DE69734722T2 - Kondensierte n-acylindole als antitumormittel - Google Patents
Kondensierte n-acylindole als antitumormittel Download PDFInfo
- Publication number
- DE69734722T2 DE69734722T2 DE69734722T DE69734722T DE69734722T2 DE 69734722 T2 DE69734722 T2 DE 69734722T2 DE 69734722 T DE69734722 T DE 69734722T DE 69734722 T DE69734722 T DE 69734722T DE 69734722 T2 DE69734722 T2 DE 69734722T2
- Authority
- DE
- Germany
- Prior art keywords
- dihydro
- indole
- chloromethyl
- mmol
- carbonyl
- 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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- 150000001875 compounds Chemical class 0.000 claims abstract description 72
- 102000004459 Nitroreductase Human genes 0.000 claims abstract description 24
- 108020001162 nitroreductase Proteins 0.000 claims abstract description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 21
- 125000003277 amino group Chemical group 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims abstract description 6
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims abstract description 3
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims abstract description 3
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 90
- 239000013598 vector Substances 0.000 claims description 28
- 206010028980 Neoplasm Diseases 0.000 claims description 25
- 238000011282 treatment Methods 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 14
- 210000004881 tumor cell Anatomy 0.000 claims description 9
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 7
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- DQUZJKNVYSYKDE-UHFFFAOYSA-N methyl 8-(chloromethyl)-4-nitro-6-(5,6,7-trimethoxy-1h-indole-2-carbonyl)-7,8-dihydro-3h-pyrrolo[3,2-e]indole-2-carboxylate Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3CC(CCl)C4=C5C=C(NC5=C([N+]([O-])=O)C=C43)C(=O)OC)=CC2=C1 DQUZJKNVYSYKDE-UHFFFAOYSA-N 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- AQRVKOAIXZBVCJ-UHFFFAOYSA-N methyl 4-amino-8-(chloromethyl)-6-(5,6,7-trimethoxy-1h-indole-2-carbonyl)-7,8-dihydro-3h-pyrrolo[3,2-e]indole-2-carboxylate Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3CC(CCl)C4=C5C=C(NC5=C(N)C=C43)C(=O)OC)=CC2=C1 AQRVKOAIXZBVCJ-UHFFFAOYSA-N 0.000 claims description 6
- BMQWJFCUALXVCK-CQSZACIVSA-N [(1s)-5-amino-1-(chloromethyl)-1,2-dihydrobenzo[e]indol-3-yl]-(5,6,7-trimethoxy-1h-indol-2-yl)methanone Chemical compound C1=C(N)C2=CC=CC=C2C([C@H](CCl)C2)=C1N2C(=O)C1=CC(C=C(C(=C2OC)OC)OC)=C2N1 BMQWJFCUALXVCK-CQSZACIVSA-N 0.000 claims description 5
- HOCHKKKVZRRJNV-UHFFFAOYSA-N [1-(chloromethyl)-5-nitro-1,2-dihydrobenzo[e]indol-3-yl]-[6-[2-(dimethylamino)ethoxy]-5-methoxy-1h-indol-2-yl]methanone Chemical compound C1=C([N+]([O-])=O)C2=CC=CC=C2C(C(CCl)C2)=C1N2C(=O)C1=CC(C=C(C(=C2)OCCN(C)C)OC)=C2N1 HOCHKKKVZRRJNV-UHFFFAOYSA-N 0.000 claims description 5
- BMQWJFCUALXVCK-UHFFFAOYSA-N [5-amino-1-(chloromethyl)-1,2-dihydrobenzo[e]indol-3-yl]-(5,6,7-trimethoxy-1h-indol-2-yl)methanone Chemical compound C1=C(N)C2=CC=CC=C2C(C(CCl)C2)=C1N2C(=O)C1=CC(C=C(C(=C2OC)OC)OC)=C2N1 BMQWJFCUALXVCK-UHFFFAOYSA-N 0.000 claims description 5
- 230000001613 neoplastic effect Effects 0.000 claims description 5
