ES2221692T5 - Epotilon, su preparacion y su utilizacion como agente citostatico o como agente fitoprotector. - Google Patents
Epotilon, su preparacion y su utilizacion como agente citostatico o como agente fitoprotector. Download PDFInfo
- Publication number
- ES2221692T5 ES2221692T5 ES97951233T ES97951233T ES2221692T5 ES 2221692 T5 ES2221692 T5 ES 2221692T5 ES 97951233 T ES97951233 T ES 97951233T ES 97951233 T ES97951233 T ES 97951233T ES 2221692 T5 ES2221692 T5 ES 2221692T5
- Authority
- ES
- Spain
- Prior art keywords
- epothilon
- fraction
- methanol
- concentrated
- agent
- 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
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 241001483078 Phyto Species 0.000 title 1
- 230000001012 protector Effects 0.000 title 1
- 239000003814 drug Substances 0.000 claims abstract description 3
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 48
- XOZIUKBZLSUILX-GIQCAXHBSA-N epothilone D Chemical compound O1C(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC\C(C)=C/C[C@H]1C(\C)=C\C1=CSC(C)=N1 XOZIUKBZLSUILX-GIQCAXHBSA-N 0.000 claims description 17
- 238000001704 evaporation Methods 0.000 claims description 10
- 230000008020 evaporation Effects 0.000 claims description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- HESCAJZNRMSMJG-KKQRBIROSA-N epothilone A 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(C)=N1 HESCAJZNRMSMJG-KKQRBIROSA-N 0.000 claims description 9
- 239000000463 material Substances 0.000 claims description 9
- 239000003463 adsorbent Substances 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000011347 resin Substances 0.000 claims description 8
- 229920005989 resin Polymers 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- 239000000287 crude extract Substances 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 claims description 3
- 229920005654 Sephadex Polymers 0.000 claims description 3
- 239000012507 Sephadex™ Substances 0.000 claims description 3
- 239000000824 cytostatic agent Substances 0.000 claims description 3
- 241000862997 Sorangium cellulosum Species 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- QXRSDHAAWVKZLJ-PVYNADRNSA-N epothilone B Chemical compound C/C([C@@H]1C[C@@H]2O[C@]2(C)CCC[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 QXRSDHAAWVKZLJ-PVYNADRNSA-N 0.000 claims description 2
- 239000000284 extract Substances 0.000 claims description 2
- 230000004060 metabolic process Effects 0.000 claims description 2
- 244000005700 microbiome Species 0.000 claims description 2
- 238000001228 spectrum Methods 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 3
- 239000001257 hydrogen Substances 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 2
- WCYWZMWISLQXQU-UHFFFAOYSA-N methyl Chemical group [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 abstract 2
- 229930013356 epothilone Natural products 0.000 description 7
- 238000006116 polymerization reaction Methods 0.000 description 5
- 125000000217 alkyl group Chemical group 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 125000002252 acyl group Chemical group 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- 238000005481 NMR spectroscopy Methods 0.000 description 2
- 102000004243 Tubulin Human genes 0.000 description 2
- 108090000704 Tubulin Proteins 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 238000001212 derivatisation Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 229910052736 halogen Inorganic materials 0.000 description 2
- 150000002367 halogens Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- LMSDCGXQALIMLM-UHFFFAOYSA-N 2-[2-[bis(carboxymethyl)amino]ethyl-(carboxymethyl)amino]acetic acid;iron Chemical compound [Fe].OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O LMSDCGXQALIMLM-UHFFFAOYSA-N 0.000 description 1
- -1 C 6 alkyl Chemical group 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 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
- 235000019764 Soybean Meal Nutrition 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 239000012445 acidic reagent Substances 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 229920001429 chelating resin Polymers 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000001085 cytostatic effect Effects 0.000 description 1
- RAABOESOVLLHRU-UHFFFAOYSA-N diazene Chemical compound N=N RAABOESOVLLHRU-UHFFFAOYSA-N 0.000 description 1
- 229910000071 diazene Inorganic materials 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000009413 insulation Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000013587 production medium Substances 0.000 description 1
- 125000002577 pseudohalo group Chemical group 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000004455 soybean meal Substances 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- MWOOGOJBHIARFG-UHFFFAOYSA-N vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 1
- FGQOOHJZONJGDT-UHFFFAOYSA-N vanillin Natural products COC1=CC(O)=CC(C=O)=C1 FGQOOHJZONJGDT-UHFFFAOYSA-N 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N43/74—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,3
- A01N43/78—1,3-Thiazoles; Hydrogenated 1,3-thiazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N63/00—Biocides, pest repellants or attractants, or plant growth regulators containing microorganisms, viruses, microbial fungi, animals or substances produced by, or obtained from, microorganisms, viruses, microbial fungi or animals, e.g. enzymes or fermentates
- A01N63/20—Bacteria; Substances produced thereby or obtained therefrom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/16—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing two or more hetero rings
- C12P17/167—Heterorings having sulfur atoms as ring heteroatoms, e.g. vitamin B1, thiamine nucleus and open chain analogs
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/18—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms containing at least two hetero rings condensed among themselves or condensed with a common carbocyclic ring system, e.g. rifamycin
- C12P17/181—Heterocyclic compounds containing oxygen atoms as the only ring heteroatoms in the condensed system, e.g. Salinomycin, Septamycin
Abstract
LA PRESENTE INVENCION TRATA DE EPOTILONA, EN PARTICULAR EPOTILONA C (R = HIDROGENO) Y EPOTILONA D (R = METILO) DE FORMULA (I), ASI COMO EPOTILONA E (R = HIDROGENO) Y EPOTILONA F (R = METILO) DE FORMULA (II), SU PREPARACION, ASI COMO SU UTILIZACION PARA LA PREPARACION DE AGENTES TERAPEUTICOS, EN PARTICULAR CITOSTATICOS ASI COMO AGENTES FITOSANITARIOS.
Description
Epotilón D, su preparación y su utilización como
agente citostático o como agente fitoprotector.
El presente invento se refiere al epotilón D, a
su preparación, así como a un agente terapéutico.
