HRP20160319T1 - Sinteza dinatrijeve soli n4-(2,2-dimetil-4-[(dihidrogen fosfonoksi)metil]-3-okso-5-pirido[1,4]oksazin-6-il)-5-fluoro-n2-(3,4,5-trimetoksifenil)-2,4-pirimidindiamina - Google Patents
Sinteza dinatrijeve soli n4-(2,2-dimetil-4-[(dihidrogen fosfonoksi)metil]-3-okso-5-pirido[1,4]oksazin-6-il)-5-fluoro-n2-(3,4,5-trimetoksifenil)-2,4-pirimidindiamina Download PDFInfo
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- HRP20160319T1 HRP20160319T1 HRP20160319TT HRP20160319T HRP20160319T1 HR P20160319 T1 HRP20160319 T1 HR P20160319T1 HR P20160319T T HRP20160319T T HR P20160319TT HR P20160319 T HRP20160319 T HR P20160319T HR P20160319 T1 HRP20160319 T1 HR P20160319T1
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- 230000015572 biosynthetic process Effects 0.000 title claims 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 title 1
- 238000003786 synthesis reaction Methods 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 21
- 150000001408 amides Chemical class 0.000 claims 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 14
- 239000012453 solvate Substances 0.000 claims 11
- 238000000034 method Methods 0.000 claims 10
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims 7
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims 6
- 239000002253 acid Substances 0.000 claims 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims 4
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 3
- 125000001931 aliphatic group Chemical group 0.000 claims 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims 2
- 229910052799 carbon Inorganic materials 0.000 claims 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims 2
- LNJAJHJFSKUCIR-UHFFFAOYSA-N ditert-butyl chloromethyl phosphate Chemical group CC(C)(C)OP(=O)(OCCl)OC(C)(C)C LNJAJHJFSKUCIR-UHFFFAOYSA-N 0.000 claims 2
- 125000005843 halogen group Chemical group 0.000 claims 2
- 229910052757 nitrogen Inorganic materials 0.000 claims 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims 2
- 239000002798 polar solvent Substances 0.000 claims 2
- 238000002360 preparation method Methods 0.000 claims 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims 2
- 229910001415 sodium ion Inorganic materials 0.000 claims 2
- 239000002904 solvent Substances 0.000 claims 2
- 150000003511 tertiary amides Chemical class 0.000 claims 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims 1
- 230000002378 acidificating effect Effects 0.000 claims 1
- 229910052736 halogen Inorganic materials 0.000 claims 1
- 150000004687 hexahydrates Chemical class 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims 1
- 150000003334 secondary amides Chemical class 0.000 claims 1
- 230000006641 stabilisation Effects 0.000 claims 1
- 238000011105 stabilization Methods 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
- C07F9/09—Esters of phosphoric acids
- C07F9/091—Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Agricultural Chemicals And Associated Chemicals (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Claims (15)
1. Postupak za pripremanje spoja s formulom I:
[image]
naznačen time da sadrži:
a) kontaktiranje kiselog solvata spoja s formulom II:
[image]
s amidom pod uvjetima pogodnim za nastajanje amidnog solvata spoja s formulom II; te
b) kontaktiranje amidnog solvata s vodenom bazom koja sadrži natrijeve ione pod uvjetima pogodnim za nastajanje spoja s formulom I.
2. Postupak prema zahtjevu 1, naznačen time da kisela komponenta kiselog solvata spoja s formulom II je karboksilna kiselina, poželjno pri čemu karboksilna kiselina je R1COOH pri čemu R1 je -H ili C1-C4 alkil proizvoljno supstituiran s do tri halo atoma.
