CA2233936A1 - Cbi analogs of cc-1065 and the duocarmycins - Google Patents
Cbi analogs of cc-1065 and the duocarmycins Download PDFInfo
- Publication number
- CA2233936A1 CA2233936A1 CA002233936A CA2233936A CA2233936A1 CA 2233936 A1 CA2233936 A1 CA 2233936A1 CA 002233936 A CA002233936 A CA 002233936A CA 2233936 A CA2233936 A CA 2233936A CA 2233936 A1 CA2233936 A1 CA 2233936A1
- Authority
- CA
- Canada
- Prior art keywords
- group
- alkyl
- cbi
- following structure
- pyrrolidine ring
- 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.)
- Abandoned
Links
- 229960005501 duocarmycin Drugs 0.000 title abstract description 8
- 229930184221 duocarmycin Natural products 0.000 title abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- -1 N-substituted pyrrolidine ring Chemical group 0.000 claims description 102
- 229910052739 hydrogen Inorganic materials 0.000 claims description 64
- 239000001257 hydrogen Substances 0.000 claims description 40
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 36
- 229910052799 carbon Inorganic materials 0.000 claims description 28
- 150000002431 hydrogen Chemical group 0.000 claims description 28
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 239000000460 chlorine Substances 0.000 claims description 16
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 5
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 125000004672 ethylcarbonyl group Chemical group [H]C([H])([H])C([H])([H])C(*)=O 0.000 claims description 2
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 2
- HOEFWOBLOGZQIQ-UHFFFAOYSA-N morpholin-4-yl morpholine-4-carbodithioate Chemical group C1COCCN1C(=S)SN1CCOCC1 HOEFWOBLOGZQIQ-UHFFFAOYSA-N 0.000 claims description 2
- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 abstract description 124
- 108020004414 DNA Proteins 0.000 abstract description 48
- 230000001472 cytotoxic effect Effects 0.000 abstract description 46
- 238000005804 alkylation reaction Methods 0.000 abstract description 42
- 230000029936 alkylation Effects 0.000 abstract description 38
- 231100000433 cytotoxic Toxicity 0.000 abstract description 32
- 229960005532 CC-1065 Drugs 0.000 abstract description 28
- 230000003389 potentiating effect Effects 0.000 abstract description 27
- 230000004568 DNA-binding Effects 0.000 abstract description 21
- UOWVMDUEMSNCAV-WYENRQIDSA-N rachelmycin Chemical compound C1([C@]23C[C@@H]2CN1C(=O)C=1NC=2C(OC)=C(O)C4=C(C=2C=1)CCN4C(=O)C1=CC=2C=4CCN(C=4C(O)=C(C=2N1)OC)C(N)=O)=CC(=O)C1=C3C(C)=CN1 UOWVMDUEMSNCAV-WYENRQIDSA-N 0.000 abstract description 19
- VQNATVDKACXKTF-XELLLNAOSA-N duocarmycin Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C([C@@]64C[C@@H]6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-XELLLNAOSA-N 0.000 abstract description 16
- 238000000338 in vitro Methods 0.000 abstract description 10
- 230000000259 anti-tumor effect Effects 0.000 abstract description 9
- 230000004048 modification Effects 0.000 abstract description 9
- 238000012986 modification Methods 0.000 abstract description 9
- VQNATVDKACXKTF-UHFFFAOYSA-N Duocarmycin SA Natural products COC1=C(OC)C(OC)=C2NC(C(=O)N3C4=CC(=O)C5=C(C64CC6C3)C=C(N5)C(=O)OC)=CC2=C1 VQNATVDKACXKTF-UHFFFAOYSA-N 0.000 abstract description 8
- 229960005510 duocarmycin SA Drugs 0.000 abstract description 8
- UIGRBLXJJABSCB-UHFFFAOYSA-N benzo[e]indol-4-one Chemical compound O=C1C=C2C=CC=CC2=C2C1=NC=C2 UIGRBLXJJABSCB-UHFFFAOYSA-N 0.000 abstract description 7
- 239000003242 anti bacterial agent Substances 0.000 abstract description 5
- 229940088710 antibiotic agent Drugs 0.000 abstract description 5
- 230000009897 systematic effect Effects 0.000 abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 89
- 238000005481 NMR spectroscopy Methods 0.000 description 81
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 75
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 71
- 238000002360 preparation method Methods 0.000 description 64
