JP2002525329A - 感覚毛細胞及び蝸牛ニューロンへの損傷を予防する／処置するための方法 - Google Patents
感覚毛細胞及び蝸牛ニューロンへの損傷を予防する／処置するための方法Info
- Publication number
- JP2002525329A JP2002525329A JP2000571925A JP2000571925A JP2002525329A JP 2002525329 A JP2002525329 A JP 2002525329A JP 2000571925 A JP2000571925 A JP 2000571925A JP 2000571925 A JP2000571925 A JP 2000571925A JP 2002525329 A JP2002525329 A JP 2002525329A
- Authority
- JP
- Japan
- Prior art keywords
- optionally substituted
- alkyl
- independently
- formula
- twenty
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 210000002768 hair cell Anatomy 0.000 title claims abstract description 260
- 238000000034 method Methods 0.000 title claims abstract description 258
- 230000001953 sensory effect Effects 0.000 title claims abstract description 155
- 210000002569 neuron Anatomy 0.000 title claims abstract description 51
- 230000006378 damage Effects 0.000 title abstract description 51
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 208000016354 hearing loss disease Diseases 0.000 claims abstract description 53
- 208000018883 loss of balance Diseases 0.000 claims abstract description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 325
- 125000000217 alkyl group Chemical group 0.000 claims description 314
- 229910052760 oxygen Inorganic materials 0.000 claims description 274
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 229
- 125000001072 heteroaryl group Chemical group 0.000 claims description 163
- 125000003118 aryl group Chemical group 0.000 claims description 153
- 229910052757 nitrogen Inorganic materials 0.000 claims description 147
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 114
- 125000003545 alkoxy group Chemical group 0.000 claims description 103
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 91
- 125000004432 carbon atom Chemical group C* 0.000 claims description 90
- QNMMYUBZGLXCCK-UHFFFAOYSA-N pyrrolo[3,2-a]carbazole Chemical compound N1=C2C=CC=CC2=C2C1=C1C=CN=C1C=C2 QNMMYUBZGLXCCK-UHFFFAOYSA-N 0.000 claims description 86
- 125000001424 substituent group Chemical group 0.000 claims description 72
- 229910052739 hydrogen Inorganic materials 0.000 claims description 69
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 69
- 229910052799 carbon Inorganic materials 0.000 claims description 66
- 229910052731 fluorine Inorganic materials 0.000 claims description 66
- 125000003342 alkenyl group Chemical group 0.000 claims description 63
- -1 heterocycloalkoxy Si Chemical group 0.000 claims description 63
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 61
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 58
- 125000004426 substituted alkynyl group Chemical group 0.000 claims description 58
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 54
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 53
- 125000003107 substituted aryl group Chemical group 0.000 claims description 52
- 239000001301 oxygen Substances 0.000 claims description 51
- 125000000304 alkynyl group Chemical group 0.000 claims description 46
- 229910052794 bromium Inorganic materials 0.000 claims description 45
- 229910052801 chlorine Inorganic materials 0.000 claims description 45
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 45
- 125000005647 linker group Chemical group 0.000 claims description 44
- 125000000623 heterocyclic group Chemical group 0.000 claims description 41
- 125000005017 substituted alkenyl group Chemical group 0.000 claims description 41
- 125000005842 heteroatom Chemical group 0.000 claims description 38
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- 150000002367 halogens Chemical class 0.000 claims description 37
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 claims description 35
- 206010070863 Toxicity to various agents Diseases 0.000 claims description 35
- 125000004452 carbocyclyl group Chemical group 0.000 claims description 35
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 35
- 229910052740 iodine Inorganic materials 0.000 claims description 35
- 150000002772 monosaccharides Chemical class 0.000 claims description 35
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 34
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 34
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 34
- 230000005779 cell damage Effects 0.000 claims description 34
- 208000037887 cell injury Diseases 0.000 claims description 34
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 claims description 34
- 239000011593 sulfur Substances 0.000 claims description 34
- 125000004001 thioalkyl group Chemical group 0.000 claims description 34
- 229910052697 platinum Inorganic materials 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 26
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 25
- 229940126575 aminoglycoside Drugs 0.000 claims description 24
- 229940079593 drug Drugs 0.000 claims description 24
- 150000001413 amino acids Chemical class 0.000 claims description 23
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 23
- 150000003839 salts Chemical group 0.000 claims description 23
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 21
- 125000002252 acyl group Chemical group 0.000 claims description 20
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 20
- 229920006395 saturated elastomer Polymers 0.000 claims description 20
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims description 19
- 229940127089 cytotoxic agent Drugs 0.000 claims description 19
- 231100000599 cytotoxic agent Toxicity 0.000 claims description 19
- 239000002254 cytotoxic agent Substances 0.000 claims description 19
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 19
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 claims description 18
- 229960004316 cisplatin Drugs 0.000 claims description 18
- 125000004434 sulfur atom Chemical group 0.000 claims description 18
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 17
- 125000002947 alkylene group Chemical group 0.000 claims description 17
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 17
- 239000003221 ear drop Substances 0.000 claims description 15
- 229940047652 ear drops Drugs 0.000 claims description 15
- 230000006870 function Effects 0.000 claims description 14
- 230000034994 death Effects 0.000 claims description 13
