DE69925133T2 - Pyrrolobenzodiazepine - Google Patents
Pyrrolobenzodiazepine Download PDFInfo
- Publication number
- DE69925133T2 DE69925133T2 DE69925133T DE69925133T DE69925133T2 DE 69925133 T2 DE69925133 T2 DE 69925133T2 DE 69925133 T DE69925133 T DE 69925133T DE 69925133 T DE69925133 T DE 69925133T DE 69925133 T2 DE69925133 T2 DE 69925133T2
- Authority
- DE
- Germany
- Prior art keywords
- mmol
- compound
- nch
- carbon atoms
- nmr
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
- YUOCYTRGANSSRY-UHFFFAOYSA-N pyrrolo[2,3-i][1,2]benzodiazepine Chemical compound C1=CN=NC2=C3C=CN=C3C=CC2=C1 YUOCYTRGANSSRY-UHFFFAOYSA-N 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 142
- -1 hydroxy, amino Chemical group 0.000 claims description 91
- 125000004432 carbon atom Chemical group C* 0.000 claims description 66
- 125000000217 alkyl group Chemical group 0.000 claims description 54
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 43
- 125000003118 aryl group Chemical group 0.000 claims description 37
- 239000000539 dimer Substances 0.000 claims description 37
- 125000005842 heteroatom Chemical group 0.000 claims description 30
- 229910052736 halogen Inorganic materials 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 23
- 229910052757 nitrogen Inorganic materials 0.000 claims description 19
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 17
- 125000000524 functional group Chemical group 0.000 claims description 15
- CREMABGTGYGIQB-UHFFFAOYSA-N carbon carbon Chemical compound C.C CREMABGTGYGIQB-UHFFFAOYSA-N 0.000 claims description 14
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 14
- 239000000178 monomer Substances 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 11
- 125000001475 halogen functional group Chemical group 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 8
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 7
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- ALARUQBUFAFMSJ-HNNXBMFYSA-N (6as)-2,3-dimethoxy-8-(4-methoxyphenyl)-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C1=CC(OC)=CC=C1C1=CN2C(=O)C3=CC(OC)=C(OC)C=C3N=C[C@@H]2C1 ALARUQBUFAFMSJ-HNNXBMFYSA-N 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 208000035143 Bacterial infection Diseases 0.000 claims description 3
- 208000030852 Parasitic disease Diseases 0.000 claims description 3
- 208000036142 Viral infection Diseases 0.000 claims description 3
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000003071 parasitic effect Effects 0.000 claims description 3
- 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
- 230000002062 proliferating effect Effects 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 230000003612 virological effect Effects 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims 1
- 125000006575 electron-withdrawing group Chemical group 0.000 claims 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 425
- 239000000243 solution Substances 0.000 description 397
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 333
- 238000005481 NMR spectroscopy Methods 0.000 description 316
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 258
- 239000011541 reaction mixture Substances 0.000 description 241
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 238
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 207
- 239000000203 mixture Substances 0.000 description 149
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 144
- 239000012267 brine Substances 0.000 description 132
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 132
- 239000000460 chlorine Substances 0.000 description 128
- 238000003818 flash chromatography Methods 0.000 description 118
- 239000002904 solvent Substances 0.000 description 115
- 238000006243 chemical reaction Methods 0.000 description 113
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 112
- 238000003756 stirring Methods 0.000 description 111
- 239000000047 product Substances 0.000 description 104
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 100
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 99
- 238000004809 thin layer chromatography Methods 0.000 description 96
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 92
- 239000012074 organic phase Substances 0.000 description 90
- 239000003921 oil Substances 0.000 description 85
- 235000019198 oils Nutrition 0.000 description 85
- 230000015572 biosynthetic process Effects 0.000 description 78
- 239000012299 nitrogen atmosphere Substances 0.000 description 77
- PUAQLLVFLMYYJJ-UHFFFAOYSA-N 2-aminopropiophenone Chemical compound CC(N)C(=O)C1=CC=CC=C1 PUAQLLVFLMYYJJ-UHFFFAOYSA-N 0.000 description 69
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 68
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 65
- 239000007787 solid Substances 0.000 description 65
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 64
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 61
- 238000001704 evaporation Methods 0.000 description 58
- 230000008020 evaporation Effects 0.000 description 58
- 239000011521 glass Substances 0.000 description 58
- 238000003786 synthesis reaction Methods 0.000 description 58
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 56
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 56
- 239000003208 petroleum Substances 0.000 description 54
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 48
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 47
- 101150065749 Churc1 gene Proteins 0.000 description 47
- 102100038239 Protein Churchill Human genes 0.000 description 47
- 230000002829 reductive effect Effects 0.000 description 46
- 239000012043 crude product Substances 0.000 description 43
- 229920006395 saturated elastomer Polymers 0.000 description 41
- 238000000034 method Methods 0.000 description 35
- 238000000746 purification Methods 0.000 description 35
- 239000007858 starting material Substances 0.000 description 35
- 150000002576 ketones Chemical class 0.000 description 34
- 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 33
- 150000002466 imines Chemical class 0.000 description 33
- 238000001819 mass spectrum Methods 0.000 description 33
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 32
- 150000001412 amines Chemical group 0.000 description 32
- 230000003197 catalytic effect Effects 0.000 description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 29
- XMYQHJDBLRZMLW-UHFFFAOYSA-N methanolamine Chemical compound NCO XMYQHJDBLRZMLW-UHFFFAOYSA-N 0.000 description 29
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 28
- 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 28
- 239000000725 suspension Substances 0.000 description 27
- 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 26
- 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 26
- 241000790917 Dioxys <bee> Species 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 24
- 235000019341 magnesium sulphate Nutrition 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 23
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 23
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 22
- 150000001408 amides Chemical class 0.000 description 22
- 238000001914 filtration Methods 0.000 description 22
- 235000019502 Orange oil Nutrition 0.000 description 21
- 239000010502 orange oil Substances 0.000 description 21
- 238000010992 reflux Methods 0.000 description 21
- 239000000741 silica gel Substances 0.000 description 21
- 229910002027 silica gel Inorganic materials 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
- 238000005755 formation reaction Methods 0.000 description 20
- HVVNJUAVDAZWCB-UHFFFAOYSA-N prolinol Chemical compound OCC1CCCN1 HVVNJUAVDAZWCB-UHFFFAOYSA-N 0.000 description 20
- 239000003480 eluent Substances 0.000 description 19
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 19
- 239000002244 precipitate Substances 0.000 description 19
- 239000000758 substrate Substances 0.000 description 19
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 19
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 18
- 239000002253 acid Substances 0.000 description 18
- 239000008346 aqueous phase Substances 0.000 description 18
- 239000012071 phase Substances 0.000 description 18
- 150000002148 esters Chemical class 0.000 description 17
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 17
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 16
- 239000007868 Raney catalyst Substances 0.000 description 16
- 229910000564 Raney nickel Inorganic materials 0.000 description 16
- 238000002390 rotary evaporation Methods 0.000 description 16
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 16
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 15
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 15
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 15
- PWDSJBHSKYBUEX-UHFFFAOYSA-N 1,4-benzodiazepin-5-one Chemical compound O=C1N=CC=NC2=CC=CC=C12 PWDSJBHSKYBUEX-UHFFFAOYSA-N 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 14
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 14
- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 14
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 14
- 150000002009 diols Chemical class 0.000 description 13
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 13
- 150000002828 nitro derivatives Chemical class 0.000 description 13
- 239000012258 stirred mixture Substances 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 229910004298 SiO 2 Inorganic materials 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000543 intermediate Substances 0.000 description 12
- 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 12
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- 125000006239 protecting group Chemical group 0.000 description 11
- 229910000104 sodium hydride Inorganic materials 0.000 description 11
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 10
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 10
- 239000003242 anti bacterial agent Substances 0.000 description 10
- 229940088710 antibiotic agent Drugs 0.000 description 10
- 229910052793 cadmium Inorganic materials 0.000 description 10
- 239000012230 colorless oil Substances 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 10
- 238000007254 oxidation reaction Methods 0.000 description 10
- 229910052763 palladium Inorganic materials 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 230000009467 reduction Effects 0.000 description 10
- 239000000377 silicon dioxide Substances 0.000 description 10
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 9
- 239000005695 Ammonium acetate Substances 0.000 description 9
- 235000019257 ammonium acetate Nutrition 0.000 description 9
- 229940043376 ammonium acetate Drugs 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 230000003647 oxidation Effects 0.000 description 9