- 239000000243 solution Substances 0.000 description 59
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 50
- 239000007787 solid Substances 0.000 description 48
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 42
- 230000036515 potency Effects 0.000 description 41
- 229910001868 water Inorganic materials 0.000 description 41
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 40
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 40
- 239000011541 reaction mixture Substances 0.000 description 40
- 230000007118 DNA alkylation Effects 0.000 description 38
- 239000002904 solvent Substances 0.000 description 37
- 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 36
- 238000006243 chemical reaction Methods 0.000 description 34
- 229910052681 coesite Inorganic materials 0.000 description 33
- 229910052906 cristobalite Inorganic materials 0.000 description 33
- 238000000034 method Methods 0.000 description 33
- 239000000203 mixture Substances 0.000 description 33
- 239000000377 silicon dioxide Substances 0.000 description 33
- 235000012239 silicon dioxide Nutrition 0.000 description 33
- 229910052682 stishovite Inorganic materials 0.000 description 33
- 238000013456 study Methods 0.000 description 33
- 229910052905 tridymite Inorganic materials 0.000 description 33
- 238000003818 flash chromatography Methods 0.000 description 31
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 30
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 28
- 230000027455 binding Effects 0.000 description 26
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 26
- 238000010828 elution Methods 0.000 description 25
- 239000000543 intermediate Substances 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 23
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 23
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 22
- 235000017557 sodium bicarbonate Nutrition 0.000 description 20
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 20
- 125000001424 substituent group Chemical group 0.000 description 18
- 238000003797 solvolysis reaction Methods 0.000 description 17
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 16
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical class CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 16
- 230000009257 reactivity Effects 0.000 description 16
- 101150041968 CDC13 gene Proteins 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 15
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 14
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 14
- 230000015572 biosynthetic process Effects 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- 239000007832 Na2SO4 Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 238000005119 centrifugation Methods 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 229940093499 ethyl acetate Drugs 0.000 description 11
- 230000002441 reversible effect Effects 0.000 description 11
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical group CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000000758 substrate Substances 0.000 description 10
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 9
- OFFSPAZVIVZPHU-UHFFFAOYSA-N 1-benzofuran-2-carboxylic acid Chemical compound C1=CC=C2OC(C(=O)O)=CC2=C1 OFFSPAZVIVZPHU-UHFFFAOYSA-N 0.000 description 9
- 235000018734 Sambucus australis Nutrition 0.000 description 9
- 244000180577 Sambucus australis Species 0.000 description 9
- 150000007942 carboxylates Chemical class 0.000 description 9
- 235000019439 ethyl acetate Nutrition 0.000 description 9
- 239000002243 precursor Substances 0.000 description 9
- 230000006641 stabilisation Effects 0.000 description 9
- 238000011105 stabilization Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 238000011156 evaluation Methods 0.000 description 8
- 150000003254 radicals Chemical class 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 230000000087 stabilizing effect Effects 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N CHCl3 Substances ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 7
