ES2610652T3 - Ésteres de ácidos amidoxima-carboxílicos de la pentamidina como profármacos y su utilización como un medicamento - Google Patents
Ésteres de ácidos amidoxima-carboxílicos de la pentamidina como profármacos y su utilización como un medicamento Download PDFInfo
- Publication number
- ES2610652T3 ES2610652T3 ES11175252.3T ES11175252T ES2610652T3 ES 2610652 T3 ES2610652 T3 ES 2610652T3 ES 11175252 T ES11175252 T ES 11175252T ES 2610652 T3 ES2610652 T3 ES 2610652T3
- Authority
- ES
- Spain
- Prior art keywords
- pentamidine
- prodrugs
- esters
- medicine
- carboxylic acids
- 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.)
- Active
Links
- -1 pentamidine amidoxime carboxylic acids Chemical class 0.000 title description 7
- 239000000651 prodrug Substances 0.000 title description 7
- 229940002612 prodrug Drugs 0.000 title description 7
- 239000003814 drug Substances 0.000 title 1
- 150000002148 esters Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 abstract description 2
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 description 19
- 229960004448 pentamidine Drugs 0.000 description 14
- 102000004169 proteins and genes Human genes 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 238000011534 incubation Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000004913 activation Effects 0.000 description 3
- 229940088598 enzyme Drugs 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- 229940079919 digestives enzyme preparation Drugs 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 210000001589 microsome Anatomy 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- UVADNHMLTJNGDH-UHFFFAOYSA-N n'-hydroxy-4-[5-[4-(n'-hydroxycarbamimidoyl)phenoxy]pentoxy]benzenecarboximidamide Chemical compound C1=CC(C(=N\O)/N)=CC=C1OCCCCCOC1=CC=C(C(\N)=N/O)C=C1 UVADNHMLTJNGDH-UHFFFAOYSA-N 0.000 description 2
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000012460 protein solution Substances 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 108090000371 Esterases Proteins 0.000 description 1
- OXPMCNJABSKCMN-DQEYMECFSA-N [(z)-[amino-[4-[5-[4-[(z)-n'-[(2s)-2-amino-3-methylbutanoyl]oxycarbamimidoyl]phenoxy]pentoxy]phenyl]methylidene]amino] (2s)-2-amino-3-methylbutanoate Chemical compound C1=CC(C(/N)=N/OC(=O)[C@@H](N)C(C)C)=CC=C1OCCCCCOC1=CC=C(C(\N)=N\OC(=O)[C@@H](N)C(C)C)C=C1 OXPMCNJABSKCMN-DQEYMECFSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 210000005084 renal tissue Anatomy 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
- C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/225—Polycarboxylic acids
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/06—Antimalarials
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P33/08—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis for Pneumocystis carinii
-
- 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Emergency Medicine (AREA)
- Tropical Medicine & Parasitology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nutrition Science (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Un compuesto de la fórmula**Fórmula** en la que n representa 2.
Description
5
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(12.000 rpm) y las muestras se midieron inmediatamente por HPLC. La evaluación de la solubilidad se efectuó a través de una calibración de la N,N'-bis(succiniloxi)pentamidina (1) en DMSO. El compuesto es bien soluble (7,5 mM) a un valor del pH fisiológico de 7,4. La solubilidad se mejoró ulteriormente cuando se aumentó el valor del pH (véase la Tabla 1).
Como comparación se investigaron otros diferentes profármacos de pentamidina, con el fin de poder evaluar mejor la solubilidad en comparación con los derivados ya descritos. La determinación de las solubilidades se llevó a cabo análogamente al método descrito para el compuesto 1.
