ES2244210T3 - Pirrolobenzodiazepinas. - Google Patents
Pirrolobenzodiazepinas.Info
- Publication number
- ES2244210T3 ES2244210T3 ES99943066T ES99943066T ES2244210T3 ES 2244210 T3 ES2244210 T3 ES 2244210T3 ES 99943066 T ES99943066 T ES 99943066T ES 99943066 T ES99943066 T ES 99943066T ES 2244210 T3 ES2244210 T3 ES 2244210T3
- Authority
- ES
- Spain
- Prior art keywords
- mmol
- compound
- compound according
- solution
- 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
- 150000001875 compounds Chemical class 0.000 claims abstract description 137
- -1 hydroxy, amino Chemical group 0.000 claims description 100
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 60
- 125000000217 alkyl group Chemical group 0.000 claims description 52
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 52
- 125000004432 carbon atom Chemical group C* 0.000 claims description 51
- 239000000539 dimer Substances 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 37
- 229910052757 nitrogen Inorganic materials 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 125000005842 heteroatom Chemical group 0.000 claims description 25
- 125000005843 halogen group Chemical group 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 16
- 125000001475 halogen functional group Chemical group 0.000 claims description 16
- 125000000524 functional group Chemical group 0.000 claims description 15
- 239000000178 monomer Substances 0.000 claims description 15
- 238000011282 treatment Methods 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000004429 atom Chemical group 0.000 claims description 10
- 239000011203 carbon fibre reinforced carbon Substances 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 230000008569 process Effects 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
- KRYRNEPMWZHETR-VIFPVBQESA-N (6as)-3-amino-6a,7,8,9-tetrahydropyrrolo[2,1-c][1,4]benzodiazepin-11-one Chemical compound N1=C[C@@H]2CCCN2C(=O)C2=CC=C(N)C=C21 KRYRNEPMWZHETR-VIFPVBQESA-N 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- 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 claims description 4
- 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 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 230000003071 parasitic effect Effects 0.000 claims description 3
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 230000001580 bacterial effect Effects 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 2
- 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
- 229940079593 drug Drugs 0.000 claims 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 484
- 239000000243 solution Substances 0.000 description 382
- 238000005481 NMR spectroscopy Methods 0.000 description 308
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 295
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 240
- 239000011541 reaction mixture Substances 0.000 description 231
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 209
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 204
- 229910001868 water Inorganic materials 0.000 description 157
- 239000000203 mixture Substances 0.000 description 142
- 238000003756 stirring Methods 0.000 description 129
- 239000012267 brine Substances 0.000 description 124
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 124
- 239000003208 petroleum Substances 0.000 description 112
- 239000002904 solvent Substances 0.000 description 111
- 239000000047 product Substances 0.000 description 107
- 238000003818 flash chromatography Methods 0.000 description 106
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 105
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 98
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 98
- 238000006243 chemical reaction Methods 0.000 description 93
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 91
- 239000003921 oil Substances 0.000 description 91
- 235000019198 oils Nutrition 0.000 description 91
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 90
- 238000004809 thin layer chromatography Methods 0.000 description 90
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 88
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 83
- 230000015572 biosynthetic process Effects 0.000 description 73
- 239000000460 chlorine Substances 0.000 description 66
