WO2014017342A1 - Dérivé d'indole ou un sel pharmacologiquement acceptable de celui-ci - Google Patents

Dérivé d'indole ou un sel pharmacologiquement acceptable de celui-ci Download PDF

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Publication number
WO2014017342A1
WO2014017342A1 PCT/JP2013/069347 JP2013069347W WO2014017342A1 WO 2014017342 A1 WO2014017342 A1 WO 2014017342A1 JP 2013069347 W JP2013069347 W JP 2013069347W WO 2014017342 A1 WO2014017342 A1 WO 2014017342A1
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Prior art keywords
methylcyclopropyl
group
indol
ylmethyl
pyridine
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PCT/JP2013/069347
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English (en)
Japanese (ja)
Inventor
田谷　和也
近藤　敦志
茂樹 瀬戸
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キッセイ薬品工業株式会社
杏林製薬株式会社
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Publication of WO2014017342A1 publication Critical patent/WO2014017342A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • 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
    • 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
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • 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
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Definitions

  • the present invention relates to an indole derivative having an EP 1 receptor antagonistic activity useful as a pharmaceutical product, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the same, and a pharmaceutical use thereof.
  • OAB overactive bladder syndrome
  • OABs are also sometimes referred to as overactive bladder (OAB).
  • OAB is a disease defined as “a symptom syndrome requiring urgency of urine, usually accompanied by frequent urination and nocturia. Imminent urinary incontinence is not essential”.
  • 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 describes a compound in which the substituent of R 2 of the above compound is a C 3-6 cycloalkyl group, and the C 3-6 cycloalkyl group is further substituted with a C 1-6 alkyl group. The compound is not described.
  • An object of the present invention is to provide a compound having a novel EP 1 receptor antagonistic action, or a pharmacologically acceptable salt thereof, a pharmaceutical composition containing the compound, and a pharmaceutical use thereof.
  • the present inventors diligently studied to find a compound having an EP 1 receptor antagonistic action. As a result, it was found that the compound (I) of the present invention or a pharmacologically acceptable salt thereof has a strong EP 1 receptor antagonistic activity, and has led to the present invention.
  • A is the following a), b), d) and h):
  • R 1 is a hydrogen atom
  • R 4 is a hydrogen atom
  • [3] The compound according to [2], or a pharmaceutically acceptable salt thereof, wherein Y 2 is a single bond, a C 2-4 alkenylene group or a C 2-4 alkynylene group.
  • R 3 is a hydrogen atom, or a pharmacologically acceptable salt thereof.
  • A is the following b) and h):
  • R 5 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group
  • R 6 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group, a haloC 1-6 alkyl, hydroxyalkyl C 1-6 alkyl group, C 1-6 alkoxy, halo C 1-6 alkoxy group, C 1-6 alkylsulfanyl group, C 1-6 alkylsulfinyl group, C 1-6 alkylsulfonyl group, A C 3-6 cycloalkyl group, a cyano group, or a C 2-6 alkenyl group, or R 5 and R 6 are bonded to
  • R 5 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group
  • R 6 is a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a haloC A 1-6 alkoxy group, a C 1-6 alkylsulfanyl group, a C 3-6 cycloalkyl group or a C 2-6 alkenyl group, or R 5 and R 6 are bonded to each other to form
  • a pharmaceutical composition comprising the compound according to any one of [1] to [9] or a pharmacologically acceptable salt thereof.
  • the pharmaceutical composition compris
  • An EP 1 receptor antagonist comprising the compound according to any one of [1] to [9], or a pharmacologically acceptable salt thereof.
  • a preventive or therapeutic agent for lower urinary tract symptoms comprising the compound according to any one of [1] to [9], or a pharmacologically acceptable salt thereof.
  • a method for preventing or treating lower urinary tract symptoms comprising administering an effective amount of the compound according to any one of [1] to [9] or a pharmacologically acceptable salt thereof.
  • a compound of any one of [1] to [9] or a pharmaceutically acceptable salt thereof for producing a pharmaceutical composition for preventing or treating lower urinary tract symptoms use.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof exhibited a strong EP 1 receptor antagonism in, for example, an EP 1 receptor antagonism confirmation test. Therefore, the compound (I) of the present invention, or a pharmacologically acceptable salt thereof, treats lower urinary tract symptoms (LUTS), particularly overactive bladder syndrome (OABs), etc., based on EP 1 receptor antagonism. Useful as a drug or prophylactic.
  • LUTS lower urinary tract symptoms
  • OABs overactive bladder syndrome
  • Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably, they are a fluorine atom or a chlorine atom.
  • C 1-6 alkyl group means an optionally branched alkyl group having 1 to 6 carbon atoms.
  • R 6 is preferably a methyl group, an ethyl group or an isopropyl group. In R 2 , a methyl group is preferable.
  • the “C 1-6 alkoxy group” means an optionally branched alkoxy group having 1 to 6 carbon atoms. Examples include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy group, hexyloxy group and the like.
  • halo C 1-6 alkyl group means the above C 1-6 alkyl group substituted with 1 to 5 of the same or different halogen atoms.
  • “Hydroxy C 1-6 alkyl group” means the above C 1-6 alkyl group substituted with a hydroxyl group. Examples thereof include a hydroxymethyl group, 1-hydroxyethyl group, 1-hydroxy-1,1-dimethylmethyl group, 2-hydroxyethyl group, 2-hydroxy-2-methylpropyl group, 3-hydroxypropyl group and the like.
  • C 1-6 alkylsulfanyl group means a group represented by (C 1-6 alkyl) -S—. Examples thereof include a methylsulfanyl group, an ethylsulfanyl group, a propylsulfanyl group, a butylsulfanyl group, a pentylsulfanyl group, and a hexylsulfanyl group.
  • C 1-6 alkylsulfinyl group means a group represented by (C 1-6 alkyl) -S ( ⁇ O) —. Examples thereof include a methylsulfinyl group, an ethylsulfinyl group, a propylsulfinyl group, a butylsulfinyl group, a pentylsulfinyl group, and a hexylsulfinyl group.
  • C 1-6 alkylsulfonyl group means a group represented by (C 1-6 alkyl) —SO 2 —. Examples thereof include a methanesulfonyl group, an ethanesulfonyl group, a propanesulfonyl group, a butanesulfonyl group, a pentanesulfonyl group, and a hexanesulfonyl group.
  • the “C 3-6 cycloalkyl group” means a monocyclic saturated alicyclic hydrocarbon group having 3 to 6 carbon atoms. Examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group. Preferably, it is a cyclopropyl group.
  • halo C 1-6 alkoxy group means the above C 1-6 alkoxy group substituted with 1 to 5 same or different halogen atoms.
  • C 7-10 aralkyl group means an alkyl group having 1 to 4 carbon atoms substituted with a phenyl group. Examples include benzyl group, phenethyl group, 1-phenylethyl group, 3-phenylpropyl group, 4-phenylbutyl group and the like.
  • the “C 1-6 alkylene group” means a saturated hydrocarbon chain having 1 to 6 carbon atoms which may be branched.
  • C 2-4 alkenylene group examples include —CH ⁇ CH—, —C (CH 3 ) ⁇ CH—, —CH ⁇ C (CH 3 ) —, —CH ⁇ CHCH 2 —, —CH 2 CH ⁇ CH— and the like.
  • C 2-4 alkynylene group examples include ethynylene group, 1-propynylene group, 2-propynylene group and the like.
  • C 2-6 alkenyl group examples include vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group, 2-butenyl group, 2-methylallyl group and the like.
  • the compound (I) of the present invention includes stereoisomers such as optical isomers and geometric isomers.
  • the optical isomer of the compound (I) of the present invention has an R configuration or a configuration at each asymmetric carbon atom. Any three-dimensional arrangement of S arrangement may be sufficient.
  • any optical isomer is included in the present invention, and a mixture of these optical isomers is also included.
  • a racemate consisting of an equal amount of each optical isomer in a mixture of optically active substances is also included in the scope of the present invention.
  • the compound (I) of the present invention when the compound (I) of the present invention is a racemic solid or crystal, racemic compounds, racemic mixtures and racemic solid solutions are also included in the scope of the present invention.
  • the present invention when a geometric isomer exists, the present invention includes any of the geometric isomers.
  • the compound (I) of the present invention when a tautomer exists, the present invention includes any of the tautomers.
  • Compound (I) of the present invention can be converted into a pharmacologically acceptable salt thereof according to a conventional method as necessary.
  • salts include acid addition salts and salts with bases.
  • Acid addition salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, Acid addition with organic acids such as p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid Mention may be made of salts.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, Acid addition with
  • salts with bases include salts with inorganic bases such as sodium salts, potassium salts, calcium salts and magnesium salts, and salts with organic bases such as piperidine, morpholine, pyrrolidine, arginine and lysine.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof includes solvates with pharmaceutically acceptable solvents such as hydrates and ethanol.
  • EP 1 receptor antagonism as used in the present invention 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 reduces or suppresses the inflow of calcium into the cell and decreases the intracellular calcium concentration.
