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

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

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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
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group
compound
furo
dihydro
pharmaceutically acceptable
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French (fr)
Japanese (ja)
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昌生 吉田
優真 梅崎
理恵子 高野
正憲 泉
中村　弘明
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第一三共株式会社
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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

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Abstract

The present invention addresses the problem of providing an acid-sensing ion channel inhibitor which is orally administrable. The solution of the present invention is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. (In the formula, the structure presented by formula (II) is an aromatic group wherein R1 and R2 are substituted; and each of R1 and R2 represents a group independently selected from among a hydrogen atom, an alkyl group, an alkoxy group, a hydroxyalkyl group, a dihydroxy alkyl group, a halogenoalkyl group, an alkylsulfonyl group, a halogen atom, a cyano group and an acyl group.)

Description

３，６－ジヒドロ－２Ｈ－フロ［２，３－ｅ］インドール化合物3,6-Dihydro-2H-furo [2,3-e] indole compound
　本発明は、3,6-ジヒドロ-2H-フロ[2,3-e]インドール化合物又はその薬学的に許容される塩に関し、さらに該化合物を含有する酸感受性イオンチャネル阻害剤に関する。 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.
　酸感受性イオンチャネル（ASIC：acid-sensing ion channel）は、細胞外プロトンにより活性化される陽イオンチャネルである。ASICには、ASIC1、ASIC2、ASIC3及びASIC4のサブタイプが存在し、それぞれのサブタイプが、ホモもしくはヘテロ3量体を形成して機能する。ASIC1及びASIC3は知覚神経に発現することから、炎症、虚血及び癌などの組織pHが低下する病態における、疼痛知覚に関与すると考えられている。 An acid-sensitive ion channel (ASIC) is a cation channel activated by extracellular protons. There 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は、知覚神経以外にも広く分布し、種々の病態への関与が示唆されている。例えば、ASIC1の遺伝子多型がパニック障害と関連すること（Neuromolecular Med. 2016, 18(1), 91-98）、間質性膀胱炎患者の膀胱でASIC2及びASIC3の発現が上昇すること（J. Urology, 2011, 186, 1509-1516）、及びヒト乳癌でASIC1の発現が増加すること（Oncogene, 2015, 1-10）が報告されている。さらに動物実験レベルでは、ASIC1及びASIC3の阻害剤が、鎮痛、神経保護、軟骨保護、血管拡張の抑制、インスリン抵抗性改善作用を示すことが報告されている（Toxicon., 2013, 75, 187-204）。したがって、ASICは様々な病態の発症及び維持に重要な分子と考えられる。 ASIC is widely distributed in addition to sensory nerves, and its involvement in various pathological conditions has been suggested. For example, ASIC1 polymorphism is associated with panic disorder (Neuromolecular Med. 2016, 18 (1), 91-98), and 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. Furthermore, at the level of animal experiments, it has been reported that 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.
　ASICの低分子阻害剤として、アミロライドが広く用いられる。しかしながらアミロライドは、上皮型ナトリウムチャネル（ENaC：Epithelial Na+ channel）も同時に阻害するため、特異性は十分ではない。近年、ASIC1特異的阻害剤であるmambalgin-1やASIC3特異的阻害剤であるAPETx2を初めとする種々のペプチド阻害剤が報告されている（Toxicon., 2013, 75, 187-204）。さらに低分子ASIC阻害剤としてA-317567（Pain, 2005, 117(1-2), 88-96）やNS383（CNS Neurosci. Ther., 2016, 22(2), 135-145）が報告された。しかしながら、アミロライド以外のASIC阻害剤の薬効評価は非経口投与で行われているため、経口吸収性を示すかは不明である。すなわち、ASICを選択的に阻害し、かつ経口吸収可能性が明示された化合物の報告は存在しない。 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. In recent years, 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). Furthermore, A-317567 (Pain, 2005, 117 (1-2), 88-96) and NS383 (CNS Neurosci. Ther., 2016, 22 (2), 135-145) were reported as small molecule ASIC inhibitors. . However, since pharmacological evaluation of ASIC inhibitors other than amiloride is performed by parenteral administration, it is unclear whether or not it exhibits oral absorbability. In other words, there are no reports of compounds that selectively inhibit ASIC and have been shown to be orally absorbable.
　ヒトにおいて、アミロライドが実験的な酸誘発疼痛を抑制すること（J. Clin. Invest., 2002, 110(8), 1185-1190）及び多発性硬化症に対して神経保護作用を示す可能性が報告されている（Brain, 2013, 136, 106-15）。さらに、ASIC阻害剤であるPPC-5650が、ヒトの食道の痛みを抑制することが報告された（Basic Clin. Pharmacol. Toxicol., 2015, 116(2), 140-5）。これらの報告は、ASIC阻害剤が、ヒトにおいて、疼痛を初めとする種々の病態に対して治療効果を示す可能性が示唆される。このような背景の下に新規ASIC阻害剤の創出が試みられている（特許文献１～１０、非特許文献１、２参照）。 In humans, 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).
　本発明に係る三環性の2H-フロ[2,3-e]インドール構造を有する化合物が、ASIC阻害阻害作用を示すことは全く明らかではなかった。 It was not clear at all that the compound having a tricyclic 2H-furo [2,3-e] indole structure according to the present invention exhibited an ASIC inhibition inhibitory action.
国際公開第2006/063466号International Publication No. 2006/063466 国際公開第2007/134434号International Publication No. 2007/134434 国際公開第2011/023812号International Publication No. 2011/023812 国際公開第2007/042816号International Publication No. 2007/042816 国際公開第2008/071944号International Publication No. 2008/071944 国際公開第2010/034796号International Publication No. 2010/034796 国際公開第2012/022793号International Publication No.2012 / 022793 国際公開第2010/132016号International Publication No. 2010/132016 国際公開第2011/077313号International Publication No. 2011/077313 国際公開第2011/131975号International Publication No. 2011/131975
　公知のASIC阻害剤については、経口吸収性を示すかは不明である。ASIC阻害剤が経口投与可能であることによって患者の利便性の向上につながり、有用性が向上する。さらに従来のASIC阻害薬は選択的な阻害特性を有しているか否かについても不明であった。ASIC阻害が選択的であることによって非選択的な阻害によってもたらされる副作用を軽減することができ、安全性を担保することが可能であり、さらに安全性が担保されることで主薬効のための投与量を増量することも可能となり、より高い治療効果を達成することも可能である。 It is unclear whether known 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.
　すなわち、本願発明は経口投与可能で選択的なASIC阻害薬を獲得することを目的とするものである。これによって優れた治療効果を達成することができる。 That is, the present invention aims to obtain a selective ASIC inhibitor that can be administered orally. Thereby, an excellent therapeutic effect can be achieved.
　本願発明者は、式（I）で示される化合物又はその薬学的に許容される塩が、選択性に優れたASIC阻害特性を有し、かつ経口吸収性を備えていることを見い出して本発明を完成させた。 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.
　すなわち本願発明は、
［１］　式（I）で示される化合物又はその薬学的に許容される塩： That is, the present invention
[1] A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof:
Figure JPOXMLDOC01-appb-C000004
Figure JPOXMLDOC01-appb-C000004
（式中、次式： (In the formula, the following formula:
Figure JPOXMLDOC01-appb-C000005
Figure JPOXMLDOC01-appb-C000005
で示される構造は、R1及びR2が置換した芳香族基を示し、R1及びR2は、次の群：
水素原子、C1-C6-アルキル基、C1-C6-アルコキシ基、ヒドロキシC1-C6-アルキル基、ジヒドロキシC2-C6-アルキル基、ハロゲノC1-C6-アルキル基、C1-C6-アルキルスルホニル基、ハロゲン原子、シアノ基及びC2-C6-アシル基
から独立して選ばれる基を示す。）
に関する。 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.
　さらに本発明は、以下の各々に関する。
［２］　芳香族基が、窒素原子及び硫黄原子から選ばれる1～3の複素原子を有する5又は6員環の芳香族複素環基及び炭化水素系芳香族基から選ばれる基である［１］に記載の化合物又はその薬学的に許容される塩。
［３］　芳香族基が、フェニル基、ピロリル基、ピラゾリル基、イミダゾリル基、チアゾリル基、チアジアゾリル基、ピリジル基、ピリダジニル基、ピリミジル基、又はピラジニル基である［１］に記載の化合物又はその薬学的に許容される塩。
［４］　芳香族基が、フェニル基、ピリジル基、ピリミジル基、又はピラジニル基である［１］から［３］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［５］　R1及びR2が、次の群：
水素原子、C1-C6-アルキル基、C1-C6-アルコキシ基、ヒドロキシC1-C6-アルキル基、ジヒドロキシC2-C6-アルキル基、C1-C6-アルキルスルホニル基及びハロゲン原子
から独立して選ばれる基である［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。 Furthermore, this invention relates to each of the following.
[2] 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.
[3] The compound according to [1] or a pharmacy thereof, wherein the aromatic group is a phenyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidyl group, or a pyrazinyl group. Acceptable salt.
[4] The compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [3], wherein the aromatic group is a phenyl group, a pyridyl group, a pyrimidyl group, or a pyrazinyl group.
[5] 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 The compound according to any one of [1] to [4] or a pharmaceutically acceptable salt thereof.
［６］　R1及びR2が、次の群：
水素原子、メチル基、フッ素原子、塩素原子、トリフルオロメチル基、メトキシ基、エトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基、メチルスルホニル基、シアノ基及びアセチル基
から独立して選ばれる基である［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［７］　R1及びR2が、次の群：
水素原子、メチル基、フッ素原子、メトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基及びメチルスルホニル基
から独立して選ばれる基である［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［８］　R1及びR2の一方が水素原子であって、他方が次の群：
メチル基、フッ素原子、塩素原子、トリフルオロメチル基、メトキシ基、エトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基、メチルスルホニル基、シアノ基及びアセチル基、
から選ばれる基である［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［９］　R1及びR2の一方が水素原子であって、他方が次の群：
メチル基、フッ素原子、トリフルオロメチル基、メトキシ基、エトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基、メチルスルホニル基及びアセチル基
から選ばれる基である［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１０］　R1及びR2の一方が水素原子であって、他方が次の群：
水素原子、メチル基、フッ素原子、メトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基及びメチルスルホニル基
から選ばれる基である［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。 [6] 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.
[7] 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.
[8] One of 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:
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, [1] A compound or a pharmaceutically acceptable salt thereof according to any one of [1] to [4], which is a group selected from 1,2-dihydroxyethyl group, methylsulfonyl group and acetyl group.
[10] One of R 1 and R 2 is a 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.
［１１］　R1及びR2の一方が水素原子であって、他方が次の群：
水素原子、メチル基、フッ素原子、メトキシ基、ヒドロキシメチル基、(1R)-1-ヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基及びメチルスルホニル基
から選ばれる基である［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１２］　R1及びR2が、
一方がヒドロキシメチル基であって、他方がメチルスルホニル基、メトキシ基、シアノ基、又はフッ素原子であるか、或は、
一方が1,2-ジヒドロキシエチル基であって、他方がフッ素原子又は塩素原子である［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１３］　R1及びR2が、
一方がヒドロキシメチル基であって、他方がメチルスルホニル基又はメトキシ基であるか、或は、
一方が1,2-ジヒドロキシエチル基であって、他方がフッ素原子である、［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１４］　R1及びR2が、
一方がヒドロキシメチル基であって、他方がメチルスルホニル基又はメトキシ基であるか、或は、
一方が(1R)-1,2-ジヒドロキシエチル基であって、他方がフッ素原子である、［１］から［４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１５］　式（I）で示される化合物が、次の群： [11] One of R 1 and R 2 is 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.
[12] 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.
[13] 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.
[14] 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.
[15] The compound represented by the formula (I) is represented by the following group:
Figure JPOXMLDOC01-appb-C000006
Figure JPOXMLDOC01-appb-C000006
（式中、A部分、R1及びR2は先の定義に等しい。）
のいずれかである［１］から［１４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１６］　式（I）で示される化合物が、次式 (Wherein the A moiety, R 1 and R 2 are equal to the previous definition.)
Or the pharmaceutically acceptable salt thereof according to any one of [1] to [14].
[16] The compound represented by the formula (I) is represented by the following formula:
Figure JPOXMLDOC01-appb-C000007
Figure JPOXMLDOC01-appb-C000007
で示される化合物である［１］から［１４］のいずれか一項に記載の化合物又はその薬学的に許容される塩。
［１７］　式（I）で示される化合物が、
7-(2-メトキシピリミジン-5-イル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン、
7-[5-(メチルスルホニル)ピリジン-2-イル]-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン、
[5-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)ピラジン-2-イル]メタノール、
(1R)-1-{5-[(3S)-3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]ピラジン-2-イル}エタノール、
(3S)-7-(2-メチルピリミジン-5-イル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン、
[5-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)-2-(メチルスルホニル)フェニル]メタノール、
[5-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)-2-メトキシピリジン-3-イル]メタノール、
1-{4-[(3S)-3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]-6-メトキシピリジン-2-イル}エタノール、
{4-[(3S)-3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]-6-メトキシピリジン-2-イル}メタノール、又は
(1R)-1-[3-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)-5-フルオロフェニル]エタン－1,2-ジオール、
である［１］に記載の化合物又はその薬学的に許容される塩。
［１８］　式（I）で示される化合物が、
[5-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)-2-(メチルスルホニル)フェニル]メタノール、
7-[5-(メチルスルホニル)ピリジン-2-イル]-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン、
7-(2-メトキシピリミジン-5-イル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン、又は
(1R)-1-{5-[(3S)-3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]ピラジン-2-イル}エタノール、
である［１］に記載の化合物又はその薬学的に許容される塩。
［１９］　［１］から［１８］のいずれかに記載の化合物又はその薬学的に許容される塩と、薬学的に許容し得る担体とを含有する医薬組成物。
［２０］　虚血性心疾患、心不全、末梢動脈疾患、不整脈、高血圧症、低血圧症、慢性関節リウマチ、関節炎関連性の炎症性疾患、炎症性腸疾患、潰瘍性大腸炎、乾癬を含む皮膚炎、湿疹、浮腫、炎症性疼痛、術後疼痛、線維筋痛症、片頭痛、関節痛、ヘルペス後神経痛、糖尿病性神経痛などの神経因性疼痛、癌に伴う疼痛、変形性関節症、間質性膀胱炎、逆流性食道炎、過敏性腸症候群、咳、味覚傷害、難聴、糖尿病網膜症や緑内障における視機能障害、結腸直腸癌、卵巣上皮癌、乳癌、胃における腫瘍形成、過換気症候群、喘息、インスリン抵抗性糖尿病、多発性硬化症、全般性不安障害、パニック障害、脳梗塞、パーキンソン病、ハンチントン病、又はアルツハイマー病からなる群から選択される疾患又は症状を治療及び／又は予防するための［１９］に記載の医薬組成物。 [1] to [14], or a pharmaceutically acceptable salt thereof.
[17] 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] indol-3-amine,
[5- (3-amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -2- (methylsulfonyl) phenyl] methanol,
[5- (3-amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -2-methoxypyridin-3-yl] methanol,
1- {4-[(3S) -3-amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl] -6-methoxypyridin-2-yl} ethanol,
{4-[(3S) -3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl] -6-methoxypyridin-2-yl} methanol, or
(1R) -1- [3- (3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -5-fluorophenyl] ethane-1,2-diol,
[1] or a pharmaceutically acceptable salt thereof.
[18] 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.
[19] 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.
[20] 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, stroma Cystitis, reflux esophagitis, irritable bowel syndrome, cough, taste damage, hearing loss, visual impairment in diabetic retinopathy and glaucoma, colorectal cancer, ovarian epithelial cancer, breast cancer, tumor formation in the stomach, hyperventilation syndrome, Treat and / or prevent a disease or condition selected from the group consisting of asthma, insulin-resistant diabetes, multiple sclerosis, generalized anxiety disorder, panic disorder, cerebral infarction, Parkinson's disease, Huntington's disease, or Alzheimer's disease A pharmaceutical composition according to [19].
［２１］　［１］から［１８］のいずれかに記載の化合物又はその薬学的に許容される塩を含有する酸感受性イオンチャネル（ASIC）阻害剤。
［２２］　［１］から［１８］のいずれかに記載の化合物又はその薬学的に許容される塩を投与することを特徴とする酸感受性イオンチャネル（ASIC）が介在する疾病を治療及び／又は予防する方法。
［２３］　酸感受性イオンチャネル（ASIC）が介在する疾病を治療及び／又は予防するための［１］から［１８］のいずれかに記載の化合物又はその薬学的に許容される塩の使用。 [21] An acid-sensitive ion channel (ASIC) inhibitor comprising the compound according to any one of [1] to [18] or a pharmaceutically acceptable salt thereof.
[22] Treating and / or treating a disease mediated by an acid-sensitive ion channel (ASIC), which comprises administering the compound according to any one of [1] to [18] or a pharmaceutically acceptable salt thereof. How to prevent.
[23] Use of the compound according to any one of [1] to [18] or a pharmaceutically acceptable salt thereof for treating and / or preventing a disease mediated by an acid-sensitive ion channel (ASIC).
　本発明の式（I）で示される化合物又はその薬学的に許容される塩は、優れた選択性の酸感受性イオンチャネル（ASIC）阻害作用を有し、かつ経口投与可能であり、したがって酸感受性イオンチャネルが関与する種々の病態の治療及び／又は予防に有用である。 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.
本発明の実施例２の化合物を10mg/kgの用量でマウスに経口投与又は静脈内投与した時の血中濃度推移（単位：ナノモル）を示す。菱形は静脈内投与時、四角は経口投与時の推移を示す。横軸は時間を示す。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.
　以下、本発明を実施するための好適な形態について以下に説明する。なお、以下に説明する実施形態は、本発明の代表的な実施形態の一例を示したものであり、これによって本発明の範囲が狭く解釈されることはない。 Hereinafter, preferred embodiments for carrying out the present invention will be described below. In addition, embodiment described below shows an example of typical embodiment of this invention, and, thereby, the range of this invention is not interpreted narrowly.
　本発明は、式（I）で示される化合物、その薬学的に許容される塩、又はそれらの水和物に関するものである。すなわち、3,6-ジヒドロフロ[2,3-e]インドールを母核とし、その3位にアミノ基を有し、7位にR1及びR2が置換した芳香族基を有する構造の化合物である。 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.
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000008
　ここで、次式 Where
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000009
で示される基のうちのA部分は、炭化水素系芳香族基であるか、或は窒素原子及び硫黄原子から選ばれる複素原子1～3を有する5員環又は6員環の芳香族複素環基である。この芳香族基上にあるR1及びR2は、次の群：
水素原子、C1-C6-アルキル基（「C1-C6-」は、炭素数が1～6であることを示す。）、C1-C6-アルコキシ基、ヒドロキシC1-C6-アルキル基、ジヒドロキシC2-C6-アルキル基、ハロゲノC1-C6-アルキル基、ハロゲン原子、シアノ基、C2-C6-アシル基及びC1-C6-アルキルスルホニル基
から独立して選ばれる基である。 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.
　以下に本化合物の構造について説明する。 The structure of this compound will be described below.
　式（I）で示される化合物は、環上にアミノ基が置換しており、このアミノ基の配位に起因して、次式： In the compound represented by the formula (I), an amino group is substituted on the ring, and due to the coordination of the amino group, the following formula:
Figure JPOXMLDOC01-appb-C000010
Figure JPOXMLDOC01-appb-C000010
のいずれかの態様となる。これらのうちではアミノ基の配位がアルファである次式：　　　　　 It becomes either aspect. Of these, the amino group coordination is alpha:
Figure JPOXMLDOC01-appb-C000011
Figure JPOXMLDOC01-appb-C000011
の構造がより好ましいと考えている。すなわち、本発明者らは、類似構造を有して酸感受性イオンチャネル（ASIC）阻害作用を示す、6位にアミノ置換された3,6,7,8-テトラヒドロシクロペンタ[e]インドール化合物を別途取得しており、当該化合物においては6位のアミノ基がアルファ配置である化合物がより高い酸感受性イオンチャネル（ASIC）阻害作用を有することを明らかにした。この化合物と本願発明化合物との構造類似性から、本発明の、2位［これは、3,6,7,8-テトラヒドロシクロペンタ[e]インドール化合物の6位に相当する位置である。］にアミノ置換された3,6-ジヒドロ-2H-フロ[2,3-e]インドール化合物においてもアミノ基の配置はアルファ体がより高活性を示す、好ましい配置であると考えている。 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.
　芳香族基として次式：  The following formula as an aromatic group: 式
Figure JPOXMLDOC01-appb-C000012
Figure JPOXMLDOC01-appb-C000012
で示される基におけるA部分は、炭化水素系芳香族基であるか、窒素原子及び硫黄原子から選ばれる複素原子1～3を有する、5員環又は6員環の芳香族複素環基である。炭化水素系芳香族基として、フェニル基を挙げることができ、複素環芳香族基として、ピロリル基、イミダゾリル基、ピラゾリル基、チアゾリル基、チアジアゾリル基、ピリジル基、ピリダジニル基、ピリミジル基、又はピラジニル基を挙げることができる。 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 . Examples of the hydrocarbon aromatic group include a phenyl group, and examples of 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. Can be mentioned.
　当該A部分として好ましくは、フェニル基、ピロリル-2-イル基、ピロリル-3-イル基、ピラゾール-3-イル基、ピラゾール-4-イル基、イミダゾール-2-イル基、イミダゾール-4-イル基、チアゾール-2-イル基、チアゾール-5-イル基、チアジアゾール-2-イル基、ピリジン-2-イル基、ピリジン-3-イル基、ピリジン-4-イル基、ピリミジン-2-イル基、ピリミジン-4-イル基及びピラジン-2-イル基を挙げることができる。 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. Group, thiazol-2-yl group, thiazol-5-yl group, thiadiazol-2-yl group, pyridin-2-yl group, pyridin-3-yl group, pyridin-4-yl group, pyrimidin-2-yl group And pyrimidin-4-yl group and pyrazin-2-yl group.
　これらのうちより好ましくは、フェニル基、ピラゾール-3-イル基、ピラゾール-4-イル基、チアゾール-2-イル基、チアゾール-5-イル基、チアジアゾール-2-イル基、ピリジン-2-イル基、ピリジン-3-イル基、ピリジン-4-イル基、ピリミジン-2-イル基、ピリミジン-4-イル基及びピラジン-2-イル基を挙げることができる。 Of these, more preferred are 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. Groups, pyridin-3-yl groups, pyridin-4-yl groups, pyrimidin-2-yl groups, pyrimidin-4-yl groups and pyrazin-2-yl groups.
　これらのうちさらに好ましくは、フェニル基、ピリジン-2-イル基、ピリジン-4-イル基、ピリミジン-2-イル基、ピリミジン-4-イル基、又はピラジン-2-イル基である。
　芳香族基上の置換基であるR1及びR2は、各々独立に、以下の置換基となることができる。 Of these, a phenyl group, a pyridin-2-yl group, a pyridin-4-yl group, a pyrimidin-2-yl group, a pyrimidin-4-yl group, or a pyrazin-2-yl group is more preferable.
R 1 and R 2 which are substituents on the aromatic group can be independently the following substituents.
　R1又はR2がC1-C6-アルキル基であるとき、好ましくは、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、又はsec-ブチル基であればよく、より好ましくは、メチル基又はエチル基である。 When 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.
　R1又はR2がC1-C6-アルコキシ基であるとき、好ましくはメトキシ基、エトキシ基、プロポキシ基、2-メチルエトキシ基、ブトキシ基、1-メチルプロポキシ基、又は2-メチルプロポキシ基であればよく、より好ましくは、メトキシ基又はエトキシ基である。 When 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.
