) to (24), or a pharmaceutically acceptable salt thereof.
  • —X— is —N (R 5 ) — (wherein R 5 has the same meaning as (1) above), (1) to (3), (3 ′), (4) to (19) , (19 ′) and (20) to (28), or a pharmaceutically acceptable salt thereof.
  • (31) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), (3 ′), (4) to (19), (19 ′) and (20) to (30) A pharmaceutical composition containing.
  • the compounds of this invention have an antagonistic effect on P2X 3 and / or P2X 2/3 receptor and are useful for the disease or condition P2X 3 and / or P2X 2/3 receptors are involved.
  • Halogen means fluorine, chlorine, bromine and iodine.
  • haloalkyl haloalkylcarbamoyl
  • haloalkyloxy haloalkyloxy
  • Alkyl includes a straight or branched monovalent hydrocarbon group having 1 to 15 carbon atoms, 1 to 10 carbon atoms in one embodiment, and 1 to 6 carbon atoms in another embodiment.
  • alkyl may be limited.
  • C3-C6 alkyl means “alkyl” having 3 to 6 carbon atoms.
  • Examples of the unsubstituted alkyl for R c include n-propyl.
  • Haloalkyl “hydroxyalkyl”, “aminoalkyl”, “alkylaminoalkyl”, “alkylamino”, “alkylimino”, “alkylsulfonyl”, “alkylsulfamoyl”, “alkylcarbamoyl”, “arylalkyl” ”,“ Alkylsilylalkynyl ”,“ alkylsulfonyl ”,“ alkylsulfinyl ”,“ alkylcarbamoyl ”,“ alkylcarbamoylalkyl ”,“ alkylcarbamoylalkyloxy ”,“ alkylsulfamoyl ”,“ alkylsulfamoylalkyl ”, “Haloalkylcarbamoyl”, “hydroxyalkylcarbamoyl”, “alkyloxycarbonylalkyl”, “alkylcarbamoylamino”, “alkyloxycarbony
  • Alkyloxy includes an alkyloxy group in which the alkyl moiety is the above “alkyl”. Examples thereof include alkyloxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
  • alkyloxy has the same meaning as the above “alkyloxy”.
  • alkylthio examples include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio and the like.
  • alkyloxycarbonyl examples include methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, tert-butyloxycarbonyl, n-pentyloxycarbonyl and the like.
  • alkylcarbamoyl examples include mono- or dialkylcarbamoyl groups such as methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, cyclopropylcarbamoyl, n-butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and dipropylcarbamoyl groups.
  • mono- or dialkylcarbamoyl groups such as methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, cyclopropylcarbamoyl, n-butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and dipropylcarbamoyl groups.
  • Alkenyl is a straight or branched chain having 2 to 15 carbon atoms having one or more double bonds at any position, one embodiment having 2 to 10 carbon atoms, and another embodiment having 2 to 6 carbon atoms.
  • alkenyl examples include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, dekenyl, undecenyl, dodecenyl, tridecenyl and the like.
  • the number of carbon atoms in “alkenyl” may be limited.
  • C3-C6 alkenyl means “alkenyl” having 3 to 6 carbon atoms.
  • alkenyl part of “alkenyloxy”, “alkenylthio”, “alkenylcarbamoyl”, “alkenylsulfamoyl” and “alkenyloxycarbonyl” has the same meaning as the above “alkenyl”.
  • Alkynyl includes linear or branched alkynyl having 2 to 15 carbon atoms, one embodiment having 2 to 10 carbon atoms, and another embodiment having 2 to 6 carbon atoms. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonyl, decynyl and the like. These have one or more triple bonds at arbitrary positions, and may further have a double bond. In the present specification, the number of carbon atoms in “alkynyl” may be limited. For example, C3-C6 alkynyl means “alkynyl” having 3 to 6 carbon atoms.
  • alkynyl part of “alkynyloxy”, “alkynylthio” and “alkynyloxycarbonyl” has the same meaning as the above “alkynyl”.
  • Acyl means R—C ( ⁇ O) — (for example, R is “hydrogen”, “alkyl”, “alkenyl”, “alkynyl” or “cycloalkyl”, “cycloalkenyl”, A group represented by “non-aromatic heterocyclic group”, “aryl” or “heteroaryl”.
  • acyl part of “acylamino” and “acylimino” has the same meaning as the above “acyl”.
  • “Cycloalkane” includes monocyclic or polycyclic saturated carbocyclic rings having 3 to 10 carbon atoms.
  • Examples of the monocyclic cycloalkane include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane.
  • Examples of the polycyclic cycloalkane include norbornane and tetrahydronaphthalene.
  • Cycloalkyl includes a monovalent group derived from the above “cycloalkane”.
  • monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
  • One embodiment includes C3-C8 cycloalkanes.
  • Other embodiments include C3-C7 cycloalkanes.
  • Examples of the polycyclic cycloalkyl include norbornyl, tetrahydronaphthalen-5-yl, tetrahydronaphthalen-6-yl and the like.
  • Examples of “cycloalkyl” in R 2 include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • Examples of “cycloalkyl” in R 3 include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • cycloalkyl part of “cycloalkylcarbonyl”, “cycloalkyloxycarbonyl” and “cycloalkyloxy” has the same meaning as the above “cycloalkyl”.
  • “Cycloalkene” includes a non-aromatic monocyclic or polycyclic ring having 3 to 10 carbon atoms and containing at least one carbon-carbon double bond.
  • One embodiment includes C3-C8 cycloalkene.
  • Other embodiments include C3-C7 cycloalkene.
  • Examples of the monocyclic cycloalkene include cyclopentene and cyclohexene.
  • Examples of the polycyclic cycloalkene include norbornene and indene.
  • Cycloalkenyl includes a monovalent group derived from the above “cycloalkene”. Examples of monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl and the like. One embodiment includes C3-C8 cycloalkyl. Other embodiments include C3-C7 cycloalkyl. Examples of polycyclic cycloalkenyl include norbornenyl, inden-1-yl, inden-2-yl, inden-3-yl and the like.
  • cycloalkenyl part of “cycloalkenyloxycarbonyl” and “cycloalkenyloxy” has the same meaning as the above “cycloalkenyl”.
  • aromatic carbocycle includes a monocyclic or condensed aromatic hydrocarbon ring. Examples thereof include benzene, naphthalene, anthracene, phenanthrene and the like.
  • Aryl means a monovalent group derived from the above “aromatic carbocycle”. Examples thereof include phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl and the like. “Aryl” in R 2 includes phenyl. “Aryl” in R 3 includes phenyl.
  • Heterocycle means a 5- to 7-membered ring having at least one nitrogen atom, oxygen atom, and / or sulfur atom in the ring, A ring in which two or more of them are independently fused, or A 5- to 7-membered ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the “aromatic carbocycle”, the “cycloalkane” or the “cycloalkene”.
  • An aromatic or non-aromatic fused ring derived from the above ring.
  • monocyclic non-aromatic heterocycles such as pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorphone, tetrahydropyran, dihydropyridine, dihydropyridazine, dioxane, oxathiolane, thiane, tetrahydrofuran, tetrahydropyran, tetrahydrothiazole, tetrahydroisothiazole, etc.
  • heterocyclic group includes a monovalent group derived from the above “heterocycle”.
  • Monocyclic non-aromatic heterocyclic groups such as, dioxanyl, oxathiolanyl, thianyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolinyl, tetrahydroisothiazolinyl
  • a cyclic group For example, indolyl, isoindolyl, indazolyl, indolinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxazolyl Diazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, benzimidazo Examples include condensed heterocyclic
  • non-aromatic carbocycle includes the above “cycloalkane” and the above “cycloalkene”, and the ring in which the “cycloalkane” or the “cycloalkene” is fused to the “aromatic carbocycle”.
  • Examples of the condensed ring include indene.
  • non-aromatic carbocyclic group includes a monovalent group derived from the above “non-aromatic carbocyclic group”. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl, norbornyl, tetrahydronaphthalen-5-yl, tetrahydronaphthalen-6-yl, norbornenyl, inden-1-yl , Inden-2-yl, inden-3-yl and the like.
  • non-aromatic carbocyclic oxy “non-aromatic carbocyclic alkyloxy” and the “non-aromatic carbocyclic” moiety are synonymous with the above “non-aromatic carbocyclic”.
  • aromatic heterocycle includes those that are aromatic rings among the above “heterocycle”.
  • a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring An aromatic ring in which two or more of them are independently fused,
  • An aromatic ring in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “aromatic carbocycles” is included.
  • indole isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzo
  • examples thereof include condensed aromatic heterocycles such as thiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, benzimidazoline and the like.
  • the “5-membered or 6-membered aromatic heterocycle” includes the 5-membered or 6-membered “aromatic heterocycle” described above.
  • Examples include thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, furan, thiophene, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine and the like.
  • the “5-membered aromatic heterocycle” includes the 6-membered “aromatic heterocycle” described above. Examples thereof include pithiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, furan, thiophene, imidazole, triazole, tetrazole and the like.
  • the “6-membered aromatic heterocycle” includes the 6-membered “aromatic heterocycle”. For example, pyridine, pyrimidine, pyrazine, pyridazine, triazine and the like can be mentioned.
  • Examples of the “aromatic heterocycle” in ring B include pyridine, pyrazine, pyridazine, thiazole, isothiazole, oxazole and isoxazole. More specifically, pyridine is mentioned.
  • Heteroaryl includes a monovalent group derived from the above “aromatic heterocycle”.
  • a 5- to 7-membered aromatic cyclic group having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring An aromatic cyclic group in which two or more of them are independently fused, An aromatic group in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “aromatic carbocycles” is included.
  • Aryl For example, isoindolyl, indazolyl, indolizinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazozolyl, benzoxiazozolyl, benzothiazozolyl Condensation such as ril, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazolothiazolyl, pyrazinopyridazinyl, benzimidazolinyl Heteroaryl.
  • Heteroaryl in R 2 includes pyridyl
  • heteroaryl in R 3 includes pyridyl, pyrimidyl, benzofuryl, benzothienyl, indolyl, benzoisoxazolyl, benzothiazolyl, and the like.
  • Heteroaryl in R 3 includes pyridyl.
  • heteroaryl part of “heteroaryloxy” and “heteroaryloxycarbonyl” has the same meaning as the above “heteroaryl”.
  • non-aromatic heterocyclic ring includes those that are non-aromatic rings among the above-mentioned “heterocyclic rings”.
  • a 4- to 7-membered non-aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring A non-aromatic ring in which two or more of them are independently fused,
  • a ring in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “cycloalkane” or “cycloalkene”;
  • a 5- to 7-membered non-aromatic heterocyclic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is one or more of the above “aromatic carbocycle” or “non-aromatic carbocycle”.
  • fused rings For example, oxetane, thietane, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine, tetrahydropyran (for example, 2-tetrahydropyran, 3-tetrahydropyran, 4- Tetrahydropyran), dihydropyridine, dihydropyridazine, dihydropyrazine, dioxane, oxathiolane, thiane, tetrahydrofuran, tetrahydropyran, tetrahydrothiazoline, tetrahydroisothiazoline and the like, Examples thereof include condensed non-aromatic heteroaromatic rings such as indoline, isoindoline, benzopyran, benzodioxane
  • non-aromatic heterocyclic group includes a monovalent group derived from the above “non-aromatic heterocyclic ring”.
  • non-aromatic heterocycle portion of “non-aromatic heterocycle oxy” and “non-aromatic heterocycle oxycarbonyl” has the same meaning as the above “non-aromatic heterocycle”.
  • nitrogen-containing non-aromatic heterocyclic group includes at least one nitrogen atom in the ring, and may further include one or more atoms arbitrarily selected from an oxygen atom and a sulfur atom in the ring. It includes a group derived from a non-aromatic 4- to 7-membered ring or a ring in which two or more thereof are condensed. Examples include pyrrolinyl, pyrrolidino, pyrrolidinyl, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino, thiomorpholino and the like.
  • non-aromatic heterocycle portion of “non-aromatic heterocycle oxycarbonyl” has the same meaning as the above “non-aromatic heterocycle”.
  • the substituent of “substituted acyl” is selected from the group consisting of the substituent of the above “substituted alkyl”, the above “alkyl”, the above “alkenyl”, and the above “alkynyl”.
  • R of acyl (R—C ( ⁇ O) —) is “cycloalkyl”, “cycloalkenyl”, “non-aromatic heterocyclic group”, “aryl”, “heteroaryl”, Ring substituents include alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (eg, CF 3 , CH 2 CF 3 , CH 2 CCl 3, etc.), alkenyl, alkynyl (eg, ethynyl) , Alkyloxy (for example, methoxy, ethoxy, isopropyloxy), halogen (for example, fluorine, chloro and the like
  • Substituents for “substituted carbamoyl” or “substituted sulfamoyl” include, but are not limited to, one or more of the same or different substituents selected from the group consisting of: Hydroxy, carboxy, carboxyalkyl (eg, carboxymethyl, carboxyethyl, etc.), halogen (F, Cl, Br, I), alkyl (eg, methyl, ethyl), alkenyl (eg, vinyl), alkynyl (eg, ethynyl) , Cycloalkyl (eg, cyclopropyl), cycloalkenyl (eg, cyclopropenyl), hydroxyalkyl (eg, hydroxyethyl), alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), alkyloxycarbonyl Alkyl (eg, meth
  • substituted sulfonyl or “substituted sulfinyl” are the above “substituted or unsubstituted alkyl”, the above “substituted or unsubstituted alkenyl”, the above “substituted or unsubstituted alkynyl”, the following “substituted or unsubstituted cycloalkyl”.
  • R in R—S ( ⁇ O) 2 — or R—S ( ⁇ O) — is “cycloalkyl”, “cycloalkenyl”, “non-aromatic heterocyclic group”, “aryl”, “heteroaryl” , Etc.
  • each ring substituent may be alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (eg, CF 3 , CH 2 CF 3 , CH 2 CCl 3, etc.), Examples include alkenyl, alkynyl (eg, ethynyl), alkyloxy (eg, methoxy, ethoxy, isopropyloxy), halogen (eg, fluorine, chloro and the like) and the like.
  • Substituents for “substituted amino”, “substituted imino” and “substituted guanidyl” include, but are not limited to, one or more of the same or different substituents selected from the group consisting of: Alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (eg, CF 3 , CH 2 CF 3 , CH 2 CCl 3, etc.), hydroxyalkyl (eg, hydroxyethyl, —C (CH 3 ) 2 CH 2 OH, etc.), alkenyl (eg, vinyl), alkynyl (eg, ethynyl), cycloalkyl (eg, cyclopropyl), cycloalkenyl (eg, cyclopropenyl), alkyloxy (eg, methoxy, ethoxy, propoxy, butoxy) Etc.),
  • Heteroaryl eg, pyridyl, thienyl, thiazolyl, furyl, etc.
  • heteroarylalkyl eg, pyridylmethyl, thienylmethyl, thiazolylmethyl, furylmethyl, etc.
  • unsubstituted non-aromatic heterocyclic oxy eg, piperazinooxy, Piperidinooxy, etc.
  • non-aromatic heterocyclic oxy unsubstituted heteroaryloxy (eg, pyridyloxy, pyrida) substituted with one or more of the same or different substituents selected from the following substituent group Z
  • Substituent group Y is hydroxyalkyl (eg, hydroxyethyl, —C (CH 3 ) 2 CH 2 OH, etc.), alkyloxycarbonyl (methoxycarbonyl, tert-butyloxycarbonyl, etc.), alkyloxycarbonylalkyl, alkylsulfonyl (Eg methanesulfonyl etc.), alkylsulfinyl (eg methanesulfinyl etc.), carbamoyl, alkylcarbamoyl (eg methylcarbamoyl etc.), alkylcarbamoylalkyl (eg methylcarbamoylmethyl etc.), carbamoylalkyl (eg carbamoylmethyl etc.
  • alkylcarbamoyl eg methylcarbamoyl etc.
  • alkylcarbamoylalkyl eg methylcarbamoy
  • Carboxyalkyl eg, carboxymethyl, etc.
  • sulfamoyl alkylsulfamoyl (eg, methylsulfamoyl, etc.)
  • alkylsulfamoylalkyl eg, methyls
  • Substituent group Z includes halogen (for example, F, Cl and the like), hydroxy, carboxy, carboxyalkyloxy (for example, carboxymethyloxy and the like), cyano, nitro, alkyl (for example, methyl and the like), hydroxyalkyl (for example, Hydroxymethyl, etc.), aminoalkyl, alkylaminoalkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylthio, alkenylthio, alkynylthio, acyl, alkyloxycarbonyl (eg, methyloxycarbonyl, ethyloxycarbonyl, etc.) , Alkenyloxycarbonyl, alkynyloxycarbonyl, carbamoyl, carbamoylalkyloxy (eg, carbamoylmethyloxy, etc.), alkylcarbamoyl (eg, methylcarbamoyl)
  • substituents of “substituted aryl” and “substituted heteroaryl” in R 2 include halogen, alkyl, alkenyl, alkynyl, alkyloxy, cycloalkyl, alkylsilylalkynyl and the like.
  • substituent of “substituted aryl” and “substituted heteroaryl” in R 2 fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, propenyl, vinyl, ethynyl, methyloxy, cyclopropyl, trimethylsilylethynyl Etc.
  • heteroaryloxy which is a substituent of “substituted aryl” and “substituted heteroaryl” in R 3 , for example, pyrrolyloxy, pyrazinyloxy, pyrazolyloxy, indolyloxy, tetrazolyloxy, furyloxy, thienyloxy, Pyridyloxy, imidazolyloxy, triazolyloxy, tetrazolyloxy, triazinyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy, thiadiazolyloxy, Oxazolyloxy, oxadiazolyloxy and the like can be mentioned.
  • Substituents for “substituted aryl” and “substituted heteroaryl” in R 3 are unsubstituted heteroaryloxy, substituted with one or more of the same or different substituents selected from the above substituent group Z. Heteroaryloxy and the like. Furthermore, in addition to the above substituents, halogen, hydroxy, carboxy, cyano, nitro, alkyl, haloalkyl, haloalkyloxy, alkyloxy, amino and the like can be mentioned.
  • the heteroaryloxy is a group selected from the following group which is unsubstituted or substituted with one or more of the same or different substituents selected from the substituent group Z: pyrrolyloxy, pyrazinyloxy, pyrazolyloxy , Indolyloxy, tetrazolyloxy, furyloxy, thienyloxy, pyridyloxy, imidazolyloxy, triazolyloxy, tetrazolyloxy, triazinyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, isoxa Examples include zolyloxy, thiazolyloxy, isothiazolyloxy, thiadiazolyloxy, oxazolyloxy, and oxadiazolyloxy.
  • the substituent of “substituted amino” in R 9 ′ includes “carbamoyl, alkylcarbamoyl (eg, methylcarbamoyl etc.), alkylcarbamoylalkyl (eg, methylcarbamoylmethyl etc.), carbamoylalkyl (eg, carbamoylmethyl etc.) or carboxy Alkyl (for example, carboxymethyl and the like) ".
  • R 9 ′ includes halogen, hydroxy, carboxy, cyano, nitro, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylthio, alkenylthio, alkynylthio, acyl , Alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, carbamoyl, alkylcarbamoyl, haloalkylcarbamoyl, hydroxyalkylcarbamoyl, cyanocarbamoyl, amino, acylamino, one or two each selected from the above substituent group Y are the same or different Examples include amino, sulfamoyl, methylsulfonyl, and methylsulfinyl substituted with a substituent.
  • R 4a and R 4b bonded to the same carbon atom together are oxo or thioxo” includes, for example, the following cases.
  • n, R 4a, R 4b and R 2 are synonymous above (1), and the like.
  • the position numbers of these atoms are different from the position numbers based on the IUPAC nomenclature. That is, “the positional relationship of carbon atom a and carbon atom b on ring D is (1, 4)” includes the following cases.
  • Q a atom, Q b atom, Q c atom and Q d atom are each independently a carbon atom or a nitrogen atom, and —X—, —L—, ring D, ring B, s, s ′, R 9 and R 9 ′ are synonymous with the above (1))
  • the position numbers of these atoms are different from the position numbers based on the IUPAC nomenclature. That is, “the positional relationship of carbon atom a and carbon atom b on ring D is (1,3)” includes the following cases.
  • Q a atom, Q b atom, Q c atom and Q d atom are each independently a carbon atom or a nitrogen atom, and —X—, —L—, ring D, ring B, s, s ′, R 9 and R 9 ′ are synonymous with the above (1))
  • R 11c and R 11d bonded to the same carbon atom are combined to form a substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted
  • the term “or an unsubstituted non-aromatic heterocyclic ring” includes the following cases.
  • vd is an integer of 0 to 3 (eg, 0 or 1, for example, 0);
  • —Wd— represents —O—, —S— or —N (R 17d ) — (for example, —O—);
  • R 17d is a hydrogen atom, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl,] and the like.
  • R 11a and R 11b bonded to the same carbon atom are combined to form a substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted
  • the term “or an unsubstituted non-aromatic heterocyclic ring” includes the following cases.
  • v is an integer of 0 to 3 (for example, 0 or 1, such as 0);
  • —W— represents —O—, —S— or —N (R 17 ) — (for example, —O—);
  • R 17 represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl].
  • R 14a and R 14b bonded to the same carbon atom are combined to form a substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted
  • the “unsubstituted non-aromatic heterocycle” includes the following cases.
  • va is an integer of 0 to 3 (for example, 0 or 1, such as 0);
  • —Wa— represents —O—, —S— or —N (R 17a ) — (for example, —O—);
  • R 17a is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl].
  • R 14a ′ and R 14b ′ bonded to the same carbon atom are combined to form a substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, “Substituted or unsubstituted non-aromatic heterocycle” includes the following cases.
  • t ′, R 14a ′ , R 14b ′ , R 15a ′ and R 15b ′ have the same meaning as the above (17);
  • vb is an integer of 0 to 3 (for example, 0 or 1, such as 0);
  • —Wb— represents —O—, —S— or —N (R 17b ) — (for example, —O—);
  • R 17b is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl].
  • R c is substituted with “3 to 5 hydroxy groups, and further substituted group A (substituent group A: halogen, cyano, substituted or unsubstituted alkyloxy, Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl Substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted
  • the compounds represented by general formula (I), general formula (II), general formula (II ') and general formula (II' ') of the present invention can be produced, for example, by the synthetic route shown below. If necessary, it can be produced with reference to the contents described in WO2010 / 092966.
  • R 10 is alkyl
  • R 27 is alkyl
  • n ′ is an integer of 0 to 3
  • Lg 1 is a leaving group, and other symbols are as defined above.
  • a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N, N′-dimethylimidazolidinone, dimethylsulfoxide, DBU, Reaction with isocyanate (ii) or 1-carbamoylimidazole (ii) ′ in the presence of a base such as triethylamine or pyridine (preferably DBU) at ⁇ 20 ° C.
  • a base such as triethylamine or pyridine (preferably DBU) at ⁇ 20 ° C.
  • reaction mixture is carbonylated or thiocarbonylated, such as 1,1′-carbonyldiimidazole, 1,1′-thiocarbonyldiimidazole, phosgene, thiophosgene, triphosgene, and DBU, triethylamine, pyridine, etc.
  • Compound (iii) can be produced by reacting with a base (preferably DBU) at ⁇ 20 ° C. to 50 ° C., preferably ⁇ 10 ° C. to ice cooling.
  • —OSO 2 (C t F 2t + 1 ) group —OTf group (trifluoromethanesulfonic acid ester) is preferable.
  • Compound (v) may be used in a solvent such as NMP, DMF, DMSO or without solvent, under microwave irradiation at 150 ° C. to 250 ° C., preferably at 200 ° C. to 230 ° C., or in a solvent such as t-butanol, acetic acid, etc.
  • the compound represented by the general formula (II ′) can be produced.
  • optically active isocyanate (ii) an optically active compound represented by general formula (II ′) can be synthesized.
  • Compound (ix) is dissolved in a solvent such as dichloromethane, chloroform, 1,2-dichloroethane in the presence of a base such as triethylamine, N, N-diisopropylethylamine, at ⁇ 20 ° C. to 30 ° C., preferably under ice-cooling.
  • Compound (x) can be produced by reacting with an isocyanate such as (chlorocarbonyl) isocyanate.
  • Pg 2 is a suitable protecting group for an amino group and R 11 is substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkenyl Substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted acyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl Or substituted or unsubstituted heteroaryl, R 12 is hydroxy or halogen, t is an integer of 1 to 4, and other symbols are as defined above.
  • Compound (xvi) can be produced by reacting compound (xv) obtained by Method A or Method B with an acid such as hydrochloric acid-dioxane solution, hydrochloric acid-methanol, hydrochloric acid-ethyl acetate solution, or trifluoroacetic acid. .
  • Compound (xviii) is produced by reacting compound (xvi) with an acid halide (xvii) (R 12 is halogen) in the presence of a base such as triethylamine or diisopropylethylamine in a solvent such as THF or dioxane. Can do. If necessary, dimethylaminopyridine or the like may be added.
  • compound (xvi) and carboxylic acid (xvii, R 12 is hydroxy) such as 1-hydroxybenzotriazole, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, etc. in a solvent such as THF and DMF
  • compound (xviii) can be produced by reacting in the presence of a condensing agent and a base such as triethylamine or diisopropylpropylamine.
  • R 13 is substituted or unsubstituted alkyl
  • R 20a and R 20b are hydrogen, halogen, cyano, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted Or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, Substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sul
  • Compound (xxi) can be produced.
  • Compound (xxi) is reacted with a lithium hydroxide aqueous solution, a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution or the like in a solvent such as methanol or ethanol, or in a mixed solvent of these and a solvent such as THF or dioxane.
  • a solvent such as methanol or ethanol, or in a mixed solvent of these and a solvent such as THF or dioxane.
  • R 14 is substituted or unsubstituted alkyl
  • R 15 and R 16 are each independently substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted acyl, substituted or unsubstituted non-aromatic heterocyclic group, (Substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, u is an integer of 1 to 4, and other symbols are as defined above.) (First step) Compound (xxiii) obtained by Method A or Method B in a solvent such as methanol or ethanol or in a mixed solvent of these
  • a compound (ixl) is produced by reacting a compound (x) obtained by Method B with an alcohol (xxxviii) and a solvent such as THF or dioxane with triphenylphosphine or the like and diethyl azodicarboxylate. be able to.
  • Compound (II) can be produced by reacting compound (ixl) with compound (vi) in the presence of an acid such as formic acid or acetic acid under heating and reflux.
  • an acid such as formic acid or acetic acid under heating and reflux.
  • Alcohol (xxxviii) used as an intermediate can be produced according to a commercially available product or a method described in the literature listed below.
  • R 21 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, etc.
  • R 22 is bromo, or iodine
  • R 23 and R 24 are each independently substituted or unsubstituted.
  • the compound (xxxix) can be produced by reacting at 120 ° C. to 200 ° C., preferably 130 ° C. to 150 ° C., preferably under heating under reflux or under microwave irradiation.
  • palladium-carbon platinum oxide
  • chlorotris tri
  • Compound (xl) can be obtained by catalytic reduction using a metal catalyst such as phenylphosphine) rhodium (I).
  • palladium-carbon platinum oxide
  • chlorotris tri-
  • the compound (xliii) can be obtained by catalytic reduction using a metal catalyst such as phenylphosphine) rhodium (I).
  • Compound (xlvi) can be obtained by performing compound (xlib) in the presence of a Lewis acid, trifluoroacetic acid or the like in the absence of a solvent or in a suitable solvent at 0 ° C. to heating under reflux.
  • Compound (xlvi) is mixed with compound (xlvii) in a solvent such as THF, dioxane and the like in the presence of a paradium catalyst and potassium carbonate, cesium carbonate, sodium carbonate aqueous solution, etc. at 50 ° C. to heating under reflux, preferably under heating under reflux, or Compound (xlviii) can be produced by reaction at 120 ° C. to 200 ° C., preferably 130 ° C. to 150 ° C. under microwave irradiation.
  • a solvent such as THF, dioxane and the like
  • a paradium catalyst and potassium carbonate, cesium carbonate, sodium carbonate aqueous solution, etc. at 50 ° C. to heating under reflux, preferably under heating under reflux
  • Compound (xlviii) can be produced by reaction at 120 ° C. to 200 ° C., preferably 130 ° C. to 150 ° C. under microwave irradiation.
  • R c is substituted with 3 to 5 hydroxy groups, and substituent group ⁇ (substituent group ⁇ : halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoy
  • Preferred embodiments of the present invention include the following compounds or pharmaceutically acceptable salts thereof.
  • R c is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group;
  • Ring B is pyridine or thiazole;
  • R c is substituted or unsubstituted alkyl; Ring B is pyridine; s ′ is an integer from 1 to 3; and at least one R 9 ′ is aryl, heteroaryl, aryloxy or heteroaryloxy, which are substituted with at least one carboxy, alkyloxycarbonyl or cyano Or a pharmaceutically acceptable salt thereof, which may further have other substituents.
  • R c is alkyl
  • R c is alkyl; in formula (I ′), s is an integer from 1 to 3;
  • the compounds of formula (I), formula (I ′), formula (I ′′), formula (II) etc. are not limited to specific isomers, but all possible isomers (eg keto Enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotational isomers, etc.), racemates or mixtures thereof.
  • the compound in which —X— is —NH— in the formula (I) includes the following tautomers.
  • one or more hydrogen, carbon or other atoms of a compound of formula (I), formula (I ′), formula (I ′′), formula (II), etc. are hydrogen, carbon or other atom isotopes. Can be replaced by the body.
  • Compounds of formula (I), formula (I ′), formula (I ′′), formula (II) and the like are represented by formula (I), formula (I ′), formula (I ′′), formula (II) and the like. Includes all radiolabeled forms of the compounds.
  • Such “radiolabeled”, “radiolabeled” and the like of compounds of formula (I), formula (I ′), formula (I ′′), formula (II) and the like are each included in the present invention. It is useful as a research and / or diagnostic tool in metabolic pharmacokinetic studies and binding assays. It is also useful as a pharmaceutical product.
  • One or more hydrogen, carbon and / or other atoms of the compounds of formula (I), formula (I ′), formula (I ′′), formula (II) etc. are hydrogen, carbon and / or respectively. It can be substituted with isotopes of other atoms. Examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included.
  • the compound represented by the formula (I), the formula (I ′), the formula (I ′′), the formula (II) and the like includes a compound substituted with such an isotope.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and all radiolabeled compounds of the compounds represented by the formula (I), the formula (I ′), the formula (I ′′), the formula (II), etc. Is included.
  • a “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
  • Radiolabeled compounds of the compounds represented by formula (I), formula (I ′), formula (I ′′), formula (II) and the like can be prepared by methods well known in the art.
  • a tritium-labeled compound represented by the formula (I), the formula (I ′), the formula (I ′′), the formula (II), or the like can be converted into a compound of the formula (I ), Formula (I ′), formula (I ′′), formula (II) and the like, can be prepared by introducing tritium into the specific compound.
  • This method can be used in formula (I), formula (I ′), formula (I ′′), formula (II), etc. in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base.
  • the compounds shown include reacting appropriately halogen substituted precursors with tritium gas. Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). 14 C-labeled compounds can be prepared by using raw materials having 14 C carbon.
  • Examples of the pharmaceutically acceptable salt of the compound represented by formula (I), formula (I ′), formula (I ′′), formula (II) and the like include, for example, a compound represented by formula (I), an alkali Metals (eg, lithium, sodium, potassium, etc.), alkaline earth metals (eg, calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexyl) Amine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphorous) Acids, hydroiodic acid, etc.) and organic acids (eg formic acid, acetic acid, propionic acid) Triflu
  • salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.
  • the compound represented by the formula (I), formula (I ′), formula (I ′′), formula (II) or the like of the present invention or a pharmaceutically acceptable salt thereof is a solvate (for example, hydrate etc. ) And / or crystalline polymorphs, and the present invention also encompasses such various solvates and crystalline polymorphs.
  • the “solvate” is an arbitrary number of solvent molecules (for example, water molecules) with respect to the compounds represented by formula (I), formula (I ′), formula (I ′′), formula (II), etc.
  • the compound represented by the formula (I), the formula (I ′), the formula (I ′′), the formula (II) or the like or a pharmaceutically acceptable salt thereof is left in the atmosphere to absorb moisture, Adsorbed water may adhere or a hydrate may be formed. Further, by recrystallizing the compound represented by the formula (I), the formula (I ′), the formula (I ′′), the formula (II) or the like or a pharmaceutically acceptable salt thereof, the crystal polymorphs thereof are obtained. May form.
  • the compound represented by the formula (I), formula (I ′), formula (I ′′), formula (II) or the like of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug.
  • the invention also encompasses such various prodrugs.
  • a prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo.
  • a prodrug is represented by the formula (I), formula (I ′), formula (I ′′), formula (II), etc. after enzymatically oxidizing, reducing, hydrolyzing and the like under physiological conditions in vivo. Including compounds converted into compounds, compounds that are hydrolyzed by gastric acid, etc., and converted into compounds represented by formula (I), formula (I ′), formula (I ′′), formula (II), etc. .
  • prodrugs such as derivatives.
  • the compounds represented by the above general formula (I), formula (I ′), formula (I ′′), formula (II) and the like have an antagonistic action on the P2X 3 and / or P2X 2/3 receptor, It is useful as a therapeutic agent for diseases involving P2X 3 and / or P2X 2/3 .
  • P2X 3 and / or P2X 2/3 receptor is believed to be involved in pain, urinary system diseases, and respiratory diseases (Nature 407, 26, 1011-1015 ( 2000), Nature, Vol.407, No.26 , 1015-1017 (2000), Non-Patent Document 1, Non-Patent Document 2, Non-Patent Documents 9 to 11, etc.), and is useful as a pharmaceutical composition having an analgesic action or an urination disorder improving action.
  • pain associated with rheumatoid arthritis pain associated with osteoarthritis, headache, migraine, oral and facial pain, toothache, glossodynia, pain associated with temporomandibular disorders, trigeminal neuralgia, shoulder pain, pain associated with disc herniation, Pain associated with degenerative cervical spondylosis, pain associated with spinal stenosis, pain associated with thoracic outlet syndrome, pain associated with brachial plexus withdrawal syndrome, shoulder-hand syndrome, pain associated with whiplash, chest pain, abdominal pain, colic, cholelithiasis Pain associated with pancreatitis, pain associated with urolithiasis, pain associated with irritable bowel syndrome, low back pain, sciatica, pain associated with fracture, pain associated with osteoporosis, joint pain, pain associated with gout, Pain associated with cauda equina syndrome, pain associated with ankylosing spinal inflammation, muscle pain, painful spasm, myofascial pain syndrome, fibromyalg
  • the “pharmaceutical composition having an effect of improving urination disorder” includes a pharmaceutical composition used for the treatment, prevention and / or improvement of the above-mentioned urination disorder.
  • ATP receptor especially high affinity for P2X 3 receptor
  • ATP receptor has high selectivity for subtype selectivity and other receptors, side effects (e.g., motion It can be a medicine with reduced functions).
  • the compound included in the present invention or the pharmaceutical composition included in the present invention has high P2X 3 receptor inhibitory activity in the presence of RSA, high metabolic stability, high oral absorption, high solubility, It also has advantages such as good bioavailability, low clearance, long half-life, high drug sustainability, low liver enzyme inhibitory activity, high protein non-binding rate, and / or high safety.
  • Oral administration may be carried out by preparing a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods.
  • a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods.
  • parenteral administration any commonly used dosage form such as an injection can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.
  • отное отное отное отное отное о ⁇ ное ком ⁇ онентs such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
  • the dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
  • reaction solution was stirred for 1 hour under ice-cooling, and further stirred at room temperature for 1 hour.
  • 2 mol / L hydrochloric acid (1.16 L) was added at 20 ° C. over 1 hour.
  • the resulting powder was collected by filtration, and 3-ethyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (73.0 g, yield: 88%) Obtained as a brown powder.
  • 1,1′-carbonyldiimidazole (7.71 g, 47.6 mmol) was added to the reaction solution, and then DBU (7.17 ml, 47.6 mmol) was added at 0 ° C. over 1 hour. After stirring at room temperature for 1 hour, the mixture was stirred at 45 ° C. for 4 hours. To the reaction solution, 2 mol / L hydrochloric acid (200 ml) was added dropwise under ice cooling.
  • the reaction mixture was ammonium chloride (39 mg, 7.20 mmol), 1-hydroxybenzotriazole hydrate (110 mg, 7.2 mmol), 4-dimethylaminopyridine (7.3 mg, 0.06 mmol), 1-ethyl-3- ( 3-Dimethylaminopropyl) carbodiimide (138 mg, 0.72 mmol) and triethylamine (0.1 mL, 0.72 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL).
  • triphenylphosphine (478 mg, 1.82 mmol) and dimethoxyethyl azadicarboxylate (478 mg, 1.82 mmol) were added, and the mixture was stirred at room temperature for 4 hours.
  • the reaction solution was concentrated under reduced pressure, and diethyl ether was added to the resulting residue.
  • the resulting powder was removed by filtration. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • 3-Aminopropanenitrile (20.0 g, 285 mmol) was dissolved in DMA (80 mL). Under ice cooling, 1,1′-carbonyldiimidazole (48.6 g, 300 mmol) and DBU (64.5 mL, 428 mmol) were slowly added to the reaction solution, followed by stirring at 0 ° C. for 30 minutes.
  • 1-Amidinopyrazole hydrochloride (41.8 g, 235 mmol) and DBU (47.3 mL, 314 mmol) were added to the reaction solution, and the mixture was stirred for 50 minutes under ice cooling.
  • 1,1′-carbonyldiimidazole 48.6 g, 300 mmol was added to the reaction solution under ice cooling, then DBU (66.7 mL, 442 mmol) was added at 0 ° C., and the mixture was stirred at 80 ° C. for 1 hour. Furthermore, 1,1′-carbonyldiimidazole (27.8 g, 171 mmol) and DBU (25.8 mL, 171 mmol) were added, and the mixture was stirred at 80 ° C. for 2 hours. 2 mol / L hydrochloric acid (1.57 L) was added to the reaction solution at 20 ° C., and ice (1 kg) was added with stirring.
  • reaction solution was purified by high performance liquid chromatography (acetonitrile / water containing 0.3% formic acid) to give 1- (4-chlorobenzyl) -3- (2-cyanoethyl) -6- [4- (4-hydroxycarbonyl-2- Pyridyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (I-227, 0.288 g, yield: 66.0%) was obtained as a colorless powder.
  • Test Example Test Example 1-1 1 stably expressing cell lines by introducing the human P2X 3 receptor inhibitory activity evaluation human P2X 3 receptor gene (GenBank Accession sequence Y07683) to C6BU-1 cells in PDL coated 96-well microplate Seeded to 8000 per well, in a medium (DMEM containing 8.3% fetal calf serum, 8.3% horse serum, 1% antibiotic antifungal mixed solution) at 37 ° C., 5% dioxide Incubated for 1 day under carbon.
  • DMEM containing 8.3% fetal calf serum, 8.3% horse serum, 1% antibiotic antifungal mixed solution
  • the medium was supplemented with 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA 0.08% Pluronic F-127, pH 7.5) and incubated at 37 ° C. under 5% carbon dioxide for 1 hour.
  • 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA 0.08% Pluronic F-127, pH 7.5
  • wash buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5) per well Filled with 40 ⁇ L of wash buffer.
  • the microplate was installed in a high-throughput screening system FDSS 3000 (Hamamatsu Photonics).
  • Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid) , 0.1% Pluronic F-127, pH 7.5)
  • dilution buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid
  • Pluronic F-127 pH 7.5
  • the ratio maximum fluorescence intensity which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, was calculated for each hole of the microplate.
  • concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%.
  • IC 50 was calculated to evaluate the inhibitory activity of the compound of the present invention.
  • the specific maximum fluorescence intensity was calculated using FDSS software (Hamamatsu Photonics).
  • IC 50 was calculated using Microsoft Excel (Microsoft) and XLfit (idbs) software.
  • the test results of the compounds of the present invention are shown in the following table.
  • Test Example 1-2 Human P2X 3 Evaluation of the receptor inhibitory activity human P2X 3 receptor gene per well of stably expressing cell lines by introducing (GenBank Accession sequence Y07683) to C6BU-1 cells in PDL coated 96-well microplate Seeded to 8000 cells in medium (7.0% fetal calf serum, 7.0% horse serum, DMEM containing 1% antibiotic antifungal mixed solution) at 37 ° C. under 5% carbon dioxide Incubate for 1 day.
  • the medium was supplemented with 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 1% BSA, 0.08% Pluronic F-127, pH 7.5) and incubate for 1 hour at 37 ° C., 5% carbon dioxide.
  • 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 1% BSA, 0.08% Pluronic F-127, pH 7.5
  • wash with washing buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5), 1 well Fill with 40 ⁇ L of wash buffer.
  • the microplate is installed in the high-throughput screening system FDSS 3000 (Hamamatsu Photonics).
  • Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid) , 0.1% Pluronic F-127, pH 7.5)
  • dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid
  • Pluronic F-127 pH 7.5
  • the DMSO solution of the present invention diluted to have different concentrations is dispensed by 40 ⁇ L per well with an automatic dispensing device built in the FDSS 3000.
  • the ratio maximum fluorescence intensity which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, is calculated for each hole of the microplate.
  • concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%.
  • IC 50 is calculated to evaluate the inhibitory activity of the compound of the present invention.
  • the specific maximum fluorescence intensity is calculated using FDSS software (Hamamatsu Photonics).
  • IC 50 is calculated using software of Microsoft Excel (Microsoft) and XLfit (idbs).
  • Test Example 1-3 Human P2X 3 Evaluation of the receptor inhibitory activity human P2X 3 receptor gene per well of stably expressing cell lines by introducing (GenBank Accession sequence Y07683) to C6BU-1 cells PDL coated 384-well microplates 3000 seeds were seeded and cultured in a medium (DMEM containing 8.3% fetal bovine serum, 8.3% horse serum, 1% antibiotic antifungal mixed solution) at 37 ° C. under 5% carbon dioxide. For 2 days.
  • DMEM containing 8.3% fetal bovine serum, 8.3% horse serum, 1% antibiotic antifungal mixed solution
  • the medium was supplemented with 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 0.5 % BSA, 0.04% Pluronic F-127, pH 7.5) and incubated at 37 ° C. under 5% carbon dioxide for 1 hour.
  • 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 0.5 % BSA, 0.04% Pluronic F-127, pH 7.5
  • wash buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5) per well Filled with 20 ⁇ L of wash buffer.
  • the microplate was installed in a high throughput screening system FLIPR 384 (Molecular Devices).
  • the ratio maximum fluorescence intensity which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, was calculated for each hole of the microplate.
  • the concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC 50 ) was calculated to evaluate the inhibitory activity of the compound of the present invention.
  • the specific maximum fluorescence intensity and IC 50 were calculated using software from Spotfire (Science Technology Systems). The test results of the compounds of the present invention are shown in the following table.
  • Test Example 2-1 was expressed by introducing the rat P2X 3 Rating rat P2X 3 receptor gene of the receptor inhibitory activity (GenBank Accession sequence NM_031075) to C6BU-1 cells.
  • C6BU-1 cells were seeded at 2500 cells per well and cultured in a medium (DMEM containing 8.3% fetal bovine serum, 8.3% horse serum, 1% antibiotic antifungal mixed solution). The cells were cultured at 5 ° C. for 5 days at 5 ° C.
  • the expression plasmid was introduced using a gene introduction reagent FuGENE6 (Roche) and further cultured at 37 ° C. under 5% carbon dioxide for 1 day.
  • the medium was supplemented with 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA 0.08% Pluronic F-127, pH 7.5) and incubated at 37 ° C. under 5% carbon dioxide for 1 hour.
  • 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA 0.08% Pluronic F-127, pH 7.5
  • wash buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5) per well Filled with 40 ⁇ L of wash buffer.
  • the microplate was installed in a high-throughput screening system FDSS 3000 (Hamamatsu Photonics).
  • Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid) , 0.1% pluronic F-127, pH 7.5), and the DMSO solution of the compound of the present invention diluted to different concentrations with an automatic dispensing device built in FDSS 3000, 40 ⁇ L per well. did.
  • the ratio maximum fluorescence intensity which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, was calculated for each hole of the microplate.
  • concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%.
  • IC 50 was calculated to evaluate the inhibitory activity of the compound of the present invention.
  • the specific maximum fluorescence intensity was calculated using FDSS software (Hamamatsu Photonics).
  • IC 50 was calculated using Microsoft Excel (Microsoft) and XLfit (idbs) software.
  • the test results of the compounds of the present invention are shown in the following table.
  • Test Example 2-2 introducing and expressing rat P2X 3 Rating rat P2X 3 receptor gene of the receptor inhibitory activity (GenBank Accession sequence NM_031075) to C6BU-1 cells.
  • C6BU-1 cells were seeded at 2500 cells per well and cultured in a medium (DMEM containing 7.0% fetal bovine serum, 7.0% horse serum, 1% antibiotic antifungal mixed solution). Incubate for 1 day at 5 ° C. and 5% carbon dioxide.
  • An expression plasmid is introduced using a gene introduction reagent FuGENE6 (manufactured by Promega) and further cultured at 37 ° C. under 5% carbon dioxide for 1 day.
  • the medium was supplemented with 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 1% BSA, 0.08% Pluronic F-127, pH 7.5) and incubate for 1 hour at 37 ° C., 5% carbon dioxide.
  • 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 1% BSA, 0.08% Pluronic F-127, pH 7.5
  • wash with washing buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5), 1 well Filled with 40 ⁇ L of wash buffer per minute.
  • the microplate is installed in the high-throughput screening system FDSS 3000 (Hamamatsu Photonics).
  • Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid) , 0.1% Pluronic F-127, pH 7.5) is used to dispense 40 ⁇ L of the DMSO solution of the compound of the present invention diluted to different concentrations with an automatic dispensing device built in FDSS 3000 per well. To do.
  • the ratio maximum fluorescence intensity which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, is calculated for each hole of the microplate.
  • concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%.
  • IC 50 is calculated to evaluate the inhibitory activity of the compound of the present invention.
  • the specific maximum fluorescence intensity is calculated using FDSS software (Hamamatsu Photonics).
  • IC 50 is calculated using software of Microsoft Excel (Microsoft) and XLfit (idbs).
  • Test Example 3-1 was expressed by introducing rat serum albumin (RSA) Evaluation rat P2X 3 receptor gene of the rat P2X3 receptor inhibitory activity in the presence of a (GenBank Accession sequence NM_031075) to C6BU-1 cells.
  • C6BU-1 cells were seeded at 2500 cells per well and cultured in a medium (DMEM containing 8.3% fetal bovine serum, 8.3% horse serum, 1% antibiotic antifungal mixed solution). The cells were cultured at 5 ° C. for 5 days at 5 ° C.
  • the expression plasmid was introduced using a gene introduction reagent FuGENE6 (Roche) and further cultured at 37 ° C. under 5% carbon dioxide for 1 day.
  • the medium was supplemented with 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA 0.08% Pluronic F-127, pH 7.5) and incubated at 37 ° C. under 5% carbon dioxide for 1 hour.
  • 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA 0.08% Pluronic F-127, pH 7.5
  • wash buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5) per well Filled with 40 ⁇ L of wash buffer.
  • the microplate was installed in a high-throughput screening system FDSS 3000 (Hamamatsu Photonics).
  • Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid) 1 solution of DMSO solution of the compound of the present invention diluted to different concentrations using a solution in which rat serum albumin is added to 0.1% Pluronic F-127, pH 7.5) to a final concentration of 1% Each 40 ⁇ L was dispensed by an automatic dispensing device built in the FDSS 3000.
  • the ratio maximum fluorescence intensity which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, was calculated for each hole of the microplate.
  • concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%.
  • IC 50 was calculated to evaluate the inhibitory activity of the compound of the present invention.
  • the specific maximum fluorescence intensity was calculated using FDSS software (Hamamatsu Photonics).
  • IC 50 was calculated using software from Microsoft Excel (Microsoft) and XLfit (idbs). The test results of the compounds of the present invention are shown in the following table.
  • Test Example 3-2 introducing and expressing rat serum albumin (RSA) Evaluation rat P2X 3 receptor gene of the rat P2X3 receptor inhibitory activity in the presence of a (GenBank Accession sequence NM_031075) to C6BU-1 cells.
  • C6BU-1 cells were seeded at 2500 cells per well and cultured in a medium (DMEM containing 7.0% fetal bovine serum, 7.0% horse serum, 1% antibiotic antifungal mixed solution). Incubate for 1 day at 5 ° C. and 5% carbon dioxide.
  • An expression plasmid is introduced using a gene introduction reagent FuGENE6 (manufactured by Promega) and further cultured at 37 ° C. under 5% carbon dioxide for 1 day.
  • the medium was supplemented with 4 ⁇ M Fluo-4-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA, 0.08% Pluronic F-127, pH 7.5) and incubate for 1 hour at 37 ° C., 5% carbon dioxide.
  • 4 ⁇ M Fluo-4-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA, 0.08% Pluronic F-127, pH 7.5
  • wash with washing buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5), 1 well Fill with 40 ⁇ L of wash buffer.
  • the microplate is installed in the high-throughput screening system FDSS 3000 (Hamamatsu Photonics).
  • Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid) 1 solution of DMSO solution of the compound of the present invention diluted to different concentrations using a solution in which rat serum albumin is added to 0.1% Pluronic F-127, pH 7.5) to a final concentration of 1% Dispense 40 ⁇ L per unit with an automatic dispenser built in FDSS 3000.
  • dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid
  • the ratio maximum fluorescence intensity which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, is calculated for each hole of the microplate.
  • concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%.
  • IC 50 is calculated to evaluate the inhibitory activity of the compound of the present invention.
  • the specific maximum fluorescence intensity is calculated using FDSS software (Hamamatsu Photonics).
  • IC 50 is calculated using software from Microsoft Excel (Microsoft) and XLfit (idbs).
  • the compounds described herein exhibit inhibitory activity against P2X 3 receptor.
  • the compound of the present invention acts on the P2X 3 subtype, it is considered that the compound of the present invention also exhibits inhibitory activity against the P2X 2/3 receptor that is also composed of the P2X 2 subtype.
  • PE-50 Polyethylene tube
  • the cannula led to the back is protected by a stainless steel spring and connected to a sieve.
  • Acetic acid injection Two days after surgery, 0.3% acetic acid is injected into the bladder at a rate of 4 mL / hr for 30 minutes via a cannula placed in the bladder to induce cystitis. An animal that is not injected with acetic acid is defined as a normal animal.
  • Cystometry measurement Two to three days after acetic acid injection, connect the other end of the cannula inserted into the bladder to a three-way stopcock, and inject the heated physiological saline from one side at a rate of 3.0 mL / hr, The intravesical pressure is continuously recorded by a pressure amplifier through a pressure transducer.
  • the intravesical pressure is measured for a stable period (about 20 minutes), followed by a pre-dose value (about 40 minutes), and after administration of the test substance, a post-dose value is measured for 120 minutes.
  • the compound of the present invention is crushed using a mortar and pestle, and a suspension or solution is prepared using 0.5% methylcellulose solution to a concentration of 0.1 to 2 mg / mL / kg. Oral administration. Simultaneously with the measurement of intravesical pressure, excreted urine is received on a balance under the cage, and its weight change is measured simultaneously. Criteria for data adoption Based on the urination interval, those with a urination interval of 10 minutes or more are adopted for normal animals, and those with less than that are excluded.
  • cystitis animals For animals that have been injected with acetic acid, those with a micturition interval of less than half of the mean value for normal animals are adopted as cystitis animals, and those beyond that are excluded. Collection of residual urine After the measurement is completed, stop injection of physiological saline immediately after urination and collect residual urine under anesthesia with sodium pentobarbital. The collected residual urine is transferred to the excretion receptacle and recorded on the chart. Analysis items Analyze the intravesical pressure (static pressure and urination pressure), urination interval, and single urination volume 1 hour to 2 hours after the start of measurement. In addition, the amount of residual urine after the measurement is analyzed. The following values are used as indicators of the effect on the urination interval.
  • Test Example 5 Evaluation of drug efficacy using the Seltzer model Rat Partial sciatic nerve ligation model (rat sciatic nerve partial ligation model) Model preparation Rats were anesthetized with isoflurane and the hair on the left foot was shaved. The skin at the upper thigh was incised, and the muscle was broken to expose the sciatic nerve. 1/3 to 1/2 of the sciatic nerve was strongly ligated with a thread, and the muscle and skin were sutured. This was the operation side. The right foot was treated in the same manner as sciatic nerve ligation, and the sham operation was performed. Evaluation (1) Two weeks after surgery, the effect on tactile allodynia was assessed by von Frey filament.
  • the compound of the present invention is crushed using a mortar and pestle, and a suspension or solution is prepared using 0.5% methylcellulose solution to a concentration of 0.1 to 2 mg / mL / kg. Orally administered. From 1 to 5 hours after administration, the pain threshold value of the left and right hind limbs was evaluated and used as a post-treatment pain threshold value. The% reversal value was calculated by the following method, and the analgesic action of the compounds was compared.
  • % reversal value (logarithm of pain threshold after operation side treatment-logarithm of pain threshold value before operation side treatment) / (logarithm of pain threshold value before surgery side treatment-logarithm of pain threshold value before operation side treatment)
  • the test results of the compounds of the present invention are shown in the following table.
  • the analgesic action of the compound of the present invention after 3 hours of oral administration at 3 mg / kg is shown in the following table as% reversal.
  • Analgesiometer is used to evaluate the effect on mechanical hyperalgesia. Two weeks after the operation, the rat's hind limb is compressed by an analgesiometer so as to increase the stimulation pressure by 16 g per second, and the pressure when the rat exhibits escape behavior is set as a pain threshold. Pain thresholds are evaluated for the left and right hind limbs and set as pre-treatment pain thresholds. Animals with a surgical threshold of 60-90 g and a sham surgical threshold of 100-175 g are employed. In order to train the animal, the same operation is performed before measuring the pre-treatment pain threshold. The compound of the present invention is administered to the adopted animal.
  • the compound of the present invention is crushed using a mortar and pestle, and a suspension or solution is prepared with a 0.5% methylcellulose solution to 0.03 to 100 mg / 2 mL / kg. Orally. 1 to 5 hours after administration, the pain threshold value of the left and right hind limbs is evaluated and set as a post-treatment pain threshold value.
  • CYP3A4 Fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of compounds by metabolic reaction.
  • 7-Benzyloxytrifluoromethylcoumarin (BFC) is CYP3A4 using E. coli-expressed CYP3A4 as an enzyme. The reaction was debenzylated with an enzyme to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (HFC) as an indicator.
  • reaction conditions are as follows: substrate, 5.6 ⁇ mol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), pre- 62.5 pmol / mL during reaction, 6.25 pmol / mL during reaction (10-fold dilution); drug concentration of the present invention, 1.56, 3.125, 6.25, 12.5, 25, 50 ⁇ mol / L (6 points).
  • the control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration of the drug solution of the present invention was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model. The case where the difference in IC 50 value was 5 ⁇ mol / L or more was designated as (+), and the case where it was 3 ⁇ mol / L or less was designated as ( ⁇ ).
  • the test results of the compounds of the present invention are shown in the following table.
  • Test Example 7 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4'-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadine hydroxylation (CYP3A4) The degree to which the amount of metabolite produced was inhibited by the compound of the present invention was evaluated.
  • reaction conditions are as follows: substrate, 0.5 ⁇ mol / L ethoxyresorufin (CYP1A2), 100 ⁇ mol / L tolbutamide (CYP2C9), 50 ⁇ mol / L S-mephenytoin (CYP2C19), 5 ⁇ mol / L dextromethorphan (CYP2D6) ), 1 ⁇ mol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; drug concentration of the present invention, 1.0, 5.0, 10, 20 ⁇ mol / L ( 4 points).
  • each of 5 types of substrates, human liver microsomes, and the drug of the present invention was added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH, a coenzyme, was added as an indicator for metabolism.
  • resorufin CYP1A2 metabolite
  • CYP1A2 metabolite resorufin in the supernatant of the centrifugation was collected using a fluorescent multilabel counter with tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite).
  • dextrorphan CYP2D6 metabolite
  • CYP3A4 metabolite terfenadine alcohol
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration of the drug solution of the present invention was calculated.
  • the IC 50 was calculated by inverse estimation using a logistic model. The test results of the compounds of the present invention are shown in the following table.
  • Test Example 8-1 FAT test (Fluctuation Ames Test) Twenty microliters of Salmonella typhimurium TA98 and TA100 were cryopreserved and inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutrient broth No. 2), and cultured at 37 ° C. for 10 hours before shaking.
  • Test substance DMSO solution (maximum dose 50mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as negative control, 50 ⁇ g / mL for TA98 strain under non-metabolic activation conditions as positive control Nitroquinoline-1-oxide in DMSO solution, TA100 strain, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution, TA98 strain under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for TA100 strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for TA100 strain, respectively, and 588 ⁇ L of the test bacterial solution (under the metabolic activation conditions, the test bacterial solution 498 ⁇ L and S9 mix 90 ⁇ L) were mixed and cultured at 37 ° C.
  • Indicator Medium containing biotin: 8 ⁇ g / mL, histidine: 0.2 ⁇ g / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 ⁇ g / mL
  • Test Example 8-2 FAT test Fluctuation Ames Test The mutagenicity of the compound of the present invention is evaluated. 20 ⁇ L of Salmonella typhimurium TA98 strain, TA100 strain, which had been cryopreserved, was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 7.70 mL of the bacterial solution is centrifuged (2000 ⁇ g, 10 minutes) to remove the culture solution. 7.
  • Micro F buffer K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate:
  • the cells are suspended in 0.25 g / L, MgSO 4 ⁇ 7H 2 0: 0.1 g / L), and 110 mL of Exposure medium (biotin: 8 ⁇ g / mL, histidine: 0.2 ⁇ g / mL, glucose: 8 mg / mL)
  • Exposure medium biotin: 8 ⁇ g / mL, histidine: 0.2 ⁇ g / mL, glucose: 8 mg / mL
  • TA100 strain is added to 120 mL of Exposure medium with respect to 3.42 mL bacterial solution to prepare a test bacterial solution.
  • Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 ⁇ g / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 ⁇ g / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 ⁇ g / mL 2-aminoanthracene DMSO solution for the strain and 20 ⁇ g / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 ⁇ L of the test bacterial solution (498 ⁇ L of the test bacterial solution and S9 under metabolic activation conditions).
  • Test Example 10 Metabolic Stability Test Using a commercially available pooled human liver microsome, the target compound is reacted for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism in the liver.
  • test compound in the centrifugal supernatant was quantified by LC / MS / MS, and the remaining amount of the test compound after the reaction was calculated with the amount of the compound at 0 minute reaction as 100%.
  • the test results of the compounds of the present invention are shown in the following table. The residual ratio at a compound concentration of 0.5 ⁇ mol / L is shown as%. The test result of I-362 was 92%.
  • HEK293 cells expressing a human ether-a-go-related gene (hERG) channel were used for the ventricular repolarization process.
  • I Kr delayed rectifier K + current
  • the cell was held at a membrane potential of ⁇ 80 mV by the whole cell patch clamp method, a leak potential of ⁇ 50 mV was applied, and then a depolarization stimulus of +40 mV was applied.
  • the absolute value of the maximum tail current was measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 2, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention was calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr was evaluated. (Result) The inhibition rate at a compound concentration of 1 ⁇ mol / L is shown.
  • hERG Test Example 11-2 For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, CHO cells expressing human ether-a-go related gene (hERG) channels were used for ventricular repolarization process.
  • hERG human ether-a-go related gene
  • the cell was held at a membrane potential of ⁇ 80 mV by a whole cell patch clamp method, and after applying a leak potential of ⁇ 50 mV, a depolarization stimulus of +20 mV for 2 seconds, further records the I Kr induced repolarization stimulated when given 2 seconds -50 mV.
  • an extracellular solution NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol
  • an extracellular solution NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol
  • Test Example 12 Metabolic stability test Using prepared rat cryopreserved hepatocytes, the target compound is allowed to react for a certain period of time, the residual rate is calculated by comparing the reaction sample with the unreacted sample, and the degree of metabolism in the liver is evaluated. To do.
  • Test Example 13 Protein binding test The serum protein non-binding rate of the inventive compound was measured using various sera.
  • Reaction conditions are as follows: evaluation method, equilibrium dialysis method; reaction time, 24 hours; reaction temperature, 37 ° C .; inventive compound concentration, 2 ⁇ g / mL.
  • Test solutions were added to various sera and stirred to prepare serum samples having the above compound concentrations.
  • a serum sample was added to one of the equilibrium dialysis cells, and phosphate buffered saline (PBS) was added to the other, followed by equilibrium dialysis at 37 ° C. for 24 hours.
  • PBS phosphate buffered saline
  • the amount of compound in the sample collected from each cell was measured by LC / MS / MS.
  • the test results of the compounds of the present invention are shown in the following table.
  • the ratio of the amount of compound in PBS to the amount of compound in serum is shown as protein non-binding rate (%).
  • Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
  • the bioavailability (BA) of the compound of the present invention was calculated from the dose ratio of the group and the AUC ratio.
  • the test results of the compounds of the present invention are shown in the following table.
  • Test Example 15 Powder solubility test An appropriate amount of the compound of the present invention is placed in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid is added to 1000 mL) and JP-2 solution are added to each container. (Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) 200 ⁇ L each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C.
  • the compound of the present invention is quantified using HPLC by the absolute calibration curve method.
  • Formulation Examples are merely illustrative and are not intended to limit the scope of the invention.
  • Formulation Example 1 Tablet 15 mg of the present compound Lactose 15mg Calcium stearate 3mg Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
  • Formulation Example 2 Capsule Compound of the present invention 10 mg Magnesium stearate 10mg Lactose 80mg Are mixed uniformly to form a powder as a powder or fine particles. It is filled into a capsule container to form a capsule.
  • Formulation Example 3 Granules Compound of the present invention 30 g Lactose 265g Magnesium stearate 5g After mixing well, compression molding, pulverizing, sizing, and sieving to make granules of appropriate size.
  • Compound represented by the general formula (I) and formula (II), have an antagonistic effect on P2X 3 and / or P2X 2/3 receptor, diseases P2X 3 and / or P2X 2/3 receptor is involved Or it may be useful for conditions such as chronic pain, dysuria, respiratory disease.

