ES2573682T3 - Agentes de interrupción vascular activados por MMP - Google Patents

Agentes de interrupción vascular activados por MMP Download PDF

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Publication number
ES2573682T3
ES2573682T3 ES12160556.2T ES12160556T ES2573682T3 ES 2573682 T3 ES2573682 T3 ES 2573682T3 ES 12160556 T ES12160556 T ES 12160556T ES 2573682 T3 ES2573682 T3 ES 2573682T3
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mmp
vascular
resin
agents activated
peptide
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Jason Gill
Paul Loadman
Robert Falconer
Laurence Patterson
Jennifer Atkinson
Michael Bibby
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Incanthera Research & Development Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/55—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Molecular Biology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Dermatology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Un compuesto, o sal farmacéuticamente aceptable del mismo, que comprende un agente de interrupción vascular (VDA) que es un agente anticancerígeno ligado a un péptido que comprende un sitio de división proteolítica de matriz de metaloproteinasa (MMP) que comprende la secuencia de aminoácidos -Arg-Ser-Cit-Gly-Hof-Tyr-Leu-.

Description

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δH (600 MHz, CDCl3), 10.08 (1 H, amplio s, NH), 8.99 (1 H, d J 10.7, C11-H), 7.71 (2 H, d, J 6.2, C23-H, C24-H),
7.55 (1 H, s, C8-H), 7.49 (2 H, dd, J 6.5 y 6.5, C20-H, C27-H), 7.41 (1 H, d, J 10.2, C10-H), 7.33 (2 H, dd, J 6.2 y 6.2, C22-H, C25-H), 7.26-7.21 (2 H, m, C21-H, C26-H), 6.91 (2 H, d, J 8.3, C14-H, C17-H), 6.56 (2 H, d, J 7.2, C15-H, C16-H), 6.45 (1 H, s, C4-H), 5.93 (1 H, amplio s, NH), 5.28 (1 H, s, NH), 4.95-4.90‘ (1 H, m, C12-H), 4.60 (1 H, ddd, J 11.7, 5.8 y 6.9, C7-H), 4.39 (1 H, dd, J 8.9 y 8.6, C18-CH2), 4.29-4.24 (1 H, m, C18-CH2), 4.12 (1 H, dd, J 6.9 y 6.9, C19-H), 3.90 (3 H, s, OCH3), 3.84 (3 H, s, OCH3), 3.54 (3 H, s, OCH3), 3.08 (2 H, d, J 5.2, C13-CH2), 2.44 (1 H, dd, J
13.4 y 6.2, C5-CH2), 2.33-2.26 (1 H, m, C5-CH2), 2.15-2.09 (1 H, m, C6-CH2), 1.82 (3 H, s, CH3), 1.75-1.69 (1 H, m, C6-CH2); ES m/z (%) 770 [M+] (100).
Preparación de 4:
Resina de cloruro de 2-Clorotritilo (Novabiochem, malla 100-200 m, sustitución 1.4 mmolg-1, 589 mg, 0.765 mmol,
1.00 eq) se suspende en una solución de 3 (589 mg, 0.765 mmol, 1.00 eq), dimetilaminopiridina (10 mg, 76.5 µmol,
0.01 eq), DiPEA (247 mg, 1.913 mmol, 333 µL, 2.50 eq) y piridina (241 mg, 3.061 mmol, 248 µL, 4.00 eq) en THF (10 mL) y se agita durante 6 horas a 50° C. La resina posteriormente se filtra y se lava profundamente con THF. La resina luego se finaliza al lavar la resina cuidadosamente con metanol (CH2Cl2:MeOH:DiPEA 17:2:1, 100 mL). La resina 4 se seca durante la noche sobre P2O5. Peso de resina seca: 593 mg (carga 56%).
Procedimiento general para síntesis de profármacos activados con endopeptidasa
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5 fluo-bala-glu-pro-cit-gly-hof-tyr-leu-tyr-colch
Como un ejemplo, el conjugado de péptido 5 se sintetiza utilizando síntesis de péptido en fase sólida convencional, a partir de derivado de colchicina inmovilizado 4, utilizando una estrategia con base en Fmoc.
Se logran ácidos de síntesis de péptido de estrategia Nα-Fmoc manualmente utilizando resina derivada de 2clorotritilo 4. La resina se hincha profundamente en DMF, seguido por eliminación del grupo protector N-Fmoc mediante tratamiento con 20% v/v de piperidina en DMF (3 x 3 min). Todos los acoplamientos se realizan en DMF, empleando 2.5 veces de exceso molar de aminoácidos protegidos de Nα-Fmoc (con grupos de protección de cadena lateral apropiados), y activados utilizando HCTU/HOBt/DiPEA. Se realizan desprotecciones de Nα-Fmoc utilizando 20% de piperidina en DMF (3 x 3 min). El éxito de acoplamientos y desprotecciones se monitoriza utilizando la prueba de Kaiser con basr rn ninhidrina. Se repiten los acoplamientos no exitosos. Después de la desprotección de Nα-Fmoc final, la cadena de péptido se finaliza con isotiocianato de fluoresceína (2.50 eq, en la presencia de DiPEA,
1.50 eq). El éxito de esta reacción también se monitoriza por la prueba de Kaiser.
Un residuo de β-alanina adicional se incorpora en la secuencia para superar la incompatibilidad del enlace de tiourea y las condiciones ácidas de la división (la tiourea se puede reorganizar, y el carbono carbonilo del enlace amida anterior se puede someter a ataque nucleófilo por la función similar sulfhihidrilo así formada. Esto conduce a la división del enlace amida, con la formación concomitante de una tiazolinona cíclica. LA tiazolinona se puede someter a redisposición en presencia de ácido acuoso para formar una tiohidantoína).
Sobre la terminación de la secuencia, la resina se lava (DMF, CH2Cl2, CH2Cl2/MeOH) y se seca en vacío sobre KOH a peso constante. Los péptidos se dividen a partir de la resina mediante acidolisis leve utilizando TFA-H2O triisopropilsilano 95:2.5:2.5 durante 2 h a temperatura ambiente, con desprotección de cadena lateral simultánea. Luego de división, el TFA se elimina bajo presión reducida. El producto crudo se extrae en 95% ácido acético acuoso y se liofiliza. El péptido crudo se analiza posteriormente utilizando HPLC de fase inversa y se purifica utilizando HPLC preparativo (pureza >97%). Las fracciones puras se combinan y se liofilizan. Se confirma la identidad mediante espectrometría de masas.
Adhesión potencial de la colchicina progenitora a una secuencia de péptidos es a través del anillo B
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Claims (1)