- 238000000376 autoradiography Methods 0.000 description 7
- 125000005605 benzo group Chemical group 0.000 description 7
- 230000004071 biological effect Effects 0.000 description 7
- 230000000368 destabilizing effect Effects 0.000 description 7
- 230000000694 effects Effects 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical class O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 7
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 6
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 6
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 230000002152 alkylating effect Effects 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
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- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 5
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- 229930024421 Adenine Natural products 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
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- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 3
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- BEAHBHCSAFZHKO-UHFFFAOYSA-N methyl 5-amino-1,3-benzoxazole-2-carboxylate Chemical compound NC1=CC=C2OC(C(=O)OC)=NC2=C1 BEAHBHCSAFZHKO-UHFFFAOYSA-N 0.000 description 3
- PTZVWKVAXNDAIR-UHFFFAOYSA-N methyl 5-nitro-1h-indole-2-carboxylate Chemical compound [O-][N+](=O)C1=CC=C2NC(C(=O)OC)=CC2=C1 PTZVWKVAXNDAIR-UHFFFAOYSA-N 0.000 description 3
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- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 231100001264 fatal toxicity Toxicity 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- ZGSWHKOALXRBBT-UHFFFAOYSA-N hexane;propan-1-ol Chemical compound CCCO.CCCCCC ZGSWHKOALXRBBT-UHFFFAOYSA-N 0.000 description 1
- 229940042795 hydrazides for tuberculosis treatment Drugs 0.000 description 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 description 1
- 230000005917 in vivo anti-tumor Effects 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- AZVARJHZBXHUSO-DZQVEHCYSA-N methyl (1R,4R,12S)-4-methyl-3,7-dioxo-10-(5,6,7-trimethoxy-1H-indole-2-carbonyl)-5,10-diazatetracyclo[7.4.0.01,12.02,6]trideca-2(6),8-diene-4-carboxylate Chemical compound COC1=C(OC)C(OC)=C2NC(C(=O)N3C[C@H]4C[C@]44C5=C(C(C=C43)=O)N[C@@](C5=O)(C)C(=O)OC)=CC2=C1 AZVARJHZBXHUSO-DZQVEHCYSA-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
- NQPIEWBAWBFGOB-UHFFFAOYSA-N methyl 1h-indole-2-carboxylate Chemical class C1=CC=C2NC(C(=O)OC)=CC2=C1 NQPIEWBAWBFGOB-UHFFFAOYSA-N 0.000 description 1
- RXYCUKSOYJWGPE-UHFFFAOYSA-N methyl 2-azidoacetate Chemical compound COC(=O)CN=[N+]=[N-] RXYCUKSOYJWGPE-UHFFFAOYSA-N 0.000 description 1
- OLLMSIUDBMURHQ-UHFFFAOYSA-N methyl 5-amino-1-benzofuran-2-carboxylate Chemical compound NC1=CC=C2OC(C(=O)OC)=CC2=C1 OLLMSIUDBMURHQ-UHFFFAOYSA-N 0.000 description 1
- FMFPOZLVAJOEHS-UHFFFAOYSA-N methyl 5-nitro-1-benzofuran-2-carboxylate Chemical compound [O-][N+](=O)C1=CC=C2OC(C(=O)OC)=CC2=C1 FMFPOZLVAJOEHS-UHFFFAOYSA-N 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- ZIUHHBKFKCYYJD-UHFFFAOYSA-N n,n'-methylenebisacrylamide Chemical compound C=CC(=O)NCNC(=O)C=C ZIUHHBKFKCYYJD-UHFFFAOYSA-N 0.000 description 1
- PUPKPAZSFZOLOR-UHFFFAOYSA-N n,n-dimethylformamide;toluene Chemical compound CN(C)C=O.CC1=CC=CC=C1 PUPKPAZSFZOLOR-UHFFFAOYSA-N 0.000 description 1
- OMTPLEBPJORDFA-LJQANCHMSA-N n-[2-[(1s)-1-(chloromethyl)-5-hydroxy-1,2-dihydrobenzo[e]indole-3-carbonyl]-1h-indol-5-yl]-1h-indole-2-carboxamide Chemical compound C1=CC=C2NC(C(=O)NC=3C=C4C=C(NC4=CC=3)C(=O)N3C=4C=C(C5=CC=CC=C5C=4[C@H](CCl)C3)O)=CC2=C1 OMTPLEBPJORDFA-LJQANCHMSA-N 0.000 description 1
- UPBAOYRENQEPJO-UHFFFAOYSA-N n-[5-[[5-[(3-amino-3-iminopropyl)carbamoyl]-1-methylpyrrol-3-yl]carbamoyl]-1-methylpyrrol-3-yl]-4-formamido-1-methylpyrrole-2-carboxamide Chemical compound CN1C=C(NC=O)C=C1C(=O)NC1=CN(C)C(C(=O)NC2=CN(C)C(C(=O)NCCC(N)=N)=C2)=C1 UPBAOYRENQEPJO-UHFFFAOYSA-N 0.000 description 1
