NO327211B1 - Epotiloner med en modifisert sidekjede, samt fremgangsmate for fremstilling derav - Google Patents
Epotiloner med en modifisert sidekjede, samt fremgangsmate for fremstilling derav Download PDFInfo
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- NO327211B1 NO327211B1 NO19994071A NO994071A NO327211B1 NO 327211 B1 NO327211 B1 NO 327211B1 NO 19994071 A NO19994071 A NO 19994071A NO 994071 A NO994071 A NO 994071A NO 327211 B1 NO327211 B1 NO 327211B1
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- 229930013356 epothilone Natural products 0.000 title claims abstract description 16
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A Chemical class C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 title description 3
- -1 Epothilone N-oxide Chemical class 0.000 claims description 8
- 150000003883 epothilone derivatives Chemical class 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000004965 peroxy acids Chemical class 0.000 claims description 3
- 150000001204 N-oxides Chemical class 0.000 claims description 2
- ASQQEOXYFGEFKQ-UHFFFAOYSA-N dioxirane Chemical compound C1OO1 ASQQEOXYFGEFKQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 79
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 18
- HESCAJZNRMSMJG-HGYUPSKWSA-N epothilone A Natural products O=C1[C@H](C)[C@H](O)[C@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(C)sc2)/C)OC(=O)C[C@H](O)C1(C)C HESCAJZNRMSMJG-HGYUPSKWSA-N 0.000 description 10
- 238000005481 NMR spectroscopy Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- 238000004809 thin layer chromatography Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- FCCNKYGSMOSYPV-DEDISHTHSA-N (-)-Epothilone E Natural products O=C1[C@H](C)[C@H](O)[C@@H](C)CCC[C@H]2O[C@H]2C[C@@H](/C(=C\c2nc(CO)sc2)/C)OC(=O)C[C@H](O)C1(C)C FCCNKYGSMOSYPV-DEDISHTHSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
- FCCNKYGSMOSYPV-UHFFFAOYSA-N epothilone E Natural products O1C(=O)CC(O)C(C)(C)C(=O)C(C)C(O)C(C)CCCC2OC2CC1C(C)=CC1=CSC(CO)=N1 FCCNKYGSMOSYPV-UHFFFAOYSA-N 0.000 description 2
- FCCNKYGSMOSYPV-OKOHHBBGSA-N epothilone e Chemical compound C/C([C@@H]1C[C@@H]2O[C@@H]2CCC[C@@H]([C@@H]([C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)O)C)=C\C1=CSC(CO)=N1 FCCNKYGSMOSYPV-OKOHHBBGSA-N 0.000 description 2
- 239000011888 foil Substances 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 238000002953 preparative HPLC Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- UWKQJZCTQGMHKD-UHFFFAOYSA-N 2,6-di-tert-butylpyridine Chemical compound CC(C)(C)C1=CC=CC(C(C)(C)C)=N1 UWKQJZCTQGMHKD-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
- 101000610640 Homo sapiens U4/U6 small nuclear ribonucleoprotein Prp3 Proteins 0.000 description 1
- 101001110823 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-A Proteins 0.000 description 1
- 101000712176 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) 60S ribosomal protein L6-B Proteins 0.000 description 1
- 102100040374 U4/U6 small nuclear ribonucleoprotein Prp3 Human genes 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- FFHWGQQFANVOHV-UHFFFAOYSA-N dimethyldioxirane Chemical compound CC1(C)OO1 FFHWGQQFANVOHV-UHFFFAOYSA-N 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
- Plural Heterocyclic Compounds (AREA)
- Epoxy Compounds (AREA)
- Polyesters Or Polycarbonates (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)
- Silicon Polymers (AREA)
Abstract
Det er beskrevet epotiloner som er modifiserte i sidekjeden.
Description
Foreliggende oppfinnelse vedrører epotiloner med en modifisert sidekjede, samt fremgangsmåte for fremstilling derav.
Epotilonene A og B er blitt beskrevet, jfr. for eksempel DE 4 138 042,
WO 93 10 121 og WO 97 19 086.
Nevnte teknikkens stand angir at nevnte epotiloner er terapeutiske midler.
I PNAS USA, 95 (1998) 1369 -1374 er epotiloner beskrevet som nyttige terapeutiske midler. Ifølge Angew, Chem., Int. Ed., 36 (1997) 2097 - 2103 er et omfattende bibilio-tek av slike forbindelser tilveiebrakt basert på deres terapeutiske effekter.
Foreliggende oppfinnelse vedrører epotilon-N-oksid (epotilon A-N-oksid eller epotilon B-N-oksid), kjennetegnet ved at det har følgende formel:
R1, R2 = H, Z = O", R = H, CH3.
Foreliggende oppfinnelse vedrører videre fremgangsmåte for fremstilling av epotilon N-oksider ifølge krav 1, kjennetegnet ved at 3,7-ubeskyttede epotiloner A eller B blir omdannet til et N-oksid ved at N-oksideringen utføres med persyre eller et dioksiran.