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    imagen2
ES12160556.2T 2007-04-12 2008-03-27 Agentes de interrupción vascular activados por MMP Active ES2573682T3 (es)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0707034 2007-04-12
GBGB0707034.5A GB0707034D0 (en) 2007-04-12 2007-04-12 Compounds

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ES2573682T3 true ES2573682T3 (es) 2016-06-09

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ES08718877.7T Active ES2573228T3 (es) 2007-04-12 2008-03-27 Agentes disruptores vasculares activados por MMP
ES12160565.3T Active ES2683168T3 (es) 2007-04-12 2008-03-27 Secuencia de escisión específica de MMP-14
ES12160556.2T Active ES2573682T3 (es) 2007-04-12 2008-03-27 Agentes de interrupción vascular activados por MMP

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ES12160565.3T Active ES2683168T3 (es) 2007-04-12 2008-03-27 Secuencia de escisión específica de MMP-14

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US (4) US8691751B2 (es)
EP (4) EP2134372B1 (es)
JP (4) JP5537413B2 (es)
CY (1) CY1120368T1 (es)
DK (3) DK2134372T3 (es)
ES (3) ES2573228T3 (es)
GB (1) GB0707034D0 (es)
HK (1) HK1258466A1 (es)
HR (1) HRP20181043T1 (es)
HU (3) HUE027528T2 (es)
LT (1) LT2481429T (es)
PL (3) PL2481429T3 (es)
PT (1) PT2481429T (es)
SI (1) SI2481429T1 (es)
TR (1) TR201807811T4 (es)
WO (1) WO2008125800A2 (es)