　R1又はR2がヒドロキシC1-C6-アルキル基であるとき、ヒドロキシ基の位置は特に制限はないが、芳香族基に結合した炭素原子、すなわちベンジル位に相当、にあることがより好ましい。ヒドロキシC1-C6-アルキル基として好ましくは、ヒドロキシメチル基、1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、2-ヒドロキプロピル基、3-ヒドロキプロピル基、1-ヒドロキシ-1-メチルエチル基、2-ヒドロキシ-1-メチルエチル基、1-ヒドロキシブチル基、2-ヒドロキシブチル基、3-ヒドロキシブチル基、4-ヒドロキシブチル基、1-ヒドロキシ-1-メチルプロピル基、1-ヒドロキシ-2-メチルプロピル基、2-ヒドロキシ-1-メチルプロピル基、3-ヒドロキシ-1-メチルプロピル基、2-ヒドロキシ-2-メチルプロピル基、又は3-ヒドロキシ-2-メチルプロピル基である。これらのうちより好ましくは、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基であり、さらに好ましくは、(1R)のヒドロキシアルキル基であり、(1R)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシプロピル基が好ましく、そして(1R)-1-ヒドロキシエチル基が好ましい。 When 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. Preferred as 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. Of these, more preferably, 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, more preferably (1R) hydroxyalkyl group, (1R) -1-hydroxyethyl group, (1R) -1-hydroxypropyl group And (1R) -1-hydroxyethyl groups are preferred.
　R1又はR2がジヒドロキシC2-C6-アルキル基であるとき、2個のヒドロキシ基の位置としては特に制限はないが、1,2-ジオール構造であるものがより好ましく、さらには(1R)ヒドロキシであるものが好ましい。ジヒドロキシC2-C6-アルキル基として好ましくは、1,2-ジヒドロキシエチル基、1,2-ジヒドロキシプロピル基、1,3-ジヒドロキシプロピル基、2,3-ジヒドロキシプロピル基、1,2-ジヒドロキシブチル基、1,3-ジヒドロキシブチル基、1,4-ジヒドロキシブチル基、2,3-ジヒドロキシブチル基、2,4-ジヒドロキシブチル基、3,4-ジヒドロキシブチル基、1,2-ジヒドロキシ-1-メチルプロピル基、1,2-ジヒドロキシ-2-メチルプロピル基、1,3-ジヒドロキシ-1-メチルプロピル基、1,3-ジヒドロキシ-2-メチルプロピル基、2,3-ジヒドロキシ-1-メチルプロピル基、又は2,3-ジヒドロキシ-2-メチルプロピル基を挙げることができる。これらのうちでより好ましくは、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、又は(1R)-1,2-ジヒドロキシエチル基を挙げることができる。さらに好ましくは、(1R)のジヒドロキシアルキル基である(1R)-1,2-ジヒドロキシエチル基が好ましい。 When 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. Among these, 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).
　R1又はR2がハロゲノC1-C6-アルキル基であるとき、置換するハロゲンの数は1からパー置換までの間で置換するものでよい。置換の位置は、アルキル基の末端の炭素原子であるものがより好ましいが、特に制限はない。ハロゲノC1-C6-アルキル基として好ましくは、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、2-フルオロエチル基、2,2,2-トリフルオロエチル基、パーフルオロエチル基、クロロメチル基、又は2-クロロエチル基を挙げることができる。これらのうちでより好ましくは、フルオロメチル基、トリフルオロメチル基、2-フルオロエチル基、又は2,2,2-トリフルオロエチル基であり、さらに好ましくはトリフルオロメチル基である。 When 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. Of these, more preferred is 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.
　R1又はR2がC1-C6-アルキルスルホニル基であるとき、メチルスルホニル基、エチルスルホニル基、プロピルスルホニル基、又は2-メチルエチルスルホニル基を挙げることができる。このうちでより好ましくは、メチルスルホニル基である。 When 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. Of these, a methylsulfonyl group is more preferable.
　R1又はR2がハロゲン原子であるとき、フッ素原子、クロロ原子、ブロモ原子、又はヨード原子を挙げることができるが、好ましくはフッ素原子又はクロロ原子であり、より好ましくはフッ素原子である。 When 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.
　R1又はR2がC2-C6-アルキルカルボニル基（アシル基）であるとき、好ましくはメチルカルボニル基（アセチル基）、エチルカルボニル基、プロピルカルボニル基、2-メチルエチルカルボニル基、ブチルカルボニル基、1-メチルプロピルカルボニル基、又は2-メチルプロピルカルボニル基を挙げることができ、より好ましくはアセチル基である。 When 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.
　R1及びR2としては、次の群：
水素原子、メチル基、フッ素原子、塩素原子、トリフルオロメチル基、メトキシ基、エトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基、メチルスルホニル基、シアノ基及びアセチル基
から独立に選ばれるものであればよい。 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.
　このうち好ましくは、R1及びR2として、次の群：
水素原子、メチル基、フッ素原子、メトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基及びメチルスルホニル基
から選ばれる基を挙げることができる。 Of these, preferably, 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.
　さらに好ましくは、R1及びR2として、次の群：
水素原子、メチル基、フッ素原子、メトキシ基、ヒドロキシメチル基、(1R)-1-ヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基及びメチルスルホニル基
から選ばれる基を挙げることができる。 More preferably, 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. .
　また、R1及びR2の一方が水素原子であるときに、他方は次の群：
メチル基、フッ素原子、塩素原子、トリフルオロメチル基、メトキシ基、エトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基、メチルスルホニル基、シアノ基及びアセチル基
から選ばれることが好ましい。 Also, 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.
　さらに好ましくは、他方が次の群：
メチル基、フッ素原子、トリフルオロメチル基、メトキシ基、エトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基、メチルスルホニル基及びアセチル基
から選ばれる場合である。 More preferably, 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.
　より好ましくは、他方が次の群：
水素原子、メチル基、フッ素原子、メトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基及びメチルスルホニル基
から選ばれる場合である。 More preferably, 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.
　さらに好ましくは、他方が次の群：
水素原子、メチル基、フッ素原子、メトキシ基、ヒドロキシメチル基、(1R)-1-ヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基及びメチルスルホニル基
から選ばれる場合である。
　さらに、R1及びR2において、
一方がヒドロキシメチル基であって、他方がメチルスルホニル基、メトキシ基、シアノ基、又はフッ素原子であるか、或は、
一方が1,2-ジヒドロキシエチル基であって、他方がフッ素原子又は塩素原子である
場合が好ましい。 More preferably, 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.
Further, in 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.
　一方が1,2-ジヒドロキシエチル基の場合、さらに好ましくは、
一方が、(1R)-1,2-ジヒドロキシエチル基であって、他方がフッ素原子又は塩素原子である場合である。 When 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.
　そして、R1及びR2において、
一方がヒドロキシメチル基であって、他方がメチルスルホニル基又はメトキシ基であるか、或は、
一方が1,2-ジヒドロキシエチル基であって、他方がフッ素原子である
場合がさらに好ましい。 And in 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.
　一方が1,2-ジヒドロキシエチル基の場合、より好ましくは、
一方が、(1R)-1,2-ジヒドロキシエチル基であって、他方がフッ素原子である場合である。 When one is a 1,2-dihydroxyethyl group, more preferably,
One is a (1R) -1,2-dihydroxyethyl group and the other is a fluorine atom.
　次式： The following formula:
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
で示される本発明化合物の置換基として好ましいものを次の群に示す： Preferred examples of the substituent of the compound of the present invention represented by the following are shown in the following group:
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　これらのうち、より好ましくは次の群： Of these, more preferably the following groups:
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
から選ばれる基である。 Is a group selected from
　そしてさらに好ましくは次の群： And more preferably the following groups:
Figure JPOXMLDOC01-appb-C000016
Figure JPOXMLDOC01-appb-C000016
から選ばれる基である。 Is a group selected from
　本発明の式（I）で表される化合物は、以下に記載するA法乃至F法に従って製造することができる。 The compound represented by the formula (I) of the present invention can be produced according to Method A to Method F described below.
　下記A法乃至F法の各工程の反応において使用される溶媒は、反応を阻害せず、反応に悪影響を及ぼさず、出発原料をある程度溶解するものであれば特に限定はない。 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.
　下記A法乃至F法の各工程の反応において、反応温度は、溶媒、出発原料、試薬等により異なり、反応時間は、溶媒、出発原料、試薬、反応温度等により異なる。 In the reaction of each step of Method A to Method F below, the reaction temperature varies depending on the solvent, starting material, reagent, and the like, and the reaction time varies depending on the solvent, starting material, reagent, reaction temperature, and the like.
　下記A法乃至F法の各工程の反応において、反応終了後、各目的化合物は、通常当該技術分野において採用される方法に従って、反応混合物から採取される。例えば、反応混合物の液性を適宜調整し、不溶物が存在する場合には濾過により除去した後、水と、酢酸エチル等の水と混和しない有機溶媒を加えて振盪する等して混和させた後、目的化合物を含む有機層を分離し、抽出液を水等で洗浄後、無水硫酸マグネシウム、無水硫酸ナトリウム等で乾燥し、乾燥剤をろ過後、ろ液の溶剤を留去することによって得ることができる。得られた目的化合物は必要に応じ、通常当該技術分野において採用される方法、例えば再結晶、再沈殿、クロマトグラフィー［例えば、シリカゲル、アルミナ、マグネシウム－シリカゲル系のフロリジル、SO3H-シリカ（富士シリシア化学株式会社）等の担体を用いた吸着カラムクロマトグラフィー法；セファデックスLH-20（GEヘルスケア・ジャパン株式会社）、アンバーライトXAD-11（ローム・アンド・ハース・ジャパン株式会社）、ダイヤイオンHP-20（三菱化学株式会社）等の担体を用いた分配カラムクロマトグラフィー等の合成吸着剤を使用する方法；イオン交換クロマトを使用する方法；シリカゲル若しくはアルキル化シリカゲルによる順相・逆相カラムクロマトグラフィー法（好適には、高速液体クロマトグラフィー）等を適宜組合せ、適切な溶離剤で溶出する。］等の、通常、有機化合物の分離精製に慣用されている方法を適宜組合せることによって分離、精製することができる。目的化合物が溶媒に難溶性である場合には、得られた固体の粗生成物を溶媒で洗浄することによって精製することができる。また、製造中間体となる各工程の目的化合物は精製することなくそのまま次の工程の反応に使用することもできる。
（製造法A）
　製造法Aは式（I）で表される化合物を製造する際に合成中間体として用いることのできるジヒドロフロインドール（IX）を製造する方法である。 In the reaction of each step of the following methods A to F, after completion of the reaction, each target compound is usually collected from the reaction mixture according to a method employed in the art. For example, 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. Thereafter, 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. If necessary, 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. Etc.] can be separated and purified by appropriately combining methods commonly used for separation and purification of organic compounds. When the target compound is sparingly soluble in a solvent, the obtained solid crude product can be purified by washing with a solvent. Moreover, the target compound of each process used as a manufacturing intermediate can also be used for reaction of the following process as it is, without refine | purifying.
(Production method A)
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.
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
(A-I工程)
　本工程は、式（II）で表される化合物に対して公知の有機化学的手法を用いてアルキル化させることにより、式（III）で表される化合物を製造する工程である。 (AI process)
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.
　式（II）で表される化合物を溶媒（例えば、ケトン類、具体的にはアセトン、メチルエチルケトン等）中、塩基として、炭酸アルカリ金属類、例えば炭酸カリウム、そしてブロモ酢酸エステル類、具体的にはtert-ブチルブロモアセテート等を用いて実施する。
(A-II工程)
　本工程は、式（III）で表される化合物に対して公知の有機化学的手法を用いてスルホニル化させることにより、式（IV）で表される化合物を製造する工程である。 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.
(Process A-II)
This step is a step of producing the compound represented by the formula (IV) by sulfonylating the compound represented by the formula (III) using a known organic chemical technique.
　式（III）で表される化合物を溶媒（例えば、アミド類、具体的にはN,N-ジメチルホルムアミド、N-メチルピロリドン、ジメチルアセトアミド等）中、塩基として水素化アルカリ金属、具体的には水素化ナトリウム、そしてスルホン酸クロリド類、具体的にはp-トルエンスルホニルクロリドを加えて実施する。
(A-III工程)
　本工程は、式（IV）で表される化合物に対して公知の有機化学的手法を用いてエステルを加水分解させることにより、式（V）で表される化合物を製造する工程である。 A compound represented by the formula (III) in a solvent (for example, amides, specifically N, N-dimethylformamide, N-methylpyrrolidone, dimethylacetamide, etc.) as a base, an alkali metal hydride, specifically This is carried out by adding sodium hydride and sulfonic acid chlorides, specifically p-toluenesulfonyl chloride.
(Process A-III)
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).
　式（IV）で表される化合物を溶媒（例えば、ハロゲン化炭化水素類、具体的にはジクロロメタン、1,2-ジクロロエタン等）中、酸としてトリフルオロ酢酸を加えて実施する。なお、t-ブチルエステル以外のエステルの場合であっても、通常行われるエステルの加水分解反応にしたがって加水分解を実施することができる。
(A-IV工程)
　本工程は、式（V）で表される化合物に対して公知の有機化学的手法を用いて、式（VI）で表されるカルボン酸クロライドを製造する工程である。 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-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).
　式（V）で表されるカルボン酸化合物を溶媒（例えば、ハロゲン化炭化水素類、具体的にはジクロロメタン、クロロホルム、1,2-ジクロロエタン等）中、酸塩化物（塩化オキサリル、チオニルクロリド等）及び少量のN,N-ジメチルホルムアミドを加えて実施する。
(A-V工程)
　本工程は、式（VI）で表される化合物に対して公知の有機化学的手法を用いてフリーデルクラフツ分子内環化反応させることにより、式（VII）で表される化合物を製造する工程である。 Acid chloride (oxalyl chloride, thionyl chloride, etc.) in a solvent (for example, halogenated hydrocarbons, specifically dichloromethane, chloroform, 1,2-dichloroethane, etc.) And a small amount of N, N-dimethylformamide is added.
(AV process)
In this step, 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.
　式（V）で表される化合物を溶媒（例えば、ハロゲン化炭化水素類、具体的には1,2-ジクロロエタン等）中、ルイス酸（例えば、塩化アルミニウム等）を加えて実施する。
(A-VI工程)
　本工程は、式（VII）で表される化合物に対して公知の有機化学的手法を用いてオキシム化反応させることにより、式（VIII）で表される化合物を製造する工程である。 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-VI process)
This step is a step of producing the compound represented by the formula (VIII) by subjecting the compound represented by the formula (VII) to an oximation reaction using a known organic chemical technique.
　式（VII）で表される化合物を溶媒（例えば、アルコール類、具体的にはエタノール等；水、或はこれらは混合溶媒として使用してもよい）中、ヒドロキシアミン塩酸塩、酢酸ナトリウムを加えて実施する。
(A-VII工程)
　本工程は、式（VIII）で表される化合物に対して公知の有機化学的手法を用いてオキシム基を還元後tert-ブトキシカルボニル化させることにより、式（IX）で表される化合物を製造する工程である。 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). To implement.
(Process A-VII)
In this step, 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.
　式（VIII）で表される化合物を溶媒（例えば、エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン；或はこれらにアルコールを加えた溶媒、例えばメタノール混合液）中、塩化ニッケル及び水素化ホウ素金属類、例えば水素化ホウ素ナトリウムを加えて還元後、水、溶媒として酢酸エチル、塩基として炭酸水素アルカリ金属水溶液類、例えば飽和炭酸水素ナトリウム水溶液、そしてジ-t-ブチルジカルボネートを加えて実施する。
（製造法B）
　製造法Bは式（I）で表される化合物を製造する際に合成中間体として用いることのできるアリールジヒドロフロインドール（IX）を、ブロモジヒドロフロインドール（VIII）を経由して製造する方法である。 In 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 and 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. To implement.
(Production method B)
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.
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
(B-I工程)
　本工程は、式（VII）で表される化合物に対して公知の有機化学的手法を用いてブロモ化させることにより、式（VIII）で表される化合物を製造する工程である。 (BI process)
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.
　式（VII）で表される化合物を溶媒（例えば、エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等）中、リチウム金属強塩基として、例えばリチウムジイソプロピルアミド、そして1,2-ジブロモ-1,1,2,2-テトラクロロエタンを加えて実施する。
(B-II工程)
　本工程は、式（VIII）で表される化合物に対して公知の有機化学的手法を用いて鈴木カップリングさせることにより、式（IX）で表される化合物を製造する工程である。 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.
(Process B-II)
This step is a step of producing the compound represented by the formula (IX) by subjecting the compound represented by the formula (VIII) to Suzuki coupling using a known organic chemical technique.
　式（VIII）で表される化合物を溶媒（例えば、エーテル類、具体的には1,4-ジオキサン；水、或はこれ等の混合溶媒）中、パラジウム触媒存在下、アリールボロン酸又はアリールボロン酸エステルを加えて実施する。マイクロウェーブ反応装置を用いてもよい。鈴木カップリンングの例として、Journal of Organic Chemistry, 68, 20, 2003, 7733-7741；Journal of Organic Chemistry, 70, 6, 2005, 2191-2194；Journal of Organic Chemistry, 68, 24, 2003, 9412-9415；Bioorganic Medicinal Chemistry, 18, 2, 2010, 707-718；Tetrahedron, 66, 49, 2010, 9552-9559；Synthetic Communications, 30, 19, 2000, 3501-3510；Chemistry A European Journal, 12, 19, 2006, 5142-5148等に記載の方法に準じて行うことができる。
（製造法C）
　製造法Cは式（I）で表される化合物を製造する際に合成中間体として用いることのできるアリールジヒドロフロインドール（IX）をトリブチルスタナニルテジヒドロフロインドール（X）を経由して製造する方法である。 A compound represented by the formula (VIII) in a solvent (for example, ethers, specifically 1,4-dioxane; water or a mixed solvent thereof) in the presence of a palladium catalyst, arylboronic acid or arylboron Carry out with the addition of the acid ester. A microwave reactor may be used. As an example of Suzuki coupling, Journal of Organic Chemistry, 68, 20, 2003, 7733-7741; Journal of Organic Chemistry, 70, 6, 2005, 2191-2194; Journal of Organic Chemistry, 68, 24, 2003, 9412 -9415; Bioorganic Medicinal Chemistry, 18, 2, 2010, 707-718; Tetrahedron, 66, 49, 2010, 9552-9559; Synthetic Communications, 30, 19, 2000, 3501-3510; Chemistry A European Journal, 12, 19 , 2006, 5142-5148 and the like.
(Production method C)
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.
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
(C-I工程)
　本工程は、式（VII）で表される化合物に対して公知の有機化学的手法を用いてトリブチルスタニル化させることにより、式（X）で表される化合物を製造する工程である。 (CI process)
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.
　式（VII）で表される化合物を溶媒（例えば、エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等）中、リチウム金属強塩基として、例えばリチウムジイソプロピルアミド、そしてヨウ化トリブチルスズを加えて実施する。
(C-II工程)
　本工程は、式（X）で表される化合物に対して公知の有機化学的手法を用いてStilleカップリングさせることにより、式（IX）で表される化合物を製造する工程である。 For example, 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.). To implement.
(C-II process)
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.
　式（X）で表される化合物を溶媒（例えば、アミド類、具体的にはN,N-ジメチルホルムアミド、N-メチルピロリドン、ジメチルアセトアミド等）中、テトラキス(トリフェニルホスフィン)パラジウム、ヨウ化銅(I)、アリールハライドを加えて実施する。マイクロウェーブ反応装置を用いてもよい。Stilleカップリングの例として、Angewandte Chemie, International Edition, 25, 6, 1986, 508-524；Tetrahedron Letters, 35, 19, 1994, 3195-3196；Synthesis, 1986, 7, 564-565等に記載の方法に準じて行うことができる。
（製造法D）
　製造法Dは式（I）で表される化合物を合成する際に合成中間体として用いることのできるアリールジヒドロフロインドールアミン（XI）を式（IX）で表される化合物から製造する方法である。 The compound represented by the formula (X) in a solvent (for example, amides, specifically N, N-dimethylformamide, N-methylpyrrolidone, dimethylacetamide, etc.), tetrakis (triphenylphosphine) palladium, copper iodide (I) Carry out with addition of aryl halide. A microwave reactor may be used. Examples of 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)
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). .
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
(D-I工程)
　本工程は、式（IX）で表される化合物に対して公知の有機化学的手法を用いて脱Boc化することにより、式（XI）で表される化合物を製造する工程である。 (DI process)
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.
　式（IX）で表される化合物を溶媒（例えば、エーテル類、具体的には1,4-ジオキサン、1,2-ジメトキシエタン；ハロゲン化炭化水素類、ジクロロメタン等）中、4規定塩酸（塩化水素）ジオキサン溶液を加えて実施する。反応条件は本条件に限らず、例えば、T.W. Greene及びP.G. Wuts著、「Protective Groups in Organic Synthesis（第３版、1999年）」に記載の方法に準じて行うことができる。
（製造法E）
　製造法Eは式（XI）で表される合成中間体を製造する別方法である。 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. 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)
Production method E is another method for producing a synthetic intermediate represented by the formula (XI).
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
(E-I工程)
　本工程は、式（XII）で表される化合物に対して公知の有機化学的手法を用いてスルホニル化させることにより、式（XIII）で表される化合物を製造する工程である。A法のA-II工程と同様に行われる。
(E-II工程)
　本工程は、式（XIII）で表される化合物に対して公知の有機化学的手法を用いて加水分解させることにより、式（XIV）で表される化合物を製造する工程である。 (EI process)
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.
(E-II process)
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.
　式（XIII）で表される化合物を溶媒（例えば、エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等；アルコール類、具体的には、メタノール、エタノール等を有機溶媒として使用すればよい。さらに溶媒として水を挙げることができるが、有機溶媒としては水と混和するものであることが好ましく、これらは混合溶媒として使用することが好ましい。）中、塩基として水酸化アルキル金属類水溶液、具体的には1規定水酸化ナトリウム水溶液等を加えて実施する。
(E-III工程)
　本工程は、式（XIV）で表される化合物に対して公知の有機化学的手法を用いてカルボン酸クロライドを合成することにより、式（XV）で表される化合物を製造する工程である。A法のA-IV工程と同様に行われる。
(E-IV工程)
　本工程は、式（XV）で表される化合物に対して公知の有機化学的手法を用いてフリーデルクラフツ分子内環化反応させることにより、式（XVI）で表される化合物を製造する工程である。A法のA-V工程と同様に行われる。
(E-V工程)
　本工程は、式（XVI）で表される化合物に対して公知の有機化学的手法を用いて還元反応させることにより、式（XVII）で表される化合物を製造する工程である。 If the compound represented by the formula (XIII) is used as a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc .; alcohols, specifically methanol, ethanol, etc.) as an organic solvent. Further, water may be mentioned as the solvent, but the organic solvent is preferably miscible with water, and these are preferably used as a mixed solvent. Specifically, it is carried out by adding a 1N aqueous sodium hydroxide solution or the like.
(E-III process)
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). This is carried out in the same manner as the A-IV step of Method A.
(E-IV process)
In this step, the compound represented by the formula (XVI) is produced by subjecting the compound represented by the formula (XV) to a Friedel-Crafts intramolecular cyclization reaction using a known organic chemical technique. It is. Performed in the same manner as the AV process of Method A.
(EV process)
This step is a step of producing a compound represented by the formula (XVII) by subjecting the compound represented by the formula (XVI) to a reduction reaction using a known organic chemical technique.
　式（XVI）で表される化合物を溶媒（例えば、エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等；アルコール類、具体的にはメタノール、エタノール等。これらは混合溶媒として使用してもよい。）中、還元剤として例えば、金属水素化ホウ素化合物類、具体的には水素化ホウ素ナトリウム等を加えて実施する。
(E-VI工程)
　本工程は、式（XVII）で表される化合物に対して公知の有機化学的手法を用いてブロモ化反応させることにより、式（XVIII）で表される化合物を製造する工程である。B法のB-I工程と同様に行われる。
(E-VII工程)
　本工程は、式（XVIII）で表される化合物に対して公知の有機化学的手法を用いて鈴木カップリングさせることにより、式（XIX）で表される化合物を製造する工程である。B法のB-II工程と同様に行われる。
(E-VIII工程)
　本工程は、式（XIX）で表される化合物に対して公知の有機化学的手法を用いて光延反応させることにより、式（XX）で表される化合物を製造する工程である。 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.). In this case, for example, a metal borohydride compound, specifically sodium borohydride or the like is added as a reducing agent.
(E-VI process)
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.
(E-VII process)
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.
(E-VIII process)
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.
