WO2014017087A1 - Dérivé pyrazolopyridine ou un sel pharmacologiquement acceptable de celui-ci - Google Patents

Dérivé pyrazolopyridine ou un sel pharmacologiquement acceptable de celui-ci Download PDF

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WO2014017087A1
WO2014017087A1 PCT/JP2013/004507 JP2013004507W WO2014017087A1 WO 2014017087 A1 WO2014017087 A1 WO 2014017087A1 JP 2013004507 W JP2013004507 W JP 2013004507W WO 2014017087 A1 WO2014017087 A1 WO 2014017087A1
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group
methyl
pyridin
compound
chloro
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PCT/JP2013/004507
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English (en)
Japanese (ja)
Inventor
茂樹 瀬戸
洋輔 西ヶ谷
麻生 谷岡
田谷　和也
近藤　敦志
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杏林製薬株式会社
キッセイ薬品工業株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a pyrazolopyridine derivative having an EP 1 receptor antagonistic action, or a pharmacologically acceptable salt thereof.
  • OABs overactive bladder syndrome
  • OABs are diseases defined as "symptom syndrome requiring urgency of urine, usually accompanied by frequent urination and nocturia. Imminent urinary incontinence is not essential.” is there.
  • anticholinergic drugs are first-line drugs for the treatment of OABs.
  • anticholinergic drugs need to be used with sufficient consideration for antimuscarinic effects such as dry mouth and residual urine, and are not necessarily effective for all patients (for example, non-patent literature). 1).
  • development of a therapeutic agent having a mechanism different from that of an anticholinergic agent is desired (see, for example, Non-Patent Document 1).
  • EP 1 there are four subtypes of receptors for PGE 2 , EP 2 , EP 3 and EP 4 .
  • the EP 1 receptor is present in the lung, skeletal muscle, kidney collecting duct and the like in addition to the bladder and urothelium (see, for example, Non-Patent Document 2).
  • it is expected that therapeutic agents for a desired disease can be developed by changing the selectivity of the PGE 2 receptor subtype and the target organ or target tissue of the drug.
  • Patent Document 1 discloses a benzofuran derivative represented by the chemical structural formula (A) as a compound having an EP 1 receptor antagonistic action.
  • R 1 represents a hydrogen atom, a halogen atom or the like
  • R 2a represents a hydrogen atom or the like
  • R 2b represents a C 1-4 alkyl group (straight or branched chain having 1 to 4 carbon atoms).
  • R 2c represents a hydrogen atom or the like
  • R 3 represents a group represented by the following general formula (B) or the like.
  • R 4 represents a carboxy group or the like.
  • Patent Document 2 discloses a benzofuran derivative represented by the chemical structural formula (C) as a compound having an EP 1 receptor antagonistic action.
  • R 1 represents a hydrogen atom, a halogen atom or the like
  • R 2 represents a thienyl group or the like
  • R 3 represents a group represented by the following general formula (B) or the like.
  • R 4 represents a carboxy group or the like.
  • these compounds differ in basic chemical structural formula from the compounds according to the present invention.
  • it cannot be overemphasized that these compounds are not contained in a claim of this application.
  • An object of the present invention is to provide a novel compound having an EP 1 receptor antagonistic action.
  • the gist of the present invention is as follows.
  • A is a group selected from the group consisting of a) to d) below:
  • R a is a group selected from the group consisting of e) to g) below: e) a hydrogen atom f) a halogen atom g) a C 1-6 alkyl group
  • W 1 is CH or a nitrogen atom
  • W 2 is an oxygen atom or a sulfur atom
  • Y 1 is C 1-6 alkylene
  • Z 1 is a hydrogen atom, a C 1-6 alkyl group or a
  • A is a group selected from the group consisting of the following a1), a2), b1), c1), d1) and d2) Zolopyridine derivative or a pharmacologically acceptable salt thereof.
  • R a has the same meaning as described above.
  • a bond marked with (*) binds to Y 1
  • a bond marked with (**) denotes bonded to R 1 .
  • A is a group selected from the group consisting of the following a1), b1) and c1): Its pharmacologically acceptable salt.
  • R a has the same meaning as described above.
  • a bond marked with (*) binds to Y 1
  • a bond marked with (**) denotes bonded to R 1 .
  • R 3 is a hydrogen atom, a halogen atom, a cyano group, a C 5-8 cycloalkenyl group, a C 2-6 alkenyl group, an acetyl group, a trifluoromethyl group, a methyl group or
  • R 2 is selected from the group consisting of A), B), C1), D1), D2), E), F1), F2), and F3) below.
  • a pyrazolopyridine derivative or a pharmaceutically acceptable salt thereof according to any one of [1] to [8].
  • the compound represented by the general formula (I) is: 5-methyl-1-[(2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -1H-pyrazole-3-carboxylic acid, 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[(5-chloro-2-phenylpyrazolo [1,5-a] pyridin-7-yl) methyl] -5-methyl-N- (methylsulfonyl) -1H-pyrazole-3-carboxamide, 5-chloro-7-[[5-methyl-3- (2H-tetrazol-5-yl) -1H-pyrazol-1-yl] methyl] -2-phenylpyrazolo [1,5-a] pyridine, 2-[(5-chloro-2-phenylpyrazolo [
  • a medicament comprising the pyrazolopyridine derivative or the pharmaceutically acceptable salt thereof according to any one of [1] to [10].
  • a therapeutic or prophylactic agent for lower urinary tract symptoms comprising the pyrazolopyridine derivative or the pharmacologically acceptable salt thereof according to any one of [1] to [10].
  • a method for treating or preventing a lower urinary tract symptom comprising administering to a patient the pyrazolopyridine derivative or the pharmacologically acceptable salt thereof according to any one of [1] to [10] .
  • a pyrazolopyridine derivative or a pharmacologically acceptable salt thereof according to any one of [1] to [10] for producing a medicament for preventing or treating lower urinary tract symptoms Use of.
  • a novel compound having an EP 1 receptor antagonistic action can be provided.
  • This embodiment relates to a pyrazolopyridine derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
  • A is a group selected from the group consisting of a) to d) below:
  • R a is a group selected from the group consisting of e) to g) below: e) a hydrogen atom f) a halogen atom g) a C 1-6 alkyl group
  • W 1 is CH or a nitrogen atom
  • W 2 is an oxygen atom or a sulfur atom
  • Y 1 is C 1-6 alkylene
  • Z 1 is a hydrogen atom, a C 1-6 alkyl group or a
  • a bond marked with (*) binds to Y 1, and a bond marked with (**) denotes bonded to R 1 .
  • Z 2 or Z 3 is an aryl group having a substituent, the aryl group has one or more (for example, 2 to 5) substituents. When the aryl group has a plurality of substituents, these substituents may be the same or different. Of course, Z 2 and Z 3 may be the same or different.
  • R 2 is an aryl group having a substituent, the aryl group has one or a plurality of (for example, 2 to 5) substituents. When the aryl group has a plurality of substituents, these substituents may be the same or different.
  • “independently” means that they may be the same or different between two or more substituents that may be present.
  • C 1-6 alkylene means a divalent straight chain or branched saturated hydrocarbon chain having 1 to 6 carbon atoms.
  • C 1-6 alkylene for example, —CH 2 —, — (CH 2 ) 2 —, —CH (CH 3 ) —, — (CH 2 ) 3 —, —CH (CH 3 ) CH 2 —, —CH 2 CH (CH 3 ) —, —CH (CH 2 CH 3 ) —, —C (CH 3 ) 2 —, — (CH 2 ) 4 —, —CH (CH 3 ) — (CH 2 ) 2 —, — (CH 2 ) 2 —CH (CH 3 ) —, —CH (CH 2 CH 3 ) —CH 2 —, —C (CH 3 ) 2 CH 2 —, —CH 2 —C (CH 3 ) 2 —, — CH (CH 3 ) —CH (CH 3 ) —, — (CH 2 —
  • C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms.
  • Examples of the C 1-6 alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, and 1-methylbutyl.
  • 2-methylbutyl group 1,2-dimethylpropyl group, 1-ethylpropyl group, hexyl group, isohexyl group and the like.
  • isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, and 1-ethylpropyl group are used.
  • the “C 1-9 alkyl group” means a linear or branched alkyl group having 1 to 9 carbon atoms. Examples of the C 1-9 alkyl group include a heptyl group, isoheptyl group, octyl group, isooctyl group, nonyl group, isononyl group and the like in addition to the above alkyl group.
  • the “C 2-6 alkenyl group” means a straight or branched unsaturated hydrocarbon group having 2 to 6 carbon atoms having at least one double bond.
  • Examples of the C 2-6 alkenyl group include a vinyl group, 2-propenyl group, 1-propenyl group, 1-buten-1-yl group, 1-buten-2-yl group, 1-buten-3-yl group, 1-buten-4-yl group, 2-buten-1-yl group, 2-buten-2-yl group, 1-penten-1-yl group, 1-penten-2-yl group, 1-pentene-3 -Yl group, 2-penten-1-yl group, 2-penten-2-yl group, 2-penten-3-yl group, 1-hexen-1-yl group, 1-hexen-2-yl group, -Hexen-3-yl group, 2-methyl-1-propen-1-yl group and the like.
  • the “C 5-8 cycloalkenyl group” means a monocyclic unsaturated alicyclic hydrocarbon group having 5 to 8 carbon atoms.
  • Examples of the C 5-8 cycloalkenyl group include a cyclopenten-1-yl group, a cyclohexen-1-yl group, a cyclohepten-1-yl group, and a cycloocten-1-yl group.
  • Halogen atom includes fluorine atom, chlorine atom, bromine atom and iodine atom.
  • the “C 1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms.
  • Examples of the C 1-6 alkoxy group include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an isobutoxy group, a butoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, and a hexyloxy group.
  • a methoxy group and an ethoxy group are mentioned.
  • the “C 1-7 alkanoyl group” means an acyl group derived from a linear or branched aliphatic carboxylic acid having 1 to 7 carbon atoms.
  • Examples of the C 1-7 alkanoyl group include formyl group, acetyl group, propanoyl group, butanoyl group, pentanoyl group, hexanoyl group and the like.
  • C 7-10 aralkyl group means an alkyl group having 1 to 4 carbon atoms substituted with a phenyl group.
  • Examples of the C 7-10 aralkyl group include benzyl group, phenethyl group, 1-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group and the like.
  • halo C 1-6 alkyl group means a C 1-6 alkyl group substituted with 1 to 5 same or different halogen atoms.
  • examples of the halo C 1-6 alkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 2-chloroethyl group, a 2,2-difluoroethyl group, and a 1,1-difluoroethyl group.
  • a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl group are mentioned.
  • C 3-6 cycloalkyl group means a monocyclic saturated alicyclic hydrocarbon group having 3 to 6 carbon atoms.
  • C 3-6 cycloalkyl groups for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group.
  • C 3-6 cycloalkyl group in which the ring is substituted with one C 1-6 alkyl group refers to the above C 3-6 cycloalkyl group in which the ring is substituted with the above C 1-6 alkyl group.