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Abstract

The present invention provides a novel compound that has P2X3 and/or P2X2/3 receptor antagonist activity, for example, a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (In the formula, Ra and Rb as well as Rd and Re are both hydrogen atoms or the like; Rc represents a hydrogen atom or the like; each of R4a and R4b represents a hydrogen atom or the like; n represents 1 or the like; R2 represents a cycloalkyl group or the like; each of -X- and -L- represents -O-, -S- or the like; ring D represents a benzene ring or the like; carbon atoms a and b are carbon atoms; ring B represents an aromatic carbon ring or the like; each of s and s' represents 0 or the like; and each of R9 and R9' represents a halogen group or the like.)

Description

置換トリアジン誘導体およびそれらを含有する医薬組成物Substituted triazine derivatives and pharmaceutical compositions containing them
 本発明は、P2X受容体、特にP2X3および/またはP2X2/3受容体が関与する疾患または状態を治療するのに有用な化合物、および該化合物を含有する医薬組成物に関する。 The present invention relates to compounds useful for treating diseases or conditions involving P2X receptors, particularly P2X 3 and / or P2X 2/3 receptors, and pharmaceutical compositions containing such compounds.
 アデノシン3リン酸(ATP)は、細胞内におけるエネルギー源やリン酸化基質として知られている。一方、細胞外における情報伝達物質としても働くことも知られている。さらに、ATPは、細胞の損傷、炎症、侵害刺激、血中酸素濃度の低下など様々な刺激により細胞外へ放出されること、他の神経伝達物質とともに一次感覚神経終末から細胞外へ放出されることが知られている。細胞外へ放出されたATPは、ATP受容体を介して各種の細胞外情報伝達を行う(非特許文献4、非特許文献5)。 Adenosine triphosphate (ATP) is known as an intracellular energy source and phosphorylated substrate. On the other hand, it is also known to work as an extracellular information transmission substance. Furthermore, ATP is released to the outside of cells by various stimuli such as cell damage, inflammation, nociceptive stimulation, reduction of blood oxygen concentration, and released from the primary sensory nerve ending together with other neurotransmitters. It is known. ATP released to the outside of the cell performs various extracellular information transmission via the ATP receptor (Non-patent Documents 4 and 5).
 ATP受容体は、イオンチャネル型のP2XファミリーとGタンパク質共役型のP2Yファミリーに大別される。P2X受容体ファミリーには7種類のサブタイプが報告されており、ホモ3量体または他のP2Xサブタイプとのヘテロ3量体を形成して非選択的カチオンチャネルとして機能する(非特許文献6)。 ATP receptors are roughly classified into an ion channel type P2X family and a G protein coupled type P2Y family. Seven types of subtypes have been reported in the P2X receptor family, and function as non-selective cation channels by forming homotrimers or heterotrimers with other P2X subtypes (Non-patent Document 6). ).
 ATPが痛みを引き起こすことは既に知られており、さらにP2X3のノックアウトやノックダウン技術を用いた研究により、P2X3受容体は慢性疼痛の伝達に関与していることが示された。P2X3受容体は末梢感覚神経特異的に発現し、ホモ複合体またはP2X2とのヘテロ複合体(P2X2/3)を形成する。(非特許文献1) It is already known that ATP causes pain, and studies using P2X 3 knockout and knockdown techniques have shown that the P2X 3 receptor is involved in the transmission of chronic pain. P2X 3 receptors peripheral sensory nerves specifically expressed to form hetero-complex with homo complex or P2X 2 a (P2X 2/3). (Non-Patent Document 1)
 その後、P2X3およびP2X2/3受容体に特異的な拮抗剤としてA-317491と称する化合物が報告された。A-317491は、次式: Subsequently, a compound called A-317491 was reported as an antagonist specific for the P2X 3 and P2X 2/3 receptors. A-317491 has the following formula:
Figure JPOXMLDOC01-appb-C000011

で示されるトリ置換-N-[(1S)-1,2,3,4-テトラヒドロ-1-タフタレニル]ベンズアミド誘導体であり(特許文献1)、P2X3およびP2X2/3受容体に対して拮抗活性を示し、ラットの神経障害性疼痛モデル、および炎症性疼痛モデルにおいて鎮痛作用を示したことが報告されている(非特許文献7)。このことは、P2X3またはP2X2/3受容体を介して痛覚が伝達されること、そしてP2X3またはP2X2/3受容体拮抗作用を有する化合物が鎮痛薬として有用であることを示している。また、特許文献2~7にもP2X3またはP2X2/3受容体拮抗作用を示す化合物が記載されている。
Figure JPOXMLDOC01-appb-C000011

Is a tri-substituted-N-[(1S) -1,2,3,4-tetrahydro-1-taphthalenyl] benzamide derivative (Patent Document 1), which antagonizes P2X 3 and P2X 2/3 receptors It has been reported that it showed activity and showed analgesic action in a rat neuropathic pain model and inflammatory pain model (Non-patent Document 7). This indicates that it pain via the P2X 3 or P2X 2/3 receptor is transmitted, and P2X 3 or P2X 2/3 compounds with receptor antagonistic activity are useful as analgesics . Patent Documents 2 to 7 also describe compounds exhibiting P2X 3 or P2X 2/3 receptor antagonism.
 また、P2X3ノックアウトマウスが、顕著な膀胱反射低下を示すことが近年報告されており(非特許文献2)、P2X3受容体拮抗作用を有する化合物が、排尿の機能異常を伴う疾患の治療においても有用であることを示唆している。また、特許文献2~7にはP2X3またはP2X2/3受容体拮抗作用を示す化合物が記載されている。 In addition, it has recently been reported that P2X 3 knockout mice show a marked decrease in bladder reflex (Non-patent Document 2), and a compound having a P2X 3 receptor antagonistic action is used in the treatment of diseases associated with abnormal urination function. It also suggests that it is useful. Patent Documents 2 to 7 describe compounds exhibiting P2X 3 or P2X 2/3 receptor antagonism.
 さらに、P2X3受容体が肺の神経上皮小体(NEB)に発現していること(非特許文献9)およびATPが咳を誘発すること(非特許文献10)等から、P2X3受容体が呼吸器での情報伝達に関与していることが示唆されている(非特許文献11)。これらの報告は、P2X3受容体拮抗作用を有する化合物が、呼吸器疾患の治療において有用である可能性を示唆している。 Furthermore, P2X 3 that the receptor is expressed in neuroepithelial bodies (NEB) of the lungs (Non-Patent Document 9), and ATP-induced cough (Non-Patent Document 10), etc., P2X 3 receptors It has been suggested that it is involved in information transmission in the respiratory organs (Non-patent Document 11). These reports, compounds having a P2X 3 receptor antagonism, suggesting potential utility in the treatment of respiratory diseases.
その後、P2X3およびP2X2/3受容体拮抗剤として知られる、上記A-317491と称する化合物が、肺疾患の迷走神経求心性A線維の活性を阻害することが報告されている(特許文献 WO2006/012639)。
 また、P2X3および/またはP2X2/3受容体拮抗剤としてビフェニルおよびフェニル-ピリジン誘導体が報告され、喘息および肺機能モデルにおいて呼吸器疾患の改善作用を示すことが示唆されている(特許文献 WO2010/149578)。また、特許文献2~7にはP2X3またはP2X2/3受容体拮抗作用を示す化合物が記載されている。
Thereafter, a compound called A-317491, known as a P2X 3 and P2X 2/3 receptor antagonist, has been reported to inhibit the activity of vagal afferent A fibers in lung diseases (Patent Document WO2006). / 012639).
In addition, biphenyl and phenyl-pyridine derivatives have been reported as P2X 3 and / or P2X 2/3 receptor antagonists, suggesting that they have an action to improve respiratory diseases in asthma and lung function models (Patent Document WO2010). / 149578). Patent Documents 2 to 7 describe compounds exhibiting P2X 3 or P2X 2/3 receptor antagonism.
 特許文献8、9、10、11および15および非特許文献14には、本発明化合物と類似の構造を有する化合物が記載されているが、鎮痛作用およびP2X3またはP2X2/3受容体拮抗作用については記載されていない。また、非特許文献8には、本発明化合物と類似の構造を有し、鎮痛活性を示す化合物が記載されているが、P2X3またはP2X2/3受容体拮抗作用については記載されていない。特許文献12、非特許文献12および13には、P2X3受容体拮抗作用を有する化合物が記載されているが、本発明化合物と構造が異なる。特許文献13および特許文献14には、トリアジン骨格を有するP2X3またはP2X2/3受容体拮抗作用を有する化合物が記載されている。
Patent Documents 8, 9, 10, 11 and 15 and Non-Patent Document 14 describe compounds having a structure similar to that of the compound of the present invention, but analgesic action and P2X 3 or P2X 2/3 receptor antagonistic action Is not described. Non-Patent Document 8 describes a compound having a structure similar to that of the compound of the present invention and showing analgesic activity, but does not describe P2X 3 or P2X 2/3 receptor antagonism. Patent Document 12 and Non-Patent Documents 12 and 13 describe compounds having a P2X 3 receptor antagonistic action, but differ in structure from the compounds of the present invention. Patent Literature 13 and Patent Literature 14 describe compounds having a P2X 3 or P2X 2/3 receptor antagonistic activity having a triazine skeleton.
国際公開第02/094767号明細書International Publication No. 02/094767 Specification 国際公開第2005/095359号明細書International Publication No. 2005/095359 Specification 米国特許出願公開第20070037974号明細書US Patent Application Publication No. 20070037974 米国特許出願公開第20070049758号明細書US Patent Application Publication No. 20070049758 米国特許出願公開第20070049610号明細書US Patent Application Publication No. 20070049610 米国特許出願公開第20070049609号明細書US Patent Application Publication No. 20070049609 米国特許出願公開第20070049534号明細書US Patent Application Publication No. 20070049534 特開平12-072757号公報Japanese Patent Laid-Open No. 12-072757 国際公開第2006/104713号明細書International Publication No. 2006/104713 Specification 国際公開第2006/104715号明細書International Publication No. 2006/104715 Specification 国際公開第2006/102112号明細書International Publication No. 2006/102112 Specification 国際公開第2010/051188号明細書International Publication No. 2010/051188 国際公開第2010/092966号明細書International Publication No. 2010/092966 国際公開第2012/020749号明細書International Publication No. 2012/020749 国際公開第2011/017347号明細書International Publication No. 2011/017347 Specification
 本発明は、新規なP2X3および/またはP2X2/3受容体拮抗作用を有する化合物を提供する。また、P2X3および/またはP2X2/3受容体拮抗作用を有する医薬組成物を提供する。 The present invention provides novel P2X 3 and / or P2X 2/3 receptor antagonistic compounds. Further, to provide a pharmaceutical composition having a P2X 3 and / or P2X 2/3 receptor antagonism.
 本発明者らは、上記課題を解決するために鋭意研究を重ねた結果、P2X3および/またはP2X2/3受容体に特異的に結合し、拮抗作用を示す新規化合物、ならびにP2X3および/またはP2X2/3受容体に特異的に結合する新規化合物を見出した。また、P2X3および/またはP2X2/3受容体拮抗作用を有する医薬組成物を見出した。
 本発明に包含される化合物または本発明に包含される医薬組成物は、P2X3受容体阻害活性、ラット血清アルブミン(以下、RSA)存在下でのP2X3受容体阻害活性等で良好な結果を示した。また、本発明に包含される化合物または本発明に包含される医薬組成物は、CYP酵素阻害確認試験、FAT試験、溶解性確認試験、代謝安定性確認試験、hERG阻害活性確認試験、バイオアベイラビリティ確認試験および/または蛋白結合確認試験等においても良好な結果を示した。
 本発明は、以下の(1)~(37)に関する。
As a result of intensive studies in order to solve the above-mentioned problems, the present inventors have found that a novel compound that specifically binds to the P2X 3 and / or P2X 2/3 receptor and exhibits antagonism, and P2X 3 and / or Alternatively, a novel compound that specifically binds to the P2X 2/3 receptor was found. Also found a pharmaceutical composition having P2X 3 and / or P2X 2/3 receptor antagonism.
The pharmaceutical compositions encompassed by the compounds or the present invention included in the present invention, P2X 3 receptor inhibiting activity, a rat serum albumin (hereinafter, RSA) good results in P2X 3 receptor inhibitory activity and the like in the presence of Indicated. In addition, the compound included in the present invention or the pharmaceutical composition included in the present invention is a CYP enzyme inhibition confirmation test, FAT test, solubility confirmation test, metabolic stability confirmation test, hERG inhibitory activity confirmation test, bioavailability confirmation. Good results were also shown in tests and / or protein binding confirmation tests.
The present invention relates to the following (1) to (37).
(1)
 式(I):
(1)
Formula (I):
Figure JPOXMLDOC01-appb-C000012

(式中、
 RおよびRは、共に水素原子、または一緒になって、オキソ、チオキソもしくは=N-R
 RおよびRは、共に水素原子、または一緒になって、オキソ、チオキソもしくは=N-R
 RおよびRは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリール;
 Rは、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアシル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリール;
 R4aは、それぞれ独立して、水素原子もしくは置換もしくは非置換のアルキル;
 R4bは、それぞれ独立して、水素原子もしくは置換もしくは非置換のアルキル;または同一の炭素原子に結合するR4aとR4bが一緒になってオキソもしくはチオキソ;
 nは1~4の整数;
 Rは、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール;
 -X-は、-O-、-S-、-N(R)-または-(C(R5a)(R5b))-;
 -L-は、-O-、-S-、-N(R5’)-または-(C(R5a’)(R5b’))-;
 RおよびR5’は、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、または置換もしくは非置換のアシル;
 R5a、R5b、R5a’ およびR5b’は、それぞれ独立して、水素原子、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルキニルオキシまたは置換もしくは非置換のアルケニルオキシ;
 環Dは、ベンゼン、ピリジン、ピリミジン、ピラジンまたはピリダジン;
 炭素原子aおよび炭素原子bは、環Dを構成する炭素原子;
 環Bは、芳香族炭素環、非芳香族炭素環、芳香族複素環または非芳香族複素環;
 sおよびs’は、それぞれ独立して、0~3の整数;
 Rは、それぞれ独立してハロゲン、ヒドロキシ、カルボキシ、シアノ、ニトロ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、置換スルホニル、置換スルフィニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシまたは置換もしくは非置換のヘテロアリールオキシ;
 R9’は、それぞれ独立してハロゲン、ヒドロキシ、カルボキシ、シアノ、ニトロ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、置換スルホニル、置換スルフィニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシまたは置換もしくは非置換のヘテロアリールオキシ;
 ただし、環Bが、シクロペンタン、ベンゼン、テトラヒドロピランまたはピペリジンのとき、s’は1~3の整数である)
で示される化合物またはその製薬上許容される塩。
Figure JPOXMLDOC01-appb-C000012

(Where
R a and R b are both a hydrogen atom or together, oxo, thioxo or ═N—R x ;
R d and R e are both hydrogen atoms or together, oxo, thioxo or ═N—R y ;
R x and R y are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Alkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R c is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
Each R 4a independently represents a hydrogen atom or substituted or unsubstituted alkyl;
R 4b is each independently a hydrogen atom or substituted or unsubstituted alkyl; or R 4a and R 4b bonded to the same carbon atom together are oxo or thioxo;
n is an integer of 1 to 4;
R 2 represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
—X— represents —O—, —S—, —N (R 5 ) — or — (C (R 5a ) (R 5b )) —;
—L— represents —O—, —S—, —N (R 5 ′ ) — or — (C (R 5a ′ ) (R 5b ′ )) —;
R 5 and R 5 ′ are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl;
R 5a , R 5b , R 5a ′ and R 5b ′ each independently represent a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or Unsubstituted alkyloxy, substituted or unsubstituted alkynyloxy or substituted or unsubstituted alkenyloxy;
Ring D is benzene, pyridine, pyrimidine, pyrazine or pyridazine;
Carbon atom a and carbon atom b are carbon atoms constituting ring D;
Ring B is an aromatic carbocycle, non-aromatic carbocycle, aromatic heterocycle or non-aromatic heterocycle;
s and s ′ are each independently an integer of 0 to 3;
R 9 is independently halogen, hydroxy, carboxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Substituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted alkyloxy Carbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfoni Ru, substituted sulfinyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy;
R 9 ′ is independently halogen, hydroxy, carboxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted alkyl Oxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfo Ru, substituted sulfinyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy;
(However, when ring B is cyclopentane, benzene, tetrahydropyran or piperidine, s ′ is an integer of 1 to 3)
Or a pharmaceutically acceptable salt thereof.
(2)
 -Rが、-(C(R11c)(R11d))m’-CN
(式中、R11cは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、もしくは置換もしくは非置換のアルキニル;
 R11dは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、もしくは置換もしくは非置換のアルキニル;または、同一の炭素原子に結合するR11cとR11dが一緒になって、置換もしくは非置換のシクロアルカン、置換もしくは非置換のシクロアルケン、もしくは置換もしくは非置換の非芳香族複素環;
 m’は、1~4の整数である)
である、上記(1)に記載の化合物またはその製薬上許容される塩。
(3)
 Rが、3~5個のヒドロキシで置換され、さらに置換基群α(置換基群α:ハロゲン、シアノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミノ、置換もしくは非置換のイミノ、置換もしくは非置換のグアニジル、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、ニトロおよびチオキソ)から選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルキル;3~5個のヒドロキシで置換され、さらに置換基群αから選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルケニル;または3~5個のヒドロキシで置換され、さらに置換基群αから選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルキニルである上記(1)に記載の化合物またはその製薬上許容される塩。
(3’)
 Rが、3~5個のヒドロキシで置換され、さらに置換基群A(置換基群A:ハロゲン、シアノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミノ、置換もしくは非置換のイミノ、置換もしくは非置換のグアニジル、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、ニトロ、オキソ、およびチオキソ)から選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルキル;3~5個のヒドロキシで置換され、さらに置換基群Aから選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルケニル;または3~5個のヒドロキシで置換され、さらに置換基群Aから選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルキニルである上記(1)に記載の化合物またはその製薬上許容される塩。
(4)
 sが1または2であり、少なくとも一つのRが、ハロゲン、ヒドロキシ、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のシクロアルキルまたは置換もしくは非置換のシクロアルケニルである、上記(1)~(3)および(3’)のいずれかに記載の化合物またはその製薬上許容される塩。
(5)
 式:
(2)
—R c is — (C (R 11c ) (R 11d )) m′-CN
(Wherein R 11c each independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
R 11d is each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R 11c and R 11d bonded to the same carbon atom are A substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted or unsubstituted non-aromatic heterocycle;
m ′ is an integer of 1 to 4)
Or a pharmaceutically acceptable salt thereof according to (1) above.
(3)
R c is substituted with 3 to 5 hydroxy groups, and substituent group α (substituent group α: halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino Substituted or unsubstituted Anidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxy One or more substituents selected from carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro and thioxo) An optionally substituted C3-C6 alkyl; a C3-C6 alkenyl optionally substituted with 3-5 hydroxy and further substituted with one or more substituents selected from substituent group α; or Substituted with 3-5 hydroxy A compound or a pharmaceutically acceptable salt thereof according to above (1) is a further one or more substituents may C3 ~ C6 alkynyl optionally substituted with selected from Substituent group alpha.
(3 ')
R c is substituted with 3 to 5 hydroxy groups, and substituent group A (substituent group A: halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino Substituted or unsubstituted Guanidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxy One or more selected from carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo) C3-C6 alkyl optionally substituted with substituents; C3-C6 optionally substituted with 3 to 5 hydroxy and further substituted with one or more substituents selected from substituent group A Alkenyl; or 3-5 hydro The compound or a pharmaceutically acceptable salt thereof according to the above (1), which is C3-C6 alkynyl substituted with cis and further substituted with one or more substituents selected from Substituent Group A .
(4)
s is 1 or 2, and at least one R 9 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, Any of (1) to (3) and (3 ′) above, which is substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkenyl Or a pharmaceutically acceptable salt thereof.
(5)
formula:
Figure JPOXMLDOC01-appb-C000013

で示される基が、式:
Figure JPOXMLDOC01-appb-C000013

The group represented by the formula:
Figure JPOXMLDOC01-appb-C000014

(式中、-X-および-L-は、上記(1)と同義;Rは、ハロゲンまたは置換もしくは非置換のアルキル;Y、YおよびYは、それぞれ独立して、CHまたはN;ただし、Y、YおよびYは、同時にNではない)で示される基である、上記(1)~(3)、(3’)および(4)のいずれかに記載の化合物またはその製薬上許容される塩。
Figure JPOXMLDOC01-appb-C000014

(Wherein —X— and —L— are as defined above (1); R 9 is halogen or substituted or unsubstituted alkyl; Y 1 , Y 2 and Y 3 are each independently CH or N; provided that Y 1 , Y 2 and Y 3 are not simultaneously N), and the compound according to any one of (1) to (3), (3 ′) and (4) above Or a pharmaceutically acceptable salt thereof.
(6)
 -L-が、-O-である、上記(1)~(3)、(3’)、(4)および(5)のいずれかに記載の化合物またはその製薬上許容される塩。
(7)
 環Bが、芳香族複素環である、上記(1)~(3)、(3’)、(4)、(5)および(6)のいずれかに記載の化合物またはその製薬上許容される塩。
(8)
 環Bが、チアゾール、イソチアゾール、オキサゾール、イソキサゾール、ピラゾール、イミダゾール、トリアゾール、フラン、チオフェン、チアジアゾール、オキサジアゾール、ピリジン、ピリミジン、ピラジン、ピリダジン、トリアジンまたはベンズオキサゾールである、上記(1)~(3)、(3’)および(4)~(7)のいずれかに記載の化合物またはその製薬上許容される塩。
(9)
 環Bが、チアゾール、イソチアゾール、オキサゾール、イソキサゾール、チアジアゾール、オキサジアゾール、ピリジン、ピリミジン、ピラジンまたはピリダジンである、上記(1)~(3)、(3’)および(4)~(8)のいずれかに記載の化合物またはその製薬上許容される塩。
(10)
 s’が1または2であり、少なくとも一つのR9’が、ヒドロキシ、カルボキシ、シアノ、置換アルキル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、置換スルホニルまたは置換スルフィニルである、上記(1)~(3)、(3’)および(4)~(9)のいずれかに記載の化合物またはその製薬上許容される塩。
(11)
 s’が1であり、R9’が、カルボキシまたは置換もしくは非置換のカルバモイルである、上記(1)~(3)、(3’)および(4)~(10)のいずれかに記載の化合物またはその製薬上許容される塩。
(12)
 環Dが、ベンゼンである、上記(1)~(3)、(3’)および(4)~(11)のいずれかに記載の化合物またはその製薬上許容される塩。
(13)
 環D上の炭素原子aと炭素原子bが、(1,4)の位置関係である、上記(1)~(3)、(3’)および(4)~(12)のいずれかに記載の化合物またはその製薬上許容される塩。
(14)
 -Rが、-(C(R11a)(R11b))m-OH
(式中、R11aは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、もしくは置換もしくは非置換のアルキニル;
 R11bは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、もしくは置換もしくは非置換のアルキニル;または、同一の炭素原子に結合するR11aとR11bが一緒になって、置換もしくは非置換のシクロアルカン、置換もしくは非置換のシクロアルケン、もしくは置換もしくは非置換の非芳香族複素環;
 mは、2~4の整数)である、上記(1)または(4)~(13)のいずれかに記載の化合物またはその製薬上許容される塩。
(15)
 -Rが、-(C(R11a)(R11b))m-OH
[式中、R11aは、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、もしくは置換もしくは非置換のアルキニル;
 R11bは、-(C(R12a)(R12b))u-OH;(式中、R12aは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、または置換もしくは非置換のアルキニル;R12bは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、または置換もしくは非置換のアルキニル;uは、0~2の整数);
 mは、2~4の整数)である、上記(1)または(4)~(14)のいずれかに記載の化合物またはその製薬上許容される塩。
(6)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), (3 ′), (4) and (5), wherein —L— is —O—.
(7)
The compound according to any one of the above (1) to (3), (3 ′), (4), (5) and (6) or a pharmaceutically acceptable salt thereof, wherein ring B is an aromatic heterocyclic ring salt.
(8)
(1) to (1) above, wherein Ring B is thiazole, isothiazole, oxazole, isoxazole, pyrazole, imidazole, triazole, furan, thiophene, thiadiazole, oxadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine or benzoxazole. 3) The compound according to any one of (3 ′) and (4) to (7) or a pharmaceutically acceptable salt thereof.
(9)
Ring (B) is thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyridine, pyrimidine, pyrazine or pyridazine, (1) to (3), (3 ′) and (4) to (8) Or a pharmaceutically acceptable salt thereof.
(10)
s ′ is 1 or 2, and at least one R 9 ′ is hydroxy, carboxy, cyano, substituted alkyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfonyl or The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), (3 ′) and (4) to (9), which is substituted sulfinyl.
(11)
any one of (1) to (3), (3 ′) and (4) to (10) above, wherein s ′ is 1 and R 9 ′ is carboxy or substituted or unsubstituted carbamoyl A compound or a pharmaceutically acceptable salt thereof.
(12)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), (3 ′) and (4) to (11), wherein Ring D is benzene.
(13)
Any one of (1) to (3), (3 ′) and (4) to (12) above, wherein the carbon atom a and the carbon atom b on the ring D are in a positional relationship of (1, 4) Or a pharmaceutically acceptable salt thereof.
(14)
—R c is — (C (R 11a ) (R 11b )) m—OH
(Wherein each R 11a independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
R 11b is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R 11a and R 11b bonded to the same carbon atom are A substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted or unsubstituted non-aromatic heterocycle;
m is an integer of 2 to 4, and the compound or a pharmaceutically acceptable salt thereof according to any one of (1) or (4) to (13) above.
(15)
—R c is — (C (R 11a ) (R 11b )) m—OH
[Wherein R 11a represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
R 11b is — (C (R 12a ) (R 12b )) u—OH; wherein R 12a is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, Or substituted or unsubstituted alkynyl; each R 12b independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; u is an integer of 0 to 2 );
m is an integer of 2 to 4, and the compound or pharmaceutically acceptable salt thereof according to any one of (1) or (4) to (14) above.
(16)
 Rが、式:
(16)
R c is of the formula:
Figure JPOXMLDOC01-appb-C000015

で示される基である、上記(1)または(4)~(15)のいずれかに記載の化合物またはその製薬上許容される塩。
(17)
 -Rが、-(C(R14a)(R14b))t-N(R15a)(R15b
(式中、R14aは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、もしくは置換もしくは非置換のアルキニル;
 R14bは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、もしくは置換もしくは非置換のアルキニル;または同一の炭素原子に結合するR14aとR14bが一緒になって、置換もしくは非置換のシクロアルカン、置換もしくは非置換のシクロアルケン、もしくは置換もしくは非置換の非芳香族複素環;
 tは、2~4の整数;
 R15aおよびR15bは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアシル、置換スルホニルまたは置換スルフィニル);または
 -Rが、-(C(R14a’ ) (R14b’ ))t’-C(=O)N(R15a’)(R15b’
(式中、R14a’は、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、もしくは置換もしくは非置換のアルキニル;
 R14b’は、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、もしくは置換もしくは非置換のアルキニル;または同一の炭素原子に結合するR14a’とR14b’が一緒になって、置換もしくは非置換のシクロアルカン、置換もしくは非置換のシクロアルケン、もしくは置換もしくは非置換の非芳香族複素環;
 t’は、1~4の整数;
 R15a’およびR15b’は、それぞれ独立して、水素原子、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアシル、置換スルホニルまたは置換スルフィニル)である、上記(1)または(4)~(13)のいずれかに記載の化合物またはその製薬上許容される塩。
Figure JPOXMLDOC01-appb-C000015

The compound or a pharmaceutically acceptable salt thereof according to any one of (1) or (4) to (15) above, which is a group represented by:
(17)
-R c is-(C (R 14a ) (R 14b )) tN (R 15a ) (R 15b )
(Wherein each R 14a independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
R 14b each independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R 14a and R 14b bonded to the same carbon atom together Substituted or unsubstituted cycloalkanes, substituted or unsubstituted cycloalkenes, or substituted or unsubstituted non-aromatic heterocycles;
t is an integer from 2 to 4;
R 15a and R 15b are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, Substituted or unsubstituted acyl, substituted sulfonyl or substituted sulfinyl); or —R c is — (C (R 14a ′ ) (R 14b ′ )) t′—C (═O) N (R 15a ′ ) (R 15b ' )
(Wherein R 14a ′ each independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
R 14b ′ is independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R 14a ′ and R 14b ′ bonded to the same carbon atom. Together, a substituted or unsubstituted cycloalkane, a substituted or unsubstituted cycloalkene, or a substituted or unsubstituted non-aromatic heterocycle;
t ′ is an integer of 1 to 4;
R 15a ′ and R 15b ′ each independently represent a hydrogen atom, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted (1) or (4) to (13) or a pharmaceutically acceptable salt thereof, which is substituted sulfamoyl, substituted or unsubstituted acyl, substituted sulfonyl or substituted sulfinyl).
(18)
 Rが、式:
(18)
R c is of the formula:
Figure JPOXMLDOC01-appb-C000016

(式中、R15a、R15b、R15a’およびR15b’は上記(17)と同義)
で示される基である、上記(1)、(4)~(13)または(17)のいずれかに記載の化合物またはその製薬上許容される塩。
Figure JPOXMLDOC01-appb-C000016

(Wherein R 15a , R 15b , R 15a ′ and R 15b ′ have the same meanings as in (17) above)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1), (4) to (13) or (17), which is a group represented by:
(19)
 式(II):
(19)
Formula (II):
Figure JPOXMLDOC01-appb-C000017

(式中、
 RおよびRは、共に水素原子、または一緒になって、オキソ、チオキソもしくは=N-R
 RおよびRは、共に水素原子、または一緒になって、オキソ、チオキソもしくは=N-R
 RおよびRは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリール;
 Rは、3~5個のヒドロキシで置換され、さらに置換基群α(置換基群α:ハロゲン、シアノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミノ、置換もしくは非置換のイミノ、置換もしくは非置換のグアニジル、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、ニトロ、およびチオキソ)から選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルキル;3~5個のヒドロキシで置換され、さらに置換基群αから選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルケニル;または3~5個のヒドロキシで置換され、さらに置換基群αから選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルキニル;
 R4aは、それぞれ独立して、水素原子もしくは置換もしくは非置換のアルキル;
 R4bは、それぞれ独立して、水素原子もしくは置換もしくは非置換のアルキル;または同一の炭素原子に結合するR4aとR4bが一緒になってオキソもしくはチオキソ;
 nは1~4の整数;
 Rは、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール;
 -X-は、-O-、-S-、-N(R)-または-(C(R5a)(R5b))-;
 Rは、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、または置換もしくは非置換のアシル;
 R5aおよびR5bは、それぞれ独立して水素原子、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルキニルオキシ、または置換もしくは非置換のアルケニルオキシ;
 Rは、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリールである)
で示される化合物またはその製薬上許容される塩。
(19’)
 式(II):
Figure JPOXMLDOC01-appb-C000017

(Where
R a and R b are both a hydrogen atom or together, oxo, thioxo or ═N—R x ;
R d and R e are both hydrogen atoms or together, oxo, thioxo or ═N—R y ;
R x and R y are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Alkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R c is substituted with 3 to 5 hydroxy groups, and further substituted group α (substituent group α: halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino Substituted or unsubstituted Anidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxy One or more substituents selected from carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, and thioxo) C3-C6 alkyl optionally substituted with C3-C6 alkenyl substituted with 3-5 hydroxy and further substituted with one or more substituents selected from substituent group α; Or substituted with 3-5 hydroxy Are further 1 or more are also may C3 ~ optionally C6 alkynyl substituted with a substituent selected from substituent group alpha;
Each R 4a independently represents a hydrogen atom or substituted or unsubstituted alkyl;
R 4b is each independently a hydrogen atom or substituted or unsubstituted alkyl; or R 4a and R 4b bonded to the same carbon atom together are oxo or thioxo;
n is an integer of 1 to 4;
R 2 represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
—X— represents —O—, —S—, —N (R 5 ) — or — (C (R 5a ) (R 5b )) —;
R 5 represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl;
R 5a and R 5b each independently represent a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Substituted alkynyloxy or substituted or unsubstituted alkenyloxy;
R 3 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl )
Or a pharmaceutically acceptable salt thereof.
(19 ')
Formula (II):
Figure JPOXMLDOC01-appb-C000018

(式中、
 RおよびRは、共に水素原子、または一緒になって、オキソ、チオキソもしくは=N-R
 RおよびRは、共に水素原子、または一緒になって、オキソ、チオキソもしくは=N-R
 RおよびRは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリール;
 Rは、3~5個のヒドロキシで置換され、さらに置換基群A(置換基群A:ハロゲン、シアノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミノ、置換もしくは非置換のイミノ、置換もしくは非置換のグアニジル、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、ニトロ、オキソ、およびチオキソ)から選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルキル;3~5個のヒドロキシで置換され、さらに置換基群Aから選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルケニル;または3~5個のヒドロキシで置換され、さらに置換基群Aから選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルキニル;
 R4aは、それぞれ独立して、水素原子もしくは置換もしくは非置換のアルキル;
 R4bは、それぞれ独立して、水素原子もしくは置換もしくは非置換のアルキル;または同一の炭素原子に結合するR4aとR4bが一緒になってオキソもしくはチオキソ;
 nは1~4の整数;
 Rは、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール;
 -X-は、-O-、-S-、-N(R)-または-(C(R5a)(R5b))-;
 Rは、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、または置換もしくは非置換のアシル;
 R5aおよびR5bは、それぞれ独立して水素原子、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルキニルオキシ、または置換もしくは非置換のアルケニルオキシ;
 Rは、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリールである)
で示される化合物またはその製薬上許容される塩。
(20)
 RおよびRが一緒になってオキソであり、
 RおよびRが一緒になってオキソであり、
 R
Figure JPOXMLDOC01-appb-C000018

(Where
R a and R b are both a hydrogen atom or together, oxo, thioxo or ═N—R x ;
R d and R e are both hydrogen atoms or together, oxo, thioxo or ═N—R y ;
R x and R y are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Alkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R c is substituted with 3 to 5 hydroxy groups, and further substituted group A (substituent group A: halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino Substituted or unsubstituted Guanidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxy One or more selected from carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, and thioxo) C3-C6 alkyl optionally substituted with substituents; C3-C6 optionally substituted with 3 to 5 hydroxy and further substituted with one or more substituents selected from substituent group A Alkenyl; or 3-5 hydro Substituted with shea further 1 or more are also may C3 ~ optionally C6 alkynyl substituted with a substituent selected from substituent group A;
Each R 4a independently represents a hydrogen atom or substituted or unsubstituted alkyl;
R 4b is each independently a hydrogen atom or substituted or unsubstituted alkyl; or R 4a and R 4b bonded to the same carbon atom together are oxo or thioxo;
n is an integer of 1 to 4;
R 2 represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
—X— represents —O—, —S—, —N (R 5 ) — or — (C (R 5a ) (R 5b )) —;
R 5 represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl;
R 5a and R 5b each independently represent a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Substituted alkynyloxy or substituted or unsubstituted alkenyloxy;
R 3 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl )
Or a pharmaceutically acceptable salt thereof.
(20)
R a and R b together are oxo,
R d and R e together are oxo,
R c is
Figure JPOXMLDOC01-appb-C000019

(式中、Alkはアルキルである)
で示される基であり、
 nが1であり、R4aおよびR4bが共に水素原子であり、
 -X-が-N(H)-であり、
 環Dがベンゼンであり、
Figure JPOXMLDOC01-appb-C000019

(Wherein Alk is alkyl)
A group represented by
n is 1, R 4a and R 4b are both hydrogen atoms,
-X- is -N (H)-;
Ring D is benzene,
Figure JPOXMLDOC01-appb-C000020

であり、その他の記号は上記(1)と同義である、上記(1)記載の化合物またはその製薬上許容される塩。
(21)
 RおよびRが一緒になってオキソであり、
 RおよびRが一緒になってオキソであり、
 R
Figure JPOXMLDOC01-appb-C000020

And the other symbols have the same meanings as in (1) above, or the pharmaceutically acceptable salt thereof.
(21)
R a and R b together are oxo,
R d and R e together are oxo,
R c is
Figure JPOXMLDOC01-appb-C000021

(式中、Alkはアルキルである)
で示される基であり、
 nが1であり、R4aおよびR4bが共に水素原子であり、
 -X-が-N(H)-であり、
 環Dがベンゼンであり、
Figure JPOXMLDOC01-appb-C000021

(Wherein Alk is alkyl)
A group represented by
n is 1, R 4a and R 4b are both hydrogen atoms,
-X- is -N (H)-;
Ring D is benzene,
Figure JPOXMLDOC01-appb-C000022

であり;
 s’が、1から3の整数であり、かつ
 少なくとも1つのR9’が、ハロゲンまたはハロアルキルであり、その他の記号は上記(1)と同義である、上記(1)記載の化合物またはその製薬上許容される塩。
(22)
 RおよびRが一緒になってオキソであり、
 RおよびRが一緒になってオキソであり、
 Rが置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、または置換もしくは非置換の非芳香族複素環式基であり;
 nが1であり、R4aおよびR4bが共に水素原子であり、
 -X-が-N(H)-であり、
 -L-が-O-であり、
 環Dがベンゼンであり、
 環Bが、ピリジンまたはチアゾールであり;
 s’が、1から3の整数であり;かつ
 少なくとも1つのR9’が、カルボキシまたはアルキルオキシカルボニルであり、その他の記号は上記(1)と同義である、上記(1)記載の化合物またはその製薬上許容される塩。
(23)
 RおよびRが一緒になってオキソであり、
 RおよびRが一緒になってオキソであり、
 Rがアルキルであり、
 nが1であり、R4aおよびR4bが共に水素原子であり、
 -X-が-N(H)-であり、
 環Dがベンゼンであり、
 sが1~3の整数であり、
Figure JPOXMLDOC01-appb-C000022

Is;
The compound according to the above (1), wherein s ′ is an integer of 1 to 3, and at least one R 9 ′ is halogen or haloalkyl, and the other symbols are as defined in the above (1), or a pharmaceutical product thereof Top acceptable salt.
(22)
R a and R b together are oxo,
R d and R e together are oxo,
R c is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group;
n is 1, R 4a and R 4b are both hydrogen atoms,
-X- is -N (H)-;
-L- is -O-,
Ring D is benzene,
Ring B is pyridine or thiazole;
s ′ is an integer from 1 to 3; and at least one R 9 ′ is carboxy or alkyloxycarbonyl, and the other symbols are as defined in (1) above, or Its pharmaceutically acceptable salt.
(23)
R a and R b together are oxo,
R d and R e together are oxo,
R c is alkyl;
n is 1, R 4a and R 4b are both hydrogen atoms,
-X- is -N (H)-;
Ring D is benzene,
s is an integer of 1 to 3,
Figure JPOXMLDOC01-appb-C000023

(式中、s’’は0~2の整数であり、その他の記号は上記(1)と同義である、上記(1)記載の化合物またはその製薬上許容される塩。
(24)
 RおよびRが一緒になってオキソであり、
 RおよびRが一緒になってオキソであり、
 R
Figure JPOXMLDOC01-appb-C000023

(Wherein s ″ is an integer of 0 to 2 and the other symbols have the same meanings as in (1) above, or a pharmaceutically acceptable salt thereof.
(24)
R a and R b together are oxo,
R d and R e together are oxo,
R c is
Figure JPOXMLDOC01-appb-C000024

(式中、Alkはアルキルである)
で示される基であり、
 nが1であり、R4aおよびR4bが共に水素原子であり、
 Rが置換もしくは非置換のシクロアルキルであり、
 -X-が-N(H)-であり、
 -L-が-O-であり、
 環Dがベンゼンであり、
その他の記号は上記(1)と同義である、上記(1)記載の化合物またはその製薬上許容される塩。
(25)
 RおよびRが、一緒になってオキソであり、RおよびRが、一緒になってオキソである、上記(1)~(3)、(3’)、(4)~(19)、(19’)および(20)~(24)のいずれかに記載の化合物またはその製薬上許容される塩。
(26)
 nが1である、上記(1)~(3)、(3’)、(4)~(19)、(19’)および(20)~(25)のいずれかに記載の化合物またはその製薬上許容される塩。
(27)
 R4aおよびR4bが共に水素原子である、上記(1)~(3)、(3’)、(4)~(19)、(19’)および(20)~(26)のいずれかに記載の化合物またはその製薬上許容される塩。
(28)
 Rが、置換もしくは非置換のシクロアルキル、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリールである、上記(1)~(3)、(3’)、(4)~(19)、(19’)および(20)~(22)のいずれかに記載の化合物またはその製薬上許容される塩。
(29)
 -X-が、-N(R)-(式中、Rは上記(1)と同義)である、上記(1)~(3)、(3’)、(4)~(19)、(19’)および(20)~(28)のいずれかに記載の化合物またはその製薬上許容される塩。
(30)
 -X-が、-NH-である、上記(1)~(3)、(3’)、(4)~(19)、(19’)および(20)~(29)のいずれかに記載の化合物またはその製薬上許容される塩。
(31)
 上記(1)~(3)、(3’)、(4)~(19)、(19’)および(20)~(30)のいずれかに記載の化合物またはその製薬上許容される塩を含有する医薬組成物。
(32)
 P2Xおよび/またはP2X2/3受容体拮抗作用を有する上記(31)記載の医薬組成物。
(33)
 上記(1)~(3)、(3’)、(4)~(19)、(19’)および(20)~(30)のいずれかに記載の化合物またはその製薬上許容される塩を含有する鎮痛作用および/または排尿障害改善作用を有する医薬組成物。
(34)
 P2X3および/またはP2X2/3受容体が関与する疾患の治療および/または予防に使用するための、上記(1)~(3)、(3’)、(4)~(19)、(19’)および(20)~(30)のいずれかに記載の化合物またはその製薬上許容される塩。
(35)
 鎮痛および/または排尿障害改善に使用するための、上記(1)~(3)、(3’)、(4)~(19)、(19’)および(20)~(30)のいずれかに記載の化合物またはその製薬上許容される塩。
(36)
 上記(1)~(3)、(3’)、(4)~(19)、(19’)および(20)~(30)のいずれかに記載の化合物またはその製薬上許容される塩を投与することを特徴とする、P2X3および/またはP2X2/3受容体が関与する疾患の治療および/または予防方法。
(37)
 上記(1)~(3)、(3’)、(4)~(19)、(19’)および(20)~(30)のいずれかに記載の化合物またはその製薬上許容される塩を投与することを特徴とする、鎮痛方法および/または排尿障害改善方法。
Figure JPOXMLDOC01-appb-C000024

