EP1794158A2 - Verfahren zur herstellung von tiotropiumsalzen und silicium-derivate als zwischenprodukte - Google Patents

Verfahren zur herstellung von tiotropiumsalzen und silicium-derivate als zwischenprodukte

Info

Publication number
EP1794158A2
EP1794158A2 EP05801688A EP05801688A EP1794158A2 EP 1794158 A2 EP1794158 A2 EP 1794158A2 EP 05801688 A EP05801688 A EP 05801688A EP 05801688 A EP05801688 A EP 05801688A EP 1794158 A2 EP1794158 A2 EP 1794158A2
Authority
EP
European Patent Office
Prior art keywords
formula
methyl
compound
ethyl
group
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.)
Ceased
Application number
EP05801688A
Other languages
German (de)
English (en)
French (fr)
Inventor
Werner Belzer
Rainer Hamm
Monika Hofmann
Ralf Lock
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.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
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
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Application filed by Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1794158A2 publication Critical patent/EP1794158A2/de
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
    • C07D451/06—Oxygen atoms
    • C07D451/10—Oxygen atoms acylated by aliphatic or araliphatic carboxylic acids, e.g. atropine, scopolamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the invention relates to a novel process for the preparation of tiotropium salts of general formula 1
  • Anticholinergics can be therapeutically useful in a variety of diseases. Special mention should be made, for example, of the treatment of asthma or COPD (chronic obstructive pulmonary disease).
  • COPD chronic obstructive pulmonary disease
  • WO 02/03289 proposes anticholinergics which have a scopin, tropenol or tropine skeleton.
  • the tiotropium bromide is disclosed in particular in the prior art as a highly potent anticholinergic. Tiotropium bromide is known, for example, from EP 418 716 A1.
  • the present invention relates to a process for the preparation of tiotropium salts of formula 1 wherein
  • X may mean a singly negatively charged anion, preferably an anion selected from the group consisting of chloride, bromide, iodide, methanesulfonate or trifluoromethanesulfonate,
  • R is a radical selected from the group consisting of N-imidazolyl, N-triazolyl,
  • R " is C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkylene-N (C 1 -C 4 -alkyl) 2 ;
  • the present invention relates to a process for the preparation of tiotropium salts of formula 1, wherein X "is a single negatively charged anion selected from the group consisting of chloride, bromide, iodide, methanesulfonate or trifluoromethanesulfonate, preferably chloride, bromide or methanesulfonate, more preferably bromide , can mean.
  • R is methyl, ethyl or cyclohexyl; R "is methyl, ethyl, cyclohexyl, C 2 -C 3 -alkylene-N (methyl) 2 or
  • a method particularly preferred according to the invention is characterized in that that the reaction takes place with an in situ generated compound of formula 3, in which
  • R is a radical selected from the group consisting of N-imidazolyl, N-triazolyl,
  • R 1 and R 2 identical or different, denote methyl, ethyl, propyl or butyl, preferably methyl or ethyl, more preferably methyl;
  • R 2 is methyl or ethyl, preferably methyl.
  • Alkyl groups and alkyl groups which are part of other groups are branched and unbranched alkyl groups having 1 to 4 carbon atoms. Examples include: methyl, ethyl, propyl, butyl. Unless otherwise stated, of the above designations, propyl, butyl includes all of the possible isomeric forms. For example, the term propyl includes the two isomeric radicals n-propyl and iso-propyl, the term butyl n-butyl, iso-butyl, sec. Butyl and tert. Butyl.
  • alkylene bridge or alkylene group unless otherwise stated, branched and unbranched alkyl groups having 1 to 4 carbon atoms, for example methylene, Etyhlen, propylene, butylene bridges referred to. Particularly preferred
  • phenyl-methyl and phenyl-NÜ2 stand for phenyl rings by
