KR20110079847A - 7-하이드록시-벤조이미다졸-4-일-메타논 유도체 및 이를 함유하는 ｐｂｋ 저해제 - Google Patents
7-하이드록시-벤조이미다졸-4-일-메타논 유도체 및 이를 함유하는 ｐｂｋ 저해제 Download PDFInfo
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- KR20110079847A KR20110079847A KR1020117011835A KR20117011835A KR20110079847A KR 20110079847 A KR20110079847 A KR 20110079847A KR 1020117011835 A KR1020117011835 A KR 1020117011835A KR 20117011835 A KR20117011835 A KR 20117011835A KR 20110079847 A KR20110079847 A KR 20110079847A
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- KR
- South Korea
- Prior art keywords
- benzo
- imidazole
- hydroxy
- carboxamide
- thiophen
- 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.)
- Withdrawn
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- 239000003112 inhibitor Substances 0.000 title claims abstract description 9
- GGRAFBSODPLTOT-UHFFFAOYSA-N 7-hydroxy-1h-benzimidazole-4-carbaldehyde Chemical class OC1=CC=C(C=O)C2=C1N=CN2 GGRAFBSODPLTOT-UHFFFAOYSA-N 0.000 title abstract description 3
- -1 nitro, cyano, amino Chemical group 0.000 claims description 248
- 150000001875 compounds Chemical class 0.000 claims description 65
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 45
- 102100026753 Lymphokine-activated killer T-cell-originated protein kinase Human genes 0.000 claims description 44
- 238000000034 method Methods 0.000 claims description 32
- 206010028980 Neoplasm Diseases 0.000 claims description 24
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 201000011510 cancer Diseases 0.000 claims description 21
- 239000008194 pharmaceutical composition Substances 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 230000001419 dependent effect Effects 0.000 claims description 14
- 201000010099 disease Diseases 0.000 claims description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 239000000203 mixture Substances 0.000 claims description 12
- WVKPYYLOFMTDHB-UHFFFAOYSA-N 2-norbornyl radical Chemical group C1CC2[CH]CC1C2 WVKPYYLOFMTDHB-UHFFFAOYSA-N 0.000 claims description 11
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 11
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 9
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 239000012453 solvate Substances 0.000 claims description 8
- 150000001409 amidines Chemical class 0.000 claims description 7
- 150000001408 amides Chemical class 0.000 claims description 6
- 150000001556 benzimidazoles Chemical class 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 6
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims description 5
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 5
- 125000006310 cycloalkyl amino group Chemical group 0.000 claims description 5
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims description 3