- QBXGPDHONUGPPB-UHFFFAOYSA-N (4-nitrophenyl)methyl n-[1-(chloromethyl)-3-(5,6,7-trimethoxy-1h-indole-2-carbonyl)-1,2-dihydrobenzo[e]indol-5-yl]carbamate Chemical compound N1C=2C(OC)=C(OC)C(OC)=CC=2C=C1C(=O)N1CC(CCl)C(C2=CC=CC=C22)=C1C=C2NC(=O)OCC1=CC=C([N+]([O-])=O)C=C1 QBXGPDHONUGPPB-UHFFFAOYSA-N 0.000 claims description 4
- BMQWJFCUALXVCK-AWEZNQCLSA-N [(1r)-5-amino-1-(chloromethyl)-1,2-dihydrobenzo[e]indol-3-yl]-(5,6,7-trimethoxy-1h-indol-2-yl)methanone Chemical compound C1=C(N)C2=CC=CC=C2C([C@@H](CCl)C2)=C1N2C(=O)C1=CC(C=C(C(=C2OC)OC)OC)=C2N1 BMQWJFCUALXVCK-AWEZNQCLSA-N 0.000 claims description 4
- DRTNXALIYSNZIV-UHFFFAOYSA-N [1-(chloromethyl)-5-(methylamino)-1,2-dihydrobenzo[e]indol-3-yl]-(5,6,7-trimethoxy-1h-indol-2-yl)methanone Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C=4C=C(C5=CC=CC=C5C=4C(CCl)C3)NC)=CC2=C1 DRTNXALIYSNZIV-UHFFFAOYSA-N 0.000 claims description 4
- GYUFCODDHMVUKY-UHFFFAOYSA-N methyl 8-(chloromethyl)-4-(methylamino)-6-(5,6,7-trimethoxy-1h-indole-2-carbonyl)-7,8-dihydro-3h-pyrrolo[3,2-e]indole-2-carboxylate Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C=4C=C(C=5NC(=CC=5C=4C(CCl)C3)C(=O)OC)NC)=CC2=C1 GYUFCODDHMVUKY-UHFFFAOYSA-N 0.000 claims description 4
- ANFHFIAKJGLDJV-UHFFFAOYSA-N methyl 8-(chloromethyl)-4-[(4-nitrophenyl)methoxycarbonylamino]-6-(5,6,7-trimethoxy-1h-indole-2-carbonyl)-7,8-dihydro-3h-pyrrolo[3,2-e]indole-2-carboxylate Chemical compound C=12NC(C(=O)OC)=CC2=C2C(CCl)CN(C(=O)C=3NC4=C(OC)C(OC)=C(OC)C=C4C=3)C2=CC=1NC(=O)OCC1=CC=C([N+]([O-])=O)C=C1 ANFHFIAKJGLDJV-UHFFFAOYSA-N 0.000 claims description 4
- VRBJCJNVLXEKKP-MDZDMXLPSA-N (e)-1-[5-amino-1-(chloromethyl)-1,2-dihydrobenzo[e]indol-3-yl]-3-(3-methoxyphenyl)prop-2-en-1-one Chemical compound COC1=CC=CC(\C=C\C(=O)N2C3=C(C4=CC=CC=C4C(N)=C3)C(CCl)C2)=C1 VRBJCJNVLXEKKP-MDZDMXLPSA-N 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 3
- HVXXVNCXGUXSCQ-CQSZACIVSA-N [(1s)-1-(chloromethyl)-5-nitro-1,2-dihydrobenzo[e]indol-3-yl]-(5,6,7-trimethoxy-1h-indol-2-yl)methanone Chemical compound C1=C([N+]([O-])=O)C2=CC=CC=C2C([C@H](CCl)C2)=C1N2C(=O)C1=CC(C=C(C(=C2OC)OC)OC)=C2N1 HVXXVNCXGUXSCQ-CQSZACIVSA-N 0.000 claims description 3
- HVXXVNCXGUXSCQ-UHFFFAOYSA-N [1-(chloromethyl)-5-nitro-1,2-dihydrobenzo[e]indol-3-yl]-(5,6,7-trimethoxy-1h-indol-2-yl)methanone Chemical compound C1=C([N+]([O-])=O)C2=CC=CC=C2C(C(CCl)C2)=C1N2C(=O)C1=CC(C=C(C(=C2OC)OC)OC)=C2N1 HVXXVNCXGUXSCQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 3
- MAMMFIUMKJUAKQ-UHFFFAOYSA-N methyl 8-(chloromethyl)-4-(dimethylamino)-6-(5,6,7-trimethoxy-1h-indole-2-carbonyl)-7,8-dihydro-3h-pyrrolo[3,2-e]indole-2-carboxylate Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3CC(CCl)C4=C5C=C(NC5=C(N(C)C)C=C43)C(=O)OC)=CC2=C1 MAMMFIUMKJUAKQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- FTGIKSLMJFBQNF-MDZDMXLPSA-N (e)-1-[1-(chloromethyl)-5-nitro-1,2-dihydrobenzo[e]indol-3-yl]-3-(3-methoxyphenyl)prop-2-en-1-one Chemical compound COC1=CC=CC(\C=C\C(=O)N2C3=C(C4=CC=CC=C4C([N+]([O-])=O)=C3)C(CCl)C2)=C1 FTGIKSLMJFBQNF-MDZDMXLPSA-N 0.000 claims description 2