3. Postupak prema zahtjevu 1, naznačen time da amid je sekundarni amid ili tercijarni amid.
4. Postupak prema zahtjevu 3, naznačen time da amid je R30CON(R2)2 gdje svaki R2 je neovisno -H ili C1-C4 alkil ili oba R2 zajedno s dušikom na koji su spojeni tvore 4 do 6 člani alifatski prsten, i R30 je -H ili C1-C4 alkil; ili R30 i jedan od R2 zajedno s odgovarajućim ugljikom i dušikom na koje su spojeni, kombiniraju se tako da tvore 4 do 6-člani alifatski prsten ring i drugi R2 je neovisno -H ili C1-C4 alkil.
5. Postupak prema zahtjevu 4, naznačen time da amid je N,N-dialkilformamid, N,N-dialkilacetamid, N-alkilpirolidinon, ili N-alkilpiperidon.
6. Postupak prema zahtjevu 5, naznačen time da amid je N,N-dialkilformamid; te pogodni uvjeti za nastanak amidnog solvata spoja s formulom II obuhvaćaju temperaturu od između oko 20 °C i oko 70 °C; poželjno pri čemu:
amid je N,N-dimetilformamid (DMF); i t pogodni uvjeti za nastanak amidnog solvata obuhvaćaju ponovno suspendiranje kiselog solvata u DMF kod temperature od oko 50 °C.
7. Postupak prema zahtjevu 1, naznačen time da vodena baza u dijelu b) sadrži natrijev hidroksid i alkohol, i pogodni uvjeti za nastanak spoja s formulom I obuhvaćaju temperaturu od između oko 40 °C oko 80 °C i pH od oko 8 do oko 10.5; poželjno pri čemu:
vodena baza u koraku b) sadrži natrijev hidroksid (NaOH) i izopropil alkohol (IPA), te pogodni uvjeti za nastanak spoja s formulom I obuhvaćaju temperaturu od oko 80 °C i pH od oko 9.
8. Spoj s formulom III:
[image]
9. Postupak za pripremanje spoja s formulom VI:
[image]
naznačen time da sadrži
osiguravanje kombinacije spoja s formulom V:
[image]
stabiliziranje s amidom; i zatim
kontaktiranje spoja s formulom IV:
[image]
s kombinacijom spoja s formulom V u prisutnosti amida, pri čemu:
R3 i R4 su svaki neovisno C1-C6 alkil; i
X je halogen;
pod uvjetima pogodnim za tvorbu spoja s formulom VI.
10. Postupak za pripremanje spoja s formulom I,
[image]
naznačen time da obuhvaća kontaktiranje spoja s formulom VI,
[image]
s kiselinom pod uvjetima pogodnim za tvorbu kiselog solvata spoja s formulom II:
[image]
kontaktiranje kiselog solvata spoja s formulom II s amidom u pod uvjetima pogodnim za tvorbu amidnog solvata spoja s formulom II; i
kontaktiranje amidnog solvata spoja s formulom II s vodenom bazom koja sadrži natrijeve ione pod uvjetima pogodnim za tvorbu spoja s formulom I.
11. Postupak prema zahtjevu 9, naznačen time da:
(a) spoj s formulom V je di-tert-butil klorometil fosfat:
[image]
ili
(b) dovoljni uvjeti za nastajanje spoja s formulom VI obuhvaćaju:
(i) kombiniranje spoja s formulom IV sa spojem s formulom V s bazom u polarnom otapalu; i
(ii) ispiranje produkta dobivenog iz koraka (i) u otopini vodene baze; poželjno pri čemu:
baza u (i) sadrži barem jedan od cezijevog karbonata (Cs2CO3) i kalijevog karbonata (K2CO3); polarno otapalo sadrži barem jedan od DMF i N,N-dimetilacetamid (DMAc); i vodena baza u (ii) sadrži barem jedan od natrijevog bikarbonata (NaHCO3) i natrijevog hidroksida (NaOH); ili
(c) spoj s formulom VI nije izoliran; ili
(d) amid je N,N-dimetilacetamid (DMAc), N,N-dimetilformamid (DMF), ili N-metilpirolidinon (NMP).
12. Pripravak naznačen time da sadrži uglavnom di-tert-butil klorometil fosfat:
[image]
i amid, proizvoljno u otapalu.