Tabla 1: Solubilidad de la N,N'-bis(succiniloxi)pentamidina (1) y de otros profármacos de la pentamidina a diferentes valores del pH
Solubilidad [µM]
- Profármaco de la pentamidina
- pH 2,0 pH 7,4 pH 9,0
- N,N'-bis(succiniloxi)pentamidina (1)
- hidrólisis 7.500 ± 340 10.780 ± 70
- Monomamidoxima de pentamidina
- 22.285 ± 1244 1.370 ± 291 1.257 ± 40
- Diamidoxima de pentamidina (3)
- 4.211 ± 231 12 ± 1 4 ± 1
- N,N'-bis(acetoxi)pentamidina
- 14 ± 8 2 ± 1 3 ± 2
- N,N'-bis(metoxi)pentamidina
- 1.304 ± 28 8 ± 1 10 ± 2
- N,N'-bis(dihidroxi)pentamidina
- > 35.000 95 ± 8 21 ± 3
- N,N'-bis(valoxi)pentamidina
- > 35.000 157 ± 19 84 ± 18
Determinación de la fijación a proteínas de la N,N'-bis(succiniloxi)pentamidina (1)
La determinación de la fijación a proteínas del plasma se llevó a cabo en tres concentraciones diferentes (10, 20 y 50 µM). Como soluciones de proteínas se utilizó una solución de albúmina al 4 %. Se pipetearon en cada caso 50 µl de una solución de la sustancia concentrada a 10 veces en 450 µl de la solución de proteína. La incubación se efectuó durante 15 min en un baño agitado de agua a 37°C. A continuación, las muestras fueron transferidas a unas unidades de ultrafiltración (Vivaspin 500, límite de exclusión 10 kDa) y se centrifugaron durante 15 min a 10.000 rpm. El material filtrado se analizó por HPLC. Adicionalmente, para cada concentración se llevó a cabo un control, que no había sido mezclado con proteínas y no había sido centrifugado. Otro control adicional sin adición de proteínas, que sin embargo había sido separado por centrifugación a través de la unidad de filtración, sirvió para la validación de la metodología.
El análisis de la muestra determinó una fijación a proteínas de 97,1 ± 1,2 % para el compuesto 1.
Investigación de la bioactivación de la N,N'-bis(succiniloxi)pentamidina (1)
Determinación de la activación de los profármaco con diferentes sistemas de enzimas subcelulares
La activación del profármaco se determinó in vitro mediante unos preparados enzimáticos subcelulares. Como preparados enzimáticos se utilizaron unos materiales sobrenadantes de 9.000xg, microsomas y mitocondrios de tejidos de hígados y riñones porcinos. Las tandas de incubación se componían de un profármaco 500 µM, NaDH 1 mM, 1 U de una esterasa y 0,3 mg de un preparado enzimático, disueltos en 250 µl de tampón fosfato 100 mM de pH 6,3. La incubación se efectuó durante 20 min a 37 °C en un baño de agua agitado. La incubación se finalizó mediante la adición de 150 µl de metanol. A continuación, las muestras se agitaron durante 10 min y la proteína precipitada se separó por centrifugación a 10.000 rpm durante 15 min. El material sobrenadante se midió con ayuda de la HPLC. Las tasas de conversión química determinadas se exponen en la Tabla 2.
Tabla 2: Activación de la N,N'-bis(succiniloxi)pentamidina (1) en la forma activa con unos preparados enzimáticos subcelulares, HL = hígado humano, HN = riñón humano, SL = hígado de cerdo, SN = riñón de cerdo 9000g = material sobrenadante de 9.000 g, MS = microsomas, Mt = mitocondrias
Fuente de la enzima Pentamidina [nmol*min-1*mg-1] HL 9000g 0,04 ± 0,01 HL Ms 0,02 ± 0,02
HL Mt 0,56 ± 0,43
HN Mt 0,08 ± 0,02
SL 9000g 0,00 ± 0,00 SN 9000g 0,49 ± 0,03 SL Ms 0,69 ± 0,13
SN Ms 2,25 ± 0,58
SL Mt 1,44 ± 0,22
SN Mt 0,41 ± 0,09
9
Claims (1)
-
imagen1 imagen2
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP11175252.3A EP2550963B1 (de) | 2011-07-25 | 2011-07-25 | Pentamidin-Amidoximsäureesters als Prodrugs und ihre Verwendung als Arzneimittel |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2610652T3 true ES2610652T3 (es) | 2017-04-28 |
Family
ID=46514404
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES11175252.3T Active ES2610652T3 (es) | 2011-07-25 | 2011-07-25 | Ésteres de ácidos amidoxima-carboxílicos de la pentamidina como profármacos y su utilización como un medicamento |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US20130085180A1 (es) |