- 125000006728 (C1-C6) alkynyl group Chemical group 0.000 claims description 3
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 125000004043 oxo group Chemical group O=* 0.000 claims description 3
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 3
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- HHWUJDYTPHLTIF-UHFFFAOYSA-N 7-hydroxy-2-phenyl-n-(piperidin-2-ylmethyl)-1h-benzimidazole-4-carboxamide Chemical compound C1=2NC(C=3C=CC=CC=3)=NC=2C(O)=CC=C1C(=O)NCC1CCCCN1 HHWUJDYTPHLTIF-UHFFFAOYSA-N 0.000 claims description 2
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- ZBNZAJFNDPPMDT-UHFFFAOYSA-N 1h-imidazole-5-carboxamide Chemical compound NC(=O)C1=CNC=N1 ZBNZAJFNDPPMDT-UHFFFAOYSA-N 0.000 claims 2
- FHHUOFULEQWBBV-UHFFFAOYSA-N (7-hydroxy-2-thiophen-2-yl-1h-benzimidazol-4-yl)-piperazin-1-ylmethanone Chemical compound C1=2N=C(C=3SC=CC=3)NC=2C(O)=CC=C1C(=O)N1CCNCC1 FHHUOFULEQWBBV-UHFFFAOYSA-N 0.000 claims 1
- PQOKBQCVPUXWDC-UHFFFAOYSA-N 2-(3-bicyclo[2.2.1]heptanyl)-7-hydroxy-n-(piperidin-3-ylmethyl)-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(C3C4CCC(C4)C3)NC=2C(O)=CC=C1C(=O)NCC1CCCNC1 PQOKBQCVPUXWDC-UHFFFAOYSA-N 0.000 claims 1
- HTUPKTNEAWAZLK-UHFFFAOYSA-N 2-(3-bicyclo[2.2.1]heptanyl)-7-hydroxy-n-piperidin-3-yl-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(C3C4CCC(C4)C3)NC=2C(O)=CC=C1C(=O)NC1CCCNC1 HTUPKTNEAWAZLK-UHFFFAOYSA-N 0.000 claims 1
- MVEAHJYWRFCHHJ-VIFPVBQESA-N 2-(5-bromothiophen-2-yl)-7-hydroxy-n-[(3s)-piperidin-3-yl]-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(C=3SC(Br)=CC=3)NC=2C(O)=CC=C1C(=O)N[C@H]1CCCNC1 MVEAHJYWRFCHHJ-VIFPVBQESA-N 0.000 claims 1
- VNAZLEQAHPPEOM-UHFFFAOYSA-N 2-cyclopentyl-7-hydroxy-n-(piperidin-2-ylmethyl)-1h-benzimidazole-4-carboxamide Chemical compound C1=2NC(C3CCCC3)=NC=2C(O)=CC=C1C(=O)NCC1CCCCN1 VNAZLEQAHPPEOM-UHFFFAOYSA-N 0.000 claims 1
- DQLLQCMTQCCTEP-UHFFFAOYSA-N 2-cyclopentyl-7-hydroxy-n-(piperidin-3-ylmethyl)-1h-benzimidazole-4-carboxamide Chemical compound C1=2NC(C3CCCC3)=NC=2C(O)=CC=C1C(=O)NCC1CCCNC1 DQLLQCMTQCCTEP-UHFFFAOYSA-N 0.000 claims 1
- DMMFTUBCYQBWJG-LBPRGKRZSA-N 2-cyclopentyl-7-hydroxy-n-[(3s)-piperidin-3-yl]-1h-benzimidazole-4-carboxamide Chemical compound C1=2NC(C3CCCC3)=NC=2C(O)=CC=C1C(=O)N[C@H]1CCCNC1 DMMFTUBCYQBWJG-LBPRGKRZSA-N 0.000 claims 1
- NUIBNWKZKSUNBU-UHFFFAOYSA-N 2-cyclopropyl-7-hydroxy-n-(1-methylpiperidin-3-yl)-1h-benzimidazole-4-carboxamide Chemical compound C1N(C)CCCC1NC(=O)C1=CC=C(O)C2=C1NC(C1CC1)=N2 NUIBNWKZKSUNBU-UHFFFAOYSA-N 0.000 claims 1
- JQLOJXHUSKTZSN-UHFFFAOYSA-N 2-cyclopropyl-7-hydroxy-n-(piperidin-2-ylmethyl)-1h-benzimidazole-4-carboxamide Chemical compound C1=2NC(C3CC3)=NC=2C(O)=CC=C1C(=O)NCC1CCCCN1 JQLOJXHUSKTZSN-UHFFFAOYSA-N 0.000 claims 1