(Wherein Alk is alkyl)
A group represented by
n is 1, R 4a and R 4b are both hydrogen atoms,
R 2 is substituted or unsubstituted cycloalkyl,
-X- is -N (H)-;
-L- is -O-,
Ring D is benzene,
The other symbols have the same meanings as in (1) above, the compound according to (1) above or a pharmaceutically acceptable salt thereof.
(25)
R a and R b are together oxo, and R d and R e are together oxo, (1) to (3), (3 ′), (4) to (19 ), (19 ′) and (20) to (24), or a pharmaceutically acceptable salt thereof.
(26)
The compound according to any one of the above (1) to (3), (3 ′), (4) to (19), (19 ′) and (20) to (25), wherein n is 1, or a pharmaceutical thereof Top acceptable salt.
(27)
Any one of (1) to (3), (3 ′), (4) to (19), (19 ′), and (20) to (26), wherein R 4a and R 4b are both hydrogen atoms. The described compound or a pharmaceutically acceptable salt thereof.
(28)
The above (1) to (3), (3 ′), (4) to (19), wherein R 2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. ), (19 ′) and (20) to (22), or a pharmaceutically acceptable salt thereof.
(29)
—X— is —N (R 5 ) — (wherein R 5 has the same meaning as (1) above), (1) to (3), (3 ′), (4) to (19) , (19 ′) and (20) to (28), or a pharmaceutically acceptable salt thereof.
(30)
Any of (1) to (3), (3 ′), (4) to (19), (19 ′) and (20) to (29) above, wherein —X— is —NH—. Or a pharmaceutically acceptable salt thereof.
(31)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), (3 ′), (4) to (19), (19 ′) and (20) to (30) A pharmaceutical composition containing.
(32)
The pharmaceutical composition according to the above (31), which has a P2X 3 and / or P2X 2/3 receptor antagonistic action.
(33)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), (3 ′), (4) to (19), (19 ′) and (20) to (30) A pharmaceutical composition having an analgesic action and / or an effect of improving dysuria.
(34)
(1) to (3), (3 ′), (4) to (19), (9) above for use in the treatment and / or prevention of diseases involving P2X 3 and / or P2X 2/3 receptors 19 ′) and the compound according to any one of (20) to (30) or a pharmaceutically acceptable salt thereof.
(35)
Any of the above (1) to (3), (3 ′), (4) to (19), (19 ′) and (20) to (30) for use in analgesia and / or dysuria improvement Or a pharmaceutically acceptable salt thereof.
(36)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), (3 ′), (4) to (19), (19 ′) and (20) to (30) A method for treating and / or preventing a disease involving a P2X 3 and / or P2X 2/3 receptor, which comprises administration.
(37)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), (3 ′), (4) to (19), (19 ′) and (20) to (30) A method for analgesia and / or a method for improving dysuria, characterized by administration.
 本発明の化合物は、P2X3および/またはP2X2/3受容体に対する拮抗作用を有し、P2X3および/またはP2X2/3受容体が関与する疾患または状態に対して有用である。 The compounds of this invention have an antagonistic effect on P2X 3 and / or P2X 2/3 receptor and are useful for the disease or condition P2X 3 and / or P2X 2/3 receptors are involved.
 本明細書中で用いる用語を以下に説明する。各用語は、特に記載しない限り以下の意味を有する。 The terms used in this specification are explained below. Each term has the following meaning unless otherwise specified.
 「ハロゲン」とはフッ素、塩素、臭素およびヨウ素を意味する。 “Halogen” means fluorine, chlorine, bromine and iodine.
 「ハロアルキル」、「ハロアルキルカルバモイル」および「ハロアルキルオキシ」のハロゲン部分は上記「ハロゲン」と同義である。 The halogen part of “haloalkyl”, “haloalkylcarbamoyl” and “haloalkyloxy” has the same meaning as the above “halogen”.
 「アルキル」とは、炭素数1~15、一つの態様として炭素数1~10、その他の態様として炭素数1~6の直鎖または分枝鎖の1価の炭化水素基を包含する。例えば、メチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、n-ペンチル、イソペンチル、ネオペンチル、n-ヘキシル、イソヘキシル、n-へプチル、イソヘプチル、n-オクチル、イソオクチル、n-ノニル、n-デシル、n-ウンデカニル、ドデカニル、トリデカニル等が挙げられる。
 本明細書において、「アルキル」における炭素数を限定する場合がある。例えば、C3~C6アルキルとは、炭素数3~6の「アルキル」を意味する。
 Rにおける非置換アルキルとしては、例えば、n-プロピルが挙げられる。
“Alkyl” includes a straight or branched monovalent hydrocarbon group having 1 to 15 carbon atoms, 1 to 10 carbon atoms in one embodiment, and 1 to 6 carbon atoms in another embodiment. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl , Isooctyl, n-nonyl, n-decyl, n-undecanyl, dodecanyl, tridecanyl and the like.
In the present specification, the number of carbon atoms in “alkyl” may be limited. For example, C3-C6 alkyl means “alkyl” having 3 to 6 carbon atoms.
Examples of the unsubstituted alkyl for R c include n-propyl.
 「ハロアルキル」、「ヒドロキシアルキル」、「アミノアルキル」、「アルキルアミノアルキル」、「アルキルアミノ」、「アルキルイミノ」、「アルキルスルホニル」、「アルキルスルファモイル」、「アルキルカルバモイル」、「アリールアルキル」、「アルキルシリルアルキニル」、「アルキルスルホニル」、「アルキルスルフィニル」、「アルキルカルバモイル」、「アルキルカルバモイルアルキル」、「アルキルカルバモイルアルキルオキシ」「アルキルスルファモイル」、「アルキルスルファモイルアルキル」、「ハロアルキルカルバモイル」、「ヒドロキシアルキルカルバモイル」、「アルキルオキシカルボニルアルキル」、「アルキルカルバモイルアミノ」、「アルキルオキシカルボニルアミノ」、「アルキルスルホニルカルバモイル」および「アリールアルキルアミノ」のアルキル部分は上記「アルキル」と同義である。 “Haloalkyl”, “hydroxyalkyl”, “aminoalkyl”, “alkylaminoalkyl”, “alkylamino”, “alkylimino”, “alkylsulfonyl”, “alkylsulfamoyl”, “alkylcarbamoyl”, “arylalkyl” ”,“ Alkylsilylalkynyl ”,“ alkylsulfonyl ”,“ alkylsulfinyl ”,“ alkylcarbamoyl ”,“ alkylcarbamoylalkyl ”,“ alkylcarbamoylalkyloxy ”,“ alkylsulfamoyl ”,“ alkylsulfamoylalkyl ”, “Haloalkylcarbamoyl”, “hydroxyalkylcarbamoyl”, “alkyloxycarbonylalkyl”, “alkylcarbamoylamino”, “alkyloxycarbonylamino”, “alkylsulfonyl” Rubamoiru "and the alkyl moiety of the" arylalkyl amino "as defined in the above" alkyl ".
 「アルキルオキシ」とは、アルキル部分が上記「アルキル」であるアルキルオキシ基を包含する。例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、sec-ブトキシ、tert-ブトキシ、ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、ヘキシルオキシ等のアルキルオキシが挙げられる。 “Alkyloxy” includes an alkyloxy group in which the alkyl moiety is the above “alkyl”. Examples thereof include alkyloxy such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy and the like.
 「ハロアルキルオキシ」、「アリールアルキルオキシ」、「アルキルオキシカルボニル」、「アルキルオキシカルボニルアルキル」、「アルキルオキシアルキルオキシ」、「アルキルカルバモイルアルキルオキシ」、「カルバモイルアルキルオキシ」、「カルボキシアルキルオキシ」および「アルキルオキシイミノ」のアルキルオキシ部分は上記「アルキルオキシ」と同義である。 “Haloalkyloxy”, “arylalkyloxy”, “alkyloxycarbonyl”, “alkyloxycarbonylalkyl”, “alkyloxyalkyloxy”, “alkylcarbamoylalkyloxy”, “carbamoylalkyloxy”, “carboxyalkyloxy” and The alkyloxy part of “alkyloxyimino” has the same meaning as the above “alkyloxy”.
 「アルキルチオ」としては、例えば、メチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ、ブチルチオ、イソブチルチオ、sec-ブチルチオ、tert-ブチルチオ、ペンチルチオ、イソペンチルチオ、ネオペンチルチオ、ヘキシルチオ等が挙げられる。 Examples of “alkylthio” include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, hexylthio and the like.
 「アルキルオキシカルボニル」としては、例えば、メチルオキシカルボニル、エチルオキシカルボニル、n-プロピルオキシカルボニル、イソプロピルオキシカルボニル、n-ブチルオキシカルボニル、tert-ブチルオキシカルボニル、n-ペンチルオキシカルボニル等が挙げられる。 Examples of “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, n-butyloxycarbonyl, tert-butyloxycarbonyl, n-pentyloxycarbonyl and the like.
 「アルキルカルバモイル」としては、例えば、メチルカルバモイル、エチルカルバモイル、n-プロピルカルバモイル、イソプロピルカルバモイル、シクロプロピルカルバモイル、n-ブチルカルバモイル、ジメチルカルバモイル、ジエチルカルバモイル、ジプロピルカルバモイル基等のモノ又はジアルキルカルバモイル基が挙げられる。 Examples of the “alkylcarbamoyl” include mono- or dialkylcarbamoyl groups such as methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, isopropylcarbamoyl, cyclopropylcarbamoyl, n-butylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl and dipropylcarbamoyl groups. Can be mentioned.
 「アルケニル」とは、任意の位置に1以上の二重結合を有する炭素数2~15、一つの態様として炭素数2~10、その他の態様として炭素数2~6の直鎖または分枝状のアルケニルを包含する。例えば、ビニル、プロペニル、イソプロペニル、ブテニル、イソブテニル、プレニル、ブタジエニル、ペンテニル、イソペンテニル、ペンタジエニル、ヘキセニル、イソヘキセニル、ヘキサジエニル、ヘプテニル、オクテニル、ノネニル、デケニル、ウンデケニル、ドデケニル、トリデケニル等が挙げられる。
 本明細書において、「アルケニル」における炭素数を限定する場合がある。例えば、C3~C6アルケニルとは、炭素数3~6の「アルケニル」を意味する。
“Alkenyl” is a straight or branched chain having 2 to 15 carbon atoms having one or more double bonds at any position, one embodiment having 2 to 10 carbon atoms, and another embodiment having 2 to 6 carbon atoms. Of alkenyl. Examples include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, dekenyl, undecenyl, dodecenyl, tridecenyl and the like.
In the present specification, the number of carbon atoms in “alkenyl” may be limited. For example, C3-C6 alkenyl means “alkenyl” having 3 to 6 carbon atoms.
 「アルケニルオキシ」、「アルケニルチオ」、「アルケニルカルバモイル」、「アルケニルスルファモイル」および「アルケニルオキシカルボニル」のアルケニル部分は、上記「アルケニル」と同義である。 The alkenyl part of “alkenyloxy”, “alkenylthio”, “alkenylcarbamoyl”, “alkenylsulfamoyl” and “alkenyloxycarbonyl” has the same meaning as the above “alkenyl”.
 「アルキニル」とは、炭素数2~15、一つの態様として炭素数2~10、その他の態様として炭素数2~6の直鎖状または分枝状のアルキニルを包含する。例えば、エチニル、プロピニル、ブチニル、ペンチニル、ヘキシニル、ヘプチニル、オクチニル、ノニル、デキニル等が挙げられる。これらは任意の位置に1以上の三重結合を有しており、さらに二重結合を有していてもよい。
 本明細書において、「アルキニル」における炭素数を限定する場合がある。例えば、C3~C6アルキニルとは、炭素数3~6の「アルキニル」を意味する。
“Alkynyl” includes linear or branched alkynyl having 2 to 15 carbon atoms, one embodiment having 2 to 10 carbon atoms, and another embodiment having 2 to 6 carbon atoms. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonyl, decynyl and the like. These have one or more triple bonds at arbitrary positions, and may further have a double bond.
In the present specification, the number of carbon atoms in “alkynyl” may be limited. For example, C3-C6 alkynyl means “alkynyl” having 3 to 6 carbon atoms.
 「アルキニルオキシ」、「アルキニルチオ」および「アルキニルオキシカルボニル」のアルキニル部分は、上記「アルキニル」と同義である。 The alkynyl part of “alkynyloxy”, “alkynylthio” and “alkynyloxycarbonyl” has the same meaning as the above “alkynyl”.
 「アシル」とは、R-C(=O)-(例えば、Rは前記、「水素」、「アルキル」、「アルケニル」、「アルキニル」または後述の、「シクロアルキル」、「シクロアルケニル」、「非芳香族複素環式基」、「アリール」もしくは「ヘテロアリール」である)で示される基を包含する。 “Acyl” means R—C (═O) — (for example, R is “hydrogen”, “alkyl”, “alkenyl”, “alkynyl” or “cycloalkyl”, “cycloalkenyl”, A group represented by “non-aromatic heterocyclic group”, “aryl” or “heteroaryl”.
 「アシルアミノ」および「アシルイミノ」の「アシル」部分は上記「アシル」と同義である。 The “acyl” part of “acylamino” and “acylimino” has the same meaning as the above “acyl”.
 「シクロアルカン」とは、炭素数が3~10の単環式または多環式飽和炭素環を包含する。単環式シクロアルカンとしては、例えば、シクロプロパン、シクロブタン、シクロペンタン、シクロヘキサン、シクロヘプタン、シクロオクタン、シクロノナン、シクロデカン等が挙げられる。多環式シクロアルカンとしては、ノルボルナン、テトラヒドロナフタレン等が挙げられる。 “Cycloalkane” includes monocyclic or polycyclic saturated carbocyclic rings having 3 to 10 carbon atoms. Examples of the monocyclic cycloalkane include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, and cyclodecane. Examples of the polycyclic cycloalkane include norbornane and tetrahydronaphthalene.
 「シクロアルキル」とは、上記「シクロアルカン」から導かれる1価の基を包含する。単環式シクロアルキルとしては、例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロノニル、シクロデシル等が挙げられる。一つの態様として、C3~C8シクロアルカンが挙げられる。その他の態様として、C3~C7シクロアルカンが挙げられる。多環式シクロアルキルとしては、ノルボルニル、テトラヒドロナフタレン-5-イル、テトラヒドロナフタレン-6-イル等が挙げられる。
 Rにおける「シクロアルキル」としては、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル等が挙げられる。
 Rにおける「シクロアルキル」としては、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル等が挙げられる。
“Cycloalkyl” includes a monovalent group derived from the above “cycloalkane”. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. One embodiment includes C3-C8 cycloalkanes. Other embodiments include C3-C7 cycloalkanes. Examples of the polycyclic cycloalkyl include norbornyl, tetrahydronaphthalen-5-yl, tetrahydronaphthalen-6-yl and the like.
Examples of “cycloalkyl” in R 2 include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
Examples of “cycloalkyl” in R 3 include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
 「シクロアルキルカルボニル」、「シクロアルキルオキシカルボニル」および「シクロアルキルオキシ」の「シクロアルキル」部分は、上記「シクロアルキル」と同義である。 The “cycloalkyl” part of “cycloalkylcarbonyl”, “cycloalkyloxycarbonyl” and “cycloalkyloxy” has the same meaning as the above “cycloalkyl”.
 「シクロアルケン」とは、少なくとも1つの炭素-炭素二重結合を含む炭素数3~10の非芳香族単環または多環式環を包含する。一つの態様として、C3~C8シクロアルケンが挙げられる。その他の態様として、C3~C7シクロアルケンが挙げられる。単環式シクロアルケンとしては、シクロペンテン、シクロヘキセン等が挙げられる。多環式シクロアルケンとしてはノルボルネン、インデン等が挙げられる。 “Cycloalkene” includes a non-aromatic monocyclic or polycyclic ring having 3 to 10 carbon atoms and containing at least one carbon-carbon double bond. One embodiment includes C3-C8 cycloalkene. Other embodiments include C3-C7 cycloalkene. Examples of the monocyclic cycloalkene include cyclopentene and cyclohexene. Examples of the polycyclic cycloalkene include norbornene and indene.
 「シクロアルケニル」とは、上記「シクロアルケン」から導かれる1価の基を包含する。単環式シクロアルケニルとしては、シクロペンテニル、シクロヘキセニル等が挙げられる。一つの態様として、C3~C8シクロアルキルが挙げられる。その他の態様として、C3~C7シクロアルキルが挙げられる。多環式シクロアルケニルとしてはノルボルネニル、インデン-1-イル、インデン-2-イル、インデン-3-イル等が挙げられる。 “Cycloalkenyl” includes a monovalent group derived from the above “cycloalkene”. Examples of monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl and the like. One embodiment includes C3-C8 cycloalkyl. Other embodiments include C3-C7 cycloalkyl. Examples of polycyclic cycloalkenyl include norbornenyl, inden-1-yl, inden-2-yl, inden-3-yl and the like.
 「シクロアルケニルオキシカルボニル」および「シクロアルケニルオキシ」の「シクロアルケニル」部分は、上記「シクロアルケニル」と同義である。 The “cycloalkenyl” part of “cycloalkenyloxycarbonyl” and “cycloalkenyloxy” has the same meaning as the above “cycloalkenyl”.
 「芳香族炭素環」とは、単環または縮合環の芳香族炭化水素環を包含する。例えば、ベンゼン、ナフタレン、アントラセン、フェナントレン等が挙げられる。 The “aromatic carbocycle” includes a monocyclic or condensed aromatic hydrocarbon ring. Examples thereof include benzene, naphthalene, anthracene, phenanthrene and the like.
 「アリール」とは、上記「芳香族炭素環」から導かれる1価の基を意味する。例えば、フェニル、1-ナフチル、2-ナフチル、アントリル、フェナントリル等が挙げられる。
 Rにおける、「アリール」としては、フェニルが挙げられる。
 Rにおける、「アリール」としては、フェニルが挙げられる。
“Aryl” means a monovalent group derived from the above “aromatic carbocycle”. Examples thereof include phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl and the like.
“Aryl” in R 2 includes phenyl.
“Aryl” in R 3 includes phenyl.
 「アリールオキシ」、「アリールチオ」および「アリールオキシカルボニル」の「アリール」部分は、上記「アリール」と同義である。 The “aryl” part of “aryloxy”, “arylthio” and “aryloxycarbonyl” has the same meaning as the above “aryl”.
 「複素環」とは、環内に窒素原子、酸素原子、及び/又は硫黄原子を少なくとも1個有する5~7員環、
それらが独立して2個以上縮合した環、または、
環内に窒素原子、酸素原子、及び/又は硫黄原子を少なくとも1個有する5~7員環が、1以上の上記「芳香族炭素環」、上記「シクロアルカン」もしくは上記「シクロアルケン」と縮合した環から誘導される、芳香族または非芳香族の縮合環を包含する。
 例えば、ピロリン、ピロリジン、ピペリジン、ピペラジン、モルホリン、チオモルホン、テトラヒドロピラン、ジヒドロピリジン、ジヒドロピリダジン、ジオキサン、オキサチオラン、チアン、テトラヒドロフラン、テトラヒドロピラン、テトラヒドロチアゾール、テトラヒドロイソチアゾール等の、単環の非芳香族複素環;
 例えば、ピロール、ピラジン、ピラゾール、テトラゾール、フラン、チオフェン、ピリジン、イミダゾール、トリアゾール、テトラゾール、トリアジン、ピリダジン、ピリミジン、イソオキサゾール、チアゾール、イソチアゾール、チアジアゾール、オキサゾール、オキサジアゾール等の、単環の芳香族複素環;
 例えば、インドール、イソインドール、インダゾール、インドリジン、インドリン、イソインドリン、キノリン、イソキノリン、シンノリン、フタラジン、キナゾリン、ナフチリジン、キノキサリン、プリン、プテリジン、ベンゾピラン、ベンズイミダゾール、ベンズイソオキサゾール、ベンズオキサゾール、ベンズオキサジアゾール、ベンゾイソチアゾール、ベンゾチアゾール、ベンゾチアジアゾール、ベンゾフラン、イソベンゾフラン、ベンゾチオフェン、ベンゾトリアゾール、イミダゾピリジン、トリアゾロピリジン、イミダゾチアゾール、ピラジノピリダジン、ベンズイミダゾール、ベンゾジオキサン、テトラヒドロキノリン、テトラヒドロベンゾチオフェン等の、縮合した複素環が挙げられる。
“Heterocycle” means a 5- to 7-membered ring having at least one nitrogen atom, oxygen atom, and / or sulfur atom in the ring,
A ring in which two or more of them are independently fused, or
A 5- to 7-membered ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the “aromatic carbocycle”, the “cycloalkane” or the “cycloalkene”. An aromatic or non-aromatic fused ring derived from the above ring.
For example, monocyclic non-aromatic heterocycles such as pyrroline, pyrrolidine, piperidine, piperazine, morpholine, thiomorphone, tetrahydropyran, dihydropyridine, dihydropyridazine, dioxane, oxathiolane, thiane, tetrahydrofuran, tetrahydropyran, tetrahydrothiazole, tetrahydroisothiazole, etc. ;
For example, pyrrole, pyrazine, pyrazole, tetrazole, furan, thiophene, pyridine, imidazole, triazole, tetrazole, triazine, pyridazine, pyrimidine, isoxazole, thiazole, isothiazole, thiadiazole, oxazole, oxadiazole, etc. Family heterocycles;
For example, indole, isoindole, indazole, indolizine, indoline, isoindoline, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzopyran, benzimidazole, benzisoxazole, benzoxazole, benzoxazidi Azole, benzoisothiazole, benzothiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, benzimidazole, benzodioxane, tetrahydroquinoline, tetrahydrobenzothiophene, etc. And a condensed heterocyclic ring.
 「複素環式基」とは、上記「複素環」から導かれる1価の基を包含する。
例えば、ピロリニル、ピロリジノ、ピロリジニル、イミダゾリニル、イミダゾリジニル、ピラゾリニル、ピラゾリジニル、ピペリジノ、ピペリジル、ピペラジノ、ピペラジニル、モルホリニル、モルホリノ、チオモルホリニル、チオモルホリノ、テトラヒドロピラニル、ジヒドロピリジル、ジヒドロピリダジニル、ジヒドロピラジニル、ジオキサニル、オキサチオラニル、チアニル、テトラヒドロフリル、テトラヒドロピラニル、テトラヒドロチアゾリニル、テトラヒドロイソチアゾリニル等の、単環の非芳香族複素環式基;
 例えば、ピロリル、ピラジニル、ピラゾリル、テトラゾリル、フリル、チエニル、ピリジル、イミダゾリル、トリアゾリル、テトラゾリル、トリアジニル、ピリダジニル、ピリミジニル、ピラジニル、イソオキサゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、オキサゾリル、オキサジアゾリル等の、単環の芳香族複素環式基;
例えば、インドリル、イソインドリル、インダゾリル、インドリジニル、インドリニル、イソインドリニル、キノリル、イソキノリル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンゾピラニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンゾイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、ベンズイミダゾリニル、ベンゾジオキサニル、テトラヒドロキノリン、テトラヒドロベンゾチエニル等の、縮合した複素環式基が挙げられる。
The “heterocyclic group” includes a monovalent group derived from the above “heterocycle”.
For example, pyrrolinyl, pyrrolidino, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydropyridyl, dihydropyridinyl, dihydropyridinyl, dihydropyridinyl Monocyclic non-aromatic heterocyclic groups such as, dioxanyl, oxathiolanyl, thianyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolinyl, tetrahydroisothiazolinyl;
For example, pyrrolyl, pyrazinyl, pyrazolyl, tetrazolyl, furyl, thienyl, pyridyl, imidazolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, etc. A cyclic group;
For example, indolyl, isoindolyl, indazolyl, indolinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzopyranyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxazolyl Diazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, benzimidazo Examples include condensed heterocyclic groups such as linyl, benzodioxanyl, tetrahydroquinoline, tetrahydrobenzothienyl and the like.
 「非芳香族炭素環」とは、上記「シクロアルカン」および上記「シクロアルケン」、ならびに、上記「シクロアルカン」または上記「シクロアルケン」が上記「芳香族炭素環」に縮合した環を包含する。縮合した環としては、インデン等が挙げられる。 The “non-aromatic carbocycle” includes the above “cycloalkane” and the above “cycloalkene”, and the ring in which the “cycloalkane” or the “cycloalkene” is fused to the “aromatic carbocycle”. . Examples of the condensed ring include indene.
 「非芳香族炭素環式基」とは、上記「非芳香族炭素環」から導かれる1価の基を包含する。例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル、シクロノニル、シクロデシル、シクロペンテニル、シクロヘキセニル、ノルボルニル、テトラヒドロナフタレン-5-イル、テトラヒドロナフタレン-6-イル、ノルボルネニル、インデン-1-イル、インデン-2-イル、インデン-3-イル等が挙げられる。 The “non-aromatic carbocyclic group” includes a monovalent group derived from the above “non-aromatic carbocyclic group”. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopentenyl, cyclohexenyl, norbornyl, tetrahydronaphthalen-5-yl, tetrahydronaphthalen-6-yl, norbornenyl, inden-1-yl , Inden-2-yl, inden-3-yl and the like.
 「非芳香族炭素環オキシ」、「非芳香族炭素環アルキルオキシ」およびの「非芳香族炭素環」部分は、上記「非芳香族炭素環」と同義である。 The “non-aromatic carbocyclic oxy”, “non-aromatic carbocyclic alkyloxy” and the “non-aromatic carbocyclic” moiety are synonymous with the above “non-aromatic carbocyclic”.
 「芳香族複素環」とは、上記「複素環」のうち、芳香環であるものを包含する。
環内に窒素原子、酸素原子、及び/又は硫黄原子を少なくとも1個有する5~7員の芳香環、
それらが独立して2個以上縮合した芳香環、
環内に窒素原子、酸素原子、及び/又は硫黄原子を少なくとも1個有する5~7員の芳香環が1以上の上記「芳香族炭素環」と縮合した芳香環を包含する。
 例えば、ピラジン、ピラゾール、テトラゾール、フラン、チオフェン、ピリジン、イミダゾール、トリアゾール、トリアジン、ピリダジン、ピリミジン、ピラジン、イソオキサゾール、チアゾール、イソチアゾール、チアジアゾール、オキサゾール、オキサジアゾール等の、単環の芳香族複素環;
 例えば、インドール、イソインドール、インダゾール、インドリジン、キノリン、イソキノリン、シンノリン、フタラジン、キナゾリン、ナフチリジン、キノキサリン、プリン、プテリジン、ベンズイミダゾール、ベンズイソオキサゾール、ベンズオキサゾール、ベンズオキサジアゾール、ベンゾイソチアゾール、ベンゾチアゾール、ベンゾチアジアゾール、ベンゾフラン、イソベンゾフラン、ベンゾチオフェン、ベンゾトリアゾール、イミダゾピリジン、トリアゾロピリジン、イミダゾチアゾール、ピラジノピリダジン、ベンズイミダゾリン等の、縮合した芳香族複素環が挙げられる。
The “aromatic heterocycle” includes those that are aromatic rings among the above “heterocycle”.
A 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring,
An aromatic ring in which two or more of them are independently fused,
An aromatic ring in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “aromatic carbocycles” is included.
For example, pyrazine, pyrazole, tetrazole, furan, thiophene, pyridine, imidazole, triazole, triazine, pyridazine, pyrimidine, pyrazine, isoxazole, thiazole, isothiazole, thiadiazole, oxazole, oxadiazole, etc. ring;
For example, indole, isoindole, indazole, indolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, naphthyridine, quinoxaline, purine, pteridine, benzimidazole, benzisoxazole, benzoxazole, benzoxadiazole, benzoisothiazole, benzo Examples thereof include condensed aromatic heterocycles such as thiazole, benzothiadiazole, benzofuran, isobenzofuran, benzothiophene, benzotriazole, imidazopyridine, triazolopyridine, imidazothiazole, pyrazinopyridazine, benzimidazoline and the like.
 「5員もしくは6員の芳香族複素環」とは、5員もしくは6員の上記「芳香族複素環」を包含する。例えば、チアゾール、イソチアゾール、オキサゾール、イソキサゾール、チアジアゾール、オキサジアゾール、ピラゾール、フラン、チオフェン、イミダゾール、トリアゾール、テトラゾール、ピリジン、ピリミジン、ピラジン、ピリダジン、トリアジン等が挙げられる。 The “5-membered or 6-membered aromatic heterocycle” includes the 5-membered or 6-membered “aromatic heterocycle” described above. Examples include thiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, furan, thiophene, imidazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine and the like.
 「5員の芳香族複素環」とは、6員の上記「芳香族複素環」を包含する。例えば、ピチアゾール、イソチアゾール、オキサゾール、イソキサゾール、チアジアゾール、オキサジアゾール、ピラゾール、フラン、チオフェン、イミダゾール、トリアゾール、テトラゾール等が挙げられる。
 「6員の芳香族複素環」とは、6員の上記「芳香族複素環」を包含する。例えば、ピリジン、ピリミジン、ピラジン、ピリダジン、トリアジン等が挙げられる。
The “5-membered aromatic heterocycle” includes the 6-membered “aromatic heterocycle” described above. Examples thereof include pithiazole, isothiazole, oxazole, isoxazole, thiadiazole, oxadiazole, pyrazole, furan, thiophene, imidazole, triazole, tetrazole and the like.
The “6-membered aromatic heterocycle” includes the 6-membered “aromatic heterocycle”. For example, pyridine, pyrimidine, pyrazine, pyridazine, triazine and the like can be mentioned.
 環Bにおける、「芳香族複素環」としては、ピリジン、ピラジン、ピリダジン、チアゾール、イソチアゾール、オキサゾールまたはイソキサゾール等が挙げられる。より具体的にはピリジンが挙げられる。 Examples of the “aromatic heterocycle” in ring B include pyridine, pyrazine, pyridazine, thiazole, isothiazole, oxazole and isoxazole. More specifically, pyridine is mentioned.
 「ヘテロアリール」とは、上記「芳香族複素環」から導かれる1価の基を包含する。環内に窒素原子、酸素原子、及び/又は硫黄原子を少なくとも1個有する5~7員の芳香環式基、
それらが独立して2個以上縮合した芳香環式基、
環内に窒素原子、酸素原子、及び/又は硫黄原子を少なくとも1個有する5~7員芳香環が1以上の上記「芳香族炭素環」と縮合した芳香環式基を包含する。
 例えば、ピロリル、ピラジニル、ピラゾリル、インドリル、テトラゾリル、フリル、チエニル、ピリジル、イミダゾリル、トリアゾリル、テトラゾリル、トリアジニル、ピリダジニル、ピリミジニル、ピラジニル、イソオキサゾリル、チアゾリル、イソチアゾリル、チアジアゾリル、オキサゾリル、オキサジアゾリル等の、単環のヘテロアリール、
例えば、イソインドリル、インダゾリル、インドリジニル、イソインドリニル、キノリル、イソキノリル、シンノリニル、フタラジニル、キナゾリニル、ナフチリジニル、キノキサリニル、プリニル、プテリジニル、ベンズイミダゾリル、ベンズイソオキサゾリル、ベンズオキサゾリル、ベンズオキサジアゾリル、ベンゾイソチアゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾフリル、イソベンゾフリル、ベンゾチエニル、ベンゾトリアゾリル、イミダゾピリジル、トリアゾロピリジル、イミダゾチアゾリル、ピラジノピリダジニル、ベンズイミダゾリニル等の、縮合したヘテロアリールが挙げられる。
“Heteroaryl” includes a monovalent group derived from the above “aromatic heterocycle”. A 5- to 7-membered aromatic cyclic group having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring,
An aromatic cyclic group in which two or more of them are independently fused,
An aromatic group in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “aromatic carbocycles” is included.
For example, pyrrolyl, pyrazinyl, pyrazolyl, indolyl, tetrazolyl, furyl, thienyl, pyridyl, imidazolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, pyrimidinyl, pyrazinyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, etc. Aryl,
For example, isoindolyl, indazolyl, indolizinyl, isoindolinyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazozolyl, benzoxiazozolyl, benzothiazozolyl Condensation such as ril, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazolothiazolyl, pyrazinopyridazinyl, benzimidazolinyl Heteroaryl.
 Rにおける、「ヘテロアリール」としては、ピリジルが挙げられる
 Rにおける、「ヘテロアリール」としては、ピリジル、ピリミジル、ベンゾフリル、ベンゾチエニル、インドリル、ベンゾイソキサゾリル、ベンゾチアゾリル等が挙げられる。
 Rにおける、「ヘテロアリール」としては、ピリジルが挙げられる。
“Heteroaryl” in R 2 includes pyridyl, and “heteroaryl” in R 3 includes pyridyl, pyrimidyl, benzofuryl, benzothienyl, indolyl, benzoisoxazolyl, benzothiazolyl, and the like.
“Heteroaryl” in R 3 includes pyridyl.
 「ヘテロアリールオキシ」および「ヘテロアリールオキシカルボニル」の「ヘテロアリール」部分は、上記「ヘテロアリール」と同義である。 The “heteroaryl” part of “heteroaryloxy” and “heteroaryloxycarbonyl” has the same meaning as the above “heteroaryl”.
 「非芳香族複素環」とは、上記「複素環」のうち、非芳香環であるものを包含する。
環内に窒素原子、酸素原子、及び/又は硫黄原子を少なくとも1個有する4~7員の非芳香族環、
それらが独立して2個以上縮合した非芳香族環、
環内に窒素原子、酸素原子、及び/又は硫黄原子を少なくとも1個有する5~7員の芳香族環が、1以上の上記「シクロアルカン」または上記「シクロアルケン」と縮合した環、
環内に窒素原子、酸素原子、及び/又は硫黄原子を少なくとも1個有する5~7員の非芳香族複素環が、1以上の上記「芳香族炭素環」または「非芳香族炭素環」と縮合した環を包含する。
 例えば、オキセタン、チエタン、アゼチジン、ピロリン、ピロリジン、イミダゾリン、イミダゾリジン、ピラゾリン、ピラゾリジン、ピペリジン、ピペラジン、モルホリン、チオモルホリン、チオモルホリン、テトラヒドロピラン(例えば、2-テトラヒドロピラン、3-テトラヒドロピラン、4-テトラヒドロピラン)、ジヒドロピリジン、ジヒドロピリダジン、ジヒドロピラジン、ジオキサン、オキサチオラン、チアン、テトラヒドロフラン、テトラヒドロピラン、テトラヒドロチアゾリン、テトラヒドロイソチアゾリン等の、単環の非芳香族複素環、
例えば、インドリン、イソインドリン、ベンゾピラン、ベンゾジオキサン、テトラヒドロキノリン、ベンゾ[d]オキサゾール-2(3H)-オン、テトラヒドロベンゾチオフェン等の、縮合した非芳香族ヘテロ芳香環が挙げられる。
The “non-aromatic heterocyclic ring” includes those that are non-aromatic rings among the above-mentioned “heterocyclic rings”.
A 4- to 7-membered non-aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring,
A non-aromatic ring in which two or more of them are independently fused,
A ring in which a 5- to 7-membered aromatic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is condensed with one or more of the above “cycloalkane” or “cycloalkene”;
A 5- to 7-membered non-aromatic heterocyclic ring having at least one nitrogen atom, oxygen atom and / or sulfur atom in the ring is one or more of the above “aromatic carbocycle” or “non-aromatic carbocycle”. Includes fused rings.
For example, oxetane, thietane, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, morpholine, thiomorpholine, thiomorpholine, tetrahydropyran (for example, 2-tetrahydropyran, 3-tetrahydropyran, 4- Tetrahydropyran), dihydropyridine, dihydropyridazine, dihydropyrazine, dioxane, oxathiolane, thiane, tetrahydrofuran, tetrahydropyran, tetrahydrothiazoline, tetrahydroisothiazoline and the like,
Examples thereof include condensed non-aromatic heteroaromatic rings such as indoline, isoindoline, benzopyran, benzodioxane, tetrahydroquinoline, benzo [d] oxazol-2 (3H) -one, tetrahydrobenzothiophene and the like.
 「非芳香族複素環式基」とは、上記「非芳香族複素環」から導かれる1価の基を包含する。
 例えば、ピロリニル、ピロリジノ、ピロリジニル、イミダゾリニル、イミダゾリジニル、ピラゾリニル、ピラゾリジニル、ピペリジノ、ピペリジル、ピペラジノ、ピペラジニル、モルホリニル、モルホリノ、チオモルホリニル、チオモルホリノ、テトラヒドロピラニル、ジヒドロピリジル、ジヒドロピリダジニル、ジヒドロピラジニル、ジオキサニル、オキサチオラニル、チアニル、テトラヒドロフリル、テトラヒドロピラニル、テトラヒドロチアゾリニル、テトラヒドロイソチアゾリニル等の、単環の非芳香族複素環式基、
ベンゾジオキサン、テトラヒドロキノリン、ベンゾ[d]オキサゾール-2(3H)-オン、テトラヒドロベンゾチオフェン等の縮合した複素環式基が挙げられる。
The “non-aromatic heterocyclic group” includes a monovalent group derived from the above “non-aromatic heterocyclic ring”.
For example, pyrrolinyl, pyrrolidino, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, tetrahydropyridyl, dihydropyridinyl, dihydropyridinyl, dihydropyridinyl Monocyclic non-aromatic heterocyclic groups such as, dioxanyl, oxathiolanyl, thianyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolinyl, tetrahydroisothiazolinyl,
Examples thereof include condensed heterocyclic groups such as benzodioxane, tetrahydroquinoline, benzo [d] oxazol-2 (3H) -one, and tetrahydrobenzothiophene.
 「非芳香族複素環オキシ」および「非芳香族複素環オキシカルボニル」の「非芳香族複素環」部分は、上記「非芳香族複素環」と同義である。 The “non-aromatic heterocycle” portion of “non-aromatic heterocycle oxy” and “non-aromatic heterocycle oxycarbonyl” has the same meaning as the above “non-aromatic heterocycle”.
 「含窒素非芳香族複素環式基」なる用語は、窒素原子を少なくとも1つ環内に含み、さらに酸素原子および硫黄原子から任意に選ばれる原子を環内に1個以上含んでいてもよい非芳香族の4~7員環またはそれらが2個以上縮合した環から誘導される基を包含する。 例えば、ピロリニル、ピロリジノ、ピロリジニル、ピペリジノ、ピペリジル、ピペラジノ、ピペラジニル、モルホリニル、モルホリノ、チオモルホリノ等が挙げられる。 The term “nitrogen-containing non-aromatic heterocyclic group” includes at least one nitrogen atom in the ring, and may further include one or more atoms arbitrarily selected from an oxygen atom and a sulfur atom in the ring. It includes a group derived from a non-aromatic 4- to 7-membered ring or a ring in which two or more thereof are condensed. Examples include pyrrolinyl, pyrrolidino, pyrrolidinyl, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino, thiomorpholino and the like.
 「非芳香族複素環オキシカルボニル」の「非芳香族複素環」部分は、上記「非芳香族複素環」と同義である。 The “non-aromatic heterocycle” portion of “non-aromatic heterocycle oxycarbonyl” has the same meaning as the above “non-aromatic heterocycle”.
 「置換アルキル」、「置換アルケニル」、「置換アルキニル」、「置換アルキルオキシ」、「置換アルケニルオキシ」、「置換アルキニルオキシ」、「置換アルキルチオ」、「置換アルケニルチオ」、「置換アルキニルチオ」、「置換アルキルオキシカルボニル」、「置換アルケニルオキシカルボニル」、「置換アルキニルオキシカルボニル」および「置換アルキルカルバモイル」の置換基としては、以下からなる群から選択される1個またはそれ以上のそれぞれ同一又は異なる置換基が挙げられるがこれに限定されない:
 ヒドロキシ、カルボキシ、ハロゲン(F、Cl、Br、I)、ハロアルキルオキシ(例えば、CF3O)、シクロアルキル(例えば、シクロプロピル)、シクロアルケニル(例えば、シクロプロペニル)、アルキルオキシ(例えば、メトキシ、エトキシ、プロポキシ、ブトキシ等)、アルケニルオキシ(例えば、ビニルオキシ、アリルオキシ等)、アルキルオキシカルボニル(例えば、メトキシカルボニル、エトキシカルボニル、tert-ブトキシカルボニル等)、ニトロ、ニトロソ、アミノ、アルキルアミノ(例えば、メチルアミノ、エチルアミノ、ジメチルアミノ等)、アシルアミノ(例えば、アセチルアミノ、ベンゾイルアミノ等)、アリールアルキルアミノ(例えば、ベンジルアミノ、トリチルアミノ)、ヒドロキシアミノ、アルキルスルホニルアミノ(例えば、メタンスルホニルアミノ)、アルキルスルフィニルアミノ(例えば、メタンスルフィニルアミノ)、非芳香族複素環式基アミノ(例えば、4-テトラヒドロピラニルアミノ)、イミノ、ヒドロキシイミノ、アルキルイミノ(例えば、メチルイミノ、エチルイミノ、ジメチルイミノ等)、アルキルオキシイミノ(例えば、メトキシイミノ、エトキシイミノ等)、アシルイミノ(例えば、アセチルイミノ、ベンゾイルイミノ等)、アジド、アリール(例えば、フェニル等)、アリールアルキル(例えば、ベンジル、フェニルエチル等)、アリールアルキルオキシ(例えば、ベンジルオキシ)、非芳香族複素環式基(例えば、ピロリニル、ピペリジル、ピペラジノピロリジノ、ピロリジニル、モルホリニル、モルホリノ、2,2-ジメチル-1,3-ジオキソラニル等)、ヘテロアリール(例えば、フリル、チエニル、ピリジル、イソオキサゾリル、チアゾリル、チアジアゾリル、オキサゾリル、オキサジアゾリル、テトラゾリル、インドリル、ベンゾフリル等)、ヘテロアリールアルキル(ピリジルメチル、ピリジルエチル等)、シアノ、イソシアノ、イソシアナト、チオシアナト、イソチオシアナト、メルカプト、アルキルチオ(例えば、メチルチオ等)、アルキルスルホニル(例えば、メタンスルホニル、エタンスルホニル)、カルバモイル、アルキルカルバモイル(例えば、メチルカルバモイル、エチルカルバモイル、ジメチルカルバモイル等)、スルファモイル、アルキルスルファモイル、アシル(例えば、ホルミル、アセチル等)、ホルミルオキシ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、スルフィノ、スルホ、ヒドラジノ、アジド、ウレイド、アミジノ、グアニジノ、フタルイミド、トリアルキルシリル(トリメチルシリル等)、ヒドロキシアルキルカルバモイル(ヒドロキシエチルカルバモイル)、テロラヒドロピラニルオキシ、カルバモイルアミノ、アルキルカルバモイルアミノ(例えば、メチルカルバモイルアミノ等)、アルキルオキシカルボニルアミノ(例えば、メチルオキシカルボニルアミノ等)、ハロアルキルカルバモイル(例えば、トリフルオロエチルカルバモイル等)、アルキルオキシアルキルオキシ(例えば、メチルオキシメチルオキシ等)、カルバモイルカルバモイル、アルキルスルホニルカルバモイル(例えば、メタンスルホニルカルバモイル)およびオキソ。
“Substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted alkyloxy”, “substituted alkenyloxy”, “substituted alkynyloxy”, “substituted alkylthio”, “substituted alkenylthio”, “substituted alkynylthio”, Substituents of “substituted alkyloxycarbonyl”, “substituted alkenyloxycarbonyl”, “substituted alkynyloxycarbonyl” and “substituted alkylcarbamoyl” are each one or more selected from the group consisting of the same or different Examples include but are not limited to substituents:
Hydroxy, carboxy, halogen (F, Cl, Br, I), haloalkyloxy (eg CF 3 O), cycloalkyl (eg cyclopropyl), cycloalkenyl (eg cyclopropenyl), alkyloxy (eg methoxy, Ethoxy, propoxy, butoxy, etc.), alkenyloxy (eg, vinyloxy, allyloxy, etc.), alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), nitro, nitroso, amino, alkylamino (eg, methyl) Amino, ethylamino, dimethylamino, etc.), acylamino (eg, acetylamino, benzoylamino, etc.), arylalkylamino (eg, benzylamino, tritylamino), hydroxyamino, alkylsulfonylamino (Eg methanesulfonylamino), alkylsulfinylamino (eg methanesulfinylamino), non-aromatic heterocyclic group amino (eg 4-tetrahydropyranylamino), imino, hydroxyimino, alkylimino (eg methylimino, Ethylimino, dimethylimino, etc.), alkyloxyimino (eg, methoxyimino, ethoxyimino, etc.), acylimino (eg, acetylimino, benzoylimino, etc.), azide, aryl (eg, phenyl, etc.), arylalkyl (eg, benzyl, Phenylethyl, etc.), arylalkyloxy (eg benzyloxy), non-aromatic heterocyclic groups (eg pyrrolinyl, piperidyl, piperazinopyrrolidino, pyrrolidinyl, morpholinyl, morpholino, 2,2-dimethyl) 1,3-dioxolanyl, etc.), heteroaryl (eg, furyl, thienyl, pyridyl, isoxazolyl, thiazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, tetrazolyl, indolyl, benzofuryl, etc.), heteroarylalkyl (pyridylmethyl, pyridylethyl, etc.) , Cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio (eg, methylthio, etc.), alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl), carbamoyl, alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, etc.) , Sulfamoyl, alkylsulfamoyl, acyl (eg, formyl, acetyl, etc.), formyloxy, thioformyl Thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, hydrazino, azide, ureido, amidino, guanidino, phthalimide, trialkylsilyl (trimethylsilyl, etc.), hydroxyalkylcarbamoyl (hydroxyethylcarbamoyl), terahydropyranyloxy, carbamoylamino Alkylcarbamoylamino (eg, methylcarbamoylamino, etc.), alkyloxycarbonylamino (eg, methyloxycarbonylamino, etc.), haloalkylcarbamoyl (eg, trifluoroethylcarbamoyl, etc.), alkyloxyalkyloxy (eg, methyloxymethyloxy, etc.) ), Carbamoylcarbamoyl, alkylsulfonylcarbamoyl (eg, methanesulfonylcarbamoyl) And oxo.
 「置換アシル」の置換基は、上記「置換アルキル」の置換基、上記「アルキル」、上記「アルケニル」、および上記「アルキニル」からなる群から選択される。特に、アシル(R-C(=O)-)のRが「シクロアルキル」、「シクロアルケニル」、「非芳香族複素環式基」、「アリール」、「ヘテロアリール」である場合、それぞれの環の置換基としては、アルキル(例えば、メチル、エチル、イソプロピル、tert-ブチル等)、ハロアルキル(例えば、CF3、CH2CF3、CH2CCl3等)、アルケニル、アルキニル(例えば、エチニル)、アルキルオキシ(例えば、メトキシ、エトキシ、イソプロピルオキシ)、ハロゲン(例えば、フッ素、クロロ等)等が挙げられる。 The substituent of “substituted acyl” is selected from the group consisting of the substituent of the above “substituted alkyl”, the above “alkyl”, the above “alkenyl”, and the above “alkynyl”. In particular, when R of acyl (R—C (═O) —) is “cycloalkyl”, “cycloalkenyl”, “non-aromatic heterocyclic group”, “aryl”, “heteroaryl”, Ring substituents include alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (eg, CF 3 , CH 2 CF 3 , CH 2 CCl 3, etc.), alkenyl, alkynyl (eg, ethynyl) , Alkyloxy (for example, methoxy, ethoxy, isopropyloxy), halogen (for example, fluorine, chloro and the like) and the like.
 「置換カルバモイル」または「置換スルファモイル」の置換基は、以下からなる群から選択される1個またはそれ以上のそれぞれ同一又は異なる置換基が挙げられるがこれに限定されない:
 ヒドロキシ、カルボキシ、カルボキシアルキル(例えば、カルボキシメチル、カルボキシエチル等)、ハロゲン(F、Cl、Br、I)、アルキル(例えば、メチル、エチル)、アルケニル(例えば、ビニル)、アルキニル(例えば、エチニル)、シクロアルキル(例えば、シクロプロピル)、シクロアルケニル(例えば、シクロプロペニル)、ヒドロキシアルキル(例えば、ヒドロキシエチル)、アルキルオキシカルボニル(例えば、メトキシカルボニル、エトキシカルボニル、tert-ブトキシカルボニル等)、アルキルオキシカルボニルアルキル(例えば、メトキシカルボニルメチル、エトキシカルボニルメチル等)、アミノ、アルキルアミノ(例えば、メチルアミノ、エチルアミノ、ジメチルアミノ等)、アシルアミノ(例えば、アセチルアミノ、ベンゾイルアミノ等)、アリールアルキルアミノ(例えば、ベンジルアミノ、トリチルアミノ)、ヒドロキシアミノ、アリール(例えば、フェニル等)、非芳香族複素環基(例えば、4-テトラヒドロピラニル)、ヘテロアリール(例えば、ピリジル)、シアノ、イソシアノ、イソシアナト、チオシアナト、イソチオシアナトおよびアシル(例えば、ホルミル、アセチル等)。
Substituents for “substituted carbamoyl” or “substituted sulfamoyl” include, but are not limited to, one or more of the same or different substituents selected from the group consisting of:
Hydroxy, carboxy, carboxyalkyl (eg, carboxymethyl, carboxyethyl, etc.), halogen (F, Cl, Br, I), alkyl (eg, methyl, ethyl), alkenyl (eg, vinyl), alkynyl (eg, ethynyl) , Cycloalkyl (eg, cyclopropyl), cycloalkenyl (eg, cyclopropenyl), hydroxyalkyl (eg, hydroxyethyl), alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), alkyloxycarbonyl Alkyl (eg, methoxycarbonylmethyl, ethoxycarbonylmethyl, etc.), amino, alkylamino (eg, methylamino, ethylamino, dimethylamino, etc.), acylamino (eg, acetylamino) Benzoylamino etc.), arylalkylamino (eg benzylamino, tritylamino), hydroxyamino, aryl (eg phenyl etc.), non-aromatic heterocyclic group (eg 4-tetrahydropyranyl), heteroaryl (eg Pyridyl), cyano, isocyano, isocyanato, thiocyanato, isothiocyanato and acyl (eg, formyl, acetyl, etc.).
 「置換スルホニル」または「置換スルフィニル」の置換基は、上記「置換もしくは非置換アルキル」、上記「置換もしくは非置換アルケニル」、上記「置換もしくは非置換アルキニル」、下記「置換もしくは非置換シクロアルキル」、下記「置換もしくは非置換シクロアルケニル」、下記「置換もしくは非置換非芳香族複素環式基」、下記「置換もしくは非置換アリール」、および下記「置換もしくは非置換ヘテロアリール」からなる群から選択される。特に、R-S(=O)-またはR-S(=O)-のRが「シクロアルキル」、「シクロアルケニル」、「非芳香族複素環式基」、「アリール」、「ヘテロアリール」等である場合、それぞれの環の置換基としては、アルキル(例えば、メチル、エチル、イソプロピル、tert-ブチル等)、ハロアルキル(例えば、CF3、CH2CF3、CH2CCl3等)、アルケニル、アルキニル(例えば、エチニル)、アルキルオキシ(例えば、メトキシ、エトキシ、イソプロピルオキシ)、ハロゲン(例えば、フッ素、クロロ等)等が挙げられる。 The substituents of “substituted sulfonyl” or “substituted sulfinyl” are the above “substituted or unsubstituted alkyl”, the above “substituted or unsubstituted alkenyl”, the above “substituted or unsubstituted alkynyl”, the following “substituted or unsubstituted cycloalkyl”. Selected from the group consisting of the following "substituted or unsubstituted cycloalkenyl", the following "substituted or unsubstituted non-aromatic heterocyclic group", the following "substituted or unsubstituted aryl", and the following "substituted or unsubstituted heteroaryl" Is done. In particular, R in R—S (═O) 2 — or R—S (═O) — is “cycloalkyl”, “cycloalkenyl”, “non-aromatic heterocyclic group”, “aryl”, “heteroaryl” , Etc., each ring substituent may be alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (eg, CF 3 , CH 2 CF 3 , CH 2 CCl 3, etc.), Examples include alkenyl, alkynyl (eg, ethynyl), alkyloxy (eg, methoxy, ethoxy, isopropyloxy), halogen (eg, fluorine, chloro and the like) and the like.
 「置換アミノ」、「置換イミノ」および「置換グアニジル」の置換基としては、以下からなる群から選択される1個またはそれ以上のそれぞれ同一又は異なる置換基が挙げられるがこれらに限定されない:
アルキル(例えば、メチル、エチル、イソプロピル、tert-ブチル等)、ハロアルキル(例えば、CF3、CH2CF3、CH2CCl3等)、ヒドロキシアルキル(例えば、ヒドロキシエチル、-C(CH32CH2OH等)、アルケニル(例えば、ビニル)、アルキニル(例えば、エチニル)、シクロアルキル(例えば、シクロプロピル)、シクロアルケニル(例えば、シクロプロペニル)、アルキルオキシ(例えば、メトキシ、エトキシ、プロポキシ、ブトキシ等)、ハロアルキルオキシ(例えば、CF3O)、アルケニルオキシ(例えば、ビニルオキシ、アリルオキシ等)、アルキルオキシカルボニル(メトキシカルボニル、tert-ブチルオキシカルボニル等)、アルキルオキシカルボニルアルキル、アミノ、アルキルアミノ(例えば、メチルアミノ、エチルアミノ、ジメチルアミノ等)、アシルアミノ(例えば、アセチルアミノ、ベンゾイルアミノ等)、アリールアルキルアミノ(例えば、ベンジルアミノ、トリチルアミノ)、ヒドロキシアミノ、イミノ、ヒドロキシイミノ、アルキルイミノ(例えば、メチルイミノ、エチルイミノ、ジメチルイミノ等)、アルキルオキシイミノ(例えば、メトキシイミノ、エトキシイミノ等)、アシルイミノ(例えば、アセチルイミノ、ベンゾイルイミノ等)、アリール(例えば、フェニル等)、アリールアルキル(例えば、ベンジル等)、アリールオキシ(例えば、フェノキシ等)、非芳香族複素環式基(例えば、ピロリニル、ピロリジノ、ピペリジノ、ピペリジル、ピペラジノ、ピペラジニル、モルホリニル、モルホリノ等)、ヘテロアリール(例えば、ピリジル、チエニル、チアゾリル、フリル等)、ヘテロアリールアルキル(例えば、ピリジルメチル、チエニルメチル、チアゾリルメチル、フリルメチル等)、非芳香族複素環オキシ(ピペラジノオキシ、ピペリジノオキシ等)、ヘテロアリールオキシ(ピリジルオキシ等)、ヒドロキシ、ハロゲン(F、Cl、Br、I)、シアノ、アシル(例えば、ホルミル、アセチル等)、非芳香族複素環カルボニル(例えば、4-テトラヒドロピラニルカルボニル等)、アルキルスルホニル(例えば、メタンスルホニル等)、非芳香族複素環スルホニル(例えば、4-テトラヒドロピラニルスルホニル等)、アルキルスルフィニル(例えば、メタンスルフィニル等)、カルバモイル、アルキルカルバモイル(例えば、メチルカルバモイル等)、アルキルカルバモイルアルキル(例えば、メチルカルバモイルメチル等)、カルバモイルアルキル(例えば、カルバモイルメチル等)、カルボキシアルキル(例えば、カルボキシメチル等)、スルファモイル、アルキルスルファモイル(例えば、メチルスルファモイル等)、アルキルスルファモイルアルキル(例えば、メチルスルファモイルメチル等)およびスルファモイルアルキル(例えば、スルファモイルメチル等)
Substituents for “substituted amino”, “substituted imino” and “substituted guanidyl” include, but are not limited to, one or more of the same or different substituents selected from the group consisting of:
Alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (eg, CF 3 , CH 2 CF 3 , CH 2 CCl 3, etc.), hydroxyalkyl (eg, hydroxyethyl, —C (CH 3 ) 2 CH 2 OH, etc.), alkenyl (eg, vinyl), alkynyl (eg, ethynyl), cycloalkyl (eg, cyclopropyl), cycloalkenyl (eg, cyclopropenyl), alkyloxy (eg, methoxy, ethoxy, propoxy, butoxy) Etc.), haloalkyloxy (eg CF 3 O), alkenyloxy (eg vinyloxy, allyloxy etc.), alkyloxycarbonyl (methoxycarbonyl, tert-butyloxycarbonyl etc.), alkyloxycarbonylalkyl, amino, alkylamino (eg , Methylamino, ethi Amino, dimethylamino, etc.), acylamino (eg, acetylamino, benzoylamino, etc.), arylalkylamino (eg, benzylamino, tritylamino), hydroxyamino, imino, hydroxyimino, alkylimino (eg, methylimino, ethylimino, dimethyl) Imino etc.), alkyloxyimino (eg methoxyimino, ethoxyimino etc.), acylimino (eg acetylimino, benzoylimino etc.), aryl (eg phenyl etc.), arylalkyl (eg benzyl etc.), aryloxy ( For example, phenoxy etc.), non-aromatic heterocyclic groups (eg pyrrolinyl, pyrrolidino, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino etc.), heteroaryl (eg pi Lysyl, thienyl, thiazolyl, furyl, etc.), heteroarylalkyl (eg, pyridylmethyl, thienylmethyl, thiazolylmethyl, furylmethyl, etc.), non-aromatic heterocyclic oxy (piperazinooxy, piperidinooxy, etc.), heteroaryloxy (pyridyloxy, etc.) , Hydroxy, halogen (F, Cl, Br, I), cyano, acyl (eg, formyl, acetyl, etc.), non-aromatic heterocyclic carbonyl (eg, 4-tetrahydropyranylcarbonyl, etc.), alkylsulfonyl (eg, methane) Sulfonyl etc.), non-aromatic heterocyclic sulfonyl (eg 4-tetrahydropyranylsulfonyl etc.), alkylsulfinyl (eg methanesulfinyl etc.), carbamoyl, alkylcarbamoyl (eg methylcarbamoyl etc.), alkylcarbamo Rualkyl (eg, methylcarbamoylmethyl, etc.), carbamoylalkyl (eg, carbamoylmethyl, etc.), carboxyalkyl (eg, carboxymethyl, etc.), sulfamoyl, alkylsulfamoyl (eg, methylsulfamoyl, etc.), alkylsulfamoyl Alkyl (eg, methylsulfamoylmethyl) and sulfamoylalkyl (eg, sulfamoylmethyl)
 「置換シクロアルキル」、「置換シクロアルケニル」、「置換アリール」、「置換フェニル」、「置換複素環式基」、「置換ヘテロアリール」、「置換非芳香族炭素環式基」「置換非芳香族複素環式基」、「置換含窒素非芳香族複素環式基」、「置換シクロアルキルオキシ」、「置換シクロアルケニルオキシ」、「置換アリールオキシ」、「置換ヘテロアリールオキシ」、「置換非芳香族複素環オキシ」、「置換シクロアルキルオキシカルボニル」、「置換シクロアルケニルオキシカルボニル」、「置換非芳香族複素環オキシカルボニル」、「置換アリールオキシカルボニル」、「置換ヘテロアリールオキシカルボニル」、「置換シクロプロパン」、「置換シクロプロペン」、「置換オキセタン」、「置換チエタン」および「置換アゼチジン」の置換基としては以下からなる群から選択される1個またはそれ以上のそれぞれ同一又は異なる置換基が挙げられるがこれに限定されない:
 アルキル(例えば、メチル、エチル、イソプロピル、tert-ブチル等)、ハロアルキル(例えば、CF3、CH2CF3、CH2CCl3等)、ハロアルキルオキシ(例えば、CF3O、CHCF2O等)、アルケニル(例えば、ビニル)、アルキニル(例えば、エチニル)、シクロアルキル(例えば、シクロプロピル)、シクロアルケニル(例えば、シクロプロペニル)、アルキルオキシ(例えば、メトキシ、エトキシ、プロポキシ、ブトキシ等)、アルケニルオキシ(例えば、ビニルオキシ、アリルオキシ等)、アルキルオキシカルボニル(例えば、メトキシカルボニル、エトキシカルボニル、tert-ブトキシカルボニル等)、ニトロ、ニトロソ、アミノ、アルキルアミノ(例えば、メチルアミノ、エチルアミノ、ジメチルアミノ等)、アシルアミノ(例えば、アセチルアミノ、ベンゾイルアミノ等)、アリールアルキルアミノ(例えば、ベンジルアミノ、トリチルアミノ)、ヒドロキシアミノ、下記置換基群Yから選択される1または2個のそれぞれ同一又は異なる置換基で置換されたアミノ、イミノ、ヒドロキシイミノ、アルキルイミノ(例えば、メチルイミノ、エチルイミノ、ジメチルイミノ等)、アルキルオキシイミノ(例えば、メトキシイミノ、エトキシイミノ等)、アシルイミノ(例えば、アセチルイミノ、ベンゾイルイミノ等)、アジド、アリール(例えば、フェニル等)、アリールアルキル(例えば、ベンジル等)、非置換の非芳香族炭素環オキシ(例えば、シクロプロピルオキシ等)、下記置換基群Zから選択される1個またはそれ以上のそれぞれ同一又は異なる置換基で置換された非芳香族炭素環オキシ、非置換の非芳香族炭素環アルキルオキシ(例えば、シクロプロピルメチルオキシ等)、下記置換基群Zから選択される1個またはそれ以上のそれぞれ同一又は異なる置換基で置換された非芳香族炭素環アルキルオキシ、非置換のアリールオキシ(例えば、フェノキシ等)、下記置換基群Zから選択される1個またはそれ以上のそれぞれ同一又は異なる置換基で置換されたアリールオキシ、非置換のアリールアルキルオキシ(例えば、ベンジルオキシ等)、下記置換基群Zから選択される1個またはそれ以上のそれぞれ同一又は異なる置換基で置換されたアリールアルキルオキシ、非芳香族複素環式基(例えば、ピロリニル、ピロリジノ、ピペリジノ、ピペリジル、ピペラジノ、ピペラジニル、モルホリニル、モルホリノ等)、ヘテロアリール(例えば、ピリジル、チエニル、チアゾリル、フリル等)、ヘテロアリールアルキル(例えば、ピリジルメチル、チエニルメチル、チアゾリルメチル、フリルメチル等)、非置換の非芳香族複素環オキシ(例えば、ピペラジノオキシ、ピペリジノオキシ等)、下記置換基群Zから選択される1個またはそれ以上のそれぞれ同一又は異なる置換基で置換された非芳香族複素環オキシ、非置換のヘテロアリールオキシ(例えば、ピリジルオキシ、ピリダジニルオキシ、ピリミジニルオキシ、ピラジニルオキシ、オキサゾリルオキシ、イソオキサゾリルオキシ、オキサジアゾリルオキシ、チアゾリルオキシ、イソチアゾリルオキシ、チアジアゾリルオキシ、フリルオキシ、チエニルオキシ等)、下記置換基群Zから選択される1個またはそれ以上のそれぞれ同一又は異なる置換基で置換されたヘテロアリールオキシ、シアノ、イソシアノ、イソシアナト、チオシアナト、イソチオシアナト、メルカプト、アルキルチオ(例えば、メチルチオ等)、アルキルスルホニル(例えば、メタンスルホニル、エタンスルホニル)、置換もしくは非置換のカルバモイル(例えば、カルバモイル、N-メチル-N-メトキシカルバモイル等)、置換もしくは非置換のアルキルカルバモイル(例えば、メチルカルバモイル、エチルカルバモイル、ジメチルカルバモイル、ヒドロキシエチルカルバモイル、トリフルオロメチルカルバモイル、トリフルオロエチルカルバモイル等)、スルファモイル、アルキルスルファモイル、ヒドロキシ、カルボキシ、アルキルオキシカルボニル、ハロゲン(F、Cl、Br、I)、アシル(例えば、ホルミル、アセチル等)、ホルミルオキシ、チオホルミル、チオカルボキシ、ジチオカルボキシ、チオカルバモイル、スルフィノ、スルホ、ヒドラジノ、アジド、ウレイド、アミジノ、グアニジノ、フタルイミドおよびオキソ。
“Substituted cycloalkyl”, “Substituted cycloalkenyl”, “Substituted aryl”, “Substituted phenyl”, “Substituted heteroaryl”, “Substituted heteroaryl”, “Substituted non-aromatic carbocyclic” “Substituted non-aromatic Group heterocyclic group "," substituted nitrogen-containing non-aromatic heterocyclic group "," substituted cycloalkyloxy "," substituted cycloalkenyloxy "," substituted aryloxy "," substituted heteroaryloxy "," substituted non-substituted "Aromatic heterocyclic oxy", "substituted cycloalkyloxycarbonyl", "substituted cycloalkenyloxycarbonyl", "substituted non-aromatic heterocyclic oxycarbonyl", "substituted aryloxycarbonyl", "substituted heteroaryloxycarbonyl", " Substituted cyclopropane, substituted cyclopropene, substituted oxetane, substituted thietane and substituted azetidine As the substituents include one or more of the same or different substituents selected from the group consisting of but not limited to:
Alkyl (eg, methyl, ethyl, isopropyl, tert-butyl, etc.), haloalkyl (eg, CF 3 , CH 2 CF 3 , CH 2 CCl 3, etc.), haloalkyloxy (eg, CF 3 O, CHCF 2 O, etc.), Alkenyl (eg vinyl), alkynyl (eg ethynyl), cycloalkyl (eg cyclopropyl), cycloalkenyl (eg cyclopropenyl), alkyloxy (eg methoxy, ethoxy, propoxy, butoxy etc.), alkenyloxy ( For example, vinyloxy, allyloxy, etc.), alkyloxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, etc.), nitro, nitroso, amino, alkylamino (eg, methylamino, ethylamino, dimethylamino, etc.), acylamino (For example, AS Ruamino, benzoylamino, etc.), arylalkylamino (eg, benzylamino, tritylamino), hydroxyamino, amino substituted with one or two identical or different substituents selected from the following substituent group Y, imino , Hydroxyimino, alkylimino (eg, methylimino, ethylimino, dimethylimino, etc.), alkyloxyimino (eg, methoxyimino, ethoxyimino, etc.), acylimino (eg, acetylimino, benzoylimino, etc.), azide, aryl (eg, Phenyl, etc.), arylalkyl (eg, benzyl, etc.), unsubstituted non-aromatic carbocyclic oxy (eg, cyclopropyloxy, etc.), one or more selected from the following substituent group Z, or the same or different Non-substituted with substituent Aromatic carbocyclic oxy, unsubstituted non-aromatic carbocyclic alkyloxy (eg, cyclopropylmethyloxy, etc.), substituted with one or more of the same or different substituents selected from the following substituent group Z Non-aromatic carbocyclic alkyloxy, unsubstituted aryloxy (for example, phenoxy and the like), aryloxy substituted with one or more each same or different substituents selected from the following substituent group Z, non- A substituted arylalkyloxy (for example, benzyloxy and the like), an arylalkyloxy substituted with one or more of the same or different substituents selected from the following substituent group Z, a non-aromatic heterocyclic group ( For example, pyrrolinyl, pyrrolidino, piperidino, piperidyl, piperazino, piperazinyl, morpholinyl, morpholino, etc. ), Heteroaryl (eg, pyridyl, thienyl, thiazolyl, furyl, etc.), heteroarylalkyl (eg, pyridylmethyl, thienylmethyl, thiazolylmethyl, furylmethyl, etc.), unsubstituted non-aromatic heterocyclic oxy (eg, piperazinooxy, Piperidinooxy, etc.), non-aromatic heterocyclic oxy, unsubstituted heteroaryloxy (eg, pyridyloxy, pyrida) substituted with one or more of the same or different substituents selected from the following substituent group Z Zinyloxy, pyrimidinyloxy, pyrazinyloxy, oxazolyloxy, isoxazolyloxy, oxadiazolyloxy, thiazolyloxy, isothiazolyloxy, thiadiazolyloxy, furyloxy, thienyloxy, etc.), the following substituent group Z 1 selected from Heteroaryloxy, cyano, isocyano, isocyanato, thiocyanato, isothiocyanato, mercapto, alkylthio (eg, methylthio, etc.), alkylsulfonyl (eg, methanesulfonyl, ethanesulfonyl), each substituted with the same or different substituents Substituted or unsubstituted carbamoyl (eg, carbamoyl, N-methyl-N-methoxycarbamoyl, etc.), substituted or unsubstituted alkylcarbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, hydroxyethylcarbamoyl, trifluoromethylcarbamoyl, Trifluoroethylcarbamoyl, etc.), sulfamoyl, alkylsulfamoyl, hydroxy, carboxy, alkyloxycarbonyl, halogen (F, Cl, Br, I), acyl (eg, formyl, acetyl, etc.), formyloxy, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, sulfino, sulfo, hydrazino, azide, ureido, amidino, guanidino, phthalimide and Oxo.
 置換基群Yとは、ヒドロキシアルキル(例えば、ヒドロキシエチル、-C(CH32CH2OH等)、アルキルオキシカルボニル(メトキシカルボニル、tert-ブチルオキシカルボニル等)、アルキルオキシカルボニルアルキル、アルキルスルホニル(例えば、メタンスルホニル等)、アルキルスルフィニル(例えば、メタンスルフィニル等)、カルバモイル、アルキルカルバモイル(例えば、メチルカルバモイル等)、アルキルカルバモイルアルキル(例えば、メチルカルバモイルメチル等)、カルバモイルアルキル(例えば、カルバモイルメチル等)、カルボキシアルキル(例えば、カルボキシメチル等)、スルファモイル、アルキルスルファモイル(例えば、メチルスルファモイル等)、アルキルスルファモイルアルキル(例えば、メチルスルファモイルメチル等)およびスルファモイルアルキル(例えば、スルファモイルメチル等)を包含する。
 置換基群Zとは、ハロゲン(例えば、F、Cl等)、ヒドロキシ、カルボキシ、カルボキシアルキルオキシ(例えば、カルボキシメチルオキシ等)、シアノ、ニトロ、アルキル(例えば、メチル等)、ヒドロキシアルキル(例えば、ヒドロキシメチル等)、アミノアルキル、アルキルアミノアルキル、アルケニル、アルキニル、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、アルキルチオ、アルケニルチオ、アルキニルチオ、アシル、アルキルオキシカルボニル(例えば、メチルオキシカルボニル、エチルオキシカルボニル等)、アルケニルオキシカルボニル、アルキニルオキシカルボニル、カルバモイル、カルバモイルアルキルオキシ(例えば、カルバモイルメチルオキシ等)、アルキルカルバモイル(例えば、メチルカルバモイルエチルカルバモイル等)、ハロアルキルカルバモイル、シクロアルキルカルバモイル(例えば、シクロプロピルカルバモイル等)、アルキルカルバモイルアルキルオキシ(例えば、メチルカルバモイルメチルオキシ等)、ヒドロキシアルキルカルバモイル(例えば、ヒドロキシエチルカルバモイル等)、シアノカルバモイル、アミノ、アシルアミノ、上記置換基群Yから選択される1または2個のそれぞれ同一又は異なる置換基で置換されたアミノ、スルファモイル、メチルスルホニル、メチルスルフィニル、シクロアルキル、シクロアルケニル、非芳香族複素環式基、アリール、ヘテロアリール(例えば、テトラゾリル等)、シクロアルキルオキシ、シクロアルケニルオキシ、非芳香族複素環オキシ、アリールオキシ、ヘテロアリールオキシおよびオキソを包含する。
Substituent group Y is hydroxyalkyl (eg, hydroxyethyl, —C (CH 3 ) 2 CH 2 OH, etc.), alkyloxycarbonyl (methoxycarbonyl, tert-butyloxycarbonyl, etc.), alkyloxycarbonylalkyl, alkylsulfonyl (Eg methanesulfonyl etc.), alkylsulfinyl (eg methanesulfinyl etc.), carbamoyl, alkylcarbamoyl (eg methylcarbamoyl etc.), alkylcarbamoylalkyl (eg methylcarbamoylmethyl etc.), carbamoylalkyl (eg carbamoylmethyl etc. ), Carboxyalkyl (eg, carboxymethyl, etc.), sulfamoyl, alkylsulfamoyl (eg, methylsulfamoyl, etc.), alkylsulfamoylalkyl (eg, methyls) Include sulfamoyl, such as methyl) and sulfamoyl alkyl (e.g., a sulfamoyl methyl, etc.).
Substituent group Z includes halogen (for example, F, Cl and the like), hydroxy, carboxy, carboxyalkyloxy (for example, carboxymethyloxy and the like), cyano, nitro, alkyl (for example, methyl and the like), hydroxyalkyl (for example, Hydroxymethyl, etc.), aminoalkyl, alkylaminoalkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylthio, alkenylthio, alkynylthio, acyl, alkyloxycarbonyl (eg, methyloxycarbonyl, ethyloxycarbonyl, etc.) , Alkenyloxycarbonyl, alkynyloxycarbonyl, carbamoyl, carbamoylalkyloxy (eg, carbamoylmethyloxy, etc.), alkylcarbamoyl (eg, methylcarbamoyl) Tilcarbamoyl etc.), haloalkylcarbamoyl, cycloalkylcarbamoyl (eg cyclopropylcarbamoyl etc.), alkylcarbamoylalkyloxy (eg methylcarbamoylmethyloxy etc.), hydroxyalkylcarbamoyl (eg hydroxyethylcarbamoyl etc.), cyanocarbamoyl, amino , Acylamino, amino, sulfamoyl, methylsulfonyl, methylsulfinyl, cycloalkyl, cycloalkenyl, non-aromatic heterocyclic group substituted with one or two same or different substituents selected from the above substituent group Y , Aryl, heteroaryl (eg, tetrazolyl, etc.), cycloalkyloxy, cycloalkenyloxy, non-aromatic heterocyclic oxy, aryloxy, heteroaryloxy And encompasses oxo.
 Rにおける、「置換アリール」および「置換へテロアリール」の置換基としては、ハロゲン、アルキル、アルケニル、アルキニル、アルキルオキシ、シクロアルキル、アルキルシリルアルキニル等が挙げられる。 Examples of the substituent of “substituted aryl” and “substituted heteroaryl” in R 2 include halogen, alkyl, alkenyl, alkynyl, alkyloxy, cycloalkyl, alkylsilylalkynyl and the like.
 Rにおける、「置換アリール」および「置換へテロアリール」の置換基としては、フルオロ、クロロ、ブロモ、ヨード、メチル、エチル、プロピル、イソプロピル、プロペニル、ビニル、エチニル、メチルオキシ、シクロプロピル、トリメチルシリルエチニル等が挙げられる。 As the substituent of “substituted aryl” and “substituted heteroaryl” in R 2 , fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, isopropyl, propenyl, vinyl, ethynyl, methyloxy, cyclopropyl, trimethylsilylethynyl Etc.
 Rにおける、「置換アリール」および「置換へテロアリール」の置換基である「ヘテロアリールオキシ」としては、例えば、ピロリルオキシ、ピラジニルオキシ、ピラゾリルオキシ、インドリルオキシ、テトラゾリルオキシ、フリルオキシ、チエニルオキシ、ピリジルオキシ、イミダゾリルオキシ、トリアゾリルオキシ、テトラゾリルオキシ、トリアジニルオキシ、ピリダジニルオキシ、ピリミジニルオキシ、ピラジニルオキシ、イソオキサゾリルオキシ、チアゾリルオキシ、イソチアゾリルオキシ、チアジアゾリルオキシ、オキサゾリルオキシ、オキサジアゾリルオキシ等が挙げられる。 As the “heteroaryloxy” which is a substituent of “substituted aryl” and “substituted heteroaryl” in R 3 , for example, pyrrolyloxy, pyrazinyloxy, pyrazolyloxy, indolyloxy, tetrazolyloxy, furyloxy, thienyloxy, Pyridyloxy, imidazolyloxy, triazolyloxy, tetrazolyloxy, triazinyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, isoxazolyloxy, thiazolyloxy, isothiazolyloxy, thiadiazolyloxy, Oxazolyloxy, oxadiazolyloxy and the like can be mentioned.
 Rにおける、「置換アリール」および「置換へテロアリール」の置換基としては、非置換のヘテロアリールオキシ、上記置換基群Zから選択される1個またはそれ以上のそれぞれ同一又は異なる置換基で置換されたヘテロアリールオキシ等が挙げられる。さらに、上記の置換基に加え、ハロゲン、ヒドロキシ、カルボキシ、シアノ、ニトロ、アルキル、ハロアルキル、ハロアルキルオキシ、アルキルオキシ、アミノ等が挙げられる。上記ヘテロアリールオキシとしては、非置換または上記置換基群Zから選択される1個またはそれ以上のそれぞれ同一又は異なる置換基で置換された、以下の群から選択される基:ピロリルオキシ、ピラジニルオキシ、ピラゾリルオキシ、インドリルオキシ、テトラゾリルオキシ、フリルオキシ、チエニルオキシ、ピリジルオキシ、イミダゾリルオキシ、トリアゾリルオキシ、テトラゾリルオキシ、トリアジニルオキシ、ピリダジニルオキシ、ピリミジニルオキシ、ピラジニルオキシ、イソオキサゾリルオキシ、チアゾリルオキシ、イソチアゾリルオキシ、チアジアゾリルオキシ、オキサゾリルオキシ、およびオキサジアゾリルオキシが挙げられる。 Substituents for “substituted aryl” and “substituted heteroaryl” in R 3 are unsubstituted heteroaryloxy, substituted with one or more of the same or different substituents selected from the above substituent group Z. Heteroaryloxy and the like. Furthermore, in addition to the above substituents, halogen, hydroxy, carboxy, cyano, nitro, alkyl, haloalkyl, haloalkyloxy, alkyloxy, amino and the like can be mentioned. The heteroaryloxy is a group selected from the following group which is unsubstituted or substituted with one or more of the same or different substituents selected from the substituent group Z: pyrrolyloxy, pyrazinyloxy, pyrazolyloxy , Indolyloxy, tetrazolyloxy, furyloxy, thienyloxy, pyridyloxy, imidazolyloxy, triazolyloxy, tetrazolyloxy, triazinyloxy, pyridazinyloxy, pyrimidinyloxy, pyrazinyloxy, isoxa Examples include zolyloxy, thiazolyloxy, isothiazolyloxy, thiadiazolyloxy, oxazolyloxy, and oxadiazolyloxy.
 R9’における「置換アミノ」の置換基としては、「カルバモイル、アルキルカルバモイル(例えば、メチルカルバモイル等)、アルキルカルバモイルアルキル(例えば、メチルカルバモイルメチル等)、カルバモイルアルキル(例えば、カルバモイルメチル等)またはカルボキシアルキル(例えば、カルボキシメチル等)」が挙げられる。 The substituent of “substituted amino” in R 9 ′ includes “carbamoyl, alkylcarbamoyl (eg, methylcarbamoyl etc.), alkylcarbamoylalkyl (eg, methylcarbamoylmethyl etc.), carbamoylalkyl (eg, carbamoylmethyl etc.) or carboxy Alkyl (for example, carboxymethyl and the like) ".
 R9’としては、ハロゲン、ヒドロキシ、カルボキシ、シアノ、ニトロ、アルキル、ヒドロキシアルキル、アミノアルキル、アルキルアミノアルキル、アルケニル、アルキニル、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、アルキルチオ、アルケニルチオ、アルキニルチオ、アシル、アルキルオキシカルボニル、アルケニルオキシカルボニル、アルキニルオキシカルボニル、カルバモイル、アルキルカルバモイル、ハロアルキルカルバモイル、ヒドロキシアルキルカルバモイル、シアノカルバモイル、アミノ、アシルアミノ、上記置換基群Yから選択される1または2個のそれぞれ同一又は異なる置換基で置換されたアミノ、スルファモイル、メチルスルホニル、メチルスルフィニルが挙げられる。 R 9 ′ includes halogen, hydroxy, carboxy, cyano, nitro, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkenyl, alkynyl, alkyloxy, alkenyloxy, alkynyloxy, alkylthio, alkenylthio, alkynylthio, acyl , Alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, carbamoyl, alkylcarbamoyl, haloalkylcarbamoyl, hydroxyalkylcarbamoyl, cyanocarbamoyl, amino, acylamino, one or two each selected from the above substituent group Y are the same or different Examples include amino, sulfamoyl, methylsulfonyl, and methylsulfinyl substituted with a substituent.
 一般式(I)または一般式(II)において、「同一の炭素原子に結合するR4aとR4bが一緒になってオキソもしくはチオキソ」であるとは、例えば以下のような場合を包含する。 In the general formula (I) or the general formula (II), “R 4a and R 4b bonded to the same carbon atom together are oxo or thioxo” includes, for example, the following cases.
Figure JPOXMLDOC01-appb-C000025

