JP5039268B2 - ベンゾイミダゾールおよび類縁体および蛋白キナーゼ阻害剤としてのその使用 - Google Patents
ベンゾイミダゾールおよび類縁体および蛋白キナーゼ阻害剤としてのその使用 Download PDFInfo
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- JP5039268B2 JP5039268B2 JP2003537632A JP2003537632A JP5039268B2 JP 5039268 B2 JP5039268 B2 JP 5039268B2 JP 2003537632 A JP2003537632 A JP 2003537632A JP 2003537632 A JP2003537632 A JP 2003537632A JP 5039268 B2 JP5039268 B2 JP 5039268B2
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- JP
- Japan
- Prior art keywords
- benzimidazol
- indazol
- carboxylic acid
- benzimidazole
- amide
- 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.)
- Expired - Fee Related
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- 239000003909 protein kinase inhibitor Substances 0.000 title description 3
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title 1
- 150000001556 benzimidazoles Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 569
- 125000000217 alkyl group Chemical group 0.000 claims description 251
- -1 3-indazolyl group Chemical group 0.000 claims description 148
- 150000003839 salts Chemical class 0.000 claims description 114
- 229910052739 hydrogen Inorganic materials 0.000 claims description 95
- 239000001257 hydrogen Substances 0.000 claims description 95
- 125000003118 aryl group Chemical group 0.000 claims description 94
- 229910005965 SO 2 Inorganic materials 0.000 claims description 85
- 125000001072 heteroaryl group Chemical group 0.000 claims description 83
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 79
- AMOPFYWXZYVTHJ-UHFFFAOYSA-N 2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylic acid Chemical compound C1=CC=C2C(C=3NC4=CC=C(C=C4N=3)C(=O)O)=NNC2=C1 AMOPFYWXZYVTHJ-UHFFFAOYSA-N 0.000 claims description 70
- 125000005843 halogen group Chemical group 0.000 claims description 65
- 239000012453 solvate Substances 0.000 claims description 57
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 56
- 125000003342 alkenyl group Chemical group 0.000 claims description 53
- XCFFZAYCRSOZLM-UHFFFAOYSA-N 2-(1H-indazol-3-yl)-6-phenyl-1H-benzimidazole Chemical compound C1=CC=CC=C1C1=CC=C(NC(=N2)C=3C4=CC=CC=C4NN=3)C2=C1 XCFFZAYCRSOZLM-UHFFFAOYSA-N 0.000 claims description 52
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 51
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 47
- 125000003545 alkoxy group Chemical group 0.000 claims description 45
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 42
- 238000011282 treatment Methods 0.000 claims description 41
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 40
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 32
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 32
- 230000005764 inhibitory process Effects 0.000 claims description 25
- 150000001408 amides Chemical class 0.000 claims description 24
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 24
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 claims description 22
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 22
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 22
- 206010028980 Neoplasm Diseases 0.000 claims description 20
- 125000004442 acylamino group Chemical group 0.000 claims description 20
- 201000010099 disease Diseases 0.000 claims description 19
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- 201000011510 cancer Diseases 0.000 claims description 16
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- 125000001424 substituent group Chemical group 0.000 claims description 15