  • Examples of the C 3-6 cycloalkyl group in which the ring is substituted with one C 1-6 alkyl group include a 1-methylcyclopropyl group, a 1-ethylcyclopropyl group, a 1-methylcyclobutyl group, and a 2-methylcyclo Examples include a butyl group, 1-methylcyclopentyl group, 2-methylcyclopentyl group, 1-methylcyclohexyl group, 2-methylcyclohexyl group and the like.
  • a 1-methylcyclopropyl group and a 1-ethylcyclopropyl group are preferable, and a 1-methylcyclopropyl group is more preferable.
  • the “C 7-10 aralkyloxy group” means an alkoxy group having 1 to 4 carbon atoms substituted with a phenyl group.
  • Examples of the C 7-10 aralkyloxy group include a benzyloxy group, a phenethyloxy group, a 1-phenylethyloxy group, a 3-phenylpropyloxy group, and a 4-phenylbutyloxy group.
  • (C 1-6 alkoxy) carbonylamino group means a linear or branched alkoxycarbonylamino group having 1 to 6 carbon atoms.
  • (C 1-6 alkoxy) carbonylamino group includes, for example, methoxycarbonylamino group, ethoxycarbonylamino group, propoxycarbonylamino group, isopropoxycarbonylamino group, isobutoxycarbonylamino group, butoxycarbonylamino group, sec-butoxycarbonyl Examples thereof include an amino group, a tert-butoxycarbonylamino group, a pentyloxycarbonylamino group, and a hexyloxycarbonylamino group. Preferable examples include methoxycarbonylamino group and tert-butoxycarbonylamino group.
  • aryl group means, for example, an aromatic hydrocarbon group having 6 to 14 carbon atoms such as a phenyl group, an indenyl group, a naphthyl group, a phenanthrenyl group, or an anthracenyl group.
  • C 6-10 aryl group is preferable, which means an aromatic hydrocarbon group having 6 to 10 carbon atoms, and examples thereof include a phenyl group, an indenyl group, and a naphthyl group.
  • Heterocyclic group means a 5- to 7-membered heterocyclic group containing 1 to 4 atoms selected from a sulfur atom, an oxygen atom, and a nitrogen atom.
  • heterocyclic groups include furyl, thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl Group, thiadiazolyl group, pyranyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group and other aromatic heterocyclic groups, pyrrolinyl group, imidazolinyl group, pyrazolinyl group, dihydropyranyl group and other unsaturated heterocyclic groups, and morpholinyl And saturated heterocyclic groups such as
  • heterocyclic group When the “heterocyclic group” is a condensed cyclic group, a monocyclic or condensed heterocyclic group and a cyclic group other than the heterocyclic ring may be condensed.
  • the heterocyclic group in which the heterocyclic group and other cyclic group other than the heterocyclic ring are condensed include, for example, an isobenzofuranyl group, a benzoxazolyl group, a benzoisoxazolyl group, a benzothiazolyl group, a benzo Isothiazolyl group, chromenyl group, chromanonyl group, xanthenyl group, phenoxathiinyl group, indolizinyl group, isoindolidinyl group, indolyl group, indazolyl group, purinyl group, quinolidinyl group, isoquinolyl group, quinolyl group, phthalazinyl group, Examples thereof include
  • the “(C 1-6 alkoxy) carbonyl group” means a linear or branched alkoxycarbonyl group having 1 to 6 carbon atoms.
  • (C 1-6 alkoxy) carbonyl group includes, for example, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, isobutoxycarbonyl group, butoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group , A pentyloxycarbonyl group, a hexyloxycarbonyl group, and the like.
  • an ethoxycarbonyl group is mentioned.
  • “5-membered aromatic heterocyclic group” means a 5-membered aromatic group containing 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur atoms in the ring. To do.
  • furyl group pyrrolyl group, thienyl group, imidazolyl group, pyrazolyl group, 1,2,4-triazolyl group, isothiazolyl group, isoxazolyl group, oxazolyl group, thiazolyl group, 1,3,4-oxadiazolyl group, 1,2 , 4-oxadiazolyl group and the like.
  • Examples of the “5-membered or 6-membered cyclic amino group” include groups selected from the group consisting of cyclic amino groups having the following structures.
  • it is a group selected from the group consisting of cyclic amino groups having the following structure.
  • the “acidic 5-membered heterocyclic group” means a 5-membered ring containing a nitrogen atom bonded to an acidic proton in the ring or a 5-membered nitrogen-containing heterocyclic ring having a phenolic hydroxyl group.
  • Examples of the acidic 5-membered heterocyclic group include groups selected from the group consisting of 5-membered nitrogen-containing heterocyclic groups having the following structures.
  • it is a group selected from the group consisting of a 5-membered nitrogen-containing heterocyclic group having the structure shown below.
  • 6-membered ring group substituted with phenolic hydroxyl group means a 6-membered heterocyclic group or aromatic ring group having a phenolic hydroxyl group.
  • 6-membered ring group substituted with a phenolic hydroxyl group include groups selected from the group consisting of 6-membered ring groups having the following structures.
  • any 6-membered cyclic group having the structure shown below is exemplified.
  • A is preferably a group represented by a) wherein W 1 is CH or a nitrogen atom, a group represented by b) wherein W 2 is an oxygen atom, W 1 is a nitrogen atom, and W 2 is oxygen
  • a group selected from the group consisting of a group represented by c) which is an atom and a group represented by d) wherein W 1 is CH or a nitrogen atom.
  • R a has the same meaning as described above.
  • A is more preferably a group selected from the group consisting of the following a1), a2), b1), c1), d1) and d2).
  • A is more preferably a group selected from the group consisting of a1), b1), c1), d1) and d2).
  • A is particularly preferably a group selected from the group consisting of a1), b1) and c1).
  • R a is preferably a hydrogen atom or a C 1-6 alkyl group.
  • Y 1 is preferably methylene.
  • R 1 is preferably —C ( ⁇ O) —OZ 1 , —C ( ⁇ O) —NHSO 2 Z 2 or an acidic 5-membered heterocyclic group. More preferably, R 1 is —C ( ⁇ O) —OZ 1 , —C ( ⁇ O) —NHSO 2 Z 2 or a tetrazolyl group. Furthermore, when R 1 is —C ( ⁇ O) —OZ 1 , Z 1 is a hydrogen atom or a C 1-6 alkyl group, and R 1 is —C ( ⁇ O) —NHSO 2 Z 2 In some cases, Z 2 is preferably a C 1-6 alkyl group. R 1 is particularly preferably —C ( ⁇ O) —OH, —C ( ⁇ O) —OEt, —C ( ⁇ O) —NHSO 2 Me, or a 5-tetrazolyl group.
  • R 2 is preferably a C 1-6 alkyl group, unsubstituted or a C 3-6 cycloalkyl group substituted with one C 1-6 alkyl group, unsubstituted or halogen atom, 1 or 2 C Amino group substituted with 1-6 alkyl group, C 1-9 alkyl group, halo C 1-6 alkyl group, C 1-6 alkoxy group, C 1-7 alkanoyl group, C 7-10 aralkyloxy group, aryl An aryl group in which the ring is substituted with a group selected from the group consisting of a group, a (C 1-6 alkoxy) carbonylamino group, and a carboxyl group, a 5-membered aromatic heterocyclic group, 1 or 2 C 1 An amino group substituted with a -6 alkyl group, or a 5- or 6-membered cyclic amino group.
  • R 2 is more preferably a C 1-6 alkyl group, an unsubstituted or C 3-6 cycloalkyl group in which the ring is substituted by one C 1-6 alkyl group, an unsubstituted or halogen atom, 1 or 2
  • R 2 is more preferably a C 1-6 alkyl group, an unsubstituted or C 3-6 cycloalkyl group in which the ring is substituted with one C 1-6 alkyl group, a phenyl group, or a halogen atom.
  • R 2 is particularly preferably a cyclohexyl group, 1-methylcyclopropyl group, phenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 2-methylphenyl group, 3- A methylphenyl group, 3- (trifluoromethyl) phenyl group, 3-thienyl group, dimethylamino group, diethylamino group,
  • R 3 is preferably a hydrogen atom, a halogen atom, a cyano group, a C 2-6 alkenyl group, a C 1-7 alkanoyl group, a C 5-8 cycloalkenyl group, a C 1-6 alkyl group, or a haloC 1-6 alkyl. Or a C 1-6 alkoxy group.
  • R 3 is more preferably a hydrogen atom, a halogen atom, a cyano group, a C 2-6 alkenyl group, an acetyl group, a C 5-8 cycloalkenyl group, a methyl group, a trifluoromethyl group, or a methoxy group.
  • R 3 is particularly preferably a hydrogen atom, chlorine atom, bromine atom, cyano group, vinyl group, 2-propenyl group, acetyl group, methyl group, trifluoromethyl group, or methoxy group.
  • R 4 is preferably a hydrogen atom.
  • R 5 is preferably a hydrogen atom.
  • the pharmacologically acceptable salt of Compound (I) means a salt of Compound (I) with a pharmaceutically acceptable non-toxic base or acid (for example, an inorganic or organic base and an inorganic or organic acid).
  • a pharmaceutically acceptable non-toxic base or acid for example, an inorganic or organic base and an inorganic or organic acid.
  • the salt derived from a pharmaceutically acceptable non-toxic base of compound (I) include aluminum, ammonium, calcium, copper, ferrous, ferric, lithium, magnesium, manganese, manganite, potassium and sodium.
  • Salts with inorganic bases are ammonium, calcium, manganese, potassium and sodium salts or primary amines, secondary amines, tertiary amines, substituted amines (eg naturally occurring substitutions) Amines), cyclic amines, and organic bases such as basic ion exchange resins (eg, arginine, betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanol) Amine, ethylenediamine, N-ethylmorpholine, N -Ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl
  • Examples of the salt derived from a pharmaceutically acceptable non-toxic acid of compound (I) include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid and lactic acid. And salts with organic acids such as malic acid, tartaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid and palmitic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid, or acetic acid, maleic acid, fumaric acid, succinic acid and lactic acid.
  • salts with organic acids such as malic acid, tartaric acid, citric acid, methanesulfonic acid, p-toluenesulfonic acid, salicylic acid, stearic acid and palmitic acid.
  • the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof may exist as a hydrate or a solvate.
  • Any hydrate and solvate formed by the pyrazolopyridine derivative represented by the general formula (I) or a salt thereof including the preferred compounds specifically described above are within the scope of the present invention. Is included.
  • Solvents that can form solvates include methanol, ethanol, 2-propanol, acetone, ethyl acetate, dichloromethane, diisopropyl ether, and the like.
  • the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof may have an optically active substance, a stereoisomer, or a rotational isomer in addition to the racemate.
  • proton tautomers may exist in the compound (I) of the present embodiment or a pharmaceutically acceptable salt thereof.
  • EP 1 receptor antagonism means an action of inhibiting the binding of prostaglandin E 2 (PGE 2 ) to prostaglandin E receptor 1 (EP 1 receptor).