  • Methyl or NO 2 are substituted. All possible isomers (ortho, meta or para) are included here, the para- or meta-substitution being of particular importance.
  • cycloalkyl radicals having 3 to 6 carbon atoms are for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the procedure may be as described below.
  • the compound of formula 3 is generated in situ.
  • the term "in situ” stands for the representation of the compound of the formula 3 without this being subsequently isolated.
  • the representation of the formula 3 takes place by reacting dithienylglycolic acid, preferably of alkali metal salts of dithienylglycolic acid, more preferably of sodium dithienyl glycolate with a coupling reagent selected from the group consisting of carbonyldiimidazole, carbonyldi-l, 2,4-triazole, dicyclohexylcarbodiimide, ethyldimethylaminopropylcarbodiimide, toluenesulfonyl chloride, pivaloyl chloride, nitrobenzoic anhydride, oxalyl chloride, Phosgene, sulfonyl chloride and phosphorus chlorides preferably carbonyldiimidazole
  • radicals R 1 and R 2 may have the abovementioned meanings and L is a leaving group, which is preferably selected from the group consisting of halide, methanesulfonate, trifluoromethanesulfonate and para-toluenesulfonate, more preferably methanesulfonate, trifluoromethanesulfonate, Bromine or chlorine, furthermore preferably bromine or chlorine, chlorine having particular importance according to the invention.
  • L is a leaving group, which is preferably selected from the group consisting of halide, methanesulfonate, trifluoromethanesulfonate and para-toluenesulfonate, more preferably methanesulfonate, trifluoromethanesulfonate, Bromine or chlorine, furthermore preferably bromine or chlorine, chlorine having particular importance according to the invention.
  • the silyl compound 5 can either be added to the mixture of dithienylglycolic acid or dithienylglycolic acid salt with coupling reagent in the abovementioned solvent, if appropriate in the presence of a base such as, for example, pyridine, imidazole or N-alkylamine, or else together with dithienylglycolic acid or the dithienylglycolic acid salt in the abovementioned solvent, optionally in the presence of a base such as pyridine, imidazole or N-alkylamine, initially charged and then added with the above-mentioned coupling reagent.
  • a base such as, for example, pyridine, imidazole or N-alkylamine
  • the abovementioned three components are added in stoichiometric amounts to form the compound of the formula 3; but also in the presence of one of the three components in excess (for example, 1.1 to 1.5 equivalent) are performed.
  • the solution obtained is mixed at the abovementioned temperature for about 5 minutes to 2 hours, preferably 10 minutes to 1 hour, particularly preferably 20-40 minutes, for example by stirring to form the compound of general formula 3.
  • the compound of formula 2 is then added to the solution thus obtained.
  • This addition can be carried out either by adding a solution or suspension of the compound of formula 2 in one or more of the abovementioned solvents or by, preferably in portions, adding the compound of formula 2 in bulk. If the compound of the formula 2 is dissolved or suspended in one or more solvents, the use of the same solvents, which is used for the in situ preparation of the compound of the formula 3, is appropriate.
  • the amount in which the compound of formula 2 is added is determined by the amount of compound of formula 3 generated in situ.
  • the three components dithienylglycolic acid or dithienylglycolic acid salt, coupling reagent and compound of formula 5 are obtained Used stoichiometric amounts, is compound of formula 3 in the molar amount, as it was chosen for the three components Dithienylglykolklare or Dithienylglykolklasalz, coupling reagent and compound of formula 5.
  • the compound of formula 3 is in the molar amount of the least portioned component of the three starting compounds dithienylglycolic acid or dithienylglycolic acid salt , Coupling reagent and compound of formula 5.
