EP2694499A1 - Procédé de préparation d'un agent antipsychotique - Google Patents

Procédé de préparation d'un agent antipsychotique

Info

Publication number
EP2694499A1
EP2694499A1 EP12713375.9A EP12713375A EP2694499A1 EP 2694499 A1 EP2694499 A1 EP 2694499A1 EP 12713375 A EP12713375 A EP 12713375A EP 2694499 A1 EP2694499 A1 EP 2694499A1
Authority
EP
European Patent Office
Prior art keywords
formula
trans
process according
cyclohexane
dicarboxylic acid
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.)
Withdrawn
Application number
EP12713375.9A
Other languages
German (de)
English (en)
Inventor
Suresh Babu Jayachandra
Udaibhan Singh GAHLOT
Tarun Kumar SINGH
Chandra Has Khanduri
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of EP2694499A1 publication Critical patent/EP2694499A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • a process for the preparation of an antipsychotic agent useful for the treatment of schizophrenia is provided.
  • Lurasidone hydrochloride is chemically (3aR,4S,7R,7aS)-2- ⁇ (lR,2R)-2- [4-(l,2-benzisothiazol-3-yl)piperazin-l-ylmethyl]cyclohexylmethyl ⁇ hexahydro-4,7- methano-2H-isoindole-l,3-dione hydrochloride having the structure as represented by Formula I.
  • Lurasidone hydrochloride is marketed in the United States under the brand name Latuda® for the treatment of schizophrenia.
  • the present invention provides an easy, cost-effective and industrially advantageous process for the preparation of highly pure lurasidone hydrochloride which involves separating the racemic trans 1, 2-cyclohexane dicarboxylic acid of Formula III into its R,R trans and S,S trans isomers and then using the desired trans R,R isomer for the preparation of lurasidone hydrochloride. Since the process of the present invention involves separating the undesired S,S trans isomer in the initial stages of the manufacturing process, no undesired isomers due to reaction with trans (S,S)-isomer are formed in the subsequent steps.
  • Lurasidone hydrochloride prepared by the process of the present invention is a highly pure, easy to filter, free-flowing solid having small average particle size.
  • a first aspect of the present invention provides a process for the preparation of lurasidone hydrochloride of Formula I
  • R' is a leaving group
  • a second aspect of the present invention provides use of trans (R,R)-1,2- cyclohexane dicarboxylic acid of Formula Ilia
  • ambient temperature refers to a temperature in the range of about 20°C to about 35°C.
  • contacting refers to dissolving, slurrying, stirring or a combination thereof.
  • Racemic trans 1,2-cyclohexane dicarboxylic acid of Formula III to be used for the preparation of lurasidone hydrochloride of Formula I of the present invention, may be obtained by methods known in the literature such as the one disclosed in U.S. Patent No. 5,532,372, which is incorporated herein by reference. It may be obtained as a solution directly from a reaction in which it is formed and used as such without isolation or it may be isolated and then used in the next step.
  • Racemic trans 1,2-cyclohexane dicarboxylic acid of Formula III may be resolved into (R,R) trans 1,2-cyclohexane dicarboxylic acid of Formula Ilia and (S,S) trans 1,2- cyclohexane dicarboxylic acid using a chiral resolving agent selected from the group comprising (R)-l-phenylethyl amine, alpha-methylbenzylamine, l-(l-naphthyl)- ethylamine, sec-butylamine l-amino-2-methylbutane, N,N-dimethyl-l-phenylethylamine, 1-cyclohexylethylamine, 2-(methoxymethyl)-pyrrolidine, l-(4-nitrophenyl)-ethylamine, 2- amino-l-butanol, l-amino-2-propanol, cinchonidine, brucine, strychnine, cinch
  • Resolution may be carried out using a solvent selected from the group comprising alcohols, ketones, alkyl acetates, chlorinated hydrocarbons, ethers, nitriles or
  • hydrocarbons examples include alcohols, ethanol, n-propanol, iso-propanol, n- butanol, iso-butanol, sec-butanol or n-pentanol.
  • ketones are acetone, methyl ethyl ketone or methyl isobutyl ketone.
  • alkyl acetates are ethyl acetate or isopropyl acetate.
  • chlorinated hydrocarbons are dichloromethane or chloroform.
  • ethers are diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofiiran or dioxane.
  • nitriles are acetonitrile or propionitrile.
  • hydrocarbons examples include benzene, xylene, toluene, hexanes, heptane or pentane.
  • Resolving agent may be added at a temperature of about 0°C to -100°C.
