WO2021079962A1 - Pharmaceutical composition for prevention and/or treatment of hearing loss - Google Patents

Pharmaceutical composition for prevention and/or treatment of hearing loss Download PDF

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WO2021079962A1
WO2021079962A1 PCT/JP2020/039813 JP2020039813W WO2021079962A1 WO 2021079962 A1 WO2021079962 A1 WO 2021079962A1 JP 2020039813 W JP2020039813 W JP 2020039813W WO 2021079962 A1 WO2021079962 A1 WO 2021079962A1
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compound
methoxy
amino
pyridin
methanone
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PCT/JP2020/039813
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French (fr)
Japanese (ja)
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龍 永田
日比野　浩
晴志朗 澤村
書晃 任
森　泰生
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国立大学法人大阪大学
国立大学法人京都大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals

Definitions

  • the present invention relates to a pharmaceutical composition for the prevention and / or treatment of deafness.
  • Hearing consists of a series of extrasensory perception systems consisting of the outer ear-middle ear-inner ear cochlea-cranial nerve system.
  • the sound which is the vibration of air, shakes the eardrum through the ear canal and is mechanically amplified by the middle ear bone to reach the inner ear cochlea.
  • the mechanical signal of sound vibration is converted into an electrical signal by hair cells, which are sensory cells, and information is finally transmitted to the auditory cortex of the brain via nerve transmission. Impairment of the components of this pathway causes diminished perception of sound, or deafness.
  • Deafness is classified into conductive hearing loss due to disorders of the inner and outer ear transmission systems and sensorineural hearing loss due to disorders of the cochlea of the inner ear to the cranial nerve system. Deafness is caused not only by exposure to strong sounds, inheritance, aging, etc., but also by side effects of anticancer drugs, especially platinum preparations (cisplatin, carboplatin, nedaplatin, oxaliplatin, etc.), side effects of antibiotics, etc. Is also triggered. Cisplatin (CDDP; cis-diaminedichloroplatinum (II)) is used in the treatment of cancer, especially childhood cancer, but its side effects are known to cause deafness.
  • CDDP cis-diaminedichloroplatinum (II)
  • drugs such as steroid hormones, vitamin B12, ATP, and vasodilators are used as treatments for deafness, but there is not enough evidence for their effects and it is still controversial. Therefore, the development of effective therapeutic agents is awaited.
  • TRP Transient receptor potential gene
  • the TRP (Transient receptor potential) gene was identified in 1989 as the causative gene of the Drosophila photoreceptor response mutant strain. Subsequent studies have found many proteins homologous to the protein encoded by the TRP gene in mammals, which basically function as cation channels in the cell membrane. TRP channels form a superfamily with enormous functional diversity and fall into groups such as TRPA, TRPV, TRPM and TRPC.
  • TRPC TRP classic or TRP canonical
  • TRPC3-deficient mice are resistant to pressure-load-induced cardiac fibrosis, and that administration of the TRPC3 channel inhibitor Pyr3 strongly suppresses pressure-load-induced cardiac fibrosis in mice.
  • Non-Patent Documents 1 and 2 TRPC6-deficient mice showed resistance to bleomycin-induced pulmonary fibrosis and renal interstitial fibrosis due to unilateral ureteral obstruction (Non-Patent Documents 3 and 4), and Pyr2 (BTP2), which is an inhibitor of TRPC3 and TRPC6 channels.
  • BTP2 Pyr2 Suppresses renal interstitial fibrosis due to unilateral ureteral obstruction in mice.
  • Non-Patent Documents 5 to 11 disclose compounds exhibiting TRPC3 inhibitory action and / or TRPC6 inhibitory action.
  • US2019 / 0169168 Patent Document 1 describes a compound showing an action of inhibiting TRPC6 channel
  • Patent Document 2 describes a compound showing an action of inhibiting TRPC3 channel and TRPC6 channel. ing.
  • TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis. Sci. Rep. 6, 39383; doi: 10.1038 / srep39383 (2016). Kitajima, N. et al. TRPC3 positively regulates reactive oxygen species driving maladaptive cardiac remodeling. Sci. Rep. 6, 37001 (2016). Y.-L. Wu et al., Inhibition of TRPC6 channels ameriorates renal fibrosis and contributions to renal protection by soluble klotho ,, Kidney Int. 2017 Apr; 91 (4): 830-841. K.
  • the subject is to provide a pharmaceutical composition for the prevention and / or treatment of deafness.
  • TRPC3 / 6 channel inhibitor
  • TRPC3 the compound represented by the general formula (1), the compound represented by (2), Pyr2, Pyr3, Pyr4, GSK2332255B, GSK2833503A, SAR7334, BI, which will be described later.
  • A is a optionally substituted benzene ring.
  • B is an aryl that may be substituted or a heteroaryl that may be substituted.
  • X is an oxygen atom or a sulfur atom.
  • Y is a nitrogen atom or a carbon atom.
  • R 1 is either independently of one another are lower alkyl, two of R 1 are bonded to each other, may form a spiro ring or a crosslinked structure, or two of R 1 are bonded to each other, A saturated condensed heterocycle may be formed together with carbon atoms and nitrogen atoms constituting a ring containing Y.
  • p is 0, 1, or 2.
  • (R 1 ) p is oxo.
  • a pharmaceutical composition for preventing and / or treating deafness which comprises a compound represented by, a salt thereof, or a prodrug thereof.
  • Item 2 The pharmaceutical composition according to Item 1, wherein in the general formula (1), B is a optionally substituted monocyclic aryl or a optionally substituted monocyclic or bicyclic nitrogen-containing heteroaryl.
  • A is the following A-1) to A-16): A-1) Halogen, A-2) Hydroxyl group, A-3) Nitro, A-4) Cyano, A-5) Carboxyl, A-6) Amino, which may be substituted, A-7) Cyclic amino, which may be substituted, A-8) Lower alkyl, which may be substituted, A-9) Substituted lower alkoxy, A-10) Lower alkoxycarbonyl, A-11) Lower alkyl sulfonyl, A-12) Carbamoyl, which may be substituted with a lower alkyl or lower alkyl sulfonyl, A-13) Cyclic aminocarbonyl, which may be substituted, A-14) Sulfamoyl, which may be substituted with a lower alkyl, Item 1 or 2, wherein A-15) a cyclic aminosulfonyl optionally substituted, and A-16) a benzene ring optionally substituted with
  • B is a monocyclic aryl or a monocyclic or bicyclic heteroaryl, and the monocyclic aryl is at least one selected from the group consisting of the following B-1) to B-16). It may be substituted with a species group, and the monocyclic or bicyclic heteroaryl may be substituted with at least one group selected from the group consisting of B-1) to B-17) below.
  • Item 3. The pharmaceutical composition according to any one of Items 1 to 3.
  • Item 5 The pharmaceutical composition according to any one of Items 1 to 4, wherein in the general formula (1), the 4-position of the benzoisoxazole or benzoisothiazole skeleton is substituted.
  • Item 6 is a substituted pyridyl or a substituted phenyl in which the carbon atom at least in the ortho position is substituted with respect to the carbon atom on the pyridine or benzene ring bonded to Y.
  • Item 8 The pharmaceutical composition according to any one of Items 1 to 3.
  • A is a benzene ring optionally substituted with at least one group selected from the group consisting of halogens, lower alkoxys, and lower alkyls optionally substituted with halogens.
  • B is pyridyl or phenyl, respectively, B-1), B-5), B-8), B-10), B-12), and B-13): B-1) Halogen, B-5) Carboxylyl, B-8) Substituted lower alkyl, B-10) Lower alkoxycarbonyl, B-12) Carbamoyl, which may be substituted with a lower alkyl or lower alkylsulfonyl, and B-13) Cyclic aminocarbonyl, which may be substituted.
  • R 1 is each other or are independently C1 ⁇ C3 alkyl, or two of R 1 are bonded to each other, a methylene group, dimethylene or trimethylene, Alternatively, (R 1 ) p is oxo, Item 8.
  • the pharmaceutical composition according to any one of Items 1 to 4.
  • Z is a nitrogen atom or CH.
  • Y is a nitrogen atom or a carbon atom.
  • R 11 is, independently of one another are methyl or ethyl, or two R 11 are bonded to each other methylene, may form a crosslinked structure by dimethylene or trimethylene.
  • p is 0, 1, or 2.
  • (R 11 ) p is oxo.
  • R 21 , R 22 , and R 23 are independent of each other and are hydrogen atoms, halogens, carbamoyls, or trifluoromethyls.
  • R 31 , R 32 , and R 33 are independent of each other, lower alkyl, methyl, carboxyl, lower alkoxycarbonyl, monomethylaminocarbonyl, or dimethylaminocarbonyl substituted with hydrogen atom, halogen, halogen.
  • R 21 is a chlorine atom or trifluoromethyl
  • R 22 and R 23 are hydrogen atoms
  • R 31 is a chlorine atom
  • R 32 is a hydrogen atom
  • R 33 is a hydrogen atom, carboxyl, or lower alkoxycarbonyl
  • Item 8 The pharmaceutical composition according to Item 8.
  • the compounds are Compound 011, Compound 021, Compound 031, Compound 041, Compound 061, Compound 071, Compound 081, Compound 091, Compound 101, Compound 111, Compound 121, Compound 131, Compound 141, Compound 151, Compound 161 and Compound 171. , Compound 191 and Compound 221 and Compound 281.
  • the pharmaceutical composition according to any one of.
  • A is a optionally substituted benzene ring.
  • B is an aryl that may be substituted or a heteroaryl that may be substituted.
  • Y is a nitrogen atom or a carbon atom.
  • R 1 is either independently of one another are lower alkyl, two of R 1 are bonded to each other, may form a spiro ring or a crosslinked structure, or two of R 1 are bonded to each other, A saturated condensed heterocycle may be formed together with carbon atoms and nitrogen atoms constituting a ring containing Y.
  • p is 0, 1, or 2.
  • (R 1 ) p is oxo.
  • a pharmaceutical composition for preventing and / or treating deafness which comprises a compound represented by, a salt thereof, or a prodrug thereof.
  • a pharmaceutical composition for preventing and / or treating deafness containing a substance having an inhibitory activity on at least one TRPC channel selected from the group consisting of TRPC3 channel and TRPC6 channel, a salt thereof, or a prodrug thereof.
  • a substance having an inhibitory activity on at least one TRPC channel selected from the group consisting of TRPC3 channel and TRPC6 channel is a compound represented by the general formula (1), a compound represented by the general formula (2), Pyr2, Pyr3. , Pyr4, GSK2332255B, GSK2833503A, SAR7334, BI-749327, compounds AA01-AA95 listed below, and at least one compound selected from the group consisting of compounds BB01-BB32 listed below, Item 12.
  • Item 14 The pharmaceutical composition according to any one of Items 1 to 13, which is for oral administration.
  • Item 15 The pharmaceutical composition according to any one of Items 1 to 14, wherein the deafness is sensorineural deafness.
  • Item 16 The pharmaceutical composition according to any one of Items 1 to 15, wherein the deafness is caused by a drug.
  • the pharmaceutical composition disclosed in the present invention is a substance having an inhibitory activity on at least one TRPC channel selected from the group consisting of TRPC3 channel and TRPC6 channel (for example, a compound represented by the general formula (1), a general formula. Compounds represented by (2), Pyr2, Pyr3, Pyr4, GSK2332255B, GSK2833503A, SAR7334, BI-749327, compounds disclosed in US2019 / 0169168, compounds disclosed in WO2019 / 215268, etc.), their salts, or them. It has a preventive or therapeutic effect on deafness by containing the prodrug of.
  • TRPC3 / 6 channel inhibitors such as compounds represented by the general formula (1) or (2), have the activity of inhibiting the activity of TRPC channels, such as TRPC3 and / or TRPC6 channels, preferably TRPC6 channels. Therefore, TRPC-related diseases, such as those caused by the activity of the TRPC3 channel, those caused by the activity of the TRPC6 channel, or those caused by both the activity of the TRPC3 channel and the activity of the TRPC6 channel (collectively referred to herein). It is sometimes referred to as "TRPC3 and / or TRPC6-related disease"), and is particularly useful for the prevention and / or treatment of hearing loss.
  • FIG. 1 is a graph showing the measurement results of changes in calcium ion concentration in TRPC6-expressing cells obtained in Test Example 1.
  • the horizontal axis is time (seconds), and the vertical axis is intracellular calcium ion concentration ([Ca 2+ ] i (nM)).
  • FIG. 2 is a graph showing the measurement results of changes in calcium ion concentration in TRPC3-expressing cells obtained in Test Example 1.
  • the horizontal axis is time (seconds), and the vertical axis is intracellular calcium ion concentration ([Ca 2+ ] i (nM)).
  • FIG. 3 is a graph showing the amount of increase in calcium ions in TRPC6-expressing cells obtained in Test Example 2.
  • the unit of the vertical axis is "%".
  • FIG. 4 is a graph showing the amount of increase in calcium ions in TRPC6-expressing cells obtained in Test Example 3.
  • the unit of the vertical axis is "%".
  • FIG. 5 is a graph showing the electrophysiological evaluation of TRPC6-expressing cells obtained in Test Example 4.
  • the vertical axis of the graph on the left is current (nA) and the horizontal axis is time (seconds).
  • a and b in the graph on the right side indicate current-voltage characteristic curves at the time points of a and b in the graph on the left side, respectively.
  • FIG. 6 is a photograph showing the results of Western blotting of Test Example 5.
  • FIG. 7 is a graph showing ⁇ -SMA expression by immunofluorescent staining method obtained using skin fibroblasts in Test Example 6.
  • FIG. 8 is a graph showing ⁇ -SMA expression by immunofluorescence staining method obtained using cardiac fibroblasts in Test Example 6. The vertical axis of the graph is the fluorescence intensity (/ pixel).
  • FIG. 9 is a graph showing the auditory threshold measured in Test Example 7.
  • FIG. 10 is a graph showing the fluctuation amount (dB) of the auditory threshold value at each wavelength (Hz) measured in Test Example 7.
  • FIG. 11 is a graph showing the plasma platinum concentration (ng / ml) measured in Test Example 8.
  • FIG. 12 is a graph showing the number of zebrafish neuromasts measured in Test Example 9.
  • One embodiment of the present invention is a pharmaceutical composition for preventing and / or treating deafness containing a compound represented by the following general formula (1), a salt thereof, or a prodrug thereof.
  • A is a optionally substituted benzene ring.
  • B is an aryl that may be substituted or a heteroaryl that may be substituted.
  • X is an oxygen atom or a sulfur atom.
  • Y is a nitrogen atom or a carbon atom.
  • R 1 is either independently of one another are lower alkyl, two of R 1 are bonded to each other, may form a spiro ring or a crosslinked structure, or two of R 1 are bonded to each other, A saturated condensed heterocycle may be formed together with carbon atoms and nitrogen atoms constituting a ring containing Y.
  • p is 0, 1, or 2.
  • (R 1 ) p is oxo. ]
  • the substituent of the "optionally substituted benzene ring” includes, for example, halogen; hydroxyl group; nitro; cyano; carboxyl; optionally substituted amino; optionally substituted cyclic amino; substituted.
  • Lower alkyl may be; lower alkoxy optionally substituted; lower alkoxycarbonyl; lower alkylsulfonyl; carboxamide optionally substituted with lower alkyl or lower alkylsulfonyl; cyclic aminocarbonyl optionally substituted; lower Sulfamoyl which may be substituted with alkyl; cyclic aminosulfonyl which may be substituted; tetrazolyl and the like can be mentioned.
  • the substituent may be one kind alone or two or more kinds.
  • examples of the "aryl” include monocyclic or bicyclic aryl, and specific examples thereof include phenyl and naphthyl.
  • the aryl in the "optionally substituted aryl" is as defined above.
  • Substituents of the optionally substituted aryl include, for example, halogen; hydroxyl group; nitro; cyano; carboxyl; optionally substituted amino; optionally substituted cyclic amino; optionally substituted lower alkyl; Lower alkoxy optionally substituted; Lower alkoxycarbonyl; Lower alkylsulfonyl; Carbamoyl optionally substituted with lower alkyl or lower alkylsulfonyl; Cyclic aminocarbonyl optionally substituted; optionally substituted with lower alkyl Good sulfamoyl; optionally substituted cyclic aminosulfonyl; tetrazolyl; oxo and the like.
  • the substituent may be one kind alone or two or more kinds.
  • heteroaryl examples include monocyclic or bicyclic nitrogen-containing heteroaryls, and specifically, one or more (for example, 1 to 3, 1 or 2, 1).
  • the nitrogen atom of the above is contained on the ring, and one or more sulfur atoms or oxygen atoms (for example, 1 to 3, 1 or 2, 1) may be contained as other heteroatoms, monocyclic or bicyclic.
  • Nitrogen-containing heteroaryl examples include monocyclic or bicyclic nitrogen-containing heteroaryls, and specifically, one or more (for example, 1 to 3, 1 or 2, 1).
  • the nitrogen atom of the above is contained on the ring, and one or more sulfur atoms or oxygen atoms (for example, 1 to 3, 1 or 2, 1) may be contained as other heteroatoms, monocyclic or bicyclic. Nitrogen-containing heteroaryl.
  • heteroaryls include pyrrolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, frill, thienyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, frazayl, oxadiazolyl, thiadiazolyl, indrill, isoindrill Isobenzofuranyl, benzothienyl, isobenzothienyl, indazolyl, quinolyl, isoquinolyl, prynyl, phthalazinyl, pteridyl, naphthyldinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, benzoflazan
  • the heteroaryl in the "optionally substituted heteroaryl” is as defined above.
  • substituent of the heteroaryl which may be substituted include halogen; hydroxyl group; nitro; cyano; carboxyl; amino which may be substituted; cyclic amino which may be substituted; lower alkyl which may be substituted.
  • Lower alkoxy optionally substituted Lower alkoxycarbonyl; Lower alkylsulfonyl; Carboxamide optionally substituted with lower alkyl or lower alkylsulfonyl; Cyclic aminocarbonyl optionally substituted; Substituted with lower alkyl May include sulfamoyl; optionally substituted cyclic aminosulfonyl; tetrazolyl; oxo and the like.
  • the substituent may be one kind alone or two or more kinds.
  • examples of the "lower alkyl” include C1 to C8 alkyls containing linear, branched or cyclic structures, preferably C1 to C6 alkyls, more preferably C1 to C4 alkyls. Particularly preferably, it is C1-C3 alkyl. Specifically, as linear or branched lower alkyl, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, isobutyl, t-butyl, n-pentyl, neopentyl, etc.
  • Examples thereof include n-hexyl, isohexyl, 3-methylpentyl and the like, and examples of the lower alkyl having a cyclic structure include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl and the like.
  • methyl, ethyl, 2-propyl, t-butyl, cyclopropyl and the like can be mentioned.
  • examples of the "halogen” include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like, and preferably a fluorine atom and a chlorine atom.
  • optionally substituted amino refers to optionally substituted acyclic amino
  • substituents include lower alkyl (for example, methyl, ethyl, propyl, etc.) and C1-C8 acyl (for example,). Acetyl, propionyl, etc.), aryl (eg, phenyl, etc.), or heteroaryl.
  • the substituent may be one kind alone or two or more kinds.
  • Preferred aminos that may be substituted include, for example, amino, methylamino, dimethylamino, ethylamino, diethylamino, cyclohexylamino, acetylamino, benzoylamino, phenylamino and the like.
  • the "cyclic amino” may have, for example, a nitrogen atom as a ring-constituting atom and may further contain one or more oxygen atoms (for example, 1 to 3, 1 or 2, 1) 5 It is a cyclic amino having up to 7 members, and examples thereof include pyrrolidino, piperidino, piperazino, morpholino and the like, and preferably pyrrolidino, morpholino and the like.
  • the cyclic amino in the "optionally substituted cyclic amino" is as defined above.
  • substituent of the cyclic amino include lower alkyl, lower alkoxy, amino, hydroxyl group, nitro, cyano, carboxyl, oxo and the like.
  • the cyclic amino may be substituted with at least one group selected from the group consisting of the above substituents. Examples of the number of substituents include 0, 1, 2, and 3, and preferably 0, 1, and 2.
  • the lower alkyl in the "optionally substituted lower alkyl” is as defined above.
  • lower alkyl substituents include hydroxyl groups; amino; C1-C8 alkylaminos (eg, methylamino, ethylamino, propylamino, t-butylamino, etc.); C1-C8 alkoxy (eg, methoxy, ethoxy, 1-propyl).
  • Preferred substituents are methylamino, ethylamino, dimethylamino, diethylamino, methoxy, ethoxy, 2-propyloxy, t-butoxycarbonyl, hydroxyl group, fluorine atom, chlorine atom, trichloromethyl, trifluoromethyl, trifluoromethoxy, morpholino.
  • the lower alkyl which may be substituted may be substituted with at least one group selected from the group consisting of the above substituents, and the number of substituents may be, for example, 0, 1, 2, 3 The number is preferably 0, 1, or 2.
  • lower alkyl substituted with halogen means that all hydrogen of alkyl is substituted with halogen.
  • the halogen and lower alkyl in the lower alkyl substituted with halogen are as defined above. It is preferable that the halogens that replace the alkyl are the same.
  • trichloromethyl or trifluoromethyl is preferable, and trifluoromethyl is preferable.
  • examples of the "lower alkoxy” include C1 to C8 alkoxys containing linear, branched or cyclic structures, preferably C1 to C6 alkoxys, more preferably C1 to C4 alkoxys. Particularly preferably, it is C1 to C3 alkoxy.
  • linear or branched alkoxy methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, isobutoxy, t-butoxy, n-pentyloxy, neopentyl Examples thereof include oxy, n-hexyloxy, isohexyloxy and 3-methylpentyloxy.
  • alkoxy containing a cyclic structure examples include cyclopropoxy, cyclopropylmethoxy, cyclobutyloxy, cyclobutylmethoxy, cyclopentyloxy, cyclopentylmethoxy, cyclohexyloxy, cyclohexylmethoxy, cyclohexylethoxy and the like.
  • methoxy, ethoxy, 2-propoxy, t-butoxy, cyclopropoxy and the like can be mentioned.
  • the lower alkoxy in the "optionally substituted lower alkoxy” is as defined above.
  • substituent of the lower alkoxy include hydroxyl groups; amino; C1-C8 alkylaminos (eg, methylamino, ethylamino, propylamino, t-butylamino, etc.); C1-C8 alkoxys (eg, methoxy, ethoxy, 1-propyl).
  • Preferred substituents include methylamino, ethylamino, dimethylamino, diethylamino, methoxy, ethoxy, 2-propyloxy, t-butoxycarbonyl, hydroxyl group, fluorine atom, chlorine atom, trifluoro, morpholino, piperidino, pyrrolidino, carboxyl, Examples thereof include methoxycarbonyl, morpholinocarbonyl, phenyl and pyridyl.
  • the lower alkoxy which may be substituted may be substituted with at least one group selected from the group consisting of the above substituents, and the number of substituents may be, for example, 0, 1, 2, 3 The number is 0, preferably 0, 1, or 2.
  • the lower alkoxy in the "lower alkoxycarbonyl” is as defined above.
  • the lower alkoxycarbonyl is a group in which the above-mentioned lower alkoxy is bonded to the carbonyl.
  • Examples of the lower alkoxycarbonyl include C1 to C8 alkoxycarbonyl containing a linear, branched or cyclic structure.
  • the linear or branched alkoxycarbonyls include methoxycarbonyl, ethoxycarbonyl, 1-propoxycarbonyl, 2-propoxycarbonyl, 1-butoxycarbonyl, 2-butoxycarbonyl, isobutoxycarbonyl, t-. Butoxycarbonyl and the like can be mentioned.
  • Examples of the C1 to C8 alkoxycarbonyl containing a cyclic structure include cyclopropoxycarbonyl, cyclopropylmethoxycarbonyl, cyclobutyloxycarbonyl, cyclobutylmethoxycarbonyl, cyclopentyroxycarbonyl, cyclopentylmethoxycarbonyl, cyclohexyloxycarbonyl, cyclohexylmethoxycarbonyl and cyclohexylethoxy.
  • Examples include carbonyl.
  • Preferred lower alkoxycarbonyls include methoxycarbonyl, ethoxycarbonyl, 2-propoxycarbonyl, cyclopropoxycarbonyl and the like.
  • the lower alkyl in the "lower alkyl sulfonyl” is as defined above.
  • the lower alkyl sulfonyl is a group in which the above lower alkyl is bonded to the sulfonyl.
  • Examples of the lower alkylsulfonyl group include C1 to C8 alkylsulfonyl group containing a linear, branched or cyclic structure, and specifically, the linear or branched alkylsulfonyl group includes methane.
  • Examples thereof include sulfonyl, ethanesulfonyl, 1-propylsulfonyl, 2-propylsulfonyl, 1-butylsulfonyl, 2-butylsulfonyl, isobutylsulfonyl, t-butylsulfonyl and the like.
  • Examples of the C1 to C8 alkylsulfonyl containing a cyclic structure include cyclopropylsulfonyl, cyclopropylmethylsulfonyl, cyclobutylsulfonyl, cyclobutylmethylsulfonyl, cyclopentylsulfonyl, cyclopentylmethylsulfonyl, cyclohexylsulfonyl, cyclohexylmethylsulfonyl, cyclohexylethylsulfonyl and the like. Be done. Preferred examples thereof include methanesulfonyl, ethanesulfonyl, 2-propanesulfonyl, cyclopropanesulfonyl and the like.
  • Carbamoyl optionally substituted with lower alkyl or lower alkyl sulfonyl the lower alkyl and lower alkyl sulfonyl are as defined above.
  • Carbamoyls optionally substituted with lower alkyl or lower alkylsulfonyls include “carbamoyls optionally substituted with lower alkyls” and “carbamoyls optionally substituted with lower alkylsulfonyls”.
  • Carbamoyl which may be substituted with lower alkyl is a group in which one or two of the above lower alkyls may be bonded to carbamoyl. When two lower alkyls are bonded, the lower alkyls may be the same or different. Carbamoyls that may be substituted with lower alkyls include, for example, carbamoyls, or aminocarbonyls substituted with C1-C8 alkyls, including linear, branched, or cyclic structures.
  • carbamoyl that may be substituted with lower alkyl
  • carbamoyl include carbamoyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, 2-propylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, and ethylmethylaminocarbonyl.
  • examples thereof include methylpropylaminocarbonyl and dicyclohexylaminocarbonyl.
  • Carbamoyl which may be substituted with a lower alkylsulfonyl is a group in which one or two of the above lower alkylsulfonyls may be bonded to the carbamoyl. When two lower alkyl sulfonyls are bonded, the lower alkyl sulfonyls may be the same or different.
  • Carbamoyls that may be substituted with lower alkylsulfonyls include, for example, carbamoyls, or aminocarbonyls substituted with C1-C8 alkylsulfonyls, including linear, branched, or cyclic structures.
  • linear or branched C1-C8 alkylsulfonylaminocarbonyl examples include methanesulfonylaminocarbonyl, ethanesulfonylaminocarbonyl, 1-propylsulfonylaminocarbonyl, 2-propylsulfonylaminocarbonyl, and 1-butylsulfonylaminocarbonyl.
  • 2-Butylsulfonylaminocarbonyl isobutylsulfonylaminocarbonyl, t-butylsulfonylaminocarbonyl and the like.
  • Examples of the C1 to C8 alkylsulfonylaminocarbonyl containing a cyclic structure include cyclopropylsulfonylaminocarbonyl, cyclopropylmethylsulfonylaminocarbonyl, cyclobutylsulfonylaminocarbonyl, cyclobutylmethylsulfonylaminocarbonyl, cyclopentylsulfonylaminocarbonyl, and cyclopentylmethylsulfonyl.
  • Carboxamides that may be substituted with preferred lower alkylsulfonyls include carboxamides, methanesulfonylaminocarbonyls, ethanesulfonylaminocarbonyls, 2-propylsulfonylaminocarbonyls, cyclopropylsulfonylaminocarbonyls and the like.
  • the optionally substituted cyclic amino in the "optionally substituted cyclic aminocarbonyl" is as defined above.
  • the optionally substituted cyclic aminocarbonyl is a group to which the above optionally substituted cyclic amino is attached to the carbonyl.
  • Specific examples of the cyclic aminocarbonyl that may be substituted include pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, 4-methylpiperidino, morpholinocarbonyl, 2-pyrrolidonylcarbonyl and the like, which are preferable. Examples include pyrrolidinocarbonyl, morpholinocarbonyl and the like.
  • the lower alkyl in "sulfamoyl which may be substituted with lower alkyl" is as defined above.
  • Sulfamoyl, which may be substituted with a lower alkyl is a group in which one or two of the above lower alkyls may be attached to sulfamoyl. When two lower alkyls are bonded, the lower alkyls may be the same or different.
  • Examples of sulfamoyl substituted with lower alkyl include sulfamoyl; aminosulfonyl substituted with C1-C8 alkyl containing a linear, branched, or cyclic structure, and specific examples thereof include.
  • Examples thereof include sulfamoyl, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, 2-propylaminosulfonyl, dimethylaminophonyl, diethylaminosulfonyl, ethylmethylaminosulfonyl, methylpropylaminosulfonyl, dicyclohexylaminosulfonyl and the like.
  • the optionally substituted cyclic amino in the "optionally substituted cyclic aminosulfonyl" is as defined above.
  • the optionally substituted cyclic aminosulfonyl is a group to which the above optionally substituted cyclic amino is attached to the sulfonyl.
  • Specific examples of the cyclic aminosulfonyls that may be substituted include pyrrolidinosulfonyl, piperidinosulfonyl, piperazinosulfonyl, 4-methylpiperidinosulfonyl, morpholinosulfonyl, 4-piperidonylsulfonyl and the like. , And preferably, pyrrolidinosulfonyl, morpholinosulfonyl and the like.
  • A is a optionally substituted benzene ring.
  • the substituent of A includes, for example, at least one selected from the group consisting of the following groups A-1) to A-16), and when a plurality of substituents are present, they may be the same or different from each other. Good.
  • the number of substituents in A is, for example, 0 to 5, 0 to 4, 0 to 3, preferably 0, 1 or 2, and more preferably 0 or 1. When a plurality of substituents are present, they may be the same or different from each other.
  • the substituent of A it consists of at least one selected from the group consisting of A-1 and A-3 to A-16 described above, A-1 and A-3 to A-16 described above. At least one selected from the group obtained by removing methoxy from the group can be mentioned.
  • the preferred substituent of A is at least one selected from the group consisting of halogen; lower alkoxy; carbamoyl optionally substituted with lower alkyl or lower alkylsulfonyl; and lower alkyl optionally substituted with halogen.
  • the more preferred substituent of A is at least one selected from the group consisting of halogen; lower alkoxy; carbamoyl; and lower alkyl which may be substituted with halogen, and the more preferred substituent of A is halogen.
  • the substituent of A may be bonded to any of the carbon atoms at the 4-position, 5-position, 6-position, and 7-position of the benzoisoxazole or benzoisothiazole skeleton. It is preferable, but it is preferably bonded to at least one of the carbon atoms at the 4-position, 5-position and 6-position, more preferably to the carbon atom at the 4-position and / or 5-position, and particularly preferably to the carbon atom at the 4-position.
  • the position numbers of the atoms constituting the benzoisoxazole or benzoisothiazole skeleton are as follows.
  • particularly preferable A is a lower alkyl in which the carbon atom at the 4-position of the benzoisoxazole or benzoisothiazole skeleton is substituted with a halogen, a lower alkoxy, or a halogen. It is a benzene ring that is bonded and the carbon atoms at positions 5, 6, and 7 are not substituted.
  • B is an aryl which may be substituted or a heteroaryl which may be substituted.
  • Aryl which may be substituted or heteroaryl which may be substituted is as defined above. Examples of the aryl include phenyl and naphthyl, and phenyl is preferable.
  • the heteroaryl a monocyclic nitrogen-containing heteroaryl that does not contain other heteroatoms as a ring-constituting atom, or benzoimidazolyl is preferable.
  • a 5- or 6-membered heteroaryl containing one nitrogen atom as the ring-constituting heteroatom is preferable, and for example, pyrrolyl and pyridyl are used. Pyridyl is preferred, and 2-pyridyl is even more preferred.
  • benzimidazolyl benzimidazol-3-yl is preferable.
  • B When B is a monocyclic aryl, B may be substituted with at least one group selected from the group consisting of B-1) to B-16) below. When B is a monocyclic or bicyclic heteroaryl, B may be substituted with at least one group selected from the group consisting of B-1) to B-17) below.
  • the number of substituents in B is, for example, 0 or at least 1, 0 to 5, 0 to 4, preferably 0 to 3, and more preferably 0, 1 or 2. When a plurality of substituents are present, they may be the same or different from each other.
  • substituents for B are halogen; carboxyl, optionally substituted lower alkyl; lower alkoxycarbonyl; optionally substituted with lower alkyl or lower alkylsulfonyl, carbamoyl; and optionally substituted cyclic aminocarbonyl. At least one selected from the group consisting of, specifically, halogen, carboxyl, methyl, ethyl, 1-propyl, 2-propyl, hydroxymethyl, carboxymethyl, trichloromethyl, trifluoromethyl, methoxycarbonyl.
  • Ethoxycarbonyl t-butoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylmethylaminocarbonyl, methanesulfonylaminocarbonyl, pyrrolidinocarbonyl, and at least one selected from the group consisting of morpholinocarbonyl.
  • the substituent of B is at least one selected from the group consisting of halogen; carboxyl; lower alkyl; halogen-substituted lower alkyl; lower alkoxycarbonyl; and optionally carbamoyl substituted with lower alkyl.
  • the substituent of B is particularly preferably at least one selected from the group consisting of chlorine atom, fluorine atom, methyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, methylaminocarbonyl, and dimethylaminocarbonyl.
  • B when Y is a nitrogen atom, B is preferably substituted phenyl or optionally substituted pyridyl, and when Y is a carbon atom, B is substituted.
  • Phenyl which may be substituted, pyridyl which may be substituted, or 2-oxobenzoimidazole-3-yl is preferable, and phenyl which may be substituted or pyridyl which may be substituted is more preferable.
  • the carbon atom at the ortho position with respect to the carbon atom on the pyridine or benzene ring bonded to Y It is preferable that one or two, preferably one, is substituted.
  • the substituent bonded to the carbon atom at the ortho position may be the above-mentioned B substituent, but is preferably a halogen, more preferably a chlorine atom or a fluorine atom, and even more preferably a chlorine atom. ..
  • B when B is a substituted pyridyl or a substituted phenyl, the carbon atom at the ortho position with respect to the carbon atom on the pyridine or benzene ring bonded to Y
  • One or two, preferably one, are substituted with chlorine or fluorine atoms, the meta-position carbon atom is not substituted, the para-position carbon atom is not substituted, or carboxyl, methoxycarbonyl, or More preferably, it is substituted with ethoxycarbonyl.
  • Y is a nitrogen atom and B is a substituted 2-pyridyl
  • the carbon atom at the ortho position is substituted with a chlorine atom or a fluorine atom with respect to the carbon atom on the pyridine ring bonded to Y. It is particularly preferable that not all of the carbon atoms at the meta position are substituted and the carbon atoms at the para position are not substituted or substituted with carboxyl.
  • Y is a nitrogen atom and B is a substituted phenyl
  • one of the two carbon atoms at the ortho position with respect to the carbon atom on the benzene ring bonded to Y is a chlorine atom.
  • Y is a carbon atom and B is a substituted 2-pyridyl
  • the carbon atom at the ortho position with respect to the carbon atom on the pyridine ring bonded to Y is substituted with a chlorine atom or a fluorine atom.
  • not all of the carbon atoms at the meta position are substituted and the carbon atom at the para position is not substituted or is substituted with carboxyl, methoxycarbonyl or ethoxycarbonyl.
  • Y is a carbon atom and B is a substituted phenyl
  • one of the two carbon atoms at the ortho position with respect to the carbon atom on the benzene ring bonded to Y is a chlorine atom.
  • it is substituted with a fluorine atom, the carbon atom at the other ortho position is not substituted, all the carbon atoms at the meta position are not substituted, the carbon atom at the para position is not substituted, or the carboxyl, It is particularly preferred that it is substituted with methoxycarbonyl or ethoxycarbonyl.
  • X is an oxygen atom or a sulfur atom, preferably an oxygen atom.
  • Y is a nitrogen atom or a carbon atom, preferably a nitrogen atom.
  • Y is a nitrogen atom or a carbon atom, preferably a nitrogen atom.
  • R 1 is either independently of one another are lower alkyl, two R 1 are bonded to each other, they may form a spiro ring or a crosslinked structure, or two of R 1 may be bonded to each other to form a ring and may form a saturated condensed heterocyclic ring together with the carbon and nitrogen atoms constituting including Y.
  • R 1 is a lower alkyl
  • preferred R 1 includes, for example, linear or branched C1-C3 alkyls, more preferably methyl, ethyl, and even more preferably methyl.
  • Two of R 1 are bonded to each other, when forming a spiro ring or a crosslinked structure, and forms a spiro ring, of the carbon atoms constituting the ring containing Y in formula (1) two R 1 are combined into one, it refers to the case of forming a ring together with the carbon atoms to the R 1 bonded to each other to each other.
  • each one of R 1 is bonded to two, it refers to the case where the R 1 are bonded to each other to each other.
  • Two of R 1 are bonded to each other, as if forming a spiro ring or a crosslinked structure, for example, two of R 1 are bonded to each other, a methylene, dimethylene, trimethylene or be a tetramethylene, in the case of forming a crosslinked structure, or the case of forming a spiro ring, and by a dimethylene or trimethylene, and preferably binds two of R 1 each other, cross-linking by comprising methylene, dimethylene or a trimethylene, This is the case when forming a structure. Particularly preferably, it is a crosslinked structure formed by dimethylene represented by the following structural formula.
  • R 1 Two of R 1 are bonded to each other, to form a saturated condensed heterocyclic ring together with the carbon and nitrogen atoms constituting the ring containing Y are formula (1) of carbon atoms constituting the ring containing Y of out adjacent to each one of R 1 is bonded to two, it refers to the case where the R 1 together form a saturated condensed heterocyclic ring together with the carbon and nitrogen atoms constituting the ring containing Y bonded to each other.
  • saturated condensed heterocyclic means a fused bicyclic Y and heterocyclic (pyrazine ring or piperidine ring) containing a saturated carbon ring containing R 1.
  • saturated condensed heterocycle examples include a fused ring of a pyrazine ring or a piperidine ring and a cyclopentane ring or a cyclohexane ring.
  • Specific examples of the saturated condensed heterocycle include octahydrocyclopentapyridine, octahydrocyclopentapyrazine, decahydroquinoline, decahydroquinoxaline and the like.
  • R 1 is a cross-linked structure formed of C1-C3 alkyl or dimethylene, and more preferred R 1 is a cross-linked structure formed of methyl, ethyl or dimethylene represented by the above structural formula.
  • p is 0, 1, or 2. ..
  • (R 1 ) p may be oxo.
  • the compound represented by the general formula (1) a salt thereof, or a prodrug thereof
  • the compound represented by the following general formula (1A), a salt thereof, or a prodrug thereof is preferable.
  • a pharmaceutical composition for preventing and / or treating deafness containing a compound represented by the following general formula (1A), a salt thereof, or a prodrug thereof is also included in the present invention.
  • Z is a nitrogen atom or CH.
  • Y is a nitrogen atom or a carbon atom.
  • R 11 is, independently of one another are methyl or ethyl, or two R 11 are bonded to each other methylene, may form a crosslinked structure by dimethylene or trimethylene.
  • p is 0, 1, or 2.
  • (R 11 ) p is oxo.
  • R 21 , R 22 , and R 23 are independent of each other and are hydrogen atoms, halogens, carbamoyls, or trifluoromethyls.
  • R 31 , R 32 , and R 33 are independent of each other, lower alkyl, methyl, carboxyl, lower alkoxycarbonyl, monomethylaminocarbonyl, or dimethylaminocarbonyl substituted with hydrogen atom, halogen, halogen. ].
  • Z is a nitrogen atom or CH.
  • Z is preferably a nitrogen atom when Y is a nitrogen atom.
  • Y is a nitrogen atom or a carbon atom.
  • R 11 is independently of one another are methyl or ethyl, or two R 11 are bonded to each other, a methylene, dimethylene, or a crosslinked structure by trimethylene It may be formed.
  • R 11 is preferably a crosslinked structure made of methyl or ethyl, or dimethylene or trimethylene, and more preferably a crosslinked structure made of methyl or diethylene.
  • R 11 are bonded to each other, methylene, dimethylene or if forming a crosslinked structure by trimethylene, two of the carbon atoms constituting the ring containing Y in the general formula (1A), each one of R 11 is bonded, without methylene, dimethylene or trimethylene and the R 11 bonded to each other to each other, refers to the case where the crosslinking structure is formed on the piperazine ring.
  • (R 11 ) p is oxo or is represented in the following structural formula.
  • R 111 represents C1-C3 alkyl.
  • Methyl or ethyl is preferable as R 111 , and methyl is more preferable.
  • (R 11 ) p may be oxo.
  • R 21 , R 22 , and R 23 are independently hydrogen atoms, halogens, carbamoyl, or trifluoromethyl, and are R 21 , R 22 , and R. It is preferred that at least one of the 23 is halogen, carbamoyl, or trifluoromethyl.
  • R 21 is preferably a chlorine atom, a fluorine atom, a carbamoyl, or trifluoromethyl, and more preferably a chlorine atom or trifluoromethyl.
  • R 22 is preferably a hydrogen atom, a chlorine atom or a trifluoromethyl, and more preferably a hydrogen atom.
  • R 23 is preferably a hydrogen atom, a chlorine atom, or trifluoromethyl, and more preferably a hydrogen atom. It is particularly preferred that R 21 is a halogen (preferably a chlorine atom or a fluorine atom) or trifluoromethyl, and that both R 22 and R 23 are hydrogen atoms.
  • R 31 , R 32 , and R 33 are independently substituted with a hydrogen atom, a halogen, and a halogen, and the lower alkyl, methyl, carboxyl, lower alkoxycarbonyl, and monomethyl are substituted.
  • the R 31 is preferably a hydrogen atom, halogen, trichloromethyl, trifluoromethyl, or methyl, more preferably halogen, trichloromethyl, trifluoromethyl, or methyl, and particularly preferably a chlorine atom.
  • the R 32 is preferably a hydrogen atom, halogen or methyl, and more preferably a hydrogen atom.
  • the R 33 is preferably a hydrogen atom, halogen, carboxyl, methoxycarbonyl, ethoxycarbonyl, monomethylaminocarbonyl, or dimethylaminocarbonyl, more preferably a hydrogen atom, carboxyl, methoxycarbonyl or ethoxycarbonyl, and particularly preferably hydrogen. It is an atom or a carboxyl.
  • R 31 , R 32 , and R 33 are that R 31 is a halogen (preferably a chlorine atom or a fluorine atom), R 32 is a hydrogen atom, and R 33 is a hydrogen atom or a carboxyl.
  • R 21 is a halogen (preferably a chlorine atom)
  • R 31 is a halogen (preferably a chlorine atom or a fluorine atom)
  • R 32 is a hydrogen atom
  • R 33 is a hydrogen atom. preferable.
  • R 21 is trihalomethyl (preferably trifluoromethyl)
  • R 31 is a halogen (preferably a chlorine atom or a fluorine atom)
  • R 32 is a hydrogen atom
  • R 33 is a hydrogen atom, a carboxyl. , Methylcarbonyl, or ethoxycarbonyl.
  • R 31 is a halogen (preferably a chlorine atom or a fluorine atom, more preferably a chlorine atom)
  • R 32 is a hydrogen atom
  • R 33 is a hydrogen atom. preferable.
  • R 21 is a chlorine atom or trifluoromethyl
  • R 22 and R 23 are hydrogen atoms
  • R 31 is a chlorine atom
  • R 32 is a hydrogen atom
  • R 33 is a hydrogen atom or carboxyl. Is preferable.
  • Specific examples of the compound represented by the general formula (1), a salt thereof, or a prodrug thereof include, for example, compound 011 and compound 021, compound 031 and compound 041, compound 051, compound 061, compound 071, and compound. 081, Compound 091, Compound 101, Compound 111, Compound 121, Compound 131, Compound 141, Compound 151, Compound 161, Compound 171, Compound 181, Compound 191 and Compound 201, Compound 211, Compound 221 and Compound 231 and Compound 241.
  • a salt thereof, or a prodrug thereof particularly preferably Compound 011 or Compound 031 or Compound 041, Compound 061, Compound 071, or Compound 191 or Compound 361, Compound 371, Compound 381, or Compound 401, a salt thereof. Or its prodrug.
  • the present invention includes a pharmaceutical composition for preventing and / or treating deafness containing a compound represented by the following general formula (2), a salt thereof, or a prodrug thereof.
  • the compound, a salt thereof, or a prodrug thereof may have a preventive and / or therapeutic effect on deafness.
  • the compound, a salt thereof, or a prodrug thereof may have an activity of regulating or inhibiting the activity of TRPC channels, such as TRPC3 and / or TRPC6 channels, preferably TRPC6 channels.
  • the compound or a salt thereof can also be an intermediate compound of the compound represented by the general formula (1).
  • the carbon atom at the ortho position has a substituent on the carbon atom of the A ring (benzene ring) bonded to the carbon atom constituting the oxime structure.
  • the substituent is the same as the substituent in the A ring (benzene ring) in the general formula (1). Therefore, the substituent may be, for example, at least one group selected from the group consisting of the above A-1) to A-16).
  • the compound represented by the general formula (2) a salt thereof, or a prodrug thereof
  • the compound represented by the following general formula (2A), a salt thereof, or a prodrug thereof is preferable.
  • the compound represented by the general formula (2) a salt thereof, or a prodrug thereof
  • the compound represented by the following general formula (2B), a salt thereof, or a prodrug thereof is preferable.
  • the compound represented by the following general formula (2B) or a salt thereof is preferable as an intermediate compound in the production of the compound represented by the general formula (1).
  • G 1 is a halogen, a lower alkyl sulfonyl optionally substituted with a halogen, or a benzenesulfonyl optionally substituted with a lower alkyl or nitro. ].
  • Examples of the halogen represented by G 1 include a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom.
  • the lower alkyl sulfonyls in the lower alkyl sulfonyls that may be substituted with the halogen represented by G 1 are as defined above.
  • the lower alkyl sulfonyl is a group in which a lower alkyl is bonded to a sulfonyl, and the lower alkyl may be substituted with a halogen.
  • the lower alkyl sulfonyl group which may be substituted with halogen include linear or branched C1 to C6 alkyl which may be substituted with 1 to 3 halogens (preferably C1 to C4 alkyl, and more.
  • Benzenesulfonyls that may be substituted with the lower alkyl represented by G 1 include, for example, 1 to 3 (preferably 1 or 2, more preferably 1) linear or branched C1 to.
  • Benzenesulfonyl which may be substituted with C6 alkyl preferably C1 to C4 alkyl, more preferably C1 to C3 alkyl
  • specific examples thereof include p-toluenesulfonyl.
  • Examples of the benzenesulfonyl that may be substituted with nitro represented by G 1 include benzenesulfonyl that may be substituted with 1 to 3 (preferably 1) nitro. Examples thereof include o-nitrobenzenesulfonyl and p-nitrobenzenesulfonyl.
  • Preferred G 1 is a chlorine atom, a fluorine atom, a bromine atom, a methanesulfonyl, an ethanesulfonyl, a trifluoromethanesulfonyl, a p-toluenesulfonyl, or a p-nitrobenzenesulfonyl. More preferred G 1 is a chlorine atom or a bromine atom.
  • the compound represented by the general formula (2), a salt thereof, or a prodrug thereof includes, for example, the following compound, a salt thereof, or a prodrug thereof.
  • the compound represented by the general formula (2), a salt thereof, or a prodrug thereof is preferably compound 062, compound 202, compound 362, or compound 372, a salt thereof, or a prodrug thereof, and more preferably compound 202.
  • the above compounds and the like can be produced, for example, by appropriately modifying or combining production methods 1 to 3 described in detail below, methods similar thereto, known methods and the like.
  • the compounds used as the raw material compounds may be used as salts, respectively.
  • the method shown below is merely an example, and can be appropriately produced by another method based on the knowledge of a person who is proficient in organic synthesis.
  • 1,2-benzoisothiazole or a derivative thereof or 1,2-benzoisoxazole or a derivative thereof, which is not a commercially available product is used as a raw material compound, it is manufactured and procured by referring to the method described in the following publication. can do.
  • the compound represented by the general formula (1) can be produced by the synthetic scheme represented by the following reaction step formula-1. That is, the compound represented by the general formula (1) can be produced from the compound represented by the general formula (3) and the compound represented by the general formula (4).
  • G 2 is a halogen, a lower alkyl sulfonyl optionally substituted with a halogen, or a benzenesulfonyl optionally substituted with a lower alkyl or nitro. ].
  • Examples of the halogen represented by G 2 include a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom.
  • the lower alkyl in the lower alkyl sulfonyls which may be substituted with the halogen represented by G 2 is as defined above.
  • the lower alkyl sulfonyl is a group in which a lower alkyl is bonded to a sulfonyl, and the lower alkyl may be substituted with a halogen.
  • the lower alkyl sulfonyl group which may be substituted with halogen include linear or branched C1 to C6 alkyl which may be substituted with 1 to 3 halogens (preferably C1 to C4 alkyl, and more.
  • benzenesulfonyl optionally substituted with lower alkyl represented by G 2, for example, one to three straight or branched C1 ⁇ C6 alkyl (preferably C1 ⁇ C4 alkyl, more preferably C1 ⁇ C3 alkyl) may be substituted with benzenesulfonyl, and specific examples thereof include p-toluenesulfonyl.
  • Examples of the benzenesulfonyl that may be substituted with nitro represented by G 2 include benzenesulfonyl that may be substituted with 1 to 3 (preferably 1) nitro. Examples thereof include o-nitrobenzenesulfonyl and p-nitrobenzenesulfonyl.
  • Preferred G 2 is chlorine atom, fluorine atom, bromine atom, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, or p-nitrobenzenesulfonyl.
  • the reaction between the compound represented by the general formula (3) and the compound represented by the general formula (4) can be carried out, for example, in an inert solvent in the presence or absence of a base. If necessary, an activator may be further added into the reaction system.
  • the compound represented by the general formula (3) and the compound represented by the general formula (4) are known compounds and can be produced by a known method.
  • the inert solvent examples include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene and xylene, and halogens such as dichloromethane, chloroform, dichloroethane and carbon tetrachloride.
  • ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxymethane
  • aromatic hydrocarbon solvents such as toluene, benzene and xylene
  • halogens such as dichloromethane, chloroform, dichloroethane and carbon tetrachloride.
  • hydrocarbon solvent examples include a hydrocarbon solvent, a ketone solvent such as acetone, dimethylsulfoxide, N, N-dimethylformamide (DMF), an aproton solvent such as
  • Examples of the base include metal hydrides such as sodium hydride and potassium hydride, metal hydroxides such as potassium hydroxide and sodium hydroxide, and metals such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and cesium carbonate.
  • metal hydrides such as sodium hydride and potassium hydride
  • metal hydroxides such as potassium hydroxide and sodium hydroxide
  • metals such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and cesium carbonate.
  • alkylamines such as carbonate, triethylamine and ethyldiisopropylamine
  • metal alkoxides such as sodium methoxide and potassium t-butoxide.
  • the amount of the base used is usually 1 mol or more, preferably 1 to 5 mol, and more preferably 1 to 2 mol with respect to 1 mol of the compound represented by the general formula (4).
  • the amount of the compound represented by the general formula (3) to be used is usually 0.2 mol or more, preferably 0.2 to 2 mol, more preferably 0.2 mol or more, based on 1 mol of the compound represented by the general formula (4). Is 0.2-1.5 mol.
  • the reaction temperature is usually ⁇ 50 ° C. to 180 ° C., preferably ⁇ 30 ° C. to 180 ° C., and more preferably ⁇ 10 ° C. to 180 ° C.
  • Microwaves may be used to promote the reaction, and the reaction temperature in that case is, for example, 80 ° C. to 180 ° C., preferably 100 ° C. to 180 ° C.
  • the reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • the compound represented by the general formula (1B) can be produced by the synthetic scheme represented by the following reaction step formula-2. That is, the compound represented by the general formula (1B) can be produced from the compound represented by the general formula (5) and the compound represented by the general formula (6).
  • G 3 is a halogen, a lower alkyl sulfonyl optionally substituted with a halogen, or a benzene sulfonyl optionally substituted with a lower alkyl or nitro. ].
  • Examples of the halogen represented by G 3 include a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom.
  • Lower alkyl in substituted lower alkylsulfonyl optionally substituted with halogen represented by G 3 are as defined above.
  • the lower alkyl sulfonyl is a group in which a lower alkyl is bonded to a sulfonyl, and the lower alkyl may be substituted with a halogen.
  • the lower alkyl sulfonyl group which may be substituted with halogen include linear or branched C1 to C6 alkyl which may be substituted with 1 to 3 halogens (preferably C1 to C4 alkyl, and more.
  • Preferred are C1-C3 alkyl) sulfonyls, and specific examples thereof include methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl and the like.
  • benzenesulfonyl optionally substituted with lower alkyl represented by G 3, for example, one to three straight or branched C1 ⁇ C6 alkyl (preferably C1 ⁇ C4 alkyl, more preferably C1 ⁇ C3 alkyl) may be substituted with benzenesulfonyl, and specific examples thereof include p-toluenesulfonyl.
  • Examples of the benzenesulfonyl that may be substituted with nitro represented by G 3 include benzenesulfonyl that may be substituted with 1 to 3 (preferably 1) nitro. Examples thereof include o-nitrobenzenesulfonyl and p-nitrobenzenesulfonyl.
  • Preferred G 3 are a chlorine atom, a fluorine atom, a bromine atom, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, p- toluenesulfonyl or p- nitrobenzenesulfonyl.
  • the compound represented by the general formula (1B) By coupling the compound represented by the general formula (5) and the compound represented by the general formula (6), the compound represented by the general formula (1B) can be obtained.
  • the compound represented by the general formula (5) and the compound represented by the general formula (6) are known compounds and can be produced by a known method.
  • This reaction can be carried out, for example, in an inert solvent in the presence of a base.
  • the inert solvent examples include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene and xylene, and halogens such as dichloromethane, chloroform, dichloroethane and carbon tetrachloride.
  • ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxymethane
  • aromatic hydrocarbon solvents such as toluene, benzene and xylene
  • halogens such as dichloromethane, chloroform, dichloroethane and carbon tetrachloride.
  • hydrocarbon solvent examples include a hydrocarbon solvent, a ketone solvent such as acetone, dimethylsulfoxide, N, N-dimethylformamide (DMF), an aproton solvent such as
  • Examples of the base include metal hydrides such as sodium hydride and potassium hydride, metal hydroxides such as potassium hydroxide and sodium hydroxide, and metals such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and cesium carbonate.
  • metal hydrides such as sodium hydride and potassium hydride
  • metal hydroxides such as potassium hydroxide and sodium hydroxide
  • metals such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and cesium carbonate.
  • alkylamines such as carbonate, triethylamine and ethyldiisopropylamine
  • metal alkoxides such as sodium methoxide and potassium t-butoxide.
  • the amount of the compound represented by the general formula (6) to be used is usually 0.5 mol or more, further 1 mol or more, preferably 0.9 to 1 mol, based on 1 mol of the compound represented by the general formula (5). It is 2 mol, more preferably 0.9 to 1.5 mol.
  • the amount of the base used is usually 1 mol or more, preferably 1 to 5 mol, and more preferably 1 to 2 mol with respect to 1 mol of the compound represented by the general formula (5).
  • the reaction temperature is usually 30 ° C. to 10 ° C. higher than the boiling point of the solvent, and preferably 80 ° C. to 10 ° C. higher than the boiling point of the solvent. Microwaves may be used to promote the reaction, and the reaction temperature in that case is, for example, 80 ° C. to 180 ° C., preferably 100 ° C. to 180 ° C.
  • the reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours.
  • reaction between the compound represented by the general formula (5) and the compound represented by the general formula (6) can also be carried out by utilizing the Buchward reaction, for example, a palladium catalyst, a phosphine ligand, and a base.
  • the compound represented by the general formula (5) is reacted with the compound represented by the general formula (6) in a solvent.
  • the palladium catalyst examples include divalent palladium such as Pd (OAc) 2 , PdCl 2 , allylpalladium (II) chloride (dimer), bis (acetaceous) palladium (II) dichloride, and bis (benzonitrile) palladium (II) dichloride.
  • Examples thereof include catalysts, Pd 2 (dba) 3 (tris (dibenzylideneacetone) dipalladium (0)), bis (dibenzylideneacetone) palladium (0), and zero-valent palladium catalysts such as palladium carbon (Pd / C). ..
  • phosphine ligand examples include BINAP ((2,2'-bis (diphenylphosphanyl) -1,1'-bisnaphthalene)) and Xphos (2-dicyclohexylphosphino-2', 4', 6'-tri.
  • Bidentate phosphine ligands such as isopropylbiphenyl can be mentioned.
  • Examples of the base include strong bases such as t-BuONa (tert-butoxysodium).
  • the amount of the compound represented by the general formula (6) to be used is usually 0.5 mol or more, more preferably 1 mol or more, preferably 1 mol or more, based on 1 mol of the compound represented by the general formula (5). It is 0.9 to 2 mol, more preferably 1 to 1.5 mol.
  • the amount of the palladium catalyst used is usually 0.005 to 1 mol, preferably 0.01 to 0.2 mol, based on 1 mol of the compound represented by the general formula (5).
  • the amount of the phosphine ligand to be used is usually 0.5 to 5 mol, preferably 1 to 2 mol, relative to 1 mol of the palladium catalyst.
  • the amount of the base used is usually 0.5 mol or more, further 1 mol or more, preferably 1 to 2 mol, relative to 1 mol of the compound represented by the general formula (5).
  • the reaction temperature is usually 40 ° C. to 150 ° C., preferably 80 ° C. to 110 ° C., and the reaction time is usually 1 to 24 hours, preferably 3 to 12 hours.
  • the compound represented by the general formula (1) or (2) can be produced by the synthetic scheme represented by the following reaction step formula-3. That is, the compound represented by the general formula (1C) is obtained by converting the compound represented by the general formula (7) into the compound represented by the general formula (8) and forming the compound represented by the general formula (4). It can be produced by reacting to produce an oxime compound represented by the general formula (2B) and closing the ring. A person skilled in the art may substitute the compound represented by the general formula (7) or (8) in the reaction represented by the reaction step formula-3, and appropriately substitute the benzene ring A. It can be understood that the compound represented by the general formula (2) can be produced by using the compound having. Further, the compound represented by the general formula (7) is a known compound and can be produced by a known method.
  • the halogen represented by G 4 for example, a chlorine atom, a fluorine atom, a bromine atom, an iodine atom.
  • Step 1 that is, the step of converting the compound represented by the general formula (7) into the compound represented by the general formula (8), is, for example, halogenating the compound represented by the general formula (7) in an inert solvent. This is possible by reacting the agent.
  • inert solvent in this reaction examples include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene and xylene, dichloromethane, chloroform, dichloroethane and carbon tetrachloride.
  • ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxymethane
  • aromatic hydrocarbon solvents such as toluene, benzene and xylene
  • dichloromethane chloroform
  • dichloroethane and carbon tetrachloride examples include halogenated hydrocarbon solvents such as, ketone solvents such as acetone, dimethylsulfoxide, N, N-dimethylformamide (DMF), aproton solvents such as acetonitrile, pyridine and the like
  • halogenating agent examples include general halogenating agents such as N-bromosuccinimide and N-chlorosuccinimide.
  • the amount of the halogenating agent used is usually equimolar to excess mol, preferably 1 to 5 times mol, and more preferably 1 to 2 times mol, relative to the compound represented by the general formula (7).
  • the reaction temperature is usually ⁇ 30 to 150 ° C., preferably ⁇ 10 to 100 ° C., and more preferably ⁇ 10 to 40 ° C.
  • the reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours, and more preferably 30 minutes to 18 hours.
  • Step 2 that is, the step of reacting the compound represented by the general formula (8) with the compound represented by the general formula (4) to synthesize the compound represented by the general formula (2B) is carried out, for example, in an inert solvent. , Can be done in the presence of a base.
  • inert solvent in this reaction examples include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene and xylene, dichloromethane, chloroform, dichloroethane and tetrachloride.
  • ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxymethane
  • aromatic hydrocarbon solvents such as toluene, benzene and xylene
  • dichloromethane chloroform
  • dichloroethane and tetrachloride examples include halogenated hydrocarbon solvents such as carbon, ketone solvents such as acetone, dimethylsulfoxide, N, N-dimethylformamide (DMF), aproton solvents such as acetonitrile, pyridine and the like.
  • Examples of the base include metal hydrides such as sodium hydride and potassium hydride, metal hydroxides such as potassium hydroxide and sodium hydroxide, and metals such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and cesium carbonate.
  • metal hydrides such as sodium hydride and potassium hydride
  • metal hydroxides such as potassium hydroxide and sodium hydroxide
  • metals such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and cesium carbonate.
  • alkylamines such as carbonate, triethylamine and ethyldiisopropylamine
  • metal alkoxides such as sodium methoxide and potassium t-butoxide.
  • the amount of the compound represented by the general formula (8) to be used is usually 0.5 mol or more, 0.8 mol or more, preferably 0.9 mol, relative to 1 mol of the compound represented by the general formula (4). It is ⁇ 2 mol, more preferably 0.9 ⁇ 1.5 mol.
  • the amount of the base used is usually 1 mol or more, preferably 1 to 5 times mol, and more preferably 1 to 2 times mol, relative to 1 mol of the compound represented by the general formula (4).
  • the reaction temperature is usually ⁇ 20 ° C. to 10 ° C. higher than the boiling point of the solvent, preferably 0 ° C. to 40 ° C. ° C.
  • the reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours, and more preferably 30 minutes to 18 hours.
  • Step 3 that is, the step of closing the ring of the compound represented by the general formula (2B) and converting it into the compound represented by the general formula (1) can be carried out, for example, in an inert solvent in the presence of a base. ..
  • the compound represented by the general formula (2B) includes geometric isomers (E) and (Z), but the (E) is preferable because heating during the ring closure reaction can be reduced.
  • inert solvent in this reaction examples include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene and xylene, dichloromethane, chloroform, dichloroethane and tetrachloride.
  • ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxymethane
  • aromatic hydrocarbon solvents such as toluene, benzene and xylene
  • dichloromethane chloroform
  • dichloroethane and tetrachloride examples include halogenated hydrocarbon solvents such as carbon, ketone solvents such as acetone, dimethylsulfoxide, N, N-dimethylformamide (DMF), aproton solvents such as acetonitrile, pyridine and the like.
  • Examples of the base include metal hydrides such as sodium hydride and potassium hydride, metal hydroxides such as potassium hydroxide and sodium hydroxide, and metals such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and cesium carbonate.
  • metal hydrides such as sodium hydride and potassium hydride
  • metal hydroxides such as potassium hydroxide and sodium hydroxide
  • metals such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and cesium carbonate.
  • alkylamines such as carbonate, triethylamine and ethyldiisopropylamine
  • metal alkoxides such as sodium methoxide and potassium t-butoxide.
  • the amount of the base used is usually 1 mol or more, preferably 1 to 5 times mol, and more preferably 1 to 2 times mol, relative to 1 mol of the compound represented by the general formula (2B).
  • the reaction temperature is usually 50 ° C. to 10 ° C. higher than the boiling point of the solvent, preferably 80 ° C. to 10 ° C. higher than the boiling point of the solvent.
  • Microwaves may be used to promote the reaction, and the reaction temperature in that case is, for example, 80 ° C. to 180 ° C., preferably 100 ° C. to 180 ° C.
  • the reaction time is usually 10 minutes to 8 hours, preferably 10 minutes to 2 hours.
  • the compound represented by the general formula (1) or (2) according to the present invention, an intermediate compound thereof and a starting material compound thereof can be produced by the above synthetic method, and are described in Examples of the present specification.
  • Known or known techniques at the time of filing eg, B.R. Kiran et al., SYNTHESIS, EVALUATION OF ANALGESIC AND ANTI-INFLAMMATORY ACTIVITIES OF SUBSTITUTED 1,2-BENZOXAZOLONE AND 3-CHLORO-1, based on the synthetic method 2-BENZOXAZOLE DERIVATIVES, International Journal of Pharmaceutical Sciences and Research, 2015; 6: 2918-2925.
  • the starting material compounds and intermediate compounds shown in each of the above reaction formulas are, if necessary, protected with a suitable protecting group using a known method before being subjected to the reaction, and after the reaction is completed,
  • the protecting group can be deprotected by a known method.
  • Each of the target compounds obtained according to the above reaction formula can be isolated and purified. For example, after cooling the reaction mixture, isolation procedures such as filtration, concentration, and extraction are performed to separate the crude reaction product, and then the crude reaction product is subjected to general column chromatography, recrystallization, etc. By subjecting to a purification procedure, it can be isolated and purified from the reaction mixture.
  • the starting material compound represented by each of the above reaction formulas and the compound represented by the general formula (1) or (2) are solvates to which a solvent is added (for example, hydrate, ethanol solvate, etc.). Includes compounds that are in the form.
  • the present invention is a substance having an activity of inhibiting at least one TRPC channel selected from the group consisting of TRPC3 channel and TRPC6 channel (in the present specification, it may be referred to as "TRPC3 / 6 channel inhibitory activity").
  • TRPC3 / 6 channel inhibitory activity includes pharmaceutical compositions for the prevention and / or treatment of hearing loss containing (TRPC3 / 6 channel inhibitors), salts thereof, or prodrugs thereof.
  • TRPC3 / 6 channel inhibitor a substance having an activity of inhibiting TRPC6 channel (sometimes referred to as “TRPC6 channel inhibitory activity" in the present specification) (in the present specification, “TRPC6 channel inhibitor”). It may be referred to.) Is preferable.
  • TRPC3 / 6 channel inhibitor examples include a compound represented by the general formula (1), a compound represented by the general formula (2), Pyr2 (also referred to as “BTP2”), Pyr3, Pyr4, GSK2332255B, GSK2833503A, Examples thereof include compounds disclosed in SAR7334, BI-749327, US2019 / 0169168, and compounds disclosed in WO2019 / 215268, preferably compounds represented by the general formula (1) and compounds represented by the general formula (2). , Pyr2, Pyr3, Pyr4, GSK2332255B, GSK2833503A, SAR7334, BI-749327, Compound AA01 to Compound AA95, Compound BB01 to Compound BB32, etc.
  • a substance having an activity of inhibiting TRPC3 channel includes
  • the compound represented by the general formula (1), the compound represented by the general formula (2), the compounds disclosed in Pyr2, Pyr3, Pyr4, GSK2332255B, GSK2833503A, WO2019 / 215268 and the like can be mentioned, and the general formula (preferably Compounds represented by 1), compounds represented by the general formula (2), Pyr2, Pyr3, Pyr4, GSK2332255B, GSK2833503A, compounds BB01 to compound BB32, etc., more preferably compounds represented by the general formula (1).
  • Pyr2, Pyr3, Pyr4, GSK2332255B, GSK2833503A and the like more preferably the compound represented by the general formula (1), the compound represented by the general formula (2), Pyr4 and the like.
  • TRPC6 channel inhibitors are disclosed in, for example, a compound represented by the general formula (1), a compound represented by the general formula (2), Pyr2, Pyr4, GSK2332255B, GSK2833503A, SAR7334, BI-749327, US2019 / 0169168.
  • Examples include compounds, compounds disclosed in WO2019 / 215268, preferably compounds represented by the general formula (1), compounds represented by the general formula (2), Pyr2, Pyr4, GSK2332255B, GSK2833503A, SAR7334, BI- 749327, Compound AA01 to Compound AA95, Compound BB01 to Compound BB32, etc., more preferably the compound represented by the general formula (1), the compound represented by the general formula (2), Pyr2, Pyr4, GSK2332255B, GSK2833503A, SAR7334. , BI-749327 and the like, more preferably the compound represented by the general formula (1), the compound represented by the general formula (2), Pyr4 and the like.
  • Pyr2 is also called BTP2 and has CAS No. 223499-30-7.
  • CAS No. 1160541-60-2 is attached to Pyr3.
  • CAS No.223499-35-2 is attached to Pyr4.
  • GSK2332255B has CAS No.1366233-41-1.
  • GSK2833503A is labeled with CAS No. 1333207-63-8.
  • SAR7334 is labeled with CAS No.1333210-07-3.
  • BI-749327 is attached with CAS No.2361241-23-6.
  • Examples of the compound according to claim 1 of US2019 / 0169168 include, for example.
  • Compound AA01 [4- (6-Amino-4-methoxy-pyridin-3-yl) -piperazine-1-yl]-[5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl] -methanone
  • Compound AA02 (6-Amino-4-methyl-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-[5- (4-fluoro-phenoxy) ) -4-Methoxy-pyridin-2-yl] -methanone
  • Compound AA03 (6-Amino-3', 4', 5', 6'-Tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-(4-Methoxy-5-phenoxy-pyridin-2- Il)-Metanon
  • Examples of the compounds described in WO2019 / 215268 include, for example.
  • Compound BB01 1- [4- (4-fluorophenyl) -2- (triazole-2-yl) cyclopentyl] piperidine-3-amine
  • Compound BB02 1- [2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl] pyrazole-4-carbonitrile
  • Compound BB03 1- [2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl] pyrazole-3-carbonitrile
  • Compound BB04 1- [2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl] pyrrole-3-carbonitrile
  • Compound BB05 1- [2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl
  • TRPC3 / 6 channel inhibitors compounds represented by the general formula (1) or (2), intermediate compounds obtained in each of the above reaction formulas, and starting material compounds with isomers in double bonds, rings, and fused rings.
  • E, Z, cis, trans isomers isomers due to the presence of asymmetric carbons (R, S isomers, ⁇ , ⁇ isomers, enantiomers, diastereomers), optically active compounds (D, L, d, l), polar isomers (high polar isomers, low polar isomers) by chromatograph separation, equilibrium compounds, rotational isomers, mixtures of any proportion of these, racemic mixtures are geometric isomers, steric isomers, optical isomers If an isomer such as a body is present, all isomers are included.
  • the optical isomers can be separated by using various known division methods (for example, optical resolution by crystallization, direct optical resolution by chromatography, etc.).
  • the salts of TRPC3 / 6 channel inhibitors include all pharmaceutically acceptable salts.
  • the pharmaceutically acceptable salt is not particularly limited, and for example, an alkali metal salt such as sodium salt and potassium salt; an alkaline earth metal salt such as calcium salt and magnesium salt; an inorganic metal salt such as zinc salt; triethylamine, Organic base salts such as triethanolamine, trihydroxymethylaminomethane, amino acids; inorganic acid salts such as hydrochlorides, hydrobromates, sulfates, phosphates, nitrates; acetates, carbonates, propionates, Organic acids such as succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, ascorbate Examples include salt. These salts can be produced according to a conventional method.
  • Various isomers can be isolated by a known separation method.
  • a racemic compound can be derived into a sterically pure isomer by a general optical resolution method (for example, optical resolution by crystallization, direct optical resolution by chromatography, etc.).
  • the optically active compound can also be produced by using an appropriate optically active raw material.
  • the starting material compound, intermediate compound, and target compound represented by each of the above reaction formulas can be used in an appropriate salt form.
  • a TRPC3 / 6 channel inhibitor for example, a compound represented by the general formula (1) or (2), etc.
  • a salt thereof, or a prodrug thereof may contain one or more atoms. It can be replaced with an isotope atom.
  • isotope atoms include deuterium (2H), tritium (3H), 13C, 14N, 18O and the like.
  • the present invention contains TRPC3 / 6 channel inhibitors (eg, compounds represented by the general formula (1) or (2), etc.), salts thereof, or prodrugs thereof for the prevention and / or treatment of deafness.
  • the pharmaceutical composition of the present invention may be a preparation of a TRPC3 / 6 channel inhibitor, a salt thereof, or a prodrug thereof in the form of a conventional pharmaceutical composition, and the compound, a salt thereof, or a prodrug thereof. It may be prepared with a pharmaceutically acceptable carrier.
  • the carrier include commonly used fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, diluents such as lubricants, and excipients.
  • a prodrug is converted into a TRPC3 / 6 channel inhibitor (for example, a compound represented by the general formula (1) or (2)) by a reaction in vivo (for example, an enzymatic reaction or a reaction with gastric acid).
  • a reaction in vivo for example, an enzymatic reaction or a reaction with gastric acid.
  • a TRPC3 / 6 channel inhibitor for example, a compound represented by the general formula (1) or (2)
  • a reaction in vivo for example, an enzymatic reaction or a reaction with gastric acid.
  • ester examples include methyl ester, ethyl ester, 1-propyl ester, 2-propyl ester, pivaloyloxymethyl ester, acetyloxymethyl ester, cyclohexylacetyloxymethyl ester, 1-methylcyclohexylcarbonyloxymethyl ester and ethyloxy.
  • ester examples include carbonyloxy-1-ethyl ester and cyclohexyloxycarbonyloxy-1-ethyl ester.
  • the pharmaceutical composition of the present invention can be selected from various forms according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, liquids, suspensions, emulsions, granules and capsules. Examples include suppositories, injections (liquids, suspensions, etc.), ointments, inhalants, ear drops, and the like. Among these, preparations for oral administration, preparations for local (preferably intraoural) administration and injections are preferable, and preparations for oral administration are more preferable.
  • carrier used for molding tablets known carriers can be widely used, for example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, water, ethanol, etc.
  • Disintegration inhibitors 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. Be done.
  • the tablet can be a tablet with a normal lock skin, for example, a sugar coating agent, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet or a double tablet, or a multi-layer tablet, if necessary.
  • a sugar coating agent for example, a sugar coating agent, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet or a double tablet, or a multi-layer tablet, if necessary.
  • Known carriers can be widely used for molding pills, for example, excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc, gum arabic powder, tragant powder, gelatin. , Binders such as ethanol, disintegrants such as laminarin and agar, and the like.
  • the carrier used for molding the suppository known ones can be widely used, and examples thereof include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glyceride and the like.
  • the liquid, emulsion and suspension are preferably sterilized and isotonic with blood.
  • emulsions and suspending agents known ones can be widely used, for example, water, ethanol, propylene glycol, polyoxylated isostearyl alcohol, ethoxylated iso. Examples thereof include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters.
  • a sufficient amount of salt, glycerin, glucose, etc. can be contained in the pharmaceutical preparation to prepare an isotonic solution, and a usual solubilizing agent, buffer, and painlessening agent.
  • Agents and the like can be contained, and if necessary, colorants, preservatives, flavors, flavoring agents, sweeteners and the like and other pharmaceuticals can be contained.
  • the ointment has a form such as a paste, a cream, or a gel, and when preparing these forms, for example, white petrolatum, paraffin, glycerin, a cellulose derivative, polyethylene glycol, silicone, bentonite, etc. are used as a diluent. it can.
  • the inhalant is a preparation intended to be applied to the bronchi or lungs by inhaling the active ingredient as an aerosol, and includes a powder inhalant, an inhalation solution, an inhalation aerosol, and the like.
  • a powder inhaler is a preparation that is inhaled as an aerosol of powdered solid particles, and is usually produced by making the active ingredient into fine particles and mixing them with an additive such as lactose to make them homogeneous. it can.
  • the inhalation solution refers to a liquid inhalation agent applied by a nebulizer or the like, and can usually be produced by adding a solvent, an appropriate tonicity agent, a pH adjuster or the like to the active ingredient and mixing them.
  • the inhalation aerosol agent is a fixed-quantity spray-type inhalant that sprays a certain amount of the active ingredient together with the propellant filled in the container.
  • Inhalation aerosols are usually prepared by adding a solvent and an appropriate dispersant, stabilizer, etc. to the active ingredient to make a solution or suspension, filling a pressure-resistant container with a liquid propellant, and installing a metering valve. It can be manufactured by.
  • the pharmaceutical composition of the present invention may contain colorants, preservatives, flavors, flavors, sweeteners and other pharmaceuticals, if necessary.
  • TRPC3 / 6 channel inhibitors eg, compounds represented by the general formula (1) or (2)
  • salts thereof, or prodrugs thereof contained in the pharmaceutical composition of the present invention is particularly high.
  • it is not limited and can be appropriately selected from a wide range, it is usually 0.5 to 90% by weight, 1 to 85% by weight, preferably 1 to 80% by weight in the pharmaceutical composition.
  • the administration method of the pharmaceutical composition of the present invention is not particularly limited, and the pharmaceutical composition is administered by a method according to various formulation forms, patient age, sex, disease state, and other conditions.
  • the pharmaceutical composition is administered by a method according to various formulation forms, patient age, sex, disease state, and other conditions.
  • tablets, pills, liquids, suspensions, emulsions, granules and capsules they are orally administered.
  • it may be administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acid, or if necessary, intramuscularly, intradermally, subcutaneously, intraperitoneally, etc.
  • suppositories it is administered intrarectally.
  • inhalants it is administered nasally.
  • ear drops it is administered by ear.
  • Preferred administration methods are oral administration, injection administration (including subcutaneous administration, intramuscular administration, intravenous administration, and intrathecal administration), and ear administration, and more preferably oral administration.
  • the dose of the pharmaceutical composition of the present invention may be selected in consideration of usage, age, sex, degree of disease, and other conditions of the patient, and is an active ingredient TRPC3 / 6 channel inhibitor (for example, general formula).
  • the amount of (1) or the compound represented by (2), the salt thereof, or the prodrug thereof is usually 0.01 to 100 mg, preferably 0.1 to 50 mg per 1 kg of body weight per day. It is administered once to several times a day, or once every two days, three days, four days, five days, six days, one week, two weeks or four weeks. Since the dose varies depending on various conditions, a dose smaller than the above range may be sufficient, or a dose exceeding the above range may be required.
  • composition of the present invention can be used as a concomitant drug in combination with another drug.
  • the present invention is pharmaceutically acceptable for TRPC3 / 6 channel inhibitors (eg, compounds represented by the general formula (1) or (2)) in patients in need of prevention and / or treatment of deafness.
  • TRPC3 / 6 channel inhibitors eg, compounds represented by the general formula (1) or (2)
  • Methods of preventing and / or treating deafness may include administration of an effective amount of salt, or a prodrug thereof.
  • TRPC3 / 6 channel inhibitors eg, compounds represented by the general formula (1) or (2)
  • salts thereof, or prodrugs thereof have the effect of preventing and / or treating deafness.
  • Deafness includes sensorineural deafness, conductive deafness, mixed deafness, non-organic deafness, and the like, preferably sensorineural deafness, mixed deafness, and more preferably sensorineural deafness.
  • the deafness includes any of mild deafness, moderate deafness, severe deafness, and severe deafness, and is preferably mild deafness, moderate deafness, severe deafness, and more preferably mild deafness and moderate deafness.
  • deafness is preferably drug-induced deafness, i.e., drug-induced deafness (eg, drug-induced deafness).
  • drug include platinum preparations, antibacterial agents, salicylic acid agents, diuretics and the like.
  • platinum preparation include cisplatin, carboplatin, nedaplatin, oxaliplatin and the like.
  • antibacterial agent include aminoglycoside antibacterial agents such as streptomycin, canamycin, amikacin, gentamicin, bekanamycin, ribostamycin, dibekacin, tobramycin, isepamycin, arbekacin and havekacin.
  • salicylic acid agent examples include aspirin and sodium salicylate.
  • diuretics examples include furosemide, torasemide, bumetanide, azosemide, pyrethanide and the like.
  • drug-induced deafness deafness caused by platinum preparations, deafness caused by antibacterial agents, and deafness caused by salicylic acid agents are preferable, deafness caused by platinum preparations and deafness caused by antibacterial agents are more preferable, and deafness caused by platinum preparations. Deafness is especially preferred.
  • TRPC3 / 6 channel inhibitors eg, compounds represented by the general formula (1) or (2), etc.
  • salts thereof, or prodrugs thereof act to regulate the activity of TRPC3 channel, the activity of TRPC6 channel. It may have a regulatory effect or an effect of regulating the activity of both TRPC3 and TRPC6 channels.
  • the compounds of the present invention, salts thereof, or prodrugs thereof have TRPC3 / 6 channel inhibitory activity.
  • TRPC3 / 6 channel inhibitors eg, compounds represented by the general formula (1) or (2), etc.
  • salts thereof, or prodrugs thereof are TRPC3 and / or TRPC6 regulators or TRPC3 and / or TRPC6.
  • TRPC3 and / or TRPC6 channels are channels that are present in the cell membrane and control the influx of cation ions into the cell. Inhibition of TRPC3 and / or TRPC6 channel, in myofibroblasts, via Ca 2 + influx, acts inhibitory to downstream phosphorylation signal of TGF-beta, collagen I, smooth muscle type actin (alpha -It acts suppressively on the production of ⁇ -Smooth Muscle Actin) (for example, Inflammatory Bowel Diseases, 2015, Mar, 21 (3), 496-506).
  • TRPC3 and / or TRPC6-related diseases are diseases in which excessive activation of TRPC3 and / or TRPC6 channels (channels open and cation ions excessively flow into cells) is observed.
  • TRPC3 and / or TRPC6-related diseases are not particularly limited as long as they are diseases caused by, for example, excessive activation or excessive inactivation of TRPC3 channels and / or TRPC6 channels, but are excessive activation or excessive activation of TRPC6 channels. Diseases caused by inactivation are preferred.
  • TRPC3 and / or TRPC6-related diseases include, for example, fibrosis (eg, pulmonary fibrosis, renal fibrosis, liver cirrhosis due to fibrosis), neurodegenerative diseases (eg, muscle atrophic lateral sclerosis (ALS)).
  • fibrosis eg, pulmonary fibrosis, renal fibrosis, liver cirrhosis due to fibrosis
  • neurodegenerative diseases eg, muscle atrophic lateral sclerosis (ALS)
  • Alzheimer's disease, etc. muscle degenerative diseases (eg, muscle dystrophy, etc.), inflammatory diseases (eg, Crohn's disease, ulcerative colitis, non-alcoholic steatosis (NASH), etc.), Williams syndrome, chronic nephropathy, cardiac hypertrophy , Pulmonary hypertension, etc.
  • a preferred disease is, for example, fibrosis.
  • compounds represented by the general formula (1) or (2) are not easily metabolized in the liver.
  • it has high PBS solubility, which is advantageous for formulation, and in addition, it has high membrane permeability, which is therefore advantageous in terms of bioavailability.
