WO2018151240A1 - COMPOSÉ 3,6,7,8-TÉTRAHYDROCYCLOPENTA[e]INDOLE - Google Patents

COMPOSÉ 3,6,7,8-TÉTRAHYDROCYCLOPENTA[e]INDOLE Download PDF

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WO2018151240A1
WO2018151240A1 PCT/JP2018/005361 JP2018005361W WO2018151240A1 WO 2018151240 A1 WO2018151240 A1 WO 2018151240A1 JP 2018005361 W JP2018005361 W JP 2018005361W WO 2018151240 A1 WO2018151240 A1 WO 2018151240A1
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group
compound
tetrahydrocyclopenta
indol
nmr
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藤井　邦彦
理恵子 高野
幸伸 沼田
優真 梅崎
アガルワル アディティ
正憲 泉
中村　弘明
昌生 吉田
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第一三共株式会社
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    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
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    • A61K31/425—Thiazoles
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07D209/56—Ring systems containing three or more rings
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Definitions

  • the present invention relates to a 3,6,7,8-tetrahydrocyclopenta [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 in humans (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 present inventors have found that the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof has ASIC inhibitory properties with excellent selectivity and has oral absorbability. Completed the invention.
  • R represents a hydrogen atom or a halogen atom
  • 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, C3-C6-cycloalkyl (hydroxy)
  • the aromatic group is a group selected from a 5- or 6-membered aromatic heterocyclic group and a hydrocarbon-based aromatic group having a heteroatom 1 to 3 selected from a nitrogen atom and a sulfur atom [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 -Dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclo Independently selected from propyl-1-hydroxyethyl group, methylsulfonyl group, cyano group, acetyl group, 1,
  • 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, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclopropyl-1 1-hydroxyethyl group, methylsulfonyl group, cyano group, acetyl group, methyl
  • 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, 1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclopropyl-1-hydroxyethyl Any one of [1] to [4], which is a group selected from a group, a methyls
  • 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 according to any one of [1] to [4], wherein one is a (1R) -1,2-dihydroxyethyl group and the other is a fluorine atom, or a pharmaceutically acceptable salt thereof.
  • the compound represented by the formula (I) is represented by the following group:
  • a compound of formula (I) is represented by the following group:
  • the compound represented by the formula (I) is: (1R) -1- ⁇ 5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl ⁇ ethanol, (1S) -1- ⁇ 5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl ⁇ ethanol, (6R) -2- [5- (methylsulfonyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine, (6R) -2- (5-methyl-1,3,4-thiadiazol-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine, (6R) -2- (5-methyl-1,3,4-thiadia
  • the compound represented by the formula (I) is: (1R) -1- ⁇ 5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl ⁇ ethanol, (1S) -1- ⁇ 5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl ⁇ ethanol, (6R) -2- [5- (methylsulfonyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine, (6R) -2- (5-methyl-1,3,4-thiadiazol-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine, (6R) -2- (1-methyl-1H-pyra
  • a pharmaceutical composition comprising the compound according to any one of [1] to [24] 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 [24] 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
  • the blood concentration transition (unit: nanomolar) when the compound of Example 25 of the present invention was orally administered to mice is shown.
  • the rhombus shows the change at the dose of 3 mg / kg, and the square shows the change at the dose of 10 mg / kg.
  • 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, 3,6,7,8-tetrahydrocyclopenta [e] indole is a mother nucleus, R 1 and R 2 are substituted at the 2- position, an amino group at the 6-position, and the 7-position Is a compound having a structure having a substituent R.
  • a part of the aromatic group represented by is a hydrocarbon-based aromatic group or a 5-membered or 6-membered aromatic having a hetero atom of 1 to 3 selected from a nitrogen atom and a sulfur atom It is a group selected from heterocyclic groups.
  • 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- C6-alkyl group, halogeno C1-C6-alkyl group, C3-C6-cycloalkyl (hydroxy) C1-C6-alkyl group, C1-C6-alkylsulfonyl group, (N-hydroxyimino) C1-C6-alkyl group, It is a group independently selected from a halogen atom, a cyano group and a C2-C6-acyl group.
  • the substituent R at the 7-position is a hydrogen atom or a halogen atom.
  • the substitution R may be a hydrogen atom or a halogen atom. That is, it may be a hydrogen atom, a fluorine atom, a chloro atom, a bromo atom, or an iodo atom. Among these, a hydrogen atom or a fluorine atom is preferable, and a hydrogen atom is more preferable.
  • the compound represented by the formula (I) has an amino group at the 6-position and a substituent R at the 7-position.
  • amino group coordination is alpha:
  • the substituent R at the 7-position is a halogen atom, it is 6,7-gem-disubstituted.
  • the amino group at the 6-position and the halogen atom at the 7-position exist in either a cis configuration or a trans configuration.
  • the ASIC inhibitor of the present invention may be any configuration, but more preferably is a cis configuration (the following formula).
  • the structure represented by is considered to be a preferable structure.
  • the A moiety 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 pyrimidyl group, or a pyrazinyl group.
  • phenyl group pyrazol-4-yl group, thiazol-2-yl group, thiazol-5-yl group, thiadiazol-2-yl group, pyridin-2-yl group, and pyridin-4-yl.
  • phenyl group pyrazol-4-yl group, thiazol-2-yl group, thiazol-5-yl group, thiadiazol-2-yl group, pyridin-2-yl group, and pyridin-4-yl.
  • pyrimidin-2-yl group pyrimidin-4-yl group
  • pyrazin-2-yl group pyrazin-2-yl group.