De acuerdo con una forma de realización, el
invento se refiere a un procedimiento para la preparación de
epotilón [D], en el que
- (a)
- se cultiva Sorangium cellulosum DSM 6773 en presencia de una resina adsorbente de una manera en sí conocida;
- (b)
- la resina adsorbente se separa con respecto del cultivo y se lava con una mezcla de agua y metanol,
- (c)
- la resina adsorbente lavada se eluye con metanol y el material eluido se concentra por evaporación para dar un extracto bruto,
- (d)
- el material concentrado obtenido se extrae con acetato de etilo, el extracto se concentra por evaporación y se reparte entre metanol y hexano,
- (e)
- la fase metanólica se concentra por evaporación para dar un material refinado y el material concentrado se fracciona en una columna con Sephadex,
- (f)
- se obtiene una fracción con productos de metabolismo del microorganismo empleado,
- (g)
- la fracción obtenida se cromatografía en presencia de una fase inversa C18 con una mezcla de metanol y agua, y en un orden de sucesión cronológico
- - después de una primera fracción con epotilón A y
- - de una segunda fracción con epotilón B,
- se obtienen
- - una tercera fracción con un primer epotilón adicional (epotilón C) y
- - una cuarta fracción con un segundo epotilón adicional (epotilón D), y
- (h)
- se aísla el epotilón de la segunda fracción adicional (epotilón D).
\vskip1.000000\baselineskip
Además, el invento se refiere al epotilón D de
la fórmula:
Epotilón D
\hskip0.5cmR = CH_{3}
\vskip1.000000\baselineskip
y de la fórmula empírica C_{27}H_{41}
NO_{5}S, caracterizado por los espectros de ^{1}H- y
^{13}C-RMN de acuerdo con la Tabla 1. El epotilón
D se puede utilizar para la preparación de compuestos de la
siguiente Fórmula 1, pudiéndose remitir, en lo que se refiere a su
derivatización, a los métodos de derivatización descritos en el
documento de solicitud de patente internacional
WO-A-97/19.086.
\vskip1.000000\baselineskip
En la Fórmula 1 precedente significan:
R = H, alquilo
C_{1}-_{4};
- R^{1}, R^{2}, R^{3}, R^{4}, R^{5} =
- H, alquilo C_{1-6},
- \quad
- acil C_{1-6}-benzoílo,
- \quad
- tri-alquil C_{1-4}-sililo,
- \quad
- bencilo,
- \quad
- fenilo,
- \quad
- bencilo o fenilo sustituido con
- \quad
- alcoxi C_{1-4}, alquilo C_{6}, hidroxi y halógeno;
realizándose también que dos de los radicales
R^{1} hasta R^{5} se pueden reunir para formar la agrupación
-(CH_{2})_{n}- con n = 1 hasta 6, y que en el caso
de los radicales que están contenidos en los grupos alquilo o acilo
se trata de radicales de cadena lineal o ramificados;
Y y Z son o bien iguales o
diferentes, y representan en cada caso hidrógeno, un halógeno, tal
como F, Cl, Br ó I, un pseudohalógeno, tal como -NCO, -NCS ó
-N_{3}, OH, O-acilo
C_{1}-_{6}, O-alquilo
C_{1}-_{6}, O-benzoílo. Y
y Z pueden ser también el átomo de O de un epóxido, o forman
uno de los enlaces C-C de un enlace doble C=C.
Así, el doble enlace situado en la posición
12,13, de una manera selectiva
- -
- se puede hidrogenar, por ejemplo por vía catalítica o con una diimina, obteniéndose un compuesto de la Fórmula 1 con Y = Z = H; o
- -
- se puede epoxidar, por ejemplo con dimetil-dioxirano o con un perácido, obteniéndose un compuesto de la Fórmula 1 con Y = Z = O; o
- -
- se puede transformar en los dihalogenuros, los di-pseudohalogenuros o las diazidas, obteniéndose un compuesto de la Fórmula 1 con Y y Z = Hal, pseudo-hal o N_{3}.
Finalmente, el invento se refiere a un agente
terapéutico, en particular para el empleo como un agente
citostático, que se compone de epotilón D, o de epotilón D junto a
uno o varios vehículo(s) y/o agente(s)
diluyente(s) usuales.
El invento se ilustra y describe más
detalladamente en lo sucesivo mediante la descripción de algunos
ejemplos de realización escogidos.
\vskip1.000000\baselineskip
Ejemplo
1
\newpage
\global\parskip0.960000\baselineskip
75 l de un cultivo se hacen crecer tal como se
ha descrito en la patente de base y se utilizan para la inoculación
de un fermentador de producción con 700 l de un medio de producción
a base de 0,8% de almidón, 0,2% de glucosa, 0,2% de harina de soja,
0,2% de extracto de levadura, 0,1% de CaCl_{2} x 2H_{2}O, 0,1%
de MgSO_{4} x 7H_{2}O, 8 mg/l de Fe-EDTA, pH =
7,4 y, opcionalmente, 15 l de la resina adsorbente Amberlite®
XAD-16. La fermentación dura de
7 - 10 días a 30ºC, aireación con 0,1 NL/m^{3} [litros en condiciones normales por metro cúbico). Mediante regulación del número de revoluciones se mantiene la pO_{2} (presión de O_{2}) en un 30% en peso.
7 - 10 días a 30ºC, aireación con 0,1 NL/m^{3} [litros en condiciones normales por metro cúbico). Mediante regulación del número de revoluciones se mantiene la pO_{2} (presión de O_{2}) en un 30% en peso.
La resina adsorbente se separa con respecto del
cultivo con un filtro de proceso de malla 100, con un área de
0,7 m^{2} y se libera de sustancias polares acompañantes mediante lavado con 3 volúmenes de lecho de una mezcla de agua y metanol 2:1. Mediante elución con 4 volúmenes de lecho de metanol se obtiene un extracto bruto, que se concentra por evaporación en vacío hasta la aparición de la fase acuosa.
0,7 m^{2} y se libera de sustancias polares acompañantes mediante lavado con 3 volúmenes de lecho de una mezcla de agua y metanol 2:1. Mediante elución con 4 volúmenes de lecho de metanol se obtiene un extracto bruto, que se concentra por evaporación en vacío hasta la aparición de la fase acuosa.
Ésta se extrae tres veces con el mismo volumen
de acetato de etilo. La concentración por evaporación de la fase
orgánica proporciona 240 g de un extracto bruto, que se reparte
entre metanol y heptano, con el fin de separar las sustancias
lipófilas acompañantes. A partir de la fase de metanol se obtienen,
mediante concentración por evaporación en vacío, 180 g de un
material refinado, que se fracciona en tres porciones a través de
Sephadex® LH-20 (columna de 20 x 100 cm, 20 ml/min
de metanol). Los epotilones están contenidos en la fracción eluida
con un período de tiempo de retención (R_{t}) de 240 - 300 min,
que tiene en total un peso de 72 g. Para la separación de los
epotilones, se cromatografía en tres porciones en presencia de
Lichrosorb® RP-18 (15 \mum, columna de 10 x 40
cm, eluyente 180 ml/min de una mezcla de metanol y agua 65:35).