Eksperiment 1: Diepoksyepotilon A. ^
En oppløsning av epotilon A (5 mg, 10 ^mol) i aceton (1 ml) ble behandlet ved 0°C med dimtyldioksiran (0,4 ml, 28 ^mol, 0,07 M i aceton). Oppløsningen ble brakt til romtemperatur i løpet av noen få timer og ble omrørt i 20 timer ved denne tem-peraturen. På grunn av at TLC bekreftet at utgangsmaterialet fortsatt var til stede, ble mer dimetyldioksiran (0,25 ml, 17 famol) tilsatt, og reaksjonsblandingen ble på ny omrørt i 20 timer ved romtemperatur. Oppløsningsmidlet ble fjernet, og resten ble renset ved hjelp av PLC (0,25 x 200 x 200 mm, 10 % MeOH:CH2CI2). Følgende ble isolert: 1. 1,4 mg (27 %) diepoksyepotilon A (3:2 epimer-blanding på C16-C17). Rf 0,63 (10 % MeOH:CH2CI2); Rt: 6,79 (isomer 1) og 7,39 (isomer 2) min (RP 18, 250 x 4 mm, MeOH:H20 65:35, 1 ml/min); MS: (m/z) = 510 (M<+>); <1>H NMR (400 MHz, CDCI3, oppsamlete signaler, isomer 1): 5 = 6,96 (s, 1H, H-19), 5,48 (dd, J = 12,2 og 2.5 Hz, 1H, H-15), 4,37 (dbr, J = 10,7 Hz, 1H, H-3), 4,10 (s, 1H, H-17), 3,67 (dd, J = 5.6 og 2,5 Hz, 1H, H-7), 3,14 (qd, J = 6,6 og 2,5 Hz, 1H, H-6), 3,00 (ddd, J = 9,7, 3,6 og 2,5 Hz, 1H, H-13), 2,88 (dt, J = 8,6 og 3,6 Hz, 1H, H-12), 2,71 (s, 3H, H-21), 2,53 (dd, J = 13,7 og 11,7 Hz, 1H, H-2a), 1,41 (s, 3H, H-22), 1,27 (s, 3H, H-26), 1,17 (d, J = 6,6 Hz, 3H, H-24), 1,08 (s, 3H, H-23), 0,97 (d, J = 7,1 Hz, 3H, H-25); (isomer 2) 5 = 6,98 (s, 1H, H-19), 5,11 (dd, J = 11,7 og 2,5 Hz, 1H, H-15), 4,27 (dbr, J = 10,7 Hz, 1H, H-3), 4,14 (s, 1H, H-17), 3,06 (qd, J = 6,6 og 2,9 Hz, 1H, H-6), 2,96 (ddd, J = 9,7, 3,6 og 2,5 Hz, 1H, H-13), 2,31 (dt, J = 14,7 og 2,0 Hz, 1H, H-14a), 1,36 (s, 3H, H-22), 1,15 (d, J = 6,6 Hz, 3H, H-24), 1,14 (s, 3H, H-26), 1,07 (s, 3H, H-23). 2. 0,8 mg (16 %) epotilon A N-oksid. Rf 0,44 (10 % MeOH:CH2CI2); Rt: 4,25 min (RP 18, 250 x 4 mm, MeOH:H20 65:35, 1 ml/min); MS: (m/z) = 510 (M<+>); <1>H NMR: se metode 1.
Eksperiment 2: Dihydroepotilon A. (l£)
Palladium på trekull (5 mg, 10 %) ble tilsatt til en oppløsning av epotilon A (11 mg, 22 ^mol) i etanol (2 ml), og den svarte suspensjonen ble eksponert for en H2-atmosfære i 24 timer ved romtemperatur. På grunn av at TLC indikerte at reaksjonen ikke enda var fullført, ble en ytterligere porsjon Pd/C tilsatt, og reaksjonsblandingen ble omrørt i ytterligere 20 timer under en H2-atmosfære. Produktene ble separert ved hjelp av PLC (1 x 200 x 200 mm, 10 % MeOH:CH2CI2). Følgende ble isolert: 1. 0,5 mg (5 %) dihydroepotilon A. Rf 0,60 (10 % MeOH:CH2CI2); Rt: 10,80 min (RP 18, 250 x 4 mm, MeOH:H20 65:35, 1 ml/min); MS: (m/z) = 496 (M<+>), 478, 407, 308; <1>H NMR (400 Mhz, CDCI3, oppsamlete signaler): 5 = 7,05 (d, J = 6,6 Hz, 1H, OH), 6,77 (s, 1H, H-19), 5,23 (dd, J = 12,4 og 2,3 Hz, 1H, H-15), 4,42 (ddd, J = 11,7, 6,6 og 3,0 Hz, 1H, H-3), 3,70 (ddd, J = 5, 3 og 2 Hz, 1H, H-7), 312 (qd, J = 6,6 og 3,0 Hz, 1H, H-6), 3,07 (d, J = 12,7 Hz, 1H, H-17a), 2,96 ddd, = 9,7, 3,6 og 2,0 Hz, 1H, H-13), 2,91, (ddd, J = 9,7, 3,6 og 2,6 Hz, 1H, H-12), 2,68 (s, 3H, H-21), 2,51 (dd, J
= 13,7 og 11,7 Hz, 1H, H-2a), 2,24 (d, J = 12,7 Hz, 1H, H-17b), 2,19 (m, 1H, H-16), 2,13 (dd, J = 13,7 og 3,0 Hz, 1H, H-2b); 1,35 (s, 3H, H-22), 1,15 (d, J = 6,6 Hz, 3H, H-24), 1,09 (s, 3H, H-23), 0,99 (d, J = 7,1 Hz, 3H, H-25), 0,93 (d, J = 6,6 Hz, 3H, H-26). 2. 8 mg (72 %) 15-deoksydihydroepotilonsyre. Rf 0,10 (10 % MeOH:CH2CI2).