  • a phenyl group, a pyrazol-4-yl group, a thiazol-2-yl group, a thiadiazol-2-yl group, a pyridin-2-yl group, a pyrimidin-4-yl group, or a pyrazin-2-yl group It is.
  • 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 dihydroxyalkyl group containing (1R) -hydroxy, and a (1R) -1,2-dihydroxyethyl group is preferred.
  • 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 is more preferable, and a trifluoromethyl group is more preferable.
  • R 1 or R 2 is a structure in which a C3-C6-cycloalkyl (hydroxy) C1-C6-alkyl group is further substituted with a hydroxy group-substituted alkyl group and a C3-C6 cycloalkyl group.
  • cyclopropylhydroxymethyl group, cyclopropylhydroxyethyl group, cyclobutylhydroxymethyl group, cyclobutylhydroxyethyl group, cyclopentylhydroxymethyl group, cyclopentylhydroxyethyl group, cyclohexylhydroxymethyl group, or cyclohexylhydroxyethyl group Can be mentioned.
  • a 2-cyclopropyl-1-hydroxyethyl group, a (1R) -2-cyclopropyl-1-hydroxyethyl group, or a (1S) -2-cyclopropyl-1-hydroxyethyl group is preferred.
  • 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 hydroxyimino C 1 -C 6 -alkyl group
  • the position of the hydroxyimino group is not particularly limited, but is more preferably a carbon atom that becomes the benzyl position (particularly, the number of carbon atoms is 2).
  • a 1- (hydroxyimino) C 1 -C 6 -alkyl group is more preferred.
  • the hydroxyimino C 1 -C 6 -alkyl group is preferably a hydroxyiminomethyl group, 1-hydroxyiminoethyl group, 2-hydroxyiminoethyl group, 1-hydroxyiminopropyl group, 2-hydroxyiminopropyl group, or 3- Examples thereof include a hydroxyiminocypropyl group, more preferably a hydroxyiminomethyl group or a 1-hydroxyiminoethyl group, and still more preferably a 1-hydroxyiminoethyl group.
  • 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 -Dihydroxyethyl group, (1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclo Independently selected from propyl-1-hydroxyethyl, methylsulfonyl, cyano, acetyl, 1,1-dimethoxy
  • 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 Group, (1R) -1,2-dihydroxyethyl group, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclopropyl-1 It is preferably selected from -hydroxyethyl group, methylsulfonyl 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, 2-cyclopropyl-1-hydroxyethyl group, (1R) -2-cyclopropyl-1-hydroxyethyl group, (1S) -2-cyclopropyl-1-hydroxyethyl A group selected from a group, a methylsulfonyl group, a cyano group, an acetyl group, a 1- (N) atom
  • 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 G described below.
  • the solvent used in the reaction in each step of the following methods A to G 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, etc.
  • reaction time varies depending on the solvent, starting material, reagent, reaction temperature, etc.
  • each target compound is usually collected from the reaction mixture according to a method employed in the technical field. For example, after adjusting the liquidity of the reaction mixture as appropriate and removing insoluble matter by filtration, mixing with water and an organic solvent that is not miscible with water, such as ethyl acetate, and mixing 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 to remove the desiccant, and then distilled off the solvent in the filtrate. Can do.
  • 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, SO3H-silica (Fuji Silysia Chemical Ltd.).
  • a suitable combination of photographic methods (preferably high performance liquid chromatography) Of] such eluting with a suitable eluent, usually separated by combining the methods which are customary for separation and purification of organic compounds as appropriate, can be purified.
  • Production method A is a method for producing tetrahydrocyclopentaindole (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 the compound represented by the formula (III) by reducing the olefin using a known organic chemical technique with respect to the compound represented by the formula (II).
  • the compound represented by formula (II) is used as a solvent (for example, alcohols, specifically ethanol, methanol, etc .; ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.). And may be carried out by catalytic hydrogenation in the presence of a transition metal catalyst (such as palladium). This reaction is usually performed in a hydrogen atmosphere, but ammonium formate, formic acid, or the like may be used as a hydrogen donor.
  • a solvent for example, alcohols, specifically ethanol, methanol, etc .; ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • a transition metal catalyst such as palladium
  • the compound represented by the formula (II) is a known compound, or can be easily produced according to a known method or a similar method using a known compound as a starting material.
  • This step is a step of producing the compound represented by the formula (IV) by hydrolyzing the ester of the compound represented by the formula (III) using a known organic chemical technique.
  • the compound represented by the formula (III) is present in the presence of a base (for example, alkyl metal hydroxides, specifically lithium hydroxide) in a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxy). Ethane, etc .; alcohols, specifically methanol, ethanol, etc. may be used as the organic solvent, and water may be mentioned as the solvent, but the organic solvent is preferably miscible with water, These are preferably used as mixed solvents).
  • a base for example, alkyl metal hydroxides, specifically lithium hydroxide
  • a solvent for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxy.
  • Ethane, etc .; alcohols, specifically methanol, ethanol, etc. may be used as the organic solvent, and water may be mentioned as the solvent, but the organic solvent is preferably miscible with water, These are preferably used as mixed solvents).
  • the carboxylic acid compound represented by the formula (IV) is converted into an acid chloride (oxalyl chloride, thionyl chloride) in a solvent (for example, halogenated hydrocarbons, specifically dichloromethane, chloroform, 1,2-dichloroethane, etc.). Etc.) and a small amount of N, N-dimethylformamide may be added.
  • a solvent for example, halogenated hydrocarbons, specifically dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • Etc. halogenated hydrocarbons, specifically dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • Etc. halogenated hydrocarbons, specifically dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • Etc. halogenated hydrocarbons, specifically dichloromethane, chloroform, 1,2-dichloroethane, etc.
