BG108206A - Нови инхибитори на тирозинкиназа - Google Patents
Нови инхибитори на тирозинкиназа Download PDFInfo
- Publication number
- BG108206A BG108206A BG108206A BG10820603A BG108206A BG 108206 A BG108206 A BG 108206A BG 108206 A BG108206 A BG 108206A BG 10820603 A BG10820603 A BG 10820603A BG 108206 A BG108206 A BG 108206A
- Authority
- BG
- Bulgaria
- Prior art keywords
- methyl
- hydroxy
- pyridin
- ethylamino
- benzimidazol
- Prior art date
Links
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 title description 6
- 239000005483 tyrosine kinase inhibitor Substances 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 199
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims abstract description 22
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims abstract description 22
- 238000011282 treatment Methods 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- -1 sulfoxy, sulfonyl Chemical group 0.000 claims description 449
- 229910052739 hydrogen Inorganic materials 0.000 claims description 140
- 239000001257 hydrogen Substances 0.000 claims description 119
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 106
- 125000000217 alkyl group Chemical group 0.000 claims description 91
- 150000002431 hydrogen Chemical class 0.000 claims description 80
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 76
- 125000001072 heteroaryl group Chemical group 0.000 claims description 60
- 239000000203 mixture Substances 0.000 claims description 54
- 125000003545 alkoxy group Chemical group 0.000 claims description 52
- 125000003118 aryl group Chemical group 0.000 claims description 52
- 239000000460 chlorine Substances 0.000 claims description 50
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 50
- 125000003342 alkenyl group Chemical group 0.000 claims description 42
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 41
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 39
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 39
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 38
- 125000005843 halogen group Chemical group 0.000 claims description 37
- 125000005309 thioalkoxy group Chemical group 0.000 claims description 35
- 150000003573 thiols Chemical class 0.000 claims description 33
- SVSARCCKBMZNMR-UHFFFAOYSA-N [1-[2-[methyl-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethyl]amino]ethyl]pyridin-4-ylidene]methyl-oxoazanium;dichloride Chemical compound [Cl-].[Cl-].C1=CC(=C[NH+]=O)C=CN1CCN(C)CCN1C=CC(=C[NH+]=O)C=C1 SVSARCCKBMZNMR-UHFFFAOYSA-N 0.000 claims description 32
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 31
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 31
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 27
- 238000002360 preparation method Methods 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 23
- 229910052736 halogen Inorganic materials 0.000 claims description 22
- 150000002367 halogens Chemical class 0.000 claims description 22
- 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 22
- 229910052731 fluorine Inorganic materials 0.000 claims description 21
- 229910052799 carbon Inorganic materials 0.000 claims description 20
- 206010028980 Neoplasm Diseases 0.000 claims description 19
- 125000000304 alkynyl group Chemical group 0.000 claims description 19
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 18
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 125000001424 substituent group Chemical group 0.000 claims description 17