Eksperiment 3: 16-hydroksyepotiloner A. (IbJ
Palladium på trekull (10 mg, 10 %) ble tilsatt til en oppløsning av diepoksyepotilon A (7 mg, 14 ^mol), 1:1 epimerblanding på C-16) i etanol (2 ml), og den svarte suspensjonen eksponert for en H2-atmosfære i 24 timer ved romtemperatur. På grunn av at TLC indikerte at reaksjonen enda ikke var fullført, ble en ytterligere porsjon Pd/C tilsatt, og reaksjonsblandingen ble omrørt i ytterligere 80 timer under en H2-atmosfære. Produktene ble separert ved hjelp av PLC (1 x 200 x 200 mm, 10 % MeOH:CH2CI2). Følgende ble isolert:
1. 3 mg (43 %) 16-hydroksyepotilon A (isomer 1).
Rf 0,38 (10 % MeOH:CH2CI2); Rt: 6.65 (RP 18, 250 x 4 mm, MeOH:H20 65:35, 1 ml/min); <1>H NMR (400 MHz, CDCI3, oppsamlete signaler): 5 = 6,85 (s, 1H, H-19), 5,02 (dd, J = 11,7 og 2,0 Hz, 1H, H-15), 4,38 (dbr, J = 11,2 Hz, 1H, H-3), 3,67 (dd, J = 4 og 3 Hz, 1H, H-7), 3,14 (qd, J = 6,8 og 3,0 Hz, 1H, H-6), 2,95 (d, J = 15,3 Hz, 1H, H-17a), 2,89 (d, J = 15,3 Hz, 1H, H-17b), 2,89 (ddd, J = 10,2, 3,6 og 2,0 Hz, 1H, H-13), 2,81 (ddd, J = 9,7, 3,6 og 2,5 Hz, 1H, H-12), 2,70 (s, 3H, H-21), 2,53 (dd, J = 15,8 og 11,7 Hz, 1H, H-2a), 2,14 (dd, J = 15,8 og 2,0 Hz, 1H, H-2b), 2,08 (dt, J = 14,3og2,0 Hz, 1H, H-14a), 1,39 (s, 3H, H-22), 1,25 (s, 3H, H-26), 1,19 (d, J = 6,6 Hz, 3H, H-24), 1,05 (s, 3H, H-23), 0,99 (d, J = 7,1 Hz, 3H, H-25).
2. 3 mg (43 %) 16-hydroksyepotilon A (isomer 2).
Rf 0,31 (10 % MeOH:CH2CI2); Rt: 6,10 min (RP 18, 250 x 4 mm, MeOH:H20 65:35, 1 ml/min); <1>H NMR (300 MHz, CDCI3, oppsamlete signaler): 5 = 6,85 (s, 1H, H-19), 5,21 (dd, J = 11,3 og 1,9 Hz, 1H, H-15), 4,42 (dbr, J = 10,5 Hz, 1H, H-3), 3,71 (sbr, 1H, H-7), 3,21 (d, J = 14,3 Hz, 1H, H-17a), 3,13 (qd, J =6,8 og 3,0 Hz, 1H, H-6), 3,09 (dt, J = 9,8 og 3,4 Hz, 1H, H-13), 2,87 (dt, J = 9,4 og 3,0 Hz, 1H, H-12), 2,73 (d, J = 14,3 Hz, 1H, H-17b), 2,68 (s, 3H, H-21), 2,63 (dd, J = 16,6 og 11,7 Hz, 1H, H-2a), 2,27 (dt, J = 14,7 og 2,3 Hz, 1H, H-14a), 2,24 (dd, J = 16,6 og 2,6 Hz, 1H, H-2b), 1,39 (s, 3H, H-22), 1,22 (s, 3H, H-26), 1,19 (d, J = 6,8 Hz, 3H, H-24), 1,05 (s,3H, H-23), 0,99 (d, J = 7,2 Hz, 3H, H-25).
Epotilon A N-oksid (2a): 100 mg 70 % m-klorperbenzosyre i 0,5 ml diklormetan ble tilsatt til 100 mg epotilon A i 1 ml diklormetan. Etter at blandingen var blitt omrørt i 6 timer ved romtemperatur, ble den fortynnet med diklormetan og ekstrahert ved risting med natriumsulfitt-oppløsning for å ødelegge persyre i overskudd og med natrium-bikarbonat-oppløsning. Oppløsningsmidlet blir avdampet i vakuum, og resten separert ved preparativ HPLC på en Nucleosil RP-18-kolonne (250 x 20 mm, elueringsmiddel/vann 60:40). Utbytte var 60 mg farveløs olje.
Rf = 0,60 (silica gel TLC aluminiumfolie, elueringsmiddel diklormetan/metanol 9:1); ESI-MS (neg. ioner m/z 510;
UV (metanol): lamda maks. 240 nm;
<13>C NMR (CDCI3): C-1 170,5, C-2 39,9, C-3 70,8, C-4 55,1, C-5 221,4, C-6 40,9, C-7 72,9, C-8 37,6, C-9 31,8, C-10 22,8, C-11 28.0, C-12 58,0,
C-13 55,8, C-14 32,2, C-15 75,5, C-16 144,5, C-17 111,4, C-18 143,4, C-19 110,3, C-20 145,6, C-21 13,5, C-22 15,4, C-23 23,3, C-24 12,0, C-25 16,5, C-27 18,2 ppm;
1H NMR(CDCI3):2a-H2,12dd, 2b-H 2,47 dd, 3-H 4,55 dd, 3-OH 6,48 bredde, 6-H 3,25 dq, 7-H 3,72 dd, 8-H 1,81 m, 9a-H 1,34 m, 9b-H 1,56 m, 10-H2 1,48 m, 11a-H 1,27 m, 11b-H 1,87 m, 12-H 2,92 ddd, 13-H 2,98 m; 14a-H 1,67 ddd, 14b-H 2,23 d, 15-H 5,33 d, 17-H 6,82 s, 19-H 7,09 s, 21-H3 2,61 s, 22-H3 1,02 s, 23-H3 1,42 s, 24-H3 1,18 d, 25-H3 0,99 d, 27-H3 2,04 s ppm.
