Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • 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
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/10—Drugs for disorders of the urinary system of the bladder
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

• the present invention relates to a benzene ring condensed nitrogen-containing 5-membered heterocyclic compound 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 compound 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.
• 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.
• the benzene ring condensed nitrogen-containing 5-membered heterocyclic ring containing Y 1 and Y 2 and having R 2 , R 3 , R 4 , R 5 and Y 3 bonded thereto is represented by the following a) to d):
• A is a group selected from the group consisting of e) to i) below:
• A is a group selected from the group consisting of the following e), f), h) and i), wherein the nitrogen-containing 5-membered benzene ring is described in [1] A heterocyclic compound or a pharmacologically acceptable salt thereof.
• R a , W 1 , W 2 , W 3 , and W 4 are as defined above.
• R a has the same meaning as described above.
• R 1 is —C ( ⁇ O) —OZ 1
• Z 1 is a hydrogen atom or a C 1-6 alkyl group
• R 1 is —C ( ⁇ O ) -NHSO 2 Z 2 , wherein Z 2 is a C 1-6 alkyl group, the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a compound thereof according to any one of [1] to [5] Pharmacologically acceptable salt.
• R 3 is selected from the group consisting of the following A), B), C), F), G), H), J), K), and M).
• R 2 is a group selected from the group consisting of the following aa1), bb), cc), dd), ee1), ff1), gg1) and hh1). Benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of [1] to [7].
• R a has the same meaning as described above.
• R 3 is substituted with a hydrogen atom, a halogen atom, a C 2-8 alkenyl group, a C 1-7 alkanoyl group, or two independent C 1-6 alkyl groups.
• the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or the drug thereof according to any one of [1] to [10], which is an amino group, a C 1-6 alkoxy group, or a halo C 1-6 alkoxy group Physically acceptable salt.
• R 2 is a group selected from the group consisting of the following bb1), cc), dd), gg2) and hh2), [1] to [11] The benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of the above.
• bb1) C 3-6 cycloalkyl group whose ring is substituted with one C 1-6 alkyl group cc) C 2-6 alkenyl group dd) C 5-8 cycloalkenyl group gg2) two independent C 1 1- Amino groups substituted with 6 alkyl groups hh2) 4-7 membered cyclic amino groups
• the benzene ring condensed nitrogen-containing 5-membered heterocyclic ring is a ring selected from the group consisting of the following a), b) and d): [1] to [12 ]
• R 2 , R 3 , R 4 , R 5 and Y 3 are as defined above.
• R 2 , R 3 , R 4 , R 5 and Y 3 are as defined above.
• the compound represented by the general formula (I) is: 1-[[6-bromo-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[6-chloro-2- (diethylamino) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[6-chloro-2- (3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazole-3-carboxylic acid, 1-[[6-Chloro-2- (5-methyl-3,6-dihydropyridin-1 (2H) -yl) benzo [d] thiazol-4-yl] methyl] -5-methyl-1H-pyrazo
• a medicament comprising the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmacologically acceptable salt thereof according to any one of [1] to [15].
• An EP 1 receptor antagonist comprising the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [15].
• a benzene ring condensed nitrogen-containing 5-membered heterocyclic compound or a drug thereof according to any one of the above [1] to [15], for producing a medicament for preventing or treating lower urinary tract symptoms The use of a physically acceptable salt.
• a benzene ring-fused nitrogen-containing 5-membered heterocyclic compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [15] for use in the prevention or treatment of lower urinary tract symptoms Salt.
• a novel compound having an EP 1 receptor antagonistic action can be provided.
• This embodiment relates to a benzene ring condensed nitrogen-containing 5-membered heterocyclic compound represented by the following general formula (I) or a pharmacologically acceptable salt thereof.
• the benzene ring condensed nitrogen-containing 5-membered heterocyclic ring containing Y 1 and Y 2 and having R 2 , R 3 , R 4 , R 5 and Y 3 bonded thereto is represented by the following a) to d):
• A is a group selected from the group consisting of e) to i) below:
• the bond marked with (*) bonded to Y 3, represents a bond with (**) attached to bond R 1.
• “Independently” and “independently” mean that they may be the same or different between two or more substituents that may be present. Of course, Z 2 and Z 3 may be the same or different.
• Halogen atom includes fluorine atom, chlorine atom, bromine atom and iodine atom.
• 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, hexyl group, isohexyl 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 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 —
• 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 2-8 alkenyl group” means a straight or branched unsaturated hydrocarbon group having 2 to 8 carbon atoms having at least one double bond.
• Examples of the C 2-8 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, 1-hepten-1-yl group, 1-octen-1-yl group, 2-methyl-1-propen-1-yl group and the like.
• 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.
• halo C 1-6 alkoxy group means a C 1-6 alkoxy group substituted with 1 to 5 same or different halogen atoms.
• examples of the halo C 1-6 alkoxy group include a monofluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 2-fluoroethoxy group, a 2-chloroethoxy group, a 2,2-difluoroethoxy group, and a 1,1-difluoro group.
• Ethoxy group 1,2-difluoroethoxy group, 2,2,2-trifluoroethoxy group, 1,1,2,2,2-pentafluoroethoxy group, 2,2,2-trichloroethoxy group, 3-fluoro Propoxy group, 2-fluoropropoxy group, 1-fluoropropoxy group, 3,3-difluoropropoxy group, 2,2-difluoropropoxy group, 1,1-difluoropropoxy group, 4-fluorobutoxy group, 5-fluoropentyloxy Group, 6-fluorohexyloxy group and the like.
