WO2016084922A1 - 1,2,4-triazine derivative and pharmaceutical composition thereof - Google Patents

1,2,4-triazine derivative and pharmaceutical composition thereof Download PDF

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Publication number
WO2016084922A1
WO2016084922A1 PCT/JP2015/083319 JP2015083319W WO2016084922A1 WO 2016084922 A1 WO2016084922 A1 WO 2016084922A1 JP 2015083319 W JP2015083319 W JP 2015083319W WO 2016084922 A1 WO2016084922 A1 WO 2016084922A1
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substituted
unsubstituted
group
aromatic heterocyclic
aromatic
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PCT/JP2015/083319
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French (fr)
Japanese (ja)
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浩幸 甲斐
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塩野義製薬株式会社
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Priority to JP2016561953A priority Critical patent/JPWO2016084922A1/en
Publication of WO2016084922A1 publication Critical patent/WO2016084922A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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 the 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 was reported as an antagonist specific for the P2X 3 and P2X 2/3 receptors.
  • A-317491 has the following formula: 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 .
  • Non-patent Document 2 a compound having a P2X 3 receptor antagonistic action is used in the treatment of diseases accompanied by abnormal dysuria. It also suggests that it is useful.
  • 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 9 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 10 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 11 describes a compound having a 1,2,4-triazine skeleton similar to the compound of the present invention, but does not describe analgesic action and P2X 3 or P2X 2/3 receptor antagonistic action.
  • Non-Patent Documents 8 and 14 describe compounds having a 1,3,5-triazine skeleton similar to the compounds of the present invention and exhibiting analgesic activity, but P2X 3 or P2X 2/3 receptors. No antagonism has been described.
  • Patent Documents 2 to 8, 15 and 16 and Non-Patent Documents 12 and 13 also describe compounds exhibiting P2X 3 or P2X 2/3 receptor antagonistic activity, but the structure is different from the compounds of the present invention.
  • Patent Documents 12 to 14 and 17 describe compounds having a P2X 3 or P2X 2/3 receptor antagonistic activity having a 1,3,5-triazine skeleton similar to the compounds of the present invention.
  • 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 an 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, pharmacokinetic test.
  • bioavailability confirmation test the whole body clearance confirmation test, etc. and / or the protein binding confirmation test, good results were also shown.
  • the present invention relates to the following (1 ′) to (26 ′) and (1) to (25).
  • R 2 and R 3 are each independently a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or The compound of the above (1 ′) or a pharmaceutically acceptable salt thereof, which is a substituted or unsubstituted aromatic heterocyclic group.
  • R 2 and R 3 are each independently a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or The compound of the above (1 ′) or a pharmaceutically acceptable salt thereof, which is a substituted or unsubstituted aromatic heterocyclic group.
  • (3 ′) —X— is —N (R 5 ) — (wherein R 5 has the same meaning as (1 ′) above), or a compound according to (2 ′) or (2′A) above, Its pharmaceutically acceptable salt.
  • R 3 is of the formula: Wherein ring A is an aromatic carbocycle or aromatic heterocycle; s is an integer from 0 to 3; Each R 6 is independently halogen, hydroxy, 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, carboxy, substituted or unsubstituted alkyl Oxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alky
  • R 3 is represented by the formula: Wherein R 7 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic A heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group; R 8 is a hydrogen atom, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2 ′) to (6 ′) or
  • R 7 is a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted Or a pharmaceutically acceptable salt thereof.
  • (10 ') The compound according to the above (1 ′) or a pharmaceutically acceptable salt thereof selected from the group consisting of Examples I-20, I-24, I-29, I-33 and I-35.
  • (11 ′) A pharmaceutical composition comprising the compound according to any one of (1 ′) to (10 ′) or (2′A) or a pharmaceutically acceptable salt thereof.
  • (12 ′) The pharmaceutical composition according to (11 ′), which is a P2X 3 and / or P2X 2/3 receptor antagonist.
  • 13 ′) The pharmaceutical composition according to the above (11 ′) or (12 ′), which has an effect of treating and / or preventing chronic pain, dysuria or respiratory disease.
  • (16 ′) P2X 3 and / or P2X characterized by administering a compound according to any one of (1 ′) to (10 ′) or (2′A) or a pharmaceutically acceptable salt thereof A method for treating and / or preventing a disease involving 2/3 receptor.
  • a pharmaceutical composition for oral administration comprising the compound according to any one of the above (1 ′) to (10 ′) or (2′A), or a pharmaceutically acceptable salt thereof.
  • composition according to (20 ′) or (21 ′) above which is an agent.
  • a pharmaceutical composition for parenteral administration comprising the compound according to any one of (1 ′) to (10 ′) or (2′A) above, or a pharmaceutically acceptable salt thereof.
  • n is an integer of 1 to 4
  • R 2 and R 3 are each independently a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or The compound or a pharmaceutically acceptable salt thereof according to (1) above, which is a substituted or unsubstituted aromatic heterocyclic group.
  • (3) The compound according to (2) or a pharmaceutically acceptable salt thereof, wherein —X— is —N (R 5 ) — (wherein R 5 has the same meaning as (1) above).
  • R 3 is represented by the formula: Wherein ring A is an aromatic carbocycle or aromatic heterocycle; s is an integer from 0 to 3; Each R 6 is independently halogen, hydroxy, 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, carboxy, substituted or unsubstituted alkyl Oxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkyn
  • R 3 is represented by the formula: Wherein R 7 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic A heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group; R 8 is a hydrogen atom, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2) to (6), which is a group represented by
  • R 7 is a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted
  • R 8 is a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof.
  • (14A) The compound according to the above (13) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of neuropathic pain or inflammatory pain.
  • a disease involving P2X 3 and / or P2X 2/3 receptor characterized by administering the compound according to any one of (1) to (9) above or a pharmaceutically acceptable salt thereof Treatment and / or prevention method.
  • (16A) The method of treatment and / or prevention according to (15) above for neuropathic pain or inflammatory pain.
  • 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 includes fluorine atom, chlorine atom, bromine atom, and iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.
  • Alkyl includes straight or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. 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 and the like.
  • alkyl examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. Further preferred examples include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
  • Alkenyl has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl, tridecenyl, decenyl Etc.
  • alkenyl include vinyl, allyl, propenyl, isopropenyl and butenyl.
  • Alkynyl has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Furthermore, you may have a double bond in arbitrary positions. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
  • aromatic carbocyclic group means a cyclic aromatic hydrocarbon group having one or more rings.
  • aromatic carbocyclic group includes phenyl.
  • non-aromatic carbocyclic group means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings.
  • the “non-aromatic carbocyclic group” having two or more rings includes those obtained by condensing the ring in the above “aromatic carbocyclic group” to a monocyclic or two or more non-aromatic carbocyclic groups.
  • the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms.
  • Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
  • Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
  • “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do.
  • the aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
  • the monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members.
  • Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
  • bicyclic aromatic heterocyclic group examples include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, Oxazolyl, benzoxiadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyr Dazinyl, oxazolopyridyl, thiazolopyridyl and the like can be mentioned
  • aromatic heterocyclic group having 3 or more rings examples include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.
  • Non-aromatic heterocyclic group means a monocyclic or bicyclic or more cyclic non-aromatic cyclic group having at least one hetero atom selected from O, S and N in the ring. Means group.
  • the non-aromatic heterocyclic group having 2 or more rings is a monocyclic or 2 or more non-aromatic heterocyclic group, the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and Also included are those in which each ring in the “aromatic heterocyclic group” is condensed.
  • non-aromatic heterocyclic group having two or more rings is the same as the above-mentioned “non-aromatic carbocyclic group” and / or “non-aromatic heterocyclic group”. Also included are those in which each ring in the “group” is condensed. Furthermore, the “non-aromatic heterocyclic group” includes a group that forms a bridge or a spiro ring as described below.
  • the monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members.
  • “Hydroxyalkyl” means a group in which one or more hydroxy groups are replaced with a hydrogen atom bonded to a carbon atom of the above “alkyl”. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like. A preferred embodiment of “hydroxyalkyl” includes hydroxymethyl.
  • Alkyloxy means a group in which the above “alkyl” is bonded to an oxygen atom. Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like. Preferable embodiments of “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy.
  • Alkenyloxy means a group in which the above “alkenyl” is bonded to an oxygen atom. Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.
  • Alkynyloxy means a group in which the above “alkynyl” is bonded to an oxygen atom. Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
  • Haloalkyl means a group in which one or more of the “halogen” is bonded to the “alkyl”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like. Preferable embodiments of “haloalkyl” include trifluoromethyl and trichloromethyl.
  • Haloalkyloxy means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like. Preferable embodiments of “haloalkyloxy” include trifluoromethoxy and trichloromethoxy.
  • Alkyloxyalkyl means a group in which the above “alkyloxy” is bonded to the above “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.
  • Alkyloxyalkyloxy means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.
  • Alkylcarbonyl means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like. Preferable embodiments of “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.
  • Alkenylcarbonyl means a group in which the above “alkenyl” is bonded to a carbonyl group.
  • alkenyl ethylenylcarbonyl, propenylcarbonyl and the like can be mentioned.
  • Alkynylcarbonyl means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
  • Alkylamino means a group in which the above “alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, N, N-diisopropylamino, N-methyl-N-ethylamino and the like can be mentioned.
  • Preferable embodiments of “alkylamino” include methylamino and ethylamino.
  • Alkylsulfonyl means a group in which the above “alkyl” is bonded to a sulfonyl group.
  • methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
  • Preferable embodiments of “alkylsulfonyl” include methylsulfonyl and ethylsulfonyl.
  • Alkenylsulfonyl means a group in which the above “alkenyl” is bonded to a sulfonyl group.
  • alkenyl ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
  • Alkynylsulfonyl means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
  • Alkylcarbonylamino means a group in which the above “alkylcarbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • Alkylsulfonylamino means a group in which the above “alkylsulfonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • Preferable embodiments of “alkylsulfonylamino” include methylsulfonylamino and ethylsulfonylamino.
  • Alkylimino means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
  • Alkenylimino means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
  • Alkynylimino means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylimino ethynylimino, propynylimino and the like can be mentioned.
  • Alkylcarbonylimino means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
  • Alkenylcarbonylimino means a group in which the above “alkenylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenylcarbonylimino ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
  • Alkynylcarbonylimino means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynylcarbonylimino ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
  • Alkyloxyimino means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
  • Alkenyloxyimino means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkenyloxyimino ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
  • Alkynyloxyimino means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group.
  • alkynyloxyimino ethynyloxyimino, propynyloxyimino and the like can be mentioned.
  • Alkylcarbonyloxy means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom.
  • methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like can be mentioned.
  • Preferable embodiments of “alkylcarbonyloxy” include methylcarbonyloxy and ethylcarbonyloxy.
  • Alkenylcarbonyloxy means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom.
  • alkenylcarbonyl ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
  • Alkynylcarbonyloxy means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom.
  • alkynylcarbonyloxy ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
  • Alkyloxycarbonyl means a group in which the above “alkyloxy” is bonded to a carbonyl group. For example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, etc. It is done.
  • Preferable embodiments of “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl.
  • Alkenyloxycarbonyl means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.
  • Alkynyloxycarbonyl means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.
  • Alkylsulfanyl means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned.
  • Alkenylsulfanyl means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkenyl ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.
  • Alkynylsulfanyl means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • alkynylsulfanyl ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
  • Alkylsulfinyl means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
  • Alkenylsulfinyl means a group in which the above “alkenyl” is bonded to a sulfinyl group.
  • alkenyl ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
  • Alkynylsulfinyl means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
  • Alkylcarbamoyl means a group in which the above “alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group.
  • methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl and the like can be mentioned.
  • Alkylsulfamoyl means a group in which the above “alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group. Examples thereof include methylsulfamoyl, dimethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl and the like.
  • Trialkylsilyl means a group in which the above three “alkyls” are bonded to a silicon atom.
  • the three alkyl groups may be the same or different.
  • trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.
  • “Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl, groups shown below Etc.
  • aromatic carbocyclic alkyl Preferable embodiments of “aromatic carbocyclic alkyl” include benzyl, phenethyl and benzhydryl.
  • Non-aromatic carbocyclic alkyl means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. .
  • pyridylmethyl furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below Etc.
  • Non-aromatic heterocyclic alkyl means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl portion is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyl For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include.
  • Non-aromatic heterocyclic alkyloxy means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • the “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included.
  • pyridylmethyloxycarbonyl furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxycarbonyl means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”.
  • non-aromatic heterocyclic alkyloxycarbonyl For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below Etc.
  • “Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic carbocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”.
  • non-aromatic carbocyclic alkyloxyalkyl means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below Etc.
  • “Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”.
  • the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”.
  • pyridylmethyloxymethyl furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below Etc.
  • Non-aromatic heterocyclic alkyloxyalkyl means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”.
  • the “non-aromatic heterocyclic alkyloxyalkyl” means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “ Also included are “non-aromatic heterocyclic alkyloxyalkyl” substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below Etc.
  • “Aromatic carbocyclic alkylamino” means a group in which the above “aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples include benzylamino, phenethylamino, phenylpropylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.
  • Non-aromatic carbocyclic alkylamino means a group in which the above “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.
  • “Aromatic heterocyclic alkylamino” means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • aromatic heterocyclic alkyl For example, pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino , Pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.
  • Non-aromatic heterocyclic alkylamino means a group in which the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group.
  • tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.
  • aromatic carbocyclic oxy means a group in which an “aromatic carbocycle” is bonded to an oxygen atom.
  • aromatic carbocyclic carbonyl means a group in which an “aromatic carbocycle” is bonded to a carbonyl group.
  • “Aromatic carbocyclic oxycarbonyl” means a group in which the above “aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • “Aromatic carbocyclic sulfanyl” means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
  • “Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group.
  • aromatic carbocycle for example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
  • Non-aromatic carbocyclic oxy “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic sulfanyl”, and “non-aromatic carbocyclic sulfonyl”
  • the “aromatic carbocyclic” moiety is the same as the above “non-aromatic carbocyclic group”.
  • Non-aromatic carbocyclic oxy means a group in which “non-aromatic carbocycle” is bonded to an oxygen atom. For example, cyclopropyloxy, cyclohexyloxy, cyclohexenyloxy and the like can be mentioned.
  • Non-aromatic carbocycle carbonyl means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group.
  • cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like can be mentioned.
  • the “non-aromatic carbocyclic oxycarbonyl” means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group.
  • cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
  • Non-aromatic carbocyclic sulfanyl means a group in which a “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, cyclohexenylsulfanyl and the like.
  • Non-aromatic carbocycle sulfonyl means a group in which “non-aromatic carbocycle” is bonded to a sulfonyl group. For example, cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.
  • aromatic heterocycle part of “aromatic heterocycle oxy”, “aromatic heterocycle carbonyl”, “aromatic heterocycle oxycarbonyl”, “aromatic heterocycle sulfanyl”, and “aromatic heterocycle sulfonyl”
  • Aromatic heterocycle oxy means a group in which “aromatic heterocycle” is bonded to an oxygen atom.
  • pyridyloxy, oxazolyloxy and the like can be mentioned.
  • Aromatic heterocycle carbonyl means a group in which “aromatic heterocycle” is bonded to a carbonyl group.
  • “Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • “Aromatic heterocycle sulfanyl” means a group in which an “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
  • “Aromatic heterocycle sulfonyl” means a group in which “aromatic heterocycle” is bonded to a sulfonyl group.
  • aromatic heterocycle for example, pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
  • Non-aromatic heterocyclic oxy means a group in which “non-aromatic heterocyclic” is bonded to an oxygen atom.
  • Non-aromatic heterocyclic oxy means a group in which “non-aromatic heterocyclic” is bonded to an oxygen atom.
  • piperidinyloxy, tetrahydrofuryloxy and the like can be mentioned.
  • Non-aromatic heterocyclic carbonyl means a group in which “non-aromatic heterocyclic” is bonded to a carbonyl group.
  • piperidinylcarbonyl, tetrahydrofurylcarbonyl and the like can be mentioned.
  • the “non-aromatic heterocyclic oxycarbonyl” means a group in which the “non-aromatic heterocyclic oxy” is bonded to a carbonyl group.
  • piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfanyl means a group in which a “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group.
  • piperidinylsulfanyl, tetrahydrofurylsulfanyl and the like can be mentioned.
  • Non-aromatic heterocyclic sulfonyl means a group in which “non-aromatic heterocyclic” is bonded to a sulfonyl group.
  • piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
  • Acyl means “formyl”, “alkylcarbonyl”, “alkenylcarbonyl”, “alkynylcarbonyl”, “aromatic heterocyclic carbonyl”, “non-aromatic heterocyclic carbonyl”, “aromatic heterocyclic carbonyl” and Includes “non-aromatic heterocyclic carbonyl”.
  • the carbon atom at any position may be bonded to one or more groups selected from the following substituents.
  • substituents halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, alkylamino, alkylsulfonyl, alkeny
  • An atom at any position on the ring may be bonded to one or more groups selected from the following substituents.
  • substituents halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkylcarbonyl, alkylcarbonyl, alkyl,
  • substituted or unsubstituted non-aromatic carbocyclic group and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted as follows.
  • Examples of the substituent of “substituted or unsubstituted alkyl” in R 1 include halogen; alkyloxycarbonyl; carboxy; alkyloxy; cyano; hydroxy; carbamoyl; It may be substituted with one or more groups selected from these.
  • Examples of the substituent of “substituted or unsubstituted carbamoyl” in R 1 include alkyl; haloalkyl; non-aromatic heterocyclic group; It may be substituted with one or more groups selected from these.
  • Examples of the substituent of “substituted or unsubstituted alkyloxycarbonyl” in R 1 include alkyl; haloalkyl; It may be substituted with one or more groups selected from these.
  • As the substituent of “substituted or unsubstituted amino” in R 1 for example, non-aromatic heterocyclic carbonyl; acyl; It may be substituted with one or more groups selected from these.
  • Examples of the substituent of the “substituted or unsubstituted aromatic heterocyclic group” in R 1 include alkyl and haloalkyl. It may be substituted with one or more groups selected from these.
  • Examples of the substituent of the “substituted or unsubstituted aromatic carbocyclic group” in R 2 include halogen; alkyloxy; cyano; alkyl; carboxy; hydroxy; Examples of the substituent of the “substituted or unsubstituted non-aromatic carbocyclic group” in R 2 include halogen; alkyloxy; cyano; alkyl; carboxy; hydroxy;
  • Examples of the substituent of the “substituted or unsubstituted aromatic heterocyclic group” in R 2 include halogen; alkyloxy; cyano; alkyl; carboxy; hydroxy; Examples of the substituent of the “substituted or unsubstituted non-aromatic heterocyclic group” in R 2 include halogen; alkyloxy; cyano; alkyl; carboxy; hydroxy;
  • substituent of the “substituted or unsubstituted aromatic carbocyclic group” in R 3 include, for example, Unsubstituted or substituted (substituted groups include carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy, alkyl) aromatic heterocyclic oxy; Unsubstituted or substituted (carboxyl, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy, alkyl) as non-aromatic heterocyclic oxy; Unsubstituted or substituted (substituted groups include carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen,
  • Substituted or unsubstituted aromatic heterocyclic oxy in R 6, "substituted or unsubstituted non-aromatic heterocyclic oxy", "substituted or unsubstituted aromatic carbocyclic oxy” or “substituted or unsubstituted non Examples of the substituent of “aromatic carbocyclic oxy” include carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy and alkyl.
  • Substituted or unsubstituted aromatic heterocycle “Substituted or unsubstituted nonaromatic heterocycle”, “Substituted or unsubstituted aromatic carbocycle” or “Substituted or unsubstituted nonaromatic carbocycle” for R 7
  • substituent of “] include carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy, and alkyl.
  • —X— includes —N (R 5 ) —.
  • R 1 includes substituted or unsubstituted alkyl.
  • R 1 includes carboxy.
  • R 1 includes cyano.
  • R 1 includes substituted or unsubstituted alkyloxycarbonyl. Examples of R 1 include substituted or unsubstituted carbamoyl.
  • R 1 includes substituted or unsubstituted amino.
  • R 2 includes a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group.
  • R 2 includes substituted or unsubstituted phenyl.
  • R 2 includes substituted or unsubstituted pyridyl or thienyl.
  • R 3 includes a substituted or unsubstituted aromatic carbocyclic group.
  • R 3 includes substituted or unsubstituted phenyl.
  • Examples of R 4a include a hydrogen atom.
  • Examples of R 4b include a hydrogen atom.
  • R 5 includes a hydrogen atom.
  • Ring A includes an aromatic carbocycle or an aromatic heterocycle.
  • Ring A includes benzene or pyridine.
  • Ring A includes benzene.
  • Examples of s include 0, 1, and 2.
  • R 6 represents substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy.
  • R 7 includes a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group.
  • R 7 includes substituted or unsubstituted pyridyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted dihydropyridyl, substituted or unsubstituted pyridazino.
  • R 8 includes a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy.
  • R 1 includes substituted or unsubstituted alkyl.
  • A-1 includes substituted alkyl.
  • A-2 includes substituted alkyl.
  • A-2 includes substituted C1-C6 alkyl.
  • A-3 R 1 includes alkyl substituted with halogen.
  • A-4 R 1 includes C1-C6 alkyl substituted with halogen.
  • R 1 includes carboxy.
  • R 1 includes cyano.
  • R 1 includes substituted or unsubstituted alkyloxycarbonyl.
  • R 1 includes alkyloxycarbonyl substituted with alkyl or haloalkyl.
  • Examples of R 1 include substituted or unsubstituted carbamoyl.
  • R 1 includes substituted carbamoyl.
  • R 1 includes carbamoyl substituted with an alkyl, haloalkyl or non-aromatic heterocyclic group.
  • R 1 includes substituted or unsubstituted amino.
  • R 1 includes unsubstituted amino.
  • R 1 includes substituted amino.
  • R 1 includes non-aromatic heterocyclic carbonyl or acyl substituted amino.
  • R 1 includes a substituted or unsubstituted aromatic heterocyclic group.
  • R 1 includes an aromatic heterocyclic group substituted with alkyl or haloalkyl.
  • R 2 includes a substituted or unsubstituted aromatic carbocyclic group.
  • B-1 R 2 includes a substituted aromatic carbocyclic group.
  • B-2 includes substituted phenyl.
  • B-3 includes an aromatic carbocyclic group substituted with halogen.
  • B-4 R 2 includes phenyl substituted with halogen.
  • R 7 includes a substituted or unsubstituted aromatic heterocyclic group.
  • C-1 R 7 includes a substituted aromatic heterocyclic group.
  • C-2 R 7 includes substituted pyridyl or substituted pyridazinyl.
  • C-3 R 7 includes an aromatic heterocyclic group substituted with carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy or alkyl.
  • R 7 includes pyridyl or pyridazinyl (substituted with carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy or alkyl).
  • R 7 includes a substituted or unsubstituted non-aromatic heterocyclic group.
  • C-6 includes a substituted non-aromatic heterocyclic group.
  • R 7 includes substituted dihydropyridyl or substituted dihydropyridazinyl.
  • R 7 includes a non-aromatic heterocyclic group substituted with carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy or alkyl.
  • R 7 includes pyridonyl or pyridazino (substituted with carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy or alkyl).
  • R 8 includes a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy.
  • D-1 R 8 includes halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy.
  • R 8 includes halogen, substituted or unsubstituted C1-C3 alkyl or substituted or unsubstituted C1-C3 alkyloxy. (Hereafter referred to as D-3)
  • the compounds of formula (I) are not limited to specific isomers, but all possible isomers (eg keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers) , Rotamers, etc.), racemates or mixtures thereof.
  • the compound in which X is —NH— includes the following tautomers.
  • One or more hydrogen, carbon and / or other atoms of the compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively.
  • 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) also includes a compound substituted with such an isotope.
  • the compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I).
  • a “radiolabeling method” for producing the “radiolabeled substance” is also encompassed in the present invention, and the “radiolabeled substance” is useful as a metabolic pharmacokinetic study, a research in a binding assay, and / or a diagnostic tool. It is.
  • the radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art.
  • the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by a catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that.
  • Other suitable methods for preparing tritium labeled compounds can be referred to “Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”.
  • the 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
  • an alkali metal for example, lithium, sodium, potassium, etc.
  • an alkaline earth metal for example, Calcium, barium, etc.
  • magnesium transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, Picolin, quinoline etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, 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, fum
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.), a co-crystal and / or a crystal polymorph. Also encompasses such various solvates, co-crystals and polymorphs.
  • the “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I).
  • solvent molecules for example, water molecules
  • a crystal polymorph may be formed by recrystallizing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • “Co-crystal” means that the compound or salt represented by the formula (I) and the counter molecule are present in the same crystal lattice, and may be formed with any number of counter molecules.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes 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 a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included.
  • a method for selecting and producing an appropriate prodrug derivative is described in, for example, “Design of Prodrugs, Elsevier, Amsterdam, 1985”. Prodrugs may themselves have activity.
  • the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group
  • prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or reacting with a condensing agent.
  • the compound represented by the formula (I) according to the present invention can be produced, for example, by the general synthesis method 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. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
  • the compounds of the present invention can be synthesized with reference to techniques known in the art. For example, it can synthesize
  • the compound represented by the general formula (I) of the present invention can be produced, for example, by the synthetic route shown below.
  • Compound (iii) is produced by reacting Compound (ii) in a solvent such as methanol, ethanol, isopropanol, acetonitrile, etc., at 0 ° C. to heating under reflux, preferably 50 ° C. to heating under reflux. can do.
  • Compound (iii) can be used in the next step as a crude product or reaction solution.
  • Compound (v) is -10 ° C to 200 ° C in a solvent such as methanol, ethanol, isopropanol, toluene, xylene or the like, and optionally in the presence of an acid such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid, preferably Compound (vi) can be produced at 0 ° C. to 150 ° C. (4th process) Compound (vi) in a solvent such as t-butanol in the presence of an acid such as acetic acid at 60 ° C. to 150 ° C., preferably 80 ° C.
  • R 12 is substituted or unsubstituted alkyl
  • R 13 and R 14 are each independently substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic alkyl, substituted or unsubstituted aromatic Heterocyclic alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted acyl, substituted or unsubstituted non-aromatic heterocyclic group, A substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, u is an integer of 1 to 4, and other symbols are as defined above.
  • Compound (ix) is mixed with a condensing agent such as 1-hydroxybenzotriazole or HOAt, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, PyBOP and the like in a solvent such as THF, DMF, and NMP.
  • a condensing agent such as 1-hydroxybenzotriazole or HOAt, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, PyBOP and the like
  • a solvent such as THF, DMF, and NMP.
  • Compound (Ib) can be produced by reacting compound (x) in the presence of a base such as isopropylpropylamine.
  • Compound (xiii) is mixed with a condensing agent such as 1-hydroxybenzotriazole or HOAt, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, PyBOP and the like in a solvent such as THF, DMF, and NMP.
  • a condensing agent such as 1-hydroxybenzotriazole or HOAt, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, PyBOP and the like
  • a solvent such as THF, DMF, and NMP.
  • Compound (Ic) can be produced by reacting compound (x) in the presence of a base such as isopropylpropylamine.
  • the compound represented by the general formula (I) has an antagonistic action on the P2X 3 and / or P2X 2/3 receptor, and is useful as a therapeutic agent for diseases involving P2X 3 and / or P2X 2/3. is there.
  • 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 urination disorder improving effect” includes a pharmaceutical composition used for treatment, prevention and / or improvement of urination disorder.
  • the compound of the present invention has not only P2X 3 and / or P2X 2/3 receptor antagonistic activity but also a usefulness as a pharmaceutical, and has any or all of the following excellent characteristics.
  • a) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
  • d) Does not show irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
  • composition of the present invention can be administered either orally or parenterally.
  • parenteral administration include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop, and intravaginal administration.
  • solid preparations for internal use eg, tablets, powders, granules, capsules, pills, films, etc.
  • liquids for internal use eg, suspensions, emulsions, elixirs, syrups
  • the tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, and the powders and granules are dry syrups.
  • the capsule may be a soft capsule, a microcapsule or a sustained release capsule.
  • injections, drops, external preparations eg eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coating agents, mouthwashes, enemas
  • Any commonly used dosage form such as an ointment, a plaster, a jelly, a cream, a patch, a patch, a powder for external use, a suppository and the like can be suitably administered.
  • the injection may be an emulsion such as O / W, W / O, O / W / O, W / O / W type.
  • 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.
  • the pharmaceutical composition can be obtained by changing the effective amount, dosage form and / or various pharmaceutical additives of the compound of the present invention as appropriate, so that it can be used for pediatric, elderly, critically ill patients or surgery. You can also
  • the pediatric pharmaceutical composition is preferably administered to a patient under the age of 12 or 15 years.
  • the pediatric pharmaceutical composition can be administered to patients less than 27 days after birth, 28 to 23 months after birth, 2 to 11 years old, or 12 to 16 years old or 18 years old.
  • the elderly pharmaceutical composition is preferably administered to a patient over 65 years of age.
  • the dose of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc., but when administered orally, usually 0.05 to 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day.
  • 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.
  • the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
  • reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in isopropanol (30 mL), and ethyl 3,3,3-trifluoro-2-oxopropanoate (1.72 mL, 13 mmol) was added under ice cooling. After that, triethylamine (2.5 mL, 18 mmol) was added dropwise for 3 minutes under ice-cooling, stirred for 5 hours under ice-cooling, and left in a refrigerator at 5 ° C. for 5 days. Water (150 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL).
  • reaction mixture was poured into ice water, acidified with 2 mol / L hydrochloric acid, and extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate.
  • reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in isopropanol (30 mL), and diethyl 2-oxohexane-1,6-dicarboxylate (2.51 g, 11.6 mmol) was added under ice-cooling.
  • Diethyl 2-oxohexane-1,6-dicarboxylate (2.51 g, 11.6 mmol) was added under ice-cooling.
  • Triethylamine (2.25 mL, 16.2 mmol) was added dropwise over 3 minutes under ice-cooling, stirred for 5 hours under ice-cooling, and then left in a refrigerator at 5 ° C. for 3 days.
  • Water 150 mL was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL).
  • the reaction mixture was concentrated under reduced pressure, acetic acid (4 ml) and diethyl 2-oxomalonate (0.170 ml, 1.112 mmol) were added to the resulting residue, and the mixture was stirred at 90 ° C. for 2 hr.
  • the reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • reaction solution was added to saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate.
  • the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4- (4-chlorobenzyl) -6- (amino) -3- [4 -(2-Pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (190 mg, 41% yield) was obtained as a yellow solid.
  • Test Example Test Example 1 Human P2X 3 Evaluation of the receptor inhibitory activity human P2X 3 receptor gene 3000 per well of stably expressing cell lines by introducing (GenBank Accession sequence Y07683) to C6BU-1 cells PDL coated 384-well microplates In a medium (DMEM containing 8.3% fetal calf serum, 8.3% horse serum, 1% antibiotic antifungal mixed solution) at 37 ° C. under 5% carbon dioxide. Cultured for 2 days.
  • 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, 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.
  • HSA Human serum albumin
  • the medium was supplemented with 4 ⁇ M Fluo-3-AM (20 mM HEPES, 137 mM NaCl, 5.37 mM KCl, 0.9 mM MgCl 2 , 1.26 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, 5.37 mM KCl, 0.9 mM MgCl 2 , 1.26 mM CaCl 2 , 5.6 mM D-glucose, 2.5 mM probenecid, 0. 5% BSA, 0.04% 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 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, 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) to a final concentration of 1% using a solution to which human serum albumin has been added to dilute the compound DMSO solution of the present invention to different concentrations per well Each 40 ⁇ L was dispensed 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, 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
  • 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.
  • Rat P2X 3 Rating rat P2X 3 receptor gene of the receptor inhibitory activity was introduced into and expressed in 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). The cells were cultured at 5 ° C. for 5 days at 5 ° C.
  • the expression plasmid was 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 incubated at 37 ° C. under 5% carbon dioxide for 1 hour.
  • 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. 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 3-2 were seeded rat P2X 3 cells stably expressing the evaluation rat P2X 3 receptor gene of the receptor inhibitory activity (GenBank Accession sequence NM_031075) was introduced into C6BU-1 cells to be 3,000 per well, The cells were cultured in a medium (DMEM containing 7.0% fetal bovine serum, 7.0% horse serum, 1% antibiotic antifungal mixed solution) at 37 ° C. and 5% carbon dioxide for 2 days.
  • DMEM containing 7.0% fetal bovine serum, 7.0% horse serum, 1% antibiotic antifungal mixed solution
  • 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 incubated at 37 ° C. under 5% carbon dioxide for 1 hour.
  • 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
  • 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 20 ⁇ L per wash buffer.
  • the microplate was installed in a high throughput screening system FLIPR 384 (Molecular Devices).
  • Fluorescence intensity measurement by FLIPR 384 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), and the DMSO solution of the compound of the present invention diluted to different concentrations with an automatic dispensing device built in FLIPR 384, 20 ⁇ 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.
  • 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.
  • the compounds described herein exhibited 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 shows an inhibitory activity against the P2X 2/3 receptor which is also composed of the P2X 2 subtype.
  • Test Example 4 rat serum albumin (RSA) Evaluation of rat P2X 3 receptor inhibitory activity in the presence of rat P2X 3 receptor gene (GenBank Accession sequence NM_031075) 1 hole per stably expressing cells introduced into C6BU-1 cells 8000 In a medium (7.0% fetal bovine serum, 7.0% horse serum, DMEM containing 1% antibiotic antifungal mixed solution) at 37 ° C. under 5% carbon dioxide. Incubate for days.
  • a medium 7.0% fetal bovine serum, 7.0% horse serum, DMEM containing 1% antibiotic antifungal mixed solution
  • 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, 10% 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, 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 7000 (Hamamatsu Photonics).
  • Fluorescence intensity measurement by FDSS 7000 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 7000.
  • 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).
  • PE-50 polyethylene tube
  • 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 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, a suspension or solution is prepared using a 0.5% methylcellulose solution, and is orally administered to an animal using an oral sonde. 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 to 2 hours after the start of measurement. Moreover, the amount of residual urine after the measurement is analyzed. The following values are used as indicators of the effect on the urination interval.
  • the rats are habituated to a plastic cage placed on a wire mesh.
  • the von Frey filament (0.4-26 g) is 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 begins to show escape behavior is taken as the pain threshold.
  • the pain threshold is evaluated for the left and right hind limbs, and set as a pretreatment pain threshold. Animals with an operating pain threshold of 0.6 to 2 g and a sham surgical pain threshold of 8 to 15 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, a suspension or solution is prepared using a 0.5% methylcellulose solution, and is orally administered to an animal using an oral sonde. 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 value (logarithm of pain threshold value after surgery on the surgery side-logarithm of pain threshold value on the surgery side before surgery) / (logarithm of pain threshold value before treatment on the sham surgery side-logarithm of pain threshold value on the surgery side before surgery) 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, a suspension or solution is prepared using a 0.5% methylcellulose solution, and is orally administered to an animal using an oral sonde. 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.
  • Test Example 6-2 Production of model animal for evaluation of drug efficacy using cauda equina nerve compression model
  • the lower back of the rat is incised under anesthesia to expose the fourth, fifth and sixth lumbar vertebrae. Incisions are made on the 4th-5th and 5th-6th lumbar joints. Silicon rubber is inserted into the 4th and 6th lumbar spinal canals from the vertebral joint incision and placed, and the incision is sutured.
  • the above-described operation is subjected to an operation excluding silicon rubber insertion and indwelling operations.
  • the compound of the present invention is crushed using a mortar and pestle, a suspension or solution is prepared using 0.5% methylcellulose solution as a medium, and is orally administered to the adopted animal using an oral sonde.
  • the pressure value of the von Frey filament at which the rat begins to show escape behavior by the same operation is measured and set as a pain threshold after administration.
  • % reversal value (logarithm of pain threshold after administration of model animal-logarithm of pain threshold before administration of model animal) / (logarithm of pain threshold before administration of sham-operated animal-logarithm of pain threshold before administration of model animal)
  • CYP3A4 Fluorescence MBI test is a test to examine the enhancement of CYP3A4 inhibition of compounds by metabolic reaction. was used as an indicator for the reaction of debenzylation with CYP3A4 enzyme to produce the fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC).
  • 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.
  • CYP3A4 (MDZ) MBI Test This test evaluates the mechanism based inhibition (MBI) ability from the enhancement by metabolic reaction with respect to CYP3A4 inhibition of the compounds of the present invention. Pooled human liver microsomes are used to evaluate CYP3A4 inhibition using midazolam (MDZ) 1-hydroxylation as an indicator.
  • reaction conditions are as follows: substrate, 10 ⁇ mol / L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; reaction temperature, 37 ° C .; pooled human liver microsome, pre-reaction 0.5 mg / mL, reaction time 0.05 mg / mL (when diluted 10-fold); concentration at the time of pre-reaction of the compound of the present invention 1, 5, 10, 20 ⁇ mol / L (4 points).
  • a control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when the compound of the present invention was added at each concentration was calculated.
  • Preincubation 0 min IC / Preincubation 30 min IC is the Shifted IC value. If the Shifted IC is 1.5 or more, it is Positive, and if the Shifted IC is 1.0 or less, it is Negative.
  • Test Example 8 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 were 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 microsomes 0.2 mg protein / mL; drug concentration of the present invention, 1.0, 5.0, 10, 20 ⁇ mol / L ( 4 points).
  • each of the five 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 supernatant was collected using a fluorescent multilabel counter or LC / MS / MS with tolbutamide hydroxide (CYP2C9 metabolite) and mephenytoin 4 ′ hydroxylated.
  • the body CYP2C19 metabolite
  • dextrorphan CYP2D6 metabolite
  • terfenadine alcohol CYP3A4 metabolite
  • a control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and calculating the residual activity (%) at each concentration to which the drug solution of the present invention was added.
  • 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.
  • 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 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).
  • SPE solid phase extraction
  • JP2 liquid composition A: About 200 mL of 0.2 mol / L sodium hydroxide test solution is added to 200 mL of 0.2 mol / L potassium dihydrogen phosphate test solution to adjust the pH to 6.8, and then 600 mL of water is added.
  • C 1 volume of water is added to 1 volume of 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water to 1000 mL.
  • Table 17 shows the results measured using the above condition A.
  • Table 18 shows the results of measurement using the above condition C.
  • Test Example 11 Metabolic Stability Test Using a commercially available pooled human liver microsome, the target compound was reacted for a certain period of time, and the residual rate was 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 or solid phase extraction (SPE) / 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%.
  • Test Example 12 Metabolic Stability Test Using the prepared rat cryopreserved hepatocytes, the target compound was reacted for a certain period of time, and the residual rate was calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism in the liver. .
  • SPE solid phase extraction
  • hERG Test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, using CHO cells in which human ether-a-go-related gene (hERG) channels are expressed, it is important for the 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 14 Protein Binding Test Serum protein non-binding rate of the inventive compound was measured using rat serum.
  • Reaction conditions are as follows: evaluation method, equilibrium dialysis method; reaction time, 24 hours; reaction temperature, 37 ° C .; inventive compound concentration, 2 ⁇ g / mL.
  • a test solution was added to rat serum and stirred to prepare a serum sample having the above compound concentration.
  • 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 or solid phase extraction (SPE) / MS.
  • SPE solid phase extraction
  • Test Example 14 Protein Binding Test Serum protein non-binding rate of the inventive compound was measured using rat or human serum.
  • the reaction conditions are as follows: evaluation method, equilibrium dialysis method; reaction time, 24 hours; reaction temperature, 37 ° C .; inventive compound concentration, 4 ⁇ mol / L.
  • a test solution was added to rat or human serum and stirred to prepare a serum sample having the above compound concentration.
  • 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 or solid phase extraction (SPE) / MS.
  • SPE solid phase extraction
  • Test Example 15 Pharmacokinetic Test Experimental Materials and Methods
  • Animals used SD rats were used.
  • Breeding conditions SD rats were allowed to freely take solid feed and sterilized tap water.
  • JP-1 solution 2.0 g of sodium chloride, 7.0 mL of hydrochloric acid is added to 1000 mL
  • JP-2 solution Dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate
  • the mixture is filtered, and 100 ⁇ L of methanol is added to 100 ⁇ L of each filtrate to perform 2-fold dilution.
  • the dilution factor was changed as necessary.
  • the compound of the present invention is quantified using HPLC by the absolute calibration curve method.
  • Test Example 17 Brain Translocation Test Rats are intravenously administered a compound according to the present invention at a dose of 0.5 mg / mL / kg, and 30 minutes later, they are exsanguinated by whole blood collection from the lower aorta under isoflurane anesthesia. Thereafter, the brain is removed and 20-25% homogenate is prepared with distilled water. On the other hand, the obtained blood is made into plasma after centrifugation. Thereafter, control plasma is added to the brain sample and control brain is added to the plasma sample at a ratio of 1: 1, and each sample is measured using LC / MS / MS. The obtained area ratio (brain / plasma) at the time of measurement is defined as the brain Kp value.
  • Test Example 18 P-gp Substrate Test
  • the compound according to the present invention is added to one side of a transwell (registered trademark, CORNING), in which human MDR1-expressing cells or parent cells are cultured in a monolayer, and allowed to react for a certain period of time.
  • the Efflux Ratio (ER value) of the MDR1-expressing cell and the parent cell is compared to determine whether the compound of the present invention is a P-gp substrate.
  • Membrane permeability coefficient in the axial direction from the axial side to the basolateral side (A ⁇ B) and from the basolateral side to the apical side (B ⁇ A) is calculated, and the Efflux Ratio (ER; B ⁇ A and A ⁇ B) of the MDR1-expressing cell and the parent cell. The ratio of membrane permeation coefficient) is calculated.
  • Test Example 19 mdr1a ( ⁇ / ⁇ ) B6 mouse P-gp substrate
  • Test material animal mdr1a ( ⁇ / ⁇ ) B6 mouse (knockout mouse) or C57BL / 6J mouse (wild mouse)
  • Animals may be fed before administration of the compounds of the present invention. 2.
  • the compound of the present invention is administered to three animals at each time point, and blood and brain samples are given at predetermined time points after administration (eg, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours or 24 hours). Time). Blood (0.3-0.7 mL) is collected with a syringe containing anticoagulants (EDTA and heparin).
  • EDTA and heparin anticoagulants
  • Blood and tissue (such as brain) samples should be ice-cold immediately. 3.
  • the blood sample is centrifuged (1780 ⁇ g, 10 minutes) to remove cells and obtain plasma.
  • the plasma sample is then transferred to a tube and stored at -70 ° C. 4).
  • Plasma and tissue (such as brain) samples are prepared using deproteinization and analyzed by LC / MS / MS. For the measurement, a quality control sample is used to confirm the accuracy and accuracy of the measurement method using a calibration curve prepared from blank plasma or blank brain. 6).
  • Plasma and brain concentration values (ng / mL and ng / g) are analyzed with an appropriate method for determining pharmacokinetic parameters, such as the WinNonlin® pharmacokinetic analysis software program.
  • 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.
  • Formulation Example 4 Orally Disintegrating Tablets
  • the compound of the present invention and crystalline cellulose are mixed and compressed after granulation to obtain an orally disintegrating tablet.
  • Formulation Example 8 Inhalant The compound of the present invention and lactose are mixed and finely pulverized to obtain an inhalant.
  • Formulation Example 9 Ointment
  • the compound of the present invention and petrolatum are mixed to form an ointment.
  • Formulation Example 10 Patch A base such as the compound of the present invention and an adhesive plaster is mixed to obtain a patch.
  • Compound represented by the general formula (I) has an antagonistic effect on P2X 3 and / or P2X 2/3 receptor, P2X 3 and / or diseases or conditions P2X 2/3 receptor is involved, for example, chronic pain It is considered useful for urination disorders, respiratory diseases and the like.