- UHCMXAGBHQCPHV-UHFFFAOYSA-N [5-amino-1-(chloromethyl)-1,2-dihydrobenzo[e]indol-3-yl]-[7-[2-(dimethylamino)ethoxy]-5-methoxy-1h-indol-2-yl]methanone Chemical compound C1=C(N)C2=CC=CC=C2C(C(CCl)C2)=C1N2C(=O)C1=CC2=CC(OC)=CC(OCCN(C)C)=C2N1 UHCMXAGBHQCPHV-UHFFFAOYSA-N 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- FMQZMGJTQXCTFI-MDZDMXLPSA-N n-[5-[(e)-3-[5-amino-1-(chloromethyl)-2,3-dihydrobenzo[e]indol-1-yl]-3-oxoprop-1-enyl]-1-methylpyrrol-3-yl]butanamide Chemical compound CN1C=C(NC(=O)CCC)C=C1\C=C\C(=O)C1(CCl)C2=C3C=CC=CC3=C(N)C=C2NC1 FMQZMGJTQXCTFI-MDZDMXLPSA-N 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- HVXXVNCXGUXSCQ-AWEZNQCLSA-N [(1r)-1-(chloromethyl)-5-nitro-1,2-dihydrobenzo[e]indol-3-yl]-(5,6,7-trimethoxy-1h-indol-2-yl)methanone Chemical compound C1=C([N+]([O-])=O)C2=CC=CC=C2C([C@@H](CCl)C2)=C1N2C(=O)C1=CC(C=C(C(=C2OC)OC)OC)=C2N1 HVXXVNCXGUXSCQ-AWEZNQCLSA-N 0.000 claims 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 2
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 1
- 102000004190 Enzymes Human genes 0.000 abstract description 41
- 108090000790 Enzymes Proteins 0.000 abstract description 41
- 150000001412 amines Chemical class 0.000 abstract description 9
- 108010006303 Carboxypeptidases Proteins 0.000 abstract description 7
- 102000005367 Carboxypeptidases Human genes 0.000 abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 abstract description 2
- 239000000758 substrate Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 156
- 239000000243 solution Substances 0.000 description 125
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 122
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 90
- 238000005481 NMR spectroscopy Methods 0.000 description 86
- 235000019439 ethyl acetate Nutrition 0.000 description 78
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 65
- 239000007787 solid Substances 0.000 description 60
- 239000003208 petroleum Substances 0.000 description 49
- 230000002829 reductive effect Effects 0.000 description 43
- 239000011734 sodium Substances 0.000 description 38
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 36
- -1 4-methoxybenzyl ester Chemical class 0.000 description 31
- 239000000651 prodrug Substances 0.000 description 30
- 229940002612 prodrug Drugs 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 28
- 238000002360 preparation method Methods 0.000 description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
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- 239000000741 silica gel Substances 0.000 description 26
- 229910002027 silica gel Inorganic materials 0.000 description 26
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 239000002253 acid Substances 0.000 description 19
- 238000010992 reflux Methods 0.000 description 19
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 18
- 238000006243 chemical reaction Methods 0.000 description 17
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 17
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- 238000004587 chromatography analysis Methods 0.000 description 16
- 239000000047 product Substances 0.000 description 16
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 14
- 239000002244 precipitate Substances 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
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- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 10