21-Acetoksyepotilon A (= 21-acetylepotilon E) (3a):
0,05 ml 2,6-di-tert-butylpyridin og 0,1 ml eddiksyre anhydrid blir tilsatt til 50 mg epotilon A N-oksid (2a) i 0,5 ml diklormetan. Etter at blandingen er blitt oppvarmet ved 75°C i 15 minutter, blir oppløsningsmiddel og reagenser avdampet i vakuum og resten separert ved preparativ HPLC på Nucleosil RP-18 (250 x 20 mm, elueringsmiddel/vann 60:40). Utbytte 30 mg farveløs olje.
Rr 0,50 (silica gel TLC aluminiumfolie, elueringsmiddel diklormetan/metanol 95:5); ESI-MS (neg. ioner) m/z 552;
UV (metanol); lamda maks. 210, 250 nm ;
<1>H NMR (CDCI3> signaler forskjellige med hensyn på 2a): 15-H 5,45 dd, 17-H
6,60 s, 19-H 7,15 s, 21-H2 5,35 s, CH3CO 2,15 s ppm.
Epotilon E (3b): 1 dråpe konsentrert ammoniumoppløsning blir tilsatt til 10 mg 21-acetoksyepotilon A (3a) i 0,5 ml metanol, og blandingen oppvarmes i 1 time ved 40°C og avdampes til tørrhet i vakuum. Resten blir separert ved preparativ TLC. Utbytte 6 mg, identisk med en autentisk prøve av epotilon E.
Eksperiment 4: 19-metylepotilon A. ( 4b)
En oppløsning av epotilon A (15 mg, 30 ^mol) i THF (1 ml) ble behandlet ved
-90°C med n-butyllitium (100 ul, 160 ^mol, 1,6 M i heksan). Oppløsningen ble øyeblikkelig farvet gylden oransje. Etter at reaksjonsoppløsningen var blitt omrørt i 15 minutter ved -90°C, ble den behandlet med metyliodid (100 ^l, 1,6 mmol). Den resulterende svakt grønn-gule oppløsning ble varmet til -30°C og stoppet med buffer pH = 7,0 (2 ml). Emulsjonen ble brakt til pH 6 med 0,1 N saltsyre. Etter at blandingen var blitt mettet med fast NaCI, ble den vandige fasen ekstrahert med CH2CI2 (2 x 5 ml) og etylacetat (5 ml), kombinerte organiske faser ble tørket over MgS04 og filtrert, og oppløsningsmidlet ble fjernet på en Rotavap. Rensingen ble utført ved PLC (1 x 200 x 200 nm, 10 % MeOH:CH2CI2) og HPLC (RP 18, 250 x 16 mm, MeOH:H20 65:35). Følgende ble isolert: 1. 2,5 mg (17 %) 19-metylepotilon A. Rf 0,50 (10 % MeOH:CH2CI2); 11,70 min (RP 18, 250 x 4 mm, MeOH:H20 65:35, 1 ml/min); MS: (m/z) = 508 (M<+>), 420, 320; <1>H NMR (300 MHz, CDCI3), oppsamlete signaler): 5 = 6,41 (s, 1H, H-17), 5,46 (dd, J = 9,0 og 2,3 Hz, 1H, H-15), 4,15 (dd, J = 10,5 og 3,0 Hz, 1H, H-3), 3,77 (dd, J = 8 og 4 Hz, 1H, H-7), 3,20 (qd, J = 6,8 og 4,5 Hz, 1H, H-6), 3,04 (dt, J = 7,5 og 3,8 Hz, 1H, H-13), 2,91 (dt, J = 7,5 og 3,8 Hz, 1H, H-12), 2,61 (s, 3H, H-21), 2,51 (dd, J = 14,4 og 10,5 Hz, 1H, H-2a), 2,38 (dd, J = 14,4 og 3,0 Hz, 1H, H-2b), 2,32 (s, 3H, H-27), 2,15 (ddd, J = 15,1, 3,8 og 3,0 Hz, 1H, H-14a), 2,01 (d, J = 1,5Hz, 3H, H-26), 1,91 (dt, J = 15,1 og 8,8 Hz, 1H, H-14b); 1,34 (s, 3H, H-22), 1,16 (d, J = 6,8 Hz, 3H, H-24), 1,10 (s, 3H, H-23), 1,00 (d, J = 6,6Hz, 3H, H-25).