- 208000015181 infectious disease Diseases 0.000 claims description 13
- 230000030833 cell death Effects 0.000 claims description 11
- 238000011200 topical administration Methods 0.000 claims description 11
- VSRXQHXAPYXROS-UHFFFAOYSA-N azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OC(=O)C1(C(O)=O)CCC1 VSRXQHXAPYXROS-UHFFFAOYSA-N 0.000 claims description 9
- 229960004562 carboplatin Drugs 0.000 claims description 9
- 230000016273 neuron death Effects 0.000 claims description 9
- 231100000433 cytotoxic Toxicity 0.000 claims 8
- 230000001472 cytotoxic effect Effects 0.000 claims 8
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims 6
- 210000003952 cochlear nucleus Anatomy 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 31
- 230000002265 prevention Effects 0.000 abstract description 3
- 241001465754 Metazoa Species 0.000 description 68
- 210000003477 cochlea Anatomy 0.000 description 59
- 208000014674 injury Diseases 0.000 description 46
- 229930193140 Neomycin Natural products 0.000 description 42
- 229960004927 neomycin Drugs 0.000 description 42
- 239000007787 solid Substances 0.000 description 34
- 230000008733 trauma Effects 0.000 description 34
- 210000004027 cell Anatomy 0.000 description 33
- 239000000203 mixture Substances 0.000 description 31
- 238000002360 preparation method Methods 0.000 description 30
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 29
- 229930182566 Gentamicin Natural products 0.000 description 29
- 229960002518 gentamicin Drugs 0.000 description 29
- 210000002985 organ of corti Anatomy 0.000 description 29
- 239000000243 solution Substances 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- 239000000460 chlorine Substances 0.000 description 27
- 238000005481 NMR spectroscopy Methods 0.000 description 26
- 210000003027 ear inner Anatomy 0.000 description 25
- 210000004940 nucleus Anatomy 0.000 description 25
- 230000000694 effects Effects 0.000 description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 230000022534 cell killing Effects 0.000 description 21
- 241000700198 Cavia Species 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 19
- 239000000047 product Substances 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- 239000011541 reaction mixture Substances 0.000 description 18
- 230000001720 vestibular Effects 0.000 description 18
- 230000003902 lesion Effects 0.000 description 17
- KPKZJLCSROULON-QKGLWVMZSA-N Phalloidin Chemical compound N1C(=O)[C@@H]([C@@H](O)C)NC(=O)[C@H](C)NC(=O)[C@H](C[C@@](C)(O)CO)NC(=O)[C@H](C2)NC(=O)[C@H](C)NC(=O)[C@@H]3C[C@H](O)CN3C(=O)[C@@H]1CSC1=C2C2=CC=CC=C2N1 KPKZJLCSROULON-QKGLWVMZSA-N 0.000 description 16
- 230000007850 degeneration Effects 0.000 description 16
- 210000000056 organ Anatomy 0.000 description 16
- 229940024606 amino acid Drugs 0.000 description 15
- 230000033001 locomotion Effects 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 15
- 108010055717 JNK Mitogen-Activated Protein Kinases Proteins 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 235000001014 amino acid Nutrition 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 241000700159 Rattus Species 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 230000004044 response Effects 0.000 description 13
- 210000000067 inner hair cell Anatomy 0.000 description 12
- 210000001519 tissue Anatomy 0.000 description 12
- 108010025020 Nerve Growth Factor Proteins 0.000 description 11
- 108090000742 Neurotrophin 3 Proteins 0.000 description 11
- 208000027418 Wounds and injury Diseases 0.000 description 11
- 238000005259 measurement Methods 0.000 description 11
- 102100029268 Neurotrophin-3 Human genes 0.000 description 10
- 150000001721 carbon Chemical group 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 238000013467 fragmentation Methods 0.000 description 10
- 238000006062 fragmentation reaction Methods 0.000 description 10
- 238000000338 in vitro Methods 0.000 description 10
- 239000012188 paraffin wax Substances 0.000 description 10
- 229940002612 prodrug Drugs 0.000 description 10
- 239000000651 prodrug Substances 0.000 description 10
- 125000005415 substituted alkoxy group Chemical group 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 9
- 230000002147 killing effect Effects 0.000 description 9
- 239000002609 medium Substances 0.000 description 9
- 239000002953 phosphate buffered saline Substances 0.000 description 9
- 229950003937 tolonium Drugs 0.000 description 9
- HNONEKILPDHFOL-UHFFFAOYSA-M tolonium chloride Chemical compound [Cl-].C1=C(C)C(N)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 HNONEKILPDHFOL-UHFFFAOYSA-M 0.000 description 9
- 108020004414 DNA Proteins 0.000 description 8
- 108010009711 Phalloidine Proteins 0.000 description 8
- 102100023132 Transcription factor Jun Human genes 0.000 description 8
- 230000003111 delayed effect Effects 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 8
- 229920005989 resin Polymers 0.000 description 8
- 239000011347 resin Substances 0.000 description 8
- 230000013707 sensory perception of sound Effects 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 7
- 206010002091 Anaesthesia Diseases 0.000 description 7
- 206010011878 Deafness Diseases 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 101001050288 Homo sapiens Transcription factor Jun Proteins 0.000 description 7
- 102000015336 Nerve Growth Factor Human genes 0.000 description 7
- 229930040373 Paraformaldehyde Natural products 0.000 description 7
- 230000037005 anaesthesia Effects 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 235000019439 ethyl acetate Nutrition 0.000 description 7
- 239000012530 fluid Substances 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 229920002866 paraformaldehyde Polymers 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 125000004122 cyclic group Chemical group 0.000 description 6
- 208000035475 disorder Diseases 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 238000002844 melting Methods 0.000 description 6
- 230000008018 melting Effects 0.000 description 6
- 230000004048 modification Effects 0.000 description 6
- 238000012986 modification Methods 0.000 description 6
- 230000026731 phosphorylation Effects 0.000 description 6