  • the EP 1 receptor antagonism exhibits actions such as smooth muscle relaxation and suppression of sensory nerve stimulation.
  • EP 1 receptor antagonists are useful as therapeutic or prophylactic agents for symptoms such as LUTS, especially OABs, by acting on the bladder, urothelium, and the like.
  • EP 1 receptor antagonism can be evaluated by the efficacy of inhibiting the amount of calcium inflow into cells by PGE 2 . 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.
  • (I-1) A is preferably a benzene ring, a pyridine ring, a pyrazine ring, a furan ring, a thiazole ring or an oxazole ring, more preferably a pyridine ring, a pyrazine ring or a thiazole ring, still more preferably a pyridine ring It is a ring.
  • Y 1 is preferably a C 1-6 alkylene group or a sulfur atom, more preferably —CH 2 —, —CH (CH 3 ) —, —C (CH 3 ) 2 — or sulfur. An atom, more preferably —CH 2 — or a sulfur atom.
  • Y 2 is preferably a single bond, a C 2-4 alkenylene group or a C 2-4 alkynylene group, and more preferably a single bond.
  • R 1 is preferably a hydrogen atom.
  • R 2 is preferably a methyl group or an ethyl group, and more preferably a methyl group.
  • R 3 is preferably a hydrogen atom, a methyl group or an ethyl group, more preferably a hydrogen atom.
  • R 4 is preferably a hydrogen atom.
  • R 5 is preferably a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group, more preferably a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, An ethyl group or a methoxy group, more preferably a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group.
  • R 6 is preferably a halogen atom, a C 1-6 alkyl group, a halo C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a C 1-6 alkyl A sulfanyl group, a C 3-6 cycloalkyl group or a C 2-6 alkenyl group, more preferably a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 3-6 cycloalkyl group or C A 2-6 alkenyl group, more preferably a methoxy group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.
  • R 7 is preferably a hydrogen atom.
  • Z is preferably a hydrogen atom or a fluorine atom, more preferably a hydrogen atom.
  • Q is preferably a methylene group or a single bond, more preferably a single bond.
  • a preferred embodiment of the compound (I) of the present invention or a pharmacologically acceptable salt thereof is a compound comprising a combination of substituents described below.
  • A is a benzene ring, pyridine ring, pyrazine ring, furan ring, thiazole ring or oxazole ring;
  • Y 1 is a C 1-6 alkylene group or a sulfur atom;
  • Y 2 is a single bond, a C 2-4 alkenylene group or a C 2-4 alkynylene group;
  • R 1 is a hydrogen atom;
  • R 2 is a methyl group or an ethyl group;
  • R 3 is a hydrogen atom, a methyl group or an ethyl group;
  • R 4 is a hydrogen atom;
  • R 5 is a hydrogen atom, a halogen atom, a C 1-6 alkyl group or a C 1-6 alkoxy group;
  • R 6 represents a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a halo C 1-6 alkoxy group, a
  • Embodiment 2 In embodiment 1, further: A is a pyridine ring, pyrazine ring or thiazole ring; Y 1 is —CH 2 — or a sulfur atom; Y 2 is a single bond; R 3 is a hydrogen atom; Z is a hydrogen atom.
  • Embodiment 3 In embodiment 2, further: R 2 is a methyl group; Q is a single bond.
  • Embodiment 4 In embodiment 3, further: A is a pyridine ring.
  • Embodiment 5 in embodiment 4, further: R 5 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group, an ethyl group or a methoxy group.
  • Embodiment 6 In embodiment 5, further: R 6 is a halogen atom, a C 1-6 alkyl group, a C 1-6 alkoxy group, a C 3-6 cycloalkyl group or a C 2-6 alkenyl group.
  • Embodiment 7 in embodiment 6, further: R 5 is a hydrogen atom, a fluorine atom, a chlorine atom, a methyl group or an ethyl group; R 6 is a methoxy group, a methyl group, an ethyl group, an isopropyl group or a cyclopropyl group.
  • Embodiment 8 In any of embodiment 1 to embodiment 4, further R 5 and R 6 are bonded to each other to form — (CH 2 ) 3 —, —O— (CH 2 ) 2 —, — (CH 2 ) 2 —O—, — (CH 2 ) 4 —, —O Selected from the group consisting of — (CH 2 ) 3 —, — (CH 2 ) 3 —O—, —CH 2 —O— (CH 2 ) 2 —, and — (CH 2 ) 2 —O—CH 2 —.
  • Embodiment 9 In embodiment 8, further: R 5 and R 6 are bonded to each other, - (CH 2) 3 - or - (CH 2) 4 - to form a.
  • Specific compounds included in this embodiment include the following compounds. 6- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 57), 6- [6-cyclopropyl-2- (1- Methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 58), 6- [6-chloro-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] Pyridine-2-carboxylic acid (Example 59), 6- [6-Methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (Example 60), 6 -[6-Ethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxy
  • Compound (I) of the present invention or a pharmacologically acceptable salt thereof can be produced according to the method shown in the following schemes 1 to 4 or a method analogous thereto. it can.
  • R 8 is a C 1-6 alkyl group or C 7-10 represents an aralkyl group
  • R 9 represents a C 1-6 alkyl group
  • L 1 represents a leaving group such as a chlorine atom, a bromine atom, an iodine atom, or a methanesulfonyloxy group.
  • Step 1-1 Compound (2) can be produced by reacting compound (1) with ditert-butyl dicarbonate in a solvent.
  • the solvent used include tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, a mixed solvent thereof and the like.
  • the reaction temperature is usually room temperature to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 1 hour to 3 days.
  • This step can also be carried out using a known method for protecting an amino group with a tert-butoxycarbonyl group. As such a method, for example, Theodora W. et al. Greene & Peter G. M.M. Edited by Wuts, “Greene's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience. Nce, 2006 can be exemplified.
  • Step 1-2 Compound (3) can be produced by reacting compound (2) treated with a base with compound (5) in a solvent.
  • the solvent used include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, a mixed solvent thereof and the like.
  • the base used include n-butyllithium, sec-butyllithium, tert-butyllithium and the like, and sec-butyllithium is preferable.
  • the reaction temperature is usually ⁇ 78 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature and the like, but is usually 30 minutes to 1 day.
  • the compound (5) used at this process can use a commercial item, can also be manufactured by the method of literature description, or the method according to them.
  • Step 1-3 Compound (4) can be produced by reacting compound (3) treated with a base with compound (6) in a solvent.
  • the solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethylimidazolidin-2-one, tetrahydrofuran, a mixed solvent thereof and the like.
  • the base used include sodium hydride, potassium tert-butoxide, cesium carbonate and the like.
  • the reaction temperature is usually ⁇ 20 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (6) used at this process can use a commercial item, and can also manufacture it by the method of literature description, or the method according to them.
  • Step 1-4 Compound (Ia) can be produced by treating compound (4) with an acid in a solvent.
  • the solvent used include dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like.
  • the acid used include trifluoroacetic acid, methanesulfonic acid, concentrated hydrochloric acid, concentrated sulfuric acid and the like.
  • the reaction temperature is usually ⁇ 78 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 1-5 Compound (Ib) can be produced by treating compound (Ia) by a general method for converting an ester group to a carboxy group. Such methods are well known to those skilled in the art and are described in, for example, Theodora W. et al. Greene & Peter G. M.M. A description by Wuts, “Green's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006 can be exemplified.
  • Step 1-6 Compound (Ic) can be produced by reacting compound (Ia) with compound (7) in the presence of a base in a solvent.
  • a solvent used include N, N-dimethylformamide, N, N-dimethylacetamide, 1,3-dimethylimidazolidin-2-one, N-methyl-2-pyrrolidinone, and mixed solvents thereof.
  • the base used include sodium hydride, potassium tert-butoxide, cesium carbonate, potassium carbonate and the like.
  • the reaction temperature is usually ⁇ 20 ° C. to 60 ° C.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (7) used at this process can use a commercial item, can also be manufactured by the method of literature description, or the method according to them.
  • Step 1-7 Compound (Id) can be produced by treating compound (Ic) by a general method for converting an ester group to a carboxy group. This step can be performed according to the above step 1-5.
  • Y 3 is a single bond or C 1. Represents a -5 alkylene group.
  • Step 2-1 Compound (9) can be produced by reacting compound (8) with compound (11) in the absence or presence of a base in the absence or presence of a solvent.
  • a solvent examples include ethanol, 2-ethoxyethanol, ethyl acetate, toluene, xylene, N, N-dimethylformamide, N, N-dimethylacetamide, a mixed solvent thereof and the like.
  • the base used examples include N, N-dimethylaniline and triethylamine.
  • the reaction temperature is usually room temperature to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (8) and (11) used at this process can use a commercial item, can also be manufactured by the method of literature description, or the method according to them.
  • Step 2-2 Compound (9) can be produced by treating compound (3) with an acid in a solvent.
  • the solvent used include dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, tetrahydrofuran, 1,4-dioxane, a mixed solvent thereof and the like.
