JP4824165B2 - ピロロベンゾジアゼピン類 - Google Patents
ピロロベンゾジアゼピン類 Download PDFInfo
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- JP4824165B2 JP4824165B2 JP2000571054A JP2000571054A JP4824165B2 JP 4824165 B2 JP4824165 B2 JP 4824165B2 JP 2000571054 A JP2000571054 A JP 2000571054A JP 2000571054 A JP2000571054 A JP 2000571054A JP 4824165 B2 JP4824165 B2 JP 4824165B2
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- Prior art keywords
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- solution
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- stirred
- Prior art date
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- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical class C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 title description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 164
- -1 hydroxy, amino Chemical group 0.000 claims description 66
- 125000004432 carbon atom Chemical group C* 0.000 claims description 58
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 51
- 125000000217 alkyl group Chemical group 0.000 claims description 49
- 238000000034 method Methods 0.000 claims description 39
- 239000000539 dimer Substances 0.000 claims description 38
- 229910052757 nitrogen Inorganic materials 0.000 claims description 36
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 125000005842 heteroatom Chemical group 0.000 claims description 29
- 125000005843 halogen group Chemical group 0.000 claims description 21
- 125000001475 halogen functional group Chemical group 0.000 claims description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 14
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 13
- 238000011282 treatment Methods 0.000 claims description 12
- 239000000178 monomer Substances 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 9
- 238000002360 preparation method Methods 0.000 claims description 9
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 7
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- KRYRNEPMWZHETR-VIFPVBQESA-N (6as)-3-amino-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1=C[C@@H]2CCCN2C(=O)C2=CC=C(N)C=C21 KRYRNEPMWZHETR-VIFPVBQESA-N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 2
- 150000001721 carbon Chemical group 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 125000004429 atom Chemical group 0.000 claims 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 528
- 239000000243 solution Substances 0.000 description 398
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene chloride Substances ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 340
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 336
- 239000011541 reaction mixture Substances 0.000 description 261
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 246
- 235000019439 ethyl acetate Nutrition 0.000 description 229
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 156
- 239000012267 brine Substances 0.000 description 136
- 239000000203 mixture Substances 0.000 description 136
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 136
- 230000002829 reductive effect Effects 0.000 description 126
- 239000003208 petroleum Substances 0.000 description 120
- 239000002904 solvent Substances 0.000 description 120
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 113
- 239000000047 product Substances 0.000 description 109
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 108
- 238000003818 flash chromatography Methods 0.000 description 105
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 104
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 99
- 238000004809 thin layer chromatography Methods 0.000 description 99
- 229910001868 water Inorganic materials 0.000 description 98
- 239000003921 oil Substances 0.000 description 97
- 235000019198 oils Nutrition 0.000 description 97
- 238000006243 chemical reaction Methods 0.000 description 96
- 238000003756 stirring Methods 0.000 description 92
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 91
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 79
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 77
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 71
- 239000007787 solid Substances 0.000 description 70
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 68
- 239000011521 glass Substances 0.000 description 66
- 239000012074 organic phase Substances 0.000 description 66
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 65
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 64
- 230000015572 biosynthetic process Effects 0.000 description 64
- 239000012299 nitrogen atmosphere Substances 0.000 description 63
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 61
- 238000003786 synthesis reaction Methods 0.000 description 56
- 238000001704 evaporation Methods 0.000 description 54
- 230000008020 evaporation Effects 0.000 description 50
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 48
- 239000012043 crude product Substances 0.000 description 46
- 238000010992 reflux Methods 0.000 description 44
- 239000007858 starting material Substances 0.000 description 37
- 238000001914 filtration Methods 0.000 description 34
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 32
- 150000002576 ketones Chemical class 0.000 description 32
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Chemical group COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 32
- XMYQHJDBLRZMLW-UHFFFAOYSA-N methanolamine Chemical compound NCO XMYQHJDBLRZMLW-UHFFFAOYSA-N 0.000 description 31
- 150000001412 amines Chemical class 0.000 description 30
- 230000003197 catalytic effect Effects 0.000 description 30