Abstract

The present invention provides a novel compound having a P2X3 and/or P2X2/3 receptor antagonistic effect. The compound is a compound represented by formula (I), or a pharmaceutically acceptable salt thereof. (In formula (I): R1 is an optionally substituted alkyl or the like; R2 is an optionally substituted aromatic carbocyclic group or the like; R3 is an optionally substituted aromatic carbocyclic group or the like; each R4a is independently a hydrogen atom or the like; each R4b is independently a hydrogen atom or the like; n is an integer of 0 to 4; X is -N(R5)- or the like; and R5 is a hydrogen atom or the like.)

Description

１，２，４－トリアジン誘導体およびその医薬組成物1,2,4-Triazine derivative and pharmaceutical composition thereof
　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 the 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：
Figure JPOXMLDOC01-appb-C000005
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。 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-C000005
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 .
　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。 In recent years, it has 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 accompanied by abnormal dysuria. It also suggests that it is useful.
　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９）。
　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１０）。 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 9). ).
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 10). ).
　特許文献１１には、本発明化合物と類似の１，２，４－トリアジン骨格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および１４には、本発明化合物と類似の１，３，５－トリアジン骨格を有し、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。
　また、特許文献２～８、１５および１６ならびに非特許文献１２および１３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が、本発明化合物と構造が異なる。
　さらには、特許文献１２～１４および１７には、本発明化合物と類似の１，３，５－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 Document 11 describes a compound having a 1,2,4-triazine skeleton similar to the compound of the present invention, but does not describe analgesic action and P2X 3 or P2X 2/3 receptor antagonistic action. .
Non-Patent Documents 8 and 14 describe compounds having a 1,3,5-triazine skeleton similar to the compounds of the present invention and exhibiting analgesic activity, but P2X 3 or P2X 2/3 receptors. No antagonism has been described.
Further, Patent Documents 2 to 8, 15 and 16 and Non-Patent Documents 12 and 13 also describe compounds exhibiting P2X 3 or P2X 2/3 receptor antagonistic activity, but the structure is different from the compounds of the present invention.
Further, Patent Documents 12 to 14 and 17 describe compounds having a P2X 3 or P2X 2/3 receptor antagonistic activity having a 1,3,5-triazine skeleton similar to the compounds of the present invention.
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２００７／００３７９７４号明細書US Patent Application Publication No. 2007/0037974 米国特許出願公開第２００７／００４９７５８号明細書US Patent Application Publication No. 2007/0049758 米国特許出願公開第２００７／００４９６１０号明細書US Patent Application Publication No. 2007/0049610 米国特許出願公開第２００７／００４９６０９号明細書US Patent Application Publication No. 2007/0049609 米国特許出願公開第２００７／００４９５３４号明細書US Patent Application Publication No. 2007/0049534 国際公開第２０１０／０５１１８８号明細書International Publication No. 2010/051188 国際公開第２００６／０１２６３９号明細書International Publication No. 2006/012639 国際公開第２０１０／１４９５７８号明細書International Publication No. 2010/149578 特開２０００－３１９２６８号公報JP 2000-319268 A 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２０１３／０８９２１２号明細書International Publication No. 2013/089212 Specification 国際公開第２０１２／０２０７４２号明細書International Publication No. 2012/020742 国際公開第２０１３／１１８８５５号明細書International Publication No. 2013/118855 Specification 国際公開第２０１４／２０００７８号明細書International Publication No. 2014/200078 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、薬物動態試験（バイオアベイラビリティ確認試験、全身クリアランス確認試験等）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。 As a result of intensive studies to solve the above 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 an 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, pharmacokinetic test. In the bioavailability confirmation test, the whole body clearance confirmation test, etc. and / or the protein binding confirmation test, good results were also shown.
　本発明は、以下の（１’）～（２６’）および（１）～（２５）に関する。
（１’）式（１）：
Figure JPOXMLDOC01-appb-C000006
（式中、－Ｘ－は、－Ｎ（Ｒ５）－、－Ｏ－または－Ｓ－であり；
　Ｒ５は、水素原子、置換若しくは非置換のアルキルまたは置換若しくは非置換のアシルであり；
　Ｒ１は、水素原子、カルボキシ、シアノ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアシル、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のカルバモイル、置換若しくは非置換のアミノ、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換の芳香族炭素環オキシまたは置換若しくは非置換の芳香族複素環オキシであり；
　Ｒ２は、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基であり；
　Ｒ３は、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基であり；
　Ｒ４ａは、それぞれ独立して、水素原子、若しくは置換若しくは非置換のアルキルであり、
Ｒ４ｂは、それぞれ独立して、水素原子、若しくは置換若しくは非置換のアルキルであり、または
　Ｒ４ａおよびＲ４ｂは、一緒になってオキソであり；
　ｎは、０～４の整数で示される化合物（ただし、以下に示される化合物：
Figure JPOXMLDOC01-appb-C000007
を除く）またはその製薬上許容される塩。
（２’）ｎが１～４の整数であり、
　Ｒ２およびＲ３が、それぞれ独立して、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基である、上記（１’）記載の化合物またはその製薬上許容される塩。
（２’Ａ）ｎが１であり、
　Ｒ２およびＲ３が、それぞれ独立して、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基である、上記（１’）記載の化合物またはその製薬上許容される塩。
（３’）－Ｘ－が、－Ｎ（Ｒ５）－（式中、Ｒ５は上記（１’）と同義）である、上記（２’）または（２’Ａ）に記載の化合物またはその製薬上許容される塩。
（４’）Ｒ２が、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基である、上記（２’）、（２’Ａ）または（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’）Ｒ１が、置換若しくは非置換のアルキル、カルボキシ、シアノ、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のカルバモイルまたは置換若しくは非置換のアミノである、上記（２’）～（４’）または（２’Ａ）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’）Ｒ３が、式：
Figure JPOXMLDOC01-appb-C000008
（式中、環Ａは、芳香族炭素環または芳香族複素環であり；
　ｓは、０～３の整数であり；
　Ｒ６は、それぞれ独立して、ハロゲン、ヒドロキシ、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のアルキニルチオ、置換若しくは非置換のアシル、カルボキシ、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、置換若しくは非置換のカルバモイル、置換若しくは非置換のアミノ、置換若しくは非置換のスルファモイル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換の芳香族炭素環オキシまたは置換若しくは非置換の芳香族複素環オキシである）で示される基である、上記（２’）～（５’）または（２’Ａ）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’）Ｒ３が、式：
Figure JPOXMLDOC01-appb-C000009
（式中、Ｒ７は、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基であり；
Ｒ８は水素原子、ハロゲン、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシまたは置換若しくは非置換のアルキニルオキシである）で示される基である、上記（２’）～（６’）または（２’Ａ）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’）Ｒ７が、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基である、上記（７’）記載の化合物またはその製薬上許容される塩。
（９’）Ｒ８が、水素原子、ハロゲン、置換若しくは非置換のアルキルまたは置換若しくは非置換のアルキルオキシである、上記（７’）または（８’）記載の化合物またはその製薬上許容される塩。
（１０’）
実施例Ｉ－２０、Ｉ－２４、Ｉ－２９、Ｉ－３３およびＩ－３５からなる群から選択される、上記（１’）記載の化合物またはその製薬上許容される塩。
（１１’）（１’）～（１０’）または（２’Ａ）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。
（１２’）Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体拮抗剤である、（１１’）記載の医薬組成物。
（１３’）慢性疼痛、排尿障害または呼吸器疾患の治療および／または予防作用を有する、上記（１１’）または（１２’）記載の医薬組成物。
（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、上記（１’）～（１０’）または（２’Ａ）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’）慢性疼痛、排尿障害または呼吸器疾患の治療および／または予防に使用するための、上記（１４’）記載の化合物またはその製薬上許容される塩。
（１５’Ａ）神経障害性疼痛または炎症性疼痛の治療および／または予防に使用するための、上記（１４’）記載の化合物またはその製薬上許容される塩。
（１６’）上記（１’）～（１０’）または（２’Ａ）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。
（１７’）慢性疼痛、排尿障害または呼吸器疾患に対する、上記（１６’）記載の治療および／または予防方法。
（１７’Ａ）神経障害性疼痛または炎症性疼痛に対する、上記（１６’）記載の治療および／または予防方法。
（１８’）Ｐ２Ｘ3および／またはＰ２Ｘ2/3受容体が関与する疾患の治療剤および／または予防剤の製造のための、上記（１’）～（１０’）または（２’Ａ）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の使用。
（１９’）慢性疼痛、排尿障害または呼吸器疾患治療剤および／または予防剤の製造のための、上記（１８’）記載の使用。
（１９’Ａ）神経障害性疼痛または炎症性疼痛治療剤および／または予防剤の製造のための、上記（１８’）記載の使用。
（２０’）上記（１’）～（１０’）または（２’Ａ）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、経口投与のための医薬組成物。
（２１’）錠剤、散剤、顆粒剤、カプセル剤、丸剤、フィルム剤、懸濁剤、乳剤、エリキシル剤、シロップ剤、リモナーデ剤、酒精剤、芳香水剤、エキス剤、煎剤またはチンキ剤である、上記（２０’）記載の医薬組成物。
（２２’）糖衣錠、フィルムコーティング錠、腸溶性コーティング錠、徐放錠、トローチ錠、舌下錠、バッカル錠、チュアブル錠、口腔内崩壊錠、ドライシロップ、ソフトカプセル剤、マイクロカプセル剤または徐放性カプセル剤である、上記（２０’）または（２１’）記載の医薬組成物。
（２３’）上記（１’）～（１０’）または（２’Ａ）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、非経口投与のための医薬組成物。
（２４’）経皮、皮下、静脈内、動脈内、筋肉内、腹腔内、経粘膜、吸入、経鼻、点眼、点耳または膣内投与のための、上記（２３’）記載の医薬組成物。
（２５’）注射剤、点滴剤、点眼剤、点鼻剤、点耳剤、エアゾール剤、吸入剤、ローション剤、注入剤、塗布剤、含嗽剤、浣腸剤、軟膏剤、硬膏剤、ゼリー剤、クリーム剤、貼付剤、パップ剤、外用散剤または坐剤である、上記（２４’）または（２５’）記載の医薬組成物。
（２６’）上記（１’）～（１０’）または（２’Ａ）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、小児用または高齢者用の医薬組成物。
（１）式（１）：
Figure JPOXMLDOC01-appb-C000010
（式中、－Ｘ－は、－Ｎ（Ｒ５）－、－Ｏ－または－Ｓ－であり；
　Ｒ５は、水素原子、置換若しくは非置換のアルキルまたは置換若しくは非置換のアシルであり；
　Ｒ１は、水素原子、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアシル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基であり；
　Ｒ２は、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基であり；
　Ｒ３は、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基であり；
　Ｒ４ａは、それぞれ独立して、水素原子、若しくは置換若しくは非置換のアルキルであり、
Ｒ４ｂは、それぞれ独立して、水素原子、若しくは置換若しくは非置換のアルキルであり、または
　Ｒ４ａおよびＲ４ｂは、一緒になってオキソであり；
　ｎは、０～４の整数で示される化合物（ただし、以下に示される化合物：
Figure JPOXMLDOC01-appb-C000011
を除く）またはその製薬上許容される塩。
（２）ｎが１～４の整数であり、
　Ｒ２およびＲ３が、それぞれ独立して、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基である、上記（１）記載の化合物またはその製薬上許容される塩。
（３）－Ｘ－が、－Ｎ（Ｒ５）－（式中、Ｒ５は上記（１）と同義）である、上記（２）記載の化合物またはその製薬上許容される塩。
（４）Ｒ２が、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基である、上記（２）または（３）記載の化合物またはその製薬上許容される塩。
（５）Ｒ１が、置換若しくは非置換のアルキルである、上記（２）～（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。
（６）Ｒ３が、式：
Figure JPOXMLDOC01-appb-C000012
（式中、環Ａは、芳香族炭素環または芳香族複素環であり；
　ｓは、０～３の整数であり；
　Ｒ６は、それぞれ独立して、ハロゲン、ヒドロキシ、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のアルキニルチオ、置換若しくは非置換のアシル、カルボキシ、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、置換若しくは非置換のカルバモイル、置換若しくは非置換のアミノ、置換若しくは非置換のスルファモイル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換の芳香族炭素環オキシまたは置換若しくは非置換の芳香族複素環オキシである）で示される基である、上記（２）～（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）Ｒ３が、式：
Figure JPOXMLDOC01-appb-C000013
（式中、Ｒ７は、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基であり；
Ｒ８は水素原子、ハロゲン、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシまたは置換若しくは非置換のアルキニルオキシである）で示される基である、上記（２）～（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）Ｒ７が、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基である、上記（７）記載の化合物またはその製薬上許容される塩。
（９）Ｒ８が、水素原子、ハロゲン、置換若しくは非置換のアルキルまたは置換若しくは非置換のアルキルオキシである、上記（７）または（８）記載の化合物またはその製薬上許容される塩。
（１０）上記（１）～（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を含有する医薬組成物。
（１１）Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体拮抗剤である、上記（１０）記載の医薬組成物。
（１２）慢性疼痛、排尿障害または呼吸器疾患の治療および／または予防作用を有する、上記（１０）または（１１）記載の医薬組成物。
（１３）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）～（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。
（１４）慢性疼痛、排尿障害または呼吸器疾患の治療および／または予防に使用するための、上記（１３）記載の化合物またはその製薬上許容される塩。
（１４Ａ）神経障害性疼痛または炎症性疼痛の治療および／または予防に使用するための、上記（１３）記載の化合物またはその製薬上許容される塩。
（１５）上記（１）～（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。
（１６）慢性疼痛、排尿障害または呼吸器疾患に対する、上記（１５）記載の治療および／または予防方法。
（１６Ａ）神経障害性疼痛または炎症性疼痛に対する、上記（１５）記載の治療および／または予防方法。
（１７）Ｐ２Ｘ3および／またはＰ２Ｘ2/3受容体が関与する疾患の治療剤および／または予防剤の製造のための、上記（１）～（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の使用。
（１８）慢性疼痛、排尿障害または呼吸器疾患治療剤および／または予防剤の製造のための、上記（１７）記載の使用。
（１８Ａ）神経障害性疼痛または炎症性疼痛治療剤および／または予防剤の製造のための、上記（１７）記載の使用。
（１９）上記（１）～（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を含有する、経口投与のための医薬組成物。
（２０）錠剤、散剤、顆粒剤、カプセル剤、丸剤、フィルム剤、懸濁剤、乳剤、エリキシル剤、シロップ剤、リモナーデ剤、酒精剤、芳香水剤、エキス剤、煎剤またはチンキ剤である、上記（１９）記載の医薬組成物。
（２１）糖衣錠、フィルムコーティング錠、腸溶性コーティング錠、徐放錠、トローチ錠、舌下錠、バッカル錠、チュアブル錠、口腔内崩壊錠、ドライシロップ、ソフトカプセル剤、マイクロカプセル剤または徐放性カプセル剤である、上記（１９）または（２０）記載の医薬組成物。
（２２）上記（１）～（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を含有する、非経口投与のための医薬組成物。
（２３）経皮、皮下、静脈内、動脈内、筋肉内、腹腔内、経粘膜、吸入、経鼻、点眼、点耳または膣内投与のための、上記（２２）記載の医薬組成物。
（２４）注射剤、点滴剤、点眼剤、点鼻剤、点耳剤、エアゾール剤、吸入剤、ローション剤、注入剤、塗布剤、含嗽剤、浣腸剤、軟膏剤、硬膏剤、ゼリー剤、クリーム剤、貼付剤、パップ剤、外用散剤または坐剤である、上記（２３）または（２４）記載の医薬組成物。
（２５）上記（１）～（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を含有する、小児用または高齢者用の医薬組成物。 The present invention relates to the following (1 ′) to (26 ′) and (1) to (25).
(1 ′) Formula (1):
Figure JPOXMLDOC01-appb-C000006
Wherein —X— is —N (R 5 ) —, —O— or —S—;
R 5 is a hydrogen atom, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 1 is a hydrogen atom, carboxy, cyano, 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 acyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted non-aromatic carbocyclic group, substituted Or an unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or Unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy or Substituted or unsubstituted aromatic heterocyclic oxy;
R 2 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group A substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;
R 3 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group A substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;
Each R 4a is independently 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 taken together are oxo;
n is a compound represented by an integer of 0 to 4 (provided that the following compounds:
Figure JPOXMLDOC01-appb-C000007
Or a pharmaceutically acceptable salt thereof.
(2 ′) n is an integer of 1 to 4,
R 2 and R 3 are each independently a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or The compound of the above (1 ′) or a pharmaceutically acceptable salt thereof, which is a substituted or unsubstituted aromatic heterocyclic group.
(2′A) n is 1,
R 2 and R 3 are each independently a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or The compound of the above (1 ′) or a pharmaceutically acceptable salt thereof, which is a substituted or unsubstituted aromatic heterocyclic group.
(3 ′) —X— is —N (R 5 ) — (wherein R 5 has the same meaning as (1 ′) above), or a compound according to (2 ′) or (2′A) above, Its pharmaceutically acceptable salt.
(4 ′) The above (2 ′), (2′A) or (3 ′), wherein R 2 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group Or a pharmaceutically acceptable salt thereof.
(5 ′) R 2 is substituted or unsubstituted alkyl, carboxy, cyano, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted amino. The compound according to any one of (4 ') and (2'A) or a pharmaceutically acceptable salt thereof.
(6 ′) R 3 is of the formula:
Figure JPOXMLDOC01-appb-C000008
Wherein ring A is an aromatic carbocycle or aromatic heterocycle;
s is an integer from 0 to 3;
Each R 6 is independently halogen, hydroxy, 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, carboxy, 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 or Is an unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted Or an unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted aromatic carbocyclic oxy or a substituted or unsubstituted aromatic heterocyclic oxy) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2 ′) to (5 ′) or (2′A), which is a group.
(7 ′) R 3 is represented by the formula:
Figure JPOXMLDOC01-appb-C000009
Wherein R 7 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic A heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;
R 8 is a hydrogen atom, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2 ′) to (6 ′) or (2′A), which is a group represented by (Alkynyloxy).
(8 ′) R 7 is a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted Or a pharmaceutically acceptable salt thereof. The compound according to (7 ′) above, which is an aromatic heterocyclic group of
(9 ′) The compound according to (7 ′) or (8 ′) above or a pharmaceutically acceptable salt thereof, wherein R 8 is a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy. salt.
(10 ')
The compound according to the above (1 ′) or a pharmaceutically acceptable salt thereof selected from the group consisting of Examples I-20, I-24, I-29, I-33 and I-35.
(11 ′) A pharmaceutical composition comprising the compound according to any one of (1 ′) to (10 ′) or (2′A) or a pharmaceutically acceptable salt thereof.
(12 ′) The pharmaceutical composition according to (11 ′), which is a P2X 3 and / or P2X 2/3 receptor antagonist.
(13 ′) The pharmaceutical composition according to the above (11 ′) or (12 ′), which has an effect of treating and / or preventing chronic pain, dysuria or respiratory disease.
(14 ′) any one of (1 ′) to (10 ′) or (2′A) above for use in the treatment and / or prevention of a disease involving P2X 3 and / or P2X 2/3 receptor Or a pharmaceutically acceptable salt thereof.
(15 ′) The compound according to the above (14 ′) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of chronic pain, dysuria or respiratory disease.
(15′A) The compound according to (14 ′) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of neuropathic pain or inflammatory pain.
(16 ′) P2X 3 and / or P2X, characterized by administering a compound according to any one of (1 ′) to (10 ′) or (2′A) or a pharmaceutically acceptable salt thereof A method for treating and / or preventing a disease involving 2/3 receptor.
(17 ′) The treatment and / or prevention method according to the above (16 ′) for chronic pain, dysuria or respiratory disease.
(17′A) The treatment and / or prevention method according to (16 ′) above for neuropathic pain or inflammatory pain.
(18 ′) The above (1 ′) to (10 ′) or (2′A) for the manufacture of a therapeutic and / or prophylactic agent for diseases involving P2X 3 and / or P2X 2/3 receptors Use of the compound according to any one or a pharmaceutically acceptable salt thereof.
(19 ′) The use according to (18 ′) above for the manufacture of a therapeutic and / or prophylactic agent for chronic pain, dysuria or respiratory disease.
(19′A) The use according to (18 ′) above for the manufacture of a therapeutic and / or prophylactic agent for neuropathic pain or inflammatory pain.
(20 ′) A pharmaceutical composition for oral administration comprising the compound according to any one of the above (1 ′) to (10 ′) or (2′A), or a pharmaceutically acceptable salt thereof.
(21 ') Tablets, powders, granules, capsules, pills, films, suspensions, emulsions, elixirs, syrups, limonades, spirits, fragrances, extracts, decoctions or tinctures The pharmaceutical composition according to (20 ′) above.
(22 ') sugar-coated tablet, film-coated tablet, enteric-coated tablet, sustained-release tablet, troche tablet, sublingual tablet, buccal tablet, chewable tablet, orally disintegrating tablet, dry syrup, soft capsule, microcapsule or sustained-release capsule The pharmaceutical composition according to (20 ′) or (21 ′) above, which is an agent.
(23 ′) A pharmaceutical composition for parenteral administration, comprising the compound according to any one of (1 ′) to (10 ′) or (2′A) above, or a pharmaceutically acceptable salt thereof.
(24 ′) The pharmaceutical composition according to the above (23 ′) for transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop or intravaginal administration object.
(25 ') Injections, drops, eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, gargles, enemas, ointments, plasters, jellys The pharmaceutical composition according to (24 ′) or (25 ′) above, which is a cream, a patch, a poultice, a powder for external use or a suppository.
(26 ′) A pharmaceutical composition for children or the elderly, comprising the compound according to any one of (1 ′) to (10 ′) or (2′A) above, or a pharmaceutically acceptable salt thereof. .
(1) Formula (1):
Figure JPOXMLDOC01-appb-C000010
Wherein —X— is —N (R 5 ) —, —O— or —S—;
R 5 is a hydrogen atom, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
R 1 is a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted acyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or An unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;
R 2 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group A substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;
R 3 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group A substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;
Each R 4a is independently 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 taken together are oxo;
n is a compound represented by an integer of 0 to 4 (provided that the following compounds:
Figure JPOXMLDOC01-appb-C000011
Or a pharmaceutically acceptable salt thereof.
(2) n is an integer of 1 to 4,
R 2 and R 3 are each independently a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or The compound or a pharmaceutically acceptable salt thereof according to (1) above, which is a substituted or unsubstituted aromatic heterocyclic group.
(3) The compound according to (2) or a pharmaceutically acceptable salt thereof, wherein —X— is —N (R 5 ) — (wherein R 5 has the same meaning as (1) above).
(4) The compound according to the above (2) or (3) or a pharmaceutically acceptable salt thereof, wherein R 2 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group. Salt.
(5) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2) to (4), wherein R 1 is substituted or unsubstituted alkyl.
(6) R 3 is represented by the formula:
Figure JPOXMLDOC01-appb-C000012
Wherein ring A is an aromatic carbocycle or aromatic heterocycle;
s is an integer from 0 to 3;
Each R 6 is independently halogen, hydroxy, 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, carboxy, 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 or Is an unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted Or an unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted aromatic carbocyclic oxy or a substituted or unsubstituted aromatic heterocyclic oxy) The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2) to (5), which is a group.
(7) R 3 is represented by the formula:
Figure JPOXMLDOC01-appb-C000013
Wherein R 7 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic A heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;
R 8 is a hydrogen atom, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted The compound or a pharmaceutically acceptable salt thereof according to any one of the above (2) to (6), which is a group represented by (Alkynyloxy).
(8) R 7 is a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted The compound of the above (7), which is an aromatic heterocyclic group, or a pharmaceutically acceptable salt thereof.
(9) The compound according to the above (7) or (8) or a pharmaceutically acceptable salt thereof, wherein R 8 is a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy.
(10) A pharmaceutical composition comprising the compound according to any one of (1) to (9) or a pharmaceutically acceptable salt thereof.
(11) The pharmaceutical composition according to the above (10), which is a P2X 3 and / or P2X 2/3 receptor antagonist.
(12) The pharmaceutical composition according to the above (10) or (11), which has a therapeutic and / or preventive action for chronic pain, dysuria or respiratory disease.
(13) The compound according to any one of (1) to (9) above 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 Salt.
(14) The compound according to the above (13) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of chronic pain, dysuria or respiratory disease.
(14A) The compound according to the above (13) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of neuropathic pain or inflammatory pain.
(15) A disease involving P2X 3 and / or P2X 2/3 receptor, characterized by administering the compound according to any one of (1) to (9) above or a pharmaceutically acceptable salt thereof Treatment and / or prevention method.
(16) The treatment and / or prevention method according to (15) above for chronic pain, dysuria or respiratory disease.
(16A) The method of treatment and / or prevention according to (15) above for neuropathic pain or inflammatory pain.
(17) The compound according to any one of (1) to (9) above or a pharmaceutical product thereof for the manufacture of a therapeutic and / or prophylactic agent for a disease involving P2X 3 and / or P2X 2/3 receptor Use of top acceptable salts.
(18) Use of (17) above for the manufacture of a therapeutic and / or prophylactic agent for chronic pain, dysuria or respiratory disease.
(18A) Use of (17) above for the manufacture of a therapeutic and / or prophylactic agent for neuropathic pain or inflammatory pain.
(19) A pharmaceutical composition for oral administration comprising the compound according to any one of (1) to (9) above or a pharmaceutically acceptable salt thereof.
(20) Tablets, powders, granules, capsules, pills, films, suspensions, emulsions, elixirs, syrups, limonades, spirits, fragrances, extracts, decoctions or tinctures The pharmaceutical composition according to (19) above.
(21) Sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troche tablets, sublingual tablets, buccal tablets, chewable tablets, orally disintegrating tablets, dry syrups, soft capsules, microcapsules or sustained-release capsules The pharmaceutical composition according to the above (19) or (20).
(22) A pharmaceutical composition for parenteral administration, comprising the compound according to any one of (1) to (9) above or a pharmaceutically acceptable salt thereof.
(23) The pharmaceutical composition according to the above (22), for transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop or intravaginal administration.
(24) Injections, drops, eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coatings, gargles, enemas, ointments, plasters, jellys, The pharmaceutical composition according to the above (23) or (24), which is a cream, a patch, a poultice, a powder for external use or a suppository.
(25) A pharmaceutical composition for children or the elderly, comprising the compound according to any one of (1) to (9) above or a pharmaceutically acceptable salt thereof.
　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.
　以下に本明細書において用いられる各用語の意味を説明する。各用語は特に断りのない限り、単独で用いられる場合も、または他の用語と組み合わせて用いられる場合も、同一の意味で用いられる。
　「からなる」という用語は、構成要件のみを有することを意味する。
　「含む」という用語は、構成要件に限定されず、記載されていない要素を排除しないことを意味する。 The meaning of each term used in this specification will be described below. Unless otherwise specified, each term is used in the same meaning when used alone or in combination with other terms.
The term “consisting of” means having only the configuration requirements.
The term “comprising” is not limited to the constituent elements and means that elements not described are not excluded.
　「ハロゲン」とは、フッ素原子、塩素原子、臭素原子、およびヨウ素原子を包含する。特にフッ素原子、および塩素原子が好ましい。 “Halogen” includes fluorine atom, chlorine atom, bromine atom, and iodine atom. In particular, a fluorine atom and a chlorine atom are preferable.
　「アルキル」とは、炭素数１～１５、好ましくは炭素数１～１０、より好ましくは炭素数１～６、さらに好ましくは炭素数１～４の直鎖又は分枝状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－デシル等が挙げられる。
　「アルキル」の好ましい態様として、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－ペンチルが挙げられる。さらに好ましい態様として、メチル、エチル、ｎ－プロピル、イソプロピル、ｔｅｒｔ－ブチルが挙げられる。 “Alkyl” includes straight or branched hydrocarbon groups having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and still more preferably 1 to 4 carbon atoms. To do. 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 and the like.
Preferred embodiments of “alkyl” include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. Further preferred examples include methyl, ethyl, n-propyl, isopropyl and tert-butyl.
　「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、好ましくは炭素数２～１０、より好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の炭化水素基を包含する。例えば、ビニル、アリル、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、デセニル、ウンデセニル、ドデセニル、トリデセニル、テトラデセニル、ペンタデセニル等が挙げられる。
　「アルケニル」の好ましい態様として、ビニル、アリル、プロペニル、イソプロペニル、ブテニルが挙げられる。 “Alkenyl” has 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms, having one or more double bonds at any position. These linear or branched hydrocarbon groups are included. For example, vinyl, allyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, decenyl, tridecenyl, decenyl Etc.
Preferred embodiments of “alkenyl” include vinyl, allyl, propenyl, isopropenyl and butenyl.
　「アルキニル」とは、任意の位置に１以上の三重結合を有する、炭素数２～１０、好ましくは炭素数２～８、さらに好ましくは炭素数２～６、さらに好ましくは炭素数２～４の直鎖又は分枝状の炭化水素基を包含する。さらに任意の位置に二重結合を有していてもよい。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、ノニニル、デシニル等を包含する。
　「アルキニル」の好ましい態様として、エチニル、プロピニル、ブチニル、ペンチニルが挙げられる。 “Alkynyl” has 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, more preferably 2 to 4 carbon atoms, having one or more triple bonds at any position. Includes straight chain or branched hydrocarbon groups. Furthermore, you may have a double bond in arbitrary positions. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like.
Preferred embodiments of “alkynyl” include ethynyl, propynyl, butynyl and pentynyl.
　「芳香族炭素環式基」とは、単環または２環以上の、環状芳香族炭化水素基を意味する。例えば、フェニル、ナフチル、アントリル、フェナントリル等が挙げられる。
　「芳香族炭素環式基」の好ましい態様として、フェニルが挙げられる。 The “aromatic carbocyclic group” means a cyclic aromatic hydrocarbon group having one or more rings. For example, phenyl, naphthyl, anthryl, phenanthryl and the like can be mentioned.
A preferred embodiment of the “aromatic carbocyclic group” includes phenyl.
　「非芳香族炭素環式基」とは、単環または２環以上の、環状飽和炭化水素基または環状非芳香族不飽和炭化水素基を意味する。２環以上の「非芳香族炭素環式基」は、単環または２環以上の非芳香族炭素環式基に、上記「芳香族炭素環式基」における環が縮合したものも包含する。
　さらに、「非芳香族炭素環式基」は、以下のように架橋している基、またはスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000014
　単環の非芳香族炭素環式基としては、炭素数３～１６が好ましく、より好ましくは炭素数３～１２、さらに好ましくは炭素数４～８である。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、シクロプロペニル、シクロブテニル、シクロペンテニル、シクロヘキセニル、シクロヘプテニル、シクロヘキサジエニル等が挙げられる。
　２環以上の非芳香族炭素環式基としては、例えば、インダニル、インデニル、アセナフチル、テトラヒドロナフチル、フルオレニル等が挙げられる。 The “non-aromatic carbocyclic group” means a cyclic saturated hydrocarbon group or a cyclic non-aromatic unsaturated hydrocarbon group having one or more rings. The “non-aromatic carbocyclic group” having two or more rings includes those obtained by condensing the ring in the above “aromatic carbocyclic group” to a monocyclic or two or more non-aromatic carbocyclic groups.
Furthermore, the “non-aromatic carbocyclic group” includes a group that forms a bridge or a spiro ring as described below.
Figure JPOXMLDOC01-appb-C000014
The monocyclic non-aromatic carbocyclic group preferably has 3 to 16 carbon atoms, more preferably 3 to 12 carbon atoms, and still more preferably 4 to 8 carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl, and the like.
Examples of the two or more non-aromatic carbocyclic groups include indanyl, indenyl, acenaphthyl, tetrahydronaphthyl, fluorenyl and the like.
　「芳香族複素環式基」とは、Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する、単環または２環以上の、芳香族環式基を意味する。２環以上の芳香族複素環式基は、単環または２環以上の芳香族複素環式基に、上記「芳香族炭素環式基」における環が縮合したものも包含する。
　単環の芳香族複素環式基としては、５～８員が好ましく、より好ましくは５員または６員である。例えば、ピロリル、イミダゾリル、ピラゾリル、ピリジル、ピリダジニル、ピリミジニル、ピラジニル、トリアゾリル、トリアジニル、テトラゾリル、フリル、チエニル、イソオキサゾリル、オキサゾリル、オキサジアゾリル、イソチアゾリル、チアゾリル、チアジアゾリル等が挙げられる。
　２環の芳香族複素環式基としては、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、キノリニル、イソキノリニル、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、ベンズイソチアゾリル、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、オキサゾロピリジル、チアゾロピリジル等が挙げられる。
　３環以上の芳香族複素環式基としては、例えば、カルバゾリル、アクリジニル、キサンテニル、フェノチアジニル、フェノキサチイニル、フェノキサジニル、ジベンゾフリル等が挙げられる。 “Aromatic heterocyclic group” means a monocyclic or bicyclic or more aromatic cyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring To do. The aromatic heterocyclic group having two or more rings includes those obtained by condensing a ring in the above “aromatic carbocyclic group” to a monocyclic or two or more aromatic heterocyclic group.
The monocyclic aromatic heterocyclic group is preferably 5 to 8 members, more preferably 5 or 6 members. Examples include pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl and the like.
Examples of the bicyclic aromatic heterocyclic group include indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzisoxazolyl, Oxazolyl, benzoxiadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyr Dazinyl, oxazolopyridyl, thiazolopyridyl and the like can be mentioned.
Examples of the aromatic heterocyclic group having 3 or more rings include carbazolyl, acridinyl, xanthenyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, dibenzofuryl and the like.
　「非芳香族複素環式基」とは、Ｏ、ＳおよびＮから任意に選択される同一または異なるヘテロ原子を環内に１以上有する、単環または２環以上の、環状非芳香族環式基を意味する。２環以上の非芳香族複素環式基は、単環または２環以上の非芳香族複素環式基に、上記「芳香族炭素環式基」、「非芳香族炭素環式基」、および／または「芳香族複素環式基」におけるそれぞれの環が縮合したものも包含する。さらに、２環以上の非芳香族複素環式基は、単環または２環以上の芳香族複素環式基に、上記「非芳香族炭素環式基」および／または「非芳香族複素環式基」におけるそれぞれの環が縮合したものも包含する。
　さらに、「非芳香族複素環式基」は、以下のように架橋している基、またはスピロ環を形成する基も包含する。
Figure JPOXMLDOC01-appb-C000015
　単環の非芳香族複素環式基としては、３～８員が好ましく、より好ましくは５員または６員である。例えば、ジオキサニル、チイラニル、オキシラニル、オキセタニル、オキサチオラニル、アゼチジニル、チアニル、チアゾリジニル、ピロリジニル、ピロリニル、イミダゾリジニル、イミダゾリニル、ピラゾリジニル、ピラゾリニル、ピペリジル、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、ジヒドロピリジル、テトラヒドロピリジル、テトラヒドロフリル、テトラヒドロピラニル、ジヒドロチアゾリル、テトラヒドロチアゾリル、テトラヒドロイソチアゾリル、ジヒドロオキサジニル、ヘキサヒドロアゼピニル、テトラヒドロジアゼピニル、テトラヒドロピリダジニル、ヘキサヒドロピリミジニル、ジオキソラニル、ジオキサジニル、アジリジニル、ジオキソリニル、オキセパニル、チオラニル、チイニル、チアジニル等が挙げられる。
　２環以上の非芳香族複素環式基としては、例えば、インドリニル、イソインドリニル、クロマニル、イソクロマニル等が挙げられる。 “Non-aromatic heterocyclic group” means a monocyclic or bicyclic or more cyclic non-aromatic cyclic group having at least one hetero atom selected from O, S and N in the ring. Means group. The non-aromatic heterocyclic group having 2 or more rings is a monocyclic or 2 or more non-aromatic heterocyclic group, the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group”, and Also included are those in which each ring in the “aromatic heterocyclic group” is condensed. Further, the non-aromatic heterocyclic group having two or more rings is the same as the above-mentioned “non-aromatic carbocyclic group” and / or “non-aromatic heterocyclic group”. Also included are those in which each ring in the “group” is condensed.
Furthermore, the “non-aromatic heterocyclic group” includes a group that forms a bridge or a spiro ring as described below.
Figure JPOXMLDOC01-appb-C000015
The monocyclic non-aromatic heterocyclic group is preferably 3 to 8 members, more preferably 5 or 6 members. For example, dioxanyl, thiranyl, oxiranyl, oxetanyl, oxathiolanyl, azetidinyl, thianyl, thiazolidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, morpholino, thiomorpholinyl, morpholino, thiomorpholinyl Furyl, tetrahydropyranyl, dihydrothiazolyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, dihydrooxazinyl, hexahydroazepinyl, tetrahydrodiazepinyl, tetrahydropyridazinyl, hexahydropyrimidinyl, dioxolanyl, dioxazinyl Aziridinyl, dioxolinyl, oxepanyl, thiolanyl, thii Le, triazinyl, and the like.
Examples of the non-aromatic heterocyclic group having two or more rings include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like.
　「ヒドロキシアルキル」とは、１以上のヒドロキシ基が、上記「アルキル」の炭素原子に結合している水素原子と置き換わった基を意味する。例えば、ヒドロキシメチル、１－ヒドロキシエチル、２－ヒドロキシエチル、１－ヒドロキシプロピル、２－ヒドロキシプロピル、１，２－ヒドロキシエチル等が挙げられる。
　「ヒドロキシアルキル」の好ましい態様として、ヒドロキシメチルが挙げられる。 “Hydroxyalkyl” means a group in which one or more hydroxy groups are replaced with a hydrogen atom bonded to a carbon atom of the above “alkyl”. Examples thereof include hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 1,2-hydroxyethyl and the like.
A preferred embodiment of “hydroxyalkyl” includes hydroxymethyl.
　「アルキルオキシ」とは、上記「アルキル」が酸素原子に結合した基を意味する。例えば、メトキシ、エトキシ、ｎ－プロピルオキシ、イソプロピルオキシ、ｎ－ブチルオキシ、ｔｅｒｔ－ブチルオキシ、イソブチルオキシ、ｓｅｃ－ブチルオキシ、ペンチルオキシ、イソペンチルオキシ、へキシルオキシ等が挙げられる。
　「アルキルオキシ」の好ましい態様として、メトキシ、エトキシ、ｎ－プロピルオキシ、イソプロピルオキシ、ｔｅｒｔ－ブチルオキシが挙げられる。 “Alkyloxy” means a group in which the above “alkyl” is bonded to an oxygen atom. Examples thereof include methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy, tert-butyloxy, isobutyloxy, sec-butyloxy, pentyloxy, isopentyloxy, hexyloxy and the like.
Preferable embodiments of “alkyloxy” include methoxy, ethoxy, n-propyloxy, isopropyloxy, tert-butyloxy.
　「アルケニルオキシ」とは、上記「アルケニル」が酸素原子に結合した基を意味する。例えば、ビニルオキシ、アリルオキシ、１－プロペニルオキシ、２－ブテニルオキシ、２－ペンテニルオキシ、２－ヘキセニルオキシ、２－ヘプテニルオキシ、２－オクテニルオキシ等が挙げられる。 “Alkenyloxy” means a group in which the above “alkenyl” is bonded to an oxygen atom. Examples thereof include vinyloxy, allyloxy, 1-propenyloxy, 2-butenyloxy, 2-pentenyloxy, 2-hexenyloxy, 2-heptenyloxy, 2-octenyloxy and the like.
　「アルキニルオキシ」とは、上記「アルキニル」が酸素原子に結合した基を意味する。
例えば、エチニルオキシ、１－プロピニルオキシ、２－プロピニルオキシ、２－ブチニルオキシ、２－ペンチニルオキシ、２－ヘキシニルオキシ、２－ヘプチニルオキシ、２－オクチニルオキシ等が挙げられる。 “Alkynyloxy” means a group in which the above “alkynyl” is bonded to an oxygen atom.
Examples include ethynyloxy, 1-propynyloxy, 2-propynyloxy, 2-butynyloxy, 2-pentynyloxy, 2-hexynyloxy, 2-heptynyloxy, 2-octynyloxy and the like.
　「ハロアルキル」とは、１以上の上記「ハロゲン」が上記「アルキル」に結合した基を意味する。例えば、モノフルオロメチル、モノフルオロエチル、モノフルオロプロピル、２，２，３，３，３－ペンタフルオロプロピル、モノクロロメチル、トリフルオロメチル、トリクロロメチル、２，２，２－トリフルオロエチル、２，２，２－トリクロロエチル、１，２－ジブロモエチル、１，１，１－トリフルオロプロパン－２－イル等が挙げられる。
　「ハロアルキル」の好ましい態様として、トリフルオロメチル、トリクロロメチルが挙げられる。 “Haloalkyl” means a group in which one or more of the “halogen” is bonded to the “alkyl”. For example, monofluoromethyl, monofluoroethyl, monofluoropropyl, 2,2,3,3,3-pentafluoropropyl, monochloromethyl, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2, Examples include 2,2-trichloroethyl, 1,2-dibromoethyl, 1,1,1-trifluoropropan-2-yl and the like.
Preferable embodiments of “haloalkyl” include trifluoromethyl and trichloromethyl.
　「ハロアルキルオキシ」とは、上記「ハロアルキル」が酸素原子に結合した基を意味する。例えば、モノフルオロメトキシ、モノフルオロエトキシ、トリフルオロメトキシ、トリクロロメトキシ、トリフルオロエトキシ、トリクロロエトキシ等が挙げられる。
　「ハロアルキルオキシ」の好ましい態様として、トリフルオロメトキシ、トリクロロメトキシが挙げられる。 “Haloalkyloxy” means a group in which the above “haloalkyl” is bonded to an oxygen atom. Examples thereof include monofluoromethoxy, monofluoroethoxy, trifluoromethoxy, trichloromethoxy, trifluoroethoxy, trichloroethoxy and the like.
Preferable embodiments of “haloalkyloxy” include trifluoromethoxy and trichloromethoxy.
　「アルキルオキシアルキル」とは、上記「アルキルオキシ」が上記「アルキル」に結合した基を意味する。例えば、メトキシメチル、メトキシエチル、エトキシメチル等が挙げられる。 “Alkyloxyalkyl” means a group in which the above “alkyloxy” is bonded to the above “alkyl”. For example, methoxymethyl, methoxyethyl, ethoxymethyl and the like can be mentioned.
　「アルキルオキシアルキルオキシ」とは、上記「アルキルオキシ」が上記「アルキルオキシ」に結合した基を意味する。例えば、メトキシメトキシ、メトキシエトキシ、エトキシメトキシ、エトキシエトキシ等が挙げられる。 “Alkyloxyalkyloxy” means a group in which the “alkyloxy” is bonded to the “alkyloxy”. Examples thereof include methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy and the like.
　「アルキルカルボニル」とは、上記「アルキル」がカルボニル基に結合した基を意味する。例えば、メチルカルボニル、エチルカルボニル、プロピルカルボニル、イソプロピルカルボニル、ｔｅｒｔ－ブチルカルボニル、イソブチルカルボニル、ｓｅｃ－ブチルカルボニル、ペンチルカルボニル、イソペンチルカルボニル、へキシルカルボニル等が挙げられる。
　「アルキルカルボニル」の好ましい態様として、メチルカルボニル、エチルカルボニル、ｎ－プロピルカルボニルが挙げられる。 “Alkylcarbonyl” means a group in which the above “alkyl” is bonded to a carbonyl group. Examples thereof include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, tert-butylcarbonyl, isobutylcarbonyl, sec-butylcarbonyl, pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like.
Preferable embodiments of “alkylcarbonyl” include methylcarbonyl, ethylcarbonyl, and n-propylcarbonyl.
　「アルケニルカルボニル」とは、上記「アルケニル」がカルボニル基に結合した基を意味する。例えば、エチレニルカルボニル、プロペニルカルボニル等が挙げられる。 “Alkenylcarbonyl” means a group in which the above “alkenyl” is bonded to a carbonyl group. For example, ethylenylcarbonyl, propenylcarbonyl and the like can be mentioned.
　「アルキニルカルボニル」とは、上記「アルキニル」がカルボニル基に結合した基を意味する。例えば、エチニルカルボニル、プロピニルカルボニル等が挙げられる。 “Alkynylcarbonyl” means a group in which the above “alkynyl” is bonded to a carbonyl group. For example, ethynylcarbonyl, propynylcarbonyl and the like can be mentioned.
　「アルキルアミノ」とは、上記「アルキル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、メチルアミノ、ジメチルアミノ、エチルアミノ、ジエチルアミノ、イソプロピルアミノ、Ｎ，Ｎ－ジイソプロピルアミノ、Ｎ－メチル－Ｎ－エチルアミノ等が挙げられる。
　「アルキルアミノ」の好ましい態様として、メチルアミノ、エチルアミノが挙げられる。 “Alkylamino” means a group in which the above “alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, N, N-diisopropylamino, N-methyl-N-ethylamino and the like can be mentioned.
Preferable embodiments of “alkylamino” include methylamino and ethylamino.
　「アルキルスルホニル」とは、上記「アルキル」がスルホニル基に結合した基を意味する。例えば、メチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、ｔｅｒｔ－ブチルスルホニル、イソブチルスルホニル、ｓｅｃ－ブチルスルホニル等が挙げられる。
　「アルキルスルホニル」の好ましい態様として、メチルスルホニル、エチルスルホニルが挙げられる。 “Alkylsulfonyl” means a group in which the above “alkyl” is bonded to a sulfonyl group. For example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl and the like can be mentioned.
Preferable embodiments of “alkylsulfonyl” include methylsulfonyl and ethylsulfonyl.
　「アルケニルスルホニル」とは、上記「アルケニル」がスルホニル基に結合した基を意味する。例えば、エチレニルスルホニル、プロペニルスルホニル等が挙げられる。 “Alkenylsulfonyl” means a group in which the above “alkenyl” is bonded to a sulfonyl group. For example, ethylenylsulfonyl, propenylsulfonyl and the like can be mentioned.
　「アルキニルスルホニル」とは、上記「アルキニル」がスルホニル基に結合した基を意味する。例えば、エチニルスルホニル、プロピニルスルホニル等が挙げられる。 “Alkynylsulfonyl” means a group in which the above “alkynyl” is bonded to a sulfonyl group. For example, ethynylsulfonyl, propynylsulfonyl and the like can be mentioned.
　「アルキルカルボニルアミノ」とは、上記「アルキルカルボニル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、メチルカルボニルアミノ、ジメチルカルボニルアミノ、エチルカルボニルアミノ、ジエチルカルボニルアミノ、プロピルカルボニルアミノ、イソプロピルカルボニルアミノ、Ｎ，Ｎ－ジイソプロピルカルボニルアミノ、ｔｅｒｔ－ブチルカルボニルアミノ、イソブチルカルボニルアミノ、ｓｅｃ－ブチルカルボニルアミノ等が挙げられる。 “Alkylcarbonylamino” means a group in which the above “alkylcarbonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, methylcarbonylamino, dimethylcarbonylamino, ethylcarbonylamino, diethylcarbonylamino, propylcarbonylamino, isopropylcarbonylamino, N, N-diisopropylcarbonylamino, tert-butylcarbonylamino, isobutylcarbonylamino, sec-butylcarbonylamino, etc. Is mentioned.
　「アルキルスルホニルアミノ」とは、上記「アルキルスルホニル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、メチルスルホニルアミノ、ジメチルスルホニルアミノ、エチルスルホニルアミノ、ジエチルスルホニルアミノ、プロピルスルホニルアミノ、イソプロピルスルホニルアミノ、Ｎ，Ｎ－ジイソプロピルスルホニルアミノ、ｔｅｒｔ－ブチルスルホニルアミノ、イソブチルスルホニルアミノ、ｓｅｃ－ブチルスルホニルアミノ等が挙げられる。
　「アルキルスルホニルアミノ」の好ましい態様としては、メチルスルホニルアミノ、エチルスルホニルアミノが挙げられる。 “Alkylsulfonylamino” means a group in which the above “alkylsulfonyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, methylsulfonylamino, dimethylsulfonylamino, ethylsulfonylamino, diethylsulfonylamino, propylsulfonylamino, isopropylsulfonylamino, N, N-diisopropylsulfonylamino, tert-butylsulfonylamino, isobutylsulfonylamino, sec-butylsulfonylamino, etc. Is mentioned.
Preferable embodiments of “alkylsulfonylamino” include methylsulfonylamino and ethylsulfonylamino.
　「アルキルイミノ」とは、上記「アルキル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、メチルイミノ、エチルイミノ、ｎ－プロピルイミノ、イソプロピルイミノ等が挙げられる。 “Alkylimino” means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, methylimino, ethylimino, n-propylimino, isopropylimino and the like can be mentioned.
　「アルケニルイミノ」とは、上記「アルケニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルイミノ、プロペニルイミノ等が挙げられる。 “Alkenylimino” means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include ethylenylimino and propenylimino.
　「アルキニルイミノ」とは、上記「アルキニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルイミノ、プロピニルイミノ等が挙げられる。 “Alkynylimino” means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynylimino, propynylimino and the like can be mentioned.
　「アルキルカルボニルイミノ」とは、上記「アルキルカルボニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、メチルカルボニルイミノ、エチルカルボニルイミノ、ｎ－プロピルカルボニルイミノ、イソプロピルカルボニルイミノ等が挙げられる。 “Alkylcarbonylimino” means a group in which the above “alkylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, methylcarbonylimino, ethylcarbonylimino, n-propylcarbonylimino, isopropylcarbonylimino and the like can be mentioned.
　「アルケニルカルボニルイミノ」とは、上記「アルケニルカルボニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルカルボニルイミノ、プロペニルカルボニルイミノ等が挙げられる。 “Alkenylcarbonylimino” means a group in which the above “alkenylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenylcarbonylimino, propenylcarbonylimino and the like can be mentioned.
　「アルキニルカルボニルイミノ」とは、上記「アルキニルカルボニル」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルカルボニルイミノ、プロピニルカルボニルイミノ等が挙げられる。 “Alkynylcarbonylimino” means a group in which the above “alkynylcarbonyl” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynylcarbonylimino, propynylcarbonylimino and the like can be mentioned.
　「アルキルオキシイミノ」とは、上記「アルキルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、メチルオキシイミノ、エチルオキシイミノ、ｎ－プロピルオキシイミノ、イソプロピルオキシイミノ等が挙げられる。 “Alkyloxyimino” means a group in which the above “alkyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. Examples thereof include methyloxyimino, ethyloxyimino, n-propyloxyimino, isopropyloxyimino and the like.
　「アルケニルオキシイミノ」とは、上記「アルケニルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルオキシイミノ、プロペニルオキシイミノ等が挙げられる。 “Alkenyloxyimino” means a group in which the above “alkenyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethylenyloxyimino, propenyloxyimino and the like can be mentioned.
　「アルキニルオキシイミノ」とは、上記「アルキニルオキシ」がイミノ基の窒素原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルオキシイミノ、プロピニルオキシイミノ等が挙げられる。 “Alkynyloxyimino” means a group in which the above “alkynyloxy” is replaced with a hydrogen atom bonded to the nitrogen atom of the imino group. For example, ethynyloxyimino, propynyloxyimino and the like can be mentioned.
　「アルキルカルボニルオキシ」とは、上記「アルキルカルボニル」が酸素原子に結合した基を意味する。例えば、メチルカルボニルオキシ、エチルカルボニルオキシ、プロピルカルボニルオキシ、イソプロピルカルボニルオキシ、ｔｅｒｔ－ブチルカルボニルオキシ、イソブチルカルボニルオキシ、ｓｅｃ－ブチルカルボニルオキシ等が挙げられる。
　「アルキルカルボニルオキシ」の好ましい態様としては、メチルカルボニルオキシ、エチルカルボニルオキシが挙げられる。 “Alkylcarbonyloxy” means a group in which the above “alkylcarbonyl” is bonded to an oxygen atom. For example, methylcarbonyloxy, ethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, tert-butylcarbonyloxy, isobutylcarbonyloxy, sec-butylcarbonyloxy and the like can be mentioned.
