HRP20150872T1 - Postupak za enzimsku sintezu (7s)-3,4-dimetoksibiciklo [4.2.0] okta-1,3,5-trien-7-karboksilne kiseline ili njezinih estera i primjena u sintezi ivabradina i njegovih soli - Google Patents
Postupak za enzimsku sintezu (7s)-3,4-dimetoksibiciklo [4.2.0] okta-1,3,5-trien-7-karboksilne kiseline ili njezinih estera i primjena u sintezi ivabradina i njegovih soli Download PDFInfo
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- HRP20150872T1 HRP20150872T1 HRP20150872TT HRP20150872T HRP20150872T1 HR P20150872 T1 HRP20150872 T1 HR P20150872T1 HR P20150872T T HRP20150872T T HR P20150872TT HR P20150872 T HRP20150872 T HR P20150872T HR P20150872 T1 HRP20150872 T1 HR P20150872T1
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- 238000000034 method Methods 0.000 title claims 24
- 230000015572 biosynthetic process Effects 0.000 title claims 22
- 238000003786 synthesis reaction Methods 0.000 title claims 22
- 150000002148 esters Chemical class 0.000 title claims 9
- 230000002255 enzymatic effect Effects 0.000 title claims 5
- ACRHBAYQBXXRTO-OAQYLSRUSA-N ivabradine Chemical compound C1CC2=CC(OC)=C(OC)C=C2CC(=O)N1CCCN(C)C[C@H]1CC2=C1C=C(OC)C(OC)=C2 ACRHBAYQBXXRTO-OAQYLSRUSA-N 0.000 title claims 3
- 229960003825 ivabradine Drugs 0.000 title claims 3
- 150000003839 salts Chemical class 0.000 title claims 3
- IHPWCJZOCLQJPX-QMMMGPOBSA-N (7s)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylic acid Chemical compound C1=C(OC)C(OC)=CC2=C1[C@@H](C(O)=O)C2 IHPWCJZOCLQJPX-QMMMGPOBSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims 12
- 239000002253 acid Substances 0.000 claims 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims 6
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric Acid Chemical compound [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims 4
- 230000007071 enzymatic hydrolysis Effects 0.000 claims 4
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 claims 4
- 230000032050 esterification Effects 0.000 claims 4
- 238000005886 esterification reaction Methods 0.000 claims 4
- 238000001308 synthesis method Methods 0.000 claims 4
- 238000006243 chemical reaction Methods 0.000 claims 3
- 239000000203 mixture Substances 0.000 claims 3
- 238000006722 reduction reaction Methods 0.000 claims 3
- 238000006268 reductive amination reaction Methods 0.000 claims 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 2
- 102000004882 Lipase Human genes 0.000 claims 2
- 108090001060 Lipase Proteins 0.000 claims 2
- 239000004367 Lipase Substances 0.000 claims 2
- 241001661345 Moesziomyces antarcticus Species 0.000 claims 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims 2
- 241000589540 Pseudomonas fluorescens Species 0.000 claims 2
- 150000001408 amides Chemical class 0.000 claims 2
- 239000000872 buffer Substances 0.000 claims 2
- 239000007853 buffer solution Substances 0.000 claims 2
- 239000006184 cosolvent Substances 0.000 claims 2
- 235000019421 lipase Nutrition 0.000 claims 2
- 150000002825 nitriles Chemical class 0.000 claims 2
- 239000000047 product Substances 0.000 claims 2
- 239000011877 solvent mixture Substances 0.000 claims 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 2
- VDFVNEFVBPFDSB-UHFFFAOYSA-N 1,3-dioxane Chemical compound C1COCOC1 VDFVNEFVBPFDSB-UHFFFAOYSA-N 0.000 claims 1
- CZLMRJZAHXYRIX-UHFFFAOYSA-N 1,3-dioxepane Chemical group C1CCOCOC1 CZLMRJZAHXYRIX-UHFFFAOYSA-N 0.000 claims 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 claims 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- 229910010084 LiAlH4 Inorganic materials 0.000 claims 1
- 229910000085 borane Inorganic materials 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 239000007795 chemical reaction product Substances 0.000 claims 1
- 239000003638 chemical reducing agent Substances 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 claims 1
- 239000001257 hydrogen Substances 0.000 claims 1
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 238000011065 in-situ storage Methods 0.000 claims 1
- 229910052740 iodine Inorganic materials 0.000 claims 1
- 238000002955 isolation Methods 0.000 claims 1
- 239000012280 lithium aluminium hydride Substances 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 239000003960 organic solvent Substances 0.000 claims 1
- 230000006340 racemization Effects 0.000 claims 1
- 238000010517 secondary reaction Methods 0.000 claims 1
- 239000012279 sodium borohydride Substances 0.000 claims 1
- 229910000033 sodium borohydride Inorganic materials 0.000 claims 1
- 239000002904 solvent Substances 0.000 claims 1
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- C12P17/10—Nitrogen as only ring hetero atom
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Claims (24)
1. Postupak za sintezu optički čistog spoja, naznačen time, da je to spoj formule (Ia):
[image]
enantioselektivnom enzimskom esterifikacijom racemične ili optički nečiste kiseline formule (X):
[image]
s pomoću lipaze iz Candida antarctica ili Pseudomonas fluorescens,
u smjesi alkohola ROH, pri čemu R predstavlja linearnu ili razgrananu C1-C6alkilnu skupinu, i organsko kootapalo,
u koncentraciji od 5 do 500 g/L spoja formule (X) po litri smjese otapala,
pri omjeru E/S od 10/1 do 1/100,
pri temperaturi od 25°C do 40°C.