(式中、n、R4a、R4bおよびRは上記(1)と同義)等である。
Figure JPOXMLDOC01-appb-C000025

(Wherein, n, R 4a, R 4b and R 2 are synonymous above (1)), and the like.
 一般式(I)において、D環であるベンゼン、ピリジン、ピリミジン、ピラジンまたはピリダジンを構成する炭素原子a、Q原子、Q原子、炭素原子b、Q原子およびQ原子の位置を、それぞれ、1位、2位、3位、4位、5位および6位とする。これらの原子の位置番号は、IUPAC命名法に基づく位置番号とは異なる。すなわち、「環D上の炭素原子aと炭素原子bが、(1,4)の位置関係」であるとは、以下のような場合を包含する。 In the general formula (I), the positions of carbon atom a, Q a atom, Q b atom, carbon atom b, Q c atom and Q d atom constituting benzene, pyridine, pyrimidine, pyrazine or pyridazine, which are D rings, The first, second, third, fourth, fifth and sixth positions, respectively. The position numbers of these atoms are different from the position numbers based on the IUPAC nomenclature. That is, “the positional relationship of carbon atom a and carbon atom b on ring D is (1, 4)” includes the following cases.
Figure JPOXMLDOC01-appb-C000026

(式中、Q原子、Qb原子、Qc原子およびQd原子は、それぞれ独立して、炭素原子または窒素原子であり、-X-、-L-、環D、環B、s、s’ 、RおよびR9’は、上記(1)と同義)
Figure JPOXMLDOC01-appb-C000026

(Wherein, Q a atom, Q b atom, Q c atom and Q d atom are each independently a carbon atom or a nitrogen atom, and —X—, —L—, ring D, ring B, s, s ′, R 9 and R 9 ′ are synonymous with the above (1))
 一般式(I)において、D環であるベンゼン、ピリジン、ピリミジン、ピラジンまたはピリダジンを構成する炭素原子a、Q原子、Q原子、炭素原子b、Q原子およびQ原子の位置を、それぞれ、1位、2位、3位、4位、5位および6位とする。これらの原子の位置番号は、IUPAC命名法に基づく位置番号とは異なる。すなわち、「環D上の炭素原子aと炭素原子bが、(1,3)の位置関係」であるとは、以下のような場合を包含する。 In the general formula (I), the positions of carbon atom a, Q a atom, Q b atom, carbon atom b, Q c atom and Q d atom constituting benzene, pyridine, pyrimidine, pyrazine or pyridazine, which are D rings, The first, second, third, fourth, fifth and sixth positions, respectively. The position numbers of these atoms are different from the position numbers based on the IUPAC nomenclature. That is, “the positional relationship of carbon atom a and carbon atom b on ring D is (1,3)” includes the following cases.
Figure JPOXMLDOC01-appb-C000027

(式中、Q原子、Qb原子、Qc原子およびQd原子は、それぞれ独立して、炭素原子または窒素原子であり、-X-、-L-、環D、環B、s、s’ 、RおよびR9’は、上記(1)と同義)
Figure JPOXMLDOC01-appb-C000027

(Wherein, Q a atom, Q b atom, Q c atom and Q d atom are each independently a carbon atom or a nitrogen atom, and —X—, —L—, ring D, ring B, s, s ′, R 9 and R 9 ′ are synonymous with the above (1))
 一般式(I)または一般式(II)において、「同一の炭素原子に結合するR11cとR11dが一緒になって、置換もしくは非置換のシクロアルカン、置換もしくは非置換のシクロアルケン、もしくは置換もしくは非置換の非芳香族複素環」であるとは、以下のような場合を包含する。 In general formula (I) or general formula (II), “R 11c and R 11d bonded to the same carbon atom are combined to form a substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted The term “or an unsubstituted non-aromatic heterocyclic ring” includes the following cases.
Figure JPOXMLDOC01-appb-C000028

[式中、m’、R11cおよびR11dは、上記(2)と同義;
 vdは、0~3の整数(例えば、0または1、例えば、0が挙げられる。);
 -Wd-は、-O-、-S-または-N(R17d)-(例えば、-O-が挙げられる。);
 R17dは、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、または置換もしくは非置換のアシル]等である。
Figure JPOXMLDOC01-appb-C000028

[Wherein, m ′, R 11c and R 11d have the same meaning as in the above (2);
vd is an integer of 0 to 3 (eg, 0 or 1, for example, 0);
—Wd— represents —O—, —S— or —N (R 17d ) — (for example, —O—);
R 17d is a hydrogen atom, a substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl,] and the like.
 一般式(I)または一般式(II)において、「同一の炭素原子に結合するR11aとR11bが一緒になって、置換もしくは非置換のシクロアルカン、置換もしくは非置換のシクロアルケン、もしくは置換もしくは非置換の非芳香族複素環」であるとは、以下のような場合を包含する。 In general formula (I) or general formula (II), “R 11a and R 11b bonded to the same carbon atom are combined to form a substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted The term “or an unsubstituted non-aromatic heterocyclic ring” includes the following cases.
Figure JPOXMLDOC01-appb-C000029

[式中、m、R11aおよびR11bは、上記(14)と同義;
 vは、0~3の整数(例えば、0または1、例えば、0が挙げられる。);
 -W-は、-O-、-S-または-N(R17)-(例えば、-O-が挙げられる。);
 R17は、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、または置換もしくは非置換のアシル]等である。
Figure JPOXMLDOC01-appb-C000029

[Wherein, m, R 11a and R 11b are as defined above (14);
v is an integer of 0 to 3 (for example, 0 or 1, such as 0);
—W— represents —O—, —S— or —N (R 17 ) — (for example, —O—);
R 17 represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl].
 一般式(I)または一般式(II)において、「同一の炭素原子に結合するR14aとR14bが一緒になって、置換もしくは非置換のシクロアルカン、置換もしくは非置換のシクロアルケン、もしくは置換もしくは非置換の非芳香族複素環」とは、以下のような場合を包含する。 In general formula (I) or general formula (II), “R 14a and R 14b bonded to the same carbon atom are combined to form a substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted The “unsubstituted non-aromatic heterocycle” includes the following cases.
Figure JPOXMLDOC01-appb-C000030

[式中、t、R14a、R14b、R15aおよびR15bは、上記(17)と同義;
 vaは、0~3の整数(例えば、0または1、例えば、0が挙げられる。);
 -Wa-は、-O-、-S-または-N(R17a)-(例えば、-O-が挙げられる。);
 R17aは、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、または置換もしくは非置換のアシル]等である。
Figure JPOXMLDOC01-appb-C000030

[Wherein, t, R 14a , R 14b , R 15a and R 15b have the same meanings as the above (17);
va is an integer of 0 to 3 (for example, 0 or 1, such as 0);
—Wa— represents —O—, —S— or —N (R 17a ) — (for example, —O—);
R 17a is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl].
 一般式(I)または一般式(II)において、「同一の炭素原子に結合するR14a’とR14b’が一緒になって、置換もしくは非置換のシクロアルカン、置換もしくは非置換のシクロアルケン、もしくは置換もしくは非置換の非芳香族複素環」とは、以下のような場合を包含する。 In general formula (I) or general formula (II), “R 14a ′ and R 14b ′ bonded to the same carbon atom are combined to form a substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, “Substituted or unsubstituted non-aromatic heterocycle” includes the following cases.
Figure JPOXMLDOC01-appb-C000031
 
Figure JPOXMLDOC01-appb-C000031
 
Figure JPOXMLDOC01-appb-C000032

[式中、t’、R14a’、R14b’、R15a’およびR15b’は、上記(17)と同義;
 vbは、0~3の整数(例えば、0または1、例えば、0が挙げられる。);
 -Wb-は、-O-、-S-または-N(R17b)-(例えば、-O-が挙げられる);
 R17bは、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、または置換もしくは非置換のアシル]等である。
Figure JPOXMLDOC01-appb-C000032

[Wherein, t ′, R 14a ′ , R 14b ′ , R 15a ′ and R 15b ′ have the same meaning as the above (17);
vb is an integer of 0 to 3 (for example, 0 or 1, such as 0);
—Wb— represents —O—, —S— or —N (R 17b ) — (for example, —O—);
R 17b is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl].
 一般式(I)または一般式(II)において、Rが「3~5個のヒドロキシで置換され、さらに置換基群A(置換基群A:ハロゲン、シアノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミノ、置換もしくは非置換のイミノ、置換もしくは非置換のグアニジル、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、ニトロ、オキソ、およびチオキソ)から選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルキル」であるとは、C3~C6アルキルが必ず3~5個のヒドロキシで置換されており、さらに該アルキルが置換基群Aから選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルキルであることを意味する。例えば、Rとしては、以下のような基を包含する。 In the general formula (I) or the general formula (II), R c is substituted with “3 to 5 hydroxy groups, and further substituted group A (substituent group A: halogen, cyano, substituted or unsubstituted alkyloxy, Substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl Substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, Substituted or unsubstituted amino, substituted Or unsubstituted imino, substituted or unsubstituted guanidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cyclo Alkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, oxo, And “C3-C6 alkyl optionally substituted with one or more substituents selected from thioxo)” means that C3-C6 alkyl is necessarily substituted with 3-5 hydroxy, The alkyl is selected from substituent group A Means that are 1 or more substituents may C3 ~ C6 alkyl which may be substituted with a group. For example, R c includes the following groups.
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
 本発明化合物の一般的合成方法を以下に示す。これら合成に用いる出発物質および反応試薬はいずれも、商業的に入手可能であるか、または商業的に入手可能な化合物を用いて当分野で周知の方法にしたがって製造することができる。 The general synthesis method of the compound of the present invention is shown below. Any of the starting materials and reaction reagents used in these syntheses are commercially available or can be prepared according to methods well known in the art using commercially available compounds.
 本発明の一般式(I)、一般式(II)、一般式(II’)および一般式(II’ ’)で表される化合物は、例えば、以下に示す合成ルートによって製造することができる。必要に応じて、WO2010/092966に記載されている内容を参考にして製造することができる。 The compounds represented by general formula (I), general formula (II), general formula (II ') and general formula (II' ') of the present invention can be produced, for example, by the synthetic route shown below. If necessary, it can be produced with reference to the contents described in WO2010 / 092966.
[A法] [Method A]
Figure JPOXMLDOC01-appb-C000038

(式中、Lgは、
Figure JPOXMLDOC01-appb-C000038

(Where Lg is
Figure JPOXMLDOC01-appb-C000039

で示される脱離基であり、R10はアルキル、R27はアルキル、n’は、0~3の整数であり、Lgは脱離基であり、その他の記号は前記と同義である。)
(第1工程)
 化合物(i)またはその塩酸塩もしくは臭素酸塩等を、N,N-ジメチルホルムアミド、N,N-ジメチルアセタミド、N,N’-ジメチルイミダゾリジノン、ジメチルスルホキシド等の溶媒中、DBU、トリエチルアミン、ピリジン等の塩基(好ましくは、DBU)の存在下、-20℃~50℃、好ましくは-10℃~氷冷下で、イソシアネート(ii)または1-カルバモイルイミダゾール(ii)’と反応させる。続けて、反応混合物を、1,1’-カルボニルジイミダゾール、1,1’-チオカルボニルジイミダゾール、ホスゲン、チオホスゲン、トリホスゲン等のカルボニル化剤またはチオカルボニル化剤、およびDBU、トリエチルアミン、ピリジン等の塩基(好ましくは、DBU)と、-20℃~50℃、好ましくは-10℃~氷冷下で、反応させることにより化合物(iii)を製造することができる。
(第2工程)
 化合物(iii)をアセトニトリル、アセトン、DMF、DMSO等の溶媒中、炭酸カリウム、炭酸ナトリウム等の塩基の存在下、50℃~加熱還流下、好ましくは加熱還流下で、化合物(iv)と反応させることで、化合物(v)を製造することができる。
 脱離基としては、例えば、ハロゲンおよび-OSO(C2t+1)(式中、tは1~4の整数)等が挙げられる。ハロゲンとしては、塩素、ヨウ素および臭素が好ましく、-OSO(C2t+1)基としては、-OTf基(トリフルオロメタンスルホン酸エステル)が好ましい。
(第3工程)
 化合物(v)をNMP、DMF、DMSO等の溶媒中または無溶媒で、マイクロウェーブ照射下150℃~250℃、好ましくは200℃~230℃で、またはt-ブタノール等の溶媒中、酢酸等の酸の存在下、60℃~150℃、好ましくは80℃~120℃で、化合物(vii)と反応させることにより、一般式(II’)で示される化合物を製造することができる。
 光学活性なイソシアネート(ii)を用いることで、光学活性である一般式(II’)で示される化合物を合成することができる。
Figure JPOXMLDOC01-appb-C000039

R 10 is alkyl, R 27 is alkyl, n ′ is an integer of 0 to 3, Lg 1 is a leaving group, and other symbols are as defined above. )
(First step)
Compound (i) or a hydrochloride or bromate thereof, etc. in a solvent such as N, N-dimethylformamide, N, N-dimethylacetamide, N, N′-dimethylimidazolidinone, dimethylsulfoxide, DBU, Reaction with isocyanate (ii) or 1-carbamoylimidazole (ii) ′ in the presence of a base such as triethylamine or pyridine (preferably DBU) at −20 ° C. to 50 ° C., preferably −10 ° C. to ice cooling . Subsequently, the reaction mixture is carbonylated or thiocarbonylated, such as 1,1′-carbonyldiimidazole, 1,1′-thiocarbonyldiimidazole, phosgene, thiophosgene, triphosgene, and DBU, triethylamine, pyridine, etc. Compound (iii) can be produced by reacting with a base (preferably DBU) at −20 ° C. to 50 ° C., preferably −10 ° C. to ice cooling.
(Second step)
Compound (iii) is reacted with compound (iv) in a solvent such as acetonitrile, acetone, DMF or DMSO in the presence of a base such as potassium carbonate or sodium carbonate at 50 ° C. to heating under reflux, preferably under heating to reflux. Thus, compound (v) can be produced.
Examples of the leaving group include halogen and —OSO 2 (C t F 2t + 1 ) (wherein t is an integer of 1 to 4). As the halogen, chlorine, iodine and bromine are preferable. As the —OSO 2 (C t F 2t + 1 ) group, —OTf group (trifluoromethanesulfonic acid ester) is preferable.
(Third step)
Compound (v) may be used in a solvent such as NMP, DMF, DMSO or without solvent, under microwave irradiation at 150 ° C. to 250 ° C., preferably at 200 ° C. to 230 ° C., or in a solvent such as t-butanol, acetic acid, etc. By reacting with the compound (vii) at 60 ° C. to 150 ° C., preferably 80 ° C. to 120 ° C. in the presence of an acid, the compound represented by the general formula (II ′) can be produced.
By using optically active isocyanate (ii), an optically active compound represented by general formula (II ′) can be synthesized.
[B法] [Method B]
Figure JPOXMLDOC01-appb-C000040

(第1工程)
(式中、HalおよびHalはハロゲンであり、その他の記号は前記と同義である。)
 化合物(vii)をメタノール、エタノール等の溶媒中、-40℃~30℃、好ましくは氷冷下で、ヨウ化メチル、ヨウ化エチル等のアルキル化剤(viii)と反応させることにより、化合物(ix)を製造することができる。
(第2工程)
 化合物(ix)をジクロロメタン、クロロホルム、1、2-ジクロロエタン等の溶媒中、トリエチルアミン、N,N-ジイソプロピルエチルアミン等の塩基の存在下、-20℃~30℃、好ましくは氷冷下で、N-(クロロカルボニル)イソシアネート等のイソシアネートと反応させることにより、化合物(x)製造することができる。
(第3工程)
 化合物(x)をt-ブタノール、イソプロパノール、エタノール、アセトニトリル等の溶媒中、酢酸、ギ酸、メタンスルホン酸等の酸の存在下、化合物(vi)と加熱還流下で反応させることにより化合物(xi)を製造することができる。
(第4工程)
 化合物(xi)とDMF、NMP等の溶媒中、カリウムt-ブトキシド、水素化ナトリウム等の塩基存在下、40℃~100℃、好ましくは50℃~70℃で化合物(xii)と反応させることにより、一般式(II’’)で示される化合物を製造することができる。
 光学活性な化合物(xii)を用いることで、光学活性である一般式(II’’)で示される化合物を合成することができる。
Figure JPOXMLDOC01-appb-C000040

(First step)
(In the formula, Hal 2 and Hal 3 are halogen, and other symbols are as defined above.)
Compound (vii) is reacted with an alkylating agent (viii) such as methyl iodide or ethyl iodide in a solvent such as methanol or ethanol at −40 ° C. to 30 ° C., preferably under ice cooling, to give compound ( ix) can be manufactured.
(Second step)
Compound (ix) is dissolved in a solvent such as dichloromethane, chloroform, 1,2-dichloroethane in the presence of a base such as triethylamine, N, N-diisopropylethylamine, at −20 ° C. to 30 ° C., preferably under ice-cooling. Compound (x) can be produced by reacting with an isocyanate such as (chlorocarbonyl) isocyanate.
(Third step)
Compound (xi) is reacted with compound (vi) under heating and reflux in the presence of an acid such as acetic acid, formic acid or methanesulfonic acid in a solvent such as t-butanol, isopropanol, ethanol or acetonitrile. Can be manufactured.
(4th process)
By reacting compound (xi) with compound (xii) in a solvent such as DMF or NMP in the presence of a base such as potassium t-butoxide or sodium hydride at 40 ° C. to 100 ° C., preferably 50 ° C. to 70 ° C. A compound represented by the general formula (II ″) can be produced.
By using the optically active compound (xii), an optically active compound represented by the general formula (II ″) can be synthesized.
[C法] [Method C]
Figure JPOXMLDOC01-appb-C000041

(式中、Pgは水酸基の適切な保護基であり、sは1~4の整数であり、他の記号は前記と同義である。)
(第1工程)
 B法で得られる化合物(x)および2-(テトラヒドロ-2H-ピラン-2-イルオキシ)エタノール等の一方の水酸基が保護されたアルコール(xii)の、THF、ジオキサン等の溶媒の混合液に、トリフェニルホスフィン等とジエチルアゾジカルボキシレート等を反応させることにより、化合物(xiii)を製造することができる。
(第2工程)
 化合物(xiii)をギ酸、酢酸等の酸の存在下、加熱還流下で化合物(vi)と反応させることにより、化合物(xiv)を製造することができる。
Figure JPOXMLDOC01-appb-C000041

(Wherein Pg 1 is a suitable protecting group for a hydroxyl group, s is an integer of 1 to 4, and the other symbols are as defined above.)
(First step)
To a mixture of a compound (x) obtained by Method B and an alcohol (xii) in which one hydroxyl group is protected, such as 2- (tetrahydro-2H-pyran-2-yloxy) ethanol, in a solvent such as THF or dioxane, Compound (xiii) can be produced by reacting triphenylphosphine or the like with diethyl azodicarboxylate or the like.
(Second step)
Compound (xiv) can be produced by reacting compound (xiii) with compound (vi) in the presence of an acid such as formic acid or acetic acid under heating and reflux.
[D法] [Method D]

(式中、Pgはアミノ基の適切な保護基であり、R11は置換もしくは非置換のアルキル、置換もしくは非置換のアリールアルキル、置換もしくは非置換のヘテロアリールアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアシル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリールであり、R12は、ヒドロキシもしくはハロゲンであり、tは1~4の整数、他の記号は前記と同義である。)
(第1工程)
 A法またはB法で得られる化合物(xv)に塩酸-ジオキサン溶液、塩酸-メタノール、塩酸-酢酸エチル溶液、トリフルオロ酢酸等の酸を反応させることにより、化合物(xvi)を製造することができる。
(第2工程)
 化合物(xvi)をTHF、ジオキサン等の溶媒中、トリエチルアミン、ジイソプロピルエチルアミン等の塩基の存在下、酸ハロゲン化物(xvii)(R12はハロゲン)と反応させることにより、化合物(xviii)を製造することができる。必要によってはジメチルアミノピリジン等を加えてもよい。
 または、化合物(xvi)およびカルボン酸(xvii、R12はヒドロキシ)を、THF、DMF等の溶媒中、1-ヒドロキシベンゾトリアゾール、塩酸1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド等の縮合剤、およびトリエチルアミン、ジイシプロピルエチルアミン等の塩基の存在下で反応させることにより、化合物(xviii)を製造することができる。

Wherein Pg 2 is a suitable protecting group for an amino group and R 11 is substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted alkenyl Substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted acyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl Or substituted or unsubstituted heteroaryl, R 12 is hydroxy or halogen, t is an integer of 1 to 4, and other symbols are as defined above.
(First step)
Compound (xvi) can be produced by reacting compound (xv) obtained by Method A or Method B with an acid such as hydrochloric acid-dioxane solution, hydrochloric acid-methanol, hydrochloric acid-ethyl acetate solution, or trifluoroacetic acid. .
(Second step)
Compound (xviii) is produced by reacting compound (xvi) with an acid halide (xvii) (R 12 is halogen) in the presence of a base such as triethylamine or diisopropylethylamine in a solvent such as THF or dioxane. Can do. If necessary, dimethylaminopyridine or the like may be added.
Alternatively, compound (xvi) and carboxylic acid (xvii, R 12 is hydroxy) such as 1-hydroxybenzotriazole, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, etc. in a solvent such as THF and DMF Compound (xviii) can be produced by reacting in the presence of a condensing agent and a base such as triethylamine or diisopropylpropylamine.
[E法] [E method]
Figure JPOXMLDOC01-appb-C000043

(式中、R13は置換もしくは非置換のアルキル、R20aおよびR20bは、水素、ハロゲン、シアノ、ヒドロキシ、カルボキシ、スルホ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミノ、置換もしくは非置換のイミノ、置換もしくは非置換のグアニジル、またはR20aおよびR20bが一緒になってオキソ、またはチオキソ、uは1~4の整数、他の記号は前記と同義である。)
(第1工程)
 B法で得られる化合物(x)をDMF、NMP、THF等の溶媒中、DBU、カリウムt-ブトキシド、水素化ナトリウム等の塩基の存在下、0℃~80℃、好ましくは30℃~50℃で化合物(xix)と反応させることにより、化合物(xx)を製造することができる。
(第2工程)
 化合物(xx)をt-ブタノール、イソプロパノール、エタノール、アセトニトリル等の溶媒中、ギ酸、酢酸、メタンスルホン酸等の酸の存在下、化合物(vi)と加熱還流下で反応させることにより.化合物(xxi)を製造することができる。
(第3工程)
 化合物(xxi)をメタノール、エタノール等の溶媒中、またはそれらとTHF、ジオキサン等の溶媒の混合溶媒中、水酸化リチウム水溶液、水酸化ナトリウム水溶液、水酸化カリウム水溶液等と反応させることにより、化合物(xxii)を製造することができる。
Figure JPOXMLDOC01-appb-C000043

Wherein R 13 is substituted or unsubstituted alkyl, R 20a and R 20b are hydrogen, halogen, cyano, hydroxy, carboxy, sulfo, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted Or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, Substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted Alternatively, unsubstituted imino, substituted or unsubstituted guanidyl, or R 20a and R 20b taken together are oxo, or thioxo, u is an integer of 1 to 4, and other symbols are as defined above.
(First step)
Compound (x) obtained by Method B is present in a solvent such as DMF, NMP, or THF in the presence of a base such as DBU, potassium t-butoxide, or sodium hydride at 0 ° C. to 80 ° C., preferably 30 ° C. to 50 ° C. The compound (xx) can be produced by reacting with the compound (xix).
(Second step)
By reacting compound (xx) with compound (vi) in a solvent such as t-butanol, isopropanol, ethanol, acetonitrile, etc. in the presence of an acid such as formic acid, acetic acid, methanesulfonic acid and the like under heating and reflux. Compound (xxi) can be produced.
(Third step)
Compound (xxi) is reacted with a lithium hydroxide aqueous solution, a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution or the like in a solvent such as methanol or ethanol, or in a mixed solvent of these and a solvent such as THF or dioxane. xxii) can be produced.
[F法] [F method]
Figure JPOXMLDOC01-appb-C000044

(式中、R14は、置換もしくは非置換のアルキル、R15およびR16は、それぞれ独立して置換もしくは非置換のアルキル、置換もしくは非置換のアリールアルキル、置換もしくは非置換のヘテロアリールアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換のアシル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリールであり、uは1~4の整数、他の記号は前記と同義である。)
(第1工程)
 A法またはB法で得られる化合物(xxiii)を、メタノール、エタノール等の溶媒中、またはそれらとジオキサン、THF等の溶媒の混合溶媒中、水酸化リチウム水溶液、水酸化ナトリウム水溶液、水酸化カリウム水溶液等と反応させることにより、化合物(xxiv)を製造することができる。
(第2工程)
 化合物(xxiv)をTHF、DMF、NMP等の溶媒中、1-ヒドロキシベンゾトリアゾールもしくはHOAt、塩酸1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド、HATU、PyBOP等の縮合剤、およびトリエチルアミン、ジイシプロピルエチルアミン等の塩基の存在下、化合物(xxv)と反応させることにより化合物(xxvi)を製造することができる。
Figure JPOXMLDOC01-appb-C000044

Wherein R 14 is substituted or unsubstituted alkyl, R 15 and R 16 are each independently substituted or unsubstituted alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, Substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted acyl, substituted or unsubstituted non-aromatic heterocyclic group, (Substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, u is an integer of 1 to 4, and other symbols are as defined above.)
(First step)
Compound (xxiii) obtained by Method A or Method B in a solvent such as methanol or ethanol or in a mixed solvent of these and a solvent such as dioxane or THF, an aqueous lithium hydroxide solution, an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution Compound (xxiv) can be produced by reacting with the above.
(Second step)
Compound (xxiv) in a solvent such as THF, DMF, NMP, 1-hydroxybenzotriazole or HOAt, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, a condensing agent such as HATU, PyBOP, and triethylamine, Compound (xxvi) can be produced by reacting with compound (xxv) in the presence of a base such as diisipropylethylamine.
[L法] [L method]
Figure JPOXMLDOC01-appb-C000045

(式中の記号は前記と同義である。)
(第1工程)
 B法で得られる化合物(x)とアルコール(xxxviii)とTHF、ジオキサン等の溶媒の混合液に、トリフェニルホスフィン等とジエチルアゾジカルボキシレート等を反応させることにより、化合物(ixl)を製造することができる。
(第2工程)
 化合物(ixl)をギ酸、酢酸等の酸の存在下、加熱還流下で化合物(vi)と反応させることにより、化合物(II)を製造することができる。
 光学活性なアルコール(xxxviii)を用いることで、光学活性な化合物(II)を合成することができる。
 中間体として用いたアルコール(xxxviii)は,市販品、または下記の挙げた文献記載の方法に準じて製造することができる.
Tetrahedron (1993), 49(11), 2325-44.
Chemical Communications (2008), (47), 6408-6410.
Tetrahedron (1990), 46(24), 8207-28.
Synlett (1994), (3), 199-200.
Bulletin of the Chemical Society of Japan (1994), 67(8), 2244-7
Canadian Journal of Chemistry (1996), 74, 1731-1737
Chemistry--A European Journal (2010), 16(2), 577-587
Bioorganic & Medicinal Chemistry Letters (2009), 19(21), 6196-6199.
Chemische Berichte (1985), 118(10), 3966-79.
Tetrahedron:  Asymmetry (1992), 3(4), 515-16. 
Organic Letters (1999), 1(6), 957-959.  
Chimia (1986), 40(5), 172-3.

[M法]
Figure JPOXMLDOC01-appb-C000045

(The symbols in the formula are as defined above.)
(First step)
A compound (ixl) is produced by reacting a compound (x) obtained by Method B with an alcohol (xxxviii) and a solvent such as THF or dioxane with triphenylphosphine or the like and diethyl azodicarboxylate. be able to.
(Second step)
Compound (II) can be produced by reacting compound (ixl) with compound (vi) in the presence of an acid such as formic acid or acetic acid under heating and reflux.
By using optically active alcohol (xxxviii), optically active compound (II) can be synthesized.
Alcohol (xxxviii) used as an intermediate can be produced according to a commercially available product or a method described in the literature listed below.
Tetrahedron (1993), 49 (11), 2325-44.
Chemical Communications (2008), (47), 6408-6410.
Tetrahedron (1990), 46 (24), 8207-28.
Synlett (1994), (3), 199-200.
Bulletin of the Chemical Society of Japan (1994), 67 (8), 2244-7
Canadian Journal of Chemistry (1996), 74, 1731-1737
Chemistry--A European Journal (2010), 16 (2), 577-587
Bioorganic & Medicinal Chemistry Letters (2009), 19 (21), 6196-6199.
Chemische Berichte (1985), 118 (10), 3966-79.
Tetrahedron: Asymmetry (1992), 3 (4), 515-16.
Organic Letters (1999), 1 (6), 957-959.
Chimia (1986), 40 (5), 172-3.

[M method]
Figure JPOXMLDOC01-appb-C000046

(式中、R21は水素,置換もしくは非置換のアルキル、または置換もしくは非置換のアルコキシ等、R22はブロモ、またはヨウ素,R23およびR24は、それぞれ独立して、置換もしくは非置換のアルキル、置換もしくは非置換のアリールアルキル、置換もしくは非置換のヘテロアリールアルキル、置換もしくは非置換のシクロアルキル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリールであり、その他の記号は前記と同義である。)
(第1工程)
 A~FまたはL法で得られる化合物(xxxvii)をTHF、ジオキサン等の溶媒中、パラジム触媒および炭酸カリウム、炭酸セシウム、炭酸ナトリウム水溶液等の存在下、化合物(xxxviii)と50℃~加熱還流下、好ましくは加熱還流下で、またはマイクロウェーブ照射下120℃~200℃、好ましくは130℃~150℃で反応させることにより、化合物(xxxix)を製造することができる。
Figure JPOXMLDOC01-appb-C000046

(Wherein R 21 is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, etc., R 22 is bromo, or iodine, and R 23 and R 24 are each independently substituted or unsubstituted. Alkyl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or (Unsubstituted heteroaryl, other symbols are as defined above.)
(First step)
The compound (xxxvii) obtained by the methods A to F or L is mixed with the compound (xxxviii) at 50 ° C. to heating under reflux in a solvent such as THF or dioxane in the presence of a paradium catalyst and potassium carbonate, cesium carbonate, sodium carbonate aqueous solution or the like. The compound (xxxix) can be produced by reacting at 120 ° C. to 200 ° C., preferably 130 ° C. to 150 ° C., preferably under heating under reflux or under microwave irradiation.
(第2工程)
 化合物(xxxix)をメタノール、エタノール等のアルコール系溶媒に溶解し、水素化反応装置(例えば、H-Cube (10%Pt-C,H2 = 1atm))またはパラジウム-炭素、酸化白金、クロロトリス(トリフェニルホスフィン)ロジウム(I)等の金属触媒を用いて接触還元を行うことにより、化合物(xl)を得ることができる。
(Second step)
A compound (xxxix) is dissolved in an alcohol solvent such as methanol or ethanol, and a hydrogenation reactor (for example, H-Cube (10% Pt-C, H2 = 1 atm)) or palladium-carbon, platinum oxide, chlorotris (tri) Compound (xl) can be obtained by catalytic reduction using a metal catalyst such as phenylphosphine) rhodium (I).
[N法] [N method]
Figure JPOXMLDOC01-appb-C000047

(式中の記号は、前記と同義である。)
(第1工程)
 A~FまたはL法で得られる化合物(xli)をTHF、ジオキサン等の溶媒中、パラジム触媒および炭酸カリウム、炭酸セシウム、炭酸ナトリウム水溶液等の存在下、化合物(xxxviii)と50℃~加熱還流下、好ましくは加熱還流下で、またはマイクロウェーブ照射下120℃~200℃、好ましくは130℃~150℃で反応させることにより、化合物(xlii)を製造することができる。
Figure JPOXMLDOC01-appb-C000047

(The symbols in the formula are as defined above.)
(First step)
The compound (xli) obtained by the methods A to F or L is heated with a compound (xxxviii) at 50 ° C. to heating under reflux in a solvent such as THF or dioxane in the presence of a paradium catalyst and potassium carbonate, cesium carbonate, sodium carbonate aqueous solution or the like. The compound (xlii) can be produced by reacting at 120 ° C. to 200 ° C., preferably 130 ° C. to 150 ° C., preferably under heating under reflux or under microwave irradiation.
(第2工程)
 化合物(xlii)をメタノール、エタノール等のアルコール系溶媒に溶解し、水素化反応装置(例えば、H-Cube (10%Pt-C,H2 = 1atm))またはパラジウム-炭素、酸化白金、クロロトリス(トリフェニルホスフィン)ロジウム(I)等の金属触媒を用いて接触還元を行うことにより、化合物(xliii)を得ることができる。
(Second step)
A compound (xlii) is dissolved in an alcohol solvent such as methanol or ethanol, and a hydrogenation reactor (eg, H-Cube (10% Pt-C, H2 = 1 atm)) or palladium-carbon, platinum oxide, chlorotris (tri- The compound (xliii) can be obtained by catalytic reduction using a metal catalyst such as phenylphosphine) rhodium (I).
[O法] [O method]
Figure JPOXMLDOC01-appb-C000048

(式中、R25は置換もしくは非置換のアルキル、または置換もしくは非置換のアルコキシ,R26はブロモまたはヨウ素,その他の記号は前記と同義である。)
(第1工程)
 化合物(xliv)をルイス酸やトリフルオロ酢酸などの存在下で無溶媒または適当な溶媒中、0℃~加熱還流下で行うことにより、化合物(xlvi)を得ることができる。
Figure JPOXMLDOC01-appb-C000048

(Wherein R 25 is substituted or unsubstituted alkyl, or substituted or unsubstituted alkoxy, R 26 is bromo or iodine, and other symbols are as defined above.)
(First step)
Compound (xlvi) can be obtained by performing compound (xlib) in the presence of a Lewis acid, trifluoroacetic acid or the like in the absence of a solvent or in a suitable solvent at 0 ° C. to heating under reflux.
(第2工程)
 化合物(xlvi)をTHF、ジオキサン等の溶媒中、パラジム触媒および炭酸カリウム、炭酸セシウム、炭酸ナトリウム水溶液等の存在下、化合物(xlvii)と50℃~加熱還流下、好ましくは加熱還流下で、またはマイクロウェーブ照射下120℃~200℃、好ましくは130℃~150℃で反応させることにより、化合物(xlviii)を製造することができる。
(Second step)
Compound (xlvi) is mixed with compound (xlvii) in a solvent such as THF, dioxane and the like in the presence of a paradium catalyst and potassium carbonate, cesium carbonate, sodium carbonate aqueous solution, etc. at 50 ° C. to heating under reflux, preferably under heating under reflux, or Compound (xlviii) can be produced by reaction at 120 ° C. to 200 ° C., preferably 130 ° C. to 150 ° C. under microwave irradiation.
[P法] [P method]
Figure JPOXMLDOC01-appb-C000049

(式中、記号は前記と同義である。)
 化合物(xli)またはその塩酸塩もしくは臭素酸塩等を、THF、ジオキサン、メタノール等の溶媒中、四塩化チタン、塩化コバルト(II)、メタンスルホン酸等のルイス酸もしくは酸の存在または非存在下、水素化アルミニウムリチウム、水素化ジイソブチルアルミニウム、ジボラン、水素化ホウ素リチウム、水素化ホウ素ナトリウム等の還元剤と、-20℃~加熱還流下、好ましくは室温中で、反応させることにより化合物(xlii)を製造することができる。
Figure JPOXMLDOC01-appb-C000049

(Wherein the symbols are as defined above.)
Compound (xli) or a hydrochloride or bromate thereof in a solvent such as THF, dioxane or methanol in the presence or absence of a Lewis acid or acid such as titanium tetrachloride, cobalt (II) chloride or methanesulfonic acid Compound (xli) by reacting with a reducing agent such as lithium aluminum hydride, diisobutylaluminum hydride, diborane, lithium borohydride, sodium borohydride and the like at −20 ° C. to heating under reflux, preferably at room temperature Can be manufactured.
 式(I)または式(II)で示される化合物またはその製薬上許容される塩の一つの態様として、
 Rが、3~5個のヒドロキシで置換され、さらに置換基群α(置換基群α:ハロゲン、シアノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミノ、置換もしくは非置換のイミノ、置換もしくは非置換のグアニジル、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、ニトロ、およびチオキソ)から選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルキル;3~5個のヒドロキシで置換され、さらに置換基群αから選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルケニル;または3~5個のヒドロキシで置換され、さらに置換基群αから選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルキニルである上記(1)に記載の化合物またはその製薬上許容される塩が挙げられる。
As one embodiment of the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof,
R c is substituted with 3 to 5 hydroxy groups, and substituent group α (substituent group α: halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino Substituted or unsubstituted Anidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxy One or more substituents selected from carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, and thioxo) C3-C6 alkyl optionally substituted with C3-C6 alkenyl substituted with 3-5 hydroxy and further substituted with one or more substituents selected from substituent group α; Or substituted with 3-5 hydroxy In addition, the compound or a pharmaceutically acceptable salt thereof according to the above (1), which is C3-C6 alkynyl optionally substituted with one or more substituents selected from substituent group α .
 本発明の好ましい態様として、以下の化合物またはその製薬上許容される塩が挙げられる。
 式(I):
Preferred embodiments of the present invention include the following compounds or pharmaceutically acceptable salts thereof.
Formula (I):
Figure JPOXMLDOC01-appb-C000050

 式(I’):
Figure JPOXMLDOC01-appb-C000050

Formula (I ′):
Figure JPOXMLDOC01-appb-C000051

 式(I’’):
Figure JPOXMLDOC01-appb-C000051

Formula (I ″):
Figure JPOXMLDOC01-appb-C000052

のいずれかにおいて、
Figure JPOXMLDOC01-appb-C000052

In either
1)Rが、 1) R c is
Figure JPOXMLDOC01-appb-C000053

(式中、Alkはアルキルである)
で示される基であり、かつ
Figure JPOXMLDOC01-appb-C000053

(Wherein Alk is alkyl)
And a group represented by
Figure JPOXMLDOC01-appb-C000054

である化合物またはその製薬上許容される塩。
Figure JPOXMLDOC01-appb-C000054

Or a pharmaceutically acceptable salt thereof.
2)Rが、 2) R c is
Figure JPOXMLDOC01-appb-C000055

(式中、Alkはアルキルである)
で示される基であり、かつ
Figure JPOXMLDOC01-appb-C000055

(Wherein Alk is alkyl)
And a group represented by
Figure JPOXMLDOC01-appb-C000056

である化合物またはその製薬上許容される塩。
Figure JPOXMLDOC01-appb-C000056

Or a pharmaceutically acceptable salt thereof.
3)Rが、 3) R c is
Figure JPOXMLDOC01-appb-C000057

(式中、Alkはアルキルである)
で示される基であり、かつ
環Bが、ピラジン、ピリダジン、チアゾール、イソチアゾール、オキサゾールまたはイソキサゾールである化合物またはその製薬上許容される塩。
Figure JPOXMLDOC01-appb-C000057

(Wherein Alk is alkyl)
Or a pharmaceutically acceptable salt thereof, wherein ring B is pyrazine, pyridazine, thiazole, isothiazole, oxazole or isoxazole.
4)Rが、 4) R c is
Figure JPOXMLDOC01-appb-C000058

(式中、Alkはアルキルである)
で示される基であり;
Figure JPOXMLDOC01-appb-C000058

(Wherein Alk is alkyl)
A group represented by:
Figure JPOXMLDOC01-appb-C000059

であり;
s’が、1から3の整数であり、かつ
少なくとも1つのR9’が、ハロゲンまたはハロアルキルである化合物またはその製薬上許容される塩。
5)Rが、
Figure JPOXMLDOC01-appb-C000059

Is;
A compound or a pharmaceutically acceptable salt thereof, wherein s ′ is an integer of 1 to 3 and at least one R 9 ′ is halogen or haloalkyl.
5) R c is
Figure JPOXMLDOC01-appb-C000060

(式中、Alkはアルキルである)
で示される基であり、かつ
Figure JPOXMLDOC01-appb-C000060

(Wherein Alk is alkyl)
And a group represented by
Figure JPOXMLDOC01-appb-C000061

であり;
s’が、1から3の整数であり、かつ
少なくとも1つのR9’が、ハロゲンまたはハロアルキルである化合物またはその製薬上許容される塩。
Figure JPOXMLDOC01-appb-C000061

Is;
A compound or a pharmaceutically acceptable salt thereof, wherein s ′ is an integer of 1 to 3 and at least one R 9 ′ is halogen or haloalkyl.
6)Rが置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、または置換もしくは非置換の非芳香族複素環式基であり;
環Bが、ピリジンまたはチアゾールであり;
s’が、1から3の整数であり;かつ
少なくとも1つのR9’が、カルボキシまたはアルキルオキシカルボニルである化合物またはその製薬上許容される塩。
6) R c is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group;
Ring B is pyridine or thiazole;
A compound or a pharmaceutically acceptable salt thereof, wherein s ′ is an integer of 1 to 3; and at least one R 9 ′ is carboxy or alkyloxycarbonyl.
7)Rが置換もしくは非置換のアルキルであり;
環Bが、ピリジンであり;
s’が、1から3の整数であり;かつ
少なくとも1つのR9’が、アリール、ヘテロアリール、アリールオキシまたはヘテロアリールオキシであり、それらが少なくとも1個のカルボキシ、アルキルオキシカルボニルまたはシアノで置換されており、さらにその他の置換基を有していてもよい、化合物またはその製薬上許容される塩。
7) R c is substituted or unsubstituted alkyl;
Ring B is pyridine;
s ′ is an integer from 1 to 3; and at least one R 9 ′ is aryl, heteroaryl, aryloxy or heteroaryloxy, which are substituted with at least one carboxy, alkyloxycarbonyl or cyano Or a pharmaceutically acceptable salt thereof, which may further have other substituents.
8)Rがアルキルであり;かつ 8) R c is alkyl; and
Figure JPOXMLDOC01-appb-C000062

(式中、s’’は0から2の整数)
である化合物またはその製薬上許容される塩。
9)Rがアルキルであり;式(I’)においてはsが1~3の整数であり;かつ
Figure JPOXMLDOC01-appb-C000062

(Where s '' is an integer from 0 to 2)
Or a pharmaceutically acceptable salt thereof.
9) R c is alkyl; in formula (I ′), s is an integer from 1 to 3;
Figure JPOXMLDOC01-appb-C000063

(式中、s’’は0から2の整数)
である化合物またはその製薬上許容される塩。
Figure JPOXMLDOC01-appb-C000063

(Where s '' is an integer from 0 to 2)
Or a pharmaceutically acceptable salt thereof.
10)R10) R c is
Figure JPOXMLDOC01-appb-C000064

(式中、Alkはアルキルである)
で示される基であり、
 Rが置換もしくは非置換のシクロアルキルであり、
その他の記号は上記(1)と同義である、上記(1)記載の化合物またはその製薬上許容される塩。
(ただし、上記1)~10)において、特に定義されていない置換基は上記(1)と同義である)
Figure JPOXMLDOC01-appb-C000064

(Wherein Alk is alkyl)
A group represented by
R 2 is substituted or unsubstituted cycloalkyl,
The other symbols have the same meanings as in (1) above, the compound according to (1) above or a pharmaceutically acceptable salt thereof.
(However, in the above 1) to 10), substituents not particularly defined are as defined in (1) above)
 式(I)、式(I’)または式(I’’)で示される化合物において、
が、
In the compound represented by formula (I), formula (I ′) or formula (I ″),
R c is
Figure JPOXMLDOC01-appb-C000065

で示される基であるとき、Rの絶対配置としては、
Figure JPOXMLDOC01-appb-C000065

As the absolute configuration of R c , the group represented by
Figure JPOXMLDOC01-appb-C000066

が挙げられる。
Figure JPOXMLDOC01-appb-C000066

Is mentioned.
 式(I)、式(I’)または式(I’’)で示される化合物において、
が、
In the compound represented by formula (I), formula (I ′) or formula (I ″),
R c is
Figure JPOXMLDOC01-appb-C000067

で示される基であるとき、Rの絶対配置としては
Figure JPOXMLDOC01-appb-C000067

As the absolute configuration of R c , the group represented by
Figure JPOXMLDOC01-appb-C000068