  • EP 1 receptor antagonism decreases the amount of calcium inflow into the cell and decreases or suppresses the intracellular calcium concentration. As a result, effects such as smooth muscle relaxation and sensory nerve stimulation inhibitory action are induced by the EP 1 receptor antagonistic action.
  • EP 1 receptor antagonism occurs in the bladder, urothelium and the like, which is useful for the treatment or prevention of symptoms such as LUTS, especially OABs.
  • the EP 1 receptor antagonism can be evaluated by the potency of inhibiting the amount of calcium inflow into cells by the stimulating action of PGE 2 on the EP 1 receptor.
  • This efficacy can be evaluated by an in vitro test or an in vivo test according to “Pharmacological Test Examples” described in JP-A-2008-214224.
  • Compound (I) of the present embodiment can be produced by various synthesis methods. Next, a typical production method of the compound (I) of this embodiment will be described.
  • R 2 , R 3 , R 4 , R 5 and A are as defined above;
  • X represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group and the like;
  • Q 1 Represents a C 1-6 alkyl group or a C 7-10 aralkyl group;
  • Q 2 and Q 3 independently represent a hydrogen atom, a C 1-6 alkyl group or the like. When Q 2 and Q 3 are C 1-6 alkyl groups, Q 2 and Q 3 may be bonded to form a ring.
  • Step 1-1 This step is a step for producing compound (2) by formylating compound (1).
  • Compound (2) can be produced, for example, by treating compound (1) with a base such as a lithium salt in a solvent and reacting with N, N-dimethylformamide or the like.
  • a base such as a lithium salt
  • the solvent used include tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, and it is preferably carried out at ⁇ 78 ° C. to 0 ° C.
  • the base such as lithium salt used include bases such as n-butyllithium.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1-2 This step is a step of producing compound (3) by reducing the aldehyde moiety of compound (2).
  • Compound (3) can be produced, for example, by reacting compound (2) with a reducing agent in a solvent.
  • the solvent used include tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, propanol, 2-propanol, butanol, water, a mixed solvent thereof and the like.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, and it is preferably carried out at ⁇ 78 ° C. to 0 ° C.
  • the reducing agent used include reducing agents such as sodium borohydride and lithium aluminum hydride.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1-3 is a step for producing a compound (3) by introducing a hydroxymethyl group into the compound (1).
  • Compound (3) can be produced, for example, by treating compound (1) with a base such as a lithium salt in a solvent to lithiate, and then reacting the resulting compound with paraformaldehyde.
  • a base such as a lithium salt
  • the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like.
  • the lithium salt used include lithium diisopropylamide, n-butyllithium, sec-butyllithium and the like.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, and is preferably carried out at ⁇ 78 ° C. to 20 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1-4 This step is a step for producing the compound (4) by converting the hydroxy group of the compound (3) into an appropriate leaving group (X).
  • Compound (4) can be produced, for example, by chlorinating compound (3) using thionyl chloride or the like in a solvent when X is a chlorine atom.
  • the solvent used include thionyl chloride, dichloromethane, chloroform, benzene, toluene, N, N, -dimethylformamide, tetrahydrofuran, pyridine, diethyl ether, a mixed solvent thereof and the like.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (4) is produced by reacting a brominating agent such as carbon tetrabromide and a phosphorus reagent such as triphenylphosphine with a compound (3) in a solvent. can do.
  • the solvent used include dichloromethane and the like.
  • the brominating agent used include carbon tetrabromide.
  • Examples of the phosphorus reagent used include triphenylphosphine.
  • the reaction temperature is usually 0 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1-5 This step is a step for producing compound (Ia) by reacting compound (4) with compound (5).
  • Compound (Ia) can be produced, for example, by treating compound (5) with a base in solvent A and reacting with compound (4) dissolved in solvent B.
  • solvent A used include dichloromethane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, N, N-dimethylformamide, 1,4-dioxane, acetonitrile, a mixed solvent thereof and the like.
  • Examples of the solvent B used include dichloromethane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, N, N-dimethylformamide, 1,4-dioxane, acetonitrile, a mixed solvent thereof and the like.
  • As the base to be used sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3. 0] non-5-ene (DBN) and the like can be used.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to the solvent reflux temperature, preferably at ⁇ 20 ° C. to 20 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1-6 This step is a step for producing compound (Ia) by reacting compound (4) with compound (6).
  • Compound (Ia) can be produced, for example, by reacting compound (4) and compound (6) in a solvent and using a palladium reagent as a catalyst in the presence or absence of a base.
  • Solvents used include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, and mixtures thereof A solvent etc. are mentioned.
  • Examples of the palladium catalyst to be used include dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), and the like.
  • Examples of the base used include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and the like. Is mentioned.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1-7 This step is a step for producing compound (Ia) by reacting compound (1) with compound (7).
  • Compound (Ia) is obtained by, for example, lithiating compound (1) using a lithium salt or the like in a solvent, and reacting zinc iodide with the resulting compound to form a zinc complex in the presence or absence of a palladium catalyst. It can be produced by reacting the obtained zinc complex with the compound (7).
  • the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like.
  • Examples of the lithium salt used include lithium diisopropylamide, n-butyllithium, sec-butyllithium and the like.
  • Examples of the palladium catalyst used include tetrakis (triphenylphosphine) palladium (0).
  • the reaction temperature can usually be carried out at -78 ° C to 20 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1-8 This step is a step of producing compound (Ib) by hydrolyzing the ester moiety of compound (Ia).
  • Compound (Ib) can be produced, for example, by reacting compound (Ia) with a base in a solvent.
  • the solvent used include tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, propanol, 2-propanol, butanol, water, a mixed solvent thereof and the like.
  • the reaction temperature is usually 0 ° C. to solvent reflux temperature.
  • the base used include alkali metal salts such as potassium hydroxide and sodium hydroxide.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (1) can be obtained, for example, by any of the following methods a, b, c, and d.
  • R 2 , R 3 , R 4 , R 5 and Q 1 are as defined above;
  • L 1 represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, etc .;
  • L 2 is an iodine atom , Mesitylsulfonyloxy group, methanesulfonyloxy group, trifluoromethanesulfonyloxy group, acetyloxy group and the like.
  • Step 2-1 This step is a step of producing compound (10) by reacting compound (8) with compound (9).
  • Compound (10) is obtained by, for example, treating a bromo compound obtained by reacting compound (8) with carbon tetrabromide and triphenylphosphine in solvent A with a base such as n-butyllithium in solvent B. It can be produced by lithiation and subsequent reaction of the compound obtained with compound (9).
  • the solvent A used include dichloromethane, 1,2-dichloroethane, benzene, toluene, tetrahydrofuran, a mixed solvent thereof and the like.
  • Examples of the solvent B used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to the solvent reflux temperature, preferably at ⁇ 20 ° C. to 20 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compounds (8) and (9) used in this step commercially available products can be used, and other methods described in the literature or a method analogous thereto can also be used.
  • Step 2-2 This step is a step for producing a compound (12) by N-amination of the compound (11).
  • Compound (12) can be produced, for example, by reacting compound (11) with ethyl O-mesitylsulfonylacetohydroxamate or the like in a solvent in the presence of an acid such as perchloric acid.
  • an acid such as perchloric acid.
  • compound (12) can be obtained as mesityl sulfonate.
  • the solvent used include 1,4-dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, a mixed solvent thereof and the like.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to the solvent reflux temperature, preferably at ⁇ 20 ° C. to 20 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (11) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, or the method according to them.
  • Step 2-3 is a step of producing compound (13) by reacting compound (10) with compound (12).
  • Compound (13) can be produced, for example, by reacting compound (10) and compound (12) in the presence of a base in a solvent.
  • the solvent used include methanol, ethanol, 2-propanol, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to the solvent reflux temperature, preferably at ⁇ 20 ° C. to 20 ° C.
  • the base used include potassium carbonate and sodium carbonate.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (10) and compound (12) used in this step those obtained in Step 2-1 and Step 2-2 can be used, and commercially available products can be used.
  • Step 2-4 is a step of producing compound (14) by hydrolyzing the ester moiety of compound (13).
  • Compound (14) can be produced, for example, by reacting compound (13) with a base in a solvent.
  • the solvent used include tetrahydrofuran, 1,4-dioxane, diethyl ether, methanol, ethanol, propanol, 2-propanol, butanol, water and the like.
  • the reaction temperature is usually 0 ° C. to solvent reflux temperature.
  • the base used include alkali metal salts such as potassium hydroxide and sodium hydroxide.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 2-5 This step is a step of producing compound (1) by decarboxylation of compound (14).
  • Compound (1) can be produced, for example, by subjecting compound (14) to a temperature condition in which decarboxylation occurs in a solvent in the presence or absence of an acid.
  • the solvent used include 1,2-dichlorobenzene, diphenyl ether, xylene, toluene, ethanol and the like.
  • the acid used include concentrated sulfuric acid.
  • the reaction temperature is usually from 50 ° C. to the solvent reflux temperature, preferably from 100 ° C. to 180 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • R 2 , R 3 , R 4 , R 5 and Q 1 are as defined above.
  • Step 3-1 This step is a step of producing compound (17) by reacting compound (15) with compound (16).
  • Compound (17) can be produced, for example, by reacting compound (15) and compound (16) in a solvent in the presence of a base.
  • the solvent used include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, diethyl ether, dimethyl sulfoxide, N, N-dimethylformamide, a mixed solvent thereof and the like.
  • Examples of the base used include lithium hexamethyldisilazide, potassium hexamethyldisilazide, sodium hexamethyldisilazide, sodium amide, potassium amide and the like.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 20 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (15) and (16) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, or the method according to them.
  • Step 3-2 This step is a step for producing compound (1) by reacting compound (17) with an aminating agent.
  • Compound (1) can be produced, for example, by reacting compound (17) with an aminating agent in a solvent and then cyclizing the compound obtained in the presence or absence of a base.
  • the solvent used include methanol, ethanol, 2-propanol, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to the solvent reflux temperature, preferably at ⁇ 20 ° C. to 20 ° C.
  • aminating agent used examples include ethyl O-mesitylsulfonylacetohydroxamic acid.
  • base used include potassium carbonate and sodium carbonate.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 3-3 is a step for producing compound (18) by reacting compound (17) with hydroxylamine.
  • Compound (18) can be produced, for example, by reacting compound (17) with hydroxylamine hydrochloride in the presence of a base in a solvent.
  • the solvent used include methanol, ethanol, N, N-dimethylformamide, a mixed solvent thereof and the like.
  • the base used include sodium hydroxide and potassium hydroxide.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 50 ° C. to the solvent reflux temperature.
  • Step 3-4 This step is a step of producing compound (1) by intramolecular cyclization of compound (18).
  • Compound (1) is produced, for example, by allowing an acid anhydride such as trifluoroacetic anhydride and a base to act on compound (18) in a solvent and then reacting a metal salt such as iron (II) chloride. can do.
  • a metal salt such as iron (II) chloride.
  • the solvent used include 1,2-dimethoxyethane.
  • Examples of the base used include triethylamine.