  • the reaction mixture may be stirred for about 30 minutes to about 2 hours, warmed to ambient temperature and stirred for about 2 hours to about 10 hours followed by isolation. Isolation may be accomplished by filtration and drying. Drying may be carried out using any suitable method such as drying under reduced pressure, drying under atmospheric pressure, air drying or drying with aeration of inert gas such as nitrogen. Drying may be carried out at a temperature of about 40°C to about 80°C for about 2 hours to about 10 hours.
  • the salt of trans 1 ,2-cyclohexane dicarboxylic acid of Formula III with the resolving agent may be further purified by crystallization from the solvent selected from the group consisting of alcohols, hydrocarbons, ketones, alkyl acetates, chlorinated hydrocarbons, ethers, nitriles and mixtures thereof.
  • alcohols are methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, and n-pentanol.
  • Examples of hydrocarbons are benzene, xylene, toluene, hexane, heptanes, and pentane.
  • ketones are acetone, methyl ethyl ketone, and methyl isobutyl ketone.
  • alkyl acetates are ethyl acetate, and isopropyl acetate.
  • chlorinated hydrocarbons are dichloromethane and chloroform.
  • ethers are diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, and dioxane.
  • salt of (R,R) trans 1,2-cyclohexane dicarboxylic acid of Formula Ilia with the resolving agent is purified by crystallization from a solvent mixture comprising an alcohol and a
  • Crystallization may be carried out by dissolving the salt of trans 1,2-cyclohexane dicarboxylic acid of Formula III with the resolving agent at a temperature of about 60°C to about 100°C.
  • the solution may be cooled to about -10°C to an ambient temperature, stirred for about 30 minutes to about 2 hours, filtered and dried.
  • the crystallization step may be repeated if required.
  • the solid material thus obtained may be dissolved in about IN hydrochloric acid solution, extracted with a solvent and isolated to obtain trans (R,R)- 1,2-cyclohexane dicarboxylic acid of Formula Ilia.
  • purification is carried out by crystallization from ethanohtoluene mixture.
  • purification is carried out by crystallization from ethanohtoluene mixture (1 :1) mixture.
  • Conversion of (R,R) trans 1,2-cyclohexane dicarboxylic acid of Formula Ilia into dicarboxylate intermediate of Formula X may be carried out by contacting with a Ci-C 4 alcohol or benzyl alcohol in the presence of sulphuric acid.
  • Ci-C 4 alcohol or benzyl alcohol examples are methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, and sec-butanol.
  • the reaction mixture may be stirred at about 25°C to 60°C for about 1 hour to 24 hours and concentrated. Isolation may be accomplished by adding de-ionized water, solvent extraction and concentration.
  • trans (R,R)-l,2-cyclohexane dicarboxylic acid of Formula Ilia may be converted into trans (R,R)-l,2-dimethyl cyclohexane dicarboxylate of Formula X by contacting with methanol in the presence of sulphuric acid.
  • the reaction mixture may be stirred at about 40°C for about 18 hours.
  • the reaction mixture may be concentrated under reduced pressure at about 50°C. De-ionized water may be added.
  • Isolation of trans (R,R)-l,2-dimethyl cyclohexane dicarboxylate may be accomplished by solvent extraction and concentration.
  • Conversion of dicarboxylate intermediate of Formula X into trans (R,R)-1,2- bis(hydroxymethyl)cyclohexane of Formula XI may be carried out by adding a reducing agent selected from the group comprising diisobutyl aluminum hydride, lithium aluminium hydride, lithium borohydride, sodium borohydride, calcium borohydride, and lithium triethylborohydride, in an inert atmosphere.
  • a solvent selected from the group comprising hydrocarbons or ethers may be added. Examples of hydrocarbons are benzene, xylene, toluene, hexane, heptanes or pentane.
  • ethers are diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, diglyme or dioxane.
  • the reducing agent may be added drop-wise at a temperature of about -10°C to 10°C.
  • the reaction mixture may be warmed to an ambient temperature and stirred for about 2 hours to 10 hours.
  • About IN hydrochloric acid solution may be added at about -5°C to 40°C.
  • the reaction mixture may be stirred for about 10 hours to 15 hours. Isolation may be accomplished by filtration and concentration.
  • conversion of dicarboxylate intermediate of Formula X into trans (R,R)-l,2-bis(hydroxymethyl)cyclohexane of Formula XI may be carried out using diisobutyl aluminum hydride in a hydrocarbon solvent.
  • conversion of dicarboxylate intermediate of Formula X into trans (R,R)-1,2- bis(hydroxymethyl)cyclohexane of Formula XI may be carried out using diisobutyl aluminum hydride in toluene.