2. omtrent 50 % epotilon A
Eksperiment 5: 19-bromepotilon A. ( 4a)
En løsning av epotilon A (25 mg, 50 ^mol) i THF (2,5 ml) ble behandlet ved
-90°C med n-butyllitium (160 ul, 225 ^mol, 1,6 M heksan). Oppløsningen ble øyeblikkelig gylden oransje. Etter at blandingen var blitt omrørt i 15 minutter ved -90°C, ble N-bromsuksinimid (27 mg, 150 ^mol), oppløst i THF (0,5 ml), tilsatt. Oppløsningen ble sakte avfarvet. Reaksjonsblandingen som nå hadde en svakt brunaktig farve, ble varmet til -30°C og brakt til pH 6,5 med 0,1 N saltstyre (1 ml). Etter at blandingen var blitt mettet med fast NaCI, ble den vandige fasen ekstrahert med CH2CI2 (2x5 ml) og etylacetat (5 ml), kombinerte organiske faser ble tørket over MgS04 og filtrert, og oppløsningsmidlet ble fjernet på en Rotavap. Rensing ble utført ved PLC (1 x 200 x 200 nm, 10 % MeOH:CH2CI2) og HPLC (RP 18, 250 x 16 nm, MeOH:H20 65:35). Følgende ble isolert: 1. 2,6 mg (9%) 19-bromepotilon A. Rf 0,53 (10 % MeOH:CH2CI2); Rt: 20,78 min (RP18, 250 x 4 nm, MEOH:H20 65:35, 1 ml/min); MS: (m/z) = 574 og 572 (M<+>), 556, 554, 468, 466, 386, 384, 341; <1>H NMR (300 MHz, CDCI3,
oppsamlete signaler): 8 = 6,43 (s, 1H, H-17), 5,46 (dd, J = 6,7 og 2,3 Hz, 1H, H-15), 4,13 (ddd, J = 9,4, 6,0 og 3,8 Hz, 1H, H-3), 3,80 (dd, J = 8 og 4 Hz, 1H, H-7), 3,38 (d, J = 6,0 Hz, 1H, OH), 3,22 (qd, J = 6,8 og 5,3 Hz, 1H, H-6), 3,05 (dt, J = 8,3 og 4,1 Hz, 1H, H-13), 2,91 (dt, J = 7,5 og 3,7 Hz, 1H, H-12), 2,66 (s, 3H, H-21), 2,55 (dd, J = 14,7 og 9,4 Hz, 1H, H-2a), 2,47 (dd, J = 14,7 og 3,8 Hz, 1H, H-2b), 2,16 (d, J = 1,1 Hz, 3H, H-26), 2,14 (dt, J = 14,7 og 3,8 Hz, 1H, H-14a), 1,90 (dt, J = 15 og 8,3 Hz, 1H, H-14b);
1,34 (2, 3H, H-22), 1,17 (d, J = 6,8 Hz, 3H, H-24), 1,11 (s, 3H, H-23), 1,01 (d, J = 6,8 Hz, 3H, H-25).
2. omtrent 60 % epotilon A
Syntese-eksemplene 1a til 5a
Claims (2)
1. Epotilon-N-oksid (epotilon A-N-oksid eller epotilon B-N-oksid), karakterisert ved at det har følgende formel:
R1, R2 = H, Z = O", R = H, CH3.
2. Fremgangsmåte for fremstilling av epotilon N-oksider ifølge krav 1, karakterisert ved at 3,7-ubeskyttede epotiloner A eller B blir omdannet til et N-oksid ved at N-oksideringen utføres med persyre eller et dioksiran.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19707505 | 1997-02-25 | ||
| PCT/EP1998/001060 WO1998038192A1 (de) | 1997-02-25 | 1998-02-25 | Seitenkettenmodifizierte epothilone |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO994071D0 NO994071D0 (no) | 1999-08-24 |
| NO994071L NO994071L (no) | 1999-10-21 |
| NO327211B1 true NO327211B1 (no) | 2009-05-11 |
Family
ID=7821415
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO19994071A NO327211B1 (no) | 1997-02-25 | 1999-08-24 | Epotiloner med en modifisert sidekjede, samt fremgangsmate for fremstilling derav |
Country Status (25)
| Country | Link |
|---|---|
| US (1) | US6359140B1 (no) |
| EP (2) | EP0975638B1 (no) |
| JP (1) | JP2001513098A (no) |
| KR (1) | KR100494179B1 (no) |
| CN (2) | CN1128803C (no) |
| AR (1) | AR011878A1 (no) |
| AT (1) | ATE221888T1 (no) |
| AU (1) | AU736062B2 (no) |
| BR (1) | BR9807742B1 (no) |
| CA (1) | CA2281105A1 (no) |
| CZ (1) | CZ298027B6 (no) |
| DE (2) | DE19880193D2 (no) |
| DK (1) | DK0975638T3 (no) |
| ES (1) | ES2183338T3 (no) |
| HK (1) | HK1023774A1 (no) |
| HU (1) | HU228851B1 (no) |
| IL (1) | IL131343A (no) |
| NO (1) | NO327211B1 (no) |
| NZ (1) | NZ337195A (no) |
| PL (1) | PL190422B1 (no) |
| PT (1) | PT975638E (no) |
| RU (1) | RU2201932C2 (no) |
| TW (1) | TW480263B (no) |
| WO (1) | WO1998038192A1 (no) |
| ZA (1) | ZA981575B (no) |
Families Citing this family (90)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2178093T5 (es) | 1995-11-17 | 2009-02-16 | Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) | Derivados de epotilon y su preparacion. |
| PT941227E (pt) * | 1996-11-18 | 2004-08-31 | Biotechnolog Forschung Mbh Gbf | Epothilona d sua preparacao e sua utilizacao como agente citostatico ou como agente de proteccao fitossanitaria |
| JP4579351B2 (ja) | 1996-12-03 | 2010-11-10 | スローン−ケッタリング インスティトュート フォア キャンサー リサーチ | エポチロンの合成とその中間体及びその類似物並びにその使用 |
| US6867305B2 (en) | 1996-12-03 | 2005-03-15 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
| US20050043376A1 (en) * | 1996-12-03 | 2005-02-24 | Danishefsky Samuel J. | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
| US6204388B1 (en) | 1996-12-03 | 2001-03-20 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