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 30
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 29
- 238000000746 purification Methods 0.000 description 29
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 28
- 229920006395 saturated elastomer Polymers 0.000 description 28
- 239000012044 organic layer Substances 0.000 description 27
- 241000790917 Dioxys <bee> Species 0.000 description 25
- 235000019341 magnesium sulphate Nutrition 0.000 description 25
- 239000000725 suspension Substances 0.000 description 25
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 24
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 23
- 239000002253 acid Substances 0.000 description 23
- PCTWLLFFEIRBIE-VHSXEESVSA-N (3r,5s)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]pyrrolidin-3-ol Chemical compound CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)CN1 PCTWLLFFEIRBIE-VHSXEESVSA-N 0.000 description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 21
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- 235000019502 Orange oil Nutrition 0.000 description 20
- 239000007868 Raney catalyst Substances 0.000 description 20
- 229910000564 Raney nickel Inorganic materials 0.000 description 20
- 239000010502 orange oil Substances 0.000 description 20
- 239000002244 precipitate Substances 0.000 description 20
- 239000000741 silica gel Substances 0.000 description 20
- 229910002027 silica gel Inorganic materials 0.000 description 20
- 239000007864 aqueous solution Substances 0.000 description 19
- 239000000758 substrate Substances 0.000 description 19
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 18
- 239000003480 eluent Substances 0.000 description 18
- HVVNJUAVDAZWCB-UHFFFAOYSA-N prolinol Chemical compound OCC1CCCN1 HVVNJUAVDAZWCB-UHFFFAOYSA-N 0.000 description 18
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 18
- PWDSJBHSKYBUEX-UHFFFAOYSA-N 1,4-benzodiazepin-5-one Chemical compound O=C1N=CC=NC2=CC=CC=C12 PWDSJBHSKYBUEX-UHFFFAOYSA-N 0.000 description 17
- 239000012071 phase Substances 0.000 description 17
- 229910052793 cadmium Inorganic materials 0.000 description 16
- 238000005859 coupling reaction Methods 0.000 description 15
- 125000000524 functional group Chemical group 0.000 description 15
- 150000002466 imines Chemical class 0.000 description 15
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 14
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 14
- 230000008878 coupling Effects 0.000 description 14
- 238000010168 coupling process Methods 0.000 description 14
- 150000002828 nitro derivatives Chemical class 0.000 description 14
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 13
- 150000001414 amino alcohols Chemical class 0.000 description 13
- 125000006239 protecting group Chemical group 0.000 description 13
- 239000000377 silicon dioxide Substances 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- 238000007254 oxidation reaction Methods 0.000 description 12
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 11
- 239000005695 Ammonium acetate Substances 0.000 description 11
- 235000019257 ammonium acetate Nutrition 0.000 description 11
- 229940043376 ammonium acetate Drugs 0.000 description 11
- 239000008346 aqueous phase Substances 0.000 description 11
- 150000002009 diols Chemical class 0.000 description 11
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 11
- 150000002148 esters Chemical class 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 11
- 238000005755 formation reaction Methods 0.000 description 11
- 230000003647 oxidation Effects 0.000 description 11
- 229910052763 palladium Inorganic materials 0.000 description 11
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 11
- GUFUWKKDHIABBW-UHFFFAOYSA-N pyrrolidin-1-ylmethanol Chemical compound OCN1CCCC1 GUFUWKKDHIABBW-UHFFFAOYSA-N 0.000 description 11
- 229910000104 sodium hydride Inorganic materials 0.000 description 11
- 239000012258 stirred mixture Substances 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 10
- 239000003242 anti bacterial agent Substances 0.000 description 10
- 229940088710 antibiotic agent Drugs 0.000 description 10
- 230000009467 reduction Effects 0.000 description 10
- 238000002390 rotary evaporation Methods 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 9
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 9
- 239000012230 colorless oil Substances 0.000 description 9
- 229920002857 polybutadiene Polymers 0.000 description 9
- 239000002002 slurry Substances 0.000 description 9
- 239000000126 substance Substances 0.000 description 9
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 9
- RWZVMMQNDHPRQD-SFTDATJTSA-N (6as)-3-[3-[[(6as)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6ah-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]propoxy]-2-methoxy-8-methylidene-7,9-dihydro-6ah-pyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1=C[C@@H]2CC(=C)CN2C(=O)C(C=C2OC)=C1C=C2OCCCOC1=CC(N=C[C@H]2N(CC(=C)C2)C2=O)=C2C=C1OC RWZVMMQNDHPRQD-SFTDATJTSA-N 0.000 description 8
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 description 8
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 8
- 206010028980 Neoplasm Diseases 0.000 description 8
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 8
- 229960000583 acetic acid Drugs 0.000 description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 8
- 230000008034 disappearance Effects 0.000 description 8
- 239000006185 dispersion Substances 0.000 description 8
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
- 150000003138 primary alcohols Chemical class 0.000 description 8
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 description 8