- 238000006366 phosphorylation reaction Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 241000700199 Cavia porcellus Species 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- 206010036626 Presbyacusis Diseases 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 210000000133 brain stem Anatomy 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 125000000524 functional group Chemical group 0.000 description 5
- 230000001771 impaired effect Effects 0.000 description 5
- 239000010410 layer Substances 0.000 description 5
- 208000009800 presbycusis Diseases 0.000 description 5
- 230000001681 protective effect Effects 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 238000004804 winding Methods 0.000 description 5
- HZNVUJQVZSTENZ-UHFFFAOYSA-N 2,3-dichloro-5,6-dicyano-1,4-benzoquinone Chemical compound ClC1=C(Cl)C(=O)C(C#N)=C(C#N)C1=O HZNVUJQVZSTENZ-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 206010063602 Exposure to noise Diseases 0.000 description 4
- 102000034615 Glial cell line-derived neurotrophic factor Human genes 0.000 description 4
- 108091010837 Glial cell line-derived neurotrophic factor Proteins 0.000 description 4
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 102000007072 Nerve Growth Factors Human genes 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 230000002238 attenuated effect Effects 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 102000014823 calbindin Human genes 0.000 description 4
- 108060001061 calbindin Proteins 0.000 description 4
- 125000002837 carbocyclic group Chemical group 0.000 description 4
- 230000003915 cell function Effects 0.000 description 4
- 231100000135 cytotoxicity Toxicity 0.000 description 4
- 230000003013 cytotoxicity Effects 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 210000000981 epithelium Anatomy 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 4
- 231100000888 hearing loss Toxicity 0.000 description 4
- 230000010370 hearing loss Effects 0.000 description 4
- 210000005036 nerve Anatomy 0.000 description 4
- 230000037361 pathway Effects 0.000 description 4
- 210000004049 perilymph Anatomy 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
- 239000012265 solid product Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical compound C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 3
- 102000007469 Actins Human genes 0.000 description 3
- 108010085238 Actins Proteins 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 102000004219 Brain-derived neurotrophic factor Human genes 0.000 description 3
- 108090000715 Brain-derived neurotrophic factor Proteins 0.000 description 3
- 208000032544 Cicatrix Diseases 0.000 description 3
- FFEARJCKVFRZRR-SCSAIBSYSA-N D-methionine Chemical compound CSCC[C@@H](N)C(O)=O FFEARJCKVFRZRR-SCSAIBSYSA-N 0.000 description 3
- 229930182818 D-methionine Natural products 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 229940123457 Free radical scavenger Drugs 0.000 description 3
- 208000003098 Ganglion Cysts Diseases 0.000 description 3
- KOZFSFOOLUUIGY-SOLYNIJKSA-N K-252a Chemical compound C12=C3N4C5=CC=CC=C5C3=C3CNC(=O)C3=C2C2=CC=CC=C2N1[C@H]1C[C@@](C(=O)OC)(O)[C@]4(C)O1 KOZFSFOOLUUIGY-SOLYNIJKSA-N 0.000 description 3
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 3
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 3
- 206010033109 Ototoxicity Diseases 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 208000005400 Synovial Cyst Diseases 0.000 description 3
- 230000032683 aging Effects 0.000 description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 3
- 125000004414 alkyl thio group Chemical group 0.000 description 3
- 229960004821 amikacin Drugs 0.000 description 3
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 210000002469 basement membrane Anatomy 0.000 description 3
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 150000001735 carboxylic acids Chemical class 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004440 column chromatography Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 231100000409 cytocidal Toxicity 0.000 description 3
- 230000000445 cytocidal effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 239000006196 drop Substances 0.000 description 3
- 210000000959 ear middle Anatomy 0.000 description 3
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 3
- 210000003128 head Anatomy 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 3
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 3
- 229960003299 ketamine Drugs 0.000 description 3
- 150000003951 lactams Chemical class 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 229940053128 nerve growth factor Drugs 0.000 description 3
- 230000000926 neurological effect Effects 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 239000012044 organic layer Substances 0.000 description 3
- 239000012285 osmium tetroxide Substances 0.000 description 3
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 3
- 231100000199 ototoxic Toxicity 0.000 description 3
- 230000002970 ototoxic effect Effects 0.000 description 3
- 231100000262 ototoxicity Toxicity 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 229920001184 polypeptide Polymers 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 102000004196 processed proteins & peptides Human genes 0.000 description 3
- 239000002516 radical scavenger Substances 0.000 description 3
- 239000003642 reactive oxygen metabolite Substances 0.000 description 3
- 108700038288 rhodamine-phalloidin Proteins 0.000 description 3
- 231100000241 scar Toxicity 0.000 description 3
- 230000037387 scars Effects 0.000 description 3
- 210000002480 semicircular canal Anatomy 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000000472 traumatic effect Effects 0.000 description 3
- 238000013042 tunel staining Methods 0.000 description 3
- 210000003454 tympanic membrane Anatomy 0.000 description 3
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 3
- 229960001600 xylazine Drugs 0.000 description 3
- 239000011701 zinc Substances 0.000 description 3
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- AVFZOVWCLRSYKC-UHFFFAOYSA-N 1-methylpyrrolidine Chemical compound CN1CCCC1 AVFZOVWCLRSYKC-UHFFFAOYSA-N 0.000 description 2
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 2