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- 239000000306 component Substances 0.000 description 9
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- 150000002148 esters Chemical class 0.000 description 8
- 239000012634 fragment Substances 0.000 description 8
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- 230000003612 virological effect Effects 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 7
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- 150000002012 dioxanes Chemical class 0.000 description 7
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- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 7
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- 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 description 6
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- YEECXRDYBLFPQF-UHFFFAOYSA-N dimethyl 5-nitro-2,3-dihydrobenzo[e]indole-1,1-dicarboxylate Chemical compound C1=CC=CC2=C3C(C(=O)OC)(C(=O)OC)CNC3=CC([N+]([O-])=O)=C21 YEECXRDYBLFPQF-UHFFFAOYSA-N 0.000 description 5
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 5
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 5
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- FNENWZWNOPCZGK-UHFFFAOYSA-N ethyl 2-methyl-3-oxobutanoate Chemical compound CCOC(=O)C(C)C(C)=O FNENWZWNOPCZGK-UHFFFAOYSA-N 0.000 description 1
- QSQXPRJUZJUTIP-UHFFFAOYSA-N ethyl 5-[2-(dimethylamino)ethoxy]-1h-indole-2-carboxylate Chemical compound CN(C)CCOC1=CC=C2NC(C(=O)OCC)=CC2=C1 QSQXPRJUZJUTIP-UHFFFAOYSA-N 0.000 description 1
- SYJFOPHTAQJBMP-UHFFFAOYSA-N ethyl 7-[2-(dimethylamino)ethoxy]-5-methoxy-1h-indole-2-carboxylate Chemical compound COC1=CC(OCCN(C)C)=C2NC(C(=O)OCC)=CC2=C1 SYJFOPHTAQJBMP-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000006846 excision repair Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 239000008241 heterogeneous mixture Substances 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 150000002443 hydroxylamines Chemical class 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 229940127121 immunoconjugate Drugs 0.000 description 1
- 230000000415 inactivating effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 201000009019 intestinal benign neoplasm Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 230000002601 intratumoral effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- YPJRHEKCFKOVRT-UHFFFAOYSA-N lerociclib Chemical compound C1CN(C(C)C)CCN1C(C=N1)=CC=C1NC1=NC=C(C=C2N3C4(CCCCC4)CNC2=O)C3=N1 YPJRHEKCFKOVRT-UHFFFAOYSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 210000005265 lung cell Anatomy 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 150000002730 mercury Chemical class 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- QRMNENFZDDYDEF-GOSISDBHSA-N methyl (8s)-8-(bromomethyl)-2-methyl-4-(4-methylpiperazine-1-carbonyl)oxy-6-(5,6,7-trimethoxy-1h-indole-2-carbonyl)-7,8-dihydro-3h-pyrrolo[3,2-e]indole-1-carboxylate Chemical compound C1([C@H](CBr)CN(C1=C1)C(=O)C=2NC3=C(OC)C(OC)=C(OC)C=C3C=2)=C2C(C(=O)OC)=C(C)NC2=C1OC(=O)N1CCN(C)CC1 QRMNENFZDDYDEF-GOSISDBHSA-N 0.000 description 1
- OKFSZCXMVHNSGZ-ONEGZZNKSA-N methyl (e)-3-(1-methyl-4-nitropyrrol-2-yl)prop-2-enoate Chemical compound COC(=O)\C=C\C1=CC([N+]([O-])=O)=CN1C OKFSZCXMVHNSGZ-ONEGZZNKSA-N 0.000 description 1