　式（XIX）で表される化合物を溶媒（例えば、エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等）中、ジフェニルホスホリルアミド、1,8-ジアザビシクロ[5.4.0]ウンデセ-7-エンを加えて実施する。
(E-IX工程)
　本工程は、式（XX）で表される化合物に対して公知の有機化学的手法を用いて還元反応させることにより、式（XI）で表される化合物を製造する工程である。 The compound represented by the formula (XIX) is dissolved in a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.), diphenylphosphorylamide, 1,8-diazabicyclo [5.4.0] undec-7 -Carry out with the addition of en.
(E-IX process)
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.
　式（XX）で表される化合物を溶媒（例えば、エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等；水、あるいはこれ等を混合溶媒として使用してもよい）中、トリフェニルホスフィンを加えて実施する。
（製造法F）
　製造法Fは式（I）で表される化合物を式（XI）で表される化合物から製造する方法である。 Triphenyl in a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc .; water or these may be used as a mixed solvent) in a solvent represented by the formula (XX) Carry out with the addition of phosphine.
(Production method F)
Production method F is a method for producing a compound represented by formula (I) from a compound represented by formula (XI).
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
(F-I工程)
　本工程は、式（XI）で表される化合物に対して公知の有機化学的手法を用いて脱アリールスルホニル化することにより、式（I）で表される化合物を製造する工程である。 (FI process)
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.
　式（XI）で表される化合物を溶媒（例えば、アルコール類、具体的には、メタノール、エタノール、n-プロパノール等；エーテル類、具体的にはテトラヒドロフラン、1,2-ジメトキシエタン等）中、塩基として例えば炭酸セシウムを加えて実施する。 In a solvent (for example, alcohols, specifically methanol, ethanol, n-propanol, etc .; ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.) For example, cesium carbonate is added as a base.
　本発明の式（I）で表される化合物は、所望により医薬的に許容される塩とすることができる。医薬的に許容される塩とは、著しい毒性を有さず、医薬として使用され得る塩をいう。本発明の式（I）で表される化合物は、塩基性部分を有しており、酸と処理することにより塩にすることができる。 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.
　塩基性置換基及び塩基性ヘテロアリール基に基づく塩としては、フッ化水素酸塩、塩酸塩、臭化水素酸塩及びヨウ化水素酸塩等のハロゲン化水素酸塩；塩酸塩、硝酸塩、過塩素酸塩、硫酸塩及びリン酸塩等の無機酸塩；メタンスルホン酸塩、トリフルオロメタンスルホン酸塩及びエタンスルホン酸塩等の低級アルカンスルホン酸塩；ベンゼンスルホン酸塩及びp-トルエンスルホン酸塩等のアリールスルホン酸塩；酢酸塩、リンゴ酸塩、フマル酸塩、コハク酸塩、クエン酸塩、アスコルビン酸塩、酒石酸塩、シュウ酸塩及びマレイン酸塩等の有機酸塩；グリシン塩、リジン塩、アルギニン塩、オルニチン塩、グルタミン酸塩及びアスパラギン酸塩等のアミノ酸塩等がある。これらのうちで好ましくは、無機酸塩又はアリールスルホン酸塩であり、より好ましくは、塩酸塩、ベンゼンスルホン酸塩、又はp-トルエンスルホン酸塩である。 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 inorganic acid salts or aryl sulfonates, and more preferred are hydrochlorides, benzene sulfonates, or p-toluene sulfonates.
　式（I）で表される化合物又はその塩は、大気中に放置したり、又は再晶析を行ったりすることにより、水分を吸収して吸着水が付き、水和物となる場合があり、そのような水和物も本発明の塩に包含される。 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.
　式（I）で表される化合物又はその塩は、ある種の溶媒を吸収し、溶媒和物となる場合があり、そのような溶媒和物も本発明の塩に包含される。 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.
　式（I）で表される化合物は、その分子内に不斉炭素原子を有するので、光学異性体が存在する。これらの異性体及びこれらの異性体の混合物がすべて単一の式、すなわち式（I）で表されている。したがって、式（I）で表される化合物は単一の光学異性体及び光学異性体の任意の割合の混合物も全て本発明の範囲に包含される。 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.
　上記のような光学異性体は、光学活性な原料化合物を用いるか、又は不斉合成もしくは不斉誘導の手法を用いて本発明に係る化合物を合成することで得ることができる。この他、合成した本発明に係る化合物を通常の光学分割法又は光学活性担体を利用した分離法等を用いて単離することにより得ることができる。 The 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. In addition, 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.
　本発明の化合物は、当該化合物を構成する原子の1以上に、原子同位体の非天然割合も含有し得る。原子同位体としては、例えば、重水素（2H）、トリチウム（3H）、ヨウ素－125（125I）、又は炭素－14（14C）等を挙げることができる。また、前記化合物は、例えば、トリチウム（3H）、ヨウ素－125（125I）、又は炭素－14（14C）等の放射性同位体で放射性標識され得る。放射性標識された化合物は、治療又は予防剤、研究試薬、例えば、アッセイ試薬及び診断剤、例えば、インビボ画像診断剤として有用である。本発明の化合物の全ての同位体変異種は、放射性であると否とを問わず、本発明の範囲に包含されるものとする。 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. Examples of atomic isotopes include deuterium ( 2 H), tritium ( 3 H), iodine-125 ( 125 I), carbon-14 ( 14 C), and the like. In addition, 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.
　本発明の式（I）で示される化合物、その薬学的に許容される塩、又はそれらの水和物は、酸感受性イオンチャネルに対して優れた阻害作用を有するのみでなく、阻害作用が酸感受性イオンチャネルに対して優れた選択性を示す優れた化合物である。このような酸感受性イオンチャネル阻害剤として、虚血性心疾患、心不全、末梢動脈疾患、不整脈、高血圧症、低血圧症、慢性関節リウマチ、関節炎関連性の炎症性疾患、炎症性腸疾患、潰瘍性大腸炎、乾癬を含む皮膚炎、湿疹、浮腫、炎症性疼痛、術後疼痛、線維筋痛症、片頭痛、関節痛、ヘルペス後神経痛、糖尿病性神経痛などの神経因性疼痛、癌に伴う疼痛、変形性関節症、間質性膀胱炎、逆流性食道炎、過敏性腸症候群、咳、味覚傷害、難聴、糖尿病網膜症や緑内障における視機能障害、結腸直腸癌、卵巣上皮癌、乳癌、胃における腫瘍形成、過換気症候群、喘息、インスリン抵抗性糖尿病、多発性硬化症、全般性不安障害、パニック障害、脳梗塞、パーキンソン病、ハンチントン病、又はアルツハイマー病等の疾患又は疾患に伴う症状に対して優れた治療効果及び／又は予防効果を期待することができる。また、疼痛の緩和のための鎮痛薬としても優れた治療効果及び／又は予防効果を期待することができる。 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's disease, Huntington's disease, or Alzheimer's disease Excellent therapeutic and / or prophylactic effect against Jo can be expected. In addition, an excellent therapeutic effect and / or preventive effect can be expected as an analgesic for pain relief.
　さらに本発明化合物は、経口投与的に投与されることによっても酸感受性イオンチャネル阻害作用が期待されることから、優れた酸感受性イオンチャネル阻害作用を簡便に発揮させることが可能であり、患者のQOLの向上が可能となる。 Furthermore, since 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.
　本発明の化合物、その薬学的に許容される塩、又はそれらの水和物は、種々の形態で投与することができる。その投与形態としては、例えば、錠剤、カプセル剤、顆粒剤、乳剤、丸剤、散剤、シロップ剤（液剤）等による経口投与、あるいは注射剤（静脈内、筋肉内、皮下、又は腹腔内投与）、点滴剤、坐剤（直腸投与）等による非経口投与を挙げることができる。これらの各種製剤は、主薬に対して賦形剤、結合剤、崩壊剤、滑沢剤、矯味矯臭剤、溶解補助剤、懸濁剤、コーティング剤等の医薬の製剤技術分野において通常使用し得る補助剤を適宜選択・添加して通常実施される方法に従って製剤化することができる。 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.
　錠剤として使用する場合、担体として、例えば、乳糖、白糖、塩化ナトリウム、グルコース、尿素、デンプン、炭酸カルシウム、カオリン、結晶セルロース及びケイ酸等の賦形剤；水、エタノール、プロパノール、単シロップ、グルコース液、デンプン液、ゼラチン溶液、カルボキシメチルセルロース、セラック、メチルセルロース、リン酸カリウム及びポリビニルピロリドン等の結合剤；乾燥デンプン、アルギン酸ナトリウム、寒天末、ラミナラン末、炭酸水素ナトリウム、炭酸カルシウム、ポリオキシエチレンソルビタン脂肪酸エステル、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、デンプン及び乳糖等の崩壊剤；白糖、ステアリン、カカオバター及び水素添加油等の崩壊抑制剤；第四級アンモニウム塩類及びラウリル硫酸ナトリウム等の吸収促進剤；グリセリン及びデンプン等の保湿剤；デンプン、乳糖、カオリン、ベントナイト及びコロイド状ケイ酸等の吸着剤；精製タルク、ステアリン酸塩、硼酸末及びポリエチレングリコール等の潤沢剤等を使用することができる。また、必要に応じ通常の剤皮を施した錠剤、例えば糖衣錠、ゼラチン被包錠、腸溶被錠及びフィルムコーティング錠あるいは二重錠、多層錠とすることができる。 When used as a tablet, as a carrier, for example, 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 starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; and lubricants such as purified talc, stearate, boric acid powder and polyethylene glycol Can be used. Moreover, it can be set as the tablet which gave the normal coating as needed, 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.
　丸剤として使用する場合、担体として、例えば、グルコース、乳糖、カカオバター、デンプン、硬化植物油、カオリン及びタルク等の賦形剤；アラビアゴム末、トラガント末、ゼラチン及びエタノール等の結合剤；ラミナラン、寒天等の崩壊剤等を使用することができる。 When used as pills, as carriers, for example, 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.
　坐剤として使用する場合、担体としてこの分野で従来公知のものを広く使用でき、例えばポリエチレングリコール、カカオバター、高級アルコール、高級アルコールのエステル類、ゼラチン及び半合成グリセリド等を挙げることができる。 When used as a suppository, 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.
　注射剤として使用する場合、液剤、乳剤、又は懸濁剤として使用することができる。これらの液剤、乳剤、又は懸濁剤は、殺菌され、血液と等張であることが好ましい。これら液剤、乳剤、又は懸濁剤の製造に用いる溶媒は、医療用の希釈剤として使用できるものであれば特に限定はなく、例えば、水、エタノール、プロピレングリコール、エトキシ化イソステアリルアルコール、ポリオキシ化イソステアリルアルコール及びポリオキシエチレンソルビタン脂肪酸エステル類等を挙げることができる。なお、この場合、等張性の溶液を調製するのに充分な量の食塩、グルコース、又はグリセリンを製剤中に含んでいてもよく、また通常の溶解補助剤、緩衝剤及び無痛化剤等を含んでいてもよい。 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. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylation Examples thereof include isostearyl alcohol and polyoxyethylene sorbitan fatty acid esters. In this case, 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.
　また、上記の製剤には、必要に応じて、着色剤、保存剤、香料、風味剤及び甘味剤等を含めることもでき、更に、他の医薬品を含めることもできる。 In addition, 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.
　上記製剤に含まれる有効成分化合物の量は、特に限定されず広範囲に適宜選択されるが、通常、全組成物中0.5から70重量%、好ましくは1から30重量％含む。 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.
　その使用量は患者（温血動物、特に人間）の症状、年齢等により異なるが、経口投与の場合には、1日あたり、上限として1000mg（好ましくは100mg）であり、下限として0.1mg（好ましくは1mg、さらに好ましくは5mg）を成人に対して、1日当り1から6回症状に応じて投与することが望ましい。 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.
　以下に示す例によって本発明を具体的に説明するが、本発明はこれらに限定されるものではない。また、これらはいかなる意味においても限定的に解釈されるものではない。 The present invention will be specifically described with reference to the following examples, but the present invention is not limited thereto. Moreover, these are not limitedly interpreted in any sense.
実施例１　[3-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)-5-クロロフェニル]メタノール
[工程１]　メチル ({1-[(4-メチルフェニル)スルホニル]-1H-インドール-4-イル}オキシ)アセテート Example 1 [3- (3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -5-chlorophenyl] methanol
[Step 1] Methyl ({1-[(4-methylphenyl) sulfonyl] -1H-indol-4-yl} oxy) acetate
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
　メチル (1H-インドール-4-イルオキシ)アセテート（1.00g）のN,N-ジメチルホルムアミド（20ml）溶液に0℃で水素化ナトリウム（123mg）を加え、0℃にて15分間攪拌した後、p-トルエンスルホニルクロライド（1.11g）を加え、60℃で6時間攪拌した。飽和塩化アンモニウム水溶液を加えて反応を停止した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［ヘキサン／酢酸エチル］にて精製し、標題化合物（400mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.77-7.72(2H,m),7.63(1H,d,J=8.2Hz),7.49(1H,d,J=3.5Hz),7.24-7.16(2H,m),6.84(1H,d,J=3.5Hz),6.51(1H,d,J=7.8Hz),4.72(2H,s),3.79(3H,s),2.34(3H,s).
[工程２]　({1-[(4-メチルフェニル)スルホニル]-1H-インドール-4-イル}オキシ)アセティックアシッド To a solution of methyl (1H-indol-4-yloxy) acetate (1.00 g) in N, N-dimethylformamide (20 ml) was added sodium hydride (123 mg) at 0 ° C, and the mixture was stirred at 0 ° C for 15 minutes. -Toluenesulfonyl chloride (1.11 g) was added and stirred at 60 ° C. for 6 hours. Saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (400 mg) as a white solid.
1 H-NMR (CDCl 3 ) δppm: 7.77-7.72 (2H, m), 7.63 (1H, d, J = 8.2Hz), 7.49 (1H, d, J = 3.5Hz), 7.24-7.16 (2H, m ), 6.84 (1H, d, J = 3.5Hz), 6.51 (1H, d, J = 7.8Hz), 4.72 (2H, s), 3.79 (3H, s), 2.34 (3H, s).
[Step 2] ({1-[(4-Methylphenyl) sulfonyl] -1H-indol-4-yl} oxy) acetic acid
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
　上記工程１で得られた化合物（1.50g）のテトラヒドロフラン（16.7ml）、メタノール（8.35ml）及び水（8.35ml）溶液に水酸化リチウム一水和物（350mg)を加え、室温で3時間攪拌した。1規定水酸化ナトリウム水溶液を加えて反応を停止し、反応混合物を酢酸エチルで抽出した。抽出液を、水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［ヘキサン／酢酸エチル］にて精製し、標題化合物（1.20g）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.77-7.72(2H,m),7.66(1H,d,J=8.2Hz),7.51(1H,d,J=3.9Hz),7.25-7.17(2H,m),6.81(1H,d,J=3.9Hz),6.56(1H,d,J=8.2Hz),4.76(2H,s),2.34(3H,s). 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. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (1.20 g) as a white solid.
1 H-NMR (CDCl 3 ) δppm: 7.77-7.72 (2H, m), 7.66 (1H, d, J = 8.2Hz), 7.51 (1H, d, J = 3.9Hz), 7.25-7.17 (2H, m ), 6.81 (1H, d, J = 3.9Hz), 6.56 (1H, d, J = 8.2Hz), 4.76 (2H, s), 2.34 (3H, s).
[工程３]　6-[(4-メチルフェニル)スルホニル]-2H-フロ[2,3-e]インドール-3(6H)-オン [Step 3] 6-[(4-Methylphenyl) sulfonyl] -2H-furo [2,3-e] indole-3 (6H) -one
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
　上記工程２で得られた化合物（1.20g）のジクロロエタン（17.4ml）溶液に塩化オキサリル（0.596ml）及び触媒量のN,N-ジメチルホルムアミドを加えて、室温で45分間攪拌した。反応混合液を減圧留去し、得られた残留物のジクロロエタン（17.4ml）溶液に三塩化アルミニウム（556mg）を加え、室温で30分間攪拌した。反応混合物に水を加え、ジクロロメタンで抽出した。抽出液を、水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。ろ過後、ろ液を減圧留去することにより標題化合物（1.14g）を粗生成物として得た。
[工程４]　6-[(4-メチルフェニル)スルホニル]-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-オール 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. After filtration, the filtrate was evaporated under reduced pressure to give the title compound (1.14 g) as a crude product.
[Step 4] 6-[(4-Methylphenyl) sulfonyl] -3,6-dihydro-2H-furo [2,3-e] indol-3-ol
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
　上記工程３で得られた化合物（1.14g）のテトラヒドロフラン（17.4ml）、メタノール（17.4ml）溶液に0℃で水素化ホウ素ナトリウム（197mg）を加え、室温で30分間攪拌した。反応混合液に飽和塩化アンモニウム水溶液を加えて反応を停止し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥し、ろ過後ろ液を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［ヘキサン／酢酸エチル］にて精製し、標題化合物（720mg）を無色油状物質として得た。
1H-NMR(CDCl3)δppm:7.80-7.76(2H,m),7.60(1H,d,J=8.6Hz),7.54(1H,d,J=3.5Hz),7.40-7.30(1H,m),7.26-7.20(2H,m),6.69(1H,d,J=3.9Hz),5.46-5.38(1H,m),4.63(1H,dd,J=10.8,6.5Hz),4.56(1H,dd,J=10.8,2.5Hz),2.34(3H,s). Sodium borohydride (197 mg) was added to a solution of the compound obtained in Step 3 (1.14 g) in tetrahydrofuran (17.4 ml) and methanol (17.4 ml) at 0 ° C., and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the filtrate after filtration was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (720 mg) as a colorless oil.
1 H-NMR (CDCl 3 ) δppm: 7.80-7.76 (2H, m), 7.60 (1H, d, J = 8.6Hz), 7.54 (1H, d, J = 3.5Hz), 7.40-7.30 (1H, m ), 7.26-7.20 (2H, m), 6.69 (1H, d, J = 3.9Hz), 5.46-5.38 (1H, m), 4.63 (1H, dd, J = 10.8,6.5Hz), 4.56 (1H, dd, J = 10.8, 2.5Hz), 2.34 (3H, s).
[工程５]　7-ブロモ-6-[(4-メチルフェニル)スルホニル]-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-オール [Step 5] 7-Bromo-6-[(4-methylphenyl) sulfonyl] -3,6-dihydro-2H-furo [2,3-e] indol-3-ol
Figure JPOXMLDOC01-appb-C000027
Figure JPOXMLDOC01-appb-C000027
　上記工程４で得られた化合物（18.2ml）溶液を-78℃に冷却し、リチウムジイソプロピルアミド（in n-Hexane-tetrahydrofuran，1.0M；1.91ml）を加え、30分間攪拌した。反応溶液へ、1,2-ジブロモ-1,1,2,2-テトラクロロエタン（890mg）のテトラヒドロフラン（1.00ml）溶液をゆっくりと滴下し、-78℃で1時間攪拌した。反応混合物に飽和塩化アンモニウム水溶液を加え、反応混合物を酢酸エチルで抽出した。抽出液を、水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。ろ過後、ろ液を減圧留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［ヘキサン／酢酸エチル］にて精製し、標題化合物（300mg）を無色油状物質として得た。
1H-NMR(CDCl3)δppm:7.95-7.88(1H,m),7.82-7.75(2H,m),7.40-7.20(4H,m),6.80-6.74(1H,m),5.50-5.40(1H,m),4.70-4.60(1H,m),4.60-4.50(1H,m),2.37(3H,s).
[工程６]　メチル 3-クロロ-5-{3-ヒドロキシ-6-[(4-メチルフェニル)スルホニル]-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル}ベンゾエート The compound (18.2 ml) solution obtained in the above Step 4 was cooled to −78 ° C., lithium diisopropylamide (in n-Hexane-tetrahydrofuran, 1.0M; 1.91 ml) was added, and the mixture was stirred for 30 minutes. To the reaction solution, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (890 mg) in tetrahydrofuran (1.00 ml) was slowly added dropwise and stirred at -78 ° C. for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the reaction mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (300 mg) as a colorless oil.
1 H-NMR (CDCl 3 ) δ ppm: 7.95-7.88 (1H, m), 7.82-7.75 (2H, m), 7.40-7.20 (4H, m), 6.80-6.74 (1H, m), 5.50-5.40 ( 1H, m), 4.70-4.60 (1H, m), 4.60-4.50 (1H, m), 2.37 (3H, s).
[Step 6] Methyl 3-chloro-5- {3-hydroxy-6-[(4-methylphenyl) sulfonyl] -3,6-dihydro-2H-furo [2,3-e] indol-7-yl} Benzoate
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000028
　上記工程５で得られた化合物（236mg）及び(3-クロロ-5-メトキシカルボニル-フェニル)ホウ酸（300mg）のジオキサン（7.35ml）及び水（1.47ml）溶液に炭酸カリウム（0.3205g）、Pd(dppf)Cl2（0.172g）を加え、100℃で2時間攪拌した。反応液を直接シリカゲルカラムクロマトグラフィー［ヘキサン／酢酸エチル］で精製することにより標題化合物（310mg）を黄色油状物質として得た。
1H-NMR(CDCl3)δppm:8.10-8.02(2H,m),7.94-7.88(1H,m),7.78-7.73(1H,m),7.67-7.62(1H,m),7.45-7.38(1H,m),7.36-7.20(1H,m),7.13-7.05(2H,m),6.66(1H,s),5.50-5.40(1H,m),4.68-4.59(1H,m),4.59-4.53(1H,m),4.03-3.89(4H,m),2.32(3H,s).
[工程７]　メチル 3-{3-アジド-6-[(4-メチルフェニル)スルホニル]-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル}-5-クロロベンゾエート To a solution of the compound obtained in Step 5 (236 mg) and (3-chloro-5-methoxycarbonyl-phenyl) boric acid (300 mg) in dioxane (7.35 ml) and water (1.47 ml), potassium carbonate (0.3205 g), Pd (dppf) Cl 2 (0.172 g) was added and stirred at 100 ° C. for 2 hours. The reaction mixture was directly purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (310 mg) as a yellow oil.
1 H-NMR (CDCl 3 ) δ ppm: 8.10-8.02 (2H, m), 7.94-7.88 (1H, m), 7.78-7.73 (1H, m), 7.67-7.62 (1H, m), 7.45-7.38 ( 1H, m), 7.36-7.20 (1H, m), 7.13-7.05 (2H, m), 6.66 (1H, s), 5.50-5.40 (1H, m), 4.68-4.59 (1H, m), 4.59- 4.53 (1H, m), 4.03-3.89 (4H, m), 2.32 (3H, s).
[Step 7] Methyl 3- {3-azido-6-[(4-methylphenyl) sulfonyl] -3,6-dihydro-2H-furo [2,3-e] indol-7-yl} -5-chloro Benzoate
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
　上記工程６で得られた化合物（300mg）のテトラヒドロフラン（4.40ml）溶液にジフェニルホスホリルアジド（0.195ml）及び1,8-ジアザビシクロ[5.4.0]ウンデセ-7-エン（0.135ml）を加え、室温で3時間攪拌した。反応液を直接ゲルろ過することにより標題化合物（315mg）を粗精製物として得た。
[工程８]　メチル 3-{3-アミノ-6-[(4-メチルフェニル)スルホニル]-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル}-5-クロロベンゾエート Diphenylphosphoryl azide (0.195 ml) and 1,8-diazabicyclo [5.4.0] undec-7-ene (0.135 ml) were added to a tetrahydrofuran (4.40 ml) solution of the compound obtained in Step 6 (300 mg) at room temperature. For 3 hours. The reaction mixture was directly gel filtered to give the titled compound (315 mg) as a crude product.
[Step 8] Methyl 3- {3-amino-6-[(4-methylphenyl) sulfonyl] -3,6-dihydro-2H-furo [2,3-e] indol-7-yl} -5-chloro Benzoate
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000030
　上記工程７で得られた化合物（315mg）のテトラヒドロフラン（6.03ml）溶液に水（0.603ml）及びトリフェニルホスフィン（316mg）を加え、室温で16時間攪拌した。反応液を直接アミノシリカゲルカラムクロマトグラフィー［ジクロロメタン／メタノール］で精製することにより標題化合物（25mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.10-8.02(2H,m),7.97-7.93(1H,m),7.89-7.86(1H,m),7.86-7.56(1H,m),7.36-7.18(2H,m),7.13-7.03(2H,m),6.62(1H,s),4.78-4.65(2H,m),4.35-4.25(1H,m),3.96(3H,s),2.31(3H,s).