  • the compound represented by the formula (V) is carried out in a solvent (for example, a halogenated hydrocarbon, specifically 1,2-dichloroethane) by adding a Lewis acid (for example, aluminum chloride).
  • a solvent for example, a halogenated hydrocarbon, specifically 1,2-dichloroethane
  • a Lewis acid for example, aluminum chloride.
  • the compound represented by formula (VI) is used as a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc .; alcohols, specifically methanol, ethanol, etc.).
  • a reducing agent for example, metal borohydride compounds, specifically sodium borohydride, etc. is added.
  • This step is a step of producing the compound represented by the formula (VIII) by subjecting the compound represented by the formula (VII) to Mitsunobu reaction using a known organic chemical technique.
  • the compound represented by formula (VII) is used as a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc .; alcohols, specifically methanol, ethanol, etc.). In this case, N-Boc-o-nitrobenzenesulfonamide, triphenylphosphine and diethyl azodicarboxylate are added.
  • This step is a step of producing a compound represented by the formula (IX) by hydrolyzing o-nitrobenzenesulfonamide using a known organic chemical method for the compound represented by the formula (VIII). It is.
  • Production method B is a method for producing fluorotetrahydrocyclopentaindole (XII), 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 (X) by subjecting the compound represented by the formula (VI) to a fluorination reaction using a known organic chemical technique.
  • the compound represented by the formula (VI) is converted into 1-fluoro-4-hydroxy-1,4-diazoniabicyclo [2,2, in a solvent (for example, alcohols, specifically methanol, ethanol, etc.). 2] Add octanebis (tetrafluoroborate) and so on. (Process B-II)
  • This step is a step of producing the compound represented by the formula (XI) by subjecting the compound represented by the formula (X) to an oximation reaction using a known organic chemical technique.
  • a compound represented by formula (X) is used as a solvent (for example, alcohols, specifically ethanol, etc .; ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc .; water, these are used as a mixed solvent. In this case, sodium acetate and O-methylhydroxyamine hydrochloride are added.
  • This reaction is a step of producing a compound represented by the formula (XII) by reducing the oxime to the compound represented by the formula (XI) using a known organic chemical technique and then Boc protecting it. is there.
  • a compound represented by the formula (XI) in a solvent for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • a solvent for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • borane-ether complexes specifically borane-tetrahydrofuran complexes, etc.
  • an alkali metal hydroxide aqueous solution for example, sodium hydroxide aqueous solution as a base, ethyl acetate and di-t-butyl dicarbonate as a solvent are added.
  • Production method C produces aryltetrahydrocyclopentaindole (XV), which can be used as a synthetic intermediate when producing the compound represented by formula (I), via bromotetrahydrocyclopentaindole (XIV). Is the method.
  • This step is a step of producing the compound represented by the formula (XIV) by brominating the compound represented by the formula (XIII) using a known organic chemical technique.
  • a compound represented by the formula (XIII) in a solvent for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • a lithium metal strong base for example, lithium diisopropylamide, and 1,2-dibromo Carry out with the addition of -1,1,2,2-tetrachloroethane.
  • C-II process This step is a step of producing a compound represented by the formula (XV) by subjecting the compound represented by the formula (XIV) to Suzuki coupling using a known organic chemical technique.
  • a compound represented by the formula (XIV) 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, arylboronic acid or arylboronic acid Carry out with the addition of the ester.
  • a microwave reactor may be used.
  • Production Method D produces aryltetrahydrocyclopentaindole (XV), which can be used as a synthetic intermediate when producing the compound represented by formula (I), via tributylstannanyltetrahydrocyclopentaindole (XVI). It is a method to do.
  • This step is a step of producing a compound represented by the formula (XVI) by subjecting the compound represented by the formula (XIII) to tributylstannylation using a known organic chemical technique.
  • lithium diisopropylamide and tributyltin iodide are added as a lithium metal strong base in a solvent (for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.) to a compound represented by the formula (XIII).
  • a solvent for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • This step is a step of producing a compound represented by the formula (XV) by subjecting a compound represented by the formula (XVI) to Stille coupling using a known organic chemical technique.
  • a compound represented by the formula (XVI) 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
  • a microwave reactor may be used.
  • Stille coupling the method 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.
  • This step is a step for producing a compound represented by the formula (XVII) by subjecting the compound represented by the formula (XIII) to alkyloxycarbonylation using a known organic chemical technique.
  • This step is a step of producing the compound represented by the formula (XVIII) by hydrolyzing the compound represented by the formula (XVII) using a known organic chemical technique. This is carried out in the same manner as in step A-II of method A.
  • a solvent for example, ethers, specifically tetrahydrofuran, 1,2-dimethoxyethane, etc.
  • This step is a step for producing a compound represented by the formula (XIX) by subjecting the compound represented by the formula (XVIII) to a condensation reaction using a known organic chemical technique.
  • a compound represented by the formula (XVIII) is mixed with O- (7-azabenzotriazole-1-form 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.
  • This step is a step of producing the compound represented by the formula (XX) by cyclizing the compound represented by the formula (XIX) using a known organic chemical technique.
  • Production method E is a method for producing aminotetrahydrocyclopentaindole (XXI), which can be used as a synthesis intermediate when synthesizing a compound represented by formula (I), from a compound represented by formula (XV). .
  • This step is a step of producing a compound represented by the formula (XXI) by de-Bocating the compound represented by the formula (XV) using a known organic chemical technique.
  • the compound represented by the formula (XV) in a solvent for example, ethers, specifically 1,4-dioxane, 1,2-dimethoxyethane; halogenated hydrocarbons, dichloromethane, etc.
  • Hydrogen Dioxane solution
  • 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 P. G. Wuts.