- XQMVBICWFFHDNN-UHFFFAOYSA-N 5-amino-4-chloro-2-phenylpyridazin-3-one;(2-ethoxy-3,3-dimethyl-2h-1-benzofuran-5-yl) methanesulfonate Chemical compound O=C1C(Cl)=C(N)C=NN1C1=CC=CC=C1.C1=C(OS(C)(=O)=O)C=C2C(C)(C)C(OCC)OC2=C1 XQMVBICWFFHDNN-UHFFFAOYSA-N 0.000 description 2
- 229910000497 Amalgam Inorganic materials 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- DRSHXJFUUPIBHX-UHFFFAOYSA-N COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 Chemical compound COc1ccc(cc1)N1N=CC2C=NC(Nc3cc(OC)c(OC)c(OCCCN4CCN(C)CC4)c3)=NC12 DRSHXJFUUPIBHX-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 108010024636 Glutathione Proteins 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 201000009906 Meningitis Diseases 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- AHVYPIQETPWLSZ-UHFFFAOYSA-N N-methyl-pyrrolidine Natural products CN1CC=CC1 AHVYPIQETPWLSZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 241000700157 Rattus norvegicus Species 0.000 description 2
- 238000000692 Student's t-test Methods 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 206010047348 Vertigo positional Diseases 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- SXEHKFHPFVVDIR-UHFFFAOYSA-N [4-(4-hydrazinylphenyl)phenyl]hydrazine Chemical compound C1=CC(NN)=CC=C1C1=CC=C(NN)C=C1 SXEHKFHPFVVDIR-UHFFFAOYSA-N 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 125000004423 acyloxy group Chemical group 0.000 description 2
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 2
- 125000005083 alkoxyalkoxy group Chemical group 0.000 description 2
- 125000003282 alkyl amino group Chemical group 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 239000003708 ampul Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 210000003030 auditory receptor cell Anatomy 0.000 description 2
- 201000000691 benign paroxysmal positional nystagmus Diseases 0.000 description 2
- 208000001870 benign paroxysmal positional vertigo Diseases 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 210000000988 bone and bone Anatomy 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- LJFIPVIYARKJOQ-UHFFFAOYSA-N carbazole-2,4-dione Chemical compound C1=CC=CC2=NC3=CC(=O)CC(=O)C3=C21 LJFIPVIYARKJOQ-UHFFFAOYSA-N 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 230000006727 cell loss Effects 0.000 description 2
- 239000002771 cell marker Substances 0.000 description 2
- UZHRKFKSACFLDG-UHFFFAOYSA-N chembl219159 Chemical compound N1C2=CC=CC=C2C2=C1C(CC=1C3=CC=CC=1)=C3C1=C2C(=O)NC1=O UZHRKFKSACFLDG-UHFFFAOYSA-N 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- ALEXXDVDDISNDU-JZYPGELDSA-N cortisol 21-acetate Chemical compound C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@@](C(=O)COC(=O)C)(O)[C@@]1(C)C[C@@H]2O ALEXXDVDDISNDU-JZYPGELDSA-N 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 231100000895 deafness Toxicity 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000010432 diamond Substances 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 210000000883 ear external Anatomy 0.000 description 2
- 238000001493 electron microscopy Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- PGBHMTALBVVCIT-VCIWKGPPSA-N framycetin Chemical compound N[C@@H]1[C@@H](O)[C@H](O)[C@H](CN)O[C@@H]1O[C@H]1[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](N)C[C@@H](N)[C@@H]2O)O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CN)O2)N)O[C@@H]1CO PGBHMTALBVVCIT-VCIWKGPPSA-N 0.000 description 2
- 230000005714 functional activity Effects 0.000 description 2
- 229960003180 glutathione Drugs 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 210000004307 hair cells vestibular Anatomy 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 125000004404 heteroalkyl group Chemical group 0.000 description 2
- 150000002430 hydrocarbons Chemical group 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 238000002513 implantation Methods 0.000 description 2
- 210000001785 incus Anatomy 0.000 description 2
- WUNJCKOTXFSWBK-UHFFFAOYSA-N indeno[2,1-a]carbazole Chemical compound C1=CC=C2C=C3C4=NC5=CC=CC=C5C4=CC=C3C2=C1 WUNJCKOTXFSWBK-UHFFFAOYSA-N 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000003550 marker Substances 0.000 description 2
- 210000004379 membrane Anatomy 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000009456 molecular mechanism Effects 0.000 description 2
- 230000000877 morphologic effect Effects 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229940053050 neomycin sulfate Drugs 0.000 description 2
- 210000001640 nerve ending Anatomy 0.000 description 2
- 101150006061 neur gene Proteins 0.000 description 2
- 201000001119 neuropathy Diseases 0.000 description 2
- 230000007823 neuropathy Effects 0.000 description 2
- 239000003900 neurotrophic factor Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 238000012758 nuclear staining Methods 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 230000000972 organotrophic effect Effects 0.000 description 2
- 238000012261 overproduction Methods 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- 208000033808 peripheral neuropathy Diseases 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 230000035939 shock Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 230000035882 stress Effects 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 210000002489 tectorial membrane Anatomy 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000003831 tetrazolyl group Chemical group 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 125000001544 thienyl group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 239000003440 toxic substance Substances 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical compound C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 description 1
- ZRMVJDIZKJYFMA-UHFFFAOYSA-N 2-(1h-inden-2-yl)-1h-indole Chemical compound C1=CC=C2NC(C=3CC4=CC=CC=C4C=3)=CC2=C1 ZRMVJDIZKJYFMA-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- IKOKHHBZFDFMJW-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-(2-morpholin-4-ylethoxy)pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)OCCN1CCOCC1 IKOKHHBZFDFMJW-UHFFFAOYSA-N 0.000 description 1
- UXGVMFHEKMGWMA-UHFFFAOYSA-N 2-benzofuran Chemical class C1=CC=CC2=COC=C21 UXGVMFHEKMGWMA-UHFFFAOYSA-N 0.000 description 1