  • the compound represented by the general formula (1) or (2) is excellent in terms of pharmacokinetics. Therefore, compared to conventional TRPC3 and / or TRPC6 inhibitors, or compared to conventional prophylactic and / or therapeutic agents for deafness, small amounts of inhibitory activity or preventive and / or deafness for a long period of time. Can exert therapeutic activity.
  • the compounds represented by the general formula (1) or (2) are TRP channels other than TRPC3 and TRPC6 channels (for example, TRPC1, TRPC2, TRPC5, TRPC7, TRPM2, TRPV1, TRPV6), or others. Is expected to have a small effect on Ca 2+ , N + , and K + channels, and is therefore highly selective for TRPC6 and TRPC3 channels and expected to have few side effects.
  • the present invention administers an effective amount of a compound represented by the general formula (1) or (2), a pharmaceutically acceptable salt thereof, or a prodrug thereof to a patient requiring TRPC3 and / or TRPC6 inhibitory treatment.
  • TRPC3 and / or TRPC6 inhibition methods including:
  • the present invention relates to TRPC3 / 6 channel inhibitors (eg, compounds represented by the general formula (1) or (2)), pharmaceuticals thereof, for patients in need of prevention or treatment of TRPC3 and / or TRPC6-related diseases.
  • TRPC3 / 6 channel inhibitors eg, compounds represented by the general formula (1) or (2)
  • the present invention relates to TRPC3 / 6 channel inhibitors (eg, compounds represented by the general formula (1) or (2)), pharmaceutically acceptable salts thereof, for patients in need of prevention or treatment of fibrosis. , Or methods of preventing or treating fibrosis, including administering an effective amount of the prodrug thereof.
  • TRPC3 / 6 channel inhibitors eg, compounds represented by the general formula (1) or (2)
  • pharmaceutically acceptable salts thereof for patients in need of prevention or treatment of fibrosis.
  • methods of preventing or treating fibrosis including administering an effective amount of the prodrug thereof.
  • the present invention relates to TRPC3 / 6 channel inhibitors for the production of prophylactic or therapeutic agents for TRPC3 and / or TRPC6-related diseases (eg, compounds represented by the general formula (1) or (2)), the pharmaceuticals thereof. May include the use of acceptable salts, or prodrugs thereof.
  • TRPC3 / 6 channel inhibitors for the production of prophylactic or therapeutic agents for TRPC3 and / or TRPC6-related diseases (eg, compounds represented by the general formula (1) or (2)), the pharmaceuticals thereof. May include the use of acceptable salts, or prodrugs thereof.
  • the present invention relates to TRPC3 / 6 channel inhibitors for the production of prophylactic or therapeutic agents for fibrosis (eg, compounds represented by the general formula (1) or (2)), pharmaceutically acceptable salts thereof. , Or the use of its prodrugs.
  • LC / MS analysis conditions Waters ACQUITY UPLC H-Class / QDa Sample Manager --FTN Quaternary Solvent Manager Column Heater A PDA e ⁇ Detector QDa Detector Column: ACQUITY UPLC BEH C18 1.7 ⁇ m (2.1 ⁇ 50 mm) Flow velocity: 0.5 mL / min Elution conditions: Mobile phase A; acetonitrile, mobile phase B; 0.1% formic acid aqueous solution
  • Step 1-1 1N aqueous sodium hydroxide solution (12.5 mL) in a solution of 2-fluoro-6- (trifluoromethyl) benzaldehyde (2 g, 10.41 mmol) and hydroxyamine hydrochloride (0.868 g, 12.49 mmol) in ethanol (10 mL). 12.5 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2-fluoro-6- (trifluoromethyl) benzaldehyde oxime (2.126 g).
  • Step 1-2 NCS (N-Chlorosuccinimide) (1.435 g, 10.75 mmol) in a solution of 2-fluoro-6- (trifluoromethyl) benzaldehyde oxime (2.12 g, 10.24 mmol) in DMF (10 mL) at 0 ° C. In addition, it was stirred overnight at room temperature. LC / MS showed that the oxime was converted to 100% chloride. A solution of 2-fluoro-N-hydroxy-6- (trifluoromethyl) benzimideyl chloride was used in the next reaction without purification.
  • Step 1-3 2-Fluoro from step 1-2 in a solution of 5-chloro-6- (piperazine-1-yl) nicotinate (1836 mg, 6.6 mmol) and triethylamine (2.93 mL, 21 mmol) in dichloromethane (10 mL).
  • a DMF solution of -N-hydroxy-6- (trifluoromethyl) benzimideyl chloride (6 mL, about 6 mmol) was added at room temperature and stirred overnight.
  • Aqueous 10% KHSO 4 was added to the reaction solution, followed by extraction with ethyl acetate.
  • Step 1-4 (E) -5-Chloro-6-(4-((2-fluoro-6- (trifluoromethyl) phenyl) (hydroxyimino) methyl) piperazine-1-yl) nicotinic acid (1026 mg) 2N potassium hydroxide A mixed solution of an aqueous solution (6 mL) and dioxane (18 mL) was stirred and heated at 105 ° C. for 3 hours. LC / MS analysis showed a conversion rate of 100%. The solution was concentrated under reduced pressure, neutralized with a 2N aqueous hydrochloric acid solution, and the obtained solid was collected by filtration. This was dried to give 876 mg of the title compound.
  • Step 6-1 2,6-dichloro-N according to the methods of steps 1-1 and 1-2 of Example 1, except that 2,6-dichlorobenzaldehyde was used instead of 2-fluoro-6- (trifluoromethyl) benzaldehyde.
  • a DMF solution of -hydroxy-6-benzimideyl chloride was obtained.
  • Step 6-2 In a solution of 1- (2-chlorophenyl) piperazine (118 mg, 0.6 mmol) and triethylamine (83 ⁇ L, 0.6 mmol) in dichloromethane (2 mL), step 6-1 2,6-dichloro-N-hydroxy-6- A DMF solution of benzimideyl chloride (0.5 mL, about 0.5 mmol) was added at room temperature and stirred for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Step 6-3 (E)-(4- (2-Chlorophenyl) piperazine-1-yl) (2,6-dichlorophenyl) methanone oxime (58.7 mg, 0.152 mmol) in 2N potassium hydroxide aqueous solution (1 mL) and dioxane (3 mL) The mixed solution with was stirred and heated at 120 ° C. for 25 hours. The solution was concentrated under reduced pressure, neutralized with 2N aqueous hydrochloric acid solution, and extracted with ethyl acetate.
  • Step 7-1 (E)-(Except that 1- (3-chloropyridin-2-yl) piperazine hydrochloride was used instead of 1- (2-chlorophenyl) piperazine, according to the method of step 6-2 of Example 6). 4- (3-Chloropyridin-2-yl) piperazine-1-yl) (2,6-dichlorophenyl) methanone oxime and Z isomer were obtained.
  • Step 7-2 (E)-(4- (3-Chloropyridin-2-yl) piperazine-1-yl) (2,6-dichlorophenyl) methanone oxime (192 mg, 0.498 mmol) in 2N potassium hydroxide aqueous solution (2 mL) and dioxane The mixed solution with (6 mL) was stirred and heated at 120 ° C. for 1 hour with a microwave. LC / MS analysis showed a conversion rate of about 50%. The solution was neutralized with 1N aqueous hydrochloric acid solution and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate.
  • Step 8-1 5 according to the method of step 6-2 of Example 6, except that 5-chloro-6- (piperazine-1-yl) nicotinate trifluoroacetate was used instead of 1- (2-chlorophenyl) piperazine.
  • -Chloro-6- (4-((2,6-dichlorophenyl) (hydroxyimino) methyl) piperazine-1-yl) nicotinic acid (Compound 082) was obtained.
  • Step 8-2 5-Chloro-6- (4-((2,6-dichlorophenyl) (hydroxyimino) methyl) piperazine-1-yl) nicotinic acid (215 mg, 0.5 mmol) in 2N potassium hydroxide aqueous solution (2 mL) and dioxane ( The mixed solution with 6 mL) was stirred and heated at 140 ° C. for 1 hour with a microwave. LC / MS analysis showed a conversion rate of about 90%. The solution was neutralized with 1N aqueous hydrochloric acid and aqueous 10% KHSO 4, and extracted with ethyl acetate.
  • a solution of (285 mg, 0.75 mmol) of DMF (3 mL) was stirred at room temperature for 3 hours, saturated brine was added, and the mixture was extracted with ethyl acetate.
  • Step 9-2 Example 6 in a solution of 5-chloro-N, N-dimethyl-6- (piperazine-1-yl) nicotinamide (159 mg, 0.415 mmol) and triethylamine (289 ⁇ L, 2.075 mmol) in DMF (2 mL).
  • a DMF solution 0.5 mL, about 0.5 mmol
  • 2,6-dichloro-N-hydroxy-6-benzimideyl chloride from step 6-1 was added at room temperature and stirred for 3 hours.
  • a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Step 9-3 (E) -5-Chloro-6- (4-((2,6-dichlorophenyl) (hydroxyimino) methyl) piperazine-1-yl) -N, N-dimethylnicotinamide (77.2 mg, 0.048 mg)
  • a mixed solution of 2N potassium hydroxide aqueous solution (2 mL) and dioxane (6 mL) was stirred and heated at 140 ° C. for 1 hour with a microwave.
  • LC / MS analysis showed a conversion rate of about 70%.
  • a 10% aqueous solution of KHSO 4 was added to the solution, and the mixture was extracted with ethyl acetate.
  • Step 10-1 3-Chloro- according to the method of step 6-2 of Example 6, except that 3-chloro-4- (piperazine-1-yl) benzoate methyl ester was used instead of 1- (2-chlorophenyl) piperazine. 4- (4-((2,6-dichlorophenyl) (hydroxyimino) methyl) piperazine-1-yl) benzoate methyl ester (Compound 102) was obtained (LC-MS: rt 2.97 min., M / z 442). (M + 1)).
  • Step 10-2 5-Chloro-6- (4-((2,6-dichlorophenyl) (hydroxyimino) methyl) piperazine-1-yl) Instead of nicotinic acid, 3-chloro-4- (4-((2,6-dichlorophenyl) ) (Hydroxyimino) methyl) piperazine-1-yl)
  • 3-chloro-4- (4-((2,6-dichlorophenyl) ) (Hydroxyimino) methyl) piperazine-1-yl
  • Step 11-1 2,5-Dichloro-N according to the methods of steps 1-1 and 1-2 of Example 1, except that 2,5-dichlorobenzaldehyde was used instead of 2-fluoro-6- (trifluoromethyl) benzaldehyde.
  • a DMF solution of -hydroxy-6-benzimideyl chloride was obtained.
  • Step 11-2 The use of 1- (3-chloropyridin-2-yl) piperazine hydrochloride in place of 1- (2-chlorophenyl) piperazine and the solution of 2,6-dichloro-N-hydroxy-6-benzimideyl chloride to the DMF solution.
  • 2-Il) piperazin-1-yl) (2,5-dichlorophenyl) methanone oxime, its Z isomer and E, Z mixture were obtained.
  • Step 11-3 (E)-(4- (3-Chloropyridin-2-yl) piperazine-1-yl) (2,5-dichlorophenyl) methanone oxime (26.8 mg, 0.069 mmol) in 2N potassium hydroxide aqueous solution (1 mL)
  • 2N potassium hydroxide aqueous solution 1 mL
  • the mixed solution of dioxane (3 mL) and dioxane (3 mL) was stirred and heated at 120 ° C. for 0.5 hours and then at 140 ° C. for 1 hour by microwave.
  • the solution was neutralized with 1N aqueous hydrochloric acid solution and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate.
  • Step 12-1 The use of 5-chloro-6- (piperazine-1-yl) nicotinate salt instead of 1- (2-chlorophenyl) piperazine, and the DMF of 2,6-dichloro-N-hydroxy-6-benzimideyl chloride.
  • Step 12-2 5-Chloro-6- (4-((2,5-dichlorophenyl) (hydroxyimino) methyl) piperazine-1-yl) with nicotinic acid (115.1 mg, 0.5 mmol) in 2N potassium hydroxide aqueous solution (2 mL)
  • the mixed solution with dioxane (6 mL) was stirred and heated at 140 ° C. for 2 hours with a microwave.
  • LC / MS analysis showed a conversion rate of about 100%.
  • the solution was neutralized with 1N aqueous hydrochloric acid and aqueous 10% KHSO 4, and extracted with ethyl acetate.
  • Step 13-1 1N aqueous sodium hydroxide solution (28.8 mL, 28) in a solution of 2-chloro-5- (trifluoromethyl) benzaldehyde (5 g, 23.97 mmol) and hydroxyamine hydrochloride (2 g, 28.8 mmol) in ethanol (20 mL). 8. mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate.
  • Step 13-2 NCS (N-Chlorosuccinimide) (2.99 g, 22.4 mmol) in a solution of 2-chloro-5- (trifluoromethyl) benzaldehyde oxime (4.77 g, 21.33 mmol) in DMF (10 mL) at 0 ° C. In addition, it was stirred overnight at room temperature. LC / MS showed that the oxime was converted to 100% chloride. A solution of 2-chloro-N-hydroxy-6- (trifluoromethyl) benzimideyl chloride was used in the next reaction without purification.
  • Step 13-3 2-Chloro from step 13-2 in a solution of 5-chloro-6- (piperazine-1-yl) nicotinate (70 mg, 0.252 mmol) and triethylamine (140 ⁇ L, 1.0 mmol) in dichloromethane (1 mL).
  • a DMF solution of -N-hydroxy-5- (trifluoromethyl) benzimideyl chloride (0.252 mL, about 0.252 mmol) was added at room temperature and stirred for 3 hours.
  • a 10% aqueous solution of KHSO 4 was added to the reaction solution, the insoluble material was filtered off, and the filtrate was extracted with ethyl acetate.
  • Step 13-4 2-N potassium hydroxide of 5-chloro-6- (4-((2-chloro-6- (trifluoromethyl) phenyl) (hydroxyimino) methyl) piperazine-1-yl) nicotinic acid (117 mg, 0.253 mmol)
  • a mixed solution of an aqueous solution (1 mL, 2 mmol) and dioxane (5 mL) was stirred and heated at 160 ° C. for 1 hour with a microwave.
  • LC / MS analysis showed a conversion rate of 100%.
  • the solution was neutralized with 10% aqueous KHSO 4 solution and extracted with ethyl acetate.
  • Step 19-1 Tert-butyl (1R, 5S) -3,8-diazabicyclo [3,2,1] octane-8-carboxylate (0.5 g, 2.355 mmol), 5,6-dichloronicotinic acid (0.452 g, 2)
  • a solution of .355 mmol) of pyridine (5 mL) was heated and stirred at 90 ° C. for 10 hours.
  • -3,8-diazabicyclo [3,2,1] octane-3-yl) -5-chloronicotinic acid was obtained. It was used in the next step without purification.
  • Step 19-2 Methanol (5 mL) of the above crude 6- (8- (Tert-butoxycarbonyl) -3,8-diazabicyclo [3,2,1] octane-3-yl) -5-chloronicotinic acid (227 mg, 0.617 mmol) ) was added with excess thionyl chloride at room temperature and left overnight. The reaction mixture was concentrated to dryness to give 208.2 mg of crude 6- (3,8-diazabicyclo [3,2,1] octane-3-yl) -5-chloronicotinate salt. It was used in the next step without purification.
  • Step 19-3 DMF of the above crude 6- (3,8-diazabicyclo [3,2,1] octane-3-yl) -5-chloronicotinate (152 mg, 0.5 mmol) and triethylamine (279 ⁇ L, 2.0 mmol) About 1N of 2-fluoro-N-hydroxy-6- (trifluoromethyl) benzimideyl chloride DMF solution (0.5 mL) was added to the (1.5 mL) solution at room temperature, and the mixture was stirred overnight.
  • Step 19-4 5-Chloro-6- (8-((2-fluoro-6- (trifluoromethyl) phenyl (hydroxyimino) methyl) -3,8-diazabicyclo [3,2,1] octane-3-yl) nicotinic acid
  • a mixed solution of (90 mg) 2N aqueous potassium hydroxide solution (0.6 mL) and dioxane (1.8 mL) was stirred and heated at 100 ° C. for 10 hours.
  • LC / MS analysis showed a conversion rate of about 95%.
  • reaction mixture was adjusted to pH about 3 with 10% KHSO 4 and saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, the organic layer was dried with magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was silica gel for preparative use. Purification by column chromatography (ethyl acetate / hexane) gave 40.1 mg of the title compound.
  • step 1-3 of the synthetic process 1-(1-((2-fluoro-6- (trifluoromethyl) phenyl (hydroxyimino) methyl) piperidine-4-yl) -1,3-dihydro- 2H-benzo [d] imidazol-2-one was obtained (Compound 282; LC-MS: rt 2.20 min., M / z 423 (M + 1)).
  • Step 34-1 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate tert-butyl (618 mg, 2 mmol), 5 , 6-Dichloronicotinic acid (384 mg, 2 mmol) and potassium carbonate (691 mg, 5 mmol), bistriphenylphosphine dichloride palladium (140 mg, 0.2 mmol) dimethoxyethane: ethanol: water (volume ratio 1: 1: 1) In addition to the mixed solution (12 mL) of, the mixture was heated at 90 ° C. for 2 hours under a nitrogen atmosphere.
  • Step 34-2 Methanol 1'-(tert-butoxycarbonyl) -3-chloro-1', 2', 3', 6'-tetrahydro- [2,4'-bipyridine] -5-carboxylic acid (696 mg, 2 mmol) In addition to (5 mL), excess thionyl chloride was then added and heated at 45 ° C. for 3 hours. The solvent is concentrated to give methyl 3-chloro-1', 2', 3', 6'-tetrahydro- [2,4'-bipyridine] -5-carboxylic acid methyl hydrochloride, and the next step without purification. Used for. LC-MS: rt 1.55 min., M / z 253 (M + 1).
  • Step 34-3 Methyl 3-chloro-1', 2', 3', 6'-tetrahydro- [2,4'-bipyridine] -5-carboxylic acid methyl hydrochloride (322 mg, 1.114 mmol) was dissolved in methanol (5 mL). Pd / C (53 mg) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The production of methyl 5-chloro-6- (piperidine-4-yl) nicotinate methyl hydrochloride (1.114 mmol) was confirmed in the reaction solution by LC / MS. The reaction was filtered through Celite to remove Pd / C, and the filtrate was concentrated and used for the next reaction. LC-MS: rt 1.57 min., M / z 255 (M + 1).
  • Step 34-4 A concentrate containing 5-chloro-6- (piperidine-4-yl) methyl nicotinate hydrochloride (1.114 mmol) and triethylamine (0.621 mL, 4.46 mmol) were added to DMF (3 mL) to prepare the first solution. .. 1.114 mmol of 2-fluoro-N-hydroxy-6- (trifluoromethyl) benzimideyl chloride was added to DMF to prepare a second solution (0.88235 mmol / mL in DMF). The total amount of the second liquid was added to the total amount of the first liquid at room temperature, and the mixture was stirred overnight.
  • Step 34-5 5-Chloro-6- (1-((2-fluoro-6- (trifluoromethyl) phenyl) (hydroxyimino) methyl) piperidine-4-yl) Methyl nicotinate (12 mg) and p-toluenesulfonic acid (1) mg) was added to DMSO (1 mL) and heated at 80 ° C. for 1 hour. DBU (diazabicycloundecene; 100 ⁇ L) was added thereto, and the mixture was heated at 100 ° C. for 90 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • DBU diazabicycloundecene
  • Step 36-1 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate tert-butyl (309 mg, 1 mmol) , 1-Chloro-2-iodobenzene (238 mg, 1 mmol) and potassium carbonate (207 mg, 1.5 mmol), bistriphenylphosphine dichloride palladium (70.2 mg, 0.1 mmol) dimethoxyethane: water (volume ratio 2: In addition to the mixed solution (12 mL) of 1), the mixture was heated at 90 ° C. for 1 hour under a nitrogen atmosphere.
  • Step 36-2 4- (2-Chlorophenyl) -3,6-dihydropyridine-1 (2H) -tert-butyl carboxylate (280.5 mg) was added to 4 N hydrochloric acid / ethyl acetate (5 mL) and left overnight at room temperature. The solvent was concentrated to give 4- (2-chlorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride, which was used in the next step without purification.
  • Step 36-3 4- (2-Chlorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride (115 mg, 0.5 mmol) and triethylamine (0.209 mL, 1.5 mmol) were added to DMF (3 mL) to prepare the first solution. did. 0.5 mmol of 2-fluoro-N-hydroxy-6- (trifluoromethyl) benzimideyl chloride was added to DMF to prepare a second solution (0.88235 mmol / mL in DMF). The total amount of the second liquid was added to the total amount of the first liquid at room temperature, and the mixture was stirred for 1 hour.
  • Step 36-4 (4- (2-Chlorophenyl) -3,6-dihydropyridine-1 (2H) -yl) (2-fluoro-6- (trifluoromethyl) phenyl) methanone oxime (Compound 362, E and Z isomers
  • the mixture 80 mg, 0.2 mmol) and p-toluenesulfonic acid (2 mg) were added to DMSO (1 mL) and heated at 80 ° C. for 30 minutes.
  • DBU 100 ⁇ L
  • a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Step 37-1 Tert-butyl 3-oxopiperazin-1-carboxylate (2.0 g, 9.99 mmol), ethyl 5,6-dichloronicotinate (2.3 g, 10.45 mmol), cesium carbonate (6.51 g, 19.98 mmol), zantphos (578 mg) , 0.999 mmol) and Pd 2 (dba) 3 (457 mg, 0.499 mmol) were added to toluene (20 mL) and heated at 120 ° C. for 3 hours in a nitrogen atmosphere. The reaction solution was passed through a silica gel pad to concentrate the filtrate.
  • Step 37-2 4- (3-Chloro-5- (ethoxycarbonyl) pyridin-2-yl) -3-oxopiperazin-1-carboxylate tert-butyl (369 mg, 0.961 mmol) in 4 N hydrochloric acid / ethyl acetate mixture (5) In addition to mL), the mixture was stirred overnight at room temperature, and the solvent was concentrated to dryness to obtain ethyl 5-chloro-6- (2-oxopiperazin-1-yl) nicotinate ethyl hydrochloride. The residue was used in the next step without purification.
  • Step 37-3 Add 5-chloro-6- (2-oxopiperazine-1-yl) ethyl nicotinate hydrochloride (296 mg, 0.925 mmol) and triethylamine (0.515 mL, 3.7 mmol) to DMF (6 mL) to add the first solution.
  • 0.925 mmol of 2-fluoro-N-hydroxy-6- (trifluoromethyl) benzimideyl chloride was added to DMF to prepare a second solution (0.88235 mmol / mL in DMF).
  • the second solution was added to the first solution at room temperature, and the mixture was stirred overnight.
  • Aqueous 10% KHSO 4 was added to the reaction solution, followed by extraction with ethyl acetate.
  • Step 37-4 Ethyl (Z) -5-chloro-6-(4-((2-fluoro-6- (trifluoromethyl) phenyl) (hydroxyimino) methyl) -2-oxopiperazin-1-yl) nicotinate (Compound 372) (Z); 128.8 mg) and p-toluenesulfonic acid (10 mg) were added to DMSO (2 mL) and heated at 80 ° C. for 1 hour. DBU (910 ⁇ L) was added thereto, and the mixture was heated at 120 ° C. for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Step 41-1 To a solution of 2-fluoro-6-iodobenzaldehyde (2.5 g, 10 mmol) in ethanol (15 mL), add a 2N aqueous sodium hydroxide solution (5.5 mL, 11 mmol) of hydroxyamine hydrochloride (0.790 g, 11 mmol). , Stirred overnight at room temperature. Water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 2-fluoro-6-iodobenzaldehyde oxime (2.505 g).
  • Step 41-2 NCS (N-chlorosuccinimide) (0.276 g, 2 mmol) was added to a solution of 2-fluoro-6-iodobenzaldehyde oxime (0.530 g, 2 mmol) in DMF (10 mL), and the mixture was stirred overnight at room temperature. LC / MS showed that the oxime was converted to 100% chloride. A solution of 2-fluoro-N-hydroxy-6-iodobenzimideyl chloride was used in the next reaction without purification.
  • Step 41-3 2-Fluoro-N-hydroxy-6-iodobenzimideyl of step 41-2 in a solution of 1- (2-chlorophenyl) piperazine (176 ⁇ L, 1 mmol) and triethylamine (168 ⁇ L, 1.2 mmol) in DMF (1 mL). A solution of chloride in DMF (5 mL, about 1 mmol) was added at room temperature and stirred overnight. A saturated aqueous ammonium chloride solution and water were added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Step 41-4 Add (4- (2-chlorophenyl) piperazine-1-yl) (2-fluoro-6-iodophenyl) methanone oxime (657 mg, 1 mmol) and p-toluenesulfonic acid (about 10 mg) to DMSO (5 mL) 80. It was heated at ° C. for 2 hours. DBU (diazabicycloundecene; 238 ⁇ L) was added thereto, and the mixture was heated at 120 ° C. for 60 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • DMSO 5 mL
  • DBU diazabicycloundecene
  • the organic layer is dried over sodium sulfate, the solvent is evaporated under reduced pressure, and the residue is purified by distillation with 100% ethyl acetate using silica gel column chromatography, followed by distillation with 5% methanol / ethyl acetate. A mixture containing the title compound was obtained. The mixture was dissolved in ethyl acetate and washed 3 times with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (27.9 mg).
  • TRPC6 calcium assay using HEK293 cells transiently expressing TRPC channels 1.
  • the TRPC6 gene was introduced into HEK293 cells (human fetal kidney-derived cells) by the lipofection method, and the TRPC6 channel was expressed on the cell membrane.
  • the plasmid DNA of TRPC6 pCI-neo (promega)
  • TRPC6 pCI-neo (promega)
  • HEK293 cells into which the TRPC3 gene was introduced were cultured to express TRPC3 channels on the cell membrane.
  • Ca 2+ -containing solution (2 mM CaCl 2 , 132 mM NaCl, 4 mM KCl, 1 mM MgCl 2 , 5 mM glucose, 5 mM HEPES (pH 7.4))
  • Ca 2+ free solution (132 mM NaCl, 4 mM KCl, 1 mM MgCl 2 , 5 mM glucose, 5 mM HEPES (pH 7.4))
  • Compound 011 is used as the test compound, and the amount added thereof is 0.01, 0.1, 0.5, 1.0, 5.0, 10, or 50 ⁇ M. In addition, 0.1% DMSO was used instead of the test compound as a control.
  • Carbacol (cch) is a TRPC channel activator, and when it is applied to cells, TRPC channels open and a large amount of Ca 2+ in the extracellular solution flows into the cells.
  • Fura-2 AM has high cell membrane permeability due to the presence of AM group (acetoxymethyl group), is easily taken up into cells, and the AM group is hydrolyzed inside the cell to become Fura-2. , Ca 2+ and chelate formation are possible, and the loss of the AM group makes it difficult for the cell to leak out of the cell.
  • the measurement results of TRPC6-expressing cells and TRPC3-expressing cells are shown in FIGS. 1 and 2 by calcium imaging, respectively.
  • the intracellular Ca 2+ concentration increased from about 100 nM to about 280 nM (TRPC6, Fig. 1) or about 100 nM to about 350 nM (TRPC3, Fig. 2) under control (DMSO) by adding carbachol (cch), but the test compound (TRPC3, Fig. 2) In compound 011), the increase was from about 100 nM to about 140 nM (TRPC6, FIG. 1) or from about 100 nM to about 180 nM (TRPC3, FIG. 2), and suppression of activation of TRPC6 and TRPC3 channels was confirmed.
  • the concentration measurement results - was created response curves TRPC6 and TRPC3 channel IC 50 for inhibition of was 4.6 ⁇ M (TRPC6), and 0.7 [mu] M (TRPC3).
  • Test Example 2 Calcium Assay Using HEK293 Cells Transiently Expressing TRPC6 Channels Using TRPC6-expressing cells prepared in the same manner as in Test Example 1, 10 ⁇ M Pyr 4, and 10 ⁇ M compounds 011, 031, 041, and as test compounds. The maximum calcium ion concentration value was measured 7 minutes after the start of measurement (that is, after replacement of the Ca 2+ -containing solution) in the same manner as in Test Example 1 except that 191 was used. The value calculated by subtracting the average value of the calcium ion concentration (initial value of the calcium ion concentration) up to 30 seconds after the start of measurement from this maximum calcium ion concentration value was defined as the amount of increase in calcium ions. The results are shown in FIG. In FIG.
  • the amount of increase in calcium ions is expressed as a relative value with the amount of increase in calcium ions in control (DMSO) as 100%.
  • the addition of the test compound reduced the amount of calcium ions flowing into the cells, confirming the suppression of TRPC6 channel activation.
  • Test Example 2-1 Calcium Assay Using HEK293 Cells Transiently Expressing TRPC6 Channel 10 ⁇ M Compounds 011, 361, 362 (E), 362 (Z), 371, 372 (Z), 381, and 401 were used as test compounds. , Pyr 4 was not used, but the calcium ion concentration was measured in the same manner as in Test Example 2 to determine the amount of increase in calcium ions. The amount of increase in calcium ions of each test compound is shown in Table 2 as a relative value with the amount of increase in calcium ions in control (DMSO) as 100%.
  • test compound reduced the calcium ions flowing into the cells, confirming the suppression of TRPC6 channel activation.
  • Test Example 3 Calcium assay using HEK293 cells transiently expressing TRPC6 channels 10 ⁇ M Pyr 4 and 10 ⁇ M compounds 202 (E), 061, and 071 as test compounds were used in place of carbacol as TRPC channel activators.
  • the calcium ion concentration was measured in the same manner as in Test Example 2 except that ATP was used, and the amount of increase in calcium ions was determined.
  • the results are shown in FIG. In FIG. 4, the amount of increase in calcium ions is represented as a relative value with the amount of increase in calcium ions in control (DMSO) as 100%.
  • the addition of the test compound reduced the amount of calcium ions flowing into the cells, confirming the suppression of TRPC6 channel activation.
  • Test Example 4 Electrophysiological evaluation using HEK293 cells transiently expressing the TRPC6 channel Evaluation was performed using TRPC6-expressing cells cultured under the same treatment as in Test Example 1. Transfected cells were placed in a microscopic chamber and TRPC6 current was measured in whole cell mode with patch glass electrodes (5-10 M ⁇ ). The extracellular solution and intracellular solution used here are as follows.
  • Extracellular solution (140 mM NaCl, 5 mM KCl, 1 mM CaCl 2 , 1.2 mM MgCl 2 , 10 mM Glucose, 10 mM HEPES (pH 7.4))
  • Intracellular solution (120 mM CsOH, 120 mM Aspartate, 20 mM CsCl, 2 mM MgCl 2 , 1.5 mM CaCl 2 , 5 mM EGTA, 10 mM Glucose, 10 mM HEPES, 2 mM ATP-Na, 0.1 mM GTP (pH 7. Four))
  • TRPC current was evoked by adding carbachol (100 ⁇ M) to the cells.
  • the current change obtained by adding 30 ⁇ M of the test compound (Compound 011) to the cells for 30 seconds 20 seconds after the addition of carbachol was evaluated.
  • Test Example 4 (carbachol: effect of compound 011 on TRPC6 current induced by cch) is shown in FIG.
  • the left figure of FIG. 5 shows a trace of -50 mV.
  • the right figure of FIG. 5 shows a current-voltage characteristic curve measured by applying a lamp wave (a linear voltage of -100 to +100 mV) for about 1 second at two time points a and b in the left figure. Since a significant decrease in the amount of current was observed after the addition of the test compound, the effect of suppressing TRPC6 channel activation was observed by the addition of the test compound.
  • Fibrosis inhibition evaluation experiment 1 (Western blotting and cell morphology observation) The expression of ⁇ -smooth muscle actin ( ⁇ -SMA) in fibroblasts was evaluated by Western blotting. Skin fibroblasts were isolated from 1-3 day old mice and 2.5x10 5 cells were seeded on a 12-well plate. After 24 hours, the medium was replaced with a medium from which fetal bovine serum had been removed, and the cells were cultured for another 24 hours, after which 10 ng / ml of transforming growth factor ⁇ 1 (TGF ⁇ 1) was added and the cells were cultured for 48 hours.
  • TGF ⁇ 1 transforming growth factor ⁇ 1
  • test compound 011 having a predetermined concentration (0.1 ⁇ M, 1 ⁇ M, 10 ⁇ M) and 10 ⁇ M Pyr 2 or DMSO (solvent control) were also added.
  • the morphology of the cells after culturing was observed using an all-in-one fluorescence microscope (Keyence BZ-X700) (magnification 20 times).
  • the cultured cells were lysed with lysis buffer (140 mM NaCl, 20 mM Tris-HCl pH7.8, 1% Triton-X100, 0.05% sodium deoxycholate, 0.1% SDS, 2 mM EDTA, proteinase inhibitor antibody) and SDS- After separation by PAGE, ⁇ -SMA was detected using an anti- ⁇ -SMA antibody (Sigma) as the primary antibody and an anti-mouse IgG antibody (Cell signaling) fused with horse radish peroxidase as the secondary antibody.
  • lysis buffer 140 mM NaCl, 20 mM Tris-HCl pH7.8, 1% Triton-X100, 0.05% sodium deoxycholate, 0.1% SDS, 2 mM EDTA, proteinase inhibitor antibody
  • FIG. 6 The results of Western blotting are shown in FIG. In FIG. 6, it is shown that the test compound (particularly 10 ⁇ M) and Pyr2 have lighter color development of the ⁇ -SMA antibody compared to the control (DMSO TGF ⁇ 1 +), and the test compound is induced by TGF ⁇ 1. It was confirmed that the expression of ⁇ -SMA was strongly inhibited.
  • Fibrosis inhibition evaluation experiment 2 (immunofluorescence staining method) Skin fibroblasts were isolated from mice in the same manner as in Test Example 5, a sterilized cover glass with a diameter of 12 mm was placed in a 12-well plate, 2.5x10 5 cells were seeded, and the cells were grown on the cover glass. I let you. After 24 hours, the medium was replaced with a medium from which fetal bovine serum had been removed, and the cells were cultured for another 24 hours. Separately, cardiac fibroblasts were isolated from 1-2 day old rats and treated in the same manner as for cutaneous fibroblasts.
  • TGF ⁇ 1 10 ng / ml TGF ⁇ 1 was added to the skin fibroblasts, and 2 ng / ml TGF ⁇ 2 was added to the heart fibroblasts, and the cells were cultured for 48 hours.
  • 10 ⁇ M test compound Compound 011
  • 10 ⁇ M Pyr 2 10 ⁇ M Pyr 2 (conventional inhibitor)
  • DMSO solvent control
  • the cells were immobilized with 4% paraformaldehyde and then permeabilized with Tris buffered saline pH 7.4 (TBS) containing 0.5% Triton-X100.
  • TBS Tris buffered saline pH 7.4
  • ⁇ -SMA was detected using anti- ⁇ -SMA antibody (Sigma) as the primary antibody and anti-mouse IgG antibody (Molecular probe) fused with Alexa488 as the secondary antibody, and fluorescence microscopy was performed. Images were acquired using a 20x objective by (Keyence). The average fluorescence intensity / pixel per cell area was calculated and analyzed using Image J software.
  • FIG. 7 skin fibroblasts
  • FIG. 8 cardiac fibroblasts
  • TGF ⁇ treatment enhanced the expression of fibrous ⁇ -SMA.
  • Compound 011 almost completely suppressed TGF ⁇ -induced expression of ⁇ -SMA, much like Pyr2.
  • Cisplatin injection (Nichi-Iko, 0.5 mg / ml) was intraperitoneally administered at 12 mg / kg to 5-8 week old male CBA / N mice purchased from Japan SLC Co., Ltd. 7 Hearing levels in mice were tested by auditory brainstem response (ABR) measurements day and 14 days later. It was confirmed that intraperitoneal administration of cisplatin (CDDP) reduced hearing levels in a wide frequency band of 5-36 kHz.
  • ABR Auditory brainstem response
  • a tone burst sound consisting of an ascending and descending phase of 0.5 ms and a stationary phase of 2 ms was given for five frequencies of 5, 10, 16, 24, and 36 kHz.
  • the potential change of nerve cells in the auditory conduction path caused by this stimulating sound is amplified 5000 times by a signal amplifier (EX-1 Differential amplifier; Dagan Corporation, MN, USA), and then a bandpass of 0.3-2 kHz. It was filtered and acquired as ABR data. Each data was used for analysis after integrating and averaging 800 stimuli.
  • the auditory threshold for each frequency was determined as the lowest sound pressure level at which ABR waves II and III were clearly visible when the sound pressure was changed in 10 dB increments.
  • the voltage-sound pressure characteristics of the speaker were pre-calibrated by a microphone (Sokolich G-II Ultrasonic Probe Microphone System; WGS / Associates, CA, USA), and stimulation sounds of each frequency were generated accordingly. After the measurement, the mice were rapidly awakened by intraperitoneal administration of antisedan 0.3 mg / kg.
  • ABR auditory brainstem response
  • the results of Group 1 indicate that cisplatin administration caused an increase in the auditory threshold.
  • the results of Group 2 indicate that administration of Compound 011 significantly suppressed the increase in the auditory threshold.
  • the results of Group 3 show that administration of Compound 011 causes little variation in the auditory threshold of normal mice. From the above, it was confirmed that compound 011 can suppress deafness by oral administration, which is easy to administer.
  • Cisplatin injection (Nichi-Iko, 0.5 mg / ml) was applied to 5-8 week old male CBA / N mice purchased from Nippon SLC Co., Ltd. at 12 mg / kg peritoneally. Blood was collected from the tail vein 1 and 2 days after administration. The blood was centrifuged at 4 ° C. and 1000 g for 5 minutes, and the supernatant was used as a plasma sample. This plasma sample was analyzed by Shimadzu Techno Research's high frequency inductively coupled plasma (ICP) mass analysis to evaluate the plasma platinum (plasma Pt) concentration, which reflects the plasma cisplatin concentration.
  • ICP inductively coupled plasma
  • PBS Flujifilm, Japan; phosphate buffer
  • compound 011 suspended in PBS at 2 mg / ml was administered at 10 mg / kg once daily from the day before cisplatin administration to 2 days after cisplatin administration.
  • a pretreatment for ICP mass spectrometry 0.5 ml of nitric acid was added to the plasma sample, the container was sealed, and then microwave decomposition (ETHOS-TC, Milestone General) was performed at 180 ° C. for 5 minutes.
  • Pyr4 is known to have TRPC3 inhibitory activity and TRPC6 inhibitory activity.
  • Hair cell death is known as a common factor in progressive hearing impairment due to various environmental factors (excessive noise, drugs (chemotherapeutic agents such as aminoglycoside antibiotics and cisplatin, aging, etc.)). Screening evaluation based on hair cell death is used for the development of therapeutic agents for deafness. Zebrafish neuromast is used for this screening (C. Ton and C. Parng, The use of zebrafish for assessing ototoxic and otoprotective agents. Hearing research, 208, 79-88 (2005)). Zebrafish have lateral lines consisting of neuromast composed of hair cells on the surface of the body, and the hair cells are morphologically and functionally similar to the hair cells of the inner ear of mammals.
  • Neuromast is useful in assessing hair cell death in animals. Since neuromast occurs at a fixed position along the head and body of zebrafish, it is possible to easily determine hair cell shedding and hair cell death by applying a drug sample by using fluorescence imaging. The effect of the drug sample on hair cells can be quantified.
  • mice Ten embryos (zebrafish fry, five embryos per well in two wells) were used in each test. 1.5 ⁇ M and 3 ⁇ M Pyr4 were used as test substances in the test.
  • As a vehicle control group untreated embryos were used in breeding medium (0.16 mM DDL 4 , 0.4 mM CaCl 2 , 0.17 mM KCl, 5 mM NaCl, 10 mM Hepes (pH 7.2-7.6) + 0.5% DMSO).
  • breeding medium 0.16 mM DDL 4 , 0.4 mM CaCl 2 , 0.17 mM KCl, 5 mM NaCl, 10 mM Hepes (pH 7.2-7.6) + 0.5% DMSO.
  • As a positive control group embryos treated with 1000 ⁇ M D-methionine in breeding medium were used.
  • As an auditory toxicity induction group cisplatin treatment group
  • Embryos (fry 5 days after fertilization) were exposed to cisplatin after pretreatment with the test substance, D-methionine, or vehicle control at 28.5 ° C. for 1 hour, respectively. Then, each of them was bred at 28.5 ° C. for 24 hours and then stained as follows. Replace the medium with 0.01% DASPEI (2- (4- (dimethylamino) styryl) -N-ethylpyridinium iodide), incubate the plate in the dark for 15 minutes at room temperature, then wash 3 times with the breeding medium for 5 minutes. It was.
  • DASPEI 2- (4- (dimethylamino) styryl) -N-ethylpyridinium iodide
  • embryos were anesthetized with 0.003% trikine, sideways to methylcellulose, and images were acquired using a Leica stereoscope and LAS AF software. Images were used to quantify the number of neuromasts present on the lateral lines of each embryo. In addition to this, embryos are classified into three different categories based on the fluorescence intensity of the neuromast (i: bright, ii: dim, iii: barely or no detect). It was classified into. The proportion of embryos belonging to each category was determined for each experimental group. After taking all the pictures, the embryos were euthanized.
  • CISP and CISPL mean cisplatin and Met means methionine.
  • the experiment was considered valid because the proportion of unchanged embryos in the untreated control group exceeded 80%.
  • the number of embryonic neuromasts in the cisplatin-treated group was statistically significantly lower than that in the vehicle control group.
  • D-methionine suppressed the decrease in the number of neuromasts due to cisplatin treatment.
  • Treatment with Pyr4 did not affect neuromast survival at any of the assessed concentrations and suppressed cisplatin treatment-induced neuromast loss. Similar effects were seen at both 1.5 and 3 ⁇ M concentrations, which may indicate that a plateau was reached.

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Abstract

A problem addressed by the present invention is to provide a pharmaceutical composition for the prevention and/or treatment of hearing loss.　The present invention relates to a pharmaceutical composition for the prevention and/or treatment of hearing loss that contains a compound represented by general formula (1) [in the formula, A is an optionally substituted benzene ring. B is an optionally substituted aryl or an optionally substituted heteroaryl. X is an oxygen atom or a sulfur atom. Y is a nitrogen atom or a carbon atom. In general formula (2), general formula (3) is a single bond or a double bond when Y is a carbon atom and a single bond when Y is a nitrogen atom. R1 are each independently a lower alkyl, or two R1 may bond to each other to form a spiro ring or a crosslinked structure, or two R1 may bond to each other to form a saturated fused heterocycle together with carbon atoms and nitrogen atoms that constitute a ring that includes Y. p is 0, 1, or 2. Or, (R1)p is an oxo.], a salt thereof, or a prodrug thereof.

Description

難聴の予防および／または治療用医薬組成物Pharmaceutical composition for the prevention and / or treatment of deafness
　本発明は、難聴の予防および／または治療用医薬組成物に関する。 The present invention relates to a pharmaceutical composition for the prevention and / or treatment of deafness.
　聴覚は、外耳－中耳－内耳蝸牛－脳神経系から構成される一連の感覚知覚システムによって成り立っている。空気の振動である音は、外耳道を通って鼓膜を揺らし、中耳骨による機械的増幅を受けて内耳蝸牛に到達する。蝸牛では、音の振動という機械的信号が感覚細胞である有毛細胞によって電気信号に変換され、神経伝達を介して最終的に脳の聴覚野へと情報が伝えられる。この経路の構成要素が障害されると、音に対する知覚能力の低下、つまり難聴が引き起こされる。難聴は、内耳及び外耳伝達系の障害による伝音難聴と、内耳蝸牛から脳神経系の障害による感音難聴とに分類される。
　難聴は、強大な音への暴露、遺伝、加齢などにより引き起こされるだけでなく、抗がん剤、特に白金製剤（シスプラチン、カルボプラチン、ネダプラチン、オキサリプラチン等）による副作用、抗生物質の副作用などによっても引き起こされる。
　シスプラチン（CDDP；シス-ジアミンジクロロ白金(II)）は、がん、特に小児がんの治療に用いられるが、その副作用により難聴が生じることが知られている。一般的に、難聴の治療薬としては、ステロイドホルモン、ビタミンB12、ATP、血管拡張剤といった薬剤が使われるが、その効果について十分なエビデンスはなく、未だ議論の余地が残されている。そのため、効果的な治療薬の開発が待ち望まれている。 Hearing consists of a series of extrasensory perception systems consisting of the outer ear-middle ear-inner ear cochlea-cranial nerve system. The sound, which is the vibration of air, shakes the eardrum through the ear canal and is mechanically amplified by the middle ear bone to reach the inner ear cochlea. In the cochlea, the mechanical signal of sound vibration is converted into an electrical signal by hair cells, which are sensory cells, and information is finally transmitted to the auditory cortex of the brain via nerve transmission. Impairment of the components of this pathway causes diminished perception of sound, or deafness. Deafness is classified into conductive hearing loss due to disorders of the inner and outer ear transmission systems and sensorineural hearing loss due to disorders of the cochlea of the inner ear to the cranial nerve system.
Deafness is caused not only by exposure to strong sounds, inheritance, aging, etc., but also by side effects of anticancer drugs, especially platinum preparations (cisplatin, carboplatin, nedaplatin, oxaliplatin, etc.), side effects of antibiotics, etc. Is also triggered.
Cisplatin (CDDP; cis-diaminedichloroplatinum (II)) is used in the treatment of cancer, especially childhood cancer, but its side effects are known to cause deafness. Generally, drugs such as steroid hormones, vitamin B12, ATP, and vasodilators are used as treatments for deafness, but there is not enough evidence for their effects and it is still controversial. Therefore, the development of effective therapeutic agents is awaited.
　TRP（Transient receptor potential）遺伝子は、１９８９年にショウジョウバエの光受容体応答変異株の原因遺伝子として同定された。その後の研究により、TRP遺伝子にコードされるタンパク質と相同性をもつタンパク質は哺乳類でも多く見出され、基本的に細胞膜において陽イオンチャネルとして機能する。TRPチャネルは莫大な機能的多様性を持つスーパーファミリーを形成しており、TRPA、TRPV、TRPM、TRPCなどのグループに分類される。TRPC（TRP classicまたはTRP canonical）グループはさらにTRPC1～C7のサブグループに分類される。 The TRP (Transient receptor potential) gene was identified in 1989 as the causative gene of the Drosophila photoreceptor response mutant strain. Subsequent studies have found many proteins homologous to the protein encoded by the TRP gene in mammals, which basically function as cation channels in the cell membrane. TRP channels form a superfamily with enormous functional diversity and fall into groups such as TRPA, TRPV, TRPM and TRPC. The TRPC (TRP classic or TRP canonical) group is further subdivided into TRPC1 to C7 subgroups.
　TRPC3欠損マウスは圧負荷誘発性の心臓線維化に対して抵抗性を示すこと、およびTRPC3チャネル阻害剤であるPyr3投与によってマウスの圧負荷誘発性心臓線維化を強力に抑制することが知られている（非特許文献１、２）。また、TRPC6欠損マウスはブレオマイシン誘発肺線維化および片側尿管閉塞による腎間質線維化に対して抵抗性を示し（非特許文献３、４）、TRPC3およびTRPC6チャネルの阻害剤であるPyr2（BTP2）の投与により、マウス片側尿管閉塞による腎間質線維化を抑制する。 It is known that TRPC3-deficient mice are resistant to pressure-load-induced cardiac fibrosis, and that administration of the TRPC3 channel inhibitor Pyr3 strongly suppresses pressure-load-induced cardiac fibrosis in mice. (Non-Patent Documents 1 and 2). In addition, TRPC6-deficient mice showed resistance to bleomycin-induced pulmonary fibrosis and renal interstitial fibrosis due to unilateral ureteral obstruction (Non-Patent Documents 3 and 4), and Pyr2 (BTP2), which is an inhibitor of TRPC3 and TRPC6 channels. ) Suppresses renal interstitial fibrosis due to unilateral ureteral obstruction in mice.
　TRPC3阻害作用および／またはTRPC6阻害作用を示す化合物としては、Pyr2（BTP2)、Pyr3、Pyr4、GSK2332255B、GSK2833503A、SAR7334、BI-749327等が報告されている（非特許文献５～１１）。また、US2019/0169168（特許文献１）にはTRPC6チャネルを阻害する作用を示す化合物が記載され、WO2019/215268（特許文献２）にはTRPC3チャネルおよびTRPC6チャネルを阻害する作用を示す化合物が記載されている。 Pyr2 (BTP2), Pyr3, Pyr4, GSK2332255B, GSK2833503A, SAR7334, BI-749327 and the like have been reported as compounds exhibiting TRPC3 inhibitory action and / or TRPC6 inhibitory action (Non-Patent Documents 5 to 11). Further, US2019 / 0169168 (Patent Document 1) describes a compound showing an action of inhibiting TRPC6 channel, and WO2019 / 215268 (Patent Document 2) describes a compound showing an action of inhibiting TRPC3 channel and TRPC6 channel. ing.
US2019/0169168A1US2019 / 0169168A1 WO2019/215268A1WO2019 / 215268A1
　難聴の予防および／または治療用医薬組成物の提供を課題とする。 The subject is to provide a pharmaceutical composition for the prevention and / or treatment of deafness.
　本発明者らは、上記課題を解決すべく、鋭意検討した結果、TRPC3チャネルおよびTRPC6チャネルからなる群から選択される少なくとも１種のTRPCチャネルの阻害活性を有する物質（本明細書中、「TRPC3/6チャネル阻害物質」と称することがある。）、例えば後述の、一般式（１）で表わされる化合物、（２）で表される化合物、Pyr2、Pyr3、Pyr4、GSK2332255B、GSK2833503A、SAR7334、BI-749327、US2019/0169168に開示された化合物（例えば化合物AA01～AA95等）、WO2019/215268に開示された化合物（例えば化合物BB01～BB32等）等、その塩、あるいはそれらのプロドラッグが難聴の予防および／または治療に有用であることを見出し、本発明を完成した。代表的な本発明は以下の通りである。　 　　　　　 As a result of diligent studies to solve the above problems, the present inventors have conducted a substance having an inhibitory activity on at least one TRPC channel selected from the group consisting of TRPC3 channel and TRPC6 channel (in the present specification, "TRPC3". / 6 channel inhibitor "), for example, the compound represented by the general formula (1), the compound represented by (2), Pyr2, Pyr3, Pyr4, GSK2332255B, GSK2833503A, SAR7334, BI, which will be described later. -749327, compounds disclosed in US2019 / 0169168 (eg, compounds AA01 to AA95, etc.), compounds disclosed in WO2019 / 215268 (eg, compounds BB01 to BB32, etc.), salts thereof, or prodrugs thereof prevent hearing loss. The present invention has been completed by finding that it is useful for treatment and / or treatment. A typical invention is as follows.
項１．
　一般式（１）
Figure JPOXMLDOC01-appb-C000007
 Item 1.
General formula (1)
Figure JPOXMLDOC01-appb-C000007
［式中、
Ａは、置換されていてもよいベンゼン環である。
Ｂは、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールである。
Ｘは、酸素原子または硫黄原子である。
Ｙは、窒素原子または炭素原子である。
Figure JPOXMLDOC01-appb-C000008
 Ｒ１は、互いに独立して低級アルキルであるか、２個のＲ１が互いに結合して、スピロ環または架橋構造を形成していてもよい、あるいは２個のＲ１が互いに結合して、Ｙを含む環を構成する炭素原子および窒素原子と共に飽和縮合複素環を形成していてもよい。
ｐは、０、１、または２である。
あるいは、（Ｒ１）ｐはオキソである。］
で表される化合物、その塩、またはそのプロドラッグを含有する難聴の予防および／または治療用医薬組成物。 [During the ceremony,
A is a optionally substituted benzene ring.
B is an aryl that may be substituted or a heteroaryl that may be substituted.
X is an oxygen atom or a sulfur atom.
Y is a nitrogen atom or a carbon atom.
Figure JPOXMLDOC01-appb-C000008
 R 1 is either independently of one another are lower alkyl, two of R 1 are bonded to each other, may form a spiro ring or a crosslinked structure, or two of R 1 are bonded to each other, A saturated condensed heterocycle may be formed together with carbon atoms and nitrogen atoms constituting a ring containing Y.
p is 0, 1, or 2.
Alternatively, (R 1 ) p is oxo. ]
A pharmaceutical composition for preventing and / or treating deafness, which comprises a compound represented by, a salt thereof, or a prodrug thereof.
項２．
　一般式（１）において、Ｂが、置換されていてもよい単環のアリールあるいは置換されていてもよい単環または二環の含窒素ヘテロアリールである、項１に記載の医薬組成物。　　　 Item 2.
Item 2. The pharmaceutical composition according to Item 1, wherein in the general formula (1), B is a optionally substituted monocyclic aryl or a optionally substituted monocyclic or bicyclic nitrogen-containing heteroaryl.
項３．
　一般式（１）において、Ａが、下記Ａ－１）～Ａ－１６）：
Ａ－１）ハロゲン、
Ａ－２）水酸基、
Ａ－３）ニトロ、
Ａ－４）シアノ、
Ａ－５）カルボキシル、
Ａ－６）置換されていてもよいアミノ、
Ａ－７）置換されていてもよい環状アミノ、
Ａ－８）置換されていてもよい低級アルキル、
Ａ－９）置換されていてもよい低級アルコキシ、
Ａ－１０）低級アルコキシカルボニル、
Ａ－１１）低級アルキルスルホニル、
Ａ－１２）低級アルキルまたは低級アルキルスルホニルで置換されていてもよいカルバモイル、
Ａ－１３）置換されていてもよい環状アミノカルボニル、
Ａ－１４）低級アルキルで置換されていてもよいスルファモイル、
Ａ－１５）置換されていてもよい環状アミノスルホニル、および
Ａ－１６）テトラゾリル
からなる群より選択される少なくとも１種の基で置換されていてもよいベンゼン環である、項１または２に記載の医薬組成物。 Item 3.
In the general formula (1), A is the following A-1) to A-16):
A-1) Halogen,
A-2) Hydroxyl group,
A-3) Nitro,
A-4) Cyano,
A-5) Carboxyl,
A-6) Amino, which may be substituted,
A-7) Cyclic amino, which may be substituted,
A-8) Lower alkyl, which may be substituted,
A-9) Substituted lower alkoxy,
A-10) Lower alkoxycarbonyl,
A-11) Lower alkyl sulfonyl,
A-12) Carbamoyl, which may be substituted with a lower alkyl or lower alkyl sulfonyl,
A-13) Cyclic aminocarbonyl, which may be substituted,
A-14) Sulfamoyl, which may be substituted with a lower alkyl,
Item 1 or 2, wherein A-15) a cyclic aminosulfonyl optionally substituted, and A-16) a benzene ring optionally substituted with at least one group selected from the group consisting of tetrazolyl. Pharmaceutical composition.
項４．
　一般式（１）において、Ｂが、単環のアリールあるいは単環または二環のヘテロアリールであり、単環のアリールは下記Ｂ－１）～Ｂ－１６）からなる群より選択される少なくとも１種の基で置換されていてもよく、単環または二環のヘテロアリールは下記Ｂ－１）～Ｂ－１７）からなる群より選択される少なくとも１種の基で置換されていてもよい、項１～３のいずれかに記載の医薬組成物：
Ｂ－１）ハロゲン、
Ｂ－２）水酸基、
Ｂ－３）ニトロ、
Ｂ－４）シアノ、
Ｂ－５）カルボキシル
Ｂ－６）置換されていてもよいアミノ、
Ｂ－７）置換されていてもよい環状アミノ、
Ｂ－８）置換されていてもよい低級アルキル、
Ｂ－９）置換されていてもよい低級アルコキシ、
Ｂ－１０）低級アルコキシカルボニル、
Ｂ－１１）低級アルキルスルホニル、
Ｂ－１２）低級アルキルまたは低級アルキルスルホニルで置換されていてもよいカルバモイル、
Ｂ－１３）置換されていてもよい環状アミノカルボニル、
Ｂ－１４）低級アルキルで置換されていてもよいスルファモイル、
Ｂ－１５）置換されていてもよい環状アミノスルホニル、
Ｂ－１６）テトラゾリル、および
Ｂ－１７）オキソ。 Item 4.
In the general formula (1), B is a monocyclic aryl or a monocyclic or bicyclic heteroaryl, and the monocyclic aryl is at least one selected from the group consisting of the following B-1) to B-16). It may be substituted with a species group, and the monocyclic or bicyclic heteroaryl may be substituted with at least one group selected from the group consisting of B-1) to B-17) below. Item 3. The pharmaceutical composition according to any one of Items 1 to 3.
B-1) Halogen,
B-2) Hydroxyl group,
B-3) Nitro,
B-4) Cyano,
B-5) Carboxyl B-6) May be substituted amino,
B-7) Cyclic amino, which may be substituted,
B-8) Substituted lower alkyl,
B-9) Substituted lower alkoxy,
B-10) Lower alkoxycarbonyl,
B-11) Lower alkyl sulfonyl,
B-12) Carbamoyl, which may be substituted with lower alkyl or lower alkyl sulfonyl,
B-13) Cyclic aminocarbonyl, which may be substituted,
B-14) Sulfamoyl, which may be substituted with a lower alkyl,
B-15) Cyclic aminosulfonyl, which may be substituted,
B-16) tetrazolyl, and B-17) oxo.
項５．
　一般式（１）において、ベンゾイソオキサゾールまたはベンゾイソチアゾール骨格の４位が置換された、項１～４のいずれかに記載の医薬組成物。 Item 5.
Item 4. The pharmaceutical composition according to any one of Items 1 to 4, wherein in the general formula (1), the 4-position of the benzoisoxazole or benzoisothiazole skeleton is substituted.
項６．
　一般式（１）において、
Ｂが、置換されたピリジルまたは置換されたフェニルであって、Ｙと結合しているピリジンまたはベンゼン環上の炭素原子に対して少なくともオルト位の炭素原子が置換されている、
項１～３のいずれかに記載の医薬組成物。 Item 6.
In the general formula (1)
B is a substituted pyridyl or a substituted phenyl in which the carbon atom at least in the ortho position is substituted with respect to the carbon atom on the pyridine or benzene ring bonded to Y.
Item 8. The pharmaceutical composition according to any one of Items 1 to 3.
項７．
　一般式（１）において、
Ａが、ハロゲン、低級アルコキシ、およびハロゲンで置換されていてもよい低級アルキル、からなる群より選択される少なくとも１種の基で置換されていてもよい、ベンゼン環であり、
Ｂが、ピリジルまたはフェニルであり、それぞれ下記Ｂ－１）、Ｂ－５）、Ｂ－８）、Ｂ－１０）、Ｂ－１２）、およびＢ－１３）：
Ｂ－１）ハロゲン、
Ｂ－５）カルボキシル、
Ｂ－８）置換されていてもよい低級アルキル、
Ｂ－１０）低級アルコキシカルボニル、
Ｂ－１２）低級アルキルまたは低級アルキルスルホニルで置換されていてもよいカルバモイル、および
Ｂ－１３）置換されていてもよい環状アミノカルボニル、
からなる群より選択される少なくとも１種の基で置換されていてもよく、
Ｒ１は、互いに独立してＣ１～Ｃ３アルキルであるか、あるいは２個のＲ１が互いに結合して、メチレン基、ジメチレン基、またはトリメチレン基であり、
あるいは、（Ｒ１）ｐはオキソである、
項１～４のいずれかに記載の医薬組成物。 Item 7.
In the general formula (1)
A is a benzene ring optionally substituted with at least one group selected from the group consisting of halogens, lower alkoxys, and lower alkyls optionally substituted with halogens.
B is pyridyl or phenyl, respectively, B-1), B-5), B-8), B-10), B-12), and B-13):
B-1) Halogen,
B-5) Carboxylyl,
B-8) Substituted lower alkyl,
B-10) Lower alkoxycarbonyl,
B-12) Carbamoyl, which may be substituted with a lower alkyl or lower alkylsulfonyl, and B-13) Cyclic aminocarbonyl, which may be substituted.
It may be substituted with at least one group selected from the group consisting of
R 1 is each other or are independently C1 ~ C3 alkyl, or two of R 1 are bonded to each other, a methylene group, dimethylene or trimethylene,
Alternatively, (R 1 ) p is oxo,
Item 8. The pharmaceutical composition according to any one of Items 1 to 4.
項８．
　一般式（１）で表される化合物が、一般式（１Ａ）
Figure JPOXMLDOC01-appb-C000009
 Item 8.
The compound represented by the general formula (1) is the general formula (1A).
Figure JPOXMLDOC01-appb-C000009
［式中、
Ｚは、窒素原子またはＣＨである。
Ｙは、窒素原子または炭素原子である。
Figure JPOXMLDOC01-appb-C000010
 Ｒ１１は、互いに独立して、メチルまたはエチルであるか、あるいは２個のＲ１１が互いに結合して、メチレン、ジメチレン、またはトリメチレンによる架橋構造を形成していてもよい。
ｐは、０、１、または２である。
あるいは、（Ｒ１１）ｐはオキソである。
Ｒ２１、Ｒ２２、およびＲ２３は、互いに独立して、水素原子、ハロゲン、カルバモイル、またはトリフルオロメチルである。
Ｒ３１、Ｒ３２、およびＲ３３は、互いに独立して、水素原子、ハロゲン、ハロゲンで置換された低級アルキル、メチル、カルボキシル、低級アルコキシカルボニル、モノメチルアミノカルボニル、またはジメチルアミノカルボニルである。］
で表される化合物である、
項１～４および７のいずれかに記載の医薬組成物。 [During the ceremony,
Z is a nitrogen atom or CH.
Y is a nitrogen atom or a carbon atom.
Figure JPOXMLDOC01-appb-C000010
 R 11 is, independently of one another are methyl or ethyl, or two R 11 are bonded to each other methylene, may form a crosslinked structure by dimethylene or trimethylene.
p is 0, 1, or 2.
Alternatively, (R 11 ) p is oxo.
R 21 , R 22 , and R 23 are independent of each other and are hydrogen atoms, halogens, carbamoyls, or trifluoromethyls.
R 31 , R 32 , and R 33 are independent of each other, lower alkyl, methyl, carboxyl, lower alkoxycarbonyl, monomethylaminocarbonyl, or dimethylaminocarbonyl substituted with hydrogen atom, halogen, halogen. ]
Is a compound represented by,
Item 8. The pharmaceutical composition according to any one of Items 1 to 4 and 7.
項９．
　一般式（１Ａ）において、
Ｒ２１が、塩素原子またはトリフルオロメチルであり、
Ｒ２２およびＲ２３が、水素原子であり、
Ｒ３１が、塩素原子であり、
Ｒ３２が、水素原子であり、
Ｒ３３が、水素原子、カルボキシル、または低級アルコキシカルボニルである、
項８に記載の医薬組成物。 Item 9.
In the general formula (1A)
R 21 is a chlorine atom or trifluoromethyl,
R 22 and R 23 are hydrogen atoms,
R 31 is a chlorine atom,
R 32 is a hydrogen atom,
R 33 is a hydrogen atom, carboxyl, or lower alkoxycarbonyl,
Item 8. The pharmaceutical composition according to Item 8.
項１０．
　化合物が、化合物０１１、化合物０２１、化合物０３１、化合物０４１、化合物０６１、化合物０７１、化合物０８１、化合物０９１、化合物１０１、化合物１１１、化合物１２１、化合物１３１、化合物１４１、化合物１５１、化合物１６１、化合物１７１、化合物１９１、化合物２２１、化合物２８１、化合物３１１、化合物３２１、化合物３３１、化合物３４１、化合物３５１、化合物３６１、化合物３７１、化合物３８１、化合物３９１、化合物４０１、または化合物４３１である、項１～４のいずれかに記載の医薬組成物。 Item 10.
The compounds are Compound 011, Compound 021, Compound 031, Compound 041, Compound 061, Compound 071, Compound 081, Compound 091, Compound 101, Compound 111, Compound 121, Compound 131, Compound 141, Compound 151, Compound 161 and Compound 171. , Compound 191 and Compound 221 and Compound 281. Compound 311, Compound 321 and Compound 331, Compound 341, Compound 351 and Compound 361, Compound 371, Compound 381, Compound 391, Compound 401, or Compound 431. The pharmaceutical composition according to any one of.
項１１．
　一般式（２）
Figure JPOXMLDOC01-appb-C000011
 Item 11.
General formula (2)
Figure JPOXMLDOC01-appb-C000011
［式中、
Ａは、置換されていてもよいベンゼン環である。
Ｂは、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールである。
Ｙは、窒素原子または炭素原子である。
Figure JPOXMLDOC01-appb-C000012
 Ｒ１は、互いに独立して低級アルキルであるか、２個のＲ１が互いに結合して、スピロ環または架橋構造を形成していてもよい、あるいは２個のＲ１が互いに結合して、Ｙを含む環を構成する炭素原子および窒素原子と共に飽和縮合複素環を形成していてもよい。
ｐは、０、１、または２である。
あるいは、（Ｒ１）ｐはオキソである。］
で表される化合物、その塩、またはそのプロドラッグを含有する難聴の予防および／または治療用医薬組成物。 [During the ceremony,
A is a optionally substituted benzene ring.
B is an aryl that may be substituted or a heteroaryl that may be substituted.
Y is a nitrogen atom or a carbon atom.
Figure JPOXMLDOC01-appb-C000012
 R 1 is either independently of one another are lower alkyl, two of R 1 are bonded to each other, may form a spiro ring or a crosslinked structure, or two of R 1 are bonded to each other, A saturated condensed heterocycle may be formed together with carbon atoms and nitrogen atoms constituting a ring containing Y.
p is 0, 1, or 2.
Alternatively, (R 1 ) p is oxo. ]
A pharmaceutical composition for preventing and / or treating deafness, which comprises a compound represented by, a salt thereof, or a prodrug thereof.
項１２．
　TRPC3チャネルおよびTRPC6チャネルからなる群から選択される少なくとも１種のTRPCチャネルの阻害活性を有する物質、その塩、またはそのプロドラッグを含有する難聴の予防および／または治療用医薬組成物。 Item 12.
A pharmaceutical composition for preventing and / or treating deafness containing a substance having an inhibitory activity on at least one TRPC channel selected from the group consisting of TRPC3 channel and TRPC6 channel, a salt thereof, or a prodrug thereof.
項１３．
　TRPC3チャネルおよびTRPC6チャネルからなる群から選択される少なくとも１種のTRPCチャネルの阻害活性を有する物質が、一般式（１）で表される化合物、一般式（２）で表わされる化合物、Pyr2、Pyr3、Pyr4、GSK2332255B、GSK2833503A、SAR7334、BI-749327、下に列挙された化合物AA01～AA95、および下に列挙された化合物BB01～BB32からなる群から選択される少なくとも１種の化合物である、項１２に記載の医薬組成物。
化合物AA01：
（4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-ピペラジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA02：
（6-アミノ-4-メチル-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA03：
（6-アミノ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA04：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA05：
（4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-ピペラジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA06：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-イソプロポキシ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA07：
（（R）-4-（6-アミノ-4-メチル-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA08：
（7-（6-アミノ-4-メトキシ-ピリジン-3-イル）-4,7-ジアザ-スピロ（2.5）オクト-4-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA09：
（7-（6-アミノ-4-メトキシ-ピリジン-3-イル）-4,7-ジアザ-スピロ（2.5）オクト-4-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA10：
（6-アミノ-4-メチル-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA11：
（4-（6-アミノ-5-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA12：
（4-（6-アミノ-ピリジン-3-イル）-ピペラジン-1-イル）-（4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル）-メタノン、
化合物AA13：
（4-（6-アミノ-ピリジン-3-イル）-ピペラジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA14：
（6-アミノ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA15：
（4-（6-アミノ-ピリジン-3-イル）-ピペラジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA16：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA17：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA18：
（（R）-4-（6-アミノ-4-メチル-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA19：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（2-フルオロ-ベンジルオキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA20：
（（R）-4-（6-アミノ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA21：
（4-（6-アミノ-5-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA22：
（6-アミノ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル）-メタノン、
化合物AA23：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA24：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-（4-トリフルオロメチル-フェノキシ）-ピリジン-2-イル）-メタノン、
化合物AA25：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-シクロブチルメトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA26：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-（1-メチル-シクロプロピルメトキシ）-ピリジン-2-イル）-メタノン、
化合物AA27：
（（R）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-メトキシメチル-ピペラジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA28：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル）-メタノン、
化合物AA29：
（4-（6-アミノ-4-メチル-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA30：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-シクロヘキシルオキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA31：
（4-（6-アミノ-4-メチル-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA32：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（4-フルオロ-ベンジルオキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA33：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-（4-トリフルオロメチル-フェノキシ）-ピリジン-2-イル）-メタノン、
化合物AA34：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-クロロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA35：
（6-アミノ-4-メトキシ-3,4,5,6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-シクロペンチルオキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA36：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-イソブトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA37：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-シクロプロピルメトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA38：
（3-（6-アミノ-4-メトキシ-ピリジン-3-イル）-3,8-ジアザ-ビシクロ（3.2.1）オクト-8-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA39：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-イソブトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA40：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-シクロプロポキシ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA41：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-フルオロ-ベンジルオキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA42：
（（R）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA43：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-ベンジルオキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA44：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル）-メタノン、
化合物AA45：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（3,3-ジフルオロ-シクロブチルメトキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA46：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-プロポキシ-ピリジン-2-イル）-メタノン、
化合物AA47：
（4-（6-アミノ-4-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA48：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（2-シクロプロピル-エトキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA49：
（4-（6-アミノ-4-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA50：
（1R）-1-（（2R）-4-（6-アミノ-4-メトキシピリジン-3-イル）-1-（5-フェノキシピリジン-2-カルボニル）ピペラジン-2-イル）エタン-1-オール、
化合物AA51：
（3-（6-アミノ-4-メトキシ-ピリジン-3-イル）-3,8-ジアザ-ビシクロ（3.2.1）オクト-8-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA52：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-フェネチルオキシ-ピリジン-2-イル）-メタノン、
化合物AA53：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-シクロブチルメトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA54：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-ジフルオロメトキシ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA55：
（（R）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-メトキシメチル-ピペラジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA56：
（4-（6-アミノ-4-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-（4-トリフルオロメチル-フェノキシ）-ピリジン-2-イル）-メタノン、
化合物AA57：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（2-フルオロ-ベンジルオキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA58：
（1S）-1-（（2R）-4-（6-アミノ-4-メトキシピリジン-3-イル）-1-（5-フェノキシピリジン-2-カルボニル）ピペラジン-2-イル）エタン-1-オール、
化合物AA59：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（2,2-ジメチル-プロポキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA60：
（4-（6-アミノ-5-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル）-メタノン、
化合物AA61：
（4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-ピペラジン-1-イル）-（5-シクロプロピルメトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA62：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-シクロヘキシルオキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA63：
（（S）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA64：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（1-フルオロメチル-シクロプロピルメトキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA65：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-エトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA66：
（4-（6-アミノ-4-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル）-メタノン、
化合物AA67：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（2-シクロプロピル-エトキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA68：
（7-（6-アミノ-4-メトキシ-ピリジン-3-イル）-3-オキサ-9-アザ-ビシクロ（3.3.1）ノン-9-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA69：
（（R）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA70：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（（S）-1-シクロプロピル-エトキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA71：
（（S）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA72：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-イソプロポキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA73：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-フェネチルオキシ-ピリジン-2-イル）-メタノン、
化合物AA74：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（2,2-ジメチル-プロポキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA75：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-（1-メチル-シクロプロピルメトキシ）-ピリジン-2-イル）-メタノン、
化合物AA76：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-プロポキシ-ピリジン-2-イル）-メタノン、
化合物AA77：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（（R）-1-シクロプロピル-エトキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA78：
（4-（6-アミノ-4-メチル-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-シクロプロピルメトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA79：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（（S）-1-シクロプロピル-エトキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA80：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-（4-トリフルオロメトキシ-フェノキシ）-ピリジン-2-イル）-メタノン、
化合物AA81：
（（R）-4-（6-アミノ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA82：
（（R）-4-（6-アミノ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル）-メタノン、
化合物AA83：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（フェノキシ）-4-エトキシ-ピリジン-2-イル）-メタノン、
化合物AA84：
（6-アミノ-4-シクロプロポキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA85：
（4-（6-アミノ-4-エトキシ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-（フェノキシ）-ピリジン-2-イル）-メタノン、
化合物AA86：
（6-アミノ-4-プロポキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA87：
（6-アミノ-4-エトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（4-トリフルオロメチル-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA88：
（4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-エトキシ-ピリジン-2-イル）-メタノン、
化合物AA89：
（3-（6-アミノ-ピリダジン-3-イル）-8-アザ-ビシクロ（3.2.1）オクト-8-イル）-（4-エトキシ-5-（4-フルオロ-フェノキシ）-ピリジン-2-イル）-メタノン、
化合物AA90：
6-{1-{4-メトキシ-5-（4-（トリフルオロメチル）フェノキシ）ピリジン-2-カルボニル}ピペリジン-4-イル）-5-メチルピリダジン-3-アミン、
化合物AA91：
5-メトキシ-6-（1-{5-（4-（トリフルオロメチル）-フェノキシ）-ピリジン-2-カルボニル}ピペリジン-4-イル）-ピリダジン-3-アミン、
化合物AA92：
4-メトキシ-5-（1-（4-メトキシ-5-{（トランス-3-（トリフルオロメチル）シクロブチル）-メトキシ}ピリジン-2-カルボニル）-ピペリジン-4-イル）ピリジン-2-アミン、
化合物AA93：
4-メトキシ-5-（1-（4-メトキシ-5-{（（シス-3-（トリフルオロメチル）-シクロブチル）メトキシ}-ピリジン-2-カルボニル）ピペリジン-4-イル）ピリジン-2-アミン、
化合物AA94：
4-メトキシ-5-（1-{4-メトキシ-5-（（2）-3,3,3-トリフルオロ-2-メチルプロポキシ）-ピリジン-2-カルボニル}ピペリジン-4-イル）ピリジン-2-アミン、
化合物AA95：
5-{1-{5-（（2,2-ジフルオロシクロブチル）-メトキシ）-4-メトキシ-ピリジン-2-カルボニル}-ピペリジン-4-イル）-4-メトキシピリジン-2-アミン、
化合物BB01：
1-（4-(4-フルオロフェニル)-2-(トリアゾール-2-イル)シクロペンチル）ピペリジン-3-アミン、
化合物BB02：
1-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル）ピラゾール-4-カルボニトリル、
化合物BB03：
1-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル）ピラゾール-3-カルボニトリル、
化合物BB04：
1-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル）ピロール-3-カルボニトリル、
化合物BB05：
1-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル）トリアゾール-4-カルボニトリル、
化合物BB06：
1-（2-(3-アミノ-5-フルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル）ピラゾール-4-カルボニトリル、
化合物BB07：
1-（2-(3-アミノ-4,4-ジフルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル）ピラゾール-4-カルボニトリル、
化合物BB08：
1-（4-(4-フルオロフェニル)-2-ピラゾール-1-イル-シクロペンチル）ピペリジン-3-アミン、
化合物BB09：
5-フルオロ-1-（4-(4-フルオロフェニル)-2-ピラゾール-1-イル-シクロペンチル）ピペリジン-3-アミン、
化合物BB10：
5-フルオロ-1-（4-(4-フルオロフェニル)-2-(1,2,4-トリアゾール-1-イル)シクロペンチル）ピペリジン-3-アミン、
化合物BB11：
5-フルオロ-1-（4-(4-フルオロフェニル)-2-(テトラゾール-2-イル)シクロペンチル）ピペリジン-3-アミン、
化合物BB12：
1-（4-(4-フルオロフェニル)-2-(テトラゾール-2-イル)シクロペンチル）ピペリジン-3-アミン、
化合物BB13：
1-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル）-1,2,4-トリアゾール-3-カルボニトリル、
化合物BB14：
4-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロ-3-ヒドロキシ-フェニル)シクロペントキシ）ベンゾニトリル、
化合物BB15：
4-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロ-3-メトキシ-フェニル)シクロペントキシ）ベンゾニトリル、
化合物BB16：
4-（2-(3-アミノ-1-ピペリジル)-4-(3-フルオロフェニル)シクロペントキシ）-3-クロロ-ベンゾニトリル、
化合物BB17：
4-（2-(3-アミノ-4,4-ジフルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）ベンゾニトリル、
化合物BB18：
4-（2-(5-アミノ-3,3-ジフルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）ベンゾニトリル、
化合物BB19：
4-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）-2-フルオロ-ベンゾニトリル、
化合物BB20：
2-（2-(3-アミノ-1-ピペリジル)-4-フェニル-シクロペントキシ）ベンゾニトリル、
化合物BB21：
4-（2-(3-アミノ-1-ピペリジル)-4-フェニル-シクロペントキシ）-3-クロロ-ベンゾニトリル、
化合物BB22：
6-（2-(3-アミノ-5-フルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）-5-メチル-ピリダジン-3-カルボニトリル、
化合物BB23：
1-（2-(4-クロロピリダジン-3-イル)オキシ-4-(4-フルオロフェニル)シクロペンチル）ピペリジン-3-アミン、
化合物BB24：
6-（2-(3-アミノ-5-フルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）ピリダジン-3-カルボニトリル、
化合物BB25：
1-（4-(4-フルオロフェニル)-2-(5-フルオロピリダジン-3-イル)オキシ-シクロペンチル）ピペリジン-3-アミン、
化合物BB26：
6-(2-((R)-3-アミノピペリジン-1-イル)-4-(4-フルオロフェニル)シクロペンチルオキシ)ニコチノニトリル、
化合物BB27：
6-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）ピリジン-3-カルボニトリル、
化合物BB28：
1-（4-(4-フルオロフェニル)-2-ピリダジン-3-イルオキシ-シクロペンチル）ピペリジン-3-アミン、
化合物BB29：
5-フルオロ-1-（4-(4-フルオロフェニル)-ピリミジン-4-イルオキシ-シクロペンチル）ピペリジン-3-アミン、
化合物BB30：
2-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）ピリミジン-5-カルボニトリル、
化合物BB31：
5-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）ピラジン-2-カルボニトリル、
化合物BB32：
5-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）ピリミジン-2-カルボニトリル。 Item 13.
A substance having an inhibitory activity on at least one TRPC channel selected from the group consisting of TRPC3 channel and TRPC6 channel is a compound represented by the general formula (1), a compound represented by the general formula (2), Pyr2, Pyr3. , Pyr4, GSK2332255B, GSK2833503A, SAR7334, BI-749327, compounds AA01-AA95 listed below, and at least one compound selected from the group consisting of compounds BB01-BB32 listed below, Item 12. The pharmaceutical composition according to.