  • the molar ratio of compound of formula 2 to in situ generated compound of formula 3 is preferably in a range from 2: 1 to 1: 5, preferably 1.5: 1 to 1: 3, more preferably 1: 1 to 1: 2, wherein a ratio of 1: 1 to 1: 1.5 particular importance according to the invention.
  • Suitable solvents according to the invention are the abovementioned solvents.
  • the solvent which has also been used to form the compound of formula 3 is used at this point.
  • the base organic or inorganic bases can be used.
  • Alkali imidazolides are preferably used as organic bases, which can be generated, for example, in situ from the alkali metals and imidazole or the alkali metal hydrides and imidazole.
  • Akaliimidazolide are preferably imidazolides of lithium, sodium or potassium, with sodium or lithium imidazolide being preferred according to the invention.
  • alkali metal alcoholates of hindered alcohols e.g., potassium tert -butylate
  • Preferred further bases are inventively selected from the group consisting of lithium diisopropylamide (LDA), lithium or sodium hexamethyldisilazane (LiHMDS or NaHMDS).
  • Suitable inorganic bases are preferably hydrides of lithium, sodium or potassium. Particular preference is given to using sodium hydride as the inorganic base.
  • the base solution or suspension preferably between 0.2 and 1.5 L, more preferably between 0.3 and 1 L of said solvent are used per mole of base.
  • the addition of the base is preferably carried out at a temperature of -20-60 ° C, preferably from 0-45 ° C, particularly preferably from 0-25 ° C. After addition of the base, the resulting mixture is stirred for about 10 minutes to 6 hours, preferably 30 minutes to 3 hours, more preferably 45 minutes to 1.5 hours at constant temperature to form the compound of formula 4.
  • a suitable acid HX is preferably carried out at a temperature of below 10 ° C, more preferably at about 0 ° C.
  • the choice of the acid is determined here by the anion X "in the desired end product of general formula 1.
  • the present invention in addition to the acid HX can be carried out in addition, the addition of a suitable Desilyl michsreagenzes, which is preferably selected from the group of ammonium fluoride in the frame, particularly preferably tetrabutylammonium fluoride, tetraethylammonium fluoride, benzyltrimethylammonium fluoride, tetrahexylammonium fluoride, tetraoctylammonium fluoride or hydrogen fluoride free or complexed, such as, for example, pyridinium fluoride, triethylamine-HF complex.
  • a suitable Desilyl istsreagenzes which is preferably selected from the group of ammonium fluoride in the frame, particularly preferably tetrabutylammonium fluoride, tetraethylammonium fluoride, benzyltrimethylammonium fluoride, tetrahexylammonium fluor
  • the release of the compound of the formula 1 can also be effected exclusively by means of the abovementioned de-silylating reagents.
  • X represents bromide
  • the following procedure for the preparation of the inventive preferred tiotropium bromide is described below.
  • Y is a cation such as a proton or a metal cation or ammonium, alkylammonium, tetraalkylammonium or pyridinium or a complex such as aluminum trifluoride HF or another fluoride donor such as diethylaminosulfur trifluoride (DAST)
  • DAST diethylaminosulfur trifluoride
  • the reaction mixture is admixed with a protic solvent, preferably with an alcohol, more preferably with methanol or ethanol or isopropanol.
  • a protic solvent preferably with an alcohol, more preferably with methanol or ethanol or isopropanol.
  • 0.5 to 20 L, more preferably 0.7 to 13 L alcohol are added according to the invention per mole of compound of formula 2 and the mixture obtained at a temperature of 0-60 ° C, preferably from 10-45 ° C, particularly preferably from 15-25 ° C for a period of about 0.5 to 6 hours, preferably 0.5 to 5 hours, more preferably 0.5 to 4 hours.