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 201000011510 cancer Diseases 0.000 claims description 13
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000003282 alkyl amino group Chemical group 0.000 claims description 12
- 229910052794 bromium Inorganic materials 0.000 claims description 12
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 12
- 239000003112 inhibitor Substances 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- RFIOZSIHFNEKFF-UHFFFAOYSA-N piperazine-1-carboxylic acid Chemical compound OC(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-N 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 11
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 11
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 11
- KXDHJXZQYSOELW-UHFFFAOYSA-N carbonic acid monoamide Natural products NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- ZNGWEEUXTBNKFR-UHFFFAOYSA-N 1,4-oxazepane Chemical compound C1CNCCOC1 ZNGWEEUXTBNKFR-UHFFFAOYSA-N 0.000 claims description 8
- 239000005411 L01XE02 - Gefitinib Substances 0.000 claims description 8
- 241000124008 Mammalia Species 0.000 claims description 8
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 claims description 8
- 229960001433 erlotinib Drugs 0.000 claims description 8
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 claims description 8
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 claims description 8
- 229940084651 iressa Drugs 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
- 229940002612 prodrug Drugs 0.000 claims description 7
- 239000000651 prodrug Substances 0.000 claims description 7
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims description 7
- KJAMZCVTJDTESW-UHFFFAOYSA-N tiracizine Chemical compound C1CC2=CC=CC=C2N(C(=O)CN(C)C)C2=CC(NC(=O)OCC)=CC=C21 KJAMZCVTJDTESW-UHFFFAOYSA-N 0.000 claims description 7
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 claims description 6
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 6
- 239000011737 fluorine Substances 0.000 claims description 6
- 150000002780 morpholines Chemical class 0.000 claims description 6
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical compound C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims description 5
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 5
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 5
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- OTPDWCMLUKMQNO-UHFFFAOYSA-N 1,2,3,4-tetrahydropyrimidine Chemical compound C1NCC=CN1 OTPDWCMLUKMQNO-UHFFFAOYSA-N 0.000 claims description 4
- WOXFMYVTSLAQMO-UHFFFAOYSA-N 2-Pyridinemethanamine Chemical compound NCC1=CC=CC=N1 WOXFMYVTSLAQMO-UHFFFAOYSA-N 0.000 claims description 4
- OTOIUCLFSQHFOX-UHFFFAOYSA-N 3-sulfonylmorpholine Chemical compound O=S(=O)=C1COCCN1 OTOIUCLFSQHFOX-UHFFFAOYSA-N 0.000 claims description 4
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 claims description 4
- 229930012538 Paclitaxel Natural products 0.000 claims description 4
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 4
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 239000004037 angiogenesis inhibitor Substances 0.000 claims description 4
- 229940043378 cyclin-dependent kinase inhibitor Drugs 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 229930013356 epothilone Natural products 0.000 claims description 4
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 claims description 4
- 229960005420 etoposide Drugs 0.000 claims description 4