が挙げられる。
Figure JPOXMLDOC01-appb-C000068

Is mentioned.
 式(I)、式(I’)、式(I’’)、式(II)等で示される化合物は、特定の異性体に限定するものではなく、全ての可能な異性体(例えば、ケト-エノール異性体、イミン-エナミン異性体、ジアステレオ異性体、光学異性体、回転異性体等)、ラセミ体またはそれらの混合物を含む。例えば、式(I)において-X-が-NH-である化合物は、以下のような互変異性体を包含する。 The compounds of formula (I), formula (I ′), formula (I ″), formula (II) etc. are not limited to specific isomers, but all possible isomers (eg keto Enol isomers, imine-enamine isomers, diastereoisomers, optical isomers, rotational isomers, etc.), racemates or mixtures thereof. For example, the compound in which —X— is —NH— in the formula (I) includes the following tautomers.
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
 さらに、式(I)、式(I’)、式(I’’)、式(II)等の化合物の一つ以上の水素、炭素または他の原子は、水素、炭素または他の原子の同位体で置換され得る。式(I)、式(I’)、式(I’’)、式(II)等の化合物は、式(I)、式(I’)、式(I’’)、式(II)等の化合物のすべての放射性標識体を包含する。式(I)、式(I’)、式(I’’)、式(II)等の化合物のそのような「放射性標識化」、「放射性標識体」などは、それぞれが本発明に包含され、代謝薬物動態研究ならびに結合アッセイにおける研究および/または診断ツールとして有用である。また、医薬品としても有用である。 In addition, one or more hydrogen, carbon or other atoms of a compound of formula (I), formula (I ′), formula (I ″), formula (II), etc. are hydrogen, carbon or other atom isotopes. Can be replaced by the body. Compounds of formula (I), formula (I ′), formula (I ″), formula (II) and the like are represented by formula (I), formula (I ′), formula (I ″), formula (II) and the like. Includes all radiolabeled forms of the compounds. Such “radiolabeled”, “radiolabeled” and the like of compounds of formula (I), formula (I ′), formula (I ″), formula (II) and the like are each included in the present invention. It is useful as a research and / or diagnostic tool in metabolic pharmacokinetic studies and binding assays. It is also useful as a pharmaceutical product.
 式(I)、式(I’)、式(I’’)、式(II)等で示される化合物の一つ以上の水素、炭素および/または他の原子は、それぞれ水素、炭素および/または他の原子の同位体で置換され得る。そのような同位体の例としては、それぞれH、H、11C、13C、14C、15N、18O、17O、31P、32P、35S、18F、123Iおよび36Clのように、水素、炭素、窒素、酸素、リン、硫黄、フッ素、ヨウ素および塩素が包含される。式(I)、式(I’)、式(I’’)、式(II)等で示される化合物は、そのような同位体で置換された化合物も包含する。該同位体で置換された化合物は、医薬品としても有用であり、式(I)、式(I’)、式(I’’)、式(II)等で示される化合物のすべての放射性標識体を包含する。また該「放射性標識体」を製造するための「放射性標識化方法」も本発明に包含され、代謝薬物動態研究、結合アッセイにおける研究および/または診断のツールとして有用である。 One or more hydrogen, carbon and / or other atoms of the compounds of formula (I), formula (I ′), formula (I ″), formula (II) etc. are hydrogen, carbon and / or respectively. It can be substituted with isotopes of other atoms. Examples of such isotopes are 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, 123 I and Like 36 Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compound represented by the formula (I), the formula (I ′), the formula (I ″), the formula (II) and the like includes a compound substituted with such an isotope. The compound substituted with the isotope is also useful as a pharmaceutical, and all radiolabeled compounds of the compounds represented by the formula (I), the formula (I ′), the formula (I ″), the formula (II), etc. Is included. A “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.
 式(I)、式(I’)、式(I’’)、式(II)等で示される化合物の放射性標識体は、当該技術分野で周知の方法で調製できる。例えば、式(I)、式(I’)、式(I’’)、式(II)等で示されるトリチウム標識化合物は、例えば、トリチウムを用いた触媒的脱ハロゲン化反応によって、式(I)、式(I’)、式(I’’)、式(II)等で示される特定の化合物にトリチウムを導入することで調製できる。この方法は、適切な触媒、例えばPd/Cの存在下、塩基の存在下または非存在下で、式(I)、式(I’)、式(I’’)、式(II)等で示される化合物が適切にハロゲン置換された前駆体とトリチウムガスとを反応させることを包含する。他のトリチウム標識化合物を調製するための適切な方法としては、文書Isotopes in the Physical and Biomedical Sciences,Vol.1,Labeled Compounds (Part A),Chapter 6 (1987年)を参照にできる。14C-標識化合物は、14C炭素を有する原料を用いることによって調製できる。 Radiolabeled compounds of the compounds represented by formula (I), formula (I ′), formula (I ″), formula (II) and the like can be prepared by methods well known in the art. For example, a tritium-labeled compound represented by the formula (I), the formula (I ′), the formula (I ″), the formula (II), or the like can be converted into a compound of the formula (I ), Formula (I ′), formula (I ″), formula (II) and the like, can be prepared by introducing tritium into the specific compound. This method can be used in formula (I), formula (I ′), formula (I ″), formula (II), etc. in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. The compounds shown include reacting appropriately halogen substituted precursors with tritium gas. Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). 14 C-labeled compounds can be prepared by using raw materials having 14 C carbon.
 式(I)、式(I’)、式(I’’)、式(II)等で示される化合物の製薬上許容される塩としては、例えば、式(I)で示される化合物と、アルカリ金属(例えば、リチウム、ナトリウム、カリウム等)、アルカリ土類金属(例えば、カルシウム、バリウム等)、マグネシウム、遷移金属(例えば、亜鉛、鉄等)、アンモニア、有機塩基(例えば、トリメチルアミン、トリエチルアミン、ジシクロヘキシルアミン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、メグルミン、ジエタノールアミン、エチレンジアミン、ピリジン、ピコリン、キノリン等)およびアミノ酸との塩、または無機酸(例えば、塩酸、硫酸、硝酸、炭酸、臭化水素酸、リン酸、ヨウ化水素酸等)、および有機酸(例えば、ギ酸、酢酸、プロピオン酸、トリフルオロ酢酸、クエン酸、乳酸、酒石酸、シュウ酸、マレイン酸、フマル酸、マンデル酸、グルタル酸、リンゴ酸、安息香酸、フタル酸、アスコルビン酸、ベンゼンスルホン酸、p-トルエンスルホン酸、メタンスルホン酸、エタンスルホン酸等)との塩が挙げられる。特に塩酸、硫酸、リン酸、酒石酸、メタンスルホン酸との塩等が挙げられる。これらの塩は、通常行われる方法によって形成させることができる。
 本発明の式(I)、式(I’)、式(I’’)、式(II)等で示される化合物またはその製薬上許容される塩は、溶媒和物(例えば、水和物等)および/または結晶多形を形成する場合があり、本発明はそのような各種の溶媒和物および結晶多形も包含する。「溶媒和物」は、式(I)、式(I’)、式(I’’)、式(II)等で示される化合物に対し、任意の数の溶媒分子(例えば、水分子等)と配位していてもよい。式(I)、式(I’)、式(I’’)、式(II)等で示される化合物またはその製薬上許容される塩を、大気中に放置することにより、水分を吸収し、吸着水が付着する場合や、水和物を形成する場合がある。また、式(I)、式(I’)、式(I’’)、式(II)等で示される化合物またはその製薬上許容される塩を、再結晶することでそれらの結晶多形を形成する場合がある。
  本発明の式(I)、式(I’)、式(I’’)、式(II)等で示される化合物またはその製薬上許容される塩は、プロドラッグを形成する場合があり、本発明はそのような各種のプロドラッグも包含する。プロドラッグは、化学的又は代謝的に分解できる基を有する本発明化合物の誘導体であり、加溶媒分解により又は生理学的条件下でインビボにおいて薬学的に活性な本発明化合物となる化合物である。プロドラッグは、生体内における生理条件下で酵素的に酸化、還元、加水分解等を受けて式(I)、式(I’)、式(I’’)、式(II)等で示される化合物に変換される化合物、胃酸等により加水分解されて式(I)、式(I’)、式(I’’)、式(II)等で示される化合物に変換される化合物等を包含する。適当なプロドラッグ誘導体を選択する方法および製造する方法は、例えばDesign of Prodrugs, Elsevier, Amsterdam 1985に記載されている。プロドラッグは、それ自身が活性を有する場合がある。
 式(I)、式(I’)、式(I’’)、式(II)等で示される化合物またはその製薬上許容される塩がヒドロキシル基を有する場合は、例えば、ヒドロキシル基を有する化合物と適当なアシルハライド、適当な酸無水物、適当なスルホニルクロリド、適当なスルホニルアンハイドライド及びミックスドアンハイドライドとを反応させることにより或いは縮合剤を用いて反応させることにより製造されるアシルオキシ誘導体やスルホニルオキシ誘導体のようなプロドラッグが例示される。例えば、CHCOO-、CCOO-、tert-BuCOO-、C1531COO-、PhCOO-、(m-NaOOCPh)COO-、NaOOCCHCHCOO-、CHCH(NH)COO-、CHN(CHCOO-、CHSO-、CHCHSO-、CFSO-、CHFSO-、CFCHSO-、p-CHO-PhSO-、PhSO-、p-CHPhSO-が挙げられる。
Examples of the pharmaceutically acceptable salt of the compound represented by formula (I), formula (I ′), formula (I ″), formula (II) and the like include, for example, a compound represented by formula (I), an alkali Metals (eg, lithium, sodium, potassium, etc.), alkaline earth metals (eg, calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexyl) Amine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, picoline, quinoline, etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphorous) Acids, hydroiodic acid, etc.) and organic acids (eg formic acid, acetic acid, propionic acid) Trifluoroacetic acid, citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, fumaric acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfone Salts with acid, ethanesulfonic acid, etc.). Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.
The compound represented by the formula (I), formula (I ′), formula (I ″), formula (II) or the like of the present invention or a pharmaceutically acceptable salt thereof is a solvate (for example, hydrate etc. ) And / or crystalline polymorphs, and the present invention also encompasses such various solvates and crystalline polymorphs. The “solvate” is an arbitrary number of solvent molecules (for example, water molecules) with respect to the compounds represented by formula (I), formula (I ′), formula (I ″), formula (II), etc. And may be coordinated. The compound represented by the formula (I), the formula (I ′), the formula (I ″), the formula (II) or the like or a pharmaceutically acceptable salt thereof is left in the atmosphere to absorb moisture, Adsorbed water may adhere or a hydrate may be formed. Further, by recrystallizing the compound represented by the formula (I), the formula (I ′), the formula (I ″), the formula (II) or the like or a pharmaceutically acceptable salt thereof, the crystal polymorphs thereof are obtained. May form.
The compound represented by the formula (I), formula (I ′), formula (I ″), formula (II) or the like of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug. The invention also encompasses such various prodrugs. A prodrug is a derivative of a compound of the present invention having a group that can be chemically or metabolically degraded, and is a compound that becomes a pharmaceutically active compound of the present invention by solvolysis or under physiological conditions in vivo. A prodrug is represented by the formula (I), formula (I ′), formula (I ″), formula (II), etc. after enzymatically oxidizing, reducing, hydrolyzing and the like under physiological conditions in vivo. Including compounds converted into compounds, compounds that are hydrolyzed by gastric acid, etc., and converted into compounds represented by formula (I), formula (I ′), formula (I ″), formula (II), etc. . Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.
When the compound represented by formula (I), formula (I ′), formula (I ″), formula (II) or the like or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, a compound having a hydroxyl group Acyloxy derivatives and sulfonyloxy produced by reacting with a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable sulfonyl anhydride and a mixed anhydride, or by reacting with a condensing agent. Examples are prodrugs such as derivatives. For example, CH 3 COO—, C 2 H 5 COO—, tert-BuCOO—, C 15 H 31 COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH 2 CH 2 COO—, CH 3 CH (NH 2 ) COO—, CH 2 N (CH 3 ) 2 COO—, CH 3 SO 3 —, CH 3 CH 2 SO 3 —, CF 3 SO 3 —, CH 2 FSO 3 —, CF 3 CH 2 SO 3 —, p -CH 3 O-PhSO 3- , PhSO 3- , p-CH 3 PhSO 3 -can be mentioned.
 上記一般式(I)、式(I’)、式(I’’)、式(II)等で表される化合物は、P2X3および/またはP2X2/3受容体に対する拮抗作用を有し、P2X3および/またはP2X2/3が関与する疾患の治療剤として有用である。P2X3および/またはP2X2/3受容体は疼痛、泌尿器系疾患および呼吸器疾患に関与すると考えられており(Nature 407, 26, 1011-1015 (2000), Nature, Vol.407, No.26, 1015-1017 (2000)、非特許文献1、非特許文献2、非特許文献9~11等)、鎮痛作用または排尿障害改善作用を有する医薬組成物として有用である。
 例えば、関節リウマチに伴う痛み、変形性関節症に伴う痛み、頭痛、偏頭痛、口腔顔面痛、歯痛、舌痛症、顎関節症に伴う痛み、三叉神経痛、肩痛、椎間板ヘルニアに伴う痛み、変形性頚椎症に伴う痛み、脊柱管狭窄症に伴う痛み、胸郭出口症候群に伴う痛み、腕神経叢引き抜き症候群に伴う痛み、肩手症候群、むち打ち症に伴う痛み、胸痛、腹痛、疝痛、胆石症に伴う痛み、膵炎に伴う痛み、尿路結石症に伴う痛み、過敏性腸症候群に伴う痛み、腰背部痛、坐骨神経痛、骨折に伴う痛み、骨粗鬆症に伴う痛み、関節痛、痛風に伴う痛み、馬尾症候群に伴う痛み、強直性脊椎炎症に伴う痛み、筋肉痛、有痛性痙攣、筋筋膜痛症候群、線維筋痛症候群、複合性局所疼痛症候群、閉塞性動脈硬化症に伴う痛み、バージャー病に伴う痛み、レイノー現象に伴う痛み、帯状疱疹に伴う痛み、カウザルギー、絞扼性神経障害に伴う痛み、手根管症候群に伴う痛み、糖尿病に伴う痛み、ギランバレー症候群に伴う痛み、ハンセン病に伴う痛み、薬物療法に伴う痛み、放射線療法に伴う痛み、脊髄損傷に伴う痛み、脊髄空洞症に伴う痛み、脳卒中に伴う痛み、視床痛、求心路遮断痛、交感神経依存性疼痛、ABC症候群に伴う痛み、多発性硬化症に伴う痛み、皮膚疾患に伴う痛み、癌性疼痛、術後痛、外傷に伴う痛み、壊疽に伴う痛み、身体表現性障害に伴う痛み、身体化障害に伴う痛み、鬱病に伴う痛み、パーキンソン病に伴う痛み、膝関節痛、関節炎に伴う痛み、生理痛、中間痛、陣痛等の神経障害性疼痛、炎症性疼痛、侵害受容性疼痛、心因性疼痛および/または子宮内膜症に伴う痛み等;
過活動膀胱、切迫性尿失禁、腹圧性尿失禁、反射性尿失禁、尿意切迫感、神経因性膀胱、不安定膀胱、尿道炎、尿路感染症、間質性膀胱炎、膀胱炎、膀胱癌、化学療法に伴う尿路障害、脳卒中等の脳障害に伴う尿路障害、前立腺肥大症および/または前立腺炎等における排尿障害および/または痛み等;
および慢性閉塞性肺疾患(COPD)、喘息、気管支痙攣、慢性咳嗽等;
の治療、症状の緩和および/または予防に有効である。
The compounds represented by the above general formula (I), formula (I ′), formula (I ″), formula (II) and the like have an antagonistic action on the P2X 3 and / or P2X 2/3 receptor, It is useful as a therapeutic agent for diseases involving P2X 3 and / or P2X 2/3 . P2X 3 and / or P2X 2/3 receptor is believed to be involved in pain, urinary system diseases, and respiratory diseases (Nature 407, 26, 1011-1015 ( 2000), Nature, Vol.407, No.26 , 1015-1017 (2000), Non-Patent Document 1, Non-Patent Document 2, Non-Patent Documents 9 to 11, etc.), and is useful as a pharmaceutical composition having an analgesic action or an urination disorder improving action.
For example, pain associated with rheumatoid arthritis, pain associated with osteoarthritis, headache, migraine, oral and facial pain, toothache, glossodynia, pain associated with temporomandibular disorders, trigeminal neuralgia, shoulder pain, pain associated with disc herniation, Pain associated with degenerative cervical spondylosis, pain associated with spinal stenosis, pain associated with thoracic outlet syndrome, pain associated with brachial plexus withdrawal syndrome, shoulder-hand syndrome, pain associated with whiplash, chest pain, abdominal pain, colic, cholelithiasis Pain associated with pancreatitis, pain associated with urolithiasis, pain associated with irritable bowel syndrome, low back pain, sciatica, pain associated with fracture, pain associated with osteoporosis, joint pain, pain associated with gout, Pain associated with cauda equina syndrome, pain associated with ankylosing spinal inflammation, muscle pain, painful spasm, myofascial pain syndrome, fibromyalgia syndrome, complex local pain syndrome, pain associated with obstructive arteriosclerosis, Buerger disease With pain, Raynaud Pain associated with elephant, pain associated with shingles, causalgia, pain associated with strangulation neuropathy, pain associated with carpal tunnel syndrome, pain associated with diabetes, pain associated with Guillain-Barre syndrome, pain associated with leprosy, associated with drug therapy Pain, pain associated with radiation therapy, pain associated with spinal cord injury, pain associated with spinal cord injury, pain associated with stroke, thalamic pain, afferent blockade pain, sympathetic nerve-dependent pain, pain associated with ABC syndrome, multiple sclerosis Pain, skin pain, cancer pain, postoperative pain, pain associated with trauma, pain associated with gangrene, pain associated with physical expression disorder, pain associated with somatization, pain associated with depression, Parkinson's disease Pain associated with pain, knee joint pain, pain associated with arthritis, menstrual pain, intermediate pain, labor pain and other neuropathic pain, inflammatory pain, nociceptive pain, psychogenic pain and / or pain associated with endometriosis etc;
Overactive bladder, urge incontinence, stress urinary incontinence, reflex urinary incontinence, urgency, neurogenic bladder, unstable bladder, urethritis, urinary tract infection, interstitial cystitis, cystitis, bladder Cancer, urinary tract disorder associated with chemotherapy, urinary tract disorder associated with brain disorder such as stroke, urination disorder and / or pain in prostatic hypertrophy and / or prostatitis, etc .;
And chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, chronic cough, etc .;
It is effective in the treatment, alleviation and / or prevention of symptoms.
 「排尿障害改善作用を有する医薬組成物」とは、上述の排尿障害の治療、予防および/または改善のために使用する医薬組成物を包含する。 The “pharmaceutical composition having an effect of improving urination disorder” includes a pharmaceutical composition used for the treatment, prevention and / or improvement of the above-mentioned urination disorder.
 本発明の化合物または本発明の医薬組成物は、ATP受容体、特にP2X3受容体に対して親和性が高く、サブタイプ選択性および他の受容体に対する選択性が高いため、副作用(たとえば運動機能への影響など)が軽減された医薬となり得る。また本発明に包含される化合物または本発明に包含される医薬組成物は、RSA存在下でのP2X3受容体阻害活性が高い、代謝安定性が高い、経口吸収性が高い、溶解度が高い、良好なバイオアベイラビリティを示す、クリアランスが低い、半減期が長い、薬効持続性が高い、肝酵素阻害活性が低い、蛋白非結合率が高い、および/または安全性が高い等の利点も有する。 Compound or pharmaceutical composition of the invention of the present invention, ATP receptor, especially high affinity for P2X 3 receptor, has high selectivity for subtype selectivity and other receptors, side effects (e.g., motion It can be a medicine with reduced functions). In addition, the compound included in the present invention or the pharmaceutical composition included in the present invention has high P2X 3 receptor inhibitory activity in the presence of RSA, high metabolic stability, high oral absorption, high solubility, It also has advantages such as good bioavailability, low clearance, long half-life, high drug sustainability, low liver enzyme inhibitory activity, high protein non-binding rate, and / or high safety.
 本発明の医薬組成物を投与する場合、経口的、非経口的のいずれの方法でも投与することができる。経口投与は常法に従って錠剤、顆粒剤、散剤、カプセル剤等の通常用いられる剤型に調製して投与すればよい。非経口投与は、注射剤等の通常用いられるいずれの剤型でも好適に投与することができる。本発明に係る化合物は経口吸収性が高いため、経口剤として好適に使用できる。 When administering the pharmaceutical composition of the present invention, it can be administered either orally or parenterally. Oral administration may be carried out by preparing a commonly used dosage form such as tablets, granules, powders, capsules and the like according to conventional methods. For parenteral administration, any commonly used dosage form such as an injection can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.
 本発明化合物の有効量にその剤型に適した賦形剤、結合剤、崩壊剤、滑沢剤等の各種医薬用添加剤を必要に応じて混合し、医薬組成物とすることができる。 Various pharmaceutical additives such as excipients, binders, disintegrants, lubricants and the like suitable for the dosage form can be mixed with the effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition.
 本発明の医薬組成物の投与量は、患者の年齢、体重、疾病の種類や程度、投与経路等を考慮した上で設定することが望ましいが、成人に経口投与する場合、通常0.05~100mg/kg/日であり、好ましくは0.1~10mg/kg/日の範囲内である。非経口投与の場合には投与経路により大きく異なるが、通常0.005~10mg/kg/日であり、好ましくは0.01~1mg/kg/日の範囲内である。これを1日1回~数回に分けて投与すれば良い。 The dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.
 併用薬剤の投与量は、臨床上用いられている用量を基準として適宜選択することができる。また、本発明化合物と併用薬剤の配合比は、投与対象、投与ルート、対象疾患、症状、組み合わせ等により適宜選択することができる。例えば、投与対象がヒトである場合、本発明化合物1重量部に対し、併用薬剤を0.01~100重量部用いればよい。 The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The compounding ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present invention.
 以下に実施例を示し、本発明を具体的に説明するが、本発明はこれらに限定されるものではない。なお、各略号は本明細書中、以下に示す意味を有する。
Me:メチル
TMS:テトラメチルシラン
DMSO:ジメチルスルホキシド
DMA:ジメチルアセトアミド
DMF:ジメチルホルムアミド
THF:テトラヒドロフラン
DBU:1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン
NMP:N-メチル-2-ピロリドン
HOAt:1-ヒドロキシ-7-アザベンゾトリアゾール
HATU:ヘキサフルオロリン酸2-(7-アザベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム
PyBOP:ベンゾトリアゾール-1-イル-オキシトリスピロリジノホスホニウムヘキサフルオロホスフェート
rt:室温
M:mol/L
EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples. In addition, each abbreviation has the meaning shown below in this specification.
Me: methyl TMS: tetramethylsilane DMSO: dimethyl sulfoxide DMA: dimethylacetamide DMF: dimethylformamide THF: tetrahydrofuran DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene NMP: N-methyl-2- Pyrrolidone HOAt: 1-hydroxy-7-azabenzotriazole HATU: 2- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium PyBOP hexafluorophosphate: benzotriazole-1 -Yl-oxytrispyrrolidinophosphonium hexafluorophosphate rt: room temperature M: mol / L
(1)3-エチル-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオンの調製 (1) Preparation of 3-ethyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000070

 1-アミジノピラゾール塩酸塩 (58.6 g, 400 mmol)、エチルイソシアネート(33.2 mL, 420 mmol)とDMA(240 mL) の混合液にDBU(63.3 mL, 420 mmol)を-10℃で15分間かけて滴下し、氷冷下で30分間攪拌した。反応液に、1,1'-カルボニルジイミダゾール(97.2 g, 600 mmol)を氷冷下で加えた後、DBU(93 mL, 620 mmol)を-5℃で30分間かけて加えた。反応液を氷冷下で1時間攪拌し、さらに室温で1時間攪拌した。反応液に、2 mol/L 塩酸 (1.16 L)を20℃で1時間かけて加えた。生じた粉末をろ取し、3-エチル-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン (73.0 g, 収率: 88%)を微褐色粉末として得た。
1H-NMR (δ ppm TMS / CDCl3): 1.30 (6H, t, J=7.0 Hz), 4.02 (2H, q, J=7.0 Hz), 6.59 (1H, m), 7.34 (1H, m), 8.48 (1H, m), 9.79 (1H, brs).
Figure JPOXMLDOC01-appb-C000070

DBU (63.3 mL, 420 mmol) was added to a mixture of 1-amidinopyrazole hydrochloride (58.6 g, 400 mmol), ethyl isocyanate (33.2 mL, 420 mmol) and DMA (240 mL) at −10 ° C. over 15 minutes. The solution was added dropwise and stirred for 30 minutes under ice cooling. 1,1′-Carbonyldiimidazole (97.2 g, 600 mmol) was added to the reaction solution under ice cooling, and then DBU (93 mL, 620 mmol) was added at −5 ° C. over 30 minutes. The reaction solution was stirred for 1 hour under ice-cooling, and further stirred at room temperature for 1 hour. To the reaction solution, 2 mol / L hydrochloric acid (1.16 L) was added at 20 ° C. over 1 hour. The resulting powder was collected by filtration, and 3-ethyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (73.0 g, yield: 88%) Obtained as a brown powder.
1H-NMR (δ ppm TMS / CDCl3): 1.30 (6H, t, J = 7.0 Hz), 4.02 (2H, q, J = 7.0 Hz), 6.59 (1H, m), 7.34 (1H, m), 8.48 (1H, m), 9.79 (1H, brs).
(2)1-(4-クロロベンジル)-3-エチル-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオンの調製
Figure JPOXMLDOC01-appb-I000071

 3-エチル-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン (89 g, 480 mmol) 、4-クロロベンジルブロミド (108 g, 528 mmol)とDMA (400 mL)の混合液に、ジイソプロピルエチルアミン (92 mL, 528 mmol)を室温で10分間かけて滴下し、60℃で2時間攪拌した。反応液に氷冷下で水 (800 mL)を40分間かけて滴下した後、ヘキサン (200 mL)を加えた。生じた粉末をろ取し、1-(4-クロロベンジル)-3-エチル-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン (156 g, 収率: 97.6%)を微褐色粉末として得た。
1H-NMR (δ ppm TMS / CDCl3): 1.30 (3H, t, J=7.1 Hz), 4.04 (2H, q, J=7.1 Hz), 5.86 (2H, s), 6.48 (1H, m), 7.02 (2H, d, J=8.6 Hz), 7.20-7.25 (2H, m), 7.84 (1H, m), 8.33 (1H, m).
(2) Preparation of 1- (4-chlorobenzyl) -3-ethyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-I000071

3-ethyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (89 g, 480 mmol), 4-chlorobenzyl bromide (108 g, 528 mmol) Diisopropylethylamine (92 mL, 528 mmol) was added dropwise to a mixture of PEG and DMA (400 mL) at room temperature over 10 minutes, and the mixture was stirred at 60 ° C. for 2 hours. Water (800 mL) was added dropwise to the reaction solution under ice-cooling over 40 minutes, and hexane (200 mL) was added. The resulting powder was collected by filtration, and 1- (4-chlorobenzyl) -3-ethyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (156 g Yield: 97.6%) as a slightly brown powder.
1H-NMR (δ ppm TMS / CDCl 3 ): 1.30 (3H, t, J = 7.1 Hz), 4.04 (2H, q, J = 7.1 Hz), 5.86 (2H, s), 6.48 (1H, m), 7.02 (2H, d, J = 8.6 Hz), 7.20-7.25 (2H, m), 7.84 (1H, m), 8.33 (1H, m).
(3)1-(4-クロロベンジル)-3-エチル6-[4-(6-ヒドロキシメチル-3-ピリダジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-248)の調製 (3) 1- (4-Chlorobenzyl) -3-ethyl 6- [4- (6-hydroxymethyl-3-pyridazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (I- 248)
Figure JPOXMLDOC01-appb-C000072

 1-(4-クロロベンジル)-2-エチル-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン(1.33 g, 4.00 mmol)、4-(6-メトキシカルボニル-3-ピリダジルオキシ)アニリン(1.01 g, 4.12 mmol)とt-ブタノール (15 mL)の混合液を加熱還流下で2時間攪拌した。反応液に50%酢酸エチル/へキサン (30 mL)を加え、生じた粉末をろ取し、1-(4-クロロベンジル)- 3-エチル-6-[4-(6-メトキシカルボニル-3-ピリダジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(1.8 g, 収率: 88 %)を淡褐色粉末として得た。
 1-(4-クロロベンジル)- 3-エチル-6-[4-(6-メトキシカルボニル-3-ピリダジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン (1.9 g, 3.73 mmol)をTHF (20 mL)とメタノール(20 mL)の混合液に溶解した。水素化ホウ素ナトリウム (0.42 g, 11.2 mmol) を氷冷下で数回に分けて加え、室温で3時間攪拌した。反応液に飽和塩化アンモニウム水溶液 (50 ml)、酢酸エチル (100 ml)を加え,室温で1時間攪拌した。有機層を食塩水で洗浄した後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残渣を酢酸エチルで洗浄し、1-(4-クロロベンジル)-3-エチル6-[4-(6-ヒドロキシメチル-3-ピリダジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオンを(I-248, 1.57 g, 収率: 87 %) 白色粉末として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.11 (3H, t, J=7.1Hz), 3.77 (2H, q, J=6.6 Hz), 4.68 (2H, d, J=5.6 Hz), 5.12 (0.5H, s), 5.29 (1.5H, s), 5.60 (1H, t, J=5.8 Hz), 6.83 (0.3H, s), 7.17-7.24 (2H, m), 7.33-7.50 (7.0H, m), 7.79 (1H, d, J = 9.12 Hz), 9.33 (0.6H, s).
Figure JPOXMLDOC01-appb-C000072

1- (4-chlorobenzyl) -2-ethyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (1.33 g, 4.00 mmol), 4- ( A mixture of 6-methoxycarbonyl-3-pyridazyloxy) aniline (1.01 g, 4.12 mmol) and t-butanol (15 mL) was stirred with heating under reflux for 2 hours. 50% ethyl acetate / hexane (30 mL) was added to the reaction mixture, and the resulting powder was collected by filtration, and 1- (4-chlorobenzyl) -3-ethyl-6- [4- (6-methoxycarbonyl-3 -Pyridazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (1.8 g, yield: 88%) was obtained as a light brown powder.
1- (4-Chlorobenzyl) -3-ethyl-6- [4- (6-methoxycarbonyl-3-pyridazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (1.9 g, 3.73 mmol) was dissolved in a mixture of THF (20 mL) and methanol (20 mL). Sodium borohydride (0.42 g, 11.2 mmol) was added in several portions under ice cooling, and the mixture was stirred at room temperature for 3 hours. Saturated aqueous ammonium chloride solution (50 ml) and ethyl acetate (100 ml) were added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. Concentrate under reduced pressure, wash the residue with ethyl acetate, 1- (4-chlorobenzyl) -3-ethyl 6- [4- (6-hydroxymethyl-3-pyridazyloxy) phenylimino] -1,3,5-triazinan -2,4-dione (I-248, 1.57 g, yield: 87%) was obtained as a white powder.
1H-NMR (δ ppm TMS / DMSO-d6): 1.11 (3H, t, J = 7.1Hz), 3.77 (2H, q, J = 6.6 Hz), 4.68 (2H, d, J = 5.6 Hz), 5.12 (0.5H, s), 5.29 (1.5H, s), 5.60 (1H, t, J = 5.8 Hz), 6.83 (0.3H, s), 7.17-7.24 (2H, m), 7.33-7.50 (7.0H , m), 7.79 (1H, d, J = 9.12 Hz), 9.33 (0.6H, s).
(1)3-プロピル-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオンの調製 (1) Preparation of 3-propyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000073

 1-アミジノピラゾール塩酸塩 (29.3 g, 200 mmol)、プロピルイソシアネート(19.68 mL, 210 mmol)とDMA(120 mL) の混合液にDBU(31.7 mL, 210 mmol)を-10℃で5分間かけて滴下し、氷冷下で30分間攪拌した。反応液に、1,1'-カルボニルジイミダゾール(48.6 g, 300 mmol)を氷冷下で加えた後、DBU(46.7 mL, 310 mmol)を-5℃で30分間かけて加えた。反応液を氷冷下で1時間攪拌し、さらに室温で1時間攪拌した。反応液に、2 mol/L 塩酸 (1580 mL)を20℃で35分間かけて加えた。生じた粉末をろ取し、3-プロピル-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン (43.18 g, 収率: 98%)を微褐色粉末として得た。
1H-NMR (δ ppm TMS / CDCl3): 1.07 (3H, t, J=7.6 Hz), 1.76 (2H, sext, J=7.6 Hz), 3.92 (2H, m), 5.13 (1H, brs), 6.59 (1H, m), 7.84 (1H, t, J=0.8 Hz), 8.50 (1H, t, J=0.7 Hz).
Figure JPOXMLDOC01-appb-C000073

DBU (31.7 mL, 210 mmol) was added to a mixture of 1-amidinopyrazole hydrochloride (29.3 g, 200 mmol), propyl isocyanate (19.68 mL, 210 mmol) and DMA (120 mL) at −10 ° C. over 5 minutes. The solution was added dropwise and stirred for 30 minutes under ice cooling. 1,1′-Carbonyldiimidazole (48.6 g, 300 mmol) was added to the reaction solution under ice cooling, and then DBU (46.7 mL, 310 mmol) was added at −5 ° C. over 30 minutes. The reaction solution was stirred for 1 hour under ice-cooling, and further stirred at room temperature for 1 hour. To the reaction solution, 2 mol / L hydrochloric acid (1580 mL) was added at 20 ° C. over 35 minutes. The resulting powder was collected by filtration to give 3-propyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (43.18 g, yield: 98%). Obtained as a brown powder.
1H-NMR (δ ppm TMS / CDCl3): 1.07 (3H, t, J = 7.6 Hz), 1.76 (2H, sext, J = 7.6 Hz), 3.92 (2H, m), 5.13 (1H, brs), 6.59 (1H, m), 7.84 (1H, t, J = 0.8 Hz), 8.50 (1H, t, J = 0.7 Hz).
(2)trans-6-[4-(5-シアノ-2-ピリジルオキシ)フェニルイミノ]-1-(4-メチルシクロヘキシル)メチル-3-プロピル-1,3,5-トリアジナン-2,4-ジオン(I-298)の調製 (2) trans-6- [4- (5-Cyano-2-pyridyloxy) phenylimino] -1- (4-methylcyclohexyl) methyl-3-propyl-1,3,5-triazinan-2,4- Preparation of dione (I-298)
Figure JPOXMLDOC01-appb-C000074

 3-プロピル-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン(0.44 g, 2 mmol)、trans-(4-メチルシクロヘキシル)メタノール(0.31 g, 2.4 mmol)、トリフェニルホスフィン (0.63 g, 2.4 mmol)とTHF(6 mL)の混合液に、ジ-2-メトキシエチルアゾジカルボキシレート(0.56, 2.4 mmol)を氷冷下で加え、室温で2時間攪拌した。反応液に水(200 mL)を加え、酢酸エチル(200 mL)で抽出した。有機層を飽和食塩水(200 mL)で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮し、trans-1-(4-メチルシクロヘキシル)メチル-3-プロピル-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオンを粗製物として得た。
 得られた粗製物に4-(5-シアノ-2-ピリジルオキシ)アニリン(0.21 g, 1 mmol)とt-ブタノール (6 mL)を加え還流下で3時間攪拌した。反応液を減圧濃縮し、残渣をシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)で精製し、trans-6-[4-(5-シアノ-2-ピリジルオキシ)フェニルイミノ]-1-(4-メチルシクロヘキシル)メチル-3-プロピル-1,3,5-トリアジナン-2,4-ジオン (I-298, 0,41 g, 収率: 86%)を白色アモルファスとして得た。
1H-NMR (δ ppm TMS / CDCl3): 0.87 (3H, t, J=6.5 Hz), 0.95 (3H, t, J=7.4 Hz), 1.07-1.96 (12H, m), 3.77-3.81 (2H, m), 3.93 (2H, d, J=7.2 Hz), 6.85-7.15 (5H, m), 7.70 (1H, s), 7.93 (1H, dd, J=6.4, 2.4 Hz), 8.43 (1H, m).
Figure JPOXMLDOC01-appb-C000074

3-propyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (0.44 g, 2 mmol), trans- (4-methylcyclohexyl) methanol (0.31 g , 2.4 mmol), di-2-methoxyethyl azodicarboxylate (0.56, 2.4 mmol) was added to a mixture of triphenylphosphine (0.63 g, 2.4 mmol) and THF (6 mL) under ice-cooling. For 2 hours. Water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (200 mL) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to obtain trans-1- (4-methylcyclohexyl) methyl-3-propyl-6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione as a crude product Obtained.
4- (5-Cyano-2-pyridyloxy) aniline (0.21 g, 1 mmol) and t-butanol (6 mL) were added to the obtained crude product, and the mixture was stirred under reflux for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate / hexane), trans-6- [4- (5-cyano-2-pyridyloxy) phenylimino] -1- (4-methylcyclohexyl). ) Methyl-3-propyl-1,3,5-triazinan-2,4-dione (I-298, 0,41 g, yield: 86%) was obtained as a white amorphous.
1H-NMR (δ ppm TMS / CDCl3): 0.87 (3H, t, J = 6.5 Hz), 0.95 (3H, t, J = 7.4 Hz), 1.07-1.96 (12H, m), 3.77-3.81 (2H, m), 3.93 (2H, d, J = 7.2 Hz), 6.85-7.15 (5H, m), 7.70 (1H, s), 7.93 (1H, dd, J = 6.4, 2.4 Hz), 8.43 (1H, m ).
trans-6-[4-(5-ヒドロキシカルボニル-2-ピリジルオキシ)フェニルイミノ]-1-(4-メチルシクロヘキシル)メチル-3-プロピル-1,3,5-トリアジナン-2,4-ジオン(I-318)の調製 trans-6- [4- (5-hydroxycarbonyl-2-pyridyloxy) phenylimino] -1- (4-methylcyclohexyl) methyl-3-propyl-1,3,5-triazinan-2,4-dione ( Preparation of I-318)
Figure JPOXMLDOC01-appb-C000075

trans-6-[4-(5-シアノ-2-ピリジルオキシ)フェニルイミノ]-1-(4-メチルシクロヘキシル)メチル-3-プロピル-1,3,5-トリアジナン-2,4-ジオン(0.38 g, 0.80 mmol)のDMSO(4 mL)溶液に、1mol/L 水酸化ナトリウム(4 mL)を加え、60℃で4.5時間攪拌した。反応液を水に注ぎ、5%クエン酸水溶液で酸性に調製した後、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した。減圧濃縮し、残渣に酢酸エチルとヘキサンを加え、生じた粉末をろ取し、trans-6-[4-(5-ヒドロキシカルボニル-2-ピリジルオキシ)フェニルイミノ]-1-(4-メチルシクロヘキシル)メチル-3-プロピル-1,3,5-トリアジナン-2,4-ジオン (I-318, 0.14 g, 収率: 34%)を淡緑色粉末として得た。
1H-NMR (δ ppm TMS / d6 DMSO): 0.80-1.80 (18H, m), 3.67 (2H, t, J=6.9 Hz), 3.85- 3.95 (2H, m), 7.14 (1H, d, J=8.4 Hz), 7.21 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=7.2 Hz), 8.30 (1H, dd, J=2.1, 8.7 Hz), 8.09 (1H, d, J=1.8 Hz), 9.19 (1H, brs).
Figure JPOXMLDOC01-appb-C000075

trans-6- [4- (5-Cyano-2-pyridyloxy) phenylimino] -1- (4-methylcyclohexyl) methyl-3-propyl-1,3,5-triazinan-2,4-dione (0.38 g, 0.80 mmol) in DMSO (4 mL) was added 1 mol / L sodium hydroxide (4 mL), and the mixture was stirred at 60 ° C. for 4.5 hours. The reaction mixture was poured into water, acidified with 5% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. Concentrate under reduced pressure, add ethyl acetate and hexane to the residue, filter the resulting powder, and trans-6- [4- (5-hydroxycarbonyl-2-pyridyloxy) phenylimino] -1- (4-methylcyclohexyl) ) Methyl-3-propyl-1,3,5-triazinan-2,4-dione (I-318, 0.14 g, yield: 34%) was obtained as a pale green powder.
1H-NMR (δ ppm TMS / d6 DMSO): 0.80-1.80 (18H, m), 3.67 (2H, t, J = 6.9 Hz), 3.85-3.95 (2H, m), 7.14 (1H, d, J = 8.4 Hz), 7.21 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 7.2 Hz), 8.30 (1H, dd, J = 2.1, 8.7 Hz), 8.09 (1H, d, J = 1.8 Hz), 9.19 (1H, brs).
(1)3,5-ジオキサヘキシルアミンの調製 (1) Preparation of 3,5-dioxahexylamine
Figure JPOXMLDOC01-appb-C000076

 ベンジル 2-ヒドロキシエチルカーバメート(25.3 g, 130 mmol) 、ジイソプロピルエチルアミン (27.2 ml, 156 mmol)と塩化メチレン (200 mL)の混合液に、クロロメチルメチルエーテル (10.8 mL, 143 mmol)を氷冷下で10分間かけて滴下し、室温で終夜攪拌した。反応液に氷冷下で水 (225 mL)を加えた後、酢酸エチル (200 mL×2)で抽出した。有機層を食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。減圧濃縮し、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)で精製し、ベンジル 3,5-ジオキサヘキシルカーバメート (28.2 g, 収率: 92%) を無色油状物として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 3.17 (2H, q, J=5.9Hz), 3.23 (3H, s), 3.45 (1H, dd, J=5.8Hz, J=6.1Hz), 4.54 (2H, s), 5.01 (2H, s), 7.20-7.40 (5H, m).
 ベンジル 3,5-ジオキサヘキシルカーバメート(9.75 g, 40.7 mmol)のエタノール(100 mL) 溶液に、10%パラジウム炭素 (0.87 g)を加え、水素雰囲気下、12時間攪拌した。反応液をろ過し、減圧濃縮した。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)で精製し、3,5-ジオキサヘキシルアミン (3.87 g, 収率: 90%)を無色油状物として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 2.66 (2H, dd, J=7.6Hz, J=8.0Hz), 2.72 (2H, brs), 3.23 (3H, s), 3.40 (2H, dd, J=6.4Hz, J=8.0Hz), 4.54 (2H, s).
Figure JPOXMLDOC01-appb-C000076

To a mixture of benzyl 2-hydroxyethyl carbamate (25.3 g, 130 mmol), diisopropylethylamine (27.2 ml, 156 mmol) and methylene chloride (200 mL), chloromethyl methyl ether (10.8 mL, 143 mmol) is cooled with ice. The solution was added dropwise over 10 minutes and stirred at room temperature overnight. Water (225 mL) was added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate (200 mL × 2). The organic layer was washed with brine and then dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate / hexane) to give benzyl 3,5-dioxahexyl carbamate (28.2 g, yield: 92%) as a colorless oil.
1H-NMR (δ ppm TMS / DMSO-d6): 3.17 (2H, q, J = 5.9Hz), 3.23 (3H, s), 3.45 (1H, dd, J = 5.8Hz, J = 6.1Hz), 4.54 (2H, s), 5.01 (2H, s), 7.20-7.40 (5H, m).
To a solution of benzyl 3,5-dioxahexyl carbamate (9.75 g, 40.7 mmol) in ethanol (100 mL) was added 10% palladium carbon (0.87 g), and the mixture was stirred under a hydrogen atmosphere for 12 hours. The reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give 3,5-dioxahexylamine (3.87 g, yield: 90%) as a colorless oil.
1H-NMR (δ ppm TMS / DMSO-d6): 2.66 (2H, dd, J = 7.6Hz, J = 8.0Hz), 2.72 (2H, brs), 3.23 (3H, s), 3.40 (2H, dd, J = 6.4Hz, J = 8.0Hz), 4.54 (2H, s).
(2)1-(4-クロロベンジル)-3-(3,5-ジオキサヘキシル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオンの調製 (2) 1- (4-Chlorobenzyl) -3- (3,5-dioxahexyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione Preparation of
Figure JPOXMLDOC01-appb-C000077

 1,1'-カルボニルジイミダゾール(6.79 g, 41.9 mol)のDMA(20 mL)溶液に3,5-ジオキサヘキシルアミン (4 g, 38 mol)を-10℃で加え、0℃で2時間攪拌した。反応液に、1-アミジノピラゾール塩酸塩 (4.65 g, 31.7 mmol)を加えた後、DBU(4.87 ml, 32.3 mmol)を-10℃で25分間かけて加えた。室温で1時間攪拌した後、45℃で1.5時間攪拌した。反応液に、1,1'-カルボニルジイミダゾール(7.71 g, 47.6 mmol)を加えた後、DBU(7.17 ml, 47.6 mmol)を0℃で1時間かけて加えた。室温で1時間攪拌した後、45℃で4時間攪拌した。反応液に、2 mol/L 塩酸 (200 ml)を氷冷下で滴下した。生じた粉末をろ取し、3-(3,5-ジオキサヘキシル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン(6.13 g, 収率: 72%)を白色粉末として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 3.20 (3H, s), 3.63 (2H, t, J=6.3 Hz), 3.95 (2H, dd, J=6.1 Hz, J=6.4 Hz), 4.52 (2H, s), 6.70 (1H, m), 8.02 (1H, m), 8.53 (1H, m).
 3-(3,5-ジオキサヘキシル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン (5.49 g, 20.5 mmol) 、4-クロロベンジルブロミド (4.64 g, 22.6 mmol)とDMA (15 mL)の混合液に、ジイソプロピルエチルアミン (4 mL, 22.6 mmol)を室温で10分間かけて滴下した。55℃で1時間攪拌した後、氷冷下で水 (225 mL)を加えた。酢酸エチル (200 mL×2)で抽出し、有機層を食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮した後、ヘキサン/酢酸エチルを加えた。生じた粉末をろ取し、1-(4-クロロベンジル)-3-(3,5-ジオキサヘキシル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン(6.58 g, 収率: 82 % ) を白色粉末として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 3.20 (3H, s), 3.66 (2H, dd, J=6.1 Hz, J=6.3 Hz), 4.00 (2H, dd, J=5.9 Hz, J=6.3 Hz), 4.53 (2H, s), 5.44 (2H, s), 6.62 (1H, m), 7.25 (2H, d, J=8.4 Hz), 7.32 (2H, d, J=8.5 Hz), 7.93 (1H, m), 8.44 (1H, m).
Figure JPOXMLDOC01-appb-C000077

To a solution of 1,1'-carbonyldiimidazole (6.79 g, 41.9 mol) in DMA (20 mL) was added 3,5-dioxahexylamine (4 g, 38 mol) at -10 ° C, and at 0 ° C for 2 hours. Stir. 1-Amidinopyrazole hydrochloride (4.65 g, 31.7 mmol) was added to the reaction solution, and then DBU (4.87 ml, 32.3 mmol) was added at −10 ° C. over 25 minutes. After stirring at room temperature for 1 hour, the mixture was stirred at 45 ° C. for 1.5 hours. 1,1′-carbonyldiimidazole (7.71 g, 47.6 mmol) was added to the reaction solution, and then DBU (7.17 ml, 47.6 mmol) was added at 0 ° C. over 1 hour. After stirring at room temperature for 1 hour, the mixture was stirred at 45 ° C. for 4 hours. To the reaction solution, 2 mol / L hydrochloric acid (200 ml) was added dropwise under ice cooling. The resulting powder was collected by filtration, and 3- (3,5-dioxahexyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (6.13 g, Yield: 72%) was obtained as a white powder.
1H-NMR (δ ppm TMS / DMSO-d6): 3.20 (3H, s), 3.63 (2H, t, J = 6.3 Hz), 3.95 (2H, dd, J = 6.1 Hz, J = 6.4 Hz), 4.52 (2H, s), 6.70 (1H, m), 8.02 (1H, m), 8.53 (1H, m).
3- (3,5-Dioxahexyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (5.49 g, 20.5 mmol), 4-chlorobenzyl To a mixture of bromide (4.64 g, 22.6 mmol) and DMA (15 mL), diisopropylethylamine (4 mL, 22.6 mmol) was added dropwise at room temperature over 10 minutes. After stirring at 55 ° C. for 1 hour, water (225 mL) was added under ice cooling. Extraction was performed with ethyl acetate (200 mL × 2), and the organic layer was washed with brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, hexane / ethyl acetate was added. The resulting powder was collected by filtration, and 1- (4-chlorobenzyl) -3- (3,5-dioxahexyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H , 3H) -dione (6.58 g, yield: 82%) was obtained as a white powder.
1H-NMR (δ ppm TMS / DMSO-d6): 3.20 (3H, s), 3.66 (2H, dd, J = 6.1 Hz, J = 6.3 Hz), 4.00 (2H, dd, J = 5.9 Hz, J = 6.3 Hz), 4.53 (2H, s), 5.44 (2H, s), 6.62 (1H, m), 7.25 (2H, d, J = 8.4 Hz), 7.32 (2H, d, J = 8.5 Hz), 7.93 (1H, m), 8.44 (1H, m).
(3)1-(4-クロロベンジル)-3-(2-ヒドロキシエチル)-6-[4-(5-メトキシカルボニル-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-204)および
1-(4-クロロベンジル)-3-(2-ヒドロキシエチル)-6-[4-(5-ヒドロキシカルボニル-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-241)の調製
(3) 1- (4-Chlorobenzyl) -3- (2-hydroxyethyl) -6- [4- (5-methoxycarbonyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2, 4-dione (I-204) and
1- (4-Chlorobenzyl) -3- (2-hydroxyethyl) -6- [4- (5-hydroxycarbonyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione Preparation of (I-241)
Figure JPOXMLDOC01-appb-C000078

 1-(4-クロロベンジル)-3-(3,5-ジオキサヘキシル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン(0.8 g, 2.04 mmol)、4-(5-メトキシカルボニル-2-ピラジルオキシ)アニリン(0.53 g, 2.14 mmol)、t-ブタノール(16 mL)の混合液を、加熱還流下で30分間攪拌した。反応液を減圧濃縮して1-(4-クロロベンジル)-3-(3,5-ジオキサヘキシル)-6-[4-(5-メトキシカルボニル-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(1.39 g)を粗製物として得た。
 得られた粗製物に水 (0.38 mL)とトリフルオロ酢酸(8 mL)を加え、室温で30分間攪拌した。反応液を減圧濃縮してメタノール(4 mL)とピリジン(4 mL)を加え、室温で2時間攪拌した。反応液を減圧濃縮し、水を加え、酢酸エチルで抽出した。有機層を水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮し、n-ヘキサンとクロロホルムを加え、生じた粉末をろ取し、1-(4-クロロベンジル)-3-(2-ヒドロキシエチル)-6-[4-(5-メトキシカルボニル-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-204, 1.04 g, 収率: 97%)を淡茶色粉末として得た。
 1-(4-クロロベンジル)-3-(2-ヒドロキシエチル)-6-[4-(5-メトキシカルボニル-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(0.25 g, 0.48 mmol)のTHF(2 mL)溶液に、1mol/L 水酸化ナトリウム(1 mL、1 mmol)を加え、室温で2.5時間攪拌した。反応液を水に注ぎ、5%クエン酸水溶液で酸性に調製した後、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した。減圧濃縮し、残渣に酢酸エチルを加えた。生じた粉末をろ取し、1-(4-クロロベンジル)-3-(2-ヒドロキシエチル)-6-[4-(5-ヒドロキシカルボニル-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-241, 0.21 g, 収率: 86%)を淡茶色粉末として得た。
1H-NMR (δ ppm TMS / d6 DMSO): 3.83 (H, t, J=6.0 Hz), 4.77 (1H, brs), 5.26 (2H, bds), 7.25 (2H, d, J=7.5 Hz), 7.35-7.50 (6H, m), 8.62 (1H, s), 8.77 (1H, s), 9.37 (1H, bds)
Figure JPOXMLDOC01-appb-C000078

1- (4-Chlorobenzyl) -3- (3,5-dioxahexyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (0.8 g , 2.04 mmol), 4- (5-methoxycarbonyl-2-pyrazyloxy) aniline (0.53 g, 2.14 mmol), and t-butanol (16 mL) were stirred with heating under reflux for 30 minutes. The reaction solution was concentrated under reduced pressure to give 1- (4-chlorobenzyl) -3- (3,5-dioxahexyl) -6- [4- (5-methoxycarbonyl-2-pyrazyloxy) phenylimino] -1,3 , 5-Triazinan-2,4-dione (1.39 g) was obtained as a crude product.
Water (0.38 mL) and trifluoroacetic acid (8 mL) were added to the obtained crude product, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, methanol (4 mL) and pyridine (4 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, n-hexane and chloroform were added, and the resulting powder was collected by filtration, and 1- (4-chlorobenzyl) -3- (2-hydroxyethyl) -6- [4- (5-methoxycarbonyl-2 -Pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (I-204, 1.04 g, yield: 97%) was obtained as a light brown powder.
1- (4-Chlorobenzyl) -3- (2-hydroxyethyl) -6- [4- (5-methoxycarbonyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione To a THF (2 mL) solution of (0.25 g, 0.48 mmol) was added 1 mol / L sodium hydroxide (1 mL, 1 mmol), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was poured into water, acidified with 5% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The resulting powder was collected by filtration, and 1- (4-chlorobenzyl) -3- (2-hydroxyethyl) -6- [4- (5-hydroxycarbonyl-2-pyrazyloxy) phenylimino] -1,3,5 -Triazinan-2,4-dione (I-241, 0.21 g, yield: 86%) was obtained as a light brown powder.
1H-NMR (δ ppm TMS / d6 DMSO): 3.83 (H, t, J = 6.0 Hz), 4.77 (1H, brs), 5.26 (2H, bds), 7.25 (2H, d, J = 7.5 Hz), 7.35-7.50 (6H, m), 8.62 (1H, s), 8.77 (1H, s), 9.37 (1H, bds)
1-(4-クロロベンジル)-3-(2-ヒドロキシエチル)-6-[4-(5-カルバモイル-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-205)の調製 1- (4-Chlorobenzyl) -3- (2-hydroxyethyl) -6- [4- (5-carbamoyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione ( Preparation of I-205)
Figure JPOXMLDOC01-appb-C000079

 1-(4-クロロベンジル)-3-(2-ヒドロキシエチル)-6-[4-(5-メトキシカルボニル-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(0.25 g, 0.48 mmol)のTHF(2 mL)溶液に、28%アンモニア水溶液(4 mL)を加え、室温で2.5時間攪拌した。反応液中に生じた粉末を濾取し、1-(4-クロロベンジル)-3-(2-ヒドロキシエチル)-6-[4-(5-カルバモイル-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-205, 0.15 g, 収率: 60%)を淡茶色粉末として得た。
1H-NMR (δ ppm TMS / d6 DMSO): 3.77 (H, t, J=6.6 Hz), 4.65 (1H, brs), 5.16 (2H, s), 7.03 (2H, d, J=9.0 Hz), 7.10 (2H, d, J=9.0 Hz), 7.34-7.44 (4H, m), 7.68 (1H, s), 8.07 (1H, s), 8.48 (1H, s), 8.72 (1H, m).
Figure JPOXMLDOC01-appb-C000079

1- (4-Chlorobenzyl) -3- (2-hydroxyethyl) -6- [4- (5-methoxycarbonyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione To a THF (2 mL) solution of (0.25 g, 0.48 mmol) was added 28% aqueous ammonia solution (4 mL), and the mixture was stirred at room temperature for 2.5 hours. The powder produced in the reaction solution was collected by filtration, and 1- (4-chlorobenzyl) -3- (2-hydroxyethyl) -6- [4- (5-carbamoyl-2-pyrazyloxy) phenylimino] -1, 3,5-Triazinan-2,4-dione (I-205, 0.15 g, yield: 60%) was obtained as a light brown powder.
1H-NMR (δ ppm TMS / d6 DMSO): 3.77 (H, t, J = 6.6 Hz), 4.65 (1H, brs), 5.16 (2H, s), 7.03 (2H, d, J = 9.0 Hz), 7.10 (2H, d, J = 9.0 Hz), 7.34-7.44 (4H, m), 7.68 (1H, s), 8.07 (1H, s), 8.48 (1H, s), 8.72 (1H, m).
(1)1-(4-クロロベンジル)-6-(エチルチオ)-1,3,5-トリアジン-2,4(1H,3H)-ジオンの調製 (1) Preparation of 1- (4-chlorobenzyl) -6- (ethylthio) -1,3,5-triazine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000080

 S-エチルチオウレア臭化水素酸塩(1.85 g, 10 mmol) とDMF(9.3 mL) の混合液に、t-ブチルイソシアネート (1.2 mL, 10.5 mmol) とDBU (1.9 mL, 12.8 mmol) を氷冷下で加え、6時間攪拌した。反応液に、1,1'-カルボニルジイミダゾール(1.95 g, 12 mmol)とDBU(1.9 mL, 12.8 mmol)を氷冷下で加え、2時間攪拌した。2mol/L 塩酸(80 mL) を氷冷下で50分間かけて加え、生じた粉末をろ取した。粉末を酢酸エチルに溶解し、無水硫酸マグネシウムで乾燥した。減圧濃縮し、6-(エチルチオ)-3-t-ブチル-1,3,5-トリアジン-2,4(1H,3H)-ジオン (1.15g, 収率: 50%)を淡褐色粉末として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.27 (3H, t, J=7.3 Hz), 1.55 (9H, s), 3.03 (2H, q, J=7.3), 12.30 (1H, brs)
 6-(エチルチオ)-3-t-ブチル-1,3,5-トリアジン-2,4(1H,3H)-ジオン (22.93 g, 100 mmol)、4-クロロベンジルブロミド (22.60 g, 110 mmol)およびアセトニトリル (200 mL) の混合液に、炭酸カリウム(17.97 g, 130 mmol)を加え,加熱還流下で3時間攪拌した。反応液をろ過し、ろ液を減圧濃縮して、3-t-ブチル-1-(4-クロロベンジル)-6-(エチルチオ)-1,3,5-トリアジン-2,4(1H,3H)-ジオンの粗製物 39.9gを微褐色油状物として得た。
 得られた粗製物にトリフルオロ酢酸 (100 mL) を氷冷下で加え、室温で17時間攪拌した。反応液を減圧濃縮し、1-(4-クロロベンジル)-6-(エチルチオ)-1,3,5-トリアジン-2,4(1H,3H)-ジオン (29.03 g, 収率: 97%)を微褐色粉末として得た。
1H-NMR (δ ppm TMS / d6-DMSO): 1.25 (3H, t, J=7.3 Hz), 3.08 (2H, q, J=7.3 Hz), 5.02 (2H, s), 7.30-7.33 (2H, m), 7.39-7.42 (2H, m), 11.61 (1H, s).
Figure JPOXMLDOC01-appb-C000080

To a mixture of S-ethylthiourea hydrobromide (1.85 g, 10 mmol) and DMF (9.3 mL), t-butyl isocyanate (1.2 mL, 10.5 mmol) and DBU (1.9 mL, 12.8 mmol) were ice-cooled. Added below and stirred for 6 hours. To the reaction solution, 1,1′-carbonyldiimidazole (1.95 g, 12 mmol) and DBU (1.9 mL, 12.8 mmol) were added under ice cooling, and the mixture was stirred for 2 hours. 2 mol / L hydrochloric acid (80 mL) was added over 50 minutes under ice cooling, and the resulting powder was collected by filtration. The powder was dissolved in ethyl acetate and dried over anhydrous magnesium sulfate. Concentration under reduced pressure gave 6- (ethylthio) -3-t-butyl-1,3,5-triazine-2,4 (1H, 3H) -dione (1.15 g, yield: 50%) as a light brown powder. It was.
1H-NMR (δ ppm TMS / DMSO-d6): 1.27 (3H, t, J = 7.3 Hz), 1.55 (9H, s), 3.03 (2H, q, J = 7.3), 12.30 (1H, brs)
6- (Ethylthio) -3-t-butyl-1,3,5-triazine-2,4 (1H, 3H) -dione (22.93 g, 100 mmol), 4-chlorobenzyl bromide (22.60 g, 110 mmol) To a mixture of acetonitrile and acetonitrile (200 mL), potassium carbonate (17.97 g, 130 mmol) was added, and the mixture was stirred for 3 hours under heating to reflux. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give 3-t-butyl-1- (4-chlorobenzyl) -6- (ethylthio) -1,3,5-triazine-2,4 (1H, 3H 39.9 g of crude) -dione was obtained as a light brown oil.
Trifluoroacetic acid (100 mL) was added to the obtained crude product under ice cooling, and the mixture was stirred at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, and 1- (4-chlorobenzyl) -6- (ethylthio) -1,3,5-triazine-2,4 (1H, 3H) -dione (29.03 g, yield: 97%) Was obtained as a fine brown powder.
1H-NMR (δ ppm TMS / d6-DMSO): 1.25 (3H, t, J = 7.3 Hz), 3.08 (2H, q, J = 7.3 Hz), 5.02 (2H, s), 7.30-7.33 (2H, m), 7.39-7.42 (2H, m), 11.61 (1H, s).
(2)1-(4-クロロベンジル)-3-(メトキシカルボニルメチル)-6-[4-(5-カルバモイル-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオンの調製 (2) 1- (4-Chlorobenzyl) -3- (methoxycarbonylmethyl) -6- [4- (5-carbamoyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4- Preparation of dione
Figure JPOXMLDOC01-appb-C000081