Después de los epotilones A y B, se eluyen, con un R_{t} =
90-95 min, el epotilón C y, con uno de
100-110 min, el epotilón D, y, después de haber
concentrado por evaporación en vacío, se obtienen en un rendimiento
de, en cada caso, 0,3 g en forma de aceites incoloros.
Epotilón D
\hskip0.5cmR = CH_{3}
C_{27}H_{41}NO_{5}S [491]
ESI-MS (espectro de masas con
ionización por proyección de electrones):
(iones positivos): 492,5 para
[M+H]^{+}
Acerca de 1H y 13C, véase la Tabla de la RMN
(resonancia magnética nuclear)
DC (cromatografía de capa fina): R_{f} =
0,82
Lámina de aluminio para DC 60 F 254 de la
entidad Merck,
agente eluyente: mezcla de diclorometano y
metanol = 9:1
Detección: Extinción de la luz ultravioleta (UV)
a 254 nm. Rociadura con un reactivo de vainillina y ácido
sulfúrico, coloración gris azulada al calentar a 120ºC.
HPLC: R_{t} = 15,3 min
Columna: Nucleosil®100 C-18 7
\mum, 125 x 4 mm
Agente eluyente: mezcla de metanol y agua =
65:35
Caudal de paso: 1 ml/min
Detección: Conjunto de diodos
\global\parskip1.000000\baselineskip
Ejemplo 2 y Ejemplos comparativos 1
hasta
5
El epotilón D de acuerdo con el invento y los
epotilones A, B, C, E y F (Ejemplos comparativos 1 hasta 5) (Tabla
2) se ensayaron en cuanto al fomento de la polimerización (Tabla
3).
\vskip1.000000\baselineskip
- Ensayo patrón con 0,9 mg de tubulina/ml y una concentración de la muestra de 1 \muM.
\vskip1.000000\baselineskip
El ensayo de polimerización es un ensayo in
vitro con una tubulina purificada procedente del cerebro de un
cerdo. La evaluación se efectúa fotométricamente. Las sustancias que
fomentan la polimerización, tales como los epotilones, acortan el
período de tiempo transcurrido hasta que se haya efectuado la
polimerización semimáxima, es decir, que cuanto más corto sea el
período de tiempo tanto más eficaz será el compuesto. w, x, y y z
son cuatro ensayos independientes, la actividad relativa en la
última columna en % del testigo; de nuevo, los valores más bajos
muestran la mejor actividad. El rango de escalafón corresponde de
manera bastante exacta al comprobado en cultivos celulares.
Claims (3)
1. Procedimiento para la preparación de epotilón
D, en el que
- (a)
- se cultiva Sorangium cellulosum DSM 6773 en presencia de una resina adsorbente de una manera en sí conocida;
- (b)
- la resina adsorbente se separa con respecto del cultivo y se lava con una mezcla de agua y metanol,
- (c)
- la resina adsorbente lavada se eluye con metanol y el material eluido se concentra por evaporación para dar un extracto bruto,
- (d)
- el material concentrado obtenido se extrae con acetato de etilo, el extracto se concentra por evaporación y se reparte entre metanol y hexano,
- (e)
- la fase metanólica se concentra por evaporación para dar un material refinado y el material concentrado se fracciona en una columna con Sephadex,
- (f)
- se obtiene una fracción con productos de metabolismo del microorganismo empleado,
- (g)
- la fracción obtenida se cromatografía en presencia de una fase inversa C18 con una mezcla de metanol y agua, y en un orden de sucesión cronológico
- - después de una primera fracción con epotilón A y
- - de una segunda fracción con epotilón B,
- se obtienen
- - una tercera fracción con un primer epotilón adicional (epotilón C) y
- - una cuarta fracción con un segundo epotilón adicional (epotilón D), y
- (h)
- se aísla el epotilón de la segunda fracción adicional (epotilón D).
\vskip1.000000\baselineskip
2. Epotilón D de la fórmula:
Epotilón D
\hskip0.5cmR = CH_{3}
\vskip1.000000\baselineskip
y de la fórmula empírica
C_{27}H_{41}NO_{5}S, caracterizado por los espectros de
^{1}H- y ^{13}C-RMN de acuerdo con la
Tabla 1.
Tabla 1.
3. Agente terapéutico, en particular para su
empleo como agente citostático, que consta de un compuesto de
acuerdo con la reivindicación 2 o de de un compuesto de acuerdo con
la reivindicación 2, junto con uno o varios vehículo(s) y/o
diluyente(s) usual(es).
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19647580 | 1996-11-18 | ||
DE19647580 | 1996-11-18 | ||
DE19707506 | 1997-02-25 | ||
DE19707506 | 1997-02-25 |
Publications (3)
Publication Number | Publication Date |
---|---|
ES2221692T3 ES2221692T3 (es) | 2005-01-01 |
ES2221692T4 ES2221692T4 (es) | 2005-10-01 |
ES2221692T5 true ES2221692T5 (es) | 2009-12-14 |
Family
ID=26031383
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ES97951233T Expired - Lifetime ES2221692T5 (es) | 1996-11-18 | 1997-11-18 | Epotilon, su preparacion y su utilizacion como agente citostatico o como agente fitoprotector. |
ES03016552T Expired - Lifetime ES2312695T3 (es) | 1996-11-18 | 1997-11-18 | Epotilones e y f. |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ES03016552T Expired - Lifetime ES2312695T3 (es) | 1996-11-18 | 1997-11-18 | Epotilones e y f. |
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JP (1) | JP4274583B2 (es) |
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Families Citing this family (174)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE59609305D1 (de) | 1995-11-17 | 2002-07-11 | Biotechnolog Forschung Gmbh | Epothilon-Derivate und deren Herstellung |
US5969145A (en) * | 1996-08-30 | 1999-10-19 | Novartis Ag | Process for the production of epothilones and intermediate products within the process |