  • the metal salt used include iron (II) chloride and iron (III) chloride.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 0 ° C. to solvent reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • R 2 , R 3 , R 4 , R 5 , L 2 , Q 1 , Q 2 and Q 3 are as defined above.
  • Step 4-1 This step is a step of producing compound (20) by reacting compound (12) with compound (19).
  • Compound (20) can be produced, for example, by reacting compound (12) and compound (19) in the presence of a base in a solvent.
  • the solvent used include methanol, ethanol, 2-propanol, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to the solvent reflux temperature, preferably at ⁇ 20 ° C. to 20 ° C.
  • the base used include potassium carbonate and sodium carbonate.
  • reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Compound (12) and compound (19) used in this step can be commercially available products, and can also be produced according to other methods described in the literature or a method analogous thereto.
  • Step 4-2 This step is a step of producing compound (21) by hydrolyzing the ester moiety of compound (20). This step can be performed according to the above-mentioned method a, step 2-4.
  • Step 4-3 This step is a step of producing compound (22) by decarboxylation of compound (21). This step can be performed according to the above-mentioned method a, step 2-5.
  • Step 4-4 is a step of producing compound (23) by substituting the amino group of compound (22) with a hydroxyl group.
  • Compound (23) can be produced, for example, by treating compound (22) with an acid in a solvent.
  • the solvent used include water.
  • the acid include hydrochloric acid, sulfuric acid, phosphoric acid and the like.
  • the reaction temperature can usually be carried out at 20 ° C. to solvent reflux temperature, and is preferably carried out at 100 ° C. to solvent reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 4-5 is a step of producing the compound (24) by trifluoromethanesulfonylation of the hydroxyl group of the compound (23).
  • Compound (24) can be produced, for example, by reacting compound (23) with a trifluoromethanesulfonylating agent in the presence of a base in a solvent.
  • the solvent used include dichloromethane, 1,2-dichloroethane, pyridine, tetrahydrofuran, N, N-dimethylformamide, 1,4-dioxane, acetonitrile, diethyl ether, a mixed solvent thereof and the like.
  • Examples of the trifluoromethanesulfonylating agent include N-phenylbis (trifluoromethanesulfonimide) and trifluoromethanesulfonic anhydride.
  • Examples of the base include potassium carbonate, sodium carbonate, sodium hydride, potassium phosphate, N, N-diisopropylethylamine, triethylamine, 2,6-lutidine and the like.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to the solvent reflux temperature, preferably at ⁇ 20 ° C. to 20 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 4-6 This step is a step for producing the compound (1) by substituting the trifluoromethanesulfonate portion of the compound (24) with R 2 .
  • Compound (1) can be produced, for example, by reacting compound (24) and compound (25) in a solvent and using a palladium reagent as a catalyst in the presence of a base.
  • Solvents used include tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, water A mixed solvent etc. are mentioned.
  • Examples of the palladium catalyst to be used include dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), and the like.
  • Examples of the base used include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and the like. Is mentioned.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 20 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • R 2 , R 3 , R 4 and R 5 are as defined above.
  • Step 5-1 This step is a step of producing compound (28) by reacting compound (26) with compound (27).
  • Compound (28) can be produced, for example, by reacting compound (26) and compound (27) in the presence of a palladium catalyst, a copper catalyst, and a base in a solvent.
  • a palladium catalyst examples include methanol, ethanol, 2-propanol, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 20 ° C.
  • the palladium catalyst used include dichlorobis (triphenylphosphine) palladium (II).
  • Examples of the copper catalyst used include copper (I) iodide.
  • Examples of the base used include triethylamine.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (26) and compound (27) used at this process can use a commercial item, and can also manufacture them according to the method of other literature description, or the method according to them.
  • Step 5-2 In this step, compound (28) is reacted with an aminating agent and then cyclized to produce compound (1). This step can be performed according to the above-mentioned method b, step 3-2.
  • Method B Among the compounds (I), the compounds (Ia) and (Ib) can also be produced, for example, by Method B described below.
  • R 2 , R 3 , R 4 , R 5 , A, Q 1 , Q 2 and Q 3 are as defined above;
  • X 1 and X 2 are each independently a chlorine atom, bromine atom, iodine An atom, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, etc. are shown.
  • Step 6-1 is a step for producing compound (30) by cyanating X 1 contained in compound (29).
  • Compound (30) can be produced, for example, by reacting compound (29) with a cyanating agent in a solvent.
  • the cyanating agent include potassium cyanide and sodium cyanide.
  • the solvent used include dimethyl sulfoxide.
  • the reaction temperature can usually be -78 ° C to 100 ° C, preferably 0 ° C to 50 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (29) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, or the method according to them.
  • Step 6-2 This step is a step for producing compound (31) by reducing the ester moiety of compound (30).
  • Compound (31) can be produced, for example, by reacting compound (30) with a reducing agent such as sodium borohydride in a solvent.
  • a reducing agent such as sodium borohydride
  • the solvent used include methanol, ethanol, tetrahydrofuran, water, a mixed solvent thereof and the like.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 0 ° C. to solvent reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 6-3 is a step for producing compound (32) by reacting compound (31) with an aminating agent. This step can be performed according to the above-mentioned method b, step 3-2.
  • Step 6-4 This step is a step for producing a compound (33) by converting the amino group of the compound (32) into a hydroxyl group. This step can be performed according to the above-mentioned method c, step 4-4.
  • Step 6-5 This step is to introduce the leaving group represented by the general formula X 2 in the compound (33) is a step for preparing a compound (34).
  • Compound (34) is produced, for example, by reacting compound (33) with a brominating agent such as carbon tetrabromide and a phosphorus reagent such as triphenylphosphine in a solvent when X 2 is a bromine atom. Can do. Examples of the solvent used include dichloromethane and the like. Examples of the brominating agent used include carbon tetrabromide. Examples of the phosphorus reagent used include triphenylphosphine.
  • the reaction temperature is usually 0 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 6-6 is a step for producing a compound (35) by converting a hydrogen atom in the hydroxyl group of the compound (34) into a trifluoromethanesulfonyl group or the like to obtain a trifluoromethanesulfonyloxy group or the like.
  • This step can be performed according to the above-mentioned method c, step 4-5.
  • Step 6-7 This step is a step for producing the compound (36) by converting the hydroxyl group of the compound (23) into a chlorine atom.
  • Compound (36) can be produced, for example, by reacting compound (23) with phosphorus oxychloride or the like. This reaction can be performed using, for example, a solution of compound (23) using phosphorus oxychloride or the like as a solvent.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to 200 ° C., preferably 100 ° C. to 150 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 6-8 This step is a step for producing a compound (37) by introducing a hydroxymethyl group into the compound (36). This step can be carried out according to the above-mentioned method A, step 1-3.
  • Step 6-9 is a step for producing a compound (38) by converting the hydroxyl group of the compound (37) into an appropriate leaving group (X 2 ). This step can be performed according to the above-mentioned method A, step 1-4.
  • Step 6-10 compound (39) is produced by reacting compound (38) with compound (5).
  • This step can be performed according to the above-mentioned Method A, Step 1-5.
  • X 1 is a chlorine atom.
  • Step 6-11 compound (39) is produced by reacting compound (35) with compound (5).
  • This step can be performed according to the above-mentioned Method A, Step 1-5.
  • X 1 is a trifluoromethanesulfonyloxy group.
  • Step 6-12 This step is a step for producing compound (Ia) by reacting compound (39) with compound (25). This step can be performed according to the above-mentioned method c, step 4-6.
  • Step 6-13 This step is a step of producing compound (41) by cyanating X 1 contained in compound (40). This step can be performed according to the above-mentioned method B, step 6-1.
  • Step 6-14 This step is a step of producing compound (42) by reacting compound (41) with an aminating agent. This step can be performed according to the above-mentioned method B, step 6-3.
  • Step 6-15 In this step, compound (43) is produced by reacting compound (42) with compound (5). This step can be performed according to the above-mentioned Method A, Step 1-5.
  • Step 6-16 This step is a step of producing compound (Ia) by alkylating the primary amino group of compound (43) when R 2 site of compound (Ia) is a mono- or dialkylamino group or a cyclic amino group. is there.
  • Compound (Ia) can be produced, for example, by reacting compound (43) with an alkylating agent such as various alkyl halides in a solvent in the presence or absence of a base.
  • an alkylating agent such as various alkyl halides in a solvent in the presence or absence of a base.
  • alkylating agent include iodomethane, iodoethane, 1,4-dibromobutane and the like.
  • Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, N, N-dimethylformamide, dichloromethane, ethanol, diethyl ether, 1,2-dimethoxyethane, a mixed solvent thereof and the like.
  • Examples of the base used include sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate, triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine, Sodium hydride etc. are mentioned.
  • the reaction temperature can usually be carried out at ⁇ 20 ° C. to solvent reflux temperature, preferably 0 ° C. to solvent reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 6-17 This step is a step of producing compound (Ib) by hydrolyzing the ester moiety of compound (Ia). This step can be performed according to the above-mentioned Method A, Step 1-8.
  • R 2 , R 3 , R 4 , R 5 , A, Q 1 , Q 2 , Q 3 and X are as defined above.
  • Step 7-1 This step is a step of producing compound (3b) by demethylating the methoxy group of compound (3a).
  • Compound (3b) can be produced, for example, by treating compound (3a) with an acid in a solvent.
  • the solvent used include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, toluene, a mixed solvent thereof and the like.
  • the acid used include boron tribromide.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 20 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (3a) used in this step is one of the compounds (3), and can be produced, for example, by the above-described Method A, Step 1-1, 1-2 or Step 1-3. .
  • Step 7-2 This step is a step for producing the compound (4a) by converting the hydroxyl group of the compound (3b) into an appropriate leaving group (X). This step can be performed according to the above-mentioned method A, step 1-4.
  • Step 7-3 compound (44) is produced by reacting compound (4a) with compound (5).
  • This step can be performed according to the above-mentioned Method A, Step 1-5.
  • Step 7-4 is a step for producing the compound (45) by trifluoromethanesulfonylation of the hydroxyl group of the compound (44). This step can be performed according to the above-mentioned method c, step 4-5.
  • Step 7-5 This step is a step for producing compound (Ia) by reacting compound (45) with compound (46). This step can be performed according to the above-mentioned method c, step 4-6.
  • Step 7-6 is a step for producing compound (Ia) in which R 3 is a cyano group by reacting compound (45) with a cyanating agent.
  • R 3 of compound (Ia) is a cyano group
  • compound (Ia) is produced by reacting compound (45) with a cyanating agent in the presence of a palladium catalyst and a phosphorus ligand in a solvent.
  • the solvent used include tetrahydrofuran, N, N-dimethylformamide, water, a mixed solvent thereof and the like.
  • the cyanating agent used include zinc cyanide.
  • Examples of the palladium catalyst used include palladium (II) acetate and bis (dibenzylideneacetone) palladium (0).
  • Examples of the phosphorus ligand used include triphenylphosphine and 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 7-7 is a step for producing a compound (Ia) in which R 3 is an acetyl group by reacting the compound (45) with an acetylating agent.