 1-(4-クロロベンジル)-6-(エチルチオ)-1,3,5-トリアジン-2,4(1H,3H)-ジオン(2.98 g, 10 mmol)、ブロモ酢酸メチル(1.04 mL, 11 mmol)とDMF (30 mL) の混合液に、炭酸カリウム(1.80 g, 13 mmol)を加え、室温で4時間攪拌した。反応液に水 (250 mL)を加え、酢酸エチル (200 mL) で抽出した。有機層を飽和食塩水 (250 mL)で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残渣に酢酸エチルとヘキサンを加えた。生じた粉末をろ取し、1-(4-クロロベンジル)-3-(メトキシカルボニルメチル)-6-(エチルチオ)-1,3,5-トリアジン-2,4(1H,3H)-ジオン (3.26 g, 収率: 88%)を無色粉末として得た。
1H-NMR (δ ppm TMS / CDCl3): 1.37 (3H, t, J=7.2 Hz), 3.23 (2H, q, J=7.2 Hz), 3.78 (3H, s), 4.68 (2H, s), 5.11 (2H, s), 7.27-7.35 (4H, m).
 1-(4-クロロベンジル)-3-(メトキシカルボニルメチル)-6-(エチルチオ)-1,3,5-トリアジン-2,4(1H,3H)-ジオン(1.0 g, 2.70 mmol)、4-(5-カルバモイル-2-ピラジルオキシ)アニリン(0.75 g, 3.24 mmol)、t-ブタノール (5.0 mL)と酢酸(2.3 mL)の混合液を加熱還流下で7時間攪拌した。反応液に50%酢酸エチル/ヘキサン(10 mL)を加え、生じた粉末を濾取し、1-(4-クロロベンジル)-3-(メトキシカルボニルメチル)-6-[4-(5-カルバモイル-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン (1.35 g, 収率: 93%)を淡茶色粉末として得た。
1H-NMR (δ ppm TMS / d6-DMSO): 3.68 (3H, s), 4.52 (2H, s), 5.29 (2H, s), 7.25 (2H, m, J=8.1 Hz), 7.32-7.50 (6H, m), 7.71 (1H, s), 8.09 (1H, m), 8.56 (1H, s), 8.73 (1H, m).
Figure JPOXMLDOC01-appb-C000081

1- (4-Chlorobenzyl) -6- (ethylthio) -1,3,5-triazine-2,4 (1H, 3H) -dione (2.98 g, 10 mmol), methyl bromoacetate (1.04 mL, 11 mmol) ) And DMF (30 mL) were added potassium carbonate (1.80 g, 13 mmol), and the mixture was stirred at room temperature for 4 hours. Water (250 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (250 mL) and dried over anhydrous magnesium sulfate. The mixture was concentrated under reduced pressure, and ethyl acetate and hexane were added to the residue. The resulting powder was collected by filtration, and 1- (4-chlorobenzyl) -3- (methoxycarbonylmethyl) -6- (ethylthio) -1,3,5-triazine-2,4 (1H, 3H) -dione ( 3.26 g, yield: 88%) was obtained as a colorless powder.
1H-NMR (δ ppm TMS / CDCl 3 ): 1.37 (3H, t, J = 7.2 Hz), 3.23 (2H, q, J = 7.2 Hz), 3.78 (3H, s), 4.68 (2H, s), 5.11 (2H, s), 7.27-7.35 (4H, m).
1- (4-chlorobenzyl) -3- (methoxycarbonylmethyl) -6- (ethylthio) -1,3,5-triazine-2,4 (1H, 3H) -dione (1.0 g, 2.70 mmol), 4 A mixture of-(5-carbamoyl-2-pyrazyloxy) aniline (0.75 g, 3.24 mmol), t-butanol (5.0 mL) and acetic acid (2.3 mL) was stirred with heating under reflux for 7 hours. 50% ethyl acetate / hexane (10 mL) was added to the reaction mixture, and the resulting powder was collected by filtration to give 1- (4-chlorobenzyl) -3- (methoxycarbonylmethyl) -6- [4- (5-carbamoyl). -2-Pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (1.35 g, yield: 93%) was obtained as a light brown powder.
1H-NMR (δ ppm TMS / d6-DMSO): 3.68 (3H, s), 4.52 (2H, s), 5.29 (2H, s), 7.25 (2H, m, J = 8.1 Hz), 7.32-7.50 ( 6H, m), 7.71 (1H, s), 8.09 (1H, m), 8.56 (1H, s), 8.73 (1H, m).
(3)1-(4-クロロベンジル)-3-(ヒドロキシルカルボニルメチル)-6-[4-(5-シアノ-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-206)の調製 (3) 1- (4-Chlorobenzyl) -3- (hydroxylcarbonylmethyl) -6- [4- (5-cyano-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4- Preparation of dione (I-206)
Figure JPOXMLDOC01-appb-C000082

 1-(4-クロロベンジル)-3-(メトキシカルボニルメチル)-6-[4-(5-カルバモイル-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(1.0 g, 1.86 mmol)のピリジン(10 mL)溶液に氷冷下で無水トリフルオロ酢酸(1.31 mL, 9.30 mmol)を加えた。反応液を氷冷下で1.5時間攪拌した後、5%クエン酸水溶液(100 mL)に注いだ。生じた粉末をろ取し、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)で精製して、1-(4-クロロベンジル)-3-(メトキシカルボニルメチル)-6-[4-(5-シアノ-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(0.93 g, 収率: 96%)を淡黄色アモルファスとして得た。
 1-(4-クロロベンジル)-3-(メトキシカルボニルメチル)-6-[4-(5-シアノ-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(0.9 g, 1.73 mmol)のTHF(14 mL)溶液に1mol/L 水酸化ナトリウム(3.5 mL、3.5 mmol)を氷冷下で加え、6時間攪拌した。反応液を氷水に注ぎ、5%クエン酸水溶液で酸性に調製した後、酢酸エチルで抽出した。有機層を無水硫酸ナトリウムで乾燥した。減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(クロロホルム/メタノール)で精製し、1-(4-クロロベンジル)-3-(ヒドロキシルカルボニルメチル)-6-[4-(5-シアノ-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-206, 97 mg, 収率: 11%)を淡茶色アモルファスとして得た。
1H-NMR (δ ppm TMS / d6-DMSO): 4.52 (2H, s), 5.30 (2H, brs), 7.40-7.50 (8H, m), 8.75 (1H, s), 8.82 (1H, s), 9.56 (1H, brs), 13.05 (1H, brs).
Figure JPOXMLDOC01-appb-C000082

1- (4-Chlorobenzyl) -3- (methoxycarbonylmethyl) -6- [4- (5-carbamoyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (1.0 g, 1.86 mmol) in pyridine (10 mL) was added trifluoroacetic anhydride (1.31 mL, 9.30 mmol) under ice cooling. The reaction solution was stirred for 1.5 hours under ice-cooling, and then poured into a 5% aqueous citric acid solution (100 mL). The resulting powder was collected by filtration and purified by silica gel column chromatography (ethyl acetate / hexane) to give 1- (4-chlorobenzyl) -3- (methoxycarbonylmethyl) -6- [4- (5-cyano- 2-Pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (0.93 g, yield: 96%) was obtained as a pale yellow amorphous.
1- (4-Chlorobenzyl) -3- (methoxycarbonylmethyl) -6- [4- (5-cyano-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (0.9 g, 1.73 mmol) in THF (14 mL) was added 1 mol / L sodium hydroxide (3.5 mL, 3.5 mmol) under ice cooling, and the mixture was stirred for 6 hours. The reaction solution was poured into ice water, acidified with 5% aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (chloroform / methanol), and 1- (4-chlorobenzyl) -3- (hydroxylcarbonylmethyl) -6- [4- (5-cyano-2-pyrazyloxy) Phenylimino] -1,3,5-triazinan-2,4-dione (I-206, 97 mg, yield: 11%) was obtained as a light brown amorphous.
1H-NMR (δ ppm TMS / d6-DMSO): 4.52 (2H, s), 5.30 (2H, brs), 7.40-7.50 (8H, m), 8.75 (1H, s), 8.82 (1H, s), 9.56 (1H, brs), 13.05 (1H, brs).
1-(4-クロロベンジル)-3-(カルバモイルメチル)-6-[4-(5-シアノ-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-254)の調製 1- (4-Chlorobenzyl) -3- (carbamoylmethyl) -6- [4- (5-cyano-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (I- 254)
Figure JPOXMLDOC01-appb-C000083

 1-(4-クロロベンジル)-3-(ヒドロキシカルボニルメチル)-6-[4-(5-シアノ-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン (304 mg, 0.6 mmol)をDMF(3 mL)に溶解した。反応液に塩化アンモニウム(39 mg, 7.20 mmol)、1-ヒドロキシベンゾトリアゾール水和物(110 mg, 7.2 mmol)、4-ジメチルアミノピリジン(7.3 mg, 0.06 mmol)、塩酸1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド(138 mg, 0.72 mmol)およびトリエチルアミン(0.1 mL, 0.72 mmol)を加えて、室温で2時間攪拌した。反応液に水 (100 mL) を加え、酢酸エチル (100 mL) で抽出した。有機層を飽和炭酸水素ナトリウム水溶液 (100 mL)および飽和食塩水 (100 mL)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮し、残渣に酢酸エチルを加え、生じた粉末をろ取して、1-(4-クロロベンジル)-3-(カルバモイルメチル)-6-[4-(5-シアノ-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン (I-254, 0.21 g, 収率: 69%)を淡黄色粉末として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 4.28 (2Hm s), 5.30 (2H, s), 6.85-7.62 (10H, m), 8.75 (1H, s), 8.80 (1H, s), 9.42 (1H, s).
Figure JPOXMLDOC01-appb-C000083

1- (4-Chlorobenzyl) -3- (hydroxycarbonylmethyl) -6- [4- (5-cyano-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (304 mg, 0.6 mmol) was dissolved in DMF (3 mL). The reaction mixture was ammonium chloride (39 mg, 7.20 mmol), 1-hydroxybenzotriazole hydrate (110 mg, 7.2 mmol), 4-dimethylaminopyridine (7.3 mg, 0.06 mmol), 1-ethyl-3- ( 3-Dimethylaminopropyl) carbodiimide (138 mg, 0.72 mmol) and triethylamine (0.1 mL, 0.72 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, ethyl acetate was added to the residue, and the resulting powder was collected by filtration to give 1- (4-chlorobenzyl) -3- (carbamoylmethyl) -6- [4- (5-cyano-2-pyrazyloxy) Phenylimino] -1,3,5-triazinan-2,4-dione (I-254, 0.21 g, yield: 69%) was obtained as a pale yellow powder.
1H-NMR (δ ppm TMS / DMSO-d6): 4.28 (2Hm s), 5.30 (2H, s), 6.85-7.62 (10H, m), 8.75 (1H, s), 8.80 (1H, s), 9.42 (1H, s).
(1)1-(4-クロロベンジル)-3-(2-テトラヒドロピラン-2-イル-2-プロペニル)-6-[4-(3-イソオキサゾリルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオンの調製 (1) 1- (4-Chlorobenzyl) -3- (2-tetrahydropyran-2-yl-2-propenyl) -6- [4- (3-isoxazolyloxy) phenylimino] -1,3 Of 1,5-triazinan-2,4-dione
Figure JPOXMLDOC01-appb-C000084

 1-(4-クロロベンジル)-6-(エチルチオ)-1,3,5-トリアジン-2,4(1H,3H)-ジオン(1090 mg, 3.65 mmol)、2-(テトラヒドロピラン-2-イルオキシ)メチル-2-プロペノール(628 mg, 3.65 mmol)とトリフェニルホスフィン(956 mg, 3.65 mmol)を1,4-ジオキサン(5.0 mL)に溶解した。反応液にジメトキシエチルアザジカルボキシレート(854 mg, 3.65 mmol)を室温で加え、3時間攪拌した。さらに、トリフェニルホスフィン(478 mg, 1.82 mmol)、ジメトキシエチルアザジカルボキシレート(478 mg, 1.82 mmol)を加え、室温で4時間攪拌した。反応液を減圧濃縮し、得られた残渣にジエチルエーテルを加えた。生じた粉末をろ過により除去した。ろ液を水および飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥し、減圧濃縮した。得られた残渣をシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)で精製し、1-(4-クロロベンジル)-6-(エチルチオ)-3-(2-テトラヒドロピラン-2-イルオキシ-2-プロペニル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン(1589 mg, 収率96%)を無色油状物として得た。
 1-(4-クロロベンジル)-6-(エチルチオ)-3-(2-テトラヒドロピラン-2-イルオキシ-2-プロペニル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン(500 mg, 1.11 mmol)にt-ブタノール (3.0 mL)、4-(3-イソキサゾリルオキシ)アニリン(292 mg, 1.66 mmol)と酢酸(0.949 mL, 16.6 mmol)を加え、9時間加熱還流した。反応液に2 mol/L 水酸化ナトリウム水溶液(8 mL)を加え、酢酸エチル(80 mL)で抽出した。有機層を水(50 mL)、5% クエン酸水溶液(50 mL x 2)、飽和炭酸水素ナトリウム水溶液(50 mL)および飽和食塩水(30 mL)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮し、残渣をシリカゲルクロマトグラフィー(酢酸エチル/ヘキサン)で精製し、1-(4-クロロベンジル)-3-(2-テトラヒドロピラン-2-イルオキシ-2-プロペニル)-6-[4-(3-イソオキサゾリルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(338 mg, 収率54%)を白色粉末として得た。
1H-NMR (CDCl3) δ: 2.55 (br s, 1H), 4.06 (s, 2H), 4.47 (s, 2H), 5.07-5.27 (m, 4H), 6.10-6.16 (m, 1H), 6.84 (d, 2H, J = 8.6 Hz), 7.25 (d, 2H, J = 9.1 Hz), 7.30 (d, 2H, J = 8.6 Hz), 7.49 (d, 2H, J = 8.1 Hz), 8.07 (s, 1H), 8.24 (d, 1H, J = 1.5 Hz).
Figure JPOXMLDOC01-appb-C000084

1- (4-Chlorobenzyl) -6- (ethylthio) -1,3,5-triazine-2,4 (1H, 3H) -dione (1090 mg, 3.65 mmol), 2- (tetrahydropyran-2-yloxy) ) Methyl-2-propenol (628 mg, 3.65 mmol) and triphenylphosphine (956 mg, 3.65 mmol) were dissolved in 1,4-dioxane (5.0 mL). Dimethoxyethyl azadicarboxylate (854 mg, 3.65 mmol) was added to the reaction solution at room temperature, and the mixture was stirred for 3 hours. Furthermore, triphenylphosphine (478 mg, 1.82 mmol) and dimethoxyethyl azadicarboxylate (478 mg, 1.82 mmol) were added, and the mixture was stirred at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, and diethyl ether was added to the resulting residue. The resulting powder was removed by filtration. The filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate / hexane) to give 1- (4-chlorobenzyl) -6- (ethylthio) -3- (2-tetrahydropyran-2-yloxy-2-propenyl)- 1,3,5-triazine-2,4 (1H, 3H) -dione (1589 mg, yield 96%) was obtained as a colorless oil.
1- (4-Chlorobenzyl) -6- (ethylthio) -3- (2-tetrahydropyran-2-yloxy-2-propenyl) -1,3,5-triazine-2,4 (1H, 3H) -dione Add t-butanol (3.0 mL), 4- (3-isoxazolyloxy) aniline (292 mg, 1.66 mmol) and acetic acid (0.949 mL, 16.6 mmol) to (500 mg, 1.11 mmol) and heat for 9 hours Refluxed. To the reaction solution was added 2 mol / L aqueous sodium hydroxide solution (8 mL), and the mixture was extracted with ethyl acetate (80 mL). The organic layer was washed with water (50 mL), 5% aqueous citric acid solution (50 mL x 2), saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (ethyl acetate / hexane) and 1- (4-chlorobenzyl) -3- (2-tetrahydropyran-2-yloxy-2-propenyl) -6- [4- (3-Isoxazolyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (338 mg, 54% yield) was obtained as a white powder.
1H-NMR (CDCl3) δ: 2.55 (br s, 1H), 4.06 (s, 2H), 4.47 (s, 2H), 5.07-5.27 (m, 4H), 6.10-6.16 (m, 1H), 6.84 ( d, 2H, J = 8.6 Hz), 7.25 (d, 2H, J = 9.1 Hz), 7.30 (d, 2H, J = 8.6 Hz), 7.49 (d, 2H, J = 8.1 Hz), 8.07 (s, 1H), 8.24 (d, 1H, J = 1.5 Hz).
(2)1-(4-クロロベンジル)-3-(2-ヒドロキシメチル-2,3-ジヒドロキシプロピル)-6-[4-(3-イソオキサゾリルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-065)の調製 (2) 1- (4-Chlorobenzyl) -3- (2-hydroxymethyl-2,3-dihydroxypropyl) -6- [4- (3-isoxazolyloxy) phenylimino] -1,3, Preparation of 5-triazinan-2,4-dione (I-065)
Figure JPOXMLDOC01-appb-C000085

 1-(4-クロロベンジル)-3-(2-テトラヒドロピラン-2-イルオキシ-2-プロペニル)-6-[4-(3-イソオキサゾリルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(247 mg, 0.436 mmol)を95% THF水溶液(2.0 mL)に溶解した。反応液にオスミウム(VI)酸カリウム二水和物(16.1  mg, 0.044 mmol)とN-メチルモルフォリン(102 mg, 0.873 mmol)を加え、室温で1.5時間攪拌した。反応液に5% 亜硫酸ナトリウム水溶液(1.0 mL)と水(20 mL)を加え、酢酸エチル(50 mL)で抽出した。有機層を5% クエン酸水溶液(20 mL x 2)、飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮して、1-(4-クロロベンジル)-3-(2-ヒドロキシメチル-2-テトラヒドロピラン-2-イルオキシメチル-3-ヒドロキシプロピル)-6-[4-(3-イソオキサゾリルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオンを粗製物として得た。
 得られた粗製物に2 mol/L 塩酸メタノール溶液(2.0 mL)を加え、室温で1時間攪拌した。減圧濃縮し、残渣をシリカゲルクロマトグラフィー(クロロホルム/メタノール)で精製し、1-(4-クロロベンジル)-3-(2-ヒドロキシメチル-2,3-ジヒドロキシプロピル)-6-[4-(3-イソオキサゾリルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-065, 164 mg, 収率73%)を白色粉末として得た。
1H-NMR (DMSO-d6) δ: 3.25-3.32 (m, 4H), 3.93 (s, 2H), 4.29 (s, 1H), 4.42 (t, 2H, J = 5.9 Hz), 5.27 (s, 2H), 6.46 (s, 1H), 7.15-7.55 (m, 8H), 8.82 (s, 1H), 9.40 (s, 1H).
Figure JPOXMLDOC01-appb-C000085

1- (4-Chlorobenzyl) -3- (2-tetrahydropyran-2-yloxy-2-propenyl) -6- [4- (3-isoxazolyloxy) phenylimino] -1,3,5- Triazinan-2,4-dione (247 mg, 0.436 mmol) was dissolved in 95% aqueous THF (2.0 mL). To the reaction solution were added potassium osmium (VI) dihydrate (16.1 mg, 0.044 mmol) and N-methylmorpholine (102 mg, 0.873 mmol), and the mixture was stirred at room temperature for 1.5 hours. To the reaction solution were added 5% aqueous sodium sulfite solution (1.0 mL) and water (20 mL), and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with 5% aqueous citric acid solution (20 mL x 2) and saturated brine, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to give 1- (4-chlorobenzyl) -3- (2-hydroxymethyl-2-tetrahydropyran-2-yloxymethyl-3-hydroxypropyl) -6- [4- (3-isoxazoly (Luoxy) phenylimino] -1,3,5-triazinan-2,4-dione was obtained as a crude product.
To the obtained crude product, 2 mol / L hydrochloric acid methanol solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hour. The residue was purified by silica gel chromatography (chloroform / methanol), and 1- (4-chlorobenzyl) -3- (2-hydroxymethyl-2,3-dihydroxypropyl) -6- [4- (3 -Isoxazolyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (I-065, 164 mg, 73% yield) was obtained as a white powder.
1 H-NMR (DMSO-d 6 ) δ: 3.25-3.32 (m, 4H), 3.93 (s, 2H), 4.29 (s, 1H), 4.42 (t, 2H, J = 5.9 Hz), 5.27 (s , 2H), 6.46 (s, 1H), 7.15-7.55 (m, 8H), 8.82 (s, 1H), 9.40 (s, 1H).
(1)3-(2-シアノエチル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオンの調製 (1) Preparation of 3- (2-cyanoethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000086

3-アミノプロパンニトリル(20.0 g, 285 mmol)をDMA(80 mL)に溶解した。反応液に氷冷下、1,1'-カルボニルジイミダゾール(48.6 g, 300 mmol)、DBU(64.5 mL, 428 mmol)をゆっくりと加え、0℃で30分間攪拌した。反応液に1-アミジノピラゾール塩酸塩 (41.8 g, 235 mmol)とDBU(47.3 mL, 314 mmol)を加え、氷冷下で50分間攪拌した。反応液に、1,1'-カルボニルジイミダゾール(48.6 g, 300 mmol)を氷冷下で加えた後、DBU(66.7 mL, 442 mmol)を0℃で加え、80℃で1時間攪拌した。さらに、1,1'-カルボニルジイミダゾール(27.8 g, 171 mmol)、DBU(25.8 mL, 171 mmol)を加え、80℃で2時間攪拌した。反応液に2 mol/L 塩酸 (1.57 L)を20℃で加え、攪拌しながら氷(1 kg)を加えた。生じた粉末をろ取し、3-(2-シアノエチル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン(20.6 g, 収率: 31%)を肌色粉末として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 2.84 (2H, t, J=5.9 Hz), 4.02 (2H, t, J=5.9 Hz), 6.70-6.72 (1H, m), 8.04 (1H, m), 8.56-8.57 (1H, m).
Figure JPOXMLDOC01-appb-C000086

3-Aminopropanenitrile (20.0 g, 285 mmol) was dissolved in DMA (80 mL). Under ice cooling, 1,1′-carbonyldiimidazole (48.6 g, 300 mmol) and DBU (64.5 mL, 428 mmol) were slowly added to the reaction solution, followed by stirring at 0 ° C. for 30 minutes. 1-Amidinopyrazole hydrochloride (41.8 g, 235 mmol) and DBU (47.3 mL, 314 mmol) were added to the reaction solution, and the mixture was stirred for 50 minutes under ice cooling. 1,1′-carbonyldiimidazole (48.6 g, 300 mmol) was added to the reaction solution under ice cooling, then DBU (66.7 mL, 442 mmol) was added at 0 ° C., and the mixture was stirred at 80 ° C. for 1 hour. Furthermore, 1,1′-carbonyldiimidazole (27.8 g, 171 mmol) and DBU (25.8 mL, 171 mmol) were added, and the mixture was stirred at 80 ° C. for 2 hours. 2 mol / L hydrochloric acid (1.57 L) was added to the reaction solution at 20 ° C., and ice (1 kg) was added with stirring. The resulting powder was collected by filtration, and 3- (2-cyanoethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (20.6 g, yield: 31 %) As a flesh-colored powder.
1H-NMR (δ ppm TMS / DMSO-d6): 2.84 (2H, t, J = 5.9 Hz), 4.02 (2H, t, J = 5.9 Hz), 6.70-6.72 (1H, m), 8.04 (1H, m), 8.56-8.57 (1H, m).
(2)1-(4-クロロベンジル)-3-(2-シアノエチル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン (2) 1- (4-Chlorobenzyl) -3- (2-cyanoethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000087

3-(2-シアノエチル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン (10.0 g, 43.1 mmol) 、4-クロロベンジルブロミド (10.2 g, 49.5 mmol)をDMA (50 mL)に溶解した。反応液にジイソプロピルエチルアミン (8.65 mL, 49.5 mmol)を室温で滴下し、80℃で50分間攪拌した。ジイソプロピルエチルアミン (0.75 mL, 4.3 mmol)、4-クロロベンジルブロミド (0.89 g, 4.31 mmol)を加え、80℃で20分間攪拌した。反応液に氷冷下で水 (70 mL)をゆっくりと滴下した後、ヘキサン (20 mL)を加え、5分間攪拌した。生じた粉末をろ取し、1-(4-クロロベンジル)-3-(2-シアノエチル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン (12.8 g, 収率: 83.2%)を黄色粉末として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 2.87(2H, t, J=6.6 Hz), 4.06 (2H, t, J=6.6 Hz), 5.45 (2H, s), 6.62-6.63 (1H, m), 7.26-7.34 (4H, m), 7.97 (1H, m), 8.45 (1H, m).
Figure JPOXMLDOC01-appb-C000087

3- (2-cyanoethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (10.0 g, 43.1 mmol), 4-chlorobenzyl bromide (10.2 g 49.5 mmol) was dissolved in DMA (50 mL). Diisopropylethylamine (8.65 mL, 49.5 mmol) was added dropwise to the reaction solution at room temperature, and the mixture was stirred at 80 ° C. for 50 minutes. Diisopropylethylamine (0.75 mL, 4.3 mmol) and 4-chlorobenzyl bromide (0.89 g, 4.31 mmol) were added, and the mixture was stirred at 80 ° C. for 20 minutes. Water (70 mL) was slowly added dropwise to the reaction mixture under ice-cooling, hexane (20 mL) was added, and the mixture was stirred for 5 min. The resulting powder was collected by filtration, and 1- (4-chlorobenzyl) -3- (2-cyanoethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H)- Dione (12.8 g, yield: 83.2%) was obtained as a yellow powder.
1H-NMR (δ ppm TMS / DMSO-d6): 2.87 (2H, t, J = 6.6 Hz), 4.06 (2H, t, J = 6.6 Hz), 5.45 (2H, s), 6.62-6.63 (1H, m), 7.26-7.34 (4H, m), 7.97 (1H, m), 8.45 (1H, m).
(3)1-(4-クロロベンジル)-3-(2-シアノエチル)-6-[4-(4-ヒドロキシカルボニル-2-ピリジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-227)の調製 (3) 1- (4-Chlorobenzyl) -3- (2-cyanoethyl) -6- [4- (4-hydroxycarbonyl-2-pyridyloxy) phenylimino] -1,3,5-triazinan-2, Preparation of 4-dione (I-227)
Figure JPOXMLDOC01-appb-C000088

3-(2-シアノエチル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン (0.300 g, 0.841 mmol)、2-(4-アミノフェノキシ)イソニコチン酸 (0.194 g, 0.841 mmol)とt-ブタノール (4 mL)の混合液を加熱還流下で2時間攪拌した。反応液を高速液体クロマトグラフィー (0.3%ギ酸含有アセトニトリル/水)で精製し、1-(4-クロロベンジル)-3-(2-シアノエチル)-6-[4-(4-ヒドロキシカルボニル-2-ピリジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-227, 0.288 g, 収率: 66.0%)を無色粉末として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 2.87(2H, t, J=6.7 Hz), 4.03 (2H, t, J=6.7 Hz), 5.32 (2H, s), 7.19-7.57 (10H, m), 8.35-8.37 (1H, m), 9.46 (1H, s).
Figure JPOXMLDOC01-appb-C000088

3- (2-Cyanoethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (0.300 g, 0.841 mmol), 2- (4-aminophenoxy) A mixture of isonicotinic acid (0.194 g, 0.841 mmol) and t-butanol (4 mL) was stirred with heating under reflux for 2 hours. The reaction solution was purified by high performance liquid chromatography (acetonitrile / water containing 0.3% formic acid) to give 1- (4-chlorobenzyl) -3- (2-cyanoethyl) -6- [4- (4-hydroxycarbonyl-2- Pyridyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (I-227, 0.288 g, yield: 66.0%) was obtained as a colorless powder.
1H-NMR (δ ppm TMS / DMSO-d6): 2.87 (2H, t, J = 6.7 Hz), 4.03 (2H, t, J = 6.7 Hz), 5.32 (2H, s), 7.19-7.57 (10H, m), 8.35-8.37 (1H, m), 9.46 (1H, s).
1-(4-クロロベンジル)-6-[4-(6-テトラゾール-5-イル-2-ピリジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-350)の調製 1- (4-Chlorobenzyl) -6- [4- (6-tetrazol-5-yl-2-pyridyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (I-350) Preparation of
Figure JPOXMLDOC01-appb-C000089

 4-(6-シアノ-2-ピリジルオキシ)アニリン(2.00 g, 9.47 mmol)をDMA(20 mL)に溶解した。反応液にアジ化ナトリウム(6.16 g, 95 mmol)と塩化アンモニウム(5.07 g, 95 mmol)を加え、100℃で1時間攪拌した。反応液に5% クエン酸水溶液(100 mL)を加え、酢酸エチル(200 mL x 2)で抽出した。有機層を5% クエン酸水溶液(100 mL)と飽和食塩水(30 mL)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮し、4-(6-テトラゾール-5-イル-2-ピリジルオキシ)アニリン(1.53 g, 収率64%)を茶色粉末として得た。
 1-(4-クロロベンジル)-6(エチルチオ)-1,3,5-トリアジン-2,4(1H,3H)-ジオン(150 mg, 0.504 mmol)にt-ブタノール(3.0 mL)、4-(6-テトラゾール-5-イル-2-ピリジルオキシ)アニリン(192 mg, 0.756 mmol)と酢酸(0.864 mL, 15.11 mmol)を加え、14時間加熱還流した。反応液に5% クエン酸水溶液(20 mL)を加え、クロロホルム(50 mL x 3)で抽出した。有機層を飽和食塩水(20 mL)で洗浄し、無水硫酸ナトリウムで乾燥した。減圧濃縮し、残渣を高速液体クロマトグラフィー(0.3%ギ酸含有アセトニトリル/水)で精製し、1-(4-クロロベンジル)-6-[4-(6-テトラゾール-5-イル-2-ピリジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-350, 166 mg, 収率67%)を白色粉末として得た。
1H-NMR (DMSO-d6) δ: 5.18 (d, 2H, J = 74.0 Hz), 6.77-7.30 (m, 4H), 7.31-7.54 (m, 5H), 7.89-8.02 (m, 1H), 8.03-8.15 (m, 1H), 9.30 (s, 0.5H), 10.21 (s, 0.5H), 11.21 (d, 1H, J = 76.5 Hz).
Figure JPOXMLDOC01-appb-C000089

4- (6-Cyano-2-pyridyloxy) aniline (2.00 g, 9.47 mmol) was dissolved in DMA (20 mL). Sodium azide (6.16 g, 95 mmol) and ammonium chloride (5.07 g, 95 mmol) were added to the reaction mixture, and the mixture was stirred at 100 ° C. for 1 hr. To the reaction solution was added 5% aqueous citric acid solution (100 mL), and the mixture was extracted with ethyl acetate (200 mL x 2). The organic layer was washed with 5% aqueous citric acid solution (100 mL) and saturated brine (30 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 4- (6-tetrazol-5-yl-2-pyridyloxy) aniline (1.53 g, yield 64%) as a brown powder.
1- (4-Chlorobenzyl) -6 (ethylthio) -1,3,5-triazine-2,4 (1H, 3H) -dione (150 mg, 0.504 mmol) to t-butanol (3.0 mL), 4- (6-Tetrazol-5-yl-2-pyridyloxy) aniline (192 mg, 0.756 mmol) and acetic acid (0.864 mL, 15.11 mmol) were added, and the mixture was heated to reflux for 14 hours. To the reaction solution was added 5% aqueous citric acid solution (20 mL), and the mixture was extracted with chloroform (50 mL x 3). The organic layer was washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by high performance liquid chromatography (acetonitrile / water containing 0.3% formic acid) to give 1- (4-chlorobenzyl) -6- [4- (6-tetrazol-5-yl-2-pyridyloxy). ) Phenylimino] -1,3,5-triazinan-2,4-dione (I-350, 166 mg, 67% yield) was obtained as a white powder.
1 H-NMR (DMSO-d 6 ) δ: 5.18 (d, 2H, J = 74.0 Hz), 6.77-7.30 (m, 4H), 7.31-7.54 (m, 5H), 7.89-8.02 (m, 1H) , 8.03-8.15 (m, 1H), 9.30 (s, 0.5H), 10.21 (s, 0.5H), 11.21 (d, 1H, J = 76.5 Hz).
1-(4-クロロベンジル)-3-(3-ヒドロキシプロピル)-6-[4-(5-カルバモイル-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-358)の調製 1- (4-Chlorobenzyl) -3- (3-hydroxypropyl) -6- [4- (5-carbamoyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione ( I-358)
Figure JPOXMLDOC01-appb-C000090

 1-(4-クロロベンジル)-6-(エチルチオ)-3-(3-テトラヒドロピラン-2-イルオキシプロピル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン(528mg, 1.2 mol)、4-(5-メトキシカルボニル-2-ピラジルオキシ)アニリン (530 mg, 2.2 mmol)、酢酸 (1 mL)とt-ブタノール (3 ml) の混合液を、加熱還流下で終夜攪拌した。反応液に2 mol/L 塩酸水溶液 (1 ml) とメタノール (1 ml)を室温で加え、3時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液(50 mL)に加え、酢酸エチル(20 mL×2)で抽出した。有機層を無水硫酸ナトリウムで乾燥した。減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(ヘキサン/酢酸エチル)で精製した。ヘキサン/酢酸エチルを加え、生じた粉末をろ取して、1-(4-クロロベンジル)-3-(3-ヒドロキシプロピル)-6-[4-(5-メトキシカルボニル-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(451mg, 収率: 70 %)を無色粉末として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.68 (2H, ddd, J = 7.3 Hz, J =3.6 Hz, J =1.8 Hz), 3.43 (2H, q, J = 5.9 Hz), 3.79 (2H, t, J = 6.8 Hz), 4.44 (1H, t, J = 5.0 Hz), 5.29 (2H, s), 7.03-7.33 (2H, m), 7.33-7.52 (6H, m), 8.67 (1H, br s), 8.80 (1H, d, J = 1.3 Hz), 9.35 (0.7H, br s), 10.65 (0.3H, br s).
 1-(4-クロロベンジル)-3-(3-ヒドロキシプロピル)-6-[4-(5-メトキシカルボニル-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(326 mg, 0.61 mmol)のメタノール(4 ml)溶液に、氷冷下、28 % アンモニア水 (3.91 ml, 181 mmol) を加え、室温で3時間攪拌した。反応液を濃縮し、残渣にメタノールを加え、生じた粉末をろ取して、1-(4-クロロベンジル)-3-(3-ヒドロキシプロピル)-6-[4-(5-カルバモイル-2-ピラジルオキシ)フェニルイミノ]-1,3,5-トリアジナン-2,4-ジオン(I-358, 227mg, 収率: 72 %)を白色粉末として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.69 (2H, ddd, J = 7.2 Hz, J = 3.6 Hz, J = 1.8 Hz), 3.43 (2H, dd, J = 11.5 Hz, 6.3 Hz), 3.79 (2H, t, J = 6.9 Hz), 4.44 (1H, t, J = 5.1 Hz), 5.01-5.44 (2H, m), 6.72-7.32 (2.5H, m), 7.36-7.49 (5.5H, m), 7.71 (1H, s), 8.08 (1H, s), 8.43-8.65 (1H, m), 8.73 (1H, d, J = 1.5 Hz), 9.34 (0.6H, s), 10.64 (0.4H, s).
Figure JPOXMLDOC01-appb-C000090

1- (4-Chlorobenzyl) -6- (ethylthio) -3- (3-tetrahydropyran-2-yloxypropyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (528mg , 1.2 mol), 4- (5-methoxycarbonyl-2-pyrazyloxy) aniline (530 mg, 2.2 mmol), a mixture of acetic acid (1 mL) and t-butanol (3 ml), and stirred under heating overnight. did. 2 mol / L hydrochloric acid aqueous solution (1 ml) and methanol (1 ml) were added to the reaction solution at room temperature, and the mixture was stirred for 3 hours. To the reaction solution was added saturated aqueous sodium hydrogencarbonate (50 mL), and the mixture was extracted with ethyl acetate (20 mL × 2). The organic layer was dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (hexane / ethyl acetate). Hexane / ethyl acetate was added, and the resulting powder was collected by filtration to give 1- (4-chlorobenzyl) -3- (3-hydroxypropyl) -6- [4- (5-methoxycarbonyl-2-pyrazyloxy) phenyl. Imino] -1,3,5-triazinan-2,4-dione (451 mg, yield: 70%) was obtained as a colorless powder.
1H-NMR (δ ppm TMS / DMSO-d6): 1.68 (2H, ddd, J = 7.3 Hz, J = 3.6 Hz, J = 1.8 Hz), 3.43 (2H, q, J = 5.9 Hz), 3.79 (2H , t, J = 6.8 Hz), 4.44 (1H, t, J = 5.0 Hz), 5.29 (2H, s), 7.03-7.33 (2H, m), 7.33-7.52 (6H, m), 8.67 (1H, br s), 8.80 (1H, d, J = 1.3 Hz), 9.35 (0.7H, br s), 10.65 (0.3H, br s).
1- (4-Chlorobenzyl) -3- (3-hydroxypropyl) -6- [4- (5-methoxycarbonyl-2-pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione To a methanol (4 ml) solution of (326 mg, 0.61 mmol), 28% aqueous ammonia (3.91 ml, 181 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, methanol was added to the residue, and the resulting powder was collected by filtration to give 1- (4-chlorobenzyl) -3- (3-hydroxypropyl) -6- [4- (5-carbamoyl-2 -Pyrazyloxy) phenylimino] -1,3,5-triazinan-2,4-dione (I-358, 227 mg, yield: 72%) was obtained as a white powder.
1H-NMR (δ ppm TMS / DMSO-d6): 1.69 (2H, ddd, J = 7.2 Hz, J = 3.6 Hz, J = 1.8 Hz), 3.43 (2H, dd, J = 11.5 Hz, 6.3 Hz), 3.79 (2H, t, J = 6.9 Hz), 4.44 (1H, t, J = 5.1 Hz), 5.01-5.44 (2H, m), 6.72-7.32 (2.5H, m), 7.36-7.49 (5.5H, m), 7.71 (1H, s), 8.08 (1H, s), 8.43-8.65 (1H, m), 8.73 (1H, d, J = 1.5 Hz), 9.34 (0.6H, s), 10.64 (0.4H , s).
(1)(S)-3-(2-メトキシカルボニルエチル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオンの調製 (1) Preparation of (S) -3- (2-methoxycarbonylethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione
Figure JPOXMLDOC01-appb-C000091

 1-アミジノピラゾール塩酸塩 (5.68 g, 38.7 mmol)、(S)-メチル-2-イソシアナトプロパノエート(5 g, 38.7 mmol)をDMA(40 mL)に溶解した。反応液にDBU(5.84 ml, 38.7 mmol)を0℃で15分間かけて滴下した。氷冷下で30分間攪拌した後、45℃で3時間攪拌した。反応液に1,1'-カルボニルジイミダゾール(6.28 g, 38.7 mmol)を氷冷下で加え、DBU(8.76 ml, 58.1 mmol)を-5℃で30分間かけて加えた。氷冷下で2時間攪拌した後、室温で1時間攪拌した。反応液に2 mol/L 塩酸 を20℃で1時間かけて加え、pHを2~3に調製した後、酢酸エチル(200 mL×2)で抽出した。有機層を飽和食塩水(300ml)で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮し、(S)-3-(2-メトキシカルボニルエチル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン (3.59 g, 収率: 35%)を黄褐色油状物として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.45 (3H, d, J=7.0 Hz), 3.61 (3H, s), 5.30 (1H, q, J=6.9Hz), 6.73 (1H, m), 8.07 (1H, m), 8.57 (1H, m).
Figure JPOXMLDOC01-appb-C000091

1-Amidinopyrazole hydrochloride (5.68 g, 38.7 mmol) and (S) -methyl-2-isocyanatopropanoate (5 g, 38.7 mmol) were dissolved in DMA (40 mL). DBU (5.84 ml, 38.7 mmol) was added dropwise to the reaction solution at 0 ° C. over 15 minutes. The mixture was stirred for 30 minutes under ice cooling, and then stirred at 45 ° C. for 3 hours. To the reaction solution, 1,1′-carbonyldiimidazole (6.28 g, 38.7 mmol) was added under ice cooling, and DBU (8.76 ml, 58.1 mmol) was added at −5 ° C. over 30 minutes. After stirring for 2 hours under ice-cooling, the mixture was stirred for 1 hour at room temperature. 2 mol / L hydrochloric acid was added to the reaction solution at 20 ° C. over 1 hour to adjust the pH to 2-3, followed by extraction with ethyl acetate (200 mL × 2). The organic layer was washed with saturated brine (300 ml) and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure to give (S) -3- (2-methoxycarbonylethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (3.59 g, yield) : 35%) as a tan oil.
1H-NMR (δ ppm TMS / DMSO-d6): 1.45 (3H, d, J = 7.0 Hz), 3.61 (3H, s), 5.30 (1H, q, J = 6.9 Hz), 6.73 (1H, m) , 8.07 (1H, m), 8.57 (1H, m).
(2)(S)1-(4-クロロベンジル)-3-(2-メトキシカルボニルエチル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオンの調製 (2) (S) 1- (4-Chlorobenzyl) -3- (2-methoxycarbonylethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H)- Preparation of dione
Figure JPOXMLDOC01-appb-C000092

 (S)-3-(2-メトキシカルボニルエチル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン (3.3 g, 12.5 mmol) 、4-クロロベンジルブロミド (2.83 g, 13.8 mmol)をDMA (15 mL)に溶解した。反応液にジイソプロピルエチルアミン (2.4 mL, 13.8 mmol)を室温で10分間かけて滴下し、55℃で1時間攪拌した。反応液に氷冷下、水 (50 mL)を加え、酢酸エチル (100 mL×2)で抽出した。有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。減圧濃縮し、(S)1-(4-クロロベンジル)-3-(2-メトキシカルボニルエチル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオンを(4.88 g, 収率: 100% )で黄褐色油状物として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.48 (3H, d, J=6.9 Hz), 3.61 (3H, s), 5.35 (1H, q, J=6.9 Hz), 5.48 (2H, s), 6.66 (1H, m), 7.23 (2H, d, J=8.5 Hz), 7.39 (2H, d, J=8.5 Hz), 7.98 (1H, m), 8.49 (1H, m).
(3)(S)-1-(4-クロロベンジル)-6-[4-(3-イソオキサゾリルオキシ)フェニルイミノ]-3-(1-ヒドロキシ-2-プロピル)-1,3,5-トリアジナン-2-オン(I-001)の調製
Figure JPOXMLDOC01-appb-C000092

(S) -3- (2-methoxycarbonylethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione (3.3 g, 12.5 mmol), 4- Chlorobenzyl bromide (2.83 g, 13.8 mmol) was dissolved in DMA (15 mL). Diisopropylethylamine (2.4 mL, 13.8 mmol) was added dropwise to the reaction solution at room temperature over 10 minutes, and the mixture was stirred at 55 ° C. for 1 hour. Water (50 mL) was added to the reaction solution under ice-cooling, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. Concentrate under reduced pressure, and (S) 1- (4-chlorobenzyl) -3- (2-methoxycarbonylethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -Dione (4.88 g, yield: 100%) was obtained as a tan oil.
1H-NMR (δ ppm TMS / DMSO-d6): 1.48 (3H, d, J = 6.9 Hz), 3.61 (3H, s), 5.35 (1H, q, J = 6.9 Hz), 5.48 (2H, s) , 6.66 (1H, m), 7.23 (2H, d, J = 8.5 Hz), 7.39 (2H, d, J = 8.5 Hz), 7.98 (1H, m), 8.49 (1H, m).
(3) (S) -1- (4-Chlorobenzyl) -6- [4- (3-isoxazolyloxy) phenylimino] -3- (1-hydroxy-2-propyl) -1,3, Preparation of 5-triazinan-2-one (I-001)
Figure JPOXMLDOC01-appb-C000093

 (S)-1-(4-クロロベンジル)-3-(2-メトキシカルボニルエチル)-6-(1-ピラゾリル)-1,3,5-トリアジン-2,4(1H,3H)-ジオン (1.17 g, 3 mmol)、4-(3-イソオキサゾリルオキシ)アニリン(0.529 g, 3 mmol)とt-ブタノール (6 mL)の混合液を120℃で0.5時間攪拌した。反応液を減圧濃縮し、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/ヘキサン)で精製し、(S)-1-(4-クロロベンジル)-6-[4-(イソオキサゾリルオキシ)フェニルイミノ]-3-(2-メトキシカルボニルエチル)-1,3,5-トリアジナン-2,4-ジオン (0.669 g, 収率: 45%)を無色油状物として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.43 (3H, d, J = 7.1 Hz), 3.59 (3H, s), 5.18-5.32 (3H, m), 6.46 (1H, s), 7.24 (2H, d, J = 8.1 Hz), 7.32-7.40 (4H, m), 7.46 (2H, d, J = 8.1 Hz), 8.82 (2H, d, J = 1.5 Hz).
(S)-1-(4-クロロベンジル)-6-[4-(イソオキサゾリルオキシ)フェニルイミノ]-3-(2-メトキシカルボニルエチル)-1,3,5-トリアジナン-2,4-ジオン (0.25 g, 0.5 mmol)をTHF (2.4 mL)に溶解した。反応液に水素化アルミニウムリチウム (26.7 mg, 0.703 mmol) を氷冷下で加え、室温で1時間攪拌した。反応液に飽和塩化アンモニウム水溶液 (1 ml)、 2 mol/L塩酸水溶液 (1 ml)、酢酸エチル (5 ml)を加え、室温で1時間攪拌した。有機層を食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。減圧濃縮し、残渣を酢酸エチルで洗浄し(S)-1-(4-クロロベンジル)-6-[4-(3-イソオキサゾリルオキシ)フェニルイミノ]-3-(1-ヒドロキシ-2-プロピル)-1,3,5-トリアジナン-2-オンを(I-001, 21 mg, 収率: 9 % ) 白色粉末として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 1.11 (3H, d, J=6.9 Hz), 3.44 (1H, m, J=5.5 Hz), 4.18 (1H, m, J=6.7 Hz, J=6.1 Hz), 4.60 (2H, s), 5.21 (2H, s), 6.49 (1H, s), 7.16-7.57 (8H, m). 8.85 (1H, d, J=1.5 Hz), 9.9 (0.3H, m), 11.2 (0.7H, m).
Figure JPOXMLDOC01-appb-C000093