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 59
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 59
- 239000007787 solid Substances 0.000 description 59
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 56
- 239000012299 nitrogen atmosphere Substances 0.000 description 56
- 238000003786 synthesis reaction Methods 0.000 description 56
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 52
- 238000001704 evaporation Methods 0.000 description 52
- 230000008020 evaporation Effects 0.000 description 52
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 48
- 239000012044 organic layer Substances 0.000 description 43
- 150000001412 amines Chemical group 0.000 description 42
- 150000002576 ketones Chemical class 0.000 description 41
- 239000012074 organic phase Substances 0.000 description 41
- 239000012043 crude product Substances 0.000 description 40
- XMYQHJDBLRZMLW-UHFFFAOYSA-N methanolamine Chemical compound NCO XMYQHJDBLRZMLW-UHFFFAOYSA-N 0.000 description 40
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 39
- 238000010992 reflux Methods 0.000 description 38
- 239000002253 acid Substances 0.000 description 37
- 238000000746 purification Methods 0.000 description 36
- 230000002829 reductive effect Effects 0.000 description 36
- 239000011521 glass Substances 0.000 description 35
- 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 34
- PWDSJBHSKYBUEX-UHFFFAOYSA-N 1,4-benzodiazepin-5-one Chemical compound O=C1N=CC=NC2=CC=CC=C12 PWDSJBHSKYBUEX-UHFFFAOYSA-N 0.000 description 33
- 150000002466 imines Chemical class 0.000 description 33
- 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 31
- 230000003197 catalytic effect Effects 0.000 description 31
- 238000001914 filtration Methods 0.000 description 31
- 238000001819 mass spectrum Methods 0.000 description 29
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 29
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 28
- 239000000725 suspension Substances 0.000 description 28
- 150000002828 nitro derivatives Chemical class 0.000 description 27
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical compound [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 26
- 239000000463 material Substances 0.000 description 26
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 26
- 239000013078 crystal Substances 0.000 description 25
- 239000010410 layer Substances 0.000 description 25
- 241000790917 Dioxys <bee> Species 0.000 description 24
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 24
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 24
- 235000019341 magnesium sulphate Nutrition 0.000 description 24
- 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 24
- 239000000377 silicon dioxide Substances 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- HVVNJUAVDAZWCB-UHFFFAOYSA-N prolinol Chemical compound OCC1CCCN1 HVVNJUAVDAZWCB-UHFFFAOYSA-N 0.000 description 21
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 20
- 235000019502 Orange oil Nutrition 0.000 description 20
- 150000001408 amides Chemical class 0.000 description 20
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 20
- 239000010502 orange oil Substances 0.000 description 20
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 19
- 239000003480 eluent Substances 0.000 description 19
- 239000000741 silica gel Substances 0.000 description 19
- 229910002027 silica gel Inorganic materials 0.000 description 19
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 19
- 150000002009 diols Chemical class 0.000 description 18
- 150000002148 esters Chemical class 0.000 description 18
- 239000000758 substrate Substances 0.000 description 18
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 18
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 17
- 238000000605 extraction Methods 0.000 description 17
- 238000005755 formation reaction Methods 0.000 description 17
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 17
- 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 16
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 16
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 16
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 15
- 101150065749 Churc1 gene Proteins 0.000 description 15
- 102100038239 Protein Churchill Human genes 0.000 description 15