- 239000002002 slurry Substances 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
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 8
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 8
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 8
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 8
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 8
- 238000005859 coupling reaction Methods 0.000 description 8
- 239000006185 dispersion Substances 0.000 description 8
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 8
- 125000001041 indolyl group Chemical group 0.000 description 8
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 description 8
- GUFUWKKDHIABBW-UHFFFAOYSA-N pyrrolidin-1-ylmethanol Chemical compound OCN1CCCC1 GUFUWKKDHIABBW-UHFFFAOYSA-N 0.000 description 8
- 235000011150 stannous chloride Nutrition 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
- 238000006859 Swern oxidation reaction Methods 0.000 description 7
- 150000001336 alkenes Chemical class 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 230000008878 coupling Effects 0.000 description 7
- 238000010168 coupling process Methods 0.000 description 7
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 7
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 229910017604 nitric acid Inorganic materials 0.000 description 7
- OCAAZRFBJBEVPS-UHFFFAOYSA-N prop-2-enyl carbamate Chemical compound NC(=O)OCC=C OCAAZRFBJBEVPS-UHFFFAOYSA-N 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 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 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
- 229960000583 acetic acid Drugs 0.000 description 6
- 150000001299 aldehydes Chemical class 0.000 description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 6
- 239000012153 distilled water Substances 0.000 description 6
- 239000006260 foam Substances 0.000 description 6
- 239000012362 glacial acetic acid Substances 0.000 description 6
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- BVWTXUYLKBHMOX-UHFFFAOYSA-N methyl vanillate Chemical compound COC(=O)C1=CC=C(O)C(OC)=C1 BVWTXUYLKBHMOX-UHFFFAOYSA-N 0.000 description 6
- 239000002808 molecular sieve Substances 0.000 description 6
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 6
- 239000010409 thin film Substances 0.000 description 6
- 238000003828 vacuum filtration Methods 0.000 description 6
- IDQIPJZFVPUDLI-INIZCTEOSA-N (6as)-2-methoxy-8-methylidene-3-phenylmethoxy-7,9-dihydro-6ah-pyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound COC1=CC(C(N2CC(=C)C[C@H]2C=N2)=O)=C2C=C1OCC1=CC=CC=C1 IDQIPJZFVPUDLI-INIZCTEOSA-N 0.000 description 5
- 101100042265 Caenorhabditis elegans sem-2 gene Proteins 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 101100042258 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) sem-1 gene Proteins 0.000 description 5
- RGFZIKBSMAAKQF-QEMIJWRASA-N [5-amino-4-[3-[2-amino-4-[(2s,4s)-2-(hydroxymethyl)-4-methylpyrrolidine-1-carbonyl]-5-methoxyphenoxy]propoxy]-2-methoxyphenyl]-[2-(hydroxymethyl)-4-methylpyrrolidin-1-yl]methanone Chemical compound NC=1C=C(C(=O)N2C(CC(C)C2)CO)C(OC)=CC=1OCCCOC(C(=C1)N)=CC(OC)=C1C(=O)N1C[C@@H](C)C[C@H]1CO RGFZIKBSMAAKQF-QEMIJWRASA-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
- 238000001816 cooling Methods 0.000 description 5
- 239000013058 crude material Substances 0.000 description 5
- 239000010779 crude oil Substances 0.000 description 5
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 5
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 238000007363 ring formation reaction Methods 0.000 description 5
- 150000003333 secondary alcohols Chemical class 0.000 description 5
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 description 5
- VXDDXZOVWMYPKW-NSHDSACASA-N tert-butyl-dimethyl-[[(2s)-4-methylidenepyrrolidin-2-yl]methoxy]silane Chemical compound CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=C)CN1 VXDDXZOVWMYPKW-NSHDSACASA-N 0.000 description 5
- PMMYEEVYMWASQN-IMJSIDKUSA-N trans-4-Hydroxy-L-proline Natural products O[C@@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-IMJSIDKUSA-N 0.000 description 5
- TXUICONDJPYNPY-UHFFFAOYSA-N (1,10,13-trimethyl-3-oxo-4,5,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-17-yl) heptanoate Chemical compound C1CC2CC(=O)C=C(C)C2(C)C2C1C1CCC(OC(=O)CCCCCC)C1(C)CC2 TXUICONDJPYNPY-UHFFFAOYSA-N 0.000 description 4
- HAYYTYCXOYDMAP-ABAIWWIYSA-N (2S,4R)-4-hydroxy-2-methoxycarbonyl-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound C(C1=CC=CC=C1)OC(=O)N1[C@@](C[C@H](C1)O)(C(=O)O)C(=O)OC HAYYTYCXOYDMAP-ABAIWWIYSA-N 0.000 description 4
- WWVCWLBEARZMAH-MNOVXSKESA-N (2s,4r)-4-hydroxy-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound C1[C@H](O)C[C@@H](C(O)=O)N1C(=O)OCC1=CC=CC=C1 WWVCWLBEARZMAH-MNOVXSKESA-N 0.000 description 4
- HNOYIBNHCFTQIK-HNNXBMFYSA-N (6as)-2,3-dimethoxy-8-phenyl-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C([C@H]1C=NC=2C=C(C(=CC=2C(=O)N1C=1)OC)OC)C=1C1=CC=CC=C1 HNOYIBNHCFTQIK-HNNXBMFYSA-N 0.000 description 4
- MOJNVJSSEAMAHS-QFIPXVFZSA-N (6as)-2-methoxy-8-[(4-methoxyphenyl)methylidene]-3-phenylmethoxy-7,9-dihydro-6ah-pyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C1=CC(OC)=CC=C1C=C1CN2C(=O)C3=CC(OC)=C(OCC=4C=CC=CC=4)C=C3N=C[C@@H]2C1 MOJNVJSSEAMAHS-QFIPXVFZSA-N 0.000 description 4
- XPTLDRHAPFTFSN-NSHDSACASA-N (6as)-8-ethenyl-2,3-dimethoxy-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1=C[C@@H]2CC(C=C)=CN2C(=O)C2=C1C=C(OC)C(OC)=C2 XPTLDRHAPFTFSN-NSHDSACASA-N 0.000 description 4
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 description 4
- BWWHTIHDQBHTHP-UHFFFAOYSA-N 2-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1C(Cl)=O BWWHTIHDQBHTHP-UHFFFAOYSA-N 0.000 description 4
- IBOFVQJTBBUKMU-UHFFFAOYSA-N 4,4'-methylene-bis-(2-chloroaniline) Chemical compound C1=C(Cl)C(N)=CC=C1CC1=CC=C(N)C(Cl)=C1 IBOFVQJTBBUKMU-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical class [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 4
- LRMXRMDTNBDGDL-BGERDNNASA-N [4-[3-[4-[(2s)-2-(hydroxymethyl)-4-methylidenepyrrolidine-1-carbonyl]-5-methoxy-2-nitrophenoxy]propoxy]-2-methoxy-5-nitrophenyl]-[2-(hydroxymethyl)-4-methylidenepyrrolidin-1-yl]methanone Chemical compound [O-][N+](=O)C=1C=C(C(=O)N2C(CC(=C)C2)CO)C(OC)=CC=1OCCCOC(C(=C1)[N+]([O-])=O)=CC(OC)=C1C(=O)N1CC(=C)C[C@H]1CO LRMXRMDTNBDGDL-BGERDNNASA-N 0.000 description 4
- XXROGKLTLUQVRX-UHFFFAOYSA-N allyl alcohol Chemical compound OCC=C XXROGKLTLUQVRX-UHFFFAOYSA-N 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 238000009835 boiling Methods 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000003776 cleavage reaction Methods 0.000 description 4
- 238000010511 deprotection reaction Methods 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- 230000007062 hydrolysis Effects 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
- 239000005457 ice water Substances 0.000 description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- CTSAXXHOGZNKJR-UHFFFAOYSA-N methyl 2-diethoxyphosphorylacetate Chemical compound CCOP(=O)(OCC)CC(=O)OC CTSAXXHOGZNKJR-UHFFFAOYSA-N 0.000 description 4
- VCIDOARSCMESCH-UHFFFAOYSA-N methyl 3-methoxy-4-[3-[(2-methylpropan-2-yl)oxycarbonylamino]propoxy]benzoate Chemical compound COC(=O)C1=CC=C(OCCCNC(=O)OC(C)(C)C)C(OC)=C1 VCIDOARSCMESCH-UHFFFAOYSA-N 0.000 description 4
- VJRFJGMPXURLEZ-UHFFFAOYSA-N methyl 3-methoxy-4-pentoxybenzoate Chemical compound CCCCCOC1=CC=C(C(=O)OC)C=C1OC VJRFJGMPXURLEZ-UHFFFAOYSA-N 0.000 description 4
- LSEFCHWGJNHZNT-UHFFFAOYSA-M methyl(triphenyl)phosphanium;bromide Chemical compound [Br-].C=1C=CC=CC=1[P+](C=1C=CC=CC=1)(C)C1=CC=CC=C1 LSEFCHWGJNHZNT-UHFFFAOYSA-M 0.000 description 4
- 239000002480 mineral oil Substances 0.000 description 4
- 235000010446 mineral oil Nutrition 0.000 description 4
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 4
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 4
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 150000003138 primary alcohols Chemical class 0.000 description 4
- 230000007017 scission Effects 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 239000001119 stannous chloride Substances 0.000 description 4
- 229940035024 thioglycerol Drugs 0.000 description 4
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 4
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 4
- HZXBGNHQZDKTJQ-UHFFFAOYSA-N (2-amino-3,5-dimethoxy-4-phenylmethoxyphenyl)-[2-(hydroxymethyl)pyrrolidin-1-yl]methanone Chemical compound NC=1C(OC)=C(OCC=2C=CC=CC=2)C(OC)=CC=1C(=O)N1CCCC1CO HZXBGNHQZDKTJQ-UHFFFAOYSA-N 0.000 description 3
- UIIQGUSVJDAGAC-JTQLQIEISA-N (2-amino-5-iodophenyl)-[(2s)-2-(hydroxymethyl)-4-methylidenepyrrolidin-1-yl]methanone Chemical compound NC1=CC=C(I)C=C1C(=O)N1[C@H](CO)CC(=C)C1 UIIQGUSVJDAGAC-JTQLQIEISA-N 0.000 description 3
- OYWWPFDNWNTKDE-INIZCTEOSA-N (2-amino-5-methoxy-4-phenylmethoxyphenyl)-[(2s)-2-(hydroxymethyl)-4-methylidenepyrrolidin-1-yl]methanone Chemical compound NC=1C=C(OCC=2C=CC=CC=2)C(OC)=CC=1C(=O)N1CC(=C)C[C@H]1CO OYWWPFDNWNTKDE-INIZCTEOSA-N 0.000 description 3
- XHZYVDPKJZQKHJ-RQJHMYQMSA-N (2s,4r)-4-hydroxy-1-prop-2-enoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound O[C@@H]1C[C@@H](C(O)=O)N(C(=O)OCC=C)C1 XHZYVDPKJZQKHJ-RQJHMYQMSA-N 0.000 description 3
- UTUQQMFNUMEJLE-QFIPXVFZSA-N (6as)-2,3-dimethoxy-8-phenyl-5-(2-trimethylsilylethoxymethyl)-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepine-6,11-dione Chemical compound C([C@H]1C(=O)N(COCC[Si](C)(C)C)C=2C=C(C(=CC=2C(=O)N1C=1)OC)OC)C=1C1=CC=CC=C1 UTUQQMFNUMEJLE-QFIPXVFZSA-N 0.000 description 3
- MICHSSPTFWNRQA-OCCSQVGLSA-N (6as,8r)-8-[tert-butyl(dimethyl)silyl]oxy-1,2-dimethoxy-6a,7,8,9-tetrahydro-5h-pyrrolo[2,1-c][1,4]benzodiazepine-6,11-dione Chemical compound N1C(=O)[C@@H]2C[C@@H](O[Si](C)(C)C(C)(C)C)CN2C(=O)C2=C(OC)C(OC)=CC=C21 MICHSSPTFWNRQA-OCCSQVGLSA-N 0.000 description 3
- SICDVWZWSDKONP-HIFRSBDPSA-N (6as,8r)-8-hydroxy-1,2-dimethoxy-5-(2-trimethylsilylethoxymethyl)-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepine-6,11-dione Chemical compound C[Si](C)(C)CCOCN1C(=O)[C@@H]2C[C@@H](O)CN2C(=O)C2=C(OC)C(OC)=CC=C21 SICDVWZWSDKONP-HIFRSBDPSA-N 0.000 description 3
- CYQRGYSTLZABLY-UHFFFAOYSA-N 1,2,3-trimethoxy-5,6,6a,7,8,9-hexahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1CC2CCCN2C(=O)C2=C1C=C(OC)C(OC)=C2OC CYQRGYSTLZABLY-UHFFFAOYSA-N 0.000 description 3
- SVUOLADPCWQTTE-UHFFFAOYSA-N 1h-1,2-benzodiazepine Chemical compound N1N=CC=CC2=CC=CC=C12 SVUOLADPCWQTTE-UHFFFAOYSA-N 0.000 description 3
- NAVCLYSJSSBIPM-QFYYESIMSA-N 2,2,2-trichloroethyl (6s,6as)-6-hydroxy-2,3,4-trimethoxy-11-oxo-6a,7,8,9-tetrahydro-6h-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate Chemical compound ClC(Cl)(Cl)COC(=O)N1[C@@H](O)[C@@H]2CCCN2C(=O)C2=C1C(OC)=C(OC)C(OC)=C2 NAVCLYSJSSBIPM-QFYYESIMSA-N 0.000 description 3