  • the acid used include trifluoroacetic acid, methanesulfonic acid, concentrated hydrochloric acid, concentrated sulfuric acid and the like.
  • the reaction temperature is usually ⁇ 78 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 2-3 Compound (Ia) can be produced by reacting compound (9) with compound (12) in a solvent in the presence of a reducing agent and an acid.
  • a solvent used include dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrahydrofuran, a mixed solvent thereof and the like.
  • An example of the reducing agent used is triethylsilane.
  • the acid used include trifluoroacetic acid, trimethylsilyl trifluoromethanesulfonate, and boron trifluoride diethyl ether complex.
  • the reaction temperature is usually ⁇ 78 ° C. to room temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • the compound (12) used at this process can use a commercial item, can also be manufactured by the method of literature description, or the method according to them.
  • Step 2-4 Compound (10) can be produced by reacting compound (9) with compound (12) in the presence of a base in a solvent.
  • a solvent include dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, toluene, methanol, ethanol, a mixed solvent thereof and the like.
  • the base used include 1,8-diazabicyclo [5,4,0] -undec-7-ene, 1,5-diazabicyclo [4,3,0] -non-5-ene, sodium methoxide, sodium ethoxy And the like.
  • the reaction temperature is usually ⁇ 20 ° C. to 50 ° C.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 2-5 Compound (Ia) can be produced by subjecting compound (10) to a reduction reaction.
  • Specific examples of the method include the following methods (a) to (c).
  • the reaction temperature is usually ⁇ 30 ° C. to room temperature.
  • the reaction time varies depending on the raw material used, solvent, reaction temperature, etc., but is usually 10 minutes to 24 hours.
  • (B) Method of reacting compound (10) with a reducing agent in the presence of an acid
  • the reaction is carried out in a solvent such as dichloromethane, chloroform, 1,2-dichloroethane, tetrahydrofuran, a mixed solvent thereof or the like.
  • the acid used include trifluoroacetic acid, trimethylsilyl trifluoromethanesulfonate, and boron trifluoride diethyl ether complex.
  • An example of the reducing agent used is triethylsilane.
  • the reaction temperature is usually ⁇ 78 ° C. to room temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • (C) Process for treating compound (10) under catalytic hydrogenation conditions
  • a method well known to those skilled in the art can be used.
  • the reaction is carried out, for example, in a hydrogen atmosphere using a reduction catalyst such as palladium-carbon or platinum oxide in a solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, acetic acid, or a mixed solvent thereof.
  • the reaction temperature is usually from 0 ° C to 60 ° C.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • R 10 is bonded to each other to form a ring.
  • Step 3-1 Compound (13) can be produced by treating compound (Ie) with an acid in a solvent.
  • the solvent used include dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, tetrahydrofuran, a mixed solvent thereof and the like.
  • the acid used include boron tribromide.
  • the reaction temperature is usually ⁇ 78 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 3-2 Compound (14) can be produced by reacting compound (13) with a trifluoromethanesulfonylating agent in the presence of a base in a solvent.
  • a solvent include dichloromethane, chloroform, 1,2-dichloroethane, toluene, acetonitrile, pyridine, tetrahydrofuran, 1,4-dioxane, diethyl ether, N, N-dimethylformamide, a mixed solvent thereof and the like.
  • Examples of the base used include triethylamine, N, N-diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 2,6-lutidine, 2,4,6-trimethylpyridine, sodium carbonate, potassium carbonate, sodium hydride, sodium tert -Butoxide, potassium tert-butoxide, potassium phosphate and the like.
  • Examples of the trifluoromethanesulfonylating agent to be used include trifluoromethanesulfonic anhydride, N-phenylbis (trifluoromethanesulfonimide) and the like.
  • the reaction temperature is usually ⁇ 78 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • Step 3-3 Compound (Ia) can be produced by reacting compound (14) with compound (15) in the presence of a palladium reagent and a base in a solvent.
  • a palladium reagent examples include 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, toluene, N, N-dimethylformamide, ethanol, water and a mixed solvent thereof.
  • Examples of the palladium reagent used include palladium (II) acetate, bis (triphenylphosphine) palladium (II) dichloride, tetrakis (triphenylphosphine) palladium (0), tris (dibenzylideneacetone) dipalladium (0) and the like. It is done.
  • Examples of the base used include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium phosphate monohydrate, cesium fluoride, sodium tert-butoxide and the like.
  • the reaction temperature is usually room temperature to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • This step can also be performed by adding a ligand such as 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, bis (diphenylphosphino) ferrocene, if necessary.
  • a ligand such as 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, bis (diphenylphosphino) ferrocene, if necessary.
  • the compound (15) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, or the method according to them.
  • Step 3-4 Compound (Ia) can be produced by reacting compound (14) with compound (16) in the presence of a palladium reagent in a solvent.
  • a solvent examples include 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxane, toluene, N, N-dimethylformamide, ethanol, water and a mixed solvent thereof.
  • Palladium reagents used include palladium (II) acetate, bis (triphenylphosphine) palladium (II) dichloride, tetrakis (triphenylphosphine) palladium (0), bis (dibenzylideneacetone) palladium (0), tris (di Benzylideneacetone) dipalladium (0) and the like.
  • Examples of the base used include sodium carbonate, potassium carbonate, cesium carbonate, potassium phosphate, potassium phosphate monohydrate, cesium fluoride, sodium tert-butoxide and the like.
  • the reaction temperature is usually room temperature to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • This step can also be performed by adding a ligand such as 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl, bis (diphenylphosphino) ferrocene, if necessary.
  • the compound (16) used at this process can use a commercial item, and can also manufacture it according to the method of other literature description, or the method according to them.
  • Step 4-1 Compound (If) can be produced by reacting compound (9) with compound (17) in the presence of an oxidizing agent in a solvent.
  • the solvent used include dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol, water, a mixed solvent thereof and the like.
  • the oxidizing agent used include iodine, N-chlorosuccinimide, [bis (trifluoroacetoxy) iodo] benzene, and oxone (registered trademark).
  • the reaction temperature is usually ⁇ 78 ° C. to reflux temperature.
  • the reaction time varies depending on the raw material used, the solvent, the reaction temperature, etc., but is usually 30 minutes to 3 days.
  • 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 4-2 Compound (Ig) can be produced by treating compound (If) by a general method for converting an ester group to a carboxy group. This step can be performed according to the above step 1-5.
  • Step 4-3 Compound (Ih) can be produced by N-alkylating compound (If). This step can be performed according to the above step 1-6.
  • Step 4-4 Compound (Ii) can be produced by treating compound (Ih) by a general method for converting an ester group to a carboxy group. This step can be performed according to the above step 1-5.
  • a protective group when required depending on the type of functional group, it can be carried out by appropriately combining introduction and desorption operations according to a conventional method.
  • introduction and elimination of the protecting group see, for example, Theodora W. Green & Peter G. M. ⁇ Wuts, edited by “Greene's Protective Groups in Organic Synthesis”, fourth edition, Wiley-Interscience, 2006.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof, and an intermediate used for producing the compound, if necessary, are isolated and purified well known to those skilled in the art. It can be isolated and purified by means such as solvent extraction, crystallization / recrystallization, chromatography, preparative high performance liquid chromatography, and the like.
  • the pharmaceutical composition containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient may be used in various dosage forms depending on the usage.
  • dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, suppositories, patches, sublinguals, etc. It is administered orally or parenterally.
  • compositions are prepared according to known methods depending on the dosage form, using appropriate excipients, disintegrants, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents. It can be prepared by appropriately mixing or diluting / dissolving with pharmaceutical additives such as emulsifiers, dispersants, stabilizers, and solubilizing agents.
  • pharmaceutical additives such as emulsifiers, dispersants, stabilizers, and solubilizing agents.
  • compound (I) or a pharmaceutically acceptable non-salt and EP 1 receptor antagonist agents of the present invention simultaneously or separately each of active ingredients, and the aforementioned It can manufacture by formulating similarly.
  • Compound (I) or a pharmaceutically acceptable salt of the present invention exhibit a strong EP 1 receptor antagonism in the EP 1 receptor antagonistic activity confirmatory test and the like. Therefore, the compound (I) of the present invention can reduce the intracellular calcium concentration. Therefore, the pharmaceutical composition containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is used for the treatment of a disease or symptom caused by the activation of EP 1 receptor by PGE 2 stimulating action. It can be used as a medicine or a prophylactic.
  • Examples of diseases that activate the EP 1 receptor by PGE 2 stimulation include lower urinary tract symptoms (LUTS), inflammatory diseases, pain diseases, osteoporosis, cancer, and the like.
  • the pharmaceutical composition containing the compound (I) of the present invention or a pharmacologically acceptable salt thereof as an active ingredient is preferably used as a therapeutic or prophylactic agent for LUTS, inflammatory disease or pain disease. . More preferably, it is LUTS.
  • 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 urine storage symptoms, urination symptoms, post-urination symptoms, and the like.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof is preferably used for the treatment or prevention of urinary retention symptoms.