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 8
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 229910052681 coesite Inorganic materials 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical class [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 7
- 229910052906 cristobalite Inorganic materials 0.000 description 7
- 239000013058 crude material Substances 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 7
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 7
- 239000010410 layer Substances 0.000 description 7
- 239000002808 molecular sieve Substances 0.000 description 7
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 7
- 235000011150 stannous chloride Nutrition 0.000 description 7
- 229910052682 stishovite Inorganic materials 0.000 description 7
- 238000007920 subcutaneous administration Methods 0.000 description 7
- 229910052905 tridymite Inorganic materials 0.000 description 7
- HCDXLUKTYFLIEM-UHFFFAOYSA-N 1,2-benzodiazepin-5-one Chemical compound O=C1C=CN=NC2=CC=CC=C12 HCDXLUKTYFLIEM-UHFFFAOYSA-N 0.000 description 6
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 6
- 150000001299 aldehydes Chemical group 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 6
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- 239000012362 glacial acetic acid Substances 0.000 description 6
- 238000011031 large-scale manufacturing process Methods 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
- 238000006396 nitration reaction Methods 0.000 description 6
- OCAAZRFBJBEVPS-UHFFFAOYSA-N prop-2-enyl carbamate Chemical compound NC(=O)OCC=C OCAAZRFBJBEVPS-UHFFFAOYSA-N 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- JMSVCTWVEWCHDZ-UHFFFAOYSA-N syringic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1O JMSVCTWVEWCHDZ-UHFFFAOYSA-N 0.000 description 6
- 238000003828 vacuum filtration Methods 0.000 description 6
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 5
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 5
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 5
- CGJUTGBTXJLTBA-UHFFFAOYSA-N acetyl 4-hydroxy-3,5-dimethoxybenzoate Chemical compound COC1=CC(C(=O)OC(C)=O)=CC(OC)=C1O CGJUTGBTXJLTBA-UHFFFAOYSA-N 0.000 description 5
- 238000003556 assay Methods 0.000 description 5
- 239000012298 atmosphere Substances 0.000 description 5
- BDOSMKKIYDKNTQ-UHFFFAOYSA-N cadmium atom Chemical compound [Cd] BDOSMKKIYDKNTQ-UHFFFAOYSA-N 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9818733.9 | 1998-08-27 | ||
| GBGB9818733.9A GB9818733D0 (en) | 1998-08-27 | 1998-08-27 | Compounds |
| GB9901929.1 | 1999-01-28 | ||
| GBGB9901929.1A GB9901929D0 (en) | 1999-01-28 | 1999-01-28 | Compounds |
| PCT/GB1999/002838 WO2000012508A2 (en) | 1998-08-27 | 1999-08-27 | Pyrrolbenzodiazepines |
Publications (3)
| Publication Number | Publication Date |
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| JP2002525285A JP2002525285A (ja) | 2002-08-13 |
| JP2002525285A5 JP2002525285A5 (cg-RX-API-DMAC7.html) | 2006-10-12 |
| JP4824165B2 true JP4824165B2 (ja) | 2011-11-30 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2000571054A Expired - Lifetime JP4824165B2 (ja) | 1998-08-27 | 1999-08-27 | ピロロベンゾジアゼピン類 |
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| AT (3) | ATE294803T1 (cg-RX-API-DMAC7.html) |
| AU (1) | AU757510C (cg-RX-API-DMAC7.html) |
| CA (1) | CA2341471C (cg-RX-API-DMAC7.html) |
| DE (3) | DE69930328T2 (cg-RX-API-DMAC7.html) |
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| ES (3) | ES2260570T3 (cg-RX-API-DMAC7.html) |
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| PT (3) | PT1109812E (cg-RX-API-DMAC7.html) |
| WO (1) | WO2000012508A2 (cg-RX-API-DMAC7.html) |
Families Citing this family (196)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9818731D0 (en) * | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Compounds |
| 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. |
| GB9818732D0 (en) * | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collection of compounds |
| GB0226593D0 (en) | 2002-11-14 | 2002-12-24 | Consultants Ltd | Compounds |
| CA2520898C (en) * | 2003-03-31 | 2009-10-20 | Council Of Scientific And Industrial Research | Non-cross-linking pyrrolo(2,1-c)(1,4)benzodiazepines as potential antitumour agents and process thereof |
| GB0321295D0 (en) * | 2003-09-11 | 2003-10-15 | Spirogen Ltd | Synthesis of protected pyrrolobenzodiazepines |
| GB0416511D0 (en) * | 2003-10-22 | 2004-08-25 | Spirogen Ltd | Pyrrolobenzodiazepines |
| WO2005040170A2 (en) | 2003-10-22 | 2005-05-06 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Pyrrolobenzodiazepine derivatives, compositions comprising the same and methods related thereto |
| JPWO2005040172A1 (ja) * | 2003-10-29 | 2007-03-08 | 協和醗酵工業株式会社 | 三環性プロリン誘導体 |
| AU2003300720A1 (en) * | 2003-12-31 | 2005-07-21 | Council Of Scientific And Industrial Research | C-8 linked pyrrolo(2,1-c)(1,4)benzodiazepine-acridone/acridine hybrids |
| GB2424883B (en) * | 2003-12-31 | 2008-10-22 | Council Scient Ind Res | Process for preparing pyrrolo[2, 1-c] [1,4] benzodiazepine hybrids |
| ATE542821T1 (de) * | 2004-03-01 | 2012-02-15 | Spirogen Ltd | 11-hydroxy-5h-pyrroloä2,1-cüä1,4übenzodiazepin- - on derivate als zwischenverbindungen für die herstellung von c2 substituierten pyrrolobenzodiazepinen |
| GB0404577D0 (en) * | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Pyrrolobenzodiazepines |
| GB0404578D0 (en) * | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Pyrrolobenzodiazepines |
| GB0404574D0 (en) * | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Amino acids |
| JP5166861B2 (ja) | 2004-03-09 | 2013-03-21 | スピロゲン リミティッド | ピロロベンゾジアゼピン |
