[go: up one dir, main page]

WO2018151239A1 - COMPOSÉ 3, 6-DIHYDRO-2H-FURO[2, 3-e]INDOLE - Google Patents

COMPOSÉ 3, 6-DIHYDRO-2H-FURO[2, 3-e]INDOLE Download PDF

Info

Publication number
WO2018151239A1
WO2018151239A1 PCT/JP2018/005360 JP2018005360W WO2018151239A1 WO 2018151239 A1 WO2018151239 A1 WO 2018151239A1 JP 2018005360 W JP2018005360 W JP 2018005360W WO 2018151239 A1 WO2018151239 A1 WO 2018151239A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
compound
furo
dihydro
pharmaceutically acceptable
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP2018/005360
Other languages
English (en)
Japanese (ja)
Inventor
昌生 吉田
優真 梅崎
理恵子 高野
正憲 泉
中村　弘明
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Daiichi Sankyo Co Ltd
Original Assignee
Daiichi Sankyo Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Daiichi Sankyo Co Ltd filed Critical Daiichi Sankyo Co Ltd
Publication of WO2018151239A1 publication Critical patent/WO2018151239A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/407—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 other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/04—Artificial tears; Irrigation solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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

Definitions

  • the present invention relates to a 3,6-dihydro-2H-furo [2,3-e] indole compound or a pharmaceutically acceptable salt thereof, and further to an acid-sensitive ion channel inhibitor containing the compound.
  • An acid-sensitive ion channel is a cation channel activated by extracellular protons.
  • ASIC1, ASIC2, ASIC3, and ASIC4 are subtypes of ASIC1, ASIC2, ASIC3, and ASIC4 in ASIC, and each subtype functions by forming a homo or hetero trimer. Since ASIC1 and ASIC3 are expressed in sensory nerves, it is considered to be involved in pain perception in pathological conditions where tissue pH decreases such as inflammation, ischemia and cancer.
  • ASIC is widely distributed in addition to sensory nerves, and its involvement in various pathological conditions has been suggested.
  • ASIC1 polymorphism is associated with panic disorder (Neuromolecular Med. 2016, 18 (1), 91-98)
  • ASIC2 and ASIC3 expression is increased in the bladder of patients with interstitial cystitis (J Urology, 2011, 186, 1509-1516), and increased expression of ASIC1 in human breast cancer (Oncogene, 2015, 1-10) have been reported.
  • inhibitors of ASIC1 and ASIC3 exhibit analgesia, neuroprotection, cartilage protection, suppression of vasodilation, and insulin resistance improvement (Toxicon., 2013, 75, 187- 204). Therefore, ASIC is considered an important molecule for the development and maintenance of various pathological conditions.
  • Amiloride is widely used as a low molecular weight inhibitor for ASIC. However, amiloride also inhibits epithelial sodium channel (ENaC: Epithelial Na + channel) at the same time, so its specificity is not sufficient.
  • EaC Epithelial Na + channel
  • various peptide inhibitors such as mambalgin-1 which is an ASIC1 specific inhibitor and APETx2 which is an ASIC3 specific inhibitor have been reported (Toxicon., 2013, 75, 187-204).
  • A-317567 Pain, 2005, 117 (1-2), 88-96
  • NS383 CNS383
  • amiloride may inhibit experimental acid-induced pain (J. Clin. Invest., 2002, 110 (8), 1185-1190) and may be neuroprotective against multiple sclerosis. It has been reported (Brain, 2013, 136, 106-15). Furthermore, PPC-5650, an ASIC inhibitor, has been reported to suppress pain in human esophagus (Basic Clin. Pharmacol. Toxicol., 2015, 116 (2), 140-5). These reports suggest that ASIC inhibitors may have therapeutic effects on various pathologies including pain in humans. Under these circumstances, attempts have been made to create novel ASIC inhibitors (see Patent Documents 1 to 10, Non-Patent Documents 1 and 2).
  • ASIC inhibitors exhibit oral absorption. Being able to orally administer ASIC inhibitors leads to improved patient convenience and improved usability. Furthermore, it is unclear whether conventional ASIC inhibitors have selective inhibitory properties.
  • the selective side effects of ASIC can reduce the side effects caused by non-selective inhibition, can ensure safety, and the safety can be ensured for the main medicinal effects. It is also possible to increase the dose and achieve a higher therapeutic effect.
  • the present invention aims to obtain a selective ASIC inhibitor that can be administered orally. Thereby, an excellent therapeutic effect can be achieved.
  • the inventor of the present application has found that the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has an ASIC inhibitory property excellent in selectivity and has oral absorbability. Was completed.
  • Structure shown in represents an aromatic group represented by R 1 or R 2 is substituted, R 1 and R 2, the following group: Hydrogen atom, C1-C6-alkyl group, C1-C6-alkoxy group, hydroxy C1-C6-alkyl group, dihydroxy C2-C6-alkyl group, halogeno C1-C6-alkyl group, C1-C6-alkylsulfonyl group, halogen A group independently selected from an atom, a cyano group and a C2-C6-acyl group; ) About.
  • the aromatic group is a group selected from a 5- or 6-membered aromatic heterocyclic group having 1 to 3 heteroatoms selected from a nitrogen atom and a sulfur atom and a hydrocarbon aromatic group [1] Or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are the following groups: A group independently selected from a hydrogen atom, a C1-C6-alkyl group, a C1-C6-alkoxy group, a hydroxy C1-C6-alkyl group, a dihydroxy C2-C6-alkyl group, a C1-C6-alkylsulfonyl group and a halogen atom
  • a group independently selected from a hydrogen atom, a C1-C6-alkyl group, a C1-C6-alkoxy group, a hydroxy C1-C6-alkyl group, a dihydroxy C2-C6-alkyl group, a C1-C6-alkylsulfonyl group and a halogen atom The compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are the following groups: Hydrogen atom, methyl group, fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxy Ethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2
  • the group according to any one of [1] to [4], which is a group independently selected from a -dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group, methylsulfonyl group, cyano group and acetyl group A compound or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are the following groups: Hydrogen atom, methyl group, fluorine atom, methoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 1,2-dihydroxyethyl group, [1] to [4], which is a group independently selected from (1S) -1,2-dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group and methylsulfonyl group Or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 is a hydrogen atom, and the other is the following group: Methyl group, fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2-dihydroxyethyl Group, (1R) -1,2-dihydroxyethyl group, methylsulfonyl group, cyano group and acetyl group,
  • the compound or pharmaceutically acceptable salt thereof according to any one of [1] to [4], which is a group selected from: [9]
  • One of R 1 and R 2 is a hydrogen atom, and the other is the following group:
  • R 1 and R 2 are hydrogen atom, and the other is the following group: Hydrogen atom, methyl group, fluorine atom, methoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 1,2-dihydroxyethyl group,
  • the compound according to any one of [1] to [4], which is a group selected from (1S) -1,2-dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group and methylsulfonyl group Its pharmaceutically acceptable salt.