2. Postupak sinteze u skladu s patentnim zahtjevom 1, naznačen time, da je omjer E/S od 1/5 do 1/10.
3. Postupak sinteze u skladu s patentnim zahtjevom 1 ili patentnim zahtjevom 2, naznačen time, da je alkohol ROH metanol, a kootapalo je acetonitril.
4. Postupak sinteze u skladu s patentnim zahtjevom 3, naznačen time, da je omjer acetonitril/metanol od 8/2 do 9/1.
5. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 1 do 4, naznačen time, da se ester konfiguracije (R), sekundarni produkt reakcije:
[image]
hidrolizira djelovanjem baze, čime se dobije racemična kiselina formule (X) kako bi se reciklirao u enzimskom procesu esterifikacije.
6. Postupak sinteze u skladu s patentnim zahtjevom 5, naznačen time, da je baza KOH.
7. Postupak sinteze u skladu s patentnim zahtjevom 5 ili patentnim zahtjevom 6, naznačen time, da se korak hidrolize/racemizacije provodi in situ.
8. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 1 do 7, naznačen time, da se kiselina formule (Ia) izolira nakon jednog ili više ciklusa enzimske esterifikacije.
9. Postupak za sintezu optički čistog spoja, naznačen time, da je to spoj formule (Ib):
[image]
pri čemu R predstavlja ravnu ili razgrananu C1-C6alkilnu skupinu,
enantioselektivnom enzimskom hidrolizom racemičnog ili optički nečistog, estera formule (XI):
[image]
pri čemu R predstavlja ravnu ili razgrananu C1-C6alkilnu skupinu,
pomoću lipaze iz Candida antarctica ili Pseudomonas fluorescens, u vodi, u otopini pufera
pH = 5 do 8, ili u smjesi organskog otapala i vode ili otopine pufera pH = 5 do 8, u koncentraciji
od 1 do 200 g/L spoja formule (XI) po litri otapala ili mješavine otapala,
pri omjeru E/S od 10/1 do 1/100,
pri temperaturi od 25°C do 40°C,
nakon čega slijedi izolacija estera formule (Ib).
10. Postupak sinteze u skladu s patentnim zahtjevom 9, naznačen time, da je omjer E/S od 1/5 do 1/10.
11. Postupak sinteze u skladu s patentnim zahtjevom 9 ili zahtjevom 10, naznačen time, da je R metilna skupina.
12. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 9 do 11, naznačen time, da se reakcija provodi u smjesi acetonitrila i pufera pH = 7.
13. Postupak sinteze u skladu s patentnim zahtjevom 12, naznačen time, da je omjer acetonitril/pufer pH = 7 od 8/2 do 9/1.
14. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 9 do 13, naznačen time, da se kiselina konfiguracije (R):
[image]
sekundarni produkt reakcije,
racemizira djelovanjem baze, a zatim se na taj način dobivena racemična kiselina alkilira da se dobije racemični ester formule (XI) koji se potom reciklira u procesu enzimske hidrolize.
15. Postupak sinteze u skladu s patentnim zahtjevom 14, naznačen time, da se kiselina konfiguracije (R) racemizira djelovanjem vruće KOH.
16. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 9 do 13, naznačen time, da se kiselina konfiguracije (R), sekundarni produkt reakcije:
[image]
najprije alkilira, a zatim se tako dobiveni ester konfiguracije (R) racemizira djelovanjem baze, da bi se reciklirao u procesu enzimske hidrolize.
17. Postupak sinteze u skladu s patentnim zahtjevom 16, naznačen time, da se ester konfiguracije (R) racemizira djelovanjem DBU u vrućem stanju ili KOH na sobnoj temperaturi.
18. Postupak za sintezu spoja, naznačen time, da je to spoj formule (III):
[image]
počevši od nitrila formule (IV):
[image]
koji se hidrolizira da se dobije racemična kiselina formule (X):
[image]
enzimska esterifikacija koja je u skladu s bilo kojim od patentnih zahtjeva 1 do 8, daje optički čistu kiselinu formule (Ia):
[image]
koja se zatim prevodi u optički čisti amid formule (XII):
[image]
čijom se redukcijom dobije spoj formule (III).
19. Postupak za sintezu spoja, naznačen time, da je to spoj formule (III):
[image]
počevši od nitrila formule (IV):
[image]
koji se hidrolizira da se dobije racemična kiselina formule (X):
[image]
i zatim alkilira kako bi se dobio racemični ester formule (XI):
[image]
pri čemu R predstavlja ravnu ili razgrananu C1-C6alkilnu skupinu,
čija enzimska hidroliza u skladu s bilo kojim od patentnih zahtjeva 9 do 17 daje optički čisti ester formule (Ib):
[image]
pri čemu R predstavlja ravnu ili razgrananu alkilnu skupinu C1-C6, koji se prevodi u optički čisti amid formule (XII):
[image]
čijom se redukcijom dobije spoj formule (III).
20. Postupak sinteze u skladu s patentnim zahtjevom 18 ili patentnim zahtjevom 19, naznačen time, da se redukcija spoja formule (XII) kako bi se dobio spoj formule (III) provodi s BH3, NaBH4 ili LiAlH4.
21. Postupak sinteze u skladu s bilo kojim od patentnih zahtjeva 18 do 20, naznačen time, da se spoj formule (III) zatim spaja ili sa spojem formule (XIII):
[image]
pri čemu X predstavlja atom halogena,
ili se može podvrgnuti reakciji reduktivne aminacije sa spojem formule (XIV) u prisutnosti redukcijskog sredstva:
[image]
pri čemu R2 predstavlja skupinu odabranu iz CHO i CHR3R4,
pri čemu R3 i R4 svaki predstavlja ravnu ili razgrananu C1-C6alkilnu skupinu, ili tvore, zajedno s ugljikovim atomom koji ih nosi, 1,3-dioksanski, 1,3-dioksolanski ili 1,3-dioksepanski prsten, kako bi se dobio ivabradin, koji se zatim pretvara u adicijske soli s farmaceutski prihvatljivom kiselinom, a navedena sol je u bezvodnom ili hidratnom obliku.
22. Postupak sinteze u skladu s patentnim zahtjevom 21, naznačen time, da je X atom joda.
23. Postupak sinteze u skladu s patentnim zahtjevom 21, naznačen time, da se spoj formule (III) koristi u reakciji reduktivne aminacije u obliku njegovog hidroklorida da se dobije ivabradin u obliku hidroklorida.