EP0941227B2 (de) | 1996-11-18 | 2009-10-14 | Gesellschaft für biotechnologische Forschung mbH (GBF) | Epothilon d, dessen herstellung und dessen verwendung als cytostatisches mittel bzw. als pflanzenschutzmittel |
US6867305B2 (en) | 1996-12-03 | 2005-03-15 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
US6204388B1 (en) | 1996-12-03 | 2001-03-20 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
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 |
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 |
US6660758B1 (en) | 1996-12-13 | 2003-12-09 | The Scripps Research Institute | Epothilone analogs |
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 |
US6194181B1 (en) | 1998-02-19 | 2001-02-27 | Novartis Ag | Fermentative preparation process for and crystal forms of cytostatics |
FR2775187B1 (fr) | 1998-02-25 | 2003-02-21 | Novartis Ag | Utilisation de l'epothilone b pour la fabrication d'une preparation pharmaceutique antiproliferative et d'une composition comprenant l'epothilone b comme agent antiproliferatif in vivo |
US6498257B1 (en) | 1998-04-21 | 2002-12-24 | Bristol-Myers Squibb Company | 2,3-olefinic epothilone derivatives |
US6380395B1 (en) | 1998-04-21 | 2002-04-30 | Bristol-Myers Squibb Company | 12, 13-cyclopropane epothilone derivatives |
DE19820599A1 (de) | 1998-05-08 | 1999-11-11 | Biotechnolog Forschung Gmbh | Epothilonderivate, Verfahren zu deren Herstellung und deren Verwendung |
NZ508326A (en) * | 1998-06-18 | 2003-10-31 | Novartis Ag | A polyketide synthase and non ribosomal peptide synthase genes, isolated from a myxobacterium, necessary for synthesis of epothiones A and B |
DE19826988A1 (de) | 1998-06-18 | 1999-12-23 | Biotechnolog Forschung Gmbh | Epothilon-Nebenkomponenten |
DE19846493A1 (de) * | 1998-10-09 | 2000-04-13 | Biotechnolog Forschung Gmbh | DNA-Sequenzen für die enzymatische Synthese von Polyketid- oder Heteropolyketidverbindungen |
US6410301B1 (en) | 1998-11-20 | 2002-06-25 | Kosan Biosciences, Inc. | Myxococcus host cells for the production of epothilones |
CA2350189A1 (en) | 1998-11-20 | 2000-06-02 | Kosan Biosciences, Inc. | Recombinant methods and materials for producing epothilone and epothilone derivatives |
JP2002533114A (ja) * | 1998-12-23 | 2002-10-08 | ブリストル−マイヤーズ スクイブ カンパニー | エポチロン製造のための微生物形質転換法 |
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 |
HUP0200076A3 (en) | 1999-02-22 | 2003-01-28 | Bristol Myers Squibb Co | C-21 modified epothilones, process for their preparation, pharmaceutical compositions containing them |
US6291684B1 (en) | 1999-03-29 | 2001-09-18 | Bristol-Myers Squibb Company | Process for the preparation of aziridinyl epothilones from oxiranyl epothilones |
RU2260592C9 (ru) | 1999-04-15 | 2017-04-07 | Бристол-Маерс Сквибб Ко. | Циклические ингибиторы протеинтирозинкиназ |
US7125875B2 (en) | 1999-04-15 | 2006-10-24 | Bristol-Myers Squibb Company | Cyclic protein tyrosine kinase inhibitors |
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 |
US6998256B2 (en) | 2000-04-28 | 2006-02-14 | Kosan Biosciences, Inc. | Methods of obtaining epothilone D using crystallization and /or by the culture of cells in the presence of methyl oleate |
AU9519501A (en) * | 2000-04-28 | 2001-11-12 | Kosan Biosciences Inc | Production of polyketides |
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 |
GB0029895D0 (en) * | 2000-12-07 | 2001-01-24 | Novartis Ag | Organic compounds |
WO2002062338A1 (en) | 2001-01-25 | 2002-08-15 | Bristol-Myers Squibb Company | Parenteral formulation containing epothilone analogs |
WO2002058699A1 (en) * | 2001-01-25 | 2002-08-01 | Bristol-Myers Squibb Company | Pharmaceutical forms of epothilones for oral administration |
BRPI0206509B8 (pt) | 2001-01-25 | 2021-05-25 | R Pharm Us Operating Llc | processo para formular, para administração parenteral, um análogo de epotilona, preparação farmacêutica, processo para formar uma composição farmacêutica para administração parental, composição farmacêutica e uso de um análogo de epotilona na preparação de uma composição farmacêutica para o tratamento de câncer |
US6893859B2 (en) | 2001-02-13 | 2005-05-17 | Kosan Biosciences, Inc. | Epothilone derivatives and methods for making and using the same |
HUP0303175A2 (hu) | 2001-02-20 | 2003-12-29 | Bristol-Myers Squibb Co. | Epotilonszármazékok alkalmazása makacs tumorok kezelésére alkalmas gyógyszerkészítmény előállítására |
EP1368030A1 (en) | 2001-02-20 | 2003-12-10 | Bristol-Myers Squibb Company | Epothilone derivatives for the treatment of refractory tumors |
PL207197B1 (pl) | 2001-02-27 | 2010-11-30 | Novartis Ag | Połączenie obejmujące inhibitor przekazywania sygnału i pochodną epotylonową, kompozycja farmaceutyczna zawierająca to połączenie oraz zastosowanie połączenia |
US7157595B2 (en) | 2001-02-27 | 2007-01-02 | Helmholtz-Zentrum Fur Infektionsforschung Gmbh | Degradation of epothilones |
CA2440555A1 (en) | 2001-03-14 | 2002-09-19 | Bristol-Myers Squibb Company | Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases |
EP1392664A4 (en) | 2001-06-01 | 2005-01-26 | Bristol Myers Squibb Co | EPOTHILONE DERIVATIVES |
TWI315982B (en) | 2001-07-19 | 2009-10-21 | Novartis Ag | Combinations comprising epothilones and pharmaceutical uses thereof |
TWI287986B (en) * | 2001-12-13 | 2007-10-11 | Novartis Ag | Use of Epothilones for the treatment of the carcinoid syndrome |