| US6660758B1 (en) | 1996-12-13 | 2003-12-09 | The Scripps Research Institute | Epothilone analogs |
| US6441186B1 (en) * | 1996-12-13 | 2002-08-27 | The Scripps Research Institute | Epothilone analogs |
| US6380394B1 (en) * | 1996-12-13 | 2002-04-30 | The Scripps Research Institute | Epothilone analogs |
| CN1128803C (zh) * | 1997-02-25 | 2003-11-26 | 生物技术研究有限公司(Gbf) | 环氧噻嗪酮b－n－氧化物及其制备方法 |
| US6605599B1 (en) | 1997-07-08 | 2003-08-12 | Bristol-Myers Squibb Company | Epothilone derivatives |
| US6365749B1 (en) | 1997-12-04 | 2002-04-02 | Bristol-Myers Squibb Company | Process for the preparation of ring-opened epothilone intermediates which are useful for the preparation of epothilone analogs |
| US6320045B1 (en) | 1997-12-04 | 2001-11-20 | Bristol-Myers Squibb Company | Process for the reduction of oxiranyl epothilones to olefinic epothilones |
| US6683100B2 (en) | 1999-01-19 | 2004-01-27 | Novartis Ag | Organic compounds |
| US6498257B1 (en) | 1998-04-21 | 2002-12-24 | Bristol-Myers Squibb Company | 2,3-olefinic epothilone derivatives |
| US6399638B1 (en) | 1998-04-21 | 2002-06-04 | Bristol-Myers Squibb Company | 12,13-modified epothilone derivatives |
| DE19826988A1 (de) * | 1998-06-18 | 1999-12-23 | Biotechnolog Forschung Gmbh | Epothilon-Nebenkomponenten |
| DE69804448T2 (de) * | 1998-08-05 | 2002-11-07 | Gesellschaft Fuer Biotechnologische Forschung Mbh (Gbf) | Epothilon A N-Oxid und/oder Epothilon B N-Oxid enthaltende pharmazeutische Agentien |
| US6780620B1 (en) | 1998-12-23 | 2004-08-24 | Bristol-Myers Squibb Company | Microbial transformation method for the preparation of an epothilone |
| US6596875B2 (en) | 2000-02-07 | 2003-07-22 | James David White | Method for synthesizing epothilones and epothilone analogs |
| US6262094B1 (en) | 1999-02-22 | 2001-07-17 | Bristol-Myers Squibb Company | C-21 modified epothilones |
| DE19907588A1 (de) * | 1999-02-22 | 2000-08-24 | Biotechnolog Forschung Gmbh | C-21 Modifizierte Epothilone |
| US20020058286A1 (en) * | 1999-02-24 | 2002-05-16 | Danishefsky Samuel J. | Synthesis of epothilones, intermediates thereto and analogues thereof |
| US6291684B1 (en) | 1999-03-29 | 2001-09-18 | Bristol-Myers Squibb Company | Process for the preparation of aziridinyl epothilones from oxiranyl epothilones |
| US7125875B2 (en) | 1999-04-15 | 2006-10-24 | Bristol-Myers Squibb Company | Cyclic protein tyrosine kinase inhibitors |
| RU2260592C9 (ru) | 1999-04-15 | 2017-04-07 | Бристол-Маерс Сквибб Ко. | Циклические ингибиторы протеинтирозинкиназ |
| AR023792A1 (es) * | 1999-04-30 | 2002-09-04 | Bayer Schering Pharma Ag | Derivados 6-alquenilo- y 6-alquinilo-epotilona, los procedimientos para prepararlos y su empleo en productos farmaceuticos |
| AU772750C (en) * | 1999-04-30 | 2005-02-24 | Schering Aktiengesellschaft | 6-alkenyl-, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations |
| WO2001024763A2 (en) | 1999-10-01 | 2001-04-12 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
| US6518421B1 (en) * | 2000-03-20 | 2003-02-11 | Bristol-Myers Squibb Company | Process for the preparation of epothilone analogs |
| US6593115B2 (en) | 2000-03-24 | 2003-07-15 | Bristol-Myers Squibb Co. | Preparation of epothilone intermediates |
| US6589968B2 (en) * | 2001-02-13 | 2003-07-08 | Kosan Biosciences, Inc. | Epothilone compounds and methods for making and using the same |
| UA75365C2 (en) | 2000-08-16 | 2006-04-17 | Bristol Myers Squibb Co | Epothilone analog polymorph modifications, a method for obtaining thereof (variants), a pharmaceutical composition based thereon |
| HU229349B1 (en) | 2001-01-25 | 2013-11-28 | Bristol Myers Squibb Co | Methods for preparation of pharmaceutical composition containing epothilone analogs useful for treatment of cancer |
| JP2004521122A (ja) | 2001-01-25 | 2004-07-15 | ブリストル−マイヤーズ スクイブ カンパニー | エポチロン類似体の非経口製剤 |
| NZ526871A (en) | 2001-01-25 | 2006-01-27 | Bristol Myers Squibb Co | Pharmaceutical dosage forms of epothilones for oral administration |
| US6893859B2 (en) * | 2001-02-13 | 2005-05-17 | Kosan Biosciences, Inc. | Epothilone derivatives and methods for making and using the same |
| CA2438598A1 (en) | 2001-02-20 | 2002-08-29 | Francis Y. F. Lee | Epothilone derivatives for the treatment of refractory tumors |
| EE200300396A (et) | 2001-02-20 | 2003-12-15 | Bristol-Myers Squibb Company | Epotilooni derivaatide kasutamine refraktaarsete kasvajate raviks |