• a monofluoromethoxy group, a difluoromethoxy group, and a trifluoromethoxy group are mentioned.
• 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.
• a methoxycarbonyl group and a tert-butoxycarbonyl group are used.
• C 1-6 alkoxy C 1-6 alkyl group means a C 1-6 alkyl group substituted with a linear or branched alkoxy group having 1 to 6 carbon atoms.
• Examples of the C 1-6 alkoxy C 1-6 alkyl group include a methoxymethyl group, an ethoxyethyl group, a propoxymethyl group, and an isopropoxymethyl group.
• C 1-6 alkylenedioxy group means a group represented by —O— (C 1-6 alkyl) -O—.
• a methylenedioxy group, an ethylenedioxy group, a propylenedioxy group, etc. 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 1-6 alkylsulfanyl group means a group represented by (C 1-6 alkyl) -S—.
• Examples of the C 1-6 alkylsulfanyl group include a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, an isopropylsulfanyl group, a butylsulfanyl group, an isobutylsulfanyl group, a sec-butylsulfanyl group, a pentylsulfanyl group, and a hexylsulfanyl group.
• 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.
• 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.
• the “C 4-10 heteroaralkyl group” means an alkyl group having 1 to 4 carbon atoms substituted with a heteroaryl group.
• Examples of the C 4-10 heteroaralkyl group include a 2-furanylmethyl group, a 3-furanylmethyl group, a 2-pyridylmethyl group, and the like.
• the “C 4-6 heterocycloalkyl group” means an alkyl group having 1 to 4 carbon atoms substituted with a saturated heterocyclic group.
• Examples of the C 4-6 heterocycloalkyl group include a 2-tetrahydrofuranylmethyl group, a 3-tetrahydrofuranylmethyl group, a 2-pyrrolidinylmethyl group, and the like.
• the “C 3-6 cycloalkyl group” means a monocyclic saturated alicyclic hydrocarbon group having 3 to 6 carbon atoms.
• Examples of the C 3-6 cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and 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 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.
• the “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.
• a “C 6-10 aryl group” which means an aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples of the C 6-10 aryl group 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, dihydrothiopyranyl group, dihydropyridyl group And unsaturated
• 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 “branched C 3-6 alkyl group” means a branched alkyl group having 3 to 6 carbon atoms.
• Examples of branched C 3-6 alkyl groups include, for example, isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group 1,2-dimethylpropyl group, 1-ethylpropyl group, isohexyl group and the like.
• Preferred are isopropyl group, isobutyl group, sec-butyl group, tert-butyl group, 1-ethylpropyl group and the like.
• the “5-membered aromatic heterocyclic group” means a 5-membered aromatic group containing 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom in the ring.
• 5-membered aromatic heterocyclic groups include furyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, 1,2,4-triazolyl, isothiazolyl, isoxazolyl, oxazolyl, thiazolyl, 1 , 3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group and the like.
• 6-membered aromatic heterocyclic group means a 6-membered aromatic group containing 1 to 4 nitrogen atoms in the ring.
• examples of the 6-membered aromatic heterocyclic group include a pyridyl group, a pyrimidyl group, a pyrazinyl group, and a pyridazinyl group.
• 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.
• a group selected from the group consisting of a 5-membered nitrogen-containing heterocyclic group having the structure shown below is exemplified.
• C 1-6 alkyl group substituted by a 6-membered aliphatic cyclic amino group means a linear or branched alkyl group having 1 to 6 carbon atoms and substituted by a morpholino group or piperidino group. To do.
• Examples of the C 1-6 alkyl group substituted with a 6-membered aliphatic cyclic amino group include, for example, morpholinomethyl group, piperidinoethyl group, 1-morpholinoethyl group, 1-piperidinoethyl group, 2-morpholinoethyl group, 2-piperidinoethyl group Etc.
• the benzene ring condensed nitrogen-containing 5-membered heterocyclic ring containing Y 1 and Y 2 and to which R 2 , R 3 , R 4 , R 5 and Y 3 are bonded is preferably from the following a), b) and d):
• the benzene ring condensed nitrogen-containing 5-membered heterocyclic ring is more preferably a ring represented by the following a).
• A preferably a group represented by e) wherein W 1 is CH or a nitrogen atom, a group represented by f) wherein W 2 is an oxygen atom or a sulfur atom, a group represented by h), and One of W 3 and W 4 is a nitrogen atom, and the other is a group represented by i), which is CH or a nitrogen atom.
• R a is as defined above, and is preferably a hydrogen atom or a C 1-6 alkyl group. More preferably, A is a group selected from the group consisting of the following e1), f1), h) and i1).
• R a is preferably a hydrogen atom or a C 1-6 alkyl group.
• the bond marked with (*) bonded to Y 3, represents a bond with (**) attached to bond R 1.
• R a is attached, even more preferably a group R a is represented as e1) a C 1-6 alkyl group, a group R a is represented as e1) a hydrogen atom, R a is hydrogen group represented by an atom f1), a group a group R a is represented as h) is a hydrogen atom, R a is represented as i1) a hydrogen atom.
• R a is a group represented by e1) wherein R 1 is a C 1-6 alkyl group, R a is a group represented by f1) wherein H is a hydrogen atom, R a is hydrogen It is a group represented as i1) which is an atom.
• R a is bonded, particularly preferred are a group represented by e1) in which R a is a C 1-6 alkyl group and a group represented by f1) in which R a is a hydrogen atom.