  • R 3 of compound (Ia) is an acetyl group
  • compound (45) is subjected to a coupling reaction with vinyl ether using a palladium catalyst and a phosphorus ligand in the presence of a base in a solvent to produce vinyl ether.
  • compound (Ia) can be produced by hydrolyzing the resulting vinyl ether with an acid.
  • the solvent used for the coupling reaction include tetrahydrofuran, N, N-dimethylformamide, a mixed solvent thereof and the like.
  • Examples of the vinyl ether used include methyl vinyl ether and n-butyl vinyl ether.
  • Examples of the palladium catalyst used include palladium (II) acetate and bis (dibenzylideneacetone) palladium (0).
  • Examples of the phosphorus ligand used include triphenylphosphine and 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 60 ° C. to 100 ° C.
  • Examples of the solvent used for the hydrolysis reaction with an acid include 1,4-dioxane, water, a mixed solvent thereof and the like.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 60 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 7-8 This step is a step of producing compound (Ib) by hydrolyzing the ester moiety of compound (Ia). This step can be performed according to the above-mentioned Method A, Step 1-8.
  • Method D Of the compound (I), the following compound (Id) can be produced, for example, by Method D described below.
  • R 2 , R 3 , R 4 , R 5 and A are as defined above.
  • Step 8-1 This step is a step of producing compound (Id) from compound (Ic).
  • Compound (Id) can be produced, for example, by reacting compound (Ic) with hydroxylamine in a solvent in the presence of a base.
  • a base examples include ethanol.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C.
  • Examples of the base used include lithium hydroxide.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (Ic) used at this process is one of the compounds (Ib), for example, can be manufactured by the above-mentioned Method A or Method C.
  • R 2 , R 3 , R 4 , R 5 , A and Z 2 are as defined above.
  • Step 9-1 is a step of producing compound (47) from compound (Ib).
  • Compound (47) can be produced, for example, by reacting compound (Ib) with a compound serving as an amine source such as ammonium chloride in the presence of a condensing agent in a solvent in the presence or absence of a base.
  • a compound serving as an amine source such as ammonium chloride
  • a condensing agent such as ammonium chloride
  • a condensing agent such as ammonium chloride
  • solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, and mixed solvents thereof.
  • condensing agent used examples include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), 2- (1H-7-azabenzotriazol-1-yl) -1 1,3,3-tetramethyluronium hexafluorophosphate metanaminium (HATU) and the like.
  • EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • DCC dicyclohexylcarbodiimide
  • N, N-dimethylaminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT) or the like can also be used as a reaction accelerator.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux
  • the base used examples include potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine and the like.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 9-2 is a step of producing compound (If) from compound (47).
  • Compound (If) can be produced, for example, by reacting compound (47) with a compound such as ethanesulfonyl chloride in the presence of a base in a solvent.
  • a compound such as ethanesulfonyl chloride
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 30 ° C. to 70 ° C.
  • the base used include sodium hydride.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 9-3 is a step of producing compound (Ie) from compound (Ib).
  • Compound (Ie) can be produced, for example, by reacting compound (Ib) with cyanamide or the like in a solvent in the presence of a condensing agent and in the presence or absence of a base.
  • the solvent used include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, and mixed solvents thereof.
  • condensing agent used examples include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), 2- (1H-7-azabenzotriazol-1-yl) -1 1,3,3-tetramethyluronium hexafluorophosphate metanaminium (HATU) and the like.
  • EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • DCC dicyclohexylcarbodiimide
  • N, N-dimethylaminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT) or the like can also be used as a reaction accelerator.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux
  • potassium carbonate sodium carbonate
  • triethylamine N, N-diisopropylethylamine or the like
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 9-4 is a step of producing compound (If) by a condensation reaction of compound (Ib) and compound (48).
  • Compound (If) can be produced, for example, by reacting compound (Ib) with compound (48) in a solvent in the presence or absence of a base in the presence of a condensing agent.
  • the solvent used include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, and mixed solvents thereof.
  • condensing agent used examples include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), dicyclohexylcarbodiimide (DCC), 2- (1H-7-azabenzotriazol-1-yl) -1 1,3,3-tetramethyluronium hexafluorophosphate metanaminium (HATU) and the like.
  • EDCI 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
  • DCC dicyclohexylcarbodiimide
  • N, N-dimethylaminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT) or the like can also be used as a reaction accelerator.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature,
  • the base used examples include potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine and the like.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • R 2 , R 3 , R 4 , R 5 and A are as defined above.
  • Step 10-1 This step is a step of producing compound (49) by dehydration reaction of compound (47).
  • Compound (49) can be produced, for example, by reacting compound (47) with trifluoroacetic anhydride in the presence of a base in a solvent.
  • the solvent used include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, toluene, a mixed solvent thereof and the like.
  • the base to be used triethylamine or the like can be used.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 10-2 This step is a step for producing compound (Ig) by reaction of compound (49) with sodium azide.
  • Compound (Ig) can be produced, for example, by reacting compound (49) with sodium azide in a solvent in the presence of an acid such as zinc bromide. Examples of the solvent used include N, N-dimethylformamide.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 50 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 10-3 is a step of producing compound (50) by reaction of compound (49) with hydroxylamine.
  • Compound (50) can be produced, for example, by reacting compound (49) with hydroxylamine in a solvent.
  • the solvent used include ethanol.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 30 ° C. to solvent reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 10-4 This step is a step for producing compound (Ih) by reaction of compound (50) with ethyl chloroformate.
  • Compound (Ih) is obtained, for example, by reacting compound (50) with ethyl chloroformate or the like in solvent A in the presence of a base such as pyridine, and then reacting the resulting compound with 1,8-diazabicyclo [ 5.4.0] can be prepared by treatment with a base such as undec-7-ene (DBU).
  • a base such as undec-7-ene
  • the solvent A include N, N-dimethylformamide.
  • Examples of the solvent B include xylene.
  • the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 100 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 10-5 compound (Ii) is produced by reacting compound (50) with 1,1′-thiocarbonyldiimidazole.
  • Compound (Ii) can be produced, for example, by reacting compound (50) with 1,1′-thiocarbonyldiimidazole in a solvent and then treating the obtained compound with silica gel. Tetrahydrofuran etc. are mentioned as a solvent used.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 10-6 compound (Ij) is produced by reacting compound (50) with 1,1′-thiocarbonyldiimidazole.
  • Compound (Ij) can be produced, for example, by reacting compound (50) with 1,1′-thiocarbonyldiimidazole in the presence of a base in a solvent.
  • the solvent used include acetonitrile.
  • the base used include 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN) and the like. It is done.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 0 ° C. to 30 ° C.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • R 2 , R 3 , R 4 , R 5 , A, Q 2 , Q 3 and Z 3 are as defined above.
  • Step 11-1 This step is a step of producing compound (51) by converting the carboxylic acid moiety of compound (Ib) into an amino group protected with a Boc group.
  • Compound (51) can be produced, for example, by reacting compound (Ib) with diphenyl phosphate azide or the like in the presence of a base in a solvent.
  • the solvent used include tert-butanol.
  • the base used include triethylamine.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 30 ° C. to solvent reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 11-2 This step is a step of producing compound (52) by removing the Boc group of compound (51) by deprotection.
  • Compound (52) can be produced, for example, by treating compound (51) with an acid in a solvent.
  • the solvent used include tetrahydrofuran and 1,4-dioxane.
  • the acid used include hydrogen chloride-1,4-dioxane, trifluoroacetic acid and the like.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 30 ° C. to solvent reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 11-3 is a step for producing a compound (53) by converting the amino group of the compound (52) into an iodine atom.
  • Compound (53) can be produced, for example, by reacting compound (52) in a solvent with a compound that forms an iodine source such as potassium iodide and a compound that forms a diazonium ion in the presence of an acid.
  • a compound that forms an iodine source such as potassium iodide and a compound that forms a diazonium ion in the presence of an acid.
  • the solvent used include acetonitrile.
  • Examples of the compound serving as an iodine source include potassium iodide.
  • Examples of the compound that forms diazonium ions include sodium nitrite.
  • the acid used include p-toluenesulfonic acid.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to the solvent reflux temperature, preferably at ⁇ 78 °
  • Step 11-4 is a step of producing compound (55) by reacting the iodine moiety of compound (53) with compound (54).
  • This step can be performed according to the above-mentioned method c, step 4-6.
  • Compound (54) can be obtained from, for example, commercially available 5-bromo-1,3-difluoro-2- (methoxymethoxy) benzene as a starting material (Journal of Medicinal Chemistry (2011), 54 (2), 433- 448).
  • 5-bromo-1,3-difluoro-2- (methoxymethoxy) benzene is present in a solvent such as 1,4-dioxane, a palladium catalyst such as dichlorodiphenylphosphinoferrocenepalladium, and a base such as potassium ethylhexanoate.
  • a solvent such as 1,4-dioxane
  • a palladium catalyst such as dichlorodiphenylphosphinoferrocenepalladium
  • a base such as potassium ethylhexanoate.
  • 2- [3,5-difluoro-4- (methoxymethoxy) phenyl] -4,4,5,5-tetramethyl-1,3,2-dioxaborolane is prepared by reacting with bispinacol diboron. be able to.
  • Step 11-5 This step is a step of producing compound (Ik) by converting a methoxymethyloxy group of compound (55) into a hydroxyl group.
  • Compound (Ik) can be produced, for example, by reacting compound (55) with an acid such as hydrogen chloride in a solvent.
  • the solvent used include 1,4-dioxane.
  • the acid used include hydrogen chloride-1,4-dioxane.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 30 ° C. to solvent reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 11-6 This step is a step of producing compound (57) by reacting compound (53) with compound (56).
  • Compound (57) can be produced, for example, by reacting compound (53) and compound (56) in a solvent using a palladium reagent as a catalyst in the presence of a phosphorus ligand and a base.
  • the solvent used include tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like.
  • the palladium catalyst used include tris (dibenzylideneacetone) dipalladium (0).
  • Examples of the phosphorus ligand used include 4,5′-bis (diphenylphosphino) -9,9′-dimethylxanthene.
  • the base used examples include N, N-diisopropylethylamine.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 30 ° C. to solvent reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 11-7 This step is a step of producing compound (Il) by converting the methoxymethyloxy group of compound (57) into a hydroxyl group. This step can be performed according to the above-mentioned Method G, Step 11-5.
  • Step 11-8 This step is a step of producing compound (Im) by acylating compound (52).
  • Compound (Im) can be produced, for example, by reacting compound (52) with an acylating agent in a solvent in the presence or absence of a base.
  • the acylating agent used include acetic anhydride, acetyl chloride, and propionyl chloride.
  • the solvent used include tetrahydrofuran and pyridine.
  • Examples of the base used include triethylamine.
  • the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 0 ° C. to solvent reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the pharmacologically acceptable salt of compound (I) of this embodiment can be produced according to a conventional method using compound (I) of this embodiment.
  • the introduction and desorption operations can be appropriately combined according to a conventional method.