  • R 1 and R 2 are a hydrogen atom, and the other is the following group: A group selected from a hydrogen atom, a methyl group, a fluorine atom, a methoxy group, a hydroxymethyl group, a (1R) -1-hydroxyethyl group, a (1R) -1,2-dihydroxyethyl group, and a methylsulfonyl group [1] To [4] or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are One is a hydroxymethyl group and the other is a methylsulfonyl group, a methoxy group, a cyano group, or a fluorine atom, or The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein one is a 1,2-dihydroxyethyl group and the other is a fluorine atom or a chlorine atom.
  • R 1 and R 2 are One is a hydroxymethyl group and the other is a methylsulfonyl group or a methoxy group, or The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein one is a 1,2-dihydroxyethyl group and the other is a fluorine atom.
  • R 1 and R 2 are One is a hydroxymethyl group and the other is a methylsulfonyl group or a methoxy group, or The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], wherein one is a (1R) -1,2-dihydroxyethyl group and the other is a fluorine atom.
  • the compound represented by the formula (I) is represented by the following group:
  • the compound represented by the formula (I) is: 7- (2-methoxypyrimidin-5-yl) -3,6-dihydro-2H-furo [2,3-e] indol-3-amine, 7- [5- (methylsulfonyl) pyridin-2-yl] -3,6-dihydro-2H-furo [2,3-e] indol-3-amine, [5- (3-amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) pyrazin-2-yl] methanol, (1R) -1- ⁇ 5-[(3S) -3-amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl] pyrazin-2-yl ⁇ ethanol, (3S) -7- (2-methylpyrimidin-5-yl) -3,6-dihydro-2H-furo [2,3-e] ind
  • a compound represented by the formula (I) is: [5- (3-amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -2- (methylsulfonyl) phenyl] methanol, 7- [5- (methylsulfonyl) pyridin-2-yl] -3,6-dihydro-2H-furo [2,3-e] indol-3-amine, 7- (2-methoxypyrimidin-5-yl) -3,6-dihydro-2H-furo [2,3-e] indol-3-amine, or (1R) -1- ⁇ 5-[(3S) -3-amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl] pyrazin-2-yl ⁇ ethanol, [1] or a pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising the compound according to any one of [1] to [18] or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • An acid-sensitive ion channel (ASIC) inhibitor comprising the compound according to any one of [1] to [18] or a pharmaceutically acceptable salt thereof.
  • the compound represented by the formula (I) of the present invention or a pharmaceutically acceptable salt thereof has an excellent selective acid-sensitive ion channel (ASIC) inhibitory action and can be administered orally, and thus is acid-sensitive. It is useful for the treatment and / or prevention of various pathological conditions involving ion channels.
  • ASIC acid-sensitive ion channel
  • Example 2 shows the change in blood concentration (unit: nanomolar) when the compound of Example 2 of the present invention was orally or intravenously administered to mice at a dose of 10 mg / kg.
  • the rhombus indicates the change during intravenous administration, and the square indicates the change during oral administration.
  • the horizontal axis indicates time.
  • the present invention relates to a compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a hydrate thereof. That is, a compound having a structure in which 3,6-dihydrofuro [2,3-e] indole is a mother nucleus, has an amino group at the 3-position, and has an aromatic group substituted with R 1 and R 2 at the 7-position. is there.
  • a part of the group represented by is a hydrocarbon-based aromatic group, or a 5-membered or 6-membered aromatic heterocycle having 1 to 3 heteroatoms selected from a nitrogen atom and a sulfur atom It is a group.
  • R 1 and R 2 on this aromatic group are the following groups: A hydrogen atom, a C1-C6-alkyl group (“C1-C6-” means 1 to 6 carbon atoms), a C1-C6-alkoxy group, a hydroxy C1-C6-alkyl group, a dihydroxy C2- It is a group independently selected from a C6-alkyl group, a halogeno C1-C6-alkyl group, a halogen atom, a cyano group, a C2-C6-acyl group, and a C1-C6-alkylsulfonyl group.
  • amino group coordination is alpha:
  • This structure is considered to be more preferable. That is, the present inventors obtained a 3,6,7,8-tetrahydrocyclopenta [e] indole compound amino-substituted at the 6-position that has an analogous structure and exhibits an acid-sensitive ion channel (ASIC) inhibitory action. It was acquired separately, and it was clarified that in the compound, the amino group at the 6-position has an alpha configuration and has a higher acid-sensitive ion channel (ASIC) inhibitory action. From the structural similarity between this compound and the compound of the present invention, the 2-position of the present invention [this is the position corresponding to the 6-position of the 3,6,7,8-tetrahydrocyclopenta [e] indole compound. In the 3,6-dihydro-2H-furo [2,3-e] indole compounds amino-substituted, the arrangement of the amino group is considered to be a preferred arrangement in which the alpha form shows higher activity.
  • ASIC acid-sensitive ion channel
  • the A moiety in the group represented by is a hydrocarbon-based aromatic group or a 5-membered or 6-membered aromatic heterocyclic group having a heteroatom 1-3 selected from a nitrogen atom and a sulfur atom .
  • the hydrocarbon aromatic group include a phenyl group
  • the heterocyclic aromatic group include a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidyl group, or a pyrazinyl group.
  • the A moiety is preferably a phenyl group, a pyrrolyl-2-yl group, a pyrrolyl-3-yl group, a pyrazol-3-yl group, a pyrazol-4-yl group, an imidazol-2-yl group, or imidazol-4-yl.
  • phenyl group pyrazol-3-yl group, pyrazol-4-yl group, thiazol-2-yl group, thiazol-5-yl group, thiadiazol-2-yl group, and pyridin-2-yl.
  • R 1 and R 2 which are substituents on the aromatic group can be independently the following substituents.
  • R 1 or R 2 is a C 1 -C 6 -alkyl group, preferably it may be a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, or a sec-butyl group, and more Preferably, it is a methyl group or an ethyl group.
  • R 1 or R 2 is a C 1 -C 6 -alkoxy group, preferably a methoxy group, an ethoxy group, a propoxy group, a 2-methylethoxy group, a butoxy group, a 1-methylpropoxy group, or a 2-methylpropoxy group More preferably, it is a methoxy group or an ethoxy group.
  • R 1 or R 2 is a hydroxy C 1 -C 6 -alkyl group
  • the position of the hydroxy group is not particularly limited, but is more preferably the carbon atom bonded to the aromatic group, that is, the benzyl position. preferable.
  • hydroxy C 1 -C 6 -alkyl groups are hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy -1-methylethyl group, 2-hydroxy-1-methylethyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 1-hydroxy-1-methylpropyl group 1-hydroxy-2-methylpropyl group, 2-hydroxy-1-methylpropyl group, 3-hydroxy-1-methylpropyl group, 2-hydroxy-2-methylpropyl group, or 3-hydroxy-2-methylpropyl group It is a group.
  • R 1 or R 2 is a dihydroxy C 2 -C 6 -alkyl group
  • the position of the two hydroxy groups is not particularly limited, but one having a 1,2-diol structure is more preferable, and ( Those which are 1R) hydroxy are preferred.
