JP4155598B2 - 抗癌剤としての縮合ｎ−アシルインドール - Google Patents
抗癌剤としての縮合ｎ−アシルインドール Download PDFInfo
- Publication number
- JP4155598B2 JP4155598B2 JP53749297A JP53749297A JP4155598B2 JP 4155598 B2 JP4155598 B2 JP 4155598B2 JP 53749297 A JP53749297 A JP 53749297A JP 53749297 A JP53749297 A JP 53749297A JP 4155598 B2 JP4155598 B2 JP 4155598B2
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- Japan
- Prior art keywords
- indole
- dihydro
- chloromethyl
- mmol
- benz
- 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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- 239000002246 antineoplastic agent Substances 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 78
- 102000004190 Enzymes Human genes 0.000 claims abstract description 41
- 108090000790 Enzymes Proteins 0.000 claims abstract description 41
- 108020001162 nitroreductase Proteins 0.000 claims abstract description 23
- 102000004459 Nitroreductase Human genes 0.000 claims abstract description 22
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims abstract description 21
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 11
- 125000003277 amino group Chemical group 0.000 claims abstract description 7
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 6
- 125000000168 pyrrolyl group Chemical group 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims abstract description 5
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 4
- 229910052717 sulfur 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
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 92
- 206010028980 Neoplasm Diseases 0.000 claims description 27
- 239000013598 vector Substances 0.000 claims description 27
- 238000000034 method Methods 0.000 claims description 23
- 238000011282 treatment Methods 0.000 claims description 20
- 210000004881 tumor cell Anatomy 0.000 claims description 11
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 241001465754 Metazoa Species 0.000 claims description 5
- 230000001613 neoplastic effect Effects 0.000 claims description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 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
- 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 2
- 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 2
- 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 2
- 125000004429 atom Chemical group 0.000 claims description 2
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 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
- 229910052698 phosphorus Inorganic materials 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 2
- 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 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
- 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 1
- 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 1
- 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 1
- 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 1
- 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 1
- 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 1
- NDBBGWXPAWNJPZ-UHFFFAOYSA-N [1-(chloromethyl)-5-nitro-1,2-dihydrobenzo[e]indol-3-yl]-[7-[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=CC2=CC(OC)=CC(OCCN(C)C)=C2N1 NDBBGWXPAWNJPZ-UHFFFAOYSA-N 0.000 claims 1
- ICDLORFTMVAAEZ-UHFFFAOYSA-N [5-amino-1-(chloromethyl)-1,2-dihydrobenzo[e]indol-3-yl]-[6-[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=CC(C=C(C(=C2)OCCN(C)C)OC)=C2N1 ICDLORFTMVAAEZ-UHFFFAOYSA-N 0.000 claims 1
- 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 1
- 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 1
- 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 1
- 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 1
- 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 1
- 150000001412 amines Chemical class 0.000 abstract description 10
- 108010006303 Carboxypeptidases Proteins 0.000 abstract description 6
- 102000005367 Carboxypeptidases Human genes 0.000 abstract description 6
- 239000000758 substrate Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 144
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 122
- 239000000243 solution Substances 0.000 description 114
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 96
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 90
- 235000019439 ethyl acetate Nutrition 0.000 description 72
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 68
- -1 azo compound Chemical class 0.000 description 64
- 239000007787 solid Substances 0.000 description 63
- 239000003208 petroleum Substances 0.000 description 59
- 239000000047 product Substances 0.000 description 59
- 230000002829 reductive effect Effects 0.000 description 44
- 238000002360 preparation method Methods 0.000 description 40
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 39