- 239000002244 precipitate Substances 0.000 description 15
- 238000002390 rotary evaporation Methods 0.000 description 15
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-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
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
- 229920006395 saturated elastomer Polymers 0.000 description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- HJKLEAOXCZIMPI-UHFFFAOYSA-N 2,2-diethoxyethanamine Chemical compound CCOC(CN)OCC HJKLEAOXCZIMPI-UHFFFAOYSA-N 0.000 description 12
- 239000007868 Raney catalyst Substances 0.000 description 12
- 229910000564 Raney nickel Inorganic materials 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 150000001414 amino alcohols Chemical class 0.000 description 12
- 229910052793 cadmium Inorganic materials 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 229910052681 coesite Inorganic materials 0.000 description 12
- 238000005859 coupling reaction Methods 0.000 description 12
- 229910052906 cristobalite Inorganic materials 0.000 description 12
- 235000012239 silicon dioxide Nutrition 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 239000012258 stirred mixture Substances 0.000 description 12
- 229910052682 stishovite Inorganic materials 0.000 description 12
- 229910052905 tridymite Inorganic materials 0.000 description 12
- 238000004587 chromatography analysis Methods 0.000 description 11
- 238000003795 desorption Methods 0.000 description 11
- 239000007788 liquid Substances 0.000 description 11
- OCAAZRFBJBEVPS-UHFFFAOYSA-N prop-2-enyl carbamate Chemical compound NC(=O)OCC=C OCAAZRFBJBEVPS-UHFFFAOYSA-N 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- PUAQLLVFLMYYJJ-UHFFFAOYSA-N 2-aminopropiophenone Chemical compound CC(N)C(=O)C1=CC=CC=C1 PUAQLLVFLMYYJJ-UHFFFAOYSA-N 0.000 description 10
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 10
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 10
- 239000003242 anti bacterial agent Substances 0.000 description 10
- 229940088710 antibiotic agent Drugs 0.000 description 10
- 239000007864 aqueous solution Substances 0.000 description 10
- 230000008878 coupling Effects 0.000 description 10
- 238000010168 coupling process Methods 0.000 description 10
- 230000009467 reduction Effects 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
- 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
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 235000019257 ammonium acetate Nutrition 0.000 description 9
- 229940043376 ammonium acetate Drugs 0.000 description 9
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 9
- 239000012298 atmosphere Substances 0.000 description 9
- 125000001041 indolyl group Chemical group 0.000 description 9
- 230000003647 oxidation Effects 0.000 description 9
- 238000007254 oxidation reaction Methods 0.000 description 9
- 229910052763 palladium Inorganic materials 0.000 description 9
- 239000012071 phase Substances 0.000 description 9
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 9
- 239000007858 starting material Substances 0.000 description 9
- 229910021626 Tin(II) chloride Inorganic materials 0.000 description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 8
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 235000011150 stannous chloride Nutrition 0.000 description 8
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 8
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 7
- 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 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 7
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 7
- 238000006859 Swern oxidation reaction Methods 0.000 description 7
- 150000001336 alkenes Chemical class 0.000 description 7
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 7
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical class [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 7
- 239000006185 dispersion Substances 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
- 150000003138 primary alcohols Chemical class 0.000 description 7
- CAEWJEXPFKNBQL-UHFFFAOYSA-N prop-2-enyl carbonochloridate Chemical compound ClC(=O)OCC=C CAEWJEXPFKNBQL-UHFFFAOYSA-N 0.000 description 7
