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WO2005073207A1 - Procede de preparation de cetirizine optiquement active ou de son sel - Google Patents

Procede de preparation de cetirizine optiquement active ou de son sel Download PDF

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Publication number
WO2005073207A1
WO2005073207A1 PCT/KR2005/000231 KR2005000231W WO2005073207A1 WO 2005073207 A1 WO2005073207 A1 WO 2005073207A1 KR 2005000231 W KR2005000231 W KR 2005000231W WO 2005073207 A1 WO2005073207 A1 WO 2005073207A1
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WO
WIPO (PCT)
Prior art keywords
formula
optically active
cetirizine
compound
chlorophenyl
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
PCT/KR2005/000231
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English (en)
Inventor
Jae-Shin Kim
Yong-Kyun Park
Mun-Choun Ha
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.)
Hanlim Pharmaceutical Co Ltd
Original Assignee
Hanlim Pharmaceutical Co 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 Hanlim Pharmaceutical Co Ltd filed Critical Hanlim Pharmaceutical Co Ltd
Priority to EP05726293A priority Critical patent/EP1718627A4/fr
Publication of WO2005073207A1 publication Critical patent/WO2005073207A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain

Definitions

  • the present invention relates to a method for optical resolution of racemic cetirizine or its salt. More particularly, the present invention relates to a process for preparing optically active cetirizine or its salt from racemic cetirizine or its salt using glutamate of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]acetic ester, and the glutamate of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]acetic ester useful as an intermediate for the preparation of the optically active cetirizine or its salt.
  • Background Art
  • Cetirizine is a material known as an antihistamine represented by the following structural formula. Generally, cetirizine is used in its dihydrochloride form and its chemical name is 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy]acetic acid.
  • U.K Patent No. 2,225,321 discloses a process for preparing an optical isomer of cetirizine, that is, a process for preparing optically active cetirizine or its salt using optically active ace- tonitrile derivative as an intermediate.
  • U.S. Patent No. 5,478,941 discloses a process for preparing optically active cetirizine or its salt using (4-mefhylphenyl)sulfonyl-piperazine derivative as an intermediate.
  