• Y 3 is preferably C 1-6 alkylene such as methylene, —O— or —S—, more preferably C 1-6 alkylene, and particularly preferably methylene.
• R 1 is preferably —C ( ⁇ O) —OZ 1 , —C ( ⁇ O) —NHSO 2 Z 2 or an acidic 5-membered heterocyclic group, and 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 2 is preferably a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 2-6 alkenyl group, C 5-8 , which is unsubstituted or substituted with one C 1-6 alkyl group. It consists of a cycloalkenyl group, a phenyl group that is unsubstituted or independently substituted with 1 to 5 halogen atoms, a 6-membered aromatic heterocyclic group, a C 1-6 alkyl group, and a C 2-6 alkenyl group.
• R 2 more preferably C 3-6 branched alkyl, unsubstituted or one C 1-6 alkyl group a C 3-6 cycloalkyl group which ring is substituted, C 2-6 alkenyl group, A C 5-8 cycloalkenyl group, a phenyl group, a pyridyl group, an amino group substituted with two independent C 1-6 alkyls, and a 4- to 7-membered cyclic amino group.
• R 2 is more preferably a C 3-6 cycloalkyl group, a C 2-6 alkenyl group, a C 5-8 cycloalkenyl group in which the ring is substituted with one C 1-6 alkyl group, two independent groups An amino group substituted with a C 1-6 alkyl group of 4 to 7-membered cyclic amino group.
• R 2 is particularly preferably a vinyl group, 2-propenyl group, 1-isobutenyl group, 1-cyclopentenyl group, 1-methylcyclopropyl group, dimethylamino group, methyl (ethyl) amino group, diethylamino group, ethyl ( n-propyl) amino group, di (n-propyl) amino group, phenyl group, pyridyl group, pyrrolidin-1-yl group, piperidin-1-yl group, morpholin-4-yl group, thiomorpholin-4-yl group 3,6-dihydropyridin-1 (2H) -yl group.
• R 3 is preferably a hydrogen atom, a halogen atom, a cyano group, a C 2-8 alkenyl group, a C 1-7 alkanoyl group, an amino group which is unsubstituted or substituted with 1 or 2 C 1-6 alkyl groups , C 1-6 alkoxy group, halo C 1-6 alkoxy group, 5-membered aromatic heterocyclic group.
• R 3 is a hydrogen atom, a halogen atom, a C 2-8 alkenyl group, a C 1-7 alkanoyl group, an amino group substituted with two C 1-6 alkyl groups, a C 1-6 alkoxy group, A halo C 1-6 alkoxy group; R 3 is more preferably a hydrogen atom, fluorine atom, chlorine atom, bromine atom, cyano group, vinyl group, 2-propenyl group, acetyl group, dimethylamino group, methoxy group or trifluoromethoxy group.
• R 4 is preferably a hydrogen atom or a halogen atom, and more preferably a hydrogen atom.
• R 5 is preferably a hydrogen atom or a halogen atom, more 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). Salts derived from non-toxic bases of pharmaceutically acceptable compounds (I) include aluminum, ammonium, calcium, copper, ferrous, ferric, lithium, magnesium, manganese, manganite, potassium and sodium, etc.
• Salts with inorganic bases are ammonium, calcium, manganese, potassium and sodium salts or primary, secondary, tertiary amines, substituted amines (eg naturally occurring substituted amines)
• Organic bases such as cyclic amines and basic ion exchange resins (for example, arginine, betaine, caffeine, choline, N, N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpipe Lysine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, tripropylamine, tripropylamine, trome
• 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.
• Arbitrary hydrates and solvates formed by the benzene ring condensed nitrogen-containing 5-membered heterocyclic compound represented by the general formula (I) or a salt thereof including the preferred compounds specifically described above are: These are all included in the scope of the present invention.
• 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.
• the compound (I) of the present embodiment or a pharmaceutically acceptable salt thereof may have a proton tautomer.
• 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, bladder, causing the urothelium like, LUTS useful in the treatment or prevention of symptoms among others OABs like.
• the EP 1 receptor antagonism can be evaluated by the potency of inhibiting calcium influx into cells due to 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.
• Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 and A are as defined above;
• L 1 represents a chlorine atom, a bromine atom, an iodine atom, a methanesulfonyloxy group or the like;
• 1 represents a C 1-6 alkyl group or a C 7-10 aralkyl group.
• Step 1-1 This step is a step for producing compound (Ia) by reacting compound (1) with compound (2).
• Compound (Ia) can be produced, for example, by reacting compound (1) and compound (2) in the presence of a base in a solvent.
• the solvent include N, N-dimethylformamide, 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, preferably 0 ° C. to 30 ° C.
• an inorganic base such as sodium hydride, potassium carbonate or sodium carbonate, or an organic base such as triethylamine, N, N-diisopropylethylamine or pyridine can be used.
• 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 (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 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.
• reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
• Compound (2) can be a commercially available product, or can be produced according to other methods described in the literature or a method analogous thereto.
• Compound (1) can be obtained, for example, by any one of the following methods a, b, c, d, e, and f.
• R 2 , R 3 , R 4 , R 5 and L 1 are as defined above; L 2 represents a chlorine atom, a bromine atom or the like.
• Step 1a-1 This step is a step of producing compound (5) by a condensation reaction between compound (3) and compound (4).
• Compound (5) can be produced, for example, by reacting compound (3) with compound (4) in a solvent in the presence or absence of a base.
• the solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like.
• the base to be used potassium carbonate, sodium carbonate, triethylamine, N, N-diisopropylethylamine or the like can be used.