(S) -1- (4-Chlorobenzyl) -3- (2-methoxycarbonylethyl) -6- (1-pyrazolyl) -1,3,5-triazine-2,4 (1H, 3H) -dione ( 1.17 g, 3 mmol), a mixture of 4- (3-isoxazolyloxy) aniline (0.529 g, 3 mmol) and t-butanol (6 mL) was stirred at 120 ° C. for 0.5 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give (S) -1- (4-chlorobenzyl) -6- [4- (isoxazolyloxy) phenylimino. ] -3- (2-methoxycarbonylethyl) -1,3,5-triazinan-2,4-dione (0.669 g, yield: 45%) was obtained as a colorless oil.
1H-NMR (δ ppm TMS / DMSO-d6): 1.43 (3H, d, J = 7.1 Hz), 3.59 (3H, s), 5.18-5.32 (3H, m), 6.46 (1H, s), 7.24 ( 2H, d, J = 8.1 Hz), 7.32-7.40 (4H, m), 7.46 (2H, d, J = 8.1 Hz), 8.82 (2H, d, J = 1.5 Hz).
(S) -1- (4-Chlorobenzyl) -6- [4- (isoxazolyloxy) phenylimino] -3- (2-methoxycarbonylethyl) -1,3,5-triazinan-2,4 -Dione (0.25 g, 0.5 mmol) was dissolved in THF (2.4 mL). Lithium aluminum hydride (26.7 mg, 0.703 mmol) was added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution (1 ml), 2 mol / L aqueous hydrochloric acid solution (1 ml) and ethyl acetate (5 ml) were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The organic layer was washed with brine and then dried over anhydrous magnesium sulfate. Concentrate under reduced pressure and wash the residue with ethyl acetate (S) -1- (4-chlorobenzyl) -6- [4- (3-isoxazolyloxy) phenylimino] -3- (1-hydroxy-2 -Propyl) -1,3,5-triazinan-2-one was obtained as a white powder (I-001, 21 mg, yield: 9%).
1H-NMR (δ ppm TMS / DMSO-d6): 1.11 (3H, d, J = 6.9 Hz), 3.44 (1H, m, J = 5.5 Hz), 4.18 (1H, m, J = 6.7 Hz, J = 6.1 Hz), 4.60 (2H, s), 5.21 (2H, s), 6.49 (1H, s), 7.16-7.57 (8H, m). 8.85 (1H, d, J = 1.5 Hz), 9.9 (0.3H , m), 11.2 (0.7H, m).
 上記の一般的製造法および実施例に記載の方法に準じて以下の本発明化合物を得た。構造および物性を以下に示す。
 (化合物の同定方法)
 本発明の化合物のLC/MSデータは、以下の5つの条件(メソッド1~5)のいずれかで測定し、保持時間(分)および[M+H]を示した。
 (メソッド1)
カラム:Luna C18(2) (5μm、i.d.4.6x50mm)(Phenomenex)
流速:3 mL/分
UV検出波長:254nm
移動相:[A]は0.1%ギ酸含有水溶液、[B]は0.1%ギ酸含有アセトニトリル溶液
グラジェント:3分間で10%-100%溶媒[B]のリニアグラジエントを行い、1分間、100%溶媒[B]を維持した。
 (メソッド2)
カラム:Xbridge C18(5μm、i.d.4.6x50mm)(Waters)
流速:3 mL/分
UV検出波長:254nm
移動相:[A]は0.1%ギ酸含有水溶液、[B]は0.1%ギ酸含有アセトニトリル溶液
グラジェント:3分間で10%-100%溶媒[B]のリニアグラジエントを行い、1分間、100%溶媒[B]を維持した。
 (メソッド3)
カラム:Shim-pack XR-ODS (2.2μm、i.d.50x3.0mm) (Shimadzu)
流速:1.6 mL/分
UV検出波長:254nm
移動相:[A]は0.1%ギ酸含有水溶液、[B]は0.1%ギ酸含有アセトニトリル溶液
グラジェント:3分間で10%-100%溶媒[B]のリニアグラジエントを行い、1分間、100%溶媒[B]を維持した。
 (メソッド4)
カラム:Develosil RPAq, (50x4.6mm)
流速:1.5 mL/分
UV検出波長:254nm
移動相:[A]は0.1%ギ酸含有水溶液、[B]は0.1%ギ酸含有アセトニトリル溶液
 0.5分間60%溶媒[B]を維持し、4.5分間60%-100%溶媒[B]のリニアグラジエントを行い、1.0分間、100%溶媒[B]を維持した。
 (メソッド5)
カラム:ACQUITY UPLC(登録商標)BEH C18 (1.7μm i.d.2.1x50mm) 
流速:0.8 mL/分
UV検出波長:254nm
移動相:[A]は0.1%ギ酸含有水溶液、[B]は0.1%ギ酸含有アセトニトリル溶液
 3.5分間で10%-100%溶媒[B]のリニアグラジエントを行い、0.5分間、100%溶媒[B]を維持した。
 (メソッド6)
カラム:Shim-pack XR-ODS (2.2μm、i.d.50x3.0mm) (Shimadzu)
流速:1.6 mL/分
UV検出波長:254nm
移動相:[A]は0.1%ギ酸含有水溶液、[B]は0.1%ギ酸含有アセトニトリル溶液
グラジェント:3分間で10%-50%溶媒[B]のリニアグラジエントを行い、1分間、50%溶媒[B]を維持した。
The following compounds of the present invention were obtained according to the above general production methods and the methods described in Examples. The structure and physical properties are shown below.
(Compound identification method)
The LC / MS data of the compound of the present invention was measured under any of the following five conditions (Methods 1 to 5), and showed the retention time (minutes) and [M + H] + .
(Method 1)
Column: Luna C18 (2) (5 μm, id 4.6 × 50 mm) (Phenomenex)
Flow rate: 3 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, [B] is 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 10% -100% solvent [B] in 3 minutes, 1 minute 100% solvent [B] was maintained.
(Method 2)
Column: Xbridge C18 (5 μm, id 4.6 × 50 mm) (Waters)
Flow rate: 3 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, [B] is 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 10% -100% solvent [B] in 3 minutes, 1 minute 100% solvent [B] was maintained.
(Method 3)
Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu)
Flow rate: 1.6 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, [B] is 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 10% -100% solvent [B] in 3 minutes, 1 minute 100% solvent [B] was maintained.
(Method 4)
Column: Develosil RPAq, (50 x 4.6 mm)
Flow rate: 1.5 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is an aqueous solution containing 0.1% formic acid, [B] is an acetonitrile solution containing 0.1% formic acid, and the 60% solvent [B] is maintained for 0.5 minutes, and 60% -100% for 4.5 minutes. A linear gradient of solvent [B] was performed and 100% solvent [B] was maintained for 1.0 minute.
(Method 5)
Column: ACQUITY UPLC® BEH C18 (1.7 μm id 2.1 × 50 mm)
Flow rate: 0.8 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution, and a linear gradient of 10% -100% solvent [B] is performed for 3.5 minutes. 100% solvent [B] was maintained for minutes.
(Method 6)
Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu)
Flow rate: 1.6 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is a 0.1% formic acid-containing aqueous solution, [B] is a 0.1% formic acid-containing acetonitrile solution Gradient: linear gradient of 10% -50% solvent [B] in 3 minutes, 1 minute , 50% solvent [B] was maintained.
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000094
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000095
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000096
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000097
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000102
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000103
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000104
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000105
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000106
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000107
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000108
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000109
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000110
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000111
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000112
Figure JPOXMLDOC01-appb-T000113
Figure JPOXMLDOC01-appb-T000113
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-T000114
Figure JPOXMLDOC01-appb-T000115
Figure JPOXMLDOC01-appb-T000115
Figure JPOXMLDOC01-appb-T000116
Figure JPOXMLDOC01-appb-T000116
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000117
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000118
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000119
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000120
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000121
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000122
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000123
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000124
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000125
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000126
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000127
Figure JPOXMLDOC01-appb-T000128
Figure JPOXMLDOC01-appb-T000128
Figure JPOXMLDOC01-appb-T000129
Figure JPOXMLDOC01-appb-T000129
Figure JPOXMLDOC01-appb-T000130
Figure JPOXMLDOC01-appb-T000130
Figure JPOXMLDOC01-appb-T000131
Figure JPOXMLDOC01-appb-T000131
Figure JPOXMLDOC01-appb-T000132
Figure JPOXMLDOC01-appb-T000132
Figure JPOXMLDOC01-appb-T000133
Figure JPOXMLDOC01-appb-T000133
Figure JPOXMLDOC01-appb-T000134
Figure JPOXMLDOC01-appb-T000134
Figure JPOXMLDOC01-appb-T000135
Figure JPOXMLDOC01-appb-T000135
Figure JPOXMLDOC01-appb-T000136
Figure JPOXMLDOC01-appb-T000136
Figure JPOXMLDOC01-appb-T000137
Figure JPOXMLDOC01-appb-T000137
Figure JPOXMLDOC01-appb-T000138
Figure JPOXMLDOC01-appb-T000138
Figure JPOXMLDOC01-appb-T000139
Figure JPOXMLDOC01-appb-T000139
Figure JPOXMLDOC01-appb-T000140
Figure JPOXMLDOC01-appb-T000140
Figure JPOXMLDOC01-appb-T000141
Figure JPOXMLDOC01-appb-T000141
Figure JPOXMLDOC01-appb-T000142
Figure JPOXMLDOC01-appb-T000142
Figure JPOXMLDOC01-appb-T000144
Figure JPOXMLDOC01-appb-T000144
Figure JPOXMLDOC01-appb-T000145
Figure JPOXMLDOC01-appb-T000145
Figure JPOXMLDOC01-appb-T000146
Figure JPOXMLDOC01-appb-T000146
Figure JPOXMLDOC01-appb-T000147
Figure JPOXMLDOC01-appb-T000147
Figure JPOXMLDOC01-appb-T000148
Figure JPOXMLDOC01-appb-T000148
Figure JPOXMLDOC01-appb-T000149
Figure JPOXMLDOC01-appb-T000149
Figure JPOXMLDOC01-appb-T000150
Figure JPOXMLDOC01-appb-T000150
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000151
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000152
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000153
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000154
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000155
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000156
Figure JPOXMLDOC01-appb-T000157
Figure JPOXMLDOC01-appb-T000157
Figure JPOXMLDOC01-appb-T000158
Figure JPOXMLDOC01-appb-T000158
Figure JPOXMLDOC01-appb-T000159
Figure JPOXMLDOC01-appb-T000159
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000160
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000161
Figure JPOXMLDOC01-appb-T000162
Figure JPOXMLDOC01-appb-T000162
Figure JPOXMLDOC01-appb-T000163
Figure JPOXMLDOC01-appb-T000163
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000164
Figure JPOXMLDOC01-appb-T000165
Figure JPOXMLDOC01-appb-T000165
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000166
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000167
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000168
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000169
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000171
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000172
Figure JPOXMLDOC01-appb-T000173
Figure JPOXMLDOC01-appb-T000173
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000174
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000175
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000176
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000177
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000178
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000179
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000180
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000181
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000182
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000183
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000184
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000185
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000186
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000187
Figure JPOXMLDOC01-appb-T000188
Figure JPOXMLDOC01-appb-T000188
Figure JPOXMLDOC01-appb-T000189
Figure JPOXMLDOC01-appb-T000189
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000190
Figure JPOXMLDOC01-appb-T000191
Figure JPOXMLDOC01-appb-T000191
Figure JPOXMLDOC01-appb-T000192
Figure JPOXMLDOC01-appb-T000192
Figure JPOXMLDOC01-appb-T000193
Figure JPOXMLDOC01-appb-T000193
Figure JPOXMLDOC01-appb-T000194
Figure JPOXMLDOC01-appb-T000194
Figure JPOXMLDOC01-appb-T000195
Figure JPOXMLDOC01-appb-T000195
Figure JPOXMLDOC01-appb-T000196
Figure JPOXMLDOC01-appb-T000196
Figure JPOXMLDOC01-appb-T000197
Figure JPOXMLDOC01-appb-T000197
Figure JPOXMLDOC01-appb-T000198
Figure JPOXMLDOC01-appb-T000198
Figure JPOXMLDOC01-appb-T000199
Figure JPOXMLDOC01-appb-T000199
Figure JPOXMLDOC01-appb-T000200
Figure JPOXMLDOC01-appb-T000200
Figure JPOXMLDOC01-appb-T000201
Figure JPOXMLDOC01-appb-T000201
Figure JPOXMLDOC01-appb-T000202
Figure JPOXMLDOC01-appb-T000202
Figure JPOXMLDOC01-appb-T000203
Figure JPOXMLDOC01-appb-T000203
Figure JPOXMLDOC01-appb-T000204
Figure JPOXMLDOC01-appb-T000204
Figure JPOXMLDOC01-appb-T000205
Figure JPOXMLDOC01-appb-T000205
Figure JPOXMLDOC01-appb-T000206
Figure JPOXMLDOC01-appb-T000206
Figure JPOXMLDOC01-appb-T000207
Figure JPOXMLDOC01-appb-T000207
Figure JPOXMLDOC01-appb-T000208
Figure JPOXMLDOC01-appb-T000208
Figure JPOXMLDOC01-appb-T000209
Figure JPOXMLDOC01-appb-T000209
Figure JPOXMLDOC01-appb-T000210
Figure JPOXMLDOC01-appb-T000210
Figure JPOXMLDOC01-appb-T000211
Figure JPOXMLDOC01-appb-T000211
Figure JPOXMLDOC01-appb-T000212
Figure JPOXMLDOC01-appb-T000212
Figure JPOXMLDOC01-appb-T000213
Figure JPOXMLDOC01-appb-T000213
Figure JPOXMLDOC01-appb-T000214
Figure JPOXMLDOC01-appb-T000214
Figure JPOXMLDOC01-appb-T000215
Figure JPOXMLDOC01-appb-T000215
Figure JPOXMLDOC01-appb-T000216
Figure JPOXMLDOC01-appb-T000216
Figure JPOXMLDOC01-appb-T000217
Figure JPOXMLDOC01-appb-T000217
Figure JPOXMLDOC01-appb-T000218
Figure JPOXMLDOC01-appb-T000218
Figure JPOXMLDOC01-appb-T000219
Figure JPOXMLDOC01-appb-T000219
Figure JPOXMLDOC01-appb-T000220
Figure JPOXMLDOC01-appb-T000220
Figure JPOXMLDOC01-appb-T000221
Figure JPOXMLDOC01-appb-T000221
Figure JPOXMLDOC01-appb-T000222
Figure JPOXMLDOC01-appb-T000222
Figure JPOXMLDOC01-appb-T000223
Figure JPOXMLDOC01-appb-T000223
Figure JPOXMLDOC01-appb-T000224
Figure JPOXMLDOC01-appb-T000224
Figure JPOXMLDOC01-appb-T000225
Figure JPOXMLDOC01-appb-T000225
Figure JPOXMLDOC01-appb-T000226
Figure JPOXMLDOC01-appb-T000226
Figure JPOXMLDOC01-appb-T000227
Figure JPOXMLDOC01-appb-T000227
Figure JPOXMLDOC01-appb-T000228
Figure JPOXMLDOC01-appb-T000228
Figure JPOXMLDOC01-appb-T000229
Figure JPOXMLDOC01-appb-T000229
Figure JPOXMLDOC01-appb-T000230
Figure JPOXMLDOC01-appb-T000230
Figure JPOXMLDOC01-appb-T000231
Figure JPOXMLDOC01-appb-T000231
Figure JPOXMLDOC01-appb-T000232
Figure JPOXMLDOC01-appb-T000232
Figure JPOXMLDOC01-appb-T000233
Figure JPOXMLDOC01-appb-T000233
Figure JPOXMLDOC01-appb-T000234
Figure JPOXMLDOC01-appb-T000234
Figure JPOXMLDOC01-appb-T000235
Figure JPOXMLDOC01-appb-T000235
Figure JPOXMLDOC01-appb-T000236
Figure JPOXMLDOC01-appb-T000236
Figure JPOXMLDOC01-appb-T000237
Figure JPOXMLDOC01-appb-T000237
Figure JPOXMLDOC01-appb-T000238
Figure JPOXMLDOC01-appb-T000238
Figure JPOXMLDOC01-appb-T000239
Figure JPOXMLDOC01-appb-T000239
Figure JPOXMLDOC01-appb-T000240
Figure JPOXMLDOC01-appb-T000240
Figure JPOXMLDOC01-appb-T000241
Figure JPOXMLDOC01-appb-T000241
Figure JPOXMLDOC01-appb-T000242
Figure JPOXMLDOC01-appb-T000242
Figure JPOXMLDOC01-appb-T000243
Figure JPOXMLDOC01-appb-T000243
Figure JPOXMLDOC01-appb-T000244
Figure JPOXMLDOC01-appb-T000244
Figure JPOXMLDOC01-appb-T000245
Figure JPOXMLDOC01-appb-T000245
Figure JPOXMLDOC01-appb-T000246
Figure JPOXMLDOC01-appb-T000246
Figure JPOXMLDOC01-appb-T000247
Figure JPOXMLDOC01-appb-T000247
Figure JPOXMLDOC01-appb-T000248
Figure JPOXMLDOC01-appb-T000248
Figure JPOXMLDOC01-appb-T000249
Figure JPOXMLDOC01-appb-T000249
Figure JPOXMLDOC01-appb-T000250
Figure JPOXMLDOC01-appb-T000250
Figure JPOXMLDOC01-appb-T000251
Figure JPOXMLDOC01-appb-T000251
Figure JPOXMLDOC01-appb-T000252
Figure JPOXMLDOC01-appb-T000252
Figure JPOXMLDOC01-appb-T000253
Figure JPOXMLDOC01-appb-T000253
Figure JPOXMLDOC01-appb-T000254
Figure JPOXMLDOC01-appb-T000254
Figure JPOXMLDOC01-appb-T000255
Figure JPOXMLDOC01-appb-T000255
Figure JPOXMLDOC01-appb-T000256
Figure JPOXMLDOC01-appb-T000256
Figure JPOXMLDOC01-appb-T000257
Figure JPOXMLDOC01-appb-T000257
Figure JPOXMLDOC01-appb-T000258
Figure JPOXMLDOC01-appb-T000258
Figure JPOXMLDOC01-appb-T000259
Figure JPOXMLDOC01-appb-T000259
Figure JPOXMLDOC01-appb-T000260
Figure JPOXMLDOC01-appb-T000260
Figure JPOXMLDOC01-appb-T000261
Figure JPOXMLDOC01-appb-T000261
Figure JPOXMLDOC01-appb-T000262
Figure JPOXMLDOC01-appb-T000262
Figure JPOXMLDOC01-appb-T000263
Figure JPOXMLDOC01-appb-T000263
Figure JPOXMLDOC01-appb-T000264
Figure JPOXMLDOC01-appb-T000264
Figure JPOXMLDOC01-appb-T000265
Figure JPOXMLDOC01-appb-T000265
Figure JPOXMLDOC01-appb-T000266
Figure JPOXMLDOC01-appb-T000266
Figure JPOXMLDOC01-appb-T000267
Figure JPOXMLDOC01-appb-T000267
Figure JPOXMLDOC01-appb-T000268
Figure JPOXMLDOC01-appb-T000268
Figure JPOXMLDOC01-appb-T000269
Figure JPOXMLDOC01-appb-T000269
Figure JPOXMLDOC01-appb-T000270
Figure JPOXMLDOC01-appb-T000270
Figure JPOXMLDOC01-appb-T000271
Figure JPOXMLDOC01-appb-T000271
Figure JPOXMLDOC01-appb-T000272
Figure JPOXMLDOC01-appb-T000272
Figure JPOXMLDOC01-appb-T000273
Figure JPOXMLDOC01-appb-T000273
Figure JPOXMLDOC01-appb-T000274
Figure JPOXMLDOC01-appb-T000274
Figure JPOXMLDOC01-appb-T000275
Figure JPOXMLDOC01-appb-T000275
Figure JPOXMLDOC01-appb-T000276
Figure JPOXMLDOC01-appb-T000276
Figure JPOXMLDOC01-appb-T000277
Figure JPOXMLDOC01-appb-T000277
Figure JPOXMLDOC01-appb-T000278
Figure JPOXMLDOC01-appb-T000278
Figure JPOXMLDOC01-appb-T000279
Figure JPOXMLDOC01-appb-T000279
Figure JPOXMLDOC01-appb-T000280
Figure JPOXMLDOC01-appb-T000280
Figure JPOXMLDOC01-appb-T000281
Figure JPOXMLDOC01-appb-T000281
Figure JPOXMLDOC01-appb-T000282
Figure JPOXMLDOC01-appb-T000282
Figure JPOXMLDOC01-appb-T000283
Figure JPOXMLDOC01-appb-T000283
Figure JPOXMLDOC01-appb-T000284
Figure JPOXMLDOC01-appb-T000284
Figure JPOXMLDOC01-appb-T000285
Figure JPOXMLDOC01-appb-T000285
Figure JPOXMLDOC01-appb-T000286
Figure JPOXMLDOC01-appb-T000286
Figure JPOXMLDOC01-appb-T000287
Figure JPOXMLDOC01-appb-T000287
Figure JPOXMLDOC01-appb-T000288
Figure JPOXMLDOC01-appb-T000288
Figure JPOXMLDOC01-appb-T000289
Figure JPOXMLDOC01-appb-T000289
Figure JPOXMLDOC01-appb-T000290
Figure JPOXMLDOC01-appb-T000290
Figure JPOXMLDOC01-appb-T000291
Figure JPOXMLDOC01-appb-T000291
Figure JPOXMLDOC01-appb-T000292
Figure JPOXMLDOC01-appb-T000292
Figure JPOXMLDOC01-appb-T000293
Figure JPOXMLDOC01-appb-T000293
Figure JPOXMLDOC01-appb-T000294
Figure JPOXMLDOC01-appb-T000294
Figure JPOXMLDOC01-appb-T000295
Figure JPOXMLDOC01-appb-T000295
Figure JPOXMLDOC01-appb-T000296
Figure JPOXMLDOC01-appb-T000296
Figure JPOXMLDOC01-appb-T000297
Figure JPOXMLDOC01-appb-T000297
Figure JPOXMLDOC01-appb-T000298
Figure JPOXMLDOC01-appb-T000298
Figure JPOXMLDOC01-appb-T000299
Figure JPOXMLDOC01-appb-T000299
Figure JPOXMLDOC01-appb-T000300
Figure JPOXMLDOC01-appb-T000300
Figure JPOXMLDOC01-appb-T000301
Figure JPOXMLDOC01-appb-T000301
Figure JPOXMLDOC01-appb-T000302
Figure JPOXMLDOC01-appb-T000302
Figure JPOXMLDOC01-appb-T000303
Figure JPOXMLDOC01-appb-T000303
Figure JPOXMLDOC01-appb-T000304
Figure JPOXMLDOC01-appb-T000304
Figure JPOXMLDOC01-appb-T000305
Figure JPOXMLDOC01-appb-T000305
Figure JPOXMLDOC01-appb-T000306
Figure JPOXMLDOC01-appb-T000306
Figure JPOXMLDOC01-appb-T000307
Figure JPOXMLDOC01-appb-T000307
Figure JPOXMLDOC01-appb-T000308
Figure JPOXMLDOC01-appb-T000308
Figure JPOXMLDOC01-appb-T000309
Figure JPOXMLDOC01-appb-T000309
Figure JPOXMLDOC01-appb-T000310
Figure JPOXMLDOC01-appb-T000310
Figure JPOXMLDOC01-appb-T000311
Figure JPOXMLDOC01-appb-T000311
Figure JPOXMLDOC01-appb-T000312
Figure JPOXMLDOC01-appb-T000312
Figure JPOXMLDOC01-appb-T000313
Figure JPOXMLDOC01-appb-T000313
Figure JPOXMLDOC01-appb-T000314
Figure JPOXMLDOC01-appb-T000314
Figure JPOXMLDOC01-appb-T000315
Figure JPOXMLDOC01-appb-T000315
Figure JPOXMLDOC01-appb-T000316
Figure JPOXMLDOC01-appb-T000316
Figure JPOXMLDOC01-appb-T000317
Figure JPOXMLDOC01-appb-T000317
Figure JPOXMLDOC01-appb-T000318
Figure JPOXMLDOC01-appb-T000318
Figure JPOXMLDOC01-appb-T000319
Figure JPOXMLDOC01-appb-T000319
Figure JPOXMLDOC01-appb-T000320
Figure JPOXMLDOC01-appb-T000320
Figure JPOXMLDOC01-appb-T000321
Figure JPOXMLDOC01-appb-T000321
Figure JPOXMLDOC01-appb-T000322
Figure JPOXMLDOC01-appb-T000322
Figure JPOXMLDOC01-appb-T000323
Figure JPOXMLDOC01-appb-T000323
Figure JPOXMLDOC01-appb-T000324
Figure JPOXMLDOC01-appb-T000324
Figure JPOXMLDOC01-appb-T000325
Figure JPOXMLDOC01-appb-T000325
Figure JPOXMLDOC01-appb-T000326
Figure JPOXMLDOC01-appb-T000326
Figure JPOXMLDOC01-appb-T000327
Figure JPOXMLDOC01-appb-T000327
Figure JPOXMLDOC01-appb-T000328
Figure JPOXMLDOC01-appb-T000328
Figure JPOXMLDOC01-appb-T000329
Figure JPOXMLDOC01-appb-T000329
Figure JPOXMLDOC01-appb-T000330
Figure JPOXMLDOC01-appb-T000330
Figure JPOXMLDOC01-appb-T000331
Figure JPOXMLDOC01-appb-T000331
Figure JPOXMLDOC01-appb-T000332
Figure JPOXMLDOC01-appb-T000332
Figure JPOXMLDOC01-appb-T000333
Figure JPOXMLDOC01-appb-T000333
Figure JPOXMLDOC01-appb-T000334
Figure JPOXMLDOC01-appb-T000334
Figure JPOXMLDOC01-appb-T000335
Figure JPOXMLDOC01-appb-T000335
Figure JPOXMLDOC01-appb-T000336
Figure JPOXMLDOC01-appb-T000336
Figure JPOXMLDOC01-appb-T000337
Figure JPOXMLDOC01-appb-T000337
Figure JPOXMLDOC01-appb-T000338
Figure JPOXMLDOC01-appb-T000338
Figure JPOXMLDOC01-appb-T000339
Figure JPOXMLDOC01-appb-T000339
Figure JPOXMLDOC01-appb-T000340
Figure JPOXMLDOC01-appb-T000340
Figure JPOXMLDOC01-appb-T000341
Figure JPOXMLDOC01-appb-T000341
Figure JPOXMLDOC01-appb-T000342
Figure JPOXMLDOC01-appb-T000342
Figure JPOXMLDOC01-appb-T000343
Figure JPOXMLDOC01-appb-T000343
Figure JPOXMLDOC01-appb-T000344
Figure JPOXMLDOC01-appb-T000344
Figure JPOXMLDOC01-appb-T000345
Figure JPOXMLDOC01-appb-T000345
Figure JPOXMLDOC01-appb-T000346
Figure JPOXMLDOC01-appb-T000346
Figure JPOXMLDOC01-appb-T000347
Figure JPOXMLDOC01-appb-T000347
Figure JPOXMLDOC01-appb-T000348
Figure JPOXMLDOC01-appb-T000348
Figure JPOXMLDOC01-appb-T000349
Figure JPOXMLDOC01-appb-T000349
Figure JPOXMLDOC01-appb-T000350
Figure JPOXMLDOC01-appb-T000350
Figure JPOXMLDOC01-appb-T000351

 さらに、以下の表に記載の化合物も合成した。
Figure JPOXMLDOC01-appb-T000351

Furthermore, the compounds described in the following table were also synthesized.
Figure JPOXMLDOC01-appb-T000352
Figure JPOXMLDOC01-appb-T000352
Figure JPOXMLDOC01-appb-T000353
Figure JPOXMLDOC01-appb-T000353
Figure JPOXMLDOC01-appb-T000354
Figure JPOXMLDOC01-appb-T000354
Figure JPOXMLDOC01-appb-T000355
Figure JPOXMLDOC01-appb-T000355
Figure JPOXMLDOC01-appb-T000356
Figure JPOXMLDOC01-appb-T000356
Figure JPOXMLDOC01-appb-T000357
Figure JPOXMLDOC01-appb-T000357
 以下に、本発明化合物の生物試験例を記載する。 Hereinafter, biological test examples of the compounds of the present invention will be described.
試験例
試験例1-1:ヒトP2X3受容体阻害活性の評価
 ヒトP2X3受容体遺伝子(GenBank登録配列Y07683)をC6BU-1細胞に導入した安定発現細胞株をPDLコート96穴マイクロプレートに1穴当たり8000個になるように播種し、培地(8.3%ウシ胎児血清、8.3%ウマ血清、1%抗生物質抗真菌剤混合溶液を含むDMEM)中で、37℃、5%二酸化炭素下で1日間培養した。培地をFluo-3-AM 4μMを含む添加液(20mM HEPES、137mM NaCl、2.7mM KCl、0.9mM MgCl2、5.0mMCaCl2、5.6mM D-グルコース、2.5mM プロベネシド、10%BSA、0.08%プルロニックF-127、pH7.5)に置換し、37℃、5%二酸化炭素下で1時間インキュベーションした。洗浄用緩衝液(20mM HEPES、137mM NaCl、2.7mMKCl、0.9mM MgCl2、5.0mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、pH7.5)により洗浄し、1穴当たり40μLの洗浄用緩衝液で満たした。マイクロプレートをハイスループットスクリーニングシステムFDSS 3000(浜松ホトニクス社)に設置した。FDSS 3000による蛍光強度の測定を開始し、希釈用緩衝液(20mM HEPES、137mM NaCl、2.7mM KCl、0.9mM MgCl2、5.0mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、0.1%プルロニックF-127、pH7.5)により異なる濃度になるように希釈した本発明化合物DMSO溶液を1穴当たり40μLずつFDSS 3000に内蔵された自動分注装置で分注した。5分後、希釈用緩衝液で希釈した50nM ATP溶液50μLをFDSS 3000に内蔵された自動分注装置で分注し、その後3分間蛍光強度の測定を継続した。測定した蛍光強度の値から、ATP溶液添加後の蛍光強度の最大値を測定開始時の蛍光強度に対する比で表した比最大蛍光強度をマイクロプレートの穴毎に算出した。本発明化合物を含まない場合の比最大蛍光強度の値を阻害0%、ATPの代わりに希釈用緩衝液を添加した場合の比最大蛍光強度の値を阻害100%とし、阻害50%となる濃度(IC50)を算出して本発明化合物の阻害活性を評価した。比最大蛍光強度の算出はFDSS ソフトウェア(浜松ホトニクス社)を用いて行った。IC50の算出はマイクロソフト・エクセル(Microsoft社)およびXLfit(idbs社)のソフトウェアを用いて行った。
本発明化合物の試験結果を以下の表に示す。
Test Example Test Example 1-1: 1 stably expressing cell lines by introducing the human P2X 3 receptor inhibitory activity evaluation human P2X 3 receptor gene (GenBank Accession sequence Y07683) to C6BU-1 cells in PDL coated 96-well microplate Seeded to 8000 per well, in a medium (DMEM containing 8.3% fetal calf serum, 8.3% horse serum, 1% antibiotic antifungal mixed solution) at 37 ° C., 5% dioxide Incubated for 1 day under carbon. The medium was supplemented with 4 μM Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA 0.08% Pluronic F-127, pH 7.5) and incubated at 37 ° C. under 5% carbon dioxide for 1 hour. Wash with wash buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5) per well Filled with 40 μL of wash buffer. The microplate was installed in a high-throughput screening system FDSS 3000 (Hamamatsu Photonics). Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid) , 0.1% Pluronic F-127, pH 7.5) The DMSO solution of the present invention diluted to have different concentrations was dispensed by 40 μL per well with an automatic dispenser built in the FDSS 3000. After 5 minutes, 50 μL of 50 nM ATP solution diluted with a dilution buffer was dispensed with an automatic dispensing device built in FDSS 3000, and then fluorescence intensity measurement was continued for 3 minutes. From the measured fluorescence intensity value, the ratio maximum fluorescence intensity, which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, was calculated for each hole of the microplate. The concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC 50 ) was calculated to evaluate the inhibitory activity of the compound of the present invention. The specific maximum fluorescence intensity was calculated using FDSS software (Hamamatsu Photonics). IC 50 was calculated using Microsoft Excel (Microsoft) and XLfit (idbs) software.
The test results of the compounds of the present invention are shown in the following table.
Figure JPOXMLDOC01-appb-T000358
Figure JPOXMLDOC01-appb-T000358
Figure JPOXMLDOC01-appb-T000359
Figure JPOXMLDOC01-appb-T000359
Figure JPOXMLDOC01-appb-T000360
Figure JPOXMLDOC01-appb-T000360
Figure JPOXMLDOC01-appb-T000361

試験例1-2:ヒトP2X3受容体阻害活性の評価
 ヒトP2X3受容体遺伝子(GenBank登録配列Y07683)をC6BU-1細胞に導入した安定発現細胞株をPDLコート96穴マイクロプレートに1穴当たり8000個になるように播種し、培地(7.0%ウシ胎児血清、7.0%ウマ血清、1%抗生物質抗真菌剤混合溶液を含むDMEM)中で、37℃、5%二酸化炭素下で1日間培養する。培地をFluo-3-AM 4μMを含む添加液(20mM HEPES、137mM NaCl、5.27mM KCl、0.9mM MgCl2、1.26mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、1%BSA、0.08%プルロニックF-127、pH7.5)に置換し、37℃、5%二酸化炭素下で1時間インキュベーションする。洗浄用緩衝液(20mM HEPES、137mM NaCl、5.27mM KCl、0.9mM MgCl2、1.26mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、pH7.5)により洗浄し、1穴当たり40μLの洗浄用緩衝液で満たす。マイクロプレートをハイスループットスクリーニングシステムFDSS 3000(浜松ホトニクス社)に設置する。FDSS 3000による蛍光強度の測定を開始し、希釈用緩衝液(20mM HEPES、137mM NaCl、5.27mM KCl、0.9mM MgCl2、1.26mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、0.1%プルロニックF-127、pH7.5)により異なる濃度になるように希釈した本発明化合物DMSO溶液を1穴当たり40μLずつFDSS 3000に内蔵された自動分注装置で分注する。5分後、希釈用緩衝液で希釈した50nM ATP溶液50μLをFDSS 3000に内蔵された自動分注装置で分注し、その後4分間蛍光強度の測定を継続する。測定した蛍光強度の値から、ATP溶液添加後の蛍光強度の最大値を測定開始時の蛍光強度に対する比で表した比最大蛍光強度をマイクロプレートの穴毎に算出する。本発明化合物を含まない場合の比最大蛍光強度の値を阻害0%、ATPの代わりに希釈用緩衝液を添加した場合の比最大蛍光強度の値を阻害100%とし、阻害50%となる濃度(IC50)を算出して本発明化合物の阻害活性を評価する。比最大蛍光強度の算出はFDSS ソフトウェア(浜松ホトニクス社)を用いて行う。IC50の算出はマイクロソフト・エクセル(Microsoft社)およびXLfit(idbs社)のソフトウェアを用いて行う。
Figure JPOXMLDOC01-appb-T000361

Test Example 1-2: Human P2X 3 Evaluation of the receptor inhibitory activity human P2X 3 receptor gene per well of stably expressing cell lines by introducing (GenBank Accession sequence Y07683) to C6BU-1 cells in PDL coated 96-well microplate Seeded to 8000 cells in medium (7.0% fetal calf serum, 7.0% horse serum, DMEM containing 1% antibiotic antifungal mixed solution) at 37 ° C. under 5% carbon dioxide Incubate for 1 day. The medium was supplemented with 4 μM Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 1% BSA, 0.08% Pluronic F-127, pH 7.5) and incubate for 1 hour at 37 ° C., 5% carbon dioxide. Wash with washing buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5), 1 well Fill with 40 μL of wash buffer. The microplate is installed in the high-throughput screening system FDSS 3000 (Hamamatsu Photonics). Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid) , 0.1% Pluronic F-127, pH 7.5) The DMSO solution of the present invention diluted to have different concentrations is dispensed by 40 μL per well with an automatic dispensing device built in the FDSS 3000. After 5 minutes, 50 μL of a 50 nM ATP solution diluted with a dilution buffer is dispensed with an automatic dispensing device built in the FDSS 3000, and then fluorescence intensity measurement is continued for 4 minutes. From the measured fluorescence intensity value, the ratio maximum fluorescence intensity, which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, is calculated for each hole of the microplate. The concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC 50 ) is calculated to evaluate the inhibitory activity of the compound of the present invention. The specific maximum fluorescence intensity is calculated using FDSS software (Hamamatsu Photonics). IC 50 is calculated using software of Microsoft Excel (Microsoft) and XLfit (idbs).
Figure JPOXMLDOC01-appb-T000362


試験例1-3:ヒトP2X3受容体阻害活性の評価
 ヒトP2X3受容体遺伝子(GenBank登録配列Y07683)をC6BU-1細胞に導入した安定発現細胞株をPDLコート384穴マイクロプレートに1穴当たり3000個になるように播種し、培地(8.3%ウシ胎児血清、8.3%ウマ血清、1%抗生物質抗真菌剤混合溶液を含むDMEM)中で、37℃、5%二酸化炭素下で2日間培養した。培地をFluo-3-AM 4μMを含む添加液(20mM HEPES、137mM NaCl、2.7mM KCl、0.9mM MgCl2、5.0mMCaCl2、5.6mM D-グルコース、2.5mM プロベネシド、0.5%BSA、0.04%プルロニックF-127、pH7.5)に置換し、37℃、5%二酸化炭素下で1時間インキュベーションした。洗浄用緩衝液(20mM HEPES、137mM NaCl、2.7mMKCl、0.9mM MgCl2、5.0mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、pH7.5)により洗浄し、1穴当たり20μLの洗浄用緩衝液で満たした。マイクロプレートをハイスループットスクリーニングシステムFLIPR 384(Molecular Devices社)に設置した。FLIPR 384による蛍光強度の測定を開始し、希釈用緩衝液(20mM HEPES、137mM NaCl、2.7mM KCl、0.9mM MgCl2、5.0mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、0.1%プルロニックF-127、pH7.5)により異なる濃度になるように希釈した本発明化合物DMSO溶液を1穴当たり20μLずつFLIPR 384に内蔵された自動分注装置で分注した。5分後、希釈用緩衝液で希釈した150nM ATP溶液25μLをFLIPR 384に内蔵された自動分注装置で分注し、その後4分間蛍光強度の測定を継続した。測定した蛍光強度の値から、ATP溶液添加後の蛍光強度の最大値を測定開始時の蛍光強度に対する比で表した比最大蛍光強度をマイクロプレートの穴毎に算出した。本発明化合物を含まない場合の比最大蛍光強度の値を阻害0%、ATPの代わりに希釈用緩衝液を添加した場合の比最大蛍光強度の値を阻害100%とし、阻害50%となる濃度(IC50)を算出して本発明化合物の阻害活性を評価した。比最大蛍光強度およびIC50の算出はSpotfire(サイエンス・テクノロジー・システムズ社)のソフトウェアを用いて行った。
本発明化合物の試験結果を以下の表に示す。
Figure JPOXMLDOC01-appb-T000362


Test Example 1-3: Human P2X 3 Evaluation of the receptor inhibitory activity human P2X 3 receptor gene per well of stably expressing cell lines by introducing (GenBank Accession sequence Y07683) to C6BU-1 cells PDL coated 384-well microplates 3000 seeds were seeded and cultured in a medium (DMEM containing 8.3% fetal bovine serum, 8.3% horse serum, 1% antibiotic antifungal mixed solution) at 37 ° C. under 5% carbon dioxide. For 2 days. The medium was supplemented with 4 μM Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 0.5 % BSA, 0.04% Pluronic F-127, pH 7.5) and incubated at 37 ° C. under 5% carbon dioxide for 1 hour. Wash with wash buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5) per well Filled with 20 μL of wash buffer. The microplate was installed in a high throughput screening system FLIPR 384 (Molecular Devices). Measurement of fluorescence intensity by FLIPR 384 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid) , 0.1% Pluronic F-127, pH 7.5) The present compound DMSO solution diluted to different concentrations was dispensed by 20 μL per well with an automatic dispensing device built in FLIPR 384. After 5 minutes, 25 μL of 150 nM ATP solution diluted with dilution buffer was dispensed with an automatic dispensing device built in FLIPR 384, and then fluorescence intensity measurement was continued for 4 minutes. From the measured fluorescence intensity value, the ratio maximum fluorescence intensity, which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, was calculated for each hole of the microplate. The concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC 50 ) was calculated to evaluate the inhibitory activity of the compound of the present invention. The specific maximum fluorescence intensity and IC 50 were calculated using software from Spotfire (Science Technology Systems).
The test results of the compounds of the present invention are shown in the following table.
Figure JPOXMLDOC01-appb-T000363
Figure JPOXMLDOC01-appb-T000363
Figure JPOXMLDOC01-appb-T000364
Figure JPOXMLDOC01-appb-T000364
試験例2-1: ラットP2X受容体阻害活性の評価
 ラットP2X3受容体遺伝子(GenBank登録配列NM_031075)をC6BU-1細胞に導入して発現させた。C6BU-1細胞を1穴当り2500個になるように播種し、培地(8.3%ウシ胎児血清、8.3%ウマ血清、1%抗生物質抗真菌剤混合溶液を含むDMEM)中で37℃、5%二酸化炭素下で1日間培養した。遺伝子導入試薬FuGENE6(Roche社製)を用いて発現プラスミドを導入し、さらに37℃、5%二酸化炭素下で1日間培養した。培地をFluo-3-AM 4μMを含む添加液(20mM HEPES、137mM NaCl、2.7mM KCl、0.9mM MgCl2、5.0mMCaCl2、5.6mM D-グルコース、2.5mM プロベネシド、10%BSA、0.08%プルロニックF-127、pH7.5)に置換し、37℃、5%二酸化炭素下で1時間インキュベーションした。洗浄用緩衝液(20mM HEPES、137mM NaCl、2.7mMKCl、0.9mM MgCl2、5.0mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、pH7.5)により洗浄し、1穴当たり40μLの洗浄用緩衝液で満たした。マイクロプレートをハイスループットスクリーニングシステムFDSS 3000(浜松ホトニクス社)に設置した。FDSS 3000による蛍光強度の測定を開始し、希釈用緩衝液(20mM HEPES、137mM NaCl、2.7mM KCl、0.9mM MgCl2、5.0mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、0.1%プルロニックF-127、pH7.5)を用いて異なる濃度になるように希釈した本発明化合物のDMSO溶液を1穴当り40μLずつFDSS 3000に内蔵された自動分注装置で分注した。5分後、希釈用緩衝液で希釈した50nM ATP溶液50μLをFDSS 3000に内蔵された自動分注装置で分注し、その後3分間蛍光強度の測定を継続した。測定した蛍光強度の値から、ATP溶液添加後の蛍光強度の最大値を測定開始時の蛍光強度に対する比で表した比最大蛍光強度をマイクロプレートの穴毎に算出した。本発明化合物を含まない場合の比最大蛍光強度の値を阻害0%、ATPの代わりに希釈用緩衝液を添加した場合の比最大蛍光強度の値を阻害100%とし、阻害50%となる濃度(IC50)を算出して本発明化合物の阻害活性を評価した。比最大蛍光強度の算出はFDSS ソフトウェア(浜松ホトニクス社)を用いて行った。IC50の算出はマイクロソフト・エクセル(Microsoft社)およびXLfit(idbs社)のソフトウェアを用いて行った。
 本発明化合物の試験結果を以下の表に示す。
Test Example 2-1: was expressed by introducing the rat P2X 3 Rating rat P2X 3 receptor gene of the receptor inhibitory activity (GenBank Accession sequence NM_031075) to C6BU-1 cells. C6BU-1 cells were seeded at 2500 cells per well and cultured in a medium (DMEM containing 8.3% fetal bovine serum, 8.3% horse serum, 1% antibiotic antifungal mixed solution). The cells were cultured at 5 ° C. for 5 days at 5 ° C. The expression plasmid was introduced using a gene introduction reagent FuGENE6 (Roche) and further cultured at 37 ° C. under 5% carbon dioxide for 1 day. The medium was supplemented with 4 μM Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA 0.08% Pluronic F-127, pH 7.5) and incubated at 37 ° C. under 5% carbon dioxide for 1 hour. Wash with wash buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5) per well Filled with 40 μL of wash buffer. The microplate was installed in a high-throughput screening system FDSS 3000 (Hamamatsu Photonics). Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid) , 0.1% pluronic F-127, pH 7.5), and the DMSO solution of the compound of the present invention diluted to different concentrations with an automatic dispensing device built in FDSS 3000, 40 μL per well. did. After 5 minutes, 50 μL of 50 nM ATP solution diluted with a dilution buffer was dispensed with an automatic dispensing device built in FDSS 3000, and then fluorescence intensity measurement was continued for 3 minutes. From the measured fluorescence intensity value, the ratio maximum fluorescence intensity, which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, was calculated for each hole of the microplate. The concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC 50 ) was calculated to evaluate the inhibitory activity of the compound of the present invention. The specific maximum fluorescence intensity was calculated using FDSS software (Hamamatsu Photonics). IC 50 was calculated using Microsoft Excel (Microsoft) and XLfit (idbs) software.
The test results of the compounds of the present invention are shown in the following table.
Figure JPOXMLDOC01-appb-T000365

試験例2-2: ラットP2X受容体阻害活性の評価
 ラットP2X3受容体遺伝子(GenBank登録配列NM_031075)をC6BU-1細胞に導入して発現させる。C6BU-1細胞を1穴当り2500個になるように播種し、培地(7.0%ウシ胎児血清、7.0%ウマ血清、1%抗生物質抗真菌剤混合溶液を含むDMEM)中で37℃、5%二酸化炭素下で1日間培養する。遺伝子導入試薬FuGENE6(Promega社製)を用いて発現プラスミドを導入し、さらに37℃、5%二酸化炭素下で1日間培養する。培地をFluo-3-AM 4μMを含む添加液(20mM HEPES、137mM NaCl、5.27mM KCl、0.9mM MgCl2、1.26mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、1%BSA、0.08%プルロニックF-127、pH7.5)に置換し、37℃、5%二酸化炭素下で1時間インキュベーションする。洗浄用緩衝液(20mM HEPES、137mM NaCl、5.27mM KCl、0.9mM MgCl2、1.26mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、pH7.5)により洗浄し、1穴当たり40μLの洗浄用緩衝液で満たした。マイクロプレートをハイスループットスクリーニングシステムFDSS 3000(浜松ホトニクス社)に設置する。FDSS 3000による蛍光強度の測定を開始し、希釈用緩衝液(20mM HEPES、137mM NaCl、5.27mM KCl、0.9mM MgCl2、1.26mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、0.1%プルロニックF-127、pH7.5)を用いて異なる濃度になるように希釈した本発明化合物のDMSO溶液を1穴当り40μLずつFDSS 3000に内蔵された自動分注装置で分注する。5分後、希釈用緩衝液で希釈した50nM ATP溶液50μLをFDSS 3000に内蔵された自動分注装置で分注し、その後4分間蛍光強度の測定を継続する。測定した蛍光強度の値から、ATP溶液添加後の蛍光強度の最大値を測定開始時の蛍光強度に対する比で表した比最大蛍光強度をマイクロプレートの穴毎に算出する。本発明化合物を含まない場合の比最大蛍光強度の値を阻害0%、ATPの代わりに希釈用緩衝液を添加した場合の比最大蛍光強度の値を阻害100%とし、阻害50%となる濃度(IC50)を算出して本発明化合物の阻害活性を評価する。比最大蛍光強度の算出はFDSS ソフトウェア(浜松ホトニクス社)を用いて行う。IC50の算出はマイクロソフト・エクセル(Microsoft社)およびXLfit(idbs社)のソフトウェアを用いて行う。
Figure JPOXMLDOC01-appb-T000365

Test Example 2-2: introducing and expressing rat P2X 3 Rating rat P2X 3 receptor gene of the receptor inhibitory activity (GenBank Accession sequence NM_031075) to C6BU-1 cells. C6BU-1 cells were seeded at 2500 cells per well and cultured in a medium (DMEM containing 7.0% fetal bovine serum, 7.0% horse serum, 1% antibiotic antifungal mixed solution). Incubate for 1 day at 5 ° C. and 5% carbon dioxide. An expression plasmid is introduced using a gene introduction reagent FuGENE6 (manufactured by Promega) and further cultured at 37 ° C. under 5% carbon dioxide for 1 day. The medium was supplemented with 4 μM Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 1% BSA, 0.08% Pluronic F-127, pH 7.5) and incubate for 1 hour at 37 ° C., 5% carbon dioxide. Wash with washing buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5), 1 well Filled with 40 μL of wash buffer per minute. The microplate is installed in the high-throughput screening system FDSS 3000 (Hamamatsu Photonics). Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid) , 0.1% Pluronic F-127, pH 7.5) is used to dispense 40 μL of the DMSO solution of the compound of the present invention diluted to different concentrations with an automatic dispensing device built in FDSS 3000 per well. To do. After 5 minutes, 50 μL of a 50 nM ATP solution diluted with a dilution buffer is dispensed with an automatic dispensing device built in the FDSS 3000, and then fluorescence intensity measurement is continued for 4 minutes. From the measured fluorescence intensity value, the ratio maximum fluorescence intensity, which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, is calculated for each hole of the microplate. The concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC 50 ) is calculated to evaluate the inhibitory activity of the compound of the present invention. The specific maximum fluorescence intensity is calculated using FDSS software (Hamamatsu Photonics). IC 50 is calculated using software of Microsoft Excel (Microsoft) and XLfit (idbs).
試験例3-1: ラット血清アルブミン(RSA)存在下でのラットP2X3受容体阻害活性の評価
 ラットP2X3受容体遺伝子(GenBank登録配列NM_031075)をC6BU-1細胞に導入して発現させた。C6BU-1細胞を1穴当り2500個になるように播種し、培地(8.3%ウシ胎児血清、8.3%ウマ血清、1%抗生物質抗真菌剤混合溶液を含むDMEM)中で37℃、5%二酸化炭素下で1日間培養した。遺伝子導入試薬FuGENE6(Roche社製)を用いて発現プラスミドを導入し、さらに37℃、5%二酸化炭素下で1日間培養した。培地をFluo-3-AM 4μMを含む添加液(20mM HEPES、137mM NaCl、2.7mM KCl、0.9mM MgCl2、5.0mMCaCl2、5.6mM D-グルコース、2.5mM プロベネシド、10%BSA、0.08%プルロニックF-127、pH7.5)に置換し、37℃、5%二酸化炭素下で1時間インキュベーションした。洗浄用緩衝液(20mM HEPES、137mM NaCl、2.7mMKCl、0.9mM MgCl2、5.0mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、pH7.5)により洗浄し、1穴当たり40μLの洗浄用緩衝液で満たした。マイクロプレートをハイスループットスクリーニングシステムFDSS 3000(浜松ホトニクス社)に設置した。FDSS 3000による蛍光強度の測定を開始し、希釈用緩衝液(20mM HEPES、137mM NaCl、2.7mM KCl、0.9mM MgCl2、5.0mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、0.1%プルロニックF-127、pH7.5)に終濃度1%になるようにラット血清アルブミンを添加した溶液を用いて異なる濃度になるように希釈した本発明化合物のDMSO溶液を1穴当り40μLずつFDSS 3000に内蔵された自動分注装置で分注した。5分後、希釈用緩衝液で希釈した50nM ATP溶液50μLをFDSS 3000に内蔵された自動分注装置で分注し、その後3分間蛍光強度の測定を継続した。測定した蛍光強度の値から、ATP溶液添加後の蛍光強度の最大値を測定開始時の蛍光強度に対する比で表した比最大蛍光強度をマイクロプレートの穴毎に算出した。本発明化合物を含まない場合の比最大蛍光強度の値を阻害0%、ATPの代わりに希釈用緩衝液を添加した場合の比最大蛍光強度の値を阻害100%とし、阻害50%となる濃度(IC50)を算出して本発明化合物の阻害活性を評価した。比最大蛍光強度の算出はFDSS ソフトウェア(浜松ホトニクス社)を用いて行った。IC50の算出はマイクロソフト・エクセル(Microsoft社)およびXLfit(idbs社)のソフトウェアを用いて行った。
 本発明化合物の試験結果を以下の表に示す。
Test Example 3-1: was expressed by introducing rat serum albumin (RSA) Evaluation rat P2X 3 receptor gene of the rat P2X3 receptor inhibitory activity in the presence of a (GenBank Accession sequence NM_031075) to C6BU-1 cells. C6BU-1 cells were seeded at 2500 cells per well and cultured in a medium (DMEM containing 8.3% fetal bovine serum, 8.3% horse serum, 1% antibiotic antifungal mixed solution). The cells were cultured at 5 ° C. for 5 days at 5 ° C. The expression plasmid was introduced using a gene introduction reagent FuGENE6 (Roche) and further cultured at 37 ° C. under 5% carbon dioxide for 1 day. The medium was supplemented with 4 μM Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA 0.08% Pluronic F-127, pH 7.5) and incubated at 37 ° C. under 5% carbon dioxide for 1 hour. Wash with wash buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5) per well Filled with 40 μL of wash buffer. The microplate was installed in a high-throughput screening system FDSS 3000 (Hamamatsu Photonics). Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl 2 , 5.0 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid) 1 solution of DMSO solution of the compound of the present invention diluted to different concentrations using a solution in which rat serum albumin is added to 0.1% Pluronic F-127, pH 7.5) to a final concentration of 1% Each 40 μL was dispensed by an automatic dispensing device built in the FDSS 3000. After 5 minutes, 50 μL of 50 nM ATP solution diluted with a dilution buffer was dispensed with an automatic dispensing device built in FDSS 3000, and then fluorescence intensity measurement was continued for 3 minutes. From the measured fluorescence intensity value, the ratio maximum fluorescence intensity, which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, was calculated for each hole of the microplate. The concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC 50 ) was calculated to evaluate the inhibitory activity of the compound of the present invention. The specific maximum fluorescence intensity was calculated using FDSS software (Hamamatsu Photonics). IC 50 was calculated using software from Microsoft Excel (Microsoft) and XLfit (idbs).
The test results of the compounds of the present invention are shown in the following table.
Figure JPOXMLDOC01-appb-T000366

試験例3-2: ラット血清アルブミン(RSA)存在下でのラットP2X3受容体阻害活性の評価
 ラットP2X3受容体遺伝子(GenBank登録配列NM_031075)をC6BU-1細胞に導入して発現させる。C6BU-1細胞を1穴当り2500個になるように播種し、培地(7.0%ウシ胎児血清、7.0%ウマ血清、1%抗生物質抗真菌剤混合溶液を含むDMEM)中で37℃、5%二酸化炭素下で1日間培養する。遺伝子導入試薬FuGENE6(Promega社製)を用いて発現プラスミドを導入し、さらに37℃、5%二酸化炭素下で1日間培養する。培地をFluo-4-AM 4μMを含む添加液(20mM HEPES、137mM NaCl、5.27mM KCl、0.9mM MgCl2、1.26mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、10%BSA、0.08%プルロニックF-127、pH7.5)に置換し、37℃、5%二酸化炭素下で1時間インキュベーションする。洗浄用緩衝液(20mM HEPES、137mM NaCl、5.27mM KCl、0.9mM MgCl2、1.26mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、pH7.5)により洗浄し、1穴当たり40μLの洗浄用緩衝液で満たす。マイクロプレートをハイスループットスクリーニングシステムFDSS 3000(浜松ホトニクス社)に設置する。FDSS 3000による蛍光強度の測定を開始し、希釈用緩衝液(20mM HEPES、137mM NaCl、5.27mM KCl、0.9mM MgCl2、1.26mM CaCl2、5.6mM D-グルコース、2.5mM プロベネシド、0.1%プルロニックF-127、pH7.5)に終濃度1%になるようにラット血清アルブミンを添加した溶液を用いて異なる濃度になるように希釈した本発明化合物のDMSO溶液を1穴当り40μLずつFDSS 3000に内蔵された自動分注装置で分注する。5分後、希釈用緩衝液で希釈した50nM ATP溶液50μLをFDSS 3000に内蔵された自動分注装置で分注し、その後4分間蛍光強度の測定を継続する。測定した蛍光強度の値から、ATP溶液添加後の蛍光強度の最大値を測定開始時の蛍光強度に対する比で表した比最大蛍光強度をマイクロプレートの穴毎に算出する。本発明化合物を含まない場合の比最大蛍光強度の値を阻害0%、ATPの代わりに希釈用緩衝液を添加した場合の比最大蛍光強度の値を阻害100%とし、阻害50%となる濃度(IC50)を算出して本発明化合物の阻害活性を評価する。比最大蛍光強度の算出はFDSS ソフトウェア(浜松ホトニクス社)を用いて行う。IC50の算出はマイクロソフト・エクセル(Microsoft社)およびXLfit(idbs社)のソフトウェアを用いて行う。

 本明細書に記載された化合物は、P2X3受容体に対する阻害活性を示す。また、本発明の化合物は、P2X3サブタイプに作用するため、同じくP2X2サブタイプを含んで構成されるP2X2/3受容体に対しても阻害活性を示すと考えられる。
Figure JPOXMLDOC01-appb-T000366

Test Example 3-2: introducing and expressing rat serum albumin (RSA) Evaluation rat P2X 3 receptor gene of the rat P2X3 receptor inhibitory activity in the presence of a (GenBank Accession sequence NM_031075) to C6BU-1 cells. C6BU-1 cells were seeded at 2500 cells per well and cultured in a medium (DMEM containing 7.0% fetal bovine serum, 7.0% horse serum, 1% antibiotic antifungal mixed solution). Incubate for 1 day at 5 ° C. and 5% carbon dioxide. An expression plasmid is introduced using a gene introduction reagent FuGENE6 (manufactured by Promega) and further cultured at 37 ° C. under 5% carbon dioxide for 1 day. The medium was supplemented with 4 μM Fluo-4-AM (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 10% BSA, 0.08% Pluronic F-127, pH 7.5) and incubate for 1 hour at 37 ° C., 5% carbon dioxide. Wash with washing buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, pH 7.5), 1 well Fill with 40 μL of wash buffer. The microplate is installed in the high-throughput screening system FDSS 3000 (Hamamatsu Photonics). Fluorescence intensity measurement by FDSS 3000 was started, and dilution buffer (20 mM HEPES, 137 mM NaCl, 5.27 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid) 1 solution of DMSO solution of the compound of the present invention diluted to different concentrations using a solution in which rat serum albumin is added to 0.1% Pluronic F-127, pH 7.5) to a final concentration of 1% Dispense 40 μL per unit with an automatic dispenser built in FDSS 3000. After 5 minutes, 50 μL of a 50 nM ATP solution diluted with a dilution buffer is dispensed with an automatic dispensing device built in the FDSS 3000, and then fluorescence intensity measurement is continued for 4 minutes. From the measured fluorescence intensity value, the ratio maximum fluorescence intensity, which is the ratio of the maximum fluorescence intensity after addition of the ATP solution to the fluorescence intensity at the start of measurement, is calculated for each hole of the microplate. The concentration at which the specific maximum fluorescence intensity when the compound of the present invention is not contained is 0% inhibition, the specific maximum fluorescence intensity when the dilution buffer is added instead of ATP is 100% inhibition, and the inhibition is 50%. (IC 50 ) is calculated to evaluate the inhibitory activity of the compound of the present invention. The specific maximum fluorescence intensity is calculated using FDSS software (Hamamatsu Photonics). IC 50 is calculated using software from Microsoft Excel (Microsoft) and XLfit (idbs).

The compounds described herein exhibit inhibitory activity against P2X 3 receptor. In addition, since the compound of the present invention acts on the P2X 3 subtype, it is considered that the compound of the present invention also exhibits inhibitory activity against the P2X 2/3 receptor that is also composed of the P2X 2 subtype.
試験例4:ラット膀胱炎モデルの排尿機能の評価
 シストメトリー手術
 ラットを2%イソフルラン(麻酔背景;笑気:酸素 = 7:3)吸入にて麻酔後、仰臥位に固定する。腹部を正中切開し、膀胱を露出させる。膀胱頂部を小切開しカニューレ(ポリエチレンチューブ(PE-50:Becton Dickinson)を加工して作製)を挿入固定し、膀胱瘻を作製する。カニューレの他端は皮下を通して背部に導き、筋層および皮膚を縫合する。背部に導いたカニューレは途中をステンレス製スプリングで保護し、シーベルに接続する。
 酢酸注入
 手術2日後、膀胱に留置したカニューレを介して0.3%酢酸を4 mL/hrの速度で30分間膀胱内に注入して、膀胱炎を惹起する。また酢酸注入を行わない動物を正常動物とする。
 シストメトリー測定
 酢酸注入2~3日後、膀胱内に挿入したカニューレの他端を三方活栓に接続して、一方から加温した生理食塩液を3.0 mL/hrの速度で注入しながら、もう一方は圧トランスデューサーを介して、圧力アンプにより膀胱内圧を連続記録する。膀胱内圧は安定期間(約20分間)測定後、投与前値(約40分間)を測定し、被験物質を投与した後、投与後値を120分間測定する。本発明化合物は乳鉢と乳棒を用いて破砕し、0.5%メチルセルロース液を用いて0.1~2 mg/mL/kgになるように懸濁液、または溶液を調製し、経口ゾンデを持ち用いて動物に経口投与する。膀胱内圧測定と同時に排泄尿はケージ下の天秤上で受け、その重量変化を同時に測定する。
 データ採用の基準
 排尿間隔を基準として、正常動物では排尿間隔が10分以上のものを採用し、それ以下のものは除外する。酢酸注入を行った動物では、排尿間隔が正常動物の平均値の半分未満のものを膀胱炎動物として採用し、それ以上のものは除外する。
 残尿の採取
 測定終了後、排尿直後に生理食塩液の注入を止め、ペントバルビタールナトリウム麻酔下で残尿を採取する。採取した残尿は排泄尿受けに移し、チャート上に記録する。
 解析項目
 測定開始1時間後から2時間後の膀胱内圧(静止時圧および排尿時圧)、排尿間隔、および1回排尿量を解析する。また測定終了後の残尿量を解析する。

排尿間隔への作用の指標として、以下の値を用いる。
排尿機能感覚改善率
=(膀胱炎動物の薬物処理後排尿間隔-膀胱炎動物の薬物処理前排尿間隔)/(正常動物の薬物処理前排尿間隔の平均値-膀胱炎動物の薬物処理前排尿間隔)×100
1回排尿量への作用の指標として、以下の値を用いる。
1回排尿量改善率
=(膀胱炎ラットの薬物処理後1回排尿量-膀胱炎動物の薬物処理前1回排尿量)/(正常動物の薬物処理前1回排尿量の平均値-膀胱炎動物の薬物処理前1回排尿量)×100
Test Example 4: Evaluation of urinary function in rat cystitis model Cystometry operation Rats are anesthetized by inhalation of 2% isoflurane (anesthetic background; laughing gas: oxygen = 7: 3) and then fixed in the supine position. A midline incision is made in the abdomen to expose the bladder. A small incision is made in the top of the bladder, a cannula (produced by processing a polyethylene tube (PE-50: Becton Dickinson)) is inserted and fixed, and a bladder fistula is produced. The other end of the cannula is guided subcutaneously to the back, and the muscle layer and skin are sutured. The cannula led to the back is protected by a stainless steel spring and connected to a sieve.
Acetic acid injection Two days after surgery, 0.3% acetic acid is injected into the bladder at a rate of 4 mL / hr for 30 minutes via a cannula placed in the bladder to induce cystitis. An animal that is not injected with acetic acid is defined as a normal animal.
Cystometry measurement Two to three days after acetic acid injection, connect the other end of the cannula inserted into the bladder to a three-way stopcock, and inject the heated physiological saline from one side at a rate of 3.0 mL / hr, The intravesical pressure is continuously recorded by a pressure amplifier through a pressure transducer. The intravesical pressure is measured for a stable period (about 20 minutes), followed by a pre-dose value (about 40 minutes), and after administration of the test substance, a post-dose value is measured for 120 minutes. The compound of the present invention is crushed using a mortar and pestle, and a suspension or solution is prepared using 0.5% methylcellulose solution to a concentration of 0.1 to 2 mg / mL / kg. Oral administration. Simultaneously with the measurement of intravesical pressure, excreted urine is received on a balance under the cage, and its weight change is measured simultaneously.
Criteria for data adoption Based on the urination interval, those with a urination interval of 10 minutes or more are adopted for normal animals, and those with less than that are excluded. For animals that have been injected with acetic acid, those with a micturition interval of less than half of the mean value for normal animals are adopted as cystitis animals, and those beyond that are excluded.
Collection of residual urine After the measurement is completed, stop injection of physiological saline immediately after urination and collect residual urine under anesthesia with sodium pentobarbital. The collected residual urine is transferred to the excretion receptacle and recorded on the chart.
Analysis items Analyze the intravesical pressure (static pressure and urination pressure), urination interval, and single urination volume 1 hour to 2 hours after the start of measurement. In addition, the amount of residual urine after the measurement is analyzed.