  • the type, introduction, and elimination of protecting groups see, for example, Theodora W. et al. Greene & Peter G. M.M. Edited by Wuts, “Greene's Protective Groups in Organic” Synthesis ", fourth edition, Wiley-Interscience, 2006.
  • the intermediate used for producing the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof may be isolated and purified by means well known to those skilled in the art, if necessary. It can be isolated and purified by certain solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography, and the like.
  • the pharmaceutical containing the compound (I) of this embodiment or a pharmacologically acceptable salt thereof The pharmaceutical containing the compound (I) of this embodiment or a pharmacologically acceptable salt thereof as an active ingredient
  • dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, sublinguals, etc. It is administered orally or parenterally.
  • medicaments are prepared by a known method according to the dosage form, as an active ingredient, compound (I) of the present embodiment or a pharmacologically acceptable salt thereof, a pharmacologically acceptable additive, It can comprise as a pharmaceutical composition containing this.
  • Additives contained in the pharmaceutical composition include excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stable agents.
  • An agent, a solubilizing agent, etc. can be mentioned.
  • the pharmaceutical composition comprises compound (I) of the present embodiment or a pharmacologically acceptable salt thereof and an appropriate additive appropriately mixed, or compound (I) or a pharmacologically acceptable salt thereof. It can be prepared by diluting and dissolving with additives. Further, when used in combination with drugs other than the EP 1 receptor antagonist, simultaneously or separately each of active ingredients, it can be prepared by formulating the same manner as described above.
  • Compound (I) or a pharmacologically acceptable salt of the present embodiment is an EP 1 receptor antagonistic confirmation test, etc. Shows strong EP 1 receptor antagonism. Therefore, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof can suppress or decrease the intracellular calcium concentration. Therefore, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is based on the EP 1 receptor antagonism confirmation test, and is a disease caused by activation of EP 1 receptor by PGE 2 stimulation. It can be used for the treatment, prevention, or suppression of symptoms.
  • Examples of the disease or symptom that activates the EP 1 receptor by PGE 2 stimulation include lower urinary tract symptoms (LUTS), inflammatory diseases, painful diseases, osteoporosis, cancer and the like. Therefore, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is used for the treatment, prevention or suppression of lower urinary tract symptoms (LUTS), inflammatory diseases, painful diseases, osteoporosis, cancer and the like. Can be used for Here, the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is preferably used for the treatment or prevention of LUTS, inflammatory disease or pain disease, and lower urinary tract symptoms More preferably it is used for the treatment or prevention of (LUTS).
  • the pharmaceutical composition containing the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof as an active ingredient has a disease or symptom caused by activation of EP 1 receptor by PGE 2 stimulating action. It can be used as a therapeutic or prophylactic agent.
  • the pharmaceutical composition containing the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof as an active ingredient includes lower urinary tract symptoms (LUTS), inflammatory diseases, pain diseases, It can be used as a therapeutic or prophylactic agent for diseases or symptoms such as osteoporosis and cancer.
  • the pharmaceutical composition according to the present embodiment is preferably used as a therapeutic or prophylactic agent for LUTS, inflammatory disease or pain disease, and more preferably used as a therapeutic or prophylactic agent for LUTS. preferable.
  • Examples of the causative diseases of lower urinary tract symptoms include overactive bladder (OAB), prostatic hypertrophy (BPH), cystitis such as interstitial cystitis, prostatitis and the like.
  • OAB overactive bladder
  • BPH prostatic hypertrophy
  • cystitis such as interstitial cystitis, prostatitis and the like.
  • “Lower urinary tract symptoms” means, for example, urine storage symptoms, urination symptoms, and post-urination symptoms.
  • the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is preferably used for the treatment or prevention of urine storage symptoms.
  • bladder perception such as increased perception, decreased bladder perception, lack of bladder perception, and nonspecific bladder perception.
  • Compound (I) or a pharmacologically acceptable salt thereof according to this embodiment includes urinary urgency, daytime frequent urination, nocturia, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturia, increased bladder perception Alternatively, it is preferably used for treatment or prevention of nonspecific bladder perception.
  • the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is used for the treatment or prevention of urgency, daytime frequent urination, nocturia, urinary urinary incontinence or increased bladder perception. Used for.
  • the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is particularly preferable for the treatment or prevention of OABs.
  • Compound (I) of the present embodiment or a pharmacologically acceptable salt thereof, or a combination thereof Compound (I) of the present embodiment or a pharmaceutically acceptable salt thereof is an EP 1 receptor antagonist It can also be used in combination with at least one kind of drug other than
  • Examples of the drug that can be used in combination with the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof include overactive bladder (OAB) and prostatic hypertrophy having a mechanism of action different from that of the EP 1 receptor antagonist.
  • OAB overactive bladder
  • prostatic hypertrophy having a mechanism of action different from that of the EP 1 receptor antagonist.
  • therapeutic agents for cystitis (BPH), cystitis such as interstitial cystitis, prostatitis and the like include interstitial cystitis, prostatitis and the like.
  • anticholinergic agents ⁇ 1 antagonists, ⁇ agonists, 5 ⁇ -reductase inhibitors, PDE inhibitors, progesterone hormones, antidiuretics, smooth muscle direct acting agents or tricyclic antidepressants.
  • the drug used in combination with the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof is specifically exemplified as follows. However, the contents of the present invention are not limited to these. In addition, specific compounds include free forms thereof and other pharmacologically acceptable salts.
  • anticholinergic agent examples include oxybutynin, propiverine, solifenacin, torte mouth gin, imidafenacin, temiverine, darifenacin, fesoterodine, trospium, propantelin and the like.
  • ⁇ 1 antagonist examples include urapidil, naphthopidyl, tamsulosin, silodosin, prazosin, terazosin, alfuzosin, doxazosin, CR-2991, feduxin and the like.
  • ⁇ agonist examples include mirabegron, KUC-7383, KRP-204, SM-350300, TRK-380, amibegron, clenbuterol, SAR-150640, sorabegron and the like.
  • Examples of the “5 ⁇ -reductase inhibitor” include dutasteride, TF-505, finasteride, and izonsteride.
  • PDE inhibitor means a phosphodiesterase inhibitor, and examples thereof include tadalafil, vardenafil, sildenafil, avanafil, UK-369003, T-0156, AKP-002, etazolate and the like.
  • acetylcholinesterase inhibitor examples include distigmine, donepezil, Z-338, rivastigmine, ganstigmine, BGC-20-1259, galantamine, itopride, NP-61, SPH-1286, tolserine, ZT-1 and the like.
  • anti-androgen examples include guestnolone, oxendron, bicalutamide, BMS-641988, CB-03-01, CH-489789, flutamide, MDV-3100, nilutamide, TAK-700, YM-580 and the like.
  • progesterone hormones include chromazinone and allylestrenol.
  • LH-RH analog means a gonadotropin releasing hormone analog. Gonadotropin releasing hormone may also be referred to as luteinizing hormone releasing hormone.
  • AEZS-108 buserelin, deslorelin, goserelin, histrelin, leuprorelin, lutropin, nafarelin, triptorelin, AEZS-019, cetrorelix, degarelix, elagorix, ganilelex, ozarelix, PTD-634, TAK-385, Taverix 448, TAK-683 and the like.
  • neurokinin inhibitor examples include KRP-103, aprepitant, AV-608, Casopitant, CP-122721, DNK-333, fosprepitant, LY-686017, netpitant, olbepitant, lolapitant, TA-5538, T-2328, Vestipitant, AZD-2624, Z-501, 1144814, MEN-15596, MEN-11420, SAR-102779, SAR-102279, Saleduant, SSR-241586, and the like.
  • antidiuretic examples include desmopressin, VA-106483 and the like.
  • calcium channel blockers include amlodipine, cilnidipine, puffer piverine, temiverine, PD-299685, alanidipine, azelnidipine, balnidipine, benidipine, bevantolol, clevidipine, CYC-381, diltiazem, efonidipine, fasudil, felodipine, gabamil Examples include isradipine, lacidipine, lercanidipine, lomerizine, manidipine, MEM-1003, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, SB-751689, verapamil, YM-58483, and ziconotide.
  • “Smooth muscle direct acting drugs” include flavoxate and the like.
  • tricyclic antidepressants examples include imipramine, clomipramine, amitriptyline and the like.
  • Examples of the “potassium channel modulator” include nicorandil, NIP-141, NS-4591, NS-1643, andlast, diazoxide, ICA-105665, minoxidil, pinacidil, tirisolol, VRX-698 and the like.
  • sodium channel blocker examples include bepridil, dronedarone, propafenone, safinamide, SUN-N8075, SMP-986, 1014802, 552-02, A-803467, brivaracetam, cibenzoline, eslicarbazepine, F-15845, flecainide Phosphenytoin, lacosamide, lamotrigine, levobupivacaine, M-58373, mexiletine, moracidin, nerispyridine, NW-3509, oxcarbazepine, pilsicainide, pirmenol, propafenone, NW-1029, ropivacaine, vanacarant, etc. it can.
  • H 1 blocker examples include acribastine, alcaftadine, bepotastine, bilastine, cetirizine, desloratadine, ebastine, efletirizine, epinastine, fexofenadine, GSK-835726, levocabastine, levocetirizine, loratadine, mequitadine, mizolastine, NBI-7, 43 -1869, terfenadine, UCB-35440, vapitadine, YM-344484, diphenhydramine, chlorpheniramine and the like.
  • “Serotonin reuptake inhibitors” include UCB-46331, 424887, AD-337, BGC-20-1259, BMS-505130, citalopram, dapoxetine, desvenlafaxine, DOV-102673, DOV-216303, DOV-21947 , Duloxetine, escitalopram, F-2695, F-98214-TA, fluoxetine, fluvoxamine, IDN-5491, milnacipran, minaprine, NS-2359, NSD-644, paroxetine, PF-184298, SD-726, SEP-225289 , SEP-227162, SEP-228425, SEP-228432, sertraline, sibutramine, tesofensin, tramadol, trazodone, UCB-46331, venlafa Singh, mention may be made Birazodon, the WAY-426, WF-516 and the like.
  • Examples of “norepinephrine reuptake inhibitors” include AD-337, desvenlafaxine, DOV-102677, DOV-216303, DOV-21947, duloxetine, F-2695, F-98214-TA, milnacipran, NS-2359 , NSD-644, PF-184298, SD-726, SEP-225289, SEP-227162, SEP-228425, SEP-228432, Sibutramine, Tesofensin, Tramadol, Venlafaxine, Bupropion, Radafaxin, Atomoxetine, DDP-225, LY -2216684, nevogramin, NRI-193, reboxetine, tapentadol, WAY-256805, WAY-260022, and the like.
  • Examples of the “dopamine reuptake inhibitor” include DOV-102777, DOV-216303, DOV-21947, IDN-5491, NS-2359, NSD-644, SEP-225289, SEP-228425, SEP-228432, sibutramine, tesofensin, Examples thereof include tramadol, brasofensin, bupropion, NS-27100, radafaxin, safinamide and the like.