- 125000000304 alkynyl group Chemical group 0.000 claims description 14
- 125000005885 heterocycloalkylalkyl group Chemical group 0.000 claims description 14
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 14
- 125000004104 aryloxy group Chemical group 0.000 claims description 12
- LBTKRCNOZTXVHD-UHFFFAOYSA-N methyl 2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxylate Chemical compound C1=CC=C2C(C=3NC4=CC=C(C=C4N=3)C(=O)OC)=NNC2=C1 LBTKRCNOZTXVHD-UHFFFAOYSA-N 0.000 claims description 12
- VLGWDXACUDRERL-UHFFFAOYSA-N 2-(1H-indazol-3-yl)-N-methyl-3H-benzimidazole-5-carboxamide Chemical compound C1=CC=C2C(C=3NC4=CC=C(C=C4N=3)C(=O)NC)=NNC2=C1 VLGWDXACUDRERL-UHFFFAOYSA-N 0.000 claims description 11
- ZJWSUBBYGLYXJW-UHFFFAOYSA-N 2-(1H-indazol-3-yl)-N-propan-2-yl-3H-benzimidazole-5-carboxamide Chemical compound C1=CC=C2C(C=3NC4=CC=C(C=C4N=3)C(=O)NC(C)C)=NNC2=C1 ZJWSUBBYGLYXJW-UHFFFAOYSA-N 0.000 claims description 11
- 230000033115 angiogenesis Effects 0.000 claims description 10
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 10
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- XRRHLCRISFQRRS-UHFFFAOYSA-N 2-(1H-indazol-3-yl)-N-(2-phenylethyl)-3H-benzimidazole-5-carboxamide Chemical compound C=1C=C2NC(C=3C4=CC=CC=C4NN=3)=NC2=CC=1C(=O)NCCC1=CC=CC=C1 XRRHLCRISFQRRS-UHFFFAOYSA-N 0.000 claims description 8
- WGNUKEBLVGQASE-UHFFFAOYSA-N 2-(1H-indazol-3-yl)-N-[(3-methylphenyl)methyl]-3H-benzimidazole-5-carboxamide Chemical compound CC1=CC=CC(CNC(=O)C=2C=C3N=C(NC3=CC=2)C=2C3=CC=CC=C3NN=2)=C1 WGNUKEBLVGQASE-UHFFFAOYSA-N 0.000 claims description 8
- RXOZHGAHKKRFRF-UHFFFAOYSA-N 2-(1H-indazol-3-yl)-N-phenyl-3H-benzimidazole-5-carboxamide Chemical compound C=1C=C2NC(C=3C4=CC=CC=C4NN=3)=NC2=CC=1C(=O)NC1=CC=CC=C1 RXOZHGAHKKRFRF-UHFFFAOYSA-N 0.000 claims description 8
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 8
- 101100481408 Danio rerio tie2 gene Proteins 0.000 claims description 8
- YDDFILVSXLPVAF-UHFFFAOYSA-N N-[(2,4-dichlorophenyl)methyl]-2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxamide Chemical compound ClC1=CC(Cl)=CC=C1CNC(=O)C1=CC=C(NC(=N2)C=3C4=CC=CC=C4NN=3)C2=C1 YDDFILVSXLPVAF-UHFFFAOYSA-N 0.000 claims description 8
- VYXGLASMUMAOKE-UHFFFAOYSA-N N-benzyl-2-(1H-indazol-3-yl)-N-methyl-3H-benzimidazole-5-carboxamide Chemical compound C=1C=C2NC(C=3C4=CC=CC=C4NN=3)=NC2=CC=1C(=O)N(C)CC1=CC=CC=C1 VYXGLASMUMAOKE-UHFFFAOYSA-N 0.000 claims description 8
- WXOXDSOEEYDPKW-UHFFFAOYSA-N N-ethyl-2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxamide Chemical compound C1=CC=C2C(C=3NC4=CC=C(C=C4N=3)C(=O)NCC)=NNC2=C1 WXOXDSOEEYDPKW-UHFFFAOYSA-N 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 8
- IICWISMKEOCYPY-UHFFFAOYSA-N 2-(1H-indazol-3-yl)-N-(2-piperidin-1-ylethyl)-3H-benzimidazole-5-carboxamide Chemical compound C=1C=C2NC(C=3C4=CC=CC=C4NN=3)=NC2=CC=1C(=O)NCCN1CCCCC1 IICWISMKEOCYPY-UHFFFAOYSA-N 0.000 claims description 7
- QMOVPSVDSGFVEH-UHFFFAOYSA-N 2-(1H-indazol-3-yl)-N-(pyridin-2-ylmethyl)-3H-benzimidazole-5-carboxamide Chemical compound C=1C=C2NC(C=3C4=CC=CC=C4NN=3)=NC2=CC=1C(=O)NCC1=CC=CC=N1 QMOVPSVDSGFVEH-UHFFFAOYSA-N 0.000 claims description 7
- ROZSHCMOINRSQO-UHFFFAOYSA-N 2-(1H-indazol-3-yl)-N-(pyridin-3-ylmethyl)-3H-benzimidazole-5-carboxamide Chemical compound C=1C=C2NC(C=3C4=CC=CC=C4NN=3)=NC2=CC=1C(=O)NCC1=CC=CN=C1 ROZSHCMOINRSQO-UHFFFAOYSA-N 0.000 claims description 7
- VEKCLODQIKNXIR-UHFFFAOYSA-N N-(1-benzothiophen-3-ylmethyl)-2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxamide Chemical compound C1=CC=C2C(C=3NC4=CC=C(C=C4N=3)C(NCC=3C4=CC=CC=C4SC=3)=O)=NNC2=C1 VEKCLODQIKNXIR-UHFFFAOYSA-N 0.000 claims description 7