- VLPNKDCTKRZGPW-JSGCOSHPSA-N 2,2,2-trichloroethyl n-[(6s,6as)-6-hydroxy-2-iodo-8-methylidene-11-oxo-6,6a,7,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-5-yl]carbamate Chemical compound ClC(Cl)(Cl)COC(=O)NN1[C@@H](O)[C@@H]2CC(=C)CN2C(=O)C2=CC(I)=CC=C21 VLPNKDCTKRZGPW-JSGCOSHPSA-N 0.000 description 3
- DFZBPSUYLVWHBD-UHFFFAOYSA-N 2,2,2-trichloroethyl n-[6-[2-(hydroxymethyl)pyrrolidine-1-carbonyl]-2,4-dimethoxy-3-methylphenyl]carbamate Chemical compound COC1=C(C)C(OC)=CC(C(=O)N2C(CCC2)CO)=C1NC(=O)OCC(Cl)(Cl)Cl DFZBPSUYLVWHBD-UHFFFAOYSA-N 0.000 description 3
- HJKLEAOXCZIMPI-UHFFFAOYSA-N 2,2-diethoxyethanamine Chemical compound CCOC(CN)OCC HJKLEAOXCZIMPI-UHFFFAOYSA-N 0.000 description 3
- GEBCBWANVVHECZ-UHFFFAOYSA-N 2,4-dimethoxy-3-methyl-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1=CC2CCCN2C(=O)C2=C1C(OC)=C(C)C(OC)=C2 GEBCBWANVVHECZ-UHFFFAOYSA-N 0.000 description 3
- MTJOQIDCOOVODV-ZVNMQXQGSA-N 3-O-(9H-fluoren-9-ylmethyl) 5-O-(2,2,2-trichloroethyl) (6S,6aS)-7-amino-6-hydroxy-11-oxo-6a,7,8,9-tetrahydro-6H-pyrrolo[2,1-c][1,4]benzodiazepine-3,5-dicarboxylate Chemical compound C(=O)(OCC1C2=CC=CC=C2C2=CC=CC=C12)C1=CC2=C(C(N3[C@H]([C@@H](N2C(=O)OCC(Cl)(Cl)Cl)O)C(CC3)N)=O)C=C1 MTJOQIDCOOVODV-ZVNMQXQGSA-N 0.000 description 3
- IBXWRQXXGJFNTB-UHFFFAOYSA-N 4-acetyloxy-3,5-dimethoxy-2-nitrobenzoic acid Chemical compound COC1=CC(C(O)=O)=C([N+]([O-])=O)C(OC)=C1OC(C)=O IBXWRQXXGJFNTB-UHFFFAOYSA-N 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000008156 Ringer's lactate solution Substances 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- SEGICYUYZGUONC-NRFANRHFSA-N [(2s)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methylidenepyrrolidin-1-yl]-(5-methoxy-2-nitro-4-phenylmethoxyphenyl)methanone Chemical compound [O-][N+](=O)C=1C=C(OCC=2C=CC=CC=2)C(OC)=CC=1C(=O)N1CC(=C)C[C@H]1CO[Si](C)(C)C(C)(C)C SEGICYUYZGUONC-NRFANRHFSA-N 0.000 description 3
- GHMLBVMBYSFXCL-INIZCTEOSA-N [(6as)-2,3-dimethoxy-6,11-dioxo-5-(2-trimethylsilylethoxymethyl)-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-8-yl] trifluoromethanesulfonate Chemical compound C[Si](C)(C)CCOCN1C(=O)[C@@H]2CC(OS(=O)(=O)C(F)(F)F)=CN2C(=O)C2=C1C=C(OC)C(OC)=C2 GHMLBVMBYSFXCL-INIZCTEOSA-N 0.000 description 3
- BARNZIQGNAATRE-UHFFFAOYSA-N [2-(hydroxymethyl)pyrrolidin-1-yl]-(2,3,4-trimethoxy-6-nitrophenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC([N+]([O-])=O)=C1C(=O)N1C(CO)CCC1 BARNZIQGNAATRE-UHFFFAOYSA-N 0.000 description 3
- WAVOVQFMPRVPKI-FSRLHOSWSA-N [4-[3-[4-[(2S)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methylidenepyrrolidine-1-carbonyl]-5-methoxy-2-nitrophenoxy]propoxy]-2-methoxy-5-nitrophenyl]-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methylidenepyrrolidin-1-yl]methanone Chemical compound COc1cc(OCCCOc2cc(OC)c(cc2[N+]([O-])=O)C(=O)N2CC(=C)C[C@H]2CO[Si](C)(C)C(C)(C)C)c(cc1C(=O)N1CC(=C)CC1CO[Si](C)(C)C(C)(C)C)[N+]([O-])=O WAVOVQFMPRVPKI-FSRLHOSWSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001414 amino alcohols Chemical class 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000007900 aqueous suspension Substances 0.000 description 3
- 239000012298 atmosphere Substances 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 3
- 235000010233 benzoic acid Nutrition 0.000 description 3
- WAQPOQIWCNXVMW-DLBZAZTESA-N benzyl (2s,4r)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)CN1C(=O)OCC1=CC=CC=C1 WAQPOQIWCNXVMW-DLBZAZTESA-N 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- ZIXVIWRPMFITIT-UHFFFAOYSA-N cadmium lead Chemical compound [Cd].[Pb] ZIXVIWRPMFITIT-UHFFFAOYSA-N 0.000 description 3
- 235000011089 carbon dioxide Nutrition 0.000 description 3
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 3
- POCFBDFTJMJWLG-UHFFFAOYSA-N dihydrosinapic acid methyl ester Natural products COC(=O)CCC1=CC(OC)=C(O)C(OC)=C1 POCFBDFTJMJWLG-UHFFFAOYSA-N 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 238000006266 etherification reaction Methods 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 150000004678 hydrides Chemical class 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- RMXWITJINZBLGF-KCJUWKMLSA-N methyl (2s,4r)-1-(4,5-dimethoxy-2-nitrobenzoyl)-4-hydroxypyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)C1=CC(OC)=C(OC)C=C1[N+]([O-])=O RMXWITJINZBLGF-KCJUWKMLSA-N 0.000 description 3
- PNHXWYIRFRLHID-KRWDZBQOSA-N methyl 2-[(2s)-1-(2-amino-5-methoxy-4-phenylmethoxybenzoyl)-2-(hydroxymethyl)-2,3-dihydropyrrol-4-yl]acetate Chemical compound OC[C@@H]1CC(CC(=O)OC)=CN1C(=O)C(C(=C1)N)=CC(OC)=C1OCC1=CC=CC=C1 PNHXWYIRFRLHID-KRWDZBQOSA-N 0.000 description 3
- IDCYVRWEDPSNGI-LBPRGKRZSA-N methyl 2-[(2s)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-2,3-dihydro-1h-pyrrol-4-yl]acetate Chemical compound COC(=O)CC1=CN[C@H](CO[Si](C)(C)C(C)(C)C)C1 IDCYVRWEDPSNGI-LBPRGKRZSA-N 0.000 description 3
- RFDMTZYZYXIADU-KRWDZBQOSA-N methyl 2-[(6as)-2-methoxy-11-oxo-3-phenylmethoxy-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-8-yl]acetate Chemical compound C([C@H]1N(C(C2=CC=3OC)=O)C=C(C1)CC(=O)OC)=NC2=CC=3OCC1=CC=CC=C1 RFDMTZYZYXIADU-KRWDZBQOSA-N 0.000 description 3
- RGZVECLEJXVVHW-UHFFFAOYSA-N methyl 5-methoxy-2-nitro-4-pentoxybenzoate Chemical compound CCCCCOC1=CC([N+]([O-])=O)=C(C(=O)OC)C=C1OC RGZVECLEJXVVHW-UHFFFAOYSA-N 0.000 description 3
- ZMXJAEGJWHJMGX-UHFFFAOYSA-N methyl syringate Chemical compound COC(=O)C1=CC(OC)=C(O)C(OC)=C1 ZMXJAEGJWHJMGX-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- FTQWRYSLUYAIRQ-UHFFFAOYSA-N n-[(octadecanoylamino)methyl]octadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NCNC(=O)CCCCCCCCCCCCCCCCC FTQWRYSLUYAIRQ-UHFFFAOYSA-N 0.000 description 3
- 238000006396 nitration reaction Methods 0.000 description 3
- YEXPOXQUZXUXJW-UHFFFAOYSA-N oxolead Chemical compound [Pb]=O YEXPOXQUZXUXJW-UHFFFAOYSA-N 0.000 description 3
- AVSAHYUZUTVYHT-JGVFFNPUSA-N prop-2-enyl (2s,4r)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound OC[C@@H]1C[C@@H](O)CN1C(=O)OCC=C AVSAHYUZUTVYHT-JGVFFNPUSA-N 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- XDJCYKMWJCYQJM-UHFFFAOYSA-N tert-butyl n-(3-hydroxypropyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCCO XDJCYKMWJCYQJM-UHFFFAOYSA-N 0.000 description 3
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 3
- 150000003555 thioacetals Chemical class 0.000 description 3
- KUZDZAVWRQKLIO-UHFFFAOYSA-N (2-amino-3,4,5-trimethoxyphenyl)-[2-(hydroxymethyl)pyrrolidin-1-yl]methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2C(CCC2)CO)=C1N KUZDZAVWRQKLIO-UHFFFAOYSA-N 0.000 description 2
- WICLPNAMPSRLGQ-UHFFFAOYSA-N (2-amino-3,5-dimethoxy-4-methylphenyl)-[2-(hydroxymethyl)pyrrolidin-1-yl]methanone Chemical compound COC1=C(C)C(OC)=CC(C(=O)N2C(CCC2)CO)=C1N WICLPNAMPSRLGQ-UHFFFAOYSA-N 0.000 description 2
- ZSJJUWGPGDVHJC-UHFFFAOYSA-N (2-amino-3-methoxyphenyl)-[2-(hydroxymethyl)pyrrolidin-1-yl]methanone Chemical compound COC1=CC=CC(C(=O)N2C(CCC2)CO)=C1N ZSJJUWGPGDVHJC-UHFFFAOYSA-N 0.000 description 2
- UBUQYNVUAFRSBZ-RISCZKNCSA-N (2s,4r)-4-hydroxy-2-(hydroxymethyl)-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid Chemical compound OC[C@]1(C(O)=O)C[C@@H](O)CN1C(=O)OCC1=CC=CC=C1 UBUQYNVUAFRSBZ-RISCZKNCSA-N 0.000 description 2
- LJBSTRHAMDWNML-UHFFFAOYSA-N (3,5-dimethoxy-2-nitro-4-phenylmethoxyphenyl)-[2-(hydroxymethyl)pyrrolidin-1-yl]methanone Chemical compound [O-][N+](=O)C=1C(OC)=C(OCC=2C=CC=CC=2)C(OC)=CC=1C(=O)N1CCCC1CO LJBSTRHAMDWNML-UHFFFAOYSA-N 0.000 description 2
- IZFAJNVBVOISPF-UHFFFAOYSA-N (3,5-dimethoxy-4-methyl-2-nitrophenyl)-[2-(hydroxymethyl)pyrrolidin-1-yl]methanone Chemical compound COC1=C(C)C(OC)=CC(C(=O)N2C(CCC2)CO)=C1[N+]([O-])=O IZFAJNVBVOISPF-UHFFFAOYSA-N 0.000 description 2
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 2
- SCSUVCQAFXQXFF-UHFFFAOYSA-N (6-amino-2,3,4-trimethoxyphenyl)-pyrrolidin-1-ylmethanone;methanol Chemical compound OC.COC1=C(OC)C(OC)=CC(N)=C1C(=O)N1CCCC1 SCSUVCQAFXQXFF-UHFFFAOYSA-N 0.000 description 2
- OFYOHMBZJWAUGY-HNNXBMFYSA-N (6as)-1,2-dimethoxy-5-(2-trimethylsilylethoxymethyl)-7,9-dihydro-6ah-pyrrolo[2,1-c][1,4]benzodiazepine-6,8,11-trione Chemical compound C[Si](C)(C)CCOCN1C(=O)[C@@H]2CC(=O)CN2C(=O)C2=C(OC)C(OC)=CC=C21 OFYOHMBZJWAUGY-HNNXBMFYSA-N 0.000 description 2
- 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 description 2
- ISARROOJUDCKJQ-VIFPVBQESA-N (6as)-4-methoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1=C[C@@H]2CCCN2C(=O)C2=C1C(OC)=CC=C2 ISARROOJUDCKJQ-VIFPVBQESA-N 0.000 description 2
- JAZOMMFSJFFPOV-QEYWNGHMSA-N (6as)-7-[3-[[(6as)-2-methoxy-8-methylidene-11-oxo-7,9-dihydro-6ah-pyrrolo[2,1-c][1,4]benzodiazepin-7-yl]oxy]propoxy]-2-methoxy-8-methylidene-7,9-dihydro-6ah-pyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C([C@H]12)=NC3=CC=C(OC)C=C3C(=O)N1CC(=C)C2OCCCOC1[C@@H]2C=NC3=CC=C(OC)C=C3C(=O)N2CC1=C JAZOMMFSJFFPOV-QEYWNGHMSA-N 0.000 description 2
- NJZMWBVXTIOVPJ-GWCFXTLKSA-N 2,2,2-trichloroethyl (6s,6as)-3-amino-6-hydroxy-11-oxo-6a,7,8,9-tetrahydro-6h-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate Chemical compound ClC(Cl)(Cl)COC(=O)N1[C@@H](O)[C@@H]2CCCN2C(=O)C2=CC=C(N)C=C21 NJZMWBVXTIOVPJ-GWCFXTLKSA-N 0.000 description 2
- JFKNODPODLSEKE-BONVTDFDSA-N 2,2,2-trichloroethyl (6s,6as)-6-hydroxy-2,3-dimethoxy-11-oxo-6a,7,8,9-tetrahydro-6h-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate Chemical compound ClC(Cl)(Cl)COC(=O)N1[C@@H](O)[C@@H]2CCCN2C(=O)C2=C1C=C(OC)C(OC)=C2 JFKNODPODLSEKE-BONVTDFDSA-N 0.000 description 2
- FONKAZVLQHYWOO-AOMKIAJQSA-N 2,2,2-trichloroethyl (6s,6as)-6-hydroxy-2,4-dimethoxy-11-oxo-3-phenylmethoxy-6a,7,8,9-tetrahydro-6h-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate Chemical compound COC1=CC(C(N2CCC[C@H]2[C@H](O)N2C(=O)OCC(Cl)(Cl)Cl)=O)=C2C(OC)=C1OCC1=CC=CC=C1 FONKAZVLQHYWOO-AOMKIAJQSA-N 0.000 description 2
- FZQVHECXFSRFIQ-JSGCOSHPSA-N 2,2,2-trichloroethyl (6s,6as)-6-hydroxy-2-methoxy-11-oxo-6a,7,8,9-tetrahydro-6h-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate Chemical compound ClC(Cl)(Cl)COC(=O)N1[C@@H](O)[C@@H]2CCCN2C(=O)C2=CC(OC)=CC=C21 FZQVHECXFSRFIQ-JSGCOSHPSA-N 0.000 description 2
- VAGZOGHDCYEXOD-UHFFFAOYSA-N 2,2,2-trichloroethyl 2-iodo-11-oxo-6a,7,8,9-tetrahydro-6h-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate Chemical compound ClC(Cl)(Cl)COC(=O)N1CC2CCCN2C(=O)C2=CC(I)=CC=C12 VAGZOGHDCYEXOD-UHFFFAOYSA-N 0.000 description 2
- QPLJYAKLSCXZSF-UHFFFAOYSA-N 2,2,2-trichloroethyl carbamate Chemical compound NC(=O)OCC(Cl)(Cl)Cl QPLJYAKLSCXZSF-UHFFFAOYSA-N 0.000 description 2
- YCBFDDRNSYVKFQ-UHFFFAOYSA-N 2,2,2-trichloroethyl n-[2-[2-(hydroxymethyl)pyrrolidine-1-carbonyl]-4,5-dimethoxyphenyl]carbamate Chemical compound C1=C(OC)C(OC)=CC(NC(=O)OCC(Cl)(Cl)Cl)=C1C(=O)N1C(CO)CCC1 YCBFDDRNSYVKFQ-UHFFFAOYSA-N 0.000 description 2