13. Pripravak prema zahtjevu 12, naznačen time da je amid također otapalo; poželjno pri čemu amid je tercijarni amid, poželjnije N,N-dimetilacetamid (DMAc).
14. Postupak prema zahtjevu 1 ili 10 naznačen time da je spoj s formulom I u obliku hidrata, poželjno u obliku heksahidrata.
15. Uporaba amida naznačena time da se koristi za stabiliziranje spoja s formulom V kako je definirano u zahtjevu 9.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US27007309P | 2009-07-02 | 2009-07-02 | |
| EP10730679.7A EP2448950B1 (en) | 2009-07-02 | 2010-07-01 | Synthesis of n4-(2,2-dimethyl-4-[(dihydrogen phosphonoxy)methyl]-3-oxo-5-pyrido[1,4]oxazin-6-yl)-5-fluoro-n2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine disodium salt |
| PCT/US2010/040792 WO2011002999A1 (en) | 2009-07-02 | 2010-07-01 | Synthesis of n4- (2, 2-dimethyl-4- [ (dihydrogen phosphonoxy ] -3-oxo-5-pyrido [1, 4] oxazin-6-yl)-5-fluoro-n2- (3, 4, 5,-trimethoxyphenyl) -2, 4- pyrimidinediamine disodium salt |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20160319T1 true HRP20160319T1 (hr) | 2016-04-22 |
Family
ID=42937685
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20160319TT HRP20160319T1 (hr) | 2009-07-02 | 2016-03-30 | Sinteza dinatrijeve soli n4-(2,2-dimetil-4-[(dihidrogen fosfonoksi)metil]-3-okso-5-pirido[1,4]oksazin-6-il)-5-fluoro-n2-(3,4,5-trimetoksifenil)-2,4-pirimidindiamina |
Country Status (22)
| Country | Link |
|---|---|
| US (3) | US8299242B2 (hr) |
| EP (1) | EP2448950B1 (hr) |
| JP (1) | JP5739882B2 (hr) |
| CN (1) | CN102482305B (hr) |
| AU (1) | AU2010266213B2 (hr) |
| BR (1) | BRPI1011888A2 (hr) |
| CA (1) | CA2766801C (hr) |
| CY (1) | CY1117489T1 (hr) |
| DK (1) | DK2448950T3 (hr) |
| EA (1) | EA021657B1 (hr) |
| ES (1) | ES2565985T3 (hr) |
| HK (1) | HK1169996A1 (hr) |
| HR (1) | HRP20160319T1 (hr) |
| HU (1) | HUE027212T2 (hr) |
| ME (1) | ME02388B (hr) |
| PL (1) | PL2448950T3 (hr) |
| RS (1) | RS54679B1 (hr) |
| SG (1) | SG176799A1 (hr) |
| SI (1) | SI2448950T1 (hr) |
| SM (1) | SMT201600084B (hr) |
| UA (1) | UA108077C2 (hr) |
| WO (1) | WO2011002999A1 (hr) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2054422B1 (en) | 2006-07-20 | 2017-06-14 | Debiopharm International SA | Acrylamide derivatives as fab i inhibitors |
| UA108077C2 (xx) | 2009-07-02 | 2015-03-25 | Синтез динатрієвої солі n4-(2,2-диметил-4-$(дигідрофосфонокси)метил]-3-оксо-5-піридо$1,4]оксазин-6-іл)-5-фтор-n2-(3,4,5-триметоксифеніл)-2,4-піримідиндіаміну | |
| CN102892770A (zh) * | 2010-02-24 | 2013-01-23 | 奥斯拜客斯制药有限公司 | 酪氨酸激酶三甲氧苯基抑制剂 |
| EA028432B1 (ru) | 2011-07-28 | 2017-11-30 | Райджел Фармасьютикалз, Инк. | Новые составы на основе (триметоксифениламино)пиримидинилов |
| TWI526437B (zh) * | 2011-09-09 | 2016-03-21 | 台灣神隆股份有限公司 | 卡巴他賽之結晶型 |