  • Urine accumulation symptoms include urinary urgency, daytime frequent urination, night frequent urination, urinary incontinence (such as stress urinary incontinence, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturia, persistent urinary incontinence), and Bladder perception (increased bladder perception, decreased bladder perception, lack of bladder perception, nonspecific bladder perception, etc.) is included.
  • Compound (I) of the present invention or a pharmacologically acceptable salt thereof is urinary urgency, daytime frequent urination, nocturia, urge urinary incontinence, mixed urinary incontinence, enuresis, nocturia, increased bladder perception, or It is preferably used for the treatment or prevention of nonspecific bladder perception. More preferred are urinary urgency, daytime frequent urination, nocturia, urge incontinence, or increased bladder perception.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof is particularly preferable for the treatment or prevention of OABs.
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof can also be used in appropriate combination with at least one drug other than the EP 1 receptor antagonist.
  • Examples of the drug that can be used in combination with the compound (I) of the present invention or a pharmacologically acceptable salt thereof include overactive bladder (OAB), prostatic hypertrophy (PD) having a mechanism of action different from that of the EP 1 receptor antagonist. BPH), cystitis such as interstitial cystitis, and therapeutic agents for prostatitis and the like.
  • Such agents anticholinergics, alpha 1 antagonists, beta agonists, 5.alpha.-reductase inhibitors, PDE inhibitors, acetylcholinesterase inhibitors, antiandrogens, progesterone-based hormone, LH-RH analogs, neurokinin inhibitors , Antidiuretic, calcium channel blocker, smooth muscle direct acting drug, tricyclic antidepressant, potassium channel modulator, sodium channel blocker, H 1 blocker, serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, dopamine reuptake Inhibitors, GABA agonists, TRPV1 modulators, endothelin antagonists, 5-HT 1A antagonists, ⁇ 1 agonists, opioid agonists, P 2 X antagonists, COX inhibitors, ⁇ agonists, muscarinic agonists, etc.
  • anticholinergic agents ⁇ 1 antagonists, ⁇ agonists, 5 ⁇ -reductase inhibitors, PDE inhibitors, progesterone hormones, antidiuretics, smooth muscle direct acting agents or tricyclic antidepressants. More preferred are anticholinergic agents, ⁇ 1 antagonists, ⁇ agonists, smooth muscle direct acting agents or tricyclic antidepressants. More preferred are anticholinergic agents, ⁇ 1 antagonists or tricyclic antidepressants. Most preferred is an anticholinergic agent.
  • anticholinergic agent examples include oxybutynin, propiverine, solifenacin, tolterodine, imidafenacin, temiverine, darifenacin, fesoterodine, trospium, propantheline and the like.
  • Oxybutynin, propiverine, solifenacin, tolterodine or imidafenacin is preferable. More preferred is solifenacin or imidafenacin.
  • ⁇ 1 antagonist examples include urapidil, naphthopidyl, tamsulosin, silodosin, prazosin, terazosin, alfuzosin, doxazosin, CR-2991, feduxin and the like.
  • ⁇ agonist examples include mirabegron, KUC-7383, KRP-204, SM-350300, TRK-380, amibegron, clenbuterol, SAR-150640, sorabegron and the like.
  • Mirabegron or KUC-7383 is preferred. More preferred is mirabegron.
  • dutasteride examples include dutasteride, TF-505, finasteride, and izonsteride. Preferred is dutasteride or 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. Tadalafil, vardenafil, sildenafil or avanafil is preferred.
  • 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, propiverine, temiverine, PD-299685, alanidipine, azelnidipine, varnidipine, benidipine, bevantolol, clevidipine, CYC-381, diltiazem, efonidipine, fasudil, felodipine, gabamil Rasidipine, lercanidipine, romeridine, manidipine, MEM-1003, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, SB-751689, verapamil, YM-58483, ziconotide and the like.
  • “Smooth muscle direct acting drugs” include flavoxate and the like.
  • tricyclic antidepressants examples include imipramine, clomipramine, amitriptyline and the like. Preferably, imipramine is used.
  • 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 includes acribastine, alcaftadine, bepotastine, bilastine, cetirizine, desloratadine, ebastine, efletirizine, epinastine, fexofenadine, GSK-835726, levocabastine, levocetirizine, loratadine, mequitadine, mizolastine, NBI-7, 43 Examples thereof include ReN-1869, terfenadine, UCB-35440, bapitazine, 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, pagoclone, 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 capsaicin, resiniferatoxin, DE-096, GRC-6221, AMG-8562, JTS-653, SB-705498, A-4256619, A-784168, ABT-102, AMG-628. AZD-1386, JNJ-17203212, NGD-8243, PF-38664086, SAR-115740, SB-784443, and the like.
  • Endothelin antagonists include SB-234551, ACT-064992, ambrisentan, atrasentan, bosentan, clazosentan, darsentan, fundsentan, S-0139, TA-0201, TBC-3711, dibotentan, 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 pharmaceutical composition of the present invention comprises the following 1) to 5): 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, It includes any one administration method selected from 4) administration at different times by the same route of administration as separate formulations, and 5) administration at different times by different routes of administration as separate formulations. Moreover, when administering at different time as a separate formulation like 4) or 5), there is no restriction
  • the compound (I) of the present invention or a pharmacologically acceptable salt thereof can be used in combination with one or more of the above drugs as appropriate, thereby providing an additive effect in preventing or treating the above diseases.
  • the above advantageous effects can be obtained.
  • the amount of use can be reduced compared with the case of using it alone, or the side effect of the combined drug can be avoided or reduced.
  • composition of the present invention can be administered systemically or locally, orally or parenterally (nasal, pulmonary, intravenous, rectal, subcutaneous, intramuscular, transdermal, etc.).
  • the dose of the compound (I) of the present invention depends on the age, sex, body weight, disease of the patient. It is appropriately determined depending on the degree of treatment. For example, in the case of oral administration, it can be appropriately administered in one or several divided doses within the range of about 3 to 1000 mg, 6 to 540 mg or 10 to 100 mg per adult day. In the case of an injection, it can be appropriately administered in a single dose or divided into several doses within the range of about 0.1 to 300 mg, 1 to 100 mg, or 3 to 30 mg per day for an adult.
  • the dose of compound (I), which is an active ingredient of the EP 1 receptor antagonist of the present invention, or a pharmacologically acceptable salt thereof depends on the dose of a drug other than the EP 1 receptor antagonist. You can lose weight.
  • Step 1 A solution of 1-methylcyclopropanecarboxylic acid (5.00 g) in dichloromethane (30 mL) was cooled in an ice-saturated saline bath under an argon atmosphere. Thereto, oxalyl chloride (4.71 mL) was added dropwise in 5 portions every 5 minutes, and the mixture was stirred under the same conditions for 2 hours and then at room temperature for 18 hours. The reaction mixture was used in Step 2 below.
  • Step 2 A suspension of N, O-dimethylhydroxylamine hydrochloride (4.87 g) in dichloromethane (50 mL) was cooled in an ice-water bath under an argon atmosphere.
  • Ethyl bromide (5.98 g) was added dropwise thereto. The mixture was stirred at ⁇ 78 ° C. for a further 3 hours and gradually warmed to room temperature. After 14 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain tert-butyl 1-ethylcyclopropanecarboxylate (2.16 g).
  • Step 1 A solution of 1-ethylcyclopropanecarboxylic acid (1.29 g) in dichloromethane (6.8 mL) was cooled in an ice-saturated saline bath under an argon atmosphere. Thereto, oxalyl chloride (1.06 mL) was added dropwise in 3 portions every 5 minutes, and the mixture was stirred under the same conditions for 2 hours and then at room temperature for 16 hours. The reaction mixture was used in Step 2 below.
  • Step 2 A suspension of N, O-dimethylhydroxylamine hydrochloride (1.10 g) in dichloromethane (11.3 mL) was cooled in an ice-water bath under an argon atmosphere.
  • Reference Example 70 5- ⁇ 2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-methylcyclopropyl) was prepared in the same manner as in Reference Example 69 using the corresponding starting materials and reactants. Methyl -3-oxopropyl ⁇ -2-fluorobenzoate was synthesized.
  • Step 2 N, N-dimethylformamide (3.2 mL) of tert-butyl ⁇ 5-methoxy-2- [2- (1-methylcyclopropyl) -2-oxoethyl] phenyl ⁇ carbamate (328 mg) under argon atmosphere The solution was cooled in an ice water bath. Sodium hydride (50-72% in oil, 52 mg) was added thereto, and the mixture was stirred for 35 minutes under the same conditions. The solution obtained in Step 1 was added dropwise thereto, and the mixture was stirred for 70 minutes under the same conditions. A saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Reference Example 84 A mixture of dimethyl 2- (1-methylcyclopropyl) -1H-indole-3,6-dicarboxylate (174 mg), 1 mol / L aqueous sodium hydroxide (6 mL) and methanol (6 mL) was placed in a sealed tube with microwaves. The mixture was stirred at 150 ° C. for 1 hour under irradiation. Another lot of reaction was carried out under the same conditions. The two reaction mixtures were combined and 1 mol / L hydrochloric acid was added thereto. The mixture was concentrated under reduced pressure to remove methanol. The residue was extracted with ethyl acetate. The aqueous layer was extracted with ethyl acetate.
  • reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [6- (acetoxymethyl) -2- (1-methylcyclopropyl) -1H-indole- Methyl 3-ylmethyl] pyridine-2-carboxylate (61.0 mg) was obtained.
  • Reference Example 101 6-Methoxy-2- (1-methylcyclopropyl) -5-propyl-1H-indole was synthesized in the same manner as in Reference Example 79 using the corresponding starting materials and reactants.
  • Methyl iodide (11.3 g) was added dropwise thereto. The mixture was stirred at ⁇ 78 ° C. for 1 hour and gradually warmed to room temperature. After 22 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain tert-butyl 1-methylcyclobutanecarboxylate (2.50 g).
  • Step 1 A solution of 1-methylcyclobutanecarboxylic acid (1.06 g) in dichloromethane (5.6 mL) was cooled in an ice-saturated saline bath under an argon atmosphere. Oxalyl chloride (0.876 mL) was added dropwise thereto, and the mixture was stirred at the same temperature for 1.5 hours and then at room temperature for 20 hours. The reaction mixture was used in Step 2 below.
  • Step 2 A suspension of N, O-dimethylhydroxylamine hydrochloride (906 mg) in dichloromethane (9.3 mL) was cooled in an ice-water bath under an argon atmosphere.
  • Triethylamine (4.5 mL) and then the reaction mixture obtained in Step 1 were added thereto. The mixture was stirred at the same temperature for 1.5 hours and then at room temperature for 24 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was separated and washed with saturated aqueous sodium bicarbonate. Silica gel was added to the organic layer and the mixture was stirred at room temperature for 2 hours. The insoluble material was filtered off and washed with diethyl ether / dichloromethane (1/1). The filtrate was concentrated under reduced pressure to obtain N-methoxy-N, 1-dimethylcyclobutanecarboxamide (1.26 g).
  • Reference Example 140 6-Methoxy-3- (6-methoxycarbonylpyridin-2-ylethynyl) -2- (1-methylcyclopropyl) -1H-indole-1-carboxylate tert-butyl (65.0 mg) in methanol (1.4 mL ) 10% palladium on carbon (water content 56.5 wt%, 22 mg) was added to the solution. Triethylsilane (0.225 mL) was added dropwise thereto, and the mixture was stirred at room temperature for 3 hours in a hydrogen atmosphere. The reaction mixture was filtered through a Celite (registered trademark) pad, and the filtrate was concentrated under reduced pressure. The residue was dissolved in methanol (1.4 mL).
  • Example 5 6- [6-Ethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 4 using the corresponding starting materials and reagents. Methyl was synthesized.
  • Example 6 [6-Isopropoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid was prepared in the same manner as in Example 4 using the corresponding starting materials and reagents. Methyl acid was synthesized.
  • reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [6-chloro-5-methoxy-2- (1-methylcyclopropyl) -1H-indole.
  • Methyl -3-ylmethyl] pyridine-2-carboxylate (71.8 mg) was obtained.
  • Example 8 6- [6-Ethyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 4 using the corresponding starting materials and reagents. Methyl was synthesized.
  • reaction mixture is purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) and then silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [5-chloro-6- Methyl methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (253 mg) was obtained.
  • Example 10 6- [6-Isopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 4 using the corresponding starting materials and reagents. Methyl was synthesized.
  • Example 11 Under an argon atmosphere, 6-methoxy-5-methyl-2- (1-methylcyclopropyl) -1H-indole (586 mg), methyl 6-formylpyridine-2-carboxylate (450 mg) and triethylsilane (1.30 mL) Of dichloromethane in 13.6 mL was cooled in an ice-water bath. Trifluoroacetic acid (0.313 mL) was added thereto, and the mixture was stirred under the same conditions for 30 minutes and then at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine.
  • Example 13 Dichloromethane of methyl 3- ⁇ 2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ benzoate (260 mg) under argon atmosphere The solution (5.5 mL) was cooled in an ice-water bath. Trifluoroacetic acid (1.1 mL) was added thereto, and the mixture was stirred at room temperature for 14 hours and then at 30 ° C. for 5 hours. Ethyl acetate and saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture, and the organic layer was separated.
  • Example 14 5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] furan-2-carboxylic acid in the same manner as in Example 13 using the corresponding starting materials and reagents. Ethyl acid was synthesized.
  • Example 15 Under ice cooling, methyl 3- ⁇ 2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ -2-fluorobenzoate ( 142 mg) was added trifluoroacetic acid (1 mL) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed successively with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example 16 Under argon atmosphere, 6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole (134 mg), ethyl 2-formylthiazole-4-carboxylate (109 mg) and triethylsilane (0.304 mL) in dichloromethane ( (2 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.071 mL) was added thereto, and the mixture was stirred for 30 minutes under the same conditions and then at room temperature for 13 hours.
  • reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole-3- Ethyl [Ilmethyl] thiazole-4-carboxylate (180 mg) was obtained.
  • Example 17 Dichloromethane of methyl 2- ⁇ 2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ isonicotinate (191 mg) under argon atmosphere (2.1 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.7 mL) was added there, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 18 Under an argon atmosphere, 6-methoxy-2- (1-methylcyclopropyl) -1H-indole (140 mg), ethyl 5-formylthiophene-2-carboxylate (128 mg) and triethylsilane (0.333 mL) in dichloromethane (3 .5 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.080 mL) was added thereto, and the mixture was stirred for 30 minutes under the same conditions and then at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
  • Example 20 Trimethyl 3- ⁇ 2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ benzoate (215 mg) under argon atmosphere Fluoroacetic acid (1 mL) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 3- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl. ] Methyl benzoate (132 mg) was obtained.
  • Example 21 5- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] furan-2-carboxylic acid in the same manner as in Example 20 using the corresponding starting materials and reagents. Ethyl was synthesized.
  • Example 22 Methyl 2-fluoro-3- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoate in the same manner as in Example 20 using the corresponding starting materials and reactants was synthesized.
  • Example 23 2- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiazole-4-carboxylic acid was prepared in the same manner as in Example 16 using the corresponding starting materials and reactants. Ethyl was synthesized.
  • Example 24 Methyl 6- ⁇ 2- [2- (tert-butoxycarbonylamino) -4,5-dimethylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ pyridine-2-carboxylate under an argon atmosphere A solution of (202 mg) in dichloromethane (2.16 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.72 mL) was added there, and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
  • Example 25 5- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-3-carboxylic acid was prepared in the same manner as in Example 18 using the corresponding starting materials and reactants. Methyl was synthesized.
  • Example 26 5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-2-carboxylic acid was prepared in the same manner as in Example 18 using the corresponding starting materials and reagents. Ethyl acid was synthesized.
  • Example 27 Under an argon atmosphere, 6-difluoromethoxy- (1-methylcyclopropyl) -1H-indole (170 mg), methyl 6-formylpyridine-2-carboxylate (118 mg) and triethylsilane (0.344 mL) in dichloromethane (3. (0 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.080 mL) was added thereto, and the mixture was stirred for 30 minutes under the same conditions and then at room temperature for 7 hours.
  • reaction mixture is purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [6-difluoromethoxy-2- (1-methylcyclopropyl) -1H-indole-3- [Ilmethyl] methyl pyridine-2-carboxylate (160 mg) was obtained.
  • Example 28 Under an argon atmosphere, methyl 2- ⁇ 2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ oxazole-4-carboxylate ( (137 mg) in dichloromethane (1.5 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.5 mL) was added thereto, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
  • Example 29 5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-3-carboxylic acid was prepared in the same manner as in Example 18 using the corresponding starting materials and reactants. Methyl acid was synthesized.
  • Example 30 To a solution of methyl 6- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (70.0 mg) in N, N-dimethylformamide (1 mL), Cesium carbonate (163 mg) and methyl iodide (0.025 mL) were added and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 31 5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] -2-fluorobenzoic acid in the same manner as in Example 20 using the corresponding starting materials and reagents. Methyl acid was synthesized.
  • Example 32 2-Fluoro-5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid in the same manner as in Example 20 using the corresponding starting materials and reagents. Methyl was synthesized.
  • reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- [5,6-dimethoxy-2- (1-methylcyclopropyl) -1H-indole-3. -Ilmethyl] methyl pyridine-2-carboxylate (265 mg) was obtained.
  • Example 34 Methyl 5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] nicotinate was synthesized in the same manner as in Example 20 using the corresponding starting materials and reactants. .
  • Example 35 Synthesis of methyl 5- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] nicotinate in the same manner as in Example 15 using the corresponding starting materials and reactants did.