| US7056913B2 (en) | 2004-03-30 | 2006-06-06 | Council Of Scientific And Industrial Research | C8—linked pyrrolo[2,1-c][1,4]benzodiazepine-acridone/acridine hybrids |
| US6951853B1 (en) | 2004-03-30 | 2005-10-04 | Council Of Scientific And Industrial Research | Process for preparing pyrrolo[2, 1-c] [1,4] benzodiazepine hybrids |
| FR2869231B1 (fr) * | 2004-04-27 | 2008-03-14 | Sod Conseils Rech Applic | Composition therapeutique contenant au moins un derive de la pyrrolobenzodiazepine et la fludarabine |
| GB0410725D0 (en) * | 2004-05-13 | 2004-06-16 | Spirogen Ltd | Pyrrolobenzodiazepine therapeutic agents |
| GB0508084D0 (en) * | 2005-04-21 | 2005-06-01 | Spirogen Ltd | Pyrrolobenzodiazepines |
| WO2006111759A1 (en) * | 2005-04-21 | 2006-10-26 | Spirogen Limited | Pyrrolobenzodiazepines |
| DE602006006199D1 (de) * | 2005-10-05 | 2009-05-20 | Spirogen Ltd | 4-ä4-(5-oxo-2,3,5,11a-tetrahydro-5h-pyrrolo ä2, 1-cüä1,4übenzodiazepin-8-yloxy)-butyrylaminoü-1h-pyrrol-2-carbonsäurealkylesterderivate und verwandte verbindung zur behandlung einer proliferativen erkrankung |
| SI1813614T1 (sl) | 2006-01-25 | 2012-01-31 | Sanofi 174 | Citotoksična sredstva, ki obsegajo nove tomajmicinske derivate |
| DE102006013678A1 (de) * | 2006-03-24 | 2007-09-27 | Bayerische Motoren Werke Ag | Gleit- oder Schmiermittel und Verfahren zum Aufziehen eines Fahrzeugreifens auf eine Felge |
| AU2007274738B2 (en) | 2006-07-18 | 2013-11-28 | Sanofi-Aventis | Antagonist antibody against EphA2 for the treatment of cancer |
| GB0619325D0 (en) | 2006-09-30 | 2006-11-08 | Univ Strathclyde | New compounds |
| EP1914242A1 (en) | 2006-10-19 | 2008-04-23 | Sanofi-Aventis | Novel anti-CD38 antibodies for the treatment of cancer |
| ES2435779T3 (es) | 2007-07-19 | 2013-12-23 | Sanofi | Agentes citotóxicos que comprenden nuevos derivados de tomaimicina y su uso terapéutico |
| KR20230003298A (ko) | 2008-04-30 | 2023-01-05 | 이뮤노젠 아이엔씨 | 가교제 및 그 용도 |
| GB0813432D0 (en) | 2008-07-22 | 2008-08-27 | Spirogen Ltd | Pyrrolobenzodiazepines |
| GB0819095D0 (en) | 2008-10-17 | 2008-11-26 | Spirogen Ltd | Pyrrolobenzodiazepines |
| GB0819097D0 (en) | 2008-10-17 | 2008-11-26 | Spirogen Ltd | Pyrrolobenzodiazepines |
| CN105175434A (zh) | 2009-02-05 | 2015-12-23 | 伊缪诺金公司 | 新型苯并二氮杂*衍生物 |
| AU2015224492B2 (en) * | 2009-02-05 | 2017-04-20 | Immunogen, Inc. | Novel benzodiazepine derivatives |
| SG176068A1 (en) | 2009-06-03 | 2011-12-29 | Immunogen Inc | Conjugation methods |
| FR2949469A1 (fr) * | 2009-08-25 | 2011-03-04 | Sanofi Aventis | Derives anticancereux, leur preparation et leur application en therapeutique |
| AR078470A1 (es) | 2009-10-02 | 2011-11-09 | Sanofi Aventis | Anticuerpos que se unen especificamente al receptor epha2 |
| GB201006340D0 (en) * | 2010-04-15 | 2010-06-02 | Spirogen Ltd | Synthesis method and intermediates |
| AU2011239507B2 (en) | 2010-04-15 | 2015-04-09 | Medimmune Limited | Pyrrolobenzodiazepines and conjugates thereof |
| BR112012026801B8 (pt) | 2010-04-15 | 2021-05-25 | Medimmune Ltd | conjugados de pirrolobenzodiazepina direcionados, composição farmacêutica, uso dos mesmos para tratamento de uma doença proliferativa ou autoimune e ligante de medicamento |
| MX368648B (es) | 2010-04-15 | 2019-10-09 | Seattle Genetics Inc | Pirrolobenzodiazepinas usadas para tratar enfermedades proliferativas. |
| FR2963007B1 (fr) | 2010-07-26 | 2013-04-05 | Sanofi Aventis | Derives anticancereux, leur preparation et leur application therapeutique |
| DK2675480T3 (en) | 2011-02-15 | 2019-04-15 | Immunogen Inc | PROCEDURES FOR PREPARING CONJUGATES |
| FR2972006B1 (fr) | 2011-02-24 | 2016-03-25 | Centre Nat Rech Scient | Nouveaux fragments d'il-33 superactifs et leurs utilisations |
| US20130058947A1 (en) | 2011-09-02 | 2013-03-07 | Stem Centrx, Inc | Novel Modulators and Methods of Use |
| EA027971B1 (ru) | 2011-09-20 | 2017-09-29 | Медимьюн Лимитед | Пирролбензодиазепины |
| EP2751111B1 (en) * | 2011-10-14 | 2017-04-26 | MedImmune Limited | Asymmetrical bis-(5H-Pyrrolo[2,1-c][1,4]benzodiazepin-5-one) derivatives for the treatment of proliferative or autoimmune diseases |
| MX375987B (es) * | 2011-10-14 | 2025-03-07 | Seagen Inc | Pirrolobenzodiazepinas y conjugados dirigidos |
| US11135303B2 (en) | 2011-10-14 | 2021-10-05 | Medimmune Limited | Pyrrolobenzodiazepines and conjugates thereof |
| JP6393617B2 (ja) | 2011-10-14 | 2018-09-19 | シアトル ジェネティクス,インコーポレーテッド | ピロロベンゾジアゼピンおよび標的コンジュゲート |
| WO2013053872A1 (en) | 2011-10-14 | 2013-04-18 | Spirogen Sàrl | Synthesis method and intermediates useful in the preparation of pyrrolobenzodiazepines |
| CA2850264C (en) | 2011-10-14 | 2019-11-05 | Spirogen Sarl | Pyrrolobenzodiazepines |
| WO2013126810A1 (en) | 2012-02-24 | 2013-08-29 | Stem Centrx, Inc. | Anti sez6 antibodies and methods of use |
| BR112014020826A8 (pt) | 2012-02-24 | 2017-09-19 | Stem Centrx Inc | Anticorpo que se liga especificamente a um epítopo, ácido nucleico, vetor ou célula hospedeira, conjugado de fármaco anticorpo, composição farmacêutica compreendendo o referido anticorpo, uso do mesmo, kit e método de preparação do conjugado |
| AR090549A1 (es) | 2012-03-30 | 2014-11-19 | Genentech Inc | Anticuerpos anti-lgr5 e inmunoconjugados |
| IN2014MN02092A (cg-RX-API-DMAC7.html) | 2012-04-30 | 2015-09-04 | Spirogen Sarl | |
| NZ701478A (en) | 2012-04-30 | 2016-08-26 | Medimmune Ltd | Pyrrolobenzodiazepines |
| EP2844300B1 (en) | 2012-05-01 | 2018-10-17 | Genentech, Inc. | Anti-pmel17 antibodies and immunoconjugates |
| CN104540526A (zh) | 2012-07-09 | 2015-04-22 | 基因泰克公司 | 包含抗cd79b抗体的免疫偶联物 |
| AU2013288929A1 (en) | 2012-07-09 | 2014-12-04 | Genentech, Inc. | Immunoconjugates comprising anti-CD22 antibodies |