- AYYOZKHMSABVRP-UHFFFAOYSA-N methyl 1h-indole-6-carboxylate Chemical compound COC(=O)C1=CC=C2C=CNC2=C1 AYYOZKHMSABVRP-UHFFFAOYSA-N 0.000 description 1
- NTNUDYROPUKXNA-UHFFFAOYSA-N methyl 2-(triphenyl-$l^{5}-phosphanylidene)acetate Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=CC(=O)OC)C1=CC=CC=C1 NTNUDYROPUKXNA-UHFFFAOYSA-N 0.000 description 1
- AAOJISXSRYZSMD-UHFFFAOYSA-N methyl 5-nitro-2,3-dihydro-1h-benzo[e]indole-1-carboxylate Chemical compound C1=CC=CC2=C3C(C(=O)OC)CNC3=CC([N+]([O-])=O)=C21 AAOJISXSRYZSMD-UHFFFAOYSA-N 0.000 description 1
- SPWSLPYCDDUJPE-UHFFFAOYSA-N methyl 6-(2-chloroethoxy)-5-methoxy-1h-indole-2-carboxylate Chemical compound COC1=C(OCCCl)C=C2NC(C(=O)OC)=CC2=C1 SPWSLPYCDDUJPE-UHFFFAOYSA-N 0.000 description 1
- WBYWAXJHAXSJNI-UHFFFAOYSA-N methyl p-hydroxycinnamate Natural products OC(=O)C=CC1=CC=CC=C1 WBYWAXJHAXSJNI-UHFFFAOYSA-N 0.000 description 1
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 1
- 229960000907 methylthioninium chloride Drugs 0.000 description 1
- 238000000520 microinjection Methods 0.000 description 1
- 239000011859 microparticle Substances 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- HHQJWDKIRXRTLS-UHFFFAOYSA-N n'-bromobutanediamide Chemical compound NC(=O)CCC(=O)NBr HHQJWDKIRXRTLS-UHFFFAOYSA-N 0.000 description 1
- 210000005170 neoplastic cell Anatomy 0.000 description 1
- 229960003966 nicotinamide Drugs 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- VLZLOWPYUQHHCG-UHFFFAOYSA-N nitromethylbenzene Chemical compound [O-][N+](=O)CC1=CC=CC=C1 VLZLOWPYUQHHCG-UHFFFAOYSA-N 0.000 description 1
- 150000002832 nitroso derivatives Chemical class 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- YLZWEPNHBVOIBC-UHFFFAOYSA-N pyrrolo[3,2-e]indole Chemical compound C1=CC2=NC=CC2=C2C=CN=C21 YLZWEPNHBVOIBC-UHFFFAOYSA-N 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000006268 reductive amination reaction Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000001177 retroviral effect Effects 0.000 description 1
- 150000008223 ribosides Chemical class 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 210000004927 skin cell Anatomy 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003463 sulfur Chemical class 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- OVXVUFRXNREXIA-UHFFFAOYSA-N tert-butyl 1-(methylsulfonyloxymethyl)-5-nitro-1,2-dihydrobenzo[e]indole-3-carboxylate Chemical compound C1=C([N+]([O-])=O)C2=CC=CC=C2C2=C1N(C(=O)OC(C)(C)C)CC2COS(C)(=O)=O OVXVUFRXNREXIA-UHFFFAOYSA-N 0.000 description 1
- KOMXZJRMAIFUFL-UHFFFAOYSA-N tert-butyl 5-amino-1-(chloromethyl)-1,2-dihydrobenzo[e]indole-3-carboxylate Chemical compound C1=C(N)C2=CC=CC=C2C2=C1N(C(=O)OC(C)(C)C)CC2CCl KOMXZJRMAIFUFL-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/58—[b]- or [c]-condensed
- C07D209/60—Naphtho [b] pyrroles; Hydrogenated naphtho [b] pyrroles
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9619082 | 1996-09-12 | ||
| GBGB9619082.2A GB9619082D0 (en) | 1996-09-12 | 1996-09-12 | Further cyclopropylindoles and their seco precursors,and their use as prodrugs |
| GB9707394 | 1997-04-10 | ||
| GBGB9707394.4A GB9707394D0 (en) | 1997-04-10 | 1997-04-10 | Further cyclopropylindoles and their seco precursors, and their use as prodrugs |