  • Production method F is another method for producing a synthetic intermediate represented by the formula (XXVIII).
  • This step is a step of producing the compound represented by the formula (XXIII) by fluorinating the compound represented by the formula (XXII) 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 the compound represented by the formula (XXIV) by reducing the compound represented by the formula (XXIII) using a known organic chemical technique. Performed in the same manner as the AV process of Method A.
  • This step is a step of producing a compound represented by the formula (XXV) by brominating the compound represented by the formula (XXIV) using a known organic chemical technique. Performed in the same manner as the CI process in Method C.
  • This step is a step of producing a compound represented by the formula (XXVI) by subjecting the compound represented by the formula (XXV) to Suzuki coupling using a known organic chemical technique. This is carried out in the same manner as the C-II step of Method C.
  • This step is a step of producing a compound represented by the formula (XXVII) by subjecting the compound represented by the formula (XXVI) to a Mitsunobu reaction using a known organic chemical technique.
  • a compound represented by the formula (XXVI) 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.
  • 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.
  • F-VI process This step is a step of producing a compound represented by the formula (XXVIII) by subjecting the compound represented by the formula (XXVII) to a reduction reaction using a known organic chemical technique.
  • Production method G is a method for producing a compound represented by formula (I) from a compound represented by formula (XXI).
  • This step is a step of producing the compound represented by the formula (I) by dearylsulfonylating the compound represented by the formula (XXI) using a known organic chemical method.
  • a compound represented by the formula (XXI) in 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 is possible to easily use 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.
  • Example 1 [3- (6-Amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl) -5-methoxy-phenyl] methanol [Step 1] Ethyl 3- ⁇ 1-[(4-methylphenyl) sulfonyl] -1H-indol-4-yl ⁇ propanoate
  • Lithium hydroxide monohydrate (17.8 g, 425 mmol) was added to a mixture of the compound (63.1 g) obtained in Step 1 above in tetrahydrofuran (300 mL), ethanol (100 mL), and water (200 mL) at room temperature. Stir. The reaction mixture was cooled to 0 ° C., 3N hydrochloric acid (150 mL) 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.
  • Oxalyl chloride (17.1 mL) was added dropwise to a solution of the compound (57.1 g) obtained in Step 2 above in dichloromethane (300 mL). After completion of dropping, the mixture was stirred at room temperature for 2 hours, N, N-dimethylformamide (3 drops) was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain the title compound (60.2 g) as a black oily substance.
  • the compound (2.2 g) obtained in the above step 7 was dissolved in tetrahydrofuran (100 mL).
  • the reaction mixture was cooled to ⁇ 78 ° C., lithium diisopropylamide (9.9 mL) was added under a nitrogen atmosphere, and the mixture was stirred for 30 min.
  • a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (5.0 g) in tetrahydrofuran (30 mL) was added in one portion, and the mixture was stirred at -78 ° C. for 2 hours.
  • a saturated aqueous ammonium solution was poured into the reaction solution, and the organic layer was extracted with ethyl acetate.
  • Example 2 [3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -5-methoxy-phenyl] methanol [Step 1] tert-Butyl N-[(6R) -2- [3- (hydroxymethyl) -5-methoxy-phenyl] -3- (p-tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [ e] Indol-6-yl] carbamate; tert-butyl N-[(6S) -2- [3- (hydroxymethyl) -5-methoxy-phenyl] -3- (p-tolylsulfonyl) -7,8- Dihydro-6H-cyclopenta [e] indol-6-yl] carbamate
  • IPA isopropyl alcohol
  • Step 3 [3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -5-methoxy-phenyl] methanol
  • Example 1 Compound (300 mg) obtained in Step 8 and methyl 3-cyano-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate (256 mg) was used to give the title compound (260 mg) as a white solid in the same manner as in Example 1, Step 9.
  • Example 4 2- [4- (Methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-butyl ⁇ 3-[(4-methylphenyl) sulfonyl] -2- [4- (methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6- Il ⁇ Carbamate
  • Example 1 Step 8 Using the compound (150 mg) obtained in Example 1 Step 8 and (4-methylsulfonylphenyl) boronic acid (89 mg), the title compound (150 mg) was obtained as a white solid by the same method as Example 1 Step 9. .
  • Example 5 [3-[(6R) -6-Amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -5-fluoro-phenyl] ethane-1,2- Diol [Step 1] Ethyl 3- ⁇ 6-[(tert-butoxycarbonyl) amino] -3-[(4-methylphenyl) sulfonyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-2- Il ⁇ -5-fluorobenzoate
  • Example 1 Compound obtained in Step 8 (350 mg), water (2.7 mL) and 3-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) The title compound (360 mg) was obtained as a yellow solid in the same manner as in Example 1, Step 9 using methyl benzoate (233 mg).
  • Step 2 The compound obtained in Step 2 (192 mg) was dissolved in dichloromethane (30 mL), and desmartin periodinane (295 mg) and sodium bicarbonate (87 mg) were added at 0 ° C. After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (190 mg) as a white solid.
  • Methyltriphenylphosphonium bromide 160 mg was dissolved in tetrahydrofuran (30 mL), n-butyllithium (1.6 mol / l in hexane, 0.30 mL, 0.4848 mmol) was added at room temperature, and the mixture was stirred for 1 hour.
  • n-butyllithium 1.6 mol / l in hexane, 0.30 mL, 0.4848 mmol
  • To the reaction solution was added a tetrahydrofuran solution (5 mL) of the compound (190 mg) obtained in Step 3 above, and the mixture was stirred at room temperature for 12 hours.
  • the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (190 mg) as a white solid.