  • GABA agonists include retigabine, eszopiclone, indipron, pagok mouth, SEP-225441, acamprosate, baclofen, AZD-7325, BL-1020, brotizolam, DP-VPA, progabide, propofol, topiramate, zopiclone EVT-201, AZD-3043, ganaxolone, NS-11394, albaclofen, AZD-3355, GS-39783, ADX-71441, ADX-71943, and the like.
  • TRPV1 modulators include force psaicin, resiniferatoxin, DE-096, GRC-6611, AMG-8562, JTS-653, SB-705498, A-4256619, A-784168, ABT-102, AMG- 628, AZD-1386, JNJ-17203212, NGD-8243, PF-386486, SAR-115740, SB-784243, and the like.
  • Endothelin antagonists include SB-234551, ACT-064992, ambrisentan, atrasentan, bosentan, clazosentan, darsentan, fundsentan, S-0139, TA-0201, TBC-3711, dibotentane, BMS-509701, PS -433540 and the like.
  • Examples of the “5-HT 1A antagonist” include espindolol, lecozotan, lurasidone, E-2110, REC-0206, SB-649915, WAY-426, WF-516 and the like.
  • ⁇ 1 agonist examples include CM-2236, armodafinil, midodrine, modafinil and the like.
  • Opioid agonists include morphine, TRK-130, DPI-125, DPI-3290, fentanyl, LIF-301, loperamide, loperamide oxide, remifentanil, tapentadol, WY-16225, oxycodone, PTI-202, PTI-721 ADL-5747, ADL-5589, DPI-221, DPI-353, IPP-102199, SN-11, ADL-10-0101, ADL-10-0116, asimadoline, buprenorphine, CR-665, CR-845, eptazosin Nalbuphine, nalflaphine, pentazocine, XEN-0548, W-212393, ZP-120, nalmefene and the like.
  • P 2 X antagonist examples include A-740003, AZ-1157312, AZD-9056, GSK-14482160, GSK-31481A and the like.
  • COX inhibitor means a cyclooxygenase inhibitor such as aceclofenac, ST-679, aspirin, bromfenac, dexketoprofen, flurbiprofen, FYO-750, ibuprofen, ketoprofen, ketorolac, lycoferon, lornoxicam, loxoprofen, LT -NS001, diclofenac, mofezolac, nabumetone, naproxen, oxaprozin, piroxicam, pranoprofen, suprofen, tenoxicam, thiaprofenic acid, tolfenamic acid, zaltoprofen, 644784, ABT-963, ajulemic acid, apricoxib, celecoxib, citricoxib, citricoxib Lumiracoxib, meloxicam, nimesulide, parecoxib, RO-26-21 8, it can be mentioned valdecoxib
  • Examples of the “ ⁇ agonist” include ANAVEX-27-1041, PRS-013, SA-4503, ANAVEX-2-73, silamesine, ANAVEX-7-1037, ANAVEX-1-41, and the like.
  • muscle agonists examples include AC-260584, cevimeline, MCD-386, NGX-267, NGX-292, subcomerin, pilocarpine, bethanechol and the like.
  • the present invention is selected from the following 1) to 5) Any one method of administration is included. 1) Simultaneous administration with combination drug, 2) As separate formulations, co-administration by the same route of administration, 3) As separate formulations, co-administration by different routes of administration, 4) Administration at different times by the same route of administration as separate formulations, or 5) Administration at different times by different routes of administration as separate formulations Also at different times as separate formulations as in 4) or 5)
  • the administration order of the compound (I) of the present invention and the above drug is not particularly limited.
  • the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof can be used as an additive effect in preventing or treating the above diseases by using one or more of the above drugs in appropriate combination.
  • the above advantageous effects can be obtained.
  • the medicament according to this embodiment can be used systemically or locally, orally or parenterally (nasal, pulmonary, intravenous, rectal, subcutaneous, muscle, transdermal). Etc.).
  • the dose of compound (I) of the present embodiment is determined by the patient's age, sex, body weight, It is determined appropriately depending on the disease and the degree of treatment.
  • an adult with a body weight of 60 kg
  • the daily dose as an oral preparation is preferably 6 to 540 mg / body, more preferably 18 to 180 mg / body.
  • parenteral administration it can be appropriately administered once or in several divided doses in the range of about 0.01 to 300 mg per day for an adult.
  • the daily dose as a parenteral preparation is preferably 1 to 100 mg / body, more preferably 6 to 60 mg / body.
  • the dose of the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof can be reduced according to the dose of a drug other than the EP 1 receptor antagonist.
  • n-butyllithium 124 mL, 2.6 M in hexane
  • a tetrahydrofuran solution (294 mL) of the obtained dibromo compound under ice cooling
  • Ethyl chloroformate 33.6 mL
  • Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.
  • Reference Examples 2-2 to 2-10 The following compounds of Reference Examples 2-2 to 2-10 were obtained in the same manner as in Reference Example 2-1, using the corresponding phenylpropiolic acid esters. Their structures and spectral data are shown in Tables 1 and 2.
  • Reference Examples 4-2 to 4-10 The following compounds of Reference Examples 4-2 to 4-10 were obtained in the same manner as in Reference Example 4-1, using the corresponding carboxylic acid compounds. Their structures and spectral data are shown in Tables 5 and 6.
  • Reference Examples 13-2 and 13-3 The corresponding compounds of Reference Examples 13-2 and 13-3 were obtained in the same manner as in Reference Example 13-1, using the corresponding acetylene compound. Their structures and spectral data are shown in Table 9.
  • the first reaction liquid was stirred at ⁇ 78 ° C. for 1 hour.
  • a saturated aqueous ammonium chloride solution was added to the first reaction solution, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate to obtain a crude product of 5-chloro-2-cyclohexylpyrazolo [1,5-a] pyridine-7-carbaldehyde.
  • Reference Examples 15-2 to 15-23 The corresponding compounds of Reference Examples 15-2 to 15-23 were obtained in the same manner as in Reference Example 15-1, using the corresponding pyrazolo [1,5-a] pyridine. Their structures and spectral data are shown in Tables 11-14.
  • the reaction solution was stirred for 1 hour under ice cooling.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off from the filtrate.
  • 1,4-Dioxane (0.60 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 4 hours.
  • a 2 mol / L sodium hydroxide aqueous solution was added to the reaction solution to adjust the pH to about 10.
  • the precipitated solid was collected by filtration and washed with water.
  • the obtained solid was extracted with dichloromethane, and the organic layer was washed with water and then dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure to obtain the title compound as a pale yellow solid (106 mg).
  • reaction solution was stirred for 1.5 hours under ice cooling.
  • a 10% aqueous sodium thiosulfate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Examples 1-2 to 1-80 The following compounds of Examples 1-2 to 1-80 were obtained in the same manner as in Example 1-1 using the corresponding esters. Their structures and spectral data are shown in Tables 15-32.
  • reaction solution was obtained.
  • the reaction was stirred at room temperature for 3 hours.
  • the organic layer was dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The precipitated solid was collected by filtration and washed with methanol to give the title compound as a colorless solid (18.4 mg).
  • Examples 5-2 and 5-3 The following compounds of Examples 5-2 and 5-3 were obtained in the same manner as in Example 5-1, using the corresponding sulfonamides. Their structure and spectral data are shown in Table 33.
  • the first reaction liquid was stirred for 70 minutes under ice cooling. Water was added to the first reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the solvent was distilled off under reduced pressure to obtain a colorless solid. To the obtained colorless solid xylene solution (0.66 mL), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (0.02 mL) was added, and the second reaction solution and did. The second reaction solution was stirred at 80 ° C. for 2.5 hours.
  • DBU 1,8-diazabicyclo [5.4.0] undec-7-ene
  • a 10% aqueous citric acid solution was added to the second reaction solution to adjust the pH to about 5, followed by extraction with dichloromethane.
  • the organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After anhydrous sodium sulfate was removed by filtration, the solvent was distilled off under reduced pressure. The precipitated solid was washed with methanol to obtain the title compound as a colorless solid (30.5 mg).
  • the reaction was stirred at room temperature for 75 minutes. 4 mol / L hydrogen chloride-1,4-dioxane (0.02 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 60 minutes. 4 mol / L hydrogen chloride-1,4-dioxane (0.02 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours. Further, 4 mol / L hydrogen chloride-1,4-dioxane (0.04 mL) was added to the reaction solution, and the mixture was stirred at room temperature for 10 hours.
  • Examples 12-2 to 12-28 The following compounds of Examples 12-2 to 12-28 were obtained in the same manner as in Example 12-1, using the corresponding alcohol. Their structures and spectral data are shown in Tables 34-39.
  • Examples 13-2 to 13-31 The following compounds of Examples 13-2 to 13-31 were obtained in the same manner as Example 13-1 using the corresponding boron compounds. Their structures and spectral data are shown in Tables 40-47.
  • Example 14-2 to 14-4 The following compounds of Examples 14-2 to 14-4 were obtained in the same manner as Example 14-1 using the corresponding boron compounds. Their structure and spectral data are shown in Table 48.
  • the first reaction solution was stirred at 100 ° C. for 5 hours.
  • the first reaction solution was subjected to filtration using celite and extracted with ethyl acetate.
  • the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After anhydrous magnesium sulfate was removed by filtration, the solvent was distilled off.
  • a hydrogen chloride solution (3 mL, 4.0 mol / L 1,4-dioxane solution) was added to the residue to obtain a second reaction solution.
  • the second reaction solution was stirred at room temperature for 30 minutes.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the second reaction solution, and the mixture was extracted with ethyl acetate.
  • Example 16-2 to 16-4 The corresponding compounds of Examples 16-2 to 16-4 were obtained in the same manner as in Example 16-1, using the corresponding aryl bromides. Their structure and spectral data are shown in Table 49.
  • reaction vessel was heated with microwave (CEM) for 15 minutes (150 W, 120 ° C.).
  • CEM microwave
  • Examples 18-2 to 18-7 The corresponding compounds of Examples 18-2 to 18-7 were obtained in the same manner as in Example 18-1, using the corresponding alkyl bromides. Their structures and spectral data are shown in Table 50 and Table 51.
  • Methyl 3- (2-phenylpyrazolo [1,5-a] pyridin-7-ylmethyl) benzoate To an aqueous solution of sodium carbonate (73.8 mg) in water (0.56 mL) was added tetrahydrofuran (2.2 mL). ), 7- (bromomethyl) -2-phenylpyrazolo [1,5-a] pyridine (100 mg), 3- (methoxycarbonyl) phenylboronic acid (65.8 mg) and tetrakis (triphenylphosphine) palladium (0) (20.1 mg) was added. The mixture was stirred at 100 ° C. for 1 hour under microwave irradiation.
  • the mixture was stirred at 100 ° C. for 1 hour under microwave irradiation.
  • the mixture was allowed to cool, diluted with ethyl acetate, and then filtered through a Celite® pad.
  • the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography (ethyl acetate-hexane) and then aminopropylated silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound (83.9 mg).
