CA2758047C - Hepatitis c virus inhibitors - Google Patents
Hepatitis c virus inhibitors Download PDFInfo
- Publication number
- CA2758047C CA2758047C CA2758047A CA2758047A CA2758047C CA 2758047 C CA2758047 C CA 2758047C CA 2758047 A CA2758047 A CA 2758047A CA 2758047 A CA2758047 A CA 2758047A CA 2758047 C CA2758047 C CA 2758047C
- Authority
- CA
- Canada
- Prior art keywords
- alkyl
- cap
- imidazol
- hydrogen
- methyl
- 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 - Fee Related
Links
- 241000711549 Hepacivirus C Species 0.000 title abstract description 56
- 239000003112 inhibitor Substances 0.000 title description 40
- 239000000203 mixture Substances 0.000 claims abstract description 202
- 150000001875 compounds Chemical class 0.000 claims abstract description 187
- 125000000217 alkyl group Chemical group 0.000 claims description 190
- 229910052739 hydrogen Inorganic materials 0.000 claims description 176
- 239000001257 hydrogen Substances 0.000 claims description 135
- 150000003839 salts Chemical class 0.000 claims description 98
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 87
- 125000003118 aryl group Chemical group 0.000 claims description 82
- 150000002431 hydrogen Chemical group 0.000 claims description 74
- -1 -NR a R b Chemical group 0.000 claims description 72
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 69
- 125000001424 substituent group Chemical group 0.000 claims description 62
- 125000000623 heterocyclic group Chemical group 0.000 claims description 58
- 125000001072 heteroaryl group Chemical group 0.000 claims description 55
- 125000001188 haloalkyl group Chemical group 0.000 claims description 49
- 229910052736 halogen Inorganic materials 0.000 claims description 49
- 150000002367 halogens Chemical class 0.000 claims description 48
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- 229910052757 nitrogen Inorganic materials 0.000 claims description 43
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 40
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 36
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 36
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 36
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 31
- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 125000002619 bicyclic group Chemical group 0.000 claims description 27
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 26
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 22
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 21
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 21
- 229910052760 oxygen Inorganic materials 0.000 claims description 19
- 239000001301 oxygen Substances 0.000 claims description 19
- 229910052717 sulfur Chemical group 0.000 claims description 19
- 229910052727 yttrium Inorganic materials 0.000 claims description 19
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 18
- 125000003342 alkenyl group Chemical group 0.000 claims description 17
- 125000005842 heteroatom Chemical group 0.000 claims description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 16
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 15
- 239000011593 sulfur Chemical group 0.000 claims description 15
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 14
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 13
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 12
- 239000003937 drug carrier Substances 0.000 claims description 9
- 208000015181 infectious disease Diseases 0.000 claims description 8
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 7
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 4
- 125000004043 oxo group Chemical group O=* 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 4
- UMPWFNPLHSVRAN-UHFFFAOYSA-N 2-(diethylamino)-2-phenylacetaldehyde Chemical compound CCN(CC)C(C=O)C1=CC=CC=C1 UMPWFNPLHSVRAN-UHFFFAOYSA-N 0.000 claims 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 89
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 13
- 101800001014 Non-structural protein 5A Proteins 0.000 abstract description 10
- 201000010099 disease Diseases 0.000 abstract description 8
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 239000003443 antiviral agent Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 291
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 269
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 220
- 229910001868 water Inorganic materials 0.000 description 208
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 197
- 239000000243 solution Substances 0.000 description 153
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 114
- 238000005160 1H NMR spectroscopy Methods 0.000 description 108
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 104
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 90