[工程９]　(3-{3-アミノ-6-[(4-メチルフェニル)スルホニル]-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル}-5-クロロフェニル)メタノール Water (0.603 ml) and triphenylphosphine (316 mg) were added to a tetrahydrofuran (6.03 ml) solution of the compound (315 mg) obtained in Step 7 above, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was directly purified by amino silica gel column chromatography [dichloromethane / methanol] to give the title compound (25 mg) as a white solid.
1 H-NMR (CDCl 3 ) δppm: 7.10-8.02 (2H, m), 7.97-7.93 (1H, m), 7.89-7.86 (1H, m), 7.86-7.56 (1H, m), 7.36-7.18 ( 2H, m), 7.13-7.03 (2H, m), 6.62 (1H, s), 4.78-4.65 (2H, m), 4.35-4.25 (1H, m), 3.96 (3H, s), 2.31 (3H, s).
[Step 9] (3- {3-Amino-6-[(4-methylphenyl) sulfonyl] -3,6-dihydro-2H-furo [2,3-e] indol-7-yl} -5-chlorophenyl )methanol
Figure JPOXMLDOC01-appb-C000031
Figure JPOXMLDOC01-appb-C000031
　上記工程８で得られた化合物（25mg）のテトラヒドロフラン（4.00ml）溶液に、0℃にてリチウムアルミニウムヒドリド（9.6mg）を加え、室温で30分間攪拌した。4規定水酸化ナトリウム水溶液を加えて反応を停止した後、セライトろ過で不溶物を除き、得られた溶液を減圧濃縮した。得られた残留物をアミノシリカゲルカラムクロマトグラフィー［ジクロロメタン／メタノール］で精製することにより標題化合物（11mg）を無色油状物質として得た。
1H-NMR(CDCl3)δppm:7.87(1H,d,J=8.2Hz),7.46-7.38(2H,m),7.35-7.25(4H,m),7.12-7.05(2H,m),6.58(1H,s),4.78-4.60(4H,m),4.32-4.24(1H,m),2.31(3H,s).
[工程１０]　[3-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)-5-クロロフェニル]メタノール 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.
1 H-NMR (CDCl 3 ) δppm: 7.87 (1H, d, J = 8.2Hz), 7.46-7.38 (2H, m), 7.35-7.25 (4H, m), 7.12-7.05 (2H, m), 6.58 (1H, s), 4.78-4.60 (4H, m), 4.32-4.24 (1H, m), 2.31 (3H, s).
[Step 10] [3- (3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -5-chlorophenyl] methanol
Figure JPOXMLDOC01-appb-C000032
Figure JPOXMLDOC01-appb-C000032
　上記工程９で得られた化合物（90mg）のテトラヒドロフラン（0.96ml）及びメタノール（0.96ml）溶液に炭酸セシウム（31mg）を加え、60℃で3時間攪拌した。反応液を減圧留去した後、得られた残留物をアミノシリカゲルカラムクロマトグラフィー［ジクロロメタン／メタノール］で精製することにより標題化合物（4mg）を白色固体として得た。
1H-NMR(MeOH-d4)δppm:7.75-7.71(2H,m),7.33(1H,s),7.20(1H,d,J=8.2Hz),7.04(1H,d,J=8.2Hz),6.84(1H,s),4.82-4.71(2H,m),4.69(2H,s),4.41(1H,dd,J=8.8,2.9Hz). Cesium carbonate (31 mg) was added to a solution of the compound obtained in the above Step 9 (90 mg) in tetrahydrofuran (0.96 ml) and methanol (0.96 ml), and the mixture was stirred at 60 ° C. for 3 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by amino silica gel column chromatography [dichloromethane / methanol] to give the title compound (4 mg) as a white solid.
1 H-NMR (MeOH-d4) δppm: 7.75-7.71 (2H, m), 7.33 (1H, s), 7.20 (1H, d, J = 8.2Hz), 7.04 (1H, d, J = 8.2Hz) , 6.84 (1H, s), 4.82-4.71 (2H, m), 4.69 (2H, s), 4.41 (1H, dd, J = 8.8, 2.9Hz).
実施例２　7-(2-メトキシピリミジン-5-イル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン
[工程１]　tert-ブチル (1H-インドール-4-イルオキシ)アセテート Example 2 7- (2-Methoxypyrimidin-5-yl) -3,6-dihydro-2H-furo [2,3-e] indole-3-amine
[Step 1] tert-Butyl (1H-indol-4-yloxy) acetate
Figure JPOXMLDOC01-appb-C000033
Figure JPOXMLDOC01-appb-C000033
　1H-インドール-4-オール（5.00g）のアセトン（37.6ml）溶液に炭酸カリウム（10.4g）及びtert-ブチル ブロモアセテート（14.6g）を加え、60℃で24時間攪拌した。反応混合液を減圧留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［ヘキサン／酢酸エチル］で精製することにより標題化合物（7.00g）を無色油状物質として得た。
1H-NMR(CDCl3)δppm:8.19(1H,s),7.14-7.12(1H,m),7.10-7.05(2H,m),6.74-6.72(1H,m),6.41(1H,dd,J=6.7,2.0Hz),4.67(1H,s),1.50(9H,s).
[工程２]　tert-ブチル {[1-(フェニルスルホニル)-1H-インドール-4-イル]オキシ}アセテート To a solution of 1H-indol-4-ol (5.00 g) in acetone (37.6 ml) were added potassium carbonate (10.4 g) and tert-butyl bromoacetate (14.6 g), and the mixture was stirred at 60 ° C. for 24 hours. The reaction mixture was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (7.00 g) as a colorless oil.
1 H-NMR (CDCl 3 ) δ ppm: 8.19 (1H, s), 7.14-7.12 (1H, m), 7.10-7.05 (2H, m), 6.74-6.72 (1H, m), 6.41 (1H, dd, J = 6.7, 2.0Hz), 4.67 (1H, s), 1.50 (9H, s).
[Step 2] tert-butyl {[1- (phenylsulfonyl) -1H-indol-4-yl] oxy} acetate
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
　上記工程１で得られた化合物（1.00g）の及びベンゼンスルホニルクロライド（1.07g）を用いて実施例１工程１と同様の手法により標題化合物（550mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.87(2H,m),7.63(1H,d,J=8.6Hz),7.57-7.75(1H,m),7.48(1H,d,J=3.9Hz),7.46-7.40(2H,m),7.20(1H,dd,J=8.2,8.2Hz),6.85(1H,d,J=3.9Hz),6.51(1H,d,J=7.8Hz),4.60(1H,s),1.55(9H,s). The title compound (550 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1 using the compound (1.00 g) obtained in the above Step 1 and benzenesulfonyl chloride (1.07 g).
1 H-NMR (CDCl 3 ) δppm: 7.87 (2H, m), 7.63 (1H, d, J = 8.6Hz), 7.57-7.75 (1H, m), 7.48 (1H, d, J = 3.9Hz), 7.46-7.40 (2H, m), 7.20 (1H, dd, J = 8.2,8.2Hz), 6.85 (1H, d, J = 3.9Hz), 6.51 (1H, d, J = 7.8Hz), 4.60 (1H , s), 1.55 (9H, s).
[工程３]　{[1-(フェニルスルホニル)-1H-インドール-4-イル]オキシ}アセティックアシッド [Step 3] {[1- (Phenylsulfonyl) -1H-indol-4-yl] oxy} acetic acid
Figure JPOXMLDOC01-appb-C000035
Figure JPOXMLDOC01-appb-C000035
　上記工程２で得られた化合物（58.0g）のジクロロメタン（150ml）溶液を0℃に冷却し、トリフルオロ酢酸（57.3ml）を加え、0℃にて30分間攪拌した。その後、室温で16時間攪拌した。反応液に水を加えてジクロロメタンで抽出した。抽出液を水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。ろ過後、ろ液を減圧留去し、得られた残留物をジクロロメタン及びジイソプロピルエーテルで洗浄することで、標題化合物（32.0g）を白色固体として得た。
1H-NMR(DMSO-d6)δppm:8.05-7-98(2H,m),7.77(1H,d,J=4.0Hz),7.76-7.70(1H,m),7.70-7.55(2H,m),7.28(1H,dd,J=8.2,8.2Hz),6.86(1H,dd,J=3.9,0.8Hz),6.71(1H,d,J=7.8Hz),4.82(2H,s).
[工程４]　6-(フェニルスルホニル)-2H-フロ[2,3-e]インドール-3(6H)-オン A solution of the compound (58.0 g) obtained in Step 2 above in dichloromethane (150 ml) was cooled to 0 ° C., trifluoroacetic acid (57.3 ml) was added, and the mixture was stirred at 0 ° C. for 30 minutes. Then, it stirred at room temperature for 16 hours. 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. After filtration, the filtrate was evaporated under reduced pressure, and the obtained residue was washed with dichloromethane and diisopropyl ether to give the title compound (32.0 g) as a white solid.
1 H-NMR (DMSO-d 6 ) δppm: 8.05-7-98 (2H, m), 7.77 (1H, d, J = 4.0Hz), 7.76-7.70 (1H, m), 7.70-7.55 (2H, m), 7.28 (1H, dd, J = 8.2, 8.2Hz), 6.86 (1H, dd, J = 3.9, 0.8Hz), 6.71 (1H, d, J = 7.8Hz), 4.82 (2H, s).
[Step 4] 6- (Phenylsulfonyl) -2H-furo [2,3-e] indole-3 (6H) -one
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
　上記工程３で得られた化合物（115g）を用いて実施例１工程３と同様の手法により標題化合物（13.0g）を茶色固体として得た。
1H-NMR(CDCl3)δppm:7.95-7.88(1H,m),7.74(1H,dd,J=8.6,0.8Hz),7.65(1H,d,J=3.6Hz),7.65-7.45(5H,m),6.87(1H,dd,J=3.6,0.8Hz),4.70(2H,s). Using the compound (115 g) obtained in the above Step 3, the title compound (13.0 g) was obtained as a brown solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 7.95-7.88 (1H, m), 7.74 (1H, dd, J = 8.6,0.8Hz), 7.65 (1H, d, J = 3.6Hz), 7.65-7.45 (5H , m), 6.87 (1H, dd, J = 3.6, 0.8Hz), 4.70 (2H, s).
[工程５]　(3Z)-N-ヒドロキシ-6-(フェニルスルホニル)-2H-フロ[2,3-e]インドール-3(6H)-イミン [Step 5] (3Z) -N-hydroxy-6- (phenylsulfonyl) -2H-furo [2,3-e] indole-3 (6H) -imine
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
　上記工程４で得られた化合物（8.50g）のエタノール（67.8ml）溶液に酢酸ナトリウム（6.68g）、ヒドロキシアミン塩酸塩（5.66g）、水（67.8ml）及びテトラヒドロフラン（67.8ml）を加え、85℃で3時間攪拌した。水を加えて酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去することにより標題化合物（5.6g）を粗生成物として得た。
[工程６]　tert-ブチル [6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート Sodium acetate (6.68 g), hydroxyamine hydrochloride (5.66 g), water (67.8 ml) and tetrahydrofuran (67.8 ml) were added to an ethanol (67.8 ml) solution of the compound (8.50 g) obtained in Step 4 above. The mixture was stirred at 85 ° C. for 3 hours. Water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure to give the title compound (5.6 g) as a crude product.
[Step 6] tert-Butyl [6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-yl] carbamate
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
　上記工程５で得られた化合物（2g）のテトラヒドロフラン（60.9ml）溶液に二塩化ニッケル（434mg）を加えた後に、0℃で水素化ホウ素ナトリウム（691mg）及びメタノール（12.2ml）を加え、0℃で30分間攪拌した。反応混合液に水、酢酸エチル、飽和炭酸水素ナトリウム水溶液及びジ-t-ブチルジカルボネートを加え、室温で30分間攪拌した。反応液を酢酸エチルで抽出し、有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。ろ過後、ろ液を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［ヘキサン／酢酸エチル］にて精製し、標題化合物（1.40g）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.89-7.83(2H,m),7.60-7.50(3H,m),7.47-7.40(2H,m),7.28-7.20(1H,m),6.67(1H,dd,J=3.6,0.8Hz),5.45-5.32(1H,m),4.85-4.65(2H,m),4.47(1H,dd,J=10.0,3.7Hz),1.45(9H,s). 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. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (1.40 g) as a white solid.
1 H-NMR (CDCl 3 ) δ ppm: 7.89-7.83 (2H, m), 7.60-7.50 (3H, m), 7.47-7.40 (2H, m), 7.28-7.20 (1H, m), 6.67 (1H, dd, J = 3.6,0.8Hz), 5.45-5.32 (1H, m), 4.85-4.65 (2H, m), 4.47 (1H, dd, J = 10.0,3.7Hz), 1.45 (9H, s).
[工程７]　tert-ブチル[7-ブロモ-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート [Step 7] tert-Butyl [7-bromo-6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-yl] carbamate
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
　上記工程６で得られた化合物（8.10g）を用いて実施例１工程５と同様の手法により標題化合物（8.50g）を茶色固体として得た。
1H-NMR(CDCl3)δppm:7.95-7.83(3H,m),7.63-7.52(1H,m),7.50-7.40(2H,m),7.30-7.21(1H,m),6.74(1H,s),5.45-5.33(1H,m),4.90-4.80(1H,m),4.75(1H,dd,J=10.2,7.6Hz),4.46(1H,dd,J=10.2,3.9Hz),1.46(9H,s).
[工程８]　tert-ブチル [7-(2-メトキシピリミジン-5-イル)-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート Using the compound (8.10 g) obtained in the above Step 6, the title compound (8.50 g) was obtained as a brown solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 7.95-7.83 (3H, m), 7.63-7.52 (1H, m), 7.50-7.40 (2H, m), 7.30-7.21 (1H, m), 6.74 (1H, s), 5.45-5.33 (1H, m), 4.90-4.80 (1H, m), 4.75 (1H, dd, J = 10.2,7.6Hz), 4.46 (1H, dd, J = 10.2,3.9Hz), 1.46 (9H, s).
[Step 8] tert-Butyl [7- (2-methoxypyrimidin-5-yl) -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-yl] Carbamate
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
　上記工程７で得られた化合物（200mg）及び(2-メトキシピリミジン-5-イル)ボロン酸（81.1mg）を用いて実施例１工程６と同様の手法により標題化合物（160mg）を茶色固体として得た。
1H-NMR(CDCl3)δppm:8.57(2H,s),7.95-7.88(1H,m),7.55-7.45(1H,m),7.43-7.36(2H,m),7.36-7.29(3H,m),6.61(1,d,J=0.8Hz),5.48-5.38(1H,m),4.90-4.82(1H,m),4.82-4.77(1H,m),4.47(1H,dd,J=10.2,3.9Hz),4.11(3H,s),1.47(9H,s). Using the compound obtained in Step 7 above (200 mg) and (2-methoxypyrimidin-5-yl) boronic acid (81.1 mg), the title compound (160 mg) was converted to a brown solid in the same manner as in Step 1 of Example 1. Obtained.
1 H-NMR (CDCl 3 ) δ ppm: 8.57 (2H, s), 7.95-7.88 (1H, m), 7.55-7.45 (1H, m), 7.43-7.36 (2H, m), 7.36-7.29 (3H, m), 6.61 (1, d, J = 0.8Hz), 5.48-5.38 (1H, m), 4.90-4.82 (1H, m), 4.82-4.77 (1H, m), 4.47 (1H, dd, J = 10.2, 3.9Hz), 4.11 (3H, s), 1.47 (9H, s).
[工程９]　7-(2-メトキシピリミジン-5-イル)-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン [Step 9] 7- (2-Methoxypyrimidin-5-yl) -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-amine
Figure JPOXMLDOC01-appb-C000041
Figure JPOXMLDOC01-appb-C000041
　上記工程８で得られた化合物（155mg）のテトラヒドロフラン（5ml）溶液にca. 4mol/l塩化水素／1,4-ジオキサン（5ml）を加え、室温で2時間攪拌した。反応液に飽和炭酸水素ナトリウム水溶液を加え反応を停止し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物をアミノシリカゲルカラムクロマトグラフィー［ジクロロメタン／メタノール］で精製することにより標題化合物（100mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.57(2H,s),7.92(1H,d,J=8.2Hz),7.55-7.44(1H,m),7.44-7.38(2H,m),7.38-7.30(3H,m),6.61(1H,s),4.80-4.65(2H,m),4.31(1H,dd,J=7.8,3.1Hz),4.11(3H,s).
[工程１０]　7-(2-メトキシピリミジン-5-イル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン To a solution of the compound obtained in Step 8 (155 mg) in tetrahydrofuran (5 ml) was added ca. 4 mol / l hydrogen chloride / 1,4-dioxane (5 ml), and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography [dichloromethane / methanol] to give the title compound (100 mg) as a white solid.
1 H-NMR (CDCl 3 ) δ ppm: 8.57 (2H, s), 7.92 (1H, d, J = 8.2Hz), 7.55-7.44 (1H, m), 7.44-7.38 (2H, m), 7.38-7.30 (3H, m), 6.61 (1H, s), 4.80-4.65 (2H, m), 4.31 (1H, dd, J = 7.8,3.1Hz), 4.11 (3H, s).
[Step 10] 7- (2-Methoxypyrimidin-5-yl) -3,6-dihydro-2H-furo [2,3-e] indole-3-amine
Figure JPOXMLDOC01-appb-C000042
Figure JPOXMLDOC01-appb-C000042
　上記工程９で得られた化合物（100mg）を用いて実施例１工程１０と同様の手法により標題化合物（45mg）を白色固体として得た。
1H-NMR(DMSO-d6)δppm:11.7(1H,s),9.12(2H,s),7.14(1H,d,J=8.2Hz),7.02(2H,m),4.73(1H,dd,J=8.4,8.4Hz),4.65(1H,dd,J=8.2,5.1Hz),4.20(1H,dd,J=8.8,4.9Hz),4.00(3H,s). Using the compound (100 mg) obtained in the above Step 9, the title compound (45 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (DMSO-d6) δ ppm: 11.7 (1H, s), 9.12 (2H, s), 7.14 (1H, d, J = 8.2Hz), 7.02 (2H, m), 4.73 (1H, dd, J = 8.4,8.4Hz), 4.65 (1H, dd, J = 8.2,5.1Hz), 4.20 (1H, dd, J = 8.8,4.9Hz), 4.00 (3H, s).
実施例３　[5-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)-2-(メチルスルホニル)フェニル]メタノール
[工程１]　メチル 5-{3-[(tert-ブトキシカルボニル)アミノ]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル}-2-(メチルスルホニル)ベンゾエート Example 3 [5- (3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -2- (methylsulfonyl) phenyl] methanol
[Step 1] Methyl 5- {3-[(tert-butoxycarbonyl) amino] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-7-yl}- 2- (Methylsulfonyl) benzoate
Figure JPOXMLDOC01-appb-C000043
Figure JPOXMLDOC01-appb-C000043
　実施例２工程７で得られた化合物（350mg）及びメチル 2-メチルスルホニル-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾエート（314mg）を用いて実施例１工程６と同様の手法により標題化合物（350mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.19(1H,d,J=8.2Hz),7.92-7.79(1H,3H,m),7.55-7.56(1H,m),7.43-7.38(2H,m),7.38-7.28(3H,m),6.71(1H,s),5.47(1H,m),4.88-4.80(1H,m),4.80-4.70(1H,m),4.46(1H,dd,J=10.2,3.9Hz),4.01(3H,s),3.44(3H,s),1.47(9H,m).
[工程２]　tert-ブチル {7-[3-(ヒドロキシメチル)-4-(メチルスルホニル)フェニル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル}カルバメート 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.
1 H-NMR (CDCl 3 ) δ ppm: 8.19 (1H, d, J = 8.2 Hz), 7.92-7.79 (1H, 3H, m), 7.55-7.56 (1H, m), 7.43-7.38 (2H, m) , 7.38-7.28 (3H, m), 6.71 (1H, s), 5.47 (1H, m), 4.88-4.80 (1H, m), 4.80-4.70 (1H, m), 4.46 (1H, dd, J = 10.2, 3.9Hz), 4.01 (3H, s), 3.44 (3H, s), 1.47 (9H, m).
[Step 2] tert-butyl {7- [3- (hydroxymethyl) -4- (methylsulfonyl) phenyl] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] Indol-3-yl} carbamate
Figure JPOXMLDOC01-appb-C000044
Figure JPOXMLDOC01-appb-C000044
　上記工程１で得られた化合物（350mg）のジクロロメタン（5.58ml）の溶液に、0℃で、1M 水素化ジイソブチルアルミニウムトルエン溶液（2.79ml）を加え、0℃で1時間攪拌した。メタノールを加えて反応を停止した後、飽和酒石酸カリウムナトリウム水溶液を加え、室温で1時間攪拌した。その後、有機層をジクロロメタンで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［ヘキサン／酢酸エチル］で精製することにより標題化合物（270mg）を粗精製物として得た。 To a solution of the compound (350 mg) obtained in Step 1 above in dichloromethane (5.58 ml) was added 1M diisobutylaluminum hydride toluene solution (2.79 ml) at 0 ° C., and the mixture was stirred at 0 ° C. for 1 hour. After adding methanol to stop the reaction, a saturated aqueous potassium sodium tartrate solution was added, and the mixture was stirred at room temperature for 1 hour. Thereafter, the organic layer was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (270 mg) as a crude product.
 [工程３]　{5-[3-アミノ-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]-2-(メチルスルホニル)フェニル}メタノール [Step 3] {5- [3-Amino-6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-7-yl] -2- (methylsulfonyl) phenyl} methanol
Figure JPOXMLDOC01-appb-C000045
Figure JPOXMLDOC01-appb-C000045
　上記工程２で得られた化合物（270mg）を用いて実施例２工程９と同様の手法により標題化合物（130mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.10(1H,d,J=8.2Hz),7.90-7.85(1H,m),7.72(1H,d,J=2.0Hz),7.68(1H,dd,J=8.2,2.0Hz),7.53-7.45(1H,m),7.45-7.38(2H,m),7.38-7.27(3H,m),6.70(1H,d,J=0.8Hz),5.02(2H,s),4.80-4.67(2H,m),4.29(1H,dd,J=8.4,3.3Hz),3.26(3H,s).
[工程４]　[5-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)-2-(メチルスルホニル)フェニル]メタノール Using the compound (270 mg) obtained in the above Step 2, the title compound (130 mg) was obtained as a white solid in the same manner as in Step 2 of Example 2.
1 H-NMR (CDCl 3 ) δ ppm: 8.10 (1H, d, J = 8.2 Hz), 7.90-7.85 (1 H, m), 7.72 ( 1 H, d, J = 2.0 Hz), 7.68 (1 H, dd, J = 8.2,2.0Hz), 7.53-7.45 (1H, m), 7.45-7.38 (2H, m), 7.38-7.27 (3H, m), 6.70 (1H, d, J = 0.8Hz), 5.02 (2H, s), 4.80-4.67 (2H, m), 4.29 (1H, dd, J = 8.4,3.3Hz), 3.26 (3H, s).
[Step 4] [5- (3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -2- (methylsulfonyl) phenyl] methanol
Figure JPOXMLDOC01-appb-C000046
Figure JPOXMLDOC01-appb-C000046
　上記工程３で得られた化合物（125mg）を用いて実施例１工程１０と同様の手法により標題化合物（45mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.17(1H,s),8.06(1H,d,J=8.2Hz),7.92(1H,d,J=8.2Hz),7.24(1H,d,J=8.2Hz),7.06(1H,d,J=8.8Hz),7.01(1H,s),5.10(2H,s),4.83-4.67(2H,m),4.41(1H,dd,J=9.2,3.7Hz),3.27(3H,s). Using the compound (125 mg) obtained in the above Step 3, the title compound (45 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.17 (1H, s), 8.06 (1H, d, J = 8.2Hz), 7.92 (1H, d, J = 8.2Hz), 7.24 (1H, d, J = 8.2 Hz), 7.06 (1H, d, J = 8.8Hz), 7.01 (1H, s), 5.10 (2H, s), 4.83-4.67 (2H, m), 4.41 (1H, dd, J = 9.2, 3.7Hz ), 3.27 (3H, s).
