US20120022091A1 - Key intermediates for the synthesis of rosuvastatin or pharmaceutically acceptable salts thereof - Google Patents

Key intermediates for the synthesis of rosuvastatin or pharmaceutically acceptable salts thereof Download PDF

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US20120022091A1
US20120022091A1 US13/145,783 US201013145783A US2012022091A1 US 20120022091 A1 US20120022091 A1 US 20120022091A1 US 201013145783 A US201013145783 A US 201013145783A US 2012022091 A1 US2012022091 A1 US 2012022091A1
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compound
formula
rosuvastatin
process according
pharmaceutically acceptable
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Zdenko Casar
Janez Kosmrlj
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Lek Pharmaceuticals dd
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Lek Pharmaceuticals dd
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Assigned to LEK PHARMACEUTICALS D.D. reassignment LEK PHARMACEUTICALS D.D. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CASAR, ZDENKO, KOSMRLJ, JANEZ
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/535—Organo-phosphoranes
    • 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
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds

Definitions

  • the present invention relates to a process for the preparation of N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide, N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide and N-(4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-methylmethanesulfonamide, useful as key intermediates for the preparation of Rosuvastatin or pharmaceutically acceptable salts thereof.
  • the present invention further relates to a process wherein the above mentioned compounds are used as intermediates.
  • HMG-CoA reductase inhibitors are commonly referred to as “statins.”
  • Statins are therapeutically effective drugs used for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. Therefore, Rosuvastatin calcium is used in the treatment of hypercholesterolemia and mixed dyslipidemia.
  • LDL low density lipoprotein
  • the EP 521471 A1 discloses Rosuvastatin and a process for its preparation, among others by a process comprising a step of preparing N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide by reduction of a suitable ester derivative thereof with diisobutylaluminium hydride (DIBAL-H) as a reduction reagent.
  • DIBAL-H diisobutylaluminium hydride
  • the object of the present invention is to provide an improved process for preparing N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide, N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide and N-(4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-methylmethanesulfonamide, so as to provide valuable intermediates for the preparation of Rosuvastatin and pharmaceutically acceptable salts thereof.
  • N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide and N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide respectively can be carried out by selecting suitable starting materials which can be converted to the desired product without the necessity of aggressive, difficult to handle and/or expensive reagents.
  • DIBAL-H diisobutylaluminium hydride
  • the reduction must be carried out at temperatures around or below 0° C. (preferably up to ⁇ 70° C.) under dry/anhydrous conditions.
  • DIBAL-His an expensive and hazardous reagent.
  • the reduction is carried out with KBH 4 /ZnCl 2 as the reducing agent, which also requires dry/anhydrous conditions.
  • KBH 4 /ZnCl 2 as the reducing agent, which also requires dry/anhydrous conditions.
  • there is the problem of unreacted starting material and generation of byproducts which are hardly removed in the subsequent Rosuvastatin synthesis steps if dry/anhydrous conditions are not employed and reaction does't go to completion.
  • Said nucleophilic substitution reaction has significant drawbacks, inter alia since HBr is a very corrosive and aggressive reagent, and the alternative reactant PBr 3 is toxic, evolves corrosive HBr, and reacts violently with water and alcohols which makes it difficult to handle.
  • nucleophilic substitution reaction for introduction of bromine with HBr or PBr 3 is not used but the compound of formula II is prepared by converting a compound of formula I by bromination into the compound of formula II as presented on the following scheme:
  • compound II N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide
  • the reaction can be carried out most efficiently by radical bromination reaction, optionally assisted by UV irridation and/or use of radical formers.
  • bromination notably when proceeding with radical reaction, significantly differs from the introduction of bromine by means of a nucleophilic substitution reaction (e.g. wherein compound of the formula III is converted into compound of the formula II).
  • a nucleophilic substitution reaction requires a leaving group such as for example —OH of the compound of the formula III.
  • the compound of the formula I does not require such a leaving group.
  • N-bromoamides provide for a constant, low concentration of bromine in the reaction mixture during reaction.
  • said N-bromoamides are selected from the group consisting of N-bromoacetamide, N,N-dibromobenzene sulfonamides; the N-bromoimides, such as N-bromosuccinimide, N-bromophthalimide, N-bromoglutarimide, 3-bromo-hydantoin, and 1,3-dibromo-5,5-dimethylhydantoin.
  • N-bromosuccinimide is the most preferred brominating agent, since it is readily commercially availably and economically priced.
  • the aforementioned bromination agents provide for mild reaction conditions resulting in less byproducts. HBr and PBr 3 , which are aggressive and difficult to handle reactants which would negatively affect purity and yield of the compound of formula II, can be avoided.
  • the initial amount of said brominating agents is from about 0.1 to about 3 times the molar stoichiometric amount based on compound I, preferably about 0.9 to about 2.5 times, more preferably about 1.4 to about 2.2 times, and in particular about 2 times. In this way, efficient bromination resulting in high yields of compound II is provided, while economical amounts of brominating agent are used.