- RSTQOEUIJQLXLN-UHFFFAOYSA-N 2,2,2-trichloroethyl n-[6-[2-(hydroxymethyl)pyrrolidine-1-carbonyl]-2,4-dimethoxy-3-phenylmethoxyphenyl]carbamate Chemical compound ClC(Cl)(Cl)COC(=O)NC=1C(OC)=C(OCC=2C=CC=CC=2)C(OC)=CC=1C(=O)N1CCCC1CO RSTQOEUIJQLXLN-UHFFFAOYSA-N 0.000 description 2
- DSONWCVMECGSKN-UHFFFAOYSA-N 2,3,4-trimethoxy-6-nitrobenzoic acid Chemical compound COC1=CC([N+]([O-])=O)=C(C(O)=O)C(OC)=C1OC DSONWCVMECGSKN-UHFFFAOYSA-N 0.000 description 2
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 2
- 125000003821 2-(trimethylsilyl)ethoxymethyl group Chemical group [H]C([H])([H])[Si](C([H])([H])[H])(C([H])([H])[H])C([H])([H])C(OC([H])([H])[*])([H])[H] 0.000 description 2
- HJVAVGOPTDJYOJ-UHFFFAOYSA-N 2-amino-4,5-dimethoxybenzoic acid Chemical compound COC1=CC(N)=C(C(O)=O)C=C1OC HJVAVGOPTDJYOJ-UHFFFAOYSA-N 0.000 description 2
- OYCAWWANTCNMPI-UHFFFAOYSA-N 2-methoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1=CC2CCCN2C(=O)C2=CC(OC)=CC=C21 OYCAWWANTCNMPI-UHFFFAOYSA-N 0.000 description 2
- RPUWJACGBJIUPQ-SFYZADRCSA-N 2-o-methyl 1-o-prop-2-enyl (2s,4r)-4-hydroxypyrrolidine-1,2-dicarboxylate Chemical compound COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCC=C RPUWJACGBJIUPQ-SFYZADRCSA-N 0.000 description 2
- JFNMPXBGBMYUTG-FNZWTVRRSA-N 2-trimethylsilylethyl (6s,6as)-6-hydroxy-2,4-dimethoxy-11-oxo-3-phenylmethoxy-6a,7,8,9-tetrahydro-6h-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate Chemical compound COC1=CC(C(N2CCC[C@H]2[C@H](O)N2C(=O)OCC[Si](C)(C)C)=O)=C2C(OC)=C1OCC1=CC=CC=C1 JFNMPXBGBMYUTG-FNZWTVRRSA-N 0.000 description 2
- VPVAFLFJAAPHKI-UHFFFAOYSA-N 3,4,5-trimethoxy-2-nitrobenzoic acid Chemical compound COC1=CC(C(O)=O)=C([N+]([O-])=O)C(OC)=C1OC VPVAFLFJAAPHKI-UHFFFAOYSA-N 0.000 description 2
- OZYLKEJIYRGJGC-UHFFFAOYSA-N 3,5-dimethoxy-2-nitro-4-phenylmethoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=C([N+]([O-])=O)C(OC)=C1OCC1=CC=CC=C1 OZYLKEJIYRGJGC-UHFFFAOYSA-N 0.000 description 2
- WTFZHTPOZMUCPU-UHFFFAOYSA-N 3,5-dimethoxy-2-nitro-4-propoxybenzoic acid Chemical compound CCCOC1=C(OC)C=C(C(O)=O)C([N+]([O-])=O)=C1OC WTFZHTPOZMUCPU-UHFFFAOYSA-N 0.000 description 2
- VDCPEHZTQHSQGS-UHFFFAOYSA-N 3,5-dimethoxy-4-methyl-2-nitrobenzoic acid Chemical compound COC1=CC(C(O)=O)=C([N+]([O-])=O)C(OC)=C1C VDCPEHZTQHSQGS-UHFFFAOYSA-N 0.000 description 2
- MRNDVCIYQGVIIY-UHFFFAOYSA-N 3-hydroxy-2,4-dimethoxy-6a,7,9,11-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-8-one Chemical compound C1N2CC(=O)CC2C=NC2=C1C=C(OC)C(O)=C2OC MRNDVCIYQGVIIY-UHFFFAOYSA-N 0.000 description 2
- RSDAUKJLYXGDMD-UHFFFAOYSA-N 3-methoxy-2-(2,2,2-trichloroethoxycarbonylamino)benzoic acid Chemical compound COC1=CC=CC(C(O)=O)=C1NC(=O)OCC(Cl)(Cl)Cl RSDAUKJLYXGDMD-UHFFFAOYSA-N 0.000 description 2
- PYAZCFCEURLPSU-UHFFFAOYSA-N 3-methoxy-4-propoxybenzoic acid Chemical compound CCCOC1=CC=C(C(O)=O)C=C1OC PYAZCFCEURLPSU-UHFFFAOYSA-N 0.000 description 2
- JSUPAIAYOZRCQH-UHFFFAOYSA-N 4,5-dimethoxy-2-(2,2,2-trichloroethoxycarbonylamino)benzoic acid Chemical compound COC1=CC(NC(=O)OCC(Cl)(Cl)Cl)=C(C(O)=O)C=C1OC JSUPAIAYOZRCQH-UHFFFAOYSA-N 0.000 description 2
- WWCMFGBGMJAJRX-UHFFFAOYSA-N 4,5-dimethoxy-2-nitrobenzoic acid Chemical compound COC1=CC(C(O)=O)=C([N+]([O-])=O)C=C1OC WWCMFGBGMJAJRX-UHFFFAOYSA-N 0.000 description 2
- GWYDGEWYBMSAGB-UHFFFAOYSA-N 4-(2-carboxyethoxy)-5-methoxy-2-nitrobenzoic acid Chemical compound COC1=CC(C(O)=O)=C([N+]([O-])=O)C=C1OCCC(O)=O GWYDGEWYBMSAGB-UHFFFAOYSA-N 0.000 description 2
- OZJDDRBSYQGPPJ-UHFFFAOYSA-N 4-nitro-2-(2,2,2-trichloroethoxycarbonylamino)benzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1NC(=O)OCC(Cl)(Cl)Cl OZJDDRBSYQGPPJ-UHFFFAOYSA-N 0.000 description 2
- UEALKTCRMBVTFN-UHFFFAOYSA-N 4-nitroanthranilic acid Chemical compound NC1=CC([N+]([O-])=O)=CC=C1C(O)=O UEALKTCRMBVTFN-UHFFFAOYSA-N 0.000 description 2
- WWZSMPGWHZPCDT-UHFFFAOYSA-N 5-iodo-2-(2,2,2-trichloroethoxycarbonylamino)benzoic acid Chemical compound OC(=O)C1=CC(I)=CC=C1NC(=O)OCC(Cl)(Cl)Cl WWZSMPGWHZPCDT-UHFFFAOYSA-N 0.000 description 2
- CFCGDLMKOMCTLQ-UHFFFAOYSA-N 5-methoxy-2-nitro-4-pentoxybenzoic acid Chemical compound CCCCCOC1=CC([N+]([O-])=O)=C(C(O)=O)C=C1OC CFCGDLMKOMCTLQ-UHFFFAOYSA-N 0.000 description 2
- DWOHOXQIYBJNJS-UHFFFAOYSA-N 5-methoxy-2-nitro-4-propoxybenzoic acid Chemical compound CCCOC1=CC([N+]([O-])=O)=C(C(O)=O)C=C1OC DWOHOXQIYBJNJS-UHFFFAOYSA-N 0.000 description 2
- LQVMZVKOVPITOO-UHFFFAOYSA-N 9h-fluoren-1-ylmethyl carbonochloridate Chemical compound C1C2=CC=CC=C2C2=C1C(COC(=O)Cl)=CC=C2 LQVMZVKOVPITOO-UHFFFAOYSA-N 0.000 description 2
- 239000005711 Benzoic acid Substances 0.000 description 2
- LRHGVQFFDCETQJ-UHFFFAOYSA-N COC1=CC(OCCCN)=C([N+]([O-])=O)C(C(O)=O)=C1 Chemical compound COC1=CC(OCCCN)=C([N+]([O-])=O)C(C(O)=O)=C1 LRHGVQFFDCETQJ-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- 108020004414 DNA Proteins 0.000 description 2
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 2
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 2
- 238000006546 Horner-Wadsworth-Emmons reaction Methods 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 101150003085 Pdcl gene Proteins 0.000 description 2
- ALQSHHUCVQOPAS-UHFFFAOYSA-N Pentane-1,5-diol Chemical compound OCCCCCO ALQSHHUCVQOPAS-UHFFFAOYSA-N 0.000 description 2
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N Propanolamine Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 2
- 229910018557 Si O Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 238000006069 Suzuki reaction reaction Methods 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 238000007295 Wittig olefination reaction Methods 0.000 description 2
- 238000007239 Wittig reaction Methods 0.000 description 2
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 2
- PPKSVDRLXHIZDT-INIZCTEOSA-N [(2s)-2-(hydroxymethyl)-4-methylidenepyrrolidin-1-yl]-(5-methoxy-2-nitro-4-phenylmethoxyphenyl)methanone Chemical compound [O-][N+](=O)C=1C=C(OCC=2C=CC=CC=2)C(OC)=CC=1C(=O)N1CC(=C)C[C@H]1CO PPKSVDRLXHIZDT-INIZCTEOSA-N 0.000 description 2
- FARDPHDVNNAHDS-UHFFFAOYSA-N [2-(hydroxymethyl)pyrrolidin-1-yl]-(3,4,5-trimethoxy-2-nitrophenyl)methanone Chemical compound COC1=C(OC)C(OC)=CC(C(=O)N2C(CCC2)CO)=C1[N+]([O-])=O FARDPHDVNNAHDS-UHFFFAOYSA-N 0.000 description 2
- AODJAXOYXSXGAX-UHFFFAOYSA-N [2-(hydroxymethyl)pyrrolidin-1-yl]-(3-methoxy-2-nitrophenyl)methanone Chemical compound COC1=CC=CC(C(=O)N2C(CCC2)CO)=C1[N+]([O-])=O AODJAXOYXSXGAX-UHFFFAOYSA-N 0.000 description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 2
- 150000001241 acetals Chemical class 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 230000002152 alkylating effect Effects 0.000 description 2
- 239000006286 aqueous extract Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 229940049706 benzodiazepine Drugs 0.000 description 2
- BMLSTPRTEKLIPM-UHFFFAOYSA-I calcium;potassium;disodium;hydrogen carbonate;dichloride;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Na+].[Na+].[Cl-].[Cl-].[K+].[Ca+2].OC([O-])=O BMLSTPRTEKLIPM-UHFFFAOYSA-I 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 2
- 208000025997 central nervous system neoplasm Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 238000004140 cleaning Methods 0.000 description 2
- 229940127204 compound 29 Drugs 0.000 description 2
- 229940126214 compound 3 Drugs 0.000 description 2
- JNGZXGGOCLZBFB-IVCQMTBJSA-N compound E Chemical compound N([C@@H](C)C(=O)N[C@@H]1C(N(C)C2=CC=CC=C2C(C=2C=CC=CC=2)=N1)=O)C(=O)CC1=CC(F)=CC(F)=C1 JNGZXGGOCLZBFB-IVCQMTBJSA-N 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate trihydrate Substances [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 150000002081 enamines Chemical class 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 2
- 229910052737 gold Inorganic materials 0.000 description 2
- 239000010931 gold Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 230000005484 gravity Effects 0.000 description 2
- 239000012456 homogeneous solution Substances 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000002147 killing effect Effects 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 208000037841 lung tumor Diseases 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- IHWFIVOWBXWQEW-QFIPXVFZSA-N methyl 2-[(2s)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-(5-methoxy-2-nitro-4-phenylmethoxybenzoyl)-2,3-dihydropyrrol-4-yl]acetate Chemical compound CC(C)(C)[Si](C)(C)OC[C@@H]1CC(CC(=O)OC)=CN1C(=O)C(C(=C1)[N+]([O-])=O)=CC(OC)=C1OCC1=CC=CC=C1 IHWFIVOWBXWQEW-QFIPXVFZSA-N 0.000 description 2
- DDQWDGYFJGEHIF-UHFFFAOYSA-N methyl 3,5-dimethoxy-2-nitro-4-phenylmethoxybenzoate Chemical compound COC1=C([N+]([O-])=O)C(C(=O)OC)=CC(OC)=C1OCC1=CC=CC=C1 DDQWDGYFJGEHIF-UHFFFAOYSA-N 0.000 description 2
- FHMBWZLKMRUKQO-UHFFFAOYSA-N methyl 3,5-dimethoxy-4-phenylmethoxybenzoate Chemical compound COC1=CC(C(=O)OC)=CC(OC)=C1OCC1=CC=CC=C1 FHMBWZLKMRUKQO-UHFFFAOYSA-N 0.000 description 2
- GYLMURWWGUPAET-UHFFFAOYSA-N methyl 4-(3-aminopropoxy)-5-methoxy-2-nitrobenzoate Chemical compound COC(=O)C1=CC(OC)=C(OCCCN)C=C1[N+]([O-])=O GYLMURWWGUPAET-UHFFFAOYSA-N 0.000 description 2
- AGYMLRZEKKNFSK-UHFFFAOYSA-N methyl 4-hydroxy-3,5-dimethoxy-2-nitrobenzoate Chemical compound COC(=O)C1=CC(OC)=C(O)C(OC)=C1[N+]([O-])=O AGYMLRZEKKNFSK-UHFFFAOYSA-N 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- 230000005012 migration Effects 0.000 description 2
- 238000013508 migration Methods 0.000 description 2
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 2
- FXMOIYLVKOALHC-UHFFFAOYSA-N neothramycin B Natural products N1=CC2CCC(O)N2C(=O)C2=C1C=C(O)C(OC)=C2 FXMOIYLVKOALHC-UHFFFAOYSA-N 0.000 description 2
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 230000008092 positive effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- CIEDOJRGCHRMGN-QWHCGFSZSA-N prop-2-enyl (2s,4r)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](O)CN1C(=O)OCC=C CIEDOJRGCHRMGN-QWHCGFSZSA-N 0.000 description 2
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 description 2
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- LIVNPJMFVYWSIS-UHFFFAOYSA-N silicon monoxide Inorganic materials [Si-]#[O+] LIVNPJMFVYWSIS-UHFFFAOYSA-N 0.000 description 2
- 150000003385 sodium Chemical class 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- JMSVCTWVEWCHDZ-UHFFFAOYSA-N syringic acid Chemical compound COC1=CC(C(O)=O)=CC(OC)=C1O JMSVCTWVEWCHDZ-UHFFFAOYSA-N 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 2
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 2
- DNIAPMSPPWPWGF-VKHMYHEASA-N (+)-propylene glycol Chemical compound C[C@H](O)CO DNIAPMSPPWPWGF-VKHMYHEASA-N 0.000 description 1
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 1
- ZFYIQPIHXRFFCZ-QMMMGPOBSA-N (2s)-2-(cyclohexylamino)butanedioic acid Chemical compound OC(=O)C[C@@H](C(O)=O)NC1CCCCC1 ZFYIQPIHXRFFCZ-QMMMGPOBSA-N 0.000 description 1