- VCFNQZLCDVKCQD-UHFFFAOYSA-N 2-cyclopropyl-7-hydroxy-n-(piperidin-3-ylmethyl)-1h-benzimidazole-4-carboxamide Chemical compound C1=2NC(C3CC3)=NC=2C(O)=CC=C1C(=O)NCC1CCCNC1 VCFNQZLCDVKCQD-UHFFFAOYSA-N 0.000 claims 1
- FOPKNXVYPWDCPH-UHFFFAOYSA-N 2-cyclopropyl-7-hydroxy-n-(piperidin-4-ylmethyl)-1h-benzimidazole-4-carboxamide Chemical compound C1=2NC(C3CC3)=NC=2C(O)=CC=C1C(=O)NCC1CCNCC1 FOPKNXVYPWDCPH-UHFFFAOYSA-N 0.000 claims 1
- VLDJPBYBKMFSBJ-JTQLQIEISA-N 2-cyclopropyl-7-hydroxy-n-[(3s)-piperidin-3-yl]-1h-benzimidazole-4-carboxamide Chemical compound C1=2NC(C3CC3)=NC=2C(O)=CC=C1C(=O)N[C@H]1CCCNC1 VLDJPBYBKMFSBJ-JTQLQIEISA-N 0.000 claims 1
- VLDJPBYBKMFSBJ-UHFFFAOYSA-N 2-cyclopropyl-7-hydroxy-n-piperidin-3-yl-1h-benzimidazole-4-carboxamide Chemical compound C1=2NC(C3CC3)=NC=2C(O)=CC=C1C(=O)NC1CCCNC1 VLDJPBYBKMFSBJ-UHFFFAOYSA-N 0.000 claims 1
- QWNYPKVETAWYSZ-UHFFFAOYSA-N 2-cyclopropyl-7-hydroxy-n-piperidin-4-yl-1h-benzimidazole-4-carboxamide Chemical compound C1=2NC(C3CC3)=NC=2C(O)=CC=C1C(=O)NC1CCNCC1 QWNYPKVETAWYSZ-UHFFFAOYSA-N 0.000 claims 1
- NEXCLKRXESRENY-UHFFFAOYSA-N 2-cyclopropyl-7-hydroxy-n-pyrrolidin-3-yl-1h-benzimidazole-4-carboxamide Chemical compound C1=2NC(C3CC3)=NC=2C(O)=CC=C1C(=O)NC1CCNC1 NEXCLKRXESRENY-UHFFFAOYSA-N 0.000 claims 1
- CWBZXCZNEOPRCN-ZDUSSCGKSA-N 7-hydroxy-2-(5-piperazin-1-ylthiophen-2-yl)-n-[(3s)-piperidin-3-yl]-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(C=3SC(=CC=3)N3CCNCC3)NC=2C(O)=CC=C1C(=O)N[C@H]1CCCNC1 CWBZXCZNEOPRCN-ZDUSSCGKSA-N 0.000 claims 1
- QUHAKLIRTFIRPF-UHFFFAOYSA-N 7-hydroxy-2-phenyl-n-(piperidin-3-ylmethyl)-1h-benzimidazole-4-carboxamide Chemical compound C1=2NC(C=3C=CC=CC=3)=NC=2C(O)=CC=C1C(=O)NCC1CCCNC1 QUHAKLIRTFIRPF-UHFFFAOYSA-N 0.000 claims 1
- HCOYOZKRGRMGIL-ZDUSSCGKSA-N 7-hydroxy-2-phenyl-n-[(3s)-piperidin-3-yl]-1h-benzimidazole-4-carboxamide Chemical compound C1=2NC(C=3C=CC=CC=3)=NC=2C(O)=CC=C1C(=O)N[C@H]1CCCNC1 HCOYOZKRGRMGIL-ZDUSSCGKSA-N 0.000 claims 1
- UHYZCMYXHGAMGC-UHFFFAOYSA-N 7-hydroxy-n-(1-methylpiperidin-3-yl)-2-thiophen-2-yl-1h-benzimidazole-4-carboxamide Chemical compound C1N(C)CCCC1NC(=O)C1=CC=C(O)C2=C1N=C(C=1SC=CC=1)N2 UHYZCMYXHGAMGC-UHFFFAOYSA-N 0.000 claims 1
- LRQSKLNGWMJWMJ-UHFFFAOYSA-N 7-hydroxy-n-(2-piperazin-1-ylethyl)-2-thiophen-2-yl-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(C=3SC=CC=3)NC=2C(O)=CC=C1C(=O)NCCN1CCNCC1 LRQSKLNGWMJWMJ-UHFFFAOYSA-N 0.000 claims 1
- DSUNIVRRAJRRDJ-UHFFFAOYSA-N 7-hydroxy-n-(4-hydroxycyclohexyl)-2-thiophen-2-yl-1h-benzimidazole-4-carboxamide Chemical compound C1CC(O)CCC1NC(=O)C1=CC=C(O)C2=C1N=C(C=1SC=CC=1)N2 DSUNIVRRAJRRDJ-UHFFFAOYSA-N 0.000 claims 1
- VYRHSZRZVBIDCD-UHFFFAOYSA-N 7-hydroxy-n-(piperidin-2-ylmethyl)-2-thiophen-2-yl-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(C=3SC=CC=3)NC=2C(O)=CC=C1C(=O)NCC1CCCCN1 VYRHSZRZVBIDCD-UHFFFAOYSA-N 0.000 claims 1