  • Step 4 The compound obtained in Step 4 (190 mg) was dissolved in 1,4-dioxane (30 mL) and water (1 mL), and osmium tetroxide (2.5 wt.% Tert-butanol solution, 0.070 mL), 4-methylmorpholine. N-oxide (61 mg) was added, and the mixture was stirred at room temperature for 4 hours. Water was poured into the reaction solution, and the organic layer was extracted with ethyl acetate and washed with brine. After drying with sodium sulfate, the solvent was distilled off under reduced pressure.
  • Example 6 [5-[(6S) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -2-methylsulfonyl-phenyl] methanol [Step 1] Methyl 5- ⁇ (6R) -6-[(tert-butoxycarbonyl) amino] -3-[(4-methylphenyl) sulfonyl] -3,6,7,8-tetrahydrocyclopenta [e] Indol-2-yl ⁇ -2- (methylsulfonyl) benzoate
  • Example 10 Compound (770 mg) obtained by the method of Example 10 steps 1 to 5 and 2-methylsulfonyl-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) The title compound (1.0 g) was obtained as a white solid in the same manner as in Example 1, Step 9 using methyl benzoate (0.67 g).
  • Example 10 Compound (2.5 g) obtained by the method of Example 10 steps 1 to 5 and 2- (3-chloro-5-vinyl-phenyl) -4,4,5,5-tetramethyl-1,3,2 The title compound (250 mg) was obtained as a white solid in the same manner as in Example 1, Step 9 using -dioxaborolane (1.00 g).
  • the compound (130 mg) obtained in the above step 1 was dissolved in tert-butyl alcohol (10 mL), AD-mix beta (1.0 g) was added, water (2 mL) was added, and the mixture was stirred at room temperature for 6 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 obtained residue was purified by diol silica gel chromatography [hexane / ethyl acetate] to give the title compound (80 mg) as a white solid.
  • Example 8 2- (6-Methoxypyrimidin-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-Butyl N- [2- (2-methoxypyrimidin-5-yl) -3- (p-toluylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] indol-6-yl] Carbamate
  • Example 1 Using the compound obtained in Step 8 (250 mg) and 6-ethoxypyrazine-2-boronic acid pinacol ester (148 mg) in the same manner as Example 1 Step 9, the title compound (87 mg) was converted to a yellow solid. Obtained.
  • Optical resolution of the compound (67.3 g) obtained in the above Step 3 was performed using column chromatography (Daicel Chiralcel OJ-H, methanol 100%). After collecting the first peak eluting first, the solvent was distilled off under reduced pressure, and tert-butyl N-[(6S) -3- (p-tolylsulfonyl) -7,8-dihydro-6H-cyclopenta [e] Indol-6-yl] carbamate (14.6 g, optical purity> 98% ee) was obtained as a white solid.
  • Example 11 Using the compound (267 g) obtained in Step 3 of Example 11, the title compound (154 g; containing about 15% of (6R) -isomer) was obtained as a white solid by the same procedure as in Step 10 of Example 10. .
  • Step 2 tert-Butyl [(2-nitrophenyl) sulfonyl] [(6R) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
  • Optical resolution of the compound (383 g) obtained in Step 3 above was performed using column chromatography (Daicel Chiralcel OJ-H, methanol 100%). After collecting the first peak eluting first, the solvent was distilled off under reduced pressure, and tert-butyl N-[(6S) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] Indol-6-yl] carbamate (46.9 g, optical purity> 98% ee) was obtained as a white solid.
  • Example 16 (6R) -2- (3-Methylpyridin-4-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-butyl [(6R) -2- (3-methylpyridin-4-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6- IL] Carbamate
  • Example 14 Using the compound (200 mg) obtained in Step 1 and 3-picoline-4-boronic acid (83.6 mg) in the same manner as in Example 1, Step 9, the title compound (117 mg) was obtained as a pale yellow oil. Obtained.
  • 1 H-NMR (CDCl 3 ) ⁇ ppm: 8.51 (1H, s), 8.48-8.46 (1H, m), 8.19-8.15 (1H, m), 7.51-7.44 (3H, m), 7.37-7.30 (3H, m), 7.06-6.99 (1H, m), 6.46 (1H, s), 5.31-5.22 (1H, m), 4.78-4.72 (1H, m), 3.09-3.00 (1H, m), 2.94-2.83 ( 1H, m), 2.70-2.60 (1H, m), 2.22 (3H, d, J 19.5Hz), 1.92-1.82 (1H, m), 1.48 (9H, s).
  • Example 13 Using the compound obtained in Step 5 of Step (240 mg) and (6-chloropyrazin-2-yl) methanol (98.9 mg) in the same manner as in Step 11 of Example 11, the title compound (190 mg) was obtained as a white solid. Got as.
  • Example 13 Using the compound (240m) obtained in Step 5 and 2-chloro-6-methylpyrazine (88.0 mg), the title compound (170 mg) was obtained as a white solid in the same manner as in Step 11 of Example 11. .
  • Example 13 Using the compound (250 mg) obtained in Step 5 and 2-chloro-3-methylpyrazine (91.6 mg), the title compound (190 mg) was obtained as a white solid in the same manner as in Example 11, Step 8. .
  • Example 20 [3-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl] methanol [Step 1] tert-butyl N-[(6R) -3- (benzenesulfonyl) -2- [3- (hydroxymethyl) pyrazin-2-yl] -7,8-dihydro-6H-cyclopenta [e] indole -6-yl] carbamate
  • Example 21 (6R) -2- (3-Fluoropyridin-4-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-butyl [(6R) -2- (3-fluoropyridin-4-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6- IL] Carbamate
  • Example 14 Using the compound (200 mg) obtained in Step 1 and 3-fluoro-4-pyridineboronic acid pinacol ester (136 mg), the title compound (154 mg) was prepared as a pale yellow oil in the same manner as in Example 1, Step 9. Obtained as material.