• the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 20 ° C.
• reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
• the compound (3) and compound (4) 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 1a-2 This step is a step of producing compound (6) from compound (5).
• Compound (6) can be produced, for example, by reacting compound (5) with a compound serving as a sulfur source such as Lawesson's reagent in a solvent.
• the solvent include toluene, dichloromethane, 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 20 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 1a-3 This step is a step of producing compound (7) from compound (6).
• Compound (7) can be produced, for example, by cyclizing compound (6) in the presence of a base in a solvent.
• the solvent include N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, a mixed solvent thereof and the like.
• the base used include 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), potassium carbonate, Sodium carbonate, cesium carbonate, sodium acetate and the like can be used.
• the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 20 ° 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 1a-4 This step is a step of producing compound (1a) having the above structure among compounds (1) from compound (7).
• Compound (1a) can be produced, for example, by brominating compound (7) with N-bromosuccinimide in a solvent when L 1 is a bromine atom.
• benzoyl peroxide, azobisisobutyronitrile and the like can be added as a radical initiator.
• the solvent include carbon tetrachloride, chloroform, dichloromethane, N, N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, and mixed solvents thereof.
• the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 20 ° 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.
• R 2 , R 3 , R 4 , R 5 and L 1 are as defined above;
• L 3 represents a chlorine atom, a bromine atom, an iodine atom, etc .;
• L 4 is a hydrogen atom,
• B (OH) 2 Q represents NH 4 or the like.
• Step 1b-1 This step is a step of producing compound (10) by reaction of compound (8) with compound (9).
• Compound (10) can be produced, for example, by reacting compound (8) and compound (9) in the presence of bromine in an acetic acid solvent.
• the reaction temperature is usually from ⁇ 20 ° C. to 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 (8) and compound (9) 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 1b-2 This step is a step for producing the compound (11) by introducing a tert-butoxycarbonyl group into the amino group of the compound (10).
• Compound (11) can be produced, for example, by reacting di-tert-butyl dicarbonate with compound (10) in a solvent or without using a solvent.
• the solvent used in the reaction include 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, N, N-dimethylformamide, a mixed solvent thereof and the like.
• a base when a base is used in this reaction, triethylamine, N, N-diisopropylethylamine, pyridine and the like can be used.
• the reaction temperature is usually from ⁇ 20 ° C. to the solvent reflux temperature, preferably 0 ° 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
• Step 1b-3 This step is a step for producing a compound (12) by converting a bromine atom of the compound (11) into a hydroxymethyl group.
• Compound (12) can be produced, for example, by converting the bromine atom of compound (11) into a lithium salt, Grignard reagent or the like in a solvent and then reacting with paraformaldehyde or the like.
• the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like.
• the reagent used when preparing the lithium salt include n-butyllithium, sec-butyllithium, lithium diisopropylamide and the like.
• Examples of the reagent used when the Grignard reagent is used include isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, and metallic magnesium.
• the reaction temperature can usually be carried out at -78 ° 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.
• Compound (12) was prepared by treating a lithium salt of Compound (11) or a Grignard reagent with N, N-dimethylformamide or the like to introduce a formyl group, and then removing the obtained compound having a formyl group in the presence of a solvent.
• the solvent used include methanol, water, ethanol, tetrahydrofuran, and mixed solvents thereof.
• 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 1b-4 This step is a step for producing the compound (13) by removing the tert-butoxycarbonyl group of the compound (12).
• Compound (13) can be produced, for example, by treating compound (12) with an appropriate acid in a solvent or without using a solvent.
• the solvent used for the reaction include dichloromethane, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, a mixed solvent thereof and the like.
• As the acid used trifluoroacetic acid, hydrogen chloride and the like can be used.
• the reaction temperature is usually from ⁇ 20 ° C. to solvent reflux temperature, 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.
• Step 1b-5 This step is a step for producing a compound (13) by converting a bromine atom of the compound (10) into a hydroxymethyl group. This step can be performed according to the above-mentioned method b and step 1b-3.
• Step 1b-6 This step is a step for producing a compound (14) by converting the amino group of the compound (13) into an appropriate leaving group (L 3 ).
• Compound (14) can be produced, for example, by reacting compound (13) with potassium iodide, sodium nitrite and the like in the presence of an acid in a solvent when L 3 is an iodine atom.
• the solvent used in the reaction include acetonitrile, water, 1,4-dioxane, tetrahydrofuran, methanol, ethanol, 2-propanol, N, N-dimethylformamide, acetic acid, and mixed solvents thereof.
• the acid used in this reaction examples include p-toluenesulfonic acid, acetic acid, hydrochloric acid, trifluoroacetic acid and the like.
• the reaction temperature is usually from ⁇ 50 ° C. to the solvent reflux temperature, preferably from ⁇ 20 ° 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 1b-7 This step is a step for producing a compound (16) by reacting the compound (14) with the compound (15) and substituting L 3 with R 2 .
• Compound (16) can be produced by replacing L 3 of compound (14) with R 2 which is a substituted amino group by a nucleophilic substitution reaction.
• This reaction proceeds by reacting compound (14) with compound (15), which is an appropriate substituted amine, in a solvent or without using a solvent. In this reaction, an excess amount of a substituted amine can be used or a base can be allowed to coexist to supplement the acid produced during the reaction.
• Examples of the solvent used include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, water, and mixed solvents thereof. Can do.
• Examples of the coexisting base include triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and the like.
• the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 0 ° 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.