  • Dihydroxy C 2 -C 6 -alkyl groups are preferably 1,2-dihydroxyethyl group, 1,2-dihydroxypropyl group, 1,3-dihydroxypropyl group, 2,3-dihydroxypropyl group, 1,2-dihydroxy Butyl group, 1,3-dihydroxybutyl group, 1,4-dihydroxybutyl group, 2,3-dihydroxybutyl group, 2,4-dihydroxybutyl group, 3,4-dihydroxybutyl group, 1,2-dihydroxy-1 -Methylpropyl group, 1,2-dihydroxy-2-methylpropyl group, 1,3-dihydroxy-1-methylpropyl group, 1,3-dihydroxy-2-methylpropyl group, 2,3-dihydroxy-1-methyl A propyl group or a 2,3-dihydroxy-2-methylpropyl group can be mentioned.
  • more preferable examples include 1,2-dihydroxyethyl group, (1S) -1,2-dihydroxyethyl group, or (1R) -1,2-dihydroxyethyl group. More preferred is a (1R) -1,2-dihydroxyethyl group which is a dihydroxyalkyl group of (1R).
  • R 1 or R 2 is a halogeno C 1 -C 6 -alkyl group
  • the number of substituted halogens may be between 1 and per substitution.
  • the substitution position is more preferably the carbon atom at the terminal of the alkyl group, but there is no particular limitation.
  • the halogeno C 1 -C 6 -alkyl group is preferably a fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, 2,2,2-trifluoroethyl group, perfluoroethyl group, chloromethyl. And a 2-chloroethyl group.
  • a fluoromethyl group a trifluoromethyl group, a 2-fluoroethyl group, or a 2,2,2-trifluoroethyl group, and even more preferred is a trifluoromethyl group.
  • R 1 or R 2 is a C 1 -C 6 -alkylsulfonyl group
  • a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, or a 2-methylethylsulfonyl group can be exemplified.
  • a methylsulfonyl group is more preferable.
  • R 1 or R 2 is a halogen atom
  • examples thereof include a fluorine atom, a chloro atom, a bromo atom, and an iodo atom, preferably a fluorine atom or a chloro atom, and more preferably a fluorine atom.
  • R 1 or R 2 is a C 2 -C 6 -alkylcarbonyl group (acyl group), preferably a methylcarbonyl group (acetyl group), ethylcarbonyl group, propylcarbonyl group, 2-methylethylcarbonyl group, butylcarbonyl Group, 1-methylpropylcarbonyl group, or 2-methylpropylcarbonyl group, and more preferably an acetyl group.
  • acyl group preferably a methylcarbonyl group (acetyl group), ethylcarbonyl group, propylcarbonyl group, 2-methylethylcarbonyl group, butylcarbonyl Group, 1-methylpropylcarbonyl group, or 2-methylpropylcarbonyl group, and more preferably an acetyl group.
  • R 1 and R 2 include the following groups: Hydrogen atom, methyl group, fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxy Ethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2 Any one selected from -dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group, methylsulfonyl group, cyano group and acetyl group may be used.
  • R 1 and R 2 are the following groups: Hydrogen atom, methyl group, fluorine atom, methoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 1,2-dihydroxyethyl group, Examples thereof include a group selected from (1S) -1,2-dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group and methylsulfonyl group.
  • R 1 and R 2 are the following groups: And a group selected from a hydrogen atom, a methyl group, a fluorine atom, a methoxy group, a hydroxymethyl group, a (1R) -1-hydroxyethyl group, a (1R) -1,2-dihydroxyethyl group, and a methylsulfonyl group. .
  • R 1 and R 2 when one of R 1 and R 2 is a hydrogen atom, the other is in the following group: Methyl group, fluorine atom, chlorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2-dihydroxyethyl It is preferably selected from a group, (1R) -1,2-dihydroxyethyl group, methylsulfonyl group, cyano group and acetyl group.
  • the other is the following group: Methyl group, fluorine atom, trifluoromethyl group, methoxy group, ethoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 2-hydroxy Ethyl group, 1-hydroxypropyl group, (1R) -1-hydroxypropyl group, (1S) -1-hydroxypropyl group, 1,2-dihydroxyethyl group, (1S) -1,2-dihydroxyethyl group, 1R) -1,2-dihydroxyethyl group, methylsulfonyl group and acetyl group.
  • the other is the following group: Hydrogen atom, methyl group, fluorine atom, methoxy group, hydroxymethyl group, 1-hydroxyethyl group, (1S) -1-hydroxyethyl group, (1R) -1-hydroxyethyl group, 1,2-dihydroxyethyl group, This is a case selected from (1S) -1,2-dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group and methylsulfonyl group.
  • the other is the following group: This is a case selected from a hydrogen atom, a methyl group, a fluorine atom, a methoxy group, a hydroxymethyl group, a (1R) -1-hydroxyethyl group, a (1R) -1,2-dihydroxyethyl group, and a methylsulfonyl group.
  • R 1 and R 2 One is a hydroxymethyl group and the other is a methylsulfonyl group, a methoxy group, a cyano group, or a fluorine atom, or It is preferable that one is a 1,2-dihydroxyethyl group and the other is a fluorine atom or a chlorine atom.
  • One is a 1,2-dihydroxyethyl group, more preferably, One is a (1R) -1,2-dihydroxyethyl group and the other is a fluorine atom or a chlorine atom.
  • R 1 and R 2 One is a hydroxymethyl group and the other is a methylsulfonyl group or a methoxy group, or More preferably, one is a 1,2-dihydroxyethyl group and the other is a fluorine atom.
  • One is a 1,2-dihydroxyethyl group, more preferably, One is a (1R) -1,2-dihydroxyethyl group and the other is a fluorine atom.
  • the compound represented by the formula (I) of the present invention can be produced according to Method A to Method F described below.
  • the solvent used in the reaction in each step of the following methods A to F is not particularly limited as long as it does not inhibit the reaction, does not adversely affect the reaction, and dissolves the starting materials to some extent.
  • reaction temperature varies depending on the solvent, starting material, reagent, and the like
  • reaction time varies depending on the solvent, starting material, reagent, reaction temperature, and the like.
  • each target compound is usually collected from the reaction mixture according to a method employed in the art.
  • the liquidity of the reaction mixture is appropriately adjusted, and if insolubles are present, they are removed by filtration, and then mixed with water and an organic solvent that is not miscible with water such as ethyl acetate and mixed by shaking.
  • the organic layer containing the target compound is separated, and the extract is washed with water, dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, etc., filtered through the desiccant, and then distilled off the solvent in the filtrate. be able to.
  • the obtained target compound may be obtained by a method usually employed in the technical field, such as recrystallization, reprecipitation, chromatography [for example, silica gel, alumina, magnesium-silica gel type florisil, SO 3 H-silica (Fuji Adsorption column chromatography method using a carrier such as Silysia Chemical Co., Ltd .; Sephadex LH-20 (GE Healthcare Japan Ltd.), Amberlite XAD-11 (Rohm and Haas Japan Ltd.), Diamond A method using a synthetic adsorbent such as partition column chromatography using a carrier such as Ion HP-20 (Mitsubishi Chemical Corporation); a method using ion exchange chromatography; a normal phase / reverse phase column using silica gel or alkylated silica gel A combination of chromatographic methods (preferably high performance liquid chromatography) and the like, Elute with an appropriate eluent.
  • chromatographic methods preferably high performance liquid chromatography
  • Production method A is a method for producing dihydrofurindole (IX), which can be used as a synthetic intermediate when the compound represented by formula (I) is produced.
  • This step is a step of producing a compound represented by the formula (III) by alkylating the compound represented by the formula (II) using a known organic chemical technique.