| US9464141B2 (en) | 2012-08-02 | 2016-10-11 | Genentech, Inc. | Anti-ETBR antibodies and immunoconjugates |
| EP2887965A1 (en) | 2012-08-22 | 2015-07-01 | ImmunoGen, Inc. | Cytotoxic benzodiazepine derivatives |
| HRP20180945T1 (hr) | 2012-10-12 | 2018-08-10 | Adc Therapeutics Sa | Konjugati protutijelo-pirolobenzodiazepin |
| JP6270859B2 (ja) | 2012-10-12 | 2018-01-31 | エイディーシー・セラピューティクス・エス・アー・エール・エルAdc Therapeutics Sarl | ピロロベンゾジアゼピン−抗体結合体 |
| EP3470086B1 (en) | 2012-10-12 | 2020-11-25 | Medimmune Limited | Pyrrolobenzodiazepines and conjugates thereof |
| AU2013328580B2 (en) | 2012-10-12 | 2016-01-21 | Medimmune Limited | Pyrrolobenzodiazepines and conjugates thereof |
| WO2014057114A1 (en) | 2012-10-12 | 2014-04-17 | Adc Therapeutics Sàrl | Pyrrolobenzodiazepine-anti-psma antibody conjugates |
| HUE042731T2 (hu) | 2012-10-12 | 2019-07-29 | Adc Therapeutics Sa | Pirrolobenzodiazepin-antitest konjugátumok |
| WO2014057120A1 (en) | 2012-10-12 | 2014-04-17 | Adc Therapeutics Sàrl | Pyrrolobenzodiazepine-antibody conjugates |
| AU2013328628B2 (en) | 2012-10-12 | 2016-12-15 | Adc Therapeutics Sa | Pyrrolobenzodiazepine-anti-CD22 antibody conjugates |
| AU2013328673B2 (en) | 2012-10-12 | 2017-07-13 | Medimmune Limited | Synthesis and intermediates of pyrrolobenzodiazepine derivatives for conjugation |
| EP2922818B1 (en) | 2012-11-24 | 2018-09-05 | Hangzhou Dac Biotech Co., Ltd | Hydrophilic linkers and their uses for conjugation of drugs to cell binding molecules |
| EP2935268B2 (en) * | 2012-12-21 | 2021-02-17 | MedImmune Limited | Pyrrolobenzodiazepines and conjugates thereof |
| JP6527466B2 (ja) | 2012-12-21 | 2019-06-05 | メドイミューン・リミテッドMedImmune Limited | 増殖性疾患および自己免疫疾患の治療に使用するための非対称ピロロベンゾジアゼピンニ量体 |
| LT2958944T (lt) | 2013-02-22 | 2019-07-10 | Abbvie Stemcentrx Llc | Antikūno prieš dll3 ir pbd konjugatai bei jų panaudojimas |
| CN105209077B (zh) | 2013-03-13 | 2019-06-11 | 麦迪穆有限责任公司 | 吡咯并苯并二氮杂卓以及其结合物 |
| MX364330B (es) | 2013-03-13 | 2019-04-23 | Medimmune Ltd | Pirrolobenzodiazepinas y conjugados de las mismas. |
| AR096287A1 (es) | 2013-03-13 | 2015-12-23 | Spirogen Sàrl | Pirrolobenzodiacepinas y conjugados |
| PE20151672A1 (es) | 2013-03-14 | 2015-11-27 | Genentech Inc | Anticuerpos e inmunoconjugados anti-b7-h4 |
| US9562099B2 (en) | 2013-03-14 | 2017-02-07 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
| MX2016001862A (es) | 2013-08-12 | 2016-08-03 | Genentech Inc | Compuestos de conjugado anticuerpo-farmaco dimerico de 1-(clorometil)-2,3-dihidro-1h-benzo[e]indol, y metodos de uso y tratamiento. |
| BR112016004242A8 (pt) | 2013-08-28 | 2018-06-12 | Stemcentrx Inc | Métodos para conjugação sítio-específica de anticorpos e composições |
| CN105792836A (zh) | 2013-08-28 | 2016-07-20 | 施特姆森特克斯股份有限公司 | 新型sez6调节剂以及应用方法 |
| EA201600252A1 (ru) | 2013-09-12 | 2017-05-31 | Галозим, Инк. | Модифицированные антитела к рецепторам антиэпидермального фактора роста и способы их использования |
| HK1218124A1 (zh) | 2013-09-17 | 2017-02-03 | 豪夫迈.罗氏有限公司 | 使用抗lgr5抗体的方法 |
| GB201317981D0 (en) | 2013-10-11 | 2013-11-27 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
| GB201317982D0 (en) | 2013-10-11 | 2013-11-27 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
| US10010624B2 (en) | 2013-10-11 | 2018-07-03 | Medimmune Limited | Pyrrolobenzodiazepine-antibody conjugates |
| WO2015052535A1 (en) | 2013-10-11 | 2015-04-16 | Spirogen Sàrl | Pyrrolobenzodiazepine-antibody conjugates |
| EP3054985B1 (en) | 2013-10-11 | 2018-12-26 | Medimmune Limited | Pyrrolobenzodiazepine-antibody conjugates |
| BR112016010169A2 (pt) | 2013-11-06 | 2017-12-05 | Stemcentrx Inc | anticorpos anticlaudina e métodos de uso |
| CN115504924A (zh) | 2013-11-27 | 2022-12-23 | 雷德伍德生物科技股份有限公司 | 肼基-吡咯并化合物及用于生成缀合物的方法 |
| PE20160993A1 (es) | 2013-12-12 | 2016-10-14 | Abbvie Stemcentrx Llc | Nuevos anticuerpos anti-dpep3 y metodos de uso |
| SG11201604784XA (en) | 2013-12-13 | 2016-07-28 | Genentech Inc | Anti-cd33 antibodies and immunoconjugates |
| BR112016013258A2 (pt) | 2013-12-16 | 2018-01-16 | Genentech Inc | composto conjugado anticorpo-droga, composição farmacêutica, método para tratar câncer e kit |
| CN106550593A (zh) | 2014-02-21 | 2017-03-29 | 艾伯维施特姆森特克斯有限责任公司 | 用于黑素瘤的抗‑dll3抗体和药物缀合物 |
| WO2015127685A1 (en) | 2014-02-28 | 2015-09-03 | Hangzhou Dac Biotech Co., Ltd | Charged linkers and their uses for conjugation |
| GB201407816D0 (en) | 2014-05-02 | 2014-06-18 | King S College London | Pyrrolobenzodiazepine Compounds |
| KR20170003582A (ko) | 2014-05-22 | 2017-01-09 | 제넨테크, 인크. | 항-gpc3 항체 및 면역접합체 |
| KR102818922B1 (ko) | 2014-08-28 | 2025-06-11 | 바이오아트라, 인코퍼레이티드 | 변형된 t 세포에 대한 조건부 활성 키메라 항원 수용체 |
| SG11201701455SA (en) | 2014-09-03 | 2017-03-30 | Immunogen Inc | Cytotoxic benzodiazepine derivatives |
| WO2016036804A1 (en) | 2014-09-03 | 2016-03-10 | Immunogen, Inc. | Cytotoxic benzodiazepine derivatives |
| TW201617368A (zh) | 2014-09-05 | 2016-05-16 | 史坦森特瑞斯公司 | 新穎抗mfi2抗體及使用方法 |
| EP3193940A1 (en) | 2014-09-10 | 2017-07-26 | Medimmune Limited | Pyrrolobenzodiazepines and conjugates thereof |
| PE20170670A1 (es) | 2014-09-12 | 2017-06-06 | Genentech Inc | Anticuerpos anti-cll-1 e inmunoconjugados |
| GB201416112D0 (en) | 2014-09-12 | 2014-10-29 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
| CN106804108B (zh) | 2014-09-12 | 2021-08-10 | 基因泰克公司 | 抗-b7-h4抗体及免疫缀合物 |
| SG11201701128YA (en) | 2014-09-12 | 2017-03-30 | Genentech Inc | Cysteine engineered antibodies and conjugates |
| SG11201701623UA (en) | 2014-09-12 | 2017-03-30 | Genentech Inc | Anti-her2 antibodies and immunoconjugates |
| CA2957148A1 (en) | 2014-09-17 | 2016-03-24 | Genentech, Inc. | Immunoconjugates comprising anti-her2 antibodies and pyrrolobenzodiazepines |