- FWOHDAGPWDEWIB-UHFFFAOYSA-N 2-bromoethoxymethylbenzene Chemical compound BrCCOCC1=CC=CC=C1 FWOHDAGPWDEWIB-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- MGADZUXDNSDTHW-UHFFFAOYSA-N 2H-pyran Chemical compound C1OC=CC=C1 MGADZUXDNSDTHW-UHFFFAOYSA-N 0.000 description 1
- HOBXBBAULASLBN-UHFFFAOYSA-N 3,13-diazahexacyclo[14.7.0.02,10.04,9.011,15.017,22]tricosa-1(16),2(10),4,6,8,11,14,17,19,21-decaene Chemical compound C1C2=CC=CC=C2C3=C1C4=C(C5=CC=CC=C5N4)C6=CNC=C63 HOBXBBAULASLBN-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 description 1
- NCGICGYLBXGBGN-UHFFFAOYSA-N 3-morpholin-4-yl-1-oxa-3-azonia-2-azanidacyclopent-3-en-5-imine;hydrochloride Chemical compound Cl.[N-]1OC(=N)C=[N+]1N1CCOCC1 NCGICGYLBXGBGN-UHFFFAOYSA-N 0.000 description 1
- UYNVMODNBIQBMV-UHFFFAOYSA-N 4-[1-hydroxy-2-[4-(phenylmethyl)-1-piperidinyl]propyl]phenol Chemical compound C1CC(CC=2C=CC=CC=2)CCN1C(C)C(O)C1=CC=C(O)C=C1 UYNVMODNBIQBMV-UHFFFAOYSA-N 0.000 description 1
- WDYVUKGVKRZQNM-UHFFFAOYSA-N 6-phosphonohexylphosphonic acid Chemical compound OP(O)(=O)CCCCCCP(O)(O)=O WDYVUKGVKRZQNM-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 241000251468 Actinopterygii Species 0.000 description 1
- 241000585703 Adelphia <angiosperm> Species 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 101100462297 Arabidopsis thaliana ORG2 gene Proteins 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 206010003694 Atrophy Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 1
- 244000025254 Cannabis sativa Species 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 230000005788 Cochlea function Effects 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 1
- 241000938605 Crocodylia Species 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 241000934790 Daphne mezereum Species 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- 206010061126 Escherichia infection Diseases 0.000 description 1
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 208000032041 Hearing impaired Diseases 0.000 description 1
- 101000950695 Homo sapiens Mitogen-activated protein kinase 8 Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 208000027601 Inner ear disease Diseases 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 241000878128 Malleus Species 0.000 description 1
- 201000005505 Measles Diseases 0.000 description 1
- 208000027530 Meniere disease Diseases 0.000 description 1
- 102100037808 Mitogen-activated protein kinase 8 Human genes 0.000 description 1
- 206010027906 Monocytosis Diseases 0.000 description 1
- 208000026072 Motor neurone disease Diseases 0.000 description 1
- 208000005647 Mumps Diseases 0.000 description 1
- HOKKHZGPKSLGJE-GSVOUGTGSA-N N-Methyl-D-aspartic acid Chemical compound CN[C@@H](C(O)=O)CC(O)=O HOKKHZGPKSLGJE-GSVOUGTGSA-N 0.000 description 1
- 206010056677 Nerve degeneration Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- 206010034620 Peripheral sensory neuropathy Diseases 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 241000539618 Salma Species 0.000 description 1
- 206010040030 Sensory loss Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 208000024799 Thyroid disease Diseases 0.000 description 1
- 108010018242 Transcription Factor AP-1 Proteins 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 206010054880 Vascular insufficiency Diseases 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- FCVHBUFELUXTLR-UHFFFAOYSA-N [Li].[AlH3] Chemical class [Li].[AlH3] FCVHBUFELUXTLR-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229960005305 adenosine Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000006851 antioxidant defense Effects 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 210000000270 basal cell Anatomy 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- ZODAOVNETBTTJX-UHFFFAOYSA-N bis(4-methoxyphenyl)methanol Chemical compound C1=CC(OC)=CC=C1C(O)C1=CC=C(OC)C=C1 ZODAOVNETBTTJX-UHFFFAOYSA-N 0.000 description 1
- 230000008933 bodily movement Effects 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 125000005708 carbonyloxy group Chemical group [*:2]OC([*:1])=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 210000003855 cell nucleus Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000007960 cellular response to stress Effects 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 210000001638 cerebellum Anatomy 0.000 description 1
- OEUUFNIKLCFNLN-LLVKDONJSA-N chembl432481 Chemical compound OC(=O)[C@@]1(C)CSC(C=2C(=CC(O)=CC=2)O)=N1 OEUUFNIKLCFNLN-LLVKDONJSA-N 0.000 description 1
- 231100000481 chemical toxicant Toxicity 0.000 description 1
- RCTYPNKXASFOBE-UHFFFAOYSA-M chloromercury Chemical compound [Hg]Cl RCTYPNKXASFOBE-UHFFFAOYSA-M 0.000 description 1
- 210000004081 cilia Anatomy 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 210000000860 cochlear nerve Anatomy 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000004624 confocal microscopy Methods 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 229960000258 corticotropin Drugs 0.000 description 1
- 150000001907 coumarones Chemical class 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 150000001916 cyano esters Chemical class 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 230000003412 degenerative effect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- 150000001993 dienes Chemical class 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 238000012137 double-staining Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 210000000613 ear canal Anatomy 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- 238000003821 enantio-separation Methods 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000003822 epoxy resin Substances 0.000 description 1
- 208000020612 escherichia coli infection Diseases 0.000 description 1
- AFAXGSQYZLGZPG-UHFFFAOYSA-N ethanedisulfonic acid Chemical compound OS(=O)(=O)CCS(O)(=O)=O AFAXGSQYZLGZPG-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- WHQLQYRFIHPMNA-UHFFFAOYSA-N ethyl acetate;oxolane Chemical compound C1CCOC1.CCOC(C)=O WHQLQYRFIHPMNA-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- FGBJXOREULPLGL-UHFFFAOYSA-N ethyl cyanoacrylate Chemical compound CCOC(=O)C(=C)C#N FGBJXOREULPLGL-UHFFFAOYSA-N 0.000 description 1
