JP4357802B2 - ベンゼン環縮合５員複素環式化合物、その製造法および用途 - Google Patents
ベンゼン環縮合５員複素環式化合物、その製造法および用途 Download PDFInfo
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- JP4357802B2 JP4357802B2 JP2002195424A JP2002195424A JP4357802B2 JP 4357802 B2 JP4357802 B2 JP 4357802B2 JP 2002195424 A JP2002195424 A JP 2002195424A JP 2002195424 A JP2002195424 A JP 2002195424A JP 4357802 B2 JP4357802 B2 JP 4357802B2
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- alkyl
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 title claims description 32
- 238000004519 manufacturing process Methods 0.000 title claims description 8
- 150000000565 5-membered heterocyclic compounds Chemical class 0.000 title description 3
- -1 carboxy, carbamoyl Chemical group 0.000 claims description 386
- 150000001875 compounds Chemical class 0.000 claims description 316
- 238000006243 chemical reaction Methods 0.000 claims description 249
- 125000001424 substituent group Chemical group 0.000 claims description 220
- 229910052757 nitrogen Inorganic materials 0.000 claims description 150
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 132
- 229910052717 sulfur Inorganic materials 0.000 claims description 130
- 125000005842 heteroatom Chemical group 0.000 claims description 127
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 97
- 229910052799 carbon Inorganic materials 0.000 claims description 96
- 150000001721 carbon Chemical group 0.000 claims description 90
- 125000004434 sulfur atom Chemical group 0.000 claims description 90
- 125000000217 alkyl group Chemical group 0.000 claims description 89
- 125000003118 aryl group Chemical group 0.000 claims description 76
- 229910052736 halogen Inorganic materials 0.000 claims description 65
- 125000006618 5- to 10-membered aromatic heterocyclic group Chemical group 0.000 claims description 60
- 239000003795 chemical substances by application Substances 0.000 claims description 60
- 150000002367 halogens Chemical class 0.000 claims description 59
- 150000003839 salts Chemical class 0.000 claims description 57
- 150000002430 hydrocarbons Chemical group 0.000 claims description 56
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 54
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 53
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 52
- 125000000623 heterocyclic group Chemical group 0.000 claims description 48
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 47
- 238000000034 method Methods 0.000 claims description 45
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 43
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 43
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 41
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 40
- 125000004432 carbon atom Chemical group C* 0.000 claims description 40
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims description 39
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 39
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 39
- 239000011593 sulfur Chemical group 0.000 claims description 39
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 38
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 38
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 37
- 125000005974 C6-C14 arylcarbonyl group Chemical group 0.000 claims description 35
- 229930195733 hydrocarbon Natural products 0.000 claims description 35
- 125000006636 (C3-C8) cycloalkylcarbonyl group Chemical group 0.000 claims description 34
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 33
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 33
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 33
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 32
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 32
- 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 31
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 31
- 125000005843 halogen group Chemical group 0.000 claims description 29
- 125000002252 acyl group Chemical group 0.000 claims description 27
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 24
- 239000003814 drug Substances 0.000 claims description 24
- 239000003112 inhibitor Substances 0.000 claims description 23
- 230000001737 promoting effect Effects 0.000 claims description 23
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 22
- 125000003545 alkoxy group Chemical group 0.000 claims description 22
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 20
- 230000004770 neurodegeneration Effects 0.000 claims description 20
- 230000004069 differentiation Effects 0.000 claims description 18
- 210000001178 neural stem cell Anatomy 0.000 claims description 18
- 229940124597 therapeutic agent Drugs 0.000 claims description 18