- MTCFCASJWUBVGX-UHFFFAOYSA-N 7-hydroxy-n-(piperidin-3-ylmethyl)-2-thiophen-2-yl-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(C=3SC=CC=3)NC=2C(O)=CC=C1C(=O)NCC1CCCNC1 MTCFCASJWUBVGX-UHFFFAOYSA-N 0.000 claims 1
- DLNUWZOWSGXCKJ-UHFFFAOYSA-N 7-hydroxy-n-(piperidin-4-ylmethyl)-2-thiophen-2-yl-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(C=3SC=CC=3)NC=2C(O)=CC=C1C(=O)NCC1CCNCC1 DLNUWZOWSGXCKJ-UHFFFAOYSA-N 0.000 claims 1
- NJKUDKWJZPVSAI-UHFFFAOYSA-N 7-hydroxy-n-(pyrrolidin-3-ylmethyl)-2-thiophen-2-yl-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(C=3SC=CC=3)NC=2C(O)=CC=C1C(=O)NCC1CCNC1 NJKUDKWJZPVSAI-UHFFFAOYSA-N 0.000 claims 1
- LJPSIRPRIUNDAT-SNVBAGLBSA-N 7-hydroxy-n-[(3r)-piperidin-3-yl]-2-thiophen-2-yl-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(C=3SC=CC=3)NC=2C(O)=CC=C1C(=O)N[C@@H]1CCCNC1 LJPSIRPRIUNDAT-SNVBAGLBSA-N 0.000 claims 1
- FMCDOLBSRBSVDW-NSHDSACASA-N 7-hydroxy-n-[(3s)-piperidin-3-yl]-2-(thiophen-2-ylmethyl)-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(CC=3SC=CC=3)NC=2C(O)=CC=C1C(=O)N[C@H]1CCCNC1 FMCDOLBSRBSVDW-NSHDSACASA-N 0.000 claims 1
- LJPSIRPRIUNDAT-JTQLQIEISA-N 7-hydroxy-n-[(3s)-piperidin-3-yl]-2-thiophen-2-yl-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(C=3SC=CC=3)NC=2C(O)=CC=C1C(=O)N[C@H]1CCCNC1 LJPSIRPRIUNDAT-JTQLQIEISA-N 0.000 claims 1
- FQTGTVOVVRVTMG-GFCCVEGCSA-N 7-hydroxy-n-[[(3r)-piperidin-3-yl]methyl]-2-(thiophen-2-ylmethyl)-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(CC=3SC=CC=3)NC=2C(O)=CC=C1C(=O)NC[C@@H]1CCCNC1 FQTGTVOVVRVTMG-GFCCVEGCSA-N 0.000 claims 1
- LJPSIRPRIUNDAT-UHFFFAOYSA-N 7-hydroxy-n-piperidin-3-yl-2-thiophen-2-yl-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(C=3SC=CC=3)NC=2C(O)=CC=C1C(=O)NC1CCCNC1 LJPSIRPRIUNDAT-UHFFFAOYSA-N 0.000 claims 1
- ITBAAQYBVUPCCT-UHFFFAOYSA-N 7-hydroxy-n-piperidin-4-yl-2-thiophen-2-yl-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(C=3SC=CC=3)NC=2C(O)=CC=C1C(=O)NC1CCNCC1 ITBAAQYBVUPCCT-UHFFFAOYSA-N 0.000 claims 1
- WTHXQDHNQUSBSY-UHFFFAOYSA-N 7-hydroxy-n-pyrrolidin-3-yl-2-thiophen-2-yl-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(C=3SC=CC=3)NC=2C(O)=CC=C1C(=O)NC1CCNC1 WTHXQDHNQUSBSY-UHFFFAOYSA-N 0.000 claims 1
- 125000002490 anilino group Chemical class [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- FLSNBMIFUBTWCA-UHFFFAOYSA-N n-(3-aminocyclohexyl)-2-(3-bicyclo[2.2.1]heptanyl)-7-hydroxy-1h-benzimidazole-4-carboxamide Chemical compound C1C(N)CCCC1NC(=O)C1=CC=C(O)C2=C1N=C(C1C3CCC(C3)C1)N2 FLSNBMIFUBTWCA-UHFFFAOYSA-N 0.000 claims 1
- KADSEBMOTREHLE-UHFFFAOYSA-N n-(4-aminocyclohexyl)-7-hydroxy-2-thiophen-2-yl-1h-benzimidazole-4-carboxamide Chemical compound C1CC(N)CCC1NC(=O)C1=CC=C(O)C2=C1N=C(C=1SC=CC=1)N2 KADSEBMOTREHLE-UHFFFAOYSA-N 0.000 claims 1