US6884608B2 (en) | 2001-12-26 | 2005-04-26 | Bristol-Myers Squibb Company | Compositions and methods for hydroxylating epothilones |
WO2003057217A1 (en) | 2002-01-14 | 2003-07-17 | Novartis Ag | Combinations comprising epothilones and anti-metabolites |
TW200303202A (en) | 2002-02-15 | 2003-09-01 | Bristol Myers Squibb Co | Method of preparation of 21-amino epothilone derivatives |
WO2003077903A1 (en) | 2002-03-12 | 2003-09-25 | Bristol-Myers Squibb Company | C12-cyano epothilone derivatives |
ES2337134T3 (es) | 2002-03-12 | 2010-04-21 | Bristol-Myers Squibb Company | Derivados de c3-ciano-epotilona. |
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 |
WO2003105828A1 (en) | 2002-06-14 | 2003-12-24 | Bristol-Myers Squibb Company | Combination of epothilone analogs and chemotherapeutic agents for the treatment of proliferative diseases |
CA2494742C (en) * | 2002-07-29 | 2015-05-12 | Optimer Pharmaceuticals, Inc. | Tiacumicin production |
MXPA05002113A (es) * | 2002-08-23 | 2005-06-03 | Sloan Kettering Inst Cancer | Sintesis de epotilonas, intermediarios para ellas, analogos y usos de los mismos. |
ES2439995T3 (es) | 2002-09-23 | 2014-01-27 | Bristol-Myers Squibb Company | Procedimientos de preparación, aislamiento y purificación de epotilona B |
DK1553938T3 (da) * | 2002-10-15 | 2007-03-26 | Univ Louisiana State | Anvendelse af epothilonderivater til behandling af hyperparathyroidisme |
AU2003302084A1 (en) | 2002-11-15 | 2004-06-15 | Bristol-Myers Squibb Company | Open chain prolyl urea-related modulators of androgen receptor function |
CN101177425B (zh) * | 2003-01-28 | 2012-07-18 | 北京华昊中天生物技术有限公司 | 一类新型埃坡霉素化合物及其制备方法和用途 |
US20050171167A1 (en) | 2003-11-04 | 2005-08-04 | Haby Thomas A. | Process and formulation containing epothilones and analogs thereof |
EP1559447A1 (en) | 2004-01-30 | 2005-08-03 | Institut National De La Sante Et De La Recherche Medicale (Inserm) | Use of epothilones in the treatment of neuronal connectivity defects such as schizophrenia and autism |
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 |
US7696241B2 (en) | 2004-03-04 | 2010-04-13 | Bristol-Myers Squibb Company | Bicyclic compounds as modulators of androgen receptor function and method |
US7625923B2 (en) | 2004-03-04 | 2009-12-01 | Bristol-Myers Squibb Company | Bicyclic modulators of androgen receptor function |
ES2394441T3 (es) | 2004-04-07 | 2013-01-31 | Novartis Ag | Inhibidores de IAP |
US10675326B2 (en) | 2004-10-07 | 2020-06-09 | The Board Of Trustees Of The University Of Illinois | Compositions comprising cupredoxins for treating cancer |
EP1824458A1 (en) * | 2004-11-18 | 2007-08-29 | Bristol-Myers Squibb Company | Enteric coated bead comprising epothilone or an epothilone analog, and preparation and administration thereof |
CN101083978A (zh) * | 2004-11-18 | 2007-12-05 | 布里斯托尔-迈尔斯斯奎布公司 | 含有伊沙贝比隆的肠衣珠粒及其制备 |
US20060121511A1 (en) | 2004-11-30 | 2006-06-08 | Hyerim Lee | Biomarkers and methods for determining sensitivity to microtubule-stabilizing agents |
GB0510390D0 (en) | 2005-05-20 | 2005-06-29 | Novartis Ag | Organic compounds |
CA2623034A1 (en) | 2005-09-27 | 2007-04-05 | Novartis Ag | Carboxyamine compounds and their use in the treatment of hdac dependent diseases |
WO2007057457A2 (en) | 2005-11-21 | 2007-05-24 | Novartis Ag | Neuroendocrine tumor treatment using mtor inhibitors |
GB0605120D0 (en) | 2006-03-14 | 2006-04-26 | Novartis Ag | Organic Compounds |
CA2647565A1 (en) | 2006-03-31 | 2007-10-18 | Bristol-Myers Squibb Company | Biomarkers and methods for determining sensitivity to microtubule-stabilizing agents |
KR20140019032A (ko) | 2006-04-05 | 2014-02-13 | 노파르티스 아게 | 암을 치료하기 위한 치료제의 조합물 |
BRPI0709749A2 (pt) | 2006-04-05 | 2011-07-26 | Novartis Ag | combinaÇÕes de agentes terapÊuticos para tratamento de cÂncer |
KR20090007635A (ko) | 2006-05-09 | 2009-01-19 | 노파르티스 아게 | 철 킬레이터 및 항-신생물 약제를 포함하는 조합물 및 그의용도 |
EP2081933B1 (en) | 2006-09-29 | 2011-03-23 | Novartis AG | Pyrazolopyrimidines as pi3k lipid kinase inhibitors |
CN101600728A (zh) | 2006-12-04 | 2009-12-09 | 伊利诺斯大学理事会 | 使用铜氧还蛋白和富含CpG的DNA治疗癌症的组合物和方法 |
MX2009008508A (es) | 2007-02-08 | 2010-04-21 | Univ Illinois | Composiciones y m?todos para prevenir el c?ncer con cupredoxinas. |
AU2008216327A1 (en) | 2007-02-15 | 2008-08-21 | Novartis Ag | Combination of LBH589 with other therapeutic agents for treating cancer |
MX2010010525A (es) | 2008-03-24 | 2010-10-25 | Novartis Ag | Inhibidores de metaloproteasa de matriz basados en aril-sulfonamida. |
AU2009228778B2 (en) | 2008-03-26 | 2012-04-19 | Novartis Ag | Hydroxamate-based inhibitors of deacetylases B |
CN101362784A (zh) * | 2008-10-06 | 2009-02-11 | 山东大学 | 埃博霉素苷类化合物和以其为活性成分的组合物及其应用 |
WO2010083617A1 (en) | 2009-01-21 | 2010-07-29 | Oncalis Ag | Pyrazolopyrimidines as protein kinase inhibitors |
DK2391366T3 (da) | 2009-01-29 | 2013-01-07 | Novartis Ag | Substituerede benzimidazoler til behandling af astrocytomer |
GEP20156250B (en) | 2009-06-26 | 2015-02-25 | Novartis Ag | 1,3-disubstituted imidazolidin-2-one derivatives as inhibitors of cyp 17 |
US8389526B2 (en) | 2009-08-07 | 2013-03-05 | Novartis Ag | 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives |
WO2011018454A1 (en) | 2009-08-12 | 2011-02-17 | Novartis Ag | Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation |
WO2011020861A1 (en) | 2009-08-20 | 2011-02-24 | Novartis Ag | Heterocyclic oxime compounds |