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 16
- 208000024827 Alzheimer disease Diseases 0.000 claims description 16
- 108091008611 Protein Kinase B Proteins 0.000 claims description 14
- 102000005765 Proto-Oncogene Proteins c-akt Human genes 0.000 claims description 14
- 230000035755 proliferation Effects 0.000 claims description 14
- 208000018737 Parkinson disease Diseases 0.000 claims description 13
- 239000012190 activator Substances 0.000 claims description 13
- 125000004442 acylamino group Chemical group 0.000 claims description 12
- 125000003277 amino group Chemical group 0.000 claims description 12
- 125000006624 (C1-C6) alkoxycarbonylamino group Chemical group 0.000 claims description 11
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 11
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 11
- 210000002569 neuron Anatomy 0.000 claims description 11
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 claims description 10
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 10
- 230000000069 prophylactic effect Effects 0.000 claims description 10
- 125000001769 aryl amino group Chemical group 0.000 claims description 9
- 125000004122 cyclic group Chemical group 0.000 claims description 9
- 210000005155 neural progenitor cell Anatomy 0.000 claims description 9
- 230000000508 neurotrophic effect Effects 0.000 claims description 9
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 8
- 208000023105 Huntington disease Diseases 0.000 claims description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical group C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 8
- 208000028173 post-traumatic stress disease Diseases 0.000 claims description 8
- 210000000130 stem cell Anatomy 0.000 claims description 8
- 238000002054 transplantation Methods 0.000 claims description 8
- 230000002265 prevention Effects 0.000 claims description 7
- 238000011069 regeneration method Methods 0.000 claims description 7
- 208000019901 Anxiety disease Diseases 0.000 claims description 6
- 208000020925 Bipolar disease Diseases 0.000 claims description 6
- 230000036506 anxiety Effects 0.000 claims description 6
- 125000005098 aryl alkoxy carbonyl group Chemical group 0.000 claims description 6
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- 208000028683 bipolar I disease Diseases 0.000 claims description 6
- 210000005036 nerve Anatomy 0.000 claims description 6
- 230000004766 neurogenesis Effects 0.000 claims description 6
- 229910052760 oxygen Chemical group 0.000 claims description 6
- 230000008929 regeneration Effects 0.000 claims description 6
- HBEDSQVIWPRPAY-UHFFFAOYSA-N 2,3-dihydrobenzofuran Chemical group C1=CC=C2OCCC2=C1 HBEDSQVIWPRPAY-UHFFFAOYSA-N 0.000 claims description 5
- 125000005914 C6-C14 aryloxy group Chemical group 0.000 claims description 5
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 125000000304 alkynyl group Chemical group 0.000 claims description 5
- 230000003449 preventive effect Effects 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 230000006974 Aβ toxicity Effects 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 125000003917 carbamoyl group Chemical class [H]N([H])C(*)=O 0.000 claims description 4
- 208000015114 central nervous system disease Diseases 0.000 claims description 4
- 238000012258 culturing Methods 0.000 claims description 4
- 239000001301 oxygen Chemical group 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- VDZLPDPBESWXGU-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-4-(2,2,4,6,7-pentamethyl-3-piperidin-1-yl-3h-1-benzofuran-5-yl)piperazine Chemical compound C1=C(OC)C(OC)=CC=C1N1CCN(C=2C(=C(C)C=3OC(C)(C)C(N4CCCCC4)C=3C=2C)C)CC1 VDZLPDPBESWXGU-UHFFFAOYSA-N 0.000 claims description 3
- ZSVRXNKFRKUSJG-UHFFFAOYSA-N 1-(3-benzyl-2,2,4,6,7-pentamethyl-3h-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C(=C(C)C=3OC(C)(C)C(CC=4C=CC=CC=4)C=3C=2C)C)CC1 ZSVRXNKFRKUSJG-UHFFFAOYSA-N 0.000 claims description 3
- PSZUUMVYLXEXKZ-UHFFFAOYSA-N 1-(4-methoxyphenyl)-4-(2,2,4,6,7-pentamethyl-3-piperidin-1-yl-3h-1-benzofuran-5-yl)piperazine Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C(=C(C)C=3OC(C)(C)C(N4CCCCC4)C=3C=2C)C)CC1 PSZUUMVYLXEXKZ-UHFFFAOYSA-N 0.000 claims description 3
- KCRJATXKXGOOHV-UHFFFAOYSA-N 1-(4-methoxyphenyl)-4-(2,2,4,6,7-pentamethyl-3-pyridin-2-yl-3h-1-benzofuran-5-yl)piperazine Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C(=C(C)C=3OC(C)(C)C(C=4N=CC=CC=4)C=3C=2C)C)CC1 KCRJATXKXGOOHV-UHFFFAOYSA-N 0.000 claims description 3
- MVKXFLDGNLOKDL-UHFFFAOYSA-N 1-(4-methoxyphenyl)-4-(2,2,4,6,7-pentamethyl-3-pyrrolidin-1-yl-3h-1-benzofuran-5-yl)piperazine Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C(=C(C)C=3OC(C)(C)C(N4CCCC4)C=3C=2C)C)CC1 MVKXFLDGNLOKDL-UHFFFAOYSA-N 0.000 claims description 3