• Compound (16) can be produced by replacing L 3 of compound (14) with R 2 which is an aryl group by Suzuki coupling reaction.
• This reaction proceeds, for example, in the presence of a base using compound (14) and arylboronic acid in a solvent and a palladium reagent as a catalyst.
• the solvent used include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, water, and mixed solvents thereof.
• solvent include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, water, and mixed solvents thereof.
• 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 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 1b-8 This step is a step for producing the compound (1a) by converting the hydroxyl group of the compound (16) into an appropriate leaving group (L 1 ).
• Compound (1a) can be produced, for example, by reacting carbon tetrabromide with compound (16) in the presence of triphenylphosphine or the like in a solvent when L 1 is a bromine atom.
• the solvent used for the reaction include tetrahydrofuran, dichloromethane, chloroform, a mixed solvent thereof and the like.
• the reaction temperature can usually be carried out at ⁇ 50 ° C. to 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.
• R 2 , R 3 , R 4 , R 5 , L 1 and L 2 are as defined above.
• Step 1c-1 This step is a step of producing compound (18) by a condensation reaction between compound (17) and compound (4). This step can be performed according to the above-mentioned method a, step 1a-1. Moreover, the compound (17) 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 1c-2 This step is a step of producing compound (19) from compound (18). This step can be performed according to the above-mentioned method a, step 1a-2.
• Step 1c-3 This step is a step of producing compound (20) from compound (19). This step can be performed according to the above-mentioned method a, step 1a-3.
• Step 1c-4 This step is a step of producing compound (1b) having the above structure among compounds (1) from compound (20). This step can be performed according to the above-mentioned method a, step 1a-4.
• R 2 , R 3 , R 4 , R 5 , L 1 and L 2 are as defined above;
• Q 2 represents a C 1-6 alkyl group or a C 7-10 aralkyl group.
• Step 1d-1 This step is a step of producing compound (22) by a condensation reaction between compound (21) and compound (4). This step can be performed according to the above-mentioned method a, step 1a-1. Moreover, the compound (21) 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 1d-2 This step is a step of producing compound (23) from compound (22). This step can be performed according to the above-mentioned method a, step 1a-2.
• Step 1d-3 This step is a step of producing compound (24) from compound (23). This step can be performed according to the above-mentioned method a, step 1a-3.
• Step 1d-4 This step is a step of producing compound (25) from compound (24).
• Compound (25) can be produced, for example, by reducing the alkoxycarbonyl group of compound (24) to a hydroxymethyl group using lithium aluminum hydride, lithium borohydride or the like in a solvent.
• the solvent used include tetrahydrofuran, diethyl ether, 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 ⁇ 20 ° 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 1d-5 This step is a step for producing the compound (1b) by converting the hydroxyl group of the compound (25) into an appropriate leaving group (L 1 ). This step can be performed according to the above-mentioned method b, step 1b-8.
• R 2 , R 3 , R 4 , R 5 , L 1 , L 2 , L 3 and L 4 are as defined above.
• Step 1e-1 This step is a step of producing compound (27) from compound (26) and compound (4).
• Compound (27) is obtained by, for example, treating a cyclization precursor obtained by a condensation reaction of compound (26) and compound (4) in a solvent according to the above method a, step 1a-1 with an appropriate acid.
• the solvent used include xylene, toluene, benzene, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like.
• the acid used in this reaction include p-toluenesulfonic acid, acetic acid, hydrochloric acid, trifluoroacetic acid and the like.
• the reaction temperature is usually from ⁇ 20 ° C.
• reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
• the compound (26) 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 1e-2 This step is a step for producing a compound (28) by converting a bromine atom of the compound (27) into a formyl group.
• Compound (28) is produced, for example, by converting the bromine atom of compound (27) into a lithium salt, Grignard reagent, or the like in a solvent and then reacting with a compound serving as a formyl source such as N, N-dimethylformamide. can do.
• the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like.
• Examples of the reagent used when preparing the lithium salt include n-butyllithium, sec-butyllithium, lithium diisopropylamide and the like.
• Examples of the reagent used when the Grignard reagent is used include isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, and metallic magnesium.
• the reaction temperature can usually be carried out at -78 ° 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.
• Step 1e-3 This step is a step for producing a compound (29) by converting a formyl group of the compound (28) into a hydroxymethyl group.
• Compound (29) can be produced, for example, by reducing compound (28) with sodium borohydride, lithium aluminum hydride, lithium borohydride or the like in the presence of a solvent.
• the solvent used include methanol, water, ethanol, tetrahydrofuran, and mixed solvents thereof.
• 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 1e-4 This step is a step of producing a compound (1c) having the above structure among the compounds (1) by converting the hydroxyl group of the compound (29) into an appropriate leaving group (L 1 ). This step can be performed according to the above-mentioned method b, step 1b-8.
• Step 1e-5 This step is a step of producing compound (30) from compound (26).
• Compound (30) can be produced, for example, by reacting compound (26) with cyanogen bromide in a solvent.
• the solvent used include ethanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like.
• the reaction temperature is usually from ⁇ 20 ° C. to the 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 1e-6 This step is a step for producing the compound (31) by introducing a tert-butoxycarbonyl group into the amino group of the compound (30). This step can be performed according to the above-mentioned method b and step 1b-2.
• Step 1e-7 This step is a step for producing a compound (32) by converting a bromine atom of the compound (31) into a formyl group. This step can be performed according to the above-mentioned e method and step 1e-2.