  • the above mentioned bromination reaction is suitably performed in organic solvent, preferably selected from the group consisting of acetone, ethyl acetate, hydrocarbons, aromatic hydrocarbons and acetonitrile. Most preferably, acetonitrile is used as organic solvent.
  • organic solvent preferably selected from the group consisting of acetone, ethyl acetate, hydrocarbons, aromatic hydrocarbons and acetonitrile. Most preferably, acetonitrile is used as organic solvent.
  • organic solvents provide for suitable solubilisation of the reactants and advantageous reaction rates. Furthermore, these organic solvents are largely less toxic than carbon tetrachloride or chlorobenzene, which have been typically used in radical bromination of hydrocarbon side chains of aromatic substrates.
  • the step of reacting a compound of formula I with brominating agent to give the compound of formula II is performed under a treatment of ultraviolet radiation, wherein said ultraviolet radiation has preferably a wavelength of about 200 to 400 nm, more preferably about 310 nm. Said ultraviolet radiation is preferably performed for 2 to 10 hours, more preferably for about 4 hours.
  • the bromination reaction is carried out at suitable temperature, preferably at a temperature between 0 to 90° C., more preferably between 10 to 65° C., even more preferably between 15 to 35° C. and in particular at an ambient temperature between 19 to 25° C.
  • suitable temperature preferably at a temperature between 0 to 90° C., more preferably between 10 to 65° C., even more preferably between 15 to 35° C. and in particular at an ambient temperature between 19 to 25° C.
  • radical bromination proceeds within relatively short reaction times and high yields, even if no radical former is applied.
  • the absence of a radical former is advantageous, since the reaction becomes more safe in view of operational safety, because radical formers are quite reactive and therefore dangerous to handle compounds. Furthermore, the costs for a radical former can be saved. Therefore, it is preferred to perform the bromination without a radical former. In addition, significantly less impurities are formed during the reaction if no radical former is used.
  • a radical former may be applied.
  • the radical former is preferably an organic peroxide, an organic peracid, an organic hydroperoxide or an organic azo compound. These radical performers are suitable for accelerating/supporting radical reactions. More preferably, the radical former is selected from benzoyl peroxide or azoisobutyronitrile, since these radical performers are readily commercially available and inexpensive.
  • the initial amount of radical former is between about 0 to 0.5 molar stoichiometric amount based on compound I, preferably about 0 to 0.07 molar stoichiometric amount based on compound I, and more preferably no radical former is applied.
  • the aforementioned amounts of radical former provide for an advantageous acceleration of the reaction, while still providing a stable and safe reaction.
  • the compound of formula II is isolated and purified, preferably by crystallization.
  • a simple and effective purification method is applied, compared to labor, time and material intensive column chromatography. Since the bromination reaction is performed under mild conditions, there are less byproducts, and therefore, crystallisation will be sufficient in order to provide an advantageously pure product. Furthermore, it was found by that crystallisation performed with an MTBE/hexane mixture, and in particular with an MTBE/hexane mixture wherein the volume ratio of MTBE to hexane is 2 to 1, preferably 1 to 1 and more preferably 2 to 3 is particularly advantageous.
  • the compound of formula I can be obtained by a targeted synthesis. Or, according to a preferred embodiment, the compound of formula I is obtained as a side product in the preparation of rosuvastatin intermediates where the compound of formula I is formed in a Wittig reaction between a phosphonium salt, phosphine oxide or phosphonate (compound of formula X) of a corresponding rosuvastatin heterocycle—or their converted reagents in the corresponding ylide or phosphorane form (for phosphonium salt) or corresponding carbanion (for phosphine oxide or phosphonate) (compound of formula X′)—and a chiral statin side chain.
  • Z in the compound of formula X and X′ is selected from the group consisting of phosphonium salt moiety, phosphine oxide moiety or phosphonate moiety:
  • Rx, Ry, Rz are the same or different and are selected from optionally substituted C 1 -C 8 alkyl or C 3 -C 6 cycloalkyl or C 1 -C 8 alkenyl or C 5 -C 6 cycloalkenyl or aryl, preferably phenyl, and X ⁇ is an anion, preferably a halogen or carboxylate anion, more preferably chloride, bromide or trifluoroacetate;
  • P 1 and P 2 independently denote conventional hydroxyl protecting groups.
  • the protecting group P 1 and P 2 may be any conventionally used protecting group for hydroxyl groups, for example selected independently from the group consisting of alkyl, branched alkyl, acyl, silyl or similar group, more particularly selected from acetonide, acetyl (Ac), pivaloyl (Piv), p-toluenesulfonyl (TOS), ⁇ -methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), p-methoxybenzyl ether (PMB), methylthiomethyl ether, t-butyl, tetrahydropyranyl (THP), benzyl (Bn), diphenylmethyl or triphenylmethyl group, preferably silyl protecting group which can be represented by a formula SiR 1 ′R 2 ′R 3 ′ in which R 1 ′, R 2 ′, R 3 ′ are
  • the protected final rosuvastatin intermediate can be used to proceed with the final synthesis steps for obtaining rosuvastatin or its salts, while alternatively or in addition the compound of formula I can be utilized by being recycled into another (same or different) rosuvastatin synthesis route.
  • reaction products obtained in the Wittig reaction can be respectively separated by appropriate and known methods into the compound of formula I and the compound selected from formulas XI or XI′.