| PCT/NZ1997/000117 WO1998011101A2 (en) | 1996-09-12 | 1997-09-12 | Condensed n-aclyindoles as antitumor agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69734722D1 DE69734722D1 (de) | 2005-12-29 |
| DE69734722T2 true DE69734722T2 (de) | 2006-07-20 |
Family
ID=26310030
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69734722T Expired - Fee Related DE69734722T2 (de) | 1996-09-12 | 1997-09-12 | Kondensierte n-acylindole als antitumormittel |
Country Status (9)
| Country | Link |
|---|---|
| EP (1) | EP0938474B1 (OSRAM) |
| JP (1) | JP4155598B2 (OSRAM) |
| AT (1) | ATE310725T1 (OSRAM) |
| AU (1) | AU721037B2 (OSRAM) |
| CA (1) | CA2265874C (OSRAM) |
| DE (1) | DE69734722T2 (OSRAM) |
| ES (1) | ES2253786T3 (OSRAM) |
| NZ (1) | NZ334344A (OSRAM) |
| WO (1) | WO1998011101A2 (OSRAM) |
Families Citing this family (26)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9818730D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collections of compounds |
| ES2260570T3 (es) | 1998-08-27 | 2006-11-01 | Spirogen Limited | Pirrolobenziodiazepinas dimericas. |
| GB9909612D0 (en) * | 1999-04-26 | 1999-06-23 | Cancer Res Campaign Tech | N-protected amines and their use as prodrugs |
| US6909006B1 (en) * | 1999-08-27 | 2005-06-21 | Spirogen Limited | Cyclopropylindole derivatives |
| BR0110414A (pt) * | 2000-04-28 | 2003-02-11 | Baxter Healthcare Sa | Derivados de 2-acil indol e seu uso como agentes antitumores |
| WO2001083448A2 (de) * | 2000-05-02 | 2001-11-08 | Tietze Lutz F | Neue prodrugs von 6-hydroxy-2,3-dihydro-1h-indolen, 5-hydroxy-1,2-dihydro-3h-pyrrolo[3,2-e]indolen und 5-hydroxy-1,2-dihydro-3h-benzo[e]indolen sowie von 6-hydroxy-1,2,3,4-tetrahydro-benzo[f]chinolin-derivaten für eine selektive krebstherapie |
| DE60211905T2 (de) * | 2001-02-22 | 2007-01-18 | School Of Pharmacy, University Of London | Benz-indol- und benzo-chinolin-derivate als prodrugs zur tumorbehandlung |
| US7235578B2 (en) * | 2002-05-17 | 2007-06-26 | Auckland Uniservices Limited | Processes for preparing 3-substituted 1-(chloromethyl)-1,2-dihydro-3H-[ring fused indol-5-yl-(amine-derived)] compounds and analogues thereof, and to products obtained therefrom |
| GB0226593D0 (en) | 2002-11-14 | 2002-12-24 | Consultants Ltd | Compounds |
| US20050032868A1 (en) * | 2003-05-02 | 2005-02-10 | Garofalo Albert W. | Selected substituted pyrazole derivatives and related compounds as bradykinin B1 receptor antagonists |
| TW200509910A (en) | 2003-05-02 | 2005-03-16 | Elan Pharm Inc | Substituted pyrazole derivatives and related compounds as bradykinin B1 receptor antagonists |
| GB0321295D0 (en) | 2003-09-11 | 2003-10-15 | Spirogen Ltd | Synthesis of protected pyrrolobenzodiazepines |
| NZ536107A (en) * | 2004-10-22 | 2007-06-29 | Auckland Uniservices Ltd | Nitrobenzindoles and their use in cancer therapy |
| WO2007059404A2 (en) * | 2005-11-10 | 2007-05-24 | Medarex, Inc. | Duocarmycin derivatives as novel cytotoxic compounds and conjugates |
| US8940784B2 (en) * | 2006-02-02 | 2015-01-27 | Syntarga B.V. | Water-soluble CC-1065 analogs and their conjugates |
| WO2008039087A2 (en) * | 2006-09-29 | 2008-04-03 | Auckland Uniservices Limited | Indoline derivatives and uses thereof |