- JECXEGGBABDWMS-UHFFFAOYSA-N 1-(4-methoxyphenyl)-4-[2,2,4,5,7-pentamethyl-3-(4-methylphenyl)-3h-1-benzofuran-6-yl]piperazine Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C(=C(C)C=3C(C(C)(C)OC=3C=2C)C=2C=CC(C)=CC=2)C)CC1 JECXEGGBABDWMS-UHFFFAOYSA-N 0.000 claims description 3
- ZYJVOTCAUPMOFB-UHFFFAOYSA-N 1-(4-methoxyphenyl)-4-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-3h-1-benzofuran-5-yl]piperazine Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C(=C(C)C=3OC(C)(C)C(C=4C=CC(C)=CC=4)C=3C=2C)C)CC1 ZYJVOTCAUPMOFB-UHFFFAOYSA-N 0.000 claims description 3
- QLIAWUXUFFTEEY-UHFFFAOYSA-N 1-(4-methoxyphenyl)-4-[2,2,4,6,7-pentamethyl-3-(6-methylpyridin-3-yl)-3h-1-benzofuran-5-yl]piperazine Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C(=C(C)C=3OC(C)(C)C(C=4C=NC(C)=CC=4)C=3C=2C)C)CC1 QLIAWUXUFFTEEY-UHFFFAOYSA-N 0.000 claims description 3
- YDPXVOCNAJJEDH-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)-1-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-3h-1-benzofuran-5-yl]piperidine Chemical compound C1=C(OC)C(OC)=CC=C1C1CCN(C=2C(=C(C)C=3OC(C)(C)C(C=4C=CC(C)=CC=4)C=3C=2C)C)CC1 YDPXVOCNAJJEDH-UHFFFAOYSA-N 0.000 claims description 3
- WGFCHKMRDCDPQQ-UHFFFAOYSA-N 4-(3,4-dimethoxyphenyl)-1-[2,2,4,6,7-pentamethyl-3-(4-propan-2-ylphenyl)-3h-1-benzofuran-5-yl]piperidine Chemical compound C1=C(OC)C(OC)=CC=C1C1CCN(C=2C(=C(C)C=3OC(C)(C)C(C=4C=CC(=CC=4)C(C)C)C=3C=2C)C)CC1 WGFCHKMRDCDPQQ-UHFFFAOYSA-N 0.000 claims description 3
- SDKQEUQLPJAYGG-GDLZYMKVSA-N 4-(4-methoxyphenyl)-1-[(3r)-2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-3h-1-benzofuran-5-yl]piperidine Chemical compound C1=CC(OC)=CC=C1C1CCN(C=2C(=C(C)C=3OC(C)(C)[C@H](C=4C=CC(C)=CC=4)C=3C=2C)C)CC1 SDKQEUQLPJAYGG-GDLZYMKVSA-N 0.000 claims description 3
- TULCWWYSHAMMAS-UHFFFAOYSA-N 5-[4-(4-methoxyphenyl)piperazin-1-yl]-1-(2,2,4,6,7-pentamethyl-3h-1-benzofuran-3-yl)-2,3-dihydroindole Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C=C3CCN(C3=CC=2)C2C(OC3=C2C(=CC(C)=C3C)C)(C)C)CC1 TULCWWYSHAMMAS-UHFFFAOYSA-N 0.000 claims description 3
- CHBFHRWCPSIWCU-UHFFFAOYSA-N 5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,2,4,6,7-pentamethyl-n-phenyl-3h-1-benzofuran-3-amine Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C(=C(C)C=3OC(C)(C)C(NC=4C=CC=CC=4)C=3C=2C)C)CC1 CHBFHRWCPSIWCU-UHFFFAOYSA-N 0.000 claims description 3
- 239000004215 Carbon black (E152) Substances 0.000 claims description 3
- 208000010877 cognitive disease Diseases 0.000 claims description 3
- 150000001924 cycloalkanes Chemical class 0.000 claims description 3
- 210000001671 embryonic stem cell Anatomy 0.000 claims description 3
- 206010027175 memory impairment Diseases 0.000 claims description 3
- 208000027061 mild cognitive impairment Diseases 0.000 claims description 3
- 230000036961 partial effect Effects 0.000 claims description 3
- 125000004193 piperazinyl group Chemical group 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- LNLITPVOXBPYHP-UHFFFAOYSA-N 1-(3,4-dimethoxyphenyl)-4-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-3h-1-benzofuran-5-yl]piperazine Chemical compound C1=C(OC)C(OC)=CC=C1N1CCN(C=2C(=C(C)C=3OC(C)(C)C(C=4C=CC(C)=CC=4)C=3C=2C)C)CC1 LNLITPVOXBPYHP-UHFFFAOYSA-N 0.000 claims description 2
- YJUFGFXVASPYFQ-UHFFFAOYSA-N 2,3-dihydro-1-benzothiophene Chemical group C1=CC=C2SCCC2=C1 YJUFGFXVASPYFQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims 8
- 125000005099 aryl alkyl carbonyl group Chemical group 0.000 claims 5
- 125000005530 alkylenedioxy group Chemical group 0.000 claims 4
- 125000005116 aryl carbamoyl group Chemical group 0.000 claims 4
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims 4
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims 3
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims 3
- 125000005194 alkoxycarbonyloxy group Chemical group 0.000 claims 2
- 125000005431 alkyl carboxamide group Chemical group 0.000 claims 2
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- ZVJPODIOXSXAHY-UHFFFAOYSA-N 1-(4-methoxyphenyl)-4-[2,2,4,6,7-pentamethyl-3-[(4-methylphenoxy)methyl]-3h-1-benzofuran-5-yl]piperazine Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C(=C(C)C=3OC(C)(C)C(COC=4C=CC(C)=CC=4)C=3C=2C)C)CC1 ZVJPODIOXSXAHY-UHFFFAOYSA-N 0.000 claims 1
- 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 1
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims 1
- 125000004658 aryl carbonyl amino group Chemical group 0.000 claims 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims 1
- 239000002904 solvent Substances 0.000 description 109
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 102
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 102