  • a compound represented by the formula (II) is used as a base in a solvent (for example, ketones, specifically acetone, methyl ethyl ketone, etc.), an alkali metal carbonate, for example, potassium carbonate, and bromoacetate, specifically, This is carried out using tert-butyl bromoacetate or the like.
  • a solvent for example, ketones, specifically acetone, methyl ethyl ketone, etc.
  • an alkali metal carbonate for example, potassium carbonate
  • bromoacetate specifically, This is carried out using tert-butyl bromoacetate or the like.
  • a compound represented by the formula (III) in a solvent for example, amides, specifically N, N-dimethylformamide, N-methylpyrrolidone, dimethylacetamide, etc.
  • a solvent for example, amides, specifically N, N-dimethylformamide, N-methylpyrrolidone, dimethylacetamide, etc.
  • an alkali metal hydride specifically This is carried out by adding sodium hydride and sulfonic acid chlorides, specifically p-toluenesulfonyl chloride.
  • This step is a step of producing the compound represented by the formula (V) by hydrolyzing the ester using a known organic chemical technique with respect to the compound represented by the formula (IV).
  • the compound represented by the formula (IV) is carried out by adding trifluoroacetic acid as an acid in a solvent (for example, halogenated hydrocarbons, specifically, dichloromethane, 1,2-dichloroethane, etc.). Even in the case of an ester other than t-butyl ester, hydrolysis can be carried out according to a usual ester hydrolysis reaction.
  • a solvent for example, halogenated hydrocarbons, specifically, dichloromethane, 1,2-dichloroethane, etc.
  • hydrolysis can be carried out according to a usual ester hydrolysis reaction.
  • A-IV process This step is a step for producing the carboxylic acid chloride represented by the formula (VI) by using a known organic chemical method for the compound represented by the formula (V).
  • Acid chloride oxalyl chloride, thionyl chloride, etc.
  • a solvent for example, halogenated hydrocarbons, specifically dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • N, N-dimethylformamide is added.
  • the compound represented by formula (VII) is produced by subjecting the compound represented by formula (VI) to a Friedel-Crafts intramolecular cyclization reaction using a known organic chemical technique. It is.
  • the compound represented by the formula (V) is carried out in a solvent (for example, halogenated hydrocarbons, specifically 1,2-dichloroethane) by adding a Lewis acid (for example, aluminum chloride).
  • a solvent for example, halogenated hydrocarbons, specifically 1,2-dichloroethane
  • a Lewis acid for example, aluminum chloride.
  • Hydroxyamine hydrochloride and sodium acetate are added to a compound represented by formula (VII) in a solvent (for example, alcohols, specifically ethanol, etc .; water or these may be used as a mixed solvent).
  • a solvent for example, alcohols, specifically ethanol, etc .; water or these may be used as a mixed solvent.
  • the compound represented by formula (IX) is produced by reducing the oxime group to tert-butoxycarbonyl using a known organic chemical method with respect to the compound represented by formula (VIII). It is a process to do.
  • a solvent for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane; or a solvent obtained by adding an alcohol to these compounds, for example, a methanol mixed solution
  • nickel chloride After reduction by adding a metal borohydride such as sodium borohydride, add water, ethyl acetate as a solvent, an alkali metal hydrogen carbonate aqueous solution such as a saturated aqueous sodium hydrogen carbonate solution as a base, and di-t-butyl dicarbonate.
  • a metal borohydride such as sodium borohydride
  • Production method B is a method of producing aryl dihydrofurindole (IX), which can be used as a synthetic intermediate when producing the compound represented by formula (I), via bromodihydrofurindole (VIII). is there.
  • This step is a step of producing the compound represented by the formula (VIII) by brominating the compound represented by the formula (VII) using a known organic chemical technique.
  • the compound represented by the formula (VII) is used as a lithium metal strong base in a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.), for example, lithium diisopropylamide, and 1,2-dibromo. Carry out with the addition of -1,1,2,2-tetrachloroethane.
  • a solvent for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • a compound represented by the formula (VIII) in a solvent for example, ethers, specifically 1,4-dioxane; water or a mixed solvent thereof
  • a solvent for example, ethers, specifically 1,4-dioxane; water or a mixed solvent thereof
  • a palladium catalyst for example, arylboronic acid or arylboron Carry out with the addition of the acid ester.
  • a microwave reactor may be used.
  • Production method C is a method for producing aryl dihydrofurindole (IX), which can be used as a synthetic intermediate in producing the compound represented by formula (I), via tributylstannanyl tedihydrofurindole (X). It is.
  • This step is a step of producing a compound represented by the formula (X) by subjecting the compound represented by the formula (VII) to tributylstannylation using a known organic chemical technique.
  • lithium diisopropylamide and tributyltin iodide are added as a lithium metal strong base to a compound represented by formula (VII) in a solvent (eg, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.).
  • a solvent eg, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • This step is a step of producing a compound represented by the formula (IX) by subjecting the compound represented by the formula (X) to Stille coupling using a known organic chemical technique.
  • the compound represented by the formula (X) in a solvent for example, amides, specifically N, N-dimethylformamide, N-methylpyrrolidone, dimethylacetamide, etc.
  • a solvent for example, amides, specifically N, N-dimethylformamide, N-methylpyrrolidone, dimethylacetamide, etc.
  • tetrakis triphenylphosphine
  • copper iodide Carry out with addition of aryl halide.
  • a microwave reactor may be used.
  • Stille couplings include the methods described in Angewandte Chemie, International Edition, 25, 6, 1986, 508-524; Tetrahedron Letters, 35, 19, 1994, 3195-3196; Synthesis, 1986, 7, 564-565, etc. It can be performed according to.
  • Production method D is a method for producing aryldihydrofurindolamine (XI), which can be used as a synthesis intermediate when synthesizing a compound represented by formula (I), from a compound represented by formula (IX). .
  • This step is a step of producing a compound represented by the formula (XI) by de-Bocating the compound represented by the formula (IX) using a known organic chemical technique.
  • the compound represented by the formula (IX) is dissolved in 4N hydrochloric acid (salt) in a solvent (for example, ethers, specifically 1,4-dioxane, 1,2-dimethoxyethane; halogenated hydrocarbons, dichloromethane, etc.). Hydrogen) Dioxane solution is added.
  • a solvent for example, ethers, specifically 1,4-dioxane, 1,2-dimethoxyethane; halogenated hydrocarbons, dichloromethane, etc.
  • Hydrogen Dioxane solution is added.
  • the reaction conditions are not limited to these conditions, and can be carried out, for example, according to the method described in “Protective Groups in Organic Synthesis (3rd edition, 1999)” by TW Greene and PG Wuts.