Preferable embodiments of “alkylcarbonyloxy” include methylcarbonyloxy and ethylcarbonyloxy.
　「アルケニルカルボニルオキシ」とは、上記「アルケニルカルボニル」が酸素原子に結合した基を意味する。例えば、エチレニルカルボニルオキシ、プロペニルカルボニルオキシ等が挙げられる。 “Alkenylcarbonyloxy” means a group in which the above “alkenylcarbonyl” is bonded to an oxygen atom. For example, ethylenylcarbonyloxy, propenylcarbonyloxy and the like can be mentioned.
　「アルキニルカルボニルオキシ」とは、上記「アルキニルカルボニル」が酸素原子に結合した基を意味する。例えば、エチニルカルボニルオキシ、プロピニルカルボニルオキシ等が挙げられる。 “Alkynylcarbonyloxy” means a group in which the above “alkynylcarbonyl” is bonded to an oxygen atom. For example, ethynylcarbonyloxy, propynylcarbonyloxy and the like can be mentioned.
　「アルキルオキシカルボニル」とは、上記「アルキルオキシ」がカルボニル基に結合した基を意味する。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、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、ｔｅｒｔ－ブチルオキシカルボニル、イソブチルオキシカルボニル、ｓｅｃ－ブチルオキシカルボニル、ペンチルオキシカルボニル、イソペンチルオキシカルボニル、へキシルオキシカルボニル等が挙げられる。
　「アルキルオキシカルボニル」の好ましい態様としては、メチルオキシカルボニル、エチルオキシカルボニル、プロピルオキシカルボニルが挙げられる。 “Alkyloxycarbonyl” means a group in which the above “alkyloxy” is bonded to a carbonyl group. For example, methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, hexyloxycarbonyl, etc. It is done.
Preferable embodiments of “alkyloxycarbonyl” include methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl.
　「アルケニルオキシカルボニル」とは、上記「アルケニルオキシ」がカルボニル基に結合した基を意味する。例えば、エチレニルオキシカルボニル、プロペニルオキシカルボニル等が挙げられる。 “Alkenyloxycarbonyl” means a group in which the above “alkenyloxy” is bonded to a carbonyl group. For example, ethylenyloxycarbonyl, propenyloxycarbonyl and the like can be mentioned.
　「アルキニルオキシカルボニル」とは、上記「アルキニルオキシ」がカルボニル基に結合した基を意味する。例えば、エチニルオキシカルボニル、プロピニルオキシカルボニル等が挙げられる。 “Alkynyloxycarbonyl” means a group in which the above “alkynyloxy” is bonded to a carbonyl group. For example, ethynyloxycarbonyl, propynyloxycarbonyl and the like can be mentioned.
　「アルキルスルファニル」とは、上記「アルキル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、メチルスルファニル、エチルスルファニル、ｎ－プロピルスルファニル、イソプロピルスルファニル等が挙げられる。 “Alkylsulfanyl” means a group in which the above “alkyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, methylsulfanyl, ethylsulfanyl, n-propylsulfanyl, isopropylsulfanyl and the like can be mentioned.
　「アルケニルスルファニル」とは、上記「アルケニル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、エチレニルスルファニル、プロペニルスルファニル等が挙げられる。 “Alkenylsulfanyl” means a group in which the above “alkenyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, ethylenylsulfanyl, propenylsulfanyl and the like can be mentioned.
　「アルキニルスルファニル」とは、上記「アルキニル」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、エチニルスルファニル、プロピニルスルファニル等が挙げられる。 “Alkynylsulfanyl” means a group in which the above “alkynyl” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, ethynylsulfanyl, propynylsulfanyl and the like can be mentioned.
　「アルキルスルフィニル」とは、上記「アルキル」がスルフィニル基に結合した基を意味する。例えば、メチルスルフィニル、エチルスルフィニル、ｎ－プロピルスルフィニル、イソプロピルスルフィニル等が挙げられる。 “Alkylsulfinyl” means a group in which the above “alkyl” is bonded to a sulfinyl group. Examples thereof include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl and the like.
　「アルケニルスルフィニル」とは、上記「アルケニル」がスルフィニル基に結合した基を意味する。例えば、エチレニルスルフィニル、プロペニルスルフィニル等が挙げられる。 “Alkenylsulfinyl” means a group in which the above “alkenyl” is bonded to a sulfinyl group. For example, ethylenylsulfinyl, propenylsulfinyl and the like can be mentioned.
　「アルキニルスルフィニル」とは、上記「アルキニル」がスルフィニル基に結合した基を意味する。例えば、エチニルスルフィニル、プロピニルスルフィニル等が挙げられる。 “Alkynylsulfinyl” means a group in which the above “alkynyl” is bonded to a sulfinyl group. For example, ethynylsulfinyl, propynylsulfinyl and the like can be mentioned.
　「アルキルカルバモイル」とは、上記「アルキル」がカルバモイル基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、メチルカルバモイル、ジメチルカルバモイル、エチルカルバモイル、ジエチルカルバモイル等が挙げられる。 “Alkylcarbamoyl” means a group in which the above “alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the carbamoyl group. For example, methylcarbamoyl, dimethylcarbamoyl, ethylcarbamoyl, diethylcarbamoyl and the like can be mentioned.
　「アルキルスルファモイル」とは、上記「アルキル」がスルファモイル基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、メチルスルファモイル、ジメチルスルファモイル、ジメチルスルファモイル、ジエチルスルファモイル等が挙げられる。 “Alkylsulfamoyl” means a group in which the above “alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the sulfamoyl group. Examples thereof include methylsulfamoyl, dimethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl and the like.
　「トリアルキルシリル」とは、上記「アルキル」３個がケイ素原子に結合している基を意味する。３個のアルキル基は同一でも異なっていてもよい。例えば、トリメチルシリル、トリエチルシリル、ｔｅｒｔ－ブチルジメチルシリル等が挙げられる。 “Trialkylsilyl” means a group in which the above three “alkyls” are bonded to a silicon atom. The three alkyl groups may be the same or different. For example, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl and the like can be mentioned.
　「芳香族炭素環アルキル」、「非芳香族炭素環アルキル」、「芳香族複素環アルキル」、および「非芳香族複素環アルキル」、
「芳香族炭素環アルキルオキシ」、「非芳香族炭素環アルキルオキシ」、「芳香族複素環アルキルオキシ」、および「非芳香族複素環アルキルオキシ」、
「芳香族炭素環アルキルオキシカルボニル」、「非芳香族炭素環アルキルオキシカルボニル」、「芳香族複素環アルキルオキシカルボニル」、および「非芳香族複素環アルキルオキシカルボニル」、
「芳香族炭素環アルキルオキシアルキル」、「非芳香族炭素環アルキルオキシアルキル」、「芳香族複素環アルキルオキシアルキル」、および「非芳香族複素環アルキルオキシアルキル」、ならびに
「芳香族炭素環アルキルアミノ」、「非芳香族炭素環アルキルアミノ」、「芳香族複素環アルキルアミノ」、および「非芳香族複素環アルキルアミノ」のアルキル部分も、上記「アルキル」と同様である。 “Aromatic carbocyclic alkyl”, “non-aromatic carbocyclic alkyl”, “aromatic heterocyclic alkyl”, and “non-aromatic heterocyclic alkyl”,
“Aromatic carbocyclic alkyloxy”, “non-aromatic carbocyclic alkyloxy”, “aromatic heterocyclic alkyloxy”, and “non-aromatic heterocyclic alkyloxy”,
“Aromatic carbocyclic alkyloxycarbonyl”, “non-aromatic carbocyclic alkyloxycarbonyl”, “aromatic heterocyclic alkyloxycarbonyl”, and “non-aromatic heterocyclic alkyloxycarbonyl”,
“Aromatic carbocyclic alkyloxyalkyl”, “non-aromatic carbocyclic alkyloxyalkyl”, “aromatic heterocyclic alkyloxyalkyl”, and “non-aromatic heterocyclic alkyloxyalkyl”, and “aromatic carbocyclic alkyl” The alkyl part of “amino”, “non-aromatic carbocyclic alkylamino”, “aromatic heterocyclic alkylamino”, and “nonaromatic heterocyclic alkylamino” is the same as the above “alkyl”.
　「芳香族炭素環アルキル」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルを意味する。例えば、ベンジル、フェネチル、フェニルプロピル、ベンズヒドリル、トリチル、ナフチルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000016
等が挙げられる。
　「芳香族炭素環アルキル」の好ましい態様としては、ベンジル、フェネチル、ベンズヒドリルが挙げられる。 “Aromatic carbocyclic alkyl” means an alkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyl, phenethyl, phenylpropyl, benzhydryl, trityl, naphthylmethyl, groups shown below
Figure JPOXMLDOC01-appb-C000016
Etc.
Preferable embodiments of “aromatic carbocyclic alkyl” include benzyl, phenethyl and benzhydryl.
　「非芳香族炭素環アルキル」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルを意味する。また、「非芳香族炭素環アルキル」は、アルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキル」も包含する。例えば、シクロプロピルメチル、シクロブチルメチル、シクロペンチルメチル、シクロへキシルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000017
等が挙げられる。 “Non-aromatic carbocyclic alkyl” means alkyl substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyl” also includes “non-aromatic carbocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, groups shown below
Figure JPOXMLDOC01-appb-C000017
Etc.
　「芳香族複素環アルキル」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルを意味する。また、「芳香族複素環アルキル」は、アルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキル」も包含する。例えば、ピリジルメチル、フラニルメチル、イミダゾリルメチル、インドリルメチル、ベンゾチオフェニルメチル、オキサゾリルメチル、イソキサゾリルメチル、チアゾリルメチル、イソチアゾリルメチル、ピラゾリルメチル、イソピラゾリルメチル、ピロリジニルメチル、ベンズオキサゾリルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000018
等が挙げられる。 “Aromatic heterocyclic alkyl” means alkyl substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyl” also includes “aromatic heterocyclic alkyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. . For example, pyridylmethyl, furanylmethyl, imidazolylmethyl, indolylmethyl, benzothiophenylmethyl, oxazolylmethyl, isoxazolylmethyl, thiazolylmethyl, isothiazolylmethyl, pyrazolylmethyl, isopyrazolylmethyl, pyrrolidinylmethyl, benz Oxazolylmethyl, group shown below
Figure JPOXMLDOC01-appb-C000018
Etc.
　「非芳香族複素環アルキル」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルを意味する。また、「非芳香族複素環アルキル」は、アルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキル」も包含する。例えば、テトラヒドロピラニルメチル、モルホリニルエチル、ピペリジニルメチル、ピペラジニルメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000019
等が挙げられる。 “Non-aromatic heterocyclic alkyl” means an alkyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyl”, the alkyl portion is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. Also included are “non-aromatic heterocyclic alkyl”. For example, tetrahydropyranylmethyl, morpholinylethyl, piperidinylmethyl, piperazinylmethyl, groups shown below
Figure JPOXMLDOC01-appb-C000019
Etc.
　「芳香族炭素環アルキルオキシ」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルオキシを意味する。例えば、ベンジルオキシ、フェネチルオキシ、フェニルプロピルオキシ、ベンズヒドリルオキシ、トリチルオキシ、ナフチルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000020
等が挙げられる。 “Aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxy, phenethyloxy, phenylpropyloxy, benzhydryloxy, trityloxy, naphthylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000020
Etc.
　「非芳香族炭素環アルキルオキシ」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルオキシを意味する。また、「非芳香族炭素環アルキルオキシ」は、アルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキルオキシ」も包含する。例えば、シクロプロピルメチルオキシ、シクロブチルメチルオキシ、シクロペンチルメチルオキシ、シクロへキシルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000021
等が挙げられる。 “Non-aromatic carbocyclic alkyloxy” means alkyloxy substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyloxy” also includes “non-aromatic carbocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000021
Etc.
　「芳香族複素環アルキルオキシ」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルオキシを意味する。また、「芳香族複素環アルキルオキシ」は、アルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキルオキシ」も包含する。例えば、ピリジルメチルオキシ、フラニルメチルオキシ、イミダゾリルメチルオキシ、インドリルメチルオキシ、ベンゾチオフェニルメチルオキシ、オキサゾリルメチルオキシ、イソキサゾリルメチルオキシ、チアゾリルメチルオキシ、イソチアゾリルメチルオキシ、ピラゾリルメチルオキシ、イソピラゾリルメチルオキシ、ピロリジニルメチルオキシ、ベンズオキサゾリルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000022
等が挙げられる。 “Aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “aromatic heterocyclic groups”. “Aromatic heterocyclic alkyloxy” also includes “aromatic heterocyclic alkyloxy” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Include. For example, pyridylmethyloxy, furanylmethyloxy, imidazolylmethyloxy, indolylmethyloxy, benzothiophenylmethyloxy, oxazolylmethyloxy, isoxazolylmethyloxy, thiazolylmethyloxy, isothiazolylmethyloxy , Pyrazolylmethyloxy, isopyrazolylmethyloxy, pyrrolidinylmethyloxy, benzoxazolylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000022
Etc.
　「非芳香族複素環アルキルオキシ」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルオキシを意味する。また、「非芳香族複素環アルキルオキシ」は、アルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキルオキシ」も包含する。例えば、テトラヒドロピラニルメチルオキシ、モルホリニルエチルオキシ、ピペリジニルメチルオキシ、ピペラジニルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000023
等が挙げられる。 “Non-aromatic heterocyclic alkyloxy” means alkyloxy substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyloxy”, the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. It also includes “non-aromatic heterocyclic alkyloxy”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000023
Etc.
　「芳香族炭素環アルキルオキシカルボニル」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルオキシカルボニルを意味する。例えば、ベンジルオキシカルボニル、フェネチルオキシカルボニル、フェニルプロピルオキシカルボニル、ベンズヒドリルオキシカルボニル、トリチルオキシカルボニル、ナフチルメチルオキシカルボニル、以下に示される基
Figure JPOXMLDOC01-appb-C000024
等が挙げられる。 “Aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxycarbonyl, phenethyloxycarbonyl, phenylpropyloxycarbonyl, benzhydryloxycarbonyl, trityloxycarbonyl, naphthylmethyloxycarbonyl, groups shown below
Figure JPOXMLDOC01-appb-C000024
Etc.
　「非芳香族炭素環アルキルオキシカルボニル」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルオキシカルボニルを意味する。また、「非芳香族炭素環アルキルオキシカルボニル」は、アルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキルオキシカルボニル」も包含する。例えば、シクロプロピルメチルオキシカルボニル、シクロブチルメチルオキシカルボニル、シクロペンチルメチルオキシカルボニル、シクロへキシルメチルオキシカルボニル、以下に示される基
Figure JPOXMLDOC01-appb-C000025
等が挙げられる。 “Non-aromatic carbocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “non-aromatic carbocyclic groups”. The “non-aromatic carbocyclic alkyloxycarbonyl” also includes “non-aromatic carbocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group”. For example, cyclopropylmethyloxycarbonyl, cyclobutylmethyloxycarbonyl, cyclopentylmethyloxycarbonyl, cyclohexylmethyloxycarbonyl, groups shown below
Figure JPOXMLDOC01-appb-C000025
Etc.
　「芳香族複素環アルキルオキシカルボニル」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルオキシカルボニルを意味する。また、「芳香族複素環アルキルオキシカルボニル」は、アルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキルオキシカルボニル」も包含する。例えば、ピリジルメチルオキシカルボニル、フラニルメチルオキシカルボニル、イミダゾリルメチルオキシカルボニル、インドリルメチルオキシカルボニル、ベンゾチオフェニルメチルオキシカルボニル、オキサゾリルメチルオキシカルボニル、イソキサゾリルメチルオキシカルボニル、チアゾリルメチルオキシカルボニル、イソチアゾリルメチルオキシカルボニル、ピラゾリルメチルオキシカルボニル、イソピラゾリルメチルオキシカルボニル、ピロリジニルメチルオキシカルボニル、ベンズオキサゾリルメチルオキシカルボニル、以下に示される基
Figure JPOXMLDOC01-appb-C000026
等が挙げられる。 “Aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “aromatic heterocyclic groups”. The “aromatic heterocyclic alkyloxycarbonyl” is an “aromatic heterocyclic alkyloxycarbonyl” in which the alkyl moiety is substituted with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Is also included. For example, pyridylmethyloxycarbonyl, furanylmethyloxycarbonyl, imidazolylmethyloxycarbonyl, indolylmethyloxycarbonyl, benzothiophenylmethyloxycarbonyl, oxazolylmethyloxycarbonyl, isoxazolylmethyloxycarbonyl, thiazolylmethyl Oxycarbonyl, isothiazolylmethyloxycarbonyl, pyrazolylmethyloxycarbonyl, isopyrazolylmethyloxycarbonyl, pyrrolidinylmethyloxycarbonyl, benzoxazolylmethyloxycarbonyl, groups shown below
Figure JPOXMLDOC01-appb-C000026
Etc.
　「非芳香族複素環アルキルオキシカルボニル」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルオキシカルボニルを意味する。また、「非芳香族複素環アルキルオキシカルボニル」は、アルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキルオキシカルボニル」も包含する。例えば、テトラヒドロピラニルメチルオキシ、モルホリニルエチルオキシ、ピペリジニルメチルオキシ、ピペラジニルメチルオキシ、以下に示される基
Figure JPOXMLDOC01-appb-C000027
等が挙げられる。 “Non-aromatic heterocyclic alkyloxycarbonyl” means alkyloxycarbonyl substituted with one or more of the above “non-aromatic heterocyclic groups”. In the “non-aromatic heterocyclic alkyloxycarbonyl”, the alkyl moiety is substituted with the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “aromatic heterocyclic group”. And “non-aromatic heterocyclic alkyloxycarbonyl”. For example, tetrahydropyranylmethyloxy, morpholinylethyloxy, piperidinylmethyloxy, piperazinylmethyloxy, groups shown below
Figure JPOXMLDOC01-appb-C000027
Etc.
　「芳香族炭素環アルキルオキシアルキル」とは、１以上の上記「芳香族炭素環式基」で置換されているアルキルオキシアルキルを意味する。例えば、ベンジルオキシメチル、フェネチルオキシメチル、フェニルプロピルオキシメチル、ベンズヒドリルオキシメチル、トリチルオキシメチル、ナフチルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000028
等が挙げられる。 “Aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic carbocyclic groups”. For example, benzyloxymethyl, phenethyloxymethyl, phenylpropyloxymethyl, benzhydryloxymethyl, trityloxymethyl, naphthylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000028
Etc.
　「非芳香族炭素環アルキルオキシアルキル」とは、１以上の上記「非芳香族炭素環式基」で置換されているアルキルオキシアルキルを意味する。また、「非芳香族炭素環アルキルオキシアルキル」は、非芳香族炭素環が結合しているアルキル部分が上記「芳香族炭素環式基」で置換されている「非芳香族炭素環アルキルオキシアルキル」も包含する。例えば、シクロプロピルメチルオキシメチル、シクロブチルメチルオキシメチル、シクロペンチルメチルオキシメチル、シクロへキシルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000029
等が挙げられる。 “Non-aromatic carbocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “non-aromatic carbocyclic groups”. In addition, “non-aromatic carbocyclic alkyloxyalkyl” means “non-aromatic carbocyclic alkyloxyalkyl” in which the alkyl moiety to which the non-aromatic carbocycle is bonded is substituted with the above “aromatic carbocyclic group”. Is also included. For example, cyclopropylmethyloxymethyl, cyclobutylmethyloxymethyl, cyclopentylmethyloxymethyl, cyclohexylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000029
Etc.
　「芳香族複素環アルキルオキシアルキル」とは、１以上の上記「芳香族複素環式基」で置換されているアルキルオキシアルキルを意味する。また、「芳香族複素環アルキルオキシアルキル」は、芳香族複素環が結合しているアルキル部分が上記「芳香族炭素環式基」および／または「非芳香族炭素環式基」で置換されている「芳香族複素環アルキルオキシアルキル」も包含する。例えば、ピリジルメチルオキシメチル、フラニルメチルオキシメチル、イミダゾリルメチルオキシメチル、インドリルメチルオキシメチル、ベンゾチオフェニルメチルオキシメチル、オキサゾリルメチルオキシメチル、イソキサゾリルメチルオキシメチル、チアゾリルメチルオキシメチル、イソチアゾリルメチルオキシメチル、ピラゾリルメチルオキシメチル、イソピラゾリルメチルオキシメチル、ピロリジニルメチルオキシメチル、ベンズオキサゾリルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000030
等が挙げられる。 “Aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “aromatic heterocyclic groups”. In addition, the “aromatic heterocyclic alkyloxyalkyl” is obtained by replacing the alkyl moiety to which the aromatic heterocyclic ring is bonded with the above “aromatic carbocyclic group” and / or “non-aromatic carbocyclic group”. Also included are “aromatic heterocyclic alkyloxyalkyl”. For example, pyridylmethyloxymethyl, furanylmethyloxymethyl, imidazolylmethyloxymethyl, indolylmethyloxymethyl, benzothiophenylmethyloxymethyl, oxazolylmethyloxymethyl, isoxazolylmethyloxymethyl, thiazolylmethyl Oxymethyl, isothiazolylmethyloxymethyl, pyrazolylmethyloxymethyl, isopyrazolylmethyloxymethyl, pyrrolidinylmethyloxymethyl, benzoxazolylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000030
Etc.
　「非芳香族複素環アルキルオキシアルキル」とは、１以上の上記「非芳香族複素環式基」で置換されているアルキルオキシアルキルを意味する。また、「非芳香族複素環アルキルオキシアルキル」は、非芳香族複素環が結合しているアルキル部分が上記「芳香族炭素環式基」、「非芳香族炭素環式基」および／または「芳香族複素環式基」で置換されている「非芳香族複素環アルキルオキシアルキル」も包含する。例えば、テトラヒドロピラニルメチルオキシメチル、モルホリニルエチルオキシメチル、ピペリジニルメチルオキシメチル、ピペラジニルメチルオキシメチル、以下に示される基
Figure JPOXMLDOC01-appb-C000031
等が挙げられる。 “Non-aromatic heterocyclic alkyloxyalkyl” means alkyloxyalkyl substituted with one or more of the above “non-aromatic heterocyclic groups”. The “non-aromatic heterocyclic alkyloxyalkyl” means that the alkyl moiety to which the non-aromatic heterocyclic ring is bonded is the above “aromatic carbocyclic group”, “non-aromatic carbocyclic group” and / or “ Also included are “non-aromatic heterocyclic alkyloxyalkyl” substituted with “aromatic heterocyclic group”. For example, tetrahydropyranylmethyloxymethyl, morpholinylethyloxymethyl, piperidinylmethyloxymethyl, piperazinylmethyloxymethyl, groups shown below
Figure JPOXMLDOC01-appb-C000031
Etc.
　「芳香族炭素環アルキルアミノ」とは、上記「芳香族炭素環アルキル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、ベンジルアミノ、フェネチルアミノ、フェニルプロピルアミノ、ベンズヒドリルアミノ、トリチルアミノ、ナフチルメチルアミノ、ジベンジルアミノ等が挙げられる。 “Aromatic carbocyclic alkylamino” means a group in which the above “aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. Examples include benzylamino, phenethylamino, phenylpropylamino, benzhydrylamino, tritylamino, naphthylmethylamino, dibenzylamino and the like.
　「非芳香族炭素環アルキルアミノ」とは、上記「非芳香族炭素環アルキル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、シクロプロピルメチルアミノ、シクロブチルメチルアミノ、シクロペンチルメチルアミノ、シクロへキシルメチルアミノ等が挙げられる。 “Non-aromatic carbocyclic alkylamino” means a group in which the above “non-aromatic carbocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, cyclopropylmethylamino, cyclobutylmethylamino, cyclopentylmethylamino, cyclohexylmethylamino and the like can be mentioned.
　「芳香族複素環アルキルアミノ」とは、上記「芳香族複素環アルキル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、ピリジルメチルアミノ、フラニルメチルアミノ、イミダゾリルメチルアミノ、インドリルメチルアミノ、ベンゾチオフェニルメチルアミノ、オキサゾリルメチルアミノ、イソキサゾリルメチルアミノ、チアゾリルメチルアミノ、イソチアゾリルメチルアミノ、ピラゾリルメチルアミノ、イソピラゾリルメチルアミノ、ピロリジニルメチルアミノ、ベンズオキサゾリルメチルアミノ等が挙げられる。 “Aromatic heterocyclic alkylamino” means a group in which the above “aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, pyridylmethylamino, furanylmethylamino, imidazolylmethylamino, indolylmethylamino, benzothiophenylmethylamino, oxazolylmethylamino, isoxazolylmethylamino, thiazolylmethylamino, isothiazolylmethylamino , Pyrazolylmethylamino, isopyrazolylmethylamino, pyrrolidinylmethylamino, benzoxazolylmethylamino and the like.
　「非芳香族複素環アルキルアミノ」とは、上記「非芳香族複素環アルキル」がアミノ基の窒素原子と結合している水素原子１個または２個と置き換わった基を意味する。例えば、テトラヒドロピラニルメチルアミノ、モルホリニルエチルアミノ、ピペリジニルメチルアミノ、ピペラジニルメチルアミノ等が挙げられる。 “Non-aromatic heterocyclic alkylamino” means a group in which the above “non-aromatic heterocyclic alkyl” is replaced with one or two hydrogen atoms bonded to the nitrogen atom of the amino group. For example, tetrahydropyranylmethylamino, morpholinylethylamino, piperidinylmethylamino, piperazinylmethylamino and the like can be mentioned.
　「芳香族炭素環オキシ」、「芳香族炭素環カルボニル」、「芳香族炭素環オキシカルボニル」、「芳香族炭素環スルファニル」、および「芳香族炭素環スルホニル」の「芳香族炭素環」部分も、上記「芳香族炭素環式基」と同様である。
　「芳香族炭素環オキシ」とは、「芳香族炭素環」が酸素原子に結合した基を意味する。例えば、フェニルオキシ、ナフチルオキシ等が挙げられる。
　「芳香族炭素環カルボニル」とは、「芳香族炭素環」がカルボニル基に結合した基を意味する。例えば、フェニルカルボニル、ナフチルカルボニル等が挙げられる。
　「芳香族炭素環オキシカルボニル」とは、上記「芳香族炭素環オキシ」がカルボニル基に結合した基を意味する。例えば、フェニルオキシカルボニル、ナフチルオキシカルボニル等が挙げられる。
　「芳香族炭素環スルファニル」とは、「芳香族炭素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、フェニルスルファニル、ナフチルスルファニル等が挙げられる。
　「芳香族炭素環スルホニル」とは、「芳香族炭素環」がスルホニル基に結合した基を意味する。例えば、フェニルスルホニル、ナフチルスルホニル等が挙げられる。 The “aromatic carbocyclic oxy”, “aromatic carbocyclic carbonyl”, “aromatic carbocyclic oxycarbonyl”, “aromatic carbocyclic sulfanyl”, and “aromatic carbocyclic sulfonyl” moieties also include The same as the above “aromatic carbocyclic group”.
“Aromatic carbocyclic oxy” means a group in which an “aromatic carbocycle” is bonded to an oxygen atom. For example, phenyloxy, naphthyloxy and the like can be mentioned.
“Aromatic carbocyclic carbonyl” means a group in which an “aromatic carbocycle” is bonded to a carbonyl group. For example, phenylcarbonyl, naphthylcarbonyl and the like can be mentioned.
“Aromatic carbocyclic oxycarbonyl” means a group in which the above “aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, phenyloxycarbonyl, naphthyloxycarbonyl and the like can be mentioned.
“Aromatic carbocyclic sulfanyl” means a group in which an “aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples thereof include phenylsulfanyl and naphthylsulfanyl.
“Aromatic carbocyclic sulfonyl” means a group in which “aromatic carbocycle” is bonded to a sulfonyl group. For example, phenylsulfonyl, naphthylsulfonyl and the like can be mentioned.
　「非芳香族炭素環オキシ」、「非芳香族炭素環カルボニル」、「非芳香族炭素環オキシカルボニル」、「非芳香族炭素環スルファニル」、および「非芳香族炭素環スルホニル」の「非芳香族炭素環」部分も、上記「非芳香族炭素環式基」と同様である。
　「非芳香族炭素環オキシ」とは、「非芳香族炭素環」が酸素原子に結合した基を意味する。例えば、シクロプロピルオキシ、シクロヘキシルオキシ、シクロへキセニルオキシ等が挙げられる。
　「非芳香族炭素環カルボニル」とは、「非芳香族炭素環」がカルボニル基に結合した基を意味する。例えば、シクロプロピルカルボニル、シクロヘキシルカルボニル、シクロへキセニルカルボニル等が挙げられる。
　「非芳香族炭素環オキシカルボニル」とは、上記「非芳香族炭素環オキシ」がカルボニル基に結合した基を意味する。例えば、シクロプロピルオキシカルボニル、シクロヘキシルオキシカルボニル、シクロへキセニルオキシカルボニル等が挙げられる。
　「非芳香族炭素環スルファニル」とは、「非芳香族炭素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、シクロプロピルスルファニル、シクロヘキシルスルファニル、シクロヘキセニルスルファニル等が挙げられる。
　「非芳香族炭素環スルホニル」とは、「非芳香族炭素環」がスルホニル基に結合した基を意味する。例えば、シクロプロピルスルホニル、シクロヘキシルスルホニル、シクロヘキセニルスルホニル等が挙げられる。 “Non-aromatic carbocyclic oxy”, “non-aromatic carbocyclic carbonyl”, “non-aromatic carbocyclic oxycarbonyl”, “non-aromatic carbocyclic sulfanyl”, and “non-aromatic carbocyclic sulfonyl” The “aromatic carbocyclic” moiety is the same as the above “non-aromatic carbocyclic group”.
“Non-aromatic carbocyclic oxy” means a group in which “non-aromatic carbocycle” is bonded to an oxygen atom. For example, cyclopropyloxy, cyclohexyloxy, cyclohexenyloxy and the like can be mentioned.
“Non-aromatic carbocycle carbonyl” means a group in which “non-aromatic carbocycle” is bonded to a carbonyl group. For example, cyclopropylcarbonyl, cyclohexylcarbonyl, cyclohexenylcarbonyl and the like can be mentioned.
The “non-aromatic carbocyclic oxycarbonyl” means a group in which the above “non-aromatic carbocyclic oxy” is bonded to a carbonyl group. For example, cyclopropyloxycarbonyl, cyclohexyloxycarbonyl, cyclohexenyloxycarbonyl and the like can be mentioned.
“Non-aromatic carbocyclic sulfanyl” means a group in which a “non-aromatic carbocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. Examples include cyclopropylsulfanyl, cyclohexylsulfanyl, cyclohexenylsulfanyl and the like.
“Non-aromatic carbocycle sulfonyl” means a group in which “non-aromatic carbocycle” is bonded to a sulfonyl group. For example, cyclopropylsulfonyl, cyclohexylsulfonyl, cyclohexenylsulfonyl and the like can be mentioned.
　「芳香族複素環オキシ」、「芳香族複素環カルボニル」、「芳香族複素環オキシカルボニル」、「芳香族複素環スルファニル」、および「芳香族複素環スルホニル」の「芳香族複素環」部分も、上記「芳香族複素環式基」と同様である。
　「芳香族複素環オキシ」とは、「芳香族複素環」が酸素原子に結合した基を意味する。例えば、ピリジルオキシ、オキサゾリルオキシ等が挙げられる。
　「芳香族複素環カルボニル」とは、「芳香族複素環」がカルボニル基に結合した基を意味する。例えば、ピリジルカルボニル、オキサゾリルカルボニル等が挙げられる。
　「芳香族複素環オキシカルボニル」とは、上記「芳香族複素環オキシ」がカルボニル基に結合した基を意味する。例えば、ピリジルオキシカルボニル、オキサゾリルオキシカルボニル等が挙げられる。
　「芳香族複素環スルファニル」とは、「芳香族複素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、ピリジルスルファニル、オキサゾリルスルファニル等が挙げられる。
　「芳香族複素環スルホニル」とは、「芳香族複素環」がスルホニル基に結合した基を意味する。例えば、ピリジルスルホニル、オキサゾリルスルホニル等が挙げられる。 The “aromatic heterocycle” part of “aromatic heterocycle oxy”, “aromatic heterocycle carbonyl”, “aromatic heterocycle oxycarbonyl”, “aromatic heterocycle sulfanyl”, and “aromatic heterocycle sulfonyl” The same as the above “aromatic heterocyclic group”.
“Aromatic heterocycle oxy” means a group in which “aromatic heterocycle” is bonded to an oxygen atom. For example, pyridyloxy, oxazolyloxy and the like can be mentioned.
“Aromatic heterocycle carbonyl” means a group in which “aromatic heterocycle” is bonded to a carbonyl group. For example, pyridylcarbonyl, oxazolylcarbonyl, etc. are mentioned.
“Aromatic heterocyclic oxycarbonyl” means a group in which the above “aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, pyridyloxycarbonyl, oxazolyloxycarbonyl and the like can be mentioned.
“Aromatic heterocycle sulfanyl” means a group in which an “aromatic heterocycle” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, pyridylsulfanyl, oxazolylsulfanyl and the like can be mentioned.
“Aromatic heterocycle sulfonyl” means a group in which “aromatic heterocycle” is bonded to a sulfonyl group. For example, pyridylsulfonyl, oxazolylsulfonyl and the like can be mentioned.
　「非芳香族複素環オキシ」、「非芳香族複素環カルボニル」、「非芳香族複素環オキシカルボニル」、「非芳香族複素環スルファニル」、および「非芳香族複素環スルホニル」の「非芳香族複素環」部分も、上記「非芳香族複素環式基」と同様である。
　「非芳香族複素環オキシ」とは、「非芳香族複素環」が酸素原子に結合した基を意味する。例えば、ピペリジニルオキシ、テトラヒドロフリルオキシ等が挙げられる。
　「非芳香族複素環カルボニル」とは、「非芳香族複素環」がカルボニル基に結合した基を意味する。例えば、ピペリジニルカルボニル、テトラヒドロフリルカルボニル等が挙げられる。
　「非芳香族複素環オキシカルボニル」とは、上記「非芳香族複素環オキシ」がカルボニル基に結合した基を意味する。例えば、ピペリジニルオキシカルボニル、テトラヒドロフリルオキシカルボニル等が挙げられる。
　「非芳香族複素環スルファニル」とは、「非芳香族複素環」がスルファニル基の硫黄原子と結合している水素原子と置き換わった基を意味する。例えば、ピペリジニルスルファニル、テトラヒドロフリルスルファニル等が挙げられる。
　「非芳香族複素環スルホニル」とは、「非芳香族複素環」がスルホニル基に結合した基を意味する。例えば、ピペリジニルスルホニル、テトラヒドロフリルスルホニル等が挙げられる。 “Non-aromatic heterocyclic oxy”, “non-aromatic heterocyclic carbonyl”, “non-aromatic heterocyclic oxycarbonyl”, “non-aromatic heterocyclic sulfanyl”, and “non-aromatic heterocyclic sulfonyl” The “heterocyclic ring” moiety is the same as the above “non-aromatic heterocyclic group”.
“Non-aromatic heterocyclic oxy” means a group in which “non-aromatic heterocyclic” is bonded to an oxygen atom. For example, piperidinyloxy, tetrahydrofuryloxy and the like can be mentioned.
“Non-aromatic heterocyclic carbonyl” means a group in which “non-aromatic heterocyclic” is bonded to a carbonyl group. For example, piperidinylcarbonyl, tetrahydrofurylcarbonyl and the like can be mentioned.
The “non-aromatic heterocyclic oxycarbonyl” means a group in which the “non-aromatic heterocyclic oxy” is bonded to a carbonyl group. For example, piperidinyloxycarbonyl, tetrahydrofuryloxycarbonyl and the like can be mentioned.
“Non-aromatic heterocyclic sulfanyl” means a group in which a “non-aromatic heterocyclic ring” is replaced with a hydrogen atom bonded to a sulfur atom of a sulfanyl group. For example, piperidinylsulfanyl, tetrahydrofurylsulfanyl and the like can be mentioned.
“Non-aromatic heterocyclic sulfonyl” means a group in which “non-aromatic heterocyclic” is bonded to a sulfonyl group. For example, piperidinylsulfonyl, tetrahydrofurylsulfonyl and the like can be mentioned.
　「アシル」とは、「ホルミル」、「アルキルカルボニル」、「アルケニルカルボニル」、「アルキニルカルボニル」、「芳香族複素環カルボニル」、「非芳香族複素環カルボニル」、「芳香族複素環カルボニル」および「非芳香族複素環カルボニル」を包含する。 “Acyl” means “formyl”, “alkylcarbonyl”, “alkenylcarbonyl”, “alkynylcarbonyl”, “aromatic heterocyclic carbonyl”, “non-aromatic heterocyclic carbonyl”, “aromatic heterocyclic carbonyl” and Includes “non-aromatic heterocyclic carbonyl”.
　「置換若しくは非置換のアルキル」、「置換若しくは非置換のアルケニル」、「置換若しくは非置換のアルキニル」、「置換若しくは非置換のアルキルオキシ」、「置換若しくは非置換のアルケニルオキシ」、「置換若しくは非置換のアルキニルオキシ」、「置換若しくは非置換のアルキルカルボニル」、「置換若しくは非置換のアルケニルカルボニル」、「置換若しくは非置換のアルキニルカルボニル」、「置換若しくは非置換のモノアルキルアミノ」、「置換若しくは非置換のアルキルアミノ」、「置換若しくは非置換のアルキルスルホニル」、「置換若しくは非置換のアルケニルスルホニル」、「置換若しくは非置換のアルキニルスルホニル」、「置換若しくは非置換のモノアルキルカルボニルアミノ」、「置換若しくは非置換のアルキルカルボニルアミノ」、「置換若しくは非置換のモノアルキルスルホニルアミノ」、「置換若しくは非置換のアルキルスルホニルアミノ」、「置換若しくは非置換のアルキルイミノ」、「置換若しくは非置換のアルケニルイミノ」、「置換若しくは非置換のアルキニルイミノ」、「置換若しくは非置換のアルキルカルボニルイミノ」、「置換若しくは非置換のアルケニルカルボニルイミノ」、「置換若しくは非置換のアルキニルカルボニルイミノ」、「置換若しくは非置換のアルキルオキシイミノ」、「置換若しくは非置換のアルケニルオキシイミノ」、「置換若しくは非置換のアルキニルオキシイミノ」、「置換若しくは非置換のアルキルカルボニルオキシ」、「置換若しくは非置換のアルケニルカルボニルオキシ」、「置換若しくは非置換のアルキニルカルボニルオキシ」、「置換若しくは非置換のアルキルオキシカルボニル」、「置換若しくは非置換のアルケニルオキシカルボニル」、「置換若しくは非置換のアルキニルオキシカルボニル」、「置換若しくは非置換のアルキルスルファニル」、「置換若しくは非置換のアルケニルスルファニル」、「置換若しくは非置換のアルキニルスルファニル」、「置換若しくは非置換のアルキルスルフィニル」、「置換若しくは非置換のアルケニルスルフィニル」、「置換若しくは非置換のアルキニルスルフィニル」、「置換若しくは非置換のモノアルキルカルバモイル」、「置換若しくは非置換のアルキルカルバモイル」、「置換若しくは非置換のモノアルキルスルファモイル」、および「置換若しくは非置換のアルキルスルファモイル」の置換基としては、次の置換基が挙げられる。任意の位置の炭素原子が次の置換基から選択される１以上の基と結合していてもよい。
　置換基：ハロゲン、ヒドロキシ、カルボキシ、アミノ、イミノ、ヒドロキシアミノ、ヒドロキシイミノ、ホルミル、ホルミルオキシ、カルバモイル、スルファモイル、スルファニル、スルフィノ、スルホ、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、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、トリアルキルシリル、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、ハロアルキルオキシ、アルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、モノアルキルアミノ、アルキルアミノ、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、モノアルキルカルボニルアミノ、アルキルカルボニルアミノ、モノアルキルスルホニルアミノ、アルキルスルホニルアミノ、アルキルイミノ、アルケニルイミノ、アルキニルイミノ、アルキルカルボニルイミノ、アルケニルカルボニルイミノ、アルキニルカルボニルイミノ、アルキルオキシイミノ、アルケニルオキシイミノ、アルキニルオキシイミノ、アルキルカルボニルオキシ、アルケニルカルボニルオキシ、アルキニルカルボニルオキシ、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、アルキルスルファニル、アルケニルスルファニル、アルキニルスルファニル、アルキルスルフィニル、アルケニルスルフィニル、アルキニルスルフィニル、モノアルキルカルバモイル、アルキルカルバモイル、モノアルキルスルファモイル、アルキルスルファモイル、芳香族炭素環式基、非芳香族炭素環式基、芳香族複素環式基、非芳香族複素環式基、芳香族炭素環オキシ、非芳香族炭素環オキシ、芳香族複素環オキシ、非芳香族複素環オキシ、芳香族炭素環カルボニル、非芳香族炭素環カルボニル、芳香族複素環カルボニル、非芳香族複素環カルボニル、芳香族炭素環オキシカルボニル、非芳香族炭素環オキシカルボニル、芳香族複素環オキシカルボニル、非芳香族複素環オキシカルボニル、芳香族炭素環アルキルオキシ、非芳香族炭素環アルキルオキシ、芳香族複素環アルキルオキシ、非芳香族複素環アルキルオキシ、芳香族炭素環アルキルオキシカルボニル、非芳香族炭素環アルキルオキシカルボニル、芳香族複素環アルキルオキシカルボニル、非芳香族複素環アルキルオキシカルボニル、芳香族炭素環アルキルアミノ、非芳香族炭素環アルキルアミノ、芳香族複素環アルキルアミノ、非芳香族複素環アルキルアミノ、芳香族炭素環スルファニル、非芳香族炭素環スルファニル、芳香族複素環スルファニル、非芳香族複素環スルファニル、非芳香族炭素環スルホニル、芳香族炭素環スルホニル、芳香族複素環スルホニル、および非芳香族複素環スルホニル。 “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 alkylcarbonyl", "substituted or unsubstituted alkenylcarbonyl", "substituted or unsubstituted alkynylcarbonyl", "substituted or unsubstituted monoalkylamino", "substituted Or “unsubstituted alkylamino”, “substituted or unsubstituted alkylsulfonyl”, “substituted or unsubstituted alkenylsulfonyl”, “substituted or unsubstituted alkynylsulfonyl”, “substituted or unsubstituted monoalkylcarbonylamino”, "Substituted or unsubstituted al Rucarbonylamino "," substituted or unsubstituted monoalkylsulfonylamino "," substituted or unsubstituted alkylsulfonylamino "," substituted or unsubstituted alkylimino "," substituted or unsubstituted alkenylimino "," substituted Or “substituted alkynylimino”, “substituted or unsubstituted alkylcarbonylimino”, “substituted or unsubstituted alkenylcarbonylimino”, “substituted or unsubstituted alkynylcarbonylimino”, “substituted or unsubstituted alkyloxyimino” ”,“ Substituted or unsubstituted alkenyloxyimino ”,“ substituted or unsubstituted alkynyloxyimino ”,“ substituted or unsubstituted alkylcarbonyloxy ”,“ substituted or unsubstituted alkenylcarbonyloxy ”,“ substituted or unsubstituted ” Substituted alkynylcarbonyloxy "," substituted or unsubstituted alkyloxycarbonyl "," substituted or unsubstituted alkenyloxycarbonyl "," substituted or unsubstituted alkynyloxycarbonyl "," substituted or unsubstituted alkylsulfanyl ", “Substituted or unsubstituted alkenylsulfinyl”, “substituted or unsubstituted alkynylsulfanyl”, “substituted or unsubstituted alkylsulfinyl”, “substituted or unsubstituted alkenylsulfinyl”, “substituted or unsubstituted alkynylsulfinyl”, “Substituted or unsubstituted monoalkylcarbamoyl”, “substituted or unsubstituted alkylcarbamoyl”, “substituted or unsubstituted monoalkylsulfamoyl”, and “substituted or unsubstituted alkylsulfamoyl” Examples of the substituent of “yl” include the following substituents. The carbon atom at any position may be bonded to one or more groups selected from the following substituents.
Substituents: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, monoalkylamino, alkylamino, alkylsulfonyl, alkenylsulfonyl, alkynyl Sulfonyl, monoalkylcarbonylamino, alkylcarbonylamino, monoalkylsulfonylamino Alkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino, alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, Alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylcarbamoyl, alkylcarbamoyl, monoalkylsulfamoyl, alkylsulfamoyl, aromatic Carbocyclic groups, non-aromatic charcoal Cyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic oxy, non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl , Non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, aromatic carbocyclic oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl , Aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy, non-aromatic heterocyclic alkyloxy, aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyloxycarbonyl, aromatic Heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic alkylamino, non-aromatic carbon Ring alkylamino, aromatic heterocyclic alkylamino, non-aromatic heterocyclic alkylamino, aromatic carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl, non-aromatic carbocyclic ring Sulfonyl, aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl, and non-aromatic heterocyclic sulfonyl.
　「置換若しくは非置換の芳香族炭素環式基」、「置換若しくは非置換の非芳香族炭素環式基」、「置換若しくは非置換の芳香族複素環式基」、および「置換若しくは非置換の非芳香族複素環式基」、
「置換若しくは非置換の芳香族炭素環オキシ」、「置換若しくは非置換の非芳香族炭素環オキシ」、「置換若しくは非置換の芳香族複素環オキシ」、および「置換若しくは非置換の非芳香族複素環オキシ」、
「置換若しくは非置換の芳香族炭素環カルボニル」、「置換若しくは非置換の非芳香族炭素環カルボニル」、「置換若しくは非置換の芳香族複素環カルボニル」、および「置換若しくは非置換の非芳香族複素環カルボニル」、
「置換若しくは非置換の芳香族炭素環オキシカルボニル」、「置換若しくは非置換の非芳香族炭素環オキシカルボニル」、「置換若しくは非置換の芳香族複素環オキシカルボニル」、および「置換若しくは非置換の非芳香族複素環オキシカルボニル」、
「置換若しくは非置換の芳香族炭素環スルファニル」、「置換若しくは非置換の非芳香族炭素環スルファニル」、「置換若しくは非置換の芳香族複素環スルファニル」、および「置換若しくは非置換の非芳香族複素環スルファニル」、ならびに
「置換若しくは非置換の芳香族炭素環スルホニル」、「置換若しくは非置換の非芳香族炭素環スルホニル」、「置換若しくは非置換の芳香族複素環スルホニル」、および「置換若しくは非置換の非芳香族複素環スルホニル」の「芳香族炭素環」、「非芳香族炭素環」、「芳香族複素環」、および「非芳香族複素環」の環上の置換基としては、次の置換基が挙げられる。環上の任意の位置の原子が次の置換基から選択される１以上の基と結合していてもよい。
　置換基：ハロゲン、ヒドロキシ、カルボキシ、アミノ、イミノ、ヒドロキシアミノ、ヒドロキシイミノ、ホルミル、ホルミルオキシ、カルバモイル、スルファモイル、スルファニル、スルフィノ、スルホ、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、シアノ、ニトロ、ニトロソ、アジド、ヒドラジノ、ウレイド、アミジノ、グアニジノ、トリアルキルシリル、アルキル、アルケニル、アルキニル、ハロアルキル、アルキルオキシ、アルケニルオキシ、アルキニルオキシ、ハロアルキルオキシ、アルキルオキシアルキル、アルキルオキシアルキルオキシ、アルキルカルボニル、アルケニルカルボニル、アルキニルカルボニル、モノアルキルアミノ、アルキルアミノ、アルキルスルホニル、アルケニルスルホニル、アルキニルスルホニル、モノアルキルカルボニルアミノ、アルキルカルボニルアミノ、モノアルキルスルホニルアミノ、アルキルスルホニルアミノ、アルキルイミノ、アルケニルイミノ、アルキニルイミノ、アルキルカルボニルイミノ、アルケニルカルボニルイミノ、アルキニルカルボニルイミノ、アルキルオキシイミノ、アルケニルオキシイミノ、アルキニルオキシイミノ、アルキルカルボニルオキシ、アルケニルカルボニルオキシ、アルキニルカルボニルオキシ、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、アルキルスルファニル、アルケニルスルファニル、アルキニルスルファニル、アルキルスルフィニル、アルケニルスルフィニル、アルキニルスルフィニル、モノアルキルカルバモイル、アルキルカルバモイル、モノアルキルスルファモイル、アルキルスルファモイル、芳香族炭素環式基、非芳香族炭素環式基、芳香族複素環式基、非芳香族複素環式基、芳香族炭素環オキシ、非芳香族炭素環オキシ、芳香族複素環オキシ、非芳香族複素環オキシ、芳香族炭素環カルボニル、非芳香族炭素環カルボニル、芳香族複素環カルボニル、非芳香族複素環カルボニル、芳香族炭素環オキシカルボニル、非芳香族炭素環オキシカルボニル、芳香族複素環オキシカルボニル、非芳香族複素環オキシカルボニル、芳香族炭素環アルキル、非芳香族炭素環アルキル、芳香族複素環アルキル、非芳香族複素環アルキル、芳香族炭素環アルキルオキシ、非芳香族炭素環アルキルオキシ、芳香族複素環アルキルオキシ、非芳香族複素環アルキルオキシ、芳香族炭素環アルキルオキシカルボニル、非芳香族炭素環アルキルオキシカルボニル、芳香族複素環アルキルオキシカルボニル、非芳香族複素環アルキルオキシカルボニル、芳香族炭素環アルキルオキシアルキル、非芳香族炭素環アルキルオキシアルキル、芳香族複素環アルキルオキシアルキル、非芳香族複素環アルキルオキシアルキル、芳香族炭素環アルキルアミノ、非芳香族炭素環アルキルアミノ、芳香族複素環アルキルアミノ、非芳香族複素環アルキルアミノ、芳香族炭素環スルファニル、非芳香族炭素環スルファニル、芳香族複素環スルファニル、非芳香族複素環スルファニル、非芳香族炭素環スルホニル、芳香族炭素環スルホニル、芳香族複素環スルホニル、および非芳香族複素環スルホニル。 “Substituted or unsubstituted aromatic carbocyclic group”, “Substituted or unsubstituted nonaromatic carbocyclic group”, “Substituted or unsubstituted aromatic heterocyclic group”, and “Substituted or unsubstituted aromatic carbocyclic group” Non-aromatic heterocyclic group ",
"Substituted or unsubstituted aromatic carbocyclic oxy", "Substituted or unsubstituted non-aromatic carbocyclic oxy", "Substituted or unsubstituted aromatic heterocyclic oxy", and "Substituted or unsubstituted non-aromatic Heterocyclic oxy ",
"Substituted or unsubstituted aromatic carbocyclic carbonyl", "Substituted or unsubstituted non-aromatic carbocyclic carbonyl", "Substituted or unsubstituted aromatic heterocyclic carbonyl", and "Substituted or unsubstituted non-aromatic Heterocyclic carbonyl ",
“Substituted or unsubstituted aromatic carbocyclic oxycarbonyl”, “substituted or unsubstituted nonaromatic carbocyclic oxycarbonyl”, “substituted or unsubstituted aromatic heterocyclic oxycarbonyl”, and “substituted or unsubstituted Non-aromatic heterocyclic oxycarbonyl ",
"Substituted or unsubstituted aromatic carbocyclic sulfanyl", "Substituted or unsubstituted non-aromatic carbocyclic sulfanyl", "Substituted or unsubstituted aromatic heterocyclic sulfanyl", and "Substituted or unsubstituted non-aromatic "Heterocyclic sulfanyl", and "substituted or unsubstituted aromatic carbocyclic sulfonyl", "substituted or unsubstituted non-aromatic carbocyclic sulfonyl", "substituted or unsubstituted aromatic heterocyclic sulfonyl", and "substituted or Substituents on the rings of “aromatic carbocycle”, “non-aromatic carbocycle”, “aromatic heterocycle”, and “non-aromatic heterocycle” of “unsubstituted non-aromatic heterocycle sulfonyl” include The following substituents are mentioned. An atom at any position on the ring may be bonded to one or more groups selected from the following substituents.
Substituents: halogen, hydroxy, carboxy, amino, imino, hydroxyamino, hydroxyimino, formyl, formyloxy, carbamoyl, sulfamoyl, sulfanyl, sulfino, sulfo, thioformyl, thiocarboxy, dithiocarboxy, thiocarbamoyl, cyano, nitro, nitroso , Azide, hydrazino, ureido, amidino, guanidino, trialkylsilyl, alkyl, alkenyl, alkynyl, haloalkyl, alkyloxy, alkenyloxy, alkynyloxy, haloalkyloxy, alkyloxyalkyl, alkyloxyalkyloxy, alkylcarbonyl, alkenylcarbonyl, Alkynylcarbonyl, monoalkylamino, alkylamino, alkylsulfonyl, alkenylsulfonyl, Quinylsulfonyl, monoalkylcarbonylamino, alkylcarbonylamino, monoalkylsulfonylamino, alkylsulfonylamino, alkylimino, alkenylimino, alkynylimino, alkylcarbonylimino, alkenylcarbonylimino, alkynylcarbonylimino, alkyloxyimino, alkenyloxyimino , Alkynyloxyimino, alkylcarbonyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkyloxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, alkylsulfanyl, alkenylsulfanyl, alkynylsulfanyl, alkylsulfinyl, alkenylsulfinyl, alkynylsulfinyl, monoalkylcarbamoyl , Alkylcarbamoyl, monoalkylsulfamoyl, alkylsulfamoyl, aromatic carbocyclic group, non-aromatic carbocyclic group, aromatic heterocyclic group, non-aromatic heterocyclic group, aromatic carbocyclic oxy, Non-aromatic carbocyclic oxy, aromatic heterocyclic oxy, non-aromatic heterocyclic oxy, aromatic carbocyclic carbonyl, non-aromatic carbocyclic carbonyl, aromatic heterocyclic carbonyl, non-aromatic heterocyclic carbonyl, aromatic carbocyclic Oxycarbonyl, non-aromatic carbocyclic oxycarbonyl, aromatic heterocyclic oxycarbonyl, non-aromatic heterocyclic oxycarbonyl, aromatic carbocyclic alkyl, non-aromatic carbocyclic alkyl, aromatic heterocyclic alkyl, non-aromatic heterocyclic Alkyl, aromatic carbocyclic alkyloxy, non-aromatic carbocyclic alkyloxy, aromatic heterocyclic alkyloxy, non-aromatic heterocyclic alkyloxy, aromatic Aromatic carbocyclic alkyloxycarbonyl, non-aromatic carbocyclic alkyloxycarbonyl, aromatic heterocyclic alkyloxycarbonyl, non-aromatic heterocyclic alkyloxycarbonyl, aromatic carbocyclic alkyloxyalkyl, non-aromatic carbocyclic alkyloxyalkyl , Aromatic heterocyclic alkyloxyalkyl, non-aromatic heterocyclic alkyloxyalkyl, aromatic carbocyclic alkylamino, non-aromatic carbocyclic alkylamino, aromatic heterocyclic alkylamino, non-aromatic heterocyclic alkylamino, aromatic Carbocyclic sulfanyl, non-aromatic carbocyclic sulfanyl, aromatic heterocyclic sulfanyl, non-aromatic heterocyclic sulfanyl, non-aromatic carbocyclic sulfonyl, aromatic carbocyclic sulfonyl, aromatic heterocyclic sulfonyl, and non-aromatic heterocyclic sulfonyl .
　また、「置換若しくは非置換の非芳香族炭素環式基」および「置換若しくは非置換の非芳香族複素環式基」は「オキソ」で置換されていてもよい。この場合、以下のように炭素原子上の２個の水素原子が置換されている基を意味する。
Figure JPOXMLDOC01-appb-C000032
 Further, the “substituted or unsubstituted non-aromatic carbocyclic group” and “substituted or unsubstituted non-aromatic heterocyclic group” may be substituted with “oxo”. In this case, it means a group in which two hydrogen atoms on a carbon atom are substituted as follows.
Figure JPOXMLDOC01-appb-C000032
　上記、「置換若しくは非置換の非芳香族炭素環オキシ」、「置換若しくは非置換の非芳香族複素環オキシ」、「置換若しくは非置換の非芳香族炭素環カルボニル」、「置換若しくは非置換の非芳香族複素環カルボニル」、「置換若しくは非置換の非芳香族炭素環オキシカルボニル」、「置換若しくは非置換の非芳香族複素環オキシカルボニル」、「置換若しくは非置換の非芳香族炭素環スルファニル」、「置換若しくは非置換の非芳香族複素環スルファニル」、「置換若しくは非置換の非芳香族炭素環スルホニル」、および「置換若しくは非置換の非芳香族複素環スルホニル」の非芳香族炭素環、および非芳香族複素環部分も上記と同様に「オキソ」で置換されていてもよい。 The above-mentioned “substituted or unsubstituted non-aromatic carbocyclic oxy”, “substituted or unsubstituted non-aromatic heterocyclic oxy”, “substituted or unsubstituted non-aromatic carbocyclic carbonyl”, “substituted or unsubstituted “Non-aromatic heterocyclic carbonyl”, “Substituted or unsubstituted non-aromatic carbocyclic oxycarbonyl”, “Substituted or unsubstituted non-aromatic heterocyclic oxycarbonyl”, “Substituted or unsubstituted non-aromatic carbocyclic sulfanyl” , “Substituted or unsubstituted non-aromatic heterocyclic sulfanyl”, “substituted or unsubstituted non-aromatic carbocyclic sulfonyl”, and “substituted or unsubstituted non-aromatic heterocyclic sulfonyl” non-aromatic carbocycle , And non-aromatic heterocyclic moieties may be substituted with “oxo” as described above.
　Ｒ１における「置換若しくは非置換のアルキル」の置換基としては、例えば、ハロゲン；アルキルオキシカルボニル；カルボキシ；アルキルオキシ；シアノ；ヒドロキシ；カルバモイル；アルキルアミノ；アシルアミノ；が挙げられる。これらから選択される１以上の基で置換されていてもよい。
　Ｒ１における「置換若しくは非置換のカルバモイル」の置換基としては、例えば、アルキル；ハロアルキル；非芳香族複素環式基；が挙げられる。これらから選択される１以上の基で置換されていてもよい。
　Ｒ１における「置換若しくは非置換のアルキルオキシカルボニル」の置換基としては、例えば、アルキル；ハロアルキル；が挙げられる。これらから選択される１以上の基で置換されていてもよい。
　Ｒ１における「置換若しくは非置換のアミノ」の置換基としては、例えば、非芳香族複素環カルボニル；アシル；が挙げられる。これらから選択される１以上の基で置換されていてもよい。
　Ｒ１における「置換若しくは非置換の芳香族複素環式基」の置換基としては、例えば、アルキル；ハロアルキル；が挙げられる。これらから選択される１以上の基で置換されていてもよい。 Examples of the substituent of “substituted or unsubstituted alkyl” in R 1 include halogen; alkyloxycarbonyl; carboxy; alkyloxy; cyano; hydroxy; carbamoyl; It may be substituted with one or more groups selected from these.
Examples of the substituent of “substituted or unsubstituted carbamoyl” in R 1 include alkyl; haloalkyl; non-aromatic heterocyclic group; It may be substituted with one or more groups selected from these.
Examples of the substituent of “substituted or unsubstituted alkyloxycarbonyl” in R 1 include alkyl; haloalkyl; It may be substituted with one or more groups selected from these.
As the substituent of “substituted or unsubstituted amino” in R 1 , for example, non-aromatic heterocyclic carbonyl; acyl; It may be substituted with one or more groups selected from these.
Examples of the substituent of the “substituted or unsubstituted aromatic heterocyclic group” in R 1 include alkyl and haloalkyl. It may be substituted with one or more groups selected from these.
　Ｒ２における「置換若しくは非置換の芳香族炭素環式基」の置換基としては、例えば、ハロゲン；アルキルオキシ；シアノ；アルキル；カルボキシ；ヒドロキシ；ハロアルキル；が挙げられる。
　Ｒ２における「置換若しくは非置換の非芳香族炭素環式基」の置換基としては、例えば、ハロゲン；アルキルオキシ；シアノ；アルキル；カルボキシ；ヒドロキシ；ハロアルキル；が挙げられる。 Examples of the substituent of the “substituted or unsubstituted aromatic carbocyclic group” in R 2 include halogen; alkyloxy; cyano; alkyl; carboxy; hydroxy;
Examples of the substituent of the “substituted or unsubstituted non-aromatic carbocyclic group” in R 2 include halogen; alkyloxy; cyano; alkyl; carboxy; hydroxy;
　Ｒ２における「置換若しくは非置換の芳香族複素環式基」の置換基としては、例えば、ハロゲン；アルキルオキシ；シアノ；アルキル；カルボキシ；ヒドロキシ；ハロアルキル；が挙げられる。
　Ｒ２における「置換若しくは非置換の非芳香族複素環式基」の置換基としては、例えば、ハロゲン；アルキルオキシ；シアノ；アルキル；カルボキシ；ヒドロキシ；ハロアルキル；が挙げられる。 Examples of the substituent of the “substituted or unsubstituted aromatic heterocyclic group” in R 2 include halogen; alkyloxy; cyano; alkyl; carboxy; hydroxy;
Examples of the substituent of the “substituted or unsubstituted non-aromatic heterocyclic group” in R 2 include halogen; alkyloxy; cyano; alkyl; carboxy; hydroxy;
　Ｒ３における「置換若しくは非置換の芳香族炭素環式基」の置換基としては、例えば、
非置換若しくは置換（置換基としては、カルボキシ、アルキルオキシカルボニル、カルバモイル、シアノ、ヒドロキシアルキル、オキソ、ハロゲン、ハロアルキル、ハロアルキルオキシ、アルキルオキシ、アルキル）芳香族複素環オキシ；
非置換若しくは置換（置換基としては、カルボキシ、アルキルオキシカルボニル、カルバモイル、シアノ、ヒドロキシアルキル、オキソ、ハロゲン、ハロアルキル、ハロアルキルオキシ、アルキルオキシ、アルキル）非芳香族複素環オキシ；
非置換若しくは置換（置換基としては、カルボキシ、アルキルオキシカルボニル、カルバモイル、シアノ、ヒドロキシアルキル、オキソ、ハロゲン、ハロアルキル、ハロアルキルオキシ、アルキルオキシ、アルキル）芳香族炭素環オキシ；
非置換若しくは置換（置換基としては、カルボキシ、アルキルオキシカルボニル、カルバモイル、シアノ、ヒドロキシアルキル、オキソ、ハロゲン、ハロアルキル、ハロアルキルオキシ、アルキルオキシ、アルキル）非芳香族炭素環オキシ；が挙げられる。 Examples of the substituent of the “substituted or unsubstituted aromatic carbocyclic group” in R 3 include, for example,