実施例４　[5-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)-2-メトキシピリジン-3-イル]メタノール
[工程１]　tert-ブチル {7-[5-(ヒドロキシメチル)-6-メトキシピリジン-3-イル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル}カルバメート Example 4 [5- (3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -2-methoxypyridin-3-yl] methanol
[Step 1] tert-butyl {7- [5- (hydroxymethyl) -6-methoxypyridin-3-yl] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e ] Indol-3-yl} carbamate
Figure JPOXMLDOC01-appb-C000047
Figure JPOXMLDOC01-appb-C000047
　実施例２工程７で得られた化合物（350mg）及び[2-メトキシ-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-3-ピリジル]メタノール（282mg）を用いて実施例１工程６と同様の手法により標題化合物（350mg）を黄色固体として得た。
1H-NMR(CDCl3)δppm:8.13(1H,m),7.93-7.86(1H,m),7.78-7.73(1H,m),7.55-7.38(3H,m),7.38-7.25(3H,m),6.58-6.52(1H,m),5.47-5.36(1H,m),4.90-4.80(1H,m),4.80-4.68(3H,m),4.50(1H,m),4.07(3H,s),2.30-2.23(1H,m),1.47(9H,s).
[工程２]　[5-[3-アミノ-6-(ベンゼンスルホニル)-2,3-ジヒドロフロ[2,3-e]インドール-7-イル]-2-メトキシ-3-ピリジル]メタノール 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).
1 H-NMR (CDCl 3 ) δ ppm: 8.13 (1H, m), 7.93-7.86 (1H, m), 7.78-7.73 (1H, m), 7.55-7.38 (3H, m), 7.38-7.25 (3H, m), 6.58-6.52 (1H, m), 5.47-5.36 (1H, m), 4.90-4.80 (1H, m), 4.80-4.68 (3H, m), 4.50 (1H, m), 4.07 (3H, s), 2.30-2.23 (1H, m), 1.47 (9H, s).
[Step 2] [5- [3-Amino-6- (benzenesulfonyl) -2,3-dihydrofuro [2,3-e] indol-7-yl] -2-methoxy-3-pyridyl] methanol
Figure JPOXMLDOC01-appb-C000048
Figure JPOXMLDOC01-appb-C000048
　上記工程１で得られた化合物（340mg）を用いて実施例２工程９と同様の手法により標題化合物（150mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.09(1H,d,J=2.3Hz),7.92-7.86(1H,m),7.80(1H,d,J=2.3Hz),7.50-7.38(3H,m),7.33-7.27(3H,m),6.55(1H,d,J=0.8Hz),4.78-4.68(4H,m),4.29(1H,dd,J=8.6,3.5Hz),4.07(3H,s).
[工程３]　[5-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)-2-メトキシピリジン-3-イル]メタノール Using the compound (340 mg) obtained in the above Step 1, the title compound (150 mg) was obtained as a white solid in the same manner as in Step 2 of Example 2.
1 H-NMR (CDCl 3 ) δ ppm: 8.09 (1H, d, J = 2.3Hz), 7.92-7.86 (1H, m), 7.80 (1H, d, J = 2.3Hz), 7.50-7.38 (3H, m ), 7.33-7.27 (3H, m), 6.55 (1H, d, J = 0.8Hz), 4.78-4.68 (4H, m), 4.29 (1H, dd, J = 8.6,3.5Hz), 4.07 (3H, s).
[Step 3] [5- (3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -2-methoxypyridin-3-yl] methanol
Figure JPOXMLDOC01-appb-C000049
Figure JPOXMLDOC01-appb-C000049
　上記工程２で得られた化合物（150mg）のテトラヒドロフラン（3.32ml）及びメタノール（3.32ml）溶液に炭酸セシウム（325mg）を加え、85℃で1時間攪拌した。反応液に水を加えて反応を停止し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物をアミノシリカゲルカラムクロマトグラフィー［ジクロロメタン／メタノール］で精製することにより標題化合物（45mg）を白色固体として得た。
1H-NMR(MeOH-d4)δppm:8.46(1H,d,J=2.4Hz),8.18-8.13(1H,m),7.17(1H,d,J=8.3Hz),7.03(1H,d,J=8.3,1.0Hz),6.72(1H,d,J=1.0Hz),4.79-4.65(4H,m),4.38(1H,d,J=9.0,3.7Hz),4.02(3H,s). Cesium carbonate (325 mg) was added to a solution of the compound obtained in Step 2 (150 mg) in tetrahydrofuran (3.32 ml) and methanol (3.32 ml), and the mixture was stirred at 85 ° C. for 1 hour. Water was added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by amino silica gel column chromatography [dichloromethane / methanol] to give the title compound (45 mg) as a white solid.
1 H-NMR (MeOH-d4) δ ppm: 8.46 (1H, d, J = 2.4Hz), 8.18-8.13 (1H, m), 7.17 (1H, d, J = 8.3Hz), 7.03 (1H, d, J = 8.3,1.0Hz), 6.72 (1H, d, J = 1.0Hz), 4.79-4.65 (4H, m), 4.38 (1H, d, J = 9.0,3.7Hz), 4.02 (3H, s).
実施例５　(1R)-1-[3-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)-5-フルオロフェニル]エタン-1,2-ジオール
[工程１]　tert-ブチル [7-(3-エテニル-5-フルオロフェニル)-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート Example 5 (1R) -1- [3- (3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -5-fluorophenyl] ethane-1,2 -Diol
[Step 1] tert-Butyl [7- (3-ethenyl-5-fluorophenyl) -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-yl] Carbamate
Figure JPOXMLDOC01-appb-C000050
Figure JPOXMLDOC01-appb-C000050
　実施例２工程７で得られた化合物（350mg）及び2-(3-フルオロ-5-ビニル-フェニル)-4,4,5,5-テトラメチル-1,3,2-ジオキサボレート（194mg）を用いて実施例１工程６と同様の手法により標題化合物（250mg）を白色固体として得た。
MS(ESI)m/z:533(M-H)+
1H-NMR(CDCl3)δppm:7.87(1H,d,J=8.6Hz),7.45(1H,t,J=7.4Hz),7.39(2H,d,J=8.2Hz),7.28-7.26(3H,m),7.20(1H,s),7.15(1H,d,J=9.4Hz),7.04(1H,d,J=9.0Hz),6.67(1H,dd,J=17.6,10.9Hz),6.55(1H,s),5.75(1H,d,J=17.6Hz),5.39-5.37(1H,m),5.33(1H,d,J=10.6Hz),4.83(1H,d,J=7.8Hz),4.72(1H,t,J=9.0Hz),4.42(1H,dd,J=10.2,3.9Hz),3.67(1H,s),1.44(9H,s).
[工程２]　tert-ブチル [7-{3-[(1R)-1,2-ジヒドロキシエチル]-5-フルオロフェニル}-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート 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.
MS (ESI) m / z: 533 (MH) +
1 H-NMR (CDCl 3 ) δ ppm: 7.87 (1H, d, J = 8.6Hz), 7.45 (1H, t, J = 7.4Hz), 7.39 (2H, d, J = 8.2Hz), 7.28-7.26 ( 3H, m), 7.20 (1H, s), 7.15 (1H, d, J = 9.4Hz), 7.04 (1H, d, J = 9.0Hz), 6.67 (1H, dd, J = 17.6, 10.9Hz), 6.55 (1H, s), 5.75 (1H, d, J = 17.6Hz), 5.39-5.37 (1H, m), 5.33 (1H, d, J = 10.6Hz), 4.83 (1H, d, J = 7.8Hz ), 4.72 (1H, t, J = 9.0Hz), 4.42 (1H, dd, J = 10.2, 3.9Hz), 3.67 (1H, s), 1.44 (9H, s).
[Step 2] tert-Butyl [7- {3-[(1R) -1,2-dihydroxyethyl] -5-fluorophenyl} -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2 , 3-e] Indol-3-yl] carbamate
Figure JPOXMLDOC01-appb-C000051
Figure JPOXMLDOC01-appb-C000051
　上記工程１で得られた化合物（250mg）をtert-ブチルアルコール（50ml）、水（20ml）に溶解し、AD-mix-β（1.60g）を加え、室温で15時間攪拌した。反応溶液を亜硫酸ナトリウム水溶液に注ぎ、有機物を酢酸エチルで抽出した。食塩水で洗浄後、硫酸ナトリウムで乾燥し、溶媒を留去した。残留物をジオールシリカゲルクロマトグラフィー［ヘキサン／酢酸エチル］で精製し、標題化合物（165mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.81(1H,d,J=8.6Hz),7.42(1H,t,J=7.4Hz),7.33(2H,d,J=7.8Hz),7.25-7.23(4H,m),7.14(1H,d,J=9.0Hz),7.01(1H,d,J=9.0Hz),6.50(1H,s),5.37-5.30(1H,m),4.96(1H,d,J=10.0Hz),4.83(1H,d,J=10.0Hz),4.68(1H,t,J=9.0Hz),4.38(1H,dd,J=10.2,3.9Hz),3.78(1H,d,J=9.8Hz),3.66(1H,t,J=9.4Hz),3.42(1H,brs),2.73(1H,brs),1.43(11H,s).
[工程３]　(1R)-1-{3-[3-アミノ-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル-5-フルオロフェニル}エタン-1,2-ジオール The compound (250 mg) obtained in the above Step 1 was dissolved in tert-butyl alcohol (50 ml) and water (20 ml), AD-mix-β (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.
1 H-NMR (CDCl 3 ) δ ppm: 7.81 (1H, d, J = 8.6 Hz), 7.42 (1 H, t, J = 7.4 Hz), 7.33 (2 H, d, J = 7.8 Hz), 7.25 to 7.23 ( 4H, m), 7.14 (1H, d, J = 9.0Hz), 7.01 (1H, d, J = 9.0Hz), 6.50 (1H, s), 5.37-5.30 (1H, m), 4.96 (1H, d , J = 10.0Hz), 4.83 (1H, d, J = 10.0Hz), 4.68 (1H, t, J = 9.0Hz), 4.38 (1H, dd, J = 10.2,3.9Hz), 3.78 (1H, d , J = 9.8Hz), 3.66 (1H, t, J = 9.4Hz), 3.42 (1H, brs), 2.73 (1H, brs), 1.43 (11H, s).
[Step 3] (1R) -1- {3- [3-Amino-6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-7-yl-5-fluoro Phenyl} ethane-1,2-diol
Figure JPOXMLDOC01-appb-C000052
Figure JPOXMLDOC01-appb-C000052
　上記工程２で得られた化合物（165mg）を用いて実施例２工程９と同様の手法により標題化合物（127mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.84(1H,d,J=8.6Hz),7.43(1H,t,J=7.4Hz),7.35(2H,d,J=7.4Hz),7.28-7.24(4H,m),7.16(1H,d,J=9.0Hz),7.05(1H,d,J=9.4Hz),6.56(1H,s),4.85(1H,dd,J=7.4,3.5Hz),4.71-4.67(2H,m),4.25(1H,dd,J=8.2,3.1Hz),3.82(1H,dd,J=11.3,3.5Hz),3.69(1H,dd,J=11.3,7.4Hz).
[工程４]　(1R)-1-[3-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)-5-フルオロフェニル]エタン-1,2-ジオール Using the compound (165 mg) obtained in the above Step 2, the title compound (127 mg) was obtained as a white solid in the same manner as in Step 2 of Example 2.
1 H-NMR (CDCl 3 ) δppm: 7.84 (1H, d, J = 8.6Hz), 7.43 (1H, t, J = 7.4Hz), 7.35 (2H, d, J = 7.4Hz), 7.28-7.24 ( 4H, m), 7.16 (1H, d, J = 9.0Hz), 7.05 (1H, d, J = 9.4Hz), 6.56 (1H, s), 4.85 (1H, dd, J = 7.4,3.5Hz), 4.71-4.67 (2H, m), 4.25 (1H, dd, J = 8.2,3.1Hz), 3.82 (1H, dd, J = 11.3,3.5Hz), 3.69 (1H, dd, J = 11.3,7.4Hz) .
[Step 4] (1R) -1- [3- (3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -5-fluorophenyl] ethane-1, 2-diol
Figure JPOXMLDOC01-appb-C000053
Figure JPOXMLDOC01-appb-C000053
　上記工程３で得られた化合物（127mg）を用いて実施例１工程１０と同様の手法により標題化合物（50mg）を白色固体として得た。
MS(ESI)m/z:312(M-NH2)+
1H-NMR(CD3OD)δppm:7.57(1H,s),7.37(1H,d,J=9.8Hz),7.12(1H,d,J=8.2Hz),7.02(1H,d,J=9.0Hz),6.95(1H,d,J=8.2Hz),6.76(1H,s),4.69-4.63(3H,m),4.31(1H,dd,J=8.8,3.3Hz),3.67-3.61(2H,m). Using the compound (127 mg) obtained in the above Step 3, the title compound (50 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 312 (M-NH2) +
1 H-NMR (CD 3 OD) δ ppm: 7.57 (1H, s), 7.37 (1 H, d, J = 9.8 Hz), 7.12 (1 H, d, J = 8.2 Hz), 7.02 (1 H, d, J = 9.0Hz), 6.95 (1H, d, J = 8.2Hz), 6.76 (1H, s), 4.69-4.63 (3H, m), 4.31 (1H, dd, J = 8.8, 3.3Hz), 3.67-3.61 ( 2H, m).
実施例６　(1R)-1-[3-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)-5-クロロフェニル]エタン-1,2-ジオール
[工程１]　tert-ブチル [7-(3-クロロ-5-エテニルフェニル)-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート Example 6 (1R) -1- [3- (3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -5-chlorophenyl] ethane-1,2- Diol
[Step 1] tert-Butyl [7- (3-Chloro-5-ethenylphenyl) -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-yl ] Carbamate
Figure JPOXMLDOC01-appb-C000054
Figure JPOXMLDOC01-appb-C000054
　実施例２工程７で得られた化合物（500mg）及び2-(3-クロロ-5-ビニル-フェニル)-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン（402mg）を用いて実施例１工程６と同様の手法により標題化合物（380mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.93(1H,d,J=8.2Hz),7.51-7.47(4H,m),7.38-7.32(5H,m),6.73(1H,dd,J=17.6,11.0Hz),6.61(1H,s),5.83(1H,d,J=17.6Hz),5.45(1H,s),5.40(1H,d,J=11.0Hz),4.93(1H,d,J=7.0Hz),4.79(1H,t,J=9.0Hz),4.49(1H,dd,J=9.8,3.9Hz),1.51(9H,s).
[工程２]　tert-ブチル [7-{3-クロロ-5-[(1R)-1,2-ジヒドロキシエチル]フェニル}-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート 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.
1 H-NMR (CDCl 3 ) δ ppm: 7.93 (1H, d, J = 8.2Hz), 7.51-7.47 (4H, m), 7.38-7.32 (5H, m), 6.73 (1H, dd, J = 17.6, 11.0Hz), 6.61 (1H, s), 5.83 (1H, d, J = 17.6Hz), 5.45 (1H, s), 5.40 (1H, d, J = 11.0Hz), 4.93 (1H, d, J = 7.0Hz), 4.79 (1H, t, J = 9.0Hz), 4.49 (1H, dd, J = 9.8,3.9Hz), 1.51 (9H, s).
[Step 2] tert-butyl [7- {3-chloro-5-[(1R) -1,2-dihydroxyethyl] phenyl} -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2 , 3-e] Indol-3-yl] carbamate
Figure JPOXMLDOC01-appb-C000055
Figure JPOXMLDOC01-appb-C000055
　上記工程１で得られた化合物（380mg）を用いて実施例５工程２と同様の手法により標題化合物（260mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.83(1H,d,J=8.2Hz),7.45(1H,d,J=7.0Hz),7.41(2H,d,J=9.4Hz),7.34(2H,d,J=7.0Hz),7.29-7.27(4H,m),6.53(1H,s),5.36(1H,s),4.89(1H,d,J=7.8Hz),4.83-4.82(1H,m),4.70(1H,t,J=8.8Hz),4.40(1H,dd,J=9.8,3.9Hz),3.84-3.78(1H,m),3.71-3.65(1H,m),3.05(1H,s),2.39(1H,s),1.43(9H,s).
[工程３]　(1R)-1-{3-[3-アミノ-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]-5-クロロフェニル}エタン-1,2-ジオール The title compound (260 mg) was obtained as a white solid in the same manner as in Step 2 of Example 5 using the compound (380 mg) obtained in the above Step 1.
1 H-NMR (CDCl 3 ) δppm: 7.83 (1H, d, J = 8.2Hz), 7.45 (1H, d, J = 7.0Hz), 7.41 (2H, d, J = 9.4Hz), 7.34 (2H, d, J = 7.0Hz), 7.29-7.27 (4H, m), 6.53 (1H, s), 5.36 (1H, s), 4.89 (1H, d, J = 7.8Hz), 4.83-4.82 (1H, m ), 4.70 (1H, t, J = 8.8Hz), 4.40 (1H, dd, J = 9.8, 3.9Hz), 3.84-3.78 (1H, m), 3.71-3.65 (1H, m), 3.05 (1H, s), 2.39 (1H, s), 1.43 (9H, s).
[Step 3] (1R) -1- {3- [3-Amino-6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-7-yl] -5- Chlorophenyl} ethane-1,2-diol
Figure JPOXMLDOC01-appb-C000056
Figure JPOXMLDOC01-appb-C000056
　上記工程２で得られた化合物（260mg）を用いて実施例２工程９と同様の手法により標題化合物（174mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.82(1H,d,J=8.6Hz),7.44-7.42(3H,m),7.34(2H,d,J=7.8Hz),7.26-7.24(4H,m),6.55(1H,s),4.81(1H,s),4.71-4.68(2H,m),4.24(1H,d,J=7.4Hz),4.08(1H,dd,J=7.0,3.5Hz),3.80(1H,d,J=11.3Hz),3.68(1H,dd,J=11.1,7.6Hz).
[工程４]　(1R)-1-[3-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)-5-クロロフェニル]エタン-1,2-ジオール Using the compound (260 mg) obtained in the above Step 2, the title compound (174 mg) was obtained as a white solid in the same manner as in Step 2 of Example 2.
1 H-NMR (CDCl 3 ) δppm: 7.82 (1H, d, J = 8.6Hz), 7.44-7.42 (3H, m), 7.34 (2H, d, J = 7.8Hz), 7.26-7.24 (4H, m ), 6.55 (1H, s), 4.81 (1H, s), 4.71-4.68 (2H, m), 4.24 (1H, d, J = 7.4Hz), 4.08 (1H, dd, J = 7.0, 3.5Hz) 3.80 (1H, d, J = 11.3Hz), 3.68 (1H, dd, J = 11.1,7.6Hz).
[Step 4] (1R) -1- [3- (3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -5-chlorophenyl] ethane-1,2 -Diol
Figure JPOXMLDOC01-appb-C000057
Figure JPOXMLDOC01-appb-C000057
　上記工程３で得られた化合物（174mg）を用いて実施例１工程１０と同様の手法により標題化合物（60mg）を白色固体として得た。
MS(ESI)m/z:318(M-NH2)+
1H-NMR(CD3OD)δppm:7.66(2H,d,J=8.6Hz),7.28(1H,s),7.12(1H,d,J=8.2Hz),6.95(1H,d,J=8.2Hz),6.76(1H,s),4.71-4.66(2H,m),4.64-4.60(1H,m),4.30(1H,td,J=6.5,3.1Hz),3.68-3.60(3H,m). Using the compound (174 mg) obtained in Step 3 above, the title compound (60 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 318 (M-NH2) +
1 H-NMR (CD 3 OD) δppm: 7.66 (2H, d, J = 8.6Hz), 7.28 (1H, s), 7.12 (1H, d, J = 8.2Hz), 6.95 (1H, d, J = 8.2Hz), 6.76 (1H, s), 4.71-4.66 (2H, m), 4.64-4.60 (1H, m), 4.30 (1H, td, J = 6.5, 3.1Hz), 3.68-3.60 (3H, m ).
実施例７　1-{4-[(3S)-3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]-6-メトキシピリジン-2-イル}エタノール
[工程１]　tert-ブチル [7-(2-アセチル-6-メトキシピリジン-4-イル)-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート 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
Figure JPOXMLDOC01-appb-C000058
Figure JPOXMLDOC01-appb-C000058
　実施例２工程７で得られた化合物（600mg）及び1-[6-メトキシ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)-2-ピリジル]エタノン（404mg）を用いて実施例１工程６と同様の手法により標題化合物（610mg）を茶色固体として得た。
1H-NMR(CDCl3)δppm:7.85(1H,d,J=8.6Hz),7.79(1H,d,J=1.6Hz),7.52-7.40(3H,m),7.36-7.28(3H,m),7.12(1H,d,J=1.2Hz),6.71(1H,s),5.50-5.33(1H,m),4.88-4.79(1H,m),4.79-4.68(1H,s),4.45(1H,dd,J=10.2,3.9Hz),4.07(3H,s),2.75(3H,s),1.46(9H,s).
[工程２]　tert-ブチル{7-[2-(1-ヒドロキシエチル)-6-メトキシピリジン-4-イル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル}カルバメート 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).
1 H-NMR (CDCl 3 ) δppm: 7.85 (1H, d, J = 8.6Hz), 7.79 (1H, d, J = 1.6Hz), 7.52-7.40 (3H, m), 7.36-7.28 (3H, m ), 7.12 (1H, d, J = 1.2Hz), 6.71 (1H, s), 5.50-5.33 (1H, m), 4.88-4.79 (1H, m), 4.79-4.68 (1H, s), 4.45 ( 1H, dd, J = 10.2,3.9Hz), 4.07 (3H, s), 2.75 (3H, s), 1.46 (9H, s).
[Step 2] tert-Butyl {7- [2- (1-hydroxyethyl) -6-methoxypyridin-4-yl] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3 -e] Indol-3-yl} carbamate
Figure JPOXMLDOC01-appb-C000059
Figure JPOXMLDOC01-appb-C000059
　上記工程１で得られた化合物（600mg）を用いて実施例１工程４と同様の手法により標題化合物（580mg）を無色油状物質として得た。
1H-NMR(CDCl3)δppm:7.87(1H,d,J=7.8Hz),7.53-7.42(3H,m),7.37-7.27(3H,m),7.00(1H,s),6.77(1H,s),6.67(1H,s),5.45-5.35(1H,m),4.93-4.80(2H,m),4.80-4.70(1H,m),4.45(1H,dd,J=9.8,3.9Hz),4.03(3H,s),3.96(1H,dd,J=5.3,1.8Hz),1.55(3H,d,J=6.8Hz),1.47(9H,s).
[工程３]　tert-ブチル [(3S)-7-[2-(1-ヒドロキシエチル)-6-メトキシピリジン-4-イル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート；tert-ブチル [(3R)-7-[2-(1-ヒドロキシエチル)-6-メトキシピリジン-4-イル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート Using the compound (600 mg) obtained in the above Step 1, the title compound (580 mg) was obtained as a colorless oily substance in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 7.87 (1H, d, J = 7.8Hz), 7.53-7.42 (3H, m), 7.37-7.27 (3H, m), 7.00 (1H, s), 6.77 (1H , s), 6.67 (1H, s), 5.45-5.35 (1H, m), 4.93-4.80 (2H, m), 4.80-4.70 (1H, m), 4.45 (1H, dd, J = 9.8,3.9Hz ), 4.03 (3H, s), 3.96 (1H, dd, J = 5.3, 1.8Hz), 1.55 (3H, d, J = 6.8Hz), 1.47 (9H, s).