• Step 1e-8 This step is a step for producing a compound (33) by converting a formyl group of the compound (32) into a hydroxymethyl group. This step can be performed according to the above-mentioned e method and step 1e-3.
• Step 1e-9 This step is a step for producing the compound (34) by converting the amino group produced by removing the tert-butoxycarbonyl group of the compound (33) into an appropriate leaving group (L 3 ).
• This step can be performed according to the above-mentioned method b, step 1b-4 and step 1b-6.
• Step 1e-10 This step is a step for producing a compound (29) by reacting the compound (34) with the compound (15) and substituting L 3 with R 2 .
• This step can be carried out according to the above-mentioned method b, step 1b-7.
• R 2 , R 3 , R 4 , R 5 , L 1 , L 2 and Q 2 are as defined above.
• Step 1f-1 This step is a step of producing compound (36) from compound (35) and compound (4). This step can be carried out according to the above-mentioned e method and step 1e-1. Moreover, the compound (35) 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 1f-2 This step is a step of producing compound (37) from compound (36). This step can be carried out according to the above-mentioned method d, step 1d-4.
• Step 1f-3 This step is a step of producing a compound (1d) having the above structure among the compounds (1) by converting the hydroxyl group of the compound (37) into an appropriate leaving group (L 1 ). This process It can be carried out according to the above-mentioned method b, step 1b-8.
• R 2 , R 3 , R 4 , R 5 , L 1 , L 3 , L 4 , Q, Q 1 , Q 2 and A are as defined above;
• L 5 is a bromine atom, an iodine atom, ZnBr , ZnCl and the like;
• L 6 represents a bromine atom, an iodine atom and the like.
• Step 2-1 This step is a step of producing compound (10) by reaction of compound (8) with compound (9). This step can be performed according to the above-mentioned method b and step 1b-1.
• Step 2-2 is a step for producing the compound (11) by introducing a tert-butoxycarbonyl group into the amino group of the compound (10). This step can be performed according to the above-mentioned method b and step 1b-2.
• Step 2-3a This step is a step for producing a compound (39) by a coupling reaction of the compound (11) and the compound (38).
• Compound (39) can be produced, for example, by converting the bromine atom of compound (11) into a lithium salt, Grignard reagent, or the like in a solvent and then reacting with compound (38).
• the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like.
• the reagent used when preparing the lithium salt include n-butyllithium, sec-butyllithium, lithium diisopropylamide and the like.
• Examples of the reagent used when the Grignard reagent is used include isopropylmagnesium chloride, isopropylmagnesium chloride lithium chloride complex, and metallic magnesium.
• the reaction temperature can usually be ⁇ 78 ° C. to 50 ° C., preferably ⁇ 20 ° 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.
• Step 2-3b This step is a step for producing the compound (40) by replacing the hydroxy group of the compound (39) with a hydrogen atom.
• Compound (40) can be produced, for example, by reacting phosphorus tribromide with compound (39) in a solvent or in the absence of a solvent. Examples of the solvent used include chloroform.
• 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 2-3c This step is a step of producing compound (40) by a coupling reaction between compound (11) and compound (41).
• Compound (40) can be produced, for example, by utilizing a Negishi coupling reaction between compound (11) and compound (41) in a solvent.
• the solvent used include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like.
• the reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, 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.
• Step 2-3d This step is a step of producing compound (43) from compound (11) and compound (42).
• Compound (43) is obtained by, for example, reacting a compound obtained by converting the bromine atom of compound (11) into a lithium salt or a Grignard reagent or the like according to the aforementioned method b, step 1b-3 in a solvent and reacting with compound (42). Thereafter, the obtained compound can be produced by treating with an appropriate acid.
• the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like.
• the acid used include hydrochloric acid.
• the reaction temperature can usually be carried out at -78 ° 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.
• Step 2-3e This step is a step for producing compound (40) by Suzuki coupling reaction of compound (43) and compound (44).
• Compound (40) can be produced, for example, by reacting compound (43) and compound (44) in a solvent and using a palladium reagent as a catalyst in the presence of a base.
• the solvent used include tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, a mixed solvent thereof and the like.
• 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 triethylamine, N, N-diisopropylethylamine, pyridine, 2,6-dimethylpyridine, 2,4,6-trimethylpyridine and the like.
• reaction temperature is usually from ⁇ 78 ° C. to the solvent reflux temperature, preferably 0 ° C. to 20 ° C.
• reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 30 minutes to 3 days.
• Step 2-3f This step is a step for producing a compound (12) by converting a bromine atom of the compound (11) into a hydroxymethyl group. This step can be performed according to the above-mentioned method b and step 1b-3.
• This step is a step for producing a compound (45) by converting the hydroxyl group of the compound (12) into an appropriate leaving group (L 1 ).
• This step can be performed according to the above-mentioned method b, step 1b-8.
• Step 2-3h This step is a step of producing compound (40) by reacting compound (45) with compound (2). This step can be performed according to the above-mentioned method A, step 1-1.
• Step 2-4 is a step for producing the compound (46) by removing the tert-butoxycarbonyl group of the compound (40). This step can be performed according to the above-mentioned method b and step 1b-4.
• Step 2-5 This step is a step of producing compound (47) by a coupling reaction between compound (10) and compound (38). This step can be performed according to the above-mentioned method B, step 2-3a.
• Step 2-6 This step is a step for producing the compound (46) by replacing the hydroxy group of the compound (47) with a hydrogen atom. This step can be performed according to the above-mentioned Method B and Step 2-3b.