Unsubstituted or substituted (substituted groups include carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy, alkyl) aromatic heterocyclic oxy;
Unsubstituted or substituted (carboxyl, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy, alkyl) as non-aromatic heterocyclic oxy;
Unsubstituted or substituted (substituted groups include carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy, alkyl) aromatic carbocyclic oxy;
Unsubstituted or substituted (substituents include carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy, alkyl) non-aromatic carbocyclic oxy;
　Ｒ６における「置換若しくは非置換の芳香族複素環オキシ」、「置換若しくは非置換の非芳香族複素環オキシ」、「置換若しくは非置換の芳香族炭素環オキシ」または「置換若しくは非置換の非芳香族炭素環オキシ」の置換基としては、例えば、カルボキシ、アルキルオキシカルボニル、カルバモイル、シアノ、ヒドロキシアルキル、オキソ、ハロゲン、ハロアルキル、ハロアルキルオキシ、アルキルオキシ、アルキルが挙げられる。 "Substituted or unsubstituted aromatic heterocyclic oxy" in R 6, "substituted or unsubstituted non-aromatic heterocyclic oxy", "substituted or unsubstituted aromatic carbocyclic oxy" or "substituted or unsubstituted non Examples of the substituent of “aromatic carbocyclic oxy” include carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy and alkyl.
　Ｒ７における「置換若しくは非置換の芳香族複素環」「置換若しくは非置換の非芳香族複素環」、「置換若しくは非置換の芳香族炭素環」または「置換若しくは非置換の非芳香族炭素環」の置換基としては、例えば、カルボキシ、アルキルオキシカルボニル、カルバモイル、シアノ、ヒドロキシアルキル、オキソ、ハロゲン、ハロアルキル、ハロアルキルオキシ、アルキルオキシ、アルキルが挙げられる。 “Substituted or unsubstituted aromatic heterocycle”, “Substituted or unsubstituted nonaromatic heterocycle”, “Substituted or unsubstituted aromatic carbocycle” or “Substituted or unsubstituted nonaromatic carbocycle” for R 7 Examples of the substituent of “] include carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy, and alkyl.
　一般式（Ｉ）中、
　－Ｘ－としては、－Ｎ（Ｒ５）－が挙げられる。
　Ｒ１としては、置換若しくは非置換のアルキルが挙げられる。
　Ｒ１としては、カルボキシが挙げられる。
　Ｒ１としては、シアノが挙げられる。
　Ｒ１としては、置換若しくは非置換のアルキルオキシカルボニルが挙げられる。
　Ｒ１としては、置換若しくは非置換のカルバモイルが挙げられる。
　Ｒ１としては、置換若しくは非置換のアミノが挙げられる。
　Ｒ２としては、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基が挙げられる。
　Ｒ２としては、置換若しくは非置換のフェニルが挙げられる。
　Ｒ２としては、置換若しくは非置換のピリジルまたはチエニルが挙げられる。
　Ｒ３としては、置換若しくは非置換の芳香族炭素環式基が挙げられる。
　Ｒ３としては、置換若しくは非置換のフェニルが挙げられる。
　Ｒ４ａとしては、水素原子が挙げられる。
　Ｒ４ｂとしては、水素原子が挙げられる。
　Ｒ５としては、水素原子が挙げられる。
　環Ａとしては、芳香族炭素環または芳香族複素環が挙げられる。
　環Ａとしては、ベンゼンまたはピリジンが挙げられる。
　環Ａとしては、ベンゼンが挙げられる。
　ｓとしては、０、１、２が挙げられる
　Ｒ６としては、置換若しくは非置換の芳香族複素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換の芳香族炭素環オキシまたは置換若しくは非置換の非芳香族炭素環オキシが挙げられる。
　Ｒ７としては、置換若しくは非置換の芳香族複素環式基または置換若しくは非置換の非芳香族複素環式基が挙げられる。
　Ｒ７としては、置換若しくは非置換のピリジル、置換若しくは非置換のピリダジニル、置換若しくは非置換のジヒドロピリジル、置換若しくは非置換のピリダジノが挙げられる。
　Ｒ８としては、水素原子、ハロゲン、置換若しくは非置換のアルキルまたは置換若しくは非置換のアルキルオキシが挙げられる。 In general formula (I),
—X— includes —N (R 5 ) —.
R 1 includes substituted or unsubstituted alkyl.
R 1 includes carboxy.
R 1 includes cyano.
R 1 includes substituted or unsubstituted alkyloxycarbonyl.
Examples of R 1 include substituted or unsubstituted carbamoyl.
R 1 includes substituted or unsubstituted amino.
R 2 includes a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group.
R 2 includes substituted or unsubstituted phenyl.
R 2 includes substituted or unsubstituted pyridyl or thienyl.
R 3 includes a substituted or unsubstituted aromatic carbocyclic group.
R 3 includes substituted or unsubstituted phenyl.
Examples of R 4a include a hydrogen atom.
Examples of R 4b include a hydrogen atom.
R 5 includes a hydrogen atom.
Ring A includes an aromatic carbocycle or an aromatic heterocycle.
Ring A includes benzene or pyridine.
Ring A includes benzene.
Examples of s include 0, 1, and 2. R 6 represents substituted or unsubstituted aromatic heterocyclic oxy, substituted or unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy. Or a substituted or unsubstituted non-aromatic carbocyclic oxy is mentioned.
R 7 includes a substituted or unsubstituted aromatic heterocyclic group or a substituted or unsubstituted non-aromatic heterocyclic group.
R 7 includes substituted or unsubstituted pyridyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted dihydropyridyl, substituted or unsubstituted pyridazino.
R 8 includes a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy.
　本発明の具体的実施形態を、以下に例示する。 Specific embodiments of the present invention are exemplified below.
　一般式（Ｉ－Ａ）：
Figure JPOXMLDOC01-appb-C000033
（式中、各記号は上記と同義である）で示される化合物またはその製薬上許容される塩。
　以下に、Ｒ１、Ｒ２、Ｒ７およびＲ８の具体例を示す。式（Ｉ－Ａ）で示される化合物としては、これら具体例の全ての組み合わせが例示される。
　Ｒ１としては、置換若しくは非置換のアルキルが挙げられる。（以下、Ａ－１とする）
　Ｒ１としては、置換アルキルが挙げられる。（以下、Ａ－２とする）
　Ｒ１としては、置換Ｃ１－Ｃ６アルキルが挙げられる。（以下、Ａ－３とする）
　Ｒ１としては、ハロゲンで置換されたアルキルが挙げられる。（以下、Ａ－４とする）
　Ｒ１としては、ハロゲンで置換されたＣ１－Ｃ６アルキルが挙げられる。（以下、Ａ－５とする）
　Ｒ１としては、カルボキシが挙げられる。（以下、Ａ－６とする）
　Ｒ１としては、シアノが挙げられる。（以下、Ａ－７とする）
　Ｒ１としては、置換若しくは非置換のアルキルオキシカルボニルが挙げられる。（以下、Ａ－８とする）
　Ｒ１としては、アルキルまたはハロアルキルで置換されたアルキルオキシカルボニルが挙げられる。（以下、Ａ－９とする）
　Ｒ１としては、置換若しくは非置換のカルバモイルが挙げられる。（以下、Ａ－１０とする）
　Ｒ１としては、置換カルバモイルが挙げられる。（以下、Ａ－１１とする）
　Ｒ１としては、アルキル、ハロアルキルまたは非芳香族複素環式基で置換されたカルバモイルが挙げられる。（以下、Ａ－１２とする）
　Ｒ１としては、置換若しくは非置換のアミノが挙げられる。（以下、Ａ－１３とする）
　Ｒ１としては、非置換アミノが挙げられる。（以下、Ａ－１４とする）
　Ｒ１としては、置換アミノが挙げられる。（以下、Ａ－１５とする）
　Ｒ１としては、非芳香族複素環カルボニルまたはアシルで置換されたアミノが挙げられる。（以下、Ａ－１６とする）
　Ｒ１としては、置換若しくは非置換の芳香族複素環式基が挙げられる。（以下、Ａ－１７とする）
　Ｒ１としては、アルキルまたはハロアルキルで置換された芳香族複素環式基が挙げられる。（以下、Ａ－１８とする）
　Ｒ２としては、置換若しくは非置換の芳香族炭素環式基が挙げられる。（以下、Ｂ－１とする）
　Ｒ２としては、置換芳香族炭素環式基が挙げられる。（以下、Ｂ－２とする）
　Ｒ２としては、置換フェニルが挙げられる。（以下、Ｂ－３とする）
　Ｒ２としては、ハロゲンで置換された芳香族炭素環式基が挙げられる。（以下、Ｂ－４とする）
　Ｒ２としては、ハロゲンで置換されたフェニルが挙げられる。（以下、Ｂ－５とする）
　Ｒ７としては、置換若しくは非置換の芳香族複素環式基が挙げられる。（以下、Ｃ－１とする）
　Ｒ７としては、置換芳香族複素環式基が挙げられる。（以下、Ｃ－２とする）
　Ｒ７としては、置換ピリジルまたは置換ピリダジニルが挙げられる。（以下、Ｃ－３とする）
　Ｒ７としては、カルボキシ、アルキルオキシカルボニル、カルバモイル、シアノ、ヒドロキシアルキル、オキソ、ハロゲン、ハロアルキル、ハロアルキルオキシ、アルキルオキシまたはアルキルで置換された芳香族複素環式基が挙げられる。（以下、Ｃ－４とする）
　Ｒ７としては、（カルボキシ、アルキルオキシカルボニル、カルバモイル、シアノ、ヒドロキシアルキル、オキソ、ハロゲン、ハロアルキル、ハロアルキルオキシ、アルキルオキシまたはアルキルで置換された）ピリジルまたはピリダジニルが挙げられる。（以下、Ｃ－５とする）
　Ｒ７としては、置換若しくは非置換の非芳香族複素環式基が挙げられる。（以下、Ｃ－６とする）
　Ｒ７としては、置換非芳香族複素環式基が挙げられる。（以下、Ｃ－７とする）
　Ｒ７としては、置換ジヒドロピリジルまたは置換ジヒドロピリダジニルが挙げられる。（以下、Ｃ－８とする）
　Ｒ７としては、カルボキシ、アルキルオキシカルボニル、カルバモイル、シアノ、ヒドロキシアルキル、オキソ、ハロゲン、ハロアルキル、ハロアルキルオキシ、アルキルオキシまたはアルキルで置換された非芳香族複素環式基が挙げられる。（以下、Ｃ－９とする）
　Ｒ７としては、（カルボキシ、アルキルオキシカルボニル、カルバモイル、シアノ、ヒドロキシアルキル、オキソ、ハロゲン、ハロアルキル、ハロアルキルオキシ、アルキルオキシまたはアルキルで置換された）ピリドニルまたはピリダジノが挙げられる。（以下、Ｃ－１０とする）
　Ｒ８としては、水素原子、ハロゲン、置換若しくは非置換のアルキルまたは置換若しくは非置換のアルキルオキシが挙げられる。（以下、Ｄ－１とする）
　Ｒ８としては、ハロゲン、置換若しくは非置換のアルキルまたは置換若しくは非置換のアルキルオキシが挙げられる。（以下、Ｄ－２とする）
　Ｒ８としては、ハロゲン、置換若しくは非置換のＣ１－Ｃ３アルキルまたは置換若しくは非置換のＣ１－Ｃ３アルキルオキシが挙げられる。（以下、Ｄ－３とする） Formula (IA):
Figure JPOXMLDOC01-appb-C000033
(Wherein each symbol is as defined above) or a pharmaceutically acceptable salt thereof.
Specific examples of R 1 , R 2 , R 7 and R 8 are shown below. Examples of the compound represented by the formula (IA) include all combinations of these specific examples.
R 1 includes substituted or unsubstituted alkyl. (Hereafter referred to as A-1)
R 1 includes substituted alkyl. (Hereafter referred to as A-2)
R 1 includes substituted C1-C6 alkyl. (Hereafter referred to as A-3)
R 1 includes alkyl substituted with halogen. (Hereafter referred to as A-4)
R 1 includes C1-C6 alkyl substituted with halogen. (Hereafter referred to as A-5)
R 1 includes carboxy. (Hereafter referred to as A-6)
R 1 includes cyano. (Hereafter referred to as A-7)
R 1 includes substituted or unsubstituted alkyloxycarbonyl. (Hereafter referred to as A-8)
R 1 includes alkyloxycarbonyl substituted with alkyl or haloalkyl. (Hereafter referred to as A-9)
Examples of R 1 include substituted or unsubstituted carbamoyl. (Hereafter referred to as A-10)
R 1 includes substituted carbamoyl. (Hereafter referred to as A-11)
R 1 includes carbamoyl substituted with an alkyl, haloalkyl or non-aromatic heterocyclic group. (Hereafter referred to as A-12)
R 1 includes substituted or unsubstituted amino. (Hereafter referred to as A-13)
R 1 includes unsubstituted amino. (Hereafter referred to as A-14)
R 1 includes substituted amino. (Hereafter referred to as A-15)
R 1 includes non-aromatic heterocyclic carbonyl or acyl substituted amino. (Hereafter referred to as A-16)
R 1 includes a substituted or unsubstituted aromatic heterocyclic group. (Hereafter referred to as A-17)
R 1 includes an aromatic heterocyclic group substituted with alkyl or haloalkyl. (Hereafter referred to as A-18)
R 2 includes a substituted or unsubstituted aromatic carbocyclic group. (Hereafter referred to as B-1)
R 2 includes a substituted aromatic carbocyclic group. (Hereafter referred to as B-2)
R 2 includes substituted phenyl. (Hereafter referred to as B-3)
R 2 includes an aromatic carbocyclic group substituted with halogen. (Hereafter referred to as B-4)
R 2 includes phenyl substituted with halogen. (Hereafter referred to as B-5)
R 7 includes a substituted or unsubstituted aromatic heterocyclic group. (Hereafter referred to as C-1)
R 7 includes a substituted aromatic heterocyclic group. (Hereafter referred to as C-2)
R 7 includes substituted pyridyl or substituted pyridazinyl. (Hereafter referred to as C-3)
R 7 includes an aromatic heterocyclic group substituted with carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy or alkyl. (Hereafter referred to as C-4)
R 7 includes pyridyl or pyridazinyl (substituted with carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy or alkyl). (Hereafter referred to as C-5)
R 7 includes a substituted or unsubstituted non-aromatic heterocyclic group. (Hereafter referred to as C-6)
R 7 includes a substituted non-aromatic heterocyclic group. (Hereafter referred to as C-7)
R 7 includes substituted dihydropyridyl or substituted dihydropyridazinyl. (Hereafter referred to as C-8)
R 7 includes a non-aromatic heterocyclic group substituted with carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy or alkyl. (Hereafter referred to as C-9)
R 7 includes pyridonyl or pyridazino (substituted with carboxy, alkyloxycarbonyl, carbamoyl, cyano, hydroxyalkyl, oxo, halogen, haloalkyl, haloalkyloxy, alkyloxy or alkyl). (Hereafter referred to as C-10)
R 8 includes a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy. (Hereafter referred to as D-1)
R 8 includes halogen, substituted or unsubstituted alkyl or substituted or unsubstituted alkyloxy. (Hereafter referred to as D-2)
R 8 includes halogen, substituted or unsubstituted C1-C3 alkyl or substituted or unsubstituted C1-C3 alkyloxy. (Hereafter referred to as D-3)
　式（Ｉ）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－で示される化合物は、以下のような互変異性体を包含する。
Figure JPOXMLDOC01-appb-C000034
 The compounds of formula (I) are not limited to specific isomers, but all possible isomers (eg keto-enol isomers, imine-enamine isomers, diastereoisomers, optical isomers) , Rotamers, etc.), racemates or mixtures thereof. For example, in the formula (I), the compound in which X is —NH— includes the following tautomers.
Figure JPOXMLDOC01-appb-C000034
　式（Ｉ）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２Ｈ、３Ｈ、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）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）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、該「放射性標識体」は、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 compound of formula (I) may be replaced with isotopes of hydrogen, carbon and / or other atoms, respectively. 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) also includes a compound substituted with such an isotope. The compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound represented by the formula (I). In addition, a “radiolabeling method” for producing the “radiolabeled substance” is also encompassed in the present invention, and the “radiolabeled substance” is useful as a metabolic pharmacokinetic study, a research in a binding assay, and / or a diagnostic tool. It is.
　式（Ｉ）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）で示されるトリチウム標識化合物は、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）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）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。トリチウム標識化合物を調製するための他の適切な方法は、“Ｉｓｏｔｏｐｅｓ　ｉｎ　ｔｈｅ　Ｐｈｙｓｉｃａｌ　ａｎｄ　Ｂｉｏｍｅｄｉｃａｌ　Ｓｃｉｅｎｃｅｓ，Ｖｏｌ．１，Ｌａｂｅｌｅｄ　Ｃｏｍｐｏｕｎｄｓ　（Ｐａｒｔ　Ａ），Ｃｈａｐｔｅｒ　６　（１９８７年）”を参照することができる。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。 The radioactive label of the compound represented by the formula (I) can be prepared by a method well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by a catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that. Other suitable methods for preparing tritium labeled compounds can be referred to “Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987)”. The 14 C-labeled compound can be prepared by using a raw material having 14 C carbon.
　式（Ｉ）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。 As the pharmaceutically acceptable salt of the compound represented by the formula (I), for example, a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, Calcium, barium, etc.), magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, diethanolamine, ethylenediamine, pyridine, Picolin, quinoline etc.) and salts with amino acids, or inorganic acids (eg hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, 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, methanesulfonic acid, ethanesulfonic acid, etc.) Salt. 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.
　本発明の式（Ｉ）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）、共結晶および／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、共結晶および結晶多形も包含する。「溶媒和物」は、式（Ｉ）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）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）で示される化合物またはその製薬上許容される塩を、再結晶することで結晶多形を形成する場合がある。「共結晶」は、式（Ｉ）で示される化合物または塩とカウンター分子が同一結晶格子内に存在することを意味し、任意の数のカウンター分子と形成していてもよい。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.), a co-crystal and / or a crystal polymorph. Also encompasses such various solvates, co-crystals and polymorphs. The “solvate” may be coordinated with an arbitrary number of solvent molecules (for example, water molecules) with respect to the compound represented by the formula (I). When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In addition, a crystal polymorph may be formed by recrystallizing the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. “Co-crystal” means that the compound or salt represented by the formula (I) and the counter molecule are present in the same crystal lattice, and may be formed with any number of counter molecules.
　本発明の式（Ｉ）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）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）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。 The compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes 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 a compound that is enzymatically oxidized, reduced, hydrolyzed, etc. under physiological conditions in vivo to be converted into a compound represented by formula (I), hydrolyzed by gastric acid, etc. The compound etc. which are converted into the compound shown are included. A method for selecting and producing an appropriate prodrug derivative is described in, for example, “Design of Prodrugs, Elsevier, Amsterdam, 1985”. Prodrugs may themselves have activity.
　式（Ｉ）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ライド、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、ＣＨ３ＣＯＯ－、Ｃ２Ｈ５ＣＯＯ－、ｔｅｒｔ－ＢｕＣＯＯ－、Ｃ１５Ｈ３１ＣＯＯ－、ＰｈＣＯＯ－、（ｍ－ＮａＯＯＣＰｈ）ＣＯＯ－、ＮａＯＯＣＣＨ２ＣＨ２ＣＯＯ－、ＣＨ３ＣＨ（ＮＨ２）ＣＯＯ－、ＣＨ２Ｎ（ＣＨ３）２ＣＯＯ－、ＣＨ３ＳＯ３－、ＣＨ３ＣＨ２ＳＯ３－、ＣＦ３ＳＯ３－、ＣＨ２ＦＳＯ３－、ＣＦ３ＣＨ２ＳＯ３－、ｐ－ＣＨ３Ｏ－ＰｈＳＯ３－、ＰｈＳＯ３－、ｐ－ＣＨ３ＰｈＳＯ３－が挙げられる。 When the compound represented by formula (I) or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, the compound having a hydroxyl group and a suitable acyl halide, a suitable acid anhydride, a suitable sulfonyl chloride, a suitable Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting sulfonyl anhydride and mixed anhydride or reacting with a condensing agent. 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.
（本発明の化合物の製造法）
　本発明に係る式（Ｉ）で示される化合物は、例えば、下記に示す一般的合成法によって製造することができる。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。抽出、精製等は、通常の有機化学の実験で行う処理を行えばよい。
　本発明の化合物は、当該分野において公知の手法を参考にしながら合成することができる。例えば、特許第４５６５２８６（ＪＰ４５６５２８６Ｂ２）を準拠して合成することができる。 (Method for producing the compound of the present invention)
The compound represented by the formula (I) according to the present invention can be produced, for example, by the general synthesis method 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. Extraction, purification, and the like may be performed in a normal organic chemistry experiment.
The compounds of the present invention can be synthesized with reference to techniques known in the art. For example, it can synthesize | combine based on patent 4565286 (JP4565286B2).
　本発明の一般式（Ｉ）で示される化合物は、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。 The compound represented by the general formula (I) of the present invention can be produced, for example, by the synthetic route shown below.
（Ａ法）
Figure JPOXMLDOC01-appb-C000035
（式中、Ｒ１０は置換若しくは非置換のアルキル、Ｒ１１は置換若しくは非置換のアルキル、Ｈａｌはハロゲンであり、その他の記号は前記と同義である。）
（第１工程）
　化合物（ｉ）を、メタノール、エタノール、イソプロパノール、アセトニトリル等の溶媒中、化合物（ｉｉ）を０℃～加熱還流下、好ましくは５０℃～加熱還流下で、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。化合物（ｉｉｉ）は、粗製物または反応液のままで次工程に使用できる。
（第２工程）
　化合物（ｉｉｉ）をメタノール、エタノール、イソプロパノール、アセトニトリル等の溶媒中、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、－１０℃～６０℃、好ましくは０℃～３０℃で、化合物（ｉｖ）を反応させることで、化合物（ｖ）を製造することができる。化合物（ｖ）は、粗製物または反応液のままで次工程に使用できる。
（第３工程）
　化合物（ｖ）をメタノール、エタノール、イソプロパノール、トルエン、キシレン等の溶媒中、必要に応じて酢酸、ｐ－トルエンスルホン酸、メタンスルホン酸等の酸の存在下、－１０℃～２００℃、好ましくは０℃～１５０℃で、化合物（ｖｉ）を製造することができる。
（第４工程）
　化合物（ｖｉ）を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、またはＮＭＰ、ＤＭＦ、ＤＭＳＯ等の溶媒中、水酸化カリウム、水素化ナトリウム等の塩基存在下、－１０℃～１２０℃、好ましくは０℃～１００℃で、化合物（ｖｉｉ）と反応させることにより一般式（Ｉ－ａ）で示される化合物を製造することができる。 (Method A)
Figure JPOXMLDOC01-appb-C000035
(Wherein R 10 is substituted or unsubstituted alkyl, R 11 is substituted or unsubstituted alkyl, Hal is halogen, and other symbols are as defined above.)
(First step)
Compound (iii) is produced by reacting Compound (ii) in a solvent such as methanol, ethanol, isopropanol, acetonitrile, etc., at 0 ° C. to heating under reflux, preferably 50 ° C. to heating under reflux. can do. Compound (iii) can be used in the next step as a crude product or reaction solution.
(Second step)
Compound (iii) is dissolved in a solvent such as methanol, ethanol, isopropanol or acetonitrile in the presence of a base such as triethylamine or N, N-diisopropylethylamine at −10 ° C. to 60 ° C., preferably 0 ° C. to 30 ° C. Compound (v) can be produced by reacting iv). Compound (v) can be used in the next step as a crude product or reaction solution.
(Third step)
Compound (v) is -10 ° C to 200 ° C in a solvent such as methanol, ethanol, isopropanol, toluene, xylene or the like, and optionally in the presence of an acid such as acetic acid, p-toluenesulfonic acid, methanesulfonic acid, preferably Compound (vi) can be produced at 0 ° C. to 150 ° C.
(4th process)
Compound (vi) in a solvent such as t-butanol in the presence of an acid such as acetic acid at 60 ° C. to 150 ° C., preferably 80 ° C. to 120 ° C., or in a solvent such as NMP, DMF, DMSO, potassium hydroxide Producing a compound represented by general formula (Ia) by reacting with compound (vii) in the presence of a base such as sodium hydride at −10 ° C. to 120 ° C., preferably 0 ° C. to 100 ° C. Can do.
（Ｂ法）
Figure JPOXMLDOC01-appb-C000036
（式中、Ｒ１２は置換若しくは非置換のアルキル、Ｒ１３およびＲ１４はそれぞれ独立して、置換若しくは非置換のアルキル、置換若しくは非置換の芳香族炭素環アルキル、置換若しくは非置換の芳香族複素環アルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換のアシル、置換若しくは非置換の非芳香族複素環基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基であり、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法に従い得られた化合物（ｖｉｉｉ）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（ｉｘ）を製造することができる。
（第２工程）
　化合物（ｉｘ）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等の縮合剤とトリエチルアミン、ジイシプロピルエチルアミン等の塩基存在下、化合物（ｘ）を反応させることにより、化合物（Ｉ－ｂ）を製造することができる。 (Method B)
Figure JPOXMLDOC01-appb-C000036
Wherein R 12 is substituted or unsubstituted alkyl, R 13 and R 14 are each independently substituted or unsubstituted alkyl, substituted or unsubstituted aromatic carbocyclic alkyl, substituted or unsubstituted aromatic Heterocyclic alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted acyl, substituted or unsubstituted non-aromatic heterocyclic group, A substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group, u is an integer of 1 to 4, and other symbols are as defined above.
(First step)
The compound (viii) obtained according to the method A 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. Compound (ix) can be produced.
(Second step)
Compound (ix) is mixed with a condensing agent such as 1-hydroxybenzotriazole or HOAt, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, PyBOP and the like in a solvent such as THF, DMF, and NMP. Compound (Ib) can be produced by reacting compound (x) in the presence of a base such as isopropylpropylamine.
（Ｃ法）
Figure JPOXMLDOC01-appb-C000037
（式中、Ｒ１５は、置換若しくは非置換のアルキル、他の記号は前記と同義である。）
（第１工程）
　Ａ法に従い得られた化合物（ｘｉｉ）に、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（ｘｉｉｉ）を製造することができる。
（第２工程）
　化合物（ｘｉｉｉ）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等の縮合剤とトリエチルアミン、ジイシプロピルエチルアミン等の塩基存在下、化合物（ｘ）を反応させることにより化合物（Ｉ－ｃ）を製造することができる。 (Method C)
Figure JPOXMLDOC01-appb-C000037
(Wherein R 15 is substituted or unsubstituted alkyl, and other symbols are as defined above.)
(First step)
Compound (xii) obtained according to Method A was mixed 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 thereof such as dioxane or THF. Compound (xiii) can be manufactured by making it react.
(Second step)
Compound (xiii) is mixed with a condensing agent such as 1-hydroxybenzotriazole or HOAt, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, HATU, PyBOP and the like in a solvent such as THF, DMF, and NMP. Compound (Ic) can be produced by reacting compound (x) in the presence of a base such as isopropylpropylamine.
　上記一般式（Ｉ）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、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、前立腺炎等における排尿機能障害、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、症状の緩和または予防に有効である。 The compound represented by the general formula (I) has an antagonistic action on the P2X 3 and / or P2X 2/3 receptor, and is useful as a therapeutic agent for diseases involving P2X 3 and / or P2X 2/3. is there. 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's 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, 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 disorders associated with chemotherapy, urinary tract disorders associated with brain disorders such as stroke, dysuria, prostatic hyperplasia, prostatitis, etc .; pain, etc .;
And chronic obstructive pulmonary disease (COPD), asthma, bronchospasm, chronic cough, etc .;
It is effective in the treatment, alleviation or prevention of symptoms.
　「排尿障害改善作用を有する医薬組成物」とは、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 urination disorder improving effect” includes a pharmaceutical composition used for treatment, prevention and / or improvement of urination disorder.
　本発明化合物は、Ｐ２Ｘ3および／またはＰ２Ｘ2/3受容体拮抗作用のみならず、医薬としての有用性を備えており、下記いずれか、あるいは全ての優れた特徴を有している。
ａ）ＣＹＰ酵素（例えば、ＣＹＰ１Ａ２、ＣＹＰ２Ｃ９、ＣＹＰ２Ｃ１９、ＣＹＰ２Ｄ６、ＣＹＰ３Ａ４等）に対する阻害作用が弱い。
ｂ）高いバイオアベイラビリティー、適度なクリアランス等良好な薬物動態を示す。
ｃ）代謝安定性が高い。
ｄ）ＣＹＰ酵素（例えば、ＣＹＰ３Ａ４）に対し、本明細書に記載する測定条件の濃度範囲内で不可逆的阻害作用を示さない。
ｅ）変異原性を有さない。
ｆ）心血管系のリスクが低い。
ｇ）高い溶解性を示す。
ｈ）高いＰ２Ｘ3および／またはＰ２Ｘ2/3受容体選択性を有している。 The compound of the present invention has not only P2X 3 and / or P2X 2/3 receptor antagonistic activity but also a usefulness as a pharmaceutical, and has any or all of the following excellent characteristics.
a) The inhibitory effect on CYP enzymes (for example, CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, etc.) is weak.
b) Good pharmacokinetics such as high bioavailability and moderate clearance.
c) High metabolic stability.
d) Does not show irreversible inhibitory action on CYP enzymes (eg CYP3A4) within the concentration range of the measurement conditions described herein.
e) Not mutagenic.
f) Low cardiovascular risk.
g) High solubility.
h) has a high P2X 3 and / or P2X 2/3 receptor selectivity.
　本発明の医薬組成物は、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。非経口投与の方法としては、経皮、皮下、静脈内、動脈内、筋肉内、腹腔内、経粘膜、吸入、経鼻、点眼、点耳、膣内投与等が挙げられる。 The pharmaceutical composition of the present invention can be administered either orally or parenterally. Examples of parenteral administration include transdermal, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, transmucosal, inhalation, nasal, eye drop, ear drop, and intravaginal administration.
　経口投与の場合は常法に従って、内用固形製剤（例えば、錠剤、散剤、顆粒剤、カプセル剤、丸剤、フィルム剤等）、内用液剤（例えば、懸濁剤、乳剤、エリキシル剤、シロップ剤、リモナーデ剤、酒精剤、芳香水剤、エキス剤、煎剤、チンキ剤等）等の通常用いられるいずれの剤型に調製して投与すればよい。錠剤は、糖衣錠、フィルムコーティング錠、腸溶性コーティング錠、徐放錠、トローチ錠、舌下錠、バッカル錠、チュアブル錠または口腔内崩壊錠であってもよく、散剤および顆粒剤はドライシロップであってもよく、カプセル剤は、ソフトカプセル剤、マイクロカプセル剤または徐放性カプセル剤であってもよい。 In the case of oral administration, solid preparations for internal use (eg, tablets, powders, granules, capsules, pills, films, etc.) and liquids for internal use (eg, suspensions, emulsions, elixirs, syrups) Preparations, limonade agents, spirits, fragrances, extracts, decoctions, tinctures, etc.), etc. The tablets may be sugar-coated tablets, film-coated tablets, enteric-coated tablets, sustained-release tablets, troches, sublingual tablets, buccal tablets, chewable tablets or orally disintegrating tablets, and the powders and granules are dry syrups. Alternatively, the capsule may be a soft capsule, a microcapsule or a sustained release capsule.
　非経口投与の場合は、注射剤、点滴剤、外用剤（例えば、点眼剤、点鼻剤、点耳剤、エアゾール剤、吸入剤、ローション剤、注入剤、塗布剤、含嗽剤、浣腸剤、軟膏剤、硬膏剤、ゼリー剤、クリーム剤、貼付剤、パップ剤、外用散剤、坐剤等）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。注射剤は、Ｏ／Ｗ、Ｗ／Ｏ、Ｏ／Ｗ／Ｏ、Ｗ／Ｏ／Ｗ型等のエマルジョンであってもよい。 In the case of parenteral administration, injections, drops, external preparations (eg eye drops, nasal drops, ear drops, aerosols, inhalants, lotions, injections, coating agents, mouthwashes, enemas, Any commonly used dosage form such as an ointment, a plaster, a jelly, a cream, a patch, a patch, a powder for external use, a suppository and the like can be suitably administered. The injection may be an emulsion such as O / W, W / O, O / W / O, W / O / W type.
　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。さらに、該医薬組成物は、本発明化合物の有効量、剤型および／または各種医薬用添加剤を適宜変更することにより、小児用、高齢者用、重症患者用または手術用の医薬組成物とすることもできる。小児用医薬組成物は、１２歳または１５歳未満の患者に投与するのが好ましい。また、小児用医薬組成物は、出生後２７日未満、出生後２８日～２３か月、２歳～１１歳または１２歳～１６歳若しくは１８歳の患者に投与されうる。高齢者用医薬組成物は、６５歳以上の患者に投与するのが好ましい。 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. Furthermore, the pharmaceutical composition can be obtained by changing the effective amount, dosage form and / or various pharmaceutical additives of the compound of the present invention as appropriate, so that it can be used for pediatric, elderly, critically ill patients or surgery. You can also The pediatric pharmaceutical composition is preferably administered to a patient under the age of 12 or 15 years. In addition, the pediatric pharmaceutical composition can be administered to patients less than 27 days after birth, 28 to 23 months after birth, 2 to 11 years old, or 12 to 16 years old or 18 years old. The elderly pharmaceutical composition is preferably administered to a patient over 65 years of age.
　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、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 dose of the pharmaceutical composition of the present invention is preferably set in consideration of the patient's age, weight, type and degree of disease, route of administration, etc., but when administered orally, usually 0.05 to 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, the concomitant drug may be used in an amount of 0.01 to 100 parts by weight per 1 part by weight of the compound of the present invention.
　以下に実施例および参考例、ならびに試験例を挙げて本発明をさらに詳しく説明するが、本発明はこれらにより限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, Reference Examples, and Test Examples, but the present invention is not limited thereto.
　また、本明細書中で用いる略語は以下の意味を表す。
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
ＴＨＦ：テトラヒドロフラン Moreover, the abbreviation used in this specification represents the following meaning.
Me: Methyl TMS: Tetramethylsilane DMSO: Dimethyl sulfoxide THF: Tetrahydrofuran
　各実施例で得られたＮＭＲ分析は４００ＭＨｚで行い、ＤＭＳＯ－ｄ６、ＣＤＣｌ３を用いて測定した。また、ＮＭＲデータを示す場合は、測定した全てのピークを記載していない場合が存在する。
　本発明の化合物のＬＣ／ＭＳデータは、以下の条件で測定し、保持時間（分）および［Ｍ＋Ｈ］＋を示した。
　（メソッド１）
カラム：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２）
カラム：ＡＣＱＵＩＴＹ　ＵＰＬＣ（Ｒ）ＢＥＨ　Ｃ１８　（１．７μｍ、ｉ．ｄ．２．１ｘ５０ｍｍ）　（Ｗａｔｅｒｓ）
流速：０．５５　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５％－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。 The NMR analysis obtained in each example was performed at 400 MHz and measured using DMSO-d 6 and CDCl 3 . Moreover, when NMR data is shown, there are cases where not all measured peaks are described.
The LC / MS data of the compound of the present invention was measured under the following conditions, and showed the retention time (min) and [M + H] + .
(Method 1)
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 2)
Column: ACQUITY UPLC® BEH C18 (1.7 μm, id 2.1 × 50 mm) (Waters)
Flow rate: 0.55 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 5% -100% solvent [B] is performed for 3 minutes. 100% solvent [B] was maintained for 5 minutes.
（１）4-(4-クロロベンジル)-3-(メチルチオ)-6-(トリフルオロメチル)-1,2,4-トリアジン-5(4H)-オンの調製
Figure JPOXMLDOC01-appb-C000038
　N-(4-クロロベンジル)チオセミカルバジド(2.15 g, 10 mmol) とエタノール(20 mL) の混合液に、ヨウ化メチル (0.81 mL, 13 mmol)を氷冷下で加え、60℃で１時間攪拌した。反応液を減圧濃縮し、得られた残渣をイソプロパノール(30 mL)に溶解し、氷冷下でエチル 3,3,3-トリフルオロ-2-オキソプロパノエート (1.72 mL, 13 mmol)を加えた後、トリエチルアミン(2.5mL, 18 mmol)を氷冷下で3分間滴下し、氷冷下で５時間攪拌後、5℃の冷蔵庫で5日間放置した。反応液に水 (150 mL)を加え、酢酸エチル (150 mL) で抽出した。有機層を飽和食塩水 (150 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、生じた粉末をろ取し、4-(4-クロロベンジル)-3-(メチルチオ)-6-(トリフルオロメチル)-1,2,4-トリアジン-5(4H)-オン (2.57 g, 収率: 76％）を淡褐色粉末として得た。
1H-NMR (δ ppm TMS / CDCl3): 2.77 (3H, s), 5.22 (2H, s), 7.33-7.37 (4H, m). (1) Preparation of 4- (4-chlorobenzyl) -3- (methylthio) -6- (trifluoromethyl) -1,2,4-triazin-5 (4H) -one
Figure JPOXMLDOC01-appb-C000038
Methyl iodide (0.81 mL, 13 mmol) was added to a mixture of N- (4-chlorobenzyl) thiosemicarbazide (2.15 g, 10 mmol) and ethanol (20 mL) under ice-cooling and then at 60 ° C. for 1 hour. Stir. The reaction mixture was concentrated under reduced pressure, and the resulting residue was dissolved in isopropanol (30 mL), and ethyl 3,3,3-trifluoro-2-oxopropanoate (1.72 mL, 13 mmol) was added under ice cooling. After that, triethylamine (2.5 mL, 18 mmol) was added dropwise for 3 minutes under ice-cooling, stirred for 5 hours under ice-cooling, and left in a refrigerator at 5 ° C. for 5 days. Water (150 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed with saturated brine (150 mL) and dried over anhydrous magnesium sulfate. Concentrated under reduced pressure, ethyl acetate and hexane were added to the residue, and the resulting powder was collected by filtration, and 4- (4-chlorobenzyl) -3- (methylthio) -6- (trifluoromethyl) -1,2,4- Triazin-5 (4H) -one (2.57 g, yield: 76%) was obtained as a light brown powder.
1H-NMR (δ ppm TMS / CDCl 3 ): 2.77 (3H, s), 5.22 (2H, s), 7.33-7.37 (4H, m).
（２）4-(4-クロロベンジル)-3-[4-(6-シアノ-2-ピリジルオキシ)フェニルアミノ]-6-(トリフルオロメチル)-1,2,4-トリアジン-5(4H)-オン（Ｉ－２２）の調製
Figure JPOXMLDOC01-appb-C000039
　4-(4-クロロベンジル)-3-(メチルチオ)-6-(トリフルオロメチル)-1,2,4-トリアジン-5(4H)-オン (0.504 g, 1.5 mmol)、4-(6-シアノ-2-ピリジルオキシ)アニリン(0.475 g, 2.25 mmol)、t-ブタノール (5 mL)と酢酸(1.3 mL)の混合液を加熱還流下で4時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液(100 mL)を加え、酢酸エチル(100 mL)で抽出した。有機層を飽和食塩水(100 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)で精製後、酢酸エチルとヘキサンを加え、生じた粉末をろ取し、4-(4-クロロベンジル)-3-[4-(6-シアノ-2-ピリジルオキシ)フェニルアミノ]-6-(トリフルオロメチル)-1,2,4-トリアジン-5(4H)-オン(0.61 g, 収率82%)を淡黄色粉末として得た。
1H-NMR (CDCl3)δ:  5.23 (2H, s), 6.93 (2H, d, J = 7.5 Hz), 7.14 (2H, d, J = 7.5 Hz), 7.25 (1H, d, J = 7.5 Hz), 7.32 (2H, d, J = 7.3 Hz), 7.42 (1H, d, J = 7.3 Hz), 7.57 (2H, d, J = 7.5 Hz), 7.85 (1H, t, J = 7.9 Hz), 10.07 (1H, s). (2) 4- (4-Chlorobenzyl) -3- [4- (6-cyano-2-pyridyloxy) phenylamino] -6- (trifluoromethyl) -1,2,4-triazine-5 (4H Preparation of) -one (I-22)
Figure JPOXMLDOC01-appb-C000039
4- (4-Chlorobenzyl) -3- (methylthio) -6- (trifluoromethyl) -1,2,4-triazin-5 (4H) -one (0.504 g, 1.5 mmol), 4- (6- A mixture of cyano-2-pyridyloxy) aniline (0.475 g, 2.25 mmol), t-butanol (5 mL) and acetic acid (1.3 mL) was stirred with heating under reflux for 4 hours. Saturated aqueous sodium hydrogen carbonate solution (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 brine (100 mL) and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate / hexane), ethyl acetate and hexane were added, and the resulting powder was collected by filtration to give 4- (4-chlorobenzyl) -3- [4- (6 -Cyano-2-pyridyloxy) phenylamino] -6- (trifluoromethyl) -1,2,4-triazin-5 (4H) -one (0.61 g, 82% yield) was obtained as a pale yellow powder .
1H-NMR (CDCl3) δ: 5.23 (2H, s), 6.93 (2H, d, J = 7.5 Hz), 7.14 (2H, d, J = 7.5 Hz), 7.25 (1H, d, J = 7.5 Hz) , 7.32 (2H, d, J = 7.3 Hz), 7.42 (1H, d, J = 7.3 Hz), 7.57 (2H, d, J = 7.5 Hz), 7.85 (1H, t, J = 7.9 Hz), 10.07 (1H, s).
（３）4-(4-クロロベンジル)-3-[4-(6-ヒドロキシカルボニル-2-ピリジルオキシ)フェニルアミノ]-6-(トリフルオロメチル)-1,2,4-トリアジン-5(4H)-オン（Ｉ－１）の調製
Figure JPOXMLDOC01-appb-C000040
　4-(4-クロロベンジル)-3-[4-(6-シアノ-2-ピリジルオキシ)フェニルアミノ]-6-(トリフルオロメチル)-1,2,4-トリアジン-5(4H)-オン(0.55 g, 1.1 mmol)とＤＭＳＯ(6 mL)の混合液に2mol/L 水酸化ナトリウム(5.5 mL、11 mmol)を加え、60℃で４時間攪拌した。反応液を氷水に注ぎ、2mol/L塩酸で酸性に調製し、酢酸エチル(100 mL)で抽出した。有機層を水(100 mL)および飽和食塩水(50 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ジエチルエーテルを加え、生じた粉末をろ取し、4-(4-クロロベンジル)-3-[4-(6-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]-6-(トリフルオロメチル)-1,2,4-トリアジン-5(4H)-オン(0.48 mg, 収率: 84％)を淡黄色粉末として得た。
1H-NMR (δ ppm TMS / d6-DMSO):  5.12 (1H, s), 5.37 (1H, s), 6.91 (1H, d, J = 7.3 Hz), 7.14-7.30 (4H, m), 7.47 (7H, dd, J = 28.0, 8.4 Hz), 7.81 (2H, t, J = 8.3 Hz), 7.97-8.05 (1H, m), 9.72 (0H, d, J = 9.8 Hz), 12.33 (1H, s), 13.20 (1H, s)． (3) 4- (4-Chlorobenzyl) -3- [4- (6-hydroxycarbonyl-2-pyridyloxy) phenylamino] -6- (trifluoromethyl) -1,2,4-triazine-5 ( Preparation of 4H) -one (I-1)
Figure JPOXMLDOC01-appb-C000040
4- (4-Chlorobenzyl) -3- [4- (6-cyano-2-pyridyloxy) phenylamino] -6- (trifluoromethyl) -1,2,4-triazin-5 (4H) -one 2 mol / L sodium hydroxide (5.5 mL, 11 mmol) was added to a mixture of (0.55 g, 1.1 mmol) and DMSO (6 mL), and the mixture was stirred at 60 ° C. for 4 hours. The reaction mixture was poured into ice water, acidified with 2 mol / L hydrochloric acid, and extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. Concentrated under reduced pressure, ethyl acetate and diethyl ether were added to the residue, and the resulting powder was collected by filtration to give 4- (4-chlorobenzyl) -3- [4- (6-hydroxycarbonyl-2-pyridyloxy) phenylimino] -6- (Trifluoromethyl) -1,2,4-triazin-5 (4H) -one (0.48 mg, yield: 84%) was obtained as a pale yellow powder.
1H-NMR (δ ppm TMS / d6-DMSO): 5.12 (1H, s), 5.37 (1H, s), 6.91 (1H, d, J = 7.3 Hz), 7.14-7.30 (4H, m), 7.47 ( 7H, dd, J = 28.0, 8.4 Hz), 7.81 (2H, t, J = 8.3 Hz), 7.97-8.05 (1H, m), 9.72 (0H, d, J = 9.8 Hz), 12.33 (1H, s ), 13.20 (1H, s).
（４）4-(4-クロロベンジル)-3-[4-(6-カルバモイル-2-ピリジルオキシ)フェニルアミノ]-6-(トリフルオロメチル)-1,2,4-トリアジン-5(4H)-オン（Ｉ－３)の調製
Figure JPOXMLDOC01-appb-C000041
　4-(4-クロロベンジル)-3-[4-(6-ヒドロキシカルボニル-2-ピリジルオキシ)フェニルアミノ]-6-(トリフルオロメチル)-1,2,4-トリアジン-5(4H)-オン (155 mg, 0.3 mmol)をＤＭＦ(2 mL)に溶解した。反応液に塩化アンモニウム(24 mg, 0.45 mmol)、1-ヒドロキシベンゾトリアゾール(61 mg, 0.45 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(86 mg, 0.45 mmol)およびトリエチルアミン(0.06 mL, 0.45 mmol)を加えて、室温で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) を加え、酢酸エチル (50 mL) で抽出した。有機層を水 (50 mL)および飽和食塩水 (50 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)で精製後、酢酸エチルとヘキサンを加え、生じた粉末をろ取し、4-(4-クロロベンジル)-3-[4-(6-カルバモイル-2-ピリジルオキシ)フェニルイミノ]-6-(トリフルオロメチル)-1,2,4-トリアジン-5(4H)-オン(0.14 g, 収率90%)を淡黄色粉末として得た。
1H-NMR (δ ppm TMS / DMSO-d6): 5.25 (2H, m), 6.92 (1H, s), 7.17 (3H, s), 7.49 (5H, t, J = 25.8 Hz), 7.66 (1H, s), 7.76 (1H, d, J = 6.9 Hz), 8.01 (1H, s), 9.71 (0H, s), 12.30 (1H, s). (4) 4- (4-Chlorobenzyl) -3- [4- (6-carbamoyl-2-pyridyloxy) phenylamino] -6- (trifluoromethyl) -1,2,4-triazine-5 (4H ) -On (I-3) Preparation
Figure JPOXMLDOC01-appb-C000041
4- (4-Chlorobenzyl) -3- [4- (6-hydroxycarbonyl-2-pyridyloxy) phenylamino] -6- (trifluoromethyl) -1,2,4-triazine-5 (4H)- On (155 mg, 0.3 mmol) was dissolved in DMF (2 mL). Ammonium chloride (24 mg, 0.45 mmol), 1-hydroxybenzotriazole (61 mg, 0.45 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (86 mg, 0.45 mmol) and triethylamine (0.06 mL, 0.45 mmol) was added and stirred at room temperature for 3 hours. Saturated aqueous sodium hydrogen carbonate solution (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (50 mL) and saturated brine (50 mL), and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel chromatography (ethyl acetate / hexane), ethyl acetate and hexane were added, and the resulting powder was collected by filtration to give 4- (4-chlorobenzyl) -3- [4- (6 -Carbamoyl-2-pyridyloxy) phenylimino] -6- (trifluoromethyl) -1,2,4-triazin-5 (4H) -one (0.14 g, 90% yield) was obtained as a pale yellow powder .
1H-NMR (δ ppm TMS / DMSO-d6): 5.25 (2H, m), 6.92 (1H, s), 7.17 (3H, s), 7.49 (5H, t, J = 25.8 Hz), 7.66 (1H, s), 7.76 (1H, d, J = 6.9 Hz), 8.01 (1H, s), 9.71 (0H, s), 12.30 (1H, s).
（１）4-(4-クロロベンジル)- 6-(エトキシカルボニルプロピル)- 3-(メチルチオ)-1,2,4-トリアジン-5(4H)-オンの調製
Figure JPOXMLDOC01-appb-C000042
　N-(4-クロロベンジル)チオセミカルバジド(2 g, 9.3 mmol) とエタノール(20 mL) の混合液に、ヨウ化メチル (0.75 mL, 12 mmol)を氷冷下で加え、60℃で１時間攪拌した。反応液を減圧濃縮し、得られた残渣をイソプロパノール(30 mL)に溶解し、氷冷下でジエチル 2-オキソヘキサン-1,6-ジカルボキシレート (2.51 g, 11.6 mmol)を加えた後、トリエチルアミン(2.25mL, 16.2 mmol)を氷冷下で3分間で滴下し、氷冷下で５時間攪拌後、5℃の冷蔵庫で3日間放置した。反応液に水 (150 mL)を加え、酢酸エチル (150 mL) で抽出した。有機層を飽和食塩水 (150 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、エチル ジエチル 2-[(4-クロロベンジルアミノ)(メチルチオ)メチレンヒドラゾノ]ヘキサン-1,6-ジカルボキシレート  (3.9 g, 収率: 98％）を淡褐色アモルファスとして得た。
1H-NMR (CDCl3)δ:  1.25 (3H, t, J = 7.0 Hz), 1.33 (3H, dd, J = 7.0 Hz), 1.89 (2H, t, J = 7.5 Hz), 2.31 (2H, t, J = 7.6 Hz), 2.47 (3H, s), 2.85 (2H, t, J = 7.5 Hz), 4.08-4.14 (2H, m), 4.28 (2H, q, J = 7.1 Hz), 4.46 (2H, d, J = 6.5 Hz), 7.08 (1H, m), 7.24-7.33 (4H, m). (1) Preparation of 4- (4-chlorobenzyl) -6- (ethoxycarbonylpropyl) -3- (methylthio) -1,2,4-triazin-5 (4H) -one
Figure JPOXMLDOC01-appb-C000042
Methyl iodide (0.75 mL, 12 mmol) was added to a mixture of N- (4-chlorobenzyl) thiosemicarbazide (2 g, 9.3 mmol) and ethanol (20 mL) under ice-cooling and then at 60 ° C. for 1 hour. Stir. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in isopropanol (30 mL), and diethyl 2-oxohexane-1,6-dicarboxylate (2.51 g, 11.6 mmol) was added under ice-cooling. Triethylamine (2.25 mL, 16.2 mmol) was added dropwise over 3 minutes under ice-cooling, stirred for 5 hours under ice-cooling, and then left in a refrigerator at 5 ° C. for 3 days. Water (150 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL). The organic layer was washed with saturated brine (150 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel chromatography (ethyl acetate / hexane), and ethyl diethyl 2-[(4-chlorobenzylamino) (methylthio) methylenehydrazono] hexane-1,6-dicarboxylate (3.9 g Yield: 98%) as a light brown amorphous.
1H-NMR (CDCl3) δ: 1.25 (3H, t, J = 7.0 Hz), 1.33 (3H, dd, J = 7.0 Hz), 1.89 (2H, t, J = 7.5 Hz), 2.31 (2H, t, J = 7.6 Hz), 2.47 (3H, s), 2.85 (2H, t, J = 7.5 Hz), 4.08-4.14 (2H, m), 4.28 (2H, q, J = 7.1 Hz), 4.46 (2H, d, J = 6.5 Hz), 7.08 (1H, m), 7.24-7.33 (4H, m).
　エチル ジエチル 2-[(4-クロロベンジルアミノ)(メチルチオ)メチレンヒドラゾノ]ヘキサン-1,6-ジカルボキシレート(3.9 g, 9.1 mmol)、p-トルエンスルホン酸・水和物 (173 mg, 0.9 mmol)とトルエン (39 mL)の混合液を還流下で４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、4-(4-クロロベンジル)- 6-(エトキシカルボニルプロピル)- 3-(メチルチオ)-1,2,4-トリアジン-5(4H)-オン(1.16 g, 収率33%)を淡黄色アモルファスとして得た。
1H-NMR (CDCl3)δ:  1.25 (3H, t, J = 7.1 Hz), 2.12 (2H, t, J = 7.3 Hz), 2.44 (2H, t, J = 7.3 Hz), 2.66 (3H, s), 2.87 (2H, t, J = 7.3 Hz), 4.09-4.14 (2H, q, J = 7.1 Hz), 5.16 (2H, s), 7.32 (4H, s). Ethyl diethyl 2-[(4-chlorobenzylamino) (methylthio) methylenehydrazono] hexane-1,6-dicarboxylate (3.9 g, 9.1 mmol), p-toluenesulfonic acid hydrate (173 mg, 0.9 mmol) and toluene (39 mL) were stirred under reflux for 4 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate / hexane) to give 4- (4-chlorobenzyl) -6- (ethoxycarbonylpropyl) -3- (methylthio) -1,2,4. -Triazin-5 (4H) -one (1.16 g, yield 33%) was obtained as a pale yellow amorphous.
1H-NMR (CDCl3) δ: 1.25 (3H, t, J = 7.1 Hz), 2.12 (2H, t, J = 7.3 Hz), 2.44 (2H, t, J = 7.3 Hz), 2.66 (3H, s) , 2.87 (2H, t, J = 7.3 Hz), 4.09-4.14 (2H, q, J = 7.1 Hz), 5.16 (2H, s), 7.32 (4H, s).
（２）4-(4-クロロベンジル)- 6-(エトキシカルボニルプロピル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン（Ｉ－１１)の調製
Figure JPOXMLDOC01-appb-C000043
　4-(4-クロロベンジル)- 6-(エトキシカルボニルプロピル)- 3-(メチルチオ)-1,2,4-トリアジン-5(4H)-オン(311 mg, 0.81 mol)、4-(2-ピリジルオキシ)アニリン (227 mg, 1.22 mmol)、酢酸 (0.45 mL)とt-ブタノール (3 ml) の混合液を、加熱還流下で２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(50 mL)で抽出した。有機層を飽和食塩水で水洗し，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）で精製して、4-(4-クロロベンジル)- 6-(エトキシカルボニルプロピル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン(369 mg, 収率: 87％）を淡黄色アモルファスとして得た。
1H-NMR (CDCl3)δ:  1.25 (3H, t, J = 7.2 Hz), 1.93 (2H, t, J = 7.4 Hz), 2.36 (2H, t, J = 7.4 Hz), 2.60 (2H, t, J = 7.4 Hz), 4.09-4.15 (2H, m), 5.21 (2H, s), 6.90 (2H, d, J = 8.4 Hz), 6.95-7.00 (2H, m), 7.12 (2H, d, J = 8.4 Hz), 7.30 (2H, t, J = 6.1 Hz), 7.55 (2H, d, J = 8.3 Hz), 7.71 (1H, t, J = 7.7 Hz), 8.12 (1H, d, J = 4.4 Hz), 8.99 (1H, s). (2) 4- (4-Chlorobenzyl) -6- (ethoxycarbonylpropyl) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one ( Preparation of I-11)
Figure JPOXMLDOC01-appb-C000043
4- (4-Chlorobenzyl) -6- (ethoxycarbonylpropyl) -3- (methylthio) -1,2,4-triazin-5 (4H) -one (311 mg, 0.81 mol), 4- (2- A mixture of pyridyloxy) aniline (227 mg, 1.22 mmol), acetic acid (0.45 mL) and t-butanol (3 ml) was stirred with heating under reflux for 2 hours. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4- (4-chlorobenzyl) -6- (ethoxycarbonylpropyl) -3- [4- (2-pyridyloxy) phenyl Amino] -1,2,4-triazin-5 (4H) -one (369 mg, yield: 87%) was obtained as a pale yellow amorphous.
1H-NMR (CDCl 3 ) δ: 1.25 (3H, t, J = 7.2 Hz), 1.93 (2H, t, J = 7.4 Hz), 2.36 (2H, t, J = 7.4 Hz), 2.60 (2H, t , J = 7.4 Hz), 4.09-4.15 (2H, m), 5.21 (2H, s), 6.90 (2H, d, J = 8.4 Hz), 6.95-7.00 (2H, m), 7.12 (2H, d, J = 8.4 Hz), 7.30 (2H, t, J = 6.1 Hz), 7.55 (2H, d, J = 8.3 Hz), 7.71 (1H, t, J = 7.7 Hz), 8.12 (1H, d, J = 4.4 Hz), 8.99 (1H, s).
4-(4-クロロベンジル)- 6-(ヒドロキシカルボニルプロピル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン（Ｉ－１４）の調製
Figure JPOXMLDOC01-appb-C000044
　4-(4-クロロベンジル)- 6-(エトキシカルボニルプロピル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン(334 mg, 0.64 mmol)，メタノール(1.5 mL)およびＴＨＦ(1.5 mL)の混合液に1mol/L 水酸化ナトリウム(1.5 mL、1.5 mmol)を氷冷下で加え、室温で4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(100 mL)で抽出した。有機層を水(50 mL)および飽和食塩水(50 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-(4-クロロベンジル)- 6-(ヒドロキシカルボニルプロピル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン(316 mg, 収率: 100％)を淡黄色アモルファスとして得た。
1H-NMR (δ ppm TMS / d6-DMSO):  1.78 (2H, t, J = 6.5 Hz), 2.28 (2H, t, J = 7.2 Hz), 5.13 (2H, s), 6.84-7.11 (6H, m), 7.32-7.43 (5H, m), 7.81 (1H, t, J = 7.6 Hz), 8.16 (1H, d, J = 4.5 Hz), 11.36 (1H, brs). 4- (4-Chlorobenzyl) -6- (hydroxycarbonylpropyl) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (I-14 Preparation of
Figure JPOXMLDOC01-appb-C000044
4- (4-Chlorobenzyl) -6- (ethoxycarbonylpropyl) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (334 mg, 0.64 mmol), methanol (1.5 mL), and THF (1.5 mL) were mixed with 1 mol / L sodium hydroxide (1.5 mL, 1.5 mmol) under ice-cooling and stirred at room temperature for 4 hours. The reaction mixture was poured into ice water, acidified with 5% aqueous citric acid solution, and extracted with ethyl acetate (100 mL). The organic layer was washed with water (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to give 4- (4-chlorobenzyl) -6- (hydroxycarbonylpropyl) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (316 mg, yield: 100%) was obtained as a pale yellow amorphous.
1H-NMR (δ ppm TMS / d6-DMSO): 1.78 (2H, t, J = 6.5 Hz), 2.28 (2H, t, J = 7.2 Hz), 5.13 (2H, s), 6.84-7.11 (6H, m), 7.32-7.43 (5H, m), 7.81 (1H, t, J = 7.6 Hz), 8.16 (1H, d, J = 4.5 Hz), 11.36 (1H, brs).
4-(4-クロロベンジル)- 6-(エトキシカルボニル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン（Ｉ－２５)の調製
Figure JPOXMLDOC01-appb-C000045
　N-(4-クロロベンジル)チオセミカルバジド(200 mg, 0.927 mmol) とエタノール(4 mL) の混合液に、ヨウ化メチル (0.075 ml, 1.205 mmol)を加え、60℃で１時間攪拌した。反応液を減圧濃縮し、得られた残渣に酢酸(4 ml)とジエチル 2-オキソマロネート (0.170 ml, 1.112 mmol)を加え、90℃で2時間攪拌した。反応液を減圧濃縮し、飽和炭酸水素ナトリウム水溶液を加え、酢酸エチル(50 mL)で抽出した。有機層を無水硫酸マグネシウムで乾燥後、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）で精製して、4-(4-クロロベンジル)- 6-(エトキシカルボニル)- 3-(メチルチオ)-1,2,4-トリアジン-5(4H)-オン(239.7 mg, 収率76%)を黄色油状物として得た。
  1H-NMR (CDCl3) δ: 1.40 (3H, t, J = 7.2 Hz), 2.58 (3H, s), 4.43 (2H, q, J = 7.2 Hz), 5.23 (2H, s), 7.29-7.36 (4H, m).