  • the hydroxyl group of trans (R,R)-l,2-bis(hydroxymethyl)cyclohexane of Formula XI may be converted into a leaving group by reaction with a halide or a sulphonyl compound to obtain a intermediate of Formula XII.
  • halides are thionyl chloride and thionyl bromide.
  • sulphonyl compounds are alkyl- or aryl-sulphonyl halides selected from the group comprising of methane sulphonyl chloride, ethane sulphonyl chloride, p-toluene sulphonyl chloride, and benzene sulphonyl chloride.
  • An organic or inorganic base may be added.
  • organic bases are triethylamine, ammonia, and pyridine.
  • inorganic bases are hydroxides, carbonates and bicarbonates of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide. Conversion may be carried out in the presence of a solvent selected from the group comprising of chlorinated hydrocarbons such as dichloromethane or chloroform or in pyridine at a temperature of about -10°C to about 10°C. The reaction mixture may be further stirred at ambient temperature for about 1 hour to 8 hours. De-ionized water may be added.
  • Organic layer may be concentrated at a temperature of about 35°C to 60°C.
  • Precipitation of the hydroxyl protected intermediate may be achieved by adding an ether solvent such as diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, diglyme or dioxane, stirring for about 30 minutes to 2 hours followed by isolation.
  • an ether solvent such as diethyl ether, diisopropyl ether, methyl butyl ether, tetrahydrofuran, diglyme or dioxane
  • trans (R,R)-l,2-iw(hydroxymethyl)cyclohexane may be converted into trans (R,R)-l,2-Z>w(methanesulfonylmethyl)cyclohexane using methane sulphonyl chloride in the presence of triethylamine.
  • methane sulphonyl chloride may be carried out at a temperature of about -10°C to 10°C in a chlorinated solvent. Reaction mixture may be stirred at ambient temperature for about 1 hour to 8 hours. De-ionized water may be added. Organic layer may be concentrated at about 45°C under reduced pressure.
  • Precipitation of trans (R, R)-l,2- >/s(methanesulfonylmethyl)cyclohexane may be achieved using di-isopropyl ether.
  • the reaction mixture may be stirred at an ambient temperature for about 30 minutes to 2 hours followed by isolation.
  • trans (R,R)-l,2-bis(methanesulfonylmethyl)cyclohexane may be converted to trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-l '-[4'-(l,2-benzoisothiazole-3- yl)]piperazine methane sulfonate of Formula Vila by contacting with 3-(l-piperazinyl-l,2- benzisothiazole) of Formula VI in a nitrile or amide solvent in the presence of a base.
  • nitriles are acetonitrile and propionitrile.
  • amide solvents are ⁇ , ⁇ -dimethyl formamide and ⁇ , ⁇ -diethylformamide.
  • bases are carbonates, bicarbonates and hydroxides of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide.
  • the reaction mixture may be refluxed for about 15 hours to 2 days, filtered and concentrated at about 40°C to 80°C under reduced pressure. Precipitation may be achieved by adding a ketone solvent, a hydrocarbon solvent or mixtures thereof.
  • ketones are acetone, methyl ethyl ketone, and methyl isobutyl ketone.
  • hydrocarbons examples include benzene, xylene, toluene, hexane, heptanes, and pentane.
  • the reaction mixture may be stirred for about 10 minutes to 1 hour followed by isolation.
  • trans (R,R)-3a,7a-octahydroisoindolium-2-spiro- -[4'-(l,2-benzoisothiazole-3- yl)]piperazine methane sulfonate of Formula Vila may be reacted with
  • the catalyst may be selected from crown ethers such as dibenzo-18- crown-6 or 18-crown-6.
  • bases are carbonates, bicarbonates and hydroxides of alkali and alkaline earth metals such as sodium carbonate, potassium carbonate, sodium bicarbonate, lithium hydroxide, sodium hydroxide, and potassium hydroxide. Hydrides of alkali metals such as sodium hydride and potassium hydride may also act as base.
  • the reaction may be carried out in a hydrocarbon solvent selected from the group comprising benzene, xylene, toluene, hexane, heptanes, and pentane.
  • the reaction mixture may be refluxed for about 1 hour to 2 days, filtered and concentrated at about 40°C to 100°C under reduced pressure.
  • Precipitation of lurasidone may be carried out by adding an alcohol selected from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol or n-pentanol followed by isolation.
  • Lurasidone may be converted into lurasidone hydrochloride by drop-wise addition of hydrogen chloride to a solution of lurasidone in a solvent.