JP2013503129A (ja) | 2009-08-26 | 2013-01-31 | ノバルティス アーゲー | テトラ−置換ヘテロアリール化合物ならびにmdm2および/またはmdm4モジュレーターとしてのそれらの使用 |
MX2012005293A (es) | 2009-11-04 | 2012-06-19 | Novartis Ag | Derivados de sulfonamida heterociclicos utiles como inhibidores de mek. |
PE20121384A1 (es) | 2009-12-08 | 2012-10-13 | Novartis Ag | Derivados de sulfonamida heterociclicos |
AU2012265844A1 (en) | 2009-12-08 | 2013-05-02 | Novartis Ag | Heterocyclic sulfonamide derivatives |
CU24130B1 (es) | 2009-12-22 | 2015-09-29 | Novartis Ag | Isoquinolinonas y quinazolinonas sustituidas |
US8440693B2 (en) | 2009-12-22 | 2013-05-14 | Novartis Ag | Substituted isoquinolinones and quinazolinones |
CA2799202C (en) | 2010-05-18 | 2016-07-05 | Cerulean Pharma Inc. | Compositions and methods for treatment of autoimmune and other diseases |
UA112517C2 (uk) | 2010-07-06 | 2016-09-26 | Новартіс Аг | Тетрагідропіридопіримідинові похідні |
WO2012035078A1 (en) | 2010-09-16 | 2012-03-22 | Novartis Ag | 17α-HYDROXYLASE/C17,20-LYASE INHIBITORS |
AU2012207142B2 (en) | 2011-01-20 | 2017-04-27 | Board Of Regents, The University Of Texas System | MRI markers, delivery and extraction systems, and methods of manufacture and use thereof |
EP2673277A1 (en) | 2011-02-10 | 2013-12-18 | Novartis AG | [1, 2, 4]triazolo [4, 3 -b]pyridazine compounds as inhibitors of the c-met tyrosine kinase |
EA023064B1 (ru) | 2011-04-28 | 2016-04-29 | Новартис Аг | ИНГИБИТОРЫ 17α-ГИДРОКСИЛАЗЫ/C-ЛИАЗЫ |
TWI597065B (zh) | 2011-06-10 | 2017-09-01 | 梅爾莎納醫療公司 | 蛋白質-聚合物-藥物共軛體 |
EP2721008B1 (en) | 2011-06-20 | 2015-04-29 | Novartis AG | Hydroxy substituted isoquinolinone derivatives as p53 (mdm2 or mdm4) inhibitors |
US8859586B2 (en) | 2011-06-20 | 2014-10-14 | Novartis Ag | Cyclohexyl isoquinolinone compounds |
EP2723740A1 (en) | 2011-06-27 | 2014-04-30 | Novartis AG | Solid forms and salts of tetrahydro-pyrido-pyrimidine derivatives |
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 |
EP2755976B1 (en) | 2011-09-15 | 2018-07-18 | Novartis AG | 6-substituted 3-(quinolin-6-ylthio)-[1,2,4]triazolo[4,3-a]pyridines as c-met tyrosine kinase inhibitors |
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 |
CN104080787B (zh) | 2011-11-29 | 2016-09-14 | 诺华股份有限公司 | 吡唑并吡咯烷化合物 |
US20150148377A1 (en) | 2011-12-22 | 2015-05-28 | Novartis Ag | Quinoline Derivatives |
AP4055A (en) | 2011-12-22 | 2017-03-07 | Novartis Ag | Dihydro-benzo-oxazine and dihydro-pyrido-oxazine derivatives |
CN104136429A (zh) | 2011-12-23 | 2014-11-05 | 诺华股份有限公司 | 用于抑制bcl2与结合配偶体相互作用的化合物 |
JP2015503518A (ja) | 2011-12-23 | 2015-02-02 | ノバルティス アーゲー | Bcl2と結合相手の相互作用を阻害するための化合物 |
MX2014007729A (es) | 2011-12-23 | 2015-01-12 | Novartis Ag | Compuestos para inhibir la interaccion de bcl2 con los componentes de enlace. |
MX2014007725A (es) | 2011-12-23 | 2015-01-12 | Novartis Ag | Compuestos para inhibir la interaccion de bcl2 con los componentes de enlace. |
CA2859876A1 (en) | 2011-12-23 | 2013-06-27 | Novartis Ag | Compounds for inhibiting the interaction of bcl2 with binding partners |
KR101372563B1 (ko) * | 2011-12-26 | 2014-03-14 | 주식회사 삼양바이오팜 | 에포틸론 함유물질로부터 에포틸론 a와 b의 추출 및 정제 방법 |
JO3357B1 (ar) | 2012-01-26 | 2019-03-13 | Novartis Ag | مركبات إيميدازوبيروليدينون |
BR112014027181A2 (pt) | 2012-05-15 | 2017-06-27 | Novartis Ag | derivados de benzamida para a inibição da atividade de abl1, abl2 e bcr-abl1 |
MX2014013376A (es) | 2012-05-15 | 2015-08-14 | Novartis Ag | Derivados de benzamida para inhibir la actividad de abl1, abl2, y bcr-abl1. |
MX357305B (es) | 2012-05-15 | 2018-07-04 | Novartis Ag | Compuestos y composiciones para inhibir la actividad de abl-1, abl-2, y bcr-abl1. |
TR201807023T4 (tr) | 2012-05-15 | 2018-06-21 | Novartis Ag | Abl1, abl2 ve bcr- abl1 aktivitesinin inhibe edilmesi için benzamid türevleri. |
US9365576B2 (en) | 2012-05-24 | 2016-06-14 | Novartis Ag | Pyrrolopyrrolidinone compounds |
US9789193B2 (en) | 2012-06-15 | 2017-10-17 | The Brigham And Women's Hospital, Inc. | Compositions for treating cancer and methods for making the same |
KR102160320B1 (ko) | 2012-10-02 | 2020-09-28 | 에피테라퓨틱스 에이피에스 | 히스톤 탈메틸효소의 저해제 |
EP2924044B1 (en) | 2012-11-17 | 2018-10-31 | Beijing Shuobai Pharmaceutical Co., LTD | Platinum compound of malonic acid derivative having leaving group containing amino or alkylamino |
TW201422625A (zh) | 2012-11-26 | 2014-06-16 | Novartis Ag | 二氫-吡啶并-□衍生物之固體形式 |
AU2013359506B2 (en) | 2012-12-10 | 2018-05-24 | Mersana Therapeutics, Inc. | Protein-polymer-drug conjugates |
WO2014093640A1 (en) | 2012-12-12 | 2014-06-19 | Mersana Therapeutics,Inc. | Hydroxy-polmer-drug-protein conjugates |
JO3464B1 (ar) | 2013-01-15 | 2020-07-05 | Astellas Pharma Europe Ltd | التركيبات الخاصة بمركبات التياكوميسين |
EP2948453B1 (en) | 2013-01-22 | 2017-08-02 | Novartis AG | Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the p53/mdm2 interaction |
EP2948451B1 (en) | 2013-01-22 | 2017-07-12 | Novartis AG | Substituted purinone compounds |
WO2014128612A1 (en) | 2013-02-20 | 2014-08-28 | Novartis Ag | Quinazolin-4-one derivatives |
WO2014131777A1 (en) | 2013-02-27 | 2014-09-04 | Epitherapeutics Aps | Inhibitors of histone demethylases |
US20150018376A1 (en) | 2013-05-17 | 2015-01-15 | Novartis Ag | Pyrimidin-4-yl)oxy)-1h-indole-1-carboxamide derivatives and use thereof |