- 229940053009 ethyl cyanoacrylate Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 210000000609 ganglia Anatomy 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 208000027096 gram-negative bacterial infections Diseases 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 238000012074 hearing test Methods 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 229960003998 ifenprodil Drugs 0.000 description 1
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000013115 immunohistochemical detection Methods 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- UMJJFEIKYGFCAT-UHFFFAOYSA-N indan-2-one Chemical compound C1=CC=C2CC(=O)CC2=C1 UMJJFEIKYGFCAT-UHFFFAOYSA-N 0.000 description 1
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 1
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- XTBAPWCYTNCZTO-UHFFFAOYSA-N isoindol-1-one Chemical class C1=CC=C2C(=O)N=CC2=C1 XTBAPWCYTNCZTO-UHFFFAOYSA-N 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- ZLTPDFXIESTBQG-UHFFFAOYSA-N isothiazole Chemical compound C=1C=NSC=1 ZLTPDFXIESTBQG-UHFFFAOYSA-N 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 230000002045 lasting effect Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229940126707 lipid peroxidation inhibitor Drugs 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 210000002331 malleus Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- NIQQIJXGUZVEBB-UHFFFAOYSA-N methanol;propan-2-one Chemical compound OC.CC(C)=O NIQQIJXGUZVEBB-UHFFFAOYSA-N 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000000386 microscopy Methods 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000003068 molecular probe Substances 0.000 description 1
- 230000003562 morphometric effect Effects 0.000 description 1
- 238000013425 morphometry Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 210000002161 motor neuron Anatomy 0.000 description 1
- 208000005264 motor neuron disease Diseases 0.000 description 1
- 208000010805 mumps infectious disease Diseases 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 1
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 230000001338 necrotic effect Effects 0.000 description 1
- 230000032405 negative regulation of neuron apoptotic process Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000002241 neurite Anatomy 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 230000004693 neuron damage Effects 0.000 description 1
- 229940032018 neurotrophin 3 Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000004533 oil dispersion Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 238000010827 pathological analysis Methods 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 description 1
- 230000008447 perception Effects 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 230000009984 peri-natal effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 208000027232 peripheral nervous system disease Diseases 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 231100000572 poisoning Toxicity 0.000 description 1
- 230000000607 poisoning effect Effects 0.000 description 1
- 229920000647 polyepoxide Polymers 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- JEXVQSWXXUJEMA-UHFFFAOYSA-N pyrazol-3-one Chemical compound O=C1C=CN=N1 JEXVQSWXXUJEMA-UHFFFAOYSA-N 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- WHMDPDGBKYUEMW-UHFFFAOYSA-N pyridine-2-thiol Chemical compound SC1=CC=CC=N1 WHMDPDGBKYUEMW-UHFFFAOYSA-N 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 230000036421 sense of balance Effects 0.000 description 1
- 201000005572 sensory peripheral neuropathy Diseases 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 235000021309 simple sugar Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 210000001323 spiral ganglion Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 210000001050 stape Anatomy 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 210000000645 stria vascularis Anatomy 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- XIUROWKZWPIAIB-UHFFFAOYSA-N sulfotep Chemical compound CCOP(=S)(OCC)OP(=S)(OCC)OCC XIUROWKZWPIAIB-UHFFFAOYSA-N 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 210000003582 temporal bone Anatomy 0.000 description 1
- 150000003527 tetrahydropyrans Chemical group 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000004867 thiadiazoles Chemical class 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 208000021510 thyroid gland disease Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 231100000167 toxic agent Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- QQJLHRRUATVHED-UHFFFAOYSA-N tramazoline Chemical compound N1CCN=C1NC1=CC=CC2=C1CCCC2 QQJLHRRUATVHED-UHFFFAOYSA-N 0.000 description 1
- 229960001262 tramazoline Drugs 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 150000003918 triazines Chemical class 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 230000001228 trophic effect Effects 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 208000023577 vascular insufficiency disease Diseases 0.000 description 1
- 208000027491 vestibular disease Diseases 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- QNLXXQBCQYDKHD-UHFFFAOYSA-K ytterbium(iii) bromide Chemical compound Br[Yb](Br)Br QNLXXQBCQYDKHD-UHFFFAOYSA-K 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Toxicology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Cosmetics (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US10176398P | 1998-09-25 | 1998-09-25 | |
| US60/101,763 | 1998-09-25 | ||
| PCT/US1999/021780 WO2000018407A1 (en) | 1998-09-25 | 1999-09-24 | Methods for preventing/treating damage to sensory hair cells and cochlear neurons |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2011014273A Division JP5190125B2 (ja) | 1998-09-25 | 2011-01-26 | 感覚毛細胞及び蝸牛ニューロンへの損傷を予防する／処置するための方法 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2002525329A true JP2002525329A (ja) | 2002-08-13 |
| JP2002525329A5 JP2002525329A5 (https=) | 2006-11-24 |
Family
ID=22286288
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000571925A Pending JP2002525329A (ja) | 1998-09-25 | 1999-09-24 | 感覚毛細胞及び蝸牛ニューロンへの損傷を予防する／処置するための方法 |
| JP2011014273A Expired - Fee Related JP5190125B2 (ja) | 1998-09-25 | 2011-01-26 | 感覚毛細胞及び蝸牛ニューロンへの損傷を予防する／処置するための方法 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2011014273A Expired - Fee Related JP5190125B2 (ja) | 1998-09-25 | 2011-01-26 | 感覚毛細胞及び蝸牛ニューロンへの損傷を予防する／処置するための方法 |