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 1
- HRECBPNLXCDPSL-UHFFFAOYSA-N (4-methoxyphenyl)methylphosphanium;bromide Chemical compound [Br-].COC1=CC=C(C[PH3+])C=C1 HRECBPNLXCDPSL-UHFFFAOYSA-N 0.000 description 1
- IARGEMKPZJEXIY-JTQLQIEISA-N (6as)-2,3-dimethoxy-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)C2=C1C=C(OC)C(OC)=C2 IARGEMKPZJEXIY-JTQLQIEISA-N 0.000 description 1
- APSDZQHWEQIJAG-HNNXBMFYSA-N (6as)-2-(3-nitrophenyl)-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound [O-][N+](=O)C1=CC=CC(C=2C=C3C(=O)N4CCC[C@H]4C=NC3=CC=2)=C1 APSDZQHWEQIJAG-HNNXBMFYSA-N 0.000 description 1
- MPQGHRDCWUNKHG-HNNXBMFYSA-N (6as)-2-(4-methoxyphenyl)-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C1=CC(OC)=CC=C1C1=CC=C(N=C[C@H]2N(CCC2)C2=O)C2=C1 MPQGHRDCWUNKHG-HNNXBMFYSA-N 0.000 description 1
- NHLKRKYDMJKRHA-HNNXBMFYSA-N (6as)-2-phenyl-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C([C@@H]1CCCN1C(C1=C2)=O)=NC1=CC=C2C1=CC=CC=C1 NHLKRKYDMJKRHA-HNNXBMFYSA-N 0.000 description 1
- OMRPLUKQNWNZAV-CONSDPRKSA-N (6as)-3-[3-[[(6as)-2-methoxy-8-(4-methoxyphenyl)-11-oxo-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]propoxy]-8-(4-aminophenyl)-2-methoxy-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C1=CC(OC)=CC=C1C1=CN2C(=O)C3=CC(OC)=C(OCCCOC=4C(=CC=5C(=O)N6C=C(C[C@H]6C=NC=5C=4)C=4C=CC(N)=CC=4)OC)C=C3N=C[C@@H]2C1 OMRPLUKQNWNZAV-CONSDPRKSA-N 0.000 description 1
- UNJCMKPTTYEFKE-PREGVCBESA-N (6as)-8-(1-hydroxyethyl)-2-methoxy-3-phenylmethoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound COC1=CC(C(N2CC(C[C@H]2C=N2)C(C)O)=O)=C2C=C1OCC1=CC=CC=C1 UNJCMKPTTYEFKE-PREGVCBESA-N 0.000 description 1
- GYUDGZRJHSDPLH-KJQCOJPZSA-N (6as,8e)-8-ethylidene-7,9-dihydro-6ah-pyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C1=NC2=CC=CC=C2C(=O)N2CC(=C/C)/C[C@H]21 GYUDGZRJHSDPLH-KJQCOJPZSA-N 0.000 description 1
- FXMOIYLVKOALHC-JVXZTZIISA-N (6as,9r)-3,9-dihydroxy-2-methoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1=C[C@@H]2CC[C@@H](O)N2C(=O)C2=C1C=C(O)C(OC)=C2 FXMOIYLVKOALHC-JVXZTZIISA-N 0.000 description 1
- FXMOIYLVKOALHC-MADCSZMMSA-N (6as,9s)-3,9-dihydroxy-2-methoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1=C[C@@H]2CC[C@H](O)N2C(=O)C2=C1C=C(O)C(OC)=C2 FXMOIYLVKOALHC-MADCSZMMSA-N 0.000 description 1
- DIPVWSTVQDONTF-NUAZBEIESA-N (8E)-2-[(2S,3R,4R,5R,6S)-3,4-dihydroxy-6-methyl-5-(methylamino)oxan-2-yl]oxy-6-methoxy-8-propylidene-6,6a,7,9-tetrahydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound CC\C=C1/CC2C(Nc3ccc(O[C@@H]4O[C@@H](C)[C@H](NC)[C@@H](O)[C@H]4O)cc3C(=O)N2C1)OC DIPVWSTVQDONTF-NUAZBEIESA-N 0.000 description 1
- JEZZKSQFJNWDCY-NSIKDUERSA-N (8z)-2-[3,4-dihydroxy-4,6-dimethyl-5-(methylamino)oxan-2-yl]oxy-8-propylidene-7,9-dihydro-6ah-pyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound C1=C2C(=O)N3CC(=C/CC)\CC3C=NC2=CC=C1OC1OC(C)C(NC)C(C)(O)C1O JEZZKSQFJNWDCY-NSIKDUERSA-N 0.000 description 1
- UQVNRKBFAXNOGA-OHLDGCSVSA-N (Z)-tomaymycin Chemical compound CO[C@H]1NC2=CC(O)=C(OC)C=C2C(=O)N2C\C(=C/C)C[C@@H]12 UQVNRKBFAXNOGA-OHLDGCSVSA-N 0.000 description 1
- OQMYRVPMCIOFHL-GCOHUWJYSA-N (e)-3-[(6r)-6-hydroxy-4-methoxy-11-oxo-5,6,6a,7-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-8-yl]-n,n-dimethylprop-2-enamide Chemical compound N1[C@H](O)C2CC(\C=C\C(=O)N(C)C)=CN2C(=O)C2=C1C(OC)=CC=C2 OQMYRVPMCIOFHL-GCOHUWJYSA-N 0.000 description 1
- HCDXLUKTYFLIEM-UHFFFAOYSA-N 1,2-benzodiazepin-5-one Chemical compound O=C1C=CN=NC2=CC=CC=C12 HCDXLUKTYFLIEM-UHFFFAOYSA-N 0.000 description 1
- KKHFRAFPESRGGD-UHFFFAOYSA-N 1,3-dimethyl-7-[3-(n-methylanilino)propyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCCN(C)C1=CC=CC=C1 KKHFRAFPESRGGD-UHFFFAOYSA-N 0.000 description 1
- YPFDHNVEDLHUCE-UHFFFAOYSA-N 1,3-propanediol Substances OCCCO YPFDHNVEDLHUCE-UHFFFAOYSA-N 0.000 description 1
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- POXWDTQUDZUOGP-UHFFFAOYSA-N 1h-1,4-diazepine Chemical compound N1C=CC=NC=C1 POXWDTQUDZUOGP-UHFFFAOYSA-N 0.000 description 1
- JIVHOVBNJUWAIK-ZBEGNZNMSA-N 2,2,2-trichloroethyl (6s,6as)-6-hydroxy-2,4-dimethoxy-3-methyl-11-oxo-6a,7,8,9-tetrahydro-6h-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate Chemical compound ClC(Cl)(Cl)COC(=O)N1[C@@H](O)[C@@H]2CCCN2C(=O)C2=C1C(OC)=C(C)C(OC)=C2 JIVHOVBNJUWAIK-ZBEGNZNMSA-N 0.000 description 1
- 125000000453 2,2,2-trichloroethyl group Chemical group [H]C([H])(*)C(Cl)(Cl)Cl 0.000 description 1
- AZUCPFMKPGFGTB-UHFFFAOYSA-N 2,2-diiodopropane Chemical compound CC(C)(I)I AZUCPFMKPGFGTB-UHFFFAOYSA-N 0.000 description 1
- LOZISMUKOVKRIP-UHFFFAOYSA-N 2,3,4-trimethoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1=CC2CCCN2C(=O)C2=C1C(OC)=C(OC)C(OC)=C2 LOZISMUKOVKRIP-UHFFFAOYSA-N 0.000 description 1
- HZNQSWJZTWOTKM-UHFFFAOYSA-N 2,3,4-trimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C(OC)=C1OC HZNQSWJZTWOTKM-UHFFFAOYSA-N 0.000 description 1
- PBYDTCOLESIYBR-UHFFFAOYSA-N 2,3-dihydro-1H-isoindole Chemical compound C1=CC=C2CNCC2=C1.C1=CC=C2CNCC2=C1 PBYDTCOLESIYBR-UHFFFAOYSA-N 0.000 description 1
- ORVGUSLXZBAOOU-UHFFFAOYSA-N 2,4-dimethoxy-3-phenylmethoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound COC1=CC(C(N2CCCC2C=N2)=O)=C2C(OC)=C1OCC1=CC=CC=C1 ORVGUSLXZBAOOU-UHFFFAOYSA-N 0.000 description 1
- QTMAZYGAVHCKKX-UHFFFAOYSA-N 2-[(4-amino-5-bromopyrrolo[2,3-d]pyrimidin-7-yl)methoxy]propane-1,3-diol Chemical compound NC1=NC=NC2=C1C(Br)=CN2COC(CO)CO QTMAZYGAVHCKKX-UHFFFAOYSA-N 0.000 description 1
- GOLGILSVWFKZRQ-UHFFFAOYSA-N 2-amino-5-iodobenzoic acid Chemical compound NC1=CC=C(I)C=C1C(O)=O GOLGILSVWFKZRQ-UHFFFAOYSA-N 0.000 description 1
- KWMBADTWRIGGGG-UHFFFAOYSA-N 2-diethoxyphosphorylacetonitrile Chemical compound CCOP(=O)(CC#N)OCC KWMBADTWRIGGGG-UHFFFAOYSA-N 0.000 description 1
- FKEXUYUBCDZLRR-UHFFFAOYSA-N 2-ethylbutanethioic s-acid Chemical compound CCC(CC)C(S)=O FKEXUYUBCDZLRR-UHFFFAOYSA-N 0.000 description 1
- 150000005341 2-nitrobenzoic acids Chemical class 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- ZNGINKJHQQQORD-UHFFFAOYSA-N 2-trimethylsilylethanol Chemical compound C[Si](C)(C)CCO ZNGINKJHQQQORD-UHFFFAOYSA-N 0.000 description 1
- BTEQQLFQAPLTLI-UHFFFAOYSA-N 2-trimethylsilylethyl carbonochloridate Chemical compound C[Si](C)(C)CCOC(Cl)=O BTEQQLFQAPLTLI-UHFFFAOYSA-N 0.000 description 1
- VHMICKWLTGFITH-UHFFFAOYSA-N 2H-isoindole Chemical compound C1=CC=CC2=CNC=C21 VHMICKWLTGFITH-UHFFFAOYSA-N 0.000 description 1
- AEXIWWWIKQCOEC-UHFFFAOYSA-N 3,4,5-trimethoxy-2-methyl-6-nitrobenzoic acid Chemical compound COC1=C(C)C(C(O)=O)=C([N+]([O-])=O)C(OC)=C1OC AEXIWWWIKQCOEC-UHFFFAOYSA-N 0.000 description 1
- FYNNNYGCBZBAGN-UHFFFAOYSA-N 3,5-dimethoxy-2-nitro-4-phenylmethoxybenzoyl chloride Chemical compound COC1=CC(C(Cl)=O)=C([N+]([O-])=O)C(OC)=C1OCC1=CC=CC=C1 FYNNNYGCBZBAGN-UHFFFAOYSA-N 0.000 description 1
- RRQWQDAOLWXJLW-UHFFFAOYSA-N 3,5-dimethoxy-4-methyl-2-nitrobenzoyl chloride Chemical compound COC1=CC(C(Cl)=O)=C([N+]([O-])=O)C(OC)=C1C RRQWQDAOLWXJLW-UHFFFAOYSA-N 0.000 description 1
- IUECMLPTGAPICD-UHFFFAOYSA-N 3-hydroxy-2,4-dimethoxy-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1=CC2CCCN2C(=O)C2=C1C(OC)=C(O)C(OC)=C2 IUECMLPTGAPICD-UHFFFAOYSA-N 0.000 description 1
- YMOMYSDAOXOCID-UHFFFAOYSA-N 3-methoxy-2-nitrobenzoic acid Chemical compound COC1=CC=CC(C(O)=O)=C1[N+]([O-])=O YMOMYSDAOXOCID-UHFFFAOYSA-N 0.000 description 1
- SXOPCLUOUFQBJV-UHFFFAOYSA-N 3-methoxyanthranilic acid Chemical compound COC1=CC=CC(C(O)=O)=C1N SXOPCLUOUFQBJV-UHFFFAOYSA-N 0.000 description 1
- ZNRGSYUVFVNSAW-UHFFFAOYSA-N 3-nitrophenylboronic acid Chemical compound OB(O)C1=CC=CC([N+]([O-])=O)=C1 ZNRGSYUVFVNSAW-UHFFFAOYSA-N 0.000 description 1
- ZXXWDXRDXZTGNL-UHFFFAOYSA-N 4-(1-carboxyethoxy)-2-hydroxy-5-methoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=C(O)C=C1OC(C)C(O)=O ZXXWDXRDXZTGNL-UHFFFAOYSA-N 0.000 description 1
- DQAZPZIYEOGZAF-UHFFFAOYSA-N 4-ethyl-n-[4-(3-ethynylanilino)-7-methoxyquinazolin-6-yl]piperazine-1-carboxamide Chemical compound C1CN(CC)CCN1C(=O)NC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(C#C)=C1 DQAZPZIYEOGZAF-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- DOBIZWYVJFIYOV-UHFFFAOYSA-N 7-hydroxynaphthalene-1,3-disulfonic acid Chemical compound C1=C(S(O)(=O)=O)C=C(S(O)(=O)=O)C2=CC(O)=CC=C21 DOBIZWYVJFIYOV-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical group NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 description 1
- 229930184471 Chicamycin Natural products 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 240000001414 Eucalyptus viminalis Species 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 238000007341 Heck reaction Methods 0.000 description 1
- 206010021143 Hypoxia Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 208000026350 Inborn Genetic disease Diseases 0.000 description 1
- 208000005016 Intestinal Neoplasms Diseases 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 102000006835 Lamins Human genes 0.000 description 1
- 108010047294 Lamins Proteins 0.000 description 1
- 239000012448 Lithium borohydride Substances 0.000 description 1
- 229930184247 Mazethramycin Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 230000006179 O-acylation Effects 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229930187104 Porothramycin Natural products 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- GYUDGZRJHSDPLH-UHFFFAOYSA-N Prothracarcin Natural products C1=NC2=CC=CC=C2C(=O)N2CC(=CC)CC21 GYUDGZRJHSDPLH-UHFFFAOYSA-N 0.000 description 1
- JEZZKSQFJNWDCY-UHFFFAOYSA-N Sibanomicin Natural products C1=C2C(=O)N3CC(=CCC)CC3C=NC2=CC=C1OC1OC(C)C(NC)C(C)(O)C1O JEZZKSQFJNWDCY-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 238000006619 Stille reaction Methods 0.000 description 1
- VGQOVCHZGQWAOI-UHFFFAOYSA-N UNPD55612 Natural products N1C(O)C2CC(C=CC(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-UHFFFAOYSA-N 0.000 description 1
- QTSIOSLAOYVJJW-BGERDNNASA-N [5-amino-4-[3-[2-amino-4-[(2s)-2-(hydroxymethyl)-4-methylidenepyrrolidine-1-carbonyl]-5-methoxyphenoxy]propoxy]-2-methoxyphenyl]-[2-(hydroxymethyl)-4-methylidenepyrrolidin-1-yl]methanone Chemical compound NC=1C=C(C(=O)N2C(CC(=C)C2)CO)C(OC)=CC=1OCCCOC(C(=C1)N)=CC(OC)=C1C(=O)N1CC(=C)C[C@H]1CO QTSIOSLAOYVJJW-BGERDNNASA-N 0.000 description 1
- SSMFXCDUJJPFBJ-UWJYBYFXSA-N abbeymycin Chemical compound CO[C@@H]1NC2=CC=CC=C2C(=O)N2C[C@@H](O)C[C@@H]12 SSMFXCDUJJPFBJ-UWJYBYFXSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000003855 acyl compounds Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 238000010640 amide synthesis reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- VGQOVCHZGQWAOI-HYUHUPJXSA-N anthramycin Chemical compound N1[C@@H](O)[C@@H]2CC(\C=C\C(N)=O)=CN2C(=O)C2=CC=C(C)C(O)=C12 VGQOVCHZGQWAOI-HYUHUPJXSA-N 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000003972 antineoplastic antibiotic Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 239000003637 basic solution Substances 0.000 description 1