[Step 3] tert-butyl [(3S) -7- [2- (1-hydroxyethyl) -6-methoxypyridin-4-yl] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] Indol-3-yl] carbamate; tert-butyl [(3R) -7- [2- (1-hydroxyethyl) -6-methoxypyridin-4-yl] -6- (phenylsulfonyl) ) -3,6-Dihydro-2H-furo [2,3-e] indol-3-yl] carbamate
Figure JPOXMLDOC01-appb-C000060
Figure JPOXMLDOC01-appb-C000060
　上記工程２で得られた化合物（580mg）の光学分割をカラムクロマトグラフィー（株式会社ダイセルキラルフラッシュIC、ヘキサン／イソプロピルアルコール＝50%→100%）を用いて行った。先に溶出する第一ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル [(3S)-7-[2-(1-ヒドロキシエチル)-6-メトキシピリジン-4-イル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート（270mg）を無色油状物質として得た。また、後から溶出する第二ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル [(3R)-7-[2-(1-ヒドロキシエチル)-6-メトキシピリジン-4-イル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート（275mg）を無色油状物質として得た。
分析条件：CHIRALPAK IC、Hexane/IPA = 20/80、流速1.0mL/min、吸収波長254nm
1st peak; 保持時間 rt= 12.0min
2nd peak; 保持時間 rt= 41.2min
[工程４]　1-{4-[(3S)-3-アミノ-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]-6-メトキシピリジン-2-イル}エタノール Optical resolution of the compound (580 mg) obtained in the above Step 2 was performed using column chromatography (Daicel Chiral Flash IC, hexane / isopropyl alcohol = 50% → 100%). After collecting the first peak eluting first, the solvent was distilled off under reduced pressure, and tert-butyl [(3S) -7- [2- (1-hydroxyethyl) -6-methoxypyridin-4-yl] was collected. ] -6- (Phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-yl] carbamate (270 mg) was obtained as a colorless oil. Further, after collecting the second peak eluting later, the solvent was distilled off under reduced pressure, and tert-butyl [(3R) -7- [2- (1-hydroxyethyl) -6-methoxypyridine-4 -Il] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-yl] carbamate (275 mg) was obtained as a colorless oil.
Analysis conditions: CHIRALPAK IC, Hexane / IPA = 20/80, flow rate 1.0 mL / min, absorption wavelength 254 nm
1st peak; retention time rt = 12.0min
2nd peak; retention time rt = 41.2min
[Step 4] 1- {4-[(3S) -3-Amino-6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-7-yl] -6- Methoxypyridin-2-yl} ethanol
Figure JPOXMLDOC01-appb-C000061
Figure JPOXMLDOC01-appb-C000061
　上記工程３で第一ピークとして得られた化合物（270mg）を用いて実施例２工程９と同様の手法により標題化合物（180mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.90-7.85(1H,m),7.53-7.43(3H,m),7.36-7.28(3H,m),7.01(1H,s),6.78(1H,s),6.68(1H,d,J=0.8Hz),4.93-4.84(1H,m),4.78-4.67(2H,m),4.28(1H,dd,J=8.6,3.5Hz),4.03(3H,s),1.55(3H,d,J=6.6Hz).
[工程５]　1-{4-[(3S)-3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]-6-メトキシピリジン-2-イル}エタノール Using the compound (270 mg) obtained as the first peak in Step 3 above, the title compound (180 mg) was obtained as a white solid in the same manner as in Step 2 of Example 2.
1 H-NMR (CDCl 3 ) δppm: 7.90-7.85 (1H, m), 7.53-7.43 (3H, m), 7.36-7.28 (3H, m), 7.01 (1H, s), 6.78 (1H, s) , 6.68 (1H, d, J = 0.8Hz), 4.93-4.84 (1H, m), 4.78-4.67 (2H, m), 4.28 (1H, dd, J = 8.6,3.5Hz), 4.03 (3H, s ), 1.55 (3H, d, J = 6.6Hz).
[Step 5] 1- {4-[(3S) -3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl] -6-methoxypyridin-2-yl} ethanol
Figure JPOXMLDOC01-appb-C000062
Figure JPOXMLDOC01-appb-C000062
　上記工程４で得られた化合物（180mg）を用いて実施例１工程１０と同様の手法により標題化合物（65mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.45(1H,m),7.20(1H,d,J=8.2Hz),7.09(1H,s),7.03-6.97(2H,m),6.83(1H,d,J=1.2Hz),4.90-4.78(2H,m),4.73(1H,dd,J=7.8,4.3Hz),4.37(1H,dd,J=9.4,4.3Hz),4.00(3H,s),1.55(3H,d,J=6.6Hz). Using the compound (180 mg) obtained in the above Step 4, the title compound (65 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 8.45 (1H, m), 7.20 (1H, d, J = 8.2Hz), 7.09 (1H, s), 7.03-6.97 (2H, m), 6.83 (1H, d , J = 1.2Hz), 4.90-4.78 (2H, m), 4.73 (1H, dd, J = 7.8,4.3Hz), 4.37 (1H, dd, J = 9.4,4.3Hz), 4.00 (3H, s) , 1.55 (3H, d, J = 6.6Hz).
実施例８　1-[4-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)-6-メトキシピリジン-2-イル]エタノン
[工程１]　1-{4-[3-アミノ-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]-6-メトキシピリジン-2-イル}エタノン Example 8 1- [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
Figure JPOXMLDOC01-appb-C000063
Figure JPOXMLDOC01-appb-C000063
　実施例７工程１で得られた化合物（300mg）を用いて実施例２工程９と同様の手法により標題化合物（140mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.85(1H,d,J=8.2Hz),7.80(1H,d,J=1.2Hz),7.53-7.43(3H,m),7.36-7.28(3H,m),7.13(1H,d,J=1.2Hz),6.72(1H,s),4.78-4.67(2H,m),4.28(1H,dd,J=8.6,3.9Hz),4.07(3H,s),2.75(3H,s).
[工程２]　1-[4-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)-6-メトキシピリジン-2-イル]エタノン 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.
1 H-NMR (CDCl 3 ) δppm: 7.85 (1H, d, J = 8.2Hz), 7.80 (1H, d, J = 1.2Hz), 7.53-7.43 (3H, m), 7.36-7.28 (3H, m ), 7.13 (1H, d, J = 1.2Hz), 6.72 (1H, s), 4.78-4.67 (2H, m), 4.28 (1H, dd, J = 8.6,3.9Hz), 4.07 (3H, s) 2.75 (3H, s).
[Step 2] 1- [4- (3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) -6-methoxypyridin-2-yl] ethanone
Figure JPOXMLDOC01-appb-C000064
Figure JPOXMLDOC01-appb-C000064
　上記工程１で得られた化合物（140mg）を用いて実施例１工程１０と同様の手法により標題化合物（15mg）を黄色固体として得た。
1H-NMR(CDCl3)δppm:8.57(1H,s),7.88(1H,d,J=1.8Hz),7.22(1H,d,J=8.2Hz),7.14(1H,d,J=1.2Hz),7.08-6.98(2H,m),4.82(1H,dd,J=9.4,7.8Hz),4.73(1H,dd,J=7.8,3.9Hz),4.37(1H,dd,J=9.4,3.9Hz),4.05(3H,s),2.72(3H,s).
実施例９　3-[(3S)-3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]-5-(1-ヒドロキシエチル)ベンゾニトリル
[工程１]　メチル 3-{3-[(tert-ブトキシカルボニル)アミノ]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル}-5-シアノベンゾエート Using the compound (140 mg) obtained in the above Step 1, the title compound (15 mg) was obtained as a yellow solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δppm: 8.57 (1H, s), 7.88 (1H, d, J = 1.8Hz), 7.22 (1H, d, J = 8.2Hz), 7.14 (1H, d, J = 1.2 Hz), 7.08-6.98 (2H, m), 4.82 (1H, dd, J = 9.4,7.8Hz), 4.73 (1H, dd, J = 7.8,3.9Hz), 4.37 (1H, dd, J = 9.4, 3.9Hz), 4.05 (3H, s), 2.72 (3H, s).
Example 9 3-[(3S) -3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl] -5- (1-hydroxyethyl) benzonitrile
[Step 1] Methyl 3- {3-[(tert-butoxycarbonyl) amino] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-7-yl}- 5-cyanobenzoate
Figure JPOXMLDOC01-appb-C000065
Figure JPOXMLDOC01-appb-C000065
　実施例２工程７で得られた化合物（600mg）及びメチル 3-シアノ-5-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ベンゾエート（0.419g）を用いて実施例１工程６と同様の手法により標題化合物（600mg）を茶色固体として得た。
1H-NMR(CDCl3)δppm:8.39(1H,ddd,J=11.5,1.5,1.5Hz),7.93(1H,dd,J=1.6,1.6Hz),7.88(1H,d,J=8.2Hz),7.55-7.48(1H,m),7.42-7.30(5H,m),6.68(1H,s),5.48-5.37(1H,m),4.90-4.80(1H,m),4.80-4.70(1H,m),4.46(1H,dd,J=10.0,4.1Hz),4.00(3H,s),1.47(9H,s).
[工程２]　tert-ブチル {7-[3-シアノ-5-(ヒドロキシメチル)フェニル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル}カルバメート 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.
1 H-NMR (CDCl 3 ) δ ppm: 8.39 (1H, ddd, J = 11.5, 1.5, 1.5 Hz), 7.93 (1 H, dd, J = 1.6, 1.6 Hz), 7.88 (1 H, d, J = 8.2 Hz) ), 7.55-7.48 (1H, m), 7.42-7.30 (5H, m), 6.68 (1H, s), 5.48-5.37 (1H, m), 4.90-4.80 (1H, m), 4.80-4.70 (1H) , m), 4.46 (1H, dd, J = 10.0, 4.1Hz), 4.00 (3H, s), 1.47 (9H, s).
[Step 2] tert-butyl {7- [3-cyano-5- (hydroxymethyl) phenyl] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indole-3 -Il} Carbamate
Figure JPOXMLDOC01-appb-C000066
Figure JPOXMLDOC01-appb-C000066
　上記工程１で得られた化合物（600mg）のテトラヒドロフラン（10.5mL）溶液に、リチウムボロハイドライド（0.228g）及びメタノール（22.09mL）を加え、室温で1時間攪拌した。水を加えて反応を停止した後、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［ヘキサン／酢酸エチル］で精製することにより標題化合物（500mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.90-7.86(1H,m),7.80-7.76(1H,m),7.76-7.73(1H,m),7.63-7.58(1H,m),7.55-7.46(1H,m),7.42-7.29(5H,m),6.63(1H,s),5.46-5.35(1H,m),4.88-4.67(3H,m),4.46(1H,dd,J=10.0,4.1Hz),1.47(9H,s).
[工程３]　tert-ブチル[7-(3-シアノ-5-ホルミルフェニル)-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート Lithium borohydride (0.228 g) and methanol (22.09 mL) were added to a solution of the compound obtained in Step 1 (600 mg) in tetrahydrofuran (10.5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction was stopped by adding water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (500 mg) as a white solid.
1 H-NMR (CDCl 3 ) δ ppm: 7.90-7.86 (1H, m), 7.80-7.76 (1H, m), 7.76-7.73 (1H, m), 7.63-7.58 (1H, m), 7.55-7.46 ( 1H, m), 7.42-7.29 (5H, m), 6.63 (1H, s), 5.46-5.35 (1H, m), 4.88-4.67 (3H, m), 4.46 (1H, dd, J = 10.0,4.1 Hz), 1.47 (9H, s).
[Step 3] tert-Butyl [7- (3-cyano-5-formylphenyl) -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-yl] Carbamate
Figure JPOXMLDOC01-appb-C000067
Figure JPOXMLDOC01-appb-C000067
　上記工程２で得られた化合物（500mg）のジクロロメタン（9.16mL）溶液に、炭酸水素ナトリウム（0.308g）及びデスマーチンペルヨージナン（DMP；0.460g）を加え、室温で1時間攪拌した。水を加えて反応を停止した後、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［ヘキサン／酢酸エチル］で精製することにより標題化合物（460mg）を無色油状物質として得た。
1H-NMR(CDCl3)δppm:10.1(1H,s),8.25(1H,s),8.21(1H,s),8.00(1H,s),7.88(1H,d,J=8.6Hz),7.56-7.48(1H,m),7.42-7.30(5H,m),6.72(1H,s),5.48-5.37(1H,m),4.90-4.82(1H,m),4.82-4.70(1H,m),4.47(1H,dd,J=10.2,3.9Hz),1.47(9H,s).
[工程４]　tert-ブチル{7-[3-シアノ-5-(1-ヒドロキシエチル)フェニル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル}カルバメート Sodium hydrogen carbonate (0.308 g) and desmartin periodinane (DMP; 0.460 g) were added to a dichloromethane (9.16 mL) solution of the compound (500 mg) obtained in Step 2 above, and the mixture was stirred at room temperature for 1 hour. The reaction was stopped by adding water, followed by extraction with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (460 mg) as a colorless oil.
1 H-NMR (CDCl 3 ) δppm: 10.1 (1H, s), 8.25 (1H, s), 8.21 (1H, s), 8.00 (1H, s), 7.88 (1H, d, J = 8.6Hz), 7.56-7.48 (1H, m), 7.42-7.30 (5H, m), 6.72 (1H, s), 5.48-5.37 (1H, m), 4.90-4.82 (1H, m), 4.82-4.70 (1H, m ), 4.47 (1H, dd, J = 10.2,3.9Hz), 1.47 (9H, s).
[Step 4] tert-Butyl {7- [3-cyano-5- (1-hydroxyethyl) phenyl] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indole -3-yl} carbamate
Figure JPOXMLDOC01-appb-C000068
Figure JPOXMLDOC01-appb-C000068
　上記工程３で得られた化合物（460mg）のテトラヒドロフラン（8.46mL）溶液に0℃で1mol/L メチルマグネシウムブロミド（2.54mL）を加え、室温で1時間攪拌した。反応液に飽和塩化アンモニウム水溶液を加え反応を停止し、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄後無水硫酸ナトリウムで乾燥してろ過後、ろ液を減圧留去した。得られた残留物をシリカゲルカラムクロマトグラフィー［ヘキサン／酢酸エチル］で精製することにより標題化合物（420mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.88(1H,d,J=8.6Hz),7.79(1H,s),7.76(1H,s),7.63-7.57(1H,m),7.54-7.48(1H,m),7.40-7.30(5H,m),6.24(1H,s),5.47-5.37(1H,m),5.06-4.97(1H,m),4.92-4.82(1H,m),4.82-4.70(1H,m),4.46(1H,dd,J=1.02,3.9Hz),1.56(3H,d,J=6.6Hz),1.47(9H,s).
[工程５]　tert-ブチル [(3S)-7-[3-シアノ-5-(1-ヒドロキシエチル)フェニル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート；tert-ブチル [(3R)-7-[3-シアノ-5-(1-ヒドロキシエチル)フェニル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート 1 mol / L methylmagnesium bromide (2.54 mL) was added to a solution of the compound (460 mg) obtained in the above Step 3 in tetrahydrofuran (8.46 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (420 mg) as a white solid.
1 H-NMR (CDCl 3 ) δppm: 7.88 (1H, d, J = 8.6Hz), 7.79 (1H, s), 7.76 (1H, s), 7.63-7.57 (1H, m), 7.54-7.48 (1H , m), 7.40-7.30 (5H, m), 6.24 (1H, s), 5.47-5.37 (1H, m), 5.06-4.97 (1H, m), 4.92-4.82 (1H, m), 4.82-4.70 (1H, m), 4.46 (1H, dd, J = 1.02,3.9Hz), 1.56 (3H, d, J = 6.6Hz), 1.47 (9H, s).
[Step 5] tert-Butyl [(3S) -7- [3-cyano-5- (1-hydroxyethyl) phenyl] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3 -e] indol-3-yl] carbamate; tert-butyl [(3R) -7- [3-cyano-5- (1-hydroxyethyl) phenyl] -6- (phenylsulfonyl) -3,6-dihydro- 2H-Furo [2,3-e] indol-3-yl] carbamate
Figure JPOXMLDOC01-appb-C000069
Figure JPOXMLDOC01-appb-C000069
　上記工程４で得られた化合物（410mg）の光学分割をカラムクロマトグラフィー（株式会社ダイセルキラルフラッシュIC、ヘキサン／イソプロピルアルコール＝50%→100%）を用いて行った。先に溶出する第一ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル [(3S)-7-[3-シアノ-5-(1-ヒドロキシエチル)フェニル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート（195mg）を無色油状物質として得た。また、後から溶出する第二ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル [(3R)-7-[3-シアノ-5-(1-ヒドロキシエチル)フェニル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート（190mg）を無色油状物質として得た。
[工程６]　3-[(3S)-3-アミノ-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]-5-(1-ヒドロキシエチル)ベンゾニトリル Optical resolution of the compound (410 mg) obtained in the above Step 4 was performed using column chromatography (Daicel Chiral Flash IC, hexane / isopropyl alcohol = 50% → 100%). After collecting the first peak eluting first, the solvent was distilled off under reduced pressure, and tert-butyl [(3S) -7- [3-cyano-5- (1-hydroxyethyl) phenyl] -6- (Phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-yl] carbamate (195 mg) was obtained as a colorless oil. Further, after collecting the second peak eluting later, the solvent was distilled off under reduced pressure, and tert-butyl [(3R) -7- [3-cyano-5- (1-hydroxyethyl) phenyl]- 6- (Phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-yl] carbamate (190 mg) was obtained as a colorless oil.
[Step 6] 3-[(3S) -3-Amino-6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-7-yl] -5- (1- Hydroxyethyl) benzonitrile
Figure JPOXMLDOC01-appb-C000070
Figure JPOXMLDOC01-appb-C000070
　上記工程５で第一ピークとして得られた化合物（185mg）を用いて実施例２工程９と同様の手法により標題化合物（100mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.89(1H,d,J=8.2Hz),7.82-7.74(2H,m),7.62-7.57(1H,m),7.53-7.46(1H,m),7.39-7.28(5H,m),6.63(1H,d,J=0.8Hz),5.06-4.97(1H,m),4.80-4.66(2H,m),4.30(1H,dd,J=8.4,3.3Hz),1.56(3H,d,J=6.6Hz).
[工程７]　3-[(3S)-3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]-5-(1-ヒドロキシエチル)ベンゾニトリル Using the compound (185 mg) obtained as the first peak in Step 5 above, the title compound (100 mg) was obtained as a white solid in the same manner as in Step 2 of Example 2.
1 H-NMR (CDCl 3 ) δppm: 7.89 (1H, d, J = 8.2Hz), 7.82-7.74 (2H, m), 7.62-7.57 (1H, m), 7.53-7.46 (1H, m), 7.39 -7.28 (5H, m), 6.63 (1H, d, J = 0.8Hz), 5.06-4.97 (1H, m), 4.80-4.66 (2H, m), 4.30 (1H, dd, J = 8.4,3.3Hz ), 1.56 (3H, d, J = 6.6Hz).
[Step 7] 3-[(3S) -3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl] -5- (1-hydroxyethyl) benzonitrile
Figure JPOXMLDOC01-appb-C000071
Figure JPOXMLDOC01-appb-C000071
　上記工程６で得られた化合物（100mg）を用いて実施例１工程１０と同様の手法により標題化合物（10mg）を白色固体として得た。
1H-NMR(MeOH-d4)δppm:8.10(1H,s),8.04(1H,s),7.66(1H,s),7.22(1H,d,J=8.2Hz),7.04(1H,d,J=8.6Hz),6.93(1H,s),5.03-4.03(1H,m),4.83-4.69(2H,m),4.44-4.37(1H,m),1.54(3H,d,J=6.3Hz). Using the compound (100 mg) obtained in the above Step 6, the title compound (10 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (MeOH-d4) δ ppm: 8.10 (1H, s), 8.04 (1H, s), 7.66 (1H, s), 7.22 (1H, d, J = 8.2Hz), 7.04 (1H, d, J = 8.6Hz), 6.93 (1H, s), 5.03-4.03 (1H, m), 4.83-4.69 (2H, m), 4.44-4.37 (1H, m), 1.54 (3H, d, J = 6.3Hz ).
実施例１０　7-[3-メトキシ-4-(メチルスルホニル)フェニル]-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン
[工程１]　tert-ブチル {7-[3-メトキシ-4-(メチルスルホニル)フェニル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル}カルバメート 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
Figure JPOXMLDOC01-appb-C000072
Figure JPOXMLDOC01-appb-C000072
　実施例２工程７で得られた化合物（400mg）及び(3-メトキシ-4-メトキシスルホニル-フェニル)ボロン酸（0.242g）を用いて実施例１工程６と同様の手法により標題化合物（430mg）を茶色固体として得た。
1H-NMR(CDCl3)δppm:8.00(1H,d,J=8.2Hz),7.91(1H,d,J=8.6Hz),7.53-7.46(1H,m),7.43-7.33(2H,m),7.33-7.27(4H,m),7.15(1H,dd,J=8.0,1.4Hz),6.67(1H,s),5.48-5.36(1H,m),4.90-4.80(1H,m),4.80-4.70(1H,m),4.46(1H,dd,J=10.2,3.9Hz),4.06(3H,s),3.30(3H,s),1.47(9H,s).
[工程２]　7-[3-メトキシ-4-(メチルスルホニル)フェニル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン 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.
1 H-NMR (CDCl 3 ) δppm: 8.00 (1H, d, J = 8.2Hz), 7.91 (1H, d, J = 8.6Hz), 7.53-7.46 (1H, m), 7.43-7.33 (2H, m ), 7.33-7.27 (4H, m), 7.15 (1H, dd, J = 8.0,1.4Hz), 6.67 (1H, s), 5.48-5.36 (1H, m), 4.90-4.80 (1H, m), 4.80-4.70 (1H, m), 4.46 (1H, dd, J = 10.2,3.9Hz), 4.06 (3H, s), 3.30 (3H, s), 1.47 (9H, s).
[Step 2] 7- [3-Methoxy-4- (methylsulfonyl) phenyl] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indole-3-amine
Figure JPOXMLDOC01-appb-C000073
Figure JPOXMLDOC01-appb-C000073
　上記工程１で得られた化合物（420mg）を用いて実施例２工程９と同様の手法により標題化合物（140mg）を粗精製物として得た。
[工程３]　7-[3-メトキシ-4-(メチルスルホニル)フェニル]-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン Using the compound (420 mg) obtained in the above Step 1, the title compound (140 mg) was obtained as a crude purified product in the same manner as in Step 2 of Example 2.
[Step 3] 7- [3-Methoxy-4- (methylsulfonyl) phenyl] -3,6-dihydro-2H-furo [2,3-e] indole-3-amine
Figure JPOXMLDOC01-appb-C000074
Figure JPOXMLDOC01-appb-C000074
　上記工程２で得られた化合物（140mg）を用いて実施例１工程１０と同様の手法により標題化合物（65mg）を黄色固体として得た。
1H-NMR(MeOH-d4)δppm:7.29(1H,d,J=8.2Hz),7.64(1H,d,J=1.6Hz),7.57(1H,dd,J=8.2,1.6Hz),7.24(1H,d,J=8.2Hz),7.07-7.02(2H,m),4.82-4.68(2H,m),4.40(1H,dd,J=9.2,3.7Hz),4.13(3H,s),3.27(3H,s). Using the compound (140 mg) obtained in the above Step 2, the title compound (65 mg) was obtained as a yellow solid in the same manner as in Step 1 of Example 1.
1 H-NMR (MeOH-d4) δ ppm: 7.29 (1H, d, J = 8.2 Hz), 7.64 (1 H, d, J = 1.6 Hz), 7.57 (1 H, dd, J = 8.2, 1.6 Hz), 7.24 (1H, d, J = 8.2Hz), 7.07-7.02 (2H, m), 4.82-4.68 (2H, m), 4.40 (1H, dd, J = 9.2,3.7Hz), 4.13 (3H, s), 3.27 (3H, s).
実施例１１　7-[5-(メチルスルホニル)ピリジン-2-イル]-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン
[工程１]　tert-ブチル [6-(フェニルスルホニル)-7-(トリブチルスタナニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート 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
Figure JPOXMLDOC01-appb-C000075
Figure JPOXMLDOC01-appb-C000075
　実施例２工程６で得られた化合物（1.00g）のテトラヒドロフラン（80.4mL）溶液を-78℃に冷却し、リチウムジイソプロピルアミド（in n-hexane-tetrahydrofuran，1.0M；5.00mL）を加え、30分間攪拌した。反応溶液へ、ヨウ化トリブチルスズ（2.31g）をゆっくりと滴下し、30分間攪拌した。反応混合物に飽和フッ化カリウム水溶液を加え、1時間攪拌した後に、反応混合物を酢酸エチルで抽出した。抽出液を、水及び飽和食塩水で順次洗浄し、無水硫酸ナトリウムで乾燥した。ろ過後、ろ液を減圧留去し、得られた残留物をシリカゲルカラムクロマトグラフィー［ヘキサン／酢酸エチル］にて精製し、標題化合物（1.50g）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.18-7.07(2H,m),7.52(1H,dd,J=7.4,7.4Hz),7.45-7.34(3H,m),7.11(1H,d,J=8.2Hz),6.82(1H,dd,J=7.0,7.0Hz),5.42-5.30(1H,m),4.84-4.69(2H,m),4.48(1H,dd,J=10.0,3.3Hz),1.68-1.48(6H,m),1.44(9H,s),1.40-1.27(6H,m),1.23-1.14(6H,m),0.88(9H,t,J=7.2Hz).