- GKTNLYAAZKKMTQ-UHFFFAOYSA-N n-[bis(dimethylamino)phosphinimyl]-n-methylmethanamine Chemical compound CN(C)P(=N)(N(C)C)N(C)C GKTNLYAAZKKMTQ-UHFFFAOYSA-N 0.000 description 1
- XOOMNEFVDUTJPP-UHFFFAOYSA-N naphthalene-1,3-diol Chemical compound C1=CC=CC2=CC(O)=CC(O)=C21 XOOMNEFVDUTJPP-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 239000012454 non-polar solvent Substances 0.000 description 1
- 239000010502 orange oil Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 238000009520 phase I clinical trial Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- IOVGROKTTNBUGK-SJCJKPOMSA-N ritodrine Chemical compound N([C@@H](C)[C@H](O)C=1C=CC(O)=CC=1)CCC1=CC=C(O)C=C1 IOVGROKTTNBUGK-SJCJKPOMSA-N 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- YZHUMGUJCQRKBT-UHFFFAOYSA-M sodium chlorate Chemical compound [Na+].[O-]Cl(=O)=O YZHUMGUJCQRKBT-UHFFFAOYSA-M 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- VVLFAAMTGMGYBS-UHFFFAOYSA-M sodium;4-[[4-(ethylamino)-3-methylphenyl]-(4-ethylimino-3-methylcyclohexa-2,5-dien-1-ylidene)methyl]-3-sulfobenzenesulfonate Chemical compound [Na+].C1=C(C)C(NCC)=CC=C1C(C=1C(=CC(=CC=1)S([O-])(=O)=O)S(O)(=O)=O)=C1C=C(C)C(=NCC)C=C1 VVLFAAMTGMGYBS-UHFFFAOYSA-M 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 108010042747 stallimycin Proteins 0.000 description 1
- LZOZLBFZGFLFBV-UHFFFAOYSA-N sulfene Chemical compound C=S(=O)=O LZOZLBFZGFLFBV-UHFFFAOYSA-N 0.000 description 1
- 238000005694 sulfonylation reaction Methods 0.000 description 1
- FKHIFSZMMVMEQY-UHFFFAOYSA-N talc Chemical compound [Mg+2].[O-][Si]([O-])=O FKHIFSZMMVMEQY-UHFFFAOYSA-N 0.000 description 1
- CNMDREPWSZVYGL-UHFFFAOYSA-N tert-butyl n-(1-iodo-4-phenylmethoxynaphthalen-2-yl)carbamate Chemical compound C=12C=CC=CC2=C(I)C(NC(=O)OC(C)(C)C)=CC=1OCC1=CC=CC=C1 CNMDREPWSZVYGL-UHFFFAOYSA-N 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 239000013638 trimer Substances 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000001429 visible spectrum Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D335/06—Benzothiopyrans; Hydrogenated benzothiopyrans
-
- 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
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C281/00—Derivatives of carbonic acid containing functional groups covered by groups C07C269/00 - C07C279/00 in which at least one nitrogen atom of these functional groups is further bound to another nitrogen atom not being part of a nitro or nitroso group
- C07C281/02—Compounds containing any of the groups, e.g. carbazates
-
- 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
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- 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
-
- 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
- C07D209/96—Spiro-condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
- C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D307/85—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero 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
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Furan Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US475295P | 1995-10-03 | 1995-10-03 | |
| US60/004,752 | 1995-10-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2233936A1 true CA2233936A1 (en) | 1997-04-10 |
Family
ID=21712350
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002233936A Abandoned CA2233936A1 (en) | 1995-10-03 | 1996-10-03 | Cbi analogs of cc-1065 and the duocarmycins |
Country Status (7)
| Country | Link |
|---|---|
| US (3) | US6548530B1 (enExample) |
| EP (1) | EP0862553A4 (enExample) |
| JP (1) | JPH11513391A (enExample) |
| AU (1) | AU727608B2 (enExample) |
| CA (1) | CA2233936A1 (enExample) |
| NZ (1) | NZ321172A (enExample) |
| WO (1) | WO1997012862A1 (enExample) |