- 150000001559 benzoic acids Chemical class 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 235000010338 boric acid Nutrition 0.000 description 1
- 125000005619 boric acid group Chemical class 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 125000002837 carbocyclic group Chemical group 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 229940125758 compound 15 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125807 compound 37 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical class [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 239000002274 desiccant Substances 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000005610 enamide group Chemical group 0.000 description 1
- VDDXQSUSMHZCLS-UHFFFAOYSA-N ethenyl trifluoromethanesulfonate Chemical compound FC(F)(F)S(=O)(=O)OC=C VDDXQSUSMHZCLS-UHFFFAOYSA-N 0.000 description 1
- BVUDYOWHSJNSGH-UHFFFAOYSA-N ethyl n-amino-n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)N(N)C(=O)OCC BVUDYOWHSJNSGH-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- IRXSLJNXXZKURP-UHFFFAOYSA-N fluorenylmethyloxycarbonyl chloride Chemical compound C1=CC=C2C(COC(=O)Cl)C3=CC=CC=C3C2=C1 IRXSLJNXXZKURP-UHFFFAOYSA-N 0.000 description 1
- 239000003269 fluorescent indicator Substances 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 208000016361 genetic disease Diseases 0.000 description 1
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 1
- 150000002334 glycols Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 230000001146 hypoxic effect Effects 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 201000009019 intestinal benign neoplasm Diseases 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000005053 lamin Anatomy 0.000 description 1
- 229910000464 lead oxide Inorganic materials 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- PRRWHBNSRJELFG-GQCTYLIASA-N mazethramycin Chemical compound OC1NC2=C(O)C(C)=CC=C2C(=O)N2C=C(/C=C/C(=O)NC)CC21 PRRWHBNSRJELFG-GQCTYLIASA-N 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- LWJROJCJINYWOX-UHFFFAOYSA-L mercury dichloride Chemical compound Cl[Hg]Cl LWJROJCJINYWOX-UHFFFAOYSA-L 0.000 description 1
- CSGATABADBTZRI-DTIOYNMSSA-N methyl 2-[(6as)-2,3-dimethoxy-11-oxo-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-8-yl]acetate Chemical compound C1=NC2=CC(OC)=C(OC)C=C2C(=O)N2CC(CC(=O)OC)C[C@H]21 CSGATABADBTZRI-DTIOYNMSSA-N 0.000 description 1
- LWIURJIQKCFNME-WMZHIEFXSA-N methyl 2-[(6r,6as)-2,6-dimethoxy-11-oxo-3-phenylmethoxy-5,6,6a,7-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-8-yl]acetate Chemical compound N([C@@H]([C@@H]1CC(CC(=O)OC)=CN1C(=O)C1=CC=2OC)OC)C1=CC=2OCC1=CC=CC=C1 LWIURJIQKCFNME-WMZHIEFXSA-N 0.000 description 1
- ZORHSASAYVIBLY-UHFFFAOYSA-N methyl 4-hydroxypyrrolidine-2-carboxylate Chemical compound COC(=O)C1CC(O)CN1 ZORHSASAYVIBLY-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000001613 neoplastic effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000006772 olefination reaction Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000007243 oxidative cyclization reaction Methods 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- UWJJYHHHVWZFEP-UHFFFAOYSA-N pentane-1,1-diol Chemical compound CCCCC(O)O UWJJYHHHVWZFEP-UHFFFAOYSA-N 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000014493 regulation of gene expression Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 238000006798 ring closing metathesis reaction Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- RAGFPHFDFVNLCG-INYQBOQCSA-N sibiromycin Chemical compound O[C@@H]1[C@@](O)(C)[C@@H](NC)[C@H](C)O[C@H]1OC(C(=C1O)C)=CC(C2=O)=C1N[C@H](O)[C@H]1N2C=C(\C=C\C)C1 RAGFPHFDFVNLCG-INYQBOQCSA-N 0.000 description 1
- RAGFPHFDFVNLCG-UHFFFAOYSA-N sibiromycin Natural products OC1C(O)(C)C(NC)C(C)OC1OC(C(=C1O)C)=CC(C2=O)=C1NC(O)C1N2C=C(C=CC)C1 RAGFPHFDFVNLCG-UHFFFAOYSA-N 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- YIBXWXOYFGZLRU-UHFFFAOYSA-N syringic aldehyde Natural products CC12CCC(C3(CCC(=O)C(C)(C)C3CC=3)C)C=3C1(C)CCC2C1COC(C)(C)C(O)C(O)C1 YIBXWXOYFGZLRU-UHFFFAOYSA-N 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- AMAZPKIIXVYKEX-UHFFFAOYSA-N tert-butyl 2-amino-2-hydroxybutanoate Chemical compound CCC(N)(O)C(=O)OC(C)(C)C AMAZPKIIXVYKEX-UHFFFAOYSA-N 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QIWRFOJWQSSRJZ-UHFFFAOYSA-N tributyl(ethenyl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C=C QIWRFOJWQSSRJZ-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Virology (AREA)
- Tropical Medicine & Parasitology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9818733 | 1998-08-27 | ||
| GBGB9818733.9A GB9818733D0 (en) | 1998-08-27 | 1998-08-27 | Compounds |
| GBGB9901929.1A GB9901929D0 (en) | 1999-01-28 | 1999-01-28 | Compounds |
| GB9901929 | 1999-01-28 | ||
| PCT/GB1999/002838 WO2000012508A2 (en) | 1998-08-27 | 1999-08-27 | Pyrrolbenzodiazepines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69925133D1 DE69925133D1 (de) | 2005-06-09 |
| DE69925133T2 true DE69925133T2 (de) | 2006-01-19 |
Family
ID=26314276
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69930328T Expired - Lifetime DE69930328T2 (de) | 1998-08-27 | 1999-08-27 | Dimere Pyrrolobenzodiazepine |
| DE69907977T Expired - Lifetime DE69907977T2 (de) | 1998-08-27 | 1999-08-27 | Pyrrolobenzodiazepine |
| DE69925133T Expired - Lifetime DE69925133T2 (de) | 1998-08-27 | 1999-08-27 | Pyrrolobenzodiazepine |
Family Applications Before (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69930328T Expired - Lifetime DE69930328T2 (de) | 1998-08-27 | 1999-08-27 | Dimere Pyrrolobenzodiazepine |
| DE69907977T Expired - Lifetime DE69907977T2 (de) | 1998-08-27 | 1999-08-27 | Pyrrolobenzodiazepine |
Country Status (12)
| Country | Link |
|---|---|
| US (3) | US7049311B1 (enExample) |
| EP (3) | EP1109812B1 (enExample) |
| JP (1) | JP4824165B2 (enExample) |
| AT (3) | ATE240334T1 (enExample) |
| AU (1) | AU757510C (enExample) |
| CA (1) | CA2341471C (enExample) |
| DE (3) | DE69930328T2 (enExample) |
| DK (3) | DK1193270T3 (enExample) |
| ES (3) | ES2244210T3 (enExample) |
| NZ (1) | NZ510493A (enExample) |
| PT (3) | PT1413582E (enExample) |
| WO (1) | WO2000012508A2 (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102006013678A1 (de) * | 2006-03-24 | 2007-09-27 | Bayerische Motoren Werke Ag | Gleit- oder Schmiermittel und Verfahren zum Aufziehen eines Fahrzeugreifens auf eine Felge |
Families Citing this family (195)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9818731D0 (en) * | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Compounds |
| ATE240334T1 (de) | 1998-08-27 | 2003-05-15 | Spirogen Ltd | Pyrrolobenzodiazepine |
| GB9818732D0 (en) * | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collection of compounds |
| GB9818730D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collections of compounds |
| GB0226593D0 (en) * | 2002-11-14 | 2002-12-24 | Consultants Ltd | Compounds |
| DE60326060D1 (de) * | 2003-03-31 | 2009-03-19 | Council Scient Ind Res | Nichtvernetzende pyrroloä2,1-cüä1,4übenzodiazepine als potentielle antitumor-agentien und ihre herstellung |
| GB0321295D0 (en) * | 2003-09-11 | 2003-10-15 | Spirogen Ltd | Synthesis of protected pyrrolobenzodiazepines |
| US7511032B2 (en) | 2003-10-22 | 2009-03-31 | The United States Of America As Represented By The Secretary, Department Of Health And Human Services | Pyrrolobenzodiazepine derivatives, compositions comprising the same and methods related thereto |
| GB0416511D0 (en) * | 2003-10-22 | 2004-08-25 | Spirogen Ltd | Pyrrolobenzodiazepines |
| WO2005040172A1 (ja) * | 2003-10-29 | 2005-05-06 | Kyowa Hakko Kogyo Co., Ltd. | 三環性プロリン誘導体 |
| JP4718328B2 (ja) * | 2003-12-31 | 2011-07-06 | カウンシル オブ サイエンティフィク アンド インダストリアル リサーチ | Ｃ８連結したピロロ［２，１−ｃ］［１，４］ベンゾジアゼピン−アクリドン／アクリジン・ハイブリッド |
| JP4520411B2 (ja) * | 2003-12-31 | 2010-08-04 | カウンシル オブ サイエンティフィク アンド インダストリアル リサーチ | ピロロ［２，１−ｃ］［１，４］ベンゾジアゼピン・ハイブリッドの調製方法 |
| GB0404577D0 (en) * | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Pyrrolobenzodiazepines |
| AU2005219626B2 (en) | 2004-03-01 | 2010-11-18 | Medimmune Limited | 11-hydroxy-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one derivatives as key intermediates for the preparation of C2 substituted pyrrolobenzodiazepines |
| GB0404574D0 (en) * | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Amino acids |
| GB0404578D0 (en) * | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Pyrrolobenzodiazepines |
| 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 |
| DE602006011300D1 (de) * | 2005-04-21 | 2010-02-04 | Spirogen Ltd | Pyrrolobenzodiazepine |
| GB0508084D0 (en) * | 2005-04-21 | 2005-06-01 | Spirogen Ltd | Pyrrolobenzodiazepines |
| WO2007039752A1 (en) * | 2005-10-05 | 2007-04-12 | Spirogen Limited | Alkyl 4- [4- (5-oxo-2, 3, 5, 11a-tetrahyd0-5h-pyrr0l0 [2, 1-c] [1, 4] benzodiazepine-8-yloxy) -butyrylamino]-1h-pyrrole-2-carboxylate derivatives and related compounds for the treatment of a proliferative disease |
| PT1813614E (pt) * | 2006-01-25 | 2012-01-09 | Sanofi Sa | Agentes citotóxicos compreendendo novos derivados de tomaimicina |
| EA020324B1 (ru) | 2006-07-18 | 2014-10-30 | Санофи-Авентис | АНТИТЕЛА К РЕЦЕПТОРУ ЭФРИНА EphA2 И ИХ ПРИМЕНЕНИЕ |
| 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 |
| DK2019104T3 (da) | 2007-07-19 | 2013-12-16 | Sanofi Sa | Cytotoksiske midler, der omfatter nye tomaymycinderivater, og terapeutisk anvendelse deraf |
| CN104524592B (zh) | 2008-04-30 | 2018-06-05 | 伊缪诺金公司 | 交联剂和它们的用途 |
| GB0813432D0 (en) * | 2008-07-22 | 2008-08-27 | Spirogen Ltd | Pyrrolobenzodiazepines |
| GB0819097D0 (en) * | 2008-10-17 | 2008-11-26 | Spirogen Ltd | Pyrrolobenzodiazepines |
| GB0819095D0 (en) | 2008-10-17 | 2008-11-26 | Spirogen Ltd | Pyrrolobenzodiazepines |
| CN102365021B (zh) * | 2009-02-05 | 2015-07-15 | 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 |
| KR101947176B1 (ko) | 2009-06-03 | 2019-02-12 | 이뮤노젠 아이엔씨 | 접합 방법 |
| FR2949469A1 (fr) * | 2009-08-25 | 2011-03-04 | Sanofi Aventis | Derives anticancereux, leur preparation et leur application en therapeutique |
| UY32914A (es) | 2009-10-02 | 2011-04-29 | Sanofi Aventis | Anticuerpos que se usan específicamente al receptor epha2 |
| GB201006340D0 (en) | 2010-04-15 | 2010-06-02 | Spirogen Ltd | Synthesis method and intermediates |
| MX2012011900A (es) | 2010-04-15 | 2013-03-21 | Seattle Genetics Inc | Conjugados de pirrolobenzodiazepina diana. |
| HRP20130953T1 (hr) | 2010-04-15 | 2013-11-22 | Spirogen Sàrl | Pirolobenzodiazepini i njihovi konjugati |
| US8697688B2 (en) | 2010-04-15 | 2014-04-15 | Seattle Genetics Inc. | Pyrrolobenzodiazepines used to treat proliferative diseases |