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 229940022353 herceptin Drugs 0.000 claims description 4
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 4
- 150000004677 hydrates Chemical class 0.000 claims description 4
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 229960001592 paclitaxel Drugs 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 claims description 4
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical group C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 claims description 3
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical group C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims description 3
- HHGVGFMWJQKOFG-KRWDZBQOSA-N 2-[4-[[(2S)-1-hydroxy-3-phenylpropan-2-yl]amino]-2-oxo-1H-pyridin-3-yl]-7-methyl-3H-benzimidazole-5-carbonitrile Chemical compound C([C@@H](CO)NC1=C(C(NC=C1)=O)C=1NC=2C=C(C=C(C=2N=1)C)C#N)C1=CC=CC=C1 HHGVGFMWJQKOFG-KRWDZBQOSA-N 0.000 claims description 3
- QEDRKDBUNJAFMZ-UHFFFAOYSA-N 2-[4-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]-2-oxo-1H-pyridin-3-yl]-7-methyl-3H-benzimidazole-5-carbonitrile Chemical compound N=1C=2C(C)=CC(C#N)=CC=2NC=1C(C(NC=C1)=O)=C1NCC(O)C1=CC=CC(Cl)=C1 QEDRKDBUNJAFMZ-UHFFFAOYSA-N 0.000 claims description 3
- FSDYMRXZPHZFJS-UHFFFAOYSA-N 4-[[2-(3-bromo-4-methoxyphenyl)-2-hydroxyethyl]amino]-3-(4-methyl-6-morpholin-4-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one Chemical compound C1=C(Br)C(OC)=CC=C1C(O)CNC1=C(C=2NC3=CC(=CC(C)=C3N=2)N2CCOCC2)C(=O)NC=C1 FSDYMRXZPHZFJS-UHFFFAOYSA-N 0.000 claims description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 3
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 claims description 3
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 claims description 3
- HZQLLKQPXMHIMZ-UHFFFAOYSA-N N-[1-[2-[4-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]-2-oxo-1H-pyridin-3-yl]-7-methyl-3H-benzimidazol-5-yl]piperidin-4-yl]-2-fluoroacetamide Chemical compound N=1C=2C(C)=CC(N3CCC(CC3)NC(=O)CF)=CC=2NC=1C(C(NC=C1)=O)=C1NCC(O)C1=CC=CC(Cl)=C1 HZQLLKQPXMHIMZ-UHFFFAOYSA-N 0.000 claims description 3
- 102000016549 Vascular Endothelial Growth Factor Receptor-2 Human genes 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 3
- 229960004679 doxorubicin Drugs 0.000 claims description 3
- 229960002949 fluorouracil Drugs 0.000 claims description 3
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 3
- OTXBWGUYZNKPMG-UHFFFAOYSA-N isofulminic acid Chemical compound O[N+]#[C-] OTXBWGUYZNKPMG-UHFFFAOYSA-N 0.000 claims description 3
- 229960000485 methotrexate Drugs 0.000 claims description 3
- 229960001603 tamoxifen Drugs 0.000 claims description 3
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 claims description 3
- 229960000303 topotecan Drugs 0.000 claims description 3
- 239000002525 vasculotropin inhibitor Substances 0.000 claims description 3
- ZLEMMUBHALJEGB-UHFFFAOYSA-N 1-[2-[4-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]-2-oxo-1H-pyridin-3-yl]-7-methyl-3H-benzimidazol-5-yl]-N-(2-methoxyethoxy)piperidine-4-carboxamide Chemical compound C1CC(C(=O)NOCCOC)CCN1C1=CC(C)=C(N=C(N2)C=3C(NC=CC=3NCC(O)C=3C=C(Cl)C=CC=3)=O)C2=C1 ZLEMMUBHALJEGB-UHFFFAOYSA-N 0.000 claims description 2
- IFNWESYYDINUHV-UHFFFAOYSA-N 2,6-dimethylpiperazine Chemical compound CC1CNCC(C)N1 IFNWESYYDINUHV-UHFFFAOYSA-N 0.000 claims description 2
- NQRCKUVJMDFGCB-KRWDZBQOSA-N 2-[4-[[(2S)-1-(3-chlorophenyl)-3-hydroxypropan-2-yl]amino]-2-oxo-1H-pyridin-3-yl]-7-methyl-3H-benzimidazole-5-carbonitrile Chemical compound C([C@@H](CO)NC1=C(C(NC=C1)=O)C=1NC=2C=C(C=C(C=2N=1)C)C#N)C1=CC=CC(Cl)=C1 NQRCKUVJMDFGCB-KRWDZBQOSA-N 0.000 claims description 2