  • Production method E is another method for producing a synthetic intermediate represented by the formula (XI).
  • This step is a step of producing a compound represented by the formula (XIII) by sulfonylating the compound represented by the formula (XII) using a known organic chemical technique. This is carried out in the same manner as in step A-II of method A.
  • This step is a step of producing the compound represented by the formula (XIV) by hydrolyzing the compound represented by the formula (XIII) using a known organic chemical technique.
  • This step is a step of producing a compound represented by the formula (XV) by synthesizing a carboxylic acid chloride using a known organic chemical method for the compound represented by the formula (XIV).
  • the compound represented by the formula (XVI) is used as a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc .; alcohols, specifically methanol, ethanol, etc.).
  • a metal borohydride compound, specifically sodium borohydride or the like is added as a reducing agent.
  • This step is a step for producing a compound represented by the formula (XVIII) by subjecting the compound represented by the formula (XVII) to a bromination reaction using a known organic chemical technique. Performed in the same manner as the BI process of Method B.
  • This step is a step of producing a compound represented by the formula (XIX) by subjecting the compound represented by the formula (XVIII) to Suzuki coupling using a known organic chemical technique. This is carried out in the same manner as the B-II step of Method B.
  • This step is a step of producing the compound represented by the formula (XX) by subjecting the compound represented by the formula (XIX) to Mitsunobu reaction using a known organic chemical technique.
  • This step is a step of producing a compound represented by the formula (XI) by subjecting the compound represented by the formula (XX) to a reduction reaction using a known organic chemical technique.
  • Production method F is a method for producing a compound represented by formula (I) from a compound represented by formula (XI).
  • This step is a step of producing the compound represented by the formula (I) by dearylsulfonylating the compound represented by the formula (XI) using a known organic chemical technique.
  • a solvent for example, alcohols, specifically methanol, ethanol, n-propanol, etc .; ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • a solvent for example, alcohols, specifically methanol, ethanol, n-propanol, etc .; ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • cesium carbonate is added as a base.
  • the compound represented by the formula (I) of the present invention can be a pharmaceutically acceptable salt if desired.
  • a pharmaceutically acceptable salt refers to a salt that has no significant toxicity and can be used as a medicament.
  • the compound represented by the formula (I) of the present invention has a basic moiety, and can be converted into a salt by treating with an acid.
  • Salts based on basic substituents and basic heteroaryl groups include hydrohalides such as hydrofluorates, hydrochlorides, hydrobromides and hydroiodides; hydrochlorides, nitrates, peroxides
  • Inorganic acid salts such as chlorate, sulfate and phosphate; lower alkane sulfonates such as methane sulfonate, trifluoromethane sulfonate and ethane sulfonate; benzene sulfonate and p-toluene sulfonate
  • Aryl sulfonates such as: acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate and maleate, etc .
  • glycine salt, lysine Examples include salts, arginine salts, ornithine salts, amino acid salts such as glutamate and aspartate. Among these, preferred are in
  • the compound represented by the formula (I) or a salt thereof When the compound represented by the formula (I) or a salt thereof is left in the atmosphere or recrystallized, it may absorb moisture and attach adsorbed water to form a hydrate. Such hydrates are also included in the salts of the present invention.
  • the compound represented by the formula (I) or a salt thereof may absorb a certain solvent and become a solvate, and such a solvate is also included in the salt of the present invention.
  • the compound represented by the formula (I) Since the compound represented by the formula (I) has an asymmetric carbon atom in its molecule, an optical isomer exists. These isomers and mixtures of these isomers are all represented by a single formula, ie, formula (I). Therefore, the compound represented by the formula (I) includes all of a single optical isomer and a mixture of optical isomers in an arbitrary ratio within the scope of the present invention.
  • optical isomers as described above can be obtained by using an optically active raw material compound, or by synthesizing the compound according to the present invention using an asymmetric synthesis or asymmetric induction method.
  • the synthesized compound according to the present invention can be obtained by isolation using a normal optical resolution method or a separation method using an optically active carrier.
  • the compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like.
  • the compound can be radiolabeled with a radioisotope such as tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C).
  • Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents such as assay reagents and diagnostic agents such as in vivo diagnostic imaging agents. All isotope variants of the compounds of the present invention, whether radioactive or not, are intended to be included within the scope of the present invention.
  • the compound represented by the formula (I) of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate thereof not only has an excellent inhibitory action on acid-sensitive ion channels, but also has an inhibitory action on acid. It is an excellent compound that exhibits excellent selectivity for sensitive ion channels.
  • Such acid-sensitive ion channel inhibitors include ischemic heart disease, heart failure, peripheral arterial disease, arrhythmia, hypertension, hypotension, rheumatoid arthritis, arthritis-related inflammatory disease, inflammatory bowel disease, ulcerative Colitis, dermatitis including psoriasis, eczema, edema, inflammatory pain, postoperative pain, fibromyalgia, migraine, joint pain, postherpetic neuralgia, neuropathic pain such as diabetic neuralgia, pain associated with cancer , Osteoarthritis, interstitial cystitis, reflux esophagitis, irritable bowel syndrome, cough, gustatory injury, hearing loss, visual impairment in diabetic retinopathy and glaucoma, colorectal cancer, ovarian epithelial cancer, breast cancer, stomach Associated with diseases or disorders such as tumorigenesis, hyperventilation syndrome, asthma, insulin resistant diabetes, multiple sclerosis, generalized anxiety disorder, panic disorder, cerebral infarction, Parkinson
  • the compound of the present invention is expected to have an acid-sensitive ion channel inhibitory action even when administered orally, it can easily exert an excellent acid-sensitive ion channel inhibitory action. QOL can be improved.
  • the compound of the present invention, a pharmaceutically acceptable salt thereof, or a hydrate thereof can be administered in various forms.
  • the administration form is, for example, oral administration such as tablets, capsules, granules, emulsions, pills, powders, syrups (solutions), or injections (intravenous, intramuscular, subcutaneous, or intraperitoneal administration). And parenteral administration such as drops, suppositories (rectal administration) and the like.