- 239000007787 solid Substances 0.000 description 89
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 86
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 85
- 239000002904 solvent Substances 0.000 description 80
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 78
- 229940093499 ethyl acetate Drugs 0.000 description 74
- 235000019439 ethyl acetate Nutrition 0.000 description 73
- 239000011541 reaction mixture Substances 0.000 description 67
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 60
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 55
- 239000003921 oil Substances 0.000 description 55
- 238000005481 NMR spectroscopy Methods 0.000 description 54
- 235000019198 oils Nutrition 0.000 description 54
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
- 239000012267 brine Substances 0.000 description 44
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 44
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 43
- 235000019341 magnesium sulphate Nutrition 0.000 description 43
- 238000006243 chemical reaction Methods 0.000 description 42
- 239000012044 organic layer Substances 0.000 description 40
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 39
- 238000003756 stirring Methods 0.000 description 39
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 36
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 35
- 230000000840 anti-viral effect Effects 0.000 description 35
- 238000000746 purification Methods 0.000 description 35
- 101150041968 CDC13 gene Proteins 0.000 description 33
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 33
- 239000000741 silica gel Substances 0.000 description 33
- 229910002027 silica gel Inorganic materials 0.000 description 33
- 239000000725 suspension Substances 0.000 description 32
- 229910003827 NRaRb Inorganic materials 0.000 description 28
- 239000000047 product Substances 0.000 description 26
- 239000012453 solvate Substances 0.000 description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- 239000013058 crude material Substances 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 24
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- 238000003818 flash chromatography Methods 0.000 description 23
- 238000003786 synthesis reaction Methods 0.000 description 23
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 22
- 239000000706 filtrate Substances 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 21
- 239000007832 Na2SO4 Substances 0.000 description 21
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 21
- 229910052938 sodium sulfate Inorganic materials 0.000 description 21
- 235000011152 sodium sulphate Nutrition 0.000 description 21
- 239000012043 crude product Substances 0.000 description 20
- 229940079322 interferon Drugs 0.000 description 20
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 19
- 239000002253 acid Substances 0.000 description 19
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 19
- 239000000463 material Substances 0.000 description 19
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- 108010050904 Interferons Proteins 0.000 description 18
- 102000014150 Interferons Human genes 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 229910052799 carbon Inorganic materials 0.000 description 18
- 239000010410 layer Substances 0.000 description 17
- 239000012071 phase Substances 0.000 description 17
- 230000002829 reductive effect Effects 0.000 description 17
- 229910052701 rubidium Inorganic materials 0.000 description 17
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 16
- 239000005909 Kieselgur Substances 0.000 description 16
- 101800001554 RNA-directed RNA polymerase Proteins 0.000 description 16
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 14
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- IWUCXVSUMQZMFG-AFCXAGJDSA-N Ribavirin Chemical compound N1=C(C(=O)N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 IWUCXVSUMQZMFG-AFCXAGJDSA-N 0.000 description 14
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Classifications
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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| PCT/US2010/028999 WO2010117704A1 (en) | 2009-03-30 | 2010-03-29 | Hepatitis c virus inhibitors |
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| CA2758047A1 CA2758047A1 (en) | 2010-10-14 |
| CA2758047C true CA2758047C (en) | 2016-05-17 |
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| CN102264737A (zh) * | 2008-12-23 | 2011-11-30 | 雅培制药有限公司 | 抗病毒化合物 |
| RU2505539C2 (ru) | 2008-12-23 | 2014-01-27 | Эбботт Лэборетриз | Антивирусные соединения |
| US8314135B2 (en) | 2009-02-09 | 2012-11-20 | Enanta Pharmaceuticals, Inc. | Linked dibenzimidazole antivirals |
| US8188132B2 (en) | 2009-02-17 | 2012-05-29 | Enanta Pharmaceuticals, Inc. | Linked dibenzimidazole derivatives |