- BXPWYRZCEDJCQW-GOSISDBHSA-N 2-[4-[[(2S)-2-hydroxy-2-phenylethyl]amino]-2-oxo-1H-pyridin-3-yl]-7-methyl-3H-benzimidazole-5-carbonitrile Chemical compound C1([C@H](O)CNC2=C(C(NC=C2)=O)C=2NC=3C=C(C=C(C=3N=2)C)C#N)=CC=CC=C1 BXPWYRZCEDJCQW-GOSISDBHSA-N 0.000 claims description 2
- YETIHONGYJNLSF-UHFFFAOYSA-N 2-[4-[[2-(3-bromophenyl)-2-hydroxyethyl]amino]-2-oxo-1H-pyridin-3-yl]-7-methyl-3H-benzimidazole-5-carbonitrile Chemical compound N=1C=2C(C)=CC(C#N)=CC=2NC=1C(C(NC=C1)=O)=C1NCC(O)C1=CC=CC(Br)=C1 YETIHONGYJNLSF-UHFFFAOYSA-N 0.000 claims description 2
- BKOVQGMNMPRQPP-UHFFFAOYSA-N 2-[4-[[2-(3-fluorophenyl)-2-hydroxyethyl]amino]-2-oxo-1H-pyridin-3-yl]-7-methyl-3H-benzimidazole-5-carbonitrile Chemical compound N=1C=2C(C)=CC(C#N)=CC=2NC=1C(C(NC=C1)=O)=C1NCC(O)C1=CC=CC(F)=C1 BKOVQGMNMPRQPP-UHFFFAOYSA-N 0.000 claims description 2
- 125000004777 2-fluoroethyl group Chemical group [H]C([H])(F)C([H])([H])* 0.000 claims description 2
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical compound CC1CNCCN1 JOMNTHCQHJPVAZ-UHFFFAOYSA-N 0.000 claims description 2
- XVTGMPIWLFRYCU-UHFFFAOYSA-N 3-(1H-benzimidazol-2-yl)-4-[[2-(3-bromo-4-methoxyphenyl)-2-hydroxyethyl]amino]-1H-pyridin-2-one Chemical compound C1=C(Br)C(OC)=CC=C1C(O)CNC1=C(C=2NC3=CC=CC=C3N=2)C(=O)NC=C1 XVTGMPIWLFRYCU-UHFFFAOYSA-N 0.000 claims description 2
- CMYZQDNEXKMVAP-UHFFFAOYSA-N 3-(1H-benzimidazol-2-yl)-4-[[2-(3-bromophenyl)-2-hydroxyethyl]amino]-1H-pyridin-2-one Chemical compound C1=CNC(=O)C(C=2NC3=CC=CC=C3N=2)=C1NCC(O)C1=CC=CC(Br)=C1 CMYZQDNEXKMVAP-UHFFFAOYSA-N 0.000 claims description 2
- SLYJOQJAIBXMFF-FQEVSTJZSA-N 4-[[(2S)-1-hydroxy-3-phenylpropan-2-yl]amino]-3-(4-methyl-6-piperidin-1-yl-1H-benzimidazol-2-yl)-1H-pyridin-2-one Chemical compound C([C@@H](CO)NC1=C(C(NC=C1)=O)C=1NC=2C=C(C=C(C=2N=1)C)N1CCCCC1)C1=CC=CC=C1 SLYJOQJAIBXMFF-FQEVSTJZSA-N 0.000 claims description 2
- DNTQJDXWGFMNLI-OPAMFIHVSA-N 4-[[(2S)-2-(3-bromo-4-methoxyphenyl)-2-hydroxyethyl]amino]-3-[4-methyl-6-[(2R)-2-methylmorpholin-4-yl]-1H-benzimidazol-2-yl]-1H-pyridin-2-one Chemical compound C1=C(Br)C(OC)=CC=C1[C@H](O)CNC1=C(C=2NC3=CC(=CC(C)=C3N=2)N2C[C@@H](C)OCC2)C(=O)NC=C1 DNTQJDXWGFMNLI-OPAMFIHVSA-N 0.000 claims description 2
- PUHIHKJDRCRYTD-OAQYLSRUSA-N 4-[[(2S)-2-(3-chloro-4-methoxyphenyl)-2-hydroxyethyl]amino]-3-[6-(5,6-dihydro-4H-pyrimidin-1-yl)-4-methyl-1H-benzimidazol-2-yl]-1H-pyridin-2-one Chemical compound C1=C(Cl)C(OC)=CC=C1[C@H](O)CNC1=C(C=2NC3=CC(=CC(C)=C3N=2)N2C=NCCC2)C(=O)NC=C1 PUHIHKJDRCRYTD-OAQYLSRUSA-N 0.000 claims description 2
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Classifications
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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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- 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
- C07D401/14—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 three or more hetero rings
-
- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| US27932701P | 2001-03-28 | 2001-03-28 |
Publications (1)
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| BG108206A true BG108206A (bg) | 2004-11-30 |
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Family Applications (1)
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| BG108206A BG108206A (bg) | 2001-03-28 | 2003-09-26 | Нови инхибитори на тирозинкиназа |
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| JP (1) | JP2004534010A (enExample) |