  • These various preparations can be usually used in the pharmaceutical preparation technical field such as excipients, binders, disintegrants, lubricants, flavoring agents, solubilizers, suspension agents, coating agents, etc. with respect to the main drug.
  • An auxiliary agent can be appropriately selected and added, and can be formulated according to a commonly practiced method.
  • excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; water, ethanol, propanol, simple syrup, glucose Solution, starch solution, gelatin solution, binders such as carboxymethylcellulose, shellac, methylcellulose, potassium phosphate and polyvinylpyrrolidone; dried starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid Disintegrators such as esters, sodium lauryl sulfate, monoglyceride stearate, starch and lactose; disintegrators such as sucrose, stearin, cocoa butter and hydrogenated oil; quaternary ammonium salts and lauryl sulfate Absorption promoters such as sodium; humectants such as glycerin and star
  • the tablet which gave the normal coating for example, a sugar-coated tablet, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, and a multilayer tablet.
  • excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin and talc; binders such as gum arabic powder, tragacanth powder, gelatin and ethanol; laminaran, Disintegrants such as agar can be used.
  • a carrier conventionally known in this field can be widely used as a carrier, and examples thereof include polyethylene glycol, cacao butter, higher alcohol, esters of higher alcohol, gelatin, and semi-synthetic glyceride.
  • solutions, emulsions or suspensions When used as an injection, it can be used as a solution, emulsion, or suspension. These solutions, emulsions or suspensions are preferably sterilized and isotonic with blood.
  • the solvent used in the production of these solutions, emulsions or suspensions is not particularly limited as long as it can be used as a medical diluent.
  • the preparation may contain a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution, and a normal solubilizing agent, buffer, soothing agent, etc. May be included.
  • the above-mentioned preparation can contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and the like as necessary, and can further contain other pharmaceuticals.
  • the amount of the active ingredient compound contained in the preparation is not particularly limited and is appropriately selected within a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight in the total composition.
  • the amount used varies depending on the symptoms, age, etc. of the patient (warm-blooded animals, particularly humans), but in the case of oral administration, the upper limit is 1000 mg (preferably 100 mg) per day, and the lower limit is 0.1 mg (preferably 1 mg, more preferably 5 mg) is preferably administered to adults 1 to 6 times daily depending on symptoms.
  • Lithium hydroxide monohydrate (350 mg) was added to a solution of the compound obtained in the above step 1 (1.50 g) in tetrahydrofuran (16.7 ml), methanol (8.35 ml) and water (8.35 ml), and stirred at room temperature for 3 hours. did. 1N aqueous sodium hydroxide solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure.
  • Oxalyl chloride (0.596 ml) and a catalytic amount of N, N-dimethylformamide were added to a solution of the compound (1.20 g) obtained in Step 2 above in dichloroethane (17.4 ml) and stirred at room temperature for 45 minutes.
  • the reaction mixture was evaporated under reduced pressure, aluminum trichloride (556 mg) was added to a solution of the obtained residue in dichloroethane (17.4 ml), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate.
  • Lithium aluminum hydride (9.6 mg) was added to a tetrahydrofuran (4.00 ml) solution of the compound (25 mg) obtained in the above Step 8 at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. 4N Aqueous sodium hydroxide solution was added to stop the reaction, insoluble material was removed by Celite filtration, and the obtained solution was concentrated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography [dichloromethane / methanol] to give the title compound (11 mg) as a colorless oil.
  • Nickel dichloride (434 mg) was added to a solution of the compound (2 g) obtained in Step 5 above in tetrahydrofuran (60.9 ml), and then sodium borohydride (691 mg) and methanol (12.2 ml) were added at 0 ° C. Stir at 30 ° C. for 30 minutes. Water, ethyl acetate, a saturated aqueous sodium hydrogen carbonate solution and di-t-butyl dicarbonate were added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was distilled off under reduced pressure.
  • Example 2 Compound obtained in Step 7 (350 mg) and methyl 2-methylsulfonyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (314 mg) was used to give the title compound (350 mg) as a white solid in the same manner as in Example 1, Step 6.
  • Example 2 Compound (350 mg) obtained in Step 7 and [2-methoxy-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3-pyridyl] The title compound (350 mg) was obtained as a yellow solid in the same manner as in Example 1, Step 6 using methanol (282 mg).
  • Example 2 Compound (350 mg) obtained in Step 7 and 2- (3-fluoro-5-vinyl-phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborate (194 mg) was used to give the title compound (250 mg) as a white solid in the same manner as in Example 1, Step 6.
  • the compound (250 mg) obtained in the above Step 1 was dissolved in tert-butyl alcohol (50 ml) and water (20 ml), AD-mix- ⁇ (1.60 g) was added, and the mixture was stirred at room temperature for 15 hours.
  • the reaction solution was poured into an aqueous sodium sulfite solution, and the organic matter was extracted with ethyl acetate. After washing with brine, it was dried over sodium sulfate and the solvent was distilled off.
  • the residue was purified by diol silica gel chromatography [hexane / ethyl acetate] to give the title compound (165 mg) as a white solid.
  • Example 2 Compound (500 mg) obtained in Step 7 and 2- (3-chloro-5-vinyl-phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (402 mg) was used to give the title compound (380 mg) as a white solid in the same manner as in Example 1, Step 6.
  • Example 7 1- ⁇ 4-[(3S) -3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl] -6-methoxypyridin-2-yl ⁇ ethanol [Step 1] tert-Butyl [7- (2-acetyl-6-methoxypyridin-4-yl) -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indole- 3-yl] carbamate
  • Example 2 Compound obtained in Step 7 (600 mg) and 1- [6-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2- The title compound (610 mg) was obtained as a brown solid in the same manner as in Example 1, Step 6 using [pyridyl] ethanone (404 mg).
  • Example 8 [4- (3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -6-methoxypyridin-2-yl] ethanone [Step 1] 1- ⁇ 4- [3-Amino-6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-7-yl] -6-methoxypyridine-2 -Ile ⁇ Ethanon
  • Example 7 Using the compound (300 mg) obtained in Step 1 of the Example, the title compound (140 mg) was obtained as a white solid in the same manner as in Step 2 of Example 2.
  • [Step 2] 1- [4- (3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -6-methoxypyridin-2-yl] ethanone