Compound AA01:
(4- (6-Amino-4-methoxy-pyridin-3-yl) -piperazine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA02:
(6-Amino-4-methyl-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (4-fluoro-phenoxy) ) -4-Methoxy-pyridin-2-yl) -methanone,
Compound AA03:
(6-Amino-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-Il)-(4-Methoxy-5-Phenoxy-Pyridine-2- Il)-Metanon,
Compound AA04:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (4-fluoro-phenoxy) ) -4-Methoxy-pyridin-2-yl) -methanone,
Compound AA05:
(4- (6-Amino-4-methoxy-pyridin-3-yl) -piperazine-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
Compound AA06:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-isopropoxy-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA07:
((R) -4- (6-amino-4-methyl-pyridine-3-yl) -2-hydroxymethyl-piperazine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy- Pyridine-2-yl) -methanone,
Compound AA08:
(7- (6-Amino-4-methoxy-Pyridine-3-yl) -4,7-Diaza-spiro (2.5) Oct-4-yl)-(4-Methoxy-5-phenoxy-pyridin-2-yl) )-Metanon,
Compound AA09:
(7- (6-amino-4-methoxy-pyridin-3-yl) -4,7-diaza-spiro (2.5) octo-4-yl)-(5- (4-fluoro-phenoxy) -4-methoxy -Pyridine-2-yl) -methanone,
Compound AA10:
(6-Amino-4-methyl-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(4-Methoxy-5-phenoxy- Pyridine-2-yl) -methanone,
Compound AA11:
(4- (6-Amino-5-methoxy-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA12:
(4- (6-Amino-Pyridine-3-yl) -Piperazine-1-yl)-(4-Methoxy-5- (4-Methoxy-phenoxy) -Pyridine-2-yl) -methanone,
Compound AA13:
(4- (6-Amino-pyridin-3-yl) -piperazine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA14:
(6-Amino-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-Il)-(5- (4-Fluoro-phenoxy) -4- Methoxy-pyridin-2-yl) -methanone,
Compound AA15:
(4- (6-Amino-pyridin-3-yl) -piperazine-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
Compound AA16:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
Compound AA17:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA18:
((R) -4- (6-amino-4-methyl-pyridine-3-yl) -2-hydroxymethyl-piperazine-1-yl)-(4-Methoxy-5-phenoxy-pyridine-2-yl) -Metanon,
Compound AA19:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (2-fluoro-benzyl) Oxy) -4-methoxy-pyridine-2-yl) -methanone,
Compound AA20:
((R) -4- (6-amino-Pyridine-3-yl) -2-hydroxymethyl-piperazin-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy-pyridine-2- Il)-Metanon,
Compound AA21:
(4- (6-Amino-5-methoxy-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
Compound AA22:
(6-Amino-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-Il)-(4-Methoxy-5- (4-Methoxy-phenoxy) )-Pyridine-2-yl) -methanone,
Compound AA23:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(4-Methoxy-5-phenoxy- Pyridine-2-yl) -methanone,
Compound AA24:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(4-Methoxy-5- (4) -Trifluoromethyl-phenoxy) -pyridin-2-yl) -methanone,
Compound AA25:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5-cyclobutylmethoxy-4-methoxy-pyridin-2-yl) -methanone,
Compound AA26:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(4-Methoxy-5- (1) -Methyl-cyclopropylmethoxy) -pyridin-2-yl) -methanone,
Compound AA27:
((R) -4- (6-Amino-4-methoxy-pyridin-3-yl) -2-methoxymethyl-piperazine-1-yl)-(4-Methoxy-5-phenoxy-pyridin-2-yl) -Metanon,
Compound AA28:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(4-Methoxy-5- (4) -Methoxy-phenoxy) -pyridin-2-yl) -methanone,
Compound AA29:
(4- (6-Amino-4-methyl-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA30:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(5-Cyclohexyloxy-4-methoxy) -Pyridine-2-yl) -methanone,
Compound AA31:
(4- (6-Amino-4-methyl-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
Compound AA32:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (4-fluoro-benzyl) Oxy) -4-methoxy-pyridine-2-yl) -methanone,
Compound AA33:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5- (4-trifluoromethyl-phenoxy) -pyridin-2-yl) -methanone,
Compound AA34:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-chloro-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA35:
(6-Amino-4-methoxy-3,4,5,6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5-cyclopentyloxy-4-methoxy-pyridine- 2-Il)-Metanon,
Compound AA36:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5-isobutoxy-4-methoxy-pyridin-2-yl) -methanone,
Compound AA37:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(5-Cyclopropylmethoxy-4- Methoxy-pyridin-2-yl) -methanone,
Compound AA38:
(3- (6-Amino-4-methoxy-pyridin-3-yl) -3,8-diaza-bicyclo (3.2.1) octo-8-yl)-(5- (4-fluoro-phenoxy) -4 -Methoxy-pyridin-2-yl) -methanone,
Compound AA39:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5-isobutoxy-4-methoxy- Pyridine-2-yl) -methanone,
Compound AA40:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-cyclopropoxy-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA41:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-fluoro-benzyloxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA42:
((R) -4- (6-amino-4-methoxy-pyridin-3-yl) -2-hydroxymethyl-piperazine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy- Pyridine-2-yl) -methanone,
Compound AA43:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5-benzyloxy-4-methoxy) -Pyridine-2-yl) -methanone,
Compound AA44:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5- (4-methoxy-phenoxy) -pyridin-2-yl) -methanone,
Compound AA45:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (3,3-difluoro) -Cyclobutylmethoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA46:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(4-Methoxy-5-propoxy- Pyridine-2-yl) -methanone,
Compound AA47:
(4- (6-Amino-4-methoxy-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
Compound AA48:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(5- (2-Cyclopropyl-) Ethoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA49:
(4- (6-Amino-4-methoxy-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA50:
(1R) -1-((2R) -4- (6-amino-4-methoxypyridin-3-yl) -1- (5-phenoxypyridine-2-carbonyl) piperazine-2-yl) ethane-1- All,
Compound AA51:
(3- (6-Amino-4-methoxy-Pyridine-3-yl) -3,8-Diaza-bicyclo (3.2.1) Oct-8-yl)-(4-Methoxy-5-Phenoxy-Pyridine-2) -Il)-Metanon,
Compound AA52:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-Il)-(4-Methoxy-5-Phenethyloxy -Pyridine-2-yl) -methanone,
Compound AA53:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(5-Cyclobutylmethoxy-4- Methoxy-pyridin-2-yl) -methanone,
Compound AA54:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-difluoromethoxy-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA55:
((R) -4- (6-amino-4-methoxy-pyridin-3-yl) -2-methoxymethyl-piperazine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy- Pyridine-2-yl) -methanone,
Compound AA56:
(4- (6-Amino-4-methoxy-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5- (4-trifluoromethyl-phenoxy) -pyridin-2-yl)- Metanon,
Compound AA57:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (2-fluoro-benzyloxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA58:
(1S) -1-((2R) -4- (6-amino-4-methoxypyridin-3-yl) -1- (5-phenoxypyridine-2-carbonyl) piperazine-2-yl) ethane-1- All,
Compound AA59:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (2,2-dimethyl) -Propoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA60:
(4- (6-Amino-5-methoxy-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5- (4-methoxy-phenoxy) -pyridin-2-yl) -methanone,
Compound AA61:
(4- (6-Amino-4-methoxy-pyridin-3-yl) -piperazine-1-yl)-(5-cyclopropylmethoxy-4-methoxy-pyridin-2-yl) -methanone,
Compound AA62:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5-cyclohexyloxy-4-methoxy-pyridin-2-yl) -methanone,
Compound AA63:
((S) -4- (6-amino-4-methoxy-pyridin-3-yl) -2-hydroxymethyl-piperazine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy- Pyridine-2-yl) -methanone,
Compound AA64:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (1-fluoromethyl-) Cyclopropylmethoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA65:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(5-ethoxy-4-methoxy- Pyridine-2-yl) -methanone,
Compound AA66:
(4- (6-Amino-4-methoxy-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5- (4-methoxy-phenoxy) -pyridin-2-yl) -methanone,
Compound AA67:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (2-cyclopropyl-ethoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA68:
(7- (6-Amino-4-methoxy-Pyridine-3-yl) -3-oxa-9-aza-bicyclo (3.3.1) non-9-yl)-(4-Methoxy-5-phenoxy-pyridine -2-Il)-Metanon,
Compound AA69:
((R) -4- (6-amino-4-methoxy-pyridin-3-yl) -2-hydroxymethyl-piperazin-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -Metanon,
Compound AA70:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5-((S) -1) -Cyclopropyl-ethoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA71:
((S) -4- (6-amino-4-methoxy-pyridin-3-yl) -2-hydroxymethyl-piperazine-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -Metanon,
Compound AA72:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5-isopropoxy-4-methoxy) -Pyridine-2-yl) -methanone,
Compound AA73:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5-phenethyloxy-pyridin-2-yl) -methanone,
Compound AA74:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (2,2-dimethyl-propoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA75:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5- (1-methyl-cyclopropylmethoxy) -pyridin-2-yl) -methanone,
Compound AA76:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5-propoxy-pyridin-2-yl) -methanone,
Compound AA77:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-Il)-(5-((R) -1) -Cyclopropyl-ethoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA78:
(4- (6-Amino-4-methyl-pyridazine-3-yl) -piperidine-1-yl)-(5-cyclopropylmethoxy-4-methoxy-pyridin-2-yl) -methanone,
Compound AA79:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5-((S) -1-cyclopropyl-ethoxy) -4-methoxy-pyridin-2-yl) -methanone ,
Compound AA80:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5- (4-trifluoromethoxy-phenoxy) -pyridin-2-yl) -methanone,
Compound AA81:
((R) -4- (6-amino-pyridin-3-yl) -2-hydroxymethyl-piperazin-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
Compound AA82:
((R) -4- (6-amino-Pyridine-3-yl) -2-hydroxymethyl-piperazine-1-yl)-(4-Methoxy-5- (4-methoxy-phenoxy) -pyridine-2- Il)-Metanon,
Compound AA83:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (phenoxy) -4-ethoxy-pyridin-2-yl) -methanone,
Compound AA84:
(6-Amino-4-cyclopropoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (phenoxy) -4 -Methoxy-pyridin-2-yl) -methanone,
Compound AA85:
(4- (6-Amino-4-ethoxy-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5- (phenoxy) -pyridin-2-yl) -methanone,
Compound AA86:
(6-Amino-4-propoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (phenoxy) -4- Methoxy-pyridin-2-yl) -methanone,
Compound AA87:
(6-Amino-4-ethoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-Il)-(5- (4-Trifluoromethyl) -Phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
Compound AA88:
(4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-fluoro-phenoxy) -4-ethoxy-pyridin-2-yl) -methanone,
Compound AA89:
(3- (6-Amino-pyridazine-3-yl) -8-aza-bicyclo (3.2.1) octo-8-yl)-(4-ethoxy-5- (4-fluoro-phenoxy) -pyridine-2 -Il)-Metanon,
Compound AA90:
6- {1- {4-Methoxy-5- (4- (trifluoromethyl) phenoxy) pyridin-2-carbonyl} piperidine-4-yl) -5-methylpyridazine-3-amine,
Compound AA91:
5-Methoxy-6-(1- {5-(4- (trifluoromethyl) -phenoxy) -pyridin-2-carbonyl} piperidine-4-yl) -pyridazine-3-amine,
Compound AA92:
4-Methoxy-5-(1- (4-Methoxy-5-{(trans-3- (trifluoromethyl) cyclobutyl) -methoxy} pyridine-2-carbonyl) -piperidine-4-yl) pyridine-2-amine ,
Compound AA93:
4-Methoxy-5-(1- (4-Methoxy-5-{((cis-3- (trifluoromethyl) -cyclobutyl) methoxy} -pyridin-2-carbonyl) piperidine-4-yl) pyridin-2- Amin,
Compound AA94:
4-Methoxy-5-(1- {4-Methoxy-5-((2) -3,3,3-trifluoro-2-methylpropoxy) -pyridin-2-carbonyl} piperidine-4-yl) pyridine- 2-amine,
Compound AA95:
5- {1- {5-((2,2-difluorocyclobutyl) -methoxy) -4-methoxy-pyridin-2-carbonyl} -piperidine-4-yl) -4-methoxypyridin-2-amine,
Compound BB01:
1-(4- (4-fluorophenyl) -2- (triazole-2-yl) cyclopentyl) piperidine-3-amine,
Compound BB02:
1-(2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl) pyrazole-4-carbonitrile,
Compound BB03:
1-(2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl) pyrazole-3-carbonitrile,
Compound BB04:
1-(2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl) pyrrole-3-carbonitrile,
Compound BB05:
1-(2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl) triazole-4-carbonitrile,
Compound BB06:
1-(2- (3-Amino-5-fluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl) pyrazole-4-carbonitrile,
Compound BB07:
1-(2- (3-Amino-4,4-difluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl) pyrazole-4-carbonitrile,
Compound BB08:
1-(4- (4-fluorophenyl) -2-pyrazol-1-yl-cyclopentyl) piperidine-3-amine,
Compound BB09:
5-Fluoro-1- (4- (4-fluorophenyl) -2-pyrazole-1-yl-cyclopentyl) piperidine-3-amine,
Compound BB10:
5-Fluoro-1- (4- (4-fluorophenyl) -2- (1,2,4-triazole-1-yl) cyclopentyl) piperidine-3-amine,
Compound BB11:
5-Fluoro-1- (4- (4-fluorophenyl) -2- (tetrazol-2-yl) cyclopentyl) piperidine-3-amine,
Compound BB12:
1-(4- (4-fluorophenyl) -2- (tetrazol-2-yl) cyclopentyl) piperidine-3-amine,
Compound BB13:
1-(2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl) -1,2,4-triazole-3-carbonitrile,
Compound BB14:
4- (2- (3-Amino-1-piperidyl) -4- (4-fluoro-3-hydroxy-phenyl) cyclopentoxy) benzonitrile,
Compound BB15:
4- (2- (3-Amino-1-piperidyl) -4- (4-fluoro-3-methoxy-phenyl) cyclopentoxy) benzonitrile,
Compound BB16:
4- (2- (3-Amino-1-piperidyl) -4- (3-fluorophenyl) cyclopentoxy) -3-chloro-benzonitrile,
Compound BB17:
4- (2- (3-Amino-4,4-difluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) benzonitrile,
Compound BB18:
4- (2- (5-Amino-3,3-difluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) benzonitrile,
Compound BB19:
4- (2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) -2-fluoro-benzonitrile,
Compound BB20:
2- (2- (3-Amino-1-piperidyl) -4-phenyl-cyclopentoxy) benzonitrile,
Compound BB21:
4- (2- (3-Amino-1-piperidyl) -4-phenyl-cyclopentoxy) -3-chloro-benzonitrile,
Compound BB22:
6-(2- (3-Amino-5-fluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) -5-methyl-pyridazine-3-carbonitrile,
Compound BB23:
1-(2- (4-chloropyridazine-3-yl) oxy-4- (4-fluorophenyl) cyclopentyl) piperidine-3-amine,
Compound BB24:
6-(2- (3-Amino-5-fluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) pyridazine-3-carbonitrile,
Compound BB25:
1-(4- (4-Fluorophenyl) -2- (5-fluoropyridazine-3-yl) oxy-cyclopentyl) piperidine-3-amine,
Compound BB26:
6-(2-((R) -3-aminopiperidine-1-yl) -4- (4-fluorophenyl) cyclopentyloxy) nicotinonitrile,
Compound BB27:
6-(2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) Pyridine-3-Carbonitrile,
Compound BB28:
1-(4- (4-fluorophenyl) -2-pyridazine-3-yloxy-cyclopentyl) piperidine-3-amine,
Compound BB29:
5-Fluoro-1- (4- (4-fluorophenyl) -pyrimidine-4-yloxy-cyclopentyl) piperidine-3-amine,
Compound BB30:
2- (2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) pyrimidine-5-carbonitrile,
Compound BB31:
5- (2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) pyrazine-2-carbonitrile,
Compound BB32:
5- (2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) pyrimidine-2-carbonitrile.
項１４．
　経口投与用である項１～１３のいずれかに記載の医薬組成物。 Item 14.
Item 8. The pharmaceutical composition according to any one of Items 1 to 13, which is for oral administration.
項１５．
　難聴が感音難聴である項１～１４のいずれかに記載の医薬組成物。 Item 15.
The pharmaceutical composition according to any one of Items 1 to 14, wherein the deafness is sensorineural deafness.
項１６．
　難聴が薬剤に起因する難聴である項１～１５のいずれかに記載の医薬組成物。 Item 16.
The pharmaceutical composition according to any one of Items 1 to 15, wherein the deafness is caused by a drug.
　本発明で開示される医薬組成物は、TRPC3チャネルおよびTRPC6チャネルからなる群から選択される少なくとも１種のTRPCチャネルの阻害活性を有する物質（例えば一般式（１）で表される化合物、一般式（２）で表される化合物、Pyr2、Pyr3、Pyr4、GSK2332255B、GSK2833503A、SAR7334、BI-749327、US2019/0169168に開示された化合物、WO2019/215268に開示された化合物等）、その塩、あるいはそれらのプロドラッグを含有することにより難聴の予防又は治療作用を有する。
　TRPC3/6チャネル阻害物質、例えば一般式（１）または（２）で表される化合物等は、TRPCチャネル、例えばTRPC3および／またはTRPC6チャネル、好ましくはTRPC6チャネルの活性を阻害する活性を有し、そのため、TRPC関連疾患、例えばTRPC3チャネルの活性に起因する疾患、TRPC6チャネルの活性に起因する疾患、またはTRPC3チャネルの活性とTRPC6チャネルの活性の両方に起因する疾患（本明細書において、これらを総称して「TRPC3および／またはTRPC6関連疾患」と称することがある。）、特に難聴の予防および／または治療に有用である。 The pharmaceutical composition disclosed in the present invention is a substance having an inhibitory activity on at least one TRPC channel selected from the group consisting of TRPC3 channel and TRPC6 channel (for example, a compound represented by the general formula (1), a general formula. Compounds represented by (2), Pyr2, Pyr3, Pyr4, GSK2332255B, GSK2833503A, SAR7334, BI-749327, compounds disclosed in US2019 / 0169168, compounds disclosed in WO2019 / 215268, etc.), their salts, or them. It has a preventive or therapeutic effect on deafness by containing the prodrug of.
TRPC3 / 6 channel inhibitors, such as compounds represented by the general formula (1) or (2), have the activity of inhibiting the activity of TRPC channels, such as TRPC3 and / or TRPC6 channels, preferably TRPC6 channels. Therefore, TRPC-related diseases, such as those caused by the activity of the TRPC3 channel, those caused by the activity of the TRPC6 channel, or those caused by both the activity of the TRPC3 channel and the activity of the TRPC6 channel (collectively referred to herein). It is sometimes referred to as "TRPC3 and / or TRPC6-related disease"), and is particularly useful for the prevention and / or treatment of hearing loss.
図１は試験例１において得られた、TRPC6発現細胞内におけるカルシウムイオン濃度変化の測定結果を示すグラフである。横軸は時間（秒）、縦軸は細胞内カルシウムイオン濃度（［Ca２＋］i（nM））である。FIG. 1 is a graph showing the measurement results of changes in calcium ion concentration in TRPC6-expressing cells obtained in Test Example 1. The horizontal axis is time (seconds), and the vertical axis is intracellular calcium ion concentration ([Ca 2+ ] i (nM)). 図２は試験例１において得られた、TRPC3発現細胞内におけるカルシウムイオン濃度変化の測定結果を示すグラフである。横軸は時間（秒）、縦軸は細胞内カルシウムイオン濃度（［Ca２＋］i（nM））である。FIG. 2 is a graph showing the measurement results of changes in calcium ion concentration in TRPC3-expressing cells obtained in Test Example 1. The horizontal axis is time (seconds), and the vertical axis is intracellular calcium ion concentration ([Ca 2+ ] i (nM)). 図３は試験例２において得られた、TRPC6発現細胞内におけるカルシウムイオン増加量を示すグラフである。縦軸の単位は「％」である。FIG. 3 is a graph showing the amount of increase in calcium ions in TRPC6-expressing cells obtained in Test Example 2. The unit of the vertical axis is "%". 図４は試験例３において得られた、TRPC6発現細胞内におけるカルシウムイオン増加量を示すグラフである。縦軸の単位は「％」である。FIG. 4 is a graph showing the amount of increase in calcium ions in TRPC6-expressing cells obtained in Test Example 3. The unit of the vertical axis is "%". 図５は試験例４において得られた、TRPC6発現細胞の電気生理的評価を示すグラフである。本図中、左側のグラフの縦軸は電流（nA）であり横軸は時間（秒）である。また、右側のグラフ中のａ、ｂは、各々、左側のグラフ中のａ、ｂの時点の電流－電圧特性カーブを示す。FIG. 5 is a graph showing the electrophysiological evaluation of TRPC6-expressing cells obtained in Test Example 4. In this figure, the vertical axis of the graph on the left is current (nA) and the horizontal axis is time (seconds). Further, a and b in the graph on the right side indicate current-voltage characteristic curves at the time points of a and b in the graph on the left side, respectively. 図６は試験例５のウエスタンブロットの結果を表す写真である。FIG. 6 is a photograph showing the results of Western blotting of Test Example 5. 図７は試験例６において皮膚線維芽細胞を用いて得られた免疫蛍光染色法によるα-SMA発現を表すグラフである。グラフの縦軸は蛍光強度（／ピクセル）である。FIG. 7 is a graph showing α-SMA expression by immunofluorescent staining method obtained using skin fibroblasts in Test Example 6. The vertical axis of the graph is the fluorescence intensity (/ pixel). 図８は試験例６において心線維芽細胞を用いて得られた免疫蛍光染色法によるα-SMA発現を表すグラフである。グラフの縦軸は蛍光強度（／ピクセル）である。FIG. 8 is a graph showing α-SMA expression by immunofluorescence staining method obtained using cardiac fibroblasts in Test Example 6. The vertical axis of the graph is the fluorescence intensity (/ pixel). 図９は試験例７において測定された聴覚閾値を表すグラフである。FIG. 9 is a graph showing the auditory threshold measured in Test Example 7. 図１０は試験例７において測定された各波長（Ｈｚ）における聴覚閾値の変動量（ｄＢ）を表すグラフである。FIG. 10 is a graph showing the fluctuation amount (dB) of the auditory threshold value at each wavelength (Hz) measured in Test Example 7. 図１１は試験例８において測定された血漿白金濃度（ng/ml）を表わすグラフである。FIG. 11 is a graph showing the plasma platinum concentration (ng / ml) measured in Test Example 8. 図１２は試験例９において測定されたゼブラフィッシュのニューロマスト数を表わすグラフである。FIG. 12 is a graph showing the number of zebrafish neuromasts measured in Test Example 9.
　本発明の一実施形態は、下記一般式（１）で表される化合物、その塩、またはそのプロドラッグを含有する難聴の予防および／または治療用医薬組成物である。 One embodiment of the present invention is a pharmaceutical composition for preventing and / or treating deafness containing a compound represented by the following general formula (1), a salt thereof, or a prodrug thereof.
　一般式（１）
Figure JPOXMLDOC01-appb-C000013
 General formula (1)
Figure JPOXMLDOC01-appb-C000013
［式中、
Ａは、置換されていてもよいベンゼン環である。
Ｂは、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールである。
Ｘは、酸素原子または硫黄原子である。
Ｙは、窒素原子または炭素原子である。
Figure JPOXMLDOC01-appb-C000014
 Ｒ１は、互いに独立して低級アルキルであるか、２個のＲ１が互いに結合して、スピロ環または架橋構造を形成していてもよい、あるいは２個のＲ１が互いに結合して、Ｙを含む環を構成する炭素原子および窒素原子と共に飽和縮合複素環を形成していてもよい。
ｐは、０、１、または２である。
あるいは、
（Ｒ１）ｐはオキソである。］ [During the ceremony,
A is a optionally substituted benzene ring.
B is an aryl that may be substituted or a heteroaryl that may be substituted.
X is an oxygen atom or a sulfur atom.
Y is a nitrogen atom or a carbon atom.
Figure JPOXMLDOC01-appb-C000014
 R 1 is either independently of one another are lower alkyl, two of R 1 are bonded to each other, may form a spiro ring or a crosslinked structure, or two of R 1 are bonded to each other, A saturated condensed heterocycle may be formed together with carbon atoms and nitrogen atoms constituting a ring containing Y.
p is 0, 1, or 2.
Or
(R 1 ) p is oxo. ]
　本発明において、「置換されていてもよいベンゼン環」の置換基としては、例えばハロゲン；水酸基；ニトロ；シアノ；カルボキシル；置換されていてもよいアミノ；置換されていてもよい環状アミノ；置換されていてもよい低級アルキル；置換されていてもよい低級アルコキシ；低級アルコキシカルボニル；低級アルキルスルホニル；低級アルキルまたは低級アルキルスルホニルで置換されていてもよいカルバモイル；置換されていてもよい環状アミノカルボニル；低級アルキルで置換されていてもよいスルファモイル；置換されていてもよい環状アミノスルホニル；テトラゾリル等が挙げられる。置換基は、１種単独でも２種以上でもよい。 In the present invention, the substituent of the "optionally substituted benzene ring" includes, for example, halogen; hydroxyl group; nitro; cyano; carboxyl; optionally substituted amino; optionally substituted cyclic amino; substituted. Lower alkyl may be; lower alkoxy optionally substituted; lower alkoxycarbonyl; lower alkylsulfonyl; carboxamide optionally substituted with lower alkyl or lower alkylsulfonyl; cyclic aminocarbonyl optionally substituted; lower Sulfamoyl which may be substituted with alkyl; cyclic aminosulfonyl which may be substituted; tetrazolyl and the like can be mentioned. The substituent may be one kind alone or two or more kinds.
　本発明において、「アリール」としては、例えば、単環または二環のアリールが挙げられ、具体的には、フェニル、ナフチル等が挙げられる。 In the present invention, examples of the "aryl" include monocyclic or bicyclic aryl, and specific examples thereof include phenyl and naphthyl.
　本発明において、「置換されていてもよいアリール」におけるアリールは上記で定義したとおりである。置換されていてもよいアリールの置換基としては、例えばハロゲン；水酸基；ニトロ；シアノ；カルボキシル；置換されていてもよいアミノ；置換されていてもよい環状アミノ；置換されていてもよい低級アルキル；置換されていてもよい低級アルコキシ；低級アルコキシカルボニル；低級アルキルスルホニル；低級アルキルまたは低級アルキルスルホニルで置換されていてもよいカルバモイル；置換されていてもよい環状アミノカルボニル；低級アルキルで置換されていてもよいスルファモイル；置換されていてもよい環状アミノスルホニル；テトラゾリル；オキソ等が挙げられる。置換基は１種単独でも２種以上でもよい。 In the present invention, the aryl in the "optionally substituted aryl" is as defined above. Substituents of the optionally substituted aryl include, for example, halogen; hydroxyl group; nitro; cyano; carboxyl; optionally substituted amino; optionally substituted cyclic amino; optionally substituted lower alkyl; Lower alkoxy optionally substituted; Lower alkoxycarbonyl; Lower alkylsulfonyl; Carbamoyl optionally substituted with lower alkyl or lower alkylsulfonyl; Cyclic aminocarbonyl optionally substituted; optionally substituted with lower alkyl Good sulfamoyl; optionally substituted cyclic aminosulfonyl; tetrazolyl; oxo and the like. The substituent may be one kind alone or two or more kinds.
　本発明において、「オキソ」は「＝Ｏ」で表される基である。 In the present invention, "oxo" is a group represented by "= O".
　本発明において、「ヘテロアリール」としては、例えば、単環または二環の含窒素ヘテロアリールが挙げられ、具体的には、１個以上（例えば１～３個、１または２個、１個）の窒素原子を環上に含み、さらに他のヘテロ原子として硫黄原子または酸素原子を１個以上（例えば１～３個、１または２個、１個）含んでいてもよい、単環または二環の含窒素ヘテロアリールが挙げられる。具体的なヘテロアリールとしては、ピロリル、イミダゾリル、トリアゾリル、テトラゾリル、ピラゾリル、ピリジル、ピラジニル、ピリミジニル、ピリダジニル、フリル、チエニル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、フラザニル、オキサジアゾリル、チアジアゾリル、インドリル、イソインドリル、ベンゾフラニル、イソベンゾフラニル、ベンゾチエニル、イソベンゾチエニル、インダゾリル、キノリル、イソキノリル、プリニル、フタラジニル、プテリジル、ナフチリジニル、キノキサリニル、キナゾリニル、シンノリニル、ベンゾオキサゾリル、ベンゾチアゾリル、ベンゾイミダゾリル、ベンゾフラザニル、ベンゾチアジアゾリル、ベンゾトリアゾリル、イソオキサゾロ［４，５－ｄ］ピリダジル、ベンゾイソオキサゾリル、ベンゾイソチアゾリル等がげられる。好ましくは、単環の含窒素ヘテロアリールまたはベンゾイミダゾリルである。 In the present invention, examples of the "heteroaryl" include monocyclic or bicyclic nitrogen-containing heteroaryls, and specifically, one or more (for example, 1 to 3, 1 or 2, 1). The nitrogen atom of the above is contained on the ring, and one or more sulfur atoms or oxygen atoms (for example, 1 to 3, 1 or 2, 1) may be contained as other heteroatoms, monocyclic or bicyclic. Nitrogen-containing heteroaryl. Specific heteroaryls include pyrrolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, frill, thienyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, frazayl, oxadiazolyl, thiadiazolyl, indrill, isoindrill Isobenzofuranyl, benzothienyl, isobenzothienyl, indazolyl, quinolyl, isoquinolyl, prynyl, phthalazinyl, pteridyl, naphthyldinyl, quinoxalinyl, quinazolinyl, cinnolinyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl, benzoflazanol, benzothiasiazolyl Zoryl, isooxazolo [4,5-d] pyridadyl, benzoisoxazolyl, benzoisothiazolyl and the like can be removed. Preferably, it is a monocyclic nitrogen-containing heteroaryl or benzoimidazolyl.
　本発明において、「置換されていてもよいヘテロアリール」におけるヘテロアリールは上記で定義したとおりである。置換されていてもよいヘテロアリールの置換基としては、例えばハロゲン；水酸基；ニトロ；シアノ；カルボキシル；置換されていてもよいアミノ；置換されていてもよい環状アミノ；置換されていてもよい低級アルキル；置換されていてもよい低級アルコキシ；低級アルコキシカルボニル；低級アルキルスルホニル；低級アルキルまたは低級アルキルスルホニルで置換されていてもよいカルバモイル；置換されていてもよい環状アミノカルボニル；低級アルキルで置換されていてもよいスルファモイル；置換されていてもよい環状アミノスルホニル；テトラゾリル；オキソ等が挙げられる。置換基は１種単独でも２種以上でもよい。 In the present invention, the heteroaryl in the "optionally substituted heteroaryl" is as defined above. Examples of the substituent of the heteroaryl which may be substituted include halogen; hydroxyl group; nitro; cyano; carboxyl; amino which may be substituted; cyclic amino which may be substituted; lower alkyl which may be substituted. Lower alkoxy optionally substituted; Lower alkoxycarbonyl; Lower alkylsulfonyl; Carboxamide optionally substituted with lower alkyl or lower alkylsulfonyl; Cyclic aminocarbonyl optionally substituted; Substituted with lower alkyl May include sulfamoyl; optionally substituted cyclic aminosulfonyl; tetrazolyl; oxo and the like. The substituent may be one kind alone or two or more kinds.
　本発明において、「低級アルキル」としては、例えば、直鎖状、分枝状、または環状構造を含む、Ｃ１～Ｃ８アルキルが挙げられ、好ましくはＣ１～Ｃ６アルキル、より好ましくはＣ１～Ｃ４アルキル、特に好ましくはＣ１～Ｃ３アルキルである。具体的には、直鎖状または分枝状の低級アルキルとしては、メチル、エチル、１－プロピル、２－プロピル、１－ブチル、２－ブチル、イソブチル、ｔ－ブチル、ｎ－ペンチル、ネオペンチル、ｎ－ヘキシル、イソヘキシル、３－メチルペンチル等が挙げられ、環状構造を含む低級アルキルとしては、シクロプロピル、シクロプロピルメチル、シクロブチル、シクロブチルメチル、シクロペンチル、シクロペンチルメチル、シクロヘキシル、シクロヘキシルメチル、シクロヘキシルエチル等が挙げられる。好ましくは、メチル、エチル、２－プロピル、ｔ－ブチル、シクロプロピル等が挙げられる。 In the present invention, examples of the "lower alkyl" include C1 to C8 alkyls containing linear, branched or cyclic structures, preferably C1 to C6 alkyls, more preferably C1 to C4 alkyls. Particularly preferably, it is C1-C3 alkyl. Specifically, as linear or branched lower alkyl, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, isobutyl, t-butyl, n-pentyl, neopentyl, etc. Examples thereof include n-hexyl, isohexyl, 3-methylpentyl and the like, and examples of the lower alkyl having a cyclic structure include cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclobutylmethyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cyclohexylmethyl, cyclohexylethyl and the like. Can be mentioned. Preferably, methyl, ethyl, 2-propyl, t-butyl, cyclopropyl and the like can be mentioned.
　本発明において、「ハロゲン」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子等が挙げられ、好ましくはフッ素原子、塩素原子が挙げられる。 In the present invention, examples of the "halogen" include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like, and preferably a fluorine atom and a chlorine atom.
　本発明において、「置換されていてもよいアミノ」は置換されていてもよい非環状アミノをいい、その置換基としては、低級アルキル（例えばメチル、エチル、プロピル等）、Ｃ１～Ｃ８アシル（例えばアセチル、プロピオニル等）、アリール（例えば、フェニル等）、またはヘテロアリールが挙げられる。置換基は１種単独でも２種以上でもよい。好ましい置換されていてもよいアミノとしては、例えば、アミノ、メチルアミノ、ジメチルアミノ、エチルアミノ、ジエチルアミノ、シクロヘキシルアミノ、アセチルアミノ、ベンゾイルアミノ、フェニルアミノ等が挙げられる。 In the present invention, "optionally substituted amino" refers to optionally substituted acyclic amino, and examples of the substituent include lower alkyl (for example, methyl, ethyl, propyl, etc.) and C1-C8 acyl (for example,). Acetyl, propionyl, etc.), aryl (eg, phenyl, etc.), or heteroaryl. The substituent may be one kind alone or two or more kinds. Preferred aminos that may be substituted include, for example, amino, methylamino, dimethylamino, ethylamino, diethylamino, cyclohexylamino, acetylamino, benzoylamino, phenylamino and the like.
　本発明において、「環状アミノ」は、例えば、環構成原子として窒素原子を有し、さらに酸素原子を１個以上（例えば１～３個、１または２個、１個）含んでいてもよい５～７員の環状アミノであり、例えば、ピロリジノ、ピペリジノ、ピペラジノ、モルホリノ等が挙げられ、好ましくは、ピロリジノ、モルホリノ等が挙げられる。 In the present invention, the "cyclic amino" may have, for example, a nitrogen atom as a ring-constituting atom and may further contain one or more oxygen atoms (for example, 1 to 3, 1 or 2, 1) 5 It is a cyclic amino having up to 7 members, and examples thereof include pyrrolidino, piperidino, piperazino, morpholino and the like, and preferably pyrrolidino, morpholino and the like.
　本発明において、「置換されていてもよい環状アミノ」における環状アミノは、上記で定義したとおりである。環状アミノの置換基としては、例えば、低級アルキル、低級アルコキシ、アミノ、水酸基、ニトロ、シアノ、カルボキシル、オキソ等が挙げられる。環状アミノは上記置換基からなる群より選択される少なくとも１種の基で置換されていてもよい。置換基の数としては、例えば０、１個、２個、３個があげられ、好ましくは０、１個、２個である。置換されていてもよい環状アミノとしては、具体的には、ピロリジノ、ピペリジノ、ピペラジノ、４－メチルピペリジノ、モルホリノ、２－ピロリドニル等が挙げられ、好ましくは、ピロリジノ、モルホリノ等が挙げられる。 In the present invention, the cyclic amino in the "optionally substituted cyclic amino" is as defined above. Examples of the substituent of the cyclic amino include lower alkyl, lower alkoxy, amino, hydroxyl group, nitro, cyano, carboxyl, oxo and the like. The cyclic amino may be substituted with at least one group selected from the group consisting of the above substituents. Examples of the number of substituents include 0, 1, 2, and 3, and preferably 0, 1, and 2. Specific examples of the cyclic amino that may be substituted include pyrrolidino, piperidino, piperazino, 4-methylpiperidino, morpholino, 2-pyrrolidonyl and the like, and preferably pyrrolidino, morpholino and the like.
　本発明において、「置換されていてもよい低級アルキル」における低級アルキルは上記で定義したとおりである。低級アルキルの置換基としては、例えば、水酸基；アミノ；Ｃ１～Ｃ８アルキルアミノ（例えばメチルアミノ、エチルアミノ、プロピルアミノ、ｔ－ブチルアミノ等）；Ｃ１～Ｃ８アルコキシ（例えばメトキシ、エトキシ、１－プロピルオキシ、２－プロピルオキシ、ｔ－ブチルオキシ等）；ハロゲン（例えばフッ素原子、塩素原子、臭素原子等）；ハロＣ１～Ｃ８アルコキシ（例えばトリフルオロメトキシ等）；脂肪族複素環基（例えばモルホリノ、ピペリジニル、ピロリジニル、４－メチル－１－ピペラジノ等）；アリール（例えばフェニル、１－ナフチル等）；ヘテロアリール（例えばピリジル、チエニル、フラニル等）；カルボキシル；Ｃ１～Ｃ８アルコキシカルボニル（例えばメトキシカルボニル、エトキシカルボニル、１－プロポキシカルボニル、２－プロポキシカルボニル、ｔ－ブトキシカルボニル等）；低級アルキルで置換されていてもよいカルバモイル（例えばカルバモイル、メチルアミノカルボニル、ジメチルアミノカルボニル、ジエチルアミノカルボニル等）；環状アミノカルボニル（例えばピロリジノカルボニル、ピペリジノカルボニル、モルホリノカルボニル等）等が挙げられる。好ましい置換基としてはメチルアミノ、エチルアミノ、ジメチルアミノ、ジエチルアミノ、メトキシ、エトキシ、２－プロピルオキシ、ｔ－ブトキシカルボニル、水酸基、フッ素原子、塩素原子、トリクロロメチル、トリフルオロメチル、トリフルオロメトキシ、モルホリノ、ピペリジノ、ピロリジノ、カルボキシル、メトキシカルボニル、エトキシカルボニル、モルホリノカルボニル、フェニル、ピリジル等が挙げられる。置換されていてもよい低級アルキルは、上記置換基からなる群より選択される少なくとも１種の基で置換されていてもよく、置換基の数としては、例えば０、１個、２個、３個が挙げられ、好ましくは０、１個、２個である。 In the present invention, the lower alkyl in the "optionally substituted lower alkyl" is as defined above. Examples of lower alkyl substituents include hydroxyl groups; amino; C1-C8 alkylaminos (eg, methylamino, ethylamino, propylamino, t-butylamino, etc.); C1-C8 alkoxy (eg, methoxy, ethoxy, 1-propyl). Oxy, 2-propyloxy, t-butyloxy, etc.); Halogen (eg, fluorine atom, chlorine atom, bromine atom, etc.); Halo C1-C8 alkoxy (eg, trifluoromethoxy, etc.); aliphatic heterocyclic group (eg, morpholino, piperidinyl, etc.) , Pyrrolidinyl, 4-methyl-1-piperazino, etc.); Aryl (eg, phenyl, 1-naphthyl, etc.); Heteroaryl (eg, pyridyl, thienyl, furanyl, etc.); carboxyl; C1-C8 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.) , 1-propoxycarbonyl, 2-propoxycarbonyl, t-butoxycarbonyl, etc.); carbamoyl optionally substituted with lower alkyl (eg, carbamoyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, etc.); cyclic aminocarbonyl (eg, cyclic aminocarbonyl) Pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, etc.) and the like. Preferred substituents are methylamino, ethylamino, dimethylamino, diethylamino, methoxy, ethoxy, 2-propyloxy, t-butoxycarbonyl, hydroxyl group, fluorine atom, chlorine atom, trichloromethyl, trifluoromethyl, trifluoromethoxy, morpholino. , Piperidino, pyrrolidino, carboxyl, methoxycarbonyl, ethoxycarbonyl, morpholinocarbonyl, phenyl, pyridyl and the like. The lower alkyl which may be substituted may be substituted with at least one group selected from the group consisting of the above substituents, and the number of substituents may be, for example, 0, 1, 2, 3 The number is preferably 0, 1, or 2.
　本発明において、「ハロゲンで置換された低級アルキル」はアルキルの水素が全てハロゲンで置換されたものをいう。ハロゲンで置換された低級アルキルにおけるハロゲンおよび低級アルキルは上記で定義したとおりである。アルキルを置換するハロゲンは同一であることが好ましい。ハロゲンで置換された低級アルキルとしては、トリクロロメチルまたはトリフルオロメチルが好ましく、トリフルオロメチルが好ましい。 In the present invention, "lower alkyl substituted with halogen" means that all hydrogen of alkyl is substituted with halogen. The halogen and lower alkyl in the lower alkyl substituted with halogen are as defined above. It is preferable that the halogens that replace the alkyl are the same. As the lower alkyl substituted with halogen, trichloromethyl or trifluoromethyl is preferable, and trifluoromethyl is preferable.
　本発明において、「低級アルコキシ」としては、例えば、直鎖状、分枝状、または環状構造を含む、Ｃ１～Ｃ８アルコキシが挙げられ、好ましくはＣ１～Ｃ６アルコキシ、より好ましくはＣ１～Ｃ４アルコキシ、特に好ましくはＣ１～Ｃ３アルコキシである。具体的には、直鎖状または分枝状のアルコキシとしては、メトキシ、エトキシ、１－プロポキシ、２－プロポキシ、１－ブトキシ 、２－ブトキシ、イソブトキシ、ｔ－ブトキシ、ｎ－ペンチルオキシ、ネオペンチルオキシ、ｎ－ヘキシルオキシ、イソヘキシルオキシ、３－メチルペンチルオキシ等が挙げられる。環状構造を含むアルコキシとしては、シクロプロポキシ、シクロプロピルメトキシ、シクロブチロキシ、シクロブチルメトキシ、シクロペンチロキシ、シクロペンチルメトキシ、シクロヘキシロキシ、シクロヘキシルメトキシ、シクロヘキシルエトキシ等が挙げられる。好ましくは、メトキシ、エトキシ、２－プロポキシ、ｔ－ブトキシ、シクロプロポキシ等が挙げられる。 In the present invention, examples of the "lower alkoxy" include C1 to C8 alkoxys containing linear, branched or cyclic structures, preferably C1 to C6 alkoxys, more preferably C1 to C4 alkoxys. Particularly preferably, it is C1 to C3 alkoxy. Specifically, as linear or branched alkoxy, methoxy, ethoxy, 1-propoxy, 2-propoxy, 1-butoxy, 2-butoxy, isobutoxy, t-butoxy, n-pentyloxy, neopentyl Examples thereof include oxy, n-hexyloxy, isohexyloxy and 3-methylpentyloxy. Examples of the alkoxy containing a cyclic structure include cyclopropoxy, cyclopropylmethoxy, cyclobutyloxy, cyclobutylmethoxy, cyclopentyloxy, cyclopentylmethoxy, cyclohexyloxy, cyclohexylmethoxy, cyclohexylethoxy and the like. Preferably, methoxy, ethoxy, 2-propoxy, t-butoxy, cyclopropoxy and the like can be mentioned.
　本発明において、「置換されていてもよい低級アルコキシ」における低級アルコキシは上記で定義したとおりである。低級アルコキシの置換基としては、例えば、水酸基；アミノ；Ｃ１～Ｃ８アルキルアミノ（例えばメチルアミノ、エチルアミノ、プロピルアミノ、ｔ－ブチルアミノ等）；Ｃ１～Ｃ８アルコキシ（例えばメトキシ、エトキシ、１－プロピルオキシ、２－プロピルオキシ、ｔ－ブトキシ等）；ハロゲン（例えばフッ素原子、塩素原子、臭素原子等）；ハロＣ１～Ｃ８アルコキシ（例えばトリフルオロメトキシ等）；脂肪族複素環基（例えばモルホリノ、ピペリジニル、ピロリジニル、４－メチル－１－ピペラジノ等）；アリール（例えばフェニル、１－ナフチル等）；ヘテロアリール（例えばピリジル、チエニル、フラニル等）；カルボキシル；Ｃ１～Ｃ８アルコキシカルボニル（例えばメトキシカルボニル、エトキシカルボニル、１－プロピルオキシカルボニル、２－プロピルオキシカルボニル、ｔ－ブトキシカルボニル等）；低級アルキルで置換されていてもよいカルバモイル（例えばカルバモイル、メチルアミノカルボニル、ジメチルアミノカルボニル、ジエチルアミノカルボニル等）；環状アミノカルボニル（例えばピロリジノカルボニル、ピペリジノカルボニル、モルホリノカルボニル等）等が挙げられる。好ましい置換基としては、メチルアミノ、エチルアミノ、ジメチルアミノ、ジエチルアミノ、メトキシ、エトキシ、２－プロピルオキシ、ｔ－ブトキシカルボニル、水酸基、フッ素原子、塩素原子、トリフルオロ、モルホリノ、ピペリジノ、ピロリジノ、カルボキシル、メトキシカルボニル、モルホリノカルボニル、フェニル、ピリジル等が挙げられる。置換されていてもよい低級アルコキシは、上記置換基からなる群より選択される少なくとも１種の基で置換されていてもよく、置換基の数としては、例えば０、１個、２個、３個があげられ、好ましくは０、１個、２個である。 In the present invention, the lower alkoxy in the "optionally substituted lower alkoxy" is as defined above. Examples of the substituent of the lower alkoxy include hydroxyl groups; amino; C1-C8 alkylaminos (eg, methylamino, ethylamino, propylamino, t-butylamino, etc.); C1-C8 alkoxys (eg, methoxy, ethoxy, 1-propyl). Oxy, 2-propyloxy, t-butoxy, etc.); Halogen (eg, fluorine atom, chlorine atom, bromine atom, etc.); Halo C1-C8 alkoxy (eg, trifluoromethoxy, etc.); aliphatic heterocyclic group (eg, morpholino, piperidinyl, etc.) , Pyrrolidinyl, 4-methyl-1-piperazino, etc.); Aryl (eg, phenyl, 1-naphthyl, etc.); Heteroaryl (eg, pyridyl, thienyl, furanyl, etc.); carboxyl; C1-C8 alkoxycarbonyl (eg, methoxycarbonyl, ethoxycarbonyl, etc.) , 1-propyloxycarbonyl, 2-propyloxycarbonyl, t-butoxycarbonyl, etc.); carbamoyl optionally substituted with lower alkyl (eg, carbamoyl, methylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, etc.); cyclic aminocarbonyl (For example, pyrrolidinocarbonyl, piperidinocarbonyl, morpholinocarbonyl, etc.) and the like. Preferred substituents include methylamino, ethylamino, dimethylamino, diethylamino, methoxy, ethoxy, 2-propyloxy, t-butoxycarbonyl, hydroxyl group, fluorine atom, chlorine atom, trifluoro, morpholino, piperidino, pyrrolidino, carboxyl, Examples thereof include methoxycarbonyl, morpholinocarbonyl, phenyl and pyridyl. The lower alkoxy which may be substituted may be substituted with at least one group selected from the group consisting of the above substituents, and the number of substituents may be, for example, 0, 1, 2, 3 The number is 0, preferably 0, 1, or 2.
　本発明において、「低級アルコキシカルボニル」における低級アルコキシは上記で定義したとおりである。低級アルコキシカルボニルはカルボニルに上記の低級アルコキシが結合した基である。低級アルコキシカルボニルとしては、例えば、直鎖状、分枝状、または環状構造を含むＣ１～Ｃ８アルコキシカルボニルが挙げられる。具体的には、直鎖状または分枝状のアルコキシカルボニルとしては、メトキシカルボニル、エトキシカルボニル、１－プロポキシカルボニル、２－プロポキシカルボニル、１－ブトキシカルボニル、２－ブトキシカルボニル、イソブトキシカルボニル、ｔ－ブトキシカルボニル等が挙げられる。環状構造を含むＣ１～Ｃ８アルコキシカルボニルとしては、シクロプロポキシカルボニル、シクロプロピルメトキシカルボニル、シクロブチロキシカルボニル、シクロブチルメトキシカルボニル、シクロペンチロキシカルボニル、シクロペンチルメトキシカルボニル、シクロヘキシロキシカルボニル、シクロヘキシルメトキシカルボニル、シクロヘキシルエトキシカルボニル等が挙げられる。好ましい低級アルコキシカルボニルとしては、メトキシカルボニル、エトキシカルボニル、２－プロポキシカルボニル、シクロプロポキシカルボニル等が挙げられる。 In the present invention, the lower alkoxy in the "lower alkoxycarbonyl" is as defined above. The lower alkoxycarbonyl is a group in which the above-mentioned lower alkoxy is bonded to the carbonyl. Examples of the lower alkoxycarbonyl include C1 to C8 alkoxycarbonyl containing a linear, branched or cyclic structure. Specifically, the linear or branched alkoxycarbonyls include methoxycarbonyl, ethoxycarbonyl, 1-propoxycarbonyl, 2-propoxycarbonyl, 1-butoxycarbonyl, 2-butoxycarbonyl, isobutoxycarbonyl, t-. Butoxycarbonyl and the like can be mentioned. Examples of the C1 to C8 alkoxycarbonyl containing a cyclic structure include cyclopropoxycarbonyl, cyclopropylmethoxycarbonyl, cyclobutyloxycarbonyl, cyclobutylmethoxycarbonyl, cyclopentyroxycarbonyl, cyclopentylmethoxycarbonyl, cyclohexyloxycarbonyl, cyclohexylmethoxycarbonyl and cyclohexylethoxy. Examples include carbonyl. Preferred lower alkoxycarbonyls include methoxycarbonyl, ethoxycarbonyl, 2-propoxycarbonyl, cyclopropoxycarbonyl and the like.
　本発明において、「低級アルキルスルホニル」における低級アルキルは上記で定義したとおりである。低級アルキルスルホニルはスルホニルに上記の低級アルキルが結合した基である。低級アルキルスルホニルとしては、例えば、直鎖状、分枝状、または環状構造を含むＣ１～Ｃ８アルキルスルホニル等が挙げられ、具体的には、直鎖状または分枝状のアルキルスルホニルとしては、メタンスルホニル、エタンスルホニル、１－プロピルスルホニル、２－プロピルスルホニル、１－ブチルスルホニル、２－ブチルスルホニル、イソブチルスルホニル、ｔ－ブチルスルホニル等が挙げられる。環状構造を含むＣ１～Ｃ８アルキルスルホニルとしては、シクロプロピルスルホニル、シクロプロピルメチルスルホニル、シクロブチルスルホニル、シクロブチルメチルスルホニル、シクロペンチルスルホニル、シクロペンチルメチルスルホニル、シクロヘキシルスルホニル、シクロヘキシルメチルスルホニル、シクロヘキシルエチルスルホニル等が挙げられる。好ましくは、メタンスルホニル、エタンスルホニル、２－プロパンスルホニル、シクロプロパンスルホニル等が挙げられる。 In the present invention, the lower alkyl in the "lower alkyl sulfonyl" is as defined above. The lower alkyl sulfonyl is a group in which the above lower alkyl is bonded to the sulfonyl. Examples of the lower alkylsulfonyl group include C1 to C8 alkylsulfonyl group containing a linear, branched or cyclic structure, and specifically, the linear or branched alkylsulfonyl group includes methane. Examples thereof include sulfonyl, ethanesulfonyl, 1-propylsulfonyl, 2-propylsulfonyl, 1-butylsulfonyl, 2-butylsulfonyl, isobutylsulfonyl, t-butylsulfonyl and the like. Examples of the C1 to C8 alkylsulfonyl containing a cyclic structure include cyclopropylsulfonyl, cyclopropylmethylsulfonyl, cyclobutylsulfonyl, cyclobutylmethylsulfonyl, cyclopentylsulfonyl, cyclopentylmethylsulfonyl, cyclohexylsulfonyl, cyclohexylmethylsulfonyl, cyclohexylethylsulfonyl and the like. Be done. Preferred examples thereof include methanesulfonyl, ethanesulfonyl, 2-propanesulfonyl, cyclopropanesulfonyl and the like.
　本発明において、「低級アルキルまたは低級アルキルスルホニルで置換されていてもよいカルバモイル」において、低級アルキルおよび低級アルキルスルホニルは上記で定義したとおりである。低級アルキルまたは低級アルキルスルホニルで置換されていてもよいカルバモイルは、「低級アルキルで置換されていてもよいカルバモイル」と「低級アルキルスルホニルで置換されていてもよいカルバモイル」を含む。 In the present invention, in "carbamoyl optionally substituted with lower alkyl or lower alkyl sulfonyl", the lower alkyl and lower alkyl sulfonyl are as defined above. Carbamoyls optionally substituted with lower alkyl or lower alkylsulfonyls include "carbamoyls optionally substituted with lower alkyls" and "carbamoyls optionally substituted with lower alkylsulfonyls".
　「低級アルキルで置換されていてもよいカルバモイル」は、カルバモイルに上記の低級アルキルが１または２個結合してもよい基である。低級アルキルが２個結合する場合、当該低級アルキルは同一であっても異なっていてもよい。低級アルキルで置換されていてもよいカルバモイルとしては、例えばカルバモイル、あるいは直鎖状、分枝状、または環状構造を含む、Ｃ１～Ｃ８アルキルで置換されたアミノカルボニル等が挙げられる。低級アルキルで置換されていてもよいカルバモイルとしては、具体的には、カルバモイル、メチルアミノカルボニル、エチルアミノカルボニル、プロピルアミノカルボニル、２－プロピルアミノカルボニル、ジメチルアミノカルボニル、ジエチルアミノカルボニル、エチルメチルアミノカルボニル、メチルプロピルアミノカルボニル、ジシクロヘキシルアミノカルボニル等が挙げられる。 "Carbamoyl which may be substituted with lower alkyl" is a group in which one or two of the above lower alkyls may be bonded to carbamoyl. When two lower alkyls are bonded, the lower alkyls may be the same or different. Carbamoyls that may be substituted with lower alkyls include, for example, carbamoyls, or aminocarbonyls substituted with C1-C8 alkyls, including linear, branched, or cyclic structures. Specific examples of carbamoyl that may be substituted with lower alkyl include carbamoyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, 2-propylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl, and ethylmethylaminocarbonyl. Examples thereof include methylpropylaminocarbonyl and dicyclohexylaminocarbonyl.
　「低級アルキルスルホニルで置換されていてもよいカルバモイル」は、カルバモイルに上記の低級アルキルスルホニルが１または２個結合してもよい基である。低級アルキルスルホニルが２個結合する場合、当該低級アルキルスルホニルは同一であっても異なっていてもよい。低級アルキルスルホニルで置換されていてもよいカルバモイルとしては、例えば、カルバモイル、あるいは直鎖状、分枝状、または環状構造を含む、Ｃ１～Ｃ８アルキルスルホニルで置換されたアミノカルボニル等が挙げられる。直鎖状または分枝状のＣ１～Ｃ８アルキルスルホニルアミノカルボニルとしては、例えば、メタンスルホニルアミノカルボニル、エタンスルホニルアミノカルボニル、１－プロピルスルホニルアミノカルボニル、２－プロピルスルホニルアミノカルボニル、１－ブチルスルホニルアミノカルボニル、２－ブチルスルホニルアミノカルボニル、イソブチルスルホニルアミノカルボニル、ｔ－ブチルスルホニルアミノカルボニル等が挙げられる。環状構造を含むＣ１～Ｃ８アルキルスルホニルアミノカルボニルとしては、例えば、シクロプロピルスルホニルアミノカルボニル、シクロプロピルメチルスルホニルアミノカルボニル、シクロブチルスルホニルアミノカルボニル、シクロブチルメチルスルホニルアミノカルボニル、シクロペンチルスルホニルアミノカルボニル、シクロペンチルメチルスルホニルアミノカルボニル、シクロヘキシルスルホニルアミノカルボニル、シクロヘキシルメチルスルホニルアミノカルボニル、シクロヘキシルエチルスルホニルアミノカルボニル等が挙げられる。好ましい低級アルキルスルホニルで置換されていてもよいカルバモイルとしては、カルバモイル、メタンスルホニルアミノカルボニル、エタンスルホニルアミノカルボニル、２－プロピルスルホニルアミノカルボニル、シクロプロピルスルホニルアミノカルボニル等が挙げられる。　　　　 "Carbamoyl which may be substituted with a lower alkylsulfonyl" is a group in which one or two of the above lower alkylsulfonyls may be bonded to the carbamoyl. When two lower alkyl sulfonyls are bonded, the lower alkyl sulfonyls may be the same or different. Carbamoyls that may be substituted with lower alkylsulfonyls include, for example, carbamoyls, or aminocarbonyls substituted with C1-C8 alkylsulfonyls, including linear, branched, or cyclic structures. Examples of the linear or branched C1-C8 alkylsulfonylaminocarbonyl include methanesulfonylaminocarbonyl, ethanesulfonylaminocarbonyl, 1-propylsulfonylaminocarbonyl, 2-propylsulfonylaminocarbonyl, and 1-butylsulfonylaminocarbonyl. , 2-Butylsulfonylaminocarbonyl, isobutylsulfonylaminocarbonyl, t-butylsulfonylaminocarbonyl and the like. Examples of the C1 to C8 alkylsulfonylaminocarbonyl containing a cyclic structure include cyclopropylsulfonylaminocarbonyl, cyclopropylmethylsulfonylaminocarbonyl, cyclobutylsulfonylaminocarbonyl, cyclobutylmethylsulfonylaminocarbonyl, cyclopentylsulfonylaminocarbonyl, and cyclopentylmethylsulfonyl. Examples thereof include aminocarbonyl, cyclohexylsulfonylaminocarbonyl, cyclohexylmethylsulfonylaminocarbonyl, cyclohexylethylsulfonylaminocarbonyl and the like. Carboxamides that may be substituted with preferred lower alkylsulfonyls include carboxamides, methanesulfonylaminocarbonyls, ethanesulfonylaminocarbonyls, 2-propylsulfonylaminocarbonyls, cyclopropylsulfonylaminocarbonyls and the like.
　本発明において、「置換されていてもよい環状アミノカルボニル」における置換されていてもよい環状アミノは上記で定義したとおりである。置換されていてもよい環状アミノカルボニルはカルボニルに上記の置換されていてもよい環状アミノが結合した基である。置換されていてもよい環状アミノカルボニルとしては、具体的には、ピロリジノカルボニル、ピペリジノカルボニル、ピペラジノカルボニル、４－メチルピペリジノ、モルホリノカルボニル、２－ピロリドニルカルボニル等が挙げられ、好ましくは、ピロリジノカルボニル、モルホリノカルボニル等が挙げられる。 In the present invention, the optionally substituted cyclic amino in the "optionally substituted cyclic aminocarbonyl" is as defined above. The optionally substituted cyclic aminocarbonyl is a group to which the above optionally substituted cyclic amino is attached to the carbonyl. Specific examples of the cyclic aminocarbonyl that may be substituted include pyrrolidinocarbonyl, piperidinocarbonyl, piperazinocarbonyl, 4-methylpiperidino, morpholinocarbonyl, 2-pyrrolidonylcarbonyl and the like, which are preferable. Examples include pyrrolidinocarbonyl, morpholinocarbonyl and the like.
　本発明において、「低級アルキルで置換されていてもよいスルファモイル」における低級アルキルは上記で定義したとおりである。低級アルキルで置換されていてもよいスルファモイルは、スルファモイルに上記の低級アルキルが１または２個結合してもよい基である。低級アルキルが２個結合する場合、当該低級アルキルは同一であっても異なっていてもよい。低級アルキルで置換されていてもよいスルファモイルとしては、例えば、スルファモイル；直鎖状、分枝状、または環状構造を含むＣ１～Ｃ８アルキルで置換されたアミノスルホニル等が挙げられ、具体的には、スルファモイル、メチルアミノスルホニル、エチルアミノスルホニル、プロピルアミノスルホニル、２－プロピルアミノスルホニル、ジメチルアミノホニル、ジエチルアミノスルホニル、エチルメチルアミノスルホニル、メチルプロピルアミノスルホニル、ジシクロヘキシルアミノスルホニル等が挙げられる。　　　　　 In the present invention, the lower alkyl in "sulfamoyl which may be substituted with lower alkyl" is as defined above. Sulfamoyl, which may be substituted with a lower alkyl, is a group in which one or two of the above lower alkyls may be attached to sulfamoyl. When two lower alkyls are bonded, the lower alkyls may be the same or different. Examples of sulfamoyl substituted with lower alkyl include sulfamoyl; aminosulfonyl substituted with C1-C8 alkyl containing a linear, branched, or cyclic structure, and specific examples thereof include. Examples thereof include sulfamoyl, methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, 2-propylaminosulfonyl, dimethylaminophonyl, diethylaminosulfonyl, ethylmethylaminosulfonyl, methylpropylaminosulfonyl, dicyclohexylaminosulfonyl and the like.
　本発明において、「置換されていてもよい環状アミノスルホニル」における置換されていてもよい環状アミノは上記で定義したとおりである。置換されていてもよい環状アミノスルホニルはスルホニルに上記の置換されていてもよい環状アミノが結合した基である。置換されていてもよい環状アミノスルホニルとしては、具体的には、ピロリジノスルホニル、ピペリジノスルホニル、ピペラジノスルホニル、４－メチルピペリジノスルホニル、モルホリノスルホニル、４－ピぺリドニルスルホニル等が挙げられ、好ましくは、ピロリジノスルホニル、モルホリノスルホニル等が挙げられる。 In the present invention, the optionally substituted cyclic amino in the "optionally substituted cyclic aminosulfonyl" is as defined above. The optionally substituted cyclic aminosulfonyl is a group to which the above optionally substituted cyclic amino is attached to the sulfonyl. Specific examples of the cyclic aminosulfonyls that may be substituted include pyrrolidinosulfonyl, piperidinosulfonyl, piperazinosulfonyl, 4-methylpiperidinosulfonyl, morpholinosulfonyl, 4-piperidonylsulfonyl and the like. , And preferably, pyrrolidinosulfonyl, morpholinosulfonyl and the like.
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　一般式（１）で表される化合物において、Ａは、置換されていてもよいベンゼン環である。Ａの置換基には、例えば、下記のＡ－１）～Ａ－１６）からなる群より選択される少なくとも１種が含まれ、置換基が複数存在する場合は、互いに同一でも異なっていてもよい。
Ａ－１）ハロゲン、
Ａ－２）水酸基、
Ａ－３）ニトロ、
Ａ－４）シアノ、
Ａ－５）カルボキシル、
Ａ－６）置換されていてもよいアミノ、
Ａ－７）置換されていてもよい環状アミノ、
Ａ－８）置換されていてもよい低級アルキル、
Ａ－９）置換されていてもよい低級アルコキシ、
Ａ－１０）低級アルコキシカルボニル、
Ａ－１１）低級アルキルスルホニル、
Ａ－１２）低級アルキルまたは低級アルキルスルホニルで置換されていてもよいカルバモイル、
Ａ－１３）置換されていてもよい環状アミノカルボニル、
Ａ－１４）低級アルキルで置換されていてもよいスルファモイル、
Ａ－１５）置換されていてもよい環状アミノスルホニル、
Ａ－１６）テトラゾリル。　 In the compound represented by the general formula (1), A is a optionally substituted benzene ring. The substituent of A includes, for example, at least one selected from the group consisting of the following groups A-1) to A-16), and when a plurality of substituents are present, they may be the same or different from each other. Good.
A-1) Halogen,
A-2) Hydroxyl group,
A-3) Nitro,
A-4) Cyano,
A-5) Carboxyl,
A-6) Amino, which may be substituted,
A-7) Cyclic amino, which may be substituted,
A-8) Lower alkyl, which may be substituted,
A-9) Substituted lower alkoxy,
A-10) Lower alkoxycarbonyl,
A-11) Lower alkyl sulfonyl,
A-12) Carbamoyl, which may be substituted with a lower alkyl or lower alkyl sulfonyl,
A-13) Cyclic aminocarbonyl, which may be substituted,
A-14) Sulfamoyl, which may be substituted with a lower alkyl,
A-15) Cyclic aminosulfonyl, which may be substituted,
A-16) Tetrazoleyl.
　Ａにおける置換基の数は、例えば、０～５個、０～４個、０～３個、好ましくは０、１または２個、より好ましくは０または１個である。置換基が複数存在する場合は、互いに同一でも異なっていてもよい。 The number of substituents in A is, for example, 0 to 5, 0 to 4, 0 to 3, preferably 0, 1 or 2, and more preferably 0 or 1. When a plurality of substituents are present, they may be the same or different from each other.
　Ａの置換基の他の例としては、上記のＡ－１およびＡ－３～Ａ－１６からなる群より選択される少なくとも１種、上記のＡ－１およびＡ－３～Ａ－１６からなる群からメトキシを除いた群より選択される少なくとも１種等が挙げられる。 As another example of the substituent of A, it consists of at least one selected from the group consisting of A-1 and A-3 to A-16 described above, A-1 and A-3 to A-16 described above. At least one selected from the group obtained by removing methoxy from the group can be mentioned.
　好ましいＡの置換基は、ハロゲン；低級アルコキシ；低級アルキルまたは低級アルキルスルホニルで置換されていてもよいカルバモイル；およびハロゲンで置換されていてもよい低級アルキルからなる群より選択される少なくとも１種であり、より好ましいＡの置換基は、ハロゲン；低級アルコキシ；カルバモイル；およびハロゲンで置換されていてもよい低級アルキルからなる群より選択される少なくとも１種であり、より一層好ましいＡの置換基は、ハロゲン、メトキシ、エトキシ、カルバモイル、フルオロメチル、ジフルオロメチル、トリフルオロメチル、フルオロエチル、ジフルオロエチル、およびトリフルオロエチルからなる群より選択される少なくとも１種であり、より好ましくはハロゲン、メトキシ、エトキシ、カルバモイル、フルオロメチル、ジフルオロメチル、トリフルオロメチル、フルオロエチル、ジフルオロエチル、およびトリフルオロエチルからなる群より選択される少なくとも１種であり、特に好ましくは、塩素原子、フッ素原子、およびトリフルオロメチルからなる群より選択される少なくとも１種である。 The preferred substituent of A is at least one selected from the group consisting of halogen; lower alkoxy; carbamoyl optionally substituted with lower alkyl or lower alkylsulfonyl; and lower alkyl optionally substituted with halogen. , The more preferred substituent of A is at least one selected from the group consisting of halogen; lower alkoxy; carbamoyl; and lower alkyl which may be substituted with halogen, and the more preferred substituent of A is halogen. , Methoxy, ethoxy, carbamoyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and trifluoroethyl, more preferably halogen, methoxy, ethoxy, carbamoyl. , Fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, difluoroethyl, and at least one selected from the group consisting of trifluoroethyl, particularly preferably consisting of a chlorine atom, a fluorine atom, and trifluoromethyl. At least one selected from the group.
　一般式（１）で表される化合物において、Ａの置換基は、ベンゾイソオキサゾールまたはベンゾイソチアゾール骨格の４位、５位、６位、および７位のいずれの炭素原子に結合していてもよいが、好ましくは４位、５位および６位の炭素原子の少なくとも１個、より好ましくは４位および／または５位の炭素原子、特に好ましくは４位の炭素原子に結合する。なお、本発明において、ベンゾイソオキサゾールまたはベンゾイソチアゾール骨格を構成する原子の位置番号は次のとおりである。
Figure JPOXMLDOC01-appb-C000016
 In the compound represented by the general formula (1), the substituent of A may be bonded to any of the carbon atoms at the 4-position, 5-position, 6-position, and 7-position of the benzoisoxazole or benzoisothiazole skeleton. It is preferable, but it is preferably bonded to at least one of the carbon atoms at the 4-position, 5-position and 6-position, more preferably to the carbon atom at the 4-position and / or 5-position, and particularly preferably to the carbon atom at the 4-position. In the present invention, the position numbers of the atoms constituting the benzoisoxazole or benzoisothiazole skeleton are as follows.
Figure JPOXMLDOC01-appb-C000016
［式中、ＡおよびＸは前記と同じ。］。 [In the formula, A and X are the same as above. ].
　一般式（１）で表される化合物において、特に好ましいＡは、ベンゾイソオキサゾールまたはベンゾイソチアゾール骨格の４位の炭素原子に、ハロゲン、低級アルコキシ、またはハロゲンで置換されていてもよい低級アルキルが結合し、５、６、および７位の炭素原子が置換されていないベンゼン環である。 In the compound represented by the general formula (1), particularly preferable A is a lower alkyl in which the carbon atom at the 4-position of the benzoisoxazole or benzoisothiazole skeleton is substituted with a halogen, a lower alkoxy, or a halogen. It is a benzene ring that is bonded and the carbon atoms at positions 5, 6, and 7 are not substituted.
　一般式（１）で表される化合物において、Ｂは、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールである。置換されていてもよいアリールまたは置換されていてもよいヘテロアリールは上記の定義のとおりである。アリールとしては、例えばフェニルまたはナフチルが挙げられ、フェニルが好ましい。ヘテロアリールとしては、環構成原子として他のヘテロ原子を含まない単環の含窒素ヘテロアリール、またはベンゾイミダゾリルが好ましい。環構成原子として他のヘテロ原子を含まない単環の含窒素ヘテロアリールとしては、環構成ヘテロ原子として１個の窒素原子を含む５員または６員のヘテロアリールが好ましく、例えば、ピロリル、ピリジルが挙げられ、ピリジルが好ましく、２－ピリジルがより一層好ましい。ベンゾイミダゾリルとしては、ベンゾイミダゾール－３－イルが好ましい。 In the compound represented by the general formula (1), B is an aryl which may be substituted or a heteroaryl which may be substituted. Aryl which may be substituted or heteroaryl which may be substituted is as defined above. Examples of the aryl include phenyl and naphthyl, and phenyl is preferable. As the heteroaryl, a monocyclic nitrogen-containing heteroaryl that does not contain other heteroatoms as a ring-constituting atom, or benzoimidazolyl is preferable. As the monocyclic nitrogen-containing heteroaryl containing no other heteroatom as the ring-constituting atom, a 5- or 6-membered heteroaryl containing one nitrogen atom as the ring-constituting heteroatom is preferable, and for example, pyrrolyl and pyridyl are used. Pyridyl is preferred, and 2-pyridyl is even more preferred. As the benzimidazolyl, benzimidazol-3-yl is preferable.
　Ｂが単環のアリールの場合、Ｂは、下記のＢ－１）～Ｂ－１６）からなる群より選択される少なくとも１種の基で置換されていてもよい。Ｂが単環または二環のヘテロアリールである場合、Ｂは下記のＢ－１)～Ｂ－１７）からなる群より選択される少なくとも１種の基で置換されていてもよい。
Ｂ－１）ハロゲン、
Ｂ－２）水酸基、
Ｂ－３）ニトロ、
Ｂ－４）シアノ、
Ｂ－５）カルボキシル
Ｂ－６）置換されていてもよいアミノ、
Ｂ－７）置換されていてもよい環状アミノ、
Ｂ－８）置換されていてもよい低級アルキル、
Ｂ－９）置換されていてもよい低級アルコキシ、
Ｂ－１０）低級アルコキシカルボニル、
Ｂ－１１）低級アルキルスルホニル、
Ｂ－１２）低級アルキルまたは低級アルキルスルホニルで置換されていてもよいカルバモイル、
Ｂ－１３）置換されていてもよい環状アミノカルボニル、
Ｂ－１４）低級アルキルで置換されていてもよいスルファモイル、
Ｂ－１５）置換されていてもよい環状アミノスルホニル、
Ｂ－１６）テトラゾリル、
Ｂ－１７）オキソ。 When B is a monocyclic aryl, B may be substituted with at least one group selected from the group consisting of B-1) to B-16) below. When B is a monocyclic or bicyclic heteroaryl, B may be substituted with at least one group selected from the group consisting of B-1) to B-17) below.
B-1) Halogen,
B-2) Hydroxyl group,
B-3) Nitro,
B-4) Cyano,
B-5) Carboxyl B-6) May be substituted amino,
B-7) Cyclic amino, which may be substituted,
B-8) Substituted lower alkyl,
B-9) Substituted lower alkoxy,
B-10) Lower alkoxycarbonyl,
B-11) Lower alkyl sulfonyl,
B-12) Carbamoyl, which may be substituted with lower alkyl or lower alkyl sulfonyl,
B-13) Cyclic aminocarbonyl, which may be substituted,
B-14) Sulfamoyl, which may be substituted with a lower alkyl,
B-15) Cyclic aminosulfonyl, which may be substituted,
B-16) Tetrazoleyl,
B-17) Oxo.
　Ｂにおける置換基の数は、例えば、０もしくは少なくとも１個、０～５個、０～４個、好ましくは０～３個、より好ましくは０、１または２個である。置換基が複数存在する場合は、互いに同一でも異なっていてもよい。 The number of substituents in B is, for example, 0 or at least 1, 0 to 5, 0 to 4, preferably 0 to 3, and more preferably 0, 1 or 2. When a plurality of substituents are present, they may be the same or different from each other.
　Ｂの置換基として好ましくは、ハロゲン；カルボキシル、置換されていてもよい低級アルキル；低級アルコキシカルボニル；低級アルキルまたは低級アルキルスルホニルで置換されていてもよいカルバモイル；および置換されていてもよい環状アミノカルボニルからなる群より選択される少なくとも１種が挙げられ、具体的には、ハロゲン、カルボキシル、メチル、エチル、１－プロピル、２－プロピル、ヒドロキシメチル、カルボキシメチル、トリクロロメチル、トリフルオロメチル、メトキシカルボニル、エトキシカルボニル、ｔ－ブトキシカルボニル、メチルアミノカルボニル、ジメチルアミノカルボニル、エチルメチルアミノカルボニル、メタンスルホニルアミノカルボニル、ピロリジノカルボニル、およびモルホリノカルボニルからなる群より選択される少なくとも１種が挙げられる。 Preferred as substituents for B are halogen; carboxyl, optionally substituted lower alkyl; lower alkoxycarbonyl; optionally substituted with lower alkyl or lower alkylsulfonyl, carbamoyl; and optionally substituted cyclic aminocarbonyl. At least one selected from the group consisting of, specifically, halogen, carboxyl, methyl, ethyl, 1-propyl, 2-propyl, hydroxymethyl, carboxymethyl, trichloromethyl, trifluoromethyl, methoxycarbonyl. , Ethoxycarbonyl, t-butoxycarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylmethylaminocarbonyl, methanesulfonylaminocarbonyl, pyrrolidinocarbonyl, and at least one selected from the group consisting of morpholinocarbonyl.
　Ｂの置換基としてより好ましくは、ハロゲン；カルボキシル；低級アルキル；ハロゲンで置換された低級アルキル；低級アルコキシカルボニル；および低級アルキルで置換されていてもよいカルバモイルからなる群より選択される少なくとも１種が挙げられ、具体的には、ハロゲン、カルボキシル、メチル、エチル、トリクロロメチル、トリフルオロメチル、メトキシカルボニル、エトキシカルボニル、ｎ－プロポキシカルボニル、イソプロポキシカルボニル、モノメチルアミノカルボニル、およびジメチルアミノカルボニルからなる群より選択される少なくとも１種が挙げられる。 More preferably, the substituent of B is at least one selected from the group consisting of halogen; carboxyl; lower alkyl; halogen-substituted lower alkyl; lower alkoxycarbonyl; and optionally carbamoyl substituted with lower alkyl. Specifically, from the group consisting of halogen, carboxyl, methyl, ethyl, trichloromethyl, trifluoromethyl, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, monomethylaminocarbonyl, and dimethylaminocarbonyl. At least one selected is included.
　Ｂの置換基として特に好ましくは、塩素原子、フッ素原子、メチル、カルボキシル、メトキシカルボニル、エトキシカルボニル、メチルアミノカルボニル、およびジメチルアミノカルボニルからなる群より選択される少なくとも１種が挙げられる。 The substituent of B is particularly preferably at least one selected from the group consisting of chlorine atom, fluorine atom, methyl, carboxyl, methoxycarbonyl, ethoxycarbonyl, methylaminocarbonyl, and dimethylaminocarbonyl.
　一般式（１）で表される化合物において、Ｙが窒素原子の場合、Ｂは置換されていてもよいフェニルまたは置換されていてもよいピリジルが好ましく、Ｙが炭素原子の場合、Ｂは置換されていてもよいフェニル、置換されていてもよいピリジル、または２－オキソベンゾイミダゾール－３－イルが好ましく、置換されていてもよいフェニル又は置換されていてもよいピリジルがより好ましい。 In the compound represented by the general formula (1), when Y is a nitrogen atom, B is preferably substituted phenyl or optionally substituted pyridyl, and when Y is a carbon atom, B is substituted. Phenyl which may be substituted, pyridyl which may be substituted, or 2-oxobenzoimidazole-3-yl is preferable, and phenyl which may be substituted or pyridyl which may be substituted is more preferable.
　一般式（１）で表される化合物において、Ｂが置換されたピリジルまたは置換されたフェニルである場合、Ｙと結合しているピリジンまたはベンゼン環上の炭素原子に対してオルト位の炭素原子の１または２個、好ましくは１個が置換されていることが好ましい。当該オルト位の炭素原子に結合する置換基は上記されたＢの置換基であればよいが、好ましくはハロゲンであり、より好ましくは塩素原子またはフッ素原子であり、より一層好ましくは塩素原子である。 In the compound represented by the general formula (1), when B is a substituted pyridyl or a substituted phenyl, the carbon atom at the ortho position with respect to the carbon atom on the pyridine or benzene ring bonded to Y It is preferable that one or two, preferably one, is substituted. The substituent bonded to the carbon atom at the ortho position may be the above-mentioned B substituent, but is preferably a halogen, more preferably a chlorine atom or a fluorine atom, and even more preferably a chlorine atom. ..
　また、一般式（１）で表される化合物において、Ｂが置換されたピリジルまたは置換されたフェニルである場合、Ｙと結合しているピリジンまたはベンゼン環上の炭素原子に対してパラ位の炭素原子が置換されていないかまたはカルボキシルで置換されていることが好ましい。 Further, in the compound represented by the general formula (1), when B is a substituted pyridyl or a substituted phenyl, the carbon at the para position with respect to the carbon atom on the pyridine or benzene ring bonded to Y. It is preferable that the atom is not substituted or is substituted with carboxyl.
　また、一般式（１）で表される化合物において、Ｂが置換されたピリジルまたは置換されたフェニルである場合、Ｙと結合しているピリジンまたはベンゼン環上の炭素原子に対してメタ位の炭素原子の全てが置換されていないことが好ましい。 Further, in the compound represented by the general formula (1), when B is a substituted pyridyl or a substituted phenyl, the carbon at the meta position with respect to the carbon atom on the pyridine or benzene ring bonded to Y. It is preferable that all of the atoms are not substituted.
　一般式（１）で表される化合物において、Ｂが置換されたピリジルまたは置換されたフェニルである場合、Ｙと結合しているピリジンまたはベンゼン環上の炭素原子に対してオルト位の炭素原子の１または２個、好ましくは１個が塩素原子またはフッ素原子で置換され、メタ位の炭素原子が置換されておらず、パラ位の炭素原子が置換されていないか、あるいはカルボキシル、メトキシカルボニル、またはエトキシカルボニルで置換されていることがより好ましい。
　Ｙが窒素原子であり、かつＢが置換された２－ピリジルである場合は、Ｙと結合しているピリジン環上の炭素原子に対してオルト位の炭素原子が塩素原子またはフッ素原子で置換され、メタ位の炭素原子の全てが置換されておらず、パラ位の炭素原子が置換されていないかまたはカルボキシルで置換されていることが特に好ましい。
　Ｙが窒素原子であり、かつＢが置換されたフェニルである場合は、Ｙと結合しているベンゼン環上の炭素原子に対してオルト位の２個の炭素原子のうちの１個が塩素原子またはフッ素原子で置換され、該フェニルを構成する他の全ての炭素原子が置換されていないことが特に好ましい。
　Ｙが炭素原子であり、かつＢが置換された２－ピリジルである場合は、Ｙと結合しているピリジン環上の炭素原子に対してオルト位の炭素原子が塩素原子またはフッ素原子で置換され、メタ位の炭素原子の全てが置換されておらず、パラ位の炭素原子が置換されていないかあるいはカルボキシル、メトキシカルボニルまたはエトキシカルボニルで置換されていることが特に好ましい。
　Ｙが炭素原子であり、かつＢが置換されたフェニルである場合は、Ｙと結合しているベンゼン環上の炭素原子に対してオルト位の２個の炭素原子のうちの１個が塩素原子またはフッ素原子で置換され、もう一方のオルト位の炭素原子が置換されておらず、メタ位の炭素原子の全てが置換されておらず、パラ位の炭素原子が置換されていないかあるいはカルボキシル、メトキシカルボニルまたはエトキシカルボニルで置換されていることが特に好ましい。 In the compound represented by the general formula (1), when B is a substituted pyridyl or a substituted phenyl, the carbon atom at the ortho position with respect to the carbon atom on the pyridine or benzene ring bonded to Y One or two, preferably one, are substituted with chlorine or fluorine atoms, the meta-position carbon atom is not substituted, the para-position carbon atom is not substituted, or carboxyl, methoxycarbonyl, or More preferably, it is substituted with ethoxycarbonyl.
When Y is a nitrogen atom and B is a substituted 2-pyridyl, the carbon atom at the ortho position is substituted with a chlorine atom or a fluorine atom with respect to the carbon atom on the pyridine ring bonded to Y. It is particularly preferable that not all of the carbon atoms at the meta position are substituted and the carbon atoms at the para position are not substituted or substituted with carboxyl.
When Y is a nitrogen atom and B is a substituted phenyl, one of the two carbon atoms at the ortho position with respect to the carbon atom on the benzene ring bonded to Y is a chlorine atom. Alternatively, it is particularly preferable that it is substituted with a fluorine atom and all other carbon atoms constituting the phenyl are not substituted.
When Y is a carbon atom and B is a substituted 2-pyridyl, the carbon atom at the ortho position with respect to the carbon atom on the pyridine ring bonded to Y is substituted with a chlorine atom or a fluorine atom. It is particularly preferable that not all of the carbon atoms at the meta position are substituted and the carbon atom at the para position is not substituted or is substituted with carboxyl, methoxycarbonyl or ethoxycarbonyl.
When Y is a carbon atom and B is a substituted phenyl, one of the two carbon atoms at the ortho position with respect to the carbon atom on the benzene ring bonded to Y is a chlorine atom. Or it is substituted with a fluorine atom, the carbon atom at the other ortho position is not substituted, all the carbon atoms at the meta position are not substituted, the carbon atom at the para position is not substituted, or the carboxyl, It is particularly preferred that it is substituted with methoxycarbonyl or ethoxycarbonyl.
　一般式（１）で表される化合物において、Ｘは、酸素原子または硫黄原子であり、好ましくは酸素原子である。 In the compound represented by the general formula (1), X is an oxygen atom or a sulfur atom, preferably an oxygen atom.
　一般式（１）で表される化合物において、Ｙは、窒素原子または炭素原子であり、好ましくは窒素原子である。 In the compound represented by the general formula (1), Y is a nitrogen atom or a carbon atom, preferably a nitrogen atom.
　一般式（１）で表される化合物において、Ｙは、窒素原子または炭素原子であり、好ましくは窒素原子である。 In the compound represented by the general formula (1), Y is a nitrogen atom or a carbon atom, preferably a nitrogen atom.
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
　一般式（１）で表される化合物において、Ｒ１は、互いに独立して低級アルキルであるか、２個のＲ１が互いに結合して、スピロ環または架橋構造を形成していてもよい、あるいは２個のＲ１が互いに結合して、Ｙを含む環を構成する炭素原子および窒素原子と共に飽和縮合複素環を形成していてもよい。 In the general formula (1) compounds represented by, R 1 is either independently of one another are lower alkyl, two R 1 are bonded to each other, they may form a spiro ring or a crosslinked structure, or two of R 1 may be bonded to each other to form a ring and may form a saturated condensed heterocyclic ring together with the carbon and nitrogen atoms constituting including Y.
　Ｒ１が低級アルキルの場合、好ましいＲ１としては、例えば直鎖状または分枝状のＣ１～Ｃ３アルキルが挙げられ、より好ましくはメチル、エチル、より一層好ましくはメチルである。 When R 1 is a lower alkyl, preferred R 1 includes, for example, linear or branched C1-C3 alkyls, more preferably methyl, ethyl, and even more preferably methyl.
　２個のＲ１が互いに結合して、スピロ環または架橋構造を形成している場合において、スピロ環を形成するとは、一般式（１）中のＹを含む環を構成する炭素原子のうちの１つに２個のＲ１が結合し、当該Ｒ１同士が互いに結合して当該炭素原子とともに環を形成する場合をいう。 Two of R 1 are bonded to each other, when forming a spiro ring or a crosslinked structure, and forms a spiro ring, of the carbon atoms constituting the ring containing Y in formula (1) two R 1 are combined into one, it refers to the case of forming a ring together with the carbon atoms to the R 1 bonded to each other to each other.
　２個のＲ１が互いに結合して、スピロ環または架橋構造を形成している場合において、架橋構造を形成するとは、一般式（１）中のＹを含む環を構成する炭素原子のうちの２つに各々１個のＲ１が結合し、当該Ｒ１同士が互いに結合する場合をいう。 Two of R 1 are bonded to each other, when forming a spiro ring or a crosslinked structure, and to form a crosslinked structure, of the carbon atoms constituting the ring containing Y in formula (1) each one of R 1 is bonded to two, it refers to the case where the R 1 are bonded to each other to each other.