- VVRIDWKVLUICFB-UHFFFAOYSA-N N-(3-imidazol-1-ylpropyl)-2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxamide Chemical compound C=1C=C2NC(C=3C4=CC=CC=C4NN=3)=NC2=CC=1C(=O)NCCCN1C=CN=C1 VVRIDWKVLUICFB-UHFFFAOYSA-N 0.000 claims description 7
- DJLIGIDFABHFTF-UHFFFAOYSA-N N-(cyclohexylmethyl)-2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxamide Chemical compound C=1C=C2NC(C=3C4=CC=CC=C4NN=3)=NC2=CC=1C(=O)NCC1CCCCC1 DJLIGIDFABHFTF-UHFFFAOYSA-N 0.000 claims description 7
- MXQXDIGBZCAQIK-UHFFFAOYSA-N 2-(1H-indazol-3-yl)-N-(2-methylpropyl)-3H-benzimidazole-5-carboxamide Chemical compound C1=CC=C2C(C=3NC4=CC=C(C=C4N=3)C(=O)NCC(C)C)=NNC2=C1 MXQXDIGBZCAQIK-UHFFFAOYSA-N 0.000 claims description 6
- APQITXHRIPHXHK-UHFFFAOYSA-N 2-(1H-indazol-3-yl)-N-(oxan-4-ylmethyl)-3H-benzimidazole-5-carboxamide Chemical compound C=1C=C2NC(C=3C4=CC=CC=C4NN=3)=NC2=CC=1C(=O)NCC1CCOCC1 APQITXHRIPHXHK-UHFFFAOYSA-N 0.000 claims description 6
- 206010009944 Colon cancer Diseases 0.000 claims description 6
- HFYKGVBEDSFCHC-UHFFFAOYSA-N N-[(4-bromo-2-fluorophenyl)methyl]-2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxamide Chemical compound FC1=CC(Br)=CC=C1CNC(=O)C1=CC=C(NC(=N2)C=3C4=CC=CC=C4NN=3)C2=C1 HFYKGVBEDSFCHC-UHFFFAOYSA-N 0.000 claims description 6
- DEFORCSNUHZVJG-UHFFFAOYSA-N N-[2-(1H-indazol-3-yl)-3H-benzimidazol-5-yl]-2-methylpropanamide Chemical compound C1=CC=C2C(C=3NC4=CC=C(C=C4N=3)NC(=O)C(C)C)=NNC2=C1 DEFORCSNUHZVJG-UHFFFAOYSA-N 0.000 claims description 6
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- 125000005160 aryl oxy alkyl group Chemical group 0.000 claims description 6
- 208000006673 asthma Diseases 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- XUWVIABDWDTJRZ-UHFFFAOYSA-N propan-2-ylazanide Chemical compound CC(C)[NH-] XUWVIABDWDTJRZ-UHFFFAOYSA-N 0.000 claims description 6
- MQUQIARIIPWGJE-UHFFFAOYSA-N 2-(1H-indazol-3-yl)-6-(4-methoxyphenyl)-1H-benzimidazole Chemical compound C1=CC(OC)=CC=C1C1=CC=C(NC(=N2)C=3C4=CC=CC=C4NN=3)C2=C1 MQUQIARIIPWGJE-UHFFFAOYSA-N 0.000 claims description 5
- KHSVXFWMHAAKGL-UHFFFAOYSA-N 2-(1H-indazol-3-yl)-N-[(6-methoxypyridin-3-yl)methyl]-3H-benzimidazole-5-carboxamide Chemical compound C1=NC(OC)=CC=C1CNC(=O)C1=CC=C(NC(=N2)C=3C4=CC=CC=C4NN=3)C2=C1 KHSVXFWMHAAKGL-UHFFFAOYSA-N 0.000 claims description 5
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- ULRFXHBMHRNONC-UHFFFAOYSA-N N-[(2,4-dichloro-6-fluorophenyl)methyl]-2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxamide Chemical compound FC1=CC(Cl)=CC(Cl)=C1CNC(=O)C1=CC=C(NC(=N2)C=3C4=CC=CC=C4NN=3)C2=C1 ULRFXHBMHRNONC-UHFFFAOYSA-N 0.000 claims description 5
- HRIVGMYZGPAGRG-UHFFFAOYSA-N N-[(2-fluorophenyl)methyl]-2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxamide Chemical compound FC1=CC=CC=C1CNC(=O)C1=CC=C(NC(=N2)C=3C4=CC=CC=C4NN=3)C2=C1 HRIVGMYZGPAGRG-UHFFFAOYSA-N 0.000 claims description 5
- LPXNVSZAQUCFDU-UHFFFAOYSA-N N-[(4-chloro-2,6-difluorophenyl)methyl]-2-(1H-indazol-3-yl)-3H-benzimidazole-5-carboxamide Chemical compound FC1=CC(Cl)=CC(F)=C1CNC(=O)C1=CC=C(NC(=N2)C=3C4=CC=CC=C4NN=3)C2=C1 LPXNVSZAQUCFDU-UHFFFAOYSA-N 0.000 claims description 5
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Classifications