  • the compound of formula I is more substantially formed when the Wittig reaction is performed with excess of the phosphonium salt (or its ylide or phosphorane), phosphine oxide (or its carbanion) or phosphonate (or its carbanion) Wittig reagent (e.g. a molar excess of compound X or X′ over compound IX or IX′ of suitably 5% or more, preferably 10% or more, and particularly 15% or more), more effectively after quenching with protic solvent, and/or when the Wittig reaction is performed in the presence of water or other protic molecules such as alcohols (e.g.
  • the starting compound of formula IX can obtained from its hydrate form in an appropriate solvent but without removal of the released water molecules, as shown in the following reaction scheme,
  • THF tetrahydrofuran
  • the compound of formula II can be directly transformed to phosphonium salt derivative, phosphine oxide or phosphonate (see e.g. US2005/0124639).
  • the compound of formula I can be transformed to the compound of formula III, which can be converted to phosphonium salt derivative, phosphine oxide or phosphonate (see e.g. WO2007/017117).
  • the compound of formula II can be prepared by prior art processes (see e.g. WO2007/017117), this process cannot be applied for the recovery of compound I to phosphonium salt derivative, phosphine oxide or phosphonate.
  • prior-art processes for the preparation of compound III as disclosed in the EP521471 cannot be used for recovery of the compound of formula I to phosphonium salt derivative, phosphine oxide or phosphonate.
  • a compound of formula III is prepared by a process comprising the step of converting a compound of formula II by hydrolysis into the compound of formula III, as depicted in the following scheme:
  • the above mentioned conversion is performed in the presence of an inorganic base, preferably an alkaline or alkaline earth carbonate or hydrogencarbonate, more preferably NaHCO 3 is used as the inorganic base.
  • an inorganic base preferably an alkaline or alkaline earth carbonate or hydrogencarbonate, more preferably NaHCO 3 is used as the inorganic base.
  • the initial amount of inorganic base is between about 1 to 10 times the molar stoichiometric amount based on compound II, preferably about 3 to 7 times and more preferably 5 to 6 times.
  • the compound of formula III is prepared by a one-pot synthesis converting compound of formula I via non-isolated compound of formula II into the compound of formula ill as depicted in the following scheme.
  • the aforementioned one-pot synthesis is carried out by converting compound of formula I into compound of formula II by the above described bromination according to the present invention, or/and converting compound of formula II into compound of formula III by the above described hydrolysis according to the invention.
  • a solvent to the resulting reaction batch after conversion of compound of formula I into compound of formula II is performed, in order to dilute the reaction batch. Conversion of compound of formula I into compound of formula II may e.g. be monitored by thin layer chromatography or high pressure liquid chromatography (HPLC).
  • said solvent for dilution is selected from the group of solvents described for the above mentioned bromination reaction, and more preferably it is the same solvent as used in the bromination reaction.
  • an advantageous degree of dissolution of the compound of the formula II is obtained, which in turn provides for a smooth hydrolysis giving rise to high yields.
  • the process for preparing the compound of the formula III further comprises the step of purifying compound of formula III, preferably by crystallization.
  • a simple and effective purification method is applied, compared to labor, time and material intensive column chromatography. Since the hydrolysis reaction provides for a full conversion of compound of the formula II into compound of the formula III, crystallisation will be sufficient in order to provide an advantageously pure product. Furthermore, it was found by that crystallisation performed with an MTBE/hexane mixture, and in particular with an MTBE/hexane mixture wherein the volume ratio of MTBE to hexane is 2 to 1, preferably 1 to 1 and more preferably 2 to 3 is particularly advantageous.
  • first Rosuvastatin or pharmaceutically acceptable salts thereof is provided by the process as described above.
  • Rosuvastatin or pharmaceutically acceptable salts thereof is suitably admixed with at least one suitable pharmaceutically acceptable excipient.
  • Pharmaceutically acceptable excipients may be selected from the group consisting of binders, diluents, disintegrating agents, stabilizing agents, preservatives, lubricants, fragrances, flavoring agents, sweeteners and other excipients known in the field of the pharmaceutical technology.
  • excipients may be selected from the group consisting of lactose, microcrystalline cellulose, cellulose derivatives, e.g. hydroxypropylcellulose, polyacrylates, calcium carbonate, starch, colloidal silicone dioxide, sodium starch glycolate, talc, magnesium stearate, polyvinylpyrrolidone, polyethylene glycol and other excipients known in the field of the pharmaceutical technology.
  • reaction mixture is stirred for 45 min at ⁇ 42° C., cooled to ⁇ 82° C., and treated with a solution of (2S,4R)-4-(tert-butyldimethylsilyloxy)-6-oxo-tetrahydro-2H-pyran-2-carbaldehyde (266 mg, 1.03 mmol) obtained by dissolution of its hydrate (284 mg, 1.03 mmol) in 15 mL of tetrahydrofurane without removal of released water. After 30 min of stirring, the solution is warmed to ⁇ 53 to ⁇ 58° C. and stirred further for 6 hours. Then, the mixture is allowed to warm to ambient temperature in 100 min and treated with saturated ammonium chloride solution (40 mL).
  • N-(4-(4-fluorophenyl)-5-methyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide 112.5 mg, 0.33 mmol, 1 equiv.
  • N-bromosuccinimide 126 mg, 0.72 mmol, 2.1 equiv.
  • N-(4-(4-fluorophenyl)-5-methyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide 112.5 mg, 0.33 mmol, 1 equiv.
  • N-bromosuccinimide N-bromosuccinimide (NBS) (118.7 mg, 0.66 mmol, 2 equiv.) were dissolved in 2 mL of acetonitrile.
  • the obtained yellow solution was diluted with 1 mL of acetonitrile.