　２個のＲ１が互いに結合して、スピロ環または架橋構造を形成している場合としては、例えば、２個のＲ１が互いに結合して、メチレン、ジメチレン、トリメチレン、またはテトラメチレンとなることで架橋構造を形成する場合、あるいはジメチレンまたはトリメチレンとなることでスピロ環を形成する場合が挙げられ、好ましくは２個のＲ１が互いに結合して、メチレン、ジメチレン、またはトリメチレンとなることで架橋構造を形成する場合である。特に好ましくは下記構造式で示されるジメチレンにより形成される架橋構造である。
Figure JPOXMLDOC01-appb-C000018
 Two of R 1 are bonded to each other, as if forming a spiro ring or a crosslinked structure, for example, two of R 1 are bonded to each other, a methylene, dimethylene, trimethylene or be a tetramethylene, in the case of forming a crosslinked structure, or the case of forming a spiro ring, and by a dimethylene or trimethylene, and preferably binds two of R 1 each other, cross-linking by comprising methylene, dimethylene or a trimethylene, This is the case when forming a structure. Particularly preferably, it is a crosslinked structure formed by dimethylene represented by the following structural formula.
Figure JPOXMLDOC01-appb-C000018
　２個のＲ１が互いに結合して、Ｙを含む環を構成する炭素原子および窒素原子と共に飽和縮合複素環を形成するとは、一般式（１）中のＹを含む環を構成する炭素原子のうちの隣接する２つに各々１個のＲ１が結合し、当該Ｒ１同士が互いに結合してＹを含む環を構成する炭素原子および窒素原子と共に飽和縮合複素環を形成する場合をいう。ここでいう飽和縮合複素環は、Ｙを含む複素環（ピラジン環またはピペリジン環）とＲ１を含む飽和炭素環との縮合２環を意味する。 Two of R 1 are bonded to each other, to form a saturated condensed heterocyclic ring together with the carbon and nitrogen atoms constituting the ring containing Y are formula (1) of carbon atoms constituting the ring containing Y of out adjacent to each one of R 1 is bonded to two, it refers to the case where the R 1 together form a saturated condensed heterocyclic ring together with the carbon and nitrogen atoms constituting the ring containing Y bonded to each other. The term saturated condensed heterocyclic means a fused bicyclic Y and heterocyclic (pyrazine ring or piperidine ring) containing a saturated carbon ring containing R 1.
　飽和縮合複素環としては、例えばピラジン環またはピペリジン環とシクロペンタン環又はシクロヘキサン環との縮合環が挙げられる。飽和縮合複素環の具体例としては、オクタヒドロシクロペンタピリジン、オクタヒドロシクロペンタピラジン、デカヒドロキノリン、デカヒドロキノキサリンなどが挙げられる。 Examples of the saturated condensed heterocycle include a fused ring of a pyrazine ring or a piperidine ring and a cyclopentane ring or a cyclohexane ring. Specific examples of the saturated condensed heterocycle include octahydrocyclopentapyridine, octahydrocyclopentapyrazine, decahydroquinoline, decahydroquinoxaline and the like.
　好ましいＲ１は、Ｃ１～Ｃ３アルキルまたはジメチレンにより形成された架橋構造であり、より好ましいＲ１は、メチル、エチルまたは上記構造式で示されるジメチレンにより形成される架橋構造である。 Preferred R 1 is a cross-linked structure formed of C1-C3 alkyl or dimethylene, and more preferred R 1 is a cross-linked structure formed of methyl, ethyl or dimethylene represented by the above structural formula.
　一般式（１）で表される化合物において、ｐは、０、１、または２である。　　　　　　　　 In the compound represented by the general formula (1), p is 0, 1, or 2. ‥
　一般式（１）で表される化合物において、（Ｒ１）ｐはオキソであってよい。　　　　　　　 In the compound represented by the general formula (1), (R 1 ) p may be oxo.
　一般式（１）で表される化合物、その塩、またはそのプロドラッグのうち、下記一般式（１Ａ）で表される化合物、その塩、またはそのプロドラッグが好ましい。下記一般式（１Ａ）で表される化合物、その塩、またはそのプロドラッグを含有する難聴の予防および／または治療用医薬組成物も本発明に包含される。
Figure JPOXMLDOC01-appb-C000019
 Of the compound represented by the general formula (1), a salt thereof, or a prodrug thereof, the compound represented by the following general formula (1A), a salt thereof, or a prodrug thereof is preferable. A pharmaceutical composition for preventing and / or treating deafness containing a compound represented by the following general formula (1A), a salt thereof, or a prodrug thereof is also included in the present invention.
Figure JPOXMLDOC01-appb-C000019
［式中、
Ｚは、窒素原子またはＣＨである。
Ｙは、窒素原子または炭素原子である。
Figure JPOXMLDOC01-appb-C000020
 Ｒ１１は、互いに独立して、メチルまたはエチルであるか、あるいは２個のＲ１１が互いに結合して、メチレン、ジメチレン、またはトリメチレンによる架橋構造を形成していてもよい。
ｐは、０、１、または２である。
あるいは、（Ｒ１１）ｐはオキソである。
Ｒ２１、Ｒ２２、およびＲ２３は、互いに独立して、水素原子、ハロゲン、カルバモイル、またはトリフルオロメチルである。
Ｒ３１、Ｒ３２、およびＲ３３は、互いに独立して、水素原子、ハロゲン、ハロゲンで置換された低級アルキル、メチル、カルボキシル、低級アルコキシカルボニル、モノメチルアミノカルボニル、またはジメチルアミノカルボニルである。］。 [During the ceremony,
Z is a nitrogen atom or CH.
Y is a nitrogen atom or a carbon atom.
Figure JPOXMLDOC01-appb-C000020
 R 11 is, independently of one another are methyl or ethyl, or two R 11 are bonded to each other methylene, may form a crosslinked structure by dimethylene or trimethylene.
p is 0, 1, or 2.
Alternatively, (R 11 ) p is oxo.
R 21 , R 22 , and R 23 are independent of each other and are hydrogen atoms, halogens, carbamoyls, or trifluoromethyls.
R 31 , R 32 , and R 33 are independent of each other, lower alkyl, methyl, carboxyl, lower alkoxycarbonyl, monomethylaminocarbonyl, or dimethylaminocarbonyl substituted with hydrogen atom, halogen, halogen. ].
　一般式（１Ａ）で表される化合物において、Ｚは、窒素原子またはＣＨである。Ｚは、Ｙが窒素原子の場合、窒素原子が好ましい。 In the compound represented by the general formula (1A), Z is a nitrogen atom or CH. Z is preferably a nitrogen atom when Y is a nitrogen atom.
　一般式（１Ａ）で表される化合物において、Ｙは、窒素原子または炭素原子である。　　　　 In the compound represented by the general formula (1A), Y is a nitrogen atom or a carbon atom.
　一般式（１Ａ）で表される化合物において、Ｒ１１は、互いに独立して、メチルまたはエチルであるか、あるいは２個のＲ１１が互いに結合して、メチレン、ジメチレン、またはトリメチレンによる架橋構造を形成していてもよい。 In the general formula (1A) a compound represented by, R 11 is independently of one another are methyl or ethyl, or two R 11 are bonded to each other, a methylene, dimethylene, or a crosslinked structure by trimethylene It may be formed.
　Ｒ１１として好ましくは、メチルまたはエチル、あるいはジメチレンまたはトリメチレンからなる架橋構造であり、より好ましくはメチル、またはジエチレンからなる架橋構造である。 R 11 is preferably a crosslinked structure made of methyl or ethyl, or dimethylene or trimethylene, and more preferably a crosslinked structure made of methyl or diethylene.
　２個のＲ１１が互いに結合して、メチレン、ジメチレン、またはトリメチレンによる架橋構造を形成している場合は、一般式（１Ａ）中のＹを含む環を構成する炭素原子のうちの２つに各々１個のＲ１１が結合し、当該Ｒ１１同士が互いに結合してメチレン、ジメチレン、またはトリメチレンをなし、ピペラジン環に架橋構造が形成される場合をいう。　　　　 Two R 11 are bonded to each other, methylene, dimethylene or if forming a crosslinked structure by trimethylene, two of the carbon atoms constituting the ring containing Y in the general formula (1A), each one of R 11 is bonded, without methylene, dimethylene or trimethylene and the R 11 bonded to each other to each other, refers to the case where the crosslinking structure is formed on the piperazine ring.
　一般式（１Ａ）中のＹを含む環がＲ１１で置換された場合に好ましいのは（Ｒ１１）ｐがオキソであるか、あるいは下記構造式中で示されるものである。
Figure JPOXMLDOC01-appb-C000021
 When the ring containing Y in the general formula (1A) is substituted with R 11 , it is preferable that (R 11 ) p is oxo or is represented in the following structural formula.
Figure JPOXMLDOC01-appb-C000021
［式中、＊は、イソベンゾオキサゾールの３位の炭素原子に結合する側を表し、Ｒ１１１は、Ｃ１～Ｃ３アルキルを表す。］。
Ｒ１１１として好ましいのはメチルまたはエチル、より好ましいのはメチルである。　　　　　 [In the formula, * represents the side bonded to the carbon atom at the 3-position of isobenzoxazole, and R 111 represents C1-C3 alkyl. ].
Methyl or ethyl is preferable as R 111 , and methyl is more preferable.
　一般式（１Ａ）において（Ｒ１１）ｐはオキソであってもよい。 In the general formula (1A), (R 11 ) p may be oxo.
　一般式（１Ａ）で表される化合物において、Ｒ２１、Ｒ２２、およびＲ２３は、互いに独立して、水素原子、ハロゲン、カルバモイル、またはトリフルオロメチルであり、Ｒ２１、Ｒ２２、およびＲ２３の少なくとも１つがハロゲン、カルバモイル、またはトリフルオロメチルであることが好ましい。Ｒ２１として好ましくは、塩素原子、フッ素原子、カルバモイル、またはトリフルオロメチルであり、より好ましくは塩素原子またはトリフルオロメチルである。Ｒ２２として好ましくは、水素原子、塩素原子またはトリフルオロメチルであり、より好ましくは水素原子である。Ｒ２３として好ましくは、水素原子、塩素原子、またはトリフルオロメチルであり、より好ましくは水素原子である。Ｒ２１がハロゲン（好ましくは塩素原子またはフッ素原子）またはトリフルオロメチルであり、かつＲ２２およびＲ２３がともに水素原子であることが特に好ましい。 In the compound represented by the general formula (1A), R 21 , R 22 , and R 23 are independently hydrogen atoms, halogens, carbamoyl, or trifluoromethyl, and are R 21 , R 22 , and R. It is preferred that at least one of the 23 is halogen, carbamoyl, or trifluoromethyl. R 21 is preferably a chlorine atom, a fluorine atom, a carbamoyl, or trifluoromethyl, and more preferably a chlorine atom or trifluoromethyl. R 22 is preferably a hydrogen atom, a chlorine atom or a trifluoromethyl, and more preferably a hydrogen atom. R 23 is preferably a hydrogen atom, a chlorine atom, or trifluoromethyl, and more preferably a hydrogen atom. It is particularly preferred that R 21 is a halogen (preferably a chlorine atom or a fluorine atom) or trifluoromethyl, and that both R 22 and R 23 are hydrogen atoms.
　一般式（１Ａ）で表される化合物において、Ｒ３１、Ｒ３２、およびＲ３３は、互いに独立して、水素原子、ハロゲン、ハロゲンで置換された低級アルキル、メチル、カルボキシル、低級アルコキシカルボニル、モノメチルアミノカルボニル、またはジメチルアミノカルボニルである。Ｒ３１として好ましくは、水素原子、ハロゲン、トリクロロメチル、トリフルオロメチル、またはメチルであり、より好ましくは、ハロゲン、トリクロロメチル、トリフルオロメチル、またはメチルであり、特に好ましくは、塩素原子である。Ｒ３２として好ましくは、水素原子、ハロゲンまたはメチルであり、より好ましくは水素原子である。Ｒ３３として好ましくは、水素原子、ハロゲン、カルボキシル、メトキシカルボニル、エトキシカルボニル、モノメチルアミノカルボニル、またはジメチルアミノカルボニルであり、より好ましくは水素原子、カルボキシル、メトキシカルボニルまたはエトキシカルボニルであり、特に好ましくは水素原子またはカルボキシルである。 In the compound represented by the general formula (1A), R 31 , R 32 , and R 33 are independently substituted with a hydrogen atom, a halogen, and a halogen, and the lower alkyl, methyl, carboxyl, lower alkoxycarbonyl, and monomethyl are substituted. Aminocarbonyl, or dimethylaminocarbonyl. The R 31 is preferably a hydrogen atom, halogen, trichloromethyl, trifluoromethyl, or methyl, more preferably halogen, trichloromethyl, trifluoromethyl, or methyl, and particularly preferably a chlorine atom. The R 32 is preferably a hydrogen atom, halogen or methyl, and more preferably a hydrogen atom. The R 33 is preferably a hydrogen atom, halogen, carboxyl, methoxycarbonyl, ethoxycarbonyl, monomethylaminocarbonyl, or dimethylaminocarbonyl, more preferably a hydrogen atom, carboxyl, methoxycarbonyl or ethoxycarbonyl, and particularly preferably hydrogen. It is an atom or a carboxyl.
　Ｒ３１、Ｒ３２、およびＲ３３の好ましい例は、Ｒ３１がハロゲン（好ましくは塩素原子またはフッ素原子）であり、かつＲ３２が水素原子であり、かつＲ３３が水素原子またはカルボキシルである。Ｒ２１がハロゲン（好ましくは塩素原子）の場合には、Ｒ３１がハロゲン（好ましくは塩素原子またはフッ素原子）であり、かつＲ３２が水素原子であり、かつＲ３３が水素原子であることが好ましい。Ｒ２１がトリハロメチル（好ましくはトリフルオロメチル）の場合には、Ｒ３１がハロゲン（好ましくは塩素原子またはフッ素原子）であり、かつＲ３２が水素原子であり、かつＲ３３が水素原子、カルボキシル、メトキシカルボニル、またはエトキシカルボニルであることが好ましい。Ｒ２１がカルバモイルの場合には、Ｒ３１がハロゲン（好ましくは塩素原子またはフッ素原子、より好ましくは塩素原子）であり、かつＲ３２が水素原子であり、かつＲ３３が水素原子であることが好ましい。また、Ｒ２１が塩素原子またはトリフルオロメチルであり、Ｒ２２およびＲ２３が水素原子であり、Ｒ３１が塩素原子であり、Ｒ３２が水素原子であり、Ｒ３３が水素原子またはカルボキシルであることが好ましい。 Preferred examples of R 31 , R 32 , and R 33 are that R 31 is a halogen (preferably a chlorine atom or a fluorine atom), R 32 is a hydrogen atom, and R 33 is a hydrogen atom or a carboxyl. When R 21 is a halogen (preferably a chlorine atom), R 31 is a halogen (preferably a chlorine atom or a fluorine atom), R 32 is a hydrogen atom, and R 33 is a hydrogen atom. preferable. When R 21 is trihalomethyl (preferably trifluoromethyl), R 31 is a halogen (preferably a chlorine atom or a fluorine atom), R 32 is a hydrogen atom, and R 33 is a hydrogen atom, a carboxyl. , Methylcarbonyl, or ethoxycarbonyl. When R 21 is carbamoyl, R 31 is a halogen (preferably a chlorine atom or a fluorine atom, more preferably a chlorine atom), R 32 is a hydrogen atom, and R 33 is a hydrogen atom. preferable. Further, R 21 is a chlorine atom or trifluoromethyl, R 22 and R 23 are hydrogen atoms, R 31 is a chlorine atom, R 32 is a hydrogen atom, and R 33 is a hydrogen atom or carboxyl. Is preferable.
　一般式（１）で表される化合物、その塩、またはそのプロドラッグの具体的な例には、例えば、化合物０１１、化合物０２１、化合物０３１、化合物０４１、化合物０５１、化合物０６１、化合物０７１、化合物０８１、化合物０９１、化合物１０１、化合物１１１、化合物１２１、化合物１３１、化合物１４１、化合物１５１、化合物１６１、化合物１７１、化合物１８１、化合物１９１、化合物２０１、化合物２１１、化合物２２１、化合物２３１、化合物２４１、化合物２５１、化合物２６１、化合物２７１、化合物２８１、化合物２９１、化合物３０１、化合物３１１、化合物３２１、化合物３３１、化合物３４１、化合物３５１、化合物３６１、化合物３７１、化合物３８１、化合物３９１、化合物４０１、化合物４１１、化合物４２１、または化合物４３１が含まれ、好ましくは、下記の化合物、その塩、またはそのプロドラッグが含まれる。 Specific examples of the compound represented by the general formula (1), a salt thereof, or a prodrug thereof include, for example, compound 011 and compound 021, compound 031 and compound 041, compound 051, compound 061, compound 071, and compound. 081, Compound 091, Compound 101, Compound 111, Compound 121, Compound 131, Compound 141, Compound 151, Compound 161, Compound 171, Compound 181, Compound 191 and Compound 201, Compound 211, Compound 221 and Compound 231 and Compound 241. Compound 251 and Compound 261 and Compound 271, Compound 281 and Compound 291 and Compound 301, Compound 311, Compound 321 and Compound 331, Compound 341, Compound 351 and Compound 361, Compound 371, Compound 381, Compound 391, Compound 401 and Compound 411. , Compound 421, or compound 431, preferably the following compounds, salts thereof, or prodrugs thereof.
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000023
Figure JPOXMLDOC01-appb-C000023
　一般式（１）で表される化合物、その塩、またはそのプロドラッグとしてより好ましくは、化合物０１１、化合物０２１、化合物０３１、化合物０４１、化合物０６１、化合物０７１、化合物０８１、化合物０９１、化合物１０１、化合物１１１、化合物１２１、化合物１３１、化合物１４１、化合物１５１、化合物１６１、化合物１７１、化合物１９１、化合物２２１、化合物２８１、化合物３１１、化合物３２１、化合物３３１、化合物３４１、化合物３５１、化合物３６１、化合物３７１、化合物３８１、化合物３９１、化合物４０１、または化合物４３１、その塩、あるいはそのプロドラッグであり、さらに好ましくは、化合物０１１、化合物０２１、化合物０３１、化合物０４１、化合物０６１、化合物０７１、化合物０８１、化合物０９１、化合物１０１、化合物１１１、化合物１２１、化合物１３１、化合物１４１、化合物１５１、化合物１６１、化合物１７１、化合物１９１、化合物３２１、化合物３５１、化合物３６１、化合物３７１、化合物３８１、化合物４０１、または化合物４３１、その塩、あるいはそのプロドラッグであり、さらに一層好ましくは、化合物０１１、化合物０３１、化合物０４１、化合物０６１、化合物０７１、または化合物１９１、化合物３６１、化合物３７１、化合物３８１、化合物４０１、または化合物４３１、その塩、あるいはそのプロドラッグであり、特に好ましくは、化合物０１１、化合物０３１、化合物０４１、化合物０６１、化合物０７１、または化合物１９１、化合物３６１、化合物３７１、化合物３８１、または化合物４０１、その塩、あるいはそのプロドラッグである。 More preferably as a compound represented by the general formula (1), a salt thereof, or a prodrug thereof, Compound 011 and Compound 021, Compound 031 and Compound 041, Compound 061, Compound 071, Compound 081, Compound 091, and Compound 101. Compound 111, Compound 121, Compound 131, Compound 141, Compound 151, Compound 161, Compound 171, Compound 191, Compound 221 and Compound 281, Compound 311, Compound 321 and Compound 331, Compound 341, Compound 351 and Compound 361, Compound 371. , Compound 381, Compound 391, Compound 401, or Compound 431, a salt thereof, or a prodrug thereof, more preferably Compound 011 091, Compound 101, Compound 111, Compound 121, Compound 131, Compound 141, Compound 151, Compound 161, Compound 171, Compound 191, Compound 321, Compound 351, Compound 361, Compound 371, Compound 381, Compound 401, or Compound 431. , A salt thereof, or a prodrug thereof, and even more preferably, Compound 011 or Compound 031 or Compound 041, Compound 061, Compound 071, or Compound 191 or Compound 361, Compound 371, Compound 381, Compound 401, or Compound 431. , A salt thereof, or a prodrug thereof, particularly preferably Compound 011 or Compound 031 or Compound 041, Compound 061, Compound 071, or Compound 191 or Compound 361, Compound 371, Compound 381, or Compound 401, a salt thereof. Or its prodrug.
　本発明は、下記一般式（２）で表される化合物、その塩、またはそれらのプロドラッグを含有する難聴の予防および／または治療用医薬組成物を含む。該化合物、その塩、またはそのプロドラッグは、難聴の予防および／または治療効果を有しうる。また、該化合物、その塩、またはそのプロドラッグは、TRPCチャネル、例えばTRPC3および／またはTRPC6チャネル、好ましくはTRPC6チャネルの活性を調節または阻害する活性を有しうる。また、該化合物またはその塩は、一般式（１）で表される化合物の中間体化合物にもなりうる。 The present invention includes a pharmaceutical composition for preventing and / or treating deafness containing a compound represented by the following general formula (2), a salt thereof, or a prodrug thereof. The compound, a salt thereof, or a prodrug thereof may have a preventive and / or therapeutic effect on deafness. In addition, the compound, a salt thereof, or a prodrug thereof may have an activity of regulating or inhibiting the activity of TRPC channels, such as TRPC3 and / or TRPC6 channels, preferably TRPC6 channels. Further, the compound or a salt thereof can also be an intermediate compound of the compound represented by the general formula (1).
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000024
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000025
Figure JPOXMLDOC01-appb-C000026
Figure JPOXMLDOC01-appb-C000026
　一般式（２）において、オキシム構造を構成する炭素原子と結合したＡ環（ベンゼン環）の炭素原子に対しオルト位の炭素原子が置換基を有することが好ましい。当該置換基は、特に断りのない限り、一般式（１）におけるＡ環（ベンゼン環）における置換基と同じである。したがって、当該置換基は、例えば、上記Ａ－１）～Ａ－１６）からなる群より選択される少なくとも１種の基であってよい。
　また、一般式（２）において窒素原子と水酸基との間の結合が波線、即ち以下で表される線、で表されることにより、一般式（２）で表される化合物が、その部分構造である「＞Ｃ＝Ｎ－ＯＨ」に起因して存在する幾何異性体のＥ体、Ｚ体、およびそれらの混合物のいずれでもよいことを示す。このことは、波線で表された、一般式（２）以外の化合物についても同様である。
Figure JPOXMLDOC01-appb-C000027
 In the general formula (2), it is preferable that the carbon atom at the ortho position has a substituent on the carbon atom of the A ring (benzene ring) bonded to the carbon atom constituting the oxime structure. Unless otherwise specified, the substituent is the same as the substituent in the A ring (benzene ring) in the general formula (1). Therefore, the substituent may be, for example, at least one group selected from the group consisting of the above A-1) to A-16).
Further, in the general formula (2), the bond between the nitrogen atom and the hydroxyl group is represented by a wavy line, that is, a line represented by the following, so that the compound represented by the general formula (2) has a partial structure thereof. It is shown that any of the E-forms, Z-forms, and mixtures thereof of geometric isomers existing due to "> C = N-OH" is acceptable. This also applies to compounds other than the general formula (2) represented by wavy lines.
Figure JPOXMLDOC01-appb-C000027
　一般式（２）で表される化合物、その塩、またはそのプロドラッグのうち、下記一般式（２Ａ）で表される化合物、その塩、またはそのプロドラッグが好ましい。
Figure JPOXMLDOC01-appb-C000028
 Of the compound represented by the general formula (2), a salt thereof, or a prodrug thereof, the compound represented by the following general formula (2A), a salt thereof, or a prodrug thereof is preferable.
Figure JPOXMLDOC01-appb-C000028
Figure JPOXMLDOC01-appb-C000029
Figure JPOXMLDOC01-appb-C000029
　一般式（２）で表される化合物、その塩、またはそのプロドラッグのうち、下記一般式（２Ｂ）で表される化合物、その塩、またはそのプロドラッグが好ましい。また、下記一般式（２Ｂ）で表される化合物またはその塩は、一般式（１）で表される化合物の製造における中間体化合物として好ましい。
Figure JPOXMLDOC01-appb-C000030
 Of the compound represented by the general formula (2), a salt thereof, or a prodrug thereof, the compound represented by the following general formula (2B), a salt thereof, or a prodrug thereof is preferable. Further, the compound represented by the following general formula (2B) or a salt thereof is preferable as an intermediate compound in the production of the compound represented by the general formula (1).
Figure JPOXMLDOC01-appb-C000030
Figure JPOXMLDOC01-appb-C000031
 Ｇ１は、ハロゲン、ハロゲンで置換されていてもよい低級アルキルスルホニル、あるいは低級アルキルまたはニトロで置換されていてもよいベンゼンスルホニルである。］。
Figure JPOXMLDOC01-appb-C000031
 G 1 is a halogen, a lower alkyl sulfonyl optionally substituted with a halogen, or a benzenesulfonyl optionally substituted with a lower alkyl or nitro. ].
Figure JPOXMLDOC01-appb-C000032
 は上記のとおりである。また、一般式（２Ｂ）で表される化合物またはその塩としては、その部分構造である「＞Ｃ＝Ｎ－ＯＨ」に起因して存在する幾何異性体のＥ体とＺ体とが存在するが、一般式（２Ｂ）で表される化合物またはその塩を一般式（１）で表される化合物の製造における中間体化合物とする場合には該Ｅ体が好ましい。
Figure JPOXMLDOC01-appb-C000032
 Is as above. Further, as the compound represented by the general formula (2B) or a salt thereof, there are E-form and Z-form of geometric isomers existing due to its partial structure “> C = N—OH”. However, when the compound represented by the general formula (2B) or a salt thereof is used as an intermediate compound in the production of the compound represented by the general formula (1), the E form is preferable.
　Ｇ１で示されるハロゲンとしては、例えば、塩素原子、フッ素原子、臭素原子、ヨウ素原子を挙げることができる。 Examples of the halogen represented by G 1 include a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom.
　Ｇ１で示されるハロゲンで置換されていてもよい低級アルキルスルホニルにおける低級アルキルスルホニルは上記で定義したとおりである。また、低級アルキルスルホニルはスルホニルに低級アルキルが結合した基であり、低級アルキルはハロゲンで置換されていてもよい。ハロゲンで置換されていてもよい低級アルキルスルホニルとしては、例えば、１～３個のハロゲンで置換されていてもよい直鎖状または分枝状のＣ１～Ｃ６アルキル（好ましくはＣ１～Ｃ４アルキル、より好ましくはＣ１～Ｃ３アルキル）スルホニルが挙げられ、具体的には、メタンスルホニル、エタンスルホニル、トリフルオロメタンスルホニル等を挙げることができる。 The lower alkyl sulfonyls in the lower alkyl sulfonyls that may be substituted with the halogen represented by G 1 are as defined above. Further, the lower alkyl sulfonyl is a group in which a lower alkyl is bonded to a sulfonyl, and the lower alkyl may be substituted with a halogen. Examples of the lower alkyl sulfonyl group which may be substituted with halogen include linear or branched C1 to C6 alkyl which may be substituted with 1 to 3 halogens (preferably C1 to C4 alkyl, and more. Preferred are C1-C3 alkyl) sulfonyls, and specific examples thereof include methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl and the like.
　Ｇ１で示される低級アルキルで置換されていてもよいベンゼンスルホニルとしては、例えば、１～３個（好ましくは１または２個、より好ましくは１個）の直鎖状または分枝状のＣ１～Ｃ６アルキル（好ましくはＣ１～Ｃ４アルキル、より好ましくはＣ１～Ｃ３アルキル）で置換されていてもよいベンゼンスルホニルが挙げられ、具体的には、ｐ－トルエンスルホニル等を挙げることができる。 Benzenesulfonyls that may be substituted with the lower alkyl represented by G 1 include, for example, 1 to 3 (preferably 1 or 2, more preferably 1) linear or branched C1 to. Benzenesulfonyl which may be substituted with C6 alkyl (preferably C1 to C4 alkyl, more preferably C1 to C3 alkyl) can be mentioned, and specific examples thereof include p-toluenesulfonyl.
　Ｇ１で示されるニトロで置換されていてもよいベンゼンスルホニルとしては、例えば、１～３個（好ましくは１個）のニトロで置換されていてもよいベンゼンスルホニルが挙げられ、具体的には、ｏ－ニトロベンゼンスルホニル、ｐ－ニトロベンゼンスルホニル等を挙げることができる。 Examples of the benzenesulfonyl that may be substituted with nitro represented by G 1 include benzenesulfonyl that may be substituted with 1 to 3 (preferably 1) nitro. Examples thereof include o-nitrobenzenesulfonyl and p-nitrobenzenesulfonyl.
　好ましいＧ１は、塩素原子、フッ素原子、臭素原子、メタンスルホニル、エタンスルホニル、トリフルオロメタンスルホニル、ｐ－トルエンスルホニル、またはｐ－ニトロベンゼンスルホニルである。より好ましいＧ１は、塩素原子または臭素原子である。 Preferred G 1 is a chlorine atom, a fluorine atom, a bromine atom, a methanesulfonyl, an ethanesulfonyl, a trifluoromethanesulfonyl, a p-toluenesulfonyl, or a p-nitrobenzenesulfonyl. More preferred G 1 is a chlorine atom or a bromine atom.
　一般式（２）で表される化合物、その塩、またはそのプロドラッグには、例えば下記の化合物、その塩、またはそのプロドラッグが含まれる。
Figure JPOXMLDOC01-appb-C000033
 The compound represented by the general formula (2), a salt thereof, or a prodrug thereof includes, for example, the following compound, a salt thereof, or a prodrug thereof.
Figure JPOXMLDOC01-appb-C000033
　一般式（２）で表される化合物、その塩、またはそのプロドラッグとして好ましくは、化合物０６２、化合物２０２、化合物３６２、または化合物３７２、その塩、あるいはそのプロドラッグであり、より好ましくは化合物２０２の（Ｅ）異性体、化合物３６２の（Ｅ）異性体、化合物３６２の（Ｚ）異性体、または化合物３７２の（Ｚ）異性体、その塩、またはそのプロドラッグである。 The compound represented by the general formula (2), a salt thereof, or a prodrug thereof is preferably compound 062, compound 202, compound 362, or compound 372, a salt thereof, or a prodrug thereof, and more preferably compound 202. (E) isomer, (E) isomer of compound 362, (Z) isomer of compound 362, or (Z) isomer of compound 372, a salt thereof, or a prodrug thereof.
　上記化合物等は、例えば以下に詳述する製造法１～３、これに準ずる方法、公知の方法等を適宜変更、組み合わせること等によって製造することができる。原料化合物として用いられる化合物は、それぞれ塩として用いてもよい。なお、以下に示す方法は単なる例示であり、有機合成に習熟している者の知識に基づき、適宜、他の方法で製造することもできる。また、市販品でない、１，２－ベンゾイソチアゾールまたはその誘導体あるいは１，２－ベンゾイソオキサゾールまたはその誘導体を原料化合物として用いる場合は以下の刊行物に記載の方法を参考にして製造し、調達することができる。
Advances in heterocyclic chemistry, Heterocyclic Chemistry in the 21st Century: A Tribute to Alan Katritzky, Elsevier, Cambridge (2017)。R. A. Shastri, Review on Synthesis of 3-Substituted 1,2-Benzisoxazole Derivatives, Chem. Sci. Trans., 2016: 5; 8-20。 The above compounds and the like can be produced, for example, by appropriately modifying or combining production methods 1 to 3 described in detail below, methods similar thereto, known methods and the like. The compounds used as the raw material compounds may be used as salts, respectively. The method shown below is merely an example, and can be appropriately produced by another method based on the knowledge of a person who is proficient in organic synthesis. When 1,2-benzoisothiazole or a derivative thereof or 1,2-benzoisoxazole or a derivative thereof, which is not a commercially available product, is used as a raw material compound, it is manufactured and procured by referring to the method described in the following publication. can do.
Advances in heterocyclic chemistry, Heterocyclic Chemistry in the 21st Century: A Tribute to Alan Katritzky, Elsevier, Cambridge (2017). R. A. Shastri, Review on Synthesis of 3-Substituted 1,2-Benzisoxazole Derivatives, Chem. Sci. Trans., 2016: 5; 8-20.
　製造における各反応において、必要に応じて、官能基を保護することができる。保護基並びにその保護および脱保護の技術は、公知の方法、例えば、T.W.Greene and P.G.M.Wuts,“Protective Groups in Organic Synthesis”,3rd Ed.,John Wiley and Sons,inc.,New York(1999)に記載の方法を適宜適用できる。 In each reaction in manufacturing, functional groups can be protected as needed. Protecting groups and their protection and deprotection techniques are described in known methods, such as TWGreene and PGM Muts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley and Sons, inc., New York (1999). The described method can be applied as appropriate.
［製造法１］
　一実施形態において、一般式（１）で表される化合物は、下記の反応工程式－１で示される合成スキームで製造することができる。すなわち、一般式（１）で表される化合物は、一般式（３）で表される化合物と一般式（４）で表される化合物から製造することができる。 [Manufacturing method 1]
In one embodiment, the compound represented by the general formula (1) can be produced by the synthetic scheme represented by the following reaction step formula-1. That is, the compound represented by the general formula (1) can be produced from the compound represented by the general formula (3) and the compound represented by the general formula (4).
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000034
Figure JPOXMLDOC01-appb-C000035
 Ｇ２は、ハロゲン、ハロゲンで置換されていてもよい低級アルキルスルホニル、あるいは低級アルキルまたはニトロで置換されていてもよいベンゼンスルホニルである。］。　　　　　
Figure JPOXMLDOC01-appb-C000035
 G 2 is a halogen, a lower alkyl sulfonyl optionally substituted with a halogen, or a benzenesulfonyl optionally substituted with a lower alkyl or nitro. ].
Figure JPOXMLDOC01-appb-C000036
Figure JPOXMLDOC01-appb-C000036
　Ｇ２で示されるハロゲンとしては、例えば、塩素原子、フッ素原子、臭素原子、ヨウ素原子を挙げることができる。 Examples of the halogen represented by G 2 include a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom.
　Ｇ２で示されるハロゲンで置換されていてもよい低級アルキルスルホニルにおける低級アルキルは上記で定義したとおりである。また、低級アルキルスルホニルはスルホニルに低級アルキルが結合した基であり、低級アルキルはハロゲンで置換されていてもよい。ハロゲンで置換されていてもよい低級アルキルスルホニルとしては、例えば、１～３個のハロゲンで置換されていてもよい直鎖状または分枝状のＣ１～Ｃ６アルキル（好ましくはＣ１～Ｃ４アルキル、より好ましくはＣ１～Ｃ３アルキル）スルホニルが挙げられ、具体的には、メタンスルホニル、エタンスルホニル、トリフルオロメタンスルホニル等を挙げることができる。 The lower alkyl in the lower alkyl sulfonyls which may be substituted with the halogen represented by G 2 is as defined above. Further, the lower alkyl sulfonyl is a group in which a lower alkyl is bonded to a sulfonyl, and the lower alkyl may be substituted with a halogen. Examples of the lower alkyl sulfonyl group which may be substituted with halogen include linear or branched C1 to C6 alkyl which may be substituted with 1 to 3 halogens (preferably C1 to C4 alkyl, and more. Preferred are C1-C3 alkyl) sulfonyls, and specific examples thereof include methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl and the like.
　Ｇ２で示される低級アルキルで置換されていてもよいベンゼンスルホニルとしては、例えば、１～３個の直鎖状または分枝状のＣ１～Ｃ６アルキル（好ましくはＣ１～Ｃ４アルキル、より好ましくはＣ１～Ｃ３アルキル）で置換されていてもよいベンゼンスルホニルが挙げられ、具体的には、ｐ－トルエンスルホニル等を挙げることができる。 As good benzenesulfonyl optionally substituted with lower alkyl represented by G 2, for example, one to three straight or branched C1 ~ C6 alkyl (preferably C1 ~ C4 alkyl, more preferably C1 ~ C3 alkyl) may be substituted with benzenesulfonyl, and specific examples thereof include p-toluenesulfonyl.
　Ｇ２で示されるニトロで置換されていてもよいベンゼンスルホニルとしては、例えば、１～３個（好ましくは１個）のニトロで置換されていてもよいベンゼンスルホニルが挙げられ、具体的には、ｏ－ニトロベンゼンスルホニル、ｐ－ニトロベンゼンスルホニル等を挙げることができる。 Examples of the benzenesulfonyl that may be substituted with nitro represented by G 2 include benzenesulfonyl that may be substituted with 1 to 3 (preferably 1) nitro. Examples thereof include o-nitrobenzenesulfonyl and p-nitrobenzenesulfonyl.
　好ましいＧ２は、塩素原子、フッ素原子、臭素原子、メタンスルホニル、エタンスルホニル、トリフルオロメタンスルホニル、ｐ－トルエンスルホニル、またはｐ－ニトロベンゼンスルホニルである。 Preferred G 2 is chlorine atom, fluorine atom, bromine atom, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, or p-nitrobenzenesulfonyl.
　一般式（３）で表される化合物と一般式（４）で表される化合物との反応は、例えば不活性溶媒中、塩基の存在下または非存在下で行うことができる。必要に応じ、さらに活性化剤を反応系内に添加してもよい。一般式（３）で表される化合物および一般式（４）で表される化合物は公知の化合物であり、公知の方法で製造できる。 The reaction between the compound represented by the general formula (3) and the compound represented by the general formula (4) can be carried out, for example, in an inert solvent in the presence or absence of a base. If necessary, an activator may be further added into the reaction system. The compound represented by the general formula (3) and the compound represented by the general formula (4) are known compounds and can be produced by a known method.
　不活性溶媒としては、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、ジオキサン、ジメトキシメタン等のエーテル系溶媒、トルエン、ベンゼン、キシレン等の芳香族炭化水素系溶媒、ジクロロメタン、クロロホルム、ジクロロエタン、四塩化炭素等のハロゲン化炭化水素系溶媒、アセトン等のケトン系溶媒、ジメチルスルホキシド、Ｎ、Ｎ－ジメチルホルムアミド（ＤＭＦ）、アセトニトリル等の非プロトン溶媒、ピリジン等が挙げられる。これらの溶媒は、２種類以上を適宜の割合で混合して用いてもよい。 Examples of the inert solvent include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene and xylene, and halogens such as dichloromethane, chloroform, dichloroethane and carbon tetrachloride. Examples thereof include a hydrocarbon solvent, a ketone solvent such as acetone, dimethylsulfoxide, N, N-dimethylformamide (DMF), an aproton solvent such as acetonitrile, pyridine and the like. Two or more kinds of these solvents may be mixed and used in an appropriate ratio.
　塩基としては、例えば水素化ナトリウム、水素化カリウム等の金属ヒドリド、水酸化カリウム、水酸化ナトリウム等の金属水酸化物、炭酸カリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸セシウム等の金属炭酸塩、トリエチルアミン、エチルジイソプロピルアミン等のアルキルアミン類、ナトリウムメトキシド、カリウムｔ－ブトキシド等の金属アルコキシドが挙げられる。 Examples of the base include metal hydrides such as sodium hydride and potassium hydride, metal hydroxides such as potassium hydroxide and sodium hydroxide, and metals such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and cesium carbonate. Examples thereof include alkylamines such as carbonate, triethylamine and ethyldiisopropylamine, and metal alkoxides such as sodium methoxide and potassium t-butoxide.
　塩基の使用量は、一般式（４）で表される化合物１モルに対して、通常１モル以上、好ましくは１～５モル、より好ましくは１～２モルである。 The amount of the base used is usually 1 mol or more, preferably 1 to 5 mol, and more preferably 1 to 2 mol with respect to 1 mol of the compound represented by the general formula (4).
　一般式（３）で表される化合物の使用量は、一般式（４）で表される化合物１モルに対して、通常、０．２モル以上、好ましくは０．２～２モル、より好ましくは０．２～１．５モルである。 The amount of the compound represented by the general formula (3) to be used is usually 0.2 mol or more, preferably 0.2 to 2 mol, more preferably 0.2 mol or more, based on 1 mol of the compound represented by the general formula (4). Is 0.2-1.5 mol.
　反応温度は、通常－５０℃～１８０℃、好ましくは－３０℃～１８０℃、より好ましくは－１０℃～１８０℃である。反応を促進するためにマイクロウェーブを用いてもよく、その場合の反応温度としては、例えば８０℃～１８０℃、好ましくは１００℃～１８０℃である。反応時間は、通常１０分～４８時間、好ましくは１０分～２４時間である。 The reaction temperature is usually −50 ° C. to 180 ° C., preferably −30 ° C. to 180 ° C., and more preferably −10 ° C. to 180 ° C. Microwaves may be used to promote the reaction, and the reaction temperature in that case is, for example, 80 ° C. to 180 ° C., preferably 100 ° C. to 180 ° C. The reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours.
　［製造法２］
　一実施形態において、一般式（１Ｂ）で表される化合物は、下記の反応工程式－２で示される合成スキームで製造することができる。すなわち、一般式（１Ｂ）で表される化合物は、一般式（５）で表される化合物と一般式（６）で表される化合物から製造することができる。 [Manufacturing method 2]
In one embodiment, the compound represented by the general formula (1B) can be produced by the synthetic scheme represented by the following reaction step formula-2. That is, the compound represented by the general formula (1B) can be produced from the compound represented by the general formula (5) and the compound represented by the general formula (6).
Figure JPOXMLDOC01-appb-C000037
Figure JPOXMLDOC01-appb-C000037
［式中、Ａ、Ｂ、Ｘ、Ｒ１、およびｐは前記に同じ。Ｇ３は、ハロゲン、ハロゲンで置換されていてもよい低級アルキルスルホニル、あるいは低級アルキルまたはニトロで置換されていてもよいベンゼンスルホニルである。］。 [In the formula, A, B, X, R 1 , and p are the same as described above. G 3 is a halogen, a lower alkyl sulfonyl optionally substituted with a halogen, or a benzene sulfonyl optionally substituted with a lower alkyl or nitro. ].
　反応工程式－２において、Ａ、Ｂ、Ｘ、Ｒ１、およびｐは上記のとおりである。 In the reaction process formula-2, A, B, X, R 1 , and p are as described above.
　Ｇ３で示されるハロゲンとしては、例えば、塩素原子、フッ素原子、臭素原子、ヨウ素原子を挙げることができる。 Examples of the halogen represented by G 3 include a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom.
　Ｇ３で示されるハロゲンで置換されていてもよい低級アルキルスルホニルにおける低級アルキルは上記で定義したとおりである。また、低級アルキルスルホニルはスルホニルに低級アルキルが結合した基であり、低級アルキルはハロゲンで置換されていてもよい。ハロゲンで置換されていてもよい低級アルキルスルホニルとしては、例えば、１～３個のハロゲンで置換されていてもよい直鎖状または分枝状のＣ１～Ｃ６アルキル（好ましくはＣ１～Ｃ４アルキル、より好ましくはＣ１～Ｃ３アルキル）スルホニルが挙げられ、具体的には、メタンスルホニル、エタンスルホニル、トリフルオロメタンスルホニル等を挙げることができる。 Lower alkyl in substituted lower alkylsulfonyl optionally substituted with halogen represented by G 3 are as defined above. Further, the lower alkyl sulfonyl is a group in which a lower alkyl is bonded to a sulfonyl, and the lower alkyl may be substituted with a halogen. Examples of the lower alkyl sulfonyl group which may be substituted with halogen include linear or branched C1 to C6 alkyl which may be substituted with 1 to 3 halogens (preferably C1 to C4 alkyl, and more. Preferred are C1-C3 alkyl) sulfonyls, and specific examples thereof include methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl and the like.
　Ｇ３で示される低級アルキルで置換されていてもよいベンゼンスルホニルとしては、例えば、１～３個の直鎖状または分枝状のＣ１～Ｃ６アルキル（好ましくはＣ１～Ｃ４アルキル、より好ましくはＣ１～Ｃ３アルキル）で置換されていてもよいベンゼンスルホニルが挙げられ、具体的には、ｐ－トルエンスルホニル等を挙げることができる。 As good benzenesulfonyl optionally substituted with lower alkyl represented by G 3, for example, one to three straight or branched C1 ~ C6 alkyl (preferably C1 ~ C4 alkyl, more preferably C1 ~ C3 alkyl) may be substituted with benzenesulfonyl, and specific examples thereof include p-toluenesulfonyl.
　Ｇ３で示されるニトロで置換されていてもよいベンゼンスルホニルとしては、例えば、１～３個（好ましくは１個）のニトロで置換されていてもよいベンゼンスルホニルが挙げられ、具体的には、ｏ－ニトロベンゼンスルホニル、ｐ－ニトロベンゼンスルホニル等を挙げることができる。 Examples of the benzenesulfonyl that may be substituted with nitro represented by G 3 include benzenesulfonyl that may be substituted with 1 to 3 (preferably 1) nitro. Examples thereof include o-nitrobenzenesulfonyl and p-nitrobenzenesulfonyl.
　好ましいＧ３は、塩素原子、フッ素原子、臭素原子、メタンスルホニル、エタンスルホニル、トリフルオロメタンスルホニル、ｐ－トルエンスルホニル、またはｐ－ニトロベンゼンスルホニルである。 Preferred G 3 are a chlorine atom, a fluorine atom, a bromine atom, methanesulfonyl, ethanesulfonyl, trifluoromethanesulfonyl, p- toluenesulfonyl or p- nitrobenzenesulfonyl.
　一般式（５）で表される化合物と一般式（６）で表される化合物とをカップリングすることで一般式（１Ｂ）で表される化合物を得ることができる。一般式（５）で表される化合物および一般式（６）で表される化合物は公知の化合物であり、公知の方法で製造できる。 By coupling the compound represented by the general formula (5) and the compound represented by the general formula (6), the compound represented by the general formula (1B) can be obtained. The compound represented by the general formula (5) and the compound represented by the general formula (6) are known compounds and can be produced by a known method.
　この反応は、例えば不活性溶媒中、塩基の存在下で行うことができる。 This reaction can be carried out, for example, in an inert solvent in the presence of a base.
　不活性溶媒としては、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、ジオキサン、ジメトキシメタン等のエーテル系溶媒、トルエン、ベンゼン、キシレン等の芳香族炭化水素系溶媒、ジクロロメタン、クロロホルム、ジクロロエタン、四塩化炭素等のハロゲン化炭化水素系溶媒、アセトン等のケトン系溶媒、ジメチルスルホキシド、Ｎ、Ｎ－ジメチルホルムアミド（ＤＭＦ）、アセトニトリル等の非プロトン溶媒、ピリジン等が挙げられる。これらの溶媒は、２種類以上を適宜の割合で混合して用いてもよい。 Examples of the inert solvent include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene and xylene, and halogens such as dichloromethane, chloroform, dichloroethane and carbon tetrachloride. Examples thereof include a hydrocarbon solvent, a ketone solvent such as acetone, dimethylsulfoxide, N, N-dimethylformamide (DMF), an aproton solvent such as acetonitrile, pyridine and the like. Two or more kinds of these solvents may be mixed and used in an appropriate ratio.
　塩基としては、例えば水素化ナトリウム、水素化カリウム等の金属ヒドリド、水酸化カリウム、水酸化ナトリウム等の金属水酸化物、炭酸カリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸セシウム等の金属炭酸塩、トリエチルアミン、エチルジイソプロピルアミン等のアルキルアミン類、ナトリウムメトキシド、カリウムｔ－ブトキシド等の金属アルコキシドが挙げられる。 Examples of the base include metal hydrides such as sodium hydride and potassium hydride, metal hydroxides such as potassium hydroxide and sodium hydroxide, and metals such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and cesium carbonate. Examples thereof include alkylamines such as carbonate, triethylamine and ethyldiisopropylamine, and metal alkoxides such as sodium methoxide and potassium t-butoxide.
　一般式（６）で表される化合物の使用量は、一般式（５）で表される化合物１モルに対して、通常、０．５モル以上、さらに１モル以上、好ましくは０．９～２モル、より好ましくは０．９～１．５モルである。 The amount of the compound represented by the general formula (6) to be used is usually 0.5 mol or more, further 1 mol or more, preferably 0.9 to 1 mol, based on 1 mol of the compound represented by the general formula (5). It is 2 mol, more preferably 0.9 to 1.5 mol.
　塩基の使用量は、一般式（５）で表される化合物１モルに対して、通常１モル以上、好ましくは１～５モル、より好ましくは１～２モルである。 The amount of the base used is usually 1 mol or more, preferably 1 to 5 mol, and more preferably 1 to 2 mol with respect to 1 mol of the compound represented by the general formula (5).
　反応温度は、通常３０℃～溶媒の沸点より１０℃高い温度であり、好ましくは８０℃～溶媒の沸点より１０℃高い温度が挙げられる。反応を促進するためにマイクロウェーブを用いてもよく、その場合の反応温度としては、例えば８０℃～１８０℃、好ましくは１００℃～１８０℃である。反応時間は、通常１０分～４８時間、好ましくは１０分～２４時間である。 The reaction temperature is usually 30 ° C. to 10 ° C. higher than the boiling point of the solvent, and preferably 80 ° C. to 10 ° C. higher than the boiling point of the solvent. Microwaves may be used to promote the reaction, and the reaction temperature in that case is, for example, 80 ° C. to 180 ° C., preferably 100 ° C. to 180 ° C. The reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours.
　さらに、一般式（５）で表される化合物と一般式（６）で表される化合物との反応は、Buchward反応を利用して行うこともでき、例えば、パラジウム触媒、ホスフィン配位子、塩基の存在下、溶媒中で一般式（５）で表される化合物と一般式（６）で表される化合物を反応させる。 Further, the reaction between the compound represented by the general formula (5) and the compound represented by the general formula (6) can also be carried out by utilizing the Buchward reaction, for example, a palladium catalyst, a phosphine ligand, and a base. In the presence of, the compound represented by the general formula (5) is reacted with the compound represented by the general formula (6) in a solvent.
　パラジウム触媒としては、例えばPd(OAc)2、PdCl2、アリルパラジウム(II)クロリド（ダイマー）、ビス(アセトニトリル)パラジウム(II)ジクロリド、ビス(ベンゾニトリル)パラジウム(II)ジクロリド等の２価パラジウム触媒、Pd２(dba)３（トリス(ジベンジリデンアセトン)ジパラジウム(0)）、ビス(ジベンジリデンアセトン)パラジウム(0)、パラジウム炭素（Pd/C）等の０価パラジウム触媒等が挙げられる。 Examples of the palladium catalyst include divalent palladium such as Pd (OAc) 2 , PdCl 2 , allylpalladium (II) chloride (dimer), bis (acetaceous) palladium (II) dichloride, and bis (benzonitrile) palladium (II) dichloride. Examples thereof include catalysts, Pd 2 (dba) 3 (tris (dibenzylideneacetone) dipalladium (0)), bis (dibenzylideneacetone) palladium (0), and zero-valent palladium catalysts such as palladium carbon (Pd / C). ..
　ホスフィン配位子としては、例えばBINAP（（２，２‘-ビス（ジフェニルホスファニル）-１、１’-ビスナフタレン）、Xphos（2-ジシクロヘキシルホスフィノ-2',4',6'-トリイソプロピルビフェニル）等の２座ホスフィン配位子が挙げられる。 Examples of the phosphine ligand include BINAP ((2,2'-bis (diphenylphosphanyl) -1,1'-bisnaphthalene)) and Xphos (2-dicyclohexylphosphino-2', 4', 6'-tri. Bidentate phosphine ligands such as isopropylbiphenyl) can be mentioned.
　塩基としては、ｔ－BuONa（tert-ブトキシナトリウム）等の強塩基が挙げられる。 Examples of the base include strong bases such as t-BuONa (tert-butoxysodium).
　この反応において、一般式（６）で表される化合物の使用量は、一般式（５）で表される化合物１モルに対して、通常、０．５モル以上、さらに１モル以上、好ましくは０．９～２モル、より好ましくは１～１．５モルである。 In this reaction, the amount of the compound represented by the general formula (6) to be used is usually 0.5 mol or more, more preferably 1 mol or more, preferably 1 mol or more, based on 1 mol of the compound represented by the general formula (5). It is 0.9 to 2 mol, more preferably 1 to 1.5 mol.
　パラジウム触媒の使用量は、一般式（５）で表される化合物１モルに対して、通常、０．００５～１モル、好ましくは０．０１～０．２モルである。 The amount of the palladium catalyst used is usually 0.005 to 1 mol, preferably 0.01 to 0.2 mol, based on 1 mol of the compound represented by the general formula (5).
　ホスフィン配位子の使用量は、パラジウム触媒１モルに対して、通常０．５～５モル、好ましくは１～２モルである。 The amount of the phosphine ligand to be used is usually 0.5 to 5 mol, preferably 1 to 2 mol, relative to 1 mol of the palladium catalyst.
　塩基の使用量は、一般式（５）で表される化合物１モルに対して、通常、０．５モル以上、さらに１モル以上、好ましくは１～２モルである。 The amount of the base used is usually 0.5 mol or more, further 1 mol or more, preferably 1 to 2 mol, relative to 1 mol of the compound represented by the general formula (5).
　反応温度は、通常４０℃～１５０℃、好ましくは８０℃～１１０℃、反応時間は、通常１～２４時間、好ましくは３～１２時間である。 The reaction temperature is usually 40 ° C. to 150 ° C., preferably 80 ° C. to 110 ° C., and the reaction time is usually 1 to 24 hours, preferably 3 to 12 hours.
　［製造法３］
　一実施形態において、一般式（１）または（２）で表される化合物は、下記の反応工程式－３で示される合成スキームで製造することができる。すなわち、一般式（１Ｃ）で表される化合物は、一般式（７）で表される化合物を一般式（８）で表される化合物へ変換し、一般式（４）で表される化合物と反応させて一般式（２Ｂ）で表されるオキシム化合物を製造し、これを閉環することで製造することができる。なお、当業者であれば、反応工程式－３で示される反応において一般式（７）または（８）で表される化合物に代えて、適切な対応する、置換されていてもよいベンゼン環Ａを有する化合物を使用することにより、一般式（２）で表される化合物を製造できることを理解できる。また、一般式（７）で表される化合物は公知の化合物であり、公知の方法で製造できる。 [Manufacturing method 3]
In one embodiment, the compound represented by the general formula (1) or (2) can be produced by the synthetic scheme represented by the following reaction step formula-3. That is, the compound represented by the general formula (1C) is obtained by converting the compound represented by the general formula (7) into the compound represented by the general formula (8) and forming the compound represented by the general formula (4). It can be produced by reacting to produce an oxime compound represented by the general formula (2B) and closing the ring. A person skilled in the art may substitute the compound represented by the general formula (7) or (8) in the reaction represented by the reaction step formula-3, and appropriately substitute the benzene ring A. It can be understood that the compound represented by the general formula (2) can be produced by using the compound having. Further, the compound represented by the general formula (7) is a known compound and can be produced by a known method.
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000038
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000039
Figure JPOXMLDOC01-appb-C000040
Figure JPOXMLDOC01-appb-C000040
　Ｇ４で示されるハロゲンとしては、例えば、塩素原子、フッ素原子、臭素原子、ヨウ素原子が挙げられる。 The halogen represented by G 4, for example, a chlorine atom, a fluorine atom, a bromine atom, an iodine atom.
　工程１、すなわち一般式（７）で表される化合物を一般式（８）で表される化合物へ変換する工程は、例えば不活性溶媒中、一般式（７）で表される化合物にハロゲン化剤を反応させることにより可能である。 Step 1, that is, the step of converting the compound represented by the general formula (7) into the compound represented by the general formula (8), is, for example, halogenating the compound represented by the general formula (7) in an inert solvent. This is possible by reacting the agent.
　この反応における不活性溶媒としては、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、ジオキサン、ジメトキシメタン等のエーテル系溶媒、トルエン、ベンゼン、キシレン等の芳香族炭化水素系溶媒、ジクロロメタン、クロロホルム、ジクロロエタン、四塩化炭素等のハロゲン化炭化水素系溶媒、アセトン等のケトン系溶媒、ジメチルスルホキシド、Ｎ、Ｎ－ジメチルホルムアミド（ＤＭＦ）、アセトニトリル等の非プロトン溶媒、ピリジン等が挙げられる。これらの溶媒は、２種類以上を適宜の割合で混合して用いてもよい。 Examples of the inert solvent in this reaction include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene and xylene, dichloromethane, chloroform, dichloroethane and carbon tetrachloride. Examples thereof include halogenated hydrocarbon solvents such as, ketone solvents such as acetone, dimethylsulfoxide, N, N-dimethylformamide (DMF), aproton solvents such as acetonitrile, pyridine and the like. Two or more kinds of these solvents may be mixed and used in an appropriate ratio.
　ハロゲン化剤としては、例えば、Ｎ－ブロモスクシンイミド、Ｎ－クロロスクシンイミドなどの一般的なハロゲン化剤が挙げられる。 Examples of the halogenating agent include general halogenating agents such as N-bromosuccinimide and N-chlorosuccinimide.
　ハロゲン化剤の使用量は、一般式（７）で表される化合物に対して、通常等モル～過剰モル、好ましくは１～５倍モル、より好ましくは１～２倍モルである。 The amount of the halogenating agent used is usually equimolar to excess mol, preferably 1 to 5 times mol, and more preferably 1 to 2 times mol, relative to the compound represented by the general formula (7).
　反応温度は、通常－３０～１５０℃、好ましくは－１０～１００℃、より好ましくは－１０～４０℃である。反応時間は、通常１０分～４８時間、好ましくは１０分～２４時間、より好ましくは３０分～１８時間である。 The reaction temperature is usually −30 to 150 ° C., preferably −10 to 100 ° C., and more preferably −10 to 40 ° C. The reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours, and more preferably 30 minutes to 18 hours.
　工程２、すなわち一般式（８）で表される化合物と一般式（４）で表される化合物を反応させて一般式（２Ｂ）で表される化合物を合成する工程は、例えば不活性溶媒中、塩基の存在下で行うことができる。 Step 2, that is, the step of reacting the compound represented by the general formula (8) with the compound represented by the general formula (4) to synthesize the compound represented by the general formula (2B) is carried out, for example, in an inert solvent. , Can be done in the presence of a base.
　この反応における、不活性溶媒としては、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、ジオキサン、ジメトキシメタン等のエーテル系溶媒、トルエン、ベンゼン、キシレン等の芳香族炭化水素系溶媒、ジクロロメタン、クロロホルム、ジクロロエタン、四塩化炭素等のハロゲン化炭化水素系溶媒、アセトン等のケトン系溶媒、ジメチルスルホキシド、Ｎ、Ｎ－ジメチルホルムアミド（ＤＭＦ）、アセトニトリル等の非プロトン溶媒、ピリジン等が挙げられる。これらの溶媒は、２種類以上を適宜の割合で混合して用いてもよい。 Examples of the inert solvent in this reaction include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene and xylene, dichloromethane, chloroform, dichloroethane and tetrachloride. Examples thereof include halogenated hydrocarbon solvents such as carbon, ketone solvents such as acetone, dimethylsulfoxide, N, N-dimethylformamide (DMF), aproton solvents such as acetonitrile, pyridine and the like. Two or more kinds of these solvents may be mixed and used in an appropriate ratio.
　塩基としては、例えば水素化ナトリウム、水素化カリウム等の金属ヒドリド、水酸化カリウム、水酸化ナトリウム等の金属水酸化物、炭酸カリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸セシウム等の金属炭酸塩、トリエチルアミン、エチルジイソプロピルアミン等のアルキルアミン類、ナトリウムメトキシド、カリウムｔ－ブトキシド等の金属アルコキシドが挙げられる。 Examples of the base include metal hydrides such as sodium hydride and potassium hydride, metal hydroxides such as potassium hydroxide and sodium hydroxide, and metals such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and cesium carbonate. Examples thereof include alkylamines such as carbonate, triethylamine and ethyldiisopropylamine, and metal alkoxides such as sodium methoxide and potassium t-butoxide.
　一般式（８）で表される化合物の使用量は、一般式（４）で表される化合物１モルに対して、通常、０．５モル以上、０．８モル以上、好ましくは０．９～２モル、より好ましくは０．９～１．５モルである。 The amount of the compound represented by the general formula (8) to be used is usually 0.5 mol or more, 0.8 mol or more, preferably 0.9 mol, relative to 1 mol of the compound represented by the general formula (4). It is ~ 2 mol, more preferably 0.9 ~ 1.5 mol.
　塩基の使用量は、一般式（４）で表される化合物１モルに対して、通常１モル以上、好ましくは１～５倍モル、より好ましくは１～２倍モルである。 The amount of the base used is usually 1 mol or more, preferably 1 to 5 times mol, and more preferably 1 to 2 times mol, relative to 1 mol of the compound represented by the general formula (4).
　反応温度は、通常－２０℃～溶媒の沸点より１０℃高い温度、好ましくは０℃～４０℃℃である。反応時間は、通常１０分～４８時間、好ましくは１０分～２４時間、より好ましくは３０分～１８時間である。 The reaction temperature is usually −20 ° C. to 10 ° C. higher than the boiling point of the solvent, preferably 0 ° C. to 40 ° C. ° C. The reaction time is usually 10 minutes to 48 hours, preferably 10 minutes to 24 hours, and more preferably 30 minutes to 18 hours.
　工程３、すなわち一般式（２Ｂ）で表される化合物を閉環させて一般式（１）で表される化合物へと変換する工程は、例えば不活性溶媒中、塩基の存在下で行うことができる。　　　 Step 3, that is, the step of closing the ring of the compound represented by the general formula (2B) and converting it into the compound represented by the general formula (1) can be carried out, for example, in an inert solvent in the presence of a base. ..
　一般式（２Ｂ）で表される化合物には幾何異性体である（Ｅ）体と（Ｚ）体とが存在するが、閉環反応に際しての加熱が少なくすむことから、（Ｅ）体が好ましい。 The compound represented by the general formula (2B) includes geometric isomers (E) and (Z), but the (E) is preferable because heating during the ring closure reaction can be reduced.
　この反応における、不活性溶媒としては、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、ジオキサン、ジメトキシメタン等のエーテル系溶媒、トルエン、ベンゼン、キシレン等の芳香族炭化水素系溶媒、ジクロロメタン、クロロホルム、ジクロロエタン、四塩化炭素等のハロゲン化炭化水素系溶媒、アセトン等のケトン系溶媒、ジメチルスルホキシド、Ｎ、Ｎ－ジメチルホルムアミド（ＤＭＦ）、アセトニトリル等の非プロトン溶媒、ピリジン等が挙げられる。これらの溶媒は、２種類以上を適宜の割合で混合して用いてもよい。 Examples of the inert solvent in this reaction include ether solvents such as diethyl ether, tetrahydrofuran (THF), dioxane and dimethoxymethane, aromatic hydrocarbon solvents such as toluene, benzene and xylene, dichloromethane, chloroform, dichloroethane and tetrachloride. Examples thereof include halogenated hydrocarbon solvents such as carbon, ketone solvents such as acetone, dimethylsulfoxide, N, N-dimethylformamide (DMF), aproton solvents such as acetonitrile, pyridine and the like. Two or more kinds of these solvents may be mixed and used in an appropriate ratio.
　塩基としては、例えば水素化ナトリウム、水素化カリウム等の金属ヒドリド、水酸化カリウム、水酸化ナトリウム等の金属水酸化物、炭酸カリウム、炭酸水素カリウム、炭酸ナトリウム、炭酸水素ナトリウム、炭酸セシウム等の金属炭酸塩、トリエチルアミン、エチルジイソプロピルアミン等のアルキルアミン類、ナトリウムメトキシド、カリウムｔ－ブトキシド等の金属アルコキシドが挙げられる。 Examples of the base include metal hydrides such as sodium hydride and potassium hydride, metal hydroxides such as potassium hydroxide and sodium hydroxide, and metals such as potassium carbonate, potassium hydrogen carbonate, sodium carbonate, sodium hydrogen carbonate and cesium carbonate. Examples thereof include alkylamines such as carbonate, triethylamine and ethyldiisopropylamine, and metal alkoxides such as sodium methoxide and potassium t-butoxide.
　塩基の使用量は、一般式（２Ｂ）で表される化合物１モルに対して、通常１モル以上、好ましくは１～５倍モル、より好ましくは１～２倍モルである。 The amount of the base used is usually 1 mol or more, preferably 1 to 5 times mol, and more preferably 1 to 2 times mol, relative to 1 mol of the compound represented by the general formula (2B).
　反応温度は、通常５０℃～溶媒の沸点より１０℃高い温度、好ましくは８０℃～溶媒の沸点より１０℃高い温度である。反応を促進するためにマイクロウェーブを用いてもよく、その場合の反応温度としては、例えば８０℃～１８０℃、好ましくは１００℃～１８０℃である。反応時間は、通常１０分～８時間、好ましくは１０分～２時間である。　　　　　　 The reaction temperature is usually 50 ° C. to 10 ° C. higher than the boiling point of the solvent, preferably 80 ° C. to 10 ° C. higher than the boiling point of the solvent. Microwaves may be used to promote the reaction, and the reaction temperature in that case is, for example, 80 ° C. to 180 ° C., preferably 100 ° C. to 180 ° C. The reaction time is usually 10 minutes to 8 hours, preferably 10 minutes to 2 hours.
　本発明による一般式（１）または（２）で表される化合物、その中間体化合物およびその出発原料化合物は、上記の合成方法により製造することができ、また、本明細書の実施例に記載された合成方法に基づき本出願時に既知または公知の技術（例えば、B. R. Kiran et al., SYNTHESIS, EVALUATION OF ANALGESIC AND ANTI-INFLAMMATORY ACTIVITIES OF SUBSTITUTED 1,2-BENZOXAZOLONE AND 3-CHLORO-1,2-BENZOXAZOLE DERIVATIVES, International Journal of Pharmaceutical Sciences and Research, 2015; 6: 2918-2925.）を参酌して製造することもできる。 The compound represented by the general formula (1) or (2) according to the present invention, an intermediate compound thereof and a starting material compound thereof can be produced by the above synthetic method, and are described in Examples of the present specification. Known or known techniques at the time of filing (eg, B.R. Kiran et al., SYNTHESIS, EVALUATION OF ANALGESIC AND ANTI-INFLAMMATORY ACTIVITIES OF SUBSTITUTED 1,2-BENZOXAZOLONE AND 3-CHLORO-1, based on the synthetic method 2-BENZOXAZOLE DERIVATIVES, International Journal of Pharmaceutical Sciences and Research, 2015; 6: 2918-2925.) Can also be taken into consideration when manufacturing.
　上記反応式のそれぞれに示された出発原料化合物および中間体化合物は、反応に供する前に、必要に応じて、公知の方法を用いて官能基を適当な保護基で保護し、反応終了後、公知の方法で当該保護基を脱保護することができる。 The starting material compounds and intermediate compounds shown in each of the above reaction formulas are, if necessary, protected with a suitable protecting group using a known method before being subjected to the reaction, and after the reaction is completed, The protecting group can be deprotected by a known method.
　上記の反応式に従って得られる目的化合物のそれぞれを単離および精製することができる。例えば、反応混合物を冷却した後に、粗反応生成物を分離するために濾過、濃縮、抽出等の単離手順を行い、その後粗反応生成物を、カラムクロマトグラフィー、再結晶化等の一般的な精製手順に供することにより、反応混合物から単離および精製することができる。 Each of the target compounds obtained according to the above reaction formula can be isolated and purified. For example, after cooling the reaction mixture, isolation procedures such as filtration, concentration, and extraction are performed to separate the crude reaction product, and then the crude reaction product is subjected to general column chromatography, recrystallization, etc. By subjecting to a purification procedure, it can be isolated and purified from the reaction mixture.
　上記反応式のそれぞれに示された出発原料化合物および一般式（１）または（２）で表される化合物には、溶媒が付加した溶媒和物（例えば、水和物、エタノール和物等）の形態である化合物が含まれる。 The starting material compound represented by each of the above reaction formulas and the compound represented by the general formula (1) or (2) are solvates to which a solvent is added (for example, hydrate, ethanol solvate, etc.). Includes compounds that are in the form.
　本発明は、TRPC3チャネル及びTRPC6チャネルからなる群から選択される少なくとも１種のTRPCチャネルを阻害する活性（本明細書中、「TRPC3/6チャネル阻害活性」と称することがある。）を有する物質（TRPC3/6チャネル阻害物質）、その塩、またはそれらのプロドラッグを含有する難聴の予防および／または治療用医薬組成物を包含する。 The present invention is a substance having an activity of inhibiting at least one TRPC channel selected from the group consisting of TRPC3 channel and TRPC6 channel (in the present specification, it may be referred to as "TRPC3 / 6 channel inhibitory activity"). Includes pharmaceutical compositions for the prevention and / or treatment of hearing loss containing (TRPC3 / 6 channel inhibitors), salts thereof, or prodrugs thereof.
　TRPC3/6チャネル阻害物質としては、TRPC6チャネルを阻害する活性（本明細書中、「TRPC6チャネル阻害活性」と称することがある。）を有する物質（本明細書中、「TRPC6チャネル阻害物質」と称することがある。）が好適である。 As the TRPC3 / 6 channel inhibitor, a substance having an activity of inhibiting TRPC6 channel (sometimes referred to as "TRPC6 channel inhibitory activity" in the present specification) (in the present specification, "TRPC6 channel inhibitor"). It may be referred to.) Is preferable.
　TRPC3/6チャネル阻害物質としては、例えば一般式（１）で表される化合物、一般式（２）で表わされる化合物、Pyr2（「BTP2」とも称される)、Pyr3、Pyr4、GSK2332255B、GSK2833503A、SAR7334、BI-749327、US2019/0169168に開示された化合物、WO2019/215268に開示された化合物等が挙げられ、好ましくは一般式（１）で表される化合物、一般式（２）で表わされる化合物、Pyr2、Pyr3、Pyr4、GSK2332255B、GSK2833503A、SAR7334、BI-749327、化合物AA01～化合物AA95、化合物BB01～化合物BB32等であり、より好ましくは一般式（１）で表される化合物、一般式（２）で表わされる化合物、Pyr2、Pyr3、Pyr4、GSK2332255B、GSK2833503A、SAR7334、BI-749327等であり、さらに好ましくは一般式（１）で表される化合物、一般式（２）で表わされる化合物、Pyr4等である。 Examples of the TRPC3 / 6 channel inhibitor include a compound represented by the general formula (1), a compound represented by the general formula (2), Pyr2 (also referred to as “BTP2”), Pyr3, Pyr4, GSK2332255B, GSK2833503A, Examples thereof include compounds disclosed in SAR7334, BI-749327, US2019 / 0169168, and compounds disclosed in WO2019 / 215268, preferably compounds represented by the general formula (1) and compounds represented by the general formula (2). , Pyr2, Pyr3, Pyr4, GSK2332255B, GSK2833503A, SAR7334, BI-749327, Compound AA01 to Compound AA95, Compound BB01 to Compound BB32, etc. ), Pyr2, Pyr3, Pyr4, GSK2332255B, GSK2833503A, SAR7334, BI-749327, etc., more preferably the compound represented by the general formula (1), the compound represented by the general formula (2), Pyr4. And so on.
　TRPC3チャネルを阻害する活性（本明細書中、「TRPC3チャネル阻害活性」と称することがある。）を有する物質（本明細書中、「TRPC3チャネル阻害物質」と称することがある。）としては、例えば一般式（１）で表される化合物、一般式（２）で表わされる化合物、Pyr2、Pyr3、Pyr4、GSK2332255B、GSK2833503A、WO2019/215268に開示された化合物等が挙げられ、好ましくは一般式（１）で表される化合物、一般式（２）で表わされる化合物、Pyr2、Pyr3、Pyr4、GSK2332255B、GSK2833503A、化合物BB01～化合物BB32等であり、より好ましくは一般式（１）で表される化合物、一般式（２）で表わされる化合物、Pyr2、Pyr3、Pyr4、GSK2332255B、GSK2833503A等であり、さらに好ましくは一般式（１）で表される化合物、一般式（２）で表わされる化合物、Pyr4等である。 A substance having an activity of inhibiting TRPC3 channel (sometimes referred to as “TRPC3 channel inhibitory activity” in the present specification) (sometimes referred to as “TRPC3 channel inhibitor” in the present specification) includes For example, the compound represented by the general formula (1), the compound represented by the general formula (2), the compounds disclosed in Pyr2, Pyr3, Pyr4, GSK2332255B, GSK2833503A, WO2019 / 215268 and the like can be mentioned, and the general formula (preferably Compounds represented by 1), compounds represented by the general formula (2), Pyr2, Pyr3, Pyr4, GSK2332255B, GSK2833503A, compounds BB01 to compound BB32, etc., more preferably compounds represented by the general formula (1). , Pyr2, Pyr3, Pyr4, GSK2332255B, GSK2833503A and the like, more preferably the compound represented by the general formula (1), the compound represented by the general formula (2), Pyr4 and the like. Is.
　TRPC6チャネル阻害物質としては、例えば一般式（１）で表される化合物、一般式（２）で表わされる化合物、Pyr2、Pyr4、GSK2332255B、GSK2833503A、SAR7334、BI-749327、US2019/0169168に開示された化合物、WO2019/215268に開示された化合物等が挙げられ、好ましくは一般式（１）で表される化合物、一般式（２）で表わされる化合物、Pyr2、Pyr4、GSK2332255B、GSK2833503A、SAR7334、BI-749327、化合物AA01～化合物AA95、化合物BB01～化合物BB32等であり、より好ましくは一般式（１）で表される化合物、一般式（２）で表わされる化合物、Pyr2、Pyr4、GSK2332255B、GSK2833503A、SAR7334、BI-749327等であり、さらに好ましくは一般式（１）で表される化合物、一般式（２）で表わされる化合物、Pyr4等である。 Examples of TRPC6 channel inhibitors are disclosed in, for example, a compound represented by the general formula (1), a compound represented by the general formula (2), Pyr2, Pyr4, GSK2332255B, GSK2833503A, SAR7334, BI-749327, US2019 / 0169168. Examples include compounds, compounds disclosed in WO2019 / 215268, preferably compounds represented by the general formula (1), compounds represented by the general formula (2), Pyr2, Pyr4, GSK2332255B, GSK2833503A, SAR7334, BI- 749327, Compound AA01 to Compound AA95, Compound BB01 to Compound BB32, etc., more preferably the compound represented by the general formula (1), the compound represented by the general formula (2), Pyr2, Pyr4, GSK2332255B, GSK2833503A, SAR7334. , BI-749327 and the like, more preferably the compound represented by the general formula (1), the compound represented by the general formula (2), Pyr4 and the like.
　Pyr2は、BTP2とも称され、CAS No.223499-30-7が付されている。
　Pyr3は、CAS No.1160541-60-2が付されている。
　Pyr4は、CAS No.223499-35-2が付されている。
　GSK2332255Bは、CAS No.1366233-41-1が付されている。
　GSK2833503Aは、CAS No.1333207-63-8が付されている。
　SAR7334は、CAS No.1333210-07-3が付されている。
　BI-749327は、CAS No.2361241-23-6が付されている。
Figure JPOXMLDOC01-appb-C000041
 Pyr2 is also called BTP2 and has CAS No. 223499-30-7.
CAS No. 1160541-60-2 is attached to Pyr3.
CAS No.223499-35-2 is attached to Pyr4.
GSK2332255B has CAS No.1366233-41-1.
GSK2833503A is labeled with CAS No. 1333207-63-8.
SAR7334 is labeled with CAS No.1333210-07-3.
BI-749327 is attached with CAS No.2361241-23-6.
Figure JPOXMLDOC01-appb-C000041
　US2019/0169168の請求項1に記載された化合物としては、例えば、
化合物AA01：
[4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-ピペラジン-1-イル]-[5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA02：
（6-アミノ-4-メチル-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA03：
（6-アミノ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA04：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA05：
[4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-ピペラジン-1-イル]-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA06：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-[5-（4-イソプロポキシ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA07：
[（R）-4-（6-アミノ-4-メチル-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル]-[5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA08：
[7-（6-アミノ-4-メトキシ-ピリジン-3-イル）-4,7-ジアザ-スピロ[2.5]オクト-4-イル]-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA09：
[7-（6-アミノ-4-メトキシ-ピリジン-3-イル）-4,7-ジアザ-スピロ[2.5]オクト-4-イル]-[5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA10：
（6-アミノ-4-メチル-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA11：
[4-（6-アミノ-5-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル]-[5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA12：
[4-（6-アミノ-ピリジン-3-イル）-ピペラジン-1-イル]-[4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル]-メタノン、
化合物AA13：
[4-（6-アミノ-ピリジン-3-イル）-ピペラジン-1-イル]-[5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA14：
（6-アミノ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA15：
[4-（6-アミノ-ピリジン-3-イル）-ピペラジン-1-イル]-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA16：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA17：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-[5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA18：
[（R）-4-（6-アミノ-4-メチル-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル]-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA19：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[5-（2-フルオロ-ベンジルオキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA20：
[（R）-4-（6-アミノ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル]-[5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA21：
[4-（6-アミノ-5-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル]-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA22：
（6-アミノ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル]-メタノン、
化合物AA23：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA24：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[4-メトキシ-5-（4-トリフルオロメチル-フェノキシ）-ピリジン-2-イル]-メタノン、
化合物AA25：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-（5-シクロブチルメトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA26：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[4-メトキシ-5-（1-メチル-シクロプロピルメトキシ）-ピリジン-2-イル]-メタノン、
化合物AA27：
[（R）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-メトキシメチル-ピペラジン-1-イル]-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA28：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル]-メタノン、
化合物AA29：
[4-（6-アミノ-4-メチル-ピリダジン-3-イル）-ピペリジン-1-イル]-[5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA30：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-（5-シクロヘキシルオキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA31：
[4-（6-アミノ-4-メチル-ピリダジン-3-イル）-ピペリジン-1-イル]-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA32：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[5-（4-フルオロ-ベンジルオキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA33：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-[4-メトキシ-5-（4-トリフルオロメチル-フェノキシ）-ピリジン-2-イル]-メタノン、
化合物AA34：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-[5-（4-クロロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA35：
（6-アミノ-4-メトキシ-3,4,5,6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-（5-シクロペンチルオキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA36：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-（5-イソブトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA37：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-（5-シクロプロピルメトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA38：
[3-（6-アミノ-4-メトキシ-ピリジン-3-イル）-3,8-ジアザ-ビシクロ[3.2.1]オクト-8-イル]-[5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA39：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-（5-イソブトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA40：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-[5-（4-シクロプロポキシ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA41：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-[5-（4-フルオロ-ベンジルオキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA42：
[（R）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル]-[5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA43：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-（5-ベンジルオキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA44：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-[4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル]-メタノン、
化合物AA45：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[5-（3,3-ジフルオロ-シクロブチルメトキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA46：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-（4-メトキシ-5-プロポキシ-ピリジン-2-イル）-メタノン、
化合物AA47：
[4-（6-アミノ-4-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル]-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA48：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[5-（2-シクロプロピル-エトキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA49：
[4-（6-アミノ-4-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル]-[5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA50：
（1R）-1-[（2R）-4-（6-アミノ-4-メトキシピリジン-3-イル）-1-（5-フェノキシピリジン-2-カルボニル）ピペラジン-2-イル]エタン-1-オール、
化合物AA51：
[3-（6-アミノ-4-メトキシ-ピリジン-3-イル）-3,8-ジアザ-ビシクロ[3.2.1]オクト-8-イル]-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA52：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-（4-メトキシ-5-フェネチルオキシ-ピリジン-2-イル）-メタノン、
化合物AA53：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-（5-シクロブチルメトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA54：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-[5-（4-ジフルオロメトキシ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA55：
[（R）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-メトキシメチル-ピペラジン-1-イル]-[5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA56：
[4-（6-アミノ-4-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル]-[4-メトキシ-5-（4-トリフルオロメチル-フェノキシ）-ピリジン-2-イル]-メタノン、
化合物AA57：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-[5-（2-フルオロ-ベンジルオキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA58：
（1S）-1-[（2R）-4-（6-アミノ-4-メトキシピリジン-3-イル）-1-（5-フェノキシピリジン-2-カルボニル）ピペラジン-2-イル]エタン-1-オール、
化合物AA59：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[5-（2,2-ジメチル-プロポキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA60：
[4-（6-アミノ-5-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル]-[4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル]-メタノン、
化合物AA61：
[4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-ピペラジン-1-イル]-（5-シクロプロピルメトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA62：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-（5-シクロヘキシルオキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA63：
[（S）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル]-[5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA64：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[5-（1-フルオロメチル-シクロプロピルメトキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA65：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-（5-エトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA66：
[4-（6-アミノ-4-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル]-[4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル]-メタノン、
化合物AA67：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-[5-（2-シクロプロピル-エトキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA68：
[7-（6-アミノ-4-メトキシ-ピリジン-3-イル）-3-オキサ-9-アザ-ビシクロ[3.3.1]ノン-9-イル]-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA69：
[（R）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル]-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA70：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[5-（（S）-1-シクロプロピル-エトキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA71：
[（S）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル]-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA72：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-（5-イソプロポキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA73：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-（4-メトキシ-5-フェネチルオキシ-ピリジン-2-イル）-メタノン、
化合物AA74：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-[5-（2,2-ジメチル-プロポキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA75：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-[4-メトキシ-5-（1-メチル-シクロプロピルメトキシ）-ピリジン-2-イル]-メタノン、
化合物AA76：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-（4-メトキシ-5-プロポキシ-ピリジン-2-イル）-メタノン、
化合物AA77：
（6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[5-（（R）-1-シクロプロピル-エトキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA78：
[4-（6-アミノ-4-メチル-ピリダジン-3-イル）-ピペリジン-1-イル]-（5-シクロプロピルメトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
化合物AA79：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-[5-（（S）-1-シクロプロピル-エトキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA80：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-[4-メトキシ-5-（4-トリフルオロメトキシ-フェノキシ）-ピリジン-2-イル]-メタノン、
化合物AA81：
[（R）-4-（6-アミノ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル]-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
化合物AA82：
[（R）-4-（6-アミノ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル]-[4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル]-メタノン、
化合物AA83：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-[5-（フェノキシ）-4-エトキシ-ピリジン-2-イル]-メタノン、
化合物AA84：
（6-アミノ-4-シクロプロポキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[5-（フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA85：
[4-（6-アミノ-4-エトキシ-ピリダジン-3-イル）-ピペリジン-1-イル]-[4-メトキシ-5-（フェノキシ）-ピリジン-2-イル]-メタノン、
化合物AA86：
（6-アミノ-4-プロポキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[5-（フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA87：
（6-アミノ-4-エトキシ-3',4',5',6'-テトラヒドロ-2'H-[3,4']ビピリジニル-1'-イル）-[5-（4-トリフルオロメチル-フェノキシ）-4-メトキシ-ピリジン-2-イル]-メタノン、
化合物AA88：
[4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル]-[5-（4-フルオロ-フェノキシ）-4-エトキシ-ピリジン-2-イル]-メタノン、
化合物AA89：
[3-（6-アミノ-ピリダジン-3-イル）-8-アザ-ビシクロ[3.2.1]オクト-8-イル]-[4-エトキシ-5-（4-フルオロ-フェノキシ）-ピリジン-2-イル]-メタノン、
化合物AA90：
6-{1-{4-メトキシ-5-[4-（トリフルオロメチル）フェノキシ]ピリジン-2-カルボニル}ピペリジン-4-イル）-5-メチルピリダジン-3-アミン、
化合物AA91：
5-メトキシ-6-（1-{5-[4-（トリフルオロメチル）-フェノキシ]-ピリジン-2-カルボニル}ピペリジン-4-イル）-ピリダジン-3-アミン、
化合物AA92：
4-メトキシ-5-[1-（4-メトキシ-5-{[トランス-3-（トリフルオロメチル）シクロブチル]-メトキシ}ピリジン-2-カルボニル）-ピペリジン-4-イル]ピリジン-2-アミン、
化合物AA93：
4-メトキシ-5-[1-（4-メトキシ-5-{[（シス-3-（トリフルオロメチル）-シクロブチル]メトキシ}-ピリジン-2-カルボニル）ピペリジン-4-イル]ピリジン-2-アミン、
化合物AA94：
4-メトキシ-5-（1-{4-メトキシ-5-[（2）-3,3,3-トリフルオロ-2-メチルプロポキシ]-ピリジン-2-カルボニル}ピペリジン-4-イル）ピリジン-2-アミン、
化合物AA95：
5-{1-{5-[（2,2-ジフルオロシクロブチル）-メトキシ]-4-メトキシ-ピリジン-2-カルボニル}-ピペリジン-4-イル）-4-メトキシピリジン-2-アミン
等が挙げられ、
好ましくは、化合物AA29、化合物AA31、化合物AA49、化合物AA56、化合物AA66、化合物AA85、化合物AA87、化合物AA90等が挙げられる。 Examples of the compound according to claim 1 of US2019 / 0169168 include, for example.