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- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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Applications Claiming Priority (11)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR0113868A FR2831537B1 (fr) | 2001-10-26 | 2001-10-26 | Nouveaux derives de benzimidazoles, leur procede de preparation, leur application a titre de medicament, compositions pharmaceutiques et nouvelle utilisation |
| FR01/13868 | 2001-10-26 | ||
| GB0206895A GB0206895D0 (en) | 2002-03-22 | 2002-03-22 | Chemical compounds |
| GB0206895.5 | 2002-03-22 | ||
| GB0206893.0 | 2002-03-22 | ||
| GB0206893A GB0206893D0 (en) | 2002-03-22 | 2002-03-22 | Chemical compounds |
| US39506002P | 2002-07-11 | 2002-07-11 | |
| US39515102P | 2002-07-11 | 2002-07-11 | |
| US60/395,060 | 2002-07-11 | ||
| US60/395,151 | 2002-07-11 | ||
| PCT/GB2002/004763 WO2003035065A1 (fr) | 2001-10-26 | 2002-10-24 | Benzimidazoles et analogues et leur utilisation comme inhibiteurs de proteines kinases |
Publications (3)
| Publication Number | Publication Date |
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| JP2005509633A JP2005509633A (ja) | 2005-04-14 |
| JP2005509633A5 JP2005509633A5 (fr) | 2012-07-12 |
| JP5039268B2 true JP5039268B2 (ja) | 2012-10-03 |
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| JP2003537632A Expired - Fee Related JP5039268B2 (ja) | 2001-10-26 | 2002-10-24 | ベンゾイミダゾールおよび類縁体および蛋白キナーゼ阻害剤としてのその使用 |
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| Country | Link |
|---|---|
| EP (1) | EP1441725A1 (fr) |
| JP (1) | JP5039268B2 (fr) |
| AU (1) | AU2002334217B2 (fr) |
| BR (1) | BR0213562A (fr) |
| CA (1) | CA2465247C (fr) |
| IL (1) | IL161576A0 (fr) |
| MX (1) | MXPA04003954A (fr) |
| UY (1) | UY27516A1 (fr) |
| WO (1) | WO2003035065A1 (fr) |
Cited By (1)
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|---|---|---|---|---|
| JP2023526548A (ja) * | 2020-05-22 | 2023-06-21 | シャンハイ ロングウッド バイオファルマシューティカルズ カンパニー リミテッド | 新規三環芳香族複素環化合物、ならびにその調製方法、医薬組成物および適用 |
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| DE2130029A1 (de) * | 1971-06-18 | 1972-12-21 | Bayer Ag | Verfahren zur Herstellung von 2-[Pyrazolyl-(1)]-benzimidazolen |
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-
2002
- 2002-10-24 JP JP2003537632A patent/JP5039268B2/ja not_active Expired - Fee Related
- 2002-10-24 CA CA2465247A patent/CA2465247C/fr not_active Expired - Fee Related
- 2002-10-24 WO PCT/GB2002/004763 patent/WO2003035065A1/fr not_active Ceased
- 2002-10-24 BR BR0213562-0A patent/BR0213562A/pt not_active Application Discontinuation
- 2002-10-24 AU AU2002334217A patent/AU2002334217B2/en not_active Ceased
- 2002-10-24 IL IL16157602A patent/IL161576A0/xx unknown
- 2002-10-24 MX MXPA04003954A patent/MXPA04003954A/es active IP Right Grant
- 2002-10-24 EP EP02801954A patent/EP1441725A1/fr not_active Withdrawn
- 2002-10-25 UY UY27516A patent/UY27516A1/es unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2023526548A (ja) * | 2020-05-22 | 2023-06-21 | シャンハイ ロングウッド バイオファルマシューティカルズ カンパニー リミテッド | 新規三環芳香族複素環化合物、ならびにその調製方法、医薬組成物および適用 |
| JP7729632B2 (ja) | 2020-05-22 | 2025-08-26 | シャンハイ ロングウッド バイオファルマシューティカルズ カンパニー リミテッド | 新規三環芳香族複素環化合物、ならびにその調製方法、医薬組成物および適用 |
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|---|---|
| AU2002334217B2 (en) | 2008-07-03 |
| CA2465247A1 (fr) | 2003-05-01 |
| MXPA04003954A (es) | 2004-11-29 |
| UY27516A1 (es) | 2003-04-30 |
| IL161576A0 (en) | 2004-09-27 |
| CA2465247C (fr) | 2010-05-18 |
| BR0213562A (pt) | 2004-08-31 |
| EP1441725A1 (fr) | 2004-08-04 |
| WO2003035065A1 (fr) | 2003-05-01 |
| JP2005509633A (ja) | 2005-04-14 |
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