　4-(4-クロロベンジル)- 6-(エトキシカルボニル)- 3-(メチルチオ)-1,2,4-トリアジン-5(4H)-オン(239.7 mg, 0.705 mmol)、4-(2-ピリジルオキシ)アニリン (197 mg, 1.058 mmol)、酢酸 (0.61 mL)とt-ブタノール (2.4 ml) の混合液を、加熱還流下で４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(50 mL)で抽出した。有機層を飽和食塩水で水洗し、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）で精製して、4-(4-クロロベンジル)- 6-(エトキシカルボニル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン(163.5 mg, 収率: 49％）を黄色固体として得た。
1H-NMR (CDCl3) δ: 1.36 (3H, t, J = 7.0 Hz), 4.37 (2H, q, J = 7.2 Hz), 5.23 (2H, s), 6.90 (2H, d, J = 8.3 Hz), 6.99 (2H, d, J = 7.5 Hz), 7.13 (2H, d, J = 7.5 Hz), 7.29-7.31 (2H, m), 7.57 (2H, d, J = 8.0 Hz), 7.71-7.73 (1H, m), 8.06 (1H, s), 9.87 (1H, s). 4- (4-Chlorobenzyl) -6- (ethoxycarbonyl) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (I-25) Preparation of
Figure JPOXMLDOC01-appb-C000045
Methyl iodide (0.075 ml, 1.205 mmol) was added to a mixture of N- (4-chlorobenzyl) thiosemicarbazide (200 mg, 0.927 mmol) and ethanol (4 mL), and the mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, acetic acid (4 ml) and diethyl 2-oxomalonate (0.170 ml, 1.112 mmol) were added to the resulting residue, and the mixture was stirred at 90 ° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4- (4-chlorobenzyl) -6- (ethoxycarbonyl) -3- ( Methylthio) -1,2,4-triazin-5 (4H) -one (239.7 mg, 76% yield) was obtained as a yellow oil.
1H-NMR (CDCl3) δ: 1.40 (3H, t, J = 7.2 Hz), 2.58 (3H, s), 4.43 (2H, q, J = 7.2 Hz), 5.23 (2H, s), 7.29-7.36 ( 4H, m).