| EP (1) | EP2550963B1 (es) |
| JP (2) | JP2014529579A (es) |
| KR (1) | KR20140097108A (es) |
| CN (1) | CN103874491A (es) |
| AU (1) | AU2012288968B2 (es) |
| BR (1) | BR112014001787A2 (es) |
| CA (1) | CA2842355A1 (es) |
| DK (1) | DK2550963T3 (es) |
| ES (1) | ES2610652T3 (es) |
| HR (1) | HRP20170013T1 (es) |
| HU (1) | HUE030245T2 (es) |
| LT (1) | LT2550963T (es) |
| PL (1) | PL2550963T3 (es) |
| PT (1) | PT2550963T (es) |
| RS (1) | RS55557B1 (es) |
| RU (1) | RU2608388C2 (es) |
| SI (1) | SI2550963T1 (es) |
| WO (1) | WO2013014059A1 (es) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20150126595A (ko) | 2012-12-21 | 2015-11-12 | 벌릭스 파마 인코포레이티드 | 간 질환 또는 증상의 치료를 위한 용도 및 방법 |
| US11420946B2 (en) | 2017-09-27 | 2022-08-23 | Ohio State Innovation Foundation | Methods and compositions for inhibition of STAT3 |
| US10835581B2 (en) | 2017-11-28 | 2020-11-17 | University of Pittsburgh—of the Commonwealth System of Higher Education | Method of treating insulin resistance |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4321444A1 (de) * | 1993-06-28 | 1995-01-05 | Bernd Prof Dr Clement | Pharmazeutische Zubereitung |
| US5723495A (en) * | 1995-11-16 | 1998-03-03 | The University Of North Carolina At Chapel Hill | Benzamidoxime prodrugs as antipneumocystic agents |
| US6569853B1 (en) * | 2000-11-06 | 2003-05-27 | Combinatorx, Incorporated | Combinations of chlorpromazine and pentamidine for the treatment of neoplastic disorders |
| DE102008007381A1 (de) * | 2008-02-01 | 2009-08-13 | Dritte Patentportfolio Beteiligungsgesellschaft Mbh & Co.Kg | Amidine und Guanidine und deren Derivate zur Behandlung von Krankheiten |
-
2011
- 2011-07-25 SI SI201131053A patent/SI2550963T1/sl unknown
- 2011-07-25 LT LTEP11175252.3T patent/LT2550963T/lt unknown
- 2011-07-25 PL PL11175252T patent/PL2550963T3/pl unknown
- 2011-07-25 HU HUE11175252A patent/HUE030245T2/en unknown
- 2011-07-25 EP EP11175252.3A patent/EP2550963B1/de active Active
- 2011-07-25 PT PT111752523T patent/PT2550963T/pt unknown
- 2011-07-25 ES ES11175252.3T patent/ES2610652T3/es active Active
- 2011-07-25 DK DK11175252.3T patent/DK2550963T3/en active
- 2011-07-25 RS RS20170002A patent/RS55557B1/sr unknown
-
2012
- 2012-07-19 WO PCT/EP2012/064171 patent/WO2013014059A1/de active Application Filing
- 2012-07-19 AU AU2012288968A patent/AU2012288968B2/en not_active Ceased
- 2012-07-19 RU RU2014106867A patent/RU2608388C2/ru not_active IP Right Cessation
- 2012-07-19 CA CA2842355A patent/CA2842355A1/en not_active Abandoned
- 2012-07-19 JP JP2014522041A patent/JP2014529579A/ja not_active Withdrawn
- 2012-07-19 BR BR112014001787A patent/BR112014001787A2/pt not_active IP Right Cessation
- 2012-07-19 KR KR1020147004770A patent/KR20140097108A/ko not_active Application Discontinuation
- 2012-07-19 CN CN201280037041.7A patent/CN103874491A/zh active Pending
- 2012-10-05 US US13/554,536 patent/US20130085180A1/en not_active Abandoned
-
2016
- 2016-09-06 JP JP2016173855A patent/JP2017039727A/ja not_active Withdrawn
-
2017
- 2017-01-05 HR HRP20170013TT patent/HRP20170013T1/hr unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU2012288968B2 (en) | 2017-01-05 |
| DK2550963T3 (en) | 2017-01-30 |
| PT2550963T (pt) | 2017-01-19 |
| RU2608388C2 (ru) | 2017-01-18 |
| EP2550963B1 (de) | 2016-10-12 |
| JP2014529579A (ja) | 2014-11-13 |
| WO2013014059A1 (de) | 2013-01-31 |
| BR112014001787A2 (pt) | 2017-02-21 |
| HUE030245T2 (en) | 2017-04-28 |
| HRP20170013T1 (hr) | 2017-03-10 |
| RU2014106867A (ru) | 2015-08-27 |
| JP2017039727A (ja) | 2017-02-23 |
| CN103874491A (zh) | 2014-06-18 |
| PL2550963T3 (pl) | 2017-08-31 |
| LT2550963T (lt) | 2017-02-27 |
| CA2842355A1 (en) | 2013-01-31 |
| AU2012288968A1 (en) | 2014-02-13 |
| SI2550963T1 (sl) | 2017-05-31 |
| RS55557B1 (sr) | 2017-05-31 |
| EP2550963A1 (de) | 2013-01-30 |
| US20130085180A1 (en) | 2013-04-04 |
| KR20140097108A (ko) | 2014-08-06 |
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