Families Citing this family (92)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5843937A (en) * | 1996-05-23 | 1998-12-01 | Panorama Research, Inc. | DNA-binding indole derivatives, their prodrugs and immunoconjugates as anticancer agents |
| WO1998011101A2 (en) * | 1996-09-12 | 1998-03-19 | Cancer Research Campaign Technology Limited | Condensed n-aclyindoles as antitumor agents |
| US6130237A (en) * | 1996-09-12 | 2000-10-10 | Cancer Research Campaign Technology Limited | Condensed N-aclyindoles as antitumor agents |
| 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 |
| DE10121215A1 (de) * | 2001-04-30 | 2002-10-31 | Merck Patent Gmbh | Dihydro-imidazo[4,5-e]indol- und 7H-Pyrrolo[3,2-f]chinoxalin Derivate als nikotinische Acetylcholinrezeptor Liganden und/oder serotonerge Liganden |
| DE10121217A1 (de) | 2001-04-30 | 2002-10-31 | Merck Patent Gmbh | 6H-Oxazolo[4,5-e]indol-Derivate als nikotinische Acetylcholinrezeptor Liganden und/oder serotonerge Liganden |
| PT1392359E (pt) | 2001-05-11 | 2010-01-27 | Ludwig Inst For Cancer Res Ltd | Proteínas de ligação específica e suas utilizações |
| US20100056762A1 (en) | 2001-05-11 | 2010-03-04 | Old Lloyd J | Specific binding proteins and uses thereof |
| US6989452B2 (en) | 2001-05-31 | 2006-01-24 | Medarex, Inc. | Disulfide prodrugs and linkers and stabilizers useful therefor |
| JP2005504789A (ja) | 2001-09-13 | 2005-02-17 | シンタ ファーマスーティカルズ コーポレイション | 癌治療のための２−アロイルイミダゾール化合物 |
| US6756397B2 (en) * | 2002-04-05 | 2004-06-29 | Immunogen, Inc. | Prodrugs of CC-1065 analogs |
| MXPA06013413A (es) | 2004-05-19 | 2007-01-23 | Medarex Inc | Enlazadores quimicos y conjugados de los mismos. |
| RU2402548C2 (ru) * | 2004-05-19 | 2010-10-27 | Медарекс, Инк. | Химические линкеры и их конъюгаты |
| US7393665B2 (en) * | 2005-02-10 | 2008-07-01 | Population Genetics Technologies Ltd | Methods and compositions for tagging and identifying polynucleotides |
| JP2008529556A (ja) * | 2005-02-18 | 2008-08-07 | メダレックス， インク． | 前立腺特異的膜抗原（ｐｓｍａ）に対するヒトモノクローナル抗体 |
| US7714016B2 (en) * | 2005-04-08 | 2010-05-11 | Medarex, Inc. | Cytotoxic compounds and conjugates with cleavable substrates |
| JP5290756B2 (ja) * | 2005-09-26 | 2013-09-18 | メダレックス インコーポレイテッド | 抗体−薬剤コンジュゲート及びその使用 |
| CA2623236A1 (en) | 2005-09-26 | 2007-04-05 | Medarex, Inc. | Human monoclonal antibodies to cd70 |
| EP1940789B1 (en) * | 2005-10-26 | 2011-11-23 | Medarex, Inc. | Methods and compounds for preparing cc-1065 analogs |
| WO2007059404A2 (en) | 2005-11-10 | 2007-05-24 | Medarex, Inc. | Duocarmycin derivatives as novel cytotoxic compounds and conjugates |
| WO2007067992A2 (en) | 2005-12-08 | 2007-06-14 | Medarex, Inc. | Human monoclonal antibodies to fucosyl-gm1 and methods for using anti-fucosyl-gm1 |
| EA017812B1 (ru) | 2005-12-08 | 2013-03-29 | Медарекс, Инк. | Выделенное моноклональное антитело или его антигенсвязывающий участок, которые связываются с протеинтирозинкиназой 7 ( ptk7) человека, и их применение |
| ES2396569T3 (es) | 2006-01-17 | 2013-02-22 | Medarex, Inc. | Anticuerpos monoclonales contra CD30 que carecen de restos fucosilo y xilosilo |
| WO2008030611A2 (en) | 2006-09-05 | 2008-03-13 | Medarex, Inc. | Antibodies to bone morphogenic proteins and receptors therefor and methods for their use |
| CN103172743B (zh) | 2006-12-01 | 2015-04-08 | 梅达雷克斯有限责任公司 | 结合cd22的人抗体及其用途 |
| CL2007003622A1 (es) | 2006-12-13 | 2009-08-07 | Medarex Inc | Anticuerpo monoclonal humano anti-cd19; composicion que lo comprende; y metodo de inhibicion del crecimiento de celulas tumorales. |
| US20100150950A1 (en) | 2006-12-14 | 2010-06-17 | Medarex, Inc. | Human antibodies that bind cd70 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 |
| WO2008091701A2 (en) | 2007-01-25 | 2008-07-31 | Dana-Farber Cancer Institute | Use of anti-egfr antibodies in treatment of egfr mutant mediated disease |
| JP2010519310A (ja) | 2007-02-21 | 2010-06-03 | メダレックス インコーポレイテッド | 単一のアミノ酸を有する化学リンカーおよびその複合体 |