| KR (1) | KR20030083016A (enExample) |
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| HR (1) | HRP20030844A2 (enExample) |
| HU (1) | HUP0400323A2 (enExample) |
| IL (1) | IL158041A0 (enExample) |
| IS (1) | IS6968A (enExample) |
| MX (1) | MXPA03008690A (enExample) |
| NO (1) | NO20034308L (enExample) |
| PE (1) | PE20021015A1 (enExample) |
| PL (1) | PL373300A1 (enExample) |
| RU (1) | RU2003131693A (enExample) |
| SK (1) | SK12002003A3 (enExample) |
| UY (1) | UY27234A1 (enExample) |
| WO (1) | WO2002079192A1 (enExample) |
| YU (1) | YU84603A (enExample) |
| ZA (1) | ZA200307466B (enExample) |
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| US7081454B2 (en) * | 2001-03-28 | 2006-07-25 | Bristol-Myers Squibb Co. | Tyrosine kinase inhibitors |
| WO2003073841A2 (en) | 2002-03-01 | 2003-09-12 | Bristol-Myers Squibb Company | Transgenic non-human mammals expressing constitutively activated tyrosine kinase receptors |
| US6921821B2 (en) * | 2002-06-12 | 2005-07-26 | Abbott Laboratories | Antagonists of melanin concentrating hormone receptor |
| US7361691B2 (en) * | 2002-12-02 | 2008-04-22 | Arqule, Inc. | Method of treating cancers using β-lapachone or analogs or derivatives thereof |
| WO2004063151A2 (en) | 2003-01-03 | 2004-07-29 | Bristol-Myers Squibb Company | Novel tyrosine kinase inhibitors |
| WO2004069160A2 (en) * | 2003-01-28 | 2004-08-19 | Smithkline Beecham Corporation | Chemical compounds |
| US7312215B2 (en) | 2003-07-29 | 2007-12-25 | Bristol-Myers Squibb Company | Benzimidazole C-2 heterocycles as kinase inhibitors |
| US8362017B2 (en) | 2003-08-29 | 2013-01-29 | Exelixis, Inc. | C-kit modulators and methods of use |
| US20050075358A1 (en) * | 2003-10-06 | 2005-04-07 | Carboni Joan M. | Methods for treating IGF1R-inhibitor induced hyperglycemia |
| JP2007514759A (ja) | 2003-12-19 | 2007-06-07 | タケダ サン ディエゴ インコーポレイテッド | キナーゼ阻害剤 |
| DE102004010207A1 (de) | 2004-03-02 | 2005-09-15 | Aventis Pharma S.A. | Neue 4-Benzimidazol-2-yl-pyridazin-3-on-Derivate |
| MXPA06011423A (es) | 2004-04-02 | 2007-01-23 | Osi Pharm Inc | Inhibidores de proteina cinasa heterobiciclica sustituida en el anillo 6,6-biciclico. |
| US7550598B2 (en) | 2004-08-18 | 2009-06-23 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
| JP2008524233A (ja) * | 2004-12-16 | 2008-07-10 | バーテックス ファーマシューティカルズ インコーポレイテッド | 炎症性疾患、増殖性疾患および免疫介在性疾患の治療のためのｔｅｃファミリータンパク質キナーゼのインヒビターとして有用なピリド−２−オン |
| US7538113B2 (en) | 2005-02-18 | 2009-05-26 | Wyeth | 4-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor |
| US7582634B2 (en) | 2005-02-18 | 2009-09-01 | Wyeth | 7-substituted imidazo[4,5-c]pyridine antagonists of gonadotropin releasing hormone receptor |
| US7534796B2 (en) | 2005-02-18 | 2009-05-19 | Wyeth | Imidazo[4,5-b]pyridine antagonists of gonadotropin releasing hormone receptor |
| US7531542B2 (en) | 2005-05-18 | 2009-05-12 | Wyeth | Benzooxazole and benzothiazole antagonists of gonadotropin releasing hormone receptor |
| US7582636B2 (en) | 2005-05-26 | 2009-09-01 | Wyeth | Piperazinylimidazopyridine and piperazinyltriazolopyridine antagonists of Gonadotropin Releasing Hormone receptor |
| US7393667B2 (en) | 2005-05-31 | 2008-07-01 | Bristol-Myers Squibb Company | Stereoselective reduction process for the preparation of pyrrolotriazine compounds |
| CA2618370A1 (en) | 2005-08-04 | 2007-02-15 | Sirtris Pharmaceuticals, Inc. | Oxazolopyridine derivatives as sirtuin modulators |