The following values are used as indicators of the effect on the urination interval.
Urinary dysfunction improvement rate = (urination interval after drug treatment for cystitis animals−urination interval before drug treatment for cystitis animals) / (mean value of urination interval before drug treatment for normal animals−urination interval before drug treatment for cystitis animals) ) X 100
The following values are used as indicators of the effect on the amount of urination once.
Improvement rate of 1 urination volume = (1 urination volume after drug treatment in cystitis rats-1 urination volume before drug treatment in cystitis animals) / (Average value of 1 urination volume before drug treatment in normal animals-cystitis) Animal urination once before drug treatment) x 100
試験例5:Seltzerモデルによる薬効評価
 ラットPartial sciatic nerve ligationモデル(ラット坐骨神経部分結紮モデル)
モデルの作製
 ラットをイソフルランにより麻酔し、左足の毛を剃った。大腿上部の皮膚を切開し、筋を割いて坐骨神経を露出させた。坐骨神経の1/3~1/2を糸で強く結紮し、筋、及び皮膚を縫合した。これを手術側とした。右足については坐骨神経結紮以外の同様の処置を行い、偽手術側とした。
 評価(1)
 手術の2週間後、von Freyフィラメントにより触知性アロディニアに対する作用を評価した。手術2週間後、金網上に載せたプラスチック製ケージにラットを入れ、馴化させた。金網側からラット脚裏をvon Freyフィラメント(0.4~26 g)を押し当て、ラットが逃避行動を示し始めるvon Frey線維の圧値を疼痛閾値とした。左右の後肢について痛覚閾値を評価し、処置前疼痛閾値とした。手術側の疼痛閾値が0.6~2g、かつ偽手術側の疼痛閾値が8~15gの動物を採用した。なお、動物の訓練のため、処置前疼痛閾値測定前に同様の操作を実施した。採用した動物に本発明化合物を投与した。本発明化合物は乳鉢と乳棒を用いて破砕し、0.5%メチルセルロース液を用いて0.1~2 mg/mL/kgになるように懸濁液、または溶液を調製し、経口ゾンデを持ち用いて動物に経口投与した。投与1~5時間後、左右後肢の疼痛閾値を評価し、処置後疼痛閾値とした。下記の方法により%reversal値を計算し、化合物の鎮痛作用を比較した。
%reversal値 =(手術側処置後疼痛閾値の対数―手術側処置前疼痛閾値の対数)/( 偽手術側処置前疼痛閾値の対数-手術側処置前疼痛閾値の対数)
 本発明化合物の試験結果を以下の表に示す。本発明化合物の、3mg/kgの経口投与3時間後における鎮痛作用を%reversalとして以下の表に示す。
Test Example 5: Evaluation of drug efficacy using the Seltzer model Rat Partial sciatic nerve ligation model (rat sciatic nerve partial ligation model)
Model preparation Rats were anesthetized with isoflurane and the hair on the left foot was shaved. The skin at the upper thigh was incised, and the muscle was broken to expose the sciatic nerve. 1/3 to 1/2 of the sciatic nerve was strongly ligated with a thread, and the muscle and skin were sutured. This was the operation side. The right foot was treated in the same manner as sciatic nerve ligation, and the sham operation was performed.
Evaluation (1)
Two weeks after surgery, the effect on tactile allodynia was assessed by von Frey filament. Two weeks after the operation, rats were placed in a plastic cage placed on a wire mesh and habituated. The von Frey filament (0.4-26 g) was pressed against the back of the rat foot from the wire mesh side, and the pressure value of the von Frey fiber at which the rat began to show escape behavior was taken as the pain threshold. The pain threshold was evaluated for the left and right hind limbs and used as the pretreatment pain threshold. Animals with a surgical threshold of 0.6 to 2 g and a sham surgical threshold of 8 to 15 g were used. In order to train the animals, the same operation was performed before measuring the pre-treatment pain threshold. The compound of the present invention was administered to the adopted animals. The compound of the present invention is crushed using a mortar and pestle, and a suspension or solution is prepared using 0.5% methylcellulose solution to a concentration of 0.1 to 2 mg / mL / kg. Orally administered. From 1 to 5 hours after administration, the pain threshold value of the left and right hind limbs was evaluated and used as a post-treatment pain threshold value. The% reversal value was calculated by the following method, and the analgesic action of the compounds was compared.
% reversal value = (logarithm of pain threshold after operation side treatment-logarithm of pain threshold value before operation side treatment) / (logarithm of pain threshold value before surgery side treatment-logarithm of pain threshold value before operation side treatment)
The test results of the compounds of the present invention are shown in the following table. The analgesic action of the compound of the present invention after 3 hours of oral administration at 3 mg / kg is shown in the following table as% reversal.
Figure JPOXMLDOC01-appb-T000367
 評価(2)
 analgesiometerにより機械痛覚過敏に対する作用を評価する。手術2週間後、analgesiometerにより1秒当り16 gずつ刺激圧が増加するようにラット後肢を圧迫し、ラットが逃避行動を示した際の圧を疼痛閾値とする。左右の後肢について疼痛閾値を評価し、処置前疼痛閾値とする。手術側の疼痛閾値が60~90g、かつ偽手術側の疼痛閾値が100~175gの動物を採用する。なお、動物の訓練のため、処置前疼痛閾値測定前に同様の操作を実施する。採用した動物に本発明化合物を投与する。本発明化合物は乳鉢と乳棒を用いて破砕し、0.5%メチルセルロース液を用いて0.03~100 mg/2 mL/kgになるように懸濁液、または溶液を調製し、経口ゾンデを持ち用いて動物に経口投与する。投与1~5時間後、左右後肢の疼痛閾値を評価し、処置後疼痛閾値とする。下記の方法により%reversal値を計算し、化合物の鎮痛作用を比較する。
%reversal =(手術側処置後疼痛閾値―手術側処置前疼痛閾値)/( 偽手術側処置前疼痛閾値-手術側処置前疼痛閾値)
Figure JPOXMLDOC01-appb-T000367
Evaluation (2)
Analgesiometer is used to evaluate the effect on mechanical hyperalgesia. Two weeks after the operation, the rat's hind limb is compressed by an analgesiometer so as to increase the stimulation pressure by 16 g per second, and the pressure when the rat exhibits escape behavior is set as a pain threshold. Pain thresholds are evaluated for the left and right hind limbs and set as pre-treatment pain thresholds. Animals with a surgical threshold of 60-90 g and a sham surgical threshold of 100-175 g are employed. In order to train the animal, the same operation is performed before measuring the pre-treatment pain threshold. The compound of the present invention is administered to the adopted animal. The compound of the present invention is crushed using a mortar and pestle, and a suspension or solution is prepared with a 0.5% methylcellulose solution to 0.03 to 100 mg / 2 mL / kg. Orally. 1 to 5 hours after administration, the pain threshold value of the left and right hind limbs is evaluated and set as a post-treatment pain threshold value. The% reversal value is calculated by the following method to compare the analgesic action of the compounds.
% reversal = (Pain threshold after surgical treatment-Pain threshold before surgery) / (Pain threshold before sham surgery-Pain threshold before surgery)
試験例6 CYP3A4蛍光MBI試験
 CYP3A4蛍光MBI試験は、代謝反応による化合物のCYP3A4阻害の増強を調べる試験であり、酵素に大腸菌発現CYP3A4を用いて、7-ベンジルオキシトリフルオロメチルクマリン(BFC)がCYP3A4酵素により脱ベンジル化し、蛍光を発する代謝物7-ハイドロキシトリフルオロメチルクマリン(HFC)を生成する反応を指標として行った。
Test Example 6 CYP3A4 Fluorescence MBI Test The CYP3A4 Fluorescence MBI test is a test for examining the enhancement of CYP3A4 inhibition of compounds by metabolic reaction. 7-Benzyloxytrifluoromethylcoumarin (BFC) is CYP3A4 using E. coli-expressed CYP3A4 as an enzyme. The reaction was debenzylated with an enzyme to produce a fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (HFC) as an indicator.
 反応条件は以下のとおり:基質、5.6 μmol/L 7-BFC;プレ反応時間、0または30分; 反応時間、15分; 反応温度、25℃(室温); CYP3A4含量(大腸菌発現酵素)、プレ反応時62.5 pmol/mL、反応時6.25 pmol/mL(10倍希釈時);本発明薬物濃度、1.56、3.125、6.25、12.5、25、50 μmol/L(6点)。 The reaction conditions are as follows: substrate, 5.6 μmol / L 7-BFC; pre-reaction time, 0 or 30 minutes; reaction time, 15 minutes; reaction temperature, 25 ° C. (room temperature); CYP3A4 content (E. coli expression enzyme), pre- 62.5 pmol / mL during reaction, 6.25 pmol / mL during reaction (10-fold dilution); drug concentration of the present invention, 1.56, 3.125, 6.25, 12.5, 25, 50 μmol / L (6 points).
 96穴プレートにプレ反応液としてK-Pi緩衝液(pH 7.4)中に酵素、本発明薬物溶液を上記のプレ反応の組成で加え、別の96穴プレートに基質とK-Pi緩衝液で1/10希釈されるようにその一部を移行し、補酵素であるNADPHを添加して指標とする反応を開始し(プレ反応無)、所定の時間反応後、アセトニトリル:0.5 mol/L Tris(トリスヒドロキシアミノメタン)=4:1を加えることによって反応を停止した。また残りのプレ反応液にもNADPHを添加しプレ反応を開始し(プレ反応有)、所定時間プレ反応後、別のプレートに基質とK-Pi緩衝液で1/10希釈されるように一部を移行し指標とする反応を開始した。所定の時間反応後、アセトニトリル:0.5 mol/L Tris(トリスヒドロキシアミノメタン)=4:1を加えることによって反応を停止した。それぞれの指標反応を行ったプレートを蛍光プレートリーダーで代謝物である7-HFCの蛍光値を測定した(Ex=420nm、Em=535nm)。 Add the enzyme and the drug solution of the present invention to the 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) with the above pre-reaction composition, and add the substrate and K-Pi buffer to the other 96-well plate. A portion thereof was transferred so as to be diluted by 10/10, and a reaction using NADPH as a coenzyme was started as an index (no pre-reaction). After reaction for a predetermined time, acetonitrile: 0.5 mol / L Tris ( The reaction was stopped by adding (trishydroxyaminomethane) = 4: 1. Also, add NADPH to the remaining pre-reaction solution to start the pre-reaction (with pre-reaction), and after the pre-reaction for a predetermined time, make sure that another plate is diluted 1/10 with the substrate and K-Pi buffer. The reaction was started by moving the part. After the reaction for a predetermined time, the reaction was stopped by adding acetonitrile: 0.5 mol / L Tris (trishydroxyaminomethane) = 4: 1. The fluorescence value of 7-HFC, which is a metabolite, was measured using a fluorescent plate reader on the plate on which each index reaction was performed (Ex = 420 nm, Em = 535 nm).
 薬物を溶解した溶媒であるDMSOのみを反応系に添加したものをコントロール(100%)とし、本発明薬物溶液を加えたそれぞれの濃度での残存活性(%)を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりIC50を算出した。IC50値の差が5μmol/L以上の場合を(+)とし、3μmol/L以下の場合を(-)とした。
 本発明化合物の試験結果を以下の表に示す。
The control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration of the drug solution of the present invention was calculated. The IC 50 was calculated by inverse estimation using a logistic model. The case where the difference in IC 50 value was 5 μmol / L or more was designated as (+), and the case where it was 3 μmol / L or less was designated as (−).
The test results of the compounds of the present invention are shown in the following table.
Figure JPOXMLDOC01-appb-T000368
Figure JPOXMLDOC01-appb-T000368
試験例7 CYP阻害試験
 市販のプールドヒト肝ミクロソームを用いて、ヒト主要CYP5分子種(CYP1A2、2C9、2C19、2D6、3A4)の典型的基質代謝反応として7-エトキシレゾルフィンのO-脱エチル化(CYP1A2)、トルブタミドのメチル-水酸化(CYP2C9)、メフェニトインの4’‐水酸化(CYP2C19)、デキストロメトルファンのO脱メチル化(CYP2D6)、テルフェナジンの水酸化(CYP3A4)を指標とし、それぞれの代謝物生成量が本発明化合物によって阻害される程度を評価した。
Test Example 7 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of human major CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes CYP1A2), tolbutamide methyl-hydroxylation (CYP2C9), mephenytoin 4'-hydroxylation (CYP2C19), dextromethorphan O-demethylation (CYP2D6), and terfenadine hydroxylation (CYP3A4) The degree to which the amount of metabolite produced was inhibited by the compound of the present invention was evaluated.
 反応条件は以下のとおり:基質、0.5 μmol/L エトキシレゾルフィン(CYP1A2)、100 μmol/L トルブタミド(CYP2C9)、50 μmol/L S-メフェニトイン(CYP2C19)、5 μmol/L デキストロメトルファン(CYP2D6)、1 μmol/L テルフェナジン(CYP3A4); 反応時間、15分; 反応温度、37℃; 酵素、プールドヒト肝ミクロソーム 0.2 mg タンパク質/mL; 本発明薬物濃度、1.0、5.0、10、20 μmol/L(4点)。 The reaction conditions are as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan (CYP2D6) ), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsome 0.2 mg protein / mL; drug concentration of the present invention, 1.0, 5.0, 10, 20 μmol / L ( 4 points).
 96穴プレートに反応溶液として、50 mmol/L Hepes 緩衝液中に各5種の基質、ヒト肝ミクロソーム、本発明薬物を上記組成で加え、補酵素であるNADPHを添加して、指標とする代謝反応を開始し、37℃、15分間反応した後、メタノール/アセトニトリル=1/1 (v/v)溶液を添加することで反応を停止した。3000 rpm、15分間の遠心操作後、遠心上清中のレゾルフィン(CYP1A2代謝物)を蛍光マルチラベルカウンタで、トルブタミド水酸化体 (CYP2C9代謝物)、メフェニトイン4’水酸化体(CYP2C19代謝物)、デキストロルファン(CYP2D6代謝物)、テルフェナジンアルコール体(CYP3A4代謝物)をLC/MS/MSで定量した。 As a reaction solution in a 96-well plate, each of 5 types of substrates, human liver microsomes, and the drug of the present invention was added in the above composition in a 50 mmol / L Hepes buffer solution, and NADPH, a coenzyme, was added as an indicator for metabolism. The reaction was started and reacted at 37 ° C. for 15 minutes, and then the reaction was stopped by adding a methanol / acetonitrile = 1/1 (v / v) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant of the centrifugation was collected using a fluorescent multilabel counter with tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite). Then, dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.
 薬物を溶解した溶媒であるDMSOのみを反応系に添加したものをコントロール(100%)とし、本発明薬物溶液を加えたそれぞれの濃度での残存活性(%)を算出し、濃度と抑制率を用いて、ロジスティックモデルによる逆推定によりIC50を算出した。
 本発明化合物の試験結果を以下の表に示す。
A control (100%) was obtained by adding only DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration of the drug solution of the present invention was calculated. The IC 50 was calculated by inverse estimation using a logistic model.
The test results of the compounds of the present invention are shown in the following table.
Figure JPOXMLDOC01-appb-T000369
Figure JPOXMLDOC01-appb-T000369
試験例8-1 FAT試験(Fluctuation Ames Test)
 凍結保存しているネズミチフス菌(Salmonella typhimurium TA98株、TA100株)20 μLを10 mL液体栄養培地(2.5% Oxoid nutrient broth No.2)に接種し37℃にて10時間、振盪前培養した。TA98株は9mLの菌液を遠心(2000×g、10分間)して培養液を除去し、9mLのMicro F緩衝液(K2HPO4:3.5 g/L、KH2PO4:1 g/L、(NH4)2SO4:1g/L、クエン酸三ナトリウム二水和物:0.25 g/L、MgSO4・7H20:0.1 g/L)に菌を懸濁し、110 mLのExposure培地(ビオチン:8 μg/mL、ヒスチジン:0.2 μg/mL、グルコース:8 mg/mLを含むMicroF緩衝液)に添加し、TA100株は3.16mL菌液に対しExposure培地120mLに添加し試験菌液を調製した。被験物質DMSO溶液(最高用量50mg/mLから2~3倍公比で数段階希釈)、陰性対照としてDMSO、陽性対照として非代謝活性化条件ではTA98株に対しては50 μg/mLの4-ニトロキノリン-1-オキシドDMSO溶液、TA100株に対しては0.25 μg/mLの2-(2-フリル)-3-(5-ニトロ-2-フリル)アクリルアミド DMSO溶液、代謝活性化条件ではTA98株に対して40 μg/mLの2-アミノアントラセンDMSO溶液、TA100株に対しては20 μg/mLの2-アミノアントラセンDMSO溶液それぞれ12 μLと試験菌液588 μL(代謝活性化条件では試験菌液498 μLとS9 mix 90 μLの混合液)を混和し、37℃にて90分間、振盪培養した。被験物質を曝露した菌液460 μLを、Indicator培地(ビオチン:8 μg/mL、ヒスチジン:0.2 μg/mL、グルコース:8 mg/mL、ブロモクレゾールパープル:37.5 μg/mLを含むMicroF緩衝液)2300 μLに混和し50 μLずつマイクロプレート48ウェル/用量に分注し、37℃にて3日間、静置培養した。アミノ酸(ヒスチジン)合成酵素遺伝子の突然変異によって増殖能を獲得した菌を含むウェルは、pH変化により紫色から黄色に変色するため、1用量あたり48ウェル中の黄色に変色した菌増殖ウェルを計数し、陰性対照群と比較して評価した。
 本発明化合物の試験結果を以下の表に示す。
Test Example 8-1 FAT test (Fluctuation Ames Test)
Twenty microliters of Salmonella typhimurium TA98 and TA100 were cryopreserved and inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutrient broth No. 2), and cultured at 37 ° C. for 10 hours before shaking. For TA98 strain, 9 mL of the bacterial solution was centrifuged (2000 × g, 10 minutes) to remove the culture solution, and 9 mL of Micro F buffer solution (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g /) L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: 0.25 g / L, MgSO 4 · 7H 2 0: 0.1 g / L), and 110 mL of Exposure Add to medium (BioF: 8 μg / mL, histidine: 0.2 μg / mL, glucose: MicroF buffer solution containing 8 mg / mL), TA100 strain to 3.16 mL bacterial solution added to 120 mL of Exposure medium and test bacterial solution Was prepared. Test substance DMSO solution (maximum dose 50mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as negative control, 50μg / mL for TA98 strain under non-metabolic activation conditions as positive control Nitroquinoline-1-oxide in DMSO solution, TA100 strain, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution, TA98 strain under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for TA100 strain and 20 μg / mL 2-aminoanthracene DMSO solution for TA100 strain, respectively, and 588 μL of the test bacterial solution (under the metabolic activation conditions, the test bacterial solution 498 μL and S9 mix 90 μL) were mixed and cultured at 37 ° C. for 90 minutes with shaking. 460 μL of the bacterial solution exposed to the test substance is added to Indicator Medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL) 2300 50 μL each was mixed in μL, dispensed into 48 microwells / dose of the microplate, and statically cultured at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability due to mutations in the amino acid (histidine) synthase gene turn from purple to yellow due to pH change, count the number of bacterial growth wells that turn yellow in 48 wells per dose. Evaluation was made in comparison with the negative control group.
The test results of the compounds of the present invention are shown in the following table.
Figure JPOXMLDOC01-appb-T000370

試験例8-2 FAT試験(Fluctuation Ames Test)
 本発明化合物の変異原性を評価する。
 凍結保存しているネズミチフス菌(Salmonella typhimurium TA98株、TA100株)20μLを10mL液体栄養培地(2.5% Oxoid nutrient broth No.2)に接種し37℃にて10時間、振盪前培養した。TA98株は7.70mLの菌液を遠心(2000×g、10分間)して培養液を除去する。7.70mLのMicro F緩衝液(KHPO:3.5g/L、KHPO:1g/L、(NHSO:1g/L、クエン酸三ナトリウム二水和物:0.25g/L、MgSO・7H0:0.1g/L)に菌を懸濁し、110mLのExposure培地(ビオチン:8μg/mL、ヒスチジン:0.2μg/mL、グルコース:8mg/mLを含むMicroF緩衝液)に添加する。TA100株は3.42mL菌液に対しExposure培地120mLに添加し試験菌液を調製する。本発明化合物DMSO溶液(最高用量50mg/mLから2~3倍公比で数段階希釈)、陰性対照としてDMSO、陽性対照として非代謝活性化条件ではTA98株に対しては50μg/mLの4-ニトロキノリン-1-オキシドDMSO溶液、TA100株に対しては0.25μg/mLの2-(2-フリル)-3-(5-ニトロ-2-フリル)アクリルアミドDMSO溶液、代謝活性化条件ではTA98株に対して40μg/mLの2-アミノアントラセンDMSO溶液、TA100株に対しては20μg/mLの2-アミノアントラセンDMSO溶液それぞれ12μLと試験菌液588μL(代謝活性化条件では試験菌液498μLとS9 mix 90μLの混合液)を混和し、37℃にて90分間、振盪培養する。本発明化合物を曝露した菌液460μLを、Indicator培地(ビオチン:8μg/mL、ヒスチジン:0.2μg/mL、グルコース:8mg/mL、ブロモクレゾールパープル:37.5μg/mLを含むMicroF緩衝液)2300μLに混和し、50μLずつマイクロプレート48ウェル/用量に分注し、37℃にて3日間、静置培養する。アミノ酸(ヒスチジン)合成酵素遺伝子の突然変異によって増殖能を獲得した菌を含むウェルは、pH変化により紫色から黄色に変色するため、1用量あたり48ウェル中の黄色に変色した菌増殖ウェルを計数し、陰性対照群と比較して評価する。変異原性が陰性のものを(-)、陽性のものを(+)として示す。
Figure JPOXMLDOC01-appb-T000370

Test Example 8-2 FAT test (Fluctuation Ames Test)
The mutagenicity of the compound of the present invention is evaluated.
20 μL of Salmonella typhimurium TA98 strain, TA100 strain, which had been cryopreserved, was inoculated into 10 mL liquid nutrient medium (2.5% Oxoid nutritive broth No. 2) and cultured at 37 ° C. for 10 hours before shaking. For the TA98 strain, 7.70 mL of the bacterial solution is centrifuged (2000 × g, 10 minutes) to remove the culture solution. 7. 70 mL of Micro F buffer (K 2 HPO 4 : 3.5 g / L, KH 2 PO 4 : 1 g / L, (NH 4 ) 2 SO 4 : 1 g / L, trisodium citrate dihydrate: The cells are suspended in 0.25 g / L, MgSO 4 · 7H 2 0: 0.1 g / L), and 110 mL of Exposure medium (biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL) To the MicroF buffer). TA100 strain is added to 120 mL of Exposure medium with respect to 3.42 mL bacterial solution to prepare a test bacterial solution. Compound DMSO solution of the present invention (maximum dose of 50 mg / mL to several-fold dilution at 2-3 times common ratio), DMSO as a negative control, and non-metabolic activation conditions as a positive control, 50 μg / mL 4-TA Nitroquinoline-1-oxide DMSO solution, 0.25 μg / mL 2- (2-furyl) -3- (5-nitro-2-furyl) acrylamide DMSO solution for TA100 strain, TA98 under metabolic activation conditions 40 μg / mL 2-aminoanthracene DMSO solution for the strain and 20 μg / mL 2-aminoanthracene DMSO solution for the TA100 strain, respectively, and 588 μL of the test bacterial solution (498 μL of the test bacterial solution and S9 under metabolic activation conditions). mix 90 μL of the mixture) and incubate with shaking at 37 ° C. for 90 minutes. 460 μL of the bacterial solution exposed to the compound of the present invention was added 2300 μL of Indicator medium (MicroF buffer containing biotin: 8 μg / mL, histidine: 0.2 μg / mL, glucose: 8 mg / mL, bromocresol purple: 37.5 μg / mL). 50 μL aliquots into 48 wells / dose of the microplate and statically cultured at 37 ° C. for 3 days. Since wells containing bacteria that have acquired growth ability due to mutation of the amino acid (histidine) synthase gene change from purple to yellow due to pH change, the number of bacterial growth wells that changed to yellow in 48 wells per dose was counted. Evaluate compared to negative control group. The negative mutagenicity is indicated as (−) and the positive mutagenicity is indicated as (+).
試験例9 溶解性試験
 化合物の溶解度は、1%DMSO添加条件下で決定した。DMSOにて10 mmol/L化合物溶液を調製し、化合物溶液6 μLをpH 6.8 人工腸液(0.2 mol/L リン酸二水素カリウム試液 250 mL に0.2 mol/L NaOH 試液 118 mL、水を加えて1000 mLとした)594 μLに添加した。25℃で16時間静置させた後、混液を吸引濾過した。濾液をメタノール/水=1/1にて2倍希釈し、絶対検量線法によりHPLCまたはLC/MS/MSを用いてろ液中濃度を測定した。
 本発明化合物の試験結果を以下の表に示す。
Test Example 9 Solubility test The solubility of the compound was determined under the condition of addition of 1% DMSO. Prepare a 10 mmol / L compound solution in DMSO, add 6 μL of the compound solution to pH 6.8 artificial intestinal juice (250 mL of 0.2 mol / L potassium dihydrogen phosphate test solution, add 118 mL of 0.2 mol / L NaOH test solution, add 1000 added to 594 μL). After allowing to stand at 25 ° C. for 16 hours, the mixed solution was subjected to suction filtration. The filtrate was diluted 2-fold with methanol / water = 1/1, and the concentration in the filtrate was measured by HPLC or LC / MS / MS by the absolute calibration curve method.
The test results of the compounds of the present invention are shown in the following table.
Figure JPOXMLDOC01-appb-T000371
Figure JPOXMLDOC01-appb-T000371
試験例10 代謝安定性試験
 市販のプールドヒト肝ミクロソームを用いて、対象化合物を一定時間反応させ、反応サンプルと未反応サンプルの比較により残存率を算出し、肝で代謝される程度を評価する。
Test Example 10 Metabolic Stability Test Using a commercially available pooled human liver microsome, the target compound is reacted for a certain period of time, and the residual rate is calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism in the liver.
 ヒト肝ミクロソーム0.5 mgタンパク質/mLを含む0.2 mLの緩衝液(50 mmol/L tris-HCl pH7.4、 150 mmol/L 塩化カリウム、 10 mmol/L 塩化マグネシウム)中で、1 mmol/L NADPH存在下で37℃、0分あるいは30分間反応させた(酸化的反応)。反応後、メタノール/アセトニトリル=1/1(v/v)溶液の100 μLに反応液50 μLを添加、混合し、3000 rpmで15分間遠心した。その遠心上清中の試験化合物をLC/MS/MSにて定量し、反応後の試験化合物の残存量を0分反応時の化合物量を100%として計算した。
 本発明化合物の試験結果を以下の表に示す。化合物濃度0.5μmol/Lでの残存率を%として示す。また、I-362の試験結果は、92%であった。
1 mmol / L NADPH present in 0.2 mL buffer (50 mmol / L tris-HCl pH7.4, 150 mmol / L potassium chloride, 10 mmol / L magnesium chloride) containing 0.5 mg protein / mL human liver microsomes The reaction was carried out at 37 ° C. for 0 or 30 minutes (oxidative reaction). After the reaction, 50 μL of the reaction solution was added to 100 μL of methanol / acetonitrile = 1/1 (v / v) solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The test compound in the centrifugal supernatant was quantified by LC / MS / MS, and the remaining amount of the test compound after the reaction was calculated with the amount of the compound at 0 minute reaction as 100%.
The test results of the compounds of the present invention are shown in the following table. The residual ratio at a compound concentration of 0.5 μmol / L is shown as%. The test result of I-362 was 92%.
Figure JPOXMLDOC01-appb-T000372
Figure JPOXMLDOC01-appb-T000372
試験例11-1 hERG試験
 本発明化合物の心電図QT間隔延長リスク評価を目的として、human ether-a-go-go related gene (hERG)チャネルを発現させたHEK293細胞を用いて、心室再分極過程に重要な役割を果たす遅延整流K電流(IKr)への本発明化合物の作用を検討する。
 全自動パッチクランプシステム(PatchXpress 7000A、AxonInstruments Inc.)を用い、ホールセルパッチクランプ法により、細胞を-80mVの膜電位に保持し、-50mVのリーク電位を与えた後、+40mVの脱分極刺激を2秒間、さらに-50mVの再分極刺激を2秒間与えた際に誘発されるIKrを記録した。発生する電流が安定した後、本発明化合物を目的の濃度で溶解させた細胞外液(NaCl:135 mmol/L、KCl:5.4 mmol/L、NaHPO:0.3mmol/L、CaCl・2HO:1.8mmol/L、MgCl・6HO:1mmol/L、グルコース:10mmol/L、HEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid、4-(2-ヒドロキシエチル)-1-ピペラジンエタンスルホン酸):10mmol/L、pH=7.4)を室温条件下で、10分間細胞に適用させた。得られたIKrから、解析ソフト(DataXpress ver.2、Molecular Devices Corporation)を使用して、保持膜電位における電流値を基準に最大テール電流の絶対値を計測した。さらに、本発明化合物適用前の最大テール電流に対する阻害率を算出し、媒体適用群(0.1%ジメチルスルホキシド溶液)と比較して、本発明化合物のIKrへの影響を評価した。
(結果)化合物濃度1μmol/Lでの阻害率を示す。
Test Example 11-1 hERG Test For the purpose of evaluating the risk of extending the electrocardiogram QT interval of the compound of the present invention, HEK293 cells expressing a human ether-a-go-related gene (hERG) channel were used for the ventricular repolarization process. Consider the action of the compounds of the present invention on the delayed rectifier K + current (I Kr ), which plays an important role.
Using a fully automatic patch clamp system (PatchXpress 7000A, Axon Instruments Inc.), the cell was held at a membrane potential of −80 mV by the whole cell patch clamp method, a leak potential of −50 mV was applied, and then a depolarization stimulus of +40 mV was applied. I Kr elicited when 2 seconds of additional -50 mV repolarization stimulation was applied for 2 seconds was recorded. After the generated current is stabilized, an extracellular fluid (NaCl: 135 mmol / L, KCl: 5.4 mmol / L, NaH 2 PO 4 : 0.3 mmol / L, in which the compound of the present invention is dissolved at a target concentration, CaCl 2 · 2H 2 O: 1.8 mmol / L, MgCl 2 · 6H 2 O: 1 mmol / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazine ethersulfonic acid, 4- (2- Hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7.4) was applied to the cells for 10 minutes at room temperature. From the obtained I Kr , the absolute value of the maximum tail current was measured based on the current value at the holding membrane potential using analysis software (DataXpress ver. 2, Molecular Devices Corporation). Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention was calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr was evaluated.
(Result) The inhibition rate at a compound concentration of 1 μmol / L is shown.
Figure JPOXMLDOC01-appb-T000373
Figure JPOXMLDOC01-appb-T000373
試験例11-2 hERG試験
 本発明化合物の心電図QT間隔延長リスク評価を目的として、human ether-a-go-go related gene (hERG)チャネルを発現させたCHO細胞を用いて、心室再分極過程に重要な役割を果たす遅延整流K電流(IKr)への本発明化合物の作用を検討する。
 全自動パッチクランプシステム(QPatch;Sophion Bioscience A/S)を用い、ホールセルパッチクランプ法により、細胞を-80mVの膜電位に保持し、-50mVのリーク電位を与えた後、+20mVの脱分極刺激を2秒間、さらに-50mVの再分極刺激を2秒間与えた際に誘発されるIKrを記録する。発生する電流が安定した後、本発明化合物を目的の濃度で溶解させた細胞外液(NaCl:145 mmol/L、KCl:4 mmol/L、CaCl:2 mmol/L、MgCl:1 mmol/L、グルコース:10 mmol/L、HEPES(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid、4-(2-ヒドロキシエチル)-1-ピペラジンエタンスルホン酸):10 mmol/L、pH=7.4)を室温条件下で、10分間細胞に適用させる。得られたIKrから、解析ソフト(Falster Patch;Sophion Bioscience A/S)を使用して、保持膜電位における電流値を基準に最大テール電流の絶対値を計測する。さらに、本発明化合物適用前の最大テール電流に対する阻害率を算出し、媒体適用群(0.1%ジメチルスルホキシド溶液)と比較して、本発明化合物のIKrへの影響を評価する。
Test Example 11-2 hERG Test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, CHO cells expressing human ether-a-go related gene (hERG) channels were used for ventricular repolarization process. Consider the action of the compounds of the present invention on the delayed rectifier K + current (I Kr ), which plays an important role.
Using a fully automatic patch clamp system (QPatch; Sophion Bioscience A / S), the cell was held at a membrane potential of −80 mV by a whole cell patch clamp method, and after applying a leak potential of −50 mV, a depolarization stimulus of +20 mV for 2 seconds, further records the I Kr induced repolarization stimulated when given 2 seconds -50 mV. After the generated current is stabilized, an extracellular solution (NaCl: 145 mmol / L, KCl: 4 mmol / L, CaCl 2 : 2 mmol / L, MgCl 2 : 1 mmol) in which the compound of the present invention is dissolved at a desired concentration. / L, glucose: 10 mmol / L, HEPES (4- (2-hydroxyethyl) -1-piperazine ethersulfonic acid, 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid): 10 mmol / L, pH = 7 4) is applied to the cells for 10 minutes at room temperature. The absolute value of the maximum tail current is measured from the obtained I Kr using analysis software (Falster Patch; Sophion Bioscience A / S) based on the current value at the holding membrane potential. Furthermore, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention is calculated, and compared with the vehicle application group (0.1% dimethyl sulfoxide solution), the effect of the compound of the present invention on I Kr is evaluated.
試験例12:代謝安定性試験
 調製したラット凍結保存肝細胞を用いて、対象化合物を一定時間反応させ、反応サンプルと未反応サンプルの比較により残存率を算出し、肝で代謝される程度を評価する。
Test Example 12: Metabolic stability test Using prepared rat cryopreserved hepatocytes, the target compound is allowed to react for a certain period of time, the residual rate is calculated by comparing the reaction sample with the unreacted sample, and the degree of metabolism in the liver is evaluated. To do.
 ラット凍結肝細胞1.0x106cells/mLを含むウイリアムE培地中で37℃、0、1あるいは2時間反応させる。反応後、反応液30 μLにメタノール/アセトニトリル=1/1(v/v)溶液120 μLを添加、混合し、3000rpmで15分間遠心する。その遠心上清中の試験化合物をLC/MS/MSにて定量し、反応後の試験化合物の残存量を0分反応時の化合物量を100%として計算する。 Incubate at 37 ° C for 0, 1 or 2 hours in William E medium containing 1.0x10 6 cells / mL of rat frozen hepatocytes. After the reaction, 120 μL of methanol / acetonitrile = 1/1 (v / v) solution is added to 30 μL of the reaction solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The test compound in the centrifugal supernatant is quantified by LC / MS / MS, and the remaining amount of the test compound after the reaction is calculated with the amount of the compound at 0 minute reaction as 100%.
試験例13:蛋白結合試験
 各種血清を用いて、発明化合物の血清蛋白非結合率を測定した。
Test Example 13: Protein binding test The serum protein non-binding rate of the inventive compound was measured using various sera.
 反応条件は以下のとおり:評価法、平衡透析法;反応時間、24時間;反応温度、37℃;発明化合物濃度、2 μg/mL。 Reaction conditions are as follows: evaluation method, equilibrium dialysis method; reaction time, 24 hours; reaction temperature, 37 ° C .; inventive compound concentration, 2 μg / mL.
 各種血清に検液を添加、攪拌し、上記化合物濃度の血清試料を調製した。平衡透析セルの一方に血清試料を、もう一方にリン酸緩衝生理食塩水 (PBS)を加え、37℃で24時間平衡透析した。各セルから採取した試料中化合物量をLC/MS/MSで測定した。
 本発明化合物の試験結果を以下の表に示す。血清中化合物量に対するPBS中化合物量の比を蛋白非結合率(%)として示す。
Test solutions were added to various sera and stirred to prepare serum samples having the above compound concentrations. A serum sample was added to one of the equilibrium dialysis cells, and phosphate buffered saline (PBS) was added to the other, followed by equilibrium dialysis at 37 ° C. for 24 hours. The amount of compound in the sample collected from each cell was measured by LC / MS / MS.
The test results of the compounds of the present invention are shown in the following table. The ratio of the amount of compound in PBS to the amount of compound in serum is shown as protein non-binding rate (%).
Figure JPOXMLDOC01-appb-T000374
Figure JPOXMLDOC01-appb-T000374
試験例14:バイオアベイラビリティ(BA)試験
経口吸収性の検討実験材料と方法
(1)使用動物:SDラットを使用した。
(2)飼育条件:SDラットは、固形飼料および滅菌水道水を自由摂取させた。
(3)投与量、群分けの設定:所定の投与量で経口及び静脈内投与した。以下のように群を設定した。(化合物ごとで投与量は変更有)
 経口投与 1mg/kg(n=2)
 静脈内投与 0.5mg/kg(n=2)
(4)投与液の調製:経口投与は懸濁液として投与した。静脈内投与は可溶化して投与した。
(5)投与方法:経口投与は、経口ゾンデにより胃内に投与した。静脈内投与は、注射針を付けたシリンジにより尾静脈から投与した。
(6)評価項目:経時的に採血し、血漿中本発明化合物濃度をLC/MS/MSを用いて測定した。
(7)統計解析:血漿中本発明化合物濃度推移について、非線形最小二乗法プログラムWinNonlin(登録商標)を用いて血漿中濃度‐時間曲線下面積(AUC)を算出し、経口投与群と静脈内投与群の投与量比およびAUC比から本発明化合物のバイオアベイラビリティ(BA)を算出した。
 本発明化合物の試験結果を以下の表に示す。
Test Example 14: Bioavailability (BA) test Examination of oral absorbability Experimental materials and methods (1) Animals used: SD rats were used.
(2) Breeding conditions: SD rats were allowed to freely take solid feed and sterilized tap water.
(3) Setting of dosage and grouping: oral and intravenous administration at a predetermined dosage. Groups were set up as follows. (Dose may vary for each compound)
Oral administration 1 mg / kg (n = 2)
Intravenous administration 0.5 mg / kg (n = 2)
(4) Preparation of administration solution: Oral administration was administered as a suspension. Intravenous administration was solubilized.
(5) Administration method: Oral administration was administered intragastrically with an oral sonde. Intravenous administration was carried out from the tail vein using a syringe with an injection needle.
(6) Evaluation items: Blood was collected over time, and the concentration of the compound of the present invention in plasma was measured using LC / MS / MS.
(7) Statistical analysis: The plasma concentration-time curve area (AUC) is calculated using the non-linear least squares program WinNonlin (Registered Trademark) for plasma compound concentration transition, and the oral administration group and intravenous administration The bioavailability (BA) of the compound of the present invention was calculated from the dose ratio of the group and the AUC ratio.
The test results of the compounds of the present invention are shown in the following table.
Figure JPOXMLDOC01-appb-T000375
Figure JPOXMLDOC01-appb-T000375
試験例15:粉末溶解度試験
 適当な容器に本発明化合物を適量入れ、各容器にJP-1液(塩化ナトリウム2.0g、塩酸7.0mLに水を加えて1000mLとする)、JP-2液(pH6.8のリン酸塩緩衝液500mLに水500mLを加える)、20mmol/L タウロコール酸ナトリウム(TCA)/JP-2液(TCA1.08gにJP-2液を加え100mLとする)を200μLずつ添加する。試験液添加後に全量溶解した場合には、適宜、本発明化合物を追加する。密閉して37℃で1時間振とう後に濾過し、各濾液100μLにメタノール100μLを添加して2倍希釈を行う。希釈倍率は、必要に応じて変更する。気泡および析出物がないかを確認し、密閉して振とうする。絶対検量線法によりHPLCを用いて本発明化合物を定量する。
Test Example 15: Powder solubility test An appropriate amount of the compound of the present invention is placed in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid is added to 1000 mL) and JP-2 solution are added to each container. (Add 500 mL of water to 500 mL of phosphate buffer solution at pH 6.8), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (JP-2 solution is added to 1.08 g of TCA to make 100 mL) 200 μL each Added. When the entire amount is dissolved after the addition of the test solution, the compound of the present invention is appropriately added. After sealing at 37 ° C. for 1 hour, the mixture is filtered, and 100 μL of methanol is added to 100 μL of each filtrate to perform 2-fold dilution. Change the dilution factor as necessary. Check for bubbles and precipitates, seal and shake. The compound of the present invention is quantified using HPLC by the absolute calibration curve method.
製剤例
 以下に示す製剤例は例示にすぎないものであり、発明の範囲を何ら限定することを意図するものではない。
製剤例1 錠剤
  本発明化合物         15mg
  乳糖             15mg
  ステアリン酸カルシウム     3mg
 ステアリン酸カルシウム以外の成分を均一に混合し、破砕造粒して乾燥し、適当な大きさの顆粒剤とする。次にステアリン酸カルシウムを添加して圧縮成形して錠剤とする。
Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1 Tablet 15 mg of the present compound
Lactose 15mg
Calcium stearate 3mg
Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.
製剤例2 カプセル剤
  本発明化合物         10mg
  ステアリン酸マグネシウム   10mg
  乳糖             80mg
を均一に混合して粉末又は細粒状として散剤をつくる。それをカプセル容器に充填してカプセル剤とする。
Formulation Example 2 Capsule Compound of the present invention 10 mg
Magnesium stearate 10mg
Lactose 80mg
Are mixed uniformly to form a powder as a powder or fine particles. It is filled into a capsule container to form a capsule.
製剤例3 顆粒剤
  本発明化合物           30g
  乳糖              265g
  ステアリン酸マグネシウム      5g
 よく混合し、圧縮成型した後、粉砕、整粒し、篩別して適当な大きさの顆粒剤とする。
Formulation Example 3 Granules Compound of the present invention 30 g
Lactose 265g
Magnesium stearate 5g
After mixing well, compression molding, pulverizing, sizing, and sieving to make granules of appropriate size.
 一般式(I)および一般式(II)で示される化合物は、P2X3および/またはP2X2/3受容体に対する拮抗作用を有し、P2X3および/またはP2X2/3受容体が関与する疾患または状態、例えば慢性疼痛、排尿障害、呼吸器疾患に対して有用であると考えられる。 Compound represented by the general formula (I) and formula (II), have an antagonistic effect on P2X 3 and / or P2X 2/3 receptor, diseases P2X 3 and / or P2X 2/3 receptor is involved Or it may be useful for conditions such as chronic pain, dysuria, respiratory disease.

Claims (15)

  1.  式(I):
    Figure JPOXMLDOC01-appb-C000001

    (式中、
     RおよびRは、共に水素原子、または一緒になって、オキソ、チオキソもしくは=N-R
     RおよびRは、共に水素原子、または一緒になって、オキソ、チオキソもしくは=N-R
     RおよびRは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリール;
     Rは、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアシル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリール;
     R4aは、それぞれ独立して、水素原子もしくは置換もしくは非置換のアルキル;
     R4bは、それぞれ独立して、水素原子もしくは置換もしくは非置換のアルキル;または同一の炭素原子に結合するR4aとR4bが一緒になってオキソもしくはチオキソ;
     nは1~4の整数;
     Rは、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール;
     -X-は、-O-、-S-、-N(R)-または-(C(R5a)(R5b))-;
     -L-は、-O-、-S-、-N(R5’)-または-(C(R5a’)(R5b’))-;
     RおよびR5’は、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、または置換もしくは非置換のアシル;
     R5a、R5b、R5a’ およびR5b’は、それぞれ独立して、水素原子、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルキニルオキシまたは置換もしくは非置換のアルケニルオキシ;
     環Dは、ベンゼン、ピリジン、ピリミジン、ピラジンまたはピリダジン;
     炭素原子aおよび炭素原子bは、環Dを構成する炭素原子;
     環Bは、芳香族炭素環、非芳香族炭素環、芳香族複素環または非芳香族複素環;
     sおよびs’は、それぞれ独立して、0~3の整数;
     Rは、それぞれ独立してハロゲン、ヒドロキシ、カルボキシ、シアノ、ニトロ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、置換スルホニル、置換スルフィニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシまたは置換もしくは非置換のヘテロアリールオキシ;
     R9’は、それぞれ独立してハロゲン、ヒドロキシ、カルボキシ、シアノ、ニトロ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のアミノ、置換もしくは非置換のスルファモイル、置換スルホニル、置換スルフィニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のシクロアルキルオキシ、置換もしくは非置換のシクロアルケニルオキシ、置換もしくは非置換の非芳香族複素環オキシ、置換もしくは非置換のアリールオキシまたは置換もしくは非置換のヘテロアリールオキシ;
     ただし、環Bが、シクロペンタン、ベンゼン、テトラヒドロピランまたはピペリジンのとき、s’は1~3の整数である)
    で示される化合物またはその製薬上許容される塩。
    Formula (I):
    Figure JPOXMLDOC01-appb-C000001

    (Where
    R a and R b are both a hydrogen atom or together, oxo, thioxo or ═N—R x ;
    R d and R e are both hydrogen atoms or together, oxo, thioxo or ═N—R y ;
    R x and R y are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Alkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
    R c is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl Substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
    Each R 4a independently represents a hydrogen atom or substituted or unsubstituted alkyl;
    R 4b is each independently a hydrogen atom or substituted or unsubstituted alkyl; or R 4a and R 4b bonded to the same carbon atom together are oxo or thioxo;
    n is an integer of 1 to 4;
    R 2 represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
    —X— represents —O—, —S—, —N (R 5 ) — or — (C (R 5a ) (R 5b )) —;
    —L— represents —O—, —S—, —N (R 5 ′ ) — or — (C (R 5a ′ ) (R 5b ′ )) —;
    R 5 and R 5 ′ are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl;
    R 5a , R 5b , R 5a ′ and R 5b ′ each independently represent a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or Unsubstituted alkyloxy, substituted or unsubstituted alkynyloxy or substituted or unsubstituted alkenyloxy;
    Ring D is benzene, pyridine, pyrimidine, pyrazine or pyridazine;
    Carbon atom a and carbon atom b are carbon atoms constituting ring D;
    Ring B is an aromatic carbocycle, non-aromatic carbocycle, aromatic heterocycle or non-aromatic heterocycle;
    s and s ′ are each independently an integer of 0 to 3;
    R 9 is independently halogen, hydroxy, carboxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Substituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted alkyloxy Carbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfoni Ru, substituted sulfinyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy;
    R 9 ′ is independently halogen, hydroxy, carboxy, cyano, nitro, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or Unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted alkyl Oxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted sulfamoyl, substituted sulfo Ru, substituted sulfinyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted Or unsubstituted cycloalkyloxy, substituted or unsubstituted cycloalkenyloxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aryloxy or substituted or unsubstituted heteroaryloxy;
    (However, when ring B is cyclopentane, benzene, tetrahydropyran or piperidine, s ′ is an integer of 1 to 3)
    Or a pharmaceutically acceptable salt thereof.
  2.  -Rが、-(C(R11c)(R11d))m’-CN
    (式中、R11cは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、もしくは置換もしくは非置換のアルキニル;
     R11dは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、もしくは置換もしくは非置換のアルキニル;または、同一の炭素原子に結合するR11cとR11dが一緒になって、置換もしくは非置換のシクロアルカン、置換もしくは非置換のシクロアルケン、もしくは置換もしくは非置換の非芳香族複素環;
     m’は、1~4の整数である)
    である、請求項1に記載の化合物またはその製薬上許容される塩。
    —R c is — (C (R 11c ) (R 11d )) m′-CN
    (Wherein R 11c each independently represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl;
    R 11d is each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, or substituted or unsubstituted alkynyl; or R 11c and R 11d bonded to the same carbon atom are A substituted or unsubstituted cycloalkane, substituted or unsubstituted cycloalkene, or substituted or unsubstituted non-aromatic heterocycle;
    m ′ is an integer of 1 to 4)
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof.
  3.  Rが、3~5個のヒドロキシで置換され、さらに置換基群α(置換基群α:ハロゲン、シアノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミノ、置換もしくは非置換のイミノ、置換もしくは非置換のグアニジル、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、ニトロおよびチオキソ)から選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルキル;3~5個のヒドロキシで置換され、さらに置換基群αから選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルケニル;または3~5個のヒドロキシで置換され、さらに置換基群αから選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルキニルである、請求項1に記載の化合物またはその製薬上許容される塩。 R c is substituted with 3 to 5 hydroxy groups, and substituent group α (substituent group α: halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino Substituted or unsubstituted Anidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxy One or more substituents selected from carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro and thioxo) An optionally substituted C3-C6 alkyl; a C3-C6 alkenyl optionally substituted with 3-5 hydroxy and further substituted with one or more substituents selected from substituent group α; or Substituted with 3-5 hydroxy Further 1 or more substituents may C3 ~ C6 alkynyl optionally substituted with selected from Substituent group alpha, a compound or a pharmaceutically acceptable salt thereof according to claim 1.
  4.  sが1または2であり、少なくとも一つのRが、ハロゲン、ヒドロキシ、シアノ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のシクロアルキルまたは置換もしくは非置換のシクロアルケニルである、請求項1~3のいずれかに記載の化合物またはその製薬上許容される塩。 s is 1 or 2, and at least one R 9 is halogen, hydroxy, cyano, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, 4. The compound according to claim 1, which is substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted cycloalkenyl, or a pharmaceutical thereof Acceptable salt.
  5.  式:
    Figure JPOXMLDOC01-appb-C000002

    で示される基が、式:
    Figure JPOXMLDOC01-appb-C000003

    (式中、-X-および-L-は、請求項1と同意義;Rは、ハロゲンまたは置換もしくは非置換のアルキル;Y、YおよびYは、それぞれ独立して、CHまたはN;ただし、Y、YおよびYは、同時にNではない)で示される基である、請求項1~4のいずれかに記載の化合物またはその製薬上許容される塩。
    formula:
    Figure JPOXMLDOC01-appb-C000002

    The group represented by the formula:
    Figure JPOXMLDOC01-appb-C000003

    Wherein -X- and -L- are as defined in claim 1; R 9 is halogen or substituted or unsubstituted alkyl; Y 1 , Y 2 and Y 3 are each independently CH or N; wherein Y 1 , Y 2 and Y 3 are not simultaneously N), or a pharmaceutically acceptable salt thereof.
  6.  式(II):
    Figure JPOXMLDOC01-appb-C000004

    (式中、
     RおよびRは、共に水素原子、または一緒になって、オキソ、チオキソもしくは=N-R
     RおよびRは、共に水素原子、または一緒になって、オキソ、チオキソもしくは=N-R
     RおよびRは、それぞれ独立して、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリールまたは置換もしくは非置換のヘテロアリール;
     Rは、3~5個のヒドロキシで置換され、さらに置換基群α(置換基群α:ハロゲン、シアノ、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルケニルオキシ、置換もしくは非置換のアルキニルオキシ、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環基、置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、置換もしくは非置換のアルキルオキシカルボニル、置換もしくは非置換のアルケニルオキシカルボニル、置換もしくは非置換のアルキニルオキシカルボニル、置換もしくは非置換のカルバモイル、置換もしくは非置換のスルファモイル、置換もしくは非置換のアミノ、置換もしくは非置換のイミノ、置換もしくは非置換のグアニジル、置換もしくは非置換のアルキルチオ、置換もしくは非置換のアルケニルチオ、置換もしくは非置換のアルキニルチオ、置換もしくは非置換のアシル、置換もしくは非置換のシクロアルキルオキシカルボニル、置換もしくは非置換のシクロアルケニルオキシカルボニル、置換もしくは非置換の非芳香族複素環オキシカルボニル、置換もしくは非置換のアリールオキシカルボニル、置換もしくは非置換のヘテロアリールオキシカルボニル、ニトロ、およびチオキソ)から選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルキル;3~5個のヒドロキシで置換され、さらに置換基群αから選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルケニル;または3~5個のヒドロキシで置換され、さらに置換基群αから選択される1またはそれ以上の置換基で置換されていてもよいC3~C6アルキニル;
     R4aは、それぞれ独立して、水素原子もしくは置換もしくは非置換のアルキル;
     R4bは、それぞれ独立して、水素原子もしくは置換もしくは非置換のアルキル;または同一の炭素原子に結合するR4aとR4bが一緒になってオキソもしくはチオキソ;
     nは1~4の整数;
     Rは、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリール;
     -X-は、-O-、-S-、-N(R)-または-(C(R5a)(R5b))-;
     Rは、水素原子、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、または置換もしくは非置換のアシル;
     R5aおよびR5bは、それぞれ独立して水素原子、ハロゲン、ヒドロキシ、置換もしくは非置換のアルキル、置換もしくは非置換のアルケニル、置換もしくは非置換のアルキニル、置換もしくは非置換のアルキルオキシ、置換もしくは非置換のアルキニルオキシ、または置換もしくは非置換のアルケニルオキシ;
     Rは、置換もしくは非置換のシクロアルキル、置換もしくは非置換のシクロアルケニル、置換もしくは非置換の非芳香族複素環式基、置換もしくは非置換のアリール、または置換もしくは非置換のヘテロアリールである)
    で示される化合物またはその製薬上許容される塩。
    Formula (II):
    Figure JPOXMLDOC01-appb-C000004

    (Where
    R a and R b are both a hydrogen atom or together, oxo, thioxo or ═N—R x ;
    R d and R e are both hydrogen atoms or together, oxo, thioxo or ═N—R y ;
    R x and R y are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cyclo Alkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
    R c is substituted with 3 to 5 hydroxy groups, and further substituted group α (substituent group α: halogen, cyano, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted Alkynyloxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted Alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amino, substituted or unsubstituted imino Substituted or unsubstituted Anidyl, substituted or unsubstituted alkylthio, substituted or unsubstituted alkenylthio, substituted or unsubstituted alkynylthio, substituted or unsubstituted acyl, substituted or unsubstituted cycloalkyloxycarbonyl, substituted or unsubstituted cycloalkenyloxy One or more substituents selected from carbonyl, substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl, substituted or unsubstituted aryloxycarbonyl, substituted or unsubstituted heteroaryloxycarbonyl, nitro, and thioxo) C3-C6 alkyl optionally substituted with C3-C6 alkenyl substituted with 3-5 hydroxy and further substituted with one or more substituents selected from substituent group α; Or substituted with 3-5 hydroxy Are further 1 or more are also may C3 ~ optionally C6 alkynyl substituted with a substituent selected from substituent group alpha;
    Each R 4a independently represents a hydrogen atom or substituted or unsubstituted alkyl;
    R 4b is each independently a hydrogen atom or substituted or unsubstituted alkyl; or R 4a and R 4b bonded to the same carbon atom together are oxo or thioxo;
    n is an integer of 1 to 4;
    R 2 represents substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
    —X— represents —O—, —S—, —N (R 5 ) — or — (C (R 5a ) (R 5b )) —;
    R 5 represents a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted acyl;
    R 5a and R 5b each independently represent a hydrogen atom, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted Substituted alkynyloxy or substituted or unsubstituted alkenyloxy;
    R 3 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl )
    Or a pharmaceutically acceptable salt thereof.
  7.  RおよびRが一緒になってオキソであり、
     RおよびRが一緒になってオキソであり、
     R
    Figure JPOXMLDOC01-appb-C000005

    (式中、Alkはアルキルである)
    で示される基であり、
     nが1であり、R4aおよびR4bが共に水素原子であり、
     -X-が-N(H)-であり、
     環Dがベンゼンであり、
    Figure JPOXMLDOC01-appb-C000006

    であり、その他の記号は請求項1と同義である、請求項1記載の化合物またはその製薬上許容される塩。
    R a and R b together are oxo,
    R d and R e together are oxo,
    R c is
    Figure JPOXMLDOC01-appb-C000005

    (Wherein Alk is alkyl)
    A group represented by
    n is 1, R 4a and R 4b are both hydrogen atoms,
    -X- is -N (H)-;
    Ring D is benzene,
    Figure JPOXMLDOC01-appb-C000006

    Wherein the other symbols are as defined in claim 1, or a pharmaceutically acceptable salt thereof.
  8.  RおよびRが一緒になってオキソであり、
     RおよびRが一緒になってオキソであり、
     R
    Figure JPOXMLDOC01-appb-C000007

    (式中、Alkはアルキルである)
    で示される基であり、
     nが1であり、R4aおよびR4bが共に水素原子であり、
     -X-が-N(H)-であり、
     環Dがベンゼンであり、
    Figure JPOXMLDOC01-appb-C000008

    であり;
     s’が、1から3の整数であり、かつ
     少なくとも1つのR9’が、ハロゲンまたはハロアルキルであり、その他の記号は請求項1と同義である、請求項1記載の化合物またはその製薬上許容される塩。
    R a and R b together are oxo,
    R d and R e together are oxo,
    R c is
    Figure JPOXMLDOC01-appb-C000007

    (Wherein Alk is alkyl)
    A group represented by
    n is 1, R 4a and R 4b are both hydrogen atoms,
    -X- is -N (H)-;
    Ring D is benzene,
    Figure JPOXMLDOC01-appb-C000008

    Is;
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein s 'is an integer of 1 to 3, and at least one R 9' is halogen or haloalkyl, and other symbols are as defined in claim 1. Salt.
  9.  RおよびRが一緒になってオキソであり、
     RおよびRが一緒になってオキソであり、
     Rが置換もしくは非置換のアリール、置換もしくは非置換のヘテロアリール、または置換もしくは非置換の非芳香族複素環式基であり;
     nが1であり、R4aおよびR4bが共に水素原子であり、
     -X-が-N(H)-であり、
     -L-が-O-であり、
     環Dがベンゼンであり、
     環Bが、ピリジンまたはチアゾールであり;
     s’が、1から3の整数であり;かつ
     少なくとも1つのR9’が、カルボキシまたはアルキルオキシカルボニルであり、その他の記号は請求項1と同義である、請求項1記載の化合物またはその製薬上許容される塩。
    R a and R b together are oxo,
    R d and R e together are oxo,
    R c is a substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or a substituted or unsubstituted non-aromatic heterocyclic group;
    n is 1, R 4a and R 4b are both hydrogen atoms,
    -X- is -N (H)-;
    -L- is -O-,
    Ring D is benzene,
    Ring B is pyridine or thiazole;
    The compound according to claim 1, wherein s 'is an integer of 1 to 3; and at least one R 9' is carboxy or alkyloxycarbonyl, and other symbols are as defined in claim 1, or a pharmaceutical thereof Top acceptable salt.
  10.  RおよびRが一緒になってオキソであり、
     RおよびRが一緒になってオキソであり、
     Rがアルキルであり、
     nが1であり、R4aおよびR4bが共に水素原子であり、
     -X-が-N(H)-であり、
     環Dがベンゼンであり、
     sが1~3の整数であり、
    Figure JPOXMLDOC01-appb-C000009

    (式中、s’’は0~2の整数であり、その他の記号は請求項1と同義である、請求項1記載の化合物またはその製薬上許容される塩。
    R a and R b together are oxo,
    R d and R e together are oxo,
    R c is alkyl;
    n is 1, R 4a and R 4b are both hydrogen atoms,
    -X- is -N (H)-;
    Ring D is benzene,
    s is an integer of 1 to 3,
    Figure JPOXMLDOC01-appb-C000009

    (Wherein s ″ is an integer of 0 to 2 and other symbols are as defined in claim 1, or a pharmaceutically acceptable salt thereof).
  11.  RおよびRが一緒になってオキソであり、
     RおよびRが一緒になってオキソであり、
     R
    Figure JPOXMLDOC01-appb-C000010

    (式中、Alkはアルキルである)
    で示される基であり、
     nが1であり、R4aおよびR4bが共に水素原子であり、
     Rが置換もしくは非置換のシクロアルキルであり、
     -X-が-N(H)-であり、
     -L-が-O-であり、
     環Dがベンゼンであり、
    その他の記号は請求項1と同義である、請求項1記載の化合物またはその製薬上許容される塩。
    R a and R b together are oxo,
    R d and R e together are oxo,
    R c is
    Figure JPOXMLDOC01-appb-C000010

    (Wherein Alk is alkyl)
    A group represented by
    n is 1, R 4a and R 4b are both hydrogen atoms,
    R 2 is substituted or unsubstituted cycloalkyl,
    -X- is -N (H)-;
    -L- is -O-,
    Ring D is benzene,
    The other symbols have the same meanings as in claim 1, or the compound or pharmaceutically acceptable salt thereof according to claim 1.
  12.  請求項1~11のいずれかに記載の化合物またはその製薬上許容される塩を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.
  13.  P2Xおよび/またはP2X2/3受容体拮抗作用を有する請求項12記載の医薬組成物。 P2X 3 and / or P2X 2/3 pharmaceutical composition according to claim 12, further comprising a receptor antagonism.
  14.  P2X3および/またはP2X2/3受容体が関与する疾患の治療および/または予防に使用するための、請求項1~11のいずれかに記載の化合物またはその製薬上許容される塩。 The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease involving P2X 3 and / or P2X 2/3 receptor.
  15.  請求項1~11のいずれかに記載の化合物またはその製薬上許容される塩を投与することを特徴とする、P2X3および/またはP2X2/3受容体が関与する疾患の治療および/または予防方法。 The treatment and / or prevention of a disease involving P2X 3 and / or P2X 2/3 receptor, which comprises administering the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof. Method.
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