| TWI412367B (zh) | 2006-12-28 | 2013-10-21 | Medarex Llc | 化學鏈接劑與可裂解基質以及其之綴合物 |
| TW200900059A (en) | 2007-02-21 | 2009-01-01 | Medarex Inc | Chemical linkers with single amino acids and conjugates thereof |
| US9901567B2 (en) | 2007-08-01 | 2018-02-27 | Syntarga B.V. | Substituted CC-1065 analogs and their conjugates |
| RU2562232C2 (ru) | 2008-11-03 | 2015-09-10 | Синтарга Б.В. | Новые аналоги сс-1065 и их конъюгаты |
| DE102009051438A1 (de) | 2009-10-30 | 2011-05-05 | Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts | Fluoreszenzfarbstoffe |
| HUE030846T2 (en) | 2010-04-21 | 2017-06-28 | Syntarga Bv | Conjugates of cc-1065 analogs and bifunctional linkers |
| PL3092010T3 (pl) | 2014-01-10 | 2019-01-31 | Synthon Biopharmaceuticals B.V. | Sposób oczyszczania połączonych cysteiną koniugatów przeciwciało-lek |
| JP6224268B2 (ja) | 2014-01-10 | 2017-11-01 | シントン・バイオファーマシューティカルズ・ビー．ブイ．Ｓｙｎｔｈｏｎ Ｂｉｏｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｂ．Ｖ． | 子宮内膜癌の治療において使用するためのデュオカルマイシンａｄｃ |
| HRP20160697T1 (hr) | 2014-01-10 | 2016-07-15 | Synthon Biopharmaceuticals B.V. | Duokarmicin adcs koji pokazuje poboljšanu antitumorsku aktivnost in vivo |
| CN108653288B (zh) * | 2018-05-29 | 2020-05-05 | 福建医科大学孟超肝胆医院(福州市传染病医院) | 一种乏氧响应聚合物纳米粒及其应用 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2598819B2 (ja) * | 1986-12-19 | 1997-04-09 | ジ・アップジョン・カンパニー | 新規なｃｃ‐１０６５同族体 |
| JP2642165B2 (ja) * | 1988-07-22 | 1997-08-20 | 協和醗酵工業株式会社 | 新規ｄｃ−８９化合物およびその製造法 |
| KR100208957B1 (ko) * | 1990-04-25 | 1999-07-15 | 로렌스 티. 마이젠헬더 | 신규한 cc-1065 유사체 |
| GB9516943D0 (en) * | 1995-08-18 | 1995-10-18 | Cancer Soc Auckland Div Nz Inc | Novel cyclopropylindoles and their secoprecursors,and their use as prodrugs |
| US6548530B1 (en) * | 1995-10-03 | 2003-04-15 | The Scripps Research Institute | CBI analogs of CC-1065 and the duocarmycins |
| EP0888301B1 (en) * | 1996-03-08 | 2005-08-10 | The Scripps Research Institute | Mcbi analogs of cc-1065 and the duocarmycins |
-
1997
- 1997-09-12 AT AT97942316T patent/ATE310725T1/de not_active IP Right Cessation
- 1997-09-12 WO PCT/NZ1997/000117 patent/WO1998011101A2/en not_active Ceased
- 1997-09-12 AU AU44039/97A patent/AU721037B2/en not_active Ceased
- 1997-09-12 ES ES97942316T patent/ES2253786T3/es not_active Expired - Lifetime
- 1997-09-12 NZ NZ334344A patent/NZ334344A/xx unknown
- 1997-09-12 CA CA002265874A patent/CA2265874C/en not_active Expired - Fee Related
- 1997-09-12 DE DE69734722T patent/DE69734722T2/de not_active Expired - Fee Related
- 1997-09-12 EP EP97942316A patent/EP0938474B1/en not_active Expired - Lifetime
- 1997-09-12 JP JP53749297A patent/JP4155598B2/ja not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP4155598B2 (ja) | 2008-09-24 |
| EP0938474A2 (en) | 1999-09-01 |
| WO1998011101A2 (en) | 1998-03-19 |
| AU721037B2 (en) | 2000-06-22 |
| AU4403997A (en) | 1998-04-02 |
| CA2265874A1 (en) | 1998-03-19 |
| CA2265874C (en) | 2007-08-28 |
| DE69734722D1 (de) | 2005-12-29 |
| WO1998011101A3 (en) | 1998-04-23 |
| EP0938474B1 (en) | 2005-11-23 |
| ES2253786T3 (es) | 2006-06-01 |
| JP2000517292A (ja) | 2000-12-26 |
| NZ334344A (en) | 2000-08-25 |
| ATE310725T1 (de) | 2005-12-15 |
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