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- 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
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- XHPGNOTXAJZTCA-KRWDZBQOSA-N methyl 2-[(2s)-2-(hydroxymethyl)-1-(5-methoxy-2-nitro-4-phenylmethoxybenzoyl)-2,3-dihydropyrrol-4-yl]acetate Chemical compound OC[C@@H]1CC(CC(=O)OC)=CN1C(=O)C(C(=C1)[N+]([O-])=O)=CC(OC)=C1OCC1=CC=CC=C1 XHPGNOTXAJZTCA-KRWDZBQOSA-N 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
- QBMWXUPUTJCZQQ-UHFFFAOYSA-N methyl(phenyl)phosphanium;bromide Chemical compound [Br-].C[PH2+]C1=CC=CC=C1 QBMWXUPUTJCZQQ-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000001613 neoplastic effect Effects 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
- 230000003287 optical effect Effects 0.000 description 1
- 238000007243 oxidative cyclization reaction Methods 0.000 description 1
- YEXPOXQUZXUXJW-UHFFFAOYSA-N oxolead Chemical compound [Pb]=O YEXPOXQUZXUXJW-UHFFFAOYSA-N 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 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
- 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
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- XXQBEVHPUKOQEO-UHFFFAOYSA-N potassium peroxide Inorganic materials [K+].[K+].[O-][O-] XXQBEVHPUKOQEO-UHFFFAOYSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 229960002429 proline Drugs 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- YQUVCSBJEUQKSH-UHFFFAOYSA-N protochatechuic acid Natural products OC(=O)C1=CC=C(O)C(O)=C1 YQUVCSBJEUQKSH-UHFFFAOYSA-N 0.000 description 1
- 239000002510 pyrogen Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 235000019719 rose oil Nutrition 0.000 description 1
- 239000010666 rose oil Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000000926 separation method Methods 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
- 238000010512 small scale reaction Methods 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 239000008354 sodium chloride injection Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- KUJFKFWQVGCSAR-UHFFFAOYSA-M sodium;ethyl acetate;hydrogen carbonate Chemical compound [Na+].OC([O-])=O.CCOC(C)=O KUJFKFWQVGCSAR-UHFFFAOYSA-M 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
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- 239000007929 subcutaneous injection Substances 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 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
- 125000001382 thioacetal group Chemical group 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 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
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 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
- WKOLLVMJNQIZCI-UHFFFAOYSA-N vanillic acid Chemical compound COC1=CC(C(O)=O)=CC=C1O WKOLLVMJNQIZCI-UHFFFAOYSA-N 0.000 description 1
- TUUBOHWZSQXCSW-UHFFFAOYSA-N vanillic acid Natural products COC1=CC(O)=CC(C(O)=O)=C1 TUUBOHWZSQXCSW-UHFFFAOYSA-N 0.000 description 1
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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)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Tropical Medicine & Parasitology (AREA)
- Virology (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 (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9818733.9A GB9818733D0 (en) | 1998-08-27 | 1998-08-27 | Compounds |
| GB9818733 | 1998-08-27 | ||
| GB9901929 | 1999-01-28 | ||
| GBGB9901929.1A GB9901929D0 (en) | 1999-01-28 | 1999-01-28 | Compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2244210T3 true ES2244210T3 (es) | 2005-12-01 |
Family
ID=26314276
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES99943066T Expired - Lifetime ES2244210T3 (es) | 1998-08-27 | 1999-08-27 | Pirrolobenzodiazepinas. |
| ES03028817T Expired - Lifetime ES2260570T3 (es) | 1998-08-27 | 1999-08-27 | Pirrolobenziodiazepinas dimericas. |
| ES01129700T Expired - Lifetime ES2199200T3 (es) | 1998-08-27 | 1999-08-27 | Pirrolobenzodiacepinas. |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES03028817T Expired - Lifetime ES2260570T3 (es) | 1998-08-27 | 1999-08-27 | Pirrolobenziodiazepinas dimericas. |
| ES01129700T Expired - Lifetime ES2199200T3 (es) | 1998-08-27 | 1999-08-27 | Pirrolobenzodiacepinas. |
Country Status (12)
| Country | Link |
|---|---|
| US (3) | US7049311B1 (enExample) |