• Step 2-7 This step is a step for producing the compound (48) by converting the amino group of the compound (46) into an appropriate leaving group (L 3 ). This step can be performed according to the above-mentioned method b, step 1b-6.
• Step 2-8 This step is a step for producing compound (Ic) by reacting compound (48) with compound (15) and substituting L 3 with R 2 .
• This step can be carried out according to the above-mentioned method b, step 1b-7.
• Step 2-9 This step is a step of producing compound (Id) by hydrolyzing the ester moiety of compound (Ic). This step can be performed according to the above-mentioned Method A, Step 1-2.
• Y 1 , Y 2 , R 2 , R 4 , R 5 , A and Q 1 are as defined above;
• Q 3 and Q 4 are a hydrogen atom and a C 1-6 alkyl group (bonded together to form a ring
• R 3a represents a C 1-6 alkyl group, a C 2-6 alkenyl group, a C 1-7 alkanoyl group, a cyano group, or the like.
• Step 3-1 This step is a step of producing compound (If) by substituting the bromine atom of compound (Ie) with R 3a .
• Compound (If) can be produced, for example, by reacting compound (Ie) with compound (49) in a solvent and using a palladium reagent as a catalyst in the presence of a base.
• the solvent used include tetrahydrofuran, 1,4-dioxane, dichloromethane, 1,2-dichloroethane, benzene, toluene, ethanol, propanol, N, N-dimethylformamide, dimethyl sulfoxide, water, and mixed solvents thereof. Can do.
• 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.
• 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.
• Compound (Ie) can be produced according to Method A or Method B.
• Step 3-2 This step is a step of producing compound (Ig) by hydrolyzing the ester moiety of compound (If). This step can be performed according to the above-mentioned Method A, Step 1-2.
• Method D Among the compounds (I), the following compound (Ih) can be produced, for example, by Method D described below.
• Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 , A and Z 2 are as defined above.
• Step 4-1 This step is a step of producing compound (Ih) by a condensation reaction between compound (Ib) and compound (50).
• Compound (Ih) can be produced, for example, by reacting compound (Ib) with compound (50) in the presence of a condensing agent in the presence or absence of a base in a solvent.
• the solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like.
• Examples of the condensing agent used 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
• 4-dimethylaminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT) or the like can also be used as a reaction accelerator.
• Y 1 , Y 2 , R 2 , R 3 , R 4 , R 5 and A are as defined above.
• Step 5-1 This step is a step of producing compound (51) from compound (Ib).
• Compound (51) 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
• the solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like.
• Examples of the condensing agent used 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
• 4-dimethylaminopyridine, pyridine, 1-hydroxybenzotriazole (HOBT) or the like can also be used as a reaction accelerator.
• Step 5-2 This step is a step of producing compound (52) by dehydration reaction of compound (51).
• Compound (52) can be produced, for example, by reacting compound (51) with thionyl chloride, phosphorus oxychloride or the like in a solvent.
• the solvent include N, N-dimethylformamide, dichloromethane, 1,4-dioxane, tetrahydrofuran, toluene, a mixed solvent thereof and the like.
• the reaction temperature can usually be carried out at ⁇ 78 ° 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 5-3 is a step for producing a compound (Ii) by converting a nitrile group of the compound (52) into a tetrazolyl group.
• Compound (Ii) can be produced, for example, by reacting compound (52) with sodium azide or the like in a solvent.
• the solvent include N, N-dimethylformamide, water, dichloromethane, 1,4-dioxane, tetrahydrofuran, a mixed solvent thereof and the like.
• zinc bromide, ammonium chloride, silver nitrate, acetic acid, etc. can be added as needed.
• the reaction temperature can usually be carried out at ⁇ 78 ° C. to solvent reflux temperature, preferably 20 ° 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.
• a protective group when required depending on the type of functional group, it can be carried out by appropriately combining the introduction and desorption operations according to a conventional method.
• a protective group For the type, introduction, and elimination of protecting groups, see, for example, Theodora W. Green & Peter G. M. The methods described in Wuts, “Green's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006 can be mentioned.
• 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.
• These 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 the compound (I) of the present embodiment or a pharmacologically acceptable salt thereof and an appropriate additive appropriately mixed, or the 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 urinary retention 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 invention 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.
• ⁇ agonists examples include mirabegron, KUC-7383, KRP-204, SM-350300, TRK-380, amibegron, clenbuterol, SAR-150640, sorabegron and the like.
• 5 ⁇ -reductase inhibitors examples 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 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, intramuscular, transdermal). Can be administered via the skin).
• the dose of compound (I) of the present embodiment is determined by the patient's age, sex, It is determined as appropriate according to body weight, disease, degree of treatment, and the like.
• 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.
• Methyl 5-chloro-2-[(1-methylcyclopropylcarbonyl) amino] benzoate To a solution of methyl 2-amino-5-chlorobenzoate (2.50 g) in dichloromethane (20 mL) under an argon atmosphere, 0 Triethylamine (8.5 mL) and 1-methylcyclopropanecarboxylic acid chloride (2.37 g) were added at 0 ° C. to prepare a reaction solution. The reaction was stirred at 0 ° C. for 5 hours. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate.
• the reaction solution was cooled to 0 ° C., water and a saturated aqueous sodium hydrogen carbonate solution were added to adjust the pH of the reaction solution to 11, and the mixture was extracted with ethyl acetate.
• the residue obtained by distilling off the solvent was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (5.0 mL) was added at room temperature to obtain a second reaction solution.
• the second reaction was stirred at room temperature for 24 hours.