4- (4-Chlorobenzyl) -6- (ethoxycarbonyl) -3- (methylthio) -1,2,4-triazin-5 (4H) -one (239.7 mg, 0.705 mmol), 4- (2-pyridyl) A mixture of oxy) aniline (197 mg, 1.058 mmol), acetic acid (0.61 mL) and t-butanol (2.4 ml) was stirred with heating under reflux for 4 hours. To the reaction solution was added saturated aqueous sodium hydrogen carbonate solution (50 mL), and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4- (4-chlorobenzyl) -6- (ethoxycarbonyl) -3- [4- (2-pyridyloxy) phenylamino. ] -1,2,4-Triazin-5 (4H) -one (163.5 mg, yield: 49%) was obtained as a yellow solid.
1H-NMR (CDCl3) δ: 1.36 (3H, t, J = 7.0 Hz), 4.37 (2H, q, J = 7.2 Hz), 5.23 (2H, s), 6.90 (2H, d, J = 8.3 Hz) , 6.99 (2H, d, J = 7.5 Hz), 7.13 (2H, d, J = 7.5 Hz), 7.29-7.31 (2H, m), 7.57 (2H, d, J = 8.0 Hz), 7.71-7.73 ( 1H, m), 8.06 (1H, s), 9.87 (1H, s).
4-(4-クロロベンジル)- 6-(ヒドロキシカルボニル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン（Ｉ－２６）の調製
Figure JPOXMLDOC01-appb-C000046
　4-(4-クロロベンジル)- 6-(エトキシカルボニル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン(131.3 mg, 0.275 mmol)、メタノール(1.3 mL)およびＴＨＦ(4 mL)の混合液に2mol/L 水酸化ナトリウム(1.4 mL)を氷冷下で加え、室温で２時間攪拌した。反応液を氷水に注ぎ、2mol/L塩酸で酸性に調製した後、減圧濃縮し、水を加え析出した固体をろ取して、4-(4-クロロベンジル)- 6-(ヒドロキシカルボニル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン(124 mg, 収率: 100％)を黄色固体として得た。
1H-NMR (CDCl3) δ: 5.27 (2H, s), 6.90-6.92 (2H, m), 6.97-7.05 (2H, m), 7.13 (2H, d, J = 8.7 Hz), 7.34 (2H, d, J = 8.4 Hz), 7.56 (2H, d, J = 8.3 Hz), 7.72-7.76 (1H, m), 7.92-7.93 (1H, m). 4- (4-Chlorobenzyl) -6- (hydroxycarbonyl) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (I-26) Preparation of
Figure JPOXMLDOC01-appb-C000046
4- (4-Chlorobenzyl) -6- (ethoxycarbonyl) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (131.3 mg, 0.275 mmol), methanol (1.3 mL) and THF (4 mL) were added with 2 mol / L sodium hydroxide (1.4 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, acidified with 2 mol / L hydrochloric acid, concentrated under reduced pressure, water was added and the precipitated solid was collected by filtration to give 4- (4-chlorobenzyl) -6- (hydroxycarbonyl)- 3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (124 mg, yield: 100%) was obtained as a yellow solid.
1H-NMR (CDCl3) δ: 5.27 (2H, s), 6.90-6.92 (2H, m), 6.97-7.05 (2H, m), 7.13 (2H, d, J = 8.7 Hz), 7.34 (2H, d , J = 8.4 Hz), 7.56 (2H, d, J = 8.3 Hz), 7.72-7.76 (1H, m), 7.92-7.93 (1H, m).
4-(4-クロロベンジル)- 6-(カルバモイル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン（Ｉ－２７)の調製
Figure JPOXMLDOC01-appb-C000047
　4-(4-クロロベンジル)- 6-(ヒドロキシカルボニル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン (50 mg, 0.111 mmol)とＤＭＦ(0.5 mL)の混合液に塩化アンモニウム(8.92 mg, 0.167 mmol)、1-ヒドロキシベンゾトリアゾール(22.53 mg, 0.167 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(632.0 mg, 0.167 mmol)、およびトリエチルアミン(23.11 μl, 0.167 mmol)を加えて、室温で2時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、生じた粉末をろ取し、4-(4-クロロベンジル)- 6-(カルバモイル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン(46.3 mg, 収率93%)を黄色固体として得た。
  1H-NMR (CDCl3) δ: 5.25 (2H, s), 6.09 (1H, s), 6.90 (2H, d, J = 8.7 Hz), 6.98-7.00 (2H, m), 7.12 (2H, d, J = 8.7 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.53 (2H, d, J = 8.5 Hz), 7.70-7.74 (1H, m), 8.01-8.03 (1H, m), 8.55 (1H, s). 4- (4-chlorobenzyl) -6- (carbamoyl) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (I-27) Preparation
Figure JPOXMLDOC01-appb-C000047
4- (4-Chlorobenzyl) -6- (hydroxycarbonyl) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (50 mg, 0.111 mmol) and DMF (0.5 mL), ammonium chloride (8.92 mg, 0.167 mmol), 1-hydroxybenzotriazole (22.53 mg, 0.167 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (632.0 mg, 0.167 mmol) and triethylamine (23.11 μl, 0.167 mmol) were added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting powder was collected by filtration, and 4- (4-chlorobenzyl) -6- (carbamoyl) -3- [4- (2-pyridyloxy) phenylamino] -1 2,4-Triazin-5 (4H) -one (46.3 mg, 93% yield) was obtained as a yellow solid.
1H-NMR (CDCl3) δ: 5.25 (2H, s), 6.09 (1H, s), 6.90 (2H, d, J = 8.7 Hz), 6.98-7.00 (2H, m), 7.12 (2H, d, J = 8.7 Hz), 7.32 (2H, d, J = 8.4 Hz), 7.53 (2H, d, J = 8.5 Hz), 7.70-7.74 (1H, m), 8.01-8.03 (1H, m), 8.55 (1H , s).
4-(4-クロロベンジル)- 6-(アミノ)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン（Ｉ－３２)の調製
Figure JPOXMLDOC01-appb-C000048
　4-(4-クロロベンジル)- 6-(ヒドロキシカルボニル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン (500 mg, 1.111 mmol)、t-ブタノール (5 ml) およびジオキサン(4 ml)の混合液にジフェニルホスホリルアジド(0.287 ml, 1.334 mmol)、およびトリエチルアミン(0.185 ml, 1.334 mmol)を加えて、100℃で３時間攪拌した。反応液にジフェニルホスホリルアジド(0.287 ml, 1.334 mmol)、およびトリエチルアミン(0.185 ml, 1.334 mmol)を加えて、100℃で３時間攪拌した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で水洗し、無水硫酸マグネシウムで乾燥した。減圧濃縮し、得られた残渣をジクロロメタン(5 ml)で溶解し、氷冷下でトリフルオロ酢酸を(5 ml)加え、室温で1.5時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液に加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、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）で精製して、4-(4-クロロベンジル)- 6-(アミノ)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン(190 mg, 収率41%)を黄色固体として得た。
  1H-NMR (DMSO-D6) δ: 5.18-5.34 (2H, m), 5.94-6.30 (2H, m), 6.84 (1H, d, J = 8.8 Hz), 6.96-6.99 (3H, m), 7.09 (1H, t, J = 6.1 Hz), 7.28-7.30 (2H, m), 7.40-7.47 (3H, m), 7.79-7.84 (1H, m), 8.13-8.16 (1H, m), 10.12 (1H, s). 4- (4-Chlorobenzyl) -6- (amino) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (I-32) Preparation
Figure JPOXMLDOC01-appb-C000048
4- (4-Chlorobenzyl) -6- (hydroxycarbonyl) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (500 mg, 1.111 mmol), t-butanol (5 ml) and dioxane (4 ml) were added diphenylphosphoryl azide (0.287 ml, 1.334 mmol) and triethylamine (0.185 ml, 1.334 mmol) and stirred at 100 ° C. for 3 hours. did. Diphenylphosphoryl azide (0.287 ml, 1.334 mmol) and triethylamine (0.185 ml, 1.334 mmol) were added to the reaction mixture, and the mixture was stirred at 100 ° C. for 3 hr. A saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the resulting residue was dissolved in dichloromethane (5 ml), trifluoroacetic acid (5 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The reaction solution was added to saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4- (4-chlorobenzyl) -6- (amino) -3- [4 -(2-Pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (190 mg, 41% yield) was obtained as a yellow solid.
1H-NMR (DMSO-D6) δ: 5.18-5.34 (2H, m), 5.94-6.30 (2H, m), 6.84 (1H, d, J = 8.8 Hz), 6.96-6.99 (3H, m), 7.09 (1H, t, J = 6.1 Hz), 7.28-7.30 (2H, m), 7.40-7.47 (3H, m), 7.79-7.84 (1H, m), 8.13-8.16 (1H, m), 10.12 (1H , s).
4-(4-クロロベンジル)- 6-(アセチルアミノ)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン（Ｉ－３４)の調製
Figure JPOXMLDOC01-appb-C000049
　4-(4-クロロベンジル)- 6-(アミノ)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン (50 mg, 0.119 mmol)とＤＭＦ(0.5 mL)の混合液に酢酸(10.19 μl, 0.178 mmol)、1-ヒドロキシベンゾトリアゾール(24.08 mg, 0.178 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(34.2 mg, 0.178 mmol)、およびトリエチルアミン(24.7 μl, 0.178 mmol)を加えて、室温で1.5時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、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）で精製して、4-(4-クロロベンジル)- 6-(アセチルアミノ)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン(8.6 mg, 収率16%)を淡黄色アモルファスとして得た。
  1H-NMR (CDCl3) δ: 2.23 (3H, s), 5.26 (2H, s), 6.91-7.01 (4H, m), 7.13 (2H, d, J = 8.3 Hz), 7.32 (2H, d, J = 7.8 Hz), 7.54 (2H, d, J = 7.5 Hz), 7.69-7.71 (1H, m), 8.08 (1H, s), 8.16-8.17 (1H, m), 8.45 (1H, s). 4- (4-Chlorobenzyl) -6- (acetylamino) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (I-34) Preparation of
Figure JPOXMLDOC01-appb-C000049
4- (4-Chlorobenzyl) -6- (amino) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (50 mg, 0.119 mmol ) And DMF (0.5 mL), acetic acid (10.19 μl, 0.178 mmol), 1-hydroxybenzotriazole (24.08 mg, 0.178 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (34.2 mg, 0.178 mmol) and triethylamine (24.7 μl, 0.178 mmol) were added, and the mixture was stirred at room temperature for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4- (4-chlorobenzyl) -6- (acetylamino) -3- [ 4- (2-Pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (8.6 mg, 16% yield) was obtained as a pale yellow amorphous.
1H-NMR (CDCl3) δ: 2.23 (3H, s), 5.26 (2H, s), 6.91-7.01 (4H, m), 7.13 (2H, d, J = 8.3 Hz), 7.32 (2H, d, J = 7.8 Hz), 7.54 (2H, d, J = 7.5 Hz), 7.69-7.71 (1H, m), 8.08 (1H, s), 8.16-8.17 (1H, m), 8.45 (1H, s).
4-(4-クロロベンジル)- 6-(シアノ)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン（Ｉ－３１）の調製
Figure JPOXMLDOC01-appb-C000050
　4-(4-クロロベンジル)- 6-(カルバモイル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン(132.9 mg, 0.296 mmol)，およびピリジン(2.7 mL)の混合液に無水トリフルオロ酢酸(104 μl, 0.740 mmol)を氷冷下で加え、０℃で１時間攪拌した。反応液に水を加え、2mol/L塩酸で酸性に調製した後、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、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）で精製して、4-(4-クロロベンジル)- 6-(シアノ)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン(73.1 mg, 収率: 57％)を黄色固体として得た。
1H-NMR (CDCl3) δ: 5.21 (2H, s), 6.88 (2H, d, J = 8.7 Hz), 6.99-7.04 (2H, m), 7.13-7.14 (2H, m), 7.32 (2H, d, J = 8.4 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.72-7.77 (1H, m), 7.98 (1H, d, J = 3.4 Hz), 10.77 (1H, s). 4- (4-Chlorobenzyl) -6- (cyano) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (I-31) Preparation
Figure JPOXMLDOC01-appb-C000050
4- (4-Chlorobenzyl) -6- (carbamoyl) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (132.9 mg, 0.296 mmol ) And pyridine (2.7 mL) were added trifluoroacetic anhydride (104 μl, 0.740 mmol) under ice cooling, and the mixture was stirred at 0 ° C. for 1 hour. Water was added to the reaction mixture, and the mixture was acidified with 2 mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4- (4-chlorobenzyl) -6- (cyano) -3- [4 -(2-Pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (73.1 mg, yield: 57%) was obtained as a yellow solid.
1H-NMR (CDCl3) δ: 5.21 (2H, s), 6.88 (2H, d, J = 8.7 Hz), 6.99-7.04 (2H, m), 7.13-7.14 (2H, m), 7.32 (2H, d , J = 8.4 Hz), 7.56 (2H, d, J = 8.4 Hz), 7.72-7.77 (1H, m), 7.98 (1H, d, J = 3.4 Hz), 10.77 (1H, s).
4-(4-クロロベンジル)- 6-(3-メチル-1,2,4-オキサジアゾール-5-イル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン（Ｉ－３５)の調製
Figure JPOXMLDOC01-appb-C000051
　4-(4-クロロベンジル)- 6-(ヒドロキシカルボニル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン (200 mg, 0.445 mmol)とＤＭＦ(2 mL)の混合液にアセトアミドオキシム(49.4 mg, 0.667 mmol)、1-ヒドロキシベンゾトリアゾール(90 mg, 0.667 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(128 mg, 0.667 mmol)、およびトリエチルアミン(92 μl, 0.667 mmol)を加えて、室温で一夜攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、減圧濃縮し、得られた残渣にＤＭＦ(2 mL)と炭酸セシウム (174 mg, 0.534 mmol)を加え、110℃で2時間攪拌した．反応液に水を加え、酢酸エチルで抽出した。有機層を無水硫酸マグネシウムで乾燥後、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）で精製して、4-(4-クロロベンジル)- 6-(3-メチル-1,2,4-オキサジアゾール-5-イル)- 3-[4-(2-ピリジルオキシ)フェニルアミノ]-1,2,4-トリアジン-5(4H)-オン (32.8 mg, 収率15%)を橙色固体として得た。
1H-NMR (CDCl3) δ: 2.51 (3H, s), 5.29 (2H, s), 6.93-7.02 (4H, m), 7.16 (2H, d, J = 7.8 Hz), 7.31 (2H, d, J = 8.0 Hz), 7.63 (2H, d, J = 7.8 Hz), 7.72-7.75 (1H, m), 8.04-8.05 (1H, m), 10.44 (1H, s). 4- (4-Chlorobenzyl) -6- (3-methyl-1,2,4-oxadiazol-5-yl) -3- [4- (2-pyridyloxy) phenylamino] -1,2, Preparation of 4-triazin-5 (4H) -one (I-35)
Figure JPOXMLDOC01-appb-C000051
4- (4-Chlorobenzyl) -6- (hydroxycarbonyl) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (200 mg, 0.445 mmol) and DMF (2 mL) to a mixture of acetamide oxime (49.4 mg, 0.667 mmol), 1-hydroxybenzotriazole (90 mg, 0.667 mmol), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (128 mg, 0.667 mmol) and triethylamine (92 μl, 0.667 mmol) were added and stirred overnight at room temperature. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. DMF (2 mL) and cesium carbonate (174 mg, 0.534 mmol) were added to the resulting residue, and the mixture was stirred at 110 ° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give 4- (4-chlorobenzyl) -6- (3-methyl-1,2 , 4-Oxadiazol-5-yl) -3- [4- (2-pyridyloxy) phenylamino] -1,2,4-triazin-5 (4H) -one (32.8 mg, 15% yield) Was obtained as an orange solid.
1H-NMR (CDCl3) δ: 2.51 (3H, s), 5.29 (2H, s), 6.93-7.02 (4H, m), 7.16 (2H, d, J = 7.8 Hz), 7.31 (2H, d, J = 8.0 Hz), 7.63 (2H, d, J = 7.8 Hz), 7.72-7.75 (1H, m), 8.04-8.05 (1H, m), 10.44 (1H, s).
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000052
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000053
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000054
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000055
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000056
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000057
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000058
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000059
Figure JPOXMLDOC01-appb-T000060
Figure JPOXMLDOC01-appb-T000060
　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　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。 Test Example Test Example 1 Human P2X 3 Evaluation of the receptor inhibitory activity human P2X 3 receptor gene 3000 per well of stably expressing cell lines by introducing (GenBank Accession sequence Y07683) to C6BU-1 cells PDL coated 384-well microplates In a medium (DMEM containing 8.3% fetal calf serum, 8.3% horse serum, 1% antibiotic antifungal mixed solution) at 37 ° C. under 5% carbon dioxide. Cultured 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 a 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-T000061
Figure JPOXMLDOC01-appb-T000061
Figure JPOXMLDOC01-appb-T000062
Figure JPOXMLDOC01-appb-T000062
試験例２　ヒト血清アルブミン(ＨＳＡ)存在下でのヒト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、２．０％グルタミンを含む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、５．３７ｍＭ ＫＣｌ、０．９ｍＭ ＭｇＣｌ2、１．２６ｍＭ ＣａＣｌ2、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、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、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％になるようにヒ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ＡＴＰ溶液５０μＬ（終濃度５０ｎＭ）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 Human serum albumin (HSA) Evaluation of human P2X 3 receptor inhibitory activity in the presence of the human P2X 3 receptor gene (GenBank Accession sequence Y07683) PDL coated 96 stably expressing cell lines by introducing the C6BU-1 cells Inoculate 8000 cells per well into a well microplate and contain medium (7.0% fetal bovine serum, 7.0% horse serum, 1% antibiotic antifungal mixed solution, 2.0% glutamine) In DMEM) 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, 5.37 mM KCl, 0.9 mM MgCl 2 , 1.26 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 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 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, 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) to a final concentration of 1% using a solution to which human serum albumin has been added to dilute the compound DMSO solution of the present invention to different concentrations per well Each 40 μL was dispensed with an automatic dispensing device built in the FDSS 3000. After 5 minutes, 50 μL of the ATP solution diluted with the buffer for dilution (final concentration 50 nM) was dispensed by an automatic dispensing device built in the FDSS 3000, and then the 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 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-T000063
Figure JPOXMLDOC01-appb-T000063
試験例３　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（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日間培養した。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日間培養した。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した。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 Rat P2X 3 Rating rat P2X 3 receptor gene of the receptor inhibitory activity (GenBank Accession sequence NM_031075) was introduced into and expressed in 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). The cells were cultured at 5 ° C. for 5 days at 5 ° C. The expression plasmid was 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 incubated at 37 ° C. under 5% carbon dioxide for 1 hour. 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. did. After 5 minutes, 50 μL of a 50 nM ATP solution diluted with a dilution buffer was dispensed with an automatic dispensing device built in the FDSS 3000, 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 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-T000064
Figure JPOXMLDOC01-appb-T000064
試験例３－２　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細胞に導入した安定発現細胞を１穴当り３０００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２日間培養した。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した。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、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。 Test Example 3-2 were seeded rat P2X 3 cells stably expressing the evaluation rat P2X 3 receptor gene of the receptor inhibitory activity (GenBank Accession sequence NM_031075) was introduced into C6BU-1 cells to be 3,000 per well, The cells were cultured in a medium (DMEM containing 7.0% fetal bovine serum, 7.0% horse serum, 1% antibiotic antifungal mixed solution) at 37 ° C. and 5% carbon dioxide for 2 days. 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 incubated at 37 ° C. under 5% carbon dioxide for 1 hour. 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 20 μL per wash buffer. The microplate was installed in a high throughput screening system FLIPR 384 (Molecular Devices). Fluorescence intensity measurement by FLIPR 384 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), and the DMSO solution of the compound of the present invention diluted to different concentrations with an automatic dispensing device built in FLIPR 384, 20 μL per well. did. After 5 minutes, 25 μL of 150 nM ATP solution diluted with a 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-T000065
　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した。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-T000065
The compounds described herein exhibited 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 shows an inhibitory activity against the P2X 2/3 receptor which is also composed of the P2X 2 subtype.
試験例４　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細胞に導入した安定発現細胞を１穴当り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、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　７０００（浜松ホトニクス社）に設置する。ＦＤＳＳ　７０００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　７０００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　７０００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。 Test Example 4 rat serum albumin (RSA) Evaluation of rat P2X 3 receptor inhibitory activity in the presence of rat P2X 3 receptor gene (GenBank Accession sequence NM_031075) 1 hole per stably expressing cells introduced into C6BU-1 cells 8000 In a medium (7.0% fetal bovine serum, 7.0% horse serum, DMEM containing 1% antibiotic antifungal mixed solution) at 37 ° C. under 5% carbon dioxide. Incubate for days. 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, 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 7000 (Hamamatsu Photonics). Fluorescence intensity measurement by FDSS 7000 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 7000. After 5 minutes, 50 μL of a 50 nM ATP solution diluted with a dilution buffer is dispensed by an automatic dispensing device built in the FDSS 7000, 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).
試験例５　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懸濁液、または溶液を調製し、経口ゾンデを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。
排尿機能間隔改善率
＝（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 5 Evaluation of urinary function in rat cystitis model Cystometry operation Rats are anesthetized by inhalation of 2% isoflurane (anesthetic background; laughter: 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 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, a suspension or solution is prepared using a 0.5% methylcellulose solution, and is orally administered to an animal using an oral sonde. 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 to 2 hours after the start of measurement. Moreover, the amount of residual urine after the measurement is analyzed.