| EP (3) | EP1193270B1 (enExample) |
| JP (1) | JP4824165B2 (enExample) |
| AT (3) | ATE240334T1 (enExample) |
| AU (1) | AU757510C (enExample) |
| CA (1) | CA2341471C (enExample) |
| DE (3) | DE69925133T2 (enExample) |
| DK (3) | DK1109812T3 (enExample) |
| ES (3) | ES2244210T3 (enExample) |
| NZ (1) | NZ510493A (enExample) |
| PT (3) | PT1109812E (enExample) |
| WO (1) | WO2000012508A2 (enExample) |
Families Citing this family (196)
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| 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 |
| ES2244210T3 (es) | 1998-08-27 | 2005-12-01 | Spirogen Limited | Pirrolobenzodiazepinas. |
| GB9818731D0 (en) * | 1998-08-27 | 1998-10-21 | Univ Portsmouth | 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 |
| GB0416511D0 (en) * | 2003-10-22 | 2004-08-25 | Spirogen Ltd | Pyrrolobenzodiazepines |
| AU2004284075A1 (en) | 2003-10-22 | 2005-05-06 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Pyrrolobenzodiazepine derivatives, compositions comprising the same and methods related thereto |
| JPWO2005040172A1 (ja) * | 2003-10-29 | 2007-03-08 | 協和醗酵工業株式会社 | 三環性プロリン誘導体 |
| 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 |
| GB0404574D0 (en) * | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Amino acids |
| ES2381858T3 (es) * | 2004-03-01 | 2012-06-01 | Spirogen Limited | Derivados de 11-hidroxi-5H-pirrolo[2,1-C][1,4]benzodiazepin-5-ona como intermedios clave para la preparación de pirrolobenzodiazepinas sustituidas en C2 |
| GB0404578D0 (en) * | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Pyrrolobenzodiazepines |
| GB0404577D0 (en) * | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Pyrrolobenzodiazepines |
| US7528126B2 (en) | 2004-03-09 | 2009-05-05 | Spirogen Limited | Pyrrolobenzodiazepines |
| US7056913B2 (en) | 2004-03-30 | 2006-06-06 | Council Of Scientific And Industrial Research | C8—linked pyrrolo[2,1-c][1,4]benzodiazepine-acridone/acridine hybrids |
| US6951853B1 (en) | 2004-03-30 | 2005-10-04 | Council Of Scientific And Industrial Research | Process for preparing pyrrolo[2, 1-c] [1,4] benzodiazepine hybrids |
| FR2869231B1 (fr) * | 2004-04-27 | 2008-03-14 | Sod Conseils Rech Applic | Composition therapeutique contenant au moins un derive de la pyrrolobenzodiazepine et la fludarabine |
| GB0410725D0 (en) * | 2004-05-13 | 2004-06-16 | Spirogen Ltd | Pyrrolobenzodiazepine therapeutic agents |
| GB0508084D0 (en) * | 2005-04-21 | 2005-06-01 | Spirogen Ltd | Pyrrolobenzodiazepines |
| WO2006111759A1 (en) * | 2005-04-21 | 2006-10-26 | Spirogen Limited | Pyrrolobenzodiazepines |
| DE602006006199D1 (de) * | 2005-10-05 | 2009-05-20 | Spirogen Ltd | 4-ä4-(5-oxo-2,3,5,11a-tetrahydro-5h-pyrrolo ä2, 1-cüä1,4übenzodiazepin-8-yloxy)-butyrylaminoü-1h-pyrrol-2-carbonsäurealkylesterderivate und verwandte verbindung zur behandlung einer proliferativen erkrankung |
| PL1813614T3 (pl) | 2006-01-25 | 2012-03-30 | Sanofi Sa | Środki cytotoksyczne zawierające nowe pochodne tomaymycyny |
| DE102006013678A1 (de) * | 2006-03-24 | 2007-09-27 | Bayerische Motoren Werke Ag | Gleit- oder Schmiermittel und Verfahren zum Aufziehen eines Fahrzeugreifens auf eine Felge |
| ES2673822T3 (es) | 2006-07-18 | 2018-06-25 | Sanofi | Anticuerpo antagonista contra EphA2 para el tratamiento de cáncer |
| 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 |
| PT2019104E (pt) | 2007-07-19 | 2013-12-03 | Sanofi Sa | Agentes citotóxicos compreendendo novos derivados de tomaimicina e sua utilização terapêutica |
| KR101764927B1 (ko) | 2008-04-30 | 2017-08-03 | 이뮤노젠 아이엔씨 | 가교제 및 그 용도 |
| GB0813432D0 (en) | 2008-07-22 | 2008-08-27 | Spirogen Ltd | Pyrrolobenzodiazepines |
| GB0819095D0 (en) * | 2008-10-17 | 2008-11-26 | Spirogen Ltd | Pyrrolobenzodiazepines |
| GB0819097D0 (en) * | 2008-10-17 | 2008-11-26 | Spirogen Ltd | Pyrrolobenzodiazepines |
| AU2015224492B2 (en) * | 2009-02-05 | 2017-04-20 | Immunogen, Inc. | Novel benzodiazepine derivatives |
| CN108727407B (zh) | 2009-02-05 | 2022-01-28 | 伊缪诺金公司 | 新型苯并二氮杂䓬衍生物 |
| WO2010141566A1 (en) | 2009-06-03 | 2010-12-09 | Immunogen, Inc. | Conjugation methods |
| FR2949469A1 (fr) * | 2009-08-25 | 2011-03-04 | Sanofi Aventis | Derives anticancereux, leur preparation et leur application en therapeutique |