  • the solvent may be selected from the group comprising alcohols, alkyl acetates, ketones, and hydrocarbons. Examples of alcohols are methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec- butanol, and n-pentanol. Examples of alkyl acetates are ethyl acetate and isopropyl acetate.
  • ketones are acetone, methyl ethyl ketone, and methyl isobutyl ketone.
  • hydrocarbons are benzene, xylene, toluene, hexane, heptanes, and pentane.
  • Conversion of lurasidone into lurasidone hydrochloride may be carried out by purging hydrogen chloride gas or by adding aqueous hydrochloric acid in a solvent selected from iso-propanol, ethyl acetate, toluene, and water at ambient temperature to about 80°C.
  • the reaction mixture may be stirred at ambient temperature to the reflux temperature of the solvent for about 10 minutes to 1 hour followed by isolation.
  • the concentration of aqueous hydrogen chloride may vary from 0.1% to 36%.
  • lurasidone may be converted to lurasidone hydrochloride by contacting a solution of lurasidone in ethyl acetate with 6% to 8% aqueous hydrogen chloride at about 40°C, stirring at ambient temperature for about 30 minutes to 5 hours followed by isolation.
  • Lurasidone hydrochloride prepared by the process of the present invention is a highly pure, easy to filter, free- flowing solid having small average particle size.
  • HPLC purity was determined using Water alliances, Model 2695 instrument.
  • trans (R,R)-l,2-dimethyl cyclohexane dicarboxylate (20 g) was dissolved in toluene (200 mL) at about 0°C to about -5°C in an inert atmosphere.
  • Diisobutyl aluminum hydride 248.5 ml, 20% solution in toluene
  • the reaction mixture was warmed to an ambient temperature and stirred for about 6 hours.
  • the reaction was quenched by drop-wise addition of about IN HC1 (125 mL) at about -5°C to about 40°C.
  • the reaction mixture was further stirred for about 13 hours to get freely filterable inorganic solids.
  • the solids were filtered out and the filtrate was concentrated under reduced pressure to obtain trans (R,R)-1,2- bis(hydroxymethyl)cyclohexane as an oil.
  • reaction mixture was stirred for about 30 minutes at ambient temperature, filtered and dried under reduced pressure at about 45°C for about 8 hours to obtain trans (R,R)-3a,7a-octahydroisoindolium-2-spiro-l '-[4'- (l,2-benzoisothiazole-3-yl)]piperazine methane sulfonate.
  • Bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide (7.5 g), potassium carbonate (7.5 g) and dibenzo-18-crown-6 (0.15 g) were added to a solution of trans (R,R)-3a,7a- octahydroisoindolium-2-spiro- -[4'-(l,2-benzoisothiazole-3-yl)]piperazine methane sulfonate (15 g) in xylene (150 mL).
  • the reaction mixture was refluxed for about 25 hours, filtered and concentrated at about 70°C under reduced pressure. Sticky residue was obtained.
  • Isopropanol (30 mL) was added.
  • the reaction mixture was cooled to ambient temperature, stirred for about 5 hours, filtered, washed with isopropanol (15 mL) and dried at about 45°C under reduced pressure for about 15 hours to obtain lurasidone.
  • Bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide (7.5 g), potassium carbonate (7.5 g) and dibenzo-18-crown-6 (0.15 g) were added to a solution of trans (R,R)-3a,7a- octahydroisoindolium-2-spiro- -[4'-(l,2-benzoisothiazole-3-yl)]piperazine methane sulfonate (15 g) in toluene (150 mL).
  • the reaction mixture was refluxed for about 12 hours, filtered and concentrated at about 55°C to 60°C under reduced pressure. Sticky residue was obtained. Denatured spirit (75 mL) was added.
  • the reaction mixture was heated to about 40°C, maintained for about 1 hour, cooled to ambient temperature and stirred for about 6 hours.
  • the solid was filtered, washed with denatured spirit (20 mL) and dried at about 45 °C under reduced pressure for about 15 hours to obtain lurasidone free base.
  • aqueous hydrochloric acid 5 mL was slowly added to a reaction mixture containing lurasidone (1.0 g) in ethyl acetate (25 mL) at about 40°C.
  • the reaction mixture was stirred at ambient temperature for about 2 hours, filtered and dried at about 45 °C under reduced pressure to obtain lurasidone hydrochloride.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un agent antipsychotique utile pour le traitement de la schizophrénie.
EP12713375.9A 2011-04-01 2012-03-28 Procédé de préparation d'un agent antipsychotique Withdrawn EP2694499A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN943DE2011 2011-04-01
PCT/IB2012/051500 WO2012131606A1 (fr) 2011-04-01 2012-03-28 Procédé de préparation d'un agent antipsychotique