| US8426450B1 (en) * | 2011-11-29 | 2013-04-23 | Helsinn Healthcare Sa | Substituted 4-phenyl pyridines having anti-emetic effect |
| JP6085026B2 (ja) | 2012-06-19 | 2017-02-22 | デビオファーム インターナショナル エスエーＤｅｂｉｏｐｈａｒｍ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｓａ | （ｅ）−ｎ−メチル−ｎ−（（３−メチルベンゾフラン−２−イル）メチル）−３−（７−オキソ−５，６，７，８−テトラヒドロ−１，８−ナフチリジン−３−イル）アクリルアミドのプロドラッグ誘導体 |
| CN102746337B (zh) * | 2012-06-21 | 2014-12-17 | 成都苑东药业有限公司 | 一种2，4-嘧啶二胺类化合物及其制备方法 |
| WO2014022728A1 (en) | 2012-08-02 | 2014-02-06 | Endo Pharmaceuticals, Inc | Substituted 5 - (quinazolin - 2 - yl) pyrimidin- 2 -amine derivatives useful as pi3k/mtor inhibitors for the treatment of cancer |
| CA3186267A1 (en) * | 2013-12-20 | 2015-06-25 | Rigel Pharmaceuticals, Inc. | Pharmaceutical process and intermediates |
| US10751351B2 (en) | 2016-02-26 | 2020-08-25 | Debiopharm International S.A. | Medicament for treatment of diabetic foot infections |
| CN110087646A (zh) | 2016-09-08 | 2019-08-02 | 格利康科技集团有限责任公司 | 单体双金属羟基柠檬酸化合物及其制备和使用方法 |
| WO2019070827A1 (en) * | 2017-10-04 | 2019-04-11 | Celgene Corporation | PROCESSES FOR THE PREPARATION OF CIS-4 [2 - {(3S, 4R) -3-FLUOROOXAN-4-YL] AMINO) -8- (2,4,6-TRICHLOROANILINO) -9H-PURIN-9-YL] -1 -MÉTHYLCYCLOHEXANE-1-carboxamide |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US324087A (en) | 1885-08-11 | Abel combs | ||
| US303022A (en) | 1884-08-05 | Egg-beater | ||
| TWI329105B (en) | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
| US20040024716A1 (en) | 2002-04-12 | 2004-02-05 | James Malatesta | Mail sorting processes and systems |
| SG176311A1 (en) | 2002-07-29 | 2011-12-29 | Rigel Pharmaceuticals | Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds |
| CN102358738A (zh) | 2003-07-30 | 2012-02-22 | 里格尔药品股份有限公司 | 2,4-嘧啶二胺化合物及其预防和治疗自体免疫疾病的用途 |
| US20060047135A1 (en) | 2004-08-30 | 2006-03-02 | Chadwick Scott T | Process for preparing chloromethyl di-tert-butylphosphate |
| CA2591948C (en) | 2005-01-19 | 2013-11-12 | Rigel Pharmaceuticals, Inc. | Prodrugs of 2,4-pyrimidinediamine compounds and their uses |
| JP4981673B2 (ja) * | 2005-09-13 | 2012-07-25 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | 安定性が改善されたクロロメチルフォスフェイト誘導体を含む組成物およびその製造方法 |
| DK2078026T3 (da) * | 2006-11-21 | 2012-04-30 | Rigel Pharmaceuticals Inc | Prodrug-salte af 2, 4-pyrimidinediamine-forbindelser og anvendelser deraf |
| UA108077C2 (xx) | 2009-07-02 | 2015-03-25 | Синтез динатрієвої солі n4-(2,2-диметил-4-$(дигідрофосфонокси)метил]-3-оксо-5-піридо$1,4]оксазин-6-іл)-5-фтор-n2-(3,4,5-триметоксифеніл)-2,4-піримідиндіаміну |
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2010
- 2010-01-07 UA UAA201201072A patent/UA108077C2/ru unknown
- 2010-07-01 SG SG2011091733A patent/SG176799A1/en unknown