| US10780096B2 (en) | 2014-11-25 | 2020-09-22 | Adc Therapeutics Sa | Pyrrolobenzodiazepine-antibody conjugates |
| KR102693806B1 (ko) | 2014-12-11 | 2024-08-09 | 피에르 파브르 메디카먼트 | 항-c10orf54 항체들 및 그들의 용도들 |
| ES2747386T3 (es) | 2015-01-14 | 2020-03-10 | Bristol Myers Squibb Co | Dímeros de benzodiacepina unidos por heteroarileno, conjugados de los mismos y métodos de preparación y uso |
| BR112017014599A2 (pt) | 2015-01-14 | 2018-01-16 | Bristol-Myers Squibb Company | dímeros de benzodiazepina, conjugados dos mesmos, e métodos de preparação e uso |
| GB201506402D0 (en) | 2015-04-15 | 2015-05-27 | Berkel Patricius H C Van And Howard Philip W | Site-specific antibody-drug conjugates |
| GB201506411D0 (en) | 2015-04-15 | 2015-05-27 | Bergenbio As | Humanized anti-axl antibodies |
| GB201510010D0 (en) | 2015-06-09 | 2015-07-22 | King S College London | PDD and BPD compounds |
| CN108026123B (zh) | 2015-06-15 | 2021-02-05 | 杭州多禧生物科技有限公司 | 用于偶联的亲水链接体 |
| AU2016284340A1 (en) | 2015-06-23 | 2018-02-08 | Bristol-Myers Squibb Company | Macrocyclic benzodiazepine dimers, conjugates thereof, preparation and uses |
| CA2991973C (en) | 2015-07-12 | 2021-12-07 | Suzhou M-Conj Biotech Co., Ltd. | Bridge linkers for conjugation of a cell-binding molecule |
| US9839687B2 (en) | 2015-07-15 | 2017-12-12 | Suzhou M-Conj Biotech Co., Ltd. | Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule |
| AU2016297087B2 (en) | 2015-07-21 | 2021-02-18 | Immunogen, Inc | Methods of preparing cytotoxic benzodiazepine derivatives |
| US20180339985A1 (en) | 2015-08-21 | 2018-11-29 | Femtogenix Limited | Pdd compounds |
| GB201514928D0 (en) | 2015-08-21 | 2015-10-07 | King S College London | PDD compounds |
| EP4477269A3 (en) | 2015-09-20 | 2025-03-19 | The United States of America, as Represented By the Secretary, Department of Health and Human Services | Monoclonal antibodies specific for fibroblast growth factor receptor 4 (fgfr4) and methods of their use |
| MA43345A (fr) | 2015-10-02 | 2018-08-08 | Hoffmann La Roche | Conjugués anticorps-médicaments de pyrrolobenzodiazépine et méthodes d'utilisation |
| MA43354A (fr) | 2015-10-16 | 2018-08-22 | Genentech Inc | Conjugués médicamenteux à pont disulfure encombré |
| US12102689B2 (en) | 2015-11-09 | 2024-10-01 | R.P. Scherer Technologies, Llc | Anti-CD22 antibody-maytansine conjugates and methods of use thereof |
| GB201601431D0 (en) | 2016-01-26 | 2016-03-09 | Medimmune Ltd | Pyrrolobenzodiazepines |
| GB201602359D0 (en) | 2016-02-10 | 2016-03-23 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
| GB201602356D0 (en) | 2016-02-10 | 2016-03-23 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
| WO2017161206A1 (en) | 2016-03-16 | 2017-09-21 | Halozyme, Inc. | Conjugates containing conditionally active antibodies or antigen-binding fragments thereof, and methods of use |
| MA45328A (fr) | 2016-04-01 | 2019-02-06 | Avidity Biosciences Llc | Compositions acide nucléique-polypeptide et utilisations de celles-ci |
| JP6735355B2 (ja) | 2016-04-15 | 2020-08-05 | バイオアトラ、エルエルシー | 抗Axl抗体、抗体断片およびそれらの免疫コンジュゲートならびにそれらの使用 |
| TW201805309A (zh) | 2016-04-21 | 2018-02-16 | 艾伯維史坦森特瑞斯有限責任公司 | 新穎抗-bmpr1b抗體及使用方法 |
| GB201607478D0 (en) | 2016-04-29 | 2016-06-15 | Medimmune Ltd | Pyrrolobenzodiazepine Conjugates |
| WO2017196847A1 (en) | 2016-05-10 | 2017-11-16 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Variable new antigen receptor (vnar) antibodies and antibody conjugates targeting tumor and viral antigens |
| TW201808336A (zh) | 2016-05-11 | 2018-03-16 | 賽諾菲公司 | 用抗muc1類美登素免疫綴合物抗體治療腫瘤的治療方案 |
| WO2017197234A1 (en) | 2016-05-13 | 2017-11-16 | Bioatla, Llc | Anti-ror2 antibodies, antibody fragments, their immunoconjugates and uses thereof |
| WO2017205741A1 (en) | 2016-05-27 | 2017-11-30 | Genentech, Inc. | Bioanalytical method for the characterization of site-specific antibody-drug conjugates |
| WO2017214182A1 (en) | 2016-06-07 | 2017-12-14 | The United States Of America. As Represented By The Secretary, Department Of Health & Human Services | Fully human antibody targeting pdi for cancer immunotherapy |
| US11066479B2 (en) | 2016-08-02 | 2021-07-20 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Monoclonal antibodies targeting glypican-2 (GPC2) and use thereof |
| CN109963871A (zh) | 2016-08-05 | 2019-07-02 | 豪夫迈·罗氏有限公司 | 具有激动活性的多价及多表位抗体以及使用方法 |
| EP3496763A1 (en) | 2016-08-11 | 2019-06-19 | Genentech, Inc. | Pyrrolobenzodiazepine prodrugs and antibody conjugates thereof |
| US20200023072A1 (en) | 2016-10-11 | 2020-01-23 | Medimmune Limited | Antibody-drug conjugates with immune-mediated therapy agents |
| GB201617466D0 (en) | 2016-10-14 | 2016-11-30 | Medimmune Ltd | Pyrrolobenzodiazepine conjugates |
| KR102345175B1 (ko) | 2016-11-14 | 2021-12-31 | 항저우 디에이씨 바이오테크 씨오, 엘티디 | 결합 링커, 그러한 결합 링커를 함유하는 세포 결합 분자-약물 결합체, 링커를 갖는 그러한 결합체의 제조 및 사용 |
| KR102221364B1 (ko) | 2016-11-21 | 2021-03-04 | 쿠레아브 게엠베하 | 항-gp73 항체 및 면역접합체 |
| FR3059550B1 (fr) | 2016-12-01 | 2020-01-03 | Universite De Rouen Normandie | Traitement des troubles causes par l'alcoolisation foetale (tcaf) |
| WO2018119279A1 (en) | 2016-12-21 | 2018-06-28 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human monoclonal antibodies specific for flt3 and uses thereof |
| EP3544636B1 (en) | 2017-02-08 | 2021-03-31 | ADC Therapeutics SA | Pyrrolobenzodiazepine-antibody conjugates |
| GB201702031D0 (en) | 2017-02-08 | 2017-03-22 | Medlmmune Ltd | Pyrrolobenzodiazepine-antibody conjugates |
| CA3059519C (en) * | 2017-04-18 | 2021-03-23 | Medimmune Limited | Pyrrolobenzodiazepine conjugates |