Country Status (13)
| Country | Link |
|---|---|
| US (2) | US6448283B1 (https=) |
| EP (1) | EP1126855B1 (https=) |
| JP (2) | JP2002525329A (https=) |
| KR (1) | KR100628847B1 (https=) |
| CN (1) | CN1329034C (https=) |
| AT (1) | ATE361752T1 (https=) |
| AU (1) | AU763435B2 (https=) |
| CA (1) | CA2345295C (https=) |
| DE (1) | DE69936059T2 (https=) |
| ES (1) | ES2288042T3 (https=) |
| HK (1) | HK1040053B (https=) |
| NZ (1) | NZ511024A (https=) |
| WO (1) | WO2000018407A1 (https=) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013518917A (ja) * | 2010-02-08 | 2013-05-23 | イーエムシー マイクロコレクションズ ゲーエムベーハー | 感覚器官及び有糸分裂後組織のための再生促進物質としての新規なアミノアルキルオキサゾール及びアミノアルキルチアゾールカルボン酸アミド |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040082509A1 (en) | 1999-10-12 | 2004-04-29 | Christophe Bonny | Cell-permeable peptide inhibitors of the JNK signal transduction pathway |
| US8183339B1 (en) | 1999-10-12 | 2012-05-22 | Xigen S.A. | Cell-permeable peptide inhibitors of the JNK signal transduction pathway |
| US20030108539A1 (en) * | 2000-02-14 | 2003-06-12 | Christophe Bonny | Cell-permeable peptide inhibitors of the JNK signal transduction pathway |
| US6630500B2 (en) * | 2000-08-25 | 2003-10-07 | Cephalon, Inc. | Selected fused pyrrolocarbazoles |
| WO2004096256A1 (en) * | 2001-01-23 | 2004-11-11 | The United States Of America, As Represented By The Secretary Of The Navy | Methods for preventing and treating loss of balance function due to oxidative stress |
| US7129225B2 (en) * | 2001-10-22 | 2006-10-31 | The Research Foundation Of State University Of New York | Protection against and treatment of hearing loss |
| US7005445B2 (en) | 2001-10-22 | 2006-02-28 | The Research Foundation Of State University Of New York | Protein kinase and phosphatase inhibitors and methods for designing them |
| US20100030301A1 (en) * | 2001-11-09 | 2010-02-04 | Cochlear Limited | Electrical stimulation for modulation of neural plasticity |
| AUPR879201A0 (en) * | 2001-11-09 | 2001-12-06 | Cochlear Limited | Subthreshold stimulation of a cochlea |
| US20100030130A1 (en) * | 2001-11-09 | 2010-02-04 | Cochlear Limited | Pharmaceutical intervention for modulation of neural plasticity |
| US20050171579A1 (en) * | 2001-11-09 | 2005-08-04 | Claudia Tasche | Stimulating device |
| DE60332215D1 (de) | 2002-02-28 | 2010-06-02 | Eisai R&D Man Co Ltd | Neue indazolverbindungen mit kondensiertem ring |
| EP1585431A2 (en) * | 2002-10-10 | 2005-10-19 | Neurorecovery, Inc. | System and method of active neuro-protection for detecting and arresting traumatic brain injury and spinal cord injury |
| CA2569724A1 (en) | 2004-06-15 | 2005-12-29 | Cochlear Americas | Automatic determination of the threshold of an evoked neural response |
| WO2007031098A1 (en) * | 2005-09-12 | 2007-03-22 | Xigen S.A. | Cell-permeable peptide inhibitors of the jnk signal transduction pathway |
| US8080517B2 (en) * | 2005-09-12 | 2011-12-20 | Xigen Sa | Cell-permeable peptide inhibitors of the JNK signal transduction pathway |
| WO2009143864A1 (en) * | 2008-05-30 | 2009-12-03 | Xigen S.A. | Use of cell-permeable peptide inhibitors of the jnk signal transduction pathway for the treatment of chronic or non-chronic inflammatory digestive diseases |
| WO2009143865A1 (en) * | 2008-05-30 | 2009-12-03 | Xigen S.A. | Use of cell-permeable peptide inhibitors of the jnk signal transduction pathway for the treatment of various diseases |
| WO2010072228A1 (en) | 2008-12-22 | 2010-07-01 | Xigen S.A. | Novel transporter constructs and transporter cargo conjugate molecules |
| JP5457813B2 (ja) * | 2009-12-16 | 2014-04-02 | ルネサスエレクトロニクス株式会社 | Ａｄｐｌｌ回路、半導体装置及び携帯情報機器 |
| WO2011160653A1 (en) | 2010-06-21 | 2011-12-29 | Xigen S.A. | Novel jnk inhibitor molecules |
| AU2010362444B2 (en) | 2010-10-14 | 2015-08-06 | Xigen Inflammation Ltd. | Use of cell-permeable peptide inhibitors of the JNK signal transduction pathway for the treatment of chronic or non-chronic inflammatory eye diseases |
| WO2013091670A1 (en) | 2011-12-21 | 2013-06-27 | Xigen S.A. | Novel jnk inhibitor molecules for treatment of various diseases |
| ES2870085T3 (es) | 2013-06-26 | 2021-10-26 | Xigen Inflammation Ltd | Inhibidores peptídicos permeables a células de la ruta de transducción de señales de JNK para el tratamiento de la cistitis |
| WO2015197097A1 (en) | 2014-06-26 | 2015-12-30 | Xigen Inflammation Ltd. | New use for jnk inhibitor molecules for treatment of various diseases |
| WO2014206427A1 (en) | 2013-06-26 | 2014-12-31 | Xigen Inflammation Ltd. | New use of cell-permeable peptide inhibitors of the jnk signal transduction pathway for the treatment of various diseases |
| CN110248650A (zh) | 2016-10-31 | 2019-09-17 | 霍夫耳科研究所 | 用于增强突触发生和神经突发生的方法 |
| US11857551B1 (en) | 2020-07-10 | 2024-01-02 | Ting Therapeutics Llc | Methods for the prevention and treatment of hearing loss |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995007911A1 (en) * | 1993-09-16 | 1995-03-23 | Cephalon, Inc. | K-252a DERIVATIVES WHICH ENHANCE NEUROTROPHIN-INDUCED ACTIVITY |
| WO1996011933A1 (en) * | 1994-10-14 | 1996-04-25 | Cephalon, Inc. | Fused pyrrolocarbazoles |
| WO1996013506A1 (en) * | 1994-10-26 | 1996-05-09 | Cephalon, Inc. | Protein kinase inhibitors for treatment of neurological disorders |
| WO1996031515A1 (en) * | 1995-04-05 | 1996-10-10 | Cephalon, Inc. | Selected soluble esters of hydroxyl-containing indolocarbazoles |
| WO1997046565A1 (en) * | 1996-06-03 | 1997-12-11 | Cephalon, Inc. | SELECTED DERIVATIVES OF K-252a |
Family Cites Families (17)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3752123T2 (de) * | 1987-03-09 | 1998-05-14 | Kyowa Hakko Kogyo Kk | Derivate des physiologisch aktiven mittels k-252 |
| US5093330A (en) | 1987-06-15 | 1992-03-03 | Ciba-Geigy Corporation | Staurosporine derivatives substituted at methylamino nitrogen |
| JPH07113027B2 (ja) | 1987-12-24 | 1995-12-06 | 協和醗酵工業株式会社 | Ｋ−２５２誘導体 |
| WO1993008809A1 (en) | 1991-11-08 | 1993-05-13 | The University Of Southern California | Compositions containing k-252 compounds for potentiation of neurotrophin activity |
| US5461146A (en) * | 1992-07-24 | 1995-10-24 | Cephalon, Inc. | Selected protein kinase inhibitors for the treatment of neurological disorders |