| NZ527557A (en) * | 2001-02-27 | 2005-05-27 | Biotechnolog Forschung Gmbh | Degradation of epothilones and ethynyl substituted epothilones |
| CZ305799B6 (cs) | 2001-03-14 | 2016-03-23 | Bristol-Myers Squibb Company | Kombinace analogů epothilonu a chemoterapeutických činidel pro léčení proliferačních nemocí |
| EP1392664A4 (en) | 2001-06-01 | 2005-01-26 | Bristol Myers Squibb Co | EPOTHILONE DERIVATIVES |
| TW200303202A (en) | 2002-02-15 | 2003-09-01 | Bristol Myers Squibb Co | Method of preparation of 21-amino epothilone derivatives |
| DE60330651D1 (en) | 2002-03-12 | 2010-02-04 | Bristol Myers Squibb Co | C3-cyanoepothilonderivate |
| AU2003218107A1 (en) | 2002-03-12 | 2003-09-29 | Bristol-Myers Squibb Company | C12-cyano epothilone derivatives |
| TW200403994A (en) | 2002-04-04 | 2004-03-16 | Bristol Myers Squibb Co | Oral administration of EPOTHILONES |
| TW200400191A (en) | 2002-05-15 | 2004-01-01 | Bristol Myers Squibb Co | Pharmaceutical compositions and methods of using C-21 modified epothilone derivatives |
| US7405234B2 (en) | 2002-05-17 | 2008-07-29 | Bristol-Myers Squibb Company | Bicyclic modulators of androgen receptor function |
| US7008936B2 (en) | 2002-06-14 | 2006-03-07 | Bristol-Myers Squibb Company | Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases |
| US7649006B2 (en) | 2002-08-23 | 2010-01-19 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
| US6921769B2 (en) | 2002-08-23 | 2005-07-26 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
| EP1506203B1 (en) | 2002-08-23 | 2007-01-03 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto, analogues and uses thereof |
| KR101406635B1 (ko) | 2002-09-23 | 2014-06-11 | 브리스톨-마이어스 스큅 컴퍼니 | 에포틸론 ｂ의 제조, 분리 및 정제 방법, 및 에포틸론 ｂ의 ｘ-선 결정 구조 |
| US7632858B2 (en) | 2002-11-15 | 2009-12-15 | Bristol-Myers Squibb Company | Open chain prolyl urea-related modulators of androgen receptor function |
| US7820702B2 (en) | 2004-02-04 | 2010-10-26 | Bristol-Myers Squibb Company | Sulfonylpyrrolidine modulators of androgen receptor function and method |
| US7378426B2 (en) | 2004-03-01 | 2008-05-27 | Bristol-Myers Squibb Company | Fused heterotricyclic compounds as inhibitors of 17β-hydroxysteroid dehydrogenase 3 |
| US7625923B2 (en) | 2004-03-04 | 2009-12-01 | Bristol-Myers Squibb Company | Bicyclic modulators of androgen receptor function |
| US7696241B2 (en) | 2004-03-04 | 2010-04-13 | Bristol-Myers Squibb Company | Bicyclic compounds as modulators of androgen receptor function and method |
| US20060134214A1 (en) * | 2004-11-18 | 2006-06-22 | Ismat Ullah | Enteric coated bead comprising epothilone or epothilone analog, and preparation and administration thereof |
| ATE397442T1 (de) * | 2004-11-18 | 2008-06-15 | Bristol Myers Squibb Co | Magensaftresistent beschichtetes pellet mit ixabepilon |
| JP4954983B2 (ja) | 2005-05-18 | 2012-06-20 | ファーマサイエンス・インコーポレイテッド | Ｂｉｒドメイン結合化合物 |
| WO2007131366A1 (en) | 2006-05-16 | 2007-11-22 | Aegera Therapeutics Inc. | Iap bir domain binding compounds |
| EP2089411A4 (en) | 2006-12-04 | 2010-01-27 | Univ Illinois | COMPOSITIONS AND METHODS FOR CANCER TREATMENT WITH CUPREDOXINES AND CPG-RICH DNA |
| AU2011214057B2 (en) | 2010-02-12 | 2016-11-17 | Pharmascience Inc. | IAP BIR domain binding compounds |
| BR112013018534B1 (pt) | 2011-01-20 | 2021-04-06 | Board Of Regents, The University Of Texas System | Agente de contraste, seus métodos de preparação, e produto de combinação |
| CN106110332B (zh) | 2011-06-10 | 2018-11-30 | 梅尔莎纳医疗公司 | 蛋白质-聚合物-药物共轭物 |
| CN102863474A (zh) | 2011-07-09 | 2013-01-09 | 陈小平 | 一类治疗细胞增殖性疾病的铂化合物、其制备方法和应用 |
| CN102993239A (zh) | 2011-09-19 | 2013-03-27 | 陈小平 | 离去基团含氨基或烷胺基的丁二酸衍生物的铂类化合物 |
| WO2014075391A1 (zh) | 2012-11-17 | 2014-05-22 | 北京市丰硕维康技术开发有限责任公司 | 离去基团是含氨基或烷氨基的丙二酸衍生物的铂类化合物 |
| WO2014093394A1 (en) | 2012-12-10 | 2014-06-19 | Mersana Therapeutics, Inc. | Protein-polymer-drug conjugates |
| WO2014093640A1 (en) | 2012-12-12 | 2014-06-19 | Mersana Therapeutics,Inc. | Hydroxy-polmer-drug-protein conjugates |
| SG11201509350RA (en) | 2013-06-11 | 2015-12-30 | Bayer Pharma AG | Combinations for the treatment of cancer comprising a mps-1 kinase inhibitor and a mitotic inhibitor |
| AU2014331714B2 (en) | 2013-10-11 | 2019-05-02 | Mersana Therapeutics, Inc. | Protein-polymer-drug conjugates |