  • Example 36 Under an argon atmosphere, 2- (1-methylcyclopropyl) -1,5,6,7-tetrahydrocyclopenta [f] indole (200 mg), methyl 6-formylpyridine-2-carboxylate (156 mg) and triethylsilane ( 0.454 mL) in dichloromethane (4.0 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.106 mL) was added thereto, and the mixture was stirred under the same conditions for 30 minutes and then at room temperature for 3.5 hours. The reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane).
  • Example 37 [1-Ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 30 using the corresponding starting materials and reactants Methyl 2-carboxylate was synthesized.
  • Example 38 Under an argon atmosphere, 5-ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indole (37.4 mg), methyl 6-formylpyridine-2-carboxylate (26.9 mg) and triethylsilane (A solution of 0.078 mL) in dichloromethane (1.6 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.019 mL) was added thereto, and the mixture was stirred under the same conditions for 35 minutes and then at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
  • Example 39 [2- (1-Methylcyclopropyl) -6- (methylsulfanyl) -1H-indol-3-ylmethyl] pyridine-2 in the same manner as in Example 18 using the corresponding starting materials and reagents. -Methyl carboxylate was synthesized.
  • Example 40 Dichloromethane of 6-methoxy-2- (1-methylcyclopropyl) -1H-indole (106 mg), methyl 6-acetylpyridine-2-carboxylate (94.4 mg) and triethylsilane (0.253 mL) under argon atmosphere (2.0 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.059 mL) was added thereto, and the mixture was stirred for 30 minutes under the same conditions and then at room temperature for 48 hours.
  • reaction mixture was purified by aminopropylated silica gel column chromatography (elution solvent: ethyl acetate-hexane) to give 6- ⁇ 1- [6-methoxy-2- (1-methylcyclopropyl) -1H-indole- Methyl 3-yl] ethyl ⁇ pyridine-2-carboxylate (149 mg) was obtained.
  • Example 41 [6- (1-Methylcyclopropyl) -5H- [1,3] dioxolo [4,5-f] indole-7 in the same manner as in Example 33, using the corresponding starting materials and reagents. -Methyl] pyridin-2-carboxylate was synthesized.
  • Example 42 A solution of methyl 6- [2- (1-methylcyclopropyl) -6- (methylsulfanyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (100 mg) in dichloromethane (1.36 mL) under an argon atmosphere. Was cooled in an ice-water bath. m-Chloroperbenzoic acid (about 25% water wet product, purity 65%, 174 mg) was added in two portions, and the mixture was stirred under the same conditions for 30 minutes and then at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate.
  • Example 43 Methyl 2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] isonicotinate was prepared in the same manner as in Example 4 using the corresponding starting materials and reactants. Synthesized.
  • Example 44 1,1,1,3,3 of methyl 6- [2- (1-methylcyclopropyl) -6- (methylsulfanyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (65.0 mg) , 3-Hexafluoropropan-2-ol (1.8 mL) solution was added 30% aqueous hydrogen peroxide (0.037 mL), and the mixture was stirred at room temperature for 1.5 hours. To the reaction mixture was added 10% aqueous sodium sulfite solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 45 Under an argon atmosphere, methyl 6- ⁇ 2- [2- (tert-butoxycarbonylamino) -4-methoxyphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ pyrazine-2-carboxylate (111 mg ) In dichloromethane (1.2 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.4 mL) was added there, and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 46 Under an argon atmosphere, methyl 6- ⁇ 2- [2- (tert-butoxycarbonylamino) -4-cyclopropylphenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ pyrazine-2-carboxylate ( A solution of 188 mg) in dichloromethane (1.95 mL) was cooled in an ice-water bath. Trifluoroacetic acid (0.65 mL) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
  • Example 47 Under argon atmosphere, methyl 6- ⁇ 2- [2- (tert-butoxycarbonylamino) phenyl] -3- (1-methylcyclopropyl) -3-oxopropyl ⁇ pyridine-2-carboxylate (227 mg) in dichloromethane ( (2.7 mL) The solution was cooled in an ice-water bath. Trifluoroacetic acid (0.9 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 48 [5-Cyclopropyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine in the same manner as in Example 38 using the corresponding starting materials and reagents. Methyl -2-carboxylate was synthesized.
  • Example 49 6- [6-Methoxy-2- (1-methylcyclopropyl) -5-propyl-1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 38 using the corresponding starting materials and reactants Methyl 2-carboxylate was synthesized.
  • Example 50 6- [6-Methoxy-2- (1-methylcyclobutyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 45 using the corresponding starting materials and reagents. Methyl was synthesized.
  • Example 51 [5-Butyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine--in the same manner as in Example 38 using the corresponding starting materials and reactants Methyl 2-carboxylate was synthesized.
  • Example 52 6- [6-Cyclopropyl-2- (1-methylcyclobutyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 45 using the corresponding starting materials and reagents. Methyl acid was synthesized.
  • Example 54 Under an argon atmosphere, 7-fluoro-6-methoxy-2- (1-methylcyclopropyl) -1H-indole (110 mg), methyl 6-formylpyridine-2-carboxylate (82.9 mg) and triethylsilane (0.
  • a solution of 240 mL) in dichloromethane (5 mL) was cooled in an ice-water bath.
  • Trifluoroacetic acid (0.058 mL) was added thereto, and the mixture was stirred under the same conditions for 1 hour and then at room temperature for 3 hours.
  • the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
  • Example 56 [6-Cyclopropyl-5-fluoro-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine in the same manner as in Example 19 using the corresponding starting materials and reagents. Methyl -2-carboxylate was synthesized.
  • Example 57 To a solution of methyl 6- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (584 mg) in tetrahydrofuran / methanol (9.92 mL / 4.25 mL). A 2 mol / L aqueous sodium hydroxide solution (2.50 mL) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (5.00 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 30 minutes.
  • Example 58 A solution of methyl 6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (355 mg) in tetrahydrofuran / methanol (5.86 mL / 2.51 mL). Was added 2 mol / L aqueous sodium hydroxide solution (1.48 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (2.96 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 30 minutes.
  • Example 59 To a solution of methyl 6- [6-chloro-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (427 mg) in tetrahydrofuran / methanol (7.16 mL / 3.07 mL). A 2 mol / L aqueous sodium hydroxide solution (1.81 mL) was added, and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (3.62 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 1 hour.
  • Example 60 To a solution of methyl 6- [6-methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (171 mg) in tetrahydrofuran / methanol (3.04 mL / 1.30 mL). 2 mol / L aqueous sodium hydroxide solution (0.768 mL) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (1.54 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 30 minutes.
  • Example 61 [6-Ethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 60 using the corresponding starting materials and reagents. Was synthesized.
  • Example 62 6- [6-Isopropoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid was prepared in the same manner as in Example 60 using the corresponding starting materials and reactants. An acid was synthesized.
  • Example 63 Methyl 6- [6-chloro-5-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (70 mg) in tetrahydrofuran / methanol (0.9 mL / 0. 9 mol) solution was added 2 mol / L aqueous sodium hydroxide solution (0.27 mL) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.27 mL) was added thereto while stirring. The mixture was stirred at room temperature for 30 minutes.
  • Example 64 [6-Ethyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 60 using the corresponding starting materials and reagents. Was synthesized.
  • Example 65 To a solution of methyl 6- [5-chloro-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (250 mg) in tetrahydrofuran / methanol (3 mL / 3 mL) A 2 mol / L aqueous sodium hydroxide solution (0.974 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.98 mL) was added thereto while stirring. The mixture was stirred at room temperature for 30 minutes.
  • Example 66 [6-Isopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 60 using the corresponding starting materials and reagents. Was synthesized.
  • Example 69 To a solution of methyl 3- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoate (44 mg) in tetrahydrofuran / methanol (0.6 mL / 0.6 mL), 2 mol / L Aqueous sodium hydroxide solution (0.183 mL) was added and the mixture was stirred at 60 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.183 mL) was added thereto while stirring. The mixture was stirred at room temperature for 10 minutes.
  • Example 70 Ethyl 5- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] furan-2-carboxylate (95.7 mg) in tetrahydrofuran / methanol (1.3 mL / 1.3 mL) ) 2 mol / L aqueous sodium hydroxide solution (0.395 mL) was added to the solution, and the mixture was stirred at 60 ° C. for 80 minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.4 mL) was added thereto while stirring. The mixture was stirred at room temperature for 10 minutes.
  • Example 71 A solution of methyl 3- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] -2-fluorobenzoate (74 mg) in tetrahydrofuran / methanol (1.0 mL / 1.0 mL) was added 2 mol / L aqueous sodium hydroxide solution (0.295 mL), and the mixture was stirred at 60 ° C. for 2.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.295 mL) was added thereto while stirring. The mixture was stirred at room temperature for 10 minutes.
  • Example 72 2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiazole-4-carboxylate (177 mg) in tetrahydrofuran / methanol (2.3 mL / 2.3 mL) solution was added 2 mol / L aqueous sodium hydroxide solution (0.697 mL), and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.7 mL) was added thereto while stirring. The mixture was stirred at room temperature for 30 minutes.