The following values are used as indicators of the effect on the urination interval.
Improvement rate of voiding function interval = (urinary interval after drug treatment for cystitis animals-urination interval before drug treatment for cystitis animals) / (average value of urination intervals 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 of cystitis rats-1 urination volume before drug treatment of cystitis animals) / (Average value of 1 urination volume before drug treatment of normal animals-cystitis) Animal urination once before drug treatment) x 100
試験例６　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、左足の毛を剃る。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る。坐骨神経の1/3～1/2を糸で強く結紮し、筋、及び皮膚を縫合する。これを手術側とする。右足については坐骨神経結紮以外の同様の処置を行い、偽手術側とする。
　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する。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、馴化させる。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する。左右の後肢について痛覚閾値を評価し、処置前疼痛閾値とする。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懸濁液、または溶液を調製し、経口ゾンデを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）
　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懸濁液、または溶液を調製し、経口ゾンデを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） Test Example 6 Evaluation of drug efficacy by Seltzer model Rat Partial sciatic nerve ligation model (rat sciatic nerve partial ligation model)
Model preparation Rats are anesthetized with isoflurane and the left leg is shaved. An incision is made in the upper thigh skin and the muscle is broken to expose the sciatic nerve. 1/3 to 1/2 of the sciatic nerve is tightly ligated with a thread, and the muscle and skin are sutured. This is the operation side. For the right foot, perform the same procedure except for sciatic nerve ligation, and make it the sham operation side.
Evaluation (1)
Two weeks after surgery, the effect on tactile allodynia is assessed by von Frey filament. Two weeks after surgery, the rats are habituated to a plastic cage placed on a wire mesh. The von Frey filament (0.4-26 g) is 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 begins to show escape behavior is taken as the pain threshold. The pain threshold is evaluated for the left and right hind limbs, and set as a pretreatment pain threshold. Animals with an operating pain threshold of 0.6 to 2 g and a sham surgical pain threshold of 8 to 15 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, a suspension or solution is prepared using a 0.5% methylcellulose solution, and is orally administered to an animal using an oral sonde. 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 value = (logarithm of pain threshold value after surgery on the surgery side-logarithm of pain threshold value on the surgery side before surgery) / (logarithm of pain threshold value before treatment on the sham surgery side-logarithm of pain threshold value on the surgery side before surgery)
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, a suspension or solution is prepared using a 0.5% methylcellulose solution, and is orally administered to an animal using an oral sonde. 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６－２　馬尾神経圧迫モデルによる薬効評価
モデル動物の作製
モデル動物を作製するため、麻酔下でラットの腰背部を切開し、第４、第５、及び第６腰椎を露出する。第４－５、及び第５－６腰椎椎関節を切開する。椎関節切開口からシリコンラバーを第４、及び第６腰椎脊柱管内に挿入して留置し、切開口を縫合する。
偽手術動物を作製するため、上記の操作からシリコンラバーの挿入、及び留置の操作を除いた手術を施す。

鎮痛効果の評価
モデル作製術の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鎮痛効果を評価する。金網上に載せたプラスチック製ケージにラットを入れて馴化させる。ラットの訓練のため、金網側からラット脚裏にvon Freyフィラメントを押し当てる操作を行う。化合物投与前に金網側からラット脚裏に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フィラメントの圧値を投与前疼痛閾値とする。疼痛閾値が低下した動物を採用する。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媒体として懸濁液、または溶液を調製し、採用した動物に経口ゾンデを用いて経口投与する。投与後、同様の操作によってラットが逃避行動を示し始めるvon Freyフィラメントの圧値を測定し、投与後疼痛閾値とする。下記の数式により%reversal値を計算し、化合物の鎮痛作用を比較する。
%reversal値 ＝ （モデル動物の投与後疼痛閾値の対数 ― モデル動物の投与前疼痛閾値の対数）／（偽手術動物の投与前疼痛閾値の対数 ― モデル動物の投与前疼痛閾値の対数） Test Example 6-2 Production of model animal for evaluation of drug efficacy using cauda equina nerve compression model To produce a model animal, the lower back of the rat is incised under anesthesia to expose the fourth, fifth and sixth lumbar vertebrae. Incisions are made on the 4th-5th and 5th-6th lumbar joints. Silicon rubber is inserted into the 4th and 6th lumbar spinal canals from the vertebral joint incision and placed, and the incision is sutured.
In order to produce a sham-operated animal, the above-described operation is subjected to an operation excluding silicon rubber insertion and indwelling operations.