  • Example 22 (6R) -2- (2-Methylpyrimidin-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-butyl [(6R) -2- (2-methylpyrimidin-5-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6- IL] Carbamate
  • Example 14 Using the compound (200 mg) obtained in Step 1 and 2-methylpyrimidine-5-boronic acid (84.2 mg), the title compound (194 mg) was obtained as a pale yellow oily substance in the same manner as in Example 1, Step 9.
  • the title compound (194 mg) was obtained as a pale yellow oily substance in the same manner as in Example 1, Step 9.
  • Example 23 [5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl] ethanone [Step 1] tert-Butyl [(6R) -2- (5-acetylpyrazin-2-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6- IL] Carbamate
  • Example 13 Using the compound (7.0 g) obtained in Step 5 and 1- (5-chloropyrazin-2-yl) ethanone (1.7 g), the title compound (5.3 g) was prepared in the same manner as in Example 11, Step 8. ) Was obtained as a white solid.
  • Example 25 (1R) -1- ⁇ 5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl ⁇ ethanol [Step 1] tert-Butyl [(6R) -2- ⁇ 5-[(1R) -1-hydroxyethyl] pyrazin-2-yl ⁇ -3- (phenylsulfonyl) -3,6,7,8-tetrahydro Cyclopenta [e] indol-6-yl] carbamate
  • Example 23 Compound (5.80 g) obtained in Step 1 and chloro [(1R, 2R) -N- (p-toluenesulfonyl) -1,2-diphenylethanediamine] (mesitylene) ruthenium (II) (350 mg) was used to give the title compound (4.98 g) as a white solid in the same manner as in Step 10 of Example 10.
  • Example 26 ⁇ 4-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxypyrimidin-2-yl ⁇ methanol [Step 1] ⁇ 4-[(6R) -6-[(tert-butoxycarbonyl) amino] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl ] -6-Methoxypyrimidin-2-yl ⁇ methyl acetate
  • Example 13 Using the compound obtained in Step 5 (400 mg) and (4-chloro-6-methoxy-pyrimidin-2-yl) methyl acetate (247 mg) in the same manner as in Example 11, Step 8, the title compound ( 230 mg) was obtained as a yellow oil.
  • Example 28 (1R) -1- ⁇ 5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl ⁇ propane-1 -All [Step 1] tert-Butyl [(6R) -2- ⁇ 5- [methoxy (methyl) carbamoyl] pyrazin-2-yl ⁇ -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [ e] Indol-6-yl] carbamate
  • Example 13 Using the compound synthesized in Step 5 (1.11 g) and 5-chloro-N-methoxy-N-methylpyrazine-2-carboxamide (319 mg) in the same manner as Example 11 Step 8, the title compound (910 mg ) was obtained as a white solid.
  • the compound (1.0 g) obtained in the above step 1 was dissolved in tetrahydrofuran (30 mL), and an ethylmagnesium bromide tetrahydrofuran solution (1.0 M, 1.53 mL) was added dropwise at 0 ° C. in a nitrogen atmosphere. After stirring at room temperature for 30 minutes, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. After washing with brine, it was dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (149 mg) as a white solid.
  • Triethylamine (0.0945 mL) and formic acid (0.0442 mL) were stirred and chloro [(1R, 2R) -N- (2 ', 6'-dimethylbenzylsulfonyl) -1,2-diphenylethanediamine] (mesitylene) ruthenium ( II) (8.8 mg) and a dichloromethane solution (3 mL) of the compound obtained in Step 2 above (149 mg) were added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (118 mg) as a white solid.
  • Example 29 (6R) -2- ⁇ 5-[(1Z) -N-hydroxyethaneimidoyl] pyrazin-2-yl ⁇ -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-butyl [(6R) -2- ⁇ 5-[(1Z) -N-hydroxyethaneimidoyl] pyrazin-2-yl ⁇ -3- (phenylsulfonyl) -3,6,7,8 -Tetrahydrocyclopenta [e] indol-6-yl] carbamate
  • Example 23 The compound (50 mg) obtained in Step 1 was dissolved in methanol (5 mL), hydroxylamine hydrochloride (9.8 mg) and sodium acetate (12 mg) were added, and the mixture was stirred at 80 ° C. for 1 hr. Water was poured into the reaction solution, and the organic matter was extracted with ethyl acetate. After washing with brine, it was dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography [hexane / ethyl acetate] to give the title compound (28 mg) as a white solid.
  • Example 30 (6R) -2- ⁇ 5-[(Z)-(Hydroxyimino) methyl] pyrazin-2-yl ⁇ -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] Methyl 5-[(6R) -6-[(tert-butoxycarbonyl) amino] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl Pyrazine-2-carboxylate
  • Example 13 Using the compound synthesized in Step 5 (1.15 g) and methyl 5-bromopyrazine-2-carboxylate (711 mg), the title compound (890 mg) was obtained as a white solid in the same manner as in Step 11 of Example 11. It was.
  • Example 31 2- ⁇ 5-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl ⁇ ethanol [Step 1] tert-Butyl [(6R) -2- (5-ethenylpyrazin-2-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl ] Carbamate
  • Triethylamine (2 mL) and a 10% carbon palladium catalyst (0.300 g) were added to a solution of the compound obtained in Step 4 (500 mg) in tetrahydrofuran (10 mL) and methanol (10 mL), and the mixture was stirred for 30 minutes in a hydrogen atmosphere. After completion of the reaction, the solution from which the palladium catalyst had been removed by Celite filtration was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography [hexane / ethyl acetate] to obtain the title compound (410 mg) as a white solid. .