| CA2927022C (en) | 2013-10-11 | 2018-08-21 | Asana Biosciences, Llc | Protein-polymer-drug conjugates |
| EP3474901A1 (en) | 2016-06-27 | 2019-05-01 | Tagworks Pharmaceuticals B.V. | Cleavable tetrazine used in bio-orthogonal drug activation |
| US11135307B2 (en) | 2016-11-23 | 2021-10-05 | Mersana Therapeutics, Inc. | Peptide-containing linkers for antibody-drug conjugates |
| WO2018237262A1 (en) | 2017-06-22 | 2018-12-27 | Mersana Therapeutics, Inc. | METHODS FOR PRODUCING POLYMERIC MATRICES TRANSPORTING MEDICAMENTS, AND PROTEIN-POLYMER-MEDICINE CONJUGATES |
| EP4382167A3 (en) | 2018-05-04 | 2024-08-28 | Tagworks Pharmaceuticals B.V. | Compounds comprising a linker for increasing transcyclooctene stability |
| AU2019262520A1 (en) | 2018-05-04 | 2021-01-14 | Tagworks Pharmaceuticals B.V. | Tetrazines for high click conjugation yield in vivo and high click release yield |
| US20230021500A1 (en) | 2018-10-29 | 2023-01-26 | Mersana Therapeutics, Inc. | Cysteine engineered antibody-drug conjugates with peptide-containing linkers |
| IL289094A (en) | 2019-06-17 | 2022-02-01 | Tagworks Pharmaceuticals B V | Tetrazines for increasing the speed and yield of the "click release" reaction |
| DK3983363T3 (da) | 2019-06-17 | 2024-06-24 | Tagworks Pharmaceuticals B V | Forbindelser til hurtig og effektiv klikfrigivelse |
| JP2024532537A (ja) | 2021-09-06 | 2024-09-05 | ヴェラクサ バイオテック ゲーエムベーハー | 真核生物における遺伝暗号の拡張のための新規アミノアシルｔＲＮＡ合成酵素変異体 |
| WO2023094525A1 (en) | 2021-11-25 | 2023-06-01 | Veraxa Biotech Gmbh | Improved antibody-payload conjugates (apcs) prepared by site-specific conjugation utilizing genetic code expansion |
| EP4186529A1 (en) | 2021-11-25 | 2023-05-31 | Veraxa Biotech GmbH | Improved antibody-payload conjugates (apcs) prepared by site-specific conjugation utilizing genetic code expansion |
| KR20240119102A (ko) | 2021-12-08 | 2024-08-06 | 유럽피안 몰레큘러 바이올로지 래보러토리 | 표적화 접합체의 제조를 위한 친수성 테트라진-관능화 페이로드 |
| AU2023221765B2 (en) | 2022-02-15 | 2024-09-19 | Tagworks Pharmaceuticals B.V. | Masked il12 protein |
| WO2024013724A1 (en) | 2022-07-15 | 2024-01-18 | Pheon Therapeutics Ltd | Antibody-drug conjugates |
| WO2024080872A1 (en) | 2022-10-12 | 2024-04-18 | Tagworks Pharmaceuticals B.V. | Strained bicyclononenes |
| WO2024153789A1 (en) | 2023-01-20 | 2024-07-25 | Basf Se | Stabilized biopolymer composition, their manufacture and use |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4138042C2 (de) * | 1991-11-19 | 1993-10-14 | Biotechnolog Forschung Gmbh | Epothilone, deren Herstellungsverfahren sowie diese Verbindungen enthaltende Mittel |
| ES2178093T5 (es) * | 1995-11-17 | 2009-02-16 | Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) | Derivados de epotilon y su preparacion. |
| US6441186B1 (en) * | 1996-12-13 | 2002-08-27 | The Scripps Research Institute | Epothilone analogs |
| CN1128803C (zh) * | 1997-02-25 | 2003-11-26 | 生物技术研究有限公司(Gbf) | 环氧噻嗪酮b－n－氧化物及其制备方法 |
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1998
- 1998-02-25 CN CN98802842A patent/CN1128803C/zh not_active Expired - Fee Related
- 1998-02-25 DK DK98912388T patent/DK0975638T3/da active
- 1998-02-25 BR BRPI9807742-2A patent/BR9807742B1/pt not_active IP Right Cessation
- 1998-02-25 PT PT98912388T patent/PT975638E/pt unknown
- 1998-02-25 CZ CZ0286599A patent/CZ298027B6/cs not_active IP Right Cessation
- 1998-02-25 PL PL98335329A patent/PL190422B1/pl unknown
- 1998-02-25 IL IL13134398A patent/IL131343A/en not_active IP Right Cessation
- 1998-02-25 NZ NZ337195A patent/NZ337195A/en unknown
- 1998-02-25 CA CA002281105A patent/CA2281105A1/en not_active Abandoned
- 1998-02-25 AT AT98912388T patent/ATE221888T1/de active
- 1998-02-25 DE DE19880193T patent/DE19880193D2/de not_active Expired - Lifetime
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- 1998-02-25 HU HU0002189A patent/HU228851B1/hu unknown
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- 1998-02-25 EP EP98912388A patent/EP0975638B1/de not_active Expired - Lifetime
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- 1998-02-25 KR KR10-1999-7007773A patent/KR100494179B1/ko not_active IP Right Cessation
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- 1998-02-25 EP EP02001063A patent/EP1201666A3/de not_active Ceased
- 1998-02-25 AU AU67249/98A patent/AU736062B2/en not_active Ceased
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1999
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