| US8394968B2 (en) | 2009-02-17 | 2013-03-12 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| TWI438200B (zh) * | 2009-02-17 | 2014-05-21 | 必治妥美雅史谷比公司 | Ｃ型肝炎病毒抑制劑 |
| US8242156B2 (en) | 2009-02-17 | 2012-08-14 | Enanta Pharmaceuticals, Inc. | Linked dibenzimidazole derivatives |
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| TW201038559A (en) | 2009-04-09 | 2010-11-01 | Bristol Myers Squibb Co | Hepatitis C virus inhibitors |
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| EP2853531A3 (en) * | 2009-06-11 | 2015-08-12 | AbbVie Bahamas Ltd. | Antiviral compounds |
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| HRP20180237T4 (hr) | 2011-09-16 | 2020-12-11 | Gilead Pharmasset Llc | Metode za liječenje hcv-a |
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| EA201690473A1 (ru) | 2013-08-27 | 2017-03-31 | ГАЙЛИД ФАРМАССЕТ ЭлЭлСи | Комбинированный состав двух противовирусных соединений |
| WO2015103490A1 (en) | 2014-01-03 | 2015-07-09 | Abbvie, Inc. | Solid antiviral dosage forms |
| US10617675B2 (en) | 2015-08-06 | 2020-04-14 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| JP2019510000A (ja) * | 2016-02-26 | 2019-04-11 | ジエンス ヘンルイ メデイシンカンパニー リミテッドＪｉａｎｇｓｕ Ｈｅｎｇｒｕｉ Ｍｅｄｉｃｉｎｅ Ｃｏ．，Ｌｔｄ． | 新規トキシン及びその中間体の製造方法 |
| CN107987083A (zh) * | 2017-11-24 | 2018-05-04 | 江苏亚盛医药开发有限公司 | 用于治疗和/或预防与肝炎病毒相关的疾病或病症的双二氮杂双环化合物 |
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| GB2438802A (en) * | 2005-02-28 | 2007-12-05 | Univ Rockefeller | Structure of the hepatitis C virus NS5A protein |
| US20100158862A1 (en) * | 2006-08-11 | 2010-06-24 | Bristol-Myers Squibb Company | Hepatitis C Virus Inhibitors |
| US7759495B2 (en) * | 2006-08-11 | 2010-07-20 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US8329159B2 (en) * | 2006-08-11 | 2012-12-11 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| US7659270B2 (en) * | 2006-08-11 | 2010-02-09 | Bristol-Myers Squibb Company | Hepatitis C virus inhibitors |
| WO2010065668A1 (en) * | 2008-12-03 | 2010-06-10 | Presidio Pharmaceuticals, Inc. | Inhibitors of hcv ns5a |
| EP2853531A3 (en) * | 2009-06-11 | 2015-08-12 | AbbVie Bahamas Ltd. | Antiviral compounds |
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2010
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- 2010-03-25 US US12/731,935 patent/US20100249190A1/en not_active Abandoned
- 2010-03-29 KR KR1020117025610A patent/KR20110134497A/ko not_active Ceased
- 2010-03-29 JP JP2012503544A patent/JP5612661B2/ja not_active Expired - Fee Related
- 2010-03-29 CN CN201080015321.9A patent/CN102378762B/zh not_active Expired - Fee Related
- 2010-03-29 EA EA201101240A patent/EA021260B1/ru not_active IP Right Cessation
- 2010-03-29 ES ES10714721.7T patent/ES2524542T3/es active Active
- 2010-03-29 PE PE2011001733A patent/PE20120517A1/es not_active Application Discontinuation
- 2010-03-29 AU AU2010234861A patent/AU2010234861A1/en not_active Abandoned
- 2010-03-29 NZ NZ594981A patent/NZ594981A/xx not_active IP Right Cessation
- 2010-03-29 BR BRPI1014084A patent/BRPI1014084A2/pt not_active IP Right Cessation
- 2010-03-29 CA CA2758047A patent/CA2758047C/en not_active Expired - Fee Related
- 2010-03-29 WO PCT/US2010/028999 patent/WO2010117704A1/en not_active Ceased
- 2010-03-29 MX MX2011009644A patent/MX2011009644A/es active IP Right Grant
- 2010-03-29 EP EP10714721.7A patent/EP2414352B1/en not_active Not-in-force
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2011
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- 2011-09-27 CO CO11126484A patent/CO6361922A2/es active IP Right Grant
- 2011-09-30 CL CL2011002453A patent/CL2011002453A1/es unknown
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2012
- 2012-07-13 US US13/548,298 patent/US8822444B2/en active Active
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|---|---|
| TW201038555A (en) | 2010-11-01 |
| PE20120517A1 (es) | 2012-05-09 |
| IL214939A0 (en) | 2011-11-30 |
| AU2010234861A1 (en) | 2011-09-22 |
| AR076170A1 (es) | 2011-05-26 |
| JP2012522056A (ja) | 2012-09-20 |
| JP5612661B2 (ja) | 2014-10-22 |
| WO2010117704A1 (en) | 2010-10-14 |
| MX2011009644A (es) | 2011-09-28 |
| US20120277266A1 (en) | 2012-11-01 |
| EA021260B1 (ru) | 2015-05-29 |
| CA2758047A1 (en) | 2010-10-14 |
| KR20110134497A (ko) | 2011-12-14 |
| EP2414352A1 (en) | 2012-02-08 |
| CN102378762B (zh) | 2014-10-29 |
| CN102378762A (zh) | 2012-03-14 |
| BRPI1014084A2 (pt) | 2016-04-19 |
| US8822444B2 (en) | 2014-09-02 |
| CL2011002453A1 (es) | 2012-03-02 |
| EP2414352B1 (en) | 2014-10-01 |
| EA201101240A1 (ru) | 2012-05-30 |
| TWI476190B (zh) | 2015-03-11 |
| ZA201106669B (en) | 2013-02-27 |
| NZ594981A (en) | 2013-05-31 |
| ES2524542T3 (es) | 2014-12-10 |
| US20100249190A1 (en) | 2010-09-30 |
| CO6361922A2 (es) | 2012-01-20 |
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