  • Example 2 Compound obtained in Step 7 (600 mg) and methyl 3-cyano-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (0.419 g) was used to give the title compound (600 mg) as a brown solid in the same manner as in Example 1, Step 6.
  • Example 10 7- [3-Methoxy-4- (methylsulfonyl) phenyl] -3,6-dihydro-2H-furo [2,3-e] indole-3-amine [Step 1] tert-butyl ⁇ 7- [3-methoxy-4- (methylsulfonyl) phenyl] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indole-3 -Il ⁇ Carbamate
  • Example 2 Using the compound (400 mg) obtained in Step 7 and (3-methoxy-4-methoxysulfonyl-phenyl) boronic acid (0.242 g), the title compound (430 mg) was prepared in the same manner as in Example 1, Step 6. Was obtained as a brown solid.
  • Example 11 7- [5- (Methylsulfonyl) pyridin-2-yl] -3,6-dihydro-2H-furo [2,3-e] indole-3-amine [Step 1] tert-Butyl [6- (phenylsulfonyl) -7- (tributylstannanyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-yl] carbamate
  • Example 2 A tetrahydrofuran (80.4 mL) solution of the compound (1.00 g) obtained in Step 6 was cooled to ⁇ 78 ° C., lithium diisopropylamide (in n-hexane-tetrahydrofuran, 1.0 M; 5.00 mL) was added, and 30 Stir for minutes. To the reaction solution, tributyltin iodide (2.31 g) was slowly added dropwise and stirred for 30 minutes. A saturated aqueous potassium fluoride solution was added to the reaction mixture, and the mixture was stirred for 1 hour, and then the reaction mixture was extracted with ethyl acetate.
  • Example 12 [5- (3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) pyrazin-2-yl] methanol [Step 1] Methyl 5- ⁇ 3-[(tert-butoxycarbonyl) amino] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-7-yl ⁇ pyrazine -2-carboxylate
  • Example 11 Using the compound obtained in Example 11, Step 1 (400 mg) and methyl 5-bromopyrazine-2-carboxylate (0.247 g), the title compound (300 mg) was obtained as a yellow oily substance in the same manner as in Example 11, Step 2. Got as.
  • Example 13 ⁇ 4-[(3S) -3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl] -6-methoxypyridin-2-yl ⁇ methanol [Step 1] Methyl 4- ⁇ 3-[(tert-butoxycarbonyl) amino] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-7-yl ⁇ - 6-Methoxypyridine-2-carboxylate
  • Example 2 Compound (400 mg) obtained in Step 7 and methyl 6-methoxy-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) pyridine-2-carboxy The title compound (400 mg) was obtained as a white solid in the same manner as in Example 1, Step 6 using the rate (0.250 g).
  • Example 14 (1R) -1- ⁇ 5-[(3S) -3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl] pyrazin-2-yl ⁇ ethanol
  • Step 1 tert-butyl [(3R) -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-yl] carbamate; tert-butyl [(3S) -6- (Phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-yl] carbamate
  • Example 2 Optical resolution of the compound (135 g) obtained in Step 6 was performed using column chromatography (Daicel Chiralcel OJ-H, 100% methanol). After collecting the first peak eluting first, the solvent was distilled off under reduced pressure, and tert-butyl [(3R) -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3 -e] Indol-3-yl] carbamate (57.9 g, optical purity> 98% ee) was obtained as a white solid.
  • Example 1 The compound of Example 2 (5 g), lactose (90 g), corn starch (34 g), crystalline cellulose (20 g) and magnesium stearate (1 g) were mixed in a blender, and then tableted to form a tablet. can get.
  • Evaluation Example 1 In vitro evaluation method of ASIC Human ASIC3-expressing cells were purchased from Millipore (catalog number: CYL3055).
  • the stable expression cell lines of Human ASIC1a, human ASIC2a, and mouse ⁇ ⁇ ASIC1a are V5-His-ASICs-vector prepared using GeneSwitch System Complate kit (Invitrogen), and GeneSwitch-2000 Transfection Reagent (Invitrogen). A gene was introduced into CHO Cells (Invitrogen). The vector preparation method and gene introduction method were in accordance with the manual attached to each kit.
  • Mouse ASIC3-expressing cells were transfected into HEK293A cells (Invitrogen) using Lipofectamine 2000 Transfection Reagent (Invitrogen) according to the method attached to the kit to produce a stable expression cell line.
  • Table 1 shows the relationship between gene names and host cells.
  • Human ASIC1a-expressing cells were treated with 1 nM Mifepristone (Sigma-Aldrich) for 18 hours to induce expression, and then used for measurement.
  • Human ASIC2a-expressing cells and Mouse ASIC1a-expressing cells were treated with 10 nM Mifepristone (Sigma-Aldrich) for 18 hours to induce expression and then used for measurement.
  • ASIC inhibitory activity was evaluated by contacting cells and compounds and measuring peak changes in acid-induced currents using a whole cell automatic patch clamp method (Patchliner, “Nanion Technologies” GmBH). The holding potential was -60 mV. The composition of the inner liquid and the outer liquid is described below.
  • Internal solution 50 CsCl, 60 CsF, 10 NaCl, 20 EGTA, and 10 HEPES, pH 7.2.
  • Nonstandard solution 135 NaCl, 4 KCl, 5 CaCl 2 , 1 MgCl 2 , 5 glucose, and 10 HEPES, pH 7.4.
  • Acid-stimulated external solution 135 NaCl, 4 KCl, 5 CaCl 2 , 1 MgCl 2 , 5 glucose, and 10 HEPES, pH 6.4 (ASIC1a, 3 function measurement), or 10 MES, pH 4.0 (ASIC2a function measurement) .
  • the reference value of the acid-induced current was defined by the current peak generated when the non-standard solution was replaced with an acid-stimulated solution containing 0.1% DMSO.
  • the ASIC current inhibition rate of the compound was defined by the change in the current peak when substituting the acid-stimulated external solution containing the compound with respect to the reference value. The inhibition rate at each concentration was plotted, and the IC 50 value was calculated from the concentration response curve fitted using the Hill equation.
  • Table 2 shows the inhibitory action of each compound of the present invention on human ASIC3.
  • Evaluation Example 2 ENac In Vitro Evaluation Method CHOK1 cells functionally co-expressing Human ENaC ⁇ , Human ENaC ⁇ , and Human ENaC ⁇ using Lipofectamine TM LTX Reagent (Invitrogen) according to the manual attached to the kit (DS pharma biochemical) was prepared and used for testing.
  • the introduced genes are shown in Table 3.
  • the measurement principle is based on the method of Krumm et al. (Bioorg. Med. Chem., 2012, 20, 3979-3984).
  • ENaC inhibitory activity was evaluated by contacting cells and compounds and measuring peak changes in current using the whole cell automatic patch clamp method (Syncropatch384PE, PENanion Technologies GmBH). The holding potential was -60 mV.
  • the composition of the inner liquid and the outer liquid is described below.
  • ENaC current was defined by the current peak generated when the non-standard solution was replaced with an evaluation solution containing 0.1% DMSO.
  • ENaC current inhibition rate of the compound was defined by the change in current peak when the compound was replaced with an evaluation liquid containing the compound with respect to the reference value. The inhibition rate at each concentration was plotted, and the IC 50 value was calculated from the concentration response curve fitted using the Hill equation.
  • the 3,6-dihydro-2H-furo [2,3-e] indole compound of the present invention, a salt thereof, or a hydrate thereof is an excellent oral acid-sensitive ion channel inhibitor and useful as a medicine. .
  • SEQ ID NO: 1 Base sequence of human ENaC ⁇ subunit
  • SEQ ID NO: 2 Base sequence of human ENaC ⁇ subunit
  • SEQ ID NO: 3 Base sequence of human ENaC ⁇ subunit