  • a non-polar organic solvent preferably with a solvent selected from the group consisting of a ketone (such as acetone or methyl ethyl ketone), an alcohol (such as methanol, ethanol, propanol, isopropanol, butanol or amyl alcohol), toluene , Ethyl acetate, n-butyl acetate, dichloromethane, diethyl ether, methyl tert-buyl ether, tetrahydrofuran and dioxane, particularly preferably isopropanol, toluene or acetone.
  • the crystallized product is separated and washed with the abovementioned solvent.
  • the crude product can be mixed with water or aqueous bromide solutions, e.g. Sodium or potassium bromide solution are treated.
  • the present invention further relates to compounds of the formula 3 wherein R, R 1 and R 2 may have the meanings given above, as such.
  • the present invention further relates to compounds of the formula 4
  • the present invention relates to the use of the abovementioned compounds of the formula 3 for the preparation of compounds of the formula 1.
  • the present invention relates to the use of the abovementioned compounds of the formula 4 for the preparation of compounds of the formula 1.
  • reaction mixture is extracted with 500 ml of toluene and crystallized after separation of the toluene phase with 150 ml of isopropanol at 0 ° C.
  • the crude product is filtered off, washed with 30 ml of cold isopropanol and dried in vacuo. Yield 14.1g (80%, with respect to Scopinmethobromid).
  • the reaction mixture is extracted twice with 200 ml of toluene and crystallized after separation of the toluene phase with 150 ml of isopropanol at 5 ° C.
  • the crude product is filtered off and recrystallized from 120 ml of methanol with the addition of 5 g of activated charcoal.
  • the tiotropium bromide obtained is filtered off, washed with 5 ml of cold methanol and dried in vacuo.
  • the crystals thus obtained are dissolved in 20 ml of water at 90 ° C and crystallized the monohydrate of tiotropium bromide by cooling to 15 ° C.
  • the product is filtered off, washed with 7 ml of water and 8 ml of acetone and sucked dry. Yield 9.8 g (40% with respect to scopine methobromide).
  • the reaction mixture is extracted twice with 200 ml of toluene and crystallized in 150 ml of isopropanol by cooling to 5 ° C.
  • the crystallized crude product is filtered off and recrystallized from 120 ml of methanol with the addition of 5 g of activated carbon.
  • the tiotropium bromide obtained is filtered off, washed with cold methanol and dried in vacuo.
  • the product is dissolved in 24 ml of water at 90 ° C. and the monohydrate of the tiotropium bromide is crystallized by cooling to 15 ° C.
  • the product is filtered off and washed with 6.5 ml of water and 10.5 ml of acetone and dried. Yield 8.1 g (42% with respect to scopine methobromide).
  • the reaction mixture is treated with 800 ml of dichloromethane and stirred for 15 min at room temperature.
  • the crystallized crude product is filtered off and recrystallized from 120 ml of methanol with the addition of 2 g of activated carbon.
  • the tiotropium bromide obtained is filtered off, washed with cold methanol and dried in vacuo.
  • the product is dissolved in 18 ml of water at 90 ° C. and the monohydrate of the tiotropium bromide is crystallized by cooling to 15 ° C.
  • the product is filtered off and washed with 5 ml of water and 8 ml of acetone and dried. Yield 6.5 g (34% with respect to Scopinmethobromid).
  • Synthscbcispicl 9 17.9 g (165 mmol) of chlorotrimethylsilane are added dropwise at 0 ° C. to a solution of 39.3 g (150 mmol) of sodium dithienylglycolate in 117 ml of tetrahydrofuran.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Pulmonology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Inorganic Compounds Of Heavy Metals (AREA)
EP05801688A 2004-08-26 2005-08-23 Verfahren zur herstellung von tiotropiumsalzen und silicium-derivate als zwischenprodukte Ceased EP1794158A2 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102004041253A DE102004041253A1 (de) 2004-08-26 2004-08-26 Neues Verfahren zur Herstellung von Tiotropiumsalzen
PCT/EP2005/054131 WO2006021559A2 (de) 2004-08-26 2005-08-23 Verfahren zur herstellung von tiotropiumsalzen und silicium-derivate als zwischenprodukte