Publications (1)

Publication Number Publication Date
EP2694499A1 true EP2694499A1 (fr) 2014-02-12

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EP12713375.9A Withdrawn EP2694499A1 (fr) 2011-04-01 2012-03-28 Procédé de préparation d'un agent antipsychotique

Country Status (4)

Country Link
EP (1) EP2694499A1 (fr)
AU (1) AU2012235724A1 (fr)
CA (1) CA2831703A1 (fr)
WO (1) WO2012131606A1 (fr)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9409899B2 (en) 2012-02-13 2016-08-09 Cadila Healthcare Limited Process for preparing benzisothiazol-3-yl-piperazin-1-yl-methyl-cyclo hexylmethanisoindol-1,3-dione and its intermediates
WO2014037886A1 (fr) * 2012-09-04 2014-03-13 Ranbaxy Laboratories Limited Procédé de préparation de chlorhydrate de lurasidone
CN102911170A (zh) * 2012-11-15 2013-02-06 苏州第壹制药有限公司 酰亚胺化合物盐酸盐的制备方法
CN102936243B (zh) * 2012-11-16 2015-08-05 上海伯倚化工科技有限公司 一种鲁拉西酮的合成方法
CN103864774B (zh) * 2012-12-14 2016-09-28 成都弘达药业有限公司 一种鲁拉西酮的制备方法
WO2014102808A1 (fr) 2012-12-25 2014-07-03 Lee Pharma Limited Procédé de préparation d'acide trans-(lr,2r)-cyclohexane 1,2-dicarboxylique
ITMI20130262A1 (it) * 2013-02-22 2014-08-23 Edmond Pharma Srl Procedimento per la preparazione di lurasidone cloridrato
ITMI20131245A1 (it) * 2013-07-24 2015-01-25 Olon Spa Procedimento per la produzione di lurasidone ad elevata purezza
CN104513182A (zh) * 2013-10-08 2015-04-15 无锡万全医药技术有限公司 一种(1r,2r)-1,2-环己烷二甲醇二磺酸酯的制备方法
ITMI20131737A1 (it) 2013-10-17 2015-04-18 Procos Spa Processo per la sintesi industriale di lurasidone
CN103724238A (zh) * 2013-12-31 2014-04-16 无锡万全医药技术有限公司 一种（1r,2r）-1,2-环己烷二甲醇二芳基磺酸酯的制备方法
PL3154967T3 (pl) 2014-06-16 2021-01-11 Johnson Matthey Public Limited Company Sposoby wytwarzania alkilowanych związków arylopiperazyny i alkilowanych związków arylopiperydyny obejmujący nowe związki pośrednie
WO2016059649A1 (fr) 2014-10-14 2016-04-21 Jubilant Generics Limited (Formerly Jubilant Life Sciences Division) Procédé amélioré de préparation de chlorhydrate de lurasidone
EP3242876A4 (fr) 2015-01-08 2019-01-02 Piramal Enterprises Limited Procédé amélioré de préparation de lurasidone et de ses intermédiaires
CN106916151A (zh) * 2015-12-28 2017-07-04 苏州二叶制药有限公司 一种盐酸鲁拉西酮的制备方法
CN106518729A (zh) * 2016-09-21 2017-03-22 北京万全德众医药生物技术有限公司 盐酸鲁拉西酮中间体的制备方法

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JP2004224764A (ja) 2003-01-27 2004-08-12 Sumitomo Pharmaceut Co Ltd 光学活性トランス−１，２−シクロヘキサンジカルボン酸誘導体の製造方法
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KIMURA K. ET AL: "Crystal Structure of (1R,2)-trans-1,2-Cyclohexanedicarboxylic Acid-(R)-1-phenylethylamine Salt", ANALYTICAL SCIENCES, vol. 15, June 1999 (1999-06-01), pages 609 - 610, XP055088781
See also references of WO2012131606A1

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WO2012131606A1 (fr) 2012-10-04
AU2012235724A1 (en) 2013-10-24
CA2831703A1 (fr) 2012-10-04

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