CA2914742A1 (en) | 2013-06-11 | 2014-12-18 | Bayer Pharma Aktiengesellschaft | Handovers with co-operating cells configured to provide coordinated multi-point transmission/reception |
UY35675A (es) | 2013-07-24 | 2015-02-27 | Novartis Ag | Derivados sustituidos de quinazolin-4-ona |
US9227969B2 (en) | 2013-08-14 | 2016-01-05 | Novartis Ag | Compounds and compositions as inhibitors of MEK |
WO2015022663A1 (en) | 2013-08-14 | 2015-02-19 | Novartis Ag | Compounds and compositions as inhibitors of mek |
WO2015022664A1 (en) | 2013-08-14 | 2015-02-19 | Novartis Ag | Compounds and compositions as inhibitors of mek |
US9657007B2 (en) | 2013-09-22 | 2017-05-23 | Calitor Sciences, Llc | Substituted aminopyrimidine compounds and methods of use |
MX2016004659A (es) | 2013-10-11 | 2017-08-02 | Asana Biosciences Llc | Conjugados proteina-polimero-farmaco. |
AU2014331714B2 (en) | 2013-10-11 | 2019-05-02 | Mersana Therapeutics, Inc. | Protein-polymer-drug conjugates |
CA2943979A1 (en) | 2014-03-28 | 2015-10-01 | Calitor Sciences, Llc | Substituted heteroaryl compounds and methods of use |
CA2943824A1 (en) | 2014-03-31 | 2015-10-08 | Gilead Sciences, Inc. | Inhibitors of histone demethylases |
CN106470681A (zh) | 2014-04-03 | 2017-03-01 | 茵维特丝肿瘤学私营有限责任公司 | 超分子组合治疗药物 |
AR101692A1 (es) | 2014-08-27 | 2017-01-04 | Epitherapeutics Aps | Compuestos y métodos para inhibir histonas demetilasas |
JP2018527362A (ja) | 2015-09-11 | 2018-09-20 | サンシャイン・レイク・ファーマ・カンパニー・リミテッドSunshine Lake Pharma Co.,Ltd. | 置換されたヘテロアリール化合物および使用方法 |
WO2018004338A1 (en) | 2016-06-27 | 2018-01-04 | 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 |
EP3710006A4 (en) | 2017-11-19 | 2021-09-01 | Sunshine Lake Pharma Co., Ltd. | SUBSTITUTED HETEROARYL COMPOUNDS AND THEIR METHODS OF USE |
AU2019209960B2 (en) | 2018-01-20 | 2023-11-23 | Sunshine Lake Pharma Co., Ltd. | Substituted aminopyrimidine compounds and methods of use |
US20210299286A1 (en) | 2018-05-04 | 2021-09-30 | Tagworks Pharmaceuticals B.V. | Tetrazines for high click conjugation yield in vivo and high click release yield |
DK3788032T3 (da) | 2018-05-04 | 2024-04-15 | Tagworks Pharmaceuticals B V | Forbindelser omfattende en linker til øgning af transcyklooctenstabilitet |
EP3873534A1 (en) | 2018-10-29 | 2021-09-08 | Mersana Therapeutics, Inc. | Cysteine engineered antibody-drug conjugates with peptide-containing linkers |
FR3087650B1 (fr) | 2018-10-31 | 2021-01-29 | Bio Even | Flavine adenine dinucleotide (fad) pour son utilisation pour la prevention et/ou le traitement de cancer |
IL289094A (en) | 2019-06-17 | 2022-02-01 | Tagworks Pharmaceuticals B V | Tetrazines for increasing the speed and yield of the "click release" reaction |
WO2020256546A1 (en) | 2019-06-17 | 2020-12-24 | Tagworks Pharmaceuticals B.V. | Compounds for fast and efficient click release |
WO2023031445A2 (en) | 2021-09-06 | 2023-03-09 | Veraxa Biotech Gmbh | Novel aminoacyl-trna synthetase variants for genetic code expansion in eukaryotes |
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 |
WO2023104941A1 (en) | 2021-12-08 | 2023-06-15 | European Molecular Biology Laboratory | Hydrophilic tetrazine-functionalized payloads for preparation of targeting conjugates |
WO2023158305A1 (en) | 2022-02-15 | 2023-08-24 | Tagworks Pharmaceuticals B.V. | Masked il12 protein |
WO2024013723A1 (en) | 2022-07-15 | 2024-01-18 | Pheon Therapeutics Ltd | Antibody drug conjugates that bind cdcp1 and uses thereof |
WO2024080872A1 (en) | 2022-10-12 | 2024-04-18 | Tagworks Pharmaceuticals B.V. | Strained bicyclononenes |
Family Cites Families (55)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0358606A3 (de) | 1988-09-09 | 1990-10-31 | Gesellschaft für Biotechnologische Forschung mbH (GBF) | Mikrobiologisches Verfahren zur Herstellung agrarchemisch verwendbarer mikrobizider makrozyklischer Lactonderivate |
GB8909737D0 (en) | 1989-04-27 | 1989-06-14 | Shell Int Research | Thiazole derivatives |
DE4138042C2 (de) * | 1991-11-19 | 1993-10-14 | Biotechnolog Forschung Gmbh | Epothilone, deren Herstellungsverfahren sowie diese Verbindungen enthaltende Mittel |
ATE201990T1 (de) | 1993-03-05 | 2001-06-15 | Hexal Ag | Kristallinische cyclodextrin-einschlusskomplexe von ranitidinhxdrochlorid und verfahren |
AU698382B2 (en) | 1994-01-11 | 1998-10-29 | Scripps Research Institute, The | Chemical switching of taxo-diterpenoids between low solubility active forms and high solubility inactive forms |
DE19542986A1 (de) * | 1995-11-17 | 1997-05-22 | Biotechnolog Forschung Gmbh | Epothilon-Derivate und deren Verwendung |
DE19639456A1 (de) | 1996-09-25 | 1998-03-26 | Biotechnolog Forschung Gmbh | Epothilon-Derivate, Herstellung und Mittel |
DE59609305D1 (de) | 1995-11-17 | 2002-07-11 | Biotechnolog Forschung Gmbh | Epothilon-Derivate und deren Herstellung |
US5969145A (en) * | 1996-08-30 | 1999-10-19 | Novartis Ag | Process for the production of epothilones and intermediate products within the process |
DE19636343C1 (de) | 1996-08-30 | 1997-10-23 | Schering Ag | Zwischenprodukte innerhalb der Totalsynthese von Epothilon A und B |
DE19645361A1 (de) | 1996-08-30 | 1998-04-30 | Ciba Geigy Ag | Zwischenprodukte innerhalb der Totalsynthese von Epothilon A und B, Teil II |
DE19645362A1 (de) | 1996-10-28 | 1998-04-30 | Ciba Geigy Ag | Verfahren zur Herstellung von Epothilon A und B und Derivaten |
EP0923583A1 (de) * | 1996-08-30 | 1999-06-23 | Novartis AG | Verfahren zur herstellung von epothilonen und zwischenprodukte innerhalb des verfahrens |