Compound AA01:
[4- (6-Amino-4-methoxy-pyridin-3-yl) -piperazine-1-yl]-[5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA02:
(6-Amino-4-methyl-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-[5- (4-fluoro-phenoxy) ) -4-Methoxy-pyridin-2-yl] -methanone,
Compound AA03:
(6-Amino-3', 4', 5', 6'-Tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-(4-Methoxy-5-phenoxy-pyridin-2- Il)-Metanon,
Compound AA04:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-[5- (4-fluoro-phenoxy) ) -4-Methoxy-pyridin-2-yl] -methanone,
Compound AA05:
[4- (6-Amino-4-methoxy-pyridin-3-yl) -piperazine-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
Compound AA06:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-[5- (4-isopropoxy-phenoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA07:
[(R) -4- (6-amino-4-methyl-pyridine-3-yl) -2-hydroxymethyl-piperazine-1-yl]-[5- (4-fluoro-phenoxy) -4-methoxy- Pyridine-2-yl] -methanone,
Compound AA08:
[7- (6-Amino-4-methoxy-Pyridine-3-yl) -4,7-Diaza-spiro [2.5] Oct-4-yl]-(4-Methoxy-5-phenoxy-pyridin-2-yl) )-Metanon,
Compound AA09:
[7- (6-amino-4-methoxy-pyridin-3-yl) -4,7-diaza-spiro [2.5] octo-4-yl]-[5- (4-fluoro-phenoxy) -4-methoxy -Pyridine-2-yl] -Metanone,
Compound AA10:
(6-Amino-4-methyl-3', 4', 5', 6'-Tetrahydro-2'H- [3,4'] Bipyridinyl-1'-yl)-(4-Methoxy-5-phenoxy- Pyridine-2-yl) -methanone,
Compound AA11:
[4- (6-Amino-5-methoxy-pyridazine-3-yl) -piperidine-1-yl]-[5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA12:
[4- (6-Amino-Pyridine-3-yl) -Piperazine-1-yl]-[4-Methoxy-5- (4-Methoxy-phenoxy) -Pyridine-2-yl] -methanone,
Compound AA13:
[4- (6-Amino-pyridin-3-yl) -piperazin-1-yl]-[5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA14:
(6-Amino-3', 4', 5', 6'-Tetrahydro-2'H- [3,4'] Bipyridinyl-1'-Il)-[5- (4-Fluoro-phenoxy) -4- Methoxy-pyridin-2-yl] -methanone,
Compound AA15:
[4- (6-Amino-pyridin-3-yl) -piperazine-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
Compound AA16:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
Compound AA17:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-[5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA18:
[(R) -4- (6-amino-4-methyl-pyridin-3-yl) -2-hydroxymethyl-piperazine-1-yl]-(4-Methoxy-5-phenoxy-pyridine-2-yl) -Metanon,
Compound AA19:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-[5- (2-fluoro-benzyl) Oxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA20:
[(R) -4- (6-amino-Pyridine-3-yl) -2-hydroxymethyl-piperazin-1-yl]-[5- (4-fluoro-phenoxy) -4-methoxy-pyridine-2- Il]-Metanon,
Compound AA21:
[4- (6-Amino-5-methoxy-pyridazine-3-yl) -piperidine-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
Compound AA22:
(6-Amino-3', 4', 5', 6'-Tetrahydro-2'H- [3,4'] Bipyridinyl-1'-yl)-[4-Methoxy-5- (4-Methoxy-phenoxy) )-Pyridine-2-yl] -methanone,
Compound AA23:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-(4-Methoxy-5-phenoxy- Pyridine-2-yl) -methanone,
Compound AA24:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-[4-Methoxy-5- (4 -Trifluoromethyl-phenoxy) -pyridin-2-yl] -methanone,
Compound AA25:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-(5-cyclobutylmethoxy-4-methoxy-pyridin-2-yl) -methanone,
Compound AA26:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- [3,4'] Bipyridinyl-1'-yl)-[4-Methoxy-5- (1) -Methyl-cyclopropylmethoxy) -pyridin-2-yl] -methanone,
Compound AA27:
[(R) -4- (6-Amino-4-methoxy-pyridin-3-yl) -2-methoxymethyl-piperazine-1-yl]-(4-Methoxy-5-phenoxy-pyridin-2-yl) -Metanon,
Compound AA28:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- [3,4'] Bipyridinyl-1'-yl)-[4-Methoxy-5- (4 -Methoxy-phenoxy) -pyridin-2-yl] -methanone,
Compound AA29:
[4- (6-Amino-4-methyl-pyridazine-3-yl) -piperidine-1-yl]-[5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA30:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- [3,4'] Bipyridinyl-1'-yl)-(5-Cyclohexyloxy-4-methoxy) -Pyridine-2-yl) -methanone,
Compound AA31:
[4- (6-Amino-4-methyl-pyridazine-3-yl) -piperidine-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
Compound AA32:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-[5- (4-fluoro-benzyl) Oxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA33:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-[4-methoxy-5- (4-trifluoromethyl-phenoxy) -pyridin-2-yl] -methanone,
Compound AA34:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-[5- (4-chloro-phenoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA35:
(6-Amino-4-methoxy-3,4,5,6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-(5-cyclopentyloxy-4-methoxy-pyridine- 2-Il)-Metanon,
Compound AA36:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-(5-isobutoxy-4-methoxy-pyridin-2-yl) -methanone,
Compound AA37:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- [3,4'] Bipyridinyl-1'-yl)-(5-Cyclopropylmethoxy-4- Methoxy-pyridin-2-yl) -methanone,
Compound AA38:
[3- (6-Amino-4-methoxy-pyridin-3-yl) -3,8-diaza-bicyclo [3.2.1] octo-8-yl]-[5- (4-fluoro-phenoxy) -4 -Methoxy-pyridin-2-yl] -methanone,
Compound AA39:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-(5-isobutoxy-4-methoxy- Pyridine-2-yl) -methanone,
Compound AA40:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-[5- (4-cyclopropoxy-phenoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA41:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-[5- (4-fluoro-benzyloxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA42:
[(R) -4- (6-amino-4-methoxy-pyridin-3-yl) -2-hydroxymethyl-piperazine-1-yl]-[5- (4-fluoro-phenoxy) -4-methoxy- Pyridine-2-yl] -methanone,
Compound AA43:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-(5-benzyloxy-4-methoxy) -Pyridine-2-yl) -methanone,
Compound AA44:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-[4-methoxy-5- (4-methoxy-phenoxy) -pyridin-2-yl] -methanone,
Compound AA45:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-[5- (3,3-difluoro) -Cyclobutylmethoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA46:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- [3,4'] Bipyridinyl-1'-yl)-(4-Methoxy-5-propoxy- Pyridine-2-yl) -methanone,
Compound AA47:
[4- (6-Amino-4-methoxy-pyridazine-3-yl) -piperidine-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
Compound AA48:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-[5- (2-cyclopropyl-) Ethoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA49:
[4- (6-Amino-4-methoxy-pyridazine-3-yl) -piperidine-1-yl]-[5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA50:
(1R) -1-[(2R) -4- (6-amino-4-methoxypyridin-3-yl) -1- (5-phenoxypyridine-2-carbonyl) piperazine-2-yl] ethane-1- All,
Compound AA51:
[3- (6-Amino-4-methoxy-Pyridine-3-yl) -3,8-Diaza-bicyclo [3.2.1] Oct-8-yl]-(4-Methoxy-5-Phenoxy-Pyridine-2) -Il)-Metanon,
Compound AA52:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-(4-Methoxy-5-phenethyloxy -Pyridine-2-yl) -methanone,
Compound AA53:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- [3,4'] Bipyridinyl-1'-yl)-(5-Cyclobutylmethoxy-4- Methoxy-pyridin-2-yl) -methanone,
Compound AA54:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-[5- (4-difluoromethoxy-phenoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA55:
[(R) -4- (6-amino-4-methoxy-pyridin-3-yl) -2-methoxymethyl-piperazine-1-yl]-[5- (4-fluoro-phenoxy) -4-methoxy- Pyridine-2-yl] -methanone,
Compound AA56:
[4- (6-Amino-4-methoxy-pyridazine-3-yl) -piperidine-1-yl]-[4-methoxy-5- (4-trifluoromethyl-phenoxy) -pyridin-2-yl]- Metanon,
Compound AA57:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-[5- (2-fluoro-benzyloxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA58:
(1S) -1-[(2R) -4- (6-amino-4-methoxypyridin-3-yl) -1- (5-phenoxypyridine-2-carbonyl) piperazine-2-yl] ethane-1- All,
Compound AA59:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-[5- (2,2-dimethyl) -Propoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA60:
[4- (6-Amino-5-methoxy-pyridazine-3-yl) -piperidine-1-yl]-[4-methoxy-5- (4-methoxy-phenoxy) -pyridin-2-yl] -methanone,
Compound AA61:
[4- (6-Amino-4-methoxy-pyridin-3-yl) -piperazine-1-yl]-(5-cyclopropylmethoxy-4-methoxy-pyridin-2-yl) -methanone,
Compound AA62:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-(5-cyclohexyloxy-4-methoxy-pyridin-2-yl) -methanone,
Compound AA63:
[(S) -4- (6-amino-4-methoxy-pyridin-3-yl) -2-hydroxymethyl-piperazine-1-yl]-[5- (4-fluoro-phenoxy) -4-methoxy- Pyridine-2-yl] -methanone,
Compound AA64:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-[5- (1-fluoromethyl-) Cyclopropylmethoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA65:
(6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- [3,4'] Bipyridinyl-1'-yl)-(5-ethoxy-4-methoxy- Pyridine-2-yl) -methanone,
Compound AA66:
[4- (6-Amino-4-methoxy-pyridazine-3-yl) -piperidine-1-yl]-[4-methoxy-5- (4-methoxy-phenoxy) -pyridin-2-yl] -methanone,
Compound AA67:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-[5- (2-cyclopropyl-ethoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA68:
[7- (6-Amino-4-methoxy-Pyridine-3-yl) -3-oxa-9-aza-bicyclo [3.3.1] non-9-yl]-(4-Methoxy-5-phenoxy-pyridine -2-Il)-Metanon,
Compound AA69:
[(R) -4- (6-amino-4-methoxy-pyridin-3-yl) -2-hydroxymethyl-piperazine-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl) -Metanon,
Compound AA70:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-[5-((S) -1 -Cyclopropyl-ethoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA71:
[(S) -4- (6-amino-4-methoxy-pyridin-3-yl) -2-hydroxymethyl-piperazine-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl) -Metanon,
Compound AA72:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-(5-isopropoxy-4-methoxy) -Pyridine-2-yl) -methanone,
Compound AA73:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-(4-methoxy-5-phenethyloxy-pyridin-2-yl) -methanone,
Compound AA74:
[4- (6-amino-pyridazine-3-yl) -piperidine-1-yl]-[5- (2,2-dimethyl-propoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA75:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-[4-methoxy-5- (1-methyl-cyclopropylmethoxy) -pyridin-2-yl] -methanone,
Compound AA76:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-(4-methoxy-5-propoxy-pyridin-2-yl) -methanone,
Compound AA77:
(6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-[5-((R) -1) -Cyclopropyl-ethoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA78:
[4- (6-Amino-4-methyl-pyridazine-3-yl) -piperidine-1-yl]-(5-cyclopropylmethoxy-4-methoxy-pyridin-2-yl) -methanone,
Compound AA79:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-[5-((S) -1-cyclopropyl-ethoxy) -4-methoxy-pyridin-2-yl] -methanone ,
Compound AA80:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-[4-methoxy-5- (4-trifluoromethoxy-phenoxy) -pyridin-2-yl] -methanone,
Compound AA81:
[(R) -4- (6-amino-pyridin-3-yl) -2-hydroxymethyl-piperazin-1-yl]-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
Compound AA82:
[(R) -4- (6-amino-Pyridine-3-yl) -2-hydroxymethyl-piperazine-1-yl]-[4-Methoxy-5- (4-methoxy-phenoxy) -pyridine-2- Il]-Metanon,
Compound AA83:
[4- (6-amino-pyridazine-3-yl) -piperidine-1-yl]-[5- (phenoxy) -4-ethoxy-pyridin-2-yl] -methanone,
Compound AA84:
(6-Amino-4-cyclopropoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-[5- (phenoxy) -4 -Methoxy-pyridin-2-yl] -methanone,
Compound AA85:
[4- (6-Amino-4-ethoxy-pyridazine-3-yl) -piperidine-1-yl]-[4-methoxy-5- (phenoxy) -pyridin-2-yl] -methanone,
Compound AA86:
(6-Amino-4-propoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-[5- (phenoxy) -4- Methoxy-pyridin-2-yl] -methanone,
Compound AA87:
(6-Amino-4-ethoxy-3', 4', 5', 6'-tetrahydro-2'H- [3,4'] bipyridinyl-1'-yl)-[5- (4-trifluoromethyl -Phenoxy) -4-methoxy-pyridin-2-yl] -methanone,
Compound AA88:
[4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl]-[5- (4-fluoro-phenoxy) -4-ethoxy-pyridin-2-yl] -methanone,
Compound AA89:
[3- (6-Amino-pyridazine-3-yl) -8-aza-bicyclo [3.2.1] octo-8-yl]-[4-ethoxy-5- (4-fluoro-phenoxy) -pyridine-2 -Il]-Metanon,
Compound AA90:
6- {1- {4-Methoxy-5- [4- (trifluoromethyl) phenoxy] pyridin-2-carbonyl} piperidine-4-yl) -5-methylpyridazine-3-amine,
Compound AA91:
5-Methoxy-6-(1- {5- [4- (trifluoromethyl) -phenoxy] -pyridin-2-carbonyl} piperidine-4-yl) -pyridazine-3-amine,
Compound AA92:
4-Methoxy-5- [1- (4-Methoxy-5-{[trans-3- (trifluoromethyl) cyclobutyl] -methoxy} pyridine-2-carbonyl) -piperidine-4-yl] pyridine-2-amine ,
Compound AA93:
4-Methoxy-5- [1-(4-Methoxy-5-{[(cis-3- (trifluoromethyl) -cyclobutyl] methoxy} -pyridin-2-carbonyl) piperidine-4-yl] pyridine-2- Amin,
Compound AA94:
4-Methoxy-5-(1- {4-Methoxy-5-[(2) -3,3,3-trifluoro-2-methylpropoxy] -pyridine-2-carbonyl} piperidine-4-yl) Pyridine- 2-amine,
Compound AA95:
5- {1- {5-[(2,2-difluorocyclobutyl) -methoxy] -4-methoxy-pyridin-2-carbonyl} -piperidine-4-yl) -4-methoxypyridin-2-amine, etc. Listed,
Preferably, compound AA29, compound AA31, compound AA49, compound AA56, compound AA66, compound AA85, compound AA87, compound AA90 and the like can be mentioned.
　WO2019/215268に記載された化合物としては、例えば、
化合物BB01：
1-[4-(4-フルオロフェニル)-2-(トリアゾール-2-イル)シクロペンチル]ピペリジン-3-アミン、
化合物BB02：
1-[2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル]ピラゾール-4-カルボニトリル、
化合物BB03：
1-[2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル]ピラゾール-3-カルボニトリル、
化合物BB04：
1-[2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル]ピロール-3-カルボニトリル、
化合物BB05：
1-[2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル]トリアゾール-4-カルボニトリル、
化合物BB06：
1-[2-(3-アミノ-5-フルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル]ピラゾール-4-カルボニトリル、
化合物BB07：
1-[2-(3-アミノ-4,4-ジフルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル]ピラゾール-4-カルボニトリル、
化合物BB08：
1-[4-(4-フルオロフェニル)-2-ピラゾール-1-イル-シクロペンチル]ピペリジン-3-アミン、
化合物BB09：
5-フルオロ-1-[4-(4-フルオロフェニル)-2-ピラゾール-1-イル-シクロペンチル]ピペリジン-3-アミン、
化合物BB10：
5-フルオロ-1-[4-(4-フルオロフェニル)-2-(1,2,4-トリアゾール-1-イル)シクロペンチル]ピペリジン-3-アミン、
化合物BB11：
5-フルオロ-1-[4-(4-フルオロフェニル)-2-(テトラゾール-2-イル)シクロペンチル]ピペリジン-3-アミン、
化合物BB12：
1-[4-(4-フルオロフェニル)-2-(テトラゾール-2-イル)シクロペンチル]ピペリジン-3-アミン、
化合物BB13：
1-[2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル]-1,2,4-トリアゾール-3-カルボニトリル、
化合物BB14：
4-[2-(3-アミノ-1-ピペリジル)-4-(4-フルオロ-3-ヒドロキシ-フェニル)シクロペントキシ]ベンゾニトリル、
化合物BB15：
4-[2-(3-アミノ-1-ピペリジル)-4-(4-フルオロ-3-メトキシ-フェニル)シクロペントキシ]ベンゾニトリル、
化合物BB16：
4-[2-(3-アミノ-1-ピペリジル)-4-(3-フルオロフェニル)シクロペントキシ]-3-クロロ-ベンゾニトリル、
化合物BB17：
4-[2-(3-アミノ-4,4-ジフルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ]ベンゾニトリル、
化合物BB18：
4-[2-(5-アミノ-3,3-ジフルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ]ベンゾニトリル、
化合物BB19：
4-[2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ]-2-フルオロ-ベンゾニトリル、
化合物BB20：
2-[2-(3-アミノ-1-ピペリジル)-4-フェニル-シクロペントキシ]ベンゾニトリル、
化合物BB21：
4-[2-(3-アミノ-1-ピペリジル)-4-フェニル-シクロペントキシ]-3-クロロ-ベンゾニトリル、
化合物BB22：
6-[2-(3-アミノ-5-フルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ]-5-メチル-ピリダジン-3-カルボニトリル、
化合物BB23：
1-[2-(4-クロロピリダジン-3-イル)オキシ-4-(4-フルオロフェニル)シクロペンチル]ピペリジン-3-アミン、
化合物BB24：
6-[2-(3-アミノ-5-フルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ]ピリダジン-3-カルボニトリル、
化合物BB25：
1-[4-(4-フルオロフェニル)-2-(5-フルオロピリダジン-3-イル)オキシ-シクロペンチル]ピペリジン-3-アミン、
化合物BB26：
6-(2-((R)-3-アミノピペリジン-1-イル)-4-(4-フルオロフェニル)シクロペンチルオキシ)ニコチノニトリル、
化合物BB27：
6-[2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ]ピリジン-3-カルボニトリル、
化合物BB28：
1-[4-(4-フルオロフェニル)-2-ピリダジン-3-イルオキシ-シクロペンチル]ピペリジン-3-アミン、
化合物BB29：
5-フルオロ-1-[4-(4-フルオロフェニル)-ピリミジン-4-イルオキシ-シクロペンチル]ピペリジン-3-アミン、
化合物BB30：
2-[2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ]ピリミジン-5-カルボニトリル、
化合物BB31：
5-[2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ]ピラジン-2-カルボニトリル、
化合物BB32：
5-[2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ]ピリミジン-2-カルボニトリル
等が挙げられる。 Examples of the compounds described in WO2019 / 215268 include, for example.
Compound BB01:
1- [4- (4-fluorophenyl) -2- (triazole-2-yl) cyclopentyl] piperidine-3-amine,
Compound BB02:
1- [2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl] pyrazole-4-carbonitrile,
Compound BB03:
1- [2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl] pyrazole-3-carbonitrile,
Compound BB04:
1- [2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl] pyrrole-3-carbonitrile,
Compound BB05:
1- [2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl] triazole-4-carbonitrile,
Compound BB06:
1- [2- (3-Amino-5-fluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl] pyrazole-4-carbonitrile,
Compound BB07:
1- [2- (3-Amino-4,4-difluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl] pyrazole-4-carbonitrile,
Compound BB08:
1- [4- (4-fluorophenyl) -2-pyrazole-1-yl-cyclopentyl] piperidine-3-amine,
Compound BB09:
5-Fluoro-1- [4- (4-fluorophenyl) -2-pyrazole-1-yl-cyclopentyl] piperidine-3-amine,
Compound BB10:
5-Fluoro-1- [4- (4-fluorophenyl) -2- (1,2,4-triazole-1-yl) cyclopentyl] piperidine-3-amine,
Compound BB11:
5-Fluoro-1- [4- (4-fluorophenyl) -2- (tetrazol-2-yl) cyclopentyl] piperidine-3-amine,
Compound BB12:
1- [4- (4-fluorophenyl) -2- (tetrazol-2-yl) cyclopentyl] piperidine-3-amine,
Compound BB13:
1- [2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl] -1,2,4-triazole-3-carbonitrile,
Compound BB14:
4- [2- (3-Amino-1-piperidyl) -4- (4-fluoro-3-hydroxy-phenyl) cyclopentoxy] benzonitrile,
Compound BB15:
4- [2- (3-Amino-1-piperidyl) -4- (4-fluoro-3-methoxy-phenyl) cyclopentoxy] benzonitrile,
Compound BB16:
4- [2- (3-Amino-1-piperidyl) -4- (3-fluorophenyl) cyclopentoxy] -3-chloro-benzonitrile,
Compound BB17:
4- [2- (3-Amino-4,4-difluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy] benzonitrile,
Compound BB18:
4- [2- (5-Amino-3,3-difluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy] benzonitrile,
Compound BB19:
4- [2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy] -2-fluoro-benzonitrile,
Compound BB20:
2- [2- (3-Amino-1-piperidyl) -4-phenyl-cyclopentoxy] benzonitrile,
Compound BB21:
4- [2- (3-Amino-1-piperidyl) -4-phenyl-cyclopentoxy] -3-chloro-benzonitrile,
Compound BB22:
6- [2- (3-Amino-5-fluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy] -5-methyl-pyridazine-3-carbonitrile,
Compound BB23:
1- [2- (4-chloropyridazine-3-yl) oxy-4- (4-fluorophenyl) cyclopentyl] piperidine-3-amine,
Compound BB24:
6- [2- (3-Amino-5-fluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy] pyridazine-3-carbonitrile,
Compound BB25:
1- [4- (4-fluorophenyl) -2- (5-fluoropyridazine-3-yl) oxy-cyclopentyl] piperidine-3-amine,
Compound BB26:
6-(2-((R) -3-aminopiperidine-1-yl) -4- (4-fluorophenyl) cyclopentyloxy) nicotinonitrile,
Compound BB27:
6- [2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy] Pyridine-3-Carbonitrile,
Compound BB28:
1- [4- (4-fluorophenyl) -2-pyridazine-3-yloxy-cyclopentyl] piperidine-3-amine,
Compound BB29:
5-Fluoro-1- [4- (4-fluorophenyl) -pyrimidine-4-yloxy-cyclopentyl] piperidine-3-amine,
Compound BB30:
2- [2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy] pyrimidine-5-carbonitrile,
Compound BB31:
5- [2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy] pyrazine-2-carbonitrile,
Compound BB32:
Examples thereof include 5- [2- (3-amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy] pyrimidine-2-carbonitrile.
　TRPC3/6チャネル阻害物質、一般式（１）または（２）で表される化合物、上記各反応式において得られる中間体化合物、および出発原料化合物に、二重結合、環、縮合環における異性体（Ｅ、Ｚ、シス、トランス体）、不斉炭素の存在等による異性体（Ｒ、Ｓ体、α、β体、エナンチオマー、ジアステレオマー）、旋光性を有する光学活性体（Ｄ、Ｌ、ｄ、ｌ体）、クロマトグラフ分離による極性体（高極性体、低極性体）、平衡化合物、回転異性体、これらの任意の割合の混合物、ラセミ混合物は幾何異性体、立体異性体、光学異性体などの異性体が存在する場合には、全ての異性体が包含される。例えば、光学異性体は、公知の各種の分割法（例えば、結晶化による光学分割、クロマトグラフィーによる直接光学分割する方法等）を利用して分離することができる。 TRPC3 / 6 channel inhibitors, compounds represented by the general formula (1) or (2), intermediate compounds obtained in each of the above reaction formulas, and starting material compounds with isomers in double bonds, rings, and fused rings. (E, Z, cis, trans isomers), isomers due to the presence of asymmetric carbons (R, S isomers, α, β isomers, enantiomers, diastereomers), optically active compounds (D, L, d, l), polar isomers (high polar isomers, low polar isomers) by chromatograph separation, equilibrium compounds, rotational isomers, mixtures of any proportion of these, racemic mixtures are geometric isomers, steric isomers, optical isomers If an isomer such as a body is present, all isomers are included. For example, the optical isomers can be separated by using various known division methods (for example, optical resolution by crystallization, direct optical resolution by chromatography, etc.).
　TRPC3/6チャネル阻害物質（例えば、一般式（１）または（２）で表される化合物等）の塩には薬学的に許容されるものがすべて含まれる。薬学的に許容される塩は、特に制限されず、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩等のアルカリ土類金属塩；亜鉛塩等の無機金属塩；トリエチルアミン、トリエタノールアミン、トリヒドロキシメチルアミノメタン、アミノ酸等の有機塩基塩；塩酸塩、臭化水素酸塩、硫酸塩、リン酸塩、硝酸塩等の無機酸塩；酢酸塩、炭酸塩、プロピオン酸塩、コハク酸塩、乳酸塩、リンゴ酸塩、酒石酸塩、クエン酸塩、マレイン酸塩、フマル酸塩、メタンスルホン酸塩、ｐ－トルエンスルホン酸塩、ベンゼンスルホン酸塩、アスコルビン酸塩等の有機酸塩等が挙げられる。これらの塩は常法に従って製造することができる。 The salts of TRPC3 / 6 channel inhibitors (for example, compounds represented by the general formula (1) or (2)) include all pharmaceutically acceptable salts. The pharmaceutically acceptable salt is not particularly limited, and for example, an alkali metal salt such as sodium salt and potassium salt; an alkaline earth metal salt such as calcium salt and magnesium salt; an inorganic metal salt such as zinc salt; triethylamine, Organic base salts such as triethanolamine, trihydroxymethylaminomethane, amino acids; inorganic acid salts such as hydrochlorides, hydrobromates, sulfates, phosphates, nitrates; acetates, carbonates, propionates, Organic acids such as succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, ascorbate Examples include salt. These salts can be produced according to a conventional method.
　各種の異性体は公知の分離法により単離できる。例えば、ラセミ化合物は一般的な光学分割法（例えば、結晶化による光学分割、クロマトグラフィーによる直接光学分割する方法等）により、立体的に純粋な異性体に導くことができる。また、光学活性な化合物は適当な光学活性な原料を用いることにより製造することもできる。 Various isomers can be isolated by a known separation method. For example, a racemic compound can be derived into a sterically pure isomer by a general optical resolution method (for example, optical resolution by crystallization, direct optical resolution by chromatography, etc.). The optically active compound can also be produced by using an appropriate optically active raw material.
　上記反応式のそれぞれに表される出発原料化合物、中間体化合物、および目的化合物を適切な塩形態で使用することができる。 The starting material compound, intermediate compound, and target compound represented by each of the above reaction formulas can be used in an appropriate salt form.
　本発明においてTRPC3/6チャネル阻害物質（例えば、一般式（１）または（２）で表される化合物等）、その塩、またはそのプロドラッグでは、１つまたは複数の原子を１つまたは複数の同位体原子で置換することができる。同位体原子の例としては重水素（２Ｈ）、三重水素（３Ｈ）、１３Ｃ、１４Ｎ、１８Ｏ等が挙げられる。 In the present invention, a TRPC3 / 6 channel inhibitor (for example, a compound represented by the general formula (1) or (2), etc.), a salt thereof, or a prodrug thereof may contain one or more atoms. It can be replaced with an isotope atom. Examples of isotope atoms include deuterium (2H), tritium (3H), 13C, 14N, 18O and the like.
　本発明には、TRPC3/6チャネル阻害物質（例えば、一般式（１）または（２）で表される化合物等）、その塩、またはそれらのプロドラッグを含有する難聴の予防および／または治療用医薬組成物が含まれる。本発明の医薬組成物は、TRPC3/6チャネル阻害物質、その塩、またはそのプロドラッグを通常の医薬組成物の形態に製剤したものであってよく、当該化合物、その塩、またはそのプロドラッグと薬学的に許容可能な担体とを用いて調製されてよい。当該担体としては、通常使用される充填剤、増量剤、結合剤、付湿剤、崩壊剤、表面活性剤、滑沢剤等の希釈剤あるいは賦形剤が挙げられる。 The present invention contains TRPC3 / 6 channel inhibitors (eg, compounds represented by the general formula (1) or (2), etc.), salts thereof, or prodrugs thereof for the prevention and / or treatment of deafness. Includes pharmaceutical compositions. The pharmaceutical composition of the present invention may be a preparation of a TRPC3 / 6 channel inhibitor, a salt thereof, or a prodrug thereof in the form of a conventional pharmaceutical composition, and the compound, a salt thereof, or a prodrug thereof. It may be prepared with a pharmaceutically acceptable carrier. Examples of the carrier include commonly used fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, diluents such as lubricants, and excipients.
　本発明においてプロドラッグは、生体内における反応（例えば酵素反応、胃酸による反応）によってTRPC3/6チャネル阻害物質（例えば、一般式（１）または（２）で表される化合物等）に変換される化合物をいう。例えば、TRPC3/6チャネル阻害物質（例えば、一般式（１）または（２）で表される化合物等）がカルボキシルを有する場合、該カルボキシルがエステルに変換された化合物である。該エステルとしては、メチルエステル、エチルエステル、１－プロピルエステル、２－プロピルエステル、ピバロイルオキシメチルエステル、アセチルオキシメチルエステル、シクロヘキシルアセチルオキシメチルエステル、１－メチルシクロヘキシルカルボニルオキシメチルエステル、エチルオキシカルボニルオキシ－１－エチルエステル、シクロヘキシルオキシカルボニルオキシ－１－エチルエステルなどが挙げられる。 In the present invention, a prodrug is converted into a TRPC3 / 6 channel inhibitor (for example, a compound represented by the general formula (1) or (2)) by a reaction in vivo (for example, an enzymatic reaction or a reaction with gastric acid). Refers to a compound. For example, when a TRPC3 / 6 channel inhibitor (for example, a compound represented by the general formula (1) or (2)) has a carboxyl, the carboxyl is converted into an ester. Examples of the ester include methyl ester, ethyl ester, 1-propyl ester, 2-propyl ester, pivaloyloxymethyl ester, acetyloxymethyl ester, cyclohexylacetyloxymethyl ester, 1-methylcyclohexylcarbonyloxymethyl ester and ethyloxy. Examples thereof include carbonyloxy-1-ethyl ester and cyclohexyloxycarbonyloxy-1-ethyl ester.
　本発明の医薬組成物としては、治療目的に応じて種々の形態の中から選択でき、その代表的なものとして錠剤、丸剤、散剤、液剤、懸濁剤、乳剤、顆粒剤、カプセル剤、坐剤、注射剤（液剤、懸濁剤等）、軟膏剤、吸入剤、点耳剤等が挙げられる。これらの中でも経口投与用の製剤、局所（好ましくは耳内）投与用の製剤および注射剤が好ましく、経口投与用の製剤がより好ましい。 The pharmaceutical composition of the present invention can be selected from various forms according to the therapeutic purpose, and typical examples thereof include tablets, pills, powders, liquids, suspensions, emulsions, granules and capsules. Examples include suppositories, injections (liquids, suspensions, etc.), ointments, inhalants, ear drops, and the like. Among these, preparations for oral administration, preparations for local (preferably intraoural) administration and injections are preferable, and preparations for oral administration are more preferable.
　錠剤の成形に使用する担体としては、公知のものを広く使用でき、例えば、乳糖、白糖、塩化ナトリウム、ブドウ糖、尿素、デンプン、炭酸カルシウム、カオリン、結晶セルロース等の賦形剤、水、エタノール、プロパノール、単シロップ、ブドウ糖液、デンプン液、ゼラチン溶液、メチルセルロース、リン酸カリウム、ポリビニルピロリドン、カルボキシメチルセルロース、セラック等の結合剤、アルギン酸ナトリウム、乾燥デンプン、寒天末、ラミナラン末、炭酸カルシウム、炭酸水素ナトリウム、ポリオキシエチレンソルビタン脂肪酸エステル類、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、乳糖等の崩壊剤、第４級アンモニウム塩基、ラウリル硫酸ナトリウム等の吸収促進剤、ステアリン、カカオバター、水素添加油等の崩壊抑制剤、グリセリン、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、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、ホウ酸末、ポリエチレングリコール等の滑沢剤等が挙げられる。 As the carrier used for molding tablets, known carriers can be widely used, for example, excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, water, ethanol, etc. Compounds such as propanol, simple syrup, glucose solution, starch solution, gelatin solution, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, carboxymethyl cellulose, cellac, sodium alginate, dried starch, agar powder, laminaran powder, calcium carbonate, sodium hydrogen carbonate , Polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, disintegrants such as lactose, absorption promoters such as quaternary ammonium base, sodium lauryl sulfate, stear, cocoa butter, hydrogenated oil, etc. Disintegration inhibitors, moisturizers 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. Be done.
　さらに、錠剤は、必要に応じて通常の錠皮を施した錠剤、例えば、糖衣剤、ゼラチン被包錠、腸溶被錠、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。　　　 Further, the tablet can be a tablet with a normal lock skin, for example, a sugar coating agent, a gelatin-encapsulated tablet, an enteric-coated tablet, a film-coated tablet or a double tablet, or a multi-layer tablet, if necessary.
　丸剤の成形に使用する担体としては、公知のものを広く使用でき、例えば、ブドウ糖、乳糖、デンプン、カカオ脂、硬化植物油、カオリン、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、エタノール等の結合剤、ラミナラン、寒天等の崩壊剤等が挙げられる。 Known carriers can be widely used for molding pills, for example, excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc, gum arabic powder, tragant powder, gelatin. , Binders such as ethanol, disintegrants such as laminarin and agar, and the like.
　坐剤の成形に使用する担体としては、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、カカオ脂、高級アルコール、高級アルコールのエステル類、ゼラチン、半合成グリセライド等が挙げられる。 As the carrier used for molding the suppository, known ones can be widely used, and examples thereof include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glyceride and the like.
　注射剤として調製される場合は、液剤、乳剤および懸濁剤は殺菌され、かつ血液と等張であるのが好ましい。これらの液剤、乳剤および懸濁剤の調製の際に使用する希釈剤としては、公知のものを広く使用することができ、例えば、水、エタノール、プロピレングリコール、ポリオキシ化イソステアリルアルコール、エトキシ化イソステアリルアルコール、ポリオキシエチレンソルビタン脂肪酸エステル類等が挙げられる。なお、注射剤の場合、等張性の溶液を調製するのに十分な量の食塩、グリセリン、ブドウ糖等を医薬製剤中に含有させることができ、また通常の溶解補助剤、緩衝剤、無痛化剤等を含有させることができ、更に必要に応じて着色剤、保存剤、香料、風味剤、甘味剤等や他の医薬品を含有させることができる。 When prepared as an injection, the liquid, emulsion and suspension are preferably sterilized and isotonic with blood. As the diluent used in the preparation of these liquids, emulsions and suspending agents, known ones can be widely used, for example, water, ethanol, propylene glycol, polyoxylated isostearyl alcohol, ethoxylated iso. Examples thereof include stearyl alcohol and polyoxyethylene sorbitan fatty acid esters. In the case of an injection, a sufficient amount of salt, glycerin, glucose, etc. can be contained in the pharmaceutical preparation to prepare an isotonic solution, and a usual solubilizing agent, buffer, and painlessening agent. Agents and the like can be contained, and if necessary, colorants, preservatives, flavors, flavoring agents, sweeteners and the like and other pharmaceuticals can be contained.
　軟膏剤は、ペースト、クリーム、またはゲルなどの形態があり、これらの形態に調製するに際しては、希釈剤として、例えば、白色ワセリン、パラフィン、グリセリン、セルロース誘導体、ポリエチレングリコール、シリコーン、ベントナイト等を使用できる。 The ointment has a form such as a paste, a cream, or a gel, and when preparing these forms, for example, white petrolatum, paraffin, glycerin, a cellulose derivative, polyethylene glycol, silicone, bentonite, etc. are used as a diluent. it can.
　吸入剤は、有効成分をエアゾールとして吸入させることにより、気管支または肺に適用することを目的とした製剤であり、粉末吸入剤、吸入液剤、吸入エアゾール剤等が含まれる。粉末吸入剤は、粉末状固体粒子のエアゾールとして吸入する製剤をいい、通常、有効成分を微細な粒子とし、必要に応じて乳糖等の添加剤と混和して均質とすることにより製造することができる。吸入液剤は、ネブライザ等により適用する液状の吸入剤をいい、通常、有効成分に溶剤および適切な等張化剤、ｐＨ調節剤等を加え、混和することにより製造できる。吸入エアゾール剤は、容器に充填した噴射剤と共に、一定量の有効成分を噴霧する定量噴霧式吸入剤である。吸入エアゾール剤は、通常、有効成分に溶剤および適切な分散剤、安定化剤等を加えて、溶液または懸濁液とし、液状の噴射剤と共に耐圧性の容器に充填し、定量バルブを装着することにより製造することができる。 The inhalant is a preparation intended to be applied to the bronchi or lungs by inhaling the active ingredient as an aerosol, and includes a powder inhalant, an inhalation solution, an inhalation aerosol, and the like. A powder inhaler is a preparation that is inhaled as an aerosol of powdered solid particles, and is usually produced by making the active ingredient into fine particles and mixing them with an additive such as lactose to make them homogeneous. it can. The inhalation solution refers to a liquid inhalation agent applied by a nebulizer or the like, and can usually be produced by adding a solvent, an appropriate tonicity agent, a pH adjuster or the like to the active ingredient and mixing them. The inhalation aerosol agent is a fixed-quantity spray-type inhalant that sprays a certain amount of the active ingredient together with the propellant filled in the container. Inhalation aerosols are usually prepared by adding a solvent and an appropriate dispersant, stabilizer, etc. to the active ingredient to make a solution or suspension, filling a pressure-resistant container with a liquid propellant, and installing a metering valve. It can be manufactured by.
　本発明の医薬組成物は、必要に応じて着色剤、保存剤、香料、風味剤、甘味剤などや他の医薬品を含有してもよい。 The pharmaceutical composition of the present invention may contain colorants, preservatives, flavors, flavors, sweeteners and other pharmaceuticals, if necessary.
　本発明の医薬組成物中に含有されるTRPC3/6チャネル阻害物質（例えば、一般式（１）または（２）で表される化合物等）、その塩、またはそれらのプロドラッグの量は、特に限定されず広い範囲内から適宜選択することができるが、医薬組成物中に、通常、０．５～９０重量％、１～８５重量％、好ましくは１～８０重量％である。 The amount of TRPC3 / 6 channel inhibitors (eg, compounds represented by the general formula (1) or (2)), salts thereof, or prodrugs thereof contained in the pharmaceutical composition of the present invention is particularly high. Although it is not limited and can be appropriately selected from a wide range, it is usually 0.5 to 90% by weight, 1 to 85% by weight, preferably 1 to 80% by weight in the pharmaceutical composition.
　本発明の医薬組成物の投与方法は特に制限されず、各種製剤形態、患者の年齢、性別、疾患の状態、その他の条件に応じた方法で投与される。例えば、錠剤、丸剤、液剤、懸濁剤、乳剤、顆粒剤およびカプセル剤の場合には経口投与される。また、注射剤の場合には、単独であるいはブドウ糖、アミノ酸等の通常の補液と混合して静脈内に投与したり、更には必要に応じて単独で筋肉内、皮内、皮下、腹腔内等に投与することができる。坐剤の場合には、直腸内に投与される。吸入剤の場合には経鼻投与される。点耳剤の場合は経耳投与される。好ましい投与方法は、経口投与、注射投与（皮下投与、筋肉内投与、静脈内投与、および髄腔内投与を含む）、経耳投与であり、より好ましくは経口投与である。　　　　 The administration method of the pharmaceutical composition of the present invention is not particularly limited, and the pharmaceutical composition is administered by a method according to various formulation forms, patient age, sex, disease state, and other conditions. For example, in the case of tablets, pills, liquids, suspensions, emulsions, granules and capsules, they are orally administered. In the case of an injection, it may be administered intravenously alone or mixed with a normal replacement fluid such as glucose or amino acid, or if necessary, intramuscularly, intradermally, subcutaneously, intraperitoneally, etc. Can be administered to. In the case of suppositories, it is administered intrarectally. In the case of inhalants, it is administered nasally. In the case of ear drops, it is administered by ear. Preferred administration methods are oral administration, injection administration (including subcutaneous administration, intramuscular administration, intravenous administration, and intrathecal administration), and ear administration, and more preferably oral administration.
　本発明の医薬組成物の投与量は、用法、患者の年齢、性別、疾患の程度、その他の条件を考慮して選択すればよく、有効成分であるTRPC3/6チャネル阻害物質（例えば、一般式（１）または（２）で表される化合物等）、その塩、またはそのプロドラッグが、通常、１日あたり体重１ｋｇに対して０．０１～１００ｍｇ、好ましくは０．１～５０ｍｇとなる量で、１日あたり１回～数回に分けて、あるいは２日、３日、４日、５日、６日、１週間、２週間または４週間に１回の間隔で投与される。投与量は、種々の条件で変動するので、上記範囲より少ない投与量で充分な場合もあるし、また上記範囲を超えた投与量が必要な場合もある。 The dose of the pharmaceutical composition of the present invention may be selected in consideration of usage, age, sex, degree of disease, and other conditions of the patient, and is an active ingredient TRPC3 / 6 channel inhibitor (for example, general formula). The amount of (1) or the compound represented by (2), the salt thereof, or the prodrug thereof is usually 0.01 to 100 mg, preferably 0.1 to 50 mg per 1 kg of body weight per day. It is administered once to several times a day, or once every two days, three days, four days, five days, six days, one week, two weeks or four weeks. Since the dose varies depending on various conditions, a dose smaller than the above range may be sufficient, or a dose exceeding the above range may be required.
　また、本発明の医薬組成物は、他の薬剤と組み合わせた併用剤とすることもできる。 Further, the pharmaceutical composition of the present invention can be used as a concomitant drug in combination with another drug.
　本発明は、難聴の予防および／または治療を必要とする患者にTRPC3/6チャネル阻害物質（例えば、一般式（１）または（２）で表される化合物等）、その薬学的に許容される塩、またはそのプロドラッグの有効量を投与することを含む、難聴の予防および／または治療方法を包含しうる。 The present invention is pharmaceutically acceptable for TRPC3 / 6 channel inhibitors (eg, compounds represented by the general formula (1) or (2)) in patients in need of prevention and / or treatment of deafness. Methods of preventing and / or treating deafness may include administration of an effective amount of salt, or a prodrug thereof.
　TRPC3/6チャネル阻害物質（例えば、一般式（１）または（２）で表される化合物等）、その塩、またはそれらのプロドラッグは、難聴を予防および／または治療する作用を有する。
　難聴は、感音難聴、伝音難聴、混合難聴、非器質性難聴などを包含し、好ましくは感音難聴、混合難聴、より好ましくは感音難聴である。
　また、難聴は、軽度難聴、中等度難聴、高度難聴、重度難聴のいずれも包含し、好ましくは軽度難聴、中等度難聴、高度難聴、より好ましくは軽度難聴、中等度難聴である。　さらにまた、難聴は、好ましくは薬剤性難聴、つまり薬剤に起因する難聴（例：薬剤によって惹起される難聴）である。
　薬剤としては白金製剤、抗菌剤、サリチル酸剤、利尿剤などが上げられる。白金製剤としてはシスプラチン、カルボプラチン、ネダプラチン、オキサリプラチン等が挙げられる。抗菌剤としてはアミノグリコシド系抗菌剤、例えばストレプトマイシン、カナマイシン、アミカシン、ゲンタマイシン、ベカナマイシン、リボスタマイシン、ジベカシン、トブラマイシン、イセパマイシン、アルベカシン、ハベカシン等が挙げられる。サリチル酸剤としてはアスピリン、サリチル酸ナトリウム等が挙げられる。利尿剤としてはフロセミド、トラセミド、ブメタニド、アゾセミド、ピレタニド等が挙げられる。
　薬剤性難聴としては、白金製剤に起因する難聴、抗菌剤に起因する難聴、サリチル酸剤に起因する難聴が好ましく、白金製剤に起因する難聴、抗菌剤に起因する難聴がより好ましく、白金製剤に起因する難聴が特に好ましい。 TRPC3 / 6 channel inhibitors (eg, compounds represented by the general formula (1) or (2)), salts thereof, or prodrugs thereof have the effect of preventing and / or treating deafness.
Deafness includes sensorineural deafness, conductive deafness, mixed deafness, non-organic deafness, and the like, preferably sensorineural deafness, mixed deafness, and more preferably sensorineural deafness.
Further, the deafness includes any of mild deafness, moderate deafness, severe deafness, and severe deafness, and is preferably mild deafness, moderate deafness, severe deafness, and more preferably mild deafness and moderate deafness. Furthermore, deafness is preferably drug-induced deafness, i.e., drug-induced deafness (eg, drug-induced deafness).
Examples of the drug include platinum preparations, antibacterial agents, salicylic acid agents, diuretics and the like. Examples of the platinum preparation include cisplatin, carboplatin, nedaplatin, oxaliplatin and the like. Examples of the antibacterial agent include aminoglycoside antibacterial agents such as streptomycin, canamycin, amikacin, gentamicin, bekanamycin, ribostamycin, dibekacin, tobramycin, isepamycin, arbekacin and havekacin. Examples of the salicylic acid agent include aspirin and sodium salicylate. Examples of diuretics include furosemide, torasemide, bumetanide, azosemide, pyrethanide and the like.
As the drug-induced deafness, deafness caused by platinum preparations, deafness caused by antibacterial agents, and deafness caused by salicylic acid agents are preferable, deafness caused by platinum preparations and deafness caused by antibacterial agents are more preferable, and deafness caused by platinum preparations. Deafness is especially preferred.
　TRPC3/6チャネル阻害物質（例えば、一般式（１）または（２）で表される化合物等）、その塩、またはそれらのプロドラッグは、TRPC3チャネルの活性を調節する作用、TRPC6チャネルの活性を調節する作用、またはTRPC3チャネルとTRPC6チャネルの両方の活性を調節する作用を有してよい。また、本発明の化合物、その塩、またはそのプロドラッグは、TRPC3/6チャネル阻害活性を有する。したがって、TRPC3/6チャネル阻害物質（例えば、一般式（１）または（２）で表される化合物等）、その塩、またはそのプロドラッグは、TRPC3および／またはTRPC6調節剤またはTRPC3および／またはTRPC6阻害剤として、あるいはTRPC3および／またはTRPC6関連疾患の予防または治療に、有効である。TRPC3および／またはTRPC6チャネルは、細胞膜に存在し、カチオンイオンの細胞内への流入制御するチャネルである。TRPC3および／またはTRPC6チャネルの阻害は、筋線維芽細胞において、Ca２ ＋流入を介した、TGF-βの下流のリン酸化シグナルに対して抑制的に働き、コラーゲンＩ、平滑筋型アクチン（α－ＳＭＡ；α-Smooth Muscle Actin）等の産生に対して抑制的に働く（例えば、Inflammatory Bowel Diseases, 2015, Mar, 21(3), 496-506）。TRPC3および／またはTRPC6関連疾患は、TRPC3および／またはTRPC6チャネルの過剰な活性化（チャネルが開口しカチオンイオンが細胞内へ過剰に流入する）が観察される疾患である。 TRPC3 / 6 channel inhibitors (eg, compounds represented by the general formula (1) or (2), etc.), salts thereof, or prodrugs thereof act to regulate the activity of TRPC3 channel, the activity of TRPC6 channel. It may have a regulatory effect or an effect of regulating the activity of both TRPC3 and TRPC6 channels. In addition, the compounds of the present invention, salts thereof, or prodrugs thereof have TRPC3 / 6 channel inhibitory activity. Thus, TRPC3 / 6 channel inhibitors (eg, compounds represented by the general formula (1) or (2), etc.), salts thereof, or prodrugs thereof are TRPC3 and / or TRPC6 regulators or TRPC3 and / or TRPC6. It is effective as an inhibitor or for the prevention or treatment of TRPC3 and / or TRPC6-related diseases. The TRPC3 and / or TRPC6 channels are channels that are present in the cell membrane and control the influx of cation ions into the cell. Inhibition of TRPC3 and / or TRPC6 channel, in myofibroblasts, via Ca 2 + influx, acts inhibitory to downstream phosphorylation signal of TGF-beta, collagen I, smooth muscle type actin (alpha -It acts suppressively on the production of α-Smooth Muscle Actin) (for example, Inflammatory Bowel Diseases, 2015, Mar, 21 (3), 496-506). TRPC3 and / or TRPC6-related diseases are diseases in which excessive activation of TRPC3 and / or TRPC6 channels (channels open and cation ions excessively flow into cells) is observed.
　本発明の医薬組成物は、TRPC3および／またはTRPC6関連疾患の予防または治療剤としても有用である。TRPC3および／またはTRPC6関連疾患は、例えばTRPC3チャネルおよび／またはTRPC6チャネルの過剰な活性化または過剰な不活性化に起因する疾患であれば特に制限されないが、TRPC6チャネルの過剰な活性化または過剰な不活性化に起因する疾患が好ましい。TRPC3および／またはTRPC6関連疾患としては、例えば、線維症（例えば、肺線維症、腎線維症、線維化に起因する肝硬変）、神経変性疾患（例えば、筋委縮性性側索硬化症（ALS）、アルツハイマー病等）、筋変性疾患（例えば、筋ジストロフィー等）、炎症性疾患（例えば、クローン病、潰瘍性大腸炎、非アルコール性脂肪肝炎（NASH）等）、ウィリアムズ症候群、慢性腎症、心肥大、肺高血圧症等が挙げられる。好ましい疾患は、例えば線維症である。 The pharmaceutical composition of the present invention is also useful as a prophylactic or therapeutic agent for TRPC3 and / or TRPC6-related diseases. TRPC3 and / or TRPC6-related diseases are not particularly limited as long as they are diseases caused by, for example, excessive activation or excessive inactivation of TRPC3 channels and / or TRPC6 channels, but are excessive activation or excessive activation of TRPC6 channels. Diseases caused by inactivation are preferred. TRPC3 and / or TRPC6-related diseases include, for example, fibrosis (eg, pulmonary fibrosis, renal fibrosis, liver cirrhosis due to fibrosis), neurodegenerative diseases (eg, muscle atrophic lateral sclerosis (ALS)). , Alzheimer's disease, etc.), muscle degenerative diseases (eg, muscle dystrophy, etc.), inflammatory diseases (eg, Crohn's disease, ulcerative colitis, non-alcoholic steatosis (NASH), etc.), Williams syndrome, chronic nephropathy, cardiac hypertrophy , Pulmonary hypertension, etc. A preferred disease is, for example, fibrosis.
　また、一般式（１）または（２）で表される化合物等は、肝臓で代謝を受けにくい。さらに、PBS溶解性が高く、したがって製剤化に有利であり、加えて、膜透過性が高く、したがってバイオアベイラビリティの点で有利である。これらのことから、一般式（１）または（２）で表される化合物等は、薬物動態の面で優れている。このため、従来のTRPC3および／またはTRPC6阻害剤と比較して、或いは、従来の難聴の予防および／または治療剤と比較して、少量で長期間、阻害活性、或いは、難聴の予防および／または治療活性を発揮しうる。 In addition, compounds represented by the general formula (1) or (2) are not easily metabolized in the liver. In addition, it has high PBS solubility, which is advantageous for formulation, and in addition, it has high membrane permeability, which is therefore advantageous in terms of bioavailability. From these facts, the compound represented by the general formula (1) or (2) is excellent in terms of pharmacokinetics. Therefore, compared to conventional TRPC3 and / or TRPC6 inhibitors, or compared to conventional prophylactic and / or therapeutic agents for deafness, small amounts of inhibitory activity or preventive and / or deafness for a long period of time. Can exert therapeutic activity.
　また、一般式（１）または（２）で表される化合物等は、TRPC3およびTRPC6チャネルを除いた他のTRPチャネル（例えば、TRPC1、TRPC2、TRPC5、TRPC7、TRPM2、TRPV1、TRPV6）、あるいは他のCa２＋チャネル、N＋チャネル、K＋チャネルに対する作用が小さいことが予想され、したがってTRPC6およびTRPC3チャネルに対する選択性が高く、副作用が小さいことが期待される。 The compounds represented by the general formula (1) or (2) are TRP channels other than TRPC3 and TRPC6 channels (for example, TRPC1, TRPC2, TRPC5, TRPC7, TRPM2, TRPV1, TRPV6), or others. Is expected to have a small effect on Ca 2+ , N + , and K + channels, and is therefore highly selective for TRPC6 and TRPC3 channels and expected to have few side effects.
　本発明は、TRPC3および／またはTRPC6阻害処理を必要とする患者に一般式（１）または（２）で表される化合物、その薬学的に許容される塩、またはそのプロドラッグの有効量を投与することを含むTRPC3および／またはTRPC6阻害方法を包含しうる。 The present invention administers an effective amount of a compound represented by the general formula (1) or (2), a pharmaceutically acceptable salt thereof, or a prodrug thereof to a patient requiring TRPC3 and / or TRPC6 inhibitory treatment. TRPC3 and / or TRPC6 inhibition methods, including:
　本発明は、TRPC3および／またはTRPC6関連疾患の予防または治療を必要とする患者にTRPC3/6チャネル阻害物質（例えば、一般式（１）または（２）で表される化合物等）、その薬学的に許容される塩、またはそのプロドラッグの有効量を投与することを含むTRPC3および／またはTRPC6関連疾患の予防または治療方法を包含しうる。 The present invention relates to TRPC3 / 6 channel inhibitors (eg, compounds represented by the general formula (1) or (2)), pharmaceuticals thereof, for patients in need of prevention or treatment of TRPC3 and / or TRPC6-related diseases. Can include prophylactic or therapeutic methods of TRPC3 and / or TRPC6-related diseases, including administration of an acceptable amount of salt, or an effective amount of a prodrug thereof.
　本発明は、線維症の予防または治療を必要とする患者にTRPC3/6チャネル阻害物質（例えば、一般式（１）または（２）で表される化合物等）、その薬学的に許容される塩、またはそのプロドラッグの有効量を投与することを含む線維症の予防または治療方法を包含しうる。 The present invention relates to TRPC3 / 6 channel inhibitors (eg, compounds represented by the general formula (1) or (2)), pharmaceutically acceptable salts thereof, for patients in need of prevention or treatment of fibrosis. , Or methods of preventing or treating fibrosis, including administering an effective amount of the prodrug thereof.
　本発明は、TRPC3および／またはTRPC6関連疾患の予防または治療剤の製造のためのTRPC3/6チャネル阻害物質（例えば、一般式（１）または（２）で表される化合物等）、その薬学的に許容される塩、またはそのプロドラッグの使用を包含しうる。 The present invention relates to TRPC3 / 6 channel inhibitors for the production of prophylactic or therapeutic agents for TRPC3 and / or TRPC6-related diseases (eg, compounds represented by the general formula (1) or (2)), the pharmaceuticals thereof. May include the use of acceptable salts, or prodrugs thereof.
　本発明は、線維症の予防または治療剤の製造のためのTRPC3/6チャネル阻害物質（例えば、一般式（１）または（２）で表される化合物等）、その薬学的に許容される塩、またはそのプロドラッグの使用を包含しうる。 The present invention relates to TRPC3 / 6 channel inhibitors for the production of prophylactic or therapeutic agents for fibrosis (eg, compounds represented by the general formula (1) or (2)), pharmaceutically acceptable salts thereof. , Or the use of its prodrugs.
　以下、参考例および実施例を参照し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ない。なお、化合物のＬＣ／ＭＳ分析には以下の条件を用いた。
［ＬＣ／ＭＳ分析条件］
ＬＣ／ＭＳシステム：Waters ACQUITY UPLC H-Class/QDa　Sample Manager - FTN　Quaternary Solvent Manager
　Column Heater A
　PDAeλ Detector
　QDa Detector
カラム：ACQUITY UPLC BEH C18 1.7 μm (2.1×50mm)流速：0.5 mL/min溶出条件：移動相Ａ；アセトニトリル、移動相Ｂ；０．１％ぎ酸水溶液 Hereinafter, the present invention will be specifically described with reference to Reference Examples and Examples, but the present invention is not limited thereto. The following conditions were used for LC / MS analysis of the compound.
[LC / MS analysis conditions]
LC / MS System: Waters ACQUITY UPLC H-Class / QDa Sample Manager --FTN Quaternary Solvent Manager
Column Heater A
PDA eλ Detector
QDa Detector
Column: ACQUITY UPLC BEH C18 1.7 μm (2.1 × 50 mm) Flow velocity: 0.5 mL / min Elution conditions: Mobile phase A; acetonitrile, mobile phase B; 0.1% formic acid aqueous solution
Figure JPOXMLDOC01-appb-T000042
Figure JPOXMLDOC01-appb-T000042
　［実施例１］
５－クロロ－６－（４－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸（化合物０１１）の合成
Figure JPOXMLDOC01-appb-C000043
 [Example 1]
Synthesis of 5-chloro-6- (4- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperazine-1-yl) nicotinic acid (Compound 011)
Figure JPOXMLDOC01-appb-C000043
　ステップ１－１
　２－フルオロ－６－（トリフルオロメチル）ベンズアルデヒド（２ｇ、１０．４１mmol）とヒドロキシアミン塩酸塩（０．８６８ｇ、１２．４９mmol）のエタノール（１０mL）の溶液に１N水酸化ナトリウム水溶液（１２．５mL、１２．５mmol）を加え、室温で３時間撹拌した。反応液を減圧濃縮し、酢酸エチルにて抽出した。有機層を水、飽和食塩水にて洗浄後、硫酸マグネシウムで乾燥、溶媒を減圧留去し、２－フルオロ－６－（トリフルオロメチル）ベンズアルデヒド　オキシム（２．１２６ｇ）を得た。 Step 1-1
1N aqueous sodium hydroxide solution (12.5 mL) in a solution of 2-fluoro-6- (trifluoromethyl) benzaldehyde (2 g, 10.41 mmol) and hydroxyamine hydrochloride (0.868 g, 12.49 mmol) in ethanol (10 mL). 12.5 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2-fluoro-6- (trifluoromethyl) benzaldehyde oxime (2.126 g).
　ステップ１－２
　２－フルオロ－６－（トリフルオロメチル）ベンズアルデヒド　オキシム（２．１２ｇ、１０．２４mmol）のDMF（１０mL）の溶液にNCS（N-クロロスクシンイミド）（１．４３５ｇ、１０．７５mmol）を０℃で加え、室温で終夜撹拌した。LC/MSはオキシムが１００％塩化物に変換したことを示した。２－フルオロ－Ｎ－ヒドロキシ－６－（トリフルオロメチル）ベンズイミドイル　クロリドの溶液は精製することなしに次の反応に用いた。 Step 1-2
NCS (N-Chlorosuccinimide) (1.435 g, 10.75 mmol) in a solution of 2-fluoro-6- (trifluoromethyl) benzaldehyde oxime (2.12 g, 10.24 mmol) in DMF (10 mL) at 0 ° C. In addition, it was stirred overnight at room temperature. LC / MS showed that the oxime was converted to 100% chloride. A solution of 2-fluoro-N-hydroxy-6- (trifluoromethyl) benzimideyl chloride was used in the next reaction without purification.
　ステップ１－３
５－クロロ－６－（ピペラジン－１－イル）ニコチン酸塩酸塩（１８３６ｍｇ、６．６mmol）とトリエチルアミン（２．９３ｍL、２１mmol）のジクロロメタン（１０ｍL）の溶液に、ステップ１－２の２－フルオロ－Ｎ－ヒドロキシ－６－（トリフルオロメチル）ベンズイミドイル　クロリドのＤＭＦ溶液（６ｍＬ、約６mmol）を室温で加え、終夜撹拌した。反応溶液に１０％ＫＨＳＯ４水溶液を加え、酢酸エチルにて抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール）で精製し、（Ｅ）－５－クロロ－６－（４－((２－フルオロ－６－（トリフルオロメチル）フェニル)（ヒドロキシイミノ）メチル)ピペラジン－１－イル）ニコチン酸（化合物０１２（Ｅ）；１２５８ｍｇ；LC-MS: r.t. 2.45 min., m/z 447 (M+1)）とそのＺ異性体（化合物０１２（Ｚ）；９３ｍｇ；LC-MS: r.t. 2.26 min., m/z 447 (M+1)）を得た。 Step 1-3
2-Fluoro from step 1-2 in a solution of 5-chloro-6- (piperazine-1-yl) nicotinate (1836 mg, 6.6 mmol) and triethylamine (2.93 mL, 21 mmol) in dichloromethane (10 mL). A DMF solution of -N-hydroxy-6- (trifluoromethyl) benzimideyl chloride (6 mL, about 6 mmol) was added at room temperature and stirred overnight. Aqueous 10% KHSO 4 was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried with magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography for preparative use (ethyl acetate / methanol). -Fluoro-6- (trifluoromethyl) phenyl) (hydroxyimino) methyl) piperazin-1-yl) nicotinic acid (Compound 012 (E); 1258 mg; LC-MS: rt 2.45 min., M / z 447 (M) +1)) and its Z isomer (Compound 012 (Z); 93 mg; LC-MS: rt 2.26 min., M / z 447 (M + 1)) were obtained.
　ステップ１－４
　（Ｅ）－５－クロロ－６－（４－((２－フルオロ－６－（トリフルオロメチル）フェニル)（ヒドロキシイミノ）メチル)ピペラジン－１－イル）ニコチン酸（１０２６ｍｇ）の２Ｎ水酸化カリウム水溶液（６ｍＬ）とジオキサン（１８ｍＬ）との混合溶液を１０５℃で３時間撹拌加熱した。ＬＣ／ＭＳ分析では変換率は１００％を示した。溶液を減圧濃縮し２Ｎ塩酸水溶液で中和し、得られた個体を濾取した。これを乾燥し８７６ｍｇの表題化合物を得た。
(Rf = 0.5, ethyl acetate)
１H NMR (DMSO, 400 MHz)δ8.68 (d, 1 H, J = 1.6 Hz), 8.06 - 8.11 (m, 2 H), 7.83 - 7.88 (m, 2 H), 3.59 - 3.64 (m, 4 H), 3.33 - 3.38 (m, 4H), LC-MS: r.t. 3.23 min., m/z 427 (M+1)。 Step 1-4
(E) -5-Chloro-6-(4-((2-fluoro-6- (trifluoromethyl) phenyl) (hydroxyimino) methyl) piperazine-1-yl) nicotinic acid (1026 mg) 2N potassium hydroxide A mixed solution of an aqueous solution (6 mL) and dioxane (18 mL) was stirred and heated at 105 ° C. for 3 hours. LC / MS analysis showed a conversion rate of 100%. The solution was concentrated under reduced pressure, neutralized with a 2N aqueous hydrochloric acid solution, and the obtained solid was collected by filtration. This was dried to give 876 mg of the title compound.
(Rf = 0.5, ethyl acetate)
1 1 H NMR (DMSO, 400 MHz) δ8.68 (d, 1 H, J = 1.6 Hz), 8.06 --8.11 (m, 2 H), 7.83 --7.88 (m, 2 H), 3.59 --3.64 (m, 4 H), 3.33 --3.38 (m, 4H), LC-MS: rt 3.23 min., M / z 427 (M + 1).
　［実施例２］
５－クロロ－Ｎ－メチル－６－（４－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチンアミド（化合物０２１）の合成
Figure JPOXMLDOC01-appb-C000044
 [Example 2]
Synthesis of 5-chloro-N-methyl-6- (4- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperazine-1-yl) nicotinamide (Compound 021)
Figure JPOXMLDOC01-appb-C000044
　５－クロロ－６－（４－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸（実施例１の化合物、２２．５ｍｇ、０．０５３mmol）、トリエチルアミン（２９．４μＬ、０．２１１mmol）、１‐［ジメチルアミノ（ジメチルイミニオ）メチル］‐１Ｈ‐１，２，３‐トリアゾロ［４，５‐ｂ］ピリジン３‐オキシド・ヘキサフルオロホスファート（以下、ＨＡＴＵと称することがある）（４０．１ｍｇ、０．１０５mmol）とメチルアミン（０．２mmol）のＴＨＦ（０．５ｍＬ）溶液を室温で終夜撹拌した。溶液を濃縮し、残渣を分取用液体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２０．８ｍｇの表題化合物を得た。
（Rf = 0.5, 1 : 2 hexane/ethyl acetate）
１H NMR (CDCl３, 400 MHz)δ8.52 (d, 1 H, J = 2.0 Hz), 8.04 (d, 1 H, J = 2.0 Hz), 7.73 (d, 1 H, J = 7.2 Hz), 7.63 (dd, 1 H, J = 7.6, 8.8 Hz), 7.64 (bs, 1 H), 6.10 (br, 1 H), 3.67 - 3.72 (m, 4 H), 3.44 - 3.48 (m, 4H), 3.02 (d, 3 H, J = 6.8 Hz), LC-MS: r.t. 2.84 min., m/z 440 (M+1)。 5-Chloro-6- (4- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperazin-1-yl) nicotinic acid (compound of Example 1, 22.5 mg, 0.053 mmol) ), Triethylamine (29.4 μL, 0.211 mmol), 1- [dimethylamino (dimethyliminio) methyl] -1H-1,2,3-triazolo [4,5-b] pyridine 3-oxide hexafluorophos A solution of fert (hereinafter sometimes referred to as HATU) (40.1 mg, 0.105 mmol) and methylamine (0.2 mmol) in THF (0.5 mL) was stirred overnight at room temperature. The solution was concentrated and the residue was purified by preparative liquid silica gel chromatography (hexane / ethyl acetate) to give 20.8 mg of the title compound.
(Rf = 0.5, 1: 2 hexane / ethyl acetate)
1 H NMR (CDCl 3 , 400 MHz) δ8.52 (d, 1 H, J = 2.0 Hz), 8.04 (d, 1 H, J = 2.0 Hz), 7.73 (d, 1 H, J = 7.2 Hz) , 7.63 (dd, 1 H, J = 7.6, 8.8 Hz), 7.64 (bs, 1 H), 6.10 (br, 1 H), 3.67 --3.72 (m, 4 H), 3.44 --3.48 (m, 4H) , 3.02 (d, 3 H, J = 6.8 Hz), LC-MS: rt 2.84 min., M / z 440 (M + 1).
　［実施例３］
（Ｓ）－５－クロロ－６－（３－メチル－４－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸（化合物０３１）の合成
Figure JPOXMLDOC01-appb-C000045
 [Example 3]
Synthesis of (S) -5-chloro-6- (3-methyl-4- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperazine-1-yl) nicotinic acid (Compound 031)
Figure JPOXMLDOC01-appb-C000045
　（Ｓ）－２－メチルピペラジン（１．００２ｇ、１０mmol）、５，６－ジクロロニコチン酸（１．９２ｇ、１０mmol）とＮ－エチル－Ｎ－イソプロピルプロパン－２－アミン（３．４８mＬ、２０mmol）のＤＭＦ（２０ｍＬ）の溶液を９０℃で１０時間加熱撹拌した。精製水で希釈後１０％ＫＨＳＯ４で中和してpHを約６にし、生成した固体を濾取、減圧乾燥し、４２９ｍｇの粗（Ｓ）－５－クロロ－６－（３－メチルピペラジン－１－イル）ニコチン酸を得た。これを精製することなしに次のステップに用いた。 (S) -2-Methylpiperazine (1.002 g, 10 mmol), 5,6-dichloronicotinic acid (1.92 g, 10 mmol) and N-ethyl-N-isopropylpropan-2-amine (3.48 mL, 20 mmol). The solution of DMF (20 mL) was heated and stirred at 90 ° C. for 10 hours. After diluting with purified water, neutralize with 10% KHSO 4 to adjust the pH to about 6, and the resulting solid was collected by filtration, dried under reduced pressure, and 429 mg of crude (S) -5-chloro-6- (3-methylpiperazine-) 1-Il) Nicotinic acid was obtained. It was used in the next step without purification.
　５－クロロ－６－（ピペラジン－１－イル）ニコチン酸塩酸塩に代えて、得られた粗（Ｓ）－５－クロロ－６－（３－メチルピペラジン－１－イル）ニコチン酸を用いた以外は、実施例１のステップ１－３およびステップ１－４の方法に従って、表題化合物を得た。(Rf = 0.25, 2 : 1 ethyl acetate/hexane).１H NMR (DMSO, 400 MHz)δ8.70 (d, 1 H, J = 2.4 Hz), 8.11 (d, 1 H, J = 2.4 Hz), 8.10 (d, 1 H, J = 7.6 Hz), 7.85 (d, 1 H, J = 7.6 Hz), 7.83 (d, 1 H, J = 7.6 Hz), 3.64 - 3.90 (m, 3 H), 3.04 - 3.52 (m, 4H), 1.08 (d, 3 H, J = 6.0 Hz), LC-MS: r.t. 3.03 min., m/z 441 (M+1)。 The obtained crude (S) -5-chloro-6- (3-methylpiperazine-1-yl) nicotinic acid was used in place of 5-chloro-6- (piperazine-1-yl) nicotinate. Except for the above, title compounds were obtained according to the methods of Steps 1-3 and 1-4 of Example 1. (Rf = 0.25, 2: 1 ethyl acetate / hexane). 1 H NMR (DMSO, 400 MHz) δ8.70 (d, 1 H, J = 2.4 Hz), 8.11 (d, 1 H, J = 2.4 Hz) , 8.10 (d, 1 H, J = 7.6 Hz), 7.85 (d, 1 H, J = 7.6 Hz), 7.83 (d, 1 H, J = 7.6 Hz), 3.64 --3.90 (m, 3 H), 3.04 --3.52 (m, 4H), 1.08 (d, 3 H, J = 6.0 Hz), LC-MS: rt 3.03 min., M / z 441 (M + 1).
　［実施例４］
（Ｒ）－５－クロロ－６－（３－メチル－４－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸（化合物０４１）の合成
Figure JPOXMLDOC01-appb-C000046
 [Example 4]
Synthesis of (R) -5-chloro-6- (3-methyl-4- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperazine-1-yl) nicotinic acid (Compound 041)
Figure JPOXMLDOC01-appb-C000046
　（Ｓ）－２－メチルピペラジンに代えて（Ｒ）－２－メチルピペラジンを用いた以外は、実施例３の方法に従って、表題化合物を得た。
１H NMR (DMSO, 400 MHz)δ8.70 (d, 1 H, J = 2.4 Hz), 8.11 (d, 1 H, J = 2.4 Hz), 8.10 (d, 1 H, J = 7.6 Hz), 7.85 (d, 1 H, J = 7.6 Hz), 7.83 (d, 1 H, J = 7.6 Hz), 3.64 - 3.90 (m, 3 H), 3.04 - 3.52 (m, 4H), 1.08 (d, 3 H, J = 6.0 Hz), LC-MS: r.t. 3.03 min., m/z 441 (M+1)。 The title compound was obtained according to the method of Example 3 except that (R) -2-methylpiperazine was used instead of (S) -2-methylpiperazine.
1 H NMR (DMSO, 400 MHz) δ8.70 (d, 1 H, J = 2.4 Hz), 8.11 (d, 1 H, J = 2.4 Hz), 8.10 (d, 1 H, J = 7.6 Hz), 7.85 (d, 1 H, J = 7.6 Hz), 7.83 (d, 1 H, J = 7.6 Hz), 3.64 --3.90 (m, 3 H), 3.04 --3.52 (m, 4H), 1.08 (d, 3) H, J = 6.0 Hz), LC-MS: rt 3.03 min., M / z 441 (M + 1).
　［実施例５］
５－クロロ－６－（４－（４－（メトキシ）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸（化合物０５１）の合成
Figure JPOXMLDOC01-appb-C000047
 [Example 5]
Synthesis of 5-chloro-6- (4- (4- (methoxy) benzo [d] isooxazole-3-yl) piperazine-1-yl) nicotinic acid (Compound 051)
Figure JPOXMLDOC01-appb-C000047
　２－フルオロ－６－（トリフルオロメチル）ベンズアルデヒドに代えて２－フルオロ－６－（メトキシ）ベンズアルデヒドを用いた以外は、実施例１の方法に従って、表題化合物を得た。
Rf = 0.2, 10%methanol/ethyl acetate
１H NMR (DMSO, 400 MHz)δ8.69 (d, 1 H, J = 1.6 Hz), 8.11 (d, 1 H, J = 1.6 Hz), 7.54 (t, 1 H, J = 8.4 Hz), 7.16 (d, 1 H, J = 8.4 Hz), 6.84 (d, 1 H, J = 8.4 Hz), 3.96 (s, 3H), 3.77 (7et, 1 H, J = 5.6 Hz), 3.63 - 3.67 (m, 4 H), 3.52 - 3.56 (m, 4H), 1.03 (d, 6H, J = 5.6 Hz), LC-MS: r.t. 2.60 min., m/z 389 (M+1)。なお、合成の過程において、５－クロロ－６－（４－（（２－フルオロ－６－メトキシフェニル（ヒドロキシイミノ）メチル）ピペラジン－１－イル）ニコチン酸（化合物０５２）が得られた（LC-MS: r.t. 2.11 min., m/z 409 (M+1)）。 The title compound was obtained according to the method of Example 1 except that 2-fluoro-6- (methoxy) benzaldehyde was used instead of 2-fluoro-6- (trifluoromethyl) benzaldehyde.
Rf = 0.2, 10% methanol / ethyl acetate
1 H NMR (DMSO, 400 MHz) δ8.69 (d, 1 H, J = 1.6 Hz), 8.11 (d, 1 H, J = 1.6 Hz), 7.54 (t, 1 H, J = 8.4 Hz), 7.16 (d, 1 H, J = 8.4 Hz), 6.84 (d, 1 H, J = 8.4 Hz), 3.96 (s, 3H), 3.77 (7et, 1 H, J = 5.6 Hz), 3.63 --3.67 ( m, 4 H), 3.52 --3.56 (m, 4H), 1.03 (d, 6H, J = 5.6 Hz), LC-MS: rt 2.60 min., M / z 389 (M + 1). In the process of synthesis, 5-chloro-6- (4-((2-fluoro-6-methoxyphenyl (hydroxyimino) methyl) piperazine-1-yl) nicotinic acid (Compound 052) was obtained (LC). -MS: rt 2.11 min., m / z 409 (M + 1)).
　［実施例６］
４－クロロ－３－（４－（２－クロロフェニル）ピペラジン－１－イル）ベンゾ[ｄ]イソオキサゾール（化合物０６１）の合成
Figure JPOXMLDOC01-appb-C000048
 [Example 6]
Synthesis of 4-chloro-3- (4- (2-chlorophenyl) piperazine-1-yl) benzo [d] isooxazole (Compound 061)
Figure JPOXMLDOC01-appb-C000048
　ステップ６－１
　２－フルオロ－６－（トリフルオロメチル）ベンズアルデヒドに代えて２，６－ジクロロベンズアルデヒドを用いた以外は、実施例１のステップ１－１および１－２の方法に従って、２，６－ジクロロ－Ｎ－ヒドロキシ－６－ベンズイミドイル　クロリドのＤＭＦ溶液を得た。 Step 6-1
2,6-dichloro-N according to the methods of steps 1-1 and 1-2 of Example 1, except that 2,6-dichlorobenzaldehyde was used instead of 2-fluoro-6- (trifluoromethyl) benzaldehyde. A DMF solution of -hydroxy-6-benzimideyl chloride was obtained.
　ステップ６－２
１－（２－クロロフェニル）ピペラジン（１１８ｍｇ、０．６mmol）とトリエチルアミン（８３μL、０．６mmol）のジクロロメタン（２ｍL）の溶液に、ステップ６－１の２，６－ジクロロ－Ｎ－ヒドロキシ－６－ベンズイミドイル　クロリドのＤＭＦ溶液（０．５ｍＬ、約０．５mmol）を室温で加え、３時間撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール）で精製し、（Ｅ）－（４－(２－クロロフェニル)ピペラジン－１－イル）(２，６－ジクロロフェニル)メタノン　オキシム（５８．７ｍｇ）とＺ異性体（５０ｍｇ）を得た。 Step 6-2
In a solution of 1- (2-chlorophenyl) piperazine (118 mg, 0.6 mmol) and triethylamine (83 μL, 0.6 mmol) in dichloromethane (2 mL), step 6-1 2,6-dichloro-N-hydroxy-6- A DMF solution of benzimideyl chloride (0.5 mL, about 0.5 mmol) was added at room temperature and stirred for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / methanol) for preparative use. (Il) (2,6-dichlorophenyl) methane oxime (58.7 mg) and Z isomer (50 mg) were obtained.
（Ｅ）－（４－(２－クロロフェニル)ピペラジン－１－イル）(２，６－ジクロロフェニル)メタノン　オキシム（化合物０６２（Ｅ））：
Rf: 0.5, 3 : 1 hexane/ethyl acetate,
１H NMR (CDCl３, 400 MHz)δ7.41 (d, 1 H, J = 1.6 Hz), 7.39 (s, 1 H), 7.36 (dd, 1 H, J =1.6, 8.0 Hz), 7.30 (dd, 1 H, J =7.2, 8.8 Hz), 7.21 (dd, 1H, J =1.2, 7.2 Hz), 7.03 (dd, 1H, J = 2.0, 8.0 Hz), 6.98 (dt, 1 H, J =1.2, 8.0 Hz), 5.72 (br, 1 H), 3.35 - 3.40 (m, 4 H), 3.04 - 3.09 (m, 4H), LC-MS: r.t. 3.03 min., m/z 384 (M+1)。
（Ｚ）－（４－(２－クロロフェニル)ピペラジン－１－イル）(２，６－ジクロロフェニル)メタノン　オキシム（化合物０６２（Ｚ））：
Rf: 0.3, 3 : 1 hexane/ethyl acetate
１H NMR (CDCl３, 400 MHz)δ7.36 (dd, 1 H, J = 1.2, 7.2 Hz), 7.35 (d, 1 H, J = 1.2, 8.0 Hz), 7.26 (dd, 1 H, J = 1.2, 8.0 Hz), 7.28 (dd, 1 H, J = 2.0, 8.0 Hz), 7.22 (dt, 1H, J = 1.2, 7.2 Hz), 7.04 (dd, 1H, J = 8.0 Hz), 6.97 (dt, 1 H, J = 1.2, 8.0 Hz), 6.46 (br, 1 H), 3.53 - 3.57 (m, 4 H), 3.09 - 3.13 (m, 4H), LC-MS : r.t. 3.03 min., m/z 384 (M+1)。 (E)-(4- (2-Chlorophenyl) piperazine-1-yl) (2,6-dichlorophenyl) methanone oxime (Compound 062 (E)):
Rf: 0.5, 3: 1 hexane / ethyl acetate,
1 1 H NMR (CDCl 3 , 400 MHz) δ7.41 (d, 1 H, J = 1.6 Hz), 7.39 (s, 1 H), 7.36 (dd, 1 H, J = 1.6, 8.0 Hz), 7.30 ( dd, 1 H, J = 7.2, 8.8 Hz), 7.21 (dd, 1H, J = 1.2, 7.2 Hz), 7.03 (dd, 1H, J = 2.0, 8.0 Hz), 6.98 (dt, 1 H, J = 1.2, 8.0 Hz), 5.72 (br, 1 H), 3.35 --3.40 (m, 4 H), 3.04 --3.09 (m, 4H), LC-MS: rt 3.03 min., M / z 384 (M + 1) ).
(Z)-(4- (2-chlorophenyl) piperazine-1-yl) (2,6-dichlorophenyl) methanone oxime (Compound 062 (Z)):
Rf: 0.3, 3: 1 hexane / ethyl acetate
1 H NMR (CDCl 3 , 400 MHz) δ7.36 (dd, 1 H, J = 1.2, 7.2 Hz), 7.35 (d, 1 H, J = 1.2, 8.0 Hz), 7.26 (dd, 1 H, J = 1.2, 8.0 Hz), 7.28 (dd, 1 H, J = 2.0, 8.0 Hz), 7.22 (dt, 1H, J = 1.2, 7.2 Hz), 7.04 (dd, 1H, J = 8.0 Hz), 6.97 ( dt, 1 H, J = 1.2, 8.0 Hz), 6.46 (br, 1 H), 3.53 --3.57 (m, 4 H), 3.09 --3.13 (m, 4H), LC-MS: rt 3.03 min., M / z 384 (M + 1).