  • Example 73 2- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] isonicotinic acid was synthesized in the same manner as in Example 60 using the corresponding starting materials and reactants. .
  • Example 74 Ethyl 5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-2-carboxylate (75.2 mg) in tetrahydrofuran / methanol (1.21 mL / 0.519 mL) To the solution was added 2 mol / L aqueous sodium hydroxide solution (0.305 mL). The mixture was stirred at room temperature for 4 hours and then at 50 ° C. for 3 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (0.710 mL) was added dropwise thereto while stirring.
  • Example 75 6- [2- (1-Ethylcyclopropyl) -6-methoxy-1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 60 using the corresponding starting materials and reagents. Was synthesized.
  • Example 76 3- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid was synthesized in the same manner as in Example 69 using the corresponding starting materials and reagents.
  • Example 77 5- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] furan-2-carboxylic acid in the same manner as in Example 69 using the corresponding starting materials and reagents. Was synthesized.
  • Example 78 2-Fluoro-3- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid in the same manner as in Example 69 using the corresponding starting materials and reactants was synthesized.
  • Example 79 2- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiazole-4-carboxylic acid in the same manner as in Example 72 using the corresponding starting materials and reagents. Was synthesized.
  • Example 81 Ethyl 5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-3-carboxylate (86.7 mg) in tetrahydrofuran / methanol (1.45 mL / 0.622 mL) To the solution was added 2 mol / L aqueous sodium hydroxide solution (0.366 mL). The mixture was stirred at room temperature for 3.5 hours and then at 60 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (0.732 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 30 minutes.
  • Example 82 A solution of ethyl 5- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-2-carboxylate (334 mg) in tetrahydrofuran / methanol (5.24 mL / 2.24 mL). Was added 2 mol / L aqueous sodium hydroxide solution (1.32 mL), and the mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (2.64 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 1 hour.
  • Example 83 [6-Difluoromethoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 65 using the corresponding starting materials and reactants An acid was synthesized.
  • Example 84 2- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] oxazole-4-carboxylic acid was prepared in the same manner as in Example 59 using the corresponding starting materials and reactants. An acid was synthesized.
  • Example 85 5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] thiophene-3-carboxylic acid was prepared in the same manner as in Example 82 using the corresponding starting materials and reagents. An acid was synthesized.
  • Example 86 [6-Methoxy-1-methyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 59 using the corresponding starting materials and reactants 2-carboxylic acid was synthesized.
  • Example 87 5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] -2-fluorobenzoic acid in the same manner as in Example 70 using the corresponding starting materials and reagents. An acid was synthesized.
  • Example 88 2-Fluoro-5- [6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] benzoic acid in the same manner as in Example 70 using the corresponding starting materials and reactants was synthesized.
  • Example 90 5- [6-Methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] nicotinic acid was synthesized in the same manner as in Example 63 using the corresponding starting materials and reactants.
  • Example 91 5- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] nicotinic acid was synthesized in the same manner as in Example 63 using the corresponding starting materials and reactants. .
  • 2 mol / L aqueous sodium hydroxide solution (0.270 mL)
  • the reaction mixture was concentrated under reduced pressure.
  • the residue was dissolved in water, and 2 mol / L hydrochloric acid (0.275 mL) was added thereto while stirring.
  • the mixture was stirred at room temperature for 10 minutes.
  • Example 93 [1-Ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 59 using the corresponding starting materials and reactants 2-carboxylic acid was synthesized.
  • Example 94 [5-Ethyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate methyl (44.2 mg) in tetrahydrofuran / methanol (0.968 mL / 0.415 mL) solution was added 2 mol / L aqueous sodium hydroxide solution (0.175 mL), and the mixture was stirred at room temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (0.350 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 1 hour.
  • a -2-carboxylic acid was synthesized.
  • Example 99 2 mol of methyl 2- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] isonicotinate (143 mg) in tetrahydrofuran / methanol (2.36 mL / 1.01 mL) / L aqueous sodium hydroxide solution (0.595 mL) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (1.19 mL) was added dropwise thereto while stirring. The mixture was stirred at room temperature for 1 hour.
  • Example 100 [2- (1-Methylcyclopropyl) -6- (methylsulfinyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (42.0 mg) in tetrahydrofuran / methanol (1.42 mL / 0 .609 mL) solution was added 2 mol / L sodium hydroxide aqueous solution (0.165 mL), and the mixture was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 1 mol / L hydrochloric acid (0.330 mL) was added dropwise thereto while stirring.
  • Example 101 6- [6- (Acetoxymethyl) -2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate methyl ester (54.5 mg) in tetrahydrofuran / methanol (0.7 mL / 0 To the solution was added 2 mol / L aqueous sodium hydroxide solution (0.28 mL), and the mixture was stirred at 40 ° C. for 1.5 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, and 2 mol / L hydrochloric acid (0.28 mL) was added dropwise thereto while stirring. The mixture was diluted with water and extracted with ethyl acetate.
  • Example 104 6- [2- (1-Methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid was synthesized in the same manner as in Example 94 using the corresponding starting materials and reactants.
  • Example 107 6- [6-Methoxy-2- (1-methylcyclobutyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid in the same manner as in Example 60 using the corresponding starting materials and reagents. Was synthesized.
  • Example 114 At room temperature, (E) -3- ⁇ 6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl ⁇ ethyl acrylate (75.0 mg) ) In ethanol (1 mL) was added 10% palladium-carbon (15 mg), and the suspension was stirred under a hydrogen gas atmosphere for 3 hours. The suspension was filtered through Celite (registered trademark), and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure.
  • Example 115 Chlorination of 6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole (85.0 mg) and methyl 3- (6-formylpyridin-2-yl) propiolate (84.0 mg) under ice cooling
  • To a methylene (1.5 mL) solution were added triethylsilane (0.27 mL) and trifluoroacetic acid (0.08 mL). The solution was stirred under the same conditions for 0.5 hour and then at room temperature for 3 hours.
  • a saturated aqueous sodium hydrogen carbonate solution was added to the solution, extracted with methylene chloride, and dried over anhydrous sodium sulfate.
  • Example 116 Methyl 6- [2- (1-methylcyclopropyl) -6- (trifluoromethylsulfonyloxy) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (60.0 mg), cyanide under argon atmosphere Zinc (30.0 mg), bis (dibenzylideneacetone) palladium (0) (7.5 mg), 2-dicyclohexylphosphino-2 ′, 6′-dimethoxybiphenyl (11.0 mg) in N, N-dimethylformamide A suspension of water (99: 1 v / v, 1.3 mL) was stirred at 60 ° C. for 6 hours.
  • the mixture was diluted with ethyl acetate, washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.
  • the residue obtained by evaporating the solvent was purified by silica gel column chromatography (elution solvent: hexane-ethyl acetate), and 6- [2- (1-methylcyclopropyl) -6- (1-propene-2- Yl) -1H-indol-3-ylmethyl] methyl pyridine-2-carboxylate (42.0 mg).
  • Example 118 A solution of 6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indole (100 mg) and methyl 6-thioxo-1,6-dihydropyridine-2-carboxylate (120 mg) in methanol (5 mL) at room temperature was added with OXONE® (210 mg) and the mixture was stirred under the same conditions for 3 hours. Water was added to the mixture, extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate.
  • Example 119 6- [6- (1-methylcyclopropyl) -3,7-dihydro-2H-furo [3,2-f] indol-5-ylmethyl] pyridine-2-carboxylate methyl ester (50.0 mg) in tetrahydrofuran ( A 2 mol / L aqueous potassium hydroxide solution (0.3 mL) was added to a 0.3 mL) -methanol (0.6 mL) solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.6 mL) was added under ice cooling.
  • Example 120 (E) -3- ⁇ 6- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl ⁇ ethyl acrylate (27.0 mg) in ethanol ( 0.7 mL) solution was added 2 mol / L potassium hydroxide aqueous solution (0.2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.4 mL) was added under ice cooling.
  • Example 121 Ethanol (1.0 mL) of ethyl 3- ⁇ 6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl ⁇ propionate (52.0 mg) To the solution was added 2 mol / L potassium hydroxide aqueous solution (0.3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.6 mL) was added under ice cooling.
  • Example 122 ⁇ 6- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridin-2-yl ⁇ methyl propiolate (60.0 mg) in methanol (0.6 mL) 2 mol / L potassium hydroxide aqueous solution (0.3 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.6 mL) was added under ice cooling.
  • Example 123 6- [6-Cyano-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (11.0 mg) in methanol (0.2 mL) in 2 mol / L water Aqueous potassium oxide (0.1 mL) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.2 mL) was added under ice cooling. The precipitate was collected by filtration to obtain 6- [6-cyano-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-2-carboxylic acid (9.8 mg).
  • Example 124 Methyl 6- [2- (1-methylcyclopropyl) -6- (1-propen-2-yl) -1H-indol-3-ylmethyl] pyridine-2-carboxylate (37.0 mg) in methanol (0. 6 mL) solution was added 2 mol / L potassium hydroxide aqueous solution (0.3 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (0.6 mL) was added under ice cooling.
