WO2021079962A1 - Composition destinée à la prévention, et/ou au traitement d'une perte d'audition - Google Patents

Composition destinée à la prévention, et/ou au traitement d'une perte d'audition 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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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

La présente invention vise à fournir une nouvelle composition pharmaceutique pour la prévention et/ou le traitement d'une perte d'audition.　La présente invention concerne une composition pharmaceutique pour la prévention et/ou le traitement d'une perte d'audition qui contient un composé représenté par la formule générale (1) [dans la formule, A est un noyau benzénique éventuellement substitué. B représente un aryle éventuellement substitué ou un hétéroaryle éventuellement substitué. X représente un atome d'oxygène ou un atome de soufre. Y représente un atome d'azote ou un atome de carbone. Dans la formule générale (2), la formule générale (3) représente une liaison simple ou une double liaison lorsqu'Y représente un atome de carbone, et représente une liaison simple lorsqu'Y représente un atome d'azote. Chaque R1 représente indépendamment un alkyle inférieur, ou deux R1 peuvent se lier l'un à l'autre pour former un noyau spiro ou une structure réticulée, ou deux R1 peuvent se lier l'un à l'autre pour former un hétérocycle fusionné saturé conjointement à des atomes de carbone et des atomes d'azote qui constituent un cycle qui comprend Y. p est 0, 1, ou 2. Ou, (R1)p est un oxo.], un sel de celui-ci, ou un promédicament de celui-ci.
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WO2023132208A1 (fr) * 2022-01-07 2023-07-13 国立大学法人大阪大学 Composition pharmaceutique destinée à prévenir ou à traiter l'insuffisance cardiaque
WO2023163203A1 (fr) * 2022-02-28 2023-08-31 国立大学法人大阪大学 Composition pharmaceutique pour prévenir et/ou traiter une maladie rénale

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WO2023163203A1 (fr) * 2022-02-28 2023-08-31 国立大学法人大阪大学 Composition pharmaceutique pour prévenir et/ou traiter une maladie rénale

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