24. Postupak sinteze u skladu s patentnim zahtjevom 21 ili patentnim zahtjevom 23, naznačen time, da se reakcija reduktivne aminacije sa spojem formule (XIV) izvodi u prisutnosti vodika kataliziranog s paladijem na ugljiku.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR1251195A FR2986804A1 (fr) | 2012-02-09 | 2012-02-09 | Procede de synthese enzymatique de l'acide (7s) 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene 7-carboxylique ou de ses esters, et application a la synthese de l'ivabradine et de ses sels |
EP13154505.5A EP2626428B1 (fr) | 2012-02-09 | 2013-02-08 | Procédé de synthèse enzymatique de l'acide (7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene-7-carboxylique ou de ses esters, et application à la synthèse de l'ivabradine et de ses sels |
Publications (1)
Publication Number | Publication Date |
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HRP20150872T1 true HRP20150872T1 (hr) | 2015-09-25 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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HRP20150872TT HRP20150872T1 (hr) | 2012-02-09 | 2015-08-17 | Postupak za enzimsku sintezu (7s)-3,4-dimetoksibiciklo [4.2.0] okta-1,3,5-trien-7-karboksilne kiseline ili njezinih estera i primjena u sintezi ivabradina i njegovih soli |
Country Status (31)
Country | Link |
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US (1) | US9506095B2 (hr) |
EP (1) | EP2626428B1 (hr) |
JP (1) | JP5764151B2 (hr) |
KR (1) | KR101463787B1 (hr) |
CN (1) | CN103243146A (hr) |
AR (1) | AR089927A1 (hr) |
AU (2) | AU2013200482A1 (hr) |
BR (1) | BR102013003214A2 (hr) |
CA (1) | CA2805831C (hr) |
CY (1) | CY1116477T1 (hr) |
DK (1) | DK2626428T3 (hr) |
EA (1) | EA024316B1 (hr) |
ES (1) | ES2546102T3 (hr) |
FR (1) | FR2986804A1 (hr) |
GE (1) | GEP20156235B (hr) |
HR (1) | HRP20150872T1 (hr) |
HU (1) | HUE026805T2 (hr) |
JO (1) | JO3054B1 (hr) |
MA (1) | MA34503B1 (hr) |
MD (1) | MD4467C1 (hr) |
MX (1) | MX341712B (hr) |
PL (1) | PL2626428T3 (hr) |
PT (1) | PT2626428E (hr) |
RS (1) | RS54076B1 (hr) |
SA (1) | SA113340275B1 (hr) |
SG (1) | SG193081A1 (hr) |
SI (1) | SI2626428T1 (hr) |
TW (1) | TWI467019B (hr) |
UA (1) | UA115765C2 (hr) |
UY (1) | UY34611A (hr) |
WO (1) | WO2013117869A2 (hr) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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FR2986804A1 (fr) * | 2012-02-09 | 2013-08-16 | Servier Lab | Procede de synthese enzymatique de l'acide (7s) 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene 7-carboxylique ou de ses esters, et application a la synthese de l'ivabradine et de ses sels |
EP3101010A1 (en) | 2015-06-03 | 2016-12-07 | Urquima S.A. | New method for the preparation of highly pure ivabradine base and salts thereof |
CN113387791B (zh) * | 2021-03-05 | 2022-08-02 | 株洲壹诺生物技术有限公司 | 一种盐酸伊伐布雷定关键中间体的合成方法 |
Family Cites Families (18)
Publication number | Priority date | Publication date | Assignee | Title |
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US4983758A (en) * | 1987-12-03 | 1991-01-08 | Sumitomo Chemical Company, Limited | Process for producing an optically active α-isopropyl-p-chlorophenylacetic acid |
US5089637A (en) * | 1990-03-21 | 1992-02-18 | Pfizer Inc. | Process and intermediates for 2r-benzyl-chroman-6-carbaldehyde |
FR2681862B1 (fr) * | 1991-09-27 | 1993-11-12 | Adir Cie | Nouvelles (benzocycloalkyl)alkylamines, leur procede de preparation, et les compositions pharmaceutiques qui les contiennent. |
CA2132411A1 (en) * | 1994-09-19 | 1996-03-20 | Michael Trani | Enzymatic esterification of long-chain racemic acids and alcohols |
NZ336376A (en) * | 1996-12-27 | 2000-11-24 | Smithkline Beecham P | Enzymatic resolution of benzodiazepine-acetic acid esters (3-oxo-2,3,4,5-1H-tetrahydro-1,4-benzodiazepine-2-acetic acid) with a lipase from Candida Antarctica |
JP2003517266A (ja) * | 1998-02-17 | 2003-05-27 | ジー・ディー・サール・アンド・カンパニー | ラクタムの酵素分割方法 |