| CN110536703B (zh) | 2017-04-20 | 2024-07-12 | Adc治疗有限公司 | 使用抗axl抗体-药物缀合物的组合疗法 |
| WO2018195243A1 (en) | 2017-04-20 | 2018-10-25 | Immunogen, Inc. | Cytotoxic benzodiazepine derivatives and conjugates thereof |
| CA3059472A1 (en) | 2017-05-19 | 2018-11-22 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human monoclonal antibody targeting tnfr2 for cancer immunotherapy |
| UA127900C2 (uk) | 2017-06-14 | 2024-02-07 | Ейдісі Терапьютікс Са | Схема дозування для введення adc до cd19 |
| CA3066953A1 (en) | 2017-06-30 | 2019-01-03 | Lentigen Technology, Inc. | Human monoclonal antibodies specific for cd33 and methods of their use |
| WO2019005208A1 (en) | 2017-06-30 | 2019-01-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | ANTIBODIES TO HUMAN MESOTHELIN AND USES IN ANTICANCER THERAPY |
| CN111201030B (zh) | 2017-07-25 | 2024-11-01 | 真和制药有限公司 | 通过阻断tim-3和其配体的相互作用治疗癌症 |
| MX384245B (es) | 2017-08-18 | 2025-03-14 | Medimmune Ltd | Conjugados de pirrolobenzodiazepina |
| IL273471B2 (en) | 2017-09-29 | 2023-09-01 | Daiichi Sankyo Co Ltd | Conjugation of an antibody with a pyrrolobenzodiazepine derivative |
| JP2021502969A (ja) | 2017-11-14 | 2021-02-04 | メドイミューン・リミテッドMedImmune Limited | ピロロベンゾジアゼピン複合体 |
| EP3724225A1 (en) | 2017-12-15 | 2020-10-21 | Juno Therapeutics, Inc. | Anti-cct5 binding molecules and methods of use thereof |
| WO2019133652A1 (en) | 2017-12-28 | 2019-07-04 | Immunogen, Inc. | Benzodiazepine derivatives |
| GB201803342D0 (en) * | 2018-03-01 | 2018-04-18 | Medimmune Ltd | Methods |
| GB201806022D0 (en) | 2018-04-12 | 2018-05-30 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
| WO2019224340A1 (en) | 2018-05-25 | 2019-11-28 | Medimmune Limited | Pyrrolobenzodiazepine conjugates |
| FR3081707A1 (fr) | 2018-05-30 | 2019-12-06 | Universite De Rouen Normandie | Traitement des troubles neurologiques causes par l'alcoolisation foetale |
| EP3820903A1 (en) | 2018-07-12 | 2021-05-19 | The United States of America, as represented by the Secretary, Department of Health and Human Services | Affinity matured cd22-specific monoclonal antibody and uses thereof |
| WO2020033430A1 (en) | 2018-08-08 | 2020-02-13 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | High affinity monoclonal antibodies targeting glypican-2 and uses thereof |
| EP3866856A1 (en) | 2018-10-19 | 2021-08-25 | MedImmune Limited | Pyrrolobenzodiazepine conjugates |
| CN112867510A (zh) | 2018-10-19 | 2021-05-28 | 免疫医疗有限公司 | 吡咯并苯并二氮杂䓬缀合物 |
| IL319265A (en) | 2018-12-21 | 2025-04-01 | Avidity Biosciences Inc | Anti-transferrin receptor antibodies and their uses |
| AU2020206308A1 (en) | 2019-01-08 | 2021-07-22 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Cross-species single domain antibodies targeting mesothelin for treating solid tumors |
| WO2020154150A1 (en) | 2019-01-22 | 2020-07-30 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | High affinity monoclonal antibodies targeting glypican-1 and methods of use |
| CA3127113A1 (en) | 2019-01-30 | 2020-08-06 | Dongxu Sun | Anti-gal3 antibodies and uses thereof |
| AU2020242747B2 (en) | 2019-03-15 | 2025-09-18 | Medimmune Limited | Azetidobenzodiazepine dimers and conjugates comprising them for use in the treatment of cancer |
| TW202102506A (zh) | 2019-03-29 | 2021-01-16 | 美商伊繆諾金公司 | 苯二氮平衍生物 |
| JP7690468B2 (ja) | 2019-10-22 | 2025-06-10 | ザ ユナイテッド ステイツ オブ アメリカ, アズ リプレゼンテッド バイ ザ セクレタリー, デパートメント オブ ヘルス アンド ヒューマン サービシーズ | 多様な固形腫瘍を処置するためのb7h3(cd276)を標的とする高親和性ナノボディ |
| WO2021118968A1 (en) | 2019-12-12 | 2021-06-17 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Antibody-drug conjugates specific for cd276 and uses thereof |
| KR20220156867A (ko) | 2020-03-19 | 2022-11-28 | 어비디티 바이오사이언시스 인크. | 안면견갑상완 근이영양증의 치료용 조성물 및 방법 |
| EP4126066B1 (en) | 2020-03-27 | 2025-11-19 | Avidity Biosciences, Inc. | Compositions and methods of treating muscle dystrophy |
| JP2023528797A (ja) | 2020-05-26 | 2023-07-06 | トゥルーバインディング,インコーポレイテッド | ガレクチン-3を遮断することにより炎症性疾患を処置する方法 |
| US20230391852A1 (en) | 2020-10-26 | 2023-12-07 | The U.S.A., As Represented By The Secretary, Department Of Health And Human Services | Single domain antibodies targeting sars coronavirus spike protein and uses thereof |
| US20240218055A1 (en) | 2021-04-29 | 2024-07-04 | The U.S.A., As Represented By The Secretary, Department Of Health And Human Services | Lassa virus-specific nanobodies and methods of their use |
| US20240270851A1 (en) | 2021-06-09 | 2024-08-15 | The U.S.A., As Represented By The Secretary, Department Of Health And Human Services | Cross species single domain antibodies targeting pd-l1 for treating solid tumors |
| US20250026838A1 (en) | 2021-07-13 | 2025-01-23 | Truebinding, Inc. | Methods of preventing protein aggregation |
| EP4401792A4 (en) | 2021-09-16 | 2025-12-03 | Avidity Biosciences Inc | COMPOSITIONS AND METHODS OF TREATMENT OF FACIO-SCAPULO-HUMERAL MUSCULAR DYSTROPHY |
| AU2021362997A1 (en) | 2021-11-03 | 2024-05-16 | Hangzhou Dac Biotech Co., Ltd. | Specific conjugation of an antibody |
| CN118524852A (zh) | 2021-11-09 | 2024-08-20 | 真和制药有限公司 | 治疗或抑制心血管疾病的方法 |
| KR20250006932A (ko) | 2022-05-03 | 2025-01-13 | 제넨테크, 인크. | 항-Ly6E 항체, 면역접합체 및 이들의 용도 |
| WO2025019228A1 (en) | 2023-07-20 | 2025-01-23 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Fully human monoclonal antibodies and chimeric antigen receptors against cd276 for the treatment of solid tumors |
| WO2025171238A1 (en) | 2024-02-07 | 2025-08-14 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Monoclonal antibodies that bind the juxta-membrane region of mesothelin and uses thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1299198A (en) * | 1968-12-30 | 1972-12-06 | Fujisawa Pharmaceutical Co | Pyrrolobenzodiazepinone derivatives |