Evaluation of analgesic effect Two weeks after the model preparation, the analgesic effect on tactile allodynia is evaluated by von Frey filament. Rats are habituated to a plastic cage placed on a wire mesh. To train the rat, the von Frey filament is pressed against the back of the rat foot from the wire mesh side. Prior to compound administration, a von Frey filament (0.4 to 26 g) is pressed from the wire mesh side to the back of the rat foot, and the pressure value of the von Frey filament at which the rat begins to show escape behavior is taken as the pre-dose pain threshold. Animals with reduced pain threshold are employed. The compound of the present invention is crushed using a mortar and pestle, a suspension or solution is prepared using 0.5% methylcellulose solution as a medium, and is orally administered to the adopted animal using an oral sonde. After the administration, the pressure value of the von Frey filament at which the rat begins to show escape behavior by the same operation is measured and set as a pain threshold after administration. Calculate% reversal value by the following formula and compare the analgesic action of the compounds.
% reversal value = (logarithm of pain threshold after administration of model animal-logarithm of pain threshold before administration of model animal) / (logarithm of pain threshold before administration of sham-operated animal-logarithm of pain threshold before administration of model animal)
試験例７　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（7-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（7-HFC）を生成する反応を指標として行った。 Test Example 7 CYP3A4 Fluorescence MBI Test The CYP3A4 Fluorescence MBI test is a test to examine the enhancement of CYP3A4 inhibition of compounds by metabolic reaction. Was used as an indicator for the reaction of debenzylation with CYP3A4 enzyme to produce the fluorescent metabolite 7-hydroxytrifluoromethylcoumarin (7-HFC).
　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 part of the solution was transferred so as to be diluted by 10/10, and the reaction using NADPH as a coenzyme was started (no pre-reaction), and after the 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). After the pre-reaction for a predetermined time, add another plate and dilute 1/10 with the substrate and K-Pi buffer. The reaction was started by shifting 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 had been 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-T000066
Figure JPOXMLDOC01-appb-T000066
試験例７－２　ＣＹＰ３Ａ４（ＭＤＺ）ＭＢＩ試験
　本発明化合物のＣＹＰ３Ａ４阻害に関して代謝反応による増強からＭｅｃｈａｎｉｓｍ　ｂａｓｅｄ　ｉｎｈｉｂｉｔｉｏｎ（ＭＢＩ）能を評価する試験である。プールドヒト肝ミクロソームを用いてミダゾラム（ＭＤＺ）の１－水酸化反応を指標としてＣＹＰ３Ａ４阻害を評価する。 Test Example 7-2 CYP3A4 (MDZ) MBI Test This test evaluates the mechanism based inhibition (MBI) ability from the enhancement by metabolic reaction with respect to CYP3A4 inhibition of the compounds of the present invention. Pooled human liver microsomes are used to evaluate CYP3A4 inhibition using midazolam (MDZ) 1-hydroxylation as an indicator.
　反応条件は以下のとおり：基質、１０μｍｏｌ／Ｌ　ＭＤＺ；プレ反応時間、０または３０分；反応時間、２分；反応温度、３７℃；プールドヒト肝ミクロソーム、プレ反応時０．５ｍｇ／ｍＬ、反応時０．０５ｍｇ／ｍＬ（１０倍希釈時）；本発明化合物プレ反応時の濃度、１、５、１０、２０μｍｏｌ／Ｌ（４点）。 The reaction conditions are as follows: substrate, 10 μmol / L MDZ; pre-reaction time, 0 or 30 minutes; reaction time, 2 minutes; reaction temperature, 37 ° C .; pooled human liver microsome, pre-reaction 0.5 mg / mL, reaction time 0.05 mg / mL (when diluted 10-fold); concentration at the time of pre-reaction of the compound of the present invention 1, 5, 10, 20 μmol / L (4 points).
　９６穴プレートにプレ反応液としてＫ－Ｐｉ緩衝液（ｐＨ７．４）中にプールドヒト肝ミクロソーム、本発明化合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、メタノール／アセトニトリル＝１／１（Ｖ／Ｖ）溶液を加えることによって反応を停止する。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する。所定の時間反応後、メタノール／アセトニトリル＝１／１（Ｖ／Ｖ）溶液を加えることによって反応を停止する。それぞれの指標反応を行ったプレートを３０００ｒｐｍ、１５分間の遠心後、遠心上清中の１－水酸化ミダゾラムをＬＣ／ＭＳ／ＭＳで定量する。 Pooled human liver microsomes and the compound solution of the present invention were added to a 96-well plate as a pre-reaction solution in K-Pi buffer (pH 7.4) in the above-mentioned pre-reaction composition, and the substrate and K-Pi buffer were added to another 96-well plate A part of the solution was transferred so that the solution was diluted to 1/10, and a reaction using NADPH as a coenzyme was started as an index (no pre-reaction). After reaction for a predetermined time, methanol / acetonitrile = 1 The reaction is stopped by adding a 1/1 (V / V) solution. In addition, NADPH is also added to the remaining pre-reaction solution to start the pre-reaction (pre-reaction is present), and after pre-reaction for a predetermined time, one plate is diluted to 1/10 with the substrate and K-Pi buffer. Start the reaction with the part as the indicator. After the reaction for a predetermined time, the reaction is stopped by adding a methanol / acetonitrile = 1/1 (V / V) solution. The plate on which each index reaction has been performed is centrifuged at 3000 rpm for 15 minutes, and 1-hydroxymidazolam in the centrifuged supernatant is quantified by LC / MS / MS.
　本発明化合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、本発明化合物をそれぞれの濃度添加したときの残存活性（％）を算出し、濃度と阻害率を用いて、ロジスティックモデルによる逆推定によりＩＣを算出する。Ｐｒｅｉｎｃｕｂａｔａｉｏｎ　０ｍｉｎのＩＣ／Ｐｒｅｉｎｃｕｂａｔａｉｏｎ　３０ｍｉｎのＩＣをＳｈｉｆｔｅｄ　ＩＣ値とし，Ｓｈｉｆｔｅｄ　ＩＣが１．５以上であればＰｏｓｉｔｉｖｅ、Ｓｈｉｆｔｅｄ　ＩＣが１．０以下であればＮｅｇａｔｉｖｅとする。 A control (100%) was obtained by adding only DMSO, which is a solvent in which the compound of the present invention was dissolved, to the reaction system, and the residual activity (%) when the compound of the present invention was added at each concentration was calculated. Is used to calculate IC by inverse estimation using a logistic model. Preincubation 0 min IC / Preincubation 30 min IC is the Shifted IC value. If the Shifted IC is 1.5 or more, it is Positive, and if the Shifted IC is 1.0 or less, it is Negative.
試験例８　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 8 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 were 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 microsomes 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またはLC/MS/MS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 the five 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 supernatant was collected using a fluorescent multilabel counter or LC / MS / MS with tolbutamide hydroxide (CYP2C9 metabolite) and mephenytoin 4 ′ hydroxylated. The body (CYP2C19 metabolite), 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 DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and calculating the residual activity (%) at each concentration to which the drug solution of the present invention was added. 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-T000067
Figure JPOXMLDOC01-appb-T000067
試験例９　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、振盪前培養する。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（Ｋ２ＨＰＯ４：３．５ｇ／Ｌ、ＫＨ２ＰＯ４：１ｇ／Ｌ、（ＮＨ４）２ＳＯ４：１ｇ／Ｌ、クエン酸三ナトリウム二水和物：０．２５ｇ／Ｌ、ＭｇＳＯ４・７Ｈ２０：０．１ｇ／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。 Test Example 9 Fluctuation Ames Test
The mutagenicity of the compound of the present invention is evaluated.
20 μL of Salmonella typhimurium TA98 strain, TA100 strain, which has been cryopreserved, is 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 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 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 (BioF: 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 by mutation of the amino acid (histidine) synthase gene change from purple to yellow due to pH change, the number of bacteria growth wells that changed to yellow in 48 wells per dose was counted. Evaluation is made in comparison with the negative control group. A negative mutagenicity is indicated as (−), and a positive mutagenicity is indicated as (+).
試験例１０　溶解性試験
　本発明化合物の溶解度は、１％ＤＭＳＯ添加条件下で決定した。ＤＭＳＯにて１０ｍｍｏｌ／Ｌ化合物溶液を調製し、本発明化合物溶液２　μＬをＪＰ－２液（下記参照）１９８μＬに添加した。室温で１時間振盪させた後、混液を吸引濾過した。濾液をメタノール／水＝１／１（Ｖ／Ｖ）またはアセトニトリル／メタノール／水＝１／１／２（Ｖ／Ｖ／Ｖ）にて１０または１００倍希釈し、絶対検量線法によりＬＣ／ＭＳまたは固相抽出(ＳＰＥ)／ＭＳを用いて濾液中濃度（Ｃ）を測定した。
ＪＰ２液組成：
Ａ: ０．２ｍｏｌ／Ｌリン酸二水素カリウム試液２００ｍＬに０．２ｍｏｌ／Ｌ水酸化ナトリウム試液約２００ｍＬを加えｐＨ６．８に調整後、水６００ｍＬを加える。
Ｂ: リン酸二水素カリウム３．４０ｇおよび無水リン酸水素二ナトリウム３．５５ｇを水に溶かし１０００ｍＬとする。
Ｃ: リン酸二水素カリウム３．４０ｇおよび無水リン酸水素二ナトリウム３．５５ｇを水に溶かし１０００ｍＬとしたもの１容量に水１容量を加える。
　本発明化合物の試験結果を以下の表に示す。上記条件Ａを用いて測定した結果を表１７に示す。また、上記条件Ｃを用いて測定した結果を表１８に示す。 Test Example 10 Solubility test The solubility of the compound of the present invention was determined under the condition of addition of 1% DMSO. A 10 mmol / L compound solution was prepared in DMSO, and 2 μL of the compound solution of the present invention was added to 198 μL of JP-2 solution (see below). After shaking for 1 hour at room temperature, the mixture was filtered with suction. The filtrate was diluted 10 or 100 times with methanol / water = 1/1 (V / V) or acetonitrile / methanol / water = 1/11/2 (V / V / V), and LC / MS was determined by the absolute calibration curve method. Alternatively, the concentration in the filtrate (C) was measured using solid phase extraction (SPE) / MS.
JP2 liquid composition:
A: About 200 mL of 0.2 mol / L sodium hydroxide test solution is added to 200 mL of 0.2 mol / L potassium dihydrogen phosphate test solution to adjust the pH to 6.8, and then 600 mL of water is added.
B: Dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in water to make 1000 mL.
C: 1 volume of water is added to 1 volume of 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate dissolved in water to 1000 mL.
The test results of the compounds of the present invention are shown in the following table. Table 17 shows the results measured using the above condition A. In addition, Table 18 shows the results of measurement using the above condition C.
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000068
Figure JPOXMLDOC01-appb-T000069
Figure JPOXMLDOC01-appb-T000069
試験例１１　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した。 Test Example 11 Metabolic Stability Test Using a commercially available pooled human liver microsome, the target compound was reacted for a certain period of time, and the residual rate was 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または固相抽出（ＳＰＥ）／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。 Presence of 1 mmol / L NADPH 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 allowed to proceed 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 or solid phase extraction (SPE) / 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%.
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000070
Figure JPOXMLDOC01-appb-T000071
Figure JPOXMLDOC01-appb-T000071
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した。 Test Example 12 Metabolic Stability Test Using the prepared rat cryopreserved hepatocytes, the target compound was reacted for a certain period of time, and the residual rate was calculated by comparing the reaction sample with the unreacted sample to evaluate the degree of metabolism in the liver. .
　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時間反応させた。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分間遠心した。その遠心上清中の試験化合物をLC/MS/MSまたは固相抽出（ＳＰＥ）／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。 Reaction was carried out at 37 ° C. for 0, 1 or 2 hours in a William E medium containing 1.0 × 10 6 cells / mL of rat frozen hepatocytes. After the reaction, 120 μL of a methanol / acetonitrile = 1/1 (v / v) solution was added to 30 μL of the reaction solution, mixed, and centrifuged at 3000 rpm for 15 minutes. The test compound in the centrifugal supernatant was quantified by LC / MS / MS or solid phase extraction (SPE) / 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%. .
Figure JPOXMLDOC01-appb-T000072
Figure JPOXMLDOC01-appb-T000072
試験例１３　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、ＣａＣｌ２：２　ｍｍｏｌ／Ｌ、ＭｇＣｌ２：１　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、本発明化合物のＩＫｒへの影響を評価する。 Test Example 13 hERG Test For the purpose of evaluating the risk of prolonging the electrocardiogram QT interval of the compound of the present invention, using CHO cells in which human ether-a-go-related gene (hERG) channels are expressed, it is important for the ventricular repolarization process. Consider the action of the compounds of the present invention on the delayed rectifier K + current (I Kr ) that plays a 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. Further, the inhibition rate with respect to the maximum tail current before application of the compound of the present invention is calculated, and the influence of the compound of the present invention on I Kr is evaluated.
試験例１４　蛋白結合試験
　ラット血清を用いて、発明化合物の血清蛋白非結合率を測定した。 Test Example 14 Protein Binding Test Serum protein non-binding rate of the inventive compound was measured using rat serum.
　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.
　ラット血清に検液を添加、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または固相抽出（SPE）/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。 A test solution was added to rat serum and stirred to prepare a serum sample having the above compound concentration. 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 or solid phase extraction (SPE) / 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-T000073
Figure JPOXMLDOC01-appb-T000073
試験例１４　蛋白結合試験
　ラットもしくはヒト血清を用いて、発明化合物の血清蛋白非結合率を測定した。
　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、４ μmol／Ｌ。
　ラットもしくはヒト血清に検液を添加、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または固相抽出（SPE）/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 Example 14 Protein Binding Test Serum protein non-binding rate of the inventive compound was measured using rat or human serum.
The reaction conditions are as follows: evaluation method, equilibrium dialysis method; reaction time, 24 hours; reaction temperature, 37 ° C .; inventive compound concentration, 4 μmol / L.
A test solution was added to rat or human serum and stirred to prepare a serum sample having the above compound concentration. 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 or solid phase extraction (SPE) / 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-T000074
Figure JPOXMLDOC01-appb-T000074
試験例１５　薬物動態試験
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。また、静脈内投与量を静脈内投与後のＡＵＣで割ることにより、全身クリアランス （ＣＬｔｏｔ）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 15 Pharmacokinetic Test 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. In addition, systemic clearance (CLtot) was calculated by dividing the intravenous dose by AUC after intravenous administration.
The test results of the compounds of the present invention are shown in the following table.
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000075
Figure JPOXMLDOC01-appb-T000076
Figure JPOXMLDOC01-appb-T000076
試験例１６　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（リン酸二水素カリウム３．４０ｇおよび無水リン酸水素二ナトリウム３．５５ｇを水に溶かし１０００ｍＬとしたもの１容量に水１容量を加える）、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、必要に応じて変更した。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 16 Powder Solubility Test An appropriate amount of the compound of the present invention is put 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), JP-2 solution ( Dissolve 3.40 g of potassium dihydrogen phosphate and 3.55 g of anhydrous disodium hydrogen phosphate in water to make 1000 mL, add 1 volume of water to 1 volume), 20 mmol / L sodium taurocholate (TCA) / JP-2 solution (Add JP-2 solution to 1.08 g of TCA to make 100 mL) 200 μL each. 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. The dilution factor was changed as necessary. Check for bubbles and deposits, seal and shake. The compound of the present invention is quantified using HPLC by the absolute calibration curve method.
試験例１７　脳移行性試験
　ラットに０．５ｍｇ／ｍＬ／ｋｇの用量で本発明に係る化合物を静脈内投与し、３０分後にイソフルラン麻酔下で下大動脈より全採血により放血死させる。
　その後、脳を摘出し、蒸留水で２０－２５％のホモジネートを調製する。
　一方、得られた血液は遠心処理後、血漿にする。その後、脳サンプルにはコントロール血漿を、血漿サンプルにはコントロール脳を１：１で添加し、それぞれのサンプルをＬＣ／ＭＳ／ＭＳを用いて測定する。得られた測定時のエリア比（脳／血漿）を脳Ｋｐ値とする。 Test Example 17 Brain Translocation Test Rats are intravenously administered a compound according to the present invention at a dose of 0.5 mg / mL / kg, and 30 minutes later, they are exsanguinated by whole blood collection from the lower aorta under isoflurane anesthesia.
Thereafter, the brain is removed and 20-25% homogenate is prepared with distilled water.
On the other hand, the obtained blood is made into plasma after centrifugation. Thereafter, control plasma is added to the brain sample and control brain is added to the plasma sample at a ratio of 1: 1, and each sample is measured using LC / MS / MS. The obtained area ratio (brain / plasma) at the time of measurement is defined as the brain Kp value.
試験例１８：Ｐ－ｇｐ基質試験
　ヒトＭＤＲ１発現細胞または親細胞を単層培養したトランスウェル（登録商標、ＣＯＲＮＩＮＧ社）の片側に本発明に係る化合物を添加し、一定時間反応させる。ＭＤＲ１発現細胞と親細胞のＥｆｆｌｕｘ　Ｒａｔｉｏ（ＥＲ値）を比較し、本発明化合物がＰ－ｇｐ基質であるか否かを判断する。Ａｐｉｃａｌ側からＢａｓｏｌａｔｅｒａｌ側方向（Ａ→Ｂ）とＢａｓｏｌａｔｅｒａｌ側からＡｐｉｃａｌ側方向（Ｂ→Ａ）の膜透過係数を算出し、ＭＤＲ１発現細胞と親細胞のＥｆｆｌｕｘ　Ｒａｔｉｏ（ＥＲ；Ｂ→ＡとＡ→Ｂの膜透過係数の比）値を算出する。 Test Example 18: P-gp Substrate Test The compound according to the present invention is added to one side of a transwell (registered trademark, CORNING), in which human MDR1-expressing cells or parent cells are cultured in a monolayer, and allowed to react for a certain period of time. The Efflux Ratio (ER value) of the MDR1-expressing cell and the parent cell is compared to determine whether the compound of the present invention is a P-gp substrate. Membrane permeability coefficient in the axial direction from the axial side to the basolateral side (A → B) and from the basolateral side to the apical side (B → A) is calculated, and the Efflux Ratio (ER; B → A and A → B) of the MDR1-expressing cell and the parent cell. The ratio of membrane permeation coefficient) is calculated.
試験例１９：ｍｄｒ１ａ（－／－）Ｂ６マウスＰ－ｇｐ基質試験
材料
動物：ｍｄｒ１ａ（－／－）Ｂ６マウス（ノックアウトマウス）またはＣ５７ＢＬ／６Ｊマウス（野生マウス）
方法
１．動物は本発明化合物の投与前に食餌を摂取させてもよい。
２．本発明化合物は３匹の動物に各時点で投与し、血液及び脳サンプルは投与後の所定時点（例：１５分、３０分、１時間、２時間、４時間、６時間、８時間または２４時間）で採取する。血液（０．３～０．７ｍＬ）は血液凝固防止剤（ＥＤＴＡおよびヘパリン）を含むシリンジで採取する。血液および組織（脳など）サンプルは直ちに氷冷する。
３．血液サンプルは遠心分離（１７８０ｘｇ、１０分間）し細胞を除去し、血漿を得る。その後、血漿サンプルをチューブに移し、－７０℃で保存する。
４．組織（脳など）サンプルは組織重量：蒸留水重量比＝１：３でホモジナイズし、チューブに移して－７０℃で保存する。
５．血漿および組織（脳など）サンプルは除タンパクを用いて調整し、ＬＣ／ＭＳ／ＭＳで分析する。測定にはブランク血漿またはブランク脳から作成した検量線を用いて、測定法の真度及び精度の確認を行うためにクオリティーコントロール用サンプルを用いる。６．血漿および脳濃度値（ｎｇ／ｍＬおよびｎｇ／ｇ）は薬物動態パラメーターを求めるための適切な方法、例えばＷｉｎＮｏｎｌｉｎ（登録商標）薬物動態解析ソフトウェアプログラムで解析する。
解析
Ｋｐ；組織／血漿中濃度比
Ｋｐ比＝ノックアウトマウス（ＫＯ）のＫｐ値／野生マウス（Ｗｉｌｄ）のＫｐ値
組織ＡＵＣ／血漿ＡＵＣのＫＯ／Ｗｉｌｄ比
　＝｛組織ＡＵＣ／血漿ＡＵＣ（ＫＯ）｝／｛組織ＡＵＣ／血漿ＡＵＣ（Ｗｉｌｄ）｝ Test Example 19: mdr1a (− / −) B6 mouse P-gp substrate Test material animal: mdr1a (− / −) B6 mouse (knockout mouse) or C57BL / 6J mouse (wild mouse)
Method 1. Animals may be fed before administration of the compounds of the present invention.
2. The compound of the present invention is administered to three animals at each time point, and blood and brain samples are given at predetermined time points after administration (eg, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours or 24 hours). Time). Blood (0.3-0.7 mL) is collected with a syringe containing anticoagulants (EDTA and heparin). Blood and tissue (such as brain) samples should be ice-cold immediately.
3. The blood sample is centrifuged (1780 × g, 10 minutes) to remove cells and obtain plasma. The plasma sample is then transferred to a tube and stored at -70 ° C.
4). Tissue (such as brain) samples are homogenized at a tissue weight: distilled water weight ratio = 1: 3, transferred to a tube and stored at −70 ° C.
5. Plasma and tissue (such as brain) samples are prepared using deproteinization and analyzed by LC / MS / MS. For the measurement, a quality control sample is used to confirm the accuracy and accuracy of the measurement method using a calibration curve prepared from blank plasma or blank brain. 6). Plasma and brain concentration values (ng / mL and ng / g) are analyzed with an appropriate method for determining pharmacokinetic parameters, such as the WinNonlin® pharmacokinetic analysis software program.
Analysis Kp; tissue / plasma concentration ratio Kp ratio = Kp value of knockout mouse (KO) / Kp value of wild mouse (Wild) tissue AUC / plasma AUC KO / Wild ratio = {tissue AUC / plasma AUC (KO)} / {Tissue AUC / Plasma AUC (Wild)}
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.
製剤例４　口腔内崩壊錠
　本発明化合物および結晶セルロースを混合し、造粒後打錠して口腔内崩壊錠とする。 Formulation Example 4 Orally Disintegrating Tablets The compound of the present invention and crystalline cellulose are mixed and compressed after granulation to obtain an orally disintegrating tablet.
製剤例５　ドライシロップ
　本発明化合物および乳糖を混合し、粉砕、整粒、篩別して適当な大きさのドライシロップとする。 Formulation Example 5 Dry Syrup The compound of the present invention and lactose are mixed, pulverized, sized and sieved to obtain a dry syrup of an appropriate size.
製剤例６　注射剤
　本発明化合物およびリン酸緩衝液を混合し、注射剤とする。 Formulation Example 6 Injection The compound of the present invention and a phosphate buffer are mixed to prepare an injection.
製剤例７　点滴剤
　本発明化合物およびリン酸緩衝液を混合し、点滴剤とする。 Formulation Example 7 Instillation A compound of the present invention and a phosphate buffer are mixed to prepare an instillation.
製剤例８　吸入剤
　本発明化合物および乳糖を混合し細かく粉砕することにより、吸入剤とする。 Formulation Example 8 Inhalant The compound of the present invention and lactose are mixed and finely pulverized to obtain an inhalant.
製剤例９　軟膏剤
　本発明化合物およびワセリンを混合し、軟膏剤とする。 Formulation Example 9 Ointment The compound of the present invention and petrolatum are mixed to form an ointment.
製剤例１０ 貼付剤
　本発明化合物および粘着プラスターなどの基剤を混合し、貼付剤とする。 Formulation Example 10 Patch A base such as the compound of the present invention and an adhesive plaster is mixed to obtain a patch.
　一般式（Ｉ）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、呼吸器疾患等に対して有用であると考えられる。 Compound represented by the general formula (I) has an antagonistic effect on P2X 3 and / or P2X 2/3 receptor, P2X 3 and / or diseases or conditions P2X 2/3 receptor is involved, for example, chronic pain It is considered useful for urination disorders, respiratory diseases and the like.

Claims (14)

  1. 　式（１）：
    Figure JPOXMLDOC01-appb-C000001
    （式中、－Ｘ－は、－Ｎ（Ｒ５）－、－Ｏ－または－Ｓ－であり；
    　Ｒ５は、水素原子、置換若しくは非置換のアルキルまたは置換若しくは非置換のアシルであり；
    　Ｒ１は、水素原子、カルボキシ、シアノ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアシル、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のカルバモイル、置換若しくは非置換のアミノ、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換の芳香族炭素環オキシまたは置換若しくは非置換の芳香族複素環オキシであり；
    　Ｒ２は、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基であり；
    　Ｒ３は、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基であり；
    　Ｒ４ａは、それぞれ独立して、水素原子、若しくは置換若しくは非置換のアルキルであり、
    Ｒ４ｂは、それぞれ独立して、水素原子、若しくは置換若しくは非置換のアルキルであり、または
    　Ｒ４ａおよびＲ４ｂは、一緒になってオキソであり；
    　ｎは、０～４の整数で示される化合物（ただし、以下に示される化合物：
    Figure JPOXMLDOC01-appb-C000002
    を除く）またはその製薬上許容される塩。     Formula (1):
    Figure JPOXMLDOC01-appb-C000001
    Wherein —X— is —N (R 5 ) —, —O— or —S—;
    R 5 is a hydrogen atom, substituted or unsubstituted alkyl or substituted or unsubstituted acyl;
    R 1 is a hydrogen atom, carboxy, cyano, 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 acyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted amino, substituted or unsubstituted non-aromatic carbocyclic group, substituted Or an unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, a substituted or unsubstituted aromatic heterocyclic group, a substituted or unsubstituted non-aromatic carbocyclic oxy, substituted or Unsubstituted non-aromatic heterocyclic oxy, substituted or unsubstituted aromatic carbocyclic oxy or Substituted or unsubstituted aromatic heterocyclic oxy;
    R 2 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group A substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;
    R 3 represents substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group A substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;
    Each R 4a is independently 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 taken together are oxo;
    n is a compound represented by an integer of 0 to 4 (provided that the following compounds:
    Figure JPOXMLDOC01-appb-C000002
    Or a pharmaceutically acceptable salt thereof.
  2. 　ｎが１～４の整数であり、
    　Ｒ２およびＲ３が、それぞれ独立して、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基である、請求項１記載の化合物またはその製薬上許容される塩。     n is an integer of 1 to 4,
    R 2 and R 3 are each independently a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is a substituted or unsubstituted aromatic heterocyclic group.
  3. 　－Ｘ－が、－Ｎ（Ｒ５）－（式中、Ｒ５は請求項１と同義）である、請求項２記載の化合物またはその製薬上許容される塩。 The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein -X- is -N (R 5 )-(wherein R 5 is as defined in claim 1).
  4. 　Ｒ２が、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基である、請求項２または３記載の化合物またはその製薬上許容される塩。 The compound according to claim 2 or 3, or a pharmaceutically acceptable salt thereof, wherein R 2 is a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group.
  5. 　Ｒ１が、置換若しくは非置換のアルキル、カルボキシ、シアノ、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のカルバモイルまたは置換若しくは非置換のアミノである、請求項２～４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。 The R 1 is substituted or unsubstituted alkyl, carboxy, cyano, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted amino. Or a pharmaceutically acceptable salt thereof.
  6. 　Ｒ３が、式：
    Figure JPOXMLDOC01-appb-C000003
    （式中、環Ａは、芳香族炭素環または芳香族複素環であり；
    　ｓは、０～３の整数であり；
    　Ｒ６は、それぞれ独立して、ハロゲン、ヒドロキシ、シアノ、ニトロ、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシ、置換若しくは非置換のアルキニルオキシ、置換若しくは非置換のアルキルチオ、置換若しくは非置換のアルケニルチオ、置換若しくは非置換のアルキニルチオ、置換若しくは非置換のアシル、カルボキシ、置換若しくは非置換のアルキルオキシカルボニル、置換若しくは非置換のアルケニルオキシカルボニル、置換若しくは非置換のアルキニルオキシカルボニル、置換若しくは非置換のカルバモイル、置換若しくは非置換のアミノ、置換若しくは非置換のスルファモイル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基、置換若しくは非置換の芳香族複素環式基、置換若しくは非置換の非芳香族炭素環オキシ、置換若しくは非置換の非芳香族複素環オキシ、置換若しくは非置換の芳香族炭素環オキシまたは置換若しくは非置換の芳香族複素環オキシである）で示される基である、請求項２～５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。     R 3 has the formula:
    Figure JPOXMLDOC01-appb-C000003
    Wherein ring A is an aromatic carbocycle or aromatic heterocycle;
    s is an integer from 0 to 3;
    Each R 6 is independently halogen, hydroxy, 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, carboxy, 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 or Is an unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic heterocyclic group, substituted or unsubstituted aromatic carbocyclic group, substituted or unsubstituted aromatic heterocyclic group, substituted Or an unsubstituted non-aromatic carbocyclic oxy, a substituted or unsubstituted non-aromatic heterocyclic oxy, a substituted or unsubstituted aromatic carbocyclic oxy or a substituted or unsubstituted aromatic heterocyclic oxy) The compound or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 5, which is a group.
  7. 　Ｒ３が、式：
    Figure JPOXMLDOC01-appb-C000004
    （式中、Ｒ７は、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基であり；
    Ｒ８は水素原子、ハロゲン、置換若しくは非置換のアルキル、置換若しくは非置換のアルケニル、置換若しくは非置換のアルキニル、置換若しくは非置換のアルキルオキシ、置換若しくは非置換のアルケニルオキシまたは置換若しくは非置換のアルキニルオキシである）で示される基である、請求項２～６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。     R 3 has the formula:
    Figure JPOXMLDOC01-appb-C000004
    Wherein R 7 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted non-aromatic carbocyclic group, substituted or unsubstituted non-aromatic A heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group or a substituted or unsubstituted aromatic heterocyclic group;
    R 8 is a hydrogen atom, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, or substituted or unsubstituted The compound or a pharmaceutically acceptable salt thereof according to any one of claims 2 to 6, which is a group represented by (Alkynyloxy).
  8. 　Ｒ７が、置換若しくは非置換の非芳香族炭素環式基、置換若しくは非置換の非芳香族複素環式基、置換若しくは非置換の芳香族炭素環式基または置換若しくは非置換の芳香族複素環式基である、請求項７記載の化合物またはその製薬上許容される塩。 R 7 represents a substituted or unsubstituted non-aromatic carbocyclic group, a substituted or unsubstituted non-aromatic heterocyclic group, a substituted or unsubstituted aromatic carbocyclic group, or a substituted or unsubstituted aromatic heterocyclic group. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, which is a cyclic group.
  9. 　Ｒ８が、水素原子、ハロゲン、置換若しくは非置換のアルキルまたは置換若しくは非置換のアルキルオキシである、請求項７または８記載の化合物またはその製薬上許容される塩。 The compound according to claim 7 or 8, or a pharmaceutically acceptable salt thereof, wherein R 8 is a hydrogen atom, halogen, substituted or unsubstituted alkyl, or substituted or unsubstituted alkyloxy.
  10. 　実施例Ｉ－２０、Ｉ－２４、Ｉ－２９、Ｉ－３３およびＩ－３５からなる群から選択される、請求項１記載の化合物またはその製薬上許容される塩。 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of Examples I-20, I-24, I-29, I-33 and I-35.
  11. 　請求項１～１０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を含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof.
  12. 　Ｐ２Ｘ３および／またはＰ２Ｘ２／３受容体拮抗剤である、請求項１１記載の医薬組成物。 P2X is 3 and / or P2X 2/3 receptor antagonist, pharmaceutical composition according to claim 11 wherein.
  13. 　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１～１０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。 The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of diseases involving P2X 3 and / or P2X 2/3 receptors.
  14. 　請求項１～１０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。 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 10 or a pharmaceutically acceptable salt thereof. Method.
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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017204318A1 (en) * 2016-05-27 2017-11-30 塩野義製薬株式会社 1,2,4-triazine derivative
US9988373B2 (en) 2013-12-26 2018-06-05 Shionogi & Co., Ltd. Nitrogen-containing six-membered cyclic derivatives and pharmaceutical composition comprising the same
CN110494141A (en) * 2016-08-10 2019-11-22 盐野义制药株式会社 Pharmaceutical composition containing substituted polycyclic Pyridione derivatives and its prodrug
US10774051B2 (en) 2015-04-24 2020-09-15 Shionogi & Co., Ltd. 6-membered heterocyclic derivatives and pharmaceutical composition comprising the same
WO2020239952A1 (en) 2019-05-31 2020-12-03 Chiesi Farmaceutici S.P.A. Amino quinazoline derivatives as p2x3 inhibitors
WO2020239953A1 (en) 2019-05-31 2020-12-03 Chiesi Farmaceutici S.P.A. Pyridopyrimidines derivatives as p2x3 inhibitors
US11066409B2 (en) 2016-10-17 2021-07-20 Shionogi & Co., Ltd. Bicyclic nitrogen-containing heterocyclic derivatives and pharmaceutical composition comprising the same
WO2022112493A1 (en) 2020-11-27 2022-06-02 Chiesi Farmaceutici S.P.A. Phthalazine derivatives as p2x3 inhibitors
WO2022112490A1 (en) 2020-11-27 2022-06-02 Chiesi Farmaceutici S.P.A. Amino quinazoline derivatives as p2x3 inhibitors
WO2022112491A1 (en) 2020-11-27 2022-06-02 Chiesi Farmaceutici S.P.A. (aza)quinoline 4-amines derivatives as p2x3 inhibitors

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3510793A1 (en) * 1985-03-25 1986-09-25 Bayer Ag, 5090 Leverkusen 4-Substituted 6-t-butyl-3-methylthio-1,2,4-triazin-5-ones
JPS63258468A (en) * 1987-03-28 1988-10-25 バイエル・アクチエンゲゼルシヤフト Novel 3, 4, 6-trisubstituted 1, 2, 4-triazin-5-(4h)-one
JP2000319268A (en) * 1999-05-11 2000-11-21 Mitsubishi Chemicals Corp 6-haloalkyl-3-(substituted amino)-1,2,4triazin-5-one derivative, agrochemical with the same as active ingredient, and intermediate for producing the same
JP2005508288A (en) * 2001-05-18 2005-03-31 アボット・ラボラトリーズ Tri-substituted-N-[(1S) -1,2,3,4-tetrahydro-1-naphthalenyl] benzamides that inhibit P2X3 and P2X2 / 3-containing receptors
JP2009504705A (en) * 2005-08-15 2009-02-05 エフ．ホフマン−ラ ロシュ アーゲー Piperidine and piperazine derivatives as P2X3 antagonists
JP2009513565A (en) * 2005-09-01 2009-04-02 エフ．ホフマン−ラ ロシュ アーゲー Diaminopyrimidines as P2X3 and P2X2 / 3 modulators
WO2010092966A1 (en) * 2009-02-13 2010-08-19 塩野義製薬株式会社 Novel triazine derivative and pharmaceutical composition containing same
WO2011079778A1 (en) * 2009-12-30 2011-07-07 China Shanghai Fochon Pharmaceutical Co Ltd 3-(3-aminopiperidin-1-yl)-5-oxo-1,2,4-triazine derivates as dipeptidyl peptidase iv(dpp-iv) inhibitors
JP2012502986A (en) * 2008-09-18 2012-02-02 エヴォテック アーゲー Modulator of P2X3 receptor activity
WO2012020742A1 (en) * 2010-08-10 2012-02-16 塩野義製薬株式会社 Novel heterocyclic derivatives and pharmaceutical composition containing same
WO2012020749A1 (en) * 2010-08-10 2012-02-16 塩野義製薬株式会社 Triazine derivative and pharmaceutical compound that contains same and exhibits analgesic activity
WO2012033548A2 (en) * 2010-09-07 2012-03-15 E. I. Du Pont De Nemours And Company Herbicidal bis-nitrogen-containing oxo and sulfono heterocycles
JP2012507533A (en) * 2008-10-31 2012-03-29 メルク・シャープ・エンド・ドーム・コーポレイション Technical field of P2X3 receptor antagonist for the treatment of pain
JP2012512222A (en) * 2008-12-16 2012-05-31 エフ．ホフマン−ラ ロシュ アーゲー Thiadiazole substituted arylamide
WO2013089212A1 (en) * 2011-12-15 2013-06-20 塩野義製薬株式会社 Substituted triazine derivative and pharmaceutical composition containing same
WO2013118855A1 (en) * 2012-02-09 2013-08-15 塩野義製薬株式会社 Heterocyclic ring and carbocyclic derivative
WO2014200078A1 (en) * 2013-06-14 2014-12-18 塩野義製薬株式会社 Amino-triazine derivatives and pharmaceutical composition containing said derivatives

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3510793A1 (en) * 1985-03-25 1986-09-25 Bayer Ag, 5090 Leverkusen 4-Substituted 6-t-butyl-3-methylthio-1,2,4-triazin-5-ones
JPS63258468A (en) * 1987-03-28 1988-10-25 バイエル・アクチエンゲゼルシヤフト Novel 3, 4, 6-trisubstituted 1, 2, 4-triazin-5-(4h)-one
JP2000319268A (en) * 1999-05-11 2000-11-21 Mitsubishi Chemicals Corp 6-haloalkyl-3-(substituted amino)-1,2,4triazin-5-one derivative, agrochemical with the same as active ingredient, and intermediate for producing the same
JP2005508288A (en) * 2001-05-18 2005-03-31 アボット・ラボラトリーズ Tri-substituted-N-[(1S) -1,2,3,4-tetrahydro-1-naphthalenyl] benzamides that inhibit P2X3 and P2X2 / 3-containing receptors
JP2009504705A (en) * 2005-08-15 2009-02-05 エフ．ホフマン−ラ ロシュ アーゲー Piperidine and piperazine derivatives as P2X3 antagonists
JP2009513565A (en) * 2005-09-01 2009-04-02 エフ．ホフマン−ラ ロシュ アーゲー Diaminopyrimidines as P2X3 and P2X2 / 3 modulators
JP2012502986A (en) * 2008-09-18 2012-02-02 エヴォテック アーゲー Modulator of P2X3 receptor activity
JP2012507533A (en) * 2008-10-31 2012-03-29 メルク・シャープ・エンド・ドーム・コーポレイション Technical field of P2X3 receptor antagonist for the treatment of pain
JP2012512222A (en) * 2008-12-16 2012-05-31 エフ．ホフマン−ラ ロシュ アーゲー Thiadiazole substituted arylamide
WO2010092966A1 (en) * 2009-02-13 2010-08-19 塩野義製薬株式会社 Novel triazine derivative and pharmaceutical composition containing same
WO2011079778A1 (en) * 2009-12-30 2011-07-07 China Shanghai Fochon Pharmaceutical Co Ltd 3-(3-aminopiperidin-1-yl)-5-oxo-1,2,4-triazine derivates as dipeptidyl peptidase iv(dpp-iv) inhibitors
WO2012020742A1 (en) * 2010-08-10 2012-02-16 塩野義製薬株式会社 Novel heterocyclic derivatives and pharmaceutical composition containing same
WO2012020749A1 (en) * 2010-08-10 2012-02-16 塩野義製薬株式会社 Triazine derivative and pharmaceutical compound that contains same and exhibits analgesic activity
WO2012033548A2 (en) * 2010-09-07 2012-03-15 E. I. Du Pont De Nemours And Company Herbicidal bis-nitrogen-containing oxo and sulfono heterocycles
WO2013089212A1 (en) * 2011-12-15 2013-06-20 塩野義製薬株式会社 Substituted triazine derivative and pharmaceutical composition containing same
WO2013118855A1 (en) * 2012-02-09 2013-08-15 塩野義製薬株式会社 Heterocyclic ring and carbocyclic derivative
WO2014200078A1 (en) * 2013-06-14 2014-12-18 塩野義製薬株式会社 Amino-triazine derivatives and pharmaceutical composition containing said derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY [O] 14 April 2006 (2006-04-14), retrieved from STN Database accession no. RN:880454-52- 4 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9988373B2 (en) 2013-12-26 2018-06-05 Shionogi & Co., Ltd. Nitrogen-containing six-membered cyclic derivatives and pharmaceutical composition comprising the same
US10774051B2 (en) 2015-04-24 2020-09-15 Shionogi & Co., Ltd. 6-membered heterocyclic derivatives and pharmaceutical composition comprising the same
US11124486B2 (en) 2015-04-24 2021-09-21 Shionogi & Co., Ltd. 6-membered heterocyclic derivatives and pharmaceutical composition comprising the same
WO2017204318A1 (en) * 2016-05-27 2017-11-30 塩野義製薬株式会社 1,2,4-triazine derivative
CN110494141A (en) * 2016-08-10 2019-11-22 盐野义制药株式会社 Pharmaceutical composition containing substituted polycyclic Pyridione derivatives and its prodrug
US11066409B2 (en) 2016-10-17 2021-07-20 Shionogi & Co., Ltd. Bicyclic nitrogen-containing heterocyclic derivatives and pharmaceutical composition comprising the same
US11685740B2 (en) 2016-10-17 2023-06-27 Shionogi & Co., Ltd. Bicyclic nitrogen-containing heterocyclic derivatives and pharmaceutical composition comprising the same
WO2020239951A1 (en) 2019-05-31 2020-12-03 Chiesi Farmaceutici S.P.A. Amino quinazoline derivatives as p2x3 inhibitors
WO2020239953A1 (en) 2019-05-31 2020-12-03 Chiesi Farmaceutici S.P.A. Pyridopyrimidines derivatives as p2x3 inhibitors
WO2020239952A1 (en) 2019-05-31 2020-12-03 Chiesi Farmaceutici S.P.A. Amino quinazoline derivatives as p2x3 inhibitors
WO2022112493A1 (en) 2020-11-27 2022-06-02 Chiesi Farmaceutici S.P.A. Phthalazine derivatives as p2x3 inhibitors
WO2022112490A1 (en) 2020-11-27 2022-06-02 Chiesi Farmaceutici S.P.A. Amino quinazoline derivatives as p2x3 inhibitors
WO2022112491A1 (en) 2020-11-27 2022-06-02 Chiesi Farmaceutici S.P.A. (aza)quinoline 4-amines derivatives as p2x3 inhibitors

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