　ステップ６－３
　（Ｅ）－（４－(２－クロロフェニル)ピペラジン－１－イル）(２，６－ジクロロフェニル)メタノン　オキシム（５８．７ｍｇ、０．１５２mmol）の２Ｎ水酸化カリウム水溶液（１ｍＬ）とジオキサン（３ｍＬ）との混合溶液を１２０℃で２５時間撹拌加熱した。溶液を減圧濃縮し２Ｎ塩酸水溶液で中和し、酢酸エチルにて抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール）で精製し６．９ｍｇの表題化合物を得た。
１H NMR (CDCl３, 400 MHz)δ7.42 (t, J = 8.0 Hz), 7.37 - 7.41 (m, 2 H), 7.44-7.52 (m, 2H), 7.21 - 7.27 (m, 2H), 7.11 (dd, 1 H, J = 1.6, 8.0 Hz), 7.00 (dt, 1 H, J = 1.6, 8.0 Hz), 3.60 - 3.67 (m, 4 H), 3.26 - 3.30 (m, 4H), LC-MS: r.t. 3.01 min., m/z 384 (M+1)。 Step 6-3
(E)-(4- (2-Chlorophenyl) piperazine-1-yl) (2,6-dichlorophenyl) methanone oxime (58.7 mg, 0.152 mmol) in 2N potassium hydroxide aqueous solution (1 mL) and dioxane (3 mL) The mixed solution with was stirred and heated at 120 ° C. for 25 hours. The solution was concentrated under reduced pressure, neutralized with 2N aqueous hydrochloric acid solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography for preparative use (ethyl acetate / methanol) to give 6.9 mg of the title compound.
1 1 H NMR (CDCl 3 , 400 MHz) δ7.42 (t, J = 8.0 Hz), 7.37 --7.41 (m, 2 H), 7.44-7.52 (m, 2H), 7.21 --7.27 (m, 2H), 7.11 (dd, 1 H, J = 1.6, 8.0 Hz), 7.00 (dt, 1 H, J = 1.6, 8.0 Hz), 3.60 --3.67 (m, 4 H), 3.26 --3.30 (m, 4H), LC -MS: rt 3.01 min., M / z 384 (M + 1).
　［実施例７］
４－クロロ－３－（４－（３－クロロピリジン－２－イル）ピペラジン－１－イル）ベンゾ[ｄ]イソオキサゾール（化合物０７１）の合成
Figure JPOXMLDOC01-appb-C000049
 [Example 7]
Synthesis of 4-chloro-3- (4- (3-chloropyridin-2-yl) piperazine-1-yl) benzo [d] isooxazole (Compound 071)
Figure JPOXMLDOC01-appb-C000049
　ステップ７－１
　１－（２－クロロフェニル）ピペラジンに代えて１－（３－クロロピリジン－２－イル）ピペラジン塩酸塩を用いたこと以外は、実施例６のステップ６－２の方法に従って、（Ｅ）－（４－(３－クロロピリジン－２－イル)ピペラジン－１－イル）(２，６－ジクロロフェニル)メタノン　オキシムとＺ異性体を得た。
（Ｅ）－（４－(３－クロロピリジン－２－イル)ピペラジン－１－イル）(２，６－ジクロロフェニル)メタノン　オキシム（化合物０７２（Ｅ））：
１H NMR (CDCl３, 400 MHz)δ8.17 (dd, 1 H, J = 1.6, 4.8 Hz), 7.58 (dd, 1 H, J = 1.2, 7.6 Hz), 7.39 (dd, 1 H, J =1.2, 7.6 Hz), 7.33 (s, 1 H), 7.28 (dd, 1H, J = 7.6, 9.2 Hz), 7.06 (br, 1H), 6.85 (dd, 1 H, J =4.8, 8.0 Hz), 5.72 (br, 1 H), 3.25 - 3.34 (m, 8 H), LC-MS: r.t. 3.03 min., m/z 384 (M+1)。（Ｚ）－（４－(３－クロロピリジン－２－イル)ピペラジン－１－イル）(２，６－ジクロロフェニル)メタノン　オキシム（化合物０７２（Ｚ））：
１H NMR (CDCl３, 400 MHz)δ8.18 (d, 1 H, J = 3.6 Hz), 7.57 (d, 1 H, J = 7.6 Hz), 7.38 (t, 1 H, J =8.0 Hz), 7.34 (d, 1 H, J = 7.6 Hz), 7.26 (t, 1H, J = 8.0 Hz), 7.08 (br, 1H), 6.84 (dd, 1 H, J =4.8, 8.0 Hz), 5.72 (br, 1 H), 3.52 - 3.58 (m, 3 H), 3.40 - 3.44 (m, 3 H), 3.35 - 3.38 (m, 2 H), LC-MS: r.t. 2.70 min., m/z 385 (M+1)。 Step 7-1
(E)-(Except that 1- (3-chloropyridin-2-yl) piperazine hydrochloride was used instead of 1- (2-chlorophenyl) piperazine, according to the method of step 6-2 of Example 6). 4- (3-Chloropyridin-2-yl) piperazine-1-yl) (2,6-dichlorophenyl) methanone oxime and Z isomer were obtained.
(E)-(4- (3-Chloropyridin-2-yl) piperazine-1-yl) (2,6-dichlorophenyl) methanone oxime (Compound 072 (E)):
1 1 H NMR (CDCl 3 , 400 MHz) δ8.17 (dd, 1 H, J = 1.6, 4.8 Hz), 7.58 (dd, 1 H, J = 1.2, 7.6 Hz), 7.39 (dd, 1 H, J = 1.2, 7.6 Hz), 7.33 (s, 1 H), 7.28 (dd, 1H, J = 7.6, 9.2 Hz), 7.06 (br, 1H), 6.85 (dd, 1 H, J = 4.8, 8.0 Hz) , 5.72 (br, 1 H), 3.25 --3.34 (m, 8 H), LC-MS: rt 3.03 min., M / z 384 (M + 1). (Z)-(4- (3-chloropyridin-2-yl) piperazine-1-yl) (2,6-dichlorophenyl) methanone oxime (Compound 072 (Z)):
1 1 H NMR (CDCl 3 , 400 MHz) δ8.18 (d, 1 H, J = 3.6 Hz), 7.57 (d, 1 H, J = 7.6 Hz), 7.38 (t, 1 H, J = 8.0 Hz) , 7.34 (d, 1 H, J = 7.6 Hz), 7.26 (t, 1H, J = 8.0 Hz), 7.08 (br, 1H), 6.84 (dd, 1 H, J = 4.8, 8.0 Hz), 5.72 ( br, 1 H), 3.52 --3.58 (m, 3 H), 3.40 --3.44 (m, 3 H), 3.35 --3.38 (m, 2 H), LC-MS: rt 2.70 min., M / z 385 ( M + 1).
　ステップ７－２
（Ｅ）－（４－(３－クロロピリジン－２－イル)ピペラジン－１－イル）(２，６－ジクロロフェニル)メタノン　オキシム（１９２ｍｇ、０．４９８mmol）の２Ｎ水酸化カリウム水溶液（２ｍＬ）とジオキサン（６ｍＬ）との混合溶液をマイクロウェーブにて１２０℃で１時間撹拌加熱した。ＬＣ／ＭＳ分析では変換率は約５０％を示した。溶液を１Ｎ塩酸水溶液と飽和塩化アンモニウム水溶液で中和し、酢酸エチルにて抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール）で精製し７０．６ｍｇの表題化合物と７９ｍｇの出発物質を得た。
１H NMR (CDCl３, 400 MHz)δ7.42 (t, 1 H, J = 8.0 Hz), 7.37 - 7.41 (m, 2 H), 7.44-7.52 (m, 2H), 7.21 - 7.27 (m, 2H), 7.11 (dd, 1 H, J = 1.6, 8.0 Hz), 7.00 (dt, 1 H, J = 1.6, 8.0 Hz), 3.60 - 3.67 (m, 4 H), 3.26 - 3.30 (m, 4H), LC-MS: r.t. 3.01 min., m/z 384 (M+1)。 Step 7-2
(E)-(4- (3-Chloropyridin-2-yl) piperazine-1-yl) (2,6-dichlorophenyl) methanone oxime (192 mg, 0.498 mmol) in 2N potassium hydroxide aqueous solution (2 mL) and dioxane The mixed solution with (6 mL) was stirred and heated at 120 ° C. for 1 hour with a microwave. LC / MS analysis showed a conversion rate of about 50%. The solution was neutralized with 1N aqueous hydrochloric acid solution and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography for preparative use (ethyl acetate / methanol) to obtain 70.6 mg of the title compound and 79 mg of the starting material.
1 1 H NMR (CDCl 3 , 400 MHz) δ7.42 (t, 1 H, J = 8.0 Hz), 7.37 --7.41 (m, 2 H), 7.44-7.52 (m, 2H), 7.21 --7.27 (m, 2H), 7.11 (dd, 1 H, J = 1.6, 8.0 Hz), 7.00 (dt, 1 H, J = 1.6, 8.0 Hz), 3.60 --3.67 (m, 4 H), 3.26 --3.30 (m, 4H) ), LC-MS: rt 3.01 min., M / z 384 (M + 1).
　［実施例８］
５－クロロ－６－（４－（４－クロロベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸（化合物０８１）の合成
Figure JPOXMLDOC01-appb-C000050
 [Example 8]
Synthesis of 5-chloro-6- (4- (4-chlorobenzo [d] isooxazole-3-yl) piperazine-1-yl) nicotinic acid (Compound 081)
Figure JPOXMLDOC01-appb-C000050
　ステップ８－１
　１－（２－クロロフェニル）ピペラジンに代えて５－クロロ－６－（ピペラジン－１－イル）ニコチン酸トリフルオロ酢酸塩を用いたこと以外は、実施例６のステップ６－２の方法に従って、５－クロロ－６－（４－((２，６－ジクロロフェニル)（ヒドロキシイミノ）メチル)ピペラジン－１－イル）ニコチン酸（化合物０８２）を得た。 Step 8-1
5 according to the method of step 6-2 of Example 6, except that 5-chloro-6- (piperazine-1-yl) nicotinate trifluoroacetate was used instead of 1- (2-chlorophenyl) piperazine. -Chloro-6- (4-((2,6-dichlorophenyl) (hydroxyimino) methyl) piperazine-1-yl) nicotinic acid (Compound 082) was obtained.
　ステップ８－２
　５－クロロ－６－（４－((２，６－ジクロロフェニル)（ヒドロキシイミノ）メチル)ピペラジン－１－イル）ニコチン酸（２１５ｍｇ、０．５mmol）の２Ｎ水酸化カリウム水溶液（２ｍＬ）とジオキサン（６ｍＬ）との混合溶液をマイクロウェーブにて１４０℃で１時間撹拌加熱した。ＬＣ／ＭＳ分析では変換率は約９０％を示した。溶液を１Ｎ塩酸水溶液と１０％ＫＨＳＯ４水溶液で中和し、酢酸エチルにて抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール）で精製し７５ｍｇの表題化合物を得た。
１H NMR (DMSO, 400 MHz)δ8.66 (d, 1 H, J = 2.0 Hz), 8.08 (d, 1 H, J = 2.0 Hz), 7.63 (d, 1 H, J = 8.0 Hz), 7.60 (t, 1 H, J = 8.0 Hz), 7.42 (d, 1 H, J = 8.0 Hz), 3.63 - 3.67 (m, 4 H), 3.43 - 3.47 (m, 4H), LC-MS: r.t. 2.87 min., m/z 393 (M+1)。 Step 8-2
5-Chloro-6- (4-((2,6-dichlorophenyl) (hydroxyimino) methyl) piperazine-1-yl) nicotinic acid (215 mg, 0.5 mmol) in 2N potassium hydroxide aqueous solution (2 mL) and dioxane ( The mixed solution with 6 mL) was stirred and heated at 140 ° C. for 1 hour with a microwave. LC / MS analysis showed a conversion rate of about 90%. The solution was neutralized with 1N aqueous hydrochloric acid and aqueous 10% KHSO 4, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography for preparative use (ethyl acetate / methanol) to give 75 mg of the title compound.
1 H NMR (DMSO, 400 MHz) δ8.66 (d, 1 H, J = 2.0 Hz), 8.08 (d, 1 H, J = 2.0 Hz), 7.63 (d, 1 H, J = 8.0 Hz), 7.60 (t, 1 H, J = 8.0 Hz), 7.42 (d, 1 H, J = 8.0 Hz), 3.63 --3.67 (m, 4 H), 3.43 --3.47 (m, 4H), LC-MS: rt 2.87 min., M / z 393 (M + 1).
　［実施例９］
５－クロロ－６－（４－（４－クロロベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）Ｎ，Ｎ－ジメチルニコチンアミド（化合物０９１）の合成
Figure JPOXMLDOC01-appb-C000051
 [Example 9]
Synthesis of 5-chloro-6- (4- (4-chlorobenzo [d] isooxazole-3-yl) piperazine-1-yl) N, N-dimethylnicotinamide (Compound 091)
Figure JPOXMLDOC01-appb-C000051
　ステップ９－１
　６－（４－（tert－ブトキシカルボニル）ピペラジン－１－イル）－５－クロロニコンチン酸（１７１ｍｇ、０．５mmol）、ジメチルアミン（０．７５mmol）、トリエチルアミン（２０９μＬ、１．５mmol）とＨＡＴＵ（２８５ｍｇ、０．７５mmol）のＤＭＦ（３ｍＬ）溶液を室温で３時間撹拌し、飽和食塩水を加え酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィーで精製し１５３．２ｍｇのtert－ブチル　４－（３－クロロ－５－（ジメチルカルバモイル）ピリジン－２－イル）ピペラジン－１－カルボキシラートを得た(Rf = 0.45, 1 : 3 hexane/ethyl acetate)。
この化合物を過剰のトリフルオロ酢酸で処理し５－クロロ－Ｎ，Ｎ－ジメチル－６－（ピペラジン－１－イル）ニコチンアミド　トリフルオロ酢酸塩を得た。 Step 9-1
6- (4- (tert-butoxycarbonyl) piperazin-1-yl) -5-chloronicontinic acid (171 mg, 0.5 mmol), dimethylamine (0.75 mmol), triethylamine (209 μL, 1.5 mmol) and HATU A solution of (285 mg, 0.75 mmol) of DMF (3 mL) was stirred at room temperature for 3 hours, saturated brine was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography for preparative use to purify 153.2 mg of tert-butyl 4- (3-chloro-5- (dimethylcarbamoyl) pyridine-2). -Il) Piperazin-1-carboxylate was obtained (Rf = 0.45, 1: 3 hexane / ethyl acetate).
This compound was treated with excess trifluoroacetic acid to give 5-chloro-N, N-dimethyl-6- (piperazine-1-yl) nicotinamide trifluoroacetate.
　ステップ９－２
　５－クロロ－Ｎ，Ｎ－ジメチル－６－（ピペラジン－１－イル）ニコチンアミド（１５９ｍｇ、０．４１５mmol）とトリエチルアミン（２８９μL、２．０７５mmol）のＤＭＦ（２ｍL）の溶液に、実施例６のステップ６－１の２，６－ジクロロ－Ｎ－ヒドロキシ－６－ベンズイミドイル　クロリドのＤＭＦ溶液（０．５ｍＬ、約０．５mmol）を室温で加え、３時間撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／メタノール）で精製し、（Ｅ）－５－クロロ－６－（４－((２，６－ジクロロフェニル)（ヒドロキシイミノ）メチル)ピペラジン－１－イル）－Ｎ，Ｎ－ジメチルニコチンアミド（化合物０９２（Ｅ）；７７．２ｍｇ；LC-MS: r.t. 2.27 min., m/z 456 (M+1)）とＺ異性体（３０ｍｇ）を得た。（Ｚ）－５－クロロ－６－（４－((２，６－ジクロロフェニル)（ヒドロキシイミノ）メチル)ピペラジン－１－イル）－Ｎ，Ｎ－ジメチルニコチンアミド（化合物０９２（Ｚ））：
１H NMR (CDCl３, 400 MHz)δ8.24 (d, 1 H, J = 2.0 Hz), 7.72 (d, 1 H, J = 2.4 Hz), 7.39 (dd, 1 H, J = 0.8, 8.0 Hz), 7.38 (s, 1 H), 7.30 (dd, 1H, J = 4.8, 8.8 Hz), 6.20 (br, 1 H), 3.43 - 3.47 (m, 4 H), 3.32 - 3.36 (m, 4 H), 3.08 (s, 6 H), LC-MS: r.t. 2.08 min., m/z 456 (M+1)。 Step 9-2
Example 6 in a solution of 5-chloro-N, N-dimethyl-6- (piperazine-1-yl) nicotinamide (159 mg, 0.415 mmol) and triethylamine (289 μL, 2.075 mmol) in DMF (2 mL). A DMF solution (0.5 mL, about 0.5 mmol) of 2,6-dichloro-N-hydroxy-6-benzimideyl chloride from step 6-1 was added at room temperature and stirred for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography for preparative use (ethyl acetate / methanol). , 6-Dichlorophenyl) (Hydroxyimino) methyl) piperazin-1-yl) -N, N-dimethylnicotinamide (Compound 092 (E); 77.2 mg; LC-MS: rt 2.27 min., M / z 456 ( M + 1)) and Z isomer (30 mg) were obtained. (Z) -5-Chloro-6- (4-((2,6-dichlorophenyl) (hydroxyimino) methyl) piperazine-1-yl) -N, N-dimethylnicotinamide (Compound 092 (Z)):
1 H NMR (CDCl 3 , 400 MHz) δ8.24 (d, 1 H, J = 2.0 Hz), 7.72 (d, 1 H, J = 2.4 Hz), 7.39 (dd, 1 H, J = 0.8, 8.0 Hz), 7.38 (s, 1 H), 7.30 (dd, 1H, J = 4.8, 8.8 Hz), 6.20 (br, 1 H), 3.43 --3.47 (m, 4 H), 3.32 --3.36 (m, 4) H), 3.08 (s, 6 H), LC-MS: rt 2.08 min., M / z 456 (M + 1).
　ステップ９－３
　（Ｅ）－５－クロロ－６－（４－((２，６－ジクロロフェニル)（ヒドロキシイミノ）メチル)ピペラジン－１－イル）－Ｎ，Ｎ－ジメチルニコチンアミド（７７．２ｍｇ、０．０４８ｍｇ）の２Ｎ水酸化カリウム水溶液（２ｍＬ）とジオキサン（６ｍＬ）との混合溶液をマイクロウェーブにて１４０℃で１時間撹拌加熱した。ＬＣ／ＭＳ分析では変換率は約７０％を示した。溶液に１０％ＫＨＳＯ４水溶液を加え、酢酸エチルにて抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、得られた個体をイソプロパノールから再結晶し２０．２ｍｇの表題化合物を得た。
１H NMR (CDCl３, 400 MHz)δ8.28 (d, 1 H, J = 2.4 Hz), 7.74 (d, 1 H, J = 2.4 Hz), 7.42 (dd, 1 H, J = 6.8, 8.8 Hz), 7.39 (dd, 1 H, J = 1.2, 8.8 Hz), 7.26 (dd, 1 H, J = 1.2, 6.8 Hz), 3.64 - 3.68 (m, 4 H), 3.58 - 3.61 (m, 4H), LC-MS: r.t. 2.89 min., m/z 420 (M+1)。 Step 9-3
(E) -5-Chloro-6- (4-((2,6-dichlorophenyl) (hydroxyimino) methyl) piperazine-1-yl) -N, N-dimethylnicotinamide (77.2 mg, 0.048 mg) A mixed solution of 2N potassium hydroxide aqueous solution (2 mL) and dioxane (6 mL) was stirred and heated at 140 ° C. for 1 hour with a microwave. LC / MS analysis showed a conversion rate of about 70%. A 10% aqueous solution of KHSO 4 was added to the solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained solid was recrystallized from isopropanol to obtain 20.2 mg of the title compound.
1 1 H NMR (CDCl 3 , 400 MHz) δ8.28 (d, 1 H, J = 2.4 Hz), 7.74 (d, 1 H, J = 2.4 Hz), 7.42 (dd, 1 H, J = 6.8, 8.8 Hz), 7.39 (dd, 1 H, J = 1.2, 8.8 Hz), 7.26 (dd, 1 H, J = 1.2, 6.8 Hz), 3.64 --3.68 (m, 4 H), 3.58 --3.61 (m, 4H) ), LC-MS: rt 2.89 min., M / z 420 (M + 1).
　［実施例１０］
３－クロロ－４－（４－（４－クロロベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）安息香酸（化合物１０１）の合成
Figure JPOXMLDOC01-appb-C000052
 [Example 10]
Synthesis of 3-chloro-4- (4- (4-chlorobenzo [d] isooxazole-3-yl) piperazine-1-yl) benzoic acid (Compound 101)
Figure JPOXMLDOC01-appb-C000052
　ステップ１０－１
　１－（２－クロロフェニル）ピペラジンに代えて３－クロロ－４－（ピペラジン－１－イル）安息香酸メチルエステルを用いた以外は、実施例６のステップ６－２の方法に従って、３－クロロ－４－（４－((２，６－ジクロロフェニル)（ヒドロキシイミノ）メチル)ピペラジン－１－イル）安息香酸メチルエステル（化合物１０２）を得た（LC-MS: r.t. 2.97 min., m/z 442 (M+1)）。 Step 10-1
3-Chloro- according to the method of step 6-2 of Example 6, except that 3-chloro-4- (piperazine-1-yl) benzoate methyl ester was used instead of 1- (2-chlorophenyl) piperazine. 4- (4-((2,6-dichlorophenyl) (hydroxyimino) methyl) piperazine-1-yl) benzoate methyl ester (Compound 102) was obtained (LC-MS: rt 2.97 min., M / z 442). (M + 1)).
　ステップ１０－２
　５－クロロ－６－（４－((２、６－ジクロロフェニル)（ヒドロキシイミノ）メチル)ピペラジン－１－イル）ニコチン酸に代えて３－クロロ－４－（４－((２，６－ジクロロフェニル)（ヒドロキシイミノ）メチル)ピペラジン－１－イル）安息香酸メチルエステルを用いたこと以外は、実施例８のステップ８－２の方法に従って、表題化合物を得た。
１H NMR (DMSO, 400 MHz)δ7.85 (d, 1 H, J = 1.6 Hz), 7.79 (dd, 1 H, J = 1.6, 8.4 Hz), 7.67 (dd, 1 H, J = 1.6, 8.4 Hz), 7.63 (dd, 1 H, J = 7.2, 8.8 Hz), 7.45 (dd, 1 H, J = 1.2, 8.0 Hz), 7.22 (bd, 1 H, J = 8.0 Hz), 3.48 - 3.53 (m, 4 H), 3.24 - 3.28 (m, 4H), LC-MS: r.t. 2.94 min., m/z 392 (M-1)。 Step 10-2
5-Chloro-6- (4-((2,6-dichlorophenyl) (hydroxyimino) methyl) piperazine-1-yl) Instead of nicotinic acid, 3-chloro-4- (4-((2,6-dichlorophenyl) ) (Hydroxyimino) methyl) piperazine-1-yl) The title compound was obtained according to the method of step 8-2 of Example 8 except that methyl benzoate was used.
1 H NMR (DMSO, 400 MHz) δ7.85 (d, 1 H, J = 1.6 Hz), 7.79 (dd, 1 H, J = 1.6, 8.4 Hz), 7.67 (dd, 1 H, J = 1.6, 8.4 Hz), 7.63 (dd, 1 H, J = 7.2, 8.8 Hz), 7.45 (dd, 1 H, J = 1.2, 8.0 Hz), 7.22 (bd, 1 H, J = 8.0 Hz), 3.48 --3.53 (m, 4 H), 3.24 --3.28 (m, 4H), LC-MS: rt 2.94 min., m / z 392 (M-1).
　［実施例１１］
５－クロロ－３－（４－（３－クロロピリジン－２－イル）ピペラジン－１－イル）ベンゾ[ｄ]イソオキサゾール（化合物１１１）の合成
Figure JPOXMLDOC01-appb-C000053
 [Example 11]
Synthesis of 5-chloro-3- (4- (3-chloropyridin-2-yl) piperazine-1-yl) benzo [d] isooxazole (Compound 111)
Figure JPOXMLDOC01-appb-C000053
　ステップ１１－１
　２－フルオロ－６－（トリフルオロメチル）ベンズアルデヒドに代えて２，５－ジクロロベンズアルデヒドを用いたこと以外は、実施例１のステップ１－１および１－２の方法に従って２，５－ジクロロ－Ｎ－ヒドロキシ－６－ベンズイミドイル　クロリドのＤＭＦ溶液を得た。 Step 11-1
2,5-Dichloro-N according to the methods of steps 1-1 and 1-2 of Example 1, except that 2,5-dichlorobenzaldehyde was used instead of 2-fluoro-6- (trifluoromethyl) benzaldehyde. A DMF solution of -hydroxy-6-benzimideyl chloride was obtained.
　ステップ１１－２
　１－（２－クロロフェニル）ピペラジンに代えて１－（３－クロロピリジン－２－イル）ピペラジン塩酸塩を用いたこと、および２，６－ジクロロ－Ｎ－ヒドロキシ－６－ベンズイミドイル　クロリドのＤＭＦ溶液に代えて２，５－ジクロロ－Ｎ－ヒドロキシ－６－ベンズイミドイル　クロリドのＤＭＦ溶液を用いたこと以外は、実施例６のステップ６－２の方法に従って、（Ｅ）－４－(３－クロロピリジン－２－イル)ピペラジン－１－イル）(２，５－ジクロロフェニル)メタノン　オキシム、そのＺ異性体とＥ，Ｚ混合物を得た。
（Ｅ）－４－(３－クロロピリジン－２－イル)ピペラジン－１－イル）(２，５－ジクロロフェニル)メタノン　オキシム（化合物１１２（Ｅ））：
１H NMR (CDCl３, 400 MHz)δ8.18 (dd, 1 H, J = 1.2, 4.8 Hz), 7.59 (dd, 1 H, J = 2.0. 8.0 Hz), 7.40 (d, 1 H, J = 8.0 Hz), 7.33 (dd, 1H, J = 4.8, 8.0 Hz), 5.83 (br, 1 H), 3.29 - 3.37 (m, 6 H), 3.18 - 3.25 (m, 2 H), LC-MS: r.t. 2.83 min., m/z 385 (M+1)。
（Ｚ）－４－(３－クロロピリジン－２－イル)ピペラジン－１－イル）(２，５－ジクロロフェニル)メタノン　オキシム（化合物１１２（Ｚ））：
１H NMR (CDCl３, 400 MHz)δ8.40 (br, 1 H), 8.17 (dd, 1 H, J = 1.6, 4.8 Hz), 7.57 (dd, 1 H, J = 2.0. 7.6 Hz), 7.41 (d, 1 H, J =2.0 Hz), 7.32 (s, 1 H), 7.31 (d, 1H, J = 2.4 Hz), 6.83 (dd, 1 H, J = 4.8, 8.0 Hz), 3.47 - 3.52 (m, 4 H), 3.36 - 3.41 (m, 4 H), LC-MS: r.t. 2.83 min., m/z 385 (M+1)。 Step 11-2
The use of 1- (3-chloropyridin-2-yl) piperazine hydrochloride in place of 1- (2-chlorophenyl) piperazine and the solution of 2,6-dichloro-N-hydroxy-6-benzimideyl chloride to the DMF solution. (E) -4- (3-chloropyridin-) according to the method of step 6-2 of Example 6, except that a DMF solution of 2,5-dichloro-N-hydroxy-6-benzimideyl chloride was used instead. 2-Il) piperazin-1-yl) (2,5-dichlorophenyl) methanone oxime, its Z isomer and E, Z mixture were obtained.
(E) -4- (3-chloropyridin-2-yl) piperazine-1-yl) (2,5-dichlorophenyl) methanone oxime (Compound 112 (E)):
1 1 H NMR (CDCl 3 , 400 MHz) δ8.18 (dd, 1 H, J = 1.2, 4.8 Hz), 7.59 (dd, 1 H, J = 2.0. 8.0 Hz), 7.40 (d, 1 H, J = 8.0 Hz), 7.33 (dd, 1H, J = 4.8, 8.0 Hz), 5.83 (br, 1 H), 3.29 --3.37 (m, 6 H), 3.18 --3.25 (m, 2 H), LC-MS : rt 2.83 min., m / z 385 (M + 1).
(Z) -4- (3-chloropyridin-2-yl) piperazine-1-yl) (2,5-dichlorophenyl) methanone oxime (Compound 112 (Z)):
1 1 H NMR (CDCl 3 , 400 MHz) δ8.40 (br, 1 H), 8.17 (dd, 1 H, J = 1.6, 4.8 Hz), 7.57 (dd, 1 H, J = 2.0. 7.6 Hz), 7.41 (d, 1 H, J = 2.0 Hz), 7.32 (s, 1 H), 7.31 (d, 1H, J = 2.4 Hz), 6.83 (dd, 1 H, J = 4.8, 8.0 Hz), 3.47- 3.52 (m, 4 H), 3.36 --3.41 (m, 4 H), LC-MS: rt 2.83 min., M / z 385 (M + 1).
　ステップ１１－３
　（Ｅ）－（４－(３－クロロピリジン－２－イル)ピペラジン－１－イル）(２，５－ジクロロフェニル)メタノン　オキシム（２６．８ｍｇ、０．０６９mmol）の２Ｎ水酸化カリウム水溶液（１ｍＬ）とジオキサン（３ｍＬ）との混合溶液をマイクロウェーブにて１２０℃で０．５時間続いて１４０℃で１時間撹拌加熱した。溶液を１Ｎ塩酸水溶液と飽和塩化アンモニウム水溶液で中和し、酢酸エチルにて抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し１７．６ｍｇの表題化合物を得た。
１H NMR (CDCl３, 400 MHz)δ8.2 (dd, 1 H, J = 1.6, 4.8 Hz), 7.71 (d, 1 H, J = 1.6 Hz), 7.63 (dd, 1 H, J = 1.2, 8.0 Hz), 7.46 (dd, 1 H, J = 2.0, 8.4 Hz), 7.40 (d, 1 H, 8.4 Hz), 6.90 (dd, 1 H, J = 4.8, 8.0 Hz), 3.68 - 3.72 (m, 4 H), 3.55 - 3.59 (m, 4H), LC-MS: r.t. 3.18 min., m/z 349 (M+1)。 Step 11-3
(E)-(4- (3-Chloropyridin-2-yl) piperazine-1-yl) (2,5-dichlorophenyl) methanone oxime (26.8 mg, 0.069 mmol) in 2N potassium hydroxide aqueous solution (1 mL) The mixed solution of dioxane (3 mL) and dioxane (3 mL) was stirred and heated at 120 ° C. for 0.5 hours and then at 140 ° C. for 1 hour by microwave. The solution was neutralized with 1N aqueous hydrochloric acid solution and saturated aqueous ammonium chloride solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) for preparative use to obtain 17.6 mg of the title compound.
1 1 H NMR (CDCl 3 , 400 MHz) δ8.2 (dd, 1 H, J = 1.6, 4.8 Hz), 7.71 (d, 1 H, J = 1.6 Hz), 7.63 (dd, 1 H, J = 1.2) , 8.0 Hz), 7.46 (dd, 1 H, J = 2.0, 8.4 Hz), 7.40 (d, 1 H, 8.4 Hz), 6.90 (dd, 1 H, J = 4.8, 8.0 Hz), 3.68 --3.72 ( m, 4 H), 3.55 --3.59 (m, 4H), LC-MS: rt 3.18 min., m / z 349 (M + 1).
　［実施例１２］
５－クロロ－６－（４－（５－クロロベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸（化合物１２１）の合成
Figure JPOXMLDOC01-appb-C000054
 [Example 12]
Synthesis of 5-chloro-6- (4- (5-chlorobenzo [d] isooxazole-3-yl) piperazine-1-yl) nicotinic acid (Compound 121)
Figure JPOXMLDOC01-appb-C000054
　ステップ１２－１
　１－（２－クロロフェニル）ピペラジンに代えて５－クロロ－６－（ピペラジン－１－イル）ニコチン酸塩酸塩を用いたこと、および２，６－ジクロロ－Ｎ－ヒドロキシ－６－ベンズイミドイル　クロリドのＤＭＦ溶液に代えて２，５－ジクロロ－Ｎ－ヒドロキシ－６－ベンズイミドイル　クロリドのＤＭＦ溶液を用いたこと以外は、実施例６のステップ６－２の方法に従って、５－クロロ－６－（４－((２，５－ジクロロフェニル)（ヒドロキシイミノ）メチル)ピペラジン－１－イル）ニコチン酸（化合物１２２）を得た（LC-MS: r.t. 2.46 min., m/z 429 (M+1)）。 Step 12-1
The use of 5-chloro-6- (piperazine-1-yl) nicotinate salt instead of 1- (2-chlorophenyl) piperazine, and the DMF of 2,6-dichloro-N-hydroxy-6-benzimideyl chloride. 5-Chloro-6- (4-(4-(4), according to the method of step 6-2 of Example 6, except that a DMF solution of 2,5-dichloro-N-hydroxy-6-benzimideyl chloride was used instead of the solution. (2,5-dichlorophenyl) (hydroxyimino) methyl) piperazine-1-yl) nicotinic acid (Compound 122) was obtained (LC-MS: rt 2.46 min., M / z 429 (M + 1)).
　ステップ１２－２
　５－クロロ－６－（４－((２，５－ジクロロフェニル)（ヒドロキシイミノ）メチル)ピペラジン－１－イル）ニコチン酸（１１５．１ｍｇ、０．５mmol）の２Ｎ水酸化カリウム水溶液（２ｍＬ）とジオキサン（６ｍＬ）との混合溶液をマイクロウェーブにて１４０℃で２時間撹拌加熱した。ＬＣ／ＭＳ分析では変換率は約１００％を示した。溶液を１Ｎ塩酸水溶液と１０％ＫＨＳＯ４水溶液で中和し、酢酸エチルにて抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣をイソプロパノールから再結晶し２６．８ｍｇの表題化合物を得た。
１H NMR (DMSO, 400 MHz)δ8.65 (d, 1 H, J = 2.0 Hz), 8.17 (bs, 1 H), 8.08 (d, 1 H, J = 1.6 Hz), 7.60 - 7.61 (m, 2 H), 3.59 - 3.61 (m, 4 H), 3.25 - 3.35 (m, 4H), LC-MS: r.t. 2.83 min., m/z 393 (M+1)。 Step 12-2
5-Chloro-6- (4-((2,5-dichlorophenyl) (hydroxyimino) methyl) piperazine-1-yl) with nicotinic acid (115.1 mg, 0.5 mmol) in 2N potassium hydroxide aqueous solution (2 mL) The mixed solution with dioxane (6 mL) was stirred and heated at 140 ° C. for 2 hours with a microwave. LC / MS analysis showed a conversion rate of about 100%. The solution was neutralized with 1N aqueous hydrochloric acid and aqueous 10% KHSO 4, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was recrystallized from isopropanol to give 26.8 mg of the title compound.
1 1 H NMR (DMSO, 400 MHz) δ8.65 (d, 1 H, J = 2.0 Hz), 8.17 (bs, 1 H), 8.08 (d, 1 H, J = 1.6 Hz), 7.60 --7.61 (m) , 2 H), 3.59 --3.61 (m, 4 H), 3.25 --3.35 (m, 4H), LC-MS: rt 2.83 min., m / z 393 (M + 1).
　［実施例１３］
５－クロロ－６－（４－（５－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸（化合物１３１）の合成
Figure JPOXMLDOC01-appb-C000055
 [Example 13]
Synthesis of 5-chloro-6- (4- (5- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperazine-1-yl) nicotinic acid (Compound 131)
Figure JPOXMLDOC01-appb-C000055
　ステップ１３－１
　２－クロロ－５－（トリフルオロメチル）ベンズアルデヒド（５ｇ、２３．９７mmol）とヒドロキシアミン塩酸塩（２ｇ、２８．８mmol）のエタノール（２０mL）の溶液に１N水酸化ナトリウム水溶液（２８．８mL、２８．８mmol）を加え、室温で３時間撹拌した。反応液を減圧濃縮し、酢酸エチルにて抽出した。有機層を水、飽和食塩水にて洗浄後、硫酸マグネシウムで乾燥、溶媒を減圧留去し、２－クロロ－５－（トリフルオロメチル）ベンズアルデヒド　オキシム（４．７７ｇ）をＺとＥの異性体の混合物として得た。 Step 13-1
1N aqueous sodium hydroxide solution (28.8 mL, 28) in a solution of 2-chloro-5- (trifluoromethyl) benzaldehyde (5 g, 23.97 mmol) and hydroxyamine hydrochloride (2 g, 28.8 mmol) in ethanol (20 mL). 8. mmol) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and 2-chloro-5- (trifluoromethyl) benzaldehyde oxime (4.77 g) was added as an isomer of Z and E. Obtained as a mixture of.
　ステップ１３－２
　２－クロロ－５－（トリフルオロメチル）ベンズアルデヒドオキシム（４．７７ｇ、２１．３３mmol）のDMF（１０mL）の溶液にNCS（N-クロロスクシンイミド）（２．９９ｇ、２２．４mmol）を０℃で加え、室温で終夜撹拌した。LC/MSはオキシムが１００％塩化物に変換したことを示した。２－クロロ－Ｎ－ヒドロキシ－６－（トリフルオロメチル）ベンズイミドイル　クロリドの溶液は精製することなしに次の反応に用いた。 Step 13-2
NCS (N-Chlorosuccinimide) (2.99 g, 22.4 mmol) in a solution of 2-chloro-5- (trifluoromethyl) benzaldehyde oxime (4.77 g, 21.33 mmol) in DMF (10 mL) at 0 ° C. In addition, it was stirred overnight at room temperature. LC / MS showed that the oxime was converted to 100% chloride. A solution of 2-chloro-N-hydroxy-6- (trifluoromethyl) benzimideyl chloride was used in the next reaction without purification.
　ステップ１３－３
　５－クロロ－６－（ピペラジン－１－イル）ニコチン酸塩酸塩（７０ｍｇ、０．２５２mmol）とトリエチルアミン（１４０μL、１．０mmol）のジクロロメタン（１ｍL）の溶液に、ステップ１３－２の２－クロロ－Ｎ－ヒドロキシ－５－（トリフルオロメチル）ベンズイミドイル　クロリドのＤＭＦ溶液（０．２５２ｍＬ、約０．２５２mmol）を室温で加え、３時間撹拌した。反応溶液に１０％ＫＨＳＯ４水溶液を加え、不溶物を濾別後濾液を酢酸エチルにて抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、粗５－クロロ－６－（４－((2－クロロ－５－（トリフルオロメチル）フェニル)（ヒドロキシイミノ）メチル)ピペラジン－１－イル）ニコチン酸（化合物１３２）を得た（LC-MS: r.t. 2.59 min., m/z 463 (M+1)）。この化合物は精製することなしに次のステップに用いた。 Step 13-3
2-Chloro from step 13-2 in a solution of 5-chloro-6- (piperazine-1-yl) nicotinate (70 mg, 0.252 mmol) and triethylamine (140 μL, 1.0 mmol) in dichloromethane (1 mL). A DMF solution of -N-hydroxy-5- (trifluoromethyl) benzimideyl chloride (0.252 mL, about 0.252 mmol) was added at room temperature and stirred for 3 hours. A 10% aqueous solution of KHSO 4 was added to the reaction solution, the insoluble material was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and crude 5-chloro-6- (4-((2-chloro-5- (trifluoromethyl) phenyl) (hydroxyimino) methyl) piperazin-1- Il) Nicotinic acid (Compound 132) was obtained (LC-MS: rt 2.59 min., M / z 463 (M + 1)). This compound was used in the next step without purification.
　ステップ１３－４
　５－クロロ－６－（４－((２－クロロ－６－（トリフルオロメチル）フェニル)（ヒドロキシイミノ）メチル)ピペラジン－１－イル）ニコチン酸（１１７ｍｇ、０．２５３mmol）の２Ｎ水酸化カリウム水溶液（１ｍＬ、２mmol）とジオキサン（５ｍＬ）との混合溶液をマイクロウェーブにて１６０℃で１時間撹拌加熱した。ＬＣ／ＭＳ分析では変換率は１００％を示した。溶液を１０％ＫＨＳＯ４水溶液で中和し、、酢酸エチルにて抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し４２ｍｇの粗表題化合物を得た。これをさらに加温したアセトニトリルで洗浄し２９．９ｍｇの表題化合物を得た。
１H NMR (DMSO, 400 MHz)δ8.70 (d, 1 H, J = 2.4 Hz), 8.50 (bs, 1 H), 8.13 (d, 1 H, J = 1.6 Hz), 7.95 (dd, 1 H, 1.6, 8.4 Hz), 7.84 (d, 1 H, J = 8.4 Hz), 3.68 - 3.71 (m, 4 H), 3.31 - 3.34 (m, 4H), LC-MS: r.t. 2.92 min., m/z 427 (M+1)。 Step 13-4
2-N potassium hydroxide of 5-chloro-6- (4-((2-chloro-6- (trifluoromethyl) phenyl) (hydroxyimino) methyl) piperazine-1-yl) nicotinic acid (117 mg, 0.253 mmol) A mixed solution of an aqueous solution (1 mL, 2 mmol) and dioxane (5 mL) was stirred and heated at 160 ° C. for 1 hour with a microwave. LC / MS analysis showed a conversion rate of 100%. The solution was neutralized with 10% aqueous KHSO 4 solution and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) for preparative use to obtain 42 mg of a crude compound. This was washed with further warmed acetonitrile to give 29.9 mg of the title compound.
1 H NMR (DMSO, 400 MHz) δ8.70 (d, 1 H, J = 2.4 Hz), 8.50 (bs, 1 H), 8.13 (d, 1 H, J = 1.6 Hz), 7.95 (dd, 1) H, 1.6, 8.4 Hz), 7.84 (d, 1 H, J = 8.4 Hz), 3.68 --3.71 (m, 4 H), 3.31 --3.34 (m, 4H), LC-MS: rt 2.92 min., M / z 427 (M + 1).
　［実施例１４］
３－（４－（ピリジン－２－イル）ピペラジン－１－イル）ベンゾ[ｄ]イソオキサゾール（化合物１４１）の合成
Figure JPOXMLDOC01-appb-C000056
 [Example 14]
Synthesis of 3- (4- (pyridin-2-yl) piperazine-1-yl) benzo [d] isooxazole (Compound 141)
Figure JPOXMLDOC01-appb-C000056
　３－クロロベンゾ[ｄ]イソオキサゾール（１００ｍｇ、０．６５１mmol）と１－（ピリジン－２－イル）ピペラジン（３１９ｍｇ、１．９５４mmol）のピリジン（１ｍＬ）の溶液をマイクロウェーブにて１５０℃で１時間撹拌加熱した。溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し６１．１ｍｇの表題化合物を得た。
１H NMR (CDCl３, 400 MHz)δ8.31 (dd, 1H, J = 4.0, 1.6 Hz), 7.72 (d, 1H, J = 8.4 Hz), 7.45-7.56 (m, 3H), 7.25 (dt, 1H, J = 1.2, 6.4 Hz), 6.72 (d, 1H, J = 8.8 Hz), 6.68 (dd, 1H, J = 4.8, 7.2 Hz) , 3.74 - 3.78 (m, 4 H), 3.67 - 3.71 (m, 4H), LC-MS: r.t. 1.52 min., m/z 281 (M+1)。 A solution of 3-chlorobenzo [d] isoxazole (100 mg, 0.651 mmol) and 1- (pyridine-2-yl) piperazine (319 mg, 1.954 mmol) in pyridine (1 mL) was microwaved at 150 ° C. for 1 hour. Stirred and heated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) for preparative use to obtain 61.1 mg of the title compound.
1 1 H NMR (CDCl 3 , 400 MHz) δ8.31 (dd, 1H, J = 4.0, 1.6 Hz), 7.72 (d, 1H, J = 8.4 Hz), 7.45-7.56 (m, 3H), 7.25 (dt) , 1H, J = 1.2, 6.4 Hz), 6.72 (d, 1H, J = 8.8 Hz), 6.68 (dd, 1H, J = 4.8, 7.2 Hz), 3.74 --3.78 (m, 4 H), 3.67 --3.71 (m, 4H), LC-MS: rt 1.52 min., m / z 281 (M + 1).
　［実施例１５］
３－（４－（２－クロロフェニル）ピペラジン－１－イル）ベンゾ[ｄ]イソオキサゾール（化合物１５１）の合成
Figure JPOXMLDOC01-appb-C000057
 [Example 15]
Synthesis of 3- (4- (2-chlorophenyl) piperazine-1-yl) benzo [d] isooxazole (Compound 151)
Figure JPOXMLDOC01-appb-C000057
　３－クロロベンゾ[ｄ]イソオキサゾール（７７．５ｍｇ、０．５０５mmol）と１－（２－クロロフェニル）ピペラジン（８４μＬ、０．５０５mmol）のピリジン（１ｍＬ）の溶液をマイクロウェーブにて１８０℃で４０分撹拌加熱した。溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し８．７ｍｇの表題化合物を得た。
Rf: 0.5 (10 : 1 hexane/ethyl acetate)
１H NMR (CDCl３, 400 MHz)δ7.74 (d, 1H, J = 8.4 Hz), 7.45-7.52 (m, 2H), 7.39 (dd, 1H, J = 1.6, 8.4 Hz), 7.20 - 7.28 (m, 3H), 7.10 (d, 1 H, J = 7.2 Hz), 7.02 (dd, 1H, J = 1.6, 7.2 Hz) , 3.74 - 3.78 (m, 4 H), 3.24 - 3.28 (m, 4H), LC-MS: r.t. 3.15 min., m/z 314 (M+1)。 A solution of 3-chlorobenzo [d] isoxazole (77.5 mg, 0.505 mmol) and 1- (2-chlorophenyl) piperazine (84 μL, 0.505 mmol) in pyridine (1 mL) was microwaved at 180 ° C. for 40 minutes. Stirred and heated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography for preparative use (ethyl acetate / hexane) to give 8.7 mg of the title compound.
Rf: 0.5 (10: 1 hexane / ethyl acetate)
1 1 H NMR (CDCl 3 , 400 MHz) δ7.74 (d, 1H, J = 8.4 Hz), 7.45-7.52 (m, 2H), 7.39 (dd, 1H, J = 1.6, 8.4 Hz), 7.20 --7.28 (m, 3H), 7.10 (d, 1 H, J = 7.2 Hz), 7.02 (dd, 1H, J = 1.6, 7.2 Hz), 3.74 --3.78 (m, 4 H), 3.24 --3.28 (m, 4H) ), LC-MS: rt 3.15 min., M / z 314 (M + 1).
　［実施例１６］
３－（４－（２，３－ジメチルフェニル）ピペラジン－１－イル）ベンゾ[ｄ]イソオキサゾール（化合物１６１）の合成
Figure JPOXMLDOC01-appb-C000058
 [Example 16]
Synthesis of 3- (4- (2,3-dimethylphenyl) piperazin-1-yl) benzo [d] isooxazole (Compound 161)
Figure JPOXMLDOC01-appb-C000058
　３－クロロベンゾ[ｄ]イソオキサゾール（５０ｍｇ、０．３２６mmol）と１－（２、３－ジメチルフェニル）ピペラジン（６２mg、０．３２６mmol）のピリジン（１ｍＬ）の溶液をマイクロウェーブにて１８０℃で３０分撹拌加熱した。溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し２.４ｍｇの表題化合物を得た。
Rf: 0.8 (5 : 1 hexane/ethyl acetate),
１H NMR (CDCl３, 400 MHz)δ7.73 (d, 1H, J = 8.0 Hz), 7.44-7.52 (m, 2H), 7.22 (dd, 1H, J = 1.6, 8.0 Hz), 7.10 (d, 1 H, J = 8.0 Hz), 6.92 - 6.97 (m, 2H), 3.64 - 3.81 (m, 4 H), 3.05 - 3.12 (m, 4H), 2.28 (s, 3 H), 2.27 (S, 3 H), LC-MS: r.t. 3.34 min., m/z 308 (M+1)。 A solution of 3-chlorobenzo [d] isoxazole (50 mg, 0.326 mmol) and 1- (2,3-dimethylphenyl) piperazine (62 mg, 0.326 mmol) in pyridine (1 mL) was microwaved at 180 ° C. for 30 The mixture was stirred and heated for minutes. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography for preparative use (ethyl acetate / hexane) to give 2.4 mg of the title compound.
Rf: 0.8 (5: 1 hexane / ethyl acetate),
1 1 H NMR (CDCl 3 , 400 MHz) δ7.73 (d, 1H, J = 8.0 Hz), 7.44-7.52 (m, 2H), 7.22 (dd, 1H, J = 1.6, 8.0 Hz), 7.10 (d , 1 H, J = 8.0 Hz), 6.92 --6.97 (m, 2H), 3.64 --3.81 (m, 4 H), 3.05 --3.12 (m, 4H), 2.28 (s, 3 H), 2.27 (S, 3 H), LC-MS: rt 3.34 min., M / z 308 (M + 1).
　［実施例１７］
３－（４－（２，４－ジクロロフェニル）ピペラジン－１－イル）ベンゾ[ｄ]イソオキサゾール（化合物１７１）の合成
Figure JPOXMLDOC01-appb-C000059
 [Example 17]
Synthesis of 3- (4- (2,4-dichlorophenyl) piperazine-1-yl) benzo [d] isooxazole (Compound 171)
Figure JPOXMLDOC01-appb-C000059
　３－クロロベンゾ[ｄ]イソオキサゾール（５５ｍｇ、０．３５８mmol）と１－（２，４－ジクロロフェニル）ピペラジン（１９０mg、０．８２２mmol）のジメトキシエタン（０.５ｍＬ）の溶液をマイクロウェーブにて１６０℃で１２０分撹拌加熱した。溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し１３.３ｍｇの表題化合物を得た。
１H NMR (CDCl３, 400 MHz)δ7.71 (d, 1 H, J = 8.4 Hz), 7.49 (t, 1 H, J = 8.0 Hz), 7.46 (d, 1 H, J = 8.0 Hz), 7.39 (d, 2H, J = 2.4 Hz), 7.19 - 7.24 (m, 2H), 7.00 (d, 1 H, J = 8.4 Hz), 3.72 - 3.77 (m, 4 H), 3.19 - 3.23 (m, 4H), LC-MS: r.t. 3.40 min., m/z 348 (M+1)。 A solution of 3-chlorobenzo [d] isoxazole (55 mg, 0.358 mmol) and 1- (2,4-dichlorophenyl) piperazine (190 mg, 0.822 mmol) in dimethoxyethane (0.5 mL) was microwaved at 160 ° C. Stirred and heated for 120 minutes. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography for preparative use (ethyl acetate / hexane) to give 13.3 mg of the title compound.
1 1 H NMR (CDCl 3 , 400 MHz) δ7.71 (d, 1 H, J = 8.4 Hz), 7.49 (t, 1 H, J = 8.0 Hz), 7.46 (d, 1 H, J = 8.0 Hz) , 7.39 (d, 2H, J = 2.4 Hz), 7.19 --7.24 (m, 2H), 7.00 (d, 1 H, J = 8.4 Hz), 3.72 --3.77 (m, 4 H), 3.19 --3.23 (m) , 4H), LC-MS: rt 3.40 min., m / z 348 (M + 1).
　［実施例１８］
３－（４－（３－クロロピリジン－２－イル）ピペラジン－１－イル）ベンゾ[ｄ]イソチアゾール（化合物１８１）の合成
Figure JPOXMLDOC01-appb-C000060
 [Example 18]
Synthesis of 3- (4- (3-chloropyridin-2-yl) piperazine-1-yl) benzo [d] isothiazole (Compound 181)
Figure JPOXMLDOC01-appb-C000060
　２-ブロモ－３-クロロピリジン（９６mg、０.５mmol）、３-（ピペラジン－１－イル）ベンゾ[ｄ]イソチアゾール（１１０mg、０.５mmol）、Pd２（dba）３（トリス(ジベンジリデンアセトン)ジパラジウム(0)、４６.８mg、０.０５mmol）、tert-ブトキシナトリウム（５７．７ｍｇ、０．６mmol）と（２，２‘-ビス（ジフェニルホスファニル）-１、１’-ビスナフタレン（６２.３mg、０.１mmol）のジオキサン（１０mL）溶液を９０℃で９時間撹拌加熱した。混合物を酢酸エチルで抽出し、有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し４２ｍｇの粗表題化合物を得た。これをさらに加温したアセトニトリルで洗浄し４４．６ｍｇの表題化合物を得た。
Rf = 0.75,（2 : 1 hexane/ethyl acetate）
１H NMR (CDCl３, 400 MHz)δ8.22 (d, 1 H, J = 4.8 Hz), 7.96 (d, 1 H, J = 8.0 Hz), 7.83 (d, 1 H, J = 8.0 Hz), 7.62 (d, 1 H, J = 8.0 Hz), 7.48 (t, 1H, J = 8.0 Hz), 7.38 (t, 1 H, J = 8.0 Hz), 6.88 (dd, 1 H, J = 4.8, 8.0 Hz), 3.69 - 3.73 (m, 4 H), 3.58 - 3.62 (m, 4H), LC-MS: r.t. 2.86 min., m/z 331 (M+1)。 2-Bromo-3-chloropyridine (96 mg, 0.5 mmol), 3- (piperazine-1-yl) benzo [d] isothiazole (110 mg, 0.5 mmol), Pd 2 (dba) 3 (tris (dibenzylidene) Acelatin) dipalladium (0), 46.8 mg, 0.05 mmol), tert-butoxysodium (57.7 mg, 0.6 mmol) and (2,2'-bis (diphenylphosphanyl) -1,1'-bis A solution of naphthalene (62.3 mg, 0.1 mmol) in dioxane (10 mL) was stirred and heated at 90 ° C. for 9 hours. The mixture was extracted with ethyl acetate, the organic layer was dried with magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue. Was purified by silica gel column chromatography for preparative use (ethyl acetate / hexane) to give 42 mg of the crude title compound. This was further washed with warmed acetonitrile to obtain 44.6 mg of the title compound.
Rf = 0.75, (2: 1 hexane / ethyl acetate)
1 H NMR (CDCl 3 , 400 MHz) δ8.22 (d, 1 H, J = 4.8 Hz), 7.96 (d, 1 H, J = 8.0 Hz), 7.83 (d, 1 H, J = 8.0 Hz) , 7.62 (d, 1 H, J = 8.0 Hz), 7.48 (t, 1H, J = 8.0 Hz), 7.38 (t, 1 H, J = 8.0 Hz), 6.88 (dd, 1 H, J = 4.8, 8.0 Hz), 3.69 --3.73 (m, 4 H), 3.58 --3.62 (m, 4H), LC-MS: rt 2.86 min., M / z 331 (M + 1).
　［実施例１９］
５－クロロ－６－（８－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）－３，８－ジアザビシクロ[３，２，１]オクタン－３－イル）ニコチン酸（化合物１９１）の合成
Figure JPOXMLDOC01-appb-C000061
 [Example 19]
5-Chloro-6- (8- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) -3,8-diazabicyclo [3,2,1] octane-3-yl) nicotinic acid ( Synthesis of compound 191)
Figure JPOXMLDOC01-appb-C000061
　ステップ１９－１
　Tert-ブチル（１Ｒ，５Ｓ）－３，８－ジアザビシクロ[３，２，１]オクタン－８－カルボキシレート（０．５ｇ、２．３５５mmol）、５，６－ジクロロニコチン酸（０．４５２ｇ、２．３５５mmol）のピリジン（５ｍＬ）の溶液を９０℃で１０時間加熱撹拌した。精製水で希釈後１０％ＫＨＳＯ４で中和してpHを約６にし、生成した固体を濾取、精製水で洗浄、減圧乾燥し、２４８ｍｇの粗６－（８－（Tert-ブトキシカルボニル）－３，８－ジアザビシクロ[３，２，１]オクタン－３－イル）－５－クロロニコチン酸を得た。これは精製することなしに次のステップに用いた。 Step 19-1
Tert-butyl (1R, 5S) -3,8-diazabicyclo [3,2,1] octane-8-carboxylate (0.5 g, 2.355 mmol), 5,6-dichloronicotinic acid (0.452 g, 2) A solution of .355 mmol) of pyridine (5 mL) was heated and stirred at 90 ° C. for 10 hours. After diluting with purified water, neutralize with 10% KHSO 4 to adjust the pH to about 6, and the resulting solid was collected by filtration, washed with purified water, dried under reduced pressure, and 248 mg of crude 6- (8- (Tert-butoxycarbonyl)). -3,8-diazabicyclo [3,2,1] octane-3-yl) -5-chloronicotinic acid was obtained. It was used in the next step without purification.
　ステップ１９－２
　上記の粗６－（８－（Tert-ブトキシカルボニル）－３，８－ジアザビシクロ[３，２，１]オクタン－３－イル）－５－クロロニコチン酸（２２７mg、０．６１７mmol）のメタノール（５mL）の溶液に過剰のチオニルクロリドを室温で加え一夜放置した。反応混合物を濃縮乾固し２０８．２mgの粗６－（３，８－ジアザビシクロ[３，２，１]オクタン－３－イル）－５－クロロニコチン酸塩酸塩を得た。これは精製することなしに次のステップに用いた。 Step 19-2
Methanol (5 mL) of the above crude 6- (8- (Tert-butoxycarbonyl) -3,8-diazabicyclo [3,2,1] octane-3-yl) -5-chloronicotinic acid (227 mg, 0.617 mmol) ) Was added with excess thionyl chloride at room temperature and left overnight. The reaction mixture was concentrated to dryness to give 208.2 mg of crude 6- (3,8-diazabicyclo [3,2,1] octane-3-yl) -5-chloronicotinate salt. It was used in the next step without purification.
　ステップ１９－３
　上記の粗６－（３，８－ジアザビシクロ[３，２，１]オクタン－３－イル）－５－クロロニコチン酸塩酸塩（１５２mg、０．５mmol）とトリエチルアミン（２７９μＬ、２．０mmol）のＤＭＦ（１．５mL）の溶液に約１Ｎの２－フルオロ－Ｎ－ヒドロキシ－６－（トリフルオロメチル）ベンズイミドイル　クロリドのＤＭＦ液（０．５mL）を室温で加え、終夜撹拌した。精製水で希釈後１０％ＫＨＳＯ４で中和してpHを約６にし、混合物を酢酸エチルで抽出し、有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し１３６．４ｍｇの５－クロロ－６－（８－（（２－フルオロ－６－（トリフルオロメチル）フェニル（ヒドロキシイミノ）メチル）－３，８－ジアザビシクロ[３，２，１]オクタン－３－イル）ニコチン酸（化合物１９２）を得た（LC-MS: r.t. 2.54 min., m/z 473 (M+1)）。(Rf = 0.1, 2 : 1 ethyl acetate/hexane)。 Step 19-3
DMF of the above crude 6- (3,8-diazabicyclo [3,2,1] octane-3-yl) -5-chloronicotinate (152 mg, 0.5 mmol) and triethylamine (279 μL, 2.0 mmol) About 1N of 2-fluoro-N-hydroxy-6- (trifluoromethyl) benzimideyl chloride DMF solution (0.5 mL) was added to the (1.5 mL) solution at room temperature, and the mixture was stirred overnight. After diluting with purified water, neutralize with 10% KHSO 4 to bring the pH to about 6, extract the mixture with ethyl acetate, dry the organic layer with magnesium sulfate, distill off the solvent under reduced pressure, and leave the residue on a silica gel column for preparative use. Purified by chromatography (ethyl acetate / hexane) and 136.4 mg of 5-chloro-6- (8-((2-fluoro-6- (trifluoromethyl) phenyl (hydroxyimino) methyl) -3,8-diazabicyclo [3,2,1] octane-3-yl) nicotinic acid (Compound 192) was obtained (LC-MS: rt 2.54 min., M / z 473 (M + 1)). (Rf = 0.1, 2: 1 ethyl acetate / hexane).
　ステップ１９－４
５－クロロ－６－（８－（（２－フルオロ－６－（トリフルオロメチル）フェニル（ヒドロキシイミノ）メチル）－３，８－ジアザビシクロ[３，２，１]オクタン－３－イル）ニコチン酸（９０ｍｇ）の２Ｎ水酸化カリウム水溶液（０．６ｍＬ）とジオキサン（１．８ｍＬ）との混合溶液を１００℃で１０時間撹拌加熱した。ＬＣ／ＭＳ分析では変換率は約９５％を示した。反応溶液を精製水で希釈後１Ｎ塩酸と１０％ＫＨＳＯ４で中和してpHを約６とし、酢酸エチルで抽出、有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製して、得られた個体を濾取し、温イソプロパノールで洗浄した。これを乾燥し１６．３ｍｇの表題化合物を得た。
Rf = 0.25（2 : 1 ethyl acetate/hexane）
１H NMR (DMSO, 400 MHz)δ8.63 (dd, 1 H, J =0.8, 1.6 Hz), 8.07 - 8.11 (m, 2 H), 7.83 - 7.87 (m, 2 H), 4.85 - 4.88 (br, 2 H), 3.33 - 3.38 (m, 6H), 2.13 (dd, 2 H. J = 12.8, 6.0 Hz), 1.91 - 1.99 (m, 2 H), LC-MS: r.t. 3.21 min., m/z 453 (M+1)。　　　 Step 19-4
5-Chloro-6- (8-((2-fluoro-6- (trifluoromethyl) phenyl (hydroxyimino) methyl) -3,8-diazabicyclo [3,2,1] octane-3-yl) nicotinic acid A mixed solution of (90 mg) 2N aqueous potassium hydroxide solution (0.6 mL) and dioxane (1.8 mL) was stirred and heated at 100 ° C. for 10 hours. LC / MS analysis showed a conversion rate of about 95%. After diluting the reaction solution with purified water, neutralize with 1N hydrochloric acid and 10% KHSO 4 to adjust the pH to about 6, extract with ethyl acetate, dry the organic layer with magnesium sulfate, distill off the solvent under reduced pressure, and separate the residue. Purification by silica gel column chromatography (ethyl acetate / hexane) was obtained, and the obtained solid was collected by filtration and washed with warm isopropanol. This was dried to obtain 16.3 mg of the title compound.
Rf = 0.25 (2: 1 ethyl acetate / hexane)
1 1 H NMR (DMSO, 400 MHz) δ8.63 (dd, 1 H, J = 0.8, 1.6 Hz), 8.07 --8.11 (m, 2 H), 7.83 --7.81 (m, 2 H), 4.85 --4.88 ( br, 2 H), 3.33 --3.38 (m, 6H), 2.13 (dd, 2 H. J = 12.8, 6.0 Hz), 1.91 --1.99 (m, 2 H), LC-MS: rt 3.21 min., m / z 453 (M + 1).
　［実施例２０］
７－クロロ－３－（４－（２－クロロフェニル）ピペラジン－１－イル）ベンゾ[ｄ]イソオキサゾール（化合物２０１）の合成
Figure JPOXMLDOC01-appb-C000062
 [Example 20]
Synthesis of 7-chloro-3- (4- (2-chlorophenyl) piperazine-1-yl) benzo [d] isooxazole (Compound 201)
Figure JPOXMLDOC01-appb-C000062
　２，６－ジクロロベンズアルデヒドに代えて２，３－ジクロロベンズアルデヒドを用いた以外は、実施例６のステップ６－１、６－２の方法に従って、（Ｅ）－（４－(２－クロロフェニル)ピペラジン－１－イル）(２，３－ジクロロフェニル)メタノン　オキシムとそのＺ異性体を得た。
（Ｅ）－（４－(２－クロロフェニル)ピペラジン－１－イル）(２，３－ジクロロフェニル)メタノン　オキシム（化合物２０２（Ｅ））：
Rf: 0.5, 3 : 1 hexane/ethyl acetate,
１H NMR (CDCl３, 400 MHz)δ7.52 (dd, 1 H, J = 1.2, 8.0 Hz), 7.36 (dd, 1 H, J = 1.2, 8.0 Hz), 7.32 (dd, 1 H, J =2.0, 8.0 Hz), 7.25 (dd, 1 H, J =2.0, 8.0 Hz), 7.21 (dd, 1H, J =2.0, 8.0 Hz), 7.04 (dd, 1H, J = 2.0, 8.0 Hz), 6.98 (dt, 1 H, J =1.2, 8.0 Hz), 3.50 - 3.54 (m, 4 H), 3.07 - 3.11 (m, 4H), LC-MS: r.t. 3.08 min., m/z 384 (M+1)
（Ｚ）－（４－(２－クロロフェニル)ピペラジン－１－イル）(２，３－ジクロロフェニル)メタノン　オキシム（化合物２０２（Ｚ））：
Rf: 0.3, 3 : 1 hexane/ethyl acetate
1H NMR (CDCl3, 400 MHz)δ7.52 (dd, 1 H, J = 1.2, 8.0 Hz), 7.36 (d, 1 H, J = 8.0 Hz), 7.31 (t, 1 H, J = 8.0 Hz), 7.25 (d, 1 H, J = 8.0 Hz), 7.21 (d, 1H, J = 8.0 Hz), 7.02 (d, 1H, J = 8.0 Hz), 6.99 (t, 1 H, J = 8.0 Hz), 5.77 - 5.89 (br, 1 H), 3.21 - 3.40 (m, 4 H), 3.03 - 3.07 (m, 4H), LC-MS: r.t. 3.08 min., m/z 384 (M+1)。 (E)-(4- (2-chlorophenyl) piperazine according to the method of steps 6-1 and 6-2 of Example 6 except that 2,3-dichlorobenzaldehyde was used instead of 2,6-dichlorobenzaldehyde. -1-yl) (2,3-dichlorophenyl) methanone oxime and its Z isomer were obtained.
(E)-(4- (2-Chlorophenyl) piperazine-1-yl) (2,3-dichlorophenyl) methanone oxime (Compound 202 (E)):
Rf: 0.5, 3: 1 hexane / ethyl acetate,
1 1 H NMR (CDCl 3 , 400 MHz) δ7.52 (dd, 1 H, J = 1.2, 8.0 Hz), 7.36 (dd, 1 H, J = 1.2, 8.0 Hz), 7.32 (dd, 1 H, J) = 2.0, 8.0 Hz), 7.25 (dd, 1 H, J = 2.0, 8.0 Hz), 7.21 (dd, 1H, J = 2.0, 8.0 Hz), 7.04 (dd, 1H, J = 2.0, 8.0 Hz), 6.98 (dt, 1 H, J = 1.2, 8.0 Hz), 3.50 --3.54 (m, 4 H), 3.07 --3.11 (m, 4H), LC-MS: rt 3.08 min., M / z 384 (M +) 1)
(Z)-(4- (2-chlorophenyl) piperazine-1-yl) (2,3-dichlorophenyl) methanone oxime (Compound 202 (Z)):
Rf: 0.3, 3: 1 hexane / ethyl acetate
1H NMR (CDCl3, 400 MHz) δ7.52 (dd, 1 H, J = 1.2, 8.0 Hz), 7.36 (d, 1 H, J = 8.0 Hz), 7.31 (t, 1 H, J = 8.0 Hz) , 7.25 (d, 1 H, J = 8.0 Hz), 7.21 (d, 1H, J = 8.0 Hz), 7.02 (d, 1H, J = 8.0 Hz), 6.99 (t, 1 H, J = 8.0 Hz) , 5.77 --- 5.89 (br, 1 H), 3.21 --- 3.40 (m, 4 H), 3.03 --3.07 (m, 4H), LC-MS: rt 3.08 min., M / z 384 (M + 1).
（Ｅ）－（４－(２－クロロフェニル)ピペラジン－１－イル）(２，６－ジクロロフェニル)メタノン　オキシムに代えて（Ｅ）－（４－(２－クロロフェニル)ピペラジン－１－イル）(２，３－ジクロロフェニル)メタノン　オキシムを用いた以外は、実施例６のステップ６－３の方法に従って表題化合物を得た。
１H NMR (CDCl３, 400 MHz)δ7.63 (d, 1 H, J = 8.8 Hz), 7.50 (d, 1 H, J = 7.6 Hz), 7.42 (dd, 1 H, J =1.2, 7.6 Hz), 7.26 (dt, 1 H, J = 1.2, 7.6 Hz), 7.20 (t, 1 H, J = 7.6 Hz), 7.08 (dd, 1 H, J = 1.2, 7.6 Hz),7.02 (dt, 1 H, J = 1.2, 7.6 Hz), 3.74 - 3.78 (m, 4 H), 3.23 - 3.28 (m, 4H), LC-MS: r.t. 3.38 min., m/z 384 (M+1)。 (E)-(4- (2-Chlorophenyl) piperazine-1-yl) (2,6-dichlorophenyl) methanone Instead of oxime, (E)-(4- (2-chlorophenyl) piperazine-1-yl) (2 , 3-Dichlorophenyl) Metanon Oxime was used to obtain the title compound according to the method of step 6-3 of Example 6.
1 1 H NMR (CDCl 3 , 400 MHz) δ7.63 (d, 1 H, J = 8.8 Hz), 7.50 (d, 1 H, J = 7.6 Hz), 7.42 (dd, 1 H, J = 1.2, 7.6 Hz), 7.26 (dt, 1 H, J = 1.2, 7.6 Hz), 7.20 (t, 1 H, J = 7.6 Hz), 7.08 (dd, 1 H, J = 1.2, 7.6 Hz), 7.02 (dt, dt, 1 H, J = 1.2, 7.6 Hz), 3.74 --3.78 (m, 4 H), 3.23 --3.28 (m, 4H), LC-MS: rt 3.38 min., M / z 384 (M + 1).
　［実施例２１］
６－クロロ－３－（４－（２－クロロフェニル）ピペラジン－１－イル）ベンゾ[ｄ]イソオキサゾール（化合物２１１）の合成
Figure JPOXMLDOC01-appb-C000063
 [Example 21]
Synthesis of 6-chloro-3- (4- (2-chlorophenyl) piperazine-1-yl) benzo [d] isooxazole (Compound 211)
Figure JPOXMLDOC01-appb-C000063
　２，６－ジクロロベンズアルデヒドに代えて２，４－ジクロロベンズアルデヒドを用いた以外は、実施例６のステップ６－１、６－２の方法に従って、（Ｅ）－（４－(２－クロロフェニル)ピペラジン－１－イル）(２，４－ジクロロフェニル)メタノン　オキシムとそのＺ異性体を得た。
（Ｅ）－（４－(２－クロロフェニル)ピペラジン－１－イル）(２，４－ジクロロフェニル)メタノン　オキシム（化合物２１２（Ｅ））：
Rf: 0.5 (3 : 1 hexane/ethyl acetate)
１H NMR (CDCl３, 400 MHz)δ7.41 (d, 1 H, J = 1.6 Hz), 7.39 (s, 1 H), 7.36 (dd, 1 H, J =1.6, 8.0 Hz), 7.30 (dd, 1 H, J =7.2, 8.8 Hz), 7.21 (dd, 1H, J =1.2, 7.2 Hz), 7.03 (dd, 1H, J = 2.0, 8.0 Hz), 6.98 (dt, 1 H, J =1.2, 8.0 Hz), 5.72 (br, 1 H), 3.35 - 3.40 (m, 4 H), 3.04 - 3.09 (m, 4H), LC-MS: r.t. 3.03 min., m/z 384 (M+1)。
（Ｚ）－（４－(２－クロロフェニル)ピペラジン－１－イル）(２，４－ジクロロフェニル)メタノン　オキシム（化合物２１２（Ｚ））：
Rf: 0.3 (3 : 1 hexane/ethyl acetate)
１H NMR (CDCl３, 400 MHz)δ7.36 (dd, 1 H, J = 1.2, 7.2 Hz), 7.35 (d, 1 H, J = 1.2, 8.0 Hz), 7.26 (dd, 1 H, J = 1.2, 8.0 Hz), 7.28 (dd, 1 H, J = 2.0, 8.0 Hz), 7.22 (dt, 1H, J = 1.2, 7.2 Hz), 7.04 (dd, 1H, J = 8.0 Hz), 6.97 (dt, 1 H, J = 1.2, 8.0 Hz), 6.46 (br, 1 H), 3.53 - 3.57 (m, 4 H), 3.09 - 3.13 (m, 4H), LC-MS: r.t. 3.03 min., m/z 384 (M+1)。 (E)-(4- (2-chlorophenyl) piperazine according to the method of steps 6-1 and 6-2 of Example 6 except that 2,4-dichlorobenzaldehyde was used instead of 2,6-dichlorobenzaldehyde. -1-yl) (2,4-dichlorophenyl) methanone oxime and its Z isomer were obtained.
(E)-(4- (2-Chlorophenyl) piperazine-1-yl) (2,4-dichlorophenyl) methanone oxime (Compound 212 (E)):
Rf: 0.5 (3: 1 hexane / ethyl acetate)
1 1 H NMR (CDCl 3 , 400 MHz) δ7.41 (d, 1 H, J = 1.6 Hz), 7.39 (s, 1 H), 7.36 (dd, 1 H, J = 1.6, 8.0 Hz), 7.30 ( dd, 1 H, J = 7.2, 8.8 Hz), 7.21 (dd, 1H, J = 1.2, 7.2 Hz), 7.03 (dd, 1H, J = 2.0, 8.0 Hz), 6.98 (dt, 1 H, J = 1.2, 8.0 Hz), 5.72 (br, 1 H), 3.35 --3.40 (m, 4 H), 3.04 --3.09 (m, 4H), LC-MS: rt 3.03 min., M / z 384 (M + 1) ).
(Z)-(4- (2-chlorophenyl) piperazine-1-yl) (2,4-dichlorophenyl) methanone oxime (Compound 212 (Z)):
Rf: 0.3 (3: 1 hexane / ethyl acetate)
1 H NMR (CDCl 3 , 400 MHz) δ7.36 (dd, 1 H, J = 1.2, 7.2 Hz), 7.35 (d, 1 H, J = 1.2, 8.0 Hz), 7.26 (dd, 1 H, J = 1.2, 8.0 Hz), 7.28 (dd, 1 H, J = 2.0, 8.0 Hz), 7.22 (dt, 1H, J = 1.2, 7.2 Hz), 7.04 (dd, 1H, J = 8.0 Hz), 6.97 ( dt, 1 H, J = 1.2, 8.0 Hz), 6.46 (br, 1 H), 3.53 --3.57 (m, 4 H), 3.09 --3.13 (m, 4H), LC-MS: rt 3.03 min., M / z 384 (M + 1).
　（Ｅ）－（４－(２－クロロフェニル)ピペラジン－１－イル）(２，６－ジクロロフェニル)メタノン　オキシムに代えて（Ｅ）－（４－(２－クロロフェニル)ピペラジン－１－イル）(２，４－ジクロロフェニル)メタノン　オキシムを用いた以外は、実施例６のステップ６－３の方法に従って表題化合物を得た。
１H NMR (CDCl３, 400 MHz)δ7.64 (d, 1 H, J = 8.8 Hz), 7.49 (d, 1 H, J = 2.0 Hz), 7.40 (dd, 1 H, J =1.6, 8.0 Hz), 7.26 (dt, 1 H, J = 1.2, 7.6 Hz), 7.22 (dd, 1 H, J = 2.0, 8.8 Hz), 7.08 (dd, 1 H, J = 1.6, 8.0 Hz),7.02 (dt, 1 H, J = 1.2, 7.6 Hz), 3.72 - 3.76 (m, 4 H), 3.23 - 3.27 (m, 4H), LC-MS: r.t. 3.42 min., m/z 384 (M+1)。 (E)-(4- (2-Chlorophenyl) piperazine-1-yl) (2,6-dichlorophenyl) methanone Instead of oxime, (E)-(4- (2-chlorophenyl) piperazine-1-yl) (2 , 4-Dichlorophenyl) Metanon Oxime was used to obtain the title compound according to the method of step 6-3 of Example 6.
1 H NMR (CDCl 3 , 400 MHz) δ7.64 (d, 1 H, J = 8.8 Hz), 7.49 (d, 1 H, J = 2.0 Hz), 7.40 (dd, 1 H, J = 1.6, 8.0 Hz), 7.26 (dt, 1 H, J = 1.2, 7.6 Hz), 7.22 (dd, 1 H, J = 2.0, 8.8 Hz), 7.08 (dd, 1 H, J = 1.6, 8.0 Hz), 7.02 ( dt, 1 H, J = 1.2, 7.6 Hz), 3.72 --3.76 (m, 4 H), 3.23 --3.27 (m, 4H), LC-MS: rt 3.42 min., M / z 384 (M + 1) ..
　［実施例２２］
５－クロロ－６－（４－（４－クロロベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ピリジン－３－イル）（モルホリノ）メタノン（化合物２２１）の合成
Figure JPOXMLDOC01-appb-C000064
 [Example 22]
Synthesis of 5-chloro-6- (4- (4-chlorobenzo [d] isooxazole-3-yl) piperazine-1-yl) pyridin-3-yl) (morpholino) methanone (Compound 221)
Figure JPOXMLDOC01-appb-C000064
　５－クロロ－６－（４－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸を５－クロロ－６－（４－（４－クロロベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸（化合物０８１）に代え、メチルアミンをモルホリンに代えた以外は、実施例２の方法に従って、表題化合物を得た。
１H NMR (CDCl３, 400 MHz)δ8.34 (d, 1 H, J = 2.0 Hz), 8.25 (d, 1 H, J = 1.6 Hz), 7.73 (d, 1 H, J = 1.6 Hz), 7.43 (dd, 1 H, J = 7.2, 8.4 Hz), 7.40 (dd, 1 H, J = 1.6, 8.4 Hz), 7.26 (dd, 1 H, J = 1.2, 6.8 Hz), 3.57 - 3.85 (m, 12 H), LC-MS: r.t. 2.80 min., m/z 413 (M+1)。 5-Chloro-6- (4- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperazine-1-yl) nicotinic acid was added to 5-chloro-6- (4- (4-chlorobenzo). [d] The title compound was obtained according to the method of Example 2 except that isooxazole-3-yl) piperazine-1-yl) nicotinic acid (Compound 081) was replaced with morpholine.
1 1 H NMR (CDCl 3 , 400 MHz) δ8.34 (d, 1 H, J = 2.0 Hz), 8.25 (d, 1 H, J = 1.6 Hz), 7.73 (d, 1 H, J = 1.6 Hz) , 7.43 (dd, 1 H, J = 7.2, 8.4 Hz), 7.40 (dd, 1 H, J = 1.6, 8.4 Hz), 7.26 (dd, 1 H, J = 1.2, 6.8 Hz), 3.57 --3.85 ( m, 12 H), LC-MS: rt 2.80 min., m / z 413 (M + 1).
　［実施例２３］
５－クロロ－６－（４－（４－クロロベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）－Ｎ－（メチルスルフォニル）ニコチンアミド（化合物２３１）の合成
Figure JPOXMLDOC01-appb-C000065
 [Example 23]
Synthesis of 5-chloro-6- (4- (4-chlorobenzo [d] isooxazole-3-yl) piperazine-1-yl) -N- (methylsulfonyl) nicotinamide (Compound 231)
Figure JPOXMLDOC01-appb-C000065
　５－クロロ－６－（４－（４－クロロベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸（化合物０８１、７９ｍｇ、０．２mmol）、メタンスルホンアミド（２８．５ｍｇ、０．３mmol）、ＤＭＡＰ（4-ジメチルアミノピリジン、３６．７mg、０．３mmol）とＥＤＣ（N-(3-ジメチルアミノプロピル)-N’-エチルカルボジイミド 塩酸塩、５７．５ｍｇ、０．３mmol）のジクロロメタン（１ｍＬ）の溶液を室温で終夜撹拌した。反応混合物を１０％ＫＨＳＯ４と飽和炭酸水素ナトリウム水溶液でｐＨを約３に合わせたのち、酢酸エチルで抽出し、有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し４０．１ｍｇの表題化合物を得た。
Rf = 0.3, 5% methanol/ethyl acetate
１H NMR (DMSO, 400 MHz)δ8.67 (s, 1 H), 8.12 (s, 1 H), 7.67 (d, 1 H, J = 8 Hz), 7.63 (t, 1 H, J = 8 Hz), 7.45 (d, 1 H, J = 7.2 Hz), 3.53 - 3.58 (m, 4 H) , 3.47 - 3.52 (m, 4 H), LC-MS: r.t. 2.78 min., m/z 470 (M+1)。 5-Chloro-6- (4- (4-chlorobenzo [d] isooxazole-3-yl) piperazin-1-yl) nicotinic acid (Compound 081, 79 mg, 0.2 mmol), methanesulfonamide (28.5 mg, 0.3 mmol), DMAP (4-dimethylaminopyridine, 36.7 mg, 0.3 mmol) and EDC (N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, 57.5 mg, 0.3 mmol) A solution of dichloromethane (1 mL) was stirred overnight at room temperature. The reaction mixture was adjusted to pH about 3 with 10% KHSO 4 and saturated aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate, the organic layer was dried with magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was silica gel for preparative use. Purification by column chromatography (ethyl acetate / hexane) gave 40.1 mg of the title compound.
Rf = 0.3, 5% methanol / ethyl acetate
1 1 H NMR (DMSO, 400 MHz) δ8.67 (s, 1 H), 8.12 (s, 1 H), 7.67 (d, 1 H, J = 8 Hz), 7.63 (t, 1 H, J = 8) Hz), 7.45 (d, 1 H, J = 7.2 Hz), 3.53 --3.58 (m, 4 H), 3.47 --3.52 (m, 4 H), LC-MS: rt 2.78 min., M / z 470 ( M + 1).