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Psychiatry (AREA)
  • Rheumatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Urology & Nephrology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Psychology (AREA)
  • Vascular Medicine (AREA)
  • Dermatology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention aborde le problème de la fourniture d'un inhibiteur de canal ionique de détection d'acide pouvant être administré par voie orale. La solution selon l'invention porte sur un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci. (Dans la formule, la structure présentée par la formule (II) est un groupe aromatique dans lequel R1 et R2 sont substitués; et chacun de R1 et R2 représente un groupe indépendamment choisi parmi un atome d'hydrogène, un groupe alkyle, un groupe alcoxy, un groupe hydroxyalkyle, un groupe dihydroxyalkyle, un groupe halogénoalkyle, un groupe alkylsulfonyle, un atome d'halogène, un groupe cyano et un groupe acyle.)
PCT/JP2018/005360 2017-02-17 2018-02-16 COMPOSÉ 3, 6-DIHYDRO-2H-FURO[2, 3-e]INDOLE Ceased WO2018151239A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2017-027806 2017-02-17
JP2017027806 2017-02-17

Publications (1)

Publication Number Publication Date
WO2018151239A1 true WO2018151239A1 (fr) 2018-08-23

Family

ID=63169873

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2018/005360 Ceased WO2018151239A1 (fr) 2017-02-17 2018-02-16 COMPOSÉ 3, 6-DIHYDRO-2H-FURO[2, 3-e]INDOLE

Country Status (1)

Country Link
WO (1) WO2018151239A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003507366A (ja) * 1999-08-11 2003-02-25 バーナリス リサーチ リミテッド 縮合インドール誘導体および５ｈｔ、特に５ｈｔ２ｃのレセプターリガンドとしてのこれらの使用
WO2009042092A1 (fr) * 2007-09-25 2009-04-02 Merck & Co., Inc. Dérivés d'indole 2-aryle ou hétéroaryle
JP2009516712A (ja) * 2005-11-23 2009-04-23 ペインセプター ファーマ コーポレーション 依存性イオンチャネルを調節するための組成物および方法
JP2009520700A (ja) * 2005-12-21 2009-05-28 ペインセプター ファーマ コーポレーション 依存性イオンチャネルを調節するための組成物および方法
JP2011524359A (ja) * 2008-06-13 2011-09-01 シェーリング コーポレイション ３環式インドール誘導体およびその使用方法
WO2012125662A1 (fr) * 2011-03-17 2012-09-20 Merck Sharp & Dohme Corp. Dérivés d'indole utiles en tant qu'antagonistes de ccr2

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003507366A (ja) * 1999-08-11 2003-02-25 バーナリス リサーチ リミテッド 縮合インドール誘導体および５ｈｔ、特に５ｈｔ２ｃのレセプターリガンドとしてのこれらの使用
JP2009516712A (ja) * 2005-11-23 2009-04-23 ペインセプター ファーマ コーポレーション 依存性イオンチャネルを調節するための組成物および方法
JP2009520700A (ja) * 2005-12-21 2009-05-28 ペインセプター ファーマ コーポレーション 依存性イオンチャネルを調節するための組成物および方法
WO2009042092A1 (fr) * 2007-09-25 2009-04-02 Merck & Co., Inc. Dérivés d'indole 2-aryle ou hétéroaryle
JP2011524359A (ja) * 2008-06-13 2011-09-01 シェーリング コーポレイション ３環式インドール誘導体およびその使用方法
WO2012125662A1 (fr) * 2011-03-17 2012-09-20 Merck Sharp & Dohme Corp. Dérivés d'indole utiles en tant qu'antagonistes de ccr2

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KUDUK, S. D. ET AL., BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 19, no. 15, 13 June 2009 (2009-06-13), pages 4059 - 4063, XP055539021, Retrieved from the Internet <URL:DOI:10.1016/j.bmcl.2009.06.021> *

Similar Documents

Publication Publication Date Title
JP7293560B2 (ja) 芳香族ビニルまたは芳香族エチル系誘導体、その製造方法、中間体、薬物組成物および使用
CA2542609C (fr) Nouveau derive d&#39;indazole
TWI714527B (zh) 醯胺類衍生物及其可藥用鹽、其製備方法及其在醫藥上的應用
KR102006684B1 (ko) Jak 억제제
EP3019482B1 (fr) Dérivés de benzotriazole trisubstitués à titre d&#39;inhibiteurs de dihydroorotate oxygénase
CN108026102A (zh) 可用于治疗与kit和pdgfr相关的病症的化合物
JP7451765B2 (ja) Ｃｄｋ阻害剤としてのピリジンアセトアミド系誘導体、その調製方法及び用途
CN114269755A (zh) 作为magl抑制剂的4,4a,5,7,8,8a-六吡啶并[4,3-b][1,4]噁嗪-3-酮化合物
CN110041333A (zh) 溴结构域抑制剂化合物及其用途
IL310872A (en) SOS1 inhibitor and its use
CN103664908A (zh) 一种具有腺苷受体拮抗活性的氨基嘧啶杂环化合物
WO2018186365A1 (fr) Agent inducteur de lecture et application pharmaceutique correspondante
WO2005035501A1 (fr) Nouveau derive d&#39;olefine
WO2019144764A1 (fr) Composé hétérocyclique aromatique, intermédiaire de celui-ci, son procédé de préparation, et composition pharmaceutique et son utilisation
WO2019144765A1 (fr) Composé oléfinique à substitution hétérocyclique aromatique, procédé de préparation de celui-ci, composition pharmaceutique associée et utilisations correspondantes
AU2016314355A1 (en) Sulfonamide compounds as voltage-gated sodium channel modulators
JP7299350B2 (ja) Ｒｉｐ－１キナーゼ阻害剤としての二環式化合物およびその使用
JP7488768B2 (ja) ［１，２，４］トリアゾロ［４、３－ａ］ピラジン－８－オン誘導体
KR102160841B1 (ko) 2-피리돈 화합물
WO2018151239A1 (fr) COMPOSÉ 3, 6-DIHYDRO-2H-FURO[2, 3-e]INDOLE
CN101006087B (zh) 作为p38MAP激酶抑制剂的三唑并吡啶基硫烷基衍生物
CN117730083A (zh) 用作map4k1抑制剂的嘧啶化合物
CN116924983A (zh) 一种新型杂环化合物
JP6052673B2 (ja) ピラゾール誘導体またはその塩ならびにそれらを含有する医薬組成物
RU2468009C2 (ru) Ингибитор связывания s1p1

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: JP

122 Ep: pct application non-entry in european phase

Ref document number: 18754505

Country of ref document: EP

Kind code of ref document: A1