- 2010-07-01 EP EP10730679.7A patent/EP2448950B1/en active Active
- 2010-07-01 EA EA201270114A patent/EA021657B1/ru unknown
- 2010-07-01 HU HUE10730679A patent/HUE027212T2/en unknown
- 2010-07-01 CN CN201080039108.1A patent/CN102482305B/zh active Active
- 2010-07-01 BR BRPI1011888A patent/BRPI1011888A2/pt not_active Application Discontinuation
- 2010-07-01 ME MEP-2016-57A patent/ME02388B/me unknown
- 2010-07-01 SI SI201031148A patent/SI2448950T1/sl unknown
- 2010-07-01 AU AU2010266213A patent/AU2010266213B2/en active Active
- 2010-07-01 JP JP2012518607A patent/JP5739882B2/ja active Active
- 2010-07-01 PL PL10730679T patent/PL2448950T3/pl unknown
- 2010-07-01 WO PCT/US2010/040792 patent/WO2011002999A1/en active Application Filing
- 2010-07-01 CA CA2766801A patent/CA2766801C/en active Active
- 2010-07-01 ES ES10730679.7T patent/ES2565985T3/es active Active
- 2010-07-01 RS RS20160220A patent/RS54679B1/en unknown
- 2010-07-01 DK DK10730679.7T patent/DK2448950T3/en active
- 2010-07-01 US US12/829,126 patent/US8299242B2/en active Active
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2012
- 2012-09-24 US US13/625,552 patent/US8481724B2/en active Active
- 2012-10-26 HK HK12110760.3A patent/HK1169996A1/zh unknown
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2013
- 2013-06-07 US US13/912,856 patent/US8691798B2/en active Active
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- 2016-03-24 SM SM201600084T patent/SMT201600084B/xx unknown
- 2016-03-30 HR HRP20160319TT patent/HRP20160319T1/hr unknown
- 2016-04-12 CY CY20161100304T patent/CY1117489T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SI2448950T1 (sl) | 2016-05-31 |
| US8299242B2 (en) | 2012-10-30 |
| WO2011002999A1 (en) | 2011-01-06 |
| US20110003986A1 (en) | 2011-01-06 |
| ME02388B (me) | 2016-09-20 |
| HK1169996A1 (zh) | 2013-02-15 |
| SG176799A1 (en) | 2012-01-30 |
| CN102482305B (zh) | 2016-07-13 |
| CA2766801A1 (en) | 2011-01-06 |
| BRPI1011888A2 (pt) | 2016-04-12 |
| JP2012532143A (ja) | 2012-12-13 |
| US8481724B2 (en) | 2013-07-09 |
| US20130274499A1 (en) | 2013-10-17 |
| EA021657B1 (ru) | 2015-08-31 |
| US20130018185A1 (en) | 2013-01-17 |
| AU2010266213A1 (en) | 2012-02-02 |
| DK2448950T3 (en) | 2016-04-04 |
| CY1117489T1 (el) | 2017-04-26 |
| CN102482305A (zh) | 2012-05-30 |
| JP5739882B2 (ja) | 2015-06-24 |
| PL2448950T3 (pl) | 2016-06-30 |
| ES2565985T3 (es) | 2016-04-08 |
| CA2766801C (en) | 2018-03-13 |
| US8691798B2 (en) | 2014-04-08 |
| EA201270114A1 (ru) | 2012-05-30 |
| UA108077C2 (xx) | 2015-03-25 |
| HUE027212T2 (en) | 2016-10-28 |
| RS54679B1 (en) | 2016-08-31 |
| EP2448950B1 (en) | 2016-01-13 |
| EP2448950A1 (en) | 2012-05-09 |
| AU2010266213B2 (en) | 2015-06-18 |
| SMT201600084B (it) | 2016-04-29 |
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