　［実施例２４］
５－クロロ－６－（４－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸　メチル（化合物２４１）の合成
Figure JPOXMLDOC01-appb-C000066
 [Example 24]
Synthesis of methyl 5-chloro-6- (4- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperazin-1-yl) methyl nicotinate (Compound 241)
Figure JPOXMLDOC01-appb-C000066
　５－クロロ－６－（４－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸（化合物０１１、１１０ｍｇ）の１Ｎ塩化水素メタノール溶液（１２ｍＬ）を２４時間６８℃で加熱撹拌した。ＬＣ／ＭＳによる解析では約９０％の変換率を示した。反応混合物を濃縮後精製水で希釈し、飽和炭酸水素ナトリウム水溶液で中和して酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し８４．９ｍｇの表題化合物を得た。
(Rf = 0.5, 2 : 1 hexane/ethyl acetate). １H NMR (CDCl３, 400 MHz)δ8.77 (d, 1 H, J = 2.0 Hz), 8.16 (d, 1 H, J = 2.0 Hz), 7.74 (dd, 1 H, J = 1.2, 7.2 Hz), 7.66 (dd, 1 H, J = 1.2, 8.0 Hz), 7.63 (t, 1 H, J = 6.8 Hz), 3.92 (s, 3 H), 3.75 - 3.78 (m, 4 H), 3.44 - 3.48 (m, 4H), LC-MS: r.t. 2.21 min., m/z 423 (M+1)。 5-Chloro-6- (4- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperazine-1-yl) nicotinic acid (Compound 011, 110 mg) in 1N hydrogen chloride methanol solution (12 mL) ) Was heated and stirred at 68 ° C. for 24 hours. Analysis by LC / MS showed a conversion rate of about 90%. The reaction mixture was concentrated, diluted with purified water, neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography for preparative use (ethyl acetate / hexane) to give 84.9 mg of the title compound.
(Rf = 0.5, 2: 1 hexane / ethyl acetate). 1 H NMR (CDCl 3 , 400 MHz) δ8.77 (d, 1 H, J = 2.0 Hz), 8.16 (d, 1 H, J = 2.0 Hz) ), 7.74 (dd, 1 H, J = 1.2, 7.2 Hz), 7.66 (dd, 1 H, J = 1.2, 8.0 Hz), 7.63 (t, 1 H, J = 6.8 Hz), 3.92 (s, 3) H), 3.75 --3.78 (m, 4 H), 3.44 --3.48 (m, 4H), LC-MS: rt 2.21 min., M / z 423 (M + 1).
　［実施例２５］
（５－クロロ－６－（４－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ピリジン－３－イル）メタノール（化合物２５１）の合成
Figure JPOXMLDOC01-appb-C000067
 [Example 25]
Synthesis of (5-chloro-6- (4- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperazine-1-yl) pyridin-3-yl) methanol (Compound 251)
Figure JPOXMLDOC01-appb-C000067
　５－クロロ－６－（４－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸　メチル（化合物２４１、２４ｍｇ）と水素化ホウ素ナトリウム（４ｍｇ）のＴＨＦ溶液にイソプロパノール（０．０８ｍＬ）を加え、６５℃で４時間加熱撹拌した。反応混合物にメタノールを加えて濃縮し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し４．７ｍｇの表題化合物を得た。
Rf = 0.27, 1 : 1 hexane/ethyl acetate
１H NMR (CDCl３, 400 MHz)δ8.18 (d, 1 H, J = 2.0 Hz), 7,73 (dd, 1 H, J = 1.2, 8 Hz), 7.69 (d, 1 H, J = 2.0 Hz), 7.65 (d, 1 H, J = 8 Hz), 7.62 (t, 1 H, J = 8 Hz), 4.66 (d, 2 H, J = 4.8 Hz), 3.55 - 3.59 (m, 4 H), 3.45 - 3.49 (m, 4H), LC-MS: r.t. 3.23 min., m/z 413 (M+1)。 5-Chloro-6- (4- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperazin-1-yl) methyl nicotinate (Compounds 241, 24 mg) and sodium borohydride (4 mg) Isopropanol (0.08 mL) was added to the THF solution of), and the mixture was heated and stirred at 65 ° C. for 4 hours. Methanol was added to the reaction mixture for concentration, and the residue was purified by silica gel column chromatography for preparative use (ethyl acetate / hexane) to give 4.7 mg of the title compound.
Rf = 0.27, 1: 1 hexane / ethyl acetate
1 1 H NMR (CDCl 3 , 400 MHz) δ8.18 (d, 1 H, J = 2.0 Hz), 7,73 (dd, 1 H, J = 1.2, 8 Hz), 7.69 (d, 1 H, J) = 2.0 Hz), 7.65 (d, 1 H, J = 8 Hz), 7.62 (t, 1 H, J = 8 Hz), 4.66 (d, 2 H, J = 4.8 Hz), 3.55 --3.59 (m, 4 H), 3.45 --3.49 (m, 4H), LC-MS: rt 3.23 min., M / z 413 (M + 1).
　［実施例２６］
３－（４－（３－メチルピリジン－２－イル）ピペラジン－１－イル）－４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール（化合物２６１）の合成
Figure JPOXMLDOC01-appb-C000068
 [Example 26]
Synthesis of 3- (4- (3-methylpyridine-2-yl) piperazine-1-yl) -4- (trifluoromethyl) benzo [d] isooxazole (Compound 261)
Figure JPOXMLDOC01-appb-C000068
　５－クロロ－６－（ピペラジン－１－イル）ニコチン酸塩酸塩に代えて１－（３－メチルピリジン－２－イル）ピペラジンを用いた以外は、実施例１のステップ１－３および１－４の方法に従って、表題化合物を得た。
１H NMR (CDCl３, 400 MHz)δ8.20 (dd, 1 H, J = 2.0, 5.2 Hz), 7,73 (dd, 1 H, J = 1.2, 8 Hz), 7.65 (d, 1 H, J = 8 Hz), 7.61 (t, 1 H, J = 8 Hz), 7.44 (d, 1 H, J = 7.2 Hz), 6.89 (dd, 1 H, J = 5.2, 7.2 Hz), 3.45 - 3.49 (m, 4H), 3.34 - 3.38 (m, 4 H), 2.33 (s, 3 H), LC-MS: r.t. 2.42 min., m/z 363 (M+1)。 Steps 1-3 and 1-of Example 1 except that 1- (3-methylpyridine-2-yl) piperazine was used in place of 5-chloro-6- (piperazine-1-yl) nicotinate. The title compound was obtained according to the method of 4.
1 H NMR (CDCl 3 , 400 MHz) δ8.20 (dd, 1 H, J = 2.0, 5.2 Hz), 7,73 (dd, 1 H, J = 1.2, 8 Hz), 7.65 (d, 1 H) , J = 8 Hz), 7.61 (t, 1 H, J = 8 Hz), 7.44 (d, 1 H, J = 7.2 Hz), 6.89 (dd, 1 H, J = 5.2, 7.2 Hz), 3.45- 3.49 (m, 4H), 3.34 --3.38 (m, 4 H), 2.33 (s, 3 H), LC-MS: rt 2.42 min., M / z 363 (M + 1).
　［実施例２７］
４－メトキシ－３－（４－（２－クロロフェニル）ピペラジン－１－イル）ベンゾ[ｄ]イソオキサゾール（化合物２７１）の合成
Figure JPOXMLDOC01-appb-C000069
 [Example 27]
Synthesis of 4-methoxy-3- (4- (2-chlorophenyl) piperazine-1-yl) benzo [d] isooxazole (Compound 271)
Figure JPOXMLDOC01-appb-C000069
　２－フルオロ－６－（トリフルオロメチル）ベンズアルデヒドに代えて２－フルオロ－６－（メトキシ）ベンズアルデヒドを用いた以外は、実施例１の方法に従って表題化合物を得た。
Rf: 0.6 (2 : 1 hexane/ethyl acetate), 
１H NMR (CDCl３, 400 MHz)δ7.43 (t, 1H, J = 8.0 Hz), 7.39 (dd, 1H, J = 1.2, 8.0 Hz), 7.25 (dt, 1 H, J = 1.2, 8.4 Hz), 7.11 (dd, 1H, J = 1.2, 8.4 Hz), 7.00 (dt, 1H, J = 1.6, 8.0 Hz), 6.62 (d, 1H, J = 8.4 Hz), 3.97 (s, 3 H), 3.68 - 3.73 (m, 4 H), 3.24 - 3.28 (m, 4H), LC-MS: r.t. 3.21 min., m/z 344 (M+1)。 The title compound was obtained according to the method of Example 1 except that 2-fluoro-6- (methoxy) benzaldehyde was used instead of 2-fluoro-6- (trifluoromethyl) benzaldehyde.
Rf: 0.6 (2: 1 hexane / ethyl acetate),
1 1 H NMR (CDCl 3 , 400 MHz) δ7.43 (t, 1H, J = 8.0 Hz), 7.39 (dd, 1H, J = 1.2, 8.0 Hz), 7.25 (dt, 1 H, J = 1.2, 8.4) Hz), 7.11 (dd, 1H, J = 1.2, 8.4 Hz), 7.00 (dt, 1H, J = 1.6, 8.0 Hz), 6.62 (d, 1H, J = 8.4 Hz), 3.97 (s, 3 H) , 3.68 --3.73 (m, 4 H), 3.24 --3.28 (m, 4H), LC-MS: rt 3.21 min., M / z 344 (M + 1).
　［実施例２８］
１－（１－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペリジン－４－イル）－１，３－ジヒドロ－２Ｈ－ベンゾ[ｄ]イミダゾール－２－オン（化合物２８１）の合成
Figure JPOXMLDOC01-appb-C000070
 [Example 28]
1- (1- (4- (Trifluoromethyl) benzo [d] isooxazole-3-yl) piperidine-4-yl) -1,3-dihydro-2H-benzo [d] imidazol-2-one (compound) 281) Synthesis
Figure JPOXMLDOC01-appb-C000070
　５－クロロ－６－（ピペラジン－１－イル）ニコチン酸塩酸塩に代えて１－（ピペリジン－４－イル）－１、３－ジヒドロ－２Ｈ－ベンゾ[ｄ]イミダゾール－２－オンを用いた以外は、実施例１のステップ１－３および１－４の方法に従って表題化合物を得た。
１H NMR (CDCl３, 400 MHz)δ7.88 (br, 1 H), 7.74 (d, 1 H, J = 8 Hz), 7.67 (d, 1 H, J = 6.4 Hz), 7.63 (t, 1H, J = 8 Hz), 7.30 (d, 1H, J = 7.6 Hz), 7.05 - 7.16 (m, 3 H), 4.65 (tt, 1 H, J = 12, 4.8 Hz), 3.79 (d, 2 H, J = 10.4 Hz), 3.16 (t, 2 H, J = 11.6 Hz), 2.69 (dq, 2 H, J = 4, 12 Hz), 1.96 (d, 2 H, J = 12 Hz), LC-MS: r.t. 2.68 min., m/z 403 (M+1)。
なお、合成の過程のステップ１－３において、１－（１－（（２－フルオロ－６－（トリフルオロメチル）フェニル（ヒドロキシイミノ）メチル）ピペリジン－４－イル）－１，３－ジヒドロ－２Ｈ－ベンゾ[ｄ]イミダゾール－２－オンが得られた（化合物２８２；LC-MS: r.t. 2.20 min., m/z 423 (M+1)）。 1- (Piperidine-4-yl) -1,3-dihydro-2H-benzo [d] imidazol-2-one was used in place of 5-chloro-6- (piperazine-1-yl) nicotinate. Except for the above, title compounds were obtained according to the methods of Steps 1-3 and 1-4 of Example 1.
1 H NMR (CDCl 3 , 400 MHz) δ7.88 (br, 1 H), 7.74 (d, 1 H, J = 8 Hz), 7.67 (d, 1 H, J = 6.4 Hz), 7.63 (t, 1H, J = 8 Hz), 7.30 (d, 1H, J = 7.6 Hz), 7.05 --7.16 (m, 3 H), 4.65 (tt, 1 H, J = 12, 4.8 Hz), 3.79 (d, 2) H, J = 10.4 Hz), 3.16 (t, 2 H, J = 11.6 Hz), 2.69 (dq, 2 H, J = 4, 12 Hz), 1.96 (d, 2 H, J = 12 Hz), LC -MS: rt 2.68 min., M / z 403 (M + 1).
In addition, in step 1-3 of the synthetic process, 1-(1-((2-fluoro-6- (trifluoromethyl) phenyl (hydroxyimino) methyl) piperidine-4-yl) -1,3-dihydro- 2H-benzo [d] imidazol-2-one was obtained (Compound 282; LC-MS: rt 2.20 min., M / z 423 (M + 1)).
　［実施例２９］
２－（２－オキソ－３－（１－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペリジン－４－イル）－２，３－ジヒドロ－１Ｈ－ベンゾ[ｄ]イミダゾール－１－イル）酢酸tert－ブチルエステル（化合物２９１）の合成
Figure JPOXMLDOC01-appb-C000071
 [Example 29]
2- (2-oxo-3- (1- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperidine-4-yl) -2,3-dihydro-1H-benzo [d] Synthesis of imidazole-1-yl) tert-butyl acetate (Compound 291)
Figure JPOXMLDOC01-appb-C000071
　１－（１－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペリジン－４－イル）－１，３－ジヒドロ－２Ｈ－ベンゾ[ｄ]イミダゾール－２－オン（化合物２８１、６７ｍｇ、０．１７１mmol）、ブロモ酢酸tert－ブチルエステル（５０ｍｇ、０．２５６mmol）と６０％水素化ナトリウム（１０．４ｍｇ、０．２５６mmol）のＤＭＦ（１ｍＬ）の溶液を室温で２時間撹拌し、飽和食塩水を加え酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥、ろ過、濃縮し、残渣を分取用液体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、表題化合物（８６．６ｍｇ）を得た。
１H NMR (CDCl３, 400 MHz)δ7.55 (d, 1 H, J = 8 Hz), 7.67 (d, 1 H, J = 6.4 Hz), 7.43 (t, 1H, J = 8 Hz), 7.31 (d, 1H, J = 7.6 Hz), 7.13 (t, 1 H, J = 7.2 Hz), 7.10 (t, 1 H, J = 7.2 Hz), 6.90 (d, 1 H, J = 7.2 Hz), 4.65 (tt, 1 H, J = 12, 4.8 Hz), 4.55 (s, 2 H), 3.77 (d, 2 H, J = 10.4 Hz), 3.15 (t, 2 H, J = 11.6 Hz), 2.70 (dq, 2 H, J = 4, 12 Hz), 1.96 (d, 2 H, J = 12 Hz), 1.46 (s, 9 H), LC-MS: r.t. 3.25 min., m/z 517 (M+1)。 1-(1- (4- (Trifluoromethyl) benzo [d] isooxazole-3-yl) piperidine-4-yl) -1,3-dihydro-2H-benzo [d] imidazole-2-one (compound) A solution of DMF (1 mL) of 281, 67 mg, 0.171 mmol), tert-butyl ester bromoacetic acid (50 mg, 0.256 mmol) and 60% sodium hydride (10.4 mg, 0.256 mmol) was stirred at room temperature for 2 hours. Then, saturated saline was added and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated, and the residue was purified by preparative liquid silica gel column chromatography (hexane / ethyl acetate) to give the title compound (86.6 mg).
1 H NMR (CDCl 3 , 400 MHz) δ7.55 (d, 1 H, J = 8 Hz), 7.67 (d, 1 H, J = 6.4 Hz), 7.43 (t, 1H, J = 8 Hz), 7.31 (d, 1H, J = 7.6 Hz), 7.13 (t, 1 H, J = 7.2 Hz), 7.10 (t, 1 H, J = 7.2 Hz), 6.90 (d, 1 H, J = 7.2 Hz) , 4.65 (tt, 1 H, J = 12, 4.8 Hz), 4.55 (s, 2 H), 3.77 (d, 2 H, J = 10.4 Hz), 3.15 (t, 2 H, J = 11.6 Hz), 2.70 (dq, 2 H, J = 4, 12 Hz), 1.96 (d, 2 H, J = 12 Hz), 1.46 (s, 9 H), LC-MS: rt 3.25 min., M / z 517 ( M + 1).
　［実施例３０］
２－（２－オキソ－３－（１－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペリジン－４－イル）－２，３－ジヒドロ－１Ｈ－ベンゾ[ｄ]イミダゾール－１－イル）酢酸（化合物３０１）の合成
Figure JPOXMLDOC01-appb-C000072
 [Example 30]
2- (2-oxo-3- (1- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperidine-4-yl) -2,3-dihydro-1H-benzo [d] Synthesis of imidazole-1-yl) acetic acid (Compound 301)
Figure JPOXMLDOC01-appb-C000072
　２－（２－オキソ－３－（１－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペリジン－４－イル）－２，３－ジヒドロ－１Ｈ－ベンゾ[ｄ]イミダゾール－１－イル）酢酸tert－ブチルエステル（化合物２９１、７８．３ｍｇ）をＤＭＥ（ジメチルエーテル、５ｍＬ）に溶かし、１Ｎ水酸化ナトリウム水溶液（２ｍＬ）を加え、室温で２時間撹拌した。１Ｎ塩酸で中和し、析出した結晶を濾取し精製水で洗浄、乾燥し表題化合物（５０．８ｍｇ）を得た。
１H NMR (DMSO, 400 MHz)δ8.06 - 8.11 (m, 1 H), 7.87 (d, 1 H, J = 7.6 Hz), 7.84 (t, 1H, J = 3.6 Hz), 7.31 (d, 1H, J = 7.2 Hz), 7.17 (t, 1 H, J = 7.2 Hz), 7.10 (dt, 1 H, J = 1.2, 7.2 Hz), 7.06 (dt, 1 H, J = 1.2, 7.2 Hz), 4.60 (s, 2 H), 4.50 (tt, 1 H, J = 12, 4 Hz), 3.12 (t, 2 H, J = 12 Hz), 2.55 - 2.68 (m, 2 H), 1.84 (d, 2 H, J = 12 Hz), LC-MS: r.t. 2.65 min., m/z 461 (M+1)。 2- (2-oxo-3- (1- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperidine-4-yl) -2,3-dihydro-1H-benzo [d] Imidazole-1-yl) tert-butyl acetate (Compound 291, 78.3 mg) was dissolved in DME (dimethyl ether, 5 mL), 1N aqueous sodium hydroxide solution (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. The crystals were neutralized with 1N hydrochloric acid, and the precipitated crystals were collected by filtration, washed with purified water and dried to give the title compound (50.8 mg).
1 H NMR (DMSO, 400 MHz) δ8.06 --8.11 (m, 1 H), 7.87 (d, 1 H, J = 7.6 Hz), 7.84 (t, 1H, J = 3.6 Hz), 7.31 (d, 1H, J = 7.2 Hz), 7.17 (t, 1 H, J = 7.2 Hz), 7.10 (dt, 1 H, J = 1.2, 7.2 Hz), 7.06 (dt, 1 H, J = 1.2, 7.2 Hz) , 4.60 (s, 2 H), 4.50 (tt, 1 H, J = 12, 4 Hz), 3.12 (t, 2 H, J = 12 Hz), 2.55 --2.68 (m, 2 H), 1.84 (d , 2 H, J = 12 Hz), LC-MS: rt 2.65 min., M / z 461 (M + 1).
　［実施例３１］
３－（４－（２－クロロピリジン－３－イル）ピペラジン－１－イル）ベンゾ[ｄ]イソオキサゾール（化合物３１１）の合成
Figure JPOXMLDOC01-appb-C000073
 [Example 31]
Synthesis of 3- (4- (2-chloropyridin-3-yl) piperazine-1-yl) benzo [d] isooxazole (Compound 311)
Figure JPOXMLDOC01-appb-C000073
１－（ピリジン－２－イル）ピペラジンに代えて１－（２－クロロピリジン－３－イル）ピペラジンを用いた以外は、実施例１４の方法に従って表題化合物を得た。
LC-MS: r.t. 2.60 min., m/z 315 (M+1)。 The title compound was obtained according to the method of Example 14, except that 1- (2-chloropyridin-3-yl) piperazine was used instead of 1- (pyridin-2-yl) piperazine.
LC-MS: rt 2.60 min., M / z 315 (M + 1).
　［実施例３２］
３－（４－（３－クロロピリジン－２－イル）ピペラジン－１－イル）ベンゾ[ｄ]イソオキサゾール（化合物３２１）の合成
Figure JPOXMLDOC01-appb-C000074
 [Example 32]
Synthesis of 3- (4- (3-chloropyridin-2-yl) piperazine-1-yl) benzo [d] isooxazole (Compound 321)
Figure JPOXMLDOC01-appb-C000074
１－（ピリジン－２－イル）ピペラジンに代えて１－（３－クロロピリジン－２－イル）ピペラジンを用いた以外は、実施例１４の方法に従って表題化合物を得た。
LC-MS: r.t. 2.89 min., m/z 315 (M+1)。 The title compound was obtained according to the method of Example 14, except that 1- (3-chloropyridin-2-yl) piperazine was used instead of 1- (pyridin-2-yl) piperazine.
LC-MS: rt 2.89 min., M / z 315 (M + 1).
　［実施例３３］
３－（４－（３，５－ジクロロフェニル）ピペラジン－１－イル）ベンゾ[ｄ]イソオキサゾール（化合物３３１）の合成
Figure JPOXMLDOC01-appb-C000075
 [Example 33]
Synthesis of 3- (4- (3,5-dichlorophenyl) piperazine-1-yl) benzo [d] isooxazole (Compound 331)
Figure JPOXMLDOC01-appb-C000075
１－（２，４－ジクロロフェニル）ピペラジンに代えて１－（３，５－ジクロロフェニル）ピペラジンを用いた以外は、実施例１７の方法に従って表題化合物を得た。
LC-MS: r.t. 3.40 min., m/z 348 (M+1) The title compound was obtained according to the method of Example 17, except that 1- (3,5-dichlorophenyl) piperazine was used instead of 1- (2,4-dichlorophenyl) piperazine.
LC-MS: rt 3.40 min., m / z 348 (M + 1)
　［実施例３４］
５－クロロ－６－（１－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペリジン－４－イル）ニコチン酸メチル（化合物３４１）の合成
Figure JPOXMLDOC01-appb-C000076
 [Example 34]
Synthesis of 5-chloro-6- (1- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperidine-4-yl) methyl nicotinate (Compound 341)
Figure JPOXMLDOC01-appb-C000076
　ステップ３４－１
　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）－３，６－ジヒドロピリジン－１（２H）－カルボン酸tert－ブチル（６１８mg、２mmol）、５，６－ジクロロニコチン酸（３８４mg、２mmol）および炭酸カリウム（６９１mg、 5 mmol）、ビストリフェニルホスフィン２塩化パラジウム（140 mg、0.2 mmol）をジメトキシエタン：エタノール：水（容積比１：１：１）の混合液（１２mL）に加え、窒素雰囲気下９０℃で２時間加熱した。反応溶液に１０％硫酸水素カリウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し、残渣を分取用ジオールシリカゲルカラムクロマトグラフィー（５％メタノール／酢酸エチル）で精製し、696 mgの１’－（tert－ブトキシカルボニル）－３－クロロ－１’，２’，３’，６’－テトラヒドロ－[２，４’－ビピリジン]－５－カルボン酸を得た（収率103％）。１H NMR (DMSO, 400 MHz)δ8.95 (d, 1 H, J = 1.6 Hz), 8.27 (d, 1 H, J = 1.6 Hz), 6.25 - 6.33 (m, 1 H), 4.02 - 4.08 (m, 2 H), 3.51 - 3.57 (m, 2 H), 3.3 (m, 2 H), 1.44 (s, 9 H)
LC-MS: r.t. 2.78 min., m/z 284 (M+1-C4H8)。 Step 34-1
4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate tert-butyl (618 mg, 2 mmol), 5 , 6-Dichloronicotinic acid (384 mg, 2 mmol) and potassium carbonate (691 mg, 5 mmol), bistriphenylphosphine dichloride palladium (140 mg, 0.2 mmol) dimethoxyethane: ethanol: water (volume ratio 1: 1: 1) In addition to the mixed solution (12 mL) of, the mixture was heated at 90 ° C. for 2 hours under a nitrogen atmosphere. A 10% aqueous potassium hydrogensulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, the residue was purified by preparative diol silica gel column chromatography (5% methanol / ethyl acetate), and 696 mg of 1'-(tert-butoxycarbonyl) was used. -3-Chloro-1', 2', 3', 6'-tetrahydro- [2,4'-bipyridine] -5-carboxylic acid was obtained (yield 103%). 1 1 H NMR (DMSO, 400 MHz) δ8.95 (d, 1 H, J = 1.6 Hz), 8.27 (d, 1 H, J = 1.6 Hz), 6.25 --6.33 (m, 1 H), 4.02 --4.08 (m, 2 H), 3.51 --3.57 (m, 2 H), 3.3 (m, 2 H), 1.44 (s, 9 H)
LC-MS: rt 2.78 min., M / z 284 (M + 1-C4H8).
　ステップ３４－２
　１’－（tert－ブトキシカルボニル）－３－クロロ－１’，２’，３’，６’－テトラヒドロ－[２，４’－ビピリジン]－５－カルボン酸（696 mg, 2 mmol）をメタノール（5 mL）に加え、次いで過剰の塩化チオニルを加え、４５℃で３時間加熱した。溶媒を濃縮し、３－クロロ－１’，２’，３’，６’－テトラヒドロ－[２，４’－ビピリジン]－５－カルボン酸メチル　塩酸塩を得、精製すること無しに次のステップに用いた。
LC-MS: r.t. 1.55 min., m/z 253 (M+1)。 Step 34-2
Methanol 1'-(tert-butoxycarbonyl) -3-chloro-1', 2', 3', 6'-tetrahydro- [2,4'-bipyridine] -5-carboxylic acid (696 mg, 2 mmol) In addition to (5 mL), excess thionyl chloride was then added and heated at 45 ° C. for 3 hours. The solvent is concentrated to give methyl 3-chloro-1', 2', 3', 6'-tetrahydro- [2,4'-bipyridine] -5-carboxylic acid methyl hydrochloride, and the next step without purification. Used for.
LC-MS: rt 1.55 min., M / z 253 (M + 1).
　ステップ３４－３
　３－クロロ－１’，２’，３’，６’－テトラヒドロ－[２，４’－ビピリジン]－５－カルボン酸メチル　塩酸塩（322 mg, 1.114 mmol）をメタノール（5 mL）に溶かし、Pd/C（53 mg）を加え水素雰囲気下室温で１時間撹拌した。LC/MSにより、５－クロロ－６－（ピペリジン－４－イル）ニコチン酸メチル　塩酸塩（1.114 mmol）の生成を反応液中に確認した。反応物をセライトで濾過してPd/Cを除去し、濾液を濃縮し次の反応に用いた。LC-MS: r.t. 1.57 min., m/z 255 (M+1)。 Step 34-3
Methyl 3-chloro-1', 2', 3', 6'-tetrahydro- [2,4'-bipyridine] -5-carboxylic acid methyl hydrochloride (322 mg, 1.114 mmol) was dissolved in methanol (5 mL). Pd / C (53 mg) was added, and the mixture was stirred at room temperature for 1 hour under a hydrogen atmosphere. The production of methyl 5-chloro-6- (piperidine-4-yl) nicotinate methyl hydrochloride (1.114 mmol) was confirmed in the reaction solution by LC / MS. The reaction was filtered through Celite to remove Pd / C, and the filtrate was concentrated and used for the next reaction. LC-MS: rt 1.57 min., M / z 255 (M + 1).
　ステップ３４－４
　５－クロロ－６－（ピペリジン－４－イル）ニコチン酸メチル　塩酸塩（1.114 mmol）を含む濃縮物とトリエチルアミン（0.621 mL, 4.46 mmol）をDMF（3 mL）に加えて第１液を作製した。1.114 mmolの２－フルオロ－Ｎ－ヒドロキシ－６－（トリフルオロメチル）ベンズイミドイル　クロリドをDMFに加えて第２液（0.88235 mmol/mL in DMF)を作製した。第１液全量に第２液全量を室温で加え、終夜撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層を硫酸マグネシウムで乾燥、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し、１２mgの５－クロロ－６－（１－((２－フルオロ－６－（トリフルオロメチル）フェニル)（ヒドロキシイミノ）メチル)ピペリジン－４－イル）ニコチン酸メチル（化合物３４２）をE/Z混合物として得た。
１H NMR (DMSO, 400 MHz)δ9.48 (s, 1 H), 8.99 (d, 1 H, J = 1.6 Hz), 8.27 (d, 1 H, J = 1.6 Hz), 7.59 - 7.73 (m, 3 H), 3.89 (s, 3 H), 3.54 (bd, 1 H, J = 14.8 Hz), 3.37 - 3.49 (m, 2 H), 2.75 - 2.89 (m, 2 H), 1.65 - 1.85 (m, 4 H).LC-MS: r.t. 3.49 min., m/z 460 (M+1)。 Step 34-4
A concentrate containing 5-chloro-6- (piperidine-4-yl) methyl nicotinate hydrochloride (1.114 mmol) and triethylamine (0.621 mL, 4.46 mmol) were added to DMF (3 mL) to prepare the first solution. .. 1.114 mmol of 2-fluoro-N-hydroxy-6- (trifluoromethyl) benzimideyl chloride was added to DMF to prepare a second solution (0.88235 mmol / mL in DMF). The total amount of the second liquid was added to the total amount of the first liquid at room temperature, and the mixture was stirred overnight. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography for preparative use (ethyl acetate / hexane), and 12 mg of 5-chloro-6- (1-((2-fluoro)) was purified. Methyl -6- (trifluoromethyl) phenyl) (hydroxyimino) methyl) piperidine-4-yl) nicotinate (Compound 342) was obtained as an E / Z mixture.
1 1 H NMR (DMSO, 400 MHz) δ9.48 (s, 1 H), 8.99 (d, 1 H, J = 1.6 Hz), 8.27 (d, 1 H, J = 1.6 Hz), 7.59 --7.73 (m) , 3 H), 3.89 (s, 3 H), 3.54 (bd, 1 H, J = 14.8 Hz), 3.37 --3.49 (m, 2 H), 2.75 --2.89 (m, 2 H), 1.65 --1.85 ( m, 4 H) .LC-MS: rt 3.49 min., m / z 460 (M + 1).
　ステップ３４－５
　５－クロロ－６－（１－((２－フルオロ－６－（トリフルオロメチル）フェニル)（ヒドロキシイミノ）メチル)ピペリジン－４－イル）ニコチン酸メチル（１２mg）とp-トルエンスルホン酸（1 mg）をDMSO（1 mL）に加え８０℃で１時間加熱した。これにDBU（ジアザビシクロウンデセン；100 μL）を加え、１００℃で９０分間加熱した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し、7.7 mgの表題化合物を得た。
１H NMR (DMSO, 400 MHz)δ9.04 (d, 1 H, J = 1.6 Hz), 8.31 (d, 1 H, J = 1.6 Hz), 8.06 (dd, 1 H, J = 2.8, 6.4 Hz), 7.80 - 7.86 (m, 2 H), 3.89 (s, 3 H), 3.64 (bd, 2 H, J = 12.4 Hz), 3.44 - 3.52 (m, 1 H), 3.06 (bt, 2 H, J = 11.2 Hz), 2.04 (dq, 2 H, J = 3.2, 11.6 Hz), 1.91 (bd, 2 H, J = 10.4 Hz).LC-MS: r.t. 4.08 min., m/z 440 (M+1)。 Step 34-5
5-Chloro-6- (1-((2-fluoro-6- (trifluoromethyl) phenyl) (hydroxyimino) methyl) piperidine-4-yl) Methyl nicotinate (12 mg) and p-toluenesulfonic acid (1) mg) was added to DMSO (1 mL) and heated at 80 ° C. for 1 hour. DBU (diazabicycloundecene; 100 μL) was added thereto, and the mixture was heated at 100 ° C. for 90 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography for preparative use (ethyl acetate / hexane) to give 7.7 mg of the title compound.
1 H NMR (DMSO, 400 MHz) δ9.04 (d, 1 H, J = 1.6 Hz), 8.31 (d, 1 H, J = 1.6 Hz), 8.06 (dd, 1 H, J = 2.8, 6.4 Hz) ), 7.80 --7.86 (m, 2 H), 3.89 (s, 3 H), 3.64 (bd, 2 H, J = 12.4 Hz), 3.44 --3.52 (m, 1 H), 3.06 (bt, 2 H, J = 11.2 Hz), 2.04 (dq, 2 H, J = 3.2, 11.6 Hz), 1.91 (bd, 2 H, J = 10.4 Hz) .LC-MS: rt 4.08 min., M / z 440 (M +) 1).
　［実施例３５］
５－クロロ－６－（１－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペリジン－４－イル）ニコチン酸（化合物３５１）の合成
Figure JPOXMLDOC01-appb-C000077
 [Example 35]
Synthesis of 5-chloro-6- (1- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperidine-4-yl) nicotinic acid (Compound 351)
Figure JPOXMLDOC01-appb-C000077
　５－クロロ－６－（１－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペリジン－４－イル）ニコチン酸メチル（化合物３４１；7.7 mg）をDME（ジメチルエーテル；1 mL）に加え、次いで1 N水酸化ナトリウム水溶液（0.2 mL）を加え、室温で終夜撹拌した。生成液を減圧濃縮し、1 N塩酸（0.2 mL）を加え中和した。生成した粉末を濾取し、減圧乾燥して3.1 mgの表題化合物を得た。１H NMR (DMSO, 400 MHz)δ8.94 (d, 1 H, J = 1.6 Hz), 8.18 (d, 1 H, J = 1.6 Hz), 8.03 (dd, 1 H, J = 2.8, 6.4 Hz), 7.77 - 7.83 (m, 2 H), 3.60 (bd, 2 H, J = 12.4 Hz), 3.37 - 3.48 (m, 1 H), 3.02 (bt, 2 H, J = 11.6 Hz), 2.02 (dq, 2 H, J = 3.2, 12.4 Hz), 1.86 (bd, 2 H, J = 11.2 Hz).
LC-MS: r.t. 3.66 min., m/z 426 (M+1)。 5-Chloro-6- (1- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperidine-4-yl) methyl nicotinate (Compound 341; 7.7 mg) was added to DME (dimethyl ether; 1). In addition to mL), 1 N aqueous sodium hydroxide solution (0.2 mL) was added, and the mixture was stirred overnight at room temperature. The product was concentrated under reduced pressure and neutralized by adding 1 N hydrochloric acid (0.2 mL). The resulting powder was collected by filtration and dried under reduced pressure to give 3.1 mg of the title compound. 1 H NMR (DMSO, 400 MHz) δ8.94 (d, 1 H, J = 1.6 Hz), 8.18 (d, 1 H, J = 1.6 Hz), 8.03 (dd, 1 H, J = 2.8, 6.4 Hz) ), 7.77 --7.83 (m, 2 H), 3.60 (bd, 2 H, J = 12.4 Hz), 3.37 --3.38 (m, 1 H), 3.02 (bt, 2 H, J = 11.6 Hz), 2.02 ( dq, 2 H, J = 3.2, 12.4 Hz), 1.86 (bd, 2 H, J = 11.2 Hz).
LC-MS: rt 3.66 min., M / z 426 (M + 1).
　［実施例３６］
３－（４－（２－クロロフェニル）－３，６－ジヒドロピリジン－１（２Ｈ）－イル）－４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール（化合物３６１）の合成
Figure JPOXMLDOC01-appb-C000078
 [Example 36]
Synthesis of 3- (4- (2-chlorophenyl) -3,6-dihydropyridine-1 (2H) -yl) -4- (trifluoromethyl) benzo [d] isoxazole (Compound 361)
Figure JPOXMLDOC01-appb-C000078
　ステップ３６－１
　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）－３，６－ジヒドロピリジン－１（２H）－カルボン酸tert－ブチル（309 mg, 1 mmol）、１－クロロ－２－ヨードベンゼン（238 mg, 1 mmol）および炭酸カリウム（207 mg, 1.5 mmol）、ビストリフェニルホスフィン２塩化パラジウム（70.2 mg, 0.1 mmol）をジメトキシエタン：水（容積比２：１）の混合液（12mL）に加え、窒素雰囲気下９０℃で１時間加熱した。反応溶液に１０％硫酸水素カリウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し、残渣を分取用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、287.2 mgの４－(２－クロロフェニル)－３，６－ジヒドロピリジン－１（２H）－カルボン酸tert－ブチルを得た（収率98％）。
１H NMR (CDCl3, 400 MHz)δ7.34 - 7.37 (m, 1 H), 7.19 - 7.23 (m, 2 H), 7.15 - 7.18 (m, 1 H), 5.62 - 5.72 (br, 1 H), 4.02 - 4.08 (br, 2 H), 3.60 - 3.66 (bt, 2 H, J = 5.4 Hz), 2.41 - 2.48 (br, 2 H), 1.50 (s, 9 H).LC-MS: r.t. 3.77 min., m/z 238 (M+1-C4H8)。 Step 36-1
4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3,6-dihydropyridine-1 (2H) -carboxylate tert-butyl (309 mg, 1 mmol) , 1-Chloro-2-iodobenzene (238 mg, 1 mmol) and potassium carbonate (207 mg, 1.5 mmol), bistriphenylphosphine dichloride palladium (70.2 mg, 0.1 mmol) dimethoxyethane: water (volume ratio 2: In addition to the mixed solution (12 mL) of 1), the mixture was heated at 90 ° C. for 1 hour under a nitrogen atmosphere. A 10% aqueous potassium hydrogensulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography for preparative use (hexane / ethyl acetate), and 287.2 mg of 4- (2-chlorophenyl) -3,6- Dihydropyridine-1 (2H) -tert-butyl carboxylate was obtained (yield 98%).
1 1 H NMR (CDCl3, 400 MHz) δ7.34 --7.37 (m, 1 H), 7.19 --7.23 (m, 2 H), 7.15 --7.18 (m, 1 H), 5.62 --5.72 (br, 1 H) , 4.02 --4.08 (br, 2 H), 3.60 --3.66 (bt, 2 H, J = 5.4 Hz), 2.41 --2.48 (br, 2 H), 1.50 (s, 9 H) .LC-MS: rt 3.77 min., m / z 238 (M + 1-C4H8).
　ステップ３６－２
　４－(２－クロロフェニル)－３，６－ジヒドロピリジン－１（２Ｈ）－カルボン酸tert－ブチル（280.5 mg）を4 N塩酸／酢酸エチル（5 mL）に加え室温で一晩放置した。溶媒を濃縮し、４－(２－クロロフェニル)－１，２，３，６－テトラヒドロピリジン塩酸塩を得、精製すること無く次のステップに用いた。
LC-MS: r.t. 1.75 min., m/z 194 (M+1)。 Step 36-2
4- (2-Chlorophenyl) -3,6-dihydropyridine-1 (2H) -tert-butyl carboxylate (280.5 mg) was added to 4 N hydrochloric acid / ethyl acetate (5 mL) and left overnight at room temperature. The solvent was concentrated to give 4- (2-chlorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride, which was used in the next step without purification.
LC-MS: rt 1.75 min., M / z 194 (M + 1).
　ステップ３６－３
　４－(２－クロロフェニル)－１，２，３，６－テトラヒドロピリジン塩酸塩（115 mg, 0.5 mmol）とトリエチルアミン（0.209 mL, 1.5 mmol）をDMF（3 mL）に加えて第１液を作製した。0.5 mmolの２－フルオロ－Ｎ－ヒドロキシ－６－（トリフルオロメチル）ベンズイミドイル　クロリドをDMFに加えて第２液（0.88235 mmol/mL in DMF)を作製した。第１液全量に第２液全量を室温で加え、１時間撹拌した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し158.5 mgのＥ－（４－（２－クロロフェニル）－３、６－ジヒドロピリジン－１（２H）－イル）(2－フルオロ－６－（トリフルオロメチル）フェニル)メタノン　オキシム（化合物３６２）をE/Z混合物として得た。そのうち80 mgを次の反応に用いるために分離し、残りを分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し、Ｅ－（４－（２－クロロフェニル）－３、６－ジヒドロピリジン－１（２H）－イル）(2－フルオロ－６－（トリフルオロメチル）フェニル)メタノン　オキシム（化合物３６２（Ｅ））とそのＺ異性体（化合物３６２（Ｚ））を得た。
（Ｅ）－（４－（２－クロロフェニル）－３、６－ジヒドロピリジン－１（２H）－イル）(2－フルオロ－６－（トリフルオロメチル）フェニル)メタノン　オキシム（27.6 mg、Rf = 0.56）
１H NMR (CDCl３, 400 MHz)δ 7.52 - 7.61 (m, 2 H), 7.32 - 7.41 (m, 2 H), 7.16 - 7.25 (m, 3 H), 6.25 (brs, 1 H), 5.69 (brm, 1 H), 3.84 - 3.99 (m, 2 H), 3.17 - 3.31 (m, 2 H), 2.33 - 2.49 (m, 2 H).
LC-MS: r.t. 3.41 min., m/z 399 (M+1)。
（Ｚ）－（４－（２－クロロフェニル）－３、６－ジヒドロピリジン－１（２H）－イル）(2－フルオロ－６－（トリフルオロメチル）フェニル)メタノン　オキシム（17.1 mg、Rf = 0.34）
１H NMR (CDCl３, 400 MHz)δ 7.51 - 7.59 (m, 2 H), 7.31 - 7.39 (m, 2 H), 7.15 - 7.23 (m, 3 H), 6.25 (brs, 1 H), 5.62 (brm, 1 H), 3.91 - 4.15 (m, 2 H), 3.50 - 3.58 (m, 2 H), 2.45 - 2.51 (m, 2 H).
LC-MS: r.t. 3.49 min., m/z 399 (M+1)。 Step 36-3
4- (2-Chlorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride (115 mg, 0.5 mmol) and triethylamine (0.209 mL, 1.5 mmol) were added to DMF (3 mL) to prepare the first solution. did. 0.5 mmol of 2-fluoro-N-hydroxy-6- (trifluoromethyl) benzimideyl chloride was added to DMF to prepare a second solution (0.88235 mmol / mL in DMF). The total amount of the second liquid was added to the total amount of the first liquid at room temperature, and the mixture was stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and 158.5 mg of E- (4- (2-chlorophenyl) -3,6-dihydropyridine-1 (2H) -yl) (2-fluoro-6- ( Trifluoromethyl) phenyl) metanon oxime (Compound 362) was obtained as an E / Z mixture. 80 mg of it was separated for use in the next reaction, and the rest was purified by preparative silica gel column chromatography (ethyl acetate / hexane) to E- (4- (2-chlorophenyl) -3,6-dihydropyridine-. 1 (2H) -yl) (2-fluoro-6- (trifluoromethyl) phenyl) methanone oxime (Compound 362 (E)) and its Z isomer (Compound 362 (Z)) were obtained.
(E)-(4- (2-Chlorophenyl) -3,6-dihydropyridine-1 (2H) -yl) (2-fluoro-6- (trifluoromethyl) phenyl) methanone oxime (27.6 mg, Rf = 0.56)
1 1 H NMR (CDCl 3 , 400 MHz) δ 7.52 --7.61 (m, 2 H), 7.32 --7.41 (m, 2 H), 7.16 --7.25 (m, 3 H), 6.25 (brs, 1 H), 5.69 (brm, 1 H), 3.84 --3.99 (m, 2 H), 3.17 --3.31 (m, 2 H), 2.33 --2.49 (m, 2 H).
LC-MS: rt 3.41 min., M / z 399 (M + 1).
(Z)-(4- (2-chlorophenyl) -3,6-dihydropyridine-1 (2H) -yl) (2-fluoro-6- (trifluoromethyl) phenyl) methanone oxime (17.1 mg, Rf = 0.34)
1 1 H NMR (CDCl 3 , 400 MHz) δ 7.51 --7.59 (m, 2 H), 7.31 --7.39 (m, 2 H), 7.15 --7.23 (m, 3 H), 6.25 (brs, 1 H), 5.62 (brm, 1 H), 3.91 --4.15 (m, 2 H), 3.50 --3.58 (m, 2 H), 2.45 --2.51 (m, 2 H).
LC-MS: rt 3.49 min., M / z 399 (M + 1).
　ステップ３６－４
　（４－（２－クロロフェニル）－３、６－ジヒドロピリジン－１（２H）－イル）(2－フルオロ－６－（トリフルオロメチル）フェニル)メタノン　オキシム（化合物３６２、E異性体とZ異性体の混合物；80 mg, 0,2 mmol）とp-トルエンスルホン酸（2 mg）をDMSO（1 mL）に加え８０℃で３０分間加熱した。これにDBU (100 μL）を加え、１００℃で９０分間加熱した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し、67.6 mgの表題化合物を得た（収率89％）。
１H NMR (CDCl３, 400 MHz)δ 7.73 (d, 1 H, J = 8.0 Hz), 7.59 - 7.67 (m, 2 H), 7.38 (dd, 1 H, J = 7.2, 2.0 Hz), 7.19 - 7.28 (m, 3 H), 5.79 - 5.83 (m, 1 H), 4.05 (dd, 2 H, J = 6, 2.8 Hz), 3.53 (t, 2 H, J = 7.6 Hz), 2.67 - 2.72 (m, 2 H).LC-MS: r.t. 4.22 min., m/z 379 (M+1)。 Step 36-4
(4- (2-Chlorophenyl) -3,6-dihydropyridine-1 (2H) -yl) (2-fluoro-6- (trifluoromethyl) phenyl) methanone oxime (Compound 362, E and Z isomers The mixture; 80 mg, 0.2 mmol) and p-toluenesulfonic acid (2 mg) were added to DMSO (1 mL) and heated at 80 ° C. for 30 minutes. DBU (100 μL) was added thereto, and the mixture was heated at 100 ° C. for 90 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography for preparative use (ethyl acetate / hexane) to give 67.6 mg of the title compound (yield 89%).
1 1 H NMR (CDCl 3 , 400 MHz) δ 7.73 (d, 1 H, J = 8.0 Hz), 7.59 --7.77 (m, 2 H), 7.38 (dd, 1 H, J = 7.2, 2.0 Hz), 7.19 --7.28 (m, 3 H), 5.79 --5.83 (m, 1 H), 4.05 (dd, 2 H, J = 6, 2.8 Hz), 3.53 (t, 2 H, J = 7.6 Hz), 2.67 --2.72 (m, 2 H) .LC-MS: rt 4.22 min., m / z 379 (M + 1).
　［実施例３７］
５－クロロ－６－（２－オキソ－４－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸エチルの合成（化合物３７１）の合成
Figure JPOXMLDOC01-appb-C000079
 [Example 37]
Synthesis of 5-chloro-6- (2-oxo-4- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperazine-1-yl) ethyl nicotinate (Compound 371)
Figure JPOXMLDOC01-appb-C000079
　ステップ３７－１
　３－オキソピペラジン－１－カルボン酸tert－ブチル（2.0 g, 9.99 mmol）、５，６－ジクロロニコチン酸エチル（2.3 g, 10.45 mmol）、炭酸セシウム（6.51 g, 19.98 mmol）、ザントフォス（578 mg, 0.999 mmol）およびPd２(dba)３（457 mg, 0.499 mmol）をトルエン（20 mL）に加え窒素雰囲気下１２０℃で３時間加熱した。反応溶液をシリカゲルパッドに通し、濾液を濃縮した。残渣を分取用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、2.67 g の４－（３－クロロ－５－（エトキシカルボニル）ピリジン－２－イル）－３－オキソピペラジン－１－カルボン酸tert－ブチルを得た（収率70％）。
１H NMR (CDCl３, 400 MHz)δ 9.05 (d, 1 H, J = 1.6 Hz), 8.40 (d, 1 H, J = 1.6 Hz), 4.43 (q, 2 H, J = 7.2 Hz), 4.20 - 4.35 (m, 2 H), 4.05 (brm, 1 H), 3.84 (brm, 2 H), 3.61 (brm, 1 H), 1.50 (s, 9 H), 1.41 (t, 3 H, J = 7.2 Hz).LC-MS: r.t. 2.82 min.,　m/z 328 (M+1)。 Step 37-1
Tert-butyl 3-oxopiperazin-1-carboxylate (2.0 g, 9.99 mmol), ethyl 5,6-dichloronicotinate (2.3 g, 10.45 mmol), cesium carbonate (6.51 g, 19.98 mmol), zantphos (578 mg) , 0.999 mmol) and Pd 2 (dba) 3 (457 mg, 0.499 mmol) were added to toluene (20 mL) and heated at 120 ° C. for 3 hours in a nitrogen atmosphere. The reaction solution was passed through a silica gel pad to concentrate the filtrate. The residue was purified by preparative silica gel column chromatography (hexane / ethyl acetate) and 2.67 g of 4- (3-chloro-5- (ethoxycarbonyl) pyridine-2-yl) -3-oxopiperazin-1-carboxylic acid was purified. A tert-butyl acid acid was obtained (yield 70%).
1 H NMR (CDCl 3 , 400 MHz) δ 9.05 (d, 1 H, J = 1.6 Hz), 8.40 (d, 1 H, J = 1.6 Hz), 4.43 (q, 2 H, J = 7.2 Hz), 4.20 --4.35 (m, 2 H), 4.05 (brm, 1 H), 3.84 (brm, 2 H), 3.61 (brm, 1 H), 1.50 (s, 9 H), 1.41 (t, 3 H, J = 7.2 Hz) .LC-MS: rt 2.82 min., M / z 328 (M + 1).
　ステップ３７－２
　４－（３－クロロ－５－（エトキシカルボニル）ピリジン－２－イル）－３－オキソピペラジン－１－カルボン酸tert－ブチル（369 mg, 0.961 mmol）を4 N塩酸／酢酸エチル混合液（5 mL）に加え室温で一晩撹拌し、溶媒を濃縮乾固し、５－クロロ－６－（２－オキソピペラジン－１－イル）ニコチン酸エチル塩酸塩を得た。残渣は精製することなく次のステップに用いた。
１H NMR (DMSO, 400 MHz)δ 8.21 (br, 1 H), 7.08 (br, 1 H), 4.06 (br, 2 H), 3.63 (q, 2 H, J = 7.2 Hz), 2.89 - 3.42 (brm, 4 H), 0.61 (t, 3 H, J = 7.2 Hz).LC-MS: r.t. 1.37 min.,　m/z 284 (M+1)。 Step 37-2
4- (3-Chloro-5- (ethoxycarbonyl) pyridin-2-yl) -3-oxopiperazin-1-carboxylate tert-butyl (369 mg, 0.961 mmol) in 4 N hydrochloric acid / ethyl acetate mixture (5) In addition to mL), the mixture was stirred overnight at room temperature, and the solvent was concentrated to dryness to obtain ethyl 5-chloro-6- (2-oxopiperazin-1-yl) nicotinate ethyl hydrochloride. The residue was used in the next step without purification.
1 H NMR (DMSO, 400 MHz) δ 8.21 (br, 1 H), 7.08 (br, 1 H), 4.06 (br, 2 H), 3.63 (q, 2 H, J = 7.2 Hz), 2.89 --3.42 (brm, 4 H), 0.61 (t, 3 H, J = 7.2 Hz). LC-MS: rt 1.37 min., M / z 284 (M + 1).
　ステップ３７－３
　５－クロロ－６－（２－オキソピペラジン－１－イル）ニコチン酸エチル塩酸塩（296 mg, 0.925 mmol）とトリエチルアミン（0.515 mL, 3.7 mmol）をDMF（6 mL）に加えて第１液を作製した。0.925 mmolの２－フルオロ－Ｎ－ヒドロキシ－６－（トリフルオロメチル）ベンズイミドイル　クロリドをDMFに加えて第２液を作製した（0.88235 mmol/mL in DMF)。第１液に第２液を室温で加え、一晩撹拌した。反応溶液に10％ＫＨＳＯ４水溶液を加え、酢酸エチルにて抽出した。有機層をＮａＨＣＯ３水溶液で洗浄し、硫酸マグネシウムで乾燥し、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し、（Ｚ）－５－クロロ－６－（４－（（２－フルオロ－６－（トリフルオロメチル）フェニル）（ヒドロキシイミノ）メチル）－２－オキソピペラジン－１－イル）ニコチン酸エチル（化合物３７２（Ｚ））（262.3 mg, Rf = 0.4, １：１ヘキサン／酢酸エチル）を得た。収率58％。
１H NMR (CDCl３, 400 MHz)δ 9.00 (d, 1 H, J = 1.6 Hz), 8.38 (d, 1 H, J = 1.6 Hz), 8.17 (br, 0.5 H), 7.54 - 7.58 (m, 2 H), 7.32 - 7.40 (m, 1 H), 4.42 (q, 2 H, J = 7.2 Hz), 3.58 - 4.30 (br, 4.5 H), 1.40 (t, 3 H, J = 7.2 Hz).LC-MS: r.t. 2.61 min.,　m/z 489 (M+1)。 Step 37-3
Add 5-chloro-6- (2-oxopiperazine-1-yl) ethyl nicotinate hydrochloride (296 mg, 0.925 mmol) and triethylamine (0.515 mL, 3.7 mmol) to DMF (6 mL) to add the first solution. Made. 0.925 mmol of 2-fluoro-N-hydroxy-6- (trifluoromethyl) benzimideyl chloride was added to DMF to prepare a second solution (0.88235 mmol / mL in DMF). The second solution was added to the first solution at room temperature, and the mixture was stirred overnight. Aqueous 10% KHSO 4 was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with an aqueous solution of NaHCO 3 , dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane) for preparative use. 6-(4-((2-Fluoro-6- (trifluoromethyl) phenyl) (hydroxyimino) methyl) -2-oxopiperazin-1-yl) ethyl nicotinate (Compound 372 (Z)) (262.3 mg, Rf = 0.4, 1: 1 hexane / ethyl acetate) was obtained. Yield 58%.
1 1 H NMR (CDCl 3 , 400 MHz) δ 9.00 (d, 1 H, J = 1.6 Hz), 8.38 (d, 1 H, J = 1.6 Hz), 8.17 (br, 0.5 H), 7.54 --7.58 (m) , 2 H), 7.32 --7.74 (m, 1 H), 4.42 (q, 2 H, J = 7.2 Hz), 3.58 --4.30 (br, 4.5 H), 1.40 (t, 3 H, J = 7.2 Hz) .LC-MS: rt 2.61 min., M / z 489 (M + 1).
　ステップ３７－４
　（Ｚ）－５－クロロ－６－（４－（（２－フルオロ－６－（トリフルオロメチル）フェニル）（ヒドロキシイミノ）メチル）－２－オキソピペラジン－１－イル）ニコチン酸エチル（化合物３７２（Ｚ）；128.8 mg）とp-トルエンスルホ酸（10 mg）をDMSO（2 mL）に加え８０℃で１時間加熱した。これにDBU (910 μL）を加え、１２０℃で３０分間加熱した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層を硫酸マグネシウムで乾燥し、溶媒を減圧留去し、残渣を分取用シリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン）で精製し、表題化合物を得た(50 mg、Rf = 0.4, １：1ヘキサン／酢酸エチル）。
１H NMR (CDCl３, 400 MHz)δ 9.04 (d, 1 H, J = 1.6 Hz), 8.43 (d, 1 H, J = 1.6 Hz), 7.79 (dd, 1 H, J = 1.6, 7.2 Hz), 7.65 - 7.71 (m, 2 H), 4.44 (q, 2 H, J = 7.2 Hz), 4.15 -4.35 (brm, 3 H), 3.72 - 3.82 (m, 3 H), 1.43 (t, 3 H, J = 7.2 Hz).LC-MS: r.t. 2.66 min.,　m/z 441 (M+1)。 Step 37-4
Ethyl (Z) -5-chloro-6-(4-((2-fluoro-6- (trifluoromethyl) phenyl) (hydroxyimino) methyl) -2-oxopiperazin-1-yl) nicotinate (Compound 372) (Z); 128.8 mg) and p-toluenesulfonic acid (10 mg) were added to DMSO (2 mL) and heated at 80 ° C. for 1 hour. DBU (910 μL) was added thereto, and the mixture was heated at 120 ° C. for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography for preparative use (ethyl acetate / hexane) to give the title compound (50 mg, Rf = 0.4, 1: 1 hexane / ethyl acetate).
1 H NMR (CDCl 3 , 400 MHz) δ 9.04 (d, 1 H, J = 1.6 Hz), 8.43 (d, 1 H, J = 1.6 Hz), 7.79 (dd, 1 H, J = 1.6, 7.2 Hz) ), 7.65 --7.71 (m, 2 H), 4.44 (q, 2 H, J = 7.2 Hz), 4.15 -4.35 (brm, 3 H), 3.72 --3.82 (m, 3 H), 1.43 (t, 3) H, J = 7.2 Hz). LC-MS: rt 2.66 min., M / z 441 (M + 1).
　［実施例３８］
５－クロロ－６－（２－オキソ－４－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸（化合物３８１）の合成
Figure JPOXMLDOC01-appb-C000080
 [Example 38]
Synthesis of 5-chloro-6- (2-oxo-4- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperazine-1-yl) nicotinic acid (Compound 381)
Figure JPOXMLDOC01-appb-C000080
　５－クロロ－６－（２－オキソ－４－（４－（トリフルオロメチル）ベンゾ[ｄ]イソオキサゾール－３－イル）ピペラジン－１－イル）ニコチン酸エチル（化合物３７１；45 mg）をDME（2 mL）に加え、さらに2 N水酸化ナトリウム水溶液（1 mL）を加え、室温で一晩撹拌した。溶液を減圧濃縮し1 N塩酸（2 mL）を加え中和した。生成した粉末を濾取し、減圧乾燥し、18.3 mgの表題化合物を得た。
１H NMR (DMSO, 400 MHz)δ 8.96 (d, 1 H, J = 1.6 Hz), 8.42 (d, 1 H, J = 1.6 Hz), 8.10 - 8.16 (m, 1 H), 7.86 - 7.89 (m, 2 H), 4.02 - 4.15 (m, 3 H), 3.62 - 3.75 (m, 3 H).
LC-MS: r.t. 2.66 min.,　m/z 441 (M+1)。 DME of 5-chloro-6- (2-oxo-4- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) piperazine-1-yl) ethyl nicotinate (Compound 371; 45 mg) In addition to (2 mL), a 2 N aqueous sodium hydroxide solution (1 mL) was further added, and the mixture was stirred overnight at room temperature. The solution was concentrated under reduced pressure and neutralized by adding 1 N hydrochloric acid (2 mL). The resulting powder was collected by filtration and dried under reduced pressure to give 18.3 mg of the title compound.
1 1 H NMR (DMSO, 400 MHz) δ 8.96 (d, 1 H, J = 1.6 Hz), 8.42 (d, 1 H, J = 1.6 Hz), 8.10 --8.16 (m, 1 H), 7.86 --7.89 ( m, 2 H), 4.02 --4.15 (m, 3 H), 3.62 --3.75 (m, 3 H).
LC-MS: rt 2.66 min., M / z 441 (M + 1).
　［実施例３９］
３－クロロ－４－（１－（４－（トリフルオロメチル）ベンゾ［ｄ］イソオキサゾール－３－イル）－１，２，３，６－テトラヒドロピリジン－４－イル）安息香酸メチル（化合物３９１）の合成
Figure JPOXMLDOC01-appb-C000081
 [Example 39]
3-Chloro-4- (1- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) -1,2,3,6-tetrahydropyridin-4-yl) methyl benzoate (Compound 391) ) Synthesis
Figure JPOXMLDOC01-appb-C000081
　１－クロロ－２－ヨードベンゼンに代えて４－ブロモ－３－クロロ安息香酸メチルを用いた以外は、実施例３６の方法に従って表題化合物を得た。
１H NMR (CDCl３, 400 MHz)δ8.05 (d, 1 H, J = 1.2 Hz), 7.92 (dd, 1 H, J = 1.2, 8.4 Hz), 7.76 (d, 1 H, J = 7.2 Hz), 7.62 - 7.68 (m, 2 H), 7.57 (d, 1 H, J = 8.4 Hz), 5.83 (m, 1 H, J = 7.6 Hz), 4.87 (dd, 1 H, J = 3.6, 8.0 Hz), 4.10 - 4.16 (m, 1 H), 3.92 (s, 3 H), 3.64 - 3.71 (m, 1 H), 3.51 - 3.58 (m, 1 H), 2.36 - 2.46 (m, 1 H), 1.86 - 1.95 (m, 1 H).
LC-MS: r.t. 3.72 min.,　m/z 437 (M+1)。 The title compound was obtained according to the method of Example 36, except that methyl 4-bromo-3-chlorobenzoate was used instead of 1-chloro-2-iodobenzene.
1 H NMR (CDCl 3 , 400 MHz) δ8.05 (d, 1 H, J = 1.2 Hz), 7.92 (dd, 1 H, J = 1.2, 8.4 Hz), 7.76 (d, 1 H, J = 7.2) Hz), 7.62 --7.68 (m, 2 H), 7.57 (d, 1 H, J = 8.4 Hz), 5.83 (m, 1 H, J = 7.6 Hz), 4.87 (dd, 1 H, J = 3.6, 8.0 Hz), 4.10 --4.16 (m, 1 H), 3.92 (s, 3 H), 3.64 --3.71 (m, 1 H), 3.51 --3.58 (m, 1 H), 2.36 --2.46 (m, 1 H) ), 1.86 --1.95 (m, 1 H).
LC-MS: rt 3.72 min., M / z 437 (M + 1).
　［実施例４０］
３－クロロ－４－（１－（４－（トリフルオロメチル）ベンゾ［ｄ］イソオキサゾール－３－イル）－１，２，３，６－テトラヒドロピリジン－４－イル）安息香酸メチル（化合物４０１）の合成
Figure JPOXMLDOC01-appb-C000082
 [Example 40]
3-Chloro-4- (1- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) -1,2,3,6-tetrahydropyridin-4-yl) methyl benzoate (Compound 401) ) Synthesis
Figure JPOXMLDOC01-appb-C000082
　化合物３７１に代えて３－クロロ－４－（１－（４－（トリフルオロメチル）ベンゾ［ｄ］イソオキサゾール－３－イル）－１，２，３，６－テトラヒドロピリジン－４－イル）安息香酸メチル（化合物３９１）を用いた以外は、実施例３８の方法に従って表題化合物を得た。
１H NMR (CDCl３, 400 MHz)δ8.13 (d, 1 H, J = 2 Hz), 7.97 (dd, 1 H, J = 2, 7.6 Hz), 7.74 (d, 1 H, J = 7.6 Hz), 7.62 - 7.68 (m, 2 H), 7.39 (d, 1 H, J = 8 Hz), 5.87 - 5.91 (m, 1 H), 4.05 - 4.09 (m, 2 H), 3.54 (t, 2 H, J = 6.8 Hz), 2.68 - 2.73 (m, 2 H). 
LC-MS: r.t. 3.40 min.,　m/z 423 (M+1)。 3-Chloro-4- (1- (4- (trifluoromethyl) benzo [d] isooxazole-3-yl) -1,2,3,6-tetrahydropyridine-4-yl) benzoic acid instead of compound 371 The title compound was obtained according to the method of Example 38, except that methyl acid (Compound 391) was used.
1 1 H NMR (CDCl 3 , 400 MHz) δ8.13 (d, 1 H, J = 2 Hz), 7.97 (dd, 1 H, J = 2, 7.6 Hz), 7.74 (d, 1 H, J = 7.6) Hz), 7.62 --7.68 (m, 2 H), 7.39 (d, 1 H, J = 8 Hz), 5.87 --5.91 (m, 1 H), 4.05 --4.09 (m, 2 H), 3.54 (t, 2 H, J = 6.8 Hz), 2.68 --2.73 (m, 2 H).
LC-MS: rt 3.40 min., M / z 423 (M + 1).
　［実施例４１］
３－（４－（２－クロロフェニル）ピぺラジン－１－イル）－４－ヨードベンゾ［ｄ］イソオキサゾール（化合物４１１）の合成
Figure JPOXMLDOC01-appb-C000083
 [Example 41]
Synthesis of 3- (4- (2-chlorophenyl) piperazin-1-yl) -4-iodobenzo [d] isooxazole (Compound 411)
Figure JPOXMLDOC01-appb-C000083
　ステップ４１－１
　２－フルオロ－６－ヨードベンズアルデヒド（２．５ｇ、１０mmol）のエタノール（１５mL）の溶液に、ヒドロキシアミン塩酸塩（０．７９０ｇ、１１mmol）の２N水酸化ナトリウム水溶液（５．５mL、１１mmol）を加え、室温で終夜撹拌した。反応液に水を加え、析出した結晶をろ取し水で洗浄、減圧乾燥して、２－フルオロ－６－ヨードベンズアルデヒド　オキシム（２．５０５ｇ）を得た。 Step 41-1
To a solution of 2-fluoro-6-iodobenzaldehyde (2.5 g, 10 mmol) in ethanol (15 mL), add a 2N aqueous sodium hydroxide solution (5.5 mL, 11 mmol) of hydroxyamine hydrochloride (0.790 g, 11 mmol). , Stirred overnight at room temperature. Water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water, and dried under reduced pressure to obtain 2-fluoro-6-iodobenzaldehyde oxime (2.505 g).
　ステップ４１－２
　２－フルオロ－６－ヨードベンズアルデヒド　オキシム（０．５３０ｇ、２mmol）のDMF（１０mL）の溶液にNCS（N-クロロスクシンイミド）（０．２７６ｇ、２mmol）を加え、室温で終夜撹拌した。LC/MSはオキシムが１００％塩化物に変換したことを示した。２－フルオロ－Ｎ－ヒドロキシ－６－ヨードベンズイミドイル　クロリドの溶液は精製することなしに次の反応に用いた。 Step 41-2
NCS (N-chlorosuccinimide) (0.276 g, 2 mmol) was added to a solution of 2-fluoro-6-iodobenzaldehyde oxime (0.530 g, 2 mmol) in DMF (10 mL), and the mixture was stirred overnight at room temperature. LC / MS showed that the oxime was converted to 100% chloride. A solution of 2-fluoro-N-hydroxy-6-iodobenzimideyl chloride was used in the next reaction without purification.
　ステップ４１－３
　１－（２－クロロフェニル）ピペラジン（１７６μL、１mmol）とトリエチルアミン（１６８μL、１．２mmol）のＤＭＦ（１ｍL）の溶液に、ステップ４１－２の２－フルオロ－Ｎ－ヒドロキシ－６－ヨードベンズイミドイル　クロリドのＤＭＦ溶液（５ｍＬ、約１mmol）を室温で加え、終夜撹拌した。反応溶液に飽和塩化アンモニウム水溶液と水を加え、酢酸エチルにて抽出した。有機層を硫酸ナトリウムで乾燥、溶媒を減圧留去し、（Ｅ）－（４－（２－クロロフェニル）ピペラジン－１－イル）(２－フルオロ－６－ヨードフェニル)メタノンオキシム（化合物４１２（Ｅ））とそのＺ異性体（化合物４１２（Ｚ））をE/Z混合物（６５７．８ｍｇ）として得た。 Step 41-3
2-Fluoro-N-hydroxy-6-iodobenzimideyl of step 41-2 in a solution of 1- (2-chlorophenyl) piperazine (176 μL, 1 mmol) and triethylamine (168 μL, 1.2 mmol) in DMF (1 mL). A solution of chloride in DMF (5 mL, about 1 mmol) was added at room temperature and stirred overnight. A saturated aqueous ammonium chloride solution and water were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the solvent was evaporated under reduced pressure, and (E)-(4- (2-chlorophenyl) piperazin-1-yl) (2-fluoro-6-iodophenyl) methanone oxime (Compound 412 (Compound 412). E)) and its Z isomer (Compound 412 (Z)) were obtained as an E / Z mixture (657.8 mg).
　ステップ４１－４
　（４－（２－クロロフェニル）ピペラジン－１－イル）(２－フルオロ－６－ヨードフェニル)メタノンオキシム（６５７ｍｇ、１mmol）とp-トルエンスルホン酸（約1０mg）をDMSO（５mL）に加え８０℃で２時間加熱した。これにDBU（ジアザビシクロウンデセン；２３８μL）を加え、１２０℃で６０分間加熱した。反応溶液に飽和塩化アンモニウム水溶液を加え、酢酸エチルにて抽出した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去して、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１０：１～３：１）で精製し、２９５．８ｍｇの表題化合物を得た。
１H NMR (CDCl３, 400 MHz)δ7.47 (t, 0.5 H, J = 7.6 Hz), 7.46 (t, 0.5 H, J = 7.6 Hz), 7.39 (dd, 1 H, J = 1.2, 8.0 Hz), 7.28 (d, 1 H, 8.0 Hz), 7.25 (dt, 1 H, J = 1.2, 7.6 Hz), 7.10 (dd, 1 H, J = 1.2, 6.8 Hz), 7.01 (dt, 1 H, J = 1.2, 7.6 Hz), 6.93 (d, 0.5 H, J = 8.0 Hz), 6.91 (d, 0.5 H, J = 8.0 Hz), 3.67 - 3.72 (m, 4 H), 3.23 - 3.28 (m, 4 H), LC-MS: r.t. 4.18 min., m/z 440 (M+1)。 Step 41-4
Add (4- (2-chlorophenyl) piperazine-1-yl) (2-fluoro-6-iodophenyl) methanone oxime (657 mg, 1 mmol) and p-toluenesulfonic acid (about 10 mg) to DMSO (5 mL) 80. It was heated at ° C. for 2 hours. DBU (diazabicycloundecene; 238 μL) was added thereto, and the mixture was heated at 120 ° C. for 60 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 10: 1 to 3: 1) to give 295.8 mg of the title compound. ..
1 H NMR (CDCl 3 , 400 MHz) δ7.47 (t, 0.5 H, J = 7.6 Hz), 7.46 (t, 0.5 H, J = 7.6 Hz), 7.39 (dd, 1 H, J = 1.2, 8.0 Hz), 7.28 (d, 1 H, 8.0 Hz), 7.25 (dt, 1 H, J = 1.2, 7.6 Hz), 7.10 (dd, 1 H, J = 1.2, 6.8 Hz), 7.01 (dt, 1 H) , J = 1.2, 7.6 Hz), 6.93 (d, 0.5 H, J = 8.0 Hz), 6.91 (d, 0.5 H, J = 8.0 Hz), 3.67 --3.72 (m, 4 H), 3.23 --3.28 (m) , 4 H), LC-MS: rt 4.18 min., m / z 440 (M + 1).
　［実施例４２］
３－（４－（２－クロロフェニル）ピぺラジン－１－イル）－４－シアノベンゾ［ｄ］イソオキサゾール（化合物４２１）の合成
Figure JPOXMLDOC01-appb-C000084
 [Example 42]
Synthesis of 3- (4- (2-chlorophenyl) piperazin-1-yl) -4-cyanobenzo [d] isooxazole (Compound 421)
Figure JPOXMLDOC01-appb-C000084
３－（４－（２－クロロフェニル）ピぺラジン－１－イル）－４－ヨードベンゾ［ｄ］イソオキサゾール（実施例４１の化合物、１８３mg、０．４２mmol）、シアン化亜鉛（７３mg、０．６２mmol）、およびテトラキストリフェニルホスフィンパラジウム（４８mg、０．０４２mmol）をDMF（５mL）に加え、窒素下80℃で７時間加熱撹拌した。反応混合物に塩化アンモニウム水溶液を加え、酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去して、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル／ヘキサン＝１０：１～３：１）で精製し、１１９mgの表題化合物を得た。
１H NMR (CDCl３, 400 MHz)δ7.76 (d, 1 H, J = 8.0 Hz), 7.68 (d, 1 H, J = 6.4 Hz), 7.62 (dd, 1 H, J = 8.0 Hz), 7.39 (dd, 1 H, J = 1.2, 7.6 Hz), 7.25 (dt, 1 H, J = 1.2, 8.0 Hz), 7.15 (dd, 1 H, J = 2.0, 8.0 Hz), 7.01 (dt, 1 H, J = 1.6, 8.0 Hz), 3.64 - 3.69 (m, 4 H), 3.32 - 3.36 (m, 4 H), LC-MS: r.t. 3.73 min., m/z 339 (M+1)。 3- (4- (2-Chlorophenyl) piperazin-1-yl) -4-iodobenzo [d] isoxazole (compound of Example 41, 183 mg, 0.42 mmol), zinc cyanide (73 mg, 0.62 mmol) ) And tetrakistriphenylphosphine palladium (48 mg, 0.042 mmol) were added to DMF (5 mL), and the mixture was heated and stirred at 80 ° C. under nitrogen for 7 hours. An aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / hexane = 10: 1 to 3: 1) to give 119 mg of the title compound.
1 H NMR (CDCl 3 , 400 MHz) δ7.76 (d, 1 H, J = 8.0 Hz), 7.68 (d, 1 H, J = 6.4 Hz), 7.62 (dd, 1 H, J = 8.0 Hz) , 7.39 (dd, 1 H, J = 1.2, 7.6 Hz), 7.25 (dt, 1 H, J = 1.2, 8.0 Hz), 7.15 (dd, 1 H, J = 2.0, 8.0 Hz), 7.01 (dt, dt, 1 H, J = 1.6, 8.0 Hz), 3.64 --3.69 (m, 4 H), 3.32 --3.36 (m, 4 H), LC-MS: rt 3.73 min., M / z 339 (M + 1).
　［実施例４３］
３－（４－（２－クロロフェニル）ピペラジン－１－イル）ベンゾ［ｄ］イソオキサゾール－４－カルボキシアミド（化合物４３１）の合成
Figure JPOXMLDOC01-appb-C000085
 [Example 43]
Synthesis of 3- (4- (2-chlorophenyl) piperazine-1-yl) benzo [d] isooxazole-4-carboxamide (Compound 431)
Figure JPOXMLDOC01-appb-C000085
３－（４－（２－クロロフェニル）ピぺラジン－１－イル）－４－シアノベンゾ［ｄ］イソオキサゾール（実施例４２の化合物、３７.８mg、０．１１mmol）を１，４－ジオキサン（２mL）とエタノール（２mL）の混合溶液に溶解させ、飽和水酸化リチウム水溶液（１mL）を加え、マイクロウェーブ反応器にて150℃で2時間反応させた。混合物を塩酸水溶液で中和し酢酸エチルで抽出した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去して、残渣をシリカゲルカラムクロマトグラフィーを用いて１００％酢酸エチルで留出させ、続いて５％メタノール／酢酸エチルで留出させることにより精製し、表題化合物を含む混合物を得た。混合物を酢酸エチルに溶解させ、飽和重曹水で3回洗浄した。有機層を硫酸ナトリウムで乾燥し、溶媒を減圧留去して、表題化合物(２７.９mg)を得た。
１H NMR (CDCl３, 400 MHz)δ8.27(bs, 1 H,), 8.04 (dd, 1 H, J = 0.8, 7.6 Hz), 7.69 (dd, 1 H, J =1.2, 8.4 Hz), 7.64 (dd, 1 H, J = 7.2, 8.4 Hz), 7.38 (dd, 1 H, J = 1.2, 7.6 Hz), 7.25 (dt, 1 H, J = 1.6, 7.6 Hz), 7.08 (dd, 1 H, J = 1.2, 7.6 Hz), 7.02 (dt, 1 H, J = 1.2, 7.6 Hz), 6.17 (bs, 1 H)3.52 - 3.57 (m, 4 H), 3.23 - 3.29 (m, 4 H), LC-MS: r.t. 3.00 min., m/z 357 (M+1)。(L-0003) 3- (4- (2-Chlorophenyl) piperazin-1-yl) -4-cyanobenzo [d] isooxazole (compound of Example 42, 37.8 mg, 0.11 mmol) was added to 1,4-dioxane (2 mL). ) And ethanol (2 mL), a saturated aqueous solution of lithium hydroxide (1 mL) was added, and the mixture was reacted at 150 ° C. for 2 hours in a microwave reactor. The mixture was neutralized with aqueous hydrochloric acid and extracted with ethyl acetate. The organic layer is dried over sodium sulfate, the solvent is evaporated under reduced pressure, and the residue is purified by distillation with 100% ethyl acetate using silica gel column chromatography, followed by distillation with 5% methanol / ethyl acetate. A mixture containing the title compound was obtained. The mixture was dissolved in ethyl acetate and washed 3 times with saturated aqueous sodium hydrogen carbonate. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (27.9 mg).
1 H NMR (CDCl 3 , 400 MHz) δ8.27 (bs, 1 H,), 8.04 (dd, 1 H, J = 0.8, 7.6 Hz), 7.69 (dd, 1 H, J = 1.2, 8.4 Hz) , 7.64 (dd, 1 H, J = 7.2, 8.4 Hz), 7.38 (dd, 1 H, J = 1.2, 7.6 Hz), 7.25 (dt, 1 H, J = 1.6, 7.6 Hz), 7.08 (dd, dd, 1 H, J = 1.2, 7.6 Hz), 7.02 (dt, 1 H, J = 1.2, 7.6 Hz), 6.17 (bs, 1 H) 3.52 --3.57 (m, 4 H), 3.23 --3.29 (m, 4) H), LC-MS: rt 3.00 min., M / z 357 (M + 1). (L-0003)
　［試験例１］
　TRPCチャネルを一過的に発現したHEK293細胞を用いたカルシウムアッセイ１．TRPCチャネルの細胞への導入および発現
　HEK293細胞（ヒト胎児腎由来細胞）にTRPC6遺伝子をリポフェクション法で導入し、細胞膜にTRPC6チャネルを発現させた。具体的には、TRPC6のプラスミドDNA（pCI-neo (promega社)）をリポフェクション剤を用いてHEK293細胞へ導入後、37℃で24～48時間培養し細胞膜にTRPC6チャネルを発現させた。同様にして、TRPC3遺伝子を導入したHEK293細胞を培養し細胞膜にTRPC3チャネルを発現させた。 [Test Example 1]
Calcium assay using HEK293 cells transiently expressing TRPC channels 1. Introduction and expression of TRPC channel into cells The TRPC6 gene was introduced into HEK293 cells (human fetal kidney-derived cells) by the lipofection method, and the TRPC6 channel was expressed on the cell membrane. Specifically, the plasmid DNA of TRPC6 (pCI-neo (promega)) was introduced into HEK293 cells using a lipofection agent, and then cultured at 37 ° C. for 24-48 hours to express the TRPC6 channel on the cell membrane. Similarly, HEK293 cells into which the TRPC3 gene was introduced were cultured to express TRPC3 channels on the cell membrane.
２．TRPC発現細胞内におけるカルシウムイオン濃度変化の測定
　培養細胞をトリプシンで剥がし、カバーガラスに撒き直したのち、再び37℃で3時間培養した。培地にカルシウム指示薬Fura-2 AMを加え30分間37℃で培養し細胞に取り込ませた。細胞外溶液にはCa２＋含有溶液およびCa２＋フリー溶液を用意した。 2. Measurement of changes in calcium ion concentration in TRPC-expressing cells The cultured cells were peeled off with trypsin, re-spread on a cover glass, and then cultured again at 37 ° C. for 3 hours. The calcium indicator Fura-2 AM was added to the medium, and the cells were cultured for 30 minutes at 37 ° C. and incorporated into cells. Ca 2+ -containing solution and Ca 2+ free solution were prepared as extracellular solutions.
Ca２＋含有溶液：(2 mM CaCl2, 132 mM NaCl, 4 mM KCl, 1mM MgCl2, 5 mMグルコース, 5 mM HEPES (pH7.4))
Ca２＋フリー溶液：(132 mM NaCl, 4 mM KCl, 1mM MgCl2, 5 mMグルコース, 5 mM HEPES (pH7.4)) Ca 2+ -containing solution: (2 mM CaCl 2 , 132 mM NaCl, 4 mM KCl, 1 mM MgCl 2 , 5 mM glucose, 5 mM HEPES (pH 7.4))
Ca 2+ free solution: (132 mM NaCl, 4 mM KCl, 1 mM MgCl 2 , 5 mM glucose, 5 mM HEPES (pH 7.4))
　Ca2+含有溶液に細胞を入れた後、室温で、Fura-2の蛍光強度（510 nm）をARGUS CA-20（Hamamatsu Photonics社）で経時的に測定しつつ以下の操作を行った。 After the cells were placed in the Ca 2+ -containing solution, the following operation was performed while measuring the fluorescence intensity (510 nm) of Fura-2 over time with ARGUS CA-20 (Hamamatsu Photonics) at room temperature.
０分：Ca２＋含有溶液を入れた測定用チャンバーにTRPC3発現細胞またはTRPC6発現細胞を入れる
３０秒後：Ca２＋含有溶液をCa2+フリー溶液に置き換える
１分後：Ca２＋フリー溶液に所定量の試験化合物を添加する
３分後：Ca２＋フリー溶液にカルバコール（100μM）を添加する
７分後：Ca２＋フリー溶液を試験化合物およびカルバコール（100μM）を含むCa２＋含有溶液に置き換える
１５分後：測定終了 0 minutes: Put TRPC3-expressing cells or TRPC6-expressing cells in the measurement chamber containing Ca 2+ -containing solution 30 seconds later: Replace Ca 2+ -containing solution with Ca 2+ free solution 1 minute later: Prescribe amount in Ca 2+ free solution after 3 to addition of test compound minutes: Ca 2+ free solution 7 min after addition of carbachol (100μM): Ca 2+ free solution of the test compound and carbachol (100μM) Ca 2+ containing solution replaced 15 minutes later including: End of measurement
　試験化合物には化合物０１１を使用し、その添加量は、0.01、0.1、0.5、1.0、5.0、10、または50μMである。また、試験化合物に代えて0.1％のDMSOを使用しコントロールとした。なお、カルバコール（cch）は、TRPCチャネル活性化剤であり、これを細胞に適用すると、TRPCチャネルが開口し、細胞外溶液中のCa２＋が細胞内に多量に流入する。また、Fura-2 AMは、AM基（アセトキシメチル基）の存在により細胞膜透過性が高く、細胞内に容易に取り込まれ、細胞内でAM基が加水分解を受けることでFura-2となる結果、Ca２＋とキレート形成が可能となるとともに、AM基を失ったことで細胞外へ漏れ出しにくくなる。 Compound 011 is used as the test compound, and the amount added thereof is 0.01, 0.1, 0.5, 1.0, 5.0, 10, or 50 μM. In addition, 0.1% DMSO was used instead of the test compound as a control. Carbacol (cch) is a TRPC channel activator, and when it is applied to cells, TRPC channels open and a large amount of Ca 2+ in the extracellular solution flows into the cells. In addition, Fura-2 AM has high cell membrane permeability due to the presence of AM group (acetoxymethyl group), is easily taken up into cells, and the AM group is hydrolyzed inside the cell to become Fura-2. , Ca 2+ and chelate formation are possible, and the loss of the AM group makes it difficult for the cell to leak out of the cell.