[工程２]　tert-ブチル{7-[5-(メチルスルホニル)ピリジン-2-イル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル}カルバメート 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. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. After filtration, the filtrate was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (1.50 g) as a white solid.
1 H-NMR (CDCl 3 ) δ ppm: 7.18-7.07 (2H, m), 7.52 (1H, dd, J = 7.4,7.4Hz), 7.45-7.34 (3H, m), 7.11 (1H, d, J = 8.2Hz), 6.82 (1H, dd, J = 7.0,7.0Hz), 5.42-5.30 (1H, m), 4.84-4.69 (2H, m), 4.48 (1H, dd, J = 10.0,3.3Hz), 1.68-1.48 (6H, m), 1.44 (9H, s), 1.40-1.27 (6H, m), 1.23-1.14 (6H, m), 0.88 (9H, t, J = 7.2Hz).
[Step 2] tert-Butyl {7- [5- (methylsulfonyl) pyridin-2-yl] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indole-3 -Il} Carbamate
Figure JPOXMLDOC01-appb-C000076
Figure JPOXMLDOC01-appb-C000076
　上記工程１で得られた化合物（400mg）、2-ブロモ-5-メチルスルホニル-ピリジン（0.268g）、テトラキス(トリフェニルホスフィン)パラジウム(0)（0.0986g）及びヨウ化銅(I)（0.0325g）のジメチルホルムアミド（2.84mL）溶液を、120℃で2時間攪拌した。反応液を直接、アミノシリカゲルカラムクロマトグラフィー［ヘキサン／酢酸エチル］で精製することにより標題化合物（290mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:9.18(1H,d,J=2.3Hz),8.27(1H,dd,J=8.2,2.3Hz),7.92(1H,d,J=8.2Hz),7.76(1H,d,J=8.6Hz),7.69-7.64(2H,m),7.55-7.45(1H,m),7.40-7.33(3H,m),7.03(1H,s),5.45-5.35(1H,m),4.88-4.80(1H,m),4.80-4.70(1H,m),4.45(1H,dd,J=10.2,3.9Hz),1.46(9H,s).
[工程３]　7-[5-(メチルスルホニル)ピリジン-2-イル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン Compound (400 mg) obtained in Step 1 above, 2-bromo-5-methylsulfonyl-pyridine (0.268 g), tetrakis (triphenylphosphine) palladium (0) (0.0986 g) and copper (I) iodide (0.0325 A solution of g) in dimethylformamide (2.84 mL) was stirred at 120 ° C. for 2 hours. The reaction mixture was directly purified by amino silica gel column chromatography [hexane / ethyl acetate] to give the title compound (290 mg) as a white solid.
1 H-NMR (CDCl 3 ) δ ppm: 9.18 (1H, d, J = 2.3 Hz), 8.27 (1 H, dd, J = 8.2, 2.3 Hz), 7.92 (1 H, d, J = 8.2 Hz), 7.76 ( 1H, d, J = 8.6Hz), 7.69-7.64 (2H, m), 7.55-7.45 (1H, m), 7.40-7.33 (3H, m), 7.03 (1H, s), 5.45-5.35 (1H, m), 4.88-4.80 (1H, m), 4.80-4.70 (1H, m), 4.45 (1H, dd, J = 10.2,3.9Hz), 1.46 (9H, s).
[Step 3] 7- [5- (Methylsulfonyl) pyridin-2-yl] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indole-3-amine
Figure JPOXMLDOC01-appb-C000077
Figure JPOXMLDOC01-appb-C000077
　上記工程２で得られた化合物（290mg）を用いて実施例２工程９と同様の手法により標題化合物（200mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:9.18(1H,d,J=2.3Hz),8.27(1H,dd,J=8.2,2.3Hz),7.95-7.9(1H,m),7.79-7.72(1H,m),7.70-7.63(2H,m),7.57-7.43(1H,m),7.40-7.30(3H,m),7.05(1H,s),4.79-4.65(2H,m),4.29(1H,dd,J=9.2,4.1Hz),3.20(3H,s).
[工程４]　7-[5-(メチルスルホニル)ピリジン-2-イル]-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン Using the compound (290 mg) obtained in the above Step 2, the title compound (200 mg) was obtained as a white solid in the same manner as in Step 2 of Example 2.
1 H-NMR (CDCl 3 ) δ ppm: 9.18 (1H, d, J = 2.3Hz), 8.27 (1H, dd, J = 8.2,2.3Hz), 7.95-7.9 (1H, m), 7.79-7.72 (1H , m), 7.70-7.63 (2H, m), 7.57-7.43 (1H, m), 7.40-7.30 (3H, m), 7.05 (1H, s), 4.79-4.65 (2H, m), 4.29 (1H , dd, J = 9.2,4.1Hz), 3.20 (3H, s).
[Step 4] 7- [5- (Methylsulfonyl) pyridin-2-yl] -3,6-dihydro-2H-furo [2,3-e] indole-3-amine
Figure JPOXMLDOC01-appb-C000078
Figure JPOXMLDOC01-appb-C000078
　上記工程３で得られた化合物（200mg）を用いて実施例１工程１０と同様の手法により標題化合物（60mg）を白色固体として得た。
1H-NMR(DMSO-d6)δppm:12.00(1H,s),9.06(1H,d,J=2.3Hz),8.36-8.28(2H,m),7.35(1H,d,J=1.2Hz),7.20(1H,d,J=8.2Hz),7.06(1H,dd,J=8.2,0.8Hz),4.75(1H,dd,J=8.6,8.6Hz),4.65(1H,dd,J=7.8,5.1Hz),4.22(1H,d,J=9.0,5.1Hz),3.39(3H,s).
実施例１２　[5-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)ピラジン-2-イル]メタノール
[工程１]　メチル 5-{3-[(tert-ブトキシカルボニル)アミノ]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル}ピラジン-2-カルボキシレート Using the compound (200 mg) obtained in the above Step 3, the title compound (60 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (DMSO-d6) δppm: 12.00 (1H, s), 9.06 (1H, d, J = 2.3Hz), 8.36-8.28 (2H, m), 7.35 (1H, d, J = 1.2Hz) , 7.20 (1H, dd, J = 8.2Hz), 7.06 (1H, dd, J = 8.2, 0.8Hz), 4.75 (1H, dd, J = 8.6, 8.6Hz), 4.65 (1H, dd, J = 7.8 , 5.1Hz), 4.22 (1H, d, J = 9.0, 5.1Hz), 3.39 (3H, s).
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
Figure JPOXMLDOC01-appb-C000079
Figure JPOXMLDOC01-appb-C000079
　実施例１１工程１で得られた化合物（400mg）及びメチル 5-ブロモピラジン-2-カルボキシレート（0.247g）を用いて実施例１１工程２と同様の手法により標題化合物（300mg）を黄色油状物質として得た。
1H-NMR(CDCl3)δppm:9.35(1H,d,J=1.2Hz),9.05(1H,d,J=1.6Hz),7.77(1H,dd,J=8.6,0.8Hz),7.64-7.61(2H,m),7.53-7.49(1H,m),7.41-7.28(3H,m),7.07(1H,m),5.47-5.34(1H,m),4.90-4.80(1H,m),4.80-4.70(1H,m),4.46(1H,dd,J=10.2,3.9Hz),4.08(3H,s),1.46(9H,s).
[工程２]　tert-ブチル {7-[5-(ヒドロキシメチル)ピラジン-2-イル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル}カルバメート 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.
1 H-NMR (CDCl 3 ) δppm: 9.35 (1H, d, J = 1.2Hz), 9.05 (1H, d, J = 1.6Hz), 7.77 (1H, dd, J = 8.6,0.8Hz), 7.64 7.61 (2H, m), 7.53-7.49 (1H, m), 7.41-7.28 (3H, m), 7.07 (1H, m), 5.47-5.34 (1H, m), 4.90-4.80 (1H, m), 4.80-4.70 (1H, m), 4.46 (1H, dd, J = 10.2,3.9Hz), 4.08 (3H, s), 1.46 (9H, s).
[Step 2] tert-butyl {7- [5- (hydroxymethyl) pyrazin-2-yl] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indole-3 -Il} Carbamate
Figure JPOXMLDOC01-appb-C000080
Figure JPOXMLDOC01-appb-C000080
　上記工程１で得られた化合物（300mg）を用いて実施例３工程２と同様の手法により標題化合物（70mg）を黄色油状物質として得た。
1H-NMR(CDCl3)δppm:.887(1H,s),8.70(1H,s),7.77(1H,d,J=8.6Hz),7.70-7.63(2H,m),7.59-7.45(1H,m),7.40-7.32(3H,m),6.93(1H,s),5.46-5.33(1H,m),4.94(2H,d,J=5.9Hz),4.90-4.80(1H,m),4.80-4.68(1H,m),4.46(1H,dd,J=10.2,3.9Hz),3.06(1H,t,J=5.5Hz),1.46(9H,s).
[工程３]　{5-[3-アミノ-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]ピラジン-2-イル}メタノール Using the compound (300 mg) obtained in the above Step 1, the title compound (70 mg) was obtained as a yellow oily substance in the same manner as in Step 3 of Example 3.
1 H-NMR (CDCl 3 ) δ ppm: .887 (1H, s), 8.70 (1H, s), 7.77 (1H, d, J = 8.6 Hz), 7.70-7.63 (2H, m), 7.59-7.45 ( 1H, m), 7.40-7.32 (3H, m), 6.93 (1H, s), 5.46-5.33 (1H, m), 4.94 (2H, d, J = 5.9Hz), 4.90-4.80 (1H, m) , 4.80-4.68 (1H, m), 4.46 (1H, dd, J = 10.2, 3.9Hz), 3.06 (1H, t, J = 5.5Hz), 1.46 (9H, s).
[Step 3] {5- [3-Amino-6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-7-yl] pyrazin-2-yl} methanol
Figure JPOXMLDOC01-appb-C000081
Figure JPOXMLDOC01-appb-C000081
　上記工程２で得られた化合物（70mg）を用いて実施例２工程９と同様の手法により標題化合物（50mg）を黄色固体として得た。
1H-NMR(CDCl3)δppm:8.80(1H,d,J=1.6Hz),8.70(1H,d,J=1.6Hz),7.83-7.75(1H,m),7.70-7.62(2H,m),7.53-7.44(1H,m),7.41-7.31(3H,m),6.94(1H,d,J=0.8Hz),4.94(2H,s),4.78-4.71(2H,m),4.29(1H,dd,J=9.0,3.9Hz).
[工程４]　[5-(3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル)ピラジン-2-イル]メタノール Using the compound (70 mg) obtained in the above Step 2, the title compound (50 mg) was obtained as a yellow solid in the same manner as in Step 2 of Example 2.
1 H-NMR (CDCl 3 ) δppm: 8.80 (1H, d, J = 1.6Hz), 8.70 (1H, d, J = 1.6Hz), 7.83-7.75 (1H, m), 7.70-7.62 (2H, m ), 7.53-7.44 (1H, m), 7.41-7.31 (3H, m), 6.94 (1H, d, J = 0.8Hz), 4.94 (2H, s), 4.78-4.71 (2H, m), 4.29 ( (1H, dd, J = 9.0,3.9Hz).
[Step 4] [5- (3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl) pyrazin-2-yl] methanol
Figure JPOXMLDOC01-appb-C000082
Figure JPOXMLDOC01-appb-C000082
　上記工程３で得られた化合物（50mg）を用いて実施例１工程１０と同様の手法により標題化合物（25mg）を黄色固体として得た。
1H-NMR(DMSO-d6)δppm:11.86(1H,s),9.24(1H,d,J=1.6Hz),8.71(1H,d,J=1.2Hz),7.26(1H,d,J=1.2Hz),7.16(1H,d,J=8.6Hz),7.04(1H,dd,J=8.2,0.8Hz),5.66(1H,t,J=5.7Hz),4.78-4.60(4H,m),4.21(1H,dd,J=8.8,5.3Hz). Using the compound (50 mg) obtained in the above Step 3, the title compound (25 mg) was obtained as a yellow solid in the same manner as in Step 1 of Example 1.
1 H-NMR (DMSO-d6) δppm: 11.86 (1H, s), 9.24 (1H, d, J = 1.6Hz), 8.71 (1H, d, J = 1.2Hz), 7.26 (1H, d, J = 1.2Hz), 7.16 (1H, d, J = 8.6Hz), 7.04 (1H, dd, J = 8.2, 0.8Hz), 5.66 (1H, t, J = 5.7Hz), 4.78-4.60 (4H, m) 4.21 (1H, dd, J = 8.8,5.3Hz).
実施例１３　{4-[(3S)-3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]-6-メトキシピリジン-2-イル}メタノール
[工程１]　メチル 4-{3-[(tert-ブトキシカルボニル)アミノ]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル}-6-メトキシピリジン-2-カルボキシレート 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
Figure JPOXMLDOC01-appb-C000083
Figure JPOXMLDOC01-appb-C000083
　実施例２工程７で得られた化合物（400mg）及びメチル 6-メトキシ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリジン-2-カルボキシレート（0.250g）を用いて実施例１工程６と同様の手法により標題化合物（400mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.90-7.83(2H,m),7.53-7.42(3H,m),7.37-7.28(3H,m),7.06(1H,d,J=1.6Hz),6.72(1H,d,J=0.8Hz),5.45-5.36(1H,m),4.90-4.80(1H,m),4.80-4.70(1H,m),4.45(1H,dd,J=10.2,3.9Hz),3.99(3H,s),1.47(9H,s).
[工程２]　tert-ブチル{7-[2-(ヒドロキシメチル)-6-メトキシピリジン-4-イル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル}カルバメート 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).
1 H-NMR (CDCl 3 ) δppm: 7.90-7.83 (2H, m), 7.53-7.42 (3H, m), 7.37-7.28 (3H, m), 7.06 (1H, d, J = 1.6Hz), 6.72 (1H, d, J = 0.8Hz), 5.45-5.36 (1H, m), 4.90-4.80 (1H, m), 4.80-4.70 (1H, m), 4.45 (1H, dd, J = 10.2,3.9Hz ), 3.99 (3H, s), 1.47 (9H, s).
[Step 2] tert-Butyl {7- [2- (hydroxymethyl) -6-methoxypyridin-4-yl] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e ] Indol-3-yl} carbamate
Figure JPOXMLDOC01-appb-C000084
Figure JPOXMLDOC01-appb-C000084
　上記工程１で得られた化合物（400mg）を用いて実施例９工程２と同様の手法により標題化合物（320mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.88-7.83(1H,m),7.53-7.43(3H,m),7.37-7.27(3H,m),7.00(1H,d,J=1.2Hz),6.78-6.75(1H,m),6.67(1H,d,J=0.8Hz),5.48-5.42(1H,m),4.90-4.80(1H,m),4.80-4.68(3H,m),4.44(1H,dd,J=10.2,3.9Hz),4.03(3H,s),3.43(1H,t,J=5.3Hz),1.46(9H,s).
[工程３]　tert-ブチル[(3S)-7-[2-(ヒドロキシメチル)-6-メトキシピリジン-4-イル]-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート Using the compound (400 mg) obtained in the above Step 1, the title compound (320 mg) was obtained as a white solid in the same manner as in Step 9 of Example 9.
1 H-NMR (CDCl 3 ) δppm: 7.88-7.83 (1H, m), 7.53-7.43 (3H, m), 7.37-7.27 (3H, m), 7.00 (1H, d, J = 1.2Hz), 6.78 -6.75 (1H, m), 6.67 (1H, d, J = 0.8Hz), 5.48-5.42 (1H, m), 4.90-4.80 (1H, m), 4.80-4.68 (3H, m), 4.44 (1H , dd, J = 10.2,3.9Hz), 4.03 (3H, s), 3.43 (1H, t, J = 5.3Hz), 1.46 (9H, s).
[Step 3] tert-Butyl [(3S) -7- [2- (hydroxymethyl) -6-methoxypyridin-4-yl] -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2 , 3-e] Indol-3-yl] carbamate
Figure JPOXMLDOC01-appb-C000085
Figure JPOXMLDOC01-appb-C000085
　上記工程２で得られた化合物（0.320g）の光学分割をカラムクロマトグラフィー（株式会社ダイセルキラルフラッシュIC、ヘキサン／イソプロピルアルコール＝50%→100%）を用いて行った。先に溶出する第一ピークを集めた後、減圧下にて溶媒を留去し、標題化合物（135mg）を無色油状物質として得た。
[工程４]　{4-[(3S)-3-アミノ-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]-6-メトキシピリジン-2-イル}メタノール Optical resolution of the compound (0.320 g) obtained in the above Step 2 was performed using column chromatography (Daicel Chiral Flash IC, hexane / isopropyl alcohol = 50% → 100%). The first peak eluting first was collected, and the solvent was evaporated under reduced pressure to give the title compound (135 mg) as a colorless oil.
[Step 4] {4-[(3S) -3-Amino-6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-7-yl] -6-methoxypyridine -2-yl} methanol
Figure JPOXMLDOC01-appb-C000086
Figure JPOXMLDOC01-appb-C000086
　上記工程３で得られた化合物（130mg）を用いて実施例２工程９と同様の手法により標題化合物（70mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:7.88-7.83(1H,m),7.50-7.44(3H,m),7.37-7.27(3H,m),7.00(1H,s),6.78(1H,s),6.68(1H,s),4.80-4.67(4H,m),4.28(1H,dd,J=8.2,3.5Hz),4.03(3H,s),3.53-3.36(1H,m).
[工程５]　{4-[(3S)-3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]-6-メトキシピリジン-2-イル}メタノール Using the compound (130 mg) obtained in the above Step 3, the title compound (70 mg) was obtained as a white solid in the same manner as in Step 2 of Example 2.
1 H-NMR (CDCl 3 ) δppm: 7.88-7.83 (1H, m), 7.50-7.44 (3H, m), 7.37-7.27 (3H, m), 7.00 (1H, s), 6.78 (1H, s) , 6.68 (1H, s), 4.80-4.67 (4H, m), 4.28 (1H, dd, J = 8.2, 3.5Hz), 4.03 (3H, s), 3.53-3.36 (1H, m).
[Step 5] {4-[(3S) -3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl] -6-methoxypyridin-2-yl} methanol
Figure JPOXMLDOC01-appb-C000087
Figure JPOXMLDOC01-appb-C000087
　上記工程４で得られた化合物（70mg）を用いて実施例１工程１０と同様の手法により標題化合物（27mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:11.8(1H,s),7.55(1H,s),7.22-7.10(2H,m),7.10-6.93(2H,m),5.47(1H,t,J=5.9Hz),4.73(1H,dd,J=8.5,8.5Hz),4.64(1H,dd,J=6.6,6.6Hz),4.55(2H,d,J=5.4Hz),4.21(1H,dd,J=9.0,5.1Hz),3.91(3H,s). Using the compound (70 mg) obtained in the above Step 4, the title compound (27 mg) was obtained as a white solid by the same method as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 11.8 (1H, s), 7.55 (1H, s), 7.22-7.10 (2H, m), 7.10-6.93 (2H, m), 5.47 (1H, t, J = 5.9Hz), 4.73 (1H, dd, J = 8.5, 8.5Hz), 4.64 (1H, dd, J = 6.6, 6.6Hz), 4.55 (2H, d, J = 5.4Hz), 4.21 (1H, dd, J = 9.0, 5.1Hz), 3.91 (3H, s).
実施例１４　(1R)-1-{5-[(3S)-3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]ピラジン-2-イル}エタノール
[工程１]　tert-ブチル [(3R)-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート；tert-ブチル [(3S)-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート 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
Figure JPOXMLDOC01-appb-C000088
Figure JPOXMLDOC01-appb-C000088
　実施例２工程６で得られた化合物（135g）の光学分割をカラムクロマトグラフィー（株式会社ダイセル キラルセルOJ-H、メタノール100%）を用いて行った。先に溶出する第一ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル [(3R)-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート（57.9g，光学純度＞98%ee）を白色固体として得た。また、後から溶出する第二ピークを集めた後、減圧下にて溶媒を留去し、tert-ブチル [(3S)-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート（60.4g，光学純度＞98%ee）を白色固体として得た。
[工程２]　tert-ブチル [(3S)-6-(フェニルスルホニル)-7-(トリブチルスタナニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート 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. Further, after collecting the second peak eluting later, the solvent was distilled off under reduced pressure, and tert-butyl [(3S) -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2 , 3-e] indol-3-yl] carbamate (60.4 g, optical purity> 98% ee) was obtained as a white solid.
[Step 2] tert-Butyl [(3S) -6- (phenylsulfonyl) -7- (tributylstannanyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-yl] carbamate
Figure JPOXMLDOC01-appb-C000089
Figure JPOXMLDOC01-appb-C000089
　上記工程１で第二ピークとして得られた化合物（2.1g）を用いて実施例１１工程１と同様の手法により標題化合物（2.7g）を白色固体として得た。
[工程３]　tert-ブチル [(3S)-7-(5-アセチルピラジン-2-イル)-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート The title compound (2.7 g) was obtained as a white solid in the same manner as in Step 11 of Example 11 using the compound (2.1 g) obtained as the second peak in Step 1 above.
[Step 3] tert-Butyl [(3S) -7- (5-acetylpyrazin-2-yl) -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indole- 3-yl] carbamate
Figure JPOXMLDOC01-appb-C000090
Figure JPOXMLDOC01-appb-C000090
　上記工程２で得られた化合物（1.6g）及び1-(5-クロロピラジン-2-イル）エタノン（430mg）を用いて実施例１１工程２と同様の手法により標題化合物（1.2g）を黄色固体として得た。
1H-NMR(CDCl3)δppm:9.23(1H,d,J=1.2Hz),8.97(1H,d,J=1.2Hz),7.75(1H,d,J=8.2Hz),7.59(2H,d,J=7.4Hz),7.47(1H,t,J=7.6Hz),7.35-7.33(3H,m),7.03(1H,s),5.37(1H,s),4.83(1H,d,J=7.8Hz),4.73(1H,t,J=8.6Hz),4.42(1H,dd,J=10.0,4.1Hz),2.75(3H,s),1.43(9H,s).
[工程４]　tert-ブチル [(3S)-7-{5-[(1R)-1-ヒドロキシエチル]ピラジン-2-イル}-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート Using the compound obtained in Step 2 above (1.6 g) and 1- (5-chloropyrazin-2-yl) ethanone (430 mg), the title compound (1.2 g) was yellowed in the same manner as in Step 2 of Example 11. Obtained as a solid.
1 H-NMR (CDCl 3 ) δppm: 9.23 (1H, d, J = 1.2Hz), 8.97 (1H, d, J = 1.2Hz), 7.75 (1H, d, J = 8.2Hz), 7.59 (2H, d, J = 7.4Hz), 7.47 (1H, t, J = 7.6Hz), 7.35-7.33 (3H, m), 7.03 (1H, s), 5.37 (1H, s), 4.83 (1H, d, J = 7.8Hz), 4.73 (1H, t, J = 8.6Hz), 4.42 (1H, dd, J = 10.0,4.1Hz), 2.75 (3H, s), 1.43 (9H, s).