  • EP 1 receptor antagonism confirmation test (1) Preparation of rat EP 1 expression vector Using Rat Kidney BD Marathon-Ready cDNA (Nippon Becton Dickinson Co., Ltd.) as a template, using the forward primer shown in SEQ ID NO: 1 and the reverse primer shown in SEQ ID NO: 2, The first PCR was performed using KOD-Plus-Ver2.0 (Toyobo Co., Ltd.). Furthermore, using this amplification product as a template, the forward primer shown in SEQ ID NO: 3 and the reverse primer shown in SEQ ID NO: 4 were used, and a second PCR was performed in the same manner.
  • the amplification product obtained by the second PCR was incorporated into a vector (pcDNA3.1 D / V5-His-TOPO (registered trademark), Invitrogen Corporation).
  • a vector pcDNA3.1 D / V5-His-TOPO (registered trademark), Invitrogen Corporation.
  • the vector incorporating this amplification product was introduced into E. coli (One-shot TOP10 competent cell, Invitrogen) and transformed.
  • the transformed E. coli was cultured on LB agar medium for 1 day. After culture, colonies were selected and cultured in LB liquid medium containing 50 ⁇ g / mL ampicillin. After culture, the vector was purified using QIAprep Spin Miniprep Kit (Qiagen).
  • C0S-1 cell culture COS-1 cells (Dainippon Sumitomo Pharma) are penicillin-streptomycin solution (Invitrogen Corporation, final concentration: 100 U / mL as benzylpenicillin; 100 ⁇ g / mL as streptomycin) as antibiotics, MEM non-essential amino acids (Invitrogen Corporation, final) 1) and 2-dimethoxyethane M liquid medium (containing high glucose and L-glutamine, Invitrogen Corporation) supplemented with fetal bovine serum (MoregateBiotech, final concentration: 10%)
  • the cells were cultured at 37 ° C. in an incubator under% CO 2 gas conditions until they reached confluence.
  • This resuspended cell suspension was poly D-lysine coated 96 well microplate (BD BioCoat (registered trademark), Nippon Becton Dickinson Co., Ltd.) in each well 5 ⁇ 10 4 cells / liquid medium 100 ⁇ L / Well in a liquid medium so that it becomes a well, 100 ⁇ L of this cell preparation was dispensed into each well and seeded. After seeding, the cells were cultured at 37 ° C. in an incubator under 5% CO 2 gas conditions. When the cells for introduction of the rat EP 1 expression vector were adhered (about 2 hours after seeding), the rat EP 1 expression vector was introduced by the following procedure.
  • rat EP 1 expression vector introduced rat EP 1 expression vector, using Lipofectamine 2000 (Invitrogen Corporation).
  • the rat EP 1 expression vector was diluted with OPTI-MEM (registered trademark) I Reduced-Serum Medium (Invitrogen Corporation) to 200 ng / 25 ⁇ L / well.
  • Lipofectamine 2000 (Invitrogen Corporation) was diluted with OPTI-MEM (registered trademark) I Reduced-Serum Medium (Invitrogen Corporation) so as to be 0.5 ⁇ L / 25 ⁇ L / well, and incubated at room temperature for 5 minutes.
  • rat EP 1 expression vector and diluted Lipofectamine 2000 were mixed and incubated at room temperature for 30 minutes for complex formation of rat EP 1 expression vector / Lipofectamine 2000. After incubation for 30 minutes, the rat EP 1 expression vector / Lipofectamine 2000 complex was dispensed into the rat EP 1 expression vector introduction cells at 50 ⁇ L / well. The complex of rat EP 1 expression vector / Lipofectamine 2000 for 24 hours at 37 ° C. The dispensed cells in an incubator at 5% CO 2 gas conditions. After culturing for 24 hours, this cell was used as a rat EP 1 receptor-expressing cell to measure intracellular calcium concentration.
  • Pluronic F-127 (Invitrogen Corporation) was mixed with a fluorescent calcium indicator (Fluo 4-AM (Dojindo Laboratories)) to a final concentration of 0.0004%, then assay buffer was added, and 4 ⁇ mol / L Fluo 4 -An AM solution was prepared. 100 ⁇ L of this solution was added to each well and incubated in an incubator at 37 ° C. for 90 minutes. Thereafter, all the cell supernatant was aspirated, and 100 ⁇ L of assay buffer containing 2.5 mM probenecid was added to each well. After incubation in the incubator for 15 minutes, the intracellular calcium concentration was measured.
  • fluorescent calcium indicator Fluo 4-AM (Dojindo Laboratories)
  • the intracellular calcium concentration was measured as a fluorescence signal using FlexStation (registered trademark) (manufactured by Molecular Devices). Twenty seconds after the start of reading the fluorescence signal, 50 ⁇ L of each test compound (final concentration: 0.1 nM to 10 ⁇ M) diluted with the assay buffer was added to each well, and the fluorescence signal was measured for 60 seconds. Then added 50 ⁇ L prostaglandin E 2 buffer solution to each well (final concentration 10 nM), was measured for 60 seconds the fluorescence signal. In the method shown above, the fluorescence signal obtained when prostaglandin E 2 was added when assay buffer was added instead of the test compound was obtained when 100% of the test signal and prostaglandin E 2 were not added. The signal obtained was 0%. The concentration showing 50% inhibition from the dose-response curve of the test compound was taken as the IC 50 value. The IC 50 values of each test compound obtained are shown in Table I below.
  • the skin of the left thigh was incised, the femoral artery was exposed and peeled, and an arterial catheter filled with 200 heparin units / mL heparin was inserted 15 mm.
  • the left femoral incision layer was closed with surgical adhesive.
  • the skin of the right thigh was incised to expose the femoral artery and ligated after peeling.
  • the drug was administered intravenously, the right femoral vein was exposed and peeled, and a venous catheter was inserted.
  • the right femoral incision layer was closed with surgical adhesive.
  • a midline incision was made in the abdomen to expose the ureters on both sides, and after ligation, the kidney side was cut.
  • Two Michel hemostatic forceps were applied to the top of the bladder at an interval of about 3 mm, an incision was made between them, a bladder catheter was inserted 5 mm therefrom, and a purse-string suture was performed. After the abdominal incision layer was sutured, the penis was exposed and ligated. A midline incision was made in the neck, the trachea was exposed, the incision was made, and the distal side was ligated. The tip of the Eppendorf tip was placed under the trachea, and the trachea was slightly lifted to secure the airway.
  • the compound of the present invention has a strong EP 1 receptor antagonism, it is useful as a therapeutic or prophylactic agent for diseases or symptoms caused by the activation of EP 1 receptor by the stimulating action of PGE 2 . Among them, it is useful as a therapeutic agent or preventive agent for lower urinary tract symptoms (LUTS), particularly overactive bladder syndrome (OABs).
  • LUTS lower urinary tract symptoms
  • OABs overactive bladder syndrome
  • SEQ ID NO: 1 is the sequence of the forward primer (5 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
  • SEQ ID NO: 2 is the sequence of the reverse primer (3 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
  • SEQ ID NO: 3 is the sequence of the forward primer (5 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
  • SEQ ID NO: 4 is the sequence of the reverse primer (3 ′ primer) used to amplify the DNA of SEQ ID NO: 5.
  • SEQ ID NO: 5> SEQ ID NO: 5 is a DNA sequence for expressing the rat EP1 receptor amplified using the primers of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4.

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Abstract

Le problème décrit par la présente invention est de fournir un nouveau composé possédant une activité antagoniste vis-à-vis du récepteur EP1. La solution selon la présente invention consiste en un dérivé pyrazolopyridine représenté par la formule générale (I) ou un sel pharmacologiquement acceptable de celui-ci qui s'est avéré présenter une activité antagoniste puissante vis-à-vis du récepteur EP1. Le composé (I) ou un sel pharmacologiquement acceptable de celui-ci est efficace comme médication thérapeutique ou médication préventive pour des symptômes des voies urinaires basses (LUTS), par exemple, et pour des syndromes de vessie hyperactive (OAB), etc., en particulier. En outre, ceux-ci sont très utiles dans le traitement, la prévention, ou la suppression d'une variété d'états impliquant les récepteurs EP1, en plus des symptômes des voies urinaires basses (LUTS), (par exemple des états inflammatoires, des états douloureux, l'ostéoporose, le cancer, etc.).
PCT/JP2013/004507 2012-07-25 2013-07-24 Dérivé pyrazolopyridine ou un sel pharmacologiquement acceptable de celui-ci WO2014017087A1 (fr)

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Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005520797A (ja) * 2001-12-14 2005-07-14 メルク フロスト カナダ アンド カンパニー プロスタグランジン受容体リガンドとしてのキノリノン
WO2008050732A1 (fr) * 2006-10-23 2008-05-02 Takeda Pharmaceutical Company Limited Dérivé de l'iminopyridine et son utilisation
JP2009532430A (ja) * 2006-04-05 2009-09-10 グラクソ グループ リミテッド Ｅｐ１受容体アンタゴニストとしてのベンゾフラン化合物
JP2010518146A (ja) * 2007-02-16 2010-05-27 グラクソ グループ リミテッド ベンゾフラン化合物
WO2011013623A1 (fr) * 2009-07-27 2011-02-03 キッセイ薬品工業株式会社 Dérivé d'indole et sel pharmacologiquement acceptable de celui-ci
WO2012102255A1 (fr) * 2011-01-25 2012-08-02 キッセイ薬品工業株式会社 Dérivé d'indole, et sel de qualité pharmacologique de celui-ci
WO2012102297A1 (fr) * 2011-01-26 2012-08-02 杏林製薬株式会社 Dérivé de pyrazolopyridine ou sel de qualité pharmacologique de celui-ci
JP2012167085A (ja) * 2011-01-25 2012-09-06 Kissei Pharmaceutical Co Ltd インドール誘導体、またはその薬理学的に許容される塩の医薬用途

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2005520797A (ja) * 2001-12-14 2005-07-14 メルク フロスト カナダ アンド カンパニー プロスタグランジン受容体リガンドとしてのキノリノン
JP2009532430A (ja) * 2006-04-05 2009-09-10 グラクソ グループ リミテッド Ｅｐ１受容体アンタゴニストとしてのベンゾフラン化合物
WO2008050732A1 (fr) * 2006-10-23 2008-05-02 Takeda Pharmaceutical Company Limited Dérivé de l'iminopyridine et son utilisation
JP2010518146A (ja) * 2007-02-16 2010-05-27 グラクソ グループ リミテッド ベンゾフラン化合物
WO2011013623A1 (fr) * 2009-07-27 2011-02-03 キッセイ薬品工業株式会社 Dérivé d'indole et sel pharmacologiquement acceptable de celui-ci
WO2012102255A1 (fr) * 2011-01-25 2012-08-02 キッセイ薬品工業株式会社 Dérivé d'indole, et sel de qualité pharmacologique de celui-ci
JP2012167085A (ja) * 2011-01-25 2012-09-06 Kissei Pharmaceutical Co Ltd インドール誘導体、またはその薬理学的に許容される塩の医薬用途
WO2012102297A1 (fr) * 2011-01-26 2012-08-02 杏林製薬株式会社 Dérivé de pyrazolopyridine ou sel de qualité pharmacologique de celui-ci

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