EP1634958B1 (en) * | 2003-06-04 | 2009-02-18 | Mitsubishi Gas Chemical Company, Inc. | Method for producing optically active chroman-carboxylate |
GB0314260D0 (en) * | 2003-06-19 | 2003-07-23 | Astrazeneca Ab | Therapeutic agents |
FR2868777B1 (fr) * | 2004-04-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
FR2870537A1 (fr) * | 2004-05-19 | 2005-11-25 | Servier Lab | Nouveau procede de synthese du (1s)-4,5-dimethoxy-1-(methyl aminomethyl-)-benzocyclobutane et de ses sels d'addition, et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable |
GB0607911D0 (en) * | 2006-04-21 | 2006-05-31 | Ineos Fluor Holdings Ltd | Process |
JP5056758B2 (ja) * | 2006-08-23 | 2012-10-24 | 日本電気株式会社 | 移動体通信システム、無線ネットワーク制御装置、携帯電話機及びそれらに用いるセル在圏表示方法 |
CN101434552B (zh) * | 2007-11-16 | 2012-05-23 | 江苏恒瑞医药股份有限公司 | 4,5-二甲氧基-1-(甲基氨基甲基)-苯并环丁烷的拆分 |
FR2933975B1 (fr) | 2008-07-17 | 2011-02-18 | Servier Lab | Nouveau procede de preparation de benzocyclobutenes fonctionnalises,et application a la synthese de l'ivabradine et de ses sels d'addition a un acide pharmaceutiquement acceptable. |
FR2935381B1 (fr) * | 2008-08-29 | 2010-12-17 | Servier Lab | Nouveau procede de resolution des enantiomerees du (3,4-dimethoxy-bicyclo°4.2.0!octa-1,3,5-trien-7-yl)nitrile et application a la synthese de l'ivabradine |
CN102203047B (zh) * | 2008-10-29 | 2013-12-11 | 三菱瓦斯化学株式会社 | 光学活性有机羧酸的制造方法 |
HUP1000245A2 (en) * | 2010-05-07 | 2011-11-28 | Richter Gedeon Nyrt | Industrial process for the production ivabradin salts |
FR2986804A1 (fr) * | 2012-02-09 | 2013-08-16 | Servier Lab | Procede de synthese enzymatique de l'acide (7s) 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-triene 7-carboxylique ou de ses esters, et application a la synthese de l'ivabradine et de ses sels |
-
2012
- 2012-02-09 FR FR1251195A patent/FR2986804A1/fr not_active Withdrawn
-
2013
- 2013-01-27 JO JOP/2013/0030A patent/JO3054B1/ar active
- 2013-01-30 AU AU2013200482A patent/AU2013200482A1/en not_active Abandoned
- 2013-01-30 SG SG2013007331A patent/SG193081A1/en unknown
- 2013-02-01 UY UY0001034611A patent/UY34611A/es unknown
- 2013-02-05 US US13/759,382 patent/US9506095B2/en not_active Expired - Fee Related
- 2013-02-06 MX MX2013001458A patent/MX341712B/es active IP Right Grant
- 2013-02-06 UA UAA201301422A patent/UA115765C2/uk unknown
- 2013-02-06 JP JP2013021114A patent/JP5764151B2/ja active Active
- 2013-02-06 SA SA113340275A patent/SA113340275B1/ar unknown
- 2013-02-07 CA CA2805831A patent/CA2805831C/fr not_active Expired - Fee Related
- 2013-02-07 CN CN2013100492641A patent/CN103243146A/zh active Pending
- 2013-02-07 GE GEAP201312992A patent/GEP20156235B/en unknown
- 2013-02-07 KR KR1020130014061A patent/KR101463787B1/ko active IP Right Grant
- 2013-02-07 AR ARP130100377A patent/AR089927A1/es unknown
- 2013-02-07 MD MDA20130008A patent/MD4467C1/ro not_active IP Right Cessation
- 2013-02-07 AU AU2013200646A patent/AU2013200646B2/en not_active Ceased
- 2013-02-08 SI SI201330060T patent/SI2626428T1/sl unknown
- 2013-02-08 MA MA35650A patent/MA34503B1/fr unknown
- 2013-02-08 EA EA201300100A patent/EA024316B1/ru not_active IP Right Cessation
- 2013-02-08 TW TW102105037A patent/TWI467019B/zh not_active IP Right Cessation
- 2013-02-08 EP EP13154505.5A patent/EP2626428B1/fr active Active
- 2013-02-08 DK DK13154505.5T patent/DK2626428T3/en active
- 2013-02-08 WO PCT/FR2013/050265 patent/WO2013117869A2/fr active Application Filing
- 2013-02-08 RS RS20150434A patent/RS54076B1/en unknown
- 2013-02-08 ES ES13154505.5T patent/ES2546102T3/es active Active
- 2013-02-08 PT PT131545055T patent/PT2626428E/pt unknown
- 2013-02-08 BR BR102013003214A patent/BR102013003214A2/pt not_active Application Discontinuation
- 2013-02-08 PL PL13154505T patent/PL2626428T3/pl unknown
- 2013-02-08 HU HUE13154505A patent/HUE026805T2/en unknown
-
2015
- 2015-07-10 CY CY20151100602T patent/CY1116477T1/el unknown
- 2015-08-17 HR HRP20150872TT patent/HRP20150872T1/hr unknown
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