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US13/145,783 2009-02-02 2010-02-01 Key intermediates for the synthesis of rosuvastatin or pharmaceutically acceptable salts thereof Abandoned US20120022091A1 (en)

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EP09151881A EP2264015A1 (en) 2009-02-02 2009-02-02 Key intermediates for the synthesis of rosuvastatin or pharmaceutically acceptable salts thereof
EP091518811 2009-02-02
PCT/EP2010/051163 WO2010086438A1 (en) 2009-02-02 2010-02-01 Key intermediates for the synthesis of rosuvastatin or pharmaceutically acceptable salts thereof

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EP2423195A1 (en) * 2010-07-26 2012-02-29 LEK Pharmaceuticals d.d. Process for the preparation of key intermediates for the synthesis of statins or pharmaceutically acceptable salts thereof
SI2665722T1 (sl) 2011-01-18 2016-12-30 Dsm Sinochem Pharmaceuticals Netherlands B.V. Postopek priprave diol sulfonov
CN102311457B (zh) * 2011-09-16 2014-04-16 苏州莱克施德药业有限公司 罗苏伐他汀的制备方法
CN102936225A (zh) * 2012-11-15 2013-02-20 江苏阿尔法药业有限公司 一种含溴甲基、羟甲基或甲酰基的瑞舒伐他汀钙中间体的制备方法
CN103420919B (zh) * 2013-08-22 2015-07-08 南京欧信医药技术有限公司 一种嘧啶类衍生物的合成方法
CN105175346B (zh) * 2015-05-19 2018-02-06 上海弈柯莱生物医药科技有限公司 一种合成瑞舒伐他汀钙中间体的方法

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EP1775299A1 (en) * 2005-10-05 2007-04-18 LEK Pharmaceuticals D.D. Process for the synthesis of HMG-CoA reductase inhibitors
US8269001B2 (en) * 2005-10-05 2012-09-18 Lek Pharmaceuticals D.D. Process for the synthesis of HMG-CoA reductase inhibitors
US8183397B2 (en) * 2007-04-03 2012-05-22 Lek Pharmaceuticals D.D. Synthesis of statins

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JP5558492B2 (ja) 2014-07-23
AU2010209650A1 (en) 2011-08-25
EP2391609A1 (en) 2011-12-07
AU2010209650B2 (en) 2015-09-17
EA021733B1 (ru) 2015-08-31
JP2012516839A (ja) 2012-07-26
EA201101150A1 (ru) 2012-03-30
US9376397B2 (en) 2016-06-28
US20150141449A1 (en) 2015-05-21
WO2010086438A1 (en) 2010-08-05
MX2011007990A (es) 2011-09-06
CA2750801C (en) 2017-08-29
BRPI1007151A2 (pt) 2016-02-23
CA2750801A1 (en) 2010-08-05
MX343273B (es) 2016-10-31
EP2391609B1 (en) 2015-01-28
CN102365272B (zh) 2014-07-16
CN102365272A (zh) 2012-02-29
EP2264015A1 (en) 2010-12-22

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