• the second reaction solution was poured into a 1 mol / L aqueous potassium carbonate solution (100 mL), and the precipitated solid was collected by filtration to give the title compound as colorless crystals (1.37 g).
• Reference Examples 15-2 to 15-7 The corresponding compounds of Reference Examples 15-2 to 15-7 were obtained in the same manner as in Reference Example 15-1, using the corresponding aldehyde compounds. Their structures and spectral data are shown in Tables 7 and 8.
• Reference Examples 16-2 to 16-14 The corresponding compounds of Reference Examples 16-2 to 16-14 were obtained in the same manner as in Reference Example 16-1, using the corresponding amino form. Their structures and spectral data are shown in Tables 9-11.
• the first reaction solution was ice-cooled, and an aqueous hydrogen chloride solution (1.0 mol / L, 300 mL) was added for extraction.
• the organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate.
• dichloromethane 450 mL
• trifluoroacetic acid 200 mL
• the second reaction solution was stirred at room temperature for 2 hours.
• acetic acid (200 mL) and ethyl 2,4-dioxoheptanoate (16.0 mL) were added to the residue to obtain a third reaction solution.
• Examples 1-2 to 1-182 The following Examples 1-2 to 1-182 were obtained in the same manner as in Example 1-1 using the corresponding esters. Their structures and spectral data are shown in Tables 17-63.
• the second reaction solution was then stirred for 3 hours under ice cooling.
• the 2nd reaction liquid was diluted with ethanol (1 mL), and after adding sodium hydroxide aqueous solution (2 mol / L, 1.0 mL), it stirred at room temperature for 2 hours.
• reaction solution was stirred at 80 ° C. for 2 hours, and then stirred at 150 ° C. for 3 hours.
• 1 mol / L hydrochloric acid was added to the 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 evaporation of the solvent, the residue was purified using silica gel column chromatography (ethyl acetate) to obtain the title compound as a yellow liquid (18 mg).
• reaction was stirred at room temperature for 2 hours.
• Examples 7-2 to 7-9 The following compounds of Examples 7-2 to 7-9 were obtained in the same manner as in Example 7-1 using the corresponding chloromethyl compounds. Their structures and spectral data are shown in Tables 64-66.
• Examples 8-2 to 8-4 The following compounds of Examples 8-2 to 8-4 were obtained in the same manner as in Example 8-1, using the corresponding methyl compound. Their structures and spectral data are shown in Table 67.
• Examples 9-2 and 9-3 The corresponding compounds of Examples 9-2 and 9-3 were obtained in the same manner as Example 9-1 using the corresponding bromomethyl compounds. Their structure and spectral data are shown in Table 68.
• reaction solution was stirred at room temperature for 0.5 hour, p-toluenesulfonic acid monohydrate (460 mg) was added, and the mixture was stirred at room temperature for 5 minutes.
• reaction mixture was stirred at room temperature for 0.5 hour, p-toluenesulfonic acid monohydrate (230 mg) was added, and the mixture was heated to reflux for 5 hours.
• Examples 11-2 to 11-93 The following compounds of Examples 11-2 to 11-93 were obtained in the same manner as Example 11-1 using the corresponding halogen compounds. Their structures and spectral data are shown in Tables 69-93.
• reaction solution was subjected to a reaction at 90 ° C. for 1 hour using a microwave (CEM, 150 W).
• Example 12-2 to 12-33 Using the corresponding halogen compounds, the following compounds of Examples 12-2 to 12-33 were obtained in the same manner as in Example 12-1. Their structures and spectral data are shown in Tables 94-101.
• Examples 13-2 to 13-23 The following compounds of Examples 13-2 to 13-23 were obtained in the same manner as in Example 13-1, using the corresponding halogen compounds. Their structures and spectral data are shown in Tables 102-109.
• reaction solution was subjected to a reaction for 40 minutes at 80 ° C. using a microwave (CEM, 150 W).
• Example 18-2 to 18-4 The following compounds of Examples 18-2 to 18-4 were obtained in the same manner as in Example 18-1, using the corresponding halogen compound. Their structure and spectral data are shown in Table 110.
• 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, forward primer and SEQ ID NO: 2 The first PCR was performed using KOD-Plus-Ver2.0 (Toyobo Co., Ltd.) using the indicated reverse primer. 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: benzylpenicillin) as an antibiotic. 100 U / mL; 100 ⁇ g / mL as streptomycin), D-MEM liquid medium (high concentration, MEM non-essential amino acid (Invitrogen Corporation, final concentration 0.1 mM)) and fetal bovine serum (MoregateBiotech, final concentration: 10%) Using glucose and L-glutamine, Invitrogen Corporation), the cells were cultured in an incubator under 5% CO 2 gas conditions at 37 ° C. until they reached confluence.
• penicillin-streptomycin solution Invitrogen Corporation, final concentration: benzylpenicillin
• D-MEM liquid medium high concentration, MEM non-essential amino acid (Invitrogen Corporation, final concentration 0.1 mM)
• fetal bovine serum (MoregateBiotech, final concentration:
• 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.
• Rats EP 1 expression vector was diluted with 200 ng / 25 [mu] L / to be well OPTI-MEM (R) I Reduced-Serum Medium (Invitrogen Corporation).
• OPTI-MEM registered trademark I Reduced-Serum Medium (Invitrogen Corp.) to 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 cells into which the complex of rat EP 1 expression vector / Lipofectamine 2000 was dispensed were cultured at 37 ° C. for 24 hours in an incubator under 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 the obtained test compounds 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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