  • Example 32 (6R) -2- [5- (S-methylsulfonimidoyl) pyridin-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-butyl [(6R) -2- [5- (methylsulfinyl) pyridin-2-yl] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -6-yl] carbamate
  • Example 33 2- [5- (2-Methoxypyridin-4-yl) -1,3,4-oxadiazol-2-yl] -3,6,7,8-tetrahydrocyclopenta [e] indole- 6-amine [Step 1] Methyl 6-[(tert-butoxycarbonyl) amino] -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole-2-carboxylate
  • Example 13 Using the compound obtained in Step 5 (300 mg) and 2-bromo-N-methoxy-N-methyl-thiazole-5-carboxamide (215 mg) in the same manner as Example 11 Step 8, the title compound ( 210 mg) was obtained as a white solid.
  • Example 36 (6R) -2- (1-Methyl-1H-pyrazol-4-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-Butyl [(6R) -2- (1-methyl-1H-pyrazol-4-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -6-yl] carbamate
  • Example 14 Compound obtained in Step 1 (200 mg) and 1-methyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) -1H pyrazole (127 mg) was used to give the title compound (171 mg) as a pale-yellow oil in the same manner as in Example 1, Step 9.
  • Example 37 (6R) -2- (1,3-thiazol-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-butyl [(6R) -3- (phenylsulfonyl) -2- (1,3-thiazol-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6 -Il] Carbamate
  • Example 13 Using the compound (200 mg) obtained in Step 5 and 5-bromothiazole (93.5 mg), the title compound (141 mg) was obtained as a crude product in the same manner as in Example 11, Step 8.
  • Step 2 (6R) -3- (Phenylsulfonyl) -2- (1,3-thiazol-5-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine
  • Example 38 (1S) -1- ⁇ 2-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -1,3-thiazol-5- Il ⁇ ethanol [Step 1] tert-butyl N-[(6R) -3- (benzenesulfonyl) -2- [5-[(1S) -1-hydroxyethyl] thiazol-2-yl] -7,8-dihydro-6H -Cyclopenta [e] indol-6-yl] carbamate
  • Example 39 (1R) -1- ⁇ 2-[(6R) -6-amino-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -1,3-thiazol-5- Il ⁇ ethanol [Step 1] tert-Butyl [(6R) -2- ⁇ 5-[(1R) -1-hydroxyethyl] -1,3-thiazol-2-yl ⁇ -3- (phenylsulfonyl) -3,6, 7,8-Tetrahydrocyclopenta [e] indol-6-yl] carbamate
  • Example 35 Compound (230 mg) obtained in Step 2 and chloro [(1R, 2R) -N- (p-toluenesulfonyl) -1,2-diphenylethanediamine] (mesitylene) ruthenium (II) (13.3 mg) was used to give the title compound (200 mg) as a white solid in the same manner as in Step 1 of Example 10.
  • Example 40 (6R) -2- (5-Methyl-1,3,4-thiadiazol-2-yl) -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] tert-butyl [(6R) -2- (5-methyl-1,3,4-thiadiazol-2-yl) -3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] Indol-6-yl] carbamate
  • Example 13 Using the compound obtained in Step 5 of Step (3.00 g) and 2-bromo-5-methyl-1,3,4-thiadiazole (1.15 g) in the same manner as in Step 11 of Example 11, the title compound (1.12 g) was obtained as a pale yellow solid.
  • Example 14 Using the compound obtained in Step 1 of Step 1 (250 mg) and N-methyl-1H-pyridone-2-one-5-boronic acid pinacol ester (239 mg) in the same manner as in Step 1 of Example 1, the title compound (160 mg) was obtained as a colorless oil.
  • Example 42 (6R * , 7S * )-7-Fluoro-2- [4- (methylsulfonyl) phenyl] -3,6,7,8-tetrahydrocyclopenta [e] indole-6-amine [Step 1] 7-Fluoro-3-[(4-methylphenyl) sulfonyl] -7,8-dihydrocyclopenta [e] indole-6 (3H) -one
  • Example 1 1-fluoro-4-hydroxy-1,4-diazoniabicyclo [2,2,2] octanebis (tetrafluoroborate) (1.09 g) in a methanol (30.7 mL) solution of the compound obtained in Step 4 And stirred at 80 ° C. for 5 hours. 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 (280 mg) as a white solid.
  • Example 42 Using the compound (600 mg) obtained in Step 3 and (2-methoxymyrimidin-5-yl) boronic acid (283 mg), the title compound (450 mg) was prepared in the same manner as in Example 1, Step 9. Obtained as a white solid.
  • Step 7 tert-butyl [(6S, 7R) -7-fluoro-2- [2- (hydroxymethyl) -6-methoxypyridin-4-yl] -3- (phenylsulfonyl) -3,6,7 , 8-tetrahydrocyclopenta [e] indol-6-yl] carbamate; tert-butyl [(6R, 7S) -7-fluoro-2- [2- (hydroxymethyl) -6-methoxypyridin-4-yl] -3- (Phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-6-yl] carbamate
  • Example 45 ⁇ 4-[(6R, 7S) -6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxypyridin-2-yl ⁇ methanol [Step 1] ⁇ 4-[(6R, 7S) -6-amino-7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl]- 6-Methoxypyridin-2-yl ⁇ methanol
  • Example 46 ⁇ 5-[(6R * , 7S * )-6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazin-2-yl ⁇ methanol [Step 1] tert-Butyl [(6R * , 7S * )-7-fluoro-3- (phenylsulfonyl) -2- (tributylstannanyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -6-yl] carbamate
  • Example 44 Using the compound (1.10 g) obtained in Step 3 of Example 44 and the procedure of Example 11 Step 7, the title compound (1.20 g) was obtained as a colorless oil.