| JPS57131791A (en) * | 1980-12-31 | 1982-08-14 | Fujisawa Pharmaceut Co Ltd | Benzodiazepine derivative and its preparation |
| JPS59101486A (ja) * | 1982-11-08 | 1984-06-12 | ブリストル―マイヤーズ スクイブ カンパニー | トマイマイシン中間体化合物とその製造法 |
Family Cites Families (35)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3523941A (en) | 1967-03-06 | 1970-08-11 | Hoffmann La Roche | Benzodiazepine compounds and process for their preparation |
| US3524849A (en) | 1967-10-27 | 1970-08-18 | Hoffmann La Roche | Process for the preparation of pyrrolo-benzodiazepine acrylamides and intermediates useful therein |
| FR2027356A1 (en) | 1968-12-30 | 1970-09-25 | Fujisawa Pharmaceutical Co | Benzodiazepinone antibiotics |
| JPS6053033B2 (ja) | 1976-12-28 | 1985-11-22 | 財団法人微生物化学研究会 | 新制癌抗生物質マゼスラマイシン及びその製造方法 |
| JPS585916B2 (ja) | 1977-12-27 | 1983-02-02 | 株式会社ミドリ十字 | 新規ベンゾジアゼピン系化合物 |
| JPS5615289A (en) | 1979-07-17 | 1981-02-14 | Green Cross Corp:The | Novel benzodiazepinnbased compound 3 |
| JPS58180487A (ja) | 1982-04-16 | 1983-10-21 | Kyowa Hakko Kogyo Co Ltd | 抗生物質dc−81およびその製造法 |
| FR2586683B1 (fr) | 1985-08-29 | 1988-07-01 | Centre Nat Rech Scient | Nouveaux derives de neothramycine, leur procede de preparation et leur application en tant que medicaments |
| GB8607679D0 (en) | 1986-03-27 | 1986-04-30 | Winter G P | Recombinant dna product |
| ATE112279T1 (de) | 1986-12-19 | 1994-10-15 | Upjohn Co | Cc-1065 analoge. |
| GB8705477D0 (en) | 1987-03-09 | 1987-04-15 | Carlton Med Prod | Drug delivery systems |
| GB8809616D0 (en) | 1988-04-22 | 1988-05-25 | Cancer Res Campaign Tech | Further improvements relating to drug delivery systems |
| US5143854A (en) * | 1989-06-07 | 1992-09-01 | Affymax Technologies N.V. | Large scale photolithographic solid phase synthesis of polypeptides and receptor binding screening thereof |
| JPH05508394A (ja) | 1990-04-25 | 1993-11-25 | ファルマシア・アンド・アップジョン・カンパニー | 新規なcc―1065アナログ |
| FR2676230B1 (fr) | 1991-05-07 | 1993-08-27 | Centre Nat Rech Scient | Nouveaux derives de pyrrolo [1,4]-benzodiazepines, leur procede de preparation et medicaments les contenant. |
| DE69233669T2 (de) | 1991-10-23 | 2007-10-25 | Cancer Research Technology Ltd. | Bakterielle nitroreduktase zur reduzierung von cb 1954 und analogen davon in eine zytotoxische form |
| GB9205051D0 (en) | 1992-03-09 | 1992-04-22 | Cancer Res Campaign Tech | Pyrrolobenzodiazepine derivatives,their preparation,and compositions containing them |
| US5288514A (en) * | 1992-09-14 | 1994-02-22 | The Regents Of The University Of California | Solid phase and combinatorial synthesis of benzodiazepine compounds on a solid support |
| US5502068A (en) | 1995-01-31 | 1996-03-26 | Synphar Laboratories, Inc. | Cyclopropylpyrroloindole-oligopeptide anticancer agents |
| JPH11508563A (ja) | 1995-06-29 | 1999-07-27 | ファーマコペイア,インコーポレイテッド | 1,4−ベンゾジアゼピン−2,5−ジオン組合わせライブラリー |
| GB9516943D0 (en) | 1995-08-18 | 1995-10-18 | Cancer Soc Auckland Div Nz Inc | Novel cyclopropylindoles and their secoprecursors,and their use as prodrugs |
| EP0938474B1 (en) | 1996-09-12 | 2005-11-23 | Auckland Uniservices Limited | Cyclopropylindole compounds and their use as prodrugs |
| JPH1087666A (ja) | 1996-09-18 | 1998-04-07 | Kyorin Pharmaceut Co Ltd | デュオカルマイシンsa及びその誘導体の製造中間体と製造方法 |
| US6310209B1 (en) | 1997-12-08 | 2001-10-30 | The Scripps Research Institute | Synthesis of CC-1065/duocarmycin analogs |
| WO1999046244A1 (en) | 1998-03-12 | 1999-09-16 | Novo Nordisk A/S | Modulators of protein tyrosine phosphatases (ptpases) |
| ES2260570T3 (es) | 1998-08-27 | 2006-11-01 | Spirogen Limited | Pirrolobenziodiazepinas dimericas. |
| GB9818730D0 (en) * | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collections of compounds |
| GB9818732D0 (en) * | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collection of compounds |
| GB9818731D0 (en) * | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Compounds |
| GB9909612D0 (en) | 1999-04-26 | 1999-06-23 | Cancer Res Campaign Tech | N-protected amines and their use as prodrugs |
| US6660856B2 (en) | 2002-03-08 | 2003-12-09 | Kaohsiung Medical University | Synthesis of pyrrolo[2,1-c][1,4]benzodiazepine analogues |
| GB0226593D0 (en) | 2002-11-14 | 2002-12-24 | Consultants Ltd | Compounds |
| GB0321295D0 (en) | 2003-09-11 | 2003-10-15 | Spirogen Ltd | Synthesis of protected pyrrolobenzodiazepines |
| WO2005040170A2 (en) | 2003-10-22 | 2005-05-06 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Pyrrolobenzodiazepine derivatives, compositions comprising the same and methods related thereto |
| ATE542821T1 (de) | 2004-03-01 | 2012-02-15 | Spirogen Ltd | 11-hydroxy-5h-pyrroloä2,1-cüä1,4übenzodiazepin- - on derivate als zwischenverbindungen für die herstellung von c2 substituierten pyrrolobenzodiazepinen |
-
1999
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- 1999-08-27 AT AT01129700T patent/ATE240334T1/de active
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- 1999-08-27 EP EP03028817A patent/EP1413582B1/en not_active Expired - Lifetime
-
2001
- 2001-12-12 US US10/021,213 patent/US7067511B2/en not_active Expired - Lifetime
-
2006
- 2006-03-02 US US11/367,241 patent/US7265105B2/en not_active Expired - Lifetime
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1299198A (en) * | 1968-12-30 | 1972-12-06 | Fujisawa Pharmaceutical Co | Pyrrolobenzodiazepinone derivatives |
| JPS57131791A (en) * | 1980-12-31 | 1982-08-14 | Fujisawa Pharmaceut Co Ltd | Benzodiazepine derivative and its preparation |
| JPS59101486A (ja) * | 1982-11-08 | 1984-06-12 | ブリストル―マイヤーズ スクイブ カンパニー | トマイマイシン中間体化合物とその製造法 |
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