- LGKPKPRXQJVEDQ-UHFFFAOYSA-N n-(azetidin-3-ylmethyl)-2-cyclopropyl-7-hydroxy-1h-benzimidazole-4-carboxamide Chemical compound C1=2NC(C3CC3)=NC=2C(O)=CC=C1C(=O)NCC1CNC1 LGKPKPRXQJVEDQ-UHFFFAOYSA-N 0.000 claims 1
- QOQKTKZYZAUZTA-UHFFFAOYSA-N n-(azetidin-3-ylmethyl)-7-hydroxy-2-thiophen-2-yl-1h-benzimidazole-4-carboxamide Chemical compound C1=2N=C(C=3SC=CC=3)NC=2C(O)=CC=C1C(=O)NCC1CNC1 QOQKTKZYZAUZTA-UHFFFAOYSA-N 0.000 claims 1
- MRGFHHVXSDCNRD-UHFFFAOYSA-N n-[(4-aminocyclohexyl)methyl]-2-(3-bicyclo[2.2.1]heptanyl)-7-hydroxy-1h-benzimidazole-4-carboxamide Chemical compound C1CC(N)CCC1CNC(=O)C1=CC=C(O)C2=C1N=C(C1C3CCC(C3)C1)N2 MRGFHHVXSDCNRD-UHFFFAOYSA-N 0.000 claims 1
- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 claims 1
- 239000000047 product Substances 0.000 description 98
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 86
- 239000007787 solid Substances 0.000 description 72
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- 238000007429 general method Methods 0.000 description 63
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 54
- 238000006243 chemical reaction Methods 0.000 description 43
- 238000004128 high performance liquid chromatography Methods 0.000 description 43
- JJDMKDXGNVJWCD-UHFFFAOYSA-N 1h-benzimidazole-4-carboxamide Chemical compound NC(=O)C1=CC=CC2=C1N=CN2 JJDMKDXGNVJWCD-UHFFFAOYSA-N 0.000 description 41
- 108010014971 PDZ-binding kinase Proteins 0.000 description 38
- 239000011541 reaction mixture Substances 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 238000003786 synthesis reaction Methods 0.000 description 27
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 24
- 239000000243 solution Substances 0.000 description 24
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 23
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 11
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 10
- 239000003921 oil Substances 0.000 description 10
- 239000004480 active ingredient Substances 0.000 description 9
- 229910021529 ammonia Inorganic materials 0.000 description 9
- 238000005342 ion exchange Methods 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 9
- 238000002953 preparative HPLC Methods 0.000 description 8
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 8
- XOOWYHRUQFDBPG-UHFFFAOYSA-N 2-(3-bicyclo[2.2.1]heptanyl)-7-methoxy-1h-benzimidazole-4-carboxylic acid Chemical compound COC1=CC=C(C(O)=O)C2=C1NC(C1C3CCC(C3)C1)=N2 XOOWYHRUQFDBPG-UHFFFAOYSA-N 0.000 description 7
- 229910019093 NaOCl Inorganic materials 0.000 description 7
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
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- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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| US10980108P | 2008-10-30 | 2008-10-30 | |