  • Example 48 (1S) -1- ⁇ 5-[(6S, 7R) -6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] pyrazine-2 -Il ⁇ ethanol [Step 1] tert-Butyl [(6S, 7R) -7-fluoro-2- ⁇ 5-[(1S) -1-hydroxyethyl] pyrazin-2-yl ⁇ -3- (phenylsulfonyl) -3,6 , 7,8-Tetrahydrocyclopenta [e] indol-6-yl] carbamate
  • Example 47 Compound (250 mg) obtained in Step 3 and chloro [(1S, 2S) -N- (2 ', 6'-dimethylbenzenesulfonyl) -1,2-diphenylethanediamine] (mesitylene) ruthenium (II ) (0.0150 g) to give the title compound (245 mg) as a crude product by the same procedure as in Example 28, step 3.
  • [Step 2] (1S) -1- ⁇ 5-[(6S, 7R) -6-amino-7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e] indole -2-yl] pyrazin-2-yl ⁇ ethanol
  • Example 50 ⁇ 4-[(6S, 7R) -6-amino-7-fluoro-3,6,7,8-tetrahydrocyclopenta [e] indol-2-yl] -6-methoxypyrimidin-2-yl ⁇ methanol [Step 1] ⁇ 4-[(6S, 7R) -6-[(tert-butoxycarbonyl) amino] -7-fluoro-3- (phenylsulfonyl) -3,6,7,8-tetrahydrocyclopenta [e ] Indol-2-yl] -6-methoxypyrimidin-2-yl ⁇ methyl acetate
  • Example 2 The compound of Example 25 (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.
  • the ASIC inhibitory activity was evaluated by contacting the cells with the compound and measuring the peak change of the acid-induced current using the 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 (mM) 50 CsCl, 60 CsF, 10 NaCl, 20 EGTA, and 10 HEPES, pH 7.2.
  • 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).
  • the ENaC inhibitory activity was evaluated by contacting the cells with the compound and measuring the peak change in current using the whole cell automatic patch clamp method (Syncropatch384PE, Nanion Technologies GmBH). The holding potential was -60 mV.
  • the composition of the inner liquid and the outer liquid is described below.
  • Nonstandard solution 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 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.
  • Evaluation Example 3 Confirmation of Oral Absorption
  • the 3,6,7,8-tetrahydrocyclopenta [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

La présente invention aborde le problème de la fourniture d'un inhibiteur de canal ionique de détection d'acide pouvant être administré par voie orale. La solution selon la présente invention porte sur un composé représenté par la formule (I), ou un sel pharmaceutiquement acceptable de celui-ci : (dans laquelle R est un atome d'hydrogène ou un atome d'halogène; et, dans la formule (II), R1 et R2 sont des groupes aromatiques substitués, et R1 et R2 représentent chacun indépendamment des groupes choisis dans le groupe constitué par des atomes d'hydrogène, un groupe alkyle, un groupe alcoxy, un groupe hydroxyalkyle, un groupe dihydroxyalkyle, un groupe halogénoalkyle, un groupe alkyle cycloalkyl(hydroxy) en C1 à C6, un groupe alkylsulfonyle, un groupe (N-hydroxyimino)alkyl, un atome d'halogène, un groupe cyano et un groupe acyle).
PCT/JP2018/005361 2017-02-17 2018-02-16 COMPOSÉ 3,6,7,8-TÉTRAHYDROCYCLOPENTA[e]INDOLE WO2018151240A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08508251A (ja) * 1993-03-25 1996-09-03 ジ・アップジョン・カンパニー ドーパミン作働性活性を有するインドールテトラリン類
JP2003507366A (ja) * 1999-08-11 2003-02-25 バーナリス リサーチ リミテッド 縮合インドール誘導体および５ｈｔ、特に５ｈｔ２ｃのレセプターリガンドとしてのこれらの使用
WO2009042092A1 (fr) * 2007-09-25 2009-04-02 Merck & Co., Inc. Dérivés d'indole 2-aryle ou hétéroaryle
JP2009516712A (ja) * 2005-11-23 2009-04-23 ペインセプター ファーマ コーポレーション 依存性イオンチャネルを調節するための組成物および方法
JP2009520700A (ja) * 2005-12-21 2009-05-28 ペインセプター ファーマ コーポレーション 依存性イオンチャネルを調節するための組成物および方法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH08508251A (ja) * 1993-03-25 1996-09-03 ジ・アップジョン・カンパニー ドーパミン作働性活性を有するインドールテトラリン類
JP2003507366A (ja) * 1999-08-11 2003-02-25 バーナリス リサーチ リミテッド 縮合インドール誘導体および５ｈｔ、特に５ｈｔ２ｃのレセプターリガンドとしてのこれらの使用
JP2009516712A (ja) * 2005-11-23 2009-04-23 ペインセプター ファーマ コーポレーション 依存性イオンチャネルを調節するための組成物および方法
JP2009520700A (ja) * 2005-12-21 2009-05-28 ペインセプター ファーマ コーポレーション 依存性イオンチャネルを調節するための組成物および方法
WO2009042092A1 (fr) * 2007-09-25 2009-04-02 Merck & Co., Inc. Dérivés d'indole 2-aryle ou hétéroaryle

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Title
KUDUK, S. D. ET AL.: "Amidine derived inhibitors of acid-sensing ion channel-3", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 19, August 2009 (2009-08-01), pages 4059 - 4063, XP029120848 *

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