- 239000011734 sodium Substances 0.000 description 37
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 33
- 239000000284 extract Substances 0.000 description 33
- 238000010992 reflux Methods 0.000 description 31
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 29
- 239000000651 prodrug Substances 0.000 description 29
- 229940002612 prodrug Drugs 0.000 description 29
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 26
- 239000000741 silica gel Substances 0.000 description 25
- 229910002027 silica gel Inorganic materials 0.000 description 25
- 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
- 210000004027 cell Anatomy 0.000 description 22
- 239000002253 acid Substances 0.000 description 21
- AYYOZKHMSABVRP-UHFFFAOYSA-N methyl 1h-indole-6-carboxylate Chemical compound COC(=O)C1=CC=C2C=CNC2=C1 AYYOZKHMSABVRP-UHFFFAOYSA-N 0.000 description 21
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 20
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 20
- 239000012043 crude product Substances 0.000 description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 238000001953 recrystallisation Methods 0.000 description 18
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 16
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- 229910019020 PtO2 Inorganic materials 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 239000002244 precipitate Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 13
- 239000003054 catalyst Substances 0.000 description 13
- 238000004587 chromatography analysis Methods 0.000 description 13
- 238000000354 decomposition reaction Methods 0.000 description 13
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000003814 drug Substances 0.000 description 12
- 150000002148 esters Chemical class 0.000 description 12
- 238000010914 gene-directed enzyme pro-drug therapy Methods 0.000 description 12
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 12
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 11
- 239000000306 component Substances 0.000 description 11
- 229940079593 drug Drugs 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- 238000002560 therapeutic procedure Methods 0.000 description 11
- 239000008096 xylene Substances 0.000 description 11
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 238000010828 elution Methods 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 9
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 9
- 239000002502 liposome Substances 0.000 description 9
- ALGIYXGLGIECNT-UHFFFAOYSA-N 3h-benzo[e]indole Chemical compound C1=CC=C2C(C=CN3)=C3C=CC2=C1 ALGIYXGLGIECNT-UHFFFAOYSA-N 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 8
- 238000010790 dilution Methods 0.000 description 8
- 239000012895 dilution Substances 0.000 description 8
- 238000001556 precipitation Methods 0.000 description 8
- 229920006395 saturated elastomer Polymers 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 230000003612 virological effect Effects 0.000 description 8
- JZMUJQGIASARGH-UHFFFAOYSA-N 5,6,7-trimethoxy-1h-indole-2-carboxylic acid Chemical compound COC1=C(OC)C(OC)=CC2=C1NC(C(O)=O)=C2 JZMUJQGIASARGH-UHFFFAOYSA-N 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 7
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 7
- 239000012452 mother liquor Substances 0.000 description 7
- 239000012299 nitrogen atmosphere Substances 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
- 108090000623 proteins and genes Proteins 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 6
- 0 Cc1cc2c(C(C*)CN3C(C(*4)=*C5C4CC(*)CCC5)=O)c3cc(*)c2[n]1 Chemical compound Cc1cc2c(C(C*)CN3C(C(*4)=*C5C4CC(*)CCC5)=O)c3cc(*)c2[n]1 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 6
- 150000003857 carboxamides Chemical class 0.000 description 6
- 239000007924 injection Substances 0.000 description 6
- 238000002347 injection Methods 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- SJJCQDRGABAVBB-UHFFFAOYSA-N 1-hydroxy-2-naphthoic acid Chemical compound C1=CC=CC2=C(O)C(C(=O)O)=CC=C21 SJJCQDRGABAVBB-UHFFFAOYSA-N 0.000 description 5
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 5
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 5
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Images
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)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9619082.2A GB9619082D0 (en) | 1996-09-12 | 1996-09-12 | Further cyclopropylindoles and their seco precursors,and their use as prodrugs |
| GB9619082.2 | 1996-09-12 | ||
| GBGB9707394.4A GB9707394D0 (en) | 1997-04-10 | 1997-04-10 | Further cyclopropylindoles and their seco precursors, and their use as prodrugs |
| GB9707394.4 | 1997-04-10 | ||
| PCT/NZ1997/000117 WO1998011101A2 (en) | 1996-09-12 | 1997-09-12 | Condensed n-aclyindoles as antitumor agents |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2000517292A JP2000517292A (ja) | 2000-12-26 |