| US61/109,801 | 2008-10-30 |
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| KR20110079847A true KR20110079847A (ko) | 2011-07-08 |
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| EP (1) | EP2364087A4 (enExample) |
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| CA2660438A1 (en) * | 2006-08-10 | 2008-02-14 | Oncotherapy Science, Inc. | Genes and polypeptides relating to breast cancers |
| WO2010014794A1 (en) * | 2008-07-30 | 2010-02-04 | Oncotherapy Science, Inc. | Benzoimidazole derivatives and glycogen synthase kinase-3 beta inhibitors containing the same |
| MX2011005369A (es) * | 2008-11-20 | 2011-06-20 | Oncotherapy Science Inc | Inhibidores de glicogeno sintasa cinasa-3 beta que contienen derivados de 7-hidroxi-benzoimidazol-4-il-metanona. |
| CN101619058A (zh) * | 2009-01-08 | 2010-01-06 | 上海交通大学 | 一种苯并咪唑-4-酰胺型衍生物 |
| AR094053A1 (es) * | 2012-12-18 | 2015-07-08 | Actelion Pharmaceuticals Ltd | Derivados de indol carboxamida como antagonistas del receptor p2x₇ |
| CN105017221B (zh) * | 2014-04-30 | 2019-05-28 | 中国医学科学院药物研究所 | 苯并咪唑衍生物及其制法和药物组合物与用途 |
| JP6009135B1 (ja) * | 2015-07-30 | 2016-10-19 | 第一三共株式会社 | 成人ｔ細胞白血病リンパ腫の治療及び／又は予防剤 |
| KR102578297B1 (ko) | 2015-07-30 | 2023-09-13 | 다이이찌 산쿄 가부시키가이샤 | 성인 t 세포 백혈병 림프종의 치료 및/또는 예방제 |
| WO2019124608A1 (ko) * | 2017-12-22 | 2019-06-27 | 경상대학교병원 | 4'-(p-톨루엔설포닐아미도)-4-하이드록시칼콘을 유효성분으로 함유하는 류마티스 관절염 예방 또는 치료용 약학 조성물 |
| CN109320461B (zh) * | 2018-12-12 | 2020-02-07 | 迪嘉药业集团有限公司 | 一种替米沙坦中间体的制备方法 |
| CN114072407A (zh) | 2019-04-02 | 2022-02-18 | 阿里戈斯治疗公司 | 靶向prmt5的化合物 |
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| US6288100B1 (en) * | 1995-06-06 | 2001-09-11 | American Home Products Corporation | Benzimidazole derivatives |
| US20040002524A1 (en) * | 2002-06-24 | 2004-01-01 | Richard Chesworth | Benzimidazole compounds and their use as estrogen agonists/antagonists |
| WO2004065370A1 (en) * | 2003-01-23 | 2004-08-05 | Crystalgenomics, Inc. | Glycogen synthase kinase 3beta inhibitor, composition and process for the preparation thereof |
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| US20110263566A1 (en) | 2011-10-27 |
| IL212544A0 (en) | 2011-06-30 |
| MX2011004414A (es) | 2011-06-21 |
| AU2009310310A2 (en) | 2011-10-06 |
| BRPI0919977A2 (pt) | 2015-08-25 |
| EP2364087A1 (en) | 2011-09-14 |
| RU2011121665A (ru) | 2012-12-10 |
| AU2009310310A1 (en) | 2010-05-06 |
| JP2012507525A (ja) | 2012-03-29 |
| WO2010051085A1 (en) | 2010-05-06 |
| CA2741988A1 (en) | 2010-05-06 |
| EP2364087A4 (en) | 2012-05-30 |
| ZA201103964B (en) | 2012-02-29 |
| CN102271514A (zh) | 2011-12-07 |
| CO6361855A2 (es) | 2012-01-20 |
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