| US5621101A (en) * | 1992-07-24 | 1997-04-15 | Cephalon, Inc. | Protein kinase inhibitors for treatment of neurological disorders |
| US5621100A (en) * | 1992-07-24 | 1997-04-15 | Cephalon, Inc. | K-252a derivatives for treatment of neurological disorders |
| DE69409641T2 (de) | 1993-05-28 | 1998-11-26 | Cephalon, Inc., West Chester, Pa. | Anwendung von indolocarbazol-derivaten zur behandlung von prostataerkrankungen |
| AU1911095A (en) | 1994-02-18 | 1995-09-04 | Cephalon, Inc. | Aqueous indolocarbazole solutions |
| US5475110A (en) | 1994-10-14 | 1995-12-12 | Cephalon, Inc. | Fused Pyrrolocarbazoles |
| US5591855A (en) | 1994-10-14 | 1997-01-07 | Cephalon, Inc. | Fused pyrrolocarbazoles |
| US5594009A (en) | 1994-10-14 | 1997-01-14 | Cephalon, Inc. | Fused pyrrolocarbazoles |
| US5616724A (en) * | 1996-02-21 | 1997-04-01 | Cephalon, Inc. | Fused pyrrolo[2,3-c]carbazole-6-ones |
| US5929041A (en) | 1996-02-23 | 1999-07-27 | Amgen Inc. | Method for preventing and treating sensorineural hearing loss and vestibular disorders using glial cell line-derived neurotrophic factor(GDNF) protein product |
| PT912184E (pt) | 1996-06-25 | 2002-12-31 | Cephalon Inc | Utilizacao de um derivado de k-252a para o tratamento de doencas do sietma nervoso central ou periferico e sobre-producao de citoquina |
| AU758241B2 (en) | 1998-03-13 | 2003-03-20 | University Of British Columbia, The | Granulatimide derivatives for use in cancer treatment |
| US6127401A (en) | 1998-06-05 | 2000-10-03 | Cephalon, Inc. | Bridged indenopyrrolocarbazoles |
-
1999
- 1999-09-24 WO PCT/US1999/021780 patent/WO2000018407A1/en not_active Ceased
- 1999-09-24 DE DE69936059T patent/DE69936059T2/de not_active Expired - Lifetime
- 1999-09-24 KR KR1020017003848A patent/KR100628847B1/ko not_active Expired - Fee Related
- 1999-09-24 ES ES99969678T patent/ES2288042T3/es not_active Expired - Lifetime
- 1999-09-24 NZ NZ511024A patent/NZ511024A/en not_active IP Right Cessation
- 1999-09-24 CA CA002345295A patent/CA2345295C/en not_active Expired - Fee Related
- 1999-09-24 AU AU60532/99A patent/AU763435B2/en not_active Ceased
- 1999-09-24 US US09/404,187 patent/US6448283B1/en not_active Expired - Lifetime
- 1999-09-24 CN CNB998136123A patent/CN1329034C/zh not_active Expired - Fee Related
- 1999-09-24 HK HK02101420.6A patent/HK1040053B/en not_active IP Right Cessation
- 1999-09-24 EP EP99969678A patent/EP1126855B1/en not_active Expired - Lifetime
- 1999-09-24 AT AT99969678T patent/ATE361752T1/de not_active IP Right Cessation
- 1999-09-24 JP JP2000571925A patent/JP2002525329A/ja active Pending
-
2002
- 2002-01-08 US US10/041,224 patent/US7789610B2/en not_active Expired - Fee Related
-
2011
- 2011-01-26 JP JP2011014273A patent/JP5190125B2/ja not_active Expired - Fee Related
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1995007911A1 (en) * | 1993-09-16 | 1995-03-23 | Cephalon, Inc. | K-252a DERIVATIVES WHICH ENHANCE NEUROTROPHIN-INDUCED ACTIVITY |
| WO1996011933A1 (en) * | 1994-10-14 | 1996-04-25 | Cephalon, Inc. | Fused pyrrolocarbazoles |
| WO1996013506A1 (en) * | 1994-10-26 | 1996-05-09 | Cephalon, Inc. | Protein kinase inhibitors for treatment of neurological disorders |
| WO1996031515A1 (en) * | 1995-04-05 | 1996-10-10 | Cephalon, Inc. | Selected soluble esters of hydroxyl-containing indolocarbazoles |
| WO1997046565A1 (en) * | 1996-06-03 | 1997-12-11 | Cephalon, Inc. | SELECTED DERIVATIVES OF K-252a |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013518917A (ja) * | 2010-02-08 | 2013-05-23 | イーエムシー マイクロコレクションズ ゲーエムベーハー | 感覚器官及び有糸分裂後組織のための再生促進物質としての新規なアミノアルキルオキサゾール及びアミノアルキルチアゾールカルボン酸アミド |
Also Published As
| Publication number | Publication date |
|---|---|
| JP2011126893A (ja) | 2011-06-30 |
| US20020115706A1 (en) | 2002-08-22 |
| CN1329034C (zh) | 2007-08-01 |
| ES2288042T3 (es) | 2007-12-16 |
| EP1126855A1 (en) | 2001-08-29 |
| US7789610B2 (en) | 2010-09-07 |
| KR100628847B1 (ko) | 2006-09-29 |
| AU6053299A (en) | 2000-04-17 |
| KR20010085848A (ko) | 2001-09-07 |
| HK1040053B (en) | 2007-09-21 |
| WO2000018407A1 (en) | 2000-04-06 |
| EP1126855A4 (en) | 2004-05-19 |
| EP1126855B1 (en) | 2007-05-09 |
| NZ511024A (en) | 2003-10-31 |
| CA2345295A1 (en) | 2000-04-06 |
| DE69936059T2 (de) | 2008-01-24 |
| CN1328461A (zh) | 2001-12-26 |
| JP5190125B2 (ja) | 2013-04-24 |
| DE69936059D1 (de) | 2007-06-21 |
| ATE361752T1 (de) | 2007-06-15 |
| US6448283B1 (en) | 2002-09-10 |
| AU763435B2 (en) | 2003-07-24 |
| HK1040053A1 (en) | 2002-05-24 |
| WO2000018407A9 (en) | 2000-09-21 |
| CA2345295C (en) | 2009-12-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5190125B2 (ja) | 感覚毛細胞及び蝸牛ニューロンへの損傷を予防する／処置するための方法 | |
| JP7474289B2 (ja) | カリウムチャンネル開口薬としての有用な新規化合物 | |
| JP5627705B2 (ja) | 聴力損傷および目まいの治療用のβ−カルボリン | |
| CA2730148A1 (en) | Neuroprotective agents for the prevention and treatment of neurodegenerative diseases | |
| CN110337291A (zh) | 治疗耳蜗突触病变的方法 | |
| US12502433B2 (en) | Phosphonate-drug conjugates | |
| WO2015029948A1 (ja) | 網膜色素上皮の障害を原因とする網膜疾患の予防または治療剤 | |
| CN110240557A (zh) | 吡咯烷酰胺衍生物及其用途 | |
| RU2779111C2 (ru) | Новые соединения, используемые в качестве открывателей калиевых каналов | |
| JP2004534751A (ja) | 応力で活性化する蛋白質キナーゼの阻害剤を用いて痛みを治療および予防する新規な方法 | |
| RU2779131C2 (ru) | Новые соединения, используемые в качестве открывателей калиевых каналов | |
| WO2023190707A1 (ja) | 感音難聴の予防または治療用組成物 | |
| US20130005698A1 (en) | Pharmaceutical for preventing or treating an inner ear disorder | |
| EP2328577A1 (en) | The treatment of hearing loss | |
| JP2010235597A (ja) | ４，６−ジクロロ−１ｈ−インドール−２−カルボン酸誘導体又はその塩を有効成分として含有する視神経障害の予防又は治療剤 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20060922 |
|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20060922 |
|
| RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20080430 |
|
| RD03 | Notification of appointment of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7423 Effective date: 20100108 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20100216 |
|
| A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20100217 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20100517 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20101026 |
|
| A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20110322 |