EP0941227B2 (de) * | 1996-11-18 | 2009-10-14 | Gesellschaft für biotechnologische Forschung mbH (GBF) | Epothilon d, dessen herstellung und dessen verwendung als cytostatisches mittel bzw. als pflanzenschutzmittel |
US6515016B2 (en) | 1996-12-02 | 2003-02-04 | Angiotech Pharmaceuticals, Inc. | Composition and methods of paclitaxel for treating psoriasis |
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 |
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 |
US6380394B1 (en) | 1996-12-13 | 2002-04-30 | The Scripps Research Institute | Epothilone analogs |
US6441186B1 (en) | 1996-12-13 | 2002-08-27 | The Scripps Research Institute | Epothilone analogs |
DE19701758A1 (de) | 1997-01-20 | 1998-07-23 | Wessjohann Ludgar A Dr | Epothilone-Synthesebausteine |
EP1201666A3 (de) | 1997-02-25 | 2003-03-05 | Gesellschaft für biotechnologische Forschung mbH (GBF) | Seitenkettenmodifizierte Epothilone |
US5828449A (en) | 1997-02-26 | 1998-10-27 | Acuity Imaging, Llc | Ring illumination reflective elements on a generally planar surface |
DE19713970B4 (de) | 1997-04-04 | 2006-08-31 | R&D-Biopharmaceuticals Gmbh | Epothilone-Synthesebausteine II - Prenylderivate |
WO1998047891A1 (de) | 1997-04-18 | 1998-10-29 | Studiengesellschaft Kohle Mbh | Selektive olefinmetathese von bi- oder polyfunktionellen substraten in komprimiertem kohlendioxid als reaktionsmedium |
DE19720312A1 (de) | 1997-05-15 | 1998-11-19 | Hoechst Ag | Zubereitung mit erhöhter in vivo Verträglichkeit |
DE19821954A1 (de) | 1997-05-15 | 1998-11-19 | Biotechnolog Forschung Gmbh | Verfahren zur Herstellung eines Epothilon-Derivats |
DE19726627A1 (de) | 1997-06-17 | 1998-12-24 | Schering Ag | Zwischenprodukte, Verfahren zu ihrer Herstellung und ihre Verwendung zur Herstellung von Epothilon |
US6605599B1 (en) | 1997-07-08 | 2003-08-12 | Bristol-Myers Squibb Company | Epothilone derivatives |
DK1001951T3 (da) | 1997-07-16 | 2002-12-23 | Schering Ag | Thiazolderivater, fremgangsmåde til fremstilling deraf og anvendelse af disse |
JP2001512723A (ja) | 1997-08-09 | 2001-08-28 | シエーリング アクチエンゲゼルシヤフト | 新規エポチロン誘導体、その製法およびその薬学的使用 |
CN100396276C (zh) | 1998-02-05 | 2008-06-25 | 诺瓦提斯公司 | 依普西龙组合物 |
US6194181B1 (en) * | 1998-02-19 | 2001-02-27 | Novartis Ag | Fermentative preparation process for and crystal forms of cytostatics |
FR2775187B1 (fr) | 1998-02-25 | 2003-02-21 | Novartis Ag | Utilisation de l'epothilone b pour la fabrication d'une preparation pharmaceutique antiproliferative et d'une composition comprenant l'epothilone b comme agent antiproliferatif in vivo |
CA2322157C (en) | 1998-02-25 | 2012-05-29 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
DE19826988A1 (de) * | 1998-06-18 | 1999-12-23 | Biotechnolog Forschung Gmbh | Epothilon-Nebenkomponenten |
AU5036999A (en) | 1998-06-30 | 2000-01-17 | Schering Aktiengesellschaft | Epothilon derivatives, their preparation process, intermediate products and their pharmaceutical use |
US6410301B1 (en) * | 1998-11-20 | 2002-06-25 | Kosan Biosciences, Inc. | Myxococcus host cells for the production of epothilones |
CA2350189A1 (en) | 1998-11-20 | 2000-06-02 | Kosan Biosciences, Inc. | Recombinant methods and materials for producing epothilone and epothilone derivatives |
DE69910831T2 (de) | 1998-12-22 | 2004-07-15 | Novartis Ag | Epothilonderivate und ihre verwendung als antitumormittel |
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 |
EE200100431A (et) | 1999-02-18 | 2002-12-16 | Schering Aktiengesellschaft | 16-halogenoepotilooni derivaadid, nende valmistamismeetod ja farmatseutiline kasutamine |
HUP0200076A3 (en) * | 1999-02-22 | 2003-01-28 | Bristol Myers Squibb Co | C-21 modified epothilones, process for their preparation, pharmaceutical compositions containing them |
US6211412B1 (en) * | 1999-03-29 | 2001-04-03 | The University Of Kansas | Synthesis of epothilones |
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 |
TWI310684B (en) * | 2000-03-27 | 2009-06-11 | Bristol Myers Squibb Co | Synergistic pharmaceutical kits for treating cancer |
US6489314B1 (en) * | 2001-04-03 | 2002-12-03 | Kosan Biosciences, Inc. | Epothilone derivatives and methods for making and using the same |
US6589968B2 (en) * | 2001-02-13 | 2003-07-08 | Kosan Biosciences, Inc. | Epothilone compounds and methods for making and using the same |
US6906188B2 (en) * | 2001-04-30 | 2005-06-14 | State Of Oregon Acting By And Through The State Board Of Higher Education On Behalf Of Oregon State University | Method for synthesizing epothilones and epothilone analogs |
WO2003029195A1 (fr) * | 2001-09-28 | 2003-04-10 | Sumika Fine Chemicals Co., Ltd. | Intermediaires pour l'elaboration d'un derive de l'epothilone, et leur procede de production |
US6884608B2 (en) * | 2001-12-26 | 2005-04-26 | Bristol-Myers Squibb Company | Compositions and methods for hydroxylating epothilones |
TW200303202A (en) | 2002-02-15 | 2003-09-01 | Bristol Myers Squibb Co | Method of preparation of 21-amino epothilone derivatives |
US6921769B2 (en) * | 2002-08-23 | 2005-07-26 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
ES2439995T3 (es) | 2002-09-23 | 2014-01-27 | Bristol-Myers Squibb Company | Procedimientos de preparación, aislamiento y purificación de epotilona B |
-
1997
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