| FR2963007B1 (fr) | 2010-07-26 | 2013-04-05 | Sanofi Aventis | Derives anticancereux, leur preparation et leur application therapeutique |
| SMT201900181T1 (it) | 2011-02-15 | 2019-05-10 | Immunogen Inc | Metodi di preparazione di coniugati |
| 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 |
| EP2751120B1 (en) | 2011-09-20 | 2018-08-22 | MedImmune Limited | Pyrrolobenzodiazepines as unsymmetrical dimeric pbd compounds for inclusion in targeted conjugates |
| CN103998450B (zh) * | 2011-10-14 | 2017-03-08 | 麦迪穆有限责任公司 | 吡咯并苯并二氮杂卓 |
| BR112014009070B1 (pt) | 2011-10-14 | 2021-11-23 | Medimmune Limited | Método de síntese e intermediários úteis na preparação de pirrolobenzo-diazepinas |
| CA2850373C (en) | 2011-10-14 | 2019-07-16 | Seattle Genetics, Inc. | Pyrrolobenzodiazepines and targeted conjugates |
| CN110183470A (zh) | 2011-10-14 | 2019-08-30 | 麦迪穆有限责任公司 | 吡咯并苯并二氮杂卓 |
| PL2750713T3 (pl) | 2011-10-14 | 2016-03-31 | Medimmune Ltd | Pirolobenzodiazepiny i ich koniugaty |
| US9387259B2 (en) * | 2011-10-14 | 2016-07-12 | Seattle Genetics, Inc. | Pyrrolobenzodiazepines and targeted conjugates |
| SMT201700467T1 (it) | 2012-02-24 | 2017-11-15 | Abbvie Stemcentrx Llc | Modulatori di dll3 e metodi di uso |
| SG11201405130UA (en) | 2012-02-24 | 2014-11-27 | Stemcentrx Inc | Anti sez6 antibodies and methods of use |
| AR090549A1 (es) | 2012-03-30 | 2014-11-19 | Genentech Inc | Anticuerpos anti-lgr5 e inmunoconjugados |
| JP6125614B2 (ja) | 2012-04-30 | 2017-05-10 | ユーシーエル ビジネス ピーエルシー | ピロロベンゾジアゼピン |
| NZ701290A (en) | 2012-04-30 | 2016-08-26 | Medimmune Ltd | Pyrrolobenzodiazepines |
| RU2014148162A (ru) | 2012-05-01 | 2016-06-20 | Дженентек, Инк. | Анти-pmel17 антитела и их иммуноконъюгаты |
| HK1209043A1 (en) | 2012-07-09 | 2016-03-24 | 基因泰克公司 | Immunoconjugates comprising anti-cd22 antibodies |
| US20140030280A1 (en) | 2012-07-09 | 2014-01-30 | Genentech, Inc. | Anti-cd79b antibodies and immunoconjugates |
| CN104717979A (zh) | 2012-08-02 | 2015-06-17 | 基因泰克公司 | 抗etbr抗体和免疫偶联物 |
| WO2014031566A1 (en) | 2012-08-22 | 2014-02-27 | Immunogen, Inc. | Cytotoxic benzodiazepine derivatives |
| MX364329B (es) | 2012-10-12 | 2019-04-23 | Medimmune Ltd | Conjugados del anticuerpo pirrolobenzodiazepina. |
| WO2014057120A1 (en) | 2012-10-12 | 2014-04-17 | Adc Therapeutics Sàrl | Pyrrolobenzodiazepine-antibody conjugates |
| CN110256469B (zh) | 2012-10-12 | 2022-05-17 | 麦迪穆有限责任公司 | 吡咯并苯并二氮杂卓及其结合物 |
| DK2906253T3 (en) | 2012-10-12 | 2018-10-22 | Adc Therapeutics Sa | Pyrrolobenzodiazepine anti-PSMA antibody conjugates |
| DK2839860T3 (da) | 2012-10-12 | 2019-06-17 | Medimmune Ltd | Pyrrolobenzodiazepiner og konjugater deraf |
| ES2680153T3 (es) | 2012-10-12 | 2018-09-04 | Adc Therapeutics Sa | Conjugados de anticuerpos anti-PSMA-pirrolobenzodiazepinas |
| EP2906249B1 (en) | 2012-10-12 | 2018-06-27 | MedImmune Limited | Synthesis and intermediates of pyrrolobenzodiazepine derivatives for conjugation |
| WO2014057119A1 (en) | 2012-10-12 | 2014-04-17 | Adc Therapeutics Sàrl | Pyrrolobenzodiazepine-antibody conjugates |
| PL2906251T3 (pl) | 2012-10-12 | 2018-02-28 | Adc Therapeutics Sa | Koniugaty pirolobenzodiazepina-przeciwciało anty-CD22 |
| JP6133431B2 (ja) | 2012-11-24 | 2017-05-24 | ハンジョウ ディーエーシー バイオテック シーオー．，エルティディ．Ｈａｎｇｚｈｏｕ Ｄａｃ Ｂｉｏｔｅｃｈ Ｃｏ．，Ｌｔｄ． | 親水性連結体及び薬物分子と細胞結合分子との共役反応における親水性連結体の使用 |
| CN105246894A (zh) | 2012-12-21 | 2016-01-13 | 斯皮罗根有限公司 | 用于治疗增殖性和自身免疫疾病的非对称吡咯并苯并二氮杂卓二聚物 |
| EA031585B1 (ru) | 2012-12-21 | 2019-01-31 | Медимьюн Лимитед | Пирролобензодиазепины и их конъюгаты |
| TR201908761T4 (tr) | 2013-02-22 | 2019-07-22 | Abbvie Stemcentrx Llc | Antidll3-antikor-pbd konjugatları ve kullanımları. |
| ES2687439T3 (es) | 2013-03-13 | 2018-10-25 | Medimmune Limited | Pirrolobenzodiazepinas y conjugados de las mismas |
| CN105142674B (zh) | 2013-03-13 | 2018-11-13 | 麦迪穆有限责任公司 | 吡咯并苯并二氮杂卓和其结合物 |
| NZ710745A (en) | 2013-03-13 | 2019-03-29 | Genentech Inc | Pyrrolobenzodiazepines and conjugates thereof |
| US9562099B2 (en) | 2013-03-14 | 2017-02-07 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
| AU2014244424A1 (en) | 2013-03-14 | 2015-08-27 | Genentech, Inc. | Anti-B7-H4 antibodies and immunoconjugates |
| BR112016002829A2 (pt) | 2013-08-12 | 2017-09-19 | Genentech Inc | Composto e processo para preparar o composto de conjugado anticorpo-¿droga, composição farmacêutica, método de tratamento do câncer, kit para o tratamento do câncer, intermediário ligante¿-droga, porção e composto de porção droga de dímero cbi |
| KR20160046914A (ko) | 2013-08-28 | 2016-04-29 | 스템센트알엑스 인코포레이티드 | 신규한 ｓｅｚ6 조절물질 및 사용방법 |
| MX377339B (es) | 2013-08-28 | 2025-03-06 | Abbvie Stemcentrx Llc | Metodos de conjugacion de anticuerpos especificos de sitio y composiciones. |
| KR20160055253A (ko) | 2013-09-12 | 2016-05-17 | 할로자임, 아이엔씨 | 변형된 항-상피세포 성장인자 수용체 항체 및 이의 사용 방법 |
| KR20160055252A (ko) | 2013-09-17 | 2016-05-17 | 제넨테크, 인크. | 항-lgr5 항체의 사용 방법 |
| US9956299B2 (en) | 2013-10-11 | 2018-05-01 | Medimmune Limited | Pyrrolobenzodiazepine—antibody conjugates |
| US9950078B2 (en) | 2013-10-11 | 2018-04-24 | Medimmune Limited | Pyrrolobenzodiazepine-antibody conjugates |
| 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 |
| US10053511B2 (en) | 2013-11-06 | 2018-08-21 | Abbvie Stemcentrx Llc | Anti-claudin antibodies and methods of use |
| CN105744935B (zh) | 2013-11-27 | 2022-09-30 | 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 |
| EP3461845B1 (en) | 2013-12-13 | 2020-09-16 | Genentech, Inc. | Anti-cd33 antibodies and immunoconjugates |
| JP6980384B2 (ja) | 2013-12-16 | 2021-12-15 | ジェネンテック， インコーポレイテッド | １−（クロロメチル）−２，３−ジヒドロ−１ｈ−ベンゾ［ｅ］インドール二量体抗体−薬物コンジュゲート化合物、並びに使用及び処置の方法 |
| EP3107576A4 (en) | 2014-02-21 | 2017-09-06 | Abbvie Stemcentrx LLC | Anti-dll3 antibodies and drug conjugates for use in melanoma |
| US10464955B2 (en) | 2014-02-28 | 2019-11-05 | 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 |
| EP3145952A2 (en) | 2014-05-22 | 2017-03-29 | Genentech, Inc. | Anti-gpc3 antibodies and immunoconjugates |
| RU2764074C2 (ru) | 2014-08-28 | 2022-01-13 | Байоатла, Ллк | Условно активные химерные антигенные рецепторы для модифицированных т-клеток |
| MX2017002758A (es) | 2014-09-03 | 2017-10-20 | Immunogen Inc | Derivados de benzodiazepina citotoxicos. |
| US9381256B2 (en) | 2014-09-03 | 2016-07-05 | 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 |
| CN106687141A (zh) | 2014-09-10 | 2017-05-17 | 麦迪穆有限责任公司 | 吡咯并苯并二氮杂卓及其缀合物 |
| GB201416112D0 (en) | 2014-09-12 | 2014-10-29 | Medimmune Ltd | Pyrrolobenzodiazepines and conjugates thereof |
| KR102508173B1 (ko) | 2014-09-12 | 2023-03-10 | 제넨테크, 인크. | 항-her2 항체 및 면역콘주게이트 |
| US9751946B2 (en) | 2014-09-12 | 2017-09-05 | Genentech, Inc. | Anti-CLL-1 antibodies and immunoconjugates |
| EP3191518B1 (en) | 2014-09-12 | 2020-01-15 | Genentech, Inc. | Anti-b7-h4 antibodies and immunoconjugates |
| EP3388449A3 (en) | 2014-09-12 | 2018-10-24 | F. Hoffmann-La Roche AG | Cysteine engineered antibodies and conjugates |
| HK1243629A1 (zh) | 2014-09-17 | 2018-07-20 | 基因泰克公司 | 包含抗her2抗体和吡咯并苯并二氮杂䓬的免疫缀合物 |
| CN107148285B (zh) | 2014-11-25 | 2022-01-04 | Adc治疗股份有限公司 | 吡咯并苯并二氮杂䓬-抗体缀合物 |
| TN2017000246A1 (en) | 2014-12-11 | 2018-10-19 | Pf Medicament | Anti-c10orf54 antibodies and uses thereof |
| MX2017009145A (es) | 2015-01-14 | 2017-11-22 | Bristol Myers Squibb Co | Dimeros de benzodiazepina, conjugados de estos, y sus metodos de preparacion y uso. |
| BR112017014937A2 (pt) | 2015-01-14 | 2018-03-13 | Bristol-Myers Squibb Company | dímeros de benzodiazepina ligados em ponte a heteroarileno, 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 |
| AU2015242210A1 (en) | 2015-06-15 | 2017-12-07 | Hangzhou Dac Biotech Co., Ltd | Hydrophilic linkers for conjugation |
| CN108391434A (zh) | 2015-06-23 | 2018-08-10 | 百时美施贵宝公司 | 大环苯并二氮杂*二聚体、其缀合物、制备和用途 |
| JP6759326B2 (ja) | 2015-07-12 | 2020-09-23 | ハンジョウ ディーエーシー バイオテック シーオー．，エルティディ．Ｈａｎｇｚｈｏｕ Ｄａｃ Ｂｉｏｔｅｃｈ Ｃｏ．，Ｌｔｄ． | 細胞結合分子の共役のための架橋連結体 |
| 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 |
| EP3325483B1 (en) | 2015-07-21 | 2019-10-02 | 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 |
| CN108463226B (zh) | 2015-11-09 | 2022-04-15 | R.P.谢勒技术有限责任公司 | 抗cd22抗体-美登木素缀合物及其使用方法 |
| 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 |
| CN109563164A (zh) | 2016-04-15 | 2019-04-02 | 生物蛋白有限公司 | 抗axl抗体、抗体片段和它们的免疫缀合物以及其用途 |
| US10934359B2 (en) | 2016-04-21 | 2021-03-02 | Abbvie Stemcentrx Llc | Anti-BMPR1B antibodies and methods of use |
| 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 |
| TWI844509B (zh) | 2016-05-13 | 2024-06-11 | 美商拜奧亞特拉公司 | 抗-ror2抗體、抗體片段、其免疫結合物及其用途 |
| CN109313200B (zh) | 2016-05-27 | 2022-10-04 | 豪夫迈·罗氏有限公司 | 用于表征位点特异性抗体-药物缀合物的生物分析性方法 |
| 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 |
| EP3494135A1 (en) | 2016-08-02 | 2019-06-12 | 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 |
| JP2019530434A (ja) | 2016-08-05 | 2019-10-24 | ジェネンテック， インコーポレイテッド | アゴニスト活性を有する多価及び多重エピトープ抗体ならびに使用方法 |
| CN109689111B (zh) | 2016-08-11 | 2024-04-05 | 基因泰克公司 | 吡咯并苯并二氮杂䓬前药及其抗体缀合物 |
| CN109862919A (zh) | 2016-10-11 | 2019-06-07 | 免疫医疗有限公司 | 抗体-药物缀合物联合免疫介导的治疗剂 |
| GB201617466D0 (en) | 2016-10-14 | 2016-11-30 | Medimmune Ltd | Pyrrolobenzodiazepine conjugates |
| CN110099682B (zh) | 2016-11-14 | 2023-03-31 | 杭州多禧生物科技有限公司 | 偶联连接体，含有此连接体的细胞结合分子-药物偶联物及其制备和应用 |
| WO2018091724A1 (en) | 2016-11-21 | 2018-05-24 | Cureab Gmbh | Anti-gp73 antibodies and immunoconjugates |
| FR3059550B1 (fr) | 2016-12-01 | 2020-01-03 | Universite De Rouen Normandie | Traitement des troubles causes par l'alcoolisation foetale (tcaf) |
| US11236171B2 (en) | 2016-12-21 | 2022-02-01 | 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 |
| GB201702031D0 (en) | 2017-02-08 | 2017-03-22 | Medlmmune Ltd | Pyrrolobenzodiazepine-antibody conjugates |
| BR112019016373B1 (pt) | 2017-02-08 | 2022-01-25 | Medimmune Limited | Conjugado anticorpo-fármaco que se liga ao axl, composição e composição farmacêutica que compreende o mesmo e uso terapêutico do dito conjugado |
| ES2926144T3 (es) | 2017-04-18 | 2022-10-24 | Medimmune Ltd | Conjugados de pirrolobenzodiazepina |
| JP7408396B2 (ja) | 2017-04-20 | 2024-01-05 | アーデーセー セラピューティクス ソシエテ アノニム | 併用療法 |
| TW201839001A (zh) | 2017-04-20 | 2018-11-01 | 美商伊繆諾金公司 | 細胞毒性苯并二氮平衍生物及其綴合物 |
| US11389480B2 (en) | 2017-05-19 | 2022-07-19 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Human monoclonal antibody targeting TNFR2 for cancer immunotherapy |
| PL3638373T3 (pl) | 2017-06-14 | 2025-04-14 | Adc Therapeutics Sa | Schematy dawkowania dla podawania ADC anty-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 |
| WO2019023247A1 (en) | 2017-07-25 | 2019-01-31 | Immutics, Inc. | TREATMENT OF CANCER BY BLOCKING THE INTERACTION OF TIM-3 AND ITS LIGAND |
| EP3668874B1 (en) | 2017-08-18 | 2021-12-22 | Medimmune Limited | Pyrrolobenzodiazepine conjugates |