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 102
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 99
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 88
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 84
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 83
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 81
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 66
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- 239000002585 base Substances 0.000 description 58
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 57
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 54
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 51
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 50
- 150000001408 amides Chemical class 0.000 description 43
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 42
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 42
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 38
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 36
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 36
- 239000012046 mixed solvent Substances 0.000 description 35
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 34
- 230000035484 reaction time Effects 0.000 description 34
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 33
- 150000002170 ethers Chemical class 0.000 description 33
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 32
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 30
- 239000003377 acid catalyst Substances 0.000 description 29
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 28
- 229910052794 bromium Inorganic materials 0.000 description 28
- 239000000460 chlorine Substances 0.000 description 28
- 229910052801 chlorine Inorganic materials 0.000 description 28
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 27
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 27
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 27
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 26
- 239000002253 acid Substances 0.000 description 26
- 229910052731 fluorine Inorganic materials 0.000 description 26
- 229910052751 metal Inorganic materials 0.000 description 26
- 239000002184 metal Substances 0.000 description 26
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 26
- 150000001298 alcohols Chemical class 0.000 description 25
- 150000003462 sulfoxides Chemical class 0.000 description 25
- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical compound CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 description 24
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 24
- 239000003054 catalyst Substances 0.000 description 24
- 239000011737 fluorine Substances 0.000 description 24
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 23
- 238000004587 chromatography analysis Methods 0.000 description 23
- 238000004821 distillation Methods 0.000 description 23
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 23
- 239000000047 product Substances 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 23
- 238000001953 recrystallisation Methods 0.000 description 23
- 238000000926 separation method Methods 0.000 description 23
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 22
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 22
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| JP2002195424A JP4357802B2 (ja) | 2001-07-05 | 2002-07-04 | ベンゼン環縮合５員複素環式化合物、その製造法および用途 |
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| JP2001-204586 | 2001-07-05 | ||
| JP2001204586 | 2001-07-05 | ||
| JP2002195424A JP4357802B2 (ja) | 2001-07-05 | 2002-07-04 | ベンゼン環縮合５員複素環式化合物、その製造法および用途 |
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| JP2003081959A JP2003081959A (ja) | 2003-03-19 |
| JP2003081959A5 JP2003081959A5 (enExample) | 2005-10-20 |
| JP4357802B2 true JP4357802B2 (ja) | 2009-11-04 |
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| JP4537011B2 (ja) * | 2002-03-01 | 2010-09-01 | 武田薬品工業株式会社 | 抗うつ剤 |
| WO2006004201A1 (ja) * | 2004-07-01 | 2006-01-12 | Eisai R & D Management Co., Ltd. | 神経再生促進剤 |
| TW200621677A (en) * | 2004-09-21 | 2006-07-01 | Astellas Pharma Inc | Cyclic amine derivative or salt thereof |
| JP4649945B2 (ja) * | 2004-10-21 | 2011-03-16 | チッソ株式会社 | ３−アリールグルタル酸無水物の製造方法 |
| KR101374593B1 (ko) * | 2006-04-26 | 2014-03-17 | 토야마 케미칼 컴퍼니 리미티드 | 알킬에테르 유도체 또는 그 염을 함유하는 신경세포 신생유도제 및 정신장해 치료제 |
| US8119625B2 (en) | 2006-04-26 | 2012-02-21 | Toyama Chemical Co., Ltd. | Neurogenesis inducer or neuropathy therapeutic agent comprising alkyl ether derivative or salt thereof |
| CN101489984B (zh) * | 2006-07-18 | 2013-04-03 | 安斯泰来制药株式会社 | 氨基茚满衍生物或其盐 |
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