| US8088928B2 (en) | 2005-08-04 | 2012-01-03 | Sirtris Pharmaceuticals, Inc. | Sirtuin modulating compounds |
| US7855289B2 (en) | 2005-08-04 | 2010-12-21 | Sirtris Pharmaceuticals, Inc. | Sirtuin modulating compounds |
| US8093401B2 (en) | 2005-08-04 | 2012-01-10 | Sirtris Pharmaceuticals, Inc. | Sirtuin modulating compounds |
| EP1919891B1 (en) | 2005-08-29 | 2012-03-07 | Vertex Pharmaceuticals Incorporated | 3,5-disubstituted pyrid-2-ones useful as inhibitors of tec family of non-receptor tyrosine kinases |
| US7786130B2 (en) | 2005-08-29 | 2010-08-31 | Vertex Pharmaceuticals Incorporated | Pyridones useful as inhibitors of kinases |
| ATE499362T1 (de) | 2005-08-29 | 2011-03-15 | Vertex Pharma | 3,5-disubstituierte pyrid-2-one, die als hemmer der tec-familie von nicht-rezeptor tyrosin- kinasen nützlich sind |
| WO2007026720A1 (ja) * | 2005-08-31 | 2007-03-08 | Taisho Pharmaceutical Co., Ltd. | 縮環ピラゾール誘導体 |
| US8575164B2 (en) | 2005-12-19 | 2013-11-05 | OSI Pharmaceuticals, LLC | Combination cancer therapy |
| WO2007145203A1 (ja) * | 2006-06-13 | 2007-12-21 | Daiichi Fine Chemical Co., Ltd. | 光学活性２－アミノ－１－（４－フルオロフェニル）エタノール |
| US8063225B2 (en) * | 2006-08-14 | 2011-11-22 | Chembridge Corporation | Tricyclic compound derivatives useful in the treatment of neoplastic diseases, inflammatory disorders and immunomodulatory disorders |
| WO2008022747A1 (en) * | 2006-08-21 | 2008-02-28 | F. Hoffmann-La Roche Ag | Tricyclic lactam derivatives, their manufacture and use as pharmaceutical agents |
| WO2008025526A1 (en) * | 2006-08-31 | 2008-03-06 | F. Hoffmann-La Roche Ag | Indole derivatives, their manufacture and use as pharmaceutical agents |
| EP2145021A2 (en) | 2007-05-17 | 2010-01-20 | Bristol-Myers Squibb Company | Biomarkers and methods for determining sensitivity to insulin growth factor-1 receptor modulators |
| CL2008001822A1 (es) | 2007-06-20 | 2009-03-13 | Sirtris Pharmaceuticals Inc | Compuestos derivados de tiazolo[5,4-b]piridina; composicion farmaceutica que comprende a dichos compuestos; y uso del compuesto en el tratamiento de la resistencia a la insulina, sindrome metabolico, diabetes, entre otras. |
| US7956190B2 (en) | 2007-06-25 | 2011-06-07 | Hoffmann-La Roche Inc. | Benzimidazole amido derivatives as kinase inhibitors |
| EP2065380A1 (en) * | 2007-08-22 | 2009-06-03 | F.Hoffmann-La Roche Ag | Pyridoneamide derivatives as focal adhesion kinase (FAK) inhibitors and their use for the treatment of cancer |
| US7816540B2 (en) * | 2007-12-21 | 2010-10-19 | Hoffmann-La Roche Inc. | Carboxyl- or hydroxyl-substituted benzimidazole derivatives |
| JP5386508B2 (ja) | 2008-01-22 | 2014-01-15 | ヴァーナリス アールアンドディー リミテッド | インドリル−ピリドン誘導体類 |
| WO2009143051A1 (en) | 2008-05-19 | 2009-11-26 | Osi Pharmaceuticals, Inc. | Substituted imidazopyr-and imidazotri-azines |
| UA104447C2 (uk) | 2008-12-19 | 2014-02-10 | Сіртріз Фармасьютікалз, Інк. | Тіазолопіридинові сполуки, що модулюють сиртуїн |
| DE102010001064A1 (de) * | 2009-03-18 | 2010-09-23 | Bayer Schering Pharma Aktiengesellschaft | Substituierte 2-Acetamido-5-Aryl-1,2,4-triazolone und deren Verwendung |
| KR20120020099A (ko) | 2009-04-20 | 2012-03-07 | 오에스아이 파마슈티컬스, 엘엘씨 | Ｃ-피라진-메틸아민의 제조 |
| JP2012528174A (ja) * | 2009-05-27 | 2012-11-12 | アボット・ラボラトリーズ | キナーゼ活性のピリミジン阻害剤 |
| US20120220594A1 (en) | 2009-10-30 | 2012-08-30 | Bristol-Meyers Squibb Company | Methods for treating cancer in patients having igf-1r inhibitor resistance |
| WO2012047538A1 (en) * | 2010-10-06 | 2012-04-12 | Glaxosmithkline Llc | Benzimidazole derivatives as pi3 kinase inhibitors |