| CA2680854C (en) * | 2007-03-15 | 2017-02-14 | Ludwig Institute For Cancer Research | Treatment method using egfr antibodies and src inhibitors and related formulations |
| US9901567B2 (en) | 2007-08-01 | 2018-02-27 | Syntarga B.V. | Substituted CC-1065 analogs and their conjugates |
| MX2010001757A (es) | 2007-08-14 | 2010-09-14 | Ludwig Inst Cancer Res | Anticuerpo monoclonal 175 que activa el receptor egf y derivados y usos del mismo. |
| CA2723883C (en) * | 2007-11-13 | 2014-10-28 | The Scripps Research Institute | Cbi derivatives subject to reductive activation |
| AU2009320481C1 (en) | 2008-11-03 | 2016-12-08 | Syntarga B.V. | Novel CC-1065 analogs and their conjugates |
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| US9181339B2 (en) | 2009-04-20 | 2015-11-10 | Oxford Bio Therapeutics Ltd. | Antibodies specific to cadherin-17 |
| US20110076232A1 (en) * | 2009-09-29 | 2011-03-31 | Ludwig Institute For Cancer Research | Specific binding proteins and uses thereof |
| US20120231004A1 (en) | 2009-10-13 | 2012-09-13 | Oxford Biotherapeutic Ltd. | Antibodies |
| DE102009051438A1 (de) | 2009-10-30 | 2011-05-05 | Georg-August-Universität Göttingen Stiftung Öffentlichen Rechts | Fluoreszenzfarbstoffe |
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| KR101972303B1 (ko) | 2011-06-10 | 2019-04-25 | 메르사나 테라퓨틱스, 인코포레이티드 | 단백질-중합체-약물 접합체 |
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| US9872918B2 (en) | 2012-12-12 | 2018-01-23 | Mersana Therapeutics, Inc. | Hydroxyl-polymer-drug-protein conjugates |
| US9089614B2 (en) | 2012-12-21 | 2015-07-28 | Bioalliance C.V. | Hydrophilic self-immolative linkers and conjugates thereof |
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| EP3092010B1 (en) | 2014-01-10 | 2018-07-11 | Synthon Biopharmaceuticals B.V. | Method for purifying cys-linked antibody-drug conjugates |
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| CN104961645A (zh) * | 2015-07-22 | 2015-10-07 | 中国药科大学 | 苯氧乙酸类衍生物、其制备方法及其作为药物的用途 |
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| WO2025021929A1 (en) | 2023-07-27 | 2025-01-30 | Veraxa Biotech Gmbh | Hydrophilic trans-cyclooctene (hytco) compounds, constructs and conjugates containing the same |
| WO2025056807A1 (en) | 2023-09-15 | 2025-03-20 | Basf Se | Stabilized biopolymer composition, their manufacture and use |
| WO2025149667A1 (en) | 2024-01-12 | 2025-07-17 | Pheon Therapeutics Ltd | Antibody drug conjugates and uses thereof |
| WO2025174248A1 (en) | 2024-02-16 | 2025-08-21 | Tagworks Pharmaceuticals B.V. | Trans-cyclooctenes with "or gate" release |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5843937A (en) * | 1996-05-23 | 1998-12-01 | Panorama Research, Inc. | DNA-binding indole derivatives, their prodrugs and immunoconjugates as anticancer agents |
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1996
- 1996-10-03 WO PCT/US1996/016481 patent/WO1997012862A1/en not_active Ceased
- 1996-10-03 NZ NZ321172A patent/NZ321172A/en unknown
- 1996-10-03 JP JP9514522A patent/JPH11513391A/ja not_active Abandoned
- 1996-10-03 US US09/051,264 patent/US6548530B1/en not_active Expired - Fee Related
- 1996-10-03 EP EP96936498A patent/EP0862553A4/en not_active Withdrawn
- 1996-10-03 AU AU74315/96A patent/AU727608B2/en not_active Ceased
- 1996-10-03 CA CA002233936A patent/CA2233936A1/en not_active Abandoned
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2003
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2004
- 2004-06-24 US US10/876,992 patent/US20050032860A1/en not_active Abandoned
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| AU7431596A (en) | 1997-04-28 |
| US20040002528A1 (en) | 2004-01-01 |
| AU727608B2 (en) | 2000-12-14 |
| EP0862553A4 (en) | 1999-02-03 |
| EP0862553A1 (en) | 1998-09-09 |
| JPH11513391A (ja) | 1999-11-16 |
| WO1997012862A1 (en) | 1997-04-10 |
| NZ321172A (en) | 2000-02-28 |
| US20050032860A1 (en) | 2005-02-10 |
| US6548530B1 (en) | 2003-04-15 |
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