WO2016084922A1 - Dérivé 1,2,4-triazine et composition pharmaceutique correspondante - Google Patents

Dérivé 1,2,4-triazine et composition pharmaceutique correspondante 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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English (en)
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/ja
Publication of WO2016084922A1 publication Critical patent/WO2016084922A1/fr

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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

La présente invention concerne un nouveau composé ayant un effet antagoniste du récepteur P2X3 et/ou P2X2/3. Le composé est un composé représenté par la formule (I), ou un sel pharmaceutiquement acceptable de celui-ci. (Dans la formule (I) : R1 est un groupe alkyle éventuellement substitué ou similaire ; R2 est un groupe carbocyclique aromatique éventuellement substitué ou similaire ; R3 est un groupe carbocyclique aromatique éventuellement substitué ou similaire ; chaque R4a est indépendamment un atome d'hydrogène ou similaire ; chaque R4b est indépendamment un atome d'hydrogène ou similaire ; n est un nombre entier d'une valeur de 0 à 4 ; X est -N(R5)- ou similaire ; et R5 est un atome d'hydrogène ou similaire.)
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WO2017204318A1 (fr) * 2016-05-27 2017-11-30 塩野義製薬株式会社 Dérivé de 1,2,4-triazine
US9988373B2 (en) 2013-12-26 2018-06-05 Shionogi & Co., Ltd. Nitrogen-containing six-membered cyclic derivatives and pharmaceutical composition comprising the same
CN110494141A (zh) * 2016-08-10 2019-11-22 盐野义制药株式会社 含有被取代的多环性吡啶酮衍生物及其前药的药物组合物
US10774051B2 (en) 2015-04-24 2020-09-15 Shionogi & Co., Ltd. 6-membered heterocyclic derivatives and pharmaceutical composition comprising the same
WO2020239951A1 (fr) 2019-05-31 2020-12-03 Chiesi Farmaceutici S.P.A. Dérivés d'amino quinazoline servant d'inhibiteurs de p2x3
WO2020239953A1 (fr) 2019-05-31 2020-12-03 Chiesi Farmaceutici S.P.A. Dérivés de pyridopyrimidines utilisés en tant qu'inhibiteurs de p2x3
US11066409B2 (en) 2016-10-17 2021-07-20 Shionogi & Co., Ltd. Bicyclic nitrogen-containing heterocyclic derivatives and pharmaceutical composition comprising the same
WO2022112491A1 (fr) 2020-11-27 2022-06-02 Chiesi Farmaceutici S.P.A. Dérivés de (aza)quinoléine 4-amines servant d'inhibiteurs de p2x3
WO2022112490A1 (fr) 2020-11-27 2022-06-02 Chiesi Farmaceutici S.P.A. Dérivés d'amino-quinazoline utilisés en tant qu'inhibiteurs de p2x3
WO2022112493A1 (fr) 2020-11-27 2022-06-02 Chiesi Farmaceutici S.P.A. Dérivés de phtalazine utilisés en tant qu'inhibiteurs de p2x3

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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 (fr) * 2016-05-27 2017-11-30 塩野義製薬株式会社 Dérivé de 1,2,4-triazine
CN110494141A (zh) * 2016-08-10 2019-11-22 盐野义制药株式会社 含有被取代的多环性吡啶酮衍生物及其前药的药物组合物
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
WO2020239952A1 (fr) 2019-05-31 2020-12-03 Chiesi Farmaceutici S.P.A. Dérivés d'amino quinazoline servant d'inhibiteurs de p2x3
WO2020239953A1 (fr) 2019-05-31 2020-12-03 Chiesi Farmaceutici S.P.A. Dérivés de pyridopyrimidines utilisés en tant qu'inhibiteurs de p2x3
WO2020239951A1 (fr) 2019-05-31 2020-12-03 Chiesi Farmaceutici S.P.A. Dérivés d'amino quinazoline servant d'inhibiteurs de p2x3
WO2022112491A1 (fr) 2020-11-27 2022-06-02 Chiesi Farmaceutici S.P.A. Dérivés de (aza)quinoléine 4-amines servant d'inhibiteurs de p2x3
WO2022112490A1 (fr) 2020-11-27 2022-06-02 Chiesi Farmaceutici S.P.A. Dérivés d'amino-quinazoline utilisés en tant qu'inhibiteurs de p2x3
WO2022112493A1 (fr) 2020-11-27 2022-06-02 Chiesi Farmaceutici S.P.A. Dérivés de phtalazine utilisés en tant qu'inhibiteurs de p2x3

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