Publications (1)

Publication Number Publication Date
EP1794158A2 true EP1794158A2 (de) 2007-06-13

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ID=35745545

Family Applications (1)

Application Number Title Priority Date Filing Date
EP05801688A Ceased EP1794158A2 (de) 2004-08-26 2005-08-23 Verfahren zur herstellung von tiotropiumsalzen und silicium-derivate als zwischenprodukte

Country Status (16)

Country Link
US (2) US7491824B2 (ko)
EP (1) EP1794158A2 (ko)
JP (1) JP5173421B2 (ko)
KR (1) KR101274455B1 (ko)
CN (1) CN100532382C (ko)
AR (1) AR050714A1 (ko)
AU (1) AU2005276432B2 (ko)
BR (1) BRPI0514643A (ko)
CA (1) CA2573373C (ko)
DE (1) DE102004041253A1 (ko)
IL (3) IL181522A (ko)
NZ (1) NZ553840A (ko)
RU (1) RU2384575C2 (ko)
TW (2) TWI387595B (ko)
WO (1) WO2006021559A2 (ko)
ZA (1) ZA200610503B (ko)

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AU2004285683C1 (en) * 2003-11-03 2011-09-08 Boehringer Ingelheim International Gmbh Method for producing tiotropium salts, tiotropium salts and pharmaceutical formulations, containing the same
RU2417224C2 (ru) * 2005-05-02 2011-04-27 Бёрингер Ингельхайм Интернациональ Гмбх Новые кристаллические формы тиотропийбромида
NZ564697A (en) * 2005-06-15 2010-04-30 Boehringer Ingelheim Int Process for preparing tiotropium salts, tiotropium salts as such and pharmaceutical compositions thereof
DE102005035112A1 (de) * 2005-07-27 2007-02-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neues Verfahren zur Herstellung von Tiotropiumsalzen unter Anwendung von in organischen Lösungsmitteln löslichen N-Methylscopiniumsalzen
US20080051582A1 (en) * 2006-07-10 2008-02-28 Sicor Inc. Process for the preparation of tiotropium bromide
TR201007108A2 (tr) * 2010-08-25 2012-03-21 B�Lg�� Mahmut Yeni tiotropyum bromür kristali ve üretim yöntemi.@
US9707375B2 (en) 2011-03-14 2017-07-18 Rochester Medical Corporation, a subsidiary of C. R. Bard, Inc. Catheter grip and method
ITRM20110508A1 (it) 2011-09-27 2013-03-28 Lusochimica Spa Processo per la preparazione degli esteri della scopina.
US8680297B2 (en) 2011-10-06 2014-03-25 Drug Process Licensing Assoc., LLC Manufacturing process for tiotropium bromide
CZ304808B6 (cs) 2012-03-16 2014-11-05 Zentiva, K.S. Způsob přípravy skopinesteru kyseliny di(2-thienyl)glykolové, intermediátu v syntéze tiotropium bromidu a jeho nová forma
CZ305012B6 (cs) 2012-03-30 2015-03-25 Zentiva, K.S. Způsob přípravy skopinesteru kyseliny di(2-thienyl)glykolové, intermediátu v syntéze tiotropium bromidu
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BRPI0514643A (pt) 2008-06-17
TW201231466A (en) 2012-08-01
US20090118511A1 (en) 2009-05-07
TWI387595B (zh) 2013-03-01
AR050714A1 (es) 2006-11-15
IL213720A (en) 2012-03-29
RU2007110951A (ru) 2008-10-10
RU2384575C2 (ru) 2010-03-20
KR20070046196A (ko) 2007-05-02
US7491824B2 (en) 2009-02-17
AU2005276432A1 (en) 2006-03-02
DE102004041253A1 (de) 2006-03-02
IL213717A0 (en) 2011-07-31
IL213720A0 (en) 2011-07-31
US8008495B2 (en) 2011-08-30
JP5173421B2 (ja) 2013-04-03
WO2006021559A3 (de) 2006-08-17
IL181522A0 (en) 2007-07-04
AU2005276432B2 (en) 2011-11-10
WO2006021559A2 (de) 2006-03-02
CN101001855A (zh) 2007-07-18
NZ553840A (en) 2010-06-25
IL181522A (en) 2011-08-31
TW200617006A (en) 2006-06-01
ZA200610503B (en) 2008-09-25
CA2573373C (en) 2014-05-06
JP2008510774A (ja) 2008-04-10
CA2573373A1 (en) 2006-03-02
TWI429646B (zh) 2014-03-11
WO2006021559A8 (de) 2006-11-16
CN100532382C (zh) 2009-08-26
US20060047120A1 (en) 2006-03-02
KR101274455B1 (ko) 2013-06-18

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