| AR078470A1 (es) | 2009-10-02 | 2011-11-09 | Sanofi Aventis | Anticuerpos que se unen especificamente al receptor epha2 |
| KR101671360B1 (ko) | 2010-04-15 | 2016-11-01 | 시애틀 지네틱스, 인크. | 표적화된 피롤로벤조디아제핀 접합체 |
| TWI540136B (zh) | 2010-04-15 | 2016-07-01 | 梅迪繆思有限公司 | 吡咯并苯并二氮呯及其共軛物 |
| GB201006340D0 (en) * | 2010-04-15 | 2010-06-02 | Spirogen Ltd | Synthesis method and intermediates |
| JP5875083B2 (ja) | 2010-04-15 | 2016-03-02 | メディミューン リミテッド | 増殖性疾患治療用ピロロベンゾジアゼピン |
| FR2963007B1 (fr) | 2010-07-26 | 2013-04-05 | Sanofi Aventis | Derives anticancereux, leur preparation et leur application therapeutique |
| WO2012112708A1 (en) | 2011-02-15 | 2012-08-23 | Immunogen, Inc. | Cytotoxic benzodiazepine derivatives and methods of preparation |
| 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 |
| MX341524B (es) | 2011-09-20 | 2016-08-24 | Medimmune Ltd | Pirrolobenzodiazepinas como compuestos pbd dimericos asimetricos para inclusion en conjugados dirigidos. |
| EA026643B1 (ru) * | 2011-10-14 | 2017-04-28 | Сиэтл Дженетикс, Инк. | Пирролбензодиазепины и конъюгаты направленного действия |
| WO2013055990A1 (en) | 2011-10-14 | 2013-04-18 | Seattle Genetics, Inc. | Pyrrolobenzodiazepines and targeted conjugates |
| EA027386B1 (ru) | 2011-10-14 | 2017-07-31 | Медимьюн Лимитед | Пирролобензодиазепины |
| SG11201401406YA (en) | 2011-10-14 | 2014-05-29 | Spirogen Sarl | Pyrrolobenzodiazepines and conjugates thereof |
| US9399073B2 (en) | 2011-10-14 | 2016-07-26 | Seattle Genetics, Inc. | Pyrrolobenzodiazepines |
| CA2850096C (en) | 2011-10-14 | 2018-07-03 | Spirogen Sarl | Synthesis method and intermediates useful in the preparation of pyrrolobenzodiazepines |
| JP6401060B2 (ja) | 2012-02-24 | 2018-10-03 | アッヴィ・ステムセントルクス・エル・エル・シー | 抗ｓｅｚ６抗体及び使用方法 |
| NZ628804A (en) | 2012-02-24 | 2017-08-25 | Abbvie Stemcentrx Llc | Dll3 modulators and methods of use |
| AR090549A1 (es) | 2012-03-30 | 2014-11-19 | Genentech Inc | Anticuerpos anti-lgr5 e inmunoconjugados |
| AU2013255612B2 (en) | 2012-04-30 | 2017-06-22 | Medimmune Limited | Pyrrolobenzodiazepines |
| US9376440B2 (en) | 2012-04-30 | 2016-06-28 | Medimmune Limited | Pyrrolobenzodiazepines as antiproliferative agents |
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-
1999
- 1999-08-27 ES ES99943066T patent/ES2244210T3/es not_active Expired - Lifetime
- 1999-08-27 DK DK99943066T patent/DK1109812T3/da active
- 1999-08-27 EP EP01129700A patent/EP1193270B1/en not_active Expired - Lifetime
- 1999-08-27 CA CA002341471A patent/CA2341471C/en not_active Expired - Lifetime
- 1999-08-27 PT PT99943066T patent/PT1109812E/pt unknown
- 1999-08-27 PT PT03028817T patent/PT1413582E/pt unknown
- 1999-08-27 DE DE69925133T patent/DE69925133T2/de not_active Expired - Lifetime
- 1999-08-27 NZ NZ510493A patent/NZ510493A/en not_active IP Right Cessation
- 1999-08-27 DK DK03028817T patent/DK1413582T3/da active
- 1999-08-27 US US09/763,767 patent/US7049311B1/en not_active Expired - Lifetime
- 1999-08-27 WO PCT/GB1999/002838 patent/WO2000012508A2/en not_active Ceased
- 1999-08-27 AU AU56351/99A patent/AU757510C/en not_active Expired
- 1999-08-27 DE DE69907977T patent/DE69907977T2/de not_active Expired - Lifetime
- 1999-08-27 PT PT01129700T patent/PT1193270E/pt unknown
- 1999-08-27 EP EP99943066A patent/EP1109812B1/en not_active Expired - Lifetime
- 1999-08-27 DK DK01129700T patent/DK1193270T3/da active
- 1999-08-27 AT AT01129700T patent/ATE240334T1/de active
- 1999-08-27 ES ES03028817T patent/ES2260570T3/es not_active Expired - Lifetime
- 1999-08-27 ES ES01129700T patent/ES2199200T3/es not_active Expired - Lifetime
- 1999-08-27 AT AT99943066T patent/ATE294803T1/de active
- 1999-08-27 AT AT03028817T patent/ATE320436T1/de active
- 1999-08-27 DE DE69930328T patent/DE69930328T2/de not_active Expired - Lifetime
- 1999-08-27 JP JP2000571054A patent/JP4824165B2/ja not_active Expired - Lifetime
- 1999-08-27 EP EP03028817A patent/EP1413582B1/en not_active Expired - Lifetime
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2001
- 2001-12-12 US US10/021,213 patent/US7067511B2/en not_active Expired - Lifetime
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2006
- 2006-03-02 US US11/367,241 patent/US7265105B2/en not_active Expired - Lifetime
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