　TRPC6発現細胞およびTRPC3発現細胞での測定結果をカルシウムイメージングでそれぞれ図１および２に示す。細胞内Ca２＋濃度は、カルバコール（cch）添加によって、コントロール（DMSO）では100nM程度から280nM程度（TRPC6、図１）または100nM程度から350nM程度（TRPC3、図２）まで上昇したが、試験化合物（化合物０１１）では100nM程度から140nM程度（TRPC6、図１）または100nM程度から180nM程度（TRPC3、図２）までの上昇であり、TRPC6およびTRPC3チャネルの活性化の抑制が確認された。また、測定結果から濃度－応答曲線を作成したところTRPC6およびTRPC3チャネルの阻害のIC５０は、4.6μM（TRPC6）および0.7μM（TRPC3）であった。 The measurement results of TRPC6-expressing cells and TRPC3-expressing cells are shown in FIGS. 1 and 2 by calcium imaging, respectively. The intracellular Ca 2+ concentration increased from about 100 nM to about 280 nM (TRPC6, Fig. 1) or about 100 nM to about 350 nM (TRPC3, Fig. 2) under control (DMSO) by adding carbachol (cch), but the test compound (TRPC3, Fig. 2) In compound 011), the increase was from about 100 nM to about 140 nM (TRPC6, FIG. 1) or from about 100 nM to about 180 nM (TRPC3, FIG. 2), and suppression of activation of TRPC6 and TRPC3 channels was confirmed. The concentration measurement results - was created response curves TRPC6 and TRPC3 channel IC 50 for inhibition of was 4.6μM (TRPC6), and 0.7 [mu] M (TRPC3).
　［試験例２］
　TRPC6チャネルを一過的に発現したHEK293細胞を用いたカルシウムアッセイ　試験例１と同様にして調製したTRPC6発現細胞を用い、10μMのPyr 4、ならびに試験化合物として10μMの化合物０１１、０３１、０４１、および１９１を使用した以外は、試験例１と同様にして、測定開始７分後以降（つまりCa２＋含有溶液置換後）における最大カルシウムイオン濃度値を計測した。この最大カルシウムイオン濃度値から、測定開始後３０秒までのカルシウムイオン濃度の平均の値（カルシウムイオン濃度の初期値）を控除して算出した値をカルシウムイオン増加量とした。結果を図３に示す。図３では、カルシウムイオン増加量を、コントロール（DMSO）でのカルシウムイオン増加量を100％とした相対値として表した。試験化合物の添加によって細胞内に流入するカルシウムイオンが減少したことから、TRPC6チャネルの活性化の抑制が確認された。 [Test Example 2]
Calcium Assay Using HEK293 Cells Transiently Expressing TRPC6 Channels Using TRPC6-expressing cells prepared in the same manner as in Test Example 1, 10 μM Pyr 4, and 10 μM compounds 011, 031, 041, and as test compounds. The maximum calcium ion concentration value was measured 7 minutes after the start of measurement (that is, after replacement of the Ca 2+ -containing solution) in the same manner as in Test Example 1 except that 191 was used. The value calculated by subtracting the average value of the calcium ion concentration (initial value of the calcium ion concentration) up to 30 seconds after the start of measurement from this maximum calcium ion concentration value was defined as the amount of increase in calcium ions. The results are shown in FIG. In FIG. 3, the amount of increase in calcium ions is expressed as a relative value with the amount of increase in calcium ions in control (DMSO) as 100%. The addition of the test compound reduced the amount of calcium ions flowing into the cells, confirming the suppression of TRPC6 channel activation.
　［試験例２－１］
　TRPC6チャネルを一過的に発現したHEK293細胞を用いたカルシウムアッセイ　試験化合物として10μMの化合物０１１、３６１、３６２（Ｅ）、３６２（Ｚ）、３７１、３７２（Ｚ）、３８１、および４０１を使用し、Pyr 4を使用しないこと以外は、試験例２と同様にしてカルシウムイオン濃度を測定し、カルシウムイオン増加量を求めた。　各試験化合物のカルシウムイオン増加量を、コントロール（DMSO）でのカルシウムイオン増加量を100％とした相対値として表２に示す。
Figure JPOXMLDOC01-appb-T000086
 [Test Example 2-1]
Calcium Assay Using HEK293 Cells Transiently Expressing TRPC6 Channel 10 μM Compounds 011, 361, 362 (E), 362 (Z), 371, 372 (Z), 381, and 401 were used as test compounds. , Pyr 4 was not used, but the calcium ion concentration was measured in the same manner as in Test Example 2 to determine the amount of increase in calcium ions. The amount of increase in calcium ions of each test compound is shown in Table 2 as a relative value with the amount of increase in calcium ions in control (DMSO) as 100%.
Figure JPOXMLDOC01-appb-T000086
　試験化合物の添加によって細胞内に流入するカルシウムイオンが減少したことから、TRPC6チャネルの活性化の抑制が確認された。 The addition of the test compound reduced the calcium ions flowing into the cells, confirming the suppression of TRPC6 channel activation.
　［試験例３］
　TRPC6チャネルを一過的に発現したHEK293細胞を用いたカルシウムアッセイ　10μMのPyr 4、ならびに試験化合物として10μMの化合物２０２（Ｅ）、０６１、および０７１を用い、TRPCチャネル活性化剤としてカルバコールに代えてATPを使用した以外は、試験例２と同様にしてカルシウムイオン濃度を測定し、カルシウムイオン増加量を求めた。結果を図４に示す。図４では、カルシウムイオン増加量を、コントロール（DMSO）でのカルシウムイオン増加量を100％とした相対値として表した。試験化合物の添加によって細胞内に流入するカルシウムイオンが減少したことから、TRPC6チャネルの活性化の抑制が確認された。 [Test Example 3]
Calcium assay using HEK293 cells transiently expressing TRPC6 channels 10 μM Pyr 4 and 10 μM compounds 202 (E), 061, and 071 as test compounds were used in place of carbacol as TRPC channel activators. The calcium ion concentration was measured in the same manner as in Test Example 2 except that ATP was used, and the amount of increase in calcium ions was determined. The results are shown in FIG. In FIG. 4, the amount of increase in calcium ions is represented as a relative value with the amount of increase in calcium ions in control (DMSO) as 100%. The addition of the test compound reduced the amount of calcium ions flowing into the cells, confirming the suppression of TRPC6 channel activation.
　［試験例４］
　TRPC6チャネルを一過的に発現したHEK293細胞を用いた電気生理的評価
　試験例１と同様の処置を施して培養したTRPC6発現細胞を用いて評価を行った。トランスフェクションされた細胞を顕微鏡に設置したチャンバー内に置き、パッチガラス電極（5～10 MΩ）にてホールセル（全細胞）モードにてTRPC6電流を測定した。ここで用いた、細胞外溶液および細胞内溶液は以下のとおりである。 [Test Example 4]
Electrophysiological evaluation using HEK293 cells transiently expressing the TRPC6 channel Evaluation was performed using TRPC6-expressing cells cultured under the same treatment as in Test Example 1. Transfected cells were placed in a microscopic chamber and TRPC6 current was measured in whole cell mode with patch glass electrodes (5-10 MΩ). The extracellular solution and intracellular solution used here are as follows.
細胞外溶液：(140 mM NaCl, 5 mM KCl, 1 mM CaCl2, 1.2 mM MgCl2, 10 mM Glucose, 10 mM HEPES (pH7.4))
細胞内溶液：(120 mM CsOH, 120 mM Aspartate, 20 mM CsCl, 2mM MgCl2, 1.5 mM CaCl2, 5 mM EGTA, 10 mM Glucose, 10 mM HEPES, 2 mM ATP-Na, 0.1 mM GTP (pH7.4)) Extracellular solution: (140 mM NaCl, 5 mM KCl, 1 mM CaCl 2 , 1.2 mM MgCl 2 , 10 mM Glucose, 10 mM HEPES (pH 7.4))
Intracellular solution: (120 mM CsOH, 120 mM Aspartate, 20 mM CsCl, 2 mM MgCl 2 , 1.5 mM CaCl 2 , 5 mM EGTA, 10 mM Glucose, 10 mM HEPES, 2 mM ATP-Na, 0.1 mM GTP (pH 7. Four))
　保持電位は-50mVに固定した。細胞にカルバコール（100 μＭ）を添加することでTRPC電流を惹起させた。カルバコール添加の２０秒後に30μMの試験化合物（化合物０１１）を細胞に３０秒間添加することで得られる電流変化を評価した。 The holding potential was fixed at -50 mV. TRPC current was evoked by adding carbachol (100 μM) to the cells. The current change obtained by adding 30 μM of the test compound (Compound 011) to the cells for 30 seconds 20 seconds after the addition of carbachol was evaluated.
　試験例４の結果（カルバコール：cchで惹起したTRPC6電流における化合物０１１の効果）を図５に示す。図５の左図は-50mVのトレースを示す。図５の右図は、左図のa, b の二つの時点で約１秒間のランプ波(-100～＋100 mVの直線的電圧)を加え測定した電流－電圧特性カーブを示す。試験化合物添加後に電流量の顕著な減少が見られたことから、試験化合物の添加によりTRPC6チャネル活性化の抑制効果が観察された。 The result of Test Example 4 (carbachol: effect of compound 011 on TRPC6 current induced by cch) is shown in FIG. The left figure of FIG. 5 shows a trace of -50 mV. The right figure of FIG. 5 shows a current-voltage characteristic curve measured by applying a lamp wave (a linear voltage of -100 to +100 mV) for about 1 second at two time points a and b in the left figure. Since a significant decrease in the amount of current was observed after the addition of the test compound, the effect of suppressing TRPC6 channel activation was observed by the addition of the test compound.
　［試験例５］
　線維化阻害評価実験１（ウエスタンブロット法と細胞形態観察）
　線維芽細胞におけるα-smooth muscle actin (α-SMA)の発現をウエスタンブロットで評価した。生後1-3日齢マウスから皮膚線維芽細胞を単離し、2.5x10５個の細胞を12ウェルプレートに播種した。24時間後に牛胎児血清を除いた培地に交換し、さらに24時間培養しその後、10 ng/mlのtransforming growth factor β1 (TGFβ1)を添加し48時間培養した。なお、TGFβ1添加と同時に、所定濃度（0.1μM、1μM、10μM）の試験化合物（化合物０１１）、10μMのPyr 2またはDMSO（溶媒コントロール）も添加した。培養後の細胞の形態観察はオールインワン蛍光顕微鏡（Keyence BZ-X700）を使用して行った（倍率20倍）。培養後の細胞をlysis buffer (140 mM NaCl, 20 mM Tris-HCl pH7.8, 1% Triton-X100, 0.05% sodium deoxycholate, 0.1% SDS, 2 mM EDTA, proteinase inhibitor cocktail)により溶解し、SDS-PAGEにより分離後、１次抗体として抗α-SMA抗体（Sigma）、２次抗体としてhorse radish peroxidaseの融合した抗マウスIgG抗体(Cell signaling)を用いてα-SMAを検出した。 [Test Example 5]
Fibrosis inhibition evaluation experiment 1 (Western blotting and cell morphology observation)
The expression of α-smooth muscle actin (α-SMA) in fibroblasts was evaluated by Western blotting. Skin fibroblasts were isolated from 1-3 day old mice and 2.5x10 5 cells were seeded on a 12-well plate. After 24 hours, the medium was replaced with a medium from which fetal bovine serum had been removed, and the cells were cultured for another 24 hours, after which 10 ng / ml of transforming growth factor β1 (TGF β1) was added and the cells were cultured for 48 hours. At the same time as the addition of TGFβ 1, the test compound (Compound 011) having a predetermined concentration (0.1 μM, 1 μM, 10 μM) and 10 μM Pyr 2 or DMSO (solvent control) were also added. The morphology of the cells after culturing was observed using an all-in-one fluorescence microscope (Keyence BZ-X700) (magnification 20 times). The cultured cells were lysed with lysis buffer (140 mM NaCl, 20 mM Tris-HCl pH7.8, 1% Triton-X100, 0.05% sodium deoxycholate, 0.1% SDS, 2 mM EDTA, proteinase inhibitor antibody) and SDS- After separation by PAGE, α-SMA was detected using an anti-α-SMA antibody (Sigma) as the primary antibody and an anti-mouse IgG antibody (Cell signaling) fused with horse radish peroxidase as the secondary antibody.
　ウエスタンブロットの結果を図６に示す。図６では、試験化合物（特に10μM）とPyr 2は、コントロール（DMSOのTGFβ1＋）と比較して、α-SMA抗体の発色が薄くなっていることが示されており、試験化合物がTGFβ1によって誘導されるα-SMAの発現を強く阻害したことが確認された。 The results of Western blotting are shown in FIG. In FIG. 6, it is shown that the test compound (particularly 10 μM) and Pyr2 have lighter color development of the α-SMA antibody compared to the control (DMSO TGFβ1 +), and the test compound is induced by TGFβ1. It was confirmed that the expression of α-SMA was strongly inhibited.
　また、顕微鏡観察の結果、Pyr 2添加により細胞の伸長が観察されたのに対し、試験化合物添加では細胞形態の変化および細胞障害性は見られなかった。 In addition, as a result of microscopic observation, cell elongation was observed with the addition of Pyr2, whereas no change in cell morphology or cytotoxicity was observed with the addition of the test compound.
　［試験例６］
　線維化阻害評価実験２（免疫蛍光染色法）
　試験例５と同様にしてマウスから皮膚線維芽細胞を単離し、滅菌処理をした直径12 mmのカバーガラスを12ウェルプレートに入れ、2.5x105個の細胞を播種し、カバーガラス上にて生育させた。24時間後に牛胎児血清を除いた培地に交換し、さらに24時間培養した。また、別途、生後1-2日齢ラットから心線維芽細胞を単離し、皮膚線維芽細胞の場合と同様の処置を加えた。その後、皮膚線維芽細胞については10 ng/mlのTGFβ1を、心線維芽細胞については2 ng/mlのTGFβ2を添加し48時間培養した。なお、TGFβ添加と同時に、10μMの試験化合物（化合物０１１）、10μMのPyr 2（従来の阻害剤）またはDMSO（溶媒コントロール）も添加した。別途、培養細胞にTGFβ無添加のリン酸緩衝生理食塩水（PBS）を添加した細胞も用意した。培養後、細胞を４％パラホルムアルデヒドにより固定化後、0.5% Triton-X100を含むTris buffered saline pH7.4 (TBS)により透過処理を行った。1% bovine serum albuminによりブロック後、１次抗体として抗α-SMA抗体（Sigma）、２次抗体としてAlexa488を融合した抗マウスIgG抗体(Molecular probe) を用いてα-SMAを検出し、蛍光顕微鏡 (Keyence)により20倍対物レンズを用いて画像を取得した。細胞面積当たりの平均蛍光輝度（Fluorescence intensity/pixel）をImage Jソフトウエアを用いて算出し解析した。 [Test Example 6]
Fibrosis inhibition evaluation experiment 2 (immunofluorescence staining method)
Skin fibroblasts were isolated from mice in the same manner as in Test Example 5, a sterilized cover glass with a diameter of 12 mm was placed in a 12-well plate, 2.5x10 5 cells were seeded, and the cells were grown on the cover glass. I let you. After 24 hours, the medium was replaced with a medium from which fetal bovine serum had been removed, and the cells were cultured for another 24 hours. Separately, cardiac fibroblasts were isolated from 1-2 day old rats and treated in the same manner as for cutaneous fibroblasts. Then, 10 ng / ml TGFβ1 was added to the skin fibroblasts, and 2 ng / ml TGFβ2 was added to the heart fibroblasts, and the cells were cultured for 48 hours. At the same time as the addition of TGFβ, 10 μM test compound (Compound 011), 10 μM Pyr 2 (conventional inhibitor) or DMSO (solvent control) was also added. Separately, cells in which TGFβ-free phosphate buffered saline (PBS) was added to cultured cells were also prepared. After culturing, the cells were immobilized with 4% paraformaldehyde and then permeabilized with Tris buffered saline pH 7.4 (TBS) containing 0.5% Triton-X100. After blocking with 1% bovine serum albumin, α-SMA was detected using anti-α-SMA antibody (Sigma) as the primary antibody and anti-mouse IgG antibody (Molecular probe) fused with Alexa488 as the secondary antibody, and fluorescence microscopy was performed. Images were acquired using a 20x objective by (Keyence). The average fluorescence intensity / pixel per cell area was calculated and analyzed using Image J software.
　蛍光染色の結果を図７（皮膚線維芽細胞）および図８（心線維芽細胞）に示す。両細胞において、TGFβ処置は線維状のα-SMAの発現を亢進させた。化合物０１１は、Pyr2とほぼ同様に、TGFβにより誘導されるα-SMAの発現をほぼ完全に抑制した。 The results of fluorescent staining are shown in FIG. 7 (skin fibroblasts) and FIG. 8 (cardiac fibroblasts). In both cells, TGFβ treatment enhanced the expression of fibrous α-SMA. Compound 011 almost completely suppressed TGFβ-induced expression of α-SMA, much like Pyr2.
　［試験例７］
　薬剤性難聴モデル動物の作成
　日本エスエルシー株式会社から購入した5-8週齢の雄性CBA/Nマウスに、シスプラチン注射液（日医工、0.5mg/ml）を12mg/kgで腹腔投与し、7日後及び14日後にマウスの聴力レベルを聴性脳幹反応（ABR）測定にて試験した。シスプラチン（CDDP）の腹腔投与により5-36kHzの広い周波数帯において聴力レベルが低下したことを確認した。 [Test Example 7]
Creation of drug-induced deafness model animals Cisplatin injection (Nichi-Iko, 0.5 mg / ml) was intraperitoneally administered at 12 mg / kg to 5-8 week old male CBA / N mice purchased from Japan SLC Co., Ltd. 7 Hearing levels in mice were tested by auditory brainstem response (ABR) measurements day and 14 days later. It was confirmed that intraperitoneal administration of cisplatin (CDDP) reduced hearing levels in a wide frequency band of 5-36 kHz.
　聴性脳幹反応（ABR）測定
　マウスに三種混合麻酔（塩酸メデトミジン 0.3mg/kg, ミダゾラム4mg/kg, 酒石酸ブトルファノール 5mg/kg）を腹腔投与し、十分に麻酔が効いていることをtoe pinchまたはcorneal reflexで確認した。まず、脳波測定用のステンレス針電極（テルモ26ゲージ）を頭頂、耳介後部および背中の皮下に挿入し、マウスの左外耳道にスピーカー（TD-250D; Fostex, Japan）の出力口を挿入した。音刺激として、5, 10, 16, 24, 36 kHzの5種の周波数について、0.5 msの上昇および下降相と2msの定常相からなるトーンバースト音を与えた。この刺激音によって惹起される聴覚伝導路の神経細胞の電位変化を、信号増幅器（EX-1 Differential amplifier; Dagan Corporation, MN, USA）によって5000倍に増幅した上で、0.3-2 kHzのバンドパスフィルターをかけ、ABRデータとして取得した。各データは、800回刺激分を積算及び平均化し、解析に用いた。各周波数の聴覚閾値は、10 dB刻みで音圧を変化させた際に、ABRのII波およびIII波が明瞭に確認される最低音圧レベルとして決定した。スピーカーの電圧－音圧特性はマイクロフォン（Sokolich G-II Ultrasonic Probe Microphone System; WGS/Associates, CA, USA）によって事前に校正しておき、それに従って各周波数の刺激音を生成した。測定後、マウスはアンチセダン0.3 mg/kgの腹腔投与によって速やかに覚醒させた。 Auditory brainstem response (ABR) measurement Toe pinch or corneal reflex was administered to mice by intraperitoneal administration of triple anesthesia (medetomidine hydrochloride 0.3 mg / kg, midazolam 4 mg / kg, butorphanol tartrate 5 mg / kg), and the anesthesia was sufficiently effective. I confirmed it in. First, a stainless needle electrode (Terumo 26 gauge) for electroencephalogram measurement was inserted under the skin of the crown, posterior pinna and back, and the output port of the speaker (TD-250D; Fostex, Japan) was inserted into the left ear canal of the mouse. As a sound stimulus, a tone burst sound consisting of an ascending and descending phase of 0.5 ms and a stationary phase of 2 ms was given for five frequencies of 5, 10, 16, 24, and 36 kHz. The potential change of nerve cells in the auditory conduction path caused by this stimulating sound is amplified 5000 times by a signal amplifier (EX-1 Differential amplifier; Dagan Corporation, MN, USA), and then a bandpass of 0.3-2 kHz. It was filtered and acquired as ABR data. Each data was used for analysis after integrating and averaging 800 stimuli. The auditory threshold for each frequency was determined as the lowest sound pressure level at which ABR waves II and III were clearly visible when the sound pressure was changed in 10 dB increments. The voltage-sound pressure characteristics of the speaker were pre-calibrated by a microphone (Sokolich G-II Ultrasonic Probe Microphone System; WGS / Associates, CA, USA), and stimulation sounds of each frequency were generated accordingly. After the measurement, the mice were rapidly awakened by intraperitoneal administration of antisedan 0.3 mg / kg.
　サンプル（化合物０１１）の評価
　化合物０１１をPBS（Fujifilm, Japan；リン酸緩衝液）に2mg/mlで懸濁した液をサンプルとした。このサンプルを5-8週齢の雄性CBA/Nマウスに、シスプラチン投与前日からシスプラチン投与の14日後まで1日1回10mg/kgで経口投与し、化合物０１１の難聴に対する抑制効果を評価した。測定に用いたマウスは以下の３群に分けた。
第1群：シスプラチンの腹腔投与およびPBS（コントロール）の経口投与を受ける群(n=12)第2群：シスプラチンの腹腔投与および化合物０１１の経口投与を受ける群 (n=12)第3群：シスプラチン投与のコントロールとして生理食塩水の腹腔投与および化合物０１１の経口投与を受ける群(n=10)
　それぞれの群について、聴性脳幹反応（ABR）測定によって、シスプラチン投与直前、投与7日後および14日の聴力レベルを決定した。結果を図９および１０に示す。
第１群の結果は、シスプラチン投与が聴覚閾値の上昇を引き起こしたことを示す。
第２群の結果は、化合物０１１投与が聴覚閾値の上昇を有意に抑制したことを示す。
第３群の結果は、化合物０１１投与は通常状態のマウスの聴覚閾値をほぼ変動させないことを示す。
　以上より、化合物０１１は、投与が簡便な経口投与により難聴を抑制できることが確認された。 Evaluation of Sample (Compound 011) A solution prepared by suspending Compound 011 in PBS (Fujifilm, Japan; phosphate buffer) at 2 mg / ml was used as a sample. This sample was orally administered to 5-8 week old male CBA / N mice at 10 mg / kg once daily from the day before cisplatin administration to 14 days after cisplatin administration, and the inhibitory effect of compound 011 on deafness was evaluated. The mice used for the measurement were divided into the following three groups.
Group 1: Cisplatin intraperitoneal administration and PBS (control) oral administration (n = 12) Group 2: Cisplatin peritoneal administration and compound 011 oral administration (n = 12) Group 3: Group receiving peritoneal administration of physiological saline and oral administration of compound 011 as control of cisplatin administration (n = 10)
For each group, auditory brainstem response (ABR) measurements were used to determine hearing levels immediately before cisplatin, 7 days after, and 14 days after cisplatin. The results are shown in FIGS. 9 and 10.
The results of Group 1 indicate that cisplatin administration caused an increase in the auditory threshold.
The results of Group 2 indicate that administration of Compound 011 significantly suppressed the increase in the auditory threshold.
The results of Group 3 show that administration of Compound 011 causes little variation in the auditory threshold of normal mice.
From the above, it was confirmed that compound 011 can suppress deafness by oral administration, which is easy to administer.
　［試験例８］
　化合物０１１腹腔投与による血漿シスプラチン動態への影響
　日本エスエルシー株式会社から購入した5～8週齢の雄性CBA/Nマウスにシスプラチン注射液（日医工、0.5 mg/ml）を12 mg/kgで腹腔投与し、1日後及び2日後に尾静脈から血液を採取した。この血液を4℃、1000 gで5分間遠心し、上清を血漿サンプルとした。この血漿サンプルを島津テクノリサーチの高周波誘導結合プラズマ（ICP）質量分析で解析し、血漿シスプラチン濃度を反映する血漿白金（血漿Pt）濃度を評価した。なお、PBS（Fujifilm, Japan；リン酸緩衝液）、あるいは化合物０１１をPBSに2 mg/mlで懸濁した液を、シスプラチン投与前日からシスプラチン投与の二日後まで1日1回10 mg/kgで経口投与し、それぞれ対照群（n=5）、化合物投与群（n=5）とした。
　ICP質量分析の前処理として、血漿サンプルに硝酸 0.5 mlを加え、容器を密閉した後、180℃で5分間マイクロウェーブ分解（ETHOS-TC、マイルストーンゼネラル）にかけた。放冷し、塩酸0.5 mlを加え、水で5 mlに容量調節した後、Agilent 7700x ICP-MS（Agilent technologies, CA, USA）によるICP質量分析にかけた（PF出力 1550W、プラズマガス 15.0 L/min、補助ガス 0.90 L/min、キャリアガス 1.0 L/min、サンプリング深さ 10 mm）。積分時間１秒、スイープ回数100回の条件で、各サンプル３回ずつ測定した。測定質量数は、分析対象であるPtを195、内部標準であるRhを103として解析した。結果を図１１に示した。 [Test Example 8]
Effect of compound 011 peritoneal administration on plasma cisplatin dynamics Cisplatin injection (Nichi-Iko, 0.5 mg / ml) was applied to 5-8 week old male CBA / N mice purchased from Nippon SLC Co., Ltd. at 12 mg / kg peritoneally. Blood was collected from the tail vein 1 and 2 days after administration. The blood was centrifuged at 4 ° C. and 1000 g for 5 minutes, and the supernatant was used as a plasma sample. This plasma sample was analyzed by Shimadzu Techno Research's high frequency inductively coupled plasma (ICP) mass analysis to evaluate the plasma platinum (plasma Pt) concentration, which reflects the plasma cisplatin concentration. PBS (Fujifilm, Japan; phosphate buffer) or compound 011 suspended in PBS at 2 mg / ml was administered at 10 mg / kg once daily from the day before cisplatin administration to 2 days after cisplatin administration. Oral administration was performed, and the control group (n = 5) and the compound administration group (n = 5) were used, respectively.
As a pretreatment for ICP mass spectrometry, 0.5 ml of nitric acid was added to the plasma sample, the container was sealed, and then microwave decomposition (ETHOS-TC, Milestone General) was performed at 180 ° C. for 5 minutes. After allowing to cool, 0.5 ml of hydrochloric acid was added, the volume was adjusted to 5 ml with water, and then ICP mass spectrometry was performed by Agilent 7700x ICP-MS (Agilent technologies, CA, USA) (PF output 1550 W, plasma gas 15.0 L / min). , Auxiliary gas 0.90 L / min, carrier gas 1.0 L / min, sampling depth 10 mm). Each sample was measured 3 times under the condition that the integration time was 1 second and the number of sweeps was 100 times. The measured mass numbers were analyzed with Pt as the analysis target as 195 and Rh as the internal standard as 103. The results are shown in FIG.
　シスプラチン投与の一日後、二日後ともに化合物０１１の有無による血漿Pt濃度の有意な変化は見られなかった。つまり、化合物０１１の投与はシスプラチンの血中動態に影響しないことを示唆した。シスプラチン誘導性難聴モデルを用いた聴力検査の結果（試験例７）と合わせて考えると、化合物０１１の聴力保護効果は、単にシスプラチンの体内濃度を下げているのではなく、聴覚に関わる細胞をシスプラチンの毒性から保護した結果であることが示唆された。 No significant change in plasma Pt concentration was observed with or without compound 011 one day and two days after cisplatin administration. That is, it was suggested that administration of compound 011 did not affect the blood kinetics of cisplatin. When combined with the results of a hearing test using a cisplatin-induced hearing loss model (Test Example 7), the hearing protection effect of Compound 011 does not simply reduce the concentration of cisplatin in the body, but cisplatin the cells involved in hearing. It was suggested that this was the result of protection from the toxicity of.
　［試験例９］
　１－（４－（４－メチル－１，２，３－チアジアゾール－５－カルボキサミド）－５－（トリフルオロメチル）－１Ｈ－ピラゾール－４－カルボン酸エチル（Pyr4）による内耳保護作用（ゼブラフィッシュのニューロマストを使用した有毛細胞死の評価） [Test Example 9]
Inner ear protection by 1- (4- (4-methyl-1,2,3-thiadiazole-5-carboxamide) -5- (trifluoromethyl) -1H-pyrazole-4-carboxylate (Pyr4)) Evaluation of hair cell death using neuromast)
　Pyr4はTRPC3阻害作用およびTRPC6阻害作用を有することが知られている。 Pyr4 is known to have TRPC3 inhibitory activity and TRPC6 inhibitory activity.
　有毛細胞死は、様々な環境因子（過度の騒音、薬物（アミノグリコシド系抗生物質やシスプラチンなどの化学療法剤、老化等）等）による進行性の聴覚障害に共通の要因として知られている。そして、難聴治療薬の開発には有毛細胞死を基準としたスクリーニング評価が利用されている。このスクリーニングにはゼブラフィッシュのニューロマストが利用される（C. Ton and C. Parng, The use of zebrafish for assessing ototoxic and otoprotective agents. Hearing research, 208, 79-88 (2005)）。ゼブラフィッシュは、体表面に有毛細胞によって構成されるニューロマストからなる側線をもち、その有毛細胞は哺乳動物の内耳の有毛細胞と形態学的および機能的に類似しているため、哺乳動物の有毛細胞死の評価にニューロマストが有用である。ニューロマストは、ゼブラフィッシュの頭と体に沿った決まった位置で発生するため、蛍光イメージングを使用することによって、薬剤サンプル適用による有毛細胞の脱落、有毛細胞死を容易に判別することができ、薬剤サンプルの有毛細胞に与える効果を定量化することができる。 Hair cell death is known as a common factor in progressive hearing impairment due to various environmental factors (excessive noise, drugs (chemotherapeutic agents such as aminoglycoside antibiotics and cisplatin, aging, etc.)). Screening evaluation based on hair cell death is used for the development of therapeutic agents for deafness. Zebrafish neuromast is used for this screening (C. Ton and C. Parng, The use of zebrafish for assessing ototoxic and otoprotective agents. Hearing research, 208, 79-88 (2005)). Zebrafish have lateral lines consisting of neuromast composed of hair cells on the surface of the body, and the hair cells are morphologically and functionally similar to the hair cells of the inner ear of mammals. Neuromast is useful in assessing hair cell death in animals. Since neuromast occurs at a fixed position along the head and body of zebrafish, it is possible to easily determine hair cell shedding and hair cell death by applying a drug sample by using fluorescence imaging. The effect of the drug sample on hair cells can be quantified.
　各試験に10個の胚（ゼブラフィッシュの稚魚、2つのウェルにウェルあたり5つの胚）を用いた。試験には被験物質として1.5μMおよび3μMのPyr4を用いた。
　ビークルコントロール群として、飼育培地（0.16 mM MgSO4, 0.4 mM CaCl2, 0.17 mM KCl, 5 mM NaCl、10 mM Hepes (pH 7.2 - 7.6) + 0.5％DMSO)中、未処置の胚を用いた。
　陽性コントロール群として飼育培地中、1000μMのD-メチオニンで処置した胚を用いた。
　聴覚毒性誘導群（シスプラチン処置群）として飼育培地中、20μMのシスプラチンで処置した胚を用いた。
　胚（受精後5日目の稚魚）は、それぞれ被験物質、D-メチオニン、またはビークルコントロールで28.5℃で1時間、前処置した後、シスプラチンに暴露した。その後、それぞれ、28.5℃で24時間飼育した後、以下のように染色した。
　培地を0.01％DASPEI (2-(4-(dimethylamino)styryl)-N-ethylpyridinium iodide) に交換し、プレートを暗所で15分間室温インキュベートし、その後、飼育培地で5分間の洗浄を3回行った。
　染色後、胚を0.003％のトリカインで麻酔して、メチルセルロースに側面を向けておき、LeicaステレオスコープとLAS AFソフトウェアを用いて画像を取得した。画像を使用して、各胚の側線に存在するニューロマストの数を定量化した。
　これに加えて、胚をニューロマストの蛍光強度に基づいて3つの異なるカテゴリー（i：明るい（bright）、ii：薄暗い（dim）、iii：検出されない、またはほとんど検出されない（barely or no detect））に分類した。胚の各カテゴリーに属する割合は、各実験グループごとに決定した。すべての写真を撮った後、胚を安楽死させた。 Ten embryos (zebrafish fry, five embryos per well in two wells) were used in each test. 1.5 μM and 3 μM Pyr4 were used as test substances in the test.
As a vehicle control group, untreated embryos were used in breeding medium (0.16 mM DDL 4 , 0.4 mM CaCl 2 , 0.17 mM KCl, 5 mM NaCl, 10 mM Hepes (pH 7.2-7.6) + 0.5% DMSO).
As a positive control group, embryos treated with 1000 μM D-methionine in breeding medium were used.
As an auditory toxicity induction group (cisplatin treatment group), embryos treated with 20 μM cisplatin in a breeding medium were used.
Embryos (fry 5 days after fertilization) were exposed to cisplatin after pretreatment with the test substance, D-methionine, or vehicle control at 28.5 ° C. for 1 hour, respectively. Then, each of them was bred at 28.5 ° C. for 24 hours and then stained as follows.
Replace the medium with 0.01% DASPEI (2- (4- (dimethylamino) styryl) -N-ethylpyridinium iodide), incubate the plate in the dark for 15 minutes at room temperature, then wash 3 times with the breeding medium for 5 minutes. It was.
After staining, embryos were anesthetized with 0.003% trikine, sideways to methylcellulose, and images were acquired using a Leica stereoscope and LAS AF software. Images were used to quantify the number of neuromasts present on the lateral lines of each embryo.
In addition to this, embryos are classified into three different categories based on the fluorescence intensity of the neuromast (i: bright, ii: dim, iii: barely or no detect). It was classified into. The proportion of embryos belonging to each category was determined for each experimental group. After taking all the pictures, the embryos were euthanized.
　ニューロマストの数を図１２に示し、蛍光強度に基づいた各カテゴリーの割合を表３にす。表３中、CISP及びCISPLはシスプラチンを、Metはメチオニンを意味する。
Figure JPOXMLDOC01-appb-T000087
 The number of neuromasts is shown in FIG. 12, and the ratio of each category based on the fluorescence intensity is shown in Table 3. In Table 3, CISP and CISPL mean cisplatin and Met means methionine.
Figure JPOXMLDOC01-appb-T000087
　未処置の対照群における未変化胚の割合が80％を超えていたため、実験は有効と見なした。さらに、シスプラチン処置群の胚のニューロマストの数はビークルコントロール群よりも統計的に有意に低値であった。D-メチオニンのみの暴露により、ニューロマストの数がわずかに減少したが、おそらく染色の通常の変動によるものであり、特定の効果とは無関係であろう。D-メチオニンはシスプラチン処置によるニューロマスト数の低下を抑制した。Pyr4による処置は、評価されたいずれの濃度でもニューロマストの生存率に影響を与えず、シスプラチン処置によって誘発されたニューロマスト喪失を抑制した。1.5および3μMのいずれの濃度でも同程度の効果が見られ、プラトーに達したことを示している可能性がある。 The experiment was considered valid because the proportion of unchanged embryos in the untreated control group exceeded 80%. In addition, the number of embryonic neuromasts in the cisplatin-treated group was statistically significantly lower than that in the vehicle control group. Exposure to D-methionine alone slightly reduced the number of neuromasts, probably due to normal variation in staining and not related to any particular effect. D-methionine suppressed the decrease in the number of neuromasts due to cisplatin treatment. Treatment with Pyr4 did not affect neuromast survival at any of the assessed concentrations and suppressed cisplatin treatment-induced neuromast loss. Similar effects were seen at both 1.5 and 3 μM concentrations, which may indicate that a plateau was reached.

Claims (16)

  1. 　一般式（１）
    Figure JPOXMLDOC01-appb-C000001
     ［式中、
    Ａは、置換されていてもよいベンゼン環である。
    Ｂは、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールである。
    Ｘは、酸素原子または硫黄原子である。
    Ｙは、窒素原子または炭素原子である。
    Figure JPOXMLDOC01-appb-C000002
     Ｒ１は、互いに独立して低級アルキルであるか、２個のＲ１が互いに結合して、スピロ環または架橋構造を形成していてもよい、あるいは２個のＲ１が互いに結合して、Ｙを含む環を構成する炭素原子および窒素原子と共に飽和縮合複素環を形成していてもよい。
    ｐは、０、１、または２である。
    あるいは、（Ｒ１）ｐはオキソである。］
    で表される化合物、その塩、またはそのプロドラッグを含有する難聴の予防および／または治療用医薬組成物。     General formula (1)
    Figure JPOXMLDOC01-appb-C000001
     [During the ceremony,
    A is a optionally substituted benzene ring.
    B is an aryl that may be substituted or a heteroaryl that may be substituted.
    X is an oxygen atom or a sulfur atom.
    Y is a nitrogen atom or a carbon atom.
    Figure JPOXMLDOC01-appb-C000002
     R 1 is either independently of one another are lower alkyl, two of R 1 are bonded to each other, may form a spiro ring or a crosslinked structure, or two of R 1 are bonded to each other, A saturated condensed heterocycle may be formed together with carbon atoms and nitrogen atoms constituting a ring containing Y.
    p is 0, 1, or 2.
    Alternatively, (R 1 ) p is oxo. ]
    A pharmaceutical composition for preventing and / or treating deafness, which comprises a compound represented by, a salt thereof, or a prodrug thereof.
  2. 　一般式（１）において、Ｂが、置換されていてもよい単環のアリールあるいは置換されていてもよい単環または二環の含窒素ヘテロアリールである、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein in the general formula (1), B is a optionally substituted monocyclic aryl or a optionally substituted monocyclic or bicyclic nitrogen-containing heteroaryl.
  3. 　一般式（１）において、Ａが、下記Ａ－１）～Ａ－１６）：
    Ａ－１）ハロゲン、
    Ａ－２）水酸基、
    Ａ－３）ニトロ、
    Ａ－４）シアノ、
    Ａ－５）カルボキシル、
    Ａ－６）置換されていてもよいアミノ、
    Ａ－７）置換されていてもよい環状アミノ、
    Ａ－８）置換されていてもよい低級アルキル、
    Ａ－９）置換されていてもよい低級アルコキシ、
    Ａ－１０）低級アルコキシカルボニル、
    Ａ－１１）低級アルキルスルホニル、
    Ａ－１２）低級アルキルまたは低級アルキルスルホニルで置換されていてもよいカルバモイル、
    Ａ－１３）置換されていてもよい環状アミノカルボニル、
    Ａ－１４）低級アルキルで置換されていてもよいスルファモイル、
    Ａ－１５）置換されていてもよい環状アミノスルホニル、および
    Ａ－１６）テトラゾリル
    からなる群より選択される少なくとも１種の基で置換されていてもよいベンゼン環である、請求項１または２に記載の医薬組成物。     In the general formula (1), A is the following A-1) to A-16):
    A-1) Halogen,
    A-2) Hydroxyl group,
    A-3) Nitro,
    A-4) Cyano,
    A-5) Carboxyl,
    A-6) Amino, which may be substituted,
    A-7) Cyclic amino, which may be substituted,
    A-8) Lower alkyl, which may be substituted,
    A-9) Substituted lower alkoxy,
    A-10) Lower alkoxycarbonyl,
    A-11) Lower alkyl sulfonyl,
    A-12) Carbamoyl, which may be substituted with a lower alkyl or lower alkyl sulfonyl,
    A-13) Cyclic aminocarbonyl, which may be substituted,
    A-14) Sulfamoyl, which may be substituted with a lower alkyl,
    A-15) a cyclic aminosulfonyl optionally substituted, and A-16) a benzene ring optionally substituted with at least one group selected from the group consisting of tetrazolyl, claim 1 or 2. The pharmaceutical composition described.
  4. 　一般式（１）において、Ｂが、単環のアリールあるいは単環または二環のヘテロアリールであり、単環のアリールは下記Ｂ－１）～Ｂ－１６）からなる群より選択される少なくとも１種の基で置換されていてもよく、単環または二環のヘテロアリールは下記Ｂ－１）～Ｂ－１７）からなる群より選択される少なくとも１種の基で置換されていてもよい、請求項１～３のいずれかに記載の医薬組成物：
    Ｂ－１）ハロゲン、
    Ｂ－２）水酸基、
    Ｂ－３）ニトロ、
    Ｂ－４）シアノ、
    Ｂ－５）カルボキシル
    Ｂ－６）置換されていてもよいアミノ、
    Ｂ－７）置換されていてもよい環状アミノ、
    Ｂ－８）置換されていてもよい低級アルキル、
    Ｂ－９）置換されていてもよい低級アルコキシ、
    Ｂ－１０）低級アルコキシカルボニル、
    Ｂ－１１）低級アルキルスルホニル、
    Ｂ－１２）低級アルキルまたは低級アルキルスルホニルで置換されていてもよいカルバモイル、
    Ｂ－１３）置換されていてもよい環状アミノカルボニル、
    Ｂ－１４）低級アルキルで置換されていてもよいスルファモイル、
    Ｂ－１５）置換されていてもよい環状アミノスルホニル、
    Ｂ－１６）テトラゾリル、および
    Ｂ－１７）オキソ。     In the general formula (1), B is a monocyclic aryl or a monocyclic or bicyclic heteroaryl, and the monocyclic aryl is at least one selected from the group consisting of the following B-1) to B-16). It may be substituted with a species group, and the monocyclic or bicyclic heteroaryl may be substituted with at least one group selected from the group consisting of B-1) to B-17) below. The pharmaceutical composition according to any one of claims 1 to 3.
    B-1) Halogen,
    B-2) Hydroxyl group,
    B-3) Nitro,
    B-4) Cyano,
    B-5) Carboxyl B-6) May be substituted amino,
    B-7) Cyclic amino, which may be substituted,
    B-8) Substituted lower alkyl,
    B-9) Substituted lower alkoxy,
    B-10) Lower alkoxycarbonyl,
    B-11) Lower alkyl sulfonyl,
    B-12) Carbamoyl, which may be substituted with lower alkyl or lower alkyl sulfonyl,
    B-13) Cyclic aminocarbonyl, which may be substituted,
    B-14) Sulfamoyl, which may be substituted with a lower alkyl,
    B-15) Cyclic aminosulfonyl, which may be substituted,
    B-16) tetrazolyl, and B-17) oxo.
  5. 　一般式（１）において、ベンゾイソオキサゾールまたはベンゾイソチアゾール骨格の４位が置換された、請求項１～４のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 4, wherein in the general formula (1), the 4-position of the benzoisoxazole or benzoisothiazole skeleton is substituted.
  6. 　一般式（１）において、
    Ｂが、置換されたピリジルまたは置換されたフェニルであって、Ｙと結合しているピリジンまたはベンゼン環上の炭素原子に対して少なくともオルト位の炭素原子が置換されている、
    請求項１～３のいずれかに記載の医薬組成物。     In the general formula (1)
    B is a substituted pyridyl or a substituted phenyl in which the carbon atom at least in the ortho position is substituted with respect to the carbon atom on the pyridine or benzene ring bonded to Y.
    The pharmaceutical composition according to any one of claims 1 to 3.
  7. 　一般式（１）において、
    Ａが、ハロゲン、低級アルコキシ、およびハロゲンで置換されていてもよい低級アルキル、からなる群より選択される少なくとも１種の基で置換されていてもよい、ベンゼン環であり、
    Ｂが、ピリジルまたはフェニルであり、それぞれ下記Ｂ－１）、Ｂ－５）、Ｂ－８）、Ｂ－１０）、Ｂ－１２）、およびＢ－１３）：
    Ｂ－１）ハロゲン、
    Ｂ－５）カルボキシル、
    Ｂ－８）置換されていてもよい低級アルキル、
    Ｂ－１０）低級アルコキシカルボニル、
    Ｂ－１２）低級アルキルまたは低級アルキルスルホニルで置換されていてもよいカルバモイル、および
    Ｂ－１３）置換されていてもよい環状アミノカルボニル、
    からなる群より選択される少なくとも１種の基で置換されていてもよく、
    Ｒ１は、互いに独立してＣ１～Ｃ３アルキルであるか、あるいは２個のＲ１が互いに結合して、メチレン基、ジメチレン基、またはトリメチレン基であり、
    あるいは、（Ｒ１）ｐはオキソである、
    請求項１～４のいずれかに記載の医薬組成物。     In the general formula (1)
    A is a benzene ring optionally substituted with at least one group selected from the group consisting of halogens, lower alkoxys, and lower alkyls optionally substituted with halogens.
    B is pyridyl or phenyl, respectively, B-1), B-5), B-8), B-10), B-12), and B-13):
    B-1) Halogen,
    B-5) Carboxylyl,
    B-8) Substituted lower alkyl,
    B-10) Lower alkoxycarbonyl,
    B-12) Carbamoyl, which may be substituted with a lower alkyl or lower alkylsulfonyl, and B-13) Cyclic aminocarbonyl, which may be substituted.
    It may be substituted with at least one group selected from the group consisting of
    R 1 is each other or are independently C1 ~ C3 alkyl, or two of R 1 are bonded to each other, a methylene group, dimethylene or trimethylene,
    Alternatively, (R 1 ) p is oxo,
    The pharmaceutical composition according to any one of claims 1 to 4.
  8. 　一般式（１）で表される化合物が、一般式（１Ａ）
    Figure JPOXMLDOC01-appb-C000003
     ［式中、
    Ｚは、窒素原子またはＣＨである。
    Ｙは、窒素原子または炭素原子である。
    Figure JPOXMLDOC01-appb-C000004
     Ｒ１１は、互いに独立して、メチルまたはエチルであるか、あるいは２個のＲ１１が互いに結合して、メチレン、ジメチレン、またはトリメチレンによる架橋構造を形成していてもよい。
    ｐは、０、１、または２である。
    あるいは、（Ｒ１１）ｐはオキソである。
    Ｒ２１、Ｒ２２、およびＲ２３は、互いに独立して、水素原子、ハロゲン、カルバモイル、またはトリフルオロメチルである。
    Ｒ３１、Ｒ３２、およびＲ３３は、互いに独立して、水素原子、ハロゲン、ハロゲンで置換された低級アルキル、メチル、カルボキシル、低級アルコキシカルボニル、モノメチルアミノカルボニル、またはジメチルアミノカルボニルである。］
    で表される化合物である、
    請求項１～４および７のいずれかに記載の医薬組成物。     The compound represented by the general formula (1) is the general formula (1A).
    Figure JPOXMLDOC01-appb-C000003
     [During the ceremony,
    Z is a nitrogen atom or CH.
    Y is a nitrogen atom or a carbon atom.
    Figure JPOXMLDOC01-appb-C000004
     R 11 is, independently of one another are methyl or ethyl, or two R 11 are bonded to each other methylene, may form a crosslinked structure by dimethylene or trimethylene.
    p is 0, 1, or 2.
    Alternatively, (R 11 ) p is oxo.
    R 21 , R 22 , and R 23 are independent of each other and are hydrogen atoms, halogens, carbamoyls, or trifluoromethyls.
    R 31 , R 32 , and R 33 are independent of each other, lower alkyl, methyl, carboxyl, lower alkoxycarbonyl, monomethylaminocarbonyl, or dimethylaminocarbonyl substituted with hydrogen atom, halogen, halogen. ]
    Is a compound represented by,
    The pharmaceutical composition according to any one of claims 1 to 4 and 7.
  9. 　一般式（１Ａ）において、
    Ｒ２１が、塩素原子またはトリフルオロメチルであり、
    Ｒ２２およびＲ２３が、水素原子であり、
    Ｒ３１が、塩素原子であり、
    Ｒ３２が、水素原子であり、
    Ｒ３３が、水素原子、カルボキシル、または低級アルコキシカルボニルである、
    請求項８に記載の組成物。     In the general formula (1A)
    R 21 is a chlorine atom or trifluoromethyl,
    R 22 and R 23 are hydrogen atoms,
    R 31 is a chlorine atom,
    R 32 is a hydrogen atom,
    R 33 is a hydrogen atom, carboxyl, or lower alkoxycarbonyl,
    The composition according to claim 8.
  10. 　化合物が、化合物０１１、化合物０２１、化合物０３１、化合物０４１、化合物０６１、化合物０７１、化合物０８１、化合物０９１、化合物１０１、化合物１１１、化合物１２１、化合物１３１、化合物１４１、化合物１５１、化合物１６１、化合物１７１、化合物１９１、化合物２２１、化合物２８１、化合物３１１、化合物３２１、化合物３３１、化合物３４１、化合物３５１、化合物３６１、化合物３７１、化合物３８１、化合物３９１、化合物４０１、または化合物４３１である、請求項１～４のいずれかに記載の医薬組成物。 The compounds are Compound 011, Compound 021, Compound 031, Compound 041, Compound 061, Compound 071, Compound 081, Compound 091, Compound 101, Compound 111, Compound 121, Compound 131, Compound 141, Compound 151, Compound 161 and Compound 171. , Compound 191 and Compound 221 and Compound 281. Compound 311, Compound 321 and Compound 331, Compound 341, Compound 351 and Compound 361, Compound 371, Compound 381, Compound 391, Compound 401, or Compound 431. 4. The pharmaceutical composition according to any one of 4.
  11. 　一般式（２）
    Figure JPOXMLDOC01-appb-C000005
     ［式中、
    Ａは、置換されていてもよいベンゼン環である。
    Ｂは、置換されていてもよいアリールまたは置換されていてもよいヘテロアリールである。
    Ｙは、窒素原子または炭素原子である。
    Figure JPOXMLDOC01-appb-C000006
     Ｒ１は、互いに独立して低級アルキルであるか、２個のＲ１が互いに結合して、スピロ環または架橋構造を形成していてもよい、あるいは２個のＲ１が互いに結合して、Ｙを含む環を構成する炭素原子および窒素原子と共に飽和縮合複素環を形成していてもよい。
    ｐは、０、１、または２である。
    あるいは、（Ｒ１）ｐはオキソである。］
    で表される化合物、その塩、またはそのプロドラッグを含有する難聴の予防および／または治療用医薬組成物。     General formula (2)
    Figure JPOXMLDOC01-appb-C000005
     [During the ceremony,
    A is a optionally substituted benzene ring.
    B is an aryl that may be substituted or a heteroaryl that may be substituted.
    Y is a nitrogen atom or a carbon atom.
    Figure JPOXMLDOC01-appb-C000006
     R 1 is either independently of one another are lower alkyl, two of R 1 are bonded to each other, may form a spiro ring or a crosslinked structure, or two of R 1 are bonded to each other, A saturated condensed heterocycle may be formed together with carbon atoms and nitrogen atoms constituting a ring containing Y.
    p is 0, 1, or 2.
    Alternatively, (R 1 ) p is oxo. ]
    A pharmaceutical composition for preventing and / or treating deafness, which comprises a compound represented by, a salt thereof, or a prodrug thereof.
  12. 　TRPC3チャネルおよびTRPC6チャネルからなる群から選択される少なくとも１種のTRPCチャネルの阻害活性を有する物質、その塩、またはそのプロドラッグを含有する難聴の予防および／または治療用医薬組成物。 A pharmaceutical composition for preventing and / or treating deafness containing a substance having an inhibitory activity on at least one TRPC channel selected from the group consisting of TRPC3 channel and TRPC6 channel, a salt thereof, or a prodrug thereof.
  13. 　TRPC3チャネルおよびTRPC6チャネルからなる群から選択される少なくとも１種のTRPCチャネルの阻害活性を有する物質が、一般式（１）で表される化合物、一般式（２）で表わされる化合物、Pyr2、Pyr3、Pyr4、GSK2332255B、GSK2833503A、SAR7334、BI-749327、下に列挙された化合物AA01～AA95、および下に列挙された化合物BB01～BB32からなる群から選択される少なくとも１種の化合物である、請求項１２に記載の医薬組成物。
    化合物AA01：
    （4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-ピペラジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA02：
    （6-アミノ-4-メチル-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA03：
    （6-アミノ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA04：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA05：
    （4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-ピペラジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA06：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-イソプロポキシ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA07：
    （（R）-4-（6-アミノ-4-メチル-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA08：
    （7-（6-アミノ-4-メトキシ-ピリジン-3-イル）-4,7-ジアザ-スピロ（2.5）オクト-4-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA09：
    （7-（6-アミノ-4-メトキシ-ピリジン-3-イル）-4,7-ジアザ-スピロ（2.5）オクト-4-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA10：
    （6-アミノ-4-メチル-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA11：
    （4-（6-アミノ-5-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA12：
    （4-（6-アミノ-ピリジン-3-イル）-ピペラジン-1-イル）-（4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル）-メタノン、
    化合物AA13：
    （4-（6-アミノ-ピリジン-3-イル）-ピペラジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA14：
    （6-アミノ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA15：
    （4-（6-アミノ-ピリジン-3-イル）-ピペラジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA16：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA17：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA18：
    （（R）-4-（6-アミノ-4-メチル-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA19：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（2-フルオロ-ベンジルオキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA20：
    （（R）-4-（6-アミノ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA21：
    （4-（6-アミノ-5-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA22：
    （6-アミノ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル）-メタノン、
    化合物AA23：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA24：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-（4-トリフルオロメチル-フェノキシ）-ピリジン-2-イル）-メタノン、
    化合物AA25：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-シクロブチルメトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA26：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-（1-メチル-シクロプロピルメトキシ）-ピリジン-2-イル）-メタノン、
    化合物AA27：
    （（R）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-メトキシメチル-ピペラジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA28：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル）-メタノン、
    化合物AA29：
    （4-（6-アミノ-4-メチル-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA30：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-シクロヘキシルオキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA31：
    （4-（6-アミノ-4-メチル-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA32：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（4-フルオロ-ベンジルオキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA33：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-（4-トリフルオロメチル-フェノキシ）-ピリジン-2-イル）-メタノン、
    化合物AA34：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-クロロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA35：
    （6-アミノ-4-メトキシ-3,4,5,6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-シクロペンチルオキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA36：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-イソブトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA37：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-シクロプロピルメトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA38：
    （3-（6-アミノ-4-メトキシ-ピリジン-3-イル）-3,8-ジアザ-ビシクロ（3.2.1）オクト-8-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA39：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-イソブトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA40：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-シクロプロポキシ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA41：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-フルオロ-ベンジルオキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA42：
    （（R）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA43：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-ベンジルオキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA44：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル）-メタノン、
    化合物AA45：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（3,3-ジフルオロ-シクロブチルメトキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA46：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-プロポキシ-ピリジン-2-イル）-メタノン、
    化合物AA47：
    （4-（6-アミノ-4-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA48：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（2-シクロプロピル-エトキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA49：
    （4-（6-アミノ-4-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA50：
    （1R）-1-（（2R）-4-（6-アミノ-4-メトキシピリジン-3-イル）-1-（5-フェノキシピリジン-2-カルボニル）ピペラジン-2-イル）エタン-1-オール、
    化合物AA51：
    （3-（6-アミノ-4-メトキシ-ピリジン-3-イル）-3,8-ジアザ-ビシクロ（3.2.1）オクト-8-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA52：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（4-メトキシ-5-フェネチルオキシ-ピリジン-2-イル）-メタノン、
    化合物AA53：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-シクロブチルメトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA54：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-ジフルオロメトキシ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA55：
    （（R）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-メトキシメチル-ピペラジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA56：
    （4-（6-アミノ-4-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-（4-トリフルオロメチル-フェノキシ）-ピリジン-2-イル）-メタノン、
    化合物AA57：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（2-フルオロ-ベンジルオキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA58：
    （1S）-1-（（2R）-4-（6-アミノ-4-メトキシピリジン-3-イル）-1-（5-フェノキシピリジン-2-カルボニル）ピペラジン-2-イル）エタン-1-オール、
    化合物AA59：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（2,2-ジメチル-プロポキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA60：
    （4-（6-アミノ-5-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル）-メタノン、
    化合物AA61：
    （4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-ピペラジン-1-イル）-（5-シクロプロピルメトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA62：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-シクロヘキシルオキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA63：
    （（S）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA64：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（1-フルオロメチル-シクロプロピルメトキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA65：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-エトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA66：
    （4-（6-アミノ-4-メトキシ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル）-メタノン、
    化合物AA67：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（2-シクロプロピル-エトキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA68：
    （7-（6-アミノ-4-メトキシ-ピリジン-3-イル）-3-オキサ-9-アザ-ビシクロ（3.3.1）ノン-9-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA69：
    （（R）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA70：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（（S）-1-シクロプロピル-エトキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA71：
    （（S）-4-（6-アミノ-4-メトキシ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA72：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-イソプロポキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA73：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-フェネチルオキシ-ピリジン-2-イル）-メタノン、
    化合物AA74：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（2,2-ジメチル-プロポキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA75：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-（1-メチル-シクロプロピルメトキシ）-ピリジン-2-イル）-メタノン、
    化合物AA76：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-プロポキシ-ピリジン-2-イル）-メタノン、
    化合物AA77：
    （6-アミノ-4-メトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（（R）-1-シクロプロピル-エトキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA78：
    （4-（6-アミノ-4-メチル-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-シクロプロピルメトキシ-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA79：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（（S）-1-シクロプロピル-エトキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA80：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-（4-トリフルオロメトキシ-フェノキシ）-ピリジン-2-イル）-メタノン、
    化合物AA81：
    （（R）-4-（6-アミノ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（4-メトキシ-5-フェノキシ-ピリジン-2-イル）-メタノン、
    化合物AA82：
    （（R）-4-（6-アミノ-ピリジン-3-イル）-2-ヒドロキシメチル-ピペラジン-1-イル）-（4-メトキシ-5-（4-メトキシ-フェノキシ）-ピリジン-2-イル）-メタノン、
    化合物AA83：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（フェノキシ）-4-エトキシ-ピリジン-2-イル）-メタノン、
    化合物AA84：
    （6-アミノ-4-シクロプロポキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA85：
    （4-（6-アミノ-4-エトキシ-ピリダジン-3-イル）-ピペリジン-1-イル）-（4-メトキシ-5-（フェノキシ）-ピリジン-2-イル）-メタノン、
    化合物AA86：
    （6-アミノ-4-プロポキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA87：
    （6-アミノ-4-エトキシ-3',4',5',6'-テトラヒドロ-2'H-（3,4'）ビピリジニル-1'-イル）-（5-（4-トリフルオロメチル-フェノキシ）-4-メトキシ-ピリジン-2-イル）-メタノン、
    化合物AA88：
    （4-（6-アミノ-ピリダジン-3-イル）-ピペリジン-1-イル）-（5-（4-フルオロ-フェノキシ）-4-エトキシ-ピリジン-2-イル）-メタノン、
    化合物AA89：
    （3-（6-アミノ-ピリダジン-3-イル）-8-アザ-ビシクロ（3.2.1）オクト-8-イル）-（4-エトキシ-5-（4-フルオロ-フェノキシ）-ピリジン-2-イル）-メタノン、
    化合物AA90：
    6-{1-{4-メトキシ-5-（4-（トリフルオロメチル）フェノキシ）ピリジン-2-カルボニル}ピペリジン-4-イル）-5-メチルピリダジン-3-アミン、
    化合物AA91：
    5-メトキシ-6-（1-{5-（4-（トリフルオロメチル）-フェノキシ）-ピリジン-2-カルボニル}ピペリジン-4-イル）-ピリダジン-3-アミン、
    化合物AA92：
    4-メトキシ-5-（1-（4-メトキシ-5-{（トランス-3-（トリフルオロメチル）シクロブチル）-メトキシ}ピリジン-2-カルボニル）-ピペリジン-4-イル）ピリジン-2-アミン、
    化合物AA93：
    4-メトキシ-5-（1-（4-メトキシ-5-{（（シス-3-（トリフルオロメチル）-シクロブチル）メトキシ}-ピリジン-2-カルボニル）ピペリジン-4-イル）ピリジン-2-アミン、
    化合物AA94：
    4-メトキシ-5-（1-{4-メトキシ-5-（（2）-3,3,3-トリフルオロ-2-メチルプロポキシ）-ピリジン-2-カルボニル}ピペリジン-4-イル）ピリジン-2-アミン、
    化合物AA95：
    5-{1-{5-（（2,2-ジフルオロシクロブチル）-メトキシ）-4-メトキシ-ピリジン-2-カルボニル}-ピペリジン-4-イル）-4-メトキシピリジン-2-アミン、
    化合物BB01：
    1-（4-(4-フルオロフェニル)-2-(トリアゾール-2-イル)シクロペンチル）ピペリジン-3-アミン、
    化合物BB02：
    1-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル）ピラゾール-4-カルボニトリル、
    化合物BB03：
    1-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル）ピラゾール-3-カルボニトリル、
    化合物BB04：
    1-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル）ピロール-3-カルボニトリル、
    化合物BB05：
    1-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル）トリアゾール-4-カルボニトリル、
    化合物BB06：
    1-（2-(3-アミノ-5-フルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル）ピラゾール-4-カルボニトリル、
    化合物BB07：
    1-（2-(3-アミノ-4,4-ジフルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル）ピラゾール-4-カルボニトリル、
    化合物BB08：
    1-（4-(4-フルオロフェニル)-2-ピラゾール-1-イル-シクロペンチル）ピペリジン-3-アミン、
    化合物BB09：
    5-フルオロ-1-（4-(4-フルオロフェニル)-2-ピラゾール-1-イル-シクロペンチル）ピペリジン-3-アミン、
    化合物BB10：
    5-フルオロ-1-（4-(4-フルオロフェニル)-2-(1,2,4-トリアゾール-1-イル)シクロペンチル）ピペリジン-3-アミン、
    化合物BB11：
    5-フルオロ-1-（4-(4-フルオロフェニル)-2-(テトラゾール-2-イル)シクロペンチル）ピペリジン-3-アミン、
    化合物BB12：
    1-（4-(4-フルオロフェニル)-2-(テトラゾール-2-イル)シクロペンチル）ピペリジン-3-アミン、
    化合物BB13：
    1-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペンチル）-1,2,4-トリアゾール-3-カルボニトリル、
    化合物BB14：
    4-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロ-3-ヒドロキシ-フェニル)シクロペントキシ）ベンゾニトリル、
    化合物BB15：
    4-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロ-3-メトキシ-フェニル)シクロペントキシ）ベンゾニトリル、
    化合物BB16：
    4-（2-(3-アミノ-1-ピペリジル)-4-(3-フルオロフェニル)シクロペントキシ）-3-クロロ-ベンゾニトリル、
    化合物BB17：
    4-（2-(3-アミノ-4,4-ジフルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）ベンゾニトリル、
    化合物BB18：
    4-（2-(5-アミノ-3,3-ジフルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）ベンゾニトリル、
    化合物BB19：
    4-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）-2-フルオロ-ベンゾニトリル、
    化合物BB20：
    2-（2-(3-アミノ-1-ピペリジル)-4-フェニル-シクロペントキシ）ベンゾニトリル、
    化合物BB21：
    4-（2-(3-アミノ-1-ピペリジル)-4-フェニル-シクロペントキシ）-3-クロロ-ベンゾニトリル、
    化合物BB22：
    6-（2-(3-アミノ-5-フルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）-5-メチル-ピリダジン-3-カルボニトリル、
    化合物BB23：
    1-（2-(4-クロロピリダジン-3-イル)オキシ-4-(4-フルオロフェニル)シクロペンチル）ピペリジン-3-アミン、
    化合物BB24：
    6-（2-(3-アミノ-5-フルオロ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）ピリダジン-3-カルボニトリル、
    化合物BB25：
    1-（4-(4-フルオロフェニル)-2-(5-フルオロピリダジン-3-イル)オキシ-シクロペンチル）ピペリジン-3-アミン、
    化合物BB26：
    6-(2-((R)-3-アミノピペリジン-1-イル)-4-(4-フルオロフェニル)シクロペンチルオキシ)ニコチノニトリル、
    化合物BB27：
    6-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）ピリジン-3-カルボニトリル、
    化合物BB28：
    1-（4-(4-フルオロフェニル)-2-ピリダジン-3-イルオキシ-シクロペンチル）ピペリジン-3-アミン、
    化合物BB29：
    5-フルオロ-1-（4-(4-フルオロフェニル)-ピリミジン-4-イルオキシ-シクロペンチル）ピペリジン-3-アミン、
    化合物BB30：
    2-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）ピリミジン-5-カルボニトリル、
    化合物BB31：
    5-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）ピラジン-2-カルボニトリル、
    化合物BB32：
    5-（2-(3-アミノ-1-ピペリジル)-4-(4-フルオロフェニル)シクロペントキシ）ピリミジン-2-カルボニトリル。     A substance having an inhibitory activity on at least one TRPC channel selected from the group consisting of TRPC3 channel and TRPC6 channel is a compound represented by the general formula (1), a compound represented by the general formula (2), Pyr2, Pyr3. , Pyr4, GSK2332255B, GSK2833503A, SAR7334, BI-749327, at least one compound selected from the group consisting of the compounds AA01-AA95 listed below, and the compounds BB01-BB32 listed below. 12. The pharmaceutical composition according to 12.
    Compound AA01:
    (4- (6-Amino-4-methoxy-pyridin-3-yl) -piperazine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA02:
    (6-Amino-4-methyl-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (4-fluoro-phenoxy) ) -4-Methoxy-pyridin-2-yl) -methanone,
    Compound AA03:
    (6-Amino-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-Il)-(4-Methoxy-5-Phenoxy-Pyridine-2- Il)-Metanon,
    Compound AA04:
    (6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (4-fluoro-phenoxy) ) -4-Methoxy-pyridin-2-yl) -methanone,
    Compound AA05:
    (4- (6-Amino-4-methoxy-pyridin-3-yl) -piperazine-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
    Compound AA06:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-isopropoxy-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA07:
    ((R) -4- (6-amino-4-methyl-pyridine-3-yl) -2-hydroxymethyl-piperazine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy- Pyridine-2-yl) -methanone,
    Compound AA08:
    (7- (6-Amino-4-methoxy-Pyridine-3-yl) -4,7-Diaza-spiro (2.5) Oct-4-yl)-(4-Methoxy-5-phenoxy-pyridin-2-yl) )-Metanon,
    Compound AA09:
    (7- (6-amino-4-methoxy-pyridin-3-yl) -4,7-diaza-spiro (2.5) octo-4-yl)-(5- (4-fluoro-phenoxy) -4-methoxy -Pyridine-2-yl) -methanone,
    Compound AA10:
    (6-Amino-4-methyl-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(4-Methoxy-5-phenoxy- Pyridine-2-yl) -methanone,
    Compound AA11:
    (4- (6-Amino-5-methoxy-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA12:
    (4- (6-Amino-Pyridine-3-yl) -Piperazine-1-yl)-(4-Methoxy-5- (4-Methoxy-phenoxy) -Pyridine-2-yl) -methanone,
    Compound AA13:
    (4- (6-Amino-pyridin-3-yl) -piperazine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA14:
    (6-Amino-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-Il)-(5- (4-Fluoro-phenoxy) -4- Methoxy-pyridin-2-yl) -methanone,
    Compound AA15:
    (4- (6-Amino-pyridin-3-yl) -piperazine-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
    Compound AA16:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
    Compound AA17:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA18:
    ((R) -4- (6-amino-4-methyl-pyridine-3-yl) -2-hydroxymethyl-piperazine-1-yl)-(4-Methoxy-5-phenoxy-pyridine-2-yl) -Metanon,
    Compound AA19:
    (6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (2-fluoro-benzyl) Oxy) -4-methoxy-pyridine-2-yl) -methanone,
    Compound AA20:
    ((R) -4- (6-amino-Pyridine-3-yl) -2-hydroxymethyl-piperazin-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy-pyridine-2- Il)-Metanon,
    Compound AA21:
    (4- (6-Amino-5-methoxy-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
    Compound AA22:
    (6-Amino-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-Il)-(4-Methoxy-5- (4-Methoxy-phenoxy) )-Pyridine-2-yl) -methanone,
    Compound AA23:
    (6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(4-Methoxy-5-phenoxy- Pyridine-2-yl) -methanone,
    Compound AA24:
    (6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(4-Methoxy-5- (4) -Trifluoromethyl-phenoxy) -pyridin-2-yl) -methanone,
    Compound AA25:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5-cyclobutylmethoxy-4-methoxy-pyridin-2-yl) -methanone,
    Compound AA26:
    (6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(4-Methoxy-5- (1) -Methyl-cyclopropylmethoxy) -pyridin-2-yl) -methanone,
    Compound AA27:
    ((R) -4- (6-Amino-4-methoxy-pyridin-3-yl) -2-methoxymethyl-piperazine-1-yl)-(4-Methoxy-5-phenoxy-pyridin-2-yl) -Metanon,
    Compound AA28:
    (6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(4-Methoxy-5- (4) -Methoxy-phenoxy) -pyridin-2-yl) -methanone,
    Compound AA29:
    (4- (6-Amino-4-methyl-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA30:
    (6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(5-Cyclohexyloxy-4-methoxy) -Pyridine-2-yl) -methanone,
    Compound AA31:
    (4- (6-Amino-4-methyl-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
    Compound AA32:
    (6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (4-fluoro-benzyl) Oxy) -4-methoxy-pyridine-2-yl) -methanone,
    Compound AA33:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5- (4-trifluoromethyl-phenoxy) -pyridin-2-yl) -methanone,
    Compound AA34:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-chloro-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA35:
    (6-Amino-4-methoxy-3,4,5,6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5-cyclopentyloxy-4-methoxy-pyridine- 2-Il)-Metanon,
    Compound AA36:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5-isobutoxy-4-methoxy-pyridin-2-yl) -methanone,
    Compound AA37:
    (6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(5-Cyclopropylmethoxy-4- Methoxy-pyridin-2-yl) -methanone,
    Compound AA38:
    (3- (6-Amino-4-methoxy-pyridin-3-yl) -3,8-diaza-bicyclo (3.2.1) octo-8-yl)-(5- (4-fluoro-phenoxy) -4 -Methoxy-pyridin-2-yl) -methanone,
    Compound AA39:
    (6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5-isobutoxy-4-methoxy- Pyridine-2-yl) -methanone,
    Compound AA40:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-cyclopropoxy-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA41:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-fluoro-benzyloxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA42:
    ((R) -4- (6-amino-4-methoxy-pyridin-3-yl) -2-hydroxymethyl-piperazine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy- Pyridine-2-yl) -methanone,
    Compound AA43:
    (6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5-benzyloxy-4-methoxy) -Pyridine-2-yl) -methanone,
    Compound AA44:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5- (4-methoxy-phenoxy) -pyridin-2-yl) -methanone,
    Compound AA45:
    (6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (3,3-difluoro) -Cyclobutylmethoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA46:
    (6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(4-Methoxy-5-propoxy- Pyridine-2-yl) -methanone,
    Compound AA47:
    (4- (6-Amino-4-methoxy-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
    Compound AA48:
    (6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(5- (2-Cyclopropyl-) Ethoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA49:
    (4- (6-Amino-4-methoxy-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA50:
    (1R) -1-((2R) -4- (6-amino-4-methoxypyridin-3-yl) -1- (5-phenoxypyridine-2-carbonyl) piperazine-2-yl) ethane-1- All,
    Compound AA51:
    (3- (6-Amino-4-methoxy-Pyridine-3-yl) -3,8-Diaza-bicyclo (3.2.1) Oct-8-yl)-(4-Methoxy-5-Phenoxy-Pyridine-2) -Il)-Metanon,
    Compound AA52:
    (6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-Il)-(4-Methoxy-5-Phenethyloxy -Pyridine-2-yl) -methanone,
    Compound AA53:
    (6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(5-Cyclobutylmethoxy-4- Methoxy-pyridin-2-yl) -methanone,
    Compound AA54:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-difluoromethoxy-phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA55:
    ((R) -4- (6-amino-4-methoxy-pyridin-3-yl) -2-methoxymethyl-piperazine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy- Pyridine-2-yl) -methanone,
    Compound AA56:
    (4- (6-Amino-4-methoxy-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5- (4-trifluoromethyl-phenoxy) -pyridin-2-yl)- Metanon,
    Compound AA57:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (2-fluoro-benzyloxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA58:
    (1S) -1-((2R) -4- (6-amino-4-methoxypyridin-3-yl) -1- (5-phenoxypyridine-2-carbonyl) piperazine-2-yl) ethane-1- All,
    Compound AA59:
    (6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (2,2-dimethyl) -Propoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA60:
    (4- (6-Amino-5-methoxy-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5- (4-methoxy-phenoxy) -pyridin-2-yl) -methanone,
    Compound AA61:
    (4- (6-Amino-4-methoxy-pyridin-3-yl) -piperazine-1-yl)-(5-cyclopropylmethoxy-4-methoxy-pyridin-2-yl) -methanone,
    Compound AA62:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5-cyclohexyloxy-4-methoxy-pyridin-2-yl) -methanone,
    Compound AA63:
    ((S) -4- (6-amino-4-methoxy-pyridin-3-yl) -2-hydroxymethyl-piperazine-1-yl)-(5- (4-fluoro-phenoxy) -4-methoxy- Pyridine-2-yl) -methanone,
    Compound AA64:
    (6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (1-fluoromethyl-) Cyclopropylmethoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA65:
    (6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-yl)-(5-ethoxy-4-methoxy- Pyridine-2-yl) -methanone,
    Compound AA66:
    (4- (6-Amino-4-methoxy-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5- (4-methoxy-phenoxy) -pyridin-2-yl) -methanone,
    Compound AA67:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (2-cyclopropyl-ethoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA68:
    (7- (6-Amino-4-methoxy-Pyridine-3-yl) -3-oxa-9-aza-bicyclo (3.3.1) non-9-yl)-(4-Methoxy-5-phenoxy-pyridine -2-Il)-Metanon,
    Compound AA69:
    ((R) -4- (6-amino-4-methoxy-pyridin-3-yl) -2-hydroxymethyl-piperazin-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -Metanon,
    Compound AA70:
    (6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5-((S) -1) -Cyclopropyl-ethoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA71:
    ((S) -4- (6-amino-4-methoxy-pyridin-3-yl) -2-hydroxymethyl-piperazine-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -Metanon,
    Compound AA72:
    (6-Amino-4-methoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5-isopropoxy-4-methoxy) -Pyridine-2-yl) -methanone,
    Compound AA73:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5-phenethyloxy-pyridin-2-yl) -methanone,
    Compound AA74:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (2,2-dimethyl-propoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA75:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5- (1-methyl-cyclopropylmethoxy) -pyridin-2-yl) -methanone,
    Compound AA76:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5-propoxy-pyridin-2-yl) -methanone,
    Compound AA77:
    (6-Amino-4-methoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-Il)-(5-((R) -1) -Cyclopropyl-ethoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA78:
    (4- (6-Amino-4-methyl-pyridazine-3-yl) -piperidine-1-yl)-(5-cyclopropylmethoxy-4-methoxy-pyridin-2-yl) -methanone,
    Compound AA79:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5-((S) -1-cyclopropyl-ethoxy) -4-methoxy-pyridin-2-yl) -methanone ,
    Compound AA80:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5- (4-trifluoromethoxy-phenoxy) -pyridin-2-yl) -methanone,
    Compound AA81:
    ((R) -4- (6-amino-pyridin-3-yl) -2-hydroxymethyl-piperazin-1-yl)-(4-methoxy-5-phenoxy-pyridin-2-yl) -methanone,
    Compound AA82:
    ((R) -4- (6-amino-Pyridine-3-yl) -2-hydroxymethyl-piperazine-1-yl)-(4-Methoxy-5- (4-methoxy-phenoxy) -pyridine-2- Il)-Metanon,
    Compound AA83:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (phenoxy) -4-ethoxy-pyridin-2-yl) -methanone,
    Compound AA84:
    (6-Amino-4-cyclopropoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (phenoxy) -4 -Methoxy-pyridin-2-yl) -methanone,
    Compound AA85:
    (4- (6-Amino-4-ethoxy-pyridazine-3-yl) -piperidine-1-yl)-(4-methoxy-5- (phenoxy) -pyridin-2-yl) -methanone,
    Compound AA86:
    (6-Amino-4-propoxy-3', 4', 5', 6'-tetrahydro-2'H- (3,4') bipyridinyl-1'-yl)-(5- (phenoxy) -4- Methoxy-pyridin-2-yl) -methanone,
    Compound AA87:
    (6-Amino-4-ethoxy-3', 4', 5', 6'-Tetrahydro-2'H- (3,4') Bipyridinyl-1'-Il)-(5- (4-Trifluoromethyl) -Phenoxy) -4-methoxy-pyridin-2-yl) -methanone,
    Compound AA88:
    (4- (6-Amino-pyridazine-3-yl) -piperidine-1-yl)-(5- (4-fluoro-phenoxy) -4-ethoxy-pyridin-2-yl) -methanone,
    Compound AA89:
    (3- (6-Amino-pyridazine-3-yl) -8-aza-bicyclo (3.2.1) octo-8-yl)-(4-ethoxy-5- (4-fluoro-phenoxy) -pyridine-2 -Il)-Metanon,
    Compound AA90:
    6- {1- {4-Methoxy-5- (4- (trifluoromethyl) phenoxy) pyridin-2-carbonyl} piperidine-4-yl) -5-methylpyridazine-3-amine,
    Compound AA91:
    5-Methoxy-6-(1- {5-(4- (trifluoromethyl) -phenoxy) -pyridin-2-carbonyl} piperidine-4-yl) -pyridazine-3-amine,
    Compound AA92:
    4-Methoxy-5-(1- (4-Methoxy-5-{(trans-3- (trifluoromethyl) cyclobutyl) -methoxy} pyridine-2-carbonyl) -piperidine-4-yl) pyridine-2-amine ,
    Compound AA93:
    4-Methoxy-5-(1- (4-Methoxy-5-{((cis-3- (trifluoromethyl) -cyclobutyl) methoxy} -pyridin-2-carbonyl) piperidine-4-yl) pyridin-2- Amin,
    Compound AA94:
    4-Methoxy-5-(1- {4-Methoxy-5-((2) -3,3,3-trifluoro-2-methylpropoxy) -pyridin-2-carbonyl} piperidine-4-yl) pyridine- 2-amine,
    Compound AA95:
    5- {1- {5-((2,2-difluorocyclobutyl) -methoxy) -4-methoxy-pyridin-2-carbonyl} -piperidine-4-yl) -4-methoxypyridin-2-amine,
    Compound BB01:
    1-(4- (4-fluorophenyl) -2- (triazole-2-yl) cyclopentyl) piperidine-3-amine,
    Compound BB02:
    1-(2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl) pyrazole-4-carbonitrile,
    Compound BB03:
    1-(2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl) pyrazole-3-carbonitrile,
    Compound BB04:
    1-(2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl) pyrrole-3-carbonitrile,
    Compound BB05:
    1-(2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl) triazole-4-carbonitrile,
    Compound BB06:
    1-(2- (3-Amino-5-fluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl) pyrazole-4-carbonitrile,
    Compound BB07:
    1-(2- (3-Amino-4,4-difluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl) pyrazole-4-carbonitrile,
    Compound BB08:
    1-(4- (4-fluorophenyl) -2-pyrazol-1-yl-cyclopentyl) piperidine-3-amine,
    Compound BB09:
    5-Fluoro-1- (4- (4-fluorophenyl) -2-pyrazole-1-yl-cyclopentyl) piperidine-3-amine,
    Compound BB10:
    5-Fluoro-1- (4- (4-fluorophenyl) -2- (1,2,4-triazole-1-yl) cyclopentyl) piperidine-3-amine,
    Compound BB11:
    5-Fluoro-1- (4- (4-fluorophenyl) -2- (tetrazol-2-yl) cyclopentyl) piperidine-3-amine,
    Compound BB12:
    1-(4- (4-fluorophenyl) -2- (tetrazol-2-yl) cyclopentyl) piperidine-3-amine,
    Compound BB13:
    1-(2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentyl) -1,2,4-triazole-3-carbonitrile,
    Compound BB14:
    4- (2- (3-Amino-1-piperidyl) -4- (4-fluoro-3-hydroxy-phenyl) cyclopentoxy) benzonitrile,
    Compound BB15:
    4- (2- (3-Amino-1-piperidyl) -4- (4-fluoro-3-methoxy-phenyl) cyclopentoxy) benzonitrile,
    Compound BB16:
    4- (2- (3-Amino-1-piperidyl) -4- (3-fluorophenyl) cyclopentoxy) -3-chloro-benzonitrile,
    Compound BB17:
    4- (2- (3-Amino-4,4-difluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) benzonitrile,
    Compound BB18:
    4- (2- (5-Amino-3,3-difluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) benzonitrile,
    Compound BB19:
    4- (2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) -2-fluoro-benzonitrile,
    Compound BB20:
    2- (2- (3-Amino-1-piperidyl) -4-phenyl-cyclopentoxy) benzonitrile,
    Compound BB21:
    4- (2- (3-Amino-1-piperidyl) -4-phenyl-cyclopentoxy) -3-chloro-benzonitrile,
    Compound BB22:
    6-(2- (3-Amino-5-fluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) -5-methyl-pyridazine-3-carbonitrile,
    Compound BB23:
    1-(2- (4-chloropyridazine-3-yl) oxy-4- (4-fluorophenyl) cyclopentyl) piperidine-3-amine,
    Compound BB24:
    6-(2- (3-Amino-5-fluoro-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) pyridazine-3-carbonitrile,
    Compound BB25:
    1-(4- (4-Fluorophenyl) -2- (5-fluoropyridazine-3-yl) oxy-cyclopentyl) piperidine-3-amine,
    Compound BB26:
    6-(2-((R) -3-aminopiperidine-1-yl) -4- (4-fluorophenyl) cyclopentyloxy) nicotinonitrile,
    Compound BB27:
    6-(2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) Pyridine-3-Carbonitrile,
    Compound BB28:
    1-(4- (4-fluorophenyl) -2-pyridazine-3-yloxy-cyclopentyl) piperidine-3-amine,
    Compound BB29:
    5-Fluoro-1- (4- (4-fluorophenyl) -pyrimidine-4-yloxy-cyclopentyl) piperidine-3-amine,
    Compound BB30:
    2- (2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) pyrimidine-5-carbonitrile,
    Compound BB31:
    5- (2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) pyrazine-2-carbonitrile,
    Compound BB32:
    5- (2- (3-Amino-1-piperidyl) -4- (4-fluorophenyl) cyclopentoxy) pyrimidine-2-carbonitrile.
  14. 　経口投与用である請求項１～１３のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 13, which is for oral administration.
  15. 　難聴が感音難聴である請求項１～１４のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 14, wherein the deafness is sensorineural deafness.
  16. 　難聴が白金製剤に起因する難聴である請求項１～１５のいずれかに記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 15, wherein the deafness is caused by a platinum preparation.
PCT/JP2020/039813 2019-10-24 2020-10-23 Pharmaceutical composition for prevention and/or treatment of hearing loss WO2021079962A1 (en)

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