  • Example 125 6- [6-Cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylsulfanyl] methyl pyridine-2-carboxylate (97.0 mg) in tetrahydrofuran (1.0 mL) -methanol (1 0.0 mL) solution was added 2 mol / L potassium hydroxide aqueous solution (0.5 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, the resulting residue was diluted with water, and 1 mol / L hydrochloric acid (1.0 mL) was added under ice cooling. The precipitate was collected by filtration to obtain 6- [6-cyclopropyl-2- (1-methylcyclopropyl) -1H-indol-3-ylsulfanyl] pyridine-2-carboxylic acid (88.5 mg).
  • Example 128 [5-Isopropyl-6-methoxy-2- (1-methylcyclopropyl) -1H-indol-3-ylmethyl] pyridine-- in the same manner as in Example 54 using the corresponding starting materials and reactants Methyl 2-carboxylate was synthesized.
  • Example 130 Of tert-butyl 6-methoxy-3- [2- (6-methoxycarbonylpyridin-2-yl) ethyl] -2- (1-methylcyclopropyl) -1H-indole-1-carboxylate (54.6 mg)
  • the dichloromethane (0.588 mL) solution was cooled in an ice water bath.
  • Trifluoroacetic acid (0.588 mL) was added thereto, and the mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate.
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Comparative Example 2 6- (2-Cyclobutyl-6-methoxy-1H-indol-3-ylmethyl) pyridine-2-carboxylic acid was synthesized in the same manner as in Comparative Example 1 using the corresponding starting materials and reactants.
  • Test example 1 EP 1 receptor antagonism confirmation test
  • 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 Escherichia coli was cultured on an LB agar medium for 1 day. After the culture, colonies were selected and cultured in an LB liquid medium containing 50 ⁇ g / mL ampicillin. After culture, the vector was purified using QIAprep Spin Miniprep Kit (Qiagen).
  • COS-1 cell culture COS-1 cells (Dainippon Sumitomo Pharma Co., Ltd.) are penicillin-streptomycin solution (Invitrogen Corporation, final concentration: 100 U / mL as benzylpenicillin; 100 ⁇ g / mL as streptomycin) as an antibiotic, D-MEM liquid medium (containing high glucose and L-glutamine) supplemented with MEM non-essential amino acids (Invitrogen Corporation, final concentration: 0.1 mM) and fetal calf serum (Sanko Junyaku Co., Ltd., final concentration: 10%) Invitrogen Corp.) was cultured in an incubator under 5% CO 2 gas conditions at 37 ° C. until confluence.
  • penicillin-streptomycin solution Invitrogen Corporation, final concentration: 100 U / mL as benzylpenicillin; 100 ⁇ g / mL as streptomycin
  • D-MEM liquid medium containing high glucose and L-glutamine
  • 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 with 5% CO 2 gas. When the cells for introduction of the rat EP 1 expression vector were adhered (after about 2 hours after seeding), the rat EP 1 expression vector was introduced by the following procedure.
  • BD BioCoat registered trademark
  • rat EP 1 expression vector For the introduction of rat EP 1 expression vector, using Lipofectamine 2000 (Invitrogen Corporation).
  • the rat EP 1 expression vector was diluted with OPTI-MEM (registered trademark) I Reduced-Serum Medium (Invitrogen Corporation) to 200 ng / 25 ⁇ L / well.
  • Lipofectamine 2000 (Invitrogen Corporation) is diluted with OPTI-MEM (registered trademark) I Reduced-Serum Medium (Invitrogen Corporation) to 0.5 ⁇ L / 25 ⁇ L / well and incubated at room temperature for 5 minutes. did.
  • 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.
  • 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 rat EP 1 expression vector / Lipofectamine 2000 complex was dispensed were cultured at 37 ° C. for 20 hours in an incubator under 5% CO 2 gas conditions. After culturing for 20 hours, the cells were used as rat EP 1 receptor-expressing cells for measurement of intracellular calcium concentration.
  • a 10 mM dimethyl sulfoxide solution of each test compound was diluted with an assay buffer (20 mM HEPES / Hank's Balanced Salt Solution (HBSS), pH 7.2). Rat EP 1 receptor-expressing cells were washed with assay buffer.
  • Fluorescent calcium indicator (Calcium kit II, Fluo4 (Dojindo Laboratories Co., Ltd.): Prepared by the same product protocol, Invitrogen Co., Ltd., containing 2.5 mM probenecid) 100 ⁇ L was added to each well, and 37 ° C. for 60 minutes. Incubated in incubator. Thereafter, the intracellular calcium concentration was measured immediately.
  • the intracellular calcium concentration was measured as a fluorescence signal using FDSS (registered trademark) 7000 (manufactured by Hamamatsu Photonics). 20 seconds after the start of reading the fluorescence signal, 50 ⁇ L of each test compound (final concentration: 1 nM to 10 ⁇ M) 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.
  • IC 50 value 100% of the fluorescence signal obtained when prostaglandin E 2 was added when assay buffer was added instead of the test compound in the above method, and the signal obtained when neither test compound nor prostaglandin E 2 was added was defined as 0%, and the concentration showing 50% inhibition from the concentration-response curve of the test compound was defined as the IC 50 value.
  • IC 50 values of the obtained test compounds are shown in Table 39 below.
  • the compounds of the present invention exhibited potent EP 1 receptor antagonism.
  • Test example 2 Inhibitory effect of compounds on sarprostone-induced bladder contraction
  • a tracheal cannula (Size8, HBIKI) and a femoral vein cannula for administration (PE50 with a 23G needle) were inserted.
  • a bladder cannula (PE50) was inserted from the top of the bladder. The bladder cannula was connected to a three-way stopcock, one connected to a pressure transducer, and the other connected to a syringe filled with saline.
  • the difference between the maximum bladder contraction rate (100%) and the average bladder contraction rate (%) after administration of the test drug was calculated according to the following formula, and was defined as the bladder contraction suppression rate of the test drug.
  • the compound of the present invention Since the compound of the present invention has a strong and long-lasting EP 1 receptor antagonistic action, it is useful as a therapeutic or prophylactic agent for diseases or symptoms caused by the activation of EP 1 receptor by stimulating action of PGE 2. . Among them, it is useful as a therapeutic or prophylactic 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 EP 1 receptor amplified using the primers of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3 and SEQ ID NO: 4.

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Abstract

La présente invention concerne un composé représenté par la formule générale (I), qui a une activité antagoniste des récepteurs EP1, ou un sel pharmacologiquement acceptable de celui-ci. Le composé (I) de la présente invention peut être utilisé comme agent thérapeutique ou agent prophylactique pour les symptômes du tractus urinaire inférieur (LUTS), notamment pour divers symptômes de vessie hyperactive (OAB). (Dans la formule, A représente un noyau pyridine ou similaire ; Y1 représente un groupe alkylène en C1-6 ou similaire ; Y2 représente une simple liaison ou similaire ; R1 représente un atome d'hydrogène ou similaire ; R2 représente un groupe alkyle en C1-6 ; R3 représente un atome d'hydrogène ou similaire ; R4 représente un atome d'hydrogène ou similaire ; R5 représente un atome d'hydrogène, un atome d'halogène, un groupe alkyle en C1-6 ou similaire ; R6 représente un groupe alkyle en C1-6 un groupe cycloalkyle en C3-6 ou similaire ; R7 représente un atome d'hydrogène ou similaire ; X représente un groupe méthylène ; et Q représente une simple liaison ou similaire).
PCT/JP2013/069347 2012-07-24 2013-07-17 Dérivé d'indole ou un sel pharmacologiquement acceptable de celui-ci WO2014017342A1 (fr)

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JP2018516880A (ja) * 2015-05-06 2018-06-28 プレキシコン インコーポレーテッドＰｌｅｘｘｉｋｏｎ Ｉｎｃ． キナーゼを修飾する１ｈ−ピロロ［２，３−ｂ］ピリジン誘導体の合成
CN114057734A (zh) * 2020-08-03 2022-02-18 江苏恒瑞医药股份有限公司 稠合三环类衍生物、其制备方法及其在医药上的应用
EP3889154A4 (fr) * 2018-12-29 2022-12-21 Wuhan LL Science And Technology Development Co., Ltd. Intermédiaire de composé hétérocyclique, son procédé de préparation et son utilisation

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JP2018516880A (ja) * 2015-05-06 2018-06-28 プレキシコン インコーポレーテッドＰｌｅｘｘｉｋｏｎ Ｉｎｃ． キナーゼを修飾する１ｈ−ピロロ［２，３−ｂ］ピリジン誘導体の合成
EP3889154A4 (fr) * 2018-12-29 2022-12-21 Wuhan LL Science And Technology Development Co., Ltd. Intermédiaire de composé hétérocyclique, son procédé de préparation et son utilisation
CN114057734A (zh) * 2020-08-03 2022-02-18 江苏恒瑞医药股份有限公司 稠合三环类衍生物、其制备方法及其在医药上的应用

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