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GB0707034D0 (en) 2007-04-12 2007-05-23 St Andrews The Compounds
GB0819287D0 (en) * 2008-10-22 2008-11-26 Univ Bradford Compounds
GB2516882A (en) * 2013-08-02 2015-02-11 Univ Bradford Tumour-targeted theranostic
US9169337B2 (en) 2014-03-12 2015-10-27 Chevron Phillips Chemical Company Lp Polymers with improved ESCR for blow molding applications
NZ731185A (en) * 2014-10-29 2024-03-22 Bicyclerd Ltd Bicyclic peptide ligands specific for mt1-mmp
GB2545169B (en) * 2015-12-01 2019-10-09 Ellipses Pharma Ltd Taxane Prodrug Comprising A Membrane Type Matrix Metalloproteinase Cleavage Site
AU2018297614B2 (en) 2017-07-07 2024-04-04 Katholieke Universiteit Leuven Treatment of avascular or hypovascular micro-tumors

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AU4583601A (en) * 2000-03-15 2001-09-24 Du Pont Pharm Co Peptidase-cleavable, targeted antineoplastic drugs and their therapeutic use
GB0018240D0 (en) * 2000-07-25 2000-09-13 Pharmacia & Upjohn Spa Polymeric conjugates of antitumor agents
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GB0707034D0 (en) 2007-04-12 2007-05-23 St Andrews The Compounds
GB0819287D0 (en) 2008-10-22 2008-11-26 Univ Bradford Compounds
GB2516882A (en) 2013-08-02 2015-02-11 Univ Bradford Tumour-targeted theranostic

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ES2683168T3 (es) 2018-09-25
HUE029080T2 (en) 2017-01-30
EP2481428A3 (en) 2013-07-24
JP5911908B2 (ja) 2016-04-27
JP2014196304A (ja) 2014-10-16
US20100168036A1 (en) 2010-07-01
GB0707034D0 (en) 2007-05-23
DK2134372T3 (en) 2016-06-06
PL2134372T3 (pl) 2016-09-30
EP2134372B1 (en) 2016-02-24
PL2481429T3 (pl) 2018-10-31
US20160243252A1 (en) 2016-08-25
EP2134372A2 (en) 2009-12-23
CY1120368T1 (el) 2019-07-10
JP2010523632A (ja) 2010-07-15
WO2008125800A3 (en) 2008-12-04
US20140179592A1 (en) 2014-06-26
ES2573228T3 (es) 2016-06-06
EP2481429A3 (en) 2013-07-03
EP2481428A2 (en) 2012-08-01
HK1258466A1 (en) 2019-11-15
PT2481429T (pt) 2018-06-19
HRP20181043T1 (hr) 2018-09-21
US10556014B2 (en) 2020-02-11
WO2008125800A2 (en) 2008-10-23
LT2481429T (lt) 2018-09-10
SI2481429T1 (en) 2018-08-31
US8691751B2 (en) 2014-04-08
PL2481428T3 (pl) 2016-09-30
HUE038633T2 (hu) 2018-11-28
JP2016190848A (ja) 2016-11-10
EP2481428B1 (en) 2016-03-02
JP5931952B2 (ja) 2016-06-08
JP6170590B2 (ja) 2017-07-26
HK1174534A1 (en) 2013-06-14
JP5537413B2 (ja) 2014-07-02
JP2014193871A (ja) 2014-10-09
US9358303B2 (en) 2016-06-07
EP2481429A2 (en) 2012-08-01
HUE027528T2 (en) 2016-10-28
DK2481428T3 (en) 2016-06-13
DK2481429T3 (en) 2018-07-30
EP3348282A1 (en) 2018-07-18
US9956296B2 (en) 2018-05-01
EP2481429B1 (en) 2018-05-09
US20180228910A1 (en) 2018-08-16
TR201807811T4 (tr) 2018-06-21

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