[Step 4] tert-Butyl [(3S) -7- {5-[(1R) -1-hydroxyethyl] pyrazin-2-yl} -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] Indol-3-yl] carbamate
Figure JPOXMLDOC01-appb-C000091
Figure JPOXMLDOC01-appb-C000091
　上記工程３で得られた化合物（560mg）をジクロロメタン（10mL）に溶解し、クロロ[(1R,2R)-N-(2',6'-ジメチルベンジルスルホニル)-1,2-ジフェニルエタンジアミン](メシチレン)ルテニウム(II)（34.1mg，0.0524mmol）を加えた。別途調製した、トリエチルアミン（0.363mL）とギ酸（0.17mL）の混合溶液を、室温で滴下し、4時間攪拌した。溶媒を留去し、残留物をシリカゲルカラムクロマトグラフィー［ヘキサン／酢酸エチル］で精製し、標題化合物（0.56g）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.80(1H,s),8.71(1H,s),7.73(1H,d,J=8.6Hz),7.64(2H,d,J=7.4Hz),7.47(1H,t,J=7.4Hz),7.35(2H,d,J=7.8Hz),7.30(1H,t,J=8.2Hz),6.89(1H,s),5.36(1H,s),5.08-5.02(1H,m),4.88(1H,d,J=7.4Hz),4.72(1H,t,J=9.2Hz),4.42(1H,dd,J=10.2,3.9Hz),3.49(1H,d,J=5.1Hz),1.62(3H,d,J=6.6Hz),1.43(9H,s)．
[工程５]　tert-ブチル [(3S)-7-{5-[(1R)-1-ヒドロキシエチル]ピラジン－2-イル}-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート The compound (560 mg) obtained in the above Step 3 was dissolved in dichloromethane (10 mL), and chloro [(1R, 2R) -N- (2 ′, 6′-dimethylbenzylsulfonyl) -1,2-diphenylethanediamine] (Mesitylene) ruthenium (II) (34.1 mg, 0.0524 mmol) was added. A separately prepared mixed solution of triethylamine (0.363 mL) and formic acid (0.17 mL) was added dropwise at room temperature and stirred for 4 hours. The solvent was evaporated, and the residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (0.56 g) as a white solid.
1 H-NMR (CDCl 3 ) δppm: 8.80 (1H, s), 8.71 (1H, s), 7.73 (1H, d, J = 8.6Hz), 7.64 (2H, d, J = 7.4Hz), 7.47 ( 1H, t, J = 7.4Hz), 7.35 (2H, d, J = 7.8Hz), 7.30 (1H, t, J = 8.2Hz), 6.89 (1H, s), 5.36 (1H, s), 5.08- 5.02 (1H, m), 4.88 (1H, d, J = 7.4Hz), 4.72 (1H, t, J = 9.2Hz), 4.42 (1H, dd, J = 10.2,3.9Hz), 3.49 (1H, d , J = 5.1Hz), 1.62 (3H, d, J = 6.6Hz), 1.43 (9H, s).
[Step 5] tert-Butyl [(3S) -7- {5-[(1R) -1-hydroxyethyl] pyrazin-2-yl} -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] Indol-3-yl] carbamate
Figure JPOXMLDOC01-appb-C000092
Figure JPOXMLDOC01-appb-C000092
　上記工程４で得られた化合物（560mg）を用いて実施例２工程９と同様の手法により標題化合物（360mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.81(1H,d,J=1.6Hz),8.70(1H,d,J=1.6Hz),7.73(1H,d,J=8.6Hz),7.63(2H,dd,J=8.4,1.4Hz),7.45(1H,t,J=7.4Hz),7.34-7.28(3H,m),6.90(1H,s),5.04(1H,q,J=6.5Hz),4.73-4.64(2H,m),4.25(1H,dd,J=9.0,3.9Hz),1.61(3H,d,J=6.6Hz).
[工程６]　(1R)-1-{5-[(3S)-3-アミノ-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-7-イル]ピラジン-2-イル}エタノール Using the compound (560 mg) obtained in the above Step 4, the title compound (360 mg) was obtained as a white solid in the same manner as in Step 2 of Example 2.
1 H-NMR (CDCl 3 ) δ ppm: 8.81 (1H, d, J = 1.6 Hz), 8.70 (1 H, d, J = 1.6 Hz), 7.73 (1 H, d, J = 8.6 Hz), 7.63 (2H, dd, J = 8.4,1.4Hz), 7.45 (1H, t, J = 7.4Hz), 7.34-7.28 (3H, m), 6.90 (1H, s), 5.04 (1H, q, J = 6.5Hz), 4.73-4.64 (2H, m), 4.25 (1H, dd, J = 9.0,3.9Hz), 1.61 (3H, d, J = 6.6Hz).
[Step 6] (1R) -1- {5-[(3S) -3-Amino-3,6-dihydro-2H-furo [2,3-e] indol-7-yl] pyrazin-2-yl} ethanol
Figure JPOXMLDOC01-appb-C000093
Figure JPOXMLDOC01-appb-C000093
　上記工程５で得られた化合物（360mg）を用いて実施例１工程１０と同様の手法により標題化合物（60mg）を白色固体として得た。
MS(ESI)m/z:280(M-NH2)+
1H-NMR(CD3OD)δppm:8.98(1H,d,J=1.6Hz),8.69(1H,d,J=1.2Hz),7.18(1H,d,J=8.2Hz),7.11(1H,s),7.01(1H,d,J=8.2Hz),4.92(1H,t,J=6.8Hz),4.72(1H,dd,J=9.4,7.8Hz),4.65(1H,dd,J=7.8,3.5Hz),4.34(1H,dd,J=9.4,3.9Hz),1.50(6H,d,J=6.6Hz). Using the compound (360 mg) obtained in Step 5 above, the title compound (60 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
MS (ESI) m / z: 280 (M-NH2) +
1 H-NMR (CD 3 OD) δppm: 8.98 (1H, d, J = 1.6Hz), 8.69 (1H, d, J = 1.2Hz), 7.18 (1H, d, J = 8.2Hz), 7.11 (1H , s), 7.01 (1H, d, J = 8.2Hz), 4.92 (1H, t, J = 6.8Hz), 4.72 (1H, dd, J = 9.4, 7.8Hz), 4.65 (1H, dd, J = 7.8, 3.5Hz), 4.34 (1H, dd, J = 9.4,3.9Hz), 1.50 (6H, d, J = 6.6Hz).
実施例１５　(3S)-7-(2-メチルピリミジン-5-イル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン
[工程１]　tert-ブチル [7-ブロモ-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート Example 15 (3S) -7- (2-Methylpyrimidin-5-yl) -3,6-dihydro-2H-furo [2,3-e] indole-3-amine
[Step 1] tert-Butyl [7-bromo-6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-yl] carbamate
Figure JPOXMLDOC01-appb-C000094
Figure JPOXMLDOC01-appb-C000094
　実施例１４工程１で第二ピークとして得られた化合物（3.00g）を用いて実施例１工程５と同様の手法により標題化合物（3.26g）を白色アモルファス状物質として得た。
[工程２]　tert-ブチル [(3S)-7-(2-メチルピリミジン-5-イル)-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-イル]カルバメート Using the compound (3.00 g) obtained as the second peak in Example 14, Step 1, the title compound (3.26 g) was obtained as a white amorphous substance by the same method as in Example 1, Step 5.
[Step 2] tert-Butyl [(3S) -7- (2-Methylpyrimidin-5-yl) -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indole- 3-yl] carbamate
Figure JPOXMLDOC01-appb-C000095
Figure JPOXMLDOC01-appb-C000095
　上記工程１で得られた化合物（1.63g）及び2-メチルピリミジン-5-ボロン酸（684mg）を用いて実施例１工程６と同様の手法により標題化合物（728mg）を淡黄色油状物質として得た。
1H-NMR(CDCl3)δppm:8.68-8.63(2H,m),7.90-7.87(1H,m),7.50-7.45(1H,m),7.37-7.28(5H,m),6.63-6.60(1H,m),5.46-5.40(1H,m),5.09-4.97(1H,m),4.75(1H,t,J=8.8Hz),4.47-4.42(1H,m),1.45(10H,s).
[工程３]　(3S)-7-(2-メチルピリミジン-5-イル)-6-(フェニルスルホニル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン Using the compound obtained in Step 1 above (1.63 g) and 2-methylpyrimidine-5-boronic acid (684 mg), the title compound (728 mg) was obtained as a pale yellow oily substance in the same manner as in Step 1 of Example 1. It was.
1 H-NMR (CDCl 3 ) δ ppm: 8.68-8.63 (2H, m), 7.90-7.87 (1H, m), 7.50-7.45 (1H, m), 7.37-7.28 (5H, m), 6.63-6.60 ( 1H, m), 5.46-5.40 (1H, m), 5.09-4.97 (1H, m), 4.75 (1H, t, J = 8.8Hz), 4.47-4.42 (1H, m), 1.45 (10H, s) .
[Step 3] (3S) -7- (2-Methylpyrimidin-5-yl) -6- (phenylsulfonyl) -3,6-dihydro-2H-furo [2,3-e] indol-3-amine
Figure JPOXMLDOC01-appb-C000096
Figure JPOXMLDOC01-appb-C000096
　上記工程２で得られた化合物（728mg）を用いて実施例２工程９と同様の手法により標題化合物（571mg）を淡黄色油状物質として得た。
1H-NMR(CDCl3)δppm:8.71-8.69(2H,m),7.89-7.86(1H,m),7.48-7.45(1H,m),7.38-7.26(5H,m),6.65-6.62(1H,m),4.75-4.69(2H,m),4.31-4.25(1H,m),2.81(3H,s).
[工程４]　(3S)-7-(2-メチルピリミジン-5-イル)-3,6-ジヒドロ-2H-フロ[2,3-e]インドール-3-アミン Using the compound (728 mg) obtained in the above Step 2, the title compound (571 mg) was obtained as a pale yellow oily substance in the same manner as in Step 2 of Example 2.
1 H-NMR (CDCl 3 ) δ ppm: 8.71-8.69 (2H, m), 7.89-7.86 (1H, m), 7.48-7.45 (1H, m), 7.38-7.26 (5H, m), 6.65-6.62 ( 1H, m), 4.75-4.69 (2H, m), 4.31-4.25 (1H, m), 2.81 (3H, s).
[Step 4] (3S) -7- (2-Methylpyrimidin-5-yl) -3,6-dihydro-2H-furo [2,3-e] indole-3-amine
Figure JPOXMLDOC01-appb-C000097
Figure JPOXMLDOC01-appb-C000097
　上記工程３で得られた化合物（571mg）を用いて実施例１工程１０と同様の手法により標題化合物（241mg）を白色固体として得た。
1H-NMR(CDCl3)δppm:8.89(2H,s),8.39(1H,s),7.21-7.16(1H,m),7.03-6.99(1H,m),6.89-6.87(1H,m),4.82-4.77(1H,m),4.74-4.70(1H,m),4.37-4.33(1H,m). Using the compound (571 mg) obtained in Step 3 above, the title compound (241 mg) was obtained as a white solid in the same manner as in Step 1 of Example 1.
1 H-NMR (CDCl 3 ) δ ppm: 8.89 (2H, s), 8.39 (1H, s), 7.21-7.16 (1H, m), 7.03-6.99 (1H, m), 6.89-6.87 (1H, m) , 4.82-4.77 (1H, m), 4.74-4.70 (1H, m), 4.37-4.33 (1H, m).
（製剤例１）
　実施例２の化合物（5g）、乳糖（90g）、トウモロコシデンプン（34g）、結晶セルロース（20g）及びステアリン酸マグネシウム（1g）をブレンダーで混合した後、錠剤機で打錠することにより、錠剤が得られる。
評価例１：ASICのin vitro評価法
　Human ASIC3発現細胞は、Millipore社から購入した（カタログ番号：CYL3055）。 (Formulation 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).
　Human ASIC1a、human ASIC2a、及びmouse ASIC1aの安定発現細胞株は、GeneSwitch System Complate kit（Invitrogen）を用いて作製したV5-His-ASICs-vectorを、Lipofectamine 2000 Transfection Reagent（Invitrogen）を用いて、GeneSwitch-CHO Cells（Invitrogen）に遺伝子導入して作製した。ベクター作成方法および遺伝子導入方法は、それぞれのキットに添付のマニュアルに準拠した。 The stable expression cell lines of Human ASIC1a, human ASIC2a, and mouse 発 現 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発現細胞は、Lipofectamine 2000 Transfection Reagent（Invitrogen）を用いて、キット添付のマニュアルに準拠した方法で、HEK293A細胞（Invitrogen）に遺伝子導入して安定発現細胞株を作製した。 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.
　遺伝子名とホスト細胞の関係を表１に示す。 Table 1 shows the relationship between gene names and host cells.
　Human ASIC1a 発現細胞は1nM Mifepristone（Sigma-Aldrich）を18時間処理して発現誘導させた後、測定に用いた。Human ASIC2a発現細胞及びMouse ASIC1a発現細胞は10nM Mifepristone（Sigma-Aldrich）を18時間処理して発現誘導させた後、測定に用いた。 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.
　細胞と化合物とを接触させ、ホールセル自動パッチクランプ法（Patchliner, Nanion Technologies GmBH）を用いて、酸誘発電流のピーク変化を測定することにより、ASIC阻害活性を評価した。保持電位は-60mVとした。内液及び外液の組成を以下に記す。 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.
内液（mM）：50 CsCl, 60 CsF, 10 NaCl, 20 EGTA, and 10 HEPES, pH 7.2。
標準外液（mM）: 135 NaCl, 4 KCl, 5 CaCl2, 1 MgCl2, 5 glucose, and 10 HEPES, pH 7.4。
酸刺激外液（mM）: 135 NaCl, 4 KCl, 5 CaCl2, 1 MgCl2, 5 glucose, and 10 HEPES, pH 6.4（ASIC1a, 3機能測定）, or 10 MES, pH 4.0（ASIC2a 機能測定）。 Internal solution (mM): 50 CsCl, 60 CsF, 10 NaCl, 20 EGTA, and 10 HEPES, pH 7.2.
Nonstandard solution (mM): 135 NaCl, 4 KCl, 5 CaCl 2 , 1 MgCl 2 , 5 glucose, and 10 HEPES, pH 7.4.
Acid-stimulated external solution (mM): 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) .
　酸誘発電流の基準値は、標準外液から0.1% DMSOを含む酸刺激外液へ置換した際に生じる電流ピークにより規定した。化合物のASIC電流阻害率は、基準値に対する、化合物を含む酸刺激外液へ置換した際の電流ピーク変化により規定した。各濃度の阻害率をプロットし、Hill式を用いてフィッティングした濃度反応曲線からIC50値を算出した。 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.
　本発明の各化合物のヒトASIC3に対する阻害作用を表２に結果を示す。 Table 2 shows the inhibitory action of each compound of the present invention on human ASIC3.
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000098
Figure JPOXMLDOC01-appb-T000099
Figure JPOXMLDOC01-appb-T000099
評価例２：ENacのin vitro評価法
　LipofectamineTM LTX Reagent（Invitrogen）を用い、キット添付のマニュアルに準拠した方法で、Human ENaCα、Human ENaCβ、Human ENaCγを機能的に共発現するCHOK1細胞（DS pharma biochemical）を作製して試験に用いた。導入した遺伝子を表３に記す。 Evaluation Example 2: ENac In Vitro Evaluation Method CHOK1 cells functionally co-expressing Human ENaCα, Human ENaCβ, and Human ENaCγ using Lipofectamine ™ 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.
　測定原理は、Krummらの方法（Bioorg. Med. Chem., 2012, 20, 3979-3984）に基づいたものである。細胞と化合物とを接触させ、ホールセル自動パッチクランプ法（Syncropatch384PE, Nanion Technologies GmBH）を用いて電流のピーク変化を測定することによりENaC阻害活性を評価した。保持電位は-60mVとした。内液及び外液の組成を以下に記す。 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.
内液（mM）： 140 CsF, 10 NaCl, 20 sucrose, 10 HEPES, 1 EGTA, pH 7.3。
標準外液（mM）: 135 NaCl, 4 KCl, 5 CaCl2, 1 MgCl2, 5 glucose, 100 amiloride and 10 HEPES, pH 7.4。
評価外液（mM）: 135 NaCl, 4 KCl, 5 CaCl2, 1 MgCl2, 5 glucose, and 10 HEPES, pH 7.4。 Internal solution (mM): 140 CsF, 10 NaCl, 20 sucrose, 10 HEPES, 1 EGTA, pH 7.3.
Nonstandard solution (mM): 135 NaCl, 4 KCl, 5 CaCl 2 , 1 MgCl 2 , 5 glucose, 100 amiloride and 10 HEPES, pH 7.4.
External solution for evaluation (mM): 135 NaCl, 4 KCl, 5 CaCl 2 , 1 MgCl 2 , 5 glucose, and 10 HEPES, pH 7.4.
　ENaC電流の基準値は、標準外液から0.1% DMSOを含む評価外液へ置換した際に生じる電流ピークにより規定した。化合物のENaC電流阻害率は、基準値に対する、化合物を含む評価外液へ置換した際の電流ピーク変化により規定した。各濃度の阻害率をプロットし、Hill式を用いてフィッティングした濃度反応曲線からIC50値を算出した。 The standard value of ENaC current was defined by the current peak generated when the non-standard solution was replaced with an evaluation solution containing 0.1% DMSO. The 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.
　実施例２の化合物での測定結果を表４に示した。同化合物は、ENacに対しては阻害作用を示さず、一方でASICに対しては選択的な強い阻害作用が確認された。 The measurement results with the compound of Example 2 are shown in Table 4. The compound showed no inhibitory action against ENac, while a strong selective inhibitory action against ASIC was confirmed.
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000100
Figure JPOXMLDOC01-appb-T000101
Figure JPOXMLDOC01-appb-T000101
評価例３：経口吸収性の確認
　4週齢の雄性ddyマウス（n=3）に実施例２の化合物を10mg/kgの用量で単回、経口又は静脈内投与し、投与後の血漿中濃度をliquid chromatography-tandem mass spectrometry（LC-MS/MS）によって測定し、得られた血漿中濃度データからファーマコキネティックパラメータを算出した。投与基剤として、静脈内投与にはスルホブチルエーテル-β-シクロデキストリン（SBE-β-CyD）、経口投与には0.5% メチルセルロースを用いた。結果を図１に示した。 Evaluation Example 3: Confirmation of Oral Absorption The 4-week-old male ddy mice (n = 3) were administered the compound of Example 2 once orally or intravenously at a dose of 10 mg / kg, and the plasma concentration after administration Was measured by liquid chromatography-tandem mass spectrometry (LC-MS / MS), and pharmacokinetic parameters were calculated from the plasma concentration data obtained. As the administration base, sulfobutyl ether-β-cyclodextrin (SBE-β-CyD) was used for intravenous administration, and 0.5% methylcellulose was used for oral administration. The results are shown in FIG.
　各々の投与で求められたAUCの値は一致しており、本化合物が優れた経口吸収性を示すことが確認された。 The AUC values determined by each administration were in agreement, and it was confirmed that this compound exhibits excellent oral absorbability.
　本発明の3,6-ジヒドロ-2H-フロ[2,3-e]インドール化合物、その塩、又はそれらの水和物は優れた経口性酸感受性イオンチャネル阻害剤であり、医薬として有用である。 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. .
配列番号１：ヒトENaCαサブユニットの塩基配列
配列番号２：ヒトENaCβサブユニットの塩基配列
配列番号３：ヒトENaCγサブユニットの塩基配列 SEQ ID NO: 1: Base sequence of human ENaCα subunit SEQ ID NO: 2: Base sequence of human ENaCβ subunit SEQ ID NO: 3: Base sequence of human ENaCγ subunit

Claims (10)

  1. 式（I）で示される化合物又はその薬学的に許容される塩：
    Figure JPOXMLDOC01-appb-C000001
     （式中、次式：
    Figure JPOXMLDOC01-appb-C000002
     で示される構造は、R1及びR2が置換した芳香族基を示し、R1及びR2は、次の群：
    水素原子、C1-C6-アルキル基、C1-C6-アルコキシ基、ヒドロキシC1-C6-アルキル基、ジヒドロキシC2-C6-アルキル基、ハロゲノC1-C6-アルキル基、C1-C6-アルキルスルホニル基、ハロゲン原子、シアノ基及びC2-C6-アシル基
    から独立して選ばれる基を示す。）。     Compound represented by formula (I) or a pharmaceutically acceptable salt thereof:
    Figure JPOXMLDOC01-appb-C000001
     (Where:
    Figure JPOXMLDOC01-appb-C000002
     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; ).
  2. 芳香族基が、窒素原子及び硫黄原子から選ばれる1～3の複素原子を有する5又は6員環の芳香族複素環基及び炭化水素系芳香族基から選ばれる基である請求項１に記載の化合物又はその薬学的に許容される塩。 2. The aromatic group is a group selected from a 5- or 6-membered aromatic heterocyclic group having 1 to 3 hetero atoms selected from a nitrogen atom and a sulfur atom and a hydrocarbon aromatic group. Or a pharmaceutically acceptable salt thereof.
  3. 芳香族基が、フェニル基、ピロリル基、ピラゾリル基、イミダゾリル基、チアゾリル基、チアジアゾリル基、ピリジル基、ピリダジニル基、ピリミジル基、又はピラジニル基である請求項１に記載の化合物又はその薬学的に許容される塩。 2. The compound according to claim 1, wherein the aromatic group is a phenyl group, a pyrrolyl group, a pyrazolyl group, an imidazolyl group, a thiazolyl group, a thiadiazolyl group, a pyridyl group, a pyridazinyl group, a pyrimidyl group, or a pyrazinyl group. Salt.
  4. R1及びR2が、次の群：
    水素原子、C1-C6-アルキル基、C1-C6-アルコキシ基、ヒドロキシC1-C6-アルキル基、ジヒドロキシC2-C6-アルキル基、C1-C6-アルキルスルホニル基及びハロゲン原子
    から独立して選ばれる基である請求項１から３のいずれか一項に記載の化合物又はその薬学的に許容される塩。     R 1 and R 2 are in 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 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.
  5. R1及びR2が、次の群：
    水素原子、メチル基、フッ素原子、塩素原子、トリフルオロメチル基、メトキシ基、エトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基、メチルスルホニル基、シアノ基及びアセチル基
    から独立して選ばれる基である請求項１から３のいずれか一項に記載の化合物又はその薬学的に許容される塩。     R 1 and R 2 are in 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 compound according to any one of claims 1 to 3, which is a group independently selected from -dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group, methylsulfonyl group, cyano group and acetyl group Its pharmaceutically acceptable salt.
  6. R1及びR2の一方が水素原子であって、他方が次の群：
    メチル基、フッ素原子、塩素原子、トリフルオロメチル基、メトキシ基、エトキシ基、ヒドロキシメチル基、1-ヒドロキシエチル基、(1S)-1-ヒドロキシエチル基、(1R)-1-ヒドロキシエチル基、2-ヒドロキシエチル基、1-ヒドロキシプロピル基、(1R)-1-ヒドロキシプロピル基、(1S)-1-ヒドロキシプロピル基、1,2-ジヒドロキシエチル基、(1S)-1,2-ジヒドロキシエチル基、(1R)-1,2-ジヒドロキシエチル基、メチルスルホニル基、シアノ基及びアセチル基
    から選ばれる基である請求項１から３のいずれか一項に記載の化合物又はその薬学的に許容される塩。     One of R 1 and R 2 is a hydrogen atom and 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 A compound selected from the group consisting of a group, (1R) -1,2-dihydroxyethyl group, methylsulfonyl group, cyano group and acetyl group, or a pharmaceutically acceptable salt thereof. Salt.
  7. R1及びR2が、
    一方がヒドロキシメチル基であって、他方がメチルスルホニル基、メトキシ基、シアノ基、又はフッ素原子であるか、或は、
    一方が1,2-ジヒドロキシエチル基であって、他方がフッ素原子又は塩素原子である請求項１から３のいずれか一項に記載の化合物又はその薬学的に許容される塩。     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 according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein one is a 1,2-dihydroxyethyl group and the other is a fluorine atom or a chlorine atom.
  8. 式（I）で示される化合物が、次の群：
    Figure JPOXMLDOC01-appb-C000003
     （式中、A部分、R1及びR2は先の定義に等しい。）
    のいずれかである請求項１から７のいずれか一項に記載の化合物又はその薬学的に許容される塩。     The compound of formula (I) has the following group:
    Figure JPOXMLDOC01-appb-C000003
     (Wherein the A moiety, R 1 and R 2 are equal to the previous definition.)
    The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.
  9. 請求項１から８のいずれかに記載の化合物又はその薬学的に許容される塩と薬学的に許容し得る担体とを含有する医薬組成物。 A pharmaceutical composition comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  10. 請求項１から８のいずれかに記載の化合物又はその薬学的に許容される塩を含有する酸感受性イオンチャネル阻害剤。
     
          An acid-sensitive ion channel inhibitor comprising the compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

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JP2009520700A (en) * 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 Compositions and methods for modulating gated ion channels
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