| JP7273716B2 (ja) | 2017-09-29 | 2023-05-15 | 第一三共株式会社 | 抗体－ピロロベンゾジアゼピン誘導体コンジュゲート |
| CN111417409B (zh) | 2017-11-14 | 2022-07-08 | 麦迪穆有限责任公司 | 吡咯并苯并二氮杂䓬缀合物 |
| CN112204048A (zh) | 2017-12-15 | 2021-01-08 | 朱诺治疗学股份有限公司 | 抗cct5结合分子及其使用方法 |
| TWI827575B (zh) | 2017-12-28 | 2024-01-01 | 美商伊繆諾金公司 | 苯二氮平衍生物 |
| 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 |
| AU2019301675B2 (en) | 2018-07-12 | 2025-09-04 | 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 |
| US12012463B2 (en) | 2018-08-08 | 2024-06-18 | 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 |
| JP7259024B2 (ja) | 2018-10-19 | 2023-04-17 | メドイミューン・リミテッド | ピロロベンゾジアゼピン複合体 |
| AU2019363153A1 (en) | 2018-10-19 | 2021-05-06 | Medimmune Limited | Pyrrolobenzodiazepine conjugates |
| IL319265A (en) | 2018-12-21 | 2025-04-01 | Avidity Biosciences Inc | Anti-transferrin receptor antibodies and their uses |
| WO2020146182A1 (en) | 2019-01-08 | 2020-07-16 | 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 |
| EP3918323A4 (en) | 2019-01-30 | 2022-12-28 | TrueBinding, Inc. | ANTI-GAL3 ANTIBODIES AND USES THEREOF |
| MX2021010477A (es) | 2019-03-15 | 2021-10-01 | Medimmune Ltd | Dimeros de azetidobenzodiazepina y conjugados que los comprenden para uso en el tratamiento de cancer. |
| TW202102506A (zh) | 2019-03-29 | 2021-01-16 | 美商伊繆諾金公司 | 苯二氮平衍生物 |
| CN119899265A (zh) | 2019-10-22 | 2025-04-29 | 美国政府(由卫生和人类服务部的部长所代表) | 用于治疗多种实体瘤的靶向b7h3（cd276）的高亲和力纳米抗体 |
| AU2020402752A1 (en) | 2019-12-12 | 2022-06-30 | 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 |
| TW202144572A (zh) | 2020-03-19 | 2021-12-01 | 美商亞維代堤生物科學公司 | 治療臉肩胛肱骨肌肉失養症之組合物及方法 |
| WO2021195469A1 (en) | 2020-03-27 | 2021-09-30 | Avidity Biosciences, Inc. | Compositions and methods of treating muscle dystrophy |
| WO2021242776A2 (en) | 2020-05-26 | 2021-12-02 | Truebinding, Inc. | Methods of treating inflammatory diseases by blocking galectin-3 |
| WO2022093745A1 (en) | 2020-10-26 | 2022-05-05 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Single domain antibodies targeting sars coronavirus spike protein and uses thereof |
| WO2022232612A1 (en) | 2021-04-29 | 2022-11-03 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Lassa virus-specific nanobodies and methods of their use |
| CA3216228A1 (en) | 2021-06-09 | 2022-12-15 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Cross species single domain antibodies targeting pd-l1 for treating solid tumors |
| JP2024526764A (ja) | 2021-07-13 | 2024-07-19 | トゥルーバインディング，インコーポレイテッド | タンパク質凝集を防止する方法 |
| CN118265544A (zh) | 2021-09-16 | 2024-06-28 | 艾维迪提生物科学公司 | 治疗面肩肱型肌营养不良的组合物和方法 |
| JP2024541058A (ja) | 2021-11-03 | 2024-11-06 | ハンジョウ ディーエーシー バイオテック シーオー．，エルティディ． | 抗体の特異的共役 |
| WO2023086768A1 (en) | 2021-11-09 | 2023-05-19 | Truebinding, Inc. | Methods of treating or inhibiting cardiovascular diseases |
| PE20242350A1 (es) | 2022-05-03 | 2024-12-16 | Genentech Inc | Anticuerpos anti-ly6e, inmunoconjugados y usos de estos |
| 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 |
Family Cites Families (38)
| 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 |
| IL33558A (en) * | 1968-12-30 | 1973-10-25 | Fujisawa Pharmaceutical Co | Antibiotic pyrrolo-benzodiazepine compound,its derivatives and processes for their production |
| 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 |
| JPS57131791A (en) * | 1980-12-31 | 1982-08-14 | Fujisawa Pharmaceut Co Ltd | Benzodiazepine derivative and its preparation |
| 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 |
| US4427588A (en) * | 1982-11-08 | 1984-01-24 | Bristol-Myers Company | Process for conversion of oxotomaymycin to tomaymycin |
| 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 |
| MX9203200A (es) | 1986-12-19 | 1992-09-01 | Upjohn Co | Analogos de cc. 1065 novedosos. |
| 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 |
| WO1991016324A1 (en) | 1990-04-25 | 1991-10-31 | The Upjohn Company | Novel cc-1065 analogs |
| 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. |
| AU681337B2 (en) | 1991-10-23 | 1997-08-28 | Cancer Research Campaign Technology Limited | Bacterial nitroreductase for the reduction of CB 1954 and analogues thereof to a cytotoxic 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 |
| CA2225914A1 (en) | 1995-06-29 | 1997-01-16 | Pharmacopeia, Inc. | Combinatorial 1,4-benzodiazepin-2,5-dione library |
| GB9516943D0 (en) | 1995-08-18 | 1995-10-18 | Cancer Soc Auckland Div Nz Inc | Novel cyclopropylindoles and their secoprecursors,and their use as prodrugs |
| ES2253786T3 (es) | 1996-09-12 | 2006-06-01 | Auckland Uniservices Limited | Compuestos de ciclopropilindola y su uso como precursores de medicamentos. |
| 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 |
| EP1037865A4 (en) | 1997-12-08 | 2004-03-31 | Scripps Research Inst | SYNTHESIS OF CC-1065 / DUOCARMYCIN ANALOGS |
| WO1999046244A1 (en) | 1998-03-12 | 1999-09-16 | Novo Nordisk A/S | Modulators of protein tyrosine phosphatases (ptpases) |
| GB9818731D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Compounds |
| GB9818730D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collections of compounds |
| ATE240334T1 (de) | 1998-08-27 | 2003-05-15 | Spirogen Ltd | Pyrrolobenzodiazepine |
| GB9818732D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Collection of 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 |
| US7511032B2 (en) | 2003-10-22 | 2009-03-31 | The United States Of America As Represented By The Secretary, Department Of Health And Human Services | Pyrrolobenzodiazepine derivatives, compositions comprising the same and methods related thereto |
| AU2005219626B2 (en) | 2004-03-01 | 2010-11-18 | Medimmune Limited | 11-hydroxy-5H-pyrrolo[2,1-c][1,4]benzodiazepin-5-one derivatives as key intermediates for the preparation of C2 substituted pyrrolobenzodiazepines |
-
1999
- 1999-08-27 AT AT01129700T patent/ATE240334T1/de active
- 1999-08-27 EP EP99943066A patent/EP1109812B1/en not_active Expired - Lifetime
- 1999-08-27 EP EP03028817A patent/EP1413582B1/en not_active Expired - Lifetime
- 1999-08-27 DK DK01129700T patent/DK1193270T3/da active
- 1999-08-27 DE DE69930328T patent/DE69930328T2/de not_active Expired - Lifetime
- 1999-08-27 ES ES99943066T patent/ES2244210T3/es not_active Expired - Lifetime
- 1999-08-27 ES ES01129700T patent/ES2199200T3/es not_active Expired - Lifetime
- 1999-08-27 JP JP2000571054A patent/JP4824165B2/ja not_active Expired - Lifetime
- 1999-08-27 DE DE69907977T patent/DE69907977T2/de not_active Expired - Lifetime
- 1999-08-27 AU AU56351/99A patent/AU757510C/en not_active Expired
- 1999-08-27 CA CA002341471A patent/CA2341471C/en not_active Expired - Lifetime
- 1999-08-27 AT AT99943066T patent/ATE294803T1/de active
- 1999-08-27 PT PT03028817T patent/PT1413582E/pt unknown
- 1999-08-27 NZ NZ510493A patent/NZ510493A/en not_active IP Right Cessation
- 1999-08-27 PT PT99943066T patent/PT1109812E/pt unknown
- 1999-08-27 WO PCT/GB1999/002838 patent/WO2000012508A2/en not_active Ceased
- 1999-08-27 DK DK03028817T patent/DK1413582T3/da active
- 1999-08-27 ES ES03028817T patent/ES2260570T3/es not_active Expired - Lifetime
- 1999-08-27 DK DK99943066T patent/DK1109812T3/da active
- 1999-08-27 DE DE69925133T patent/DE69925133T2/de not_active Expired - Lifetime
- 1999-08-27 AT AT03028817T patent/ATE320436T1/de active
- 1999-08-27 PT PT01129700T patent/PT1193270E/pt unknown
- 1999-08-27 US US09/763,767 patent/US7049311B1/en not_active Expired - Lifetime
- 1999-08-27 EP EP01129700A patent/EP1193270B1/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
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102006013678A1 (de) * | 2006-03-24 | 2007-09-27 | Bayerische Motoren Werke Ag | Gleit- oder Schmiermittel und Verfahren zum Aufziehen eines Fahrzeugreifens auf eine Felge |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| DE69925133T2 (de) | Pyrrolobenzodiazepine | |
| DE69910227T2 (de) | Pyrrolobenzodiazepine | |
| EP0801651B1 (de) | Hydroxymethyl-imidazodiazepine und deren ester | |
| DE3750596T2 (de) | 1,2,3,3a,8,8a-Hexahydro-1,3a,8-Trimethylpyrrolo[2,3-b]indole, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel. | |
| DE69734722T2 (de) | Kondensierte n-acylindole als antitumormittel | |
| EP0027214A1 (de) | Imidazodiazepin-Derivate, Verfahren und Zwischenprodukte zu ihrer Herstellung, diese enthaltende Arzneimittel und deren therapeutische Verwendung | |
| EP1181294B1 (de) | Neue derivate und analoga von galanthamin | |
| DE69508421T2 (de) | SPIRO[HETEROZYCLISCHE-IMIDAZO[1,2-a]INDENO[1,2-e]PYRAZIN]-4'-ONE, IHRE HERSTELLUNG UND DIESE ENTHALTENDE ARZNEIMITTEL | |
| DE69401716T2 (de) | Imidazo [1,2-a] pyrasin-4-on-derivate welche als ampa und nmda receptor antagonisten dienen | |
| EP0031080A1 (de) | 2-Acylaminomethyl-1,4-benzodiazepine und deren Salze sowie Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende Arzneimittel | |
| DE69808921T2 (de) | 4-OXO-3,5-DIHYDRO-4H-PYRIDAZINO[4,5-b]INDOL-1-ACETAMID-DERIVATE, IHRE HERSTELLUNG UND THERAPEUTISCHE ANWENDUNG | |
| DE112007000079B4 (de) | Neuartige Bis-Pyrrolo[2,1-c][1,4]benzodiazepin-anthrachinon Konjugate und ein Verfahren zu deren Herstellung | |
| DE2947773A1 (de) | 4,1-benzoxazepin- oder 4,1-benzothiazepinderivate, verfahren zu ihrer herstellung und ihre verwendung | |
| JPH0322390B2 (enExample) | ||
| DE69512419T2 (de) | IMIDAZO[1,2-a]INDENO[1,2-e]PYRAZIN-2-CARBONSÄURE DERIVATE, IHRE HERSTELLUNG UND SIE ENTHALTENDE ARZNEIMITTEL | |
| DE68905363T2 (de) | Heterotetracyclische laktamderivate, verfahren zu ihrer herstellung und pharmazeutische zubereitungen, die sie enthalten. | |
| WO1998043976A1 (en) | Biphenyl derivatives and medicinal compositions | |
| EP0072029B1 (de) | Triazolobenzazepine, Verfahren und Zwischenprodukte zu deren Herstellung und diese enthaltende Arzneimittel | |
| DE69125962T2 (de) | 3H,6H-1,4,5a,8a-Tetraazaacenaphthylen-3,5-(4H)dione | |
| DE69230110T2 (de) | An drei ringen substituierte tetrahydropyridin-derivate | |
| DE68911951T2 (de) | 5-(Substituierte Amino)-8-(phenyl oder substituierte phenyl)-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one. | |
| EP0357043A2 (de) | Imidazodiazepin-Derivate | |
| DE112012000807B4 (de) | Pyrrolo[2,1-c][1,4]naphthodiazepin-verknüpfte Piperazinverbindungen und Verfahren zu deren Herstellung | |
| DE102004002885A1 (de) | Neue medizinisch einsetzbare Pyrrolalkaloide: Verfahren zu ihrer Isolierung, Synthese, sie enthaltende Arzneimittel und deren Verwendung | |
| EP0094668A2 (de) | Pyrrolo(3,4-d)(2)benzazepin-Derivate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 8364 | No opposition during term of opposition | ||
| R082 | Change of representative |
Ref document number: 1109812 Country of ref document: EP Representative=s name: LEINWEBER & ZIMMERMANN, DE |