| JP2000517292A5 JP2000517292A5 (https=) | 2005-01-13 |
| JP4155598B2 true JP4155598B2 (ja) | 2008-09-24 |
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| JP53749297A Expired - Fee Related JP4155598B2 (ja) | 1996-09-12 | 1997-09-12 | 抗癌剤としての縮合ｎ−アシルインドール |
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|---|---|
| EP (1) | EP0938474B1 (https=) |
| JP (1) | JP4155598B2 (https=) |
| AT (1) | ATE310725T1 (https=) |
| AU (1) | AU721037B2 (https=) |
| CA (1) | CA2265874C (https=) |
| DE (1) | DE69734722T2 (https=) |
| ES (1) | ES2253786T3 (https=) |
| NZ (1) | NZ334344A (https=) |
| WO (1) | WO1998011101A2 (https=) |
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| GB9818730D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collections of compounds |
| DE69930328T2 (de) | 1998-08-27 | 2006-12-14 | Spirogen Ltd., Ryde | Dimere Pyrrolobenzodiazepine |
| 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 |
| CZ20023544A3 (cs) * | 2000-04-28 | 2004-07-14 | Baxter Healthcare Sa | Deriváty 2-acylindolu a jejich použití jako protinádorové činidlo |
| DE50104114D1 (de) * | 2000-05-02 | 2004-11-18 | 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 |
| JP4862120B2 (ja) * | 2001-02-22 | 2012-01-25 | ユニヴァーシティ オブ ブラッドフォード | 腫瘍治療のためのプロドラッグとしてのベンズ−インドールおよびベンゾ−キノリン誘導体 |
| WO2003097635A1 (en) * | 2002-05-17 | 2003-11-27 | 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 |
| WO2004099155A2 (en) * | 2003-05-02 | 2004-11-18 | Elan Pharmaceuticals, Inc. | 4-bromo-5-(2-chloro-benzoylamino)-1h-pyrazole-3-carboxylic acid (phenyl) amide derivates and related compounds as bradykinin b1 receptor antagonists for the treatment of inflamatory diseases |
| ATE410161T1 (de) | 2003-05-02 | 2008-10-15 | Elan Pharm Inc | 4-bromo-5-(2-chloro-benzoylamino)-1h-pyrazol-3- carbonsäureamid-derivate und verwandte verbindungen als bradykinin b1 rezeptor antagonisten zur behandlung von entzündlichen erkrankungen |
| 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 |
| CA2627190A1 (en) * | 2005-11-10 | 2007-05-24 | Medarex, Inc. | Duocarmycin derivatives as novel cytotoxic compounds and conjugates |
| EP1994000B1 (en) * | 2006-02-02 | 2017-08-23 | 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 | 梅達雷克斯有限責任公司 | 化學鏈接劑與可裂解基質以及其之綴合物 |
| CA2678514A1 (en) | 2007-02-21 | 2008-08-28 | 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 |
| AU2009320481C1 (en) | 2008-11-03 | 2016-12-08 | Syntarga B.V. | Novel CC-1065 analogs and their conjugates |
| DE102009051438A1 (de) | 2009-10-30 | 2011-05-05 | Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts | Fluoreszenzfarbstoffe |
| AU2011243294C1 (en) | 2010-04-21 | 2015-12-03 | Syntarga B.V. | Novel conjugates of CC-1065 analogs and bifunctional linkers |
| AU2015205574B2 (en) | 2014-01-10 | 2019-08-15 | Byondis B.V. | Method for purifying Cys-linked antibody-drug conjugates |
| HUE029672T2 (en) | 2014-01-10 | 2017-03-28 | Synthon Biopharmaceuticals Bv | Duokarmicin-ADCs for use in the treatment of endometrial cancer |
| CN105899236B (zh) | 2014-01-10 | 2019-07-26 | 斯索恩生物制药有限公司 | 表现出改进的体内抗肿瘤活性的倍癌霉素adc |
| 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 |
|---|---|---|---|---|
| EP0340243B1 (en) * | 1986-12-19 | 1994-09-28 | The Upjohn Company | Cc-1065 analogs |
| 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 |
| AU648313B2 (en) * | 1990-04-25 | 1994-04-21 | Pharmacia & Upjohn Company | Novel CC-1065 analogs |
| 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 |
| ES2244991T3 (es) * | 1996-03-08 | 2005-12-16 | The Scripps Research Institute | Analogosmcbi de cc-1065 y las duocarmicinas. |
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1997
- 1997-09-12 NZ NZ334344A patent/NZ334344A/xx unknown
- 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 AT AT97942316T patent/ATE310725T1/de not_active IP Right Cessation
- 1997-09-12 AU AU44039/97A patent/AU721037B2/en not_active Ceased
- 1997-09-12 CA CA002265874A patent/CA2265874C/en not_active Expired - Fee Related
- 1997-09-12 WO PCT/NZ1997/000117 patent/WO1998011101A2/en not_active Ceased
- 1997-09-12 JP JP53749297A patent/JP4155598B2/ja not_active Expired - Fee Related
- 1997-09-12 ES ES97942316T patent/ES2253786T3/es not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| DE69734722T2 (de) | 2006-07-20 |
| AU721037B2 (en) | 2000-06-22 |
| AU4403997A (en) | 1998-04-02 |
| NZ334344A (en) | 2000-08-25 |
| ES2253786T3 (es) | 2006-06-01 |
| CA2265874A1 (en) | 1998-03-19 |
| ATE310725T1 (de) | 2005-12-15 |
| EP0938474B1 (en) | 2005-11-23 |
| CA2265874C (en) | 2007-08-28 |
| JP2000517292A (ja) | 2000-12-26 |
| WO1998011101A3 (en) | 1998-04-23 |
| WO1998011101A2 (en) | 1998-03-19 |
| DE69734722D1 (de) | 2005-12-29 |
| EP0938474A2 (en) | 1999-09-01 |
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