| JP5789888B2 (ja) * | 2010-11-01 | 2015-10-07 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | ロイコトリエン生成のベンゾイミダゾールインヒビター |
| EP2766497A1 (en) | 2011-10-13 | 2014-08-20 | Bristol-Myers Squibb Company | Methods for selecting and treating cancer in patients with igf-1r/ir inhibitors |
| EP3010918B1 (en) | 2013-06-21 | 2018-08-15 | Zenith Epigenetics Ltd. | Novel substituted bicyclic compounds as bromodomain inhibitors |
| PT3010503T (pt) | 2013-06-21 | 2020-06-16 | Zenith Epigenetics Corp | Novos inibidores bicíclicos de bromodomínios |
| KR20160038008A (ko) | 2013-07-31 | 2016-04-06 | 제니쓰 에피제네틱스 코포레이션 | 브로모도메인 억제제로서 신규 퀴나졸리논 |
| CN103936719A (zh) * | 2014-05-14 | 2014-07-23 | 中国药科大学 | 苯并咪唑类衍生物制备方法及用途 |
| WO2016016894A1 (en) | 2014-07-30 | 2016-02-04 | Yeda Research And Development Co. Ltd. | Media for culturing pluripotent stem cells |
| CA2966298A1 (en) | 2014-12-01 | 2016-06-09 | Zenith Epigenetics Ltd. | Substituted pyridinones as bromodomain inhibitors |
| CA2966449A1 (en) | 2014-12-11 | 2016-06-16 | Zenith Epigenetics Ltd. | Substituted heterocycles as bromodomain inhibitors |
| EP3233846A4 (en) | 2014-12-17 | 2018-07-18 | Zenith Epigenetics Ltd. | Inhibitors of bromodomains |
| US10179777B2 (en) * | 2015-04-16 | 2019-01-15 | Merck Patent Gmbh | 3-(1H-benzimidazol-2-yl)-1H-pyridin-2-one derivatives |
| WO2020152686A1 (en) | 2019-01-23 | 2020-07-30 | Yeda Research And Development Co. Ltd. | Culture media for pluripotent stem cells |
| CN117069696B (zh) * | 2023-08-17 | 2024-04-26 | 中国药科大学 | 一种双靶点小分子抑制剂及其制备方法和应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6162804A (en) * | 1997-09-26 | 2000-12-19 | Merck & Co., Inc. | Tyrosine kinase inhibitors |
| CA2377085C (en) * | 1999-06-23 | 2011-02-15 | Aventis Pharma Deutschland Gmbh | Substituted benzimidazoles |
| US7081454B2 (en) * | 2001-03-28 | 2006-07-25 | Bristol-Myers Squibb Co. | Tyrosine kinase inhibitors |
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- 2002-03-26 EE EEP200300475A patent/EE200300475A/xx unknown
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- 2002-03-26 PL PL02373300A patent/PL373300A1/xx not_active Application Discontinuation
- 2002-03-26 JP JP2002577817A patent/JP2004534010A/ja not_active Withdrawn
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- 2002-03-26 GE GE5363A patent/GEP20053660B/en unknown
- 2002-03-26 CA CA002442428A patent/CA2442428A1/en not_active Abandoned
- 2002-03-26 YU YU84603A patent/YU84603A/sh unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| EP1381598A1 (en) | 2004-01-21 |
| YU84603A (sh) | 2006-03-03 |
| HUP0400323A2 (hu) | 2005-11-28 |
| KR20030083016A (ko) | 2003-10-23 |
| JP2004534010A (ja) | 2004-11-11 |
| ZA200307466B (en) | 2005-01-13 |
| SK12002003A3 (en) | 2004-10-05 |
| IL158041A0 (en) | 2004-03-28 |
| BR0208373A (pt) | 2005-02-22 |
| MXPA03008690A (es) | 2003-12-12 |
| CA2442428A1 (en) | 2002-10-10 |
| UY27234A1 (es) | 2002-10-31 |
| WO2002079192A1 (en) | 2002-10-10 |
| EE200300475A (et) | 2004-02-16 |
| CZ20032615A3 (en) | 2004-03-17 |
| NO20034308L (no) | 2003-11-26 |
| IS6968A (is) | 2003-09-26 |
| RU2003131693A (ru) | 2005-05-10 |
| NO20034308D0 (no) | 2003-09-26 |
| CN1514833A (zh) | 2004-07-21 |
| PL373300A1 (en) | 2005-08-22 |
| EP1381598A4 (en) | 2008-03-19 |
| PE20021015A1 (es) | 2002-11-10 |
| HRP20030844A2 (en) | 2005-08-31 |
| GEP20053660B (en) | 2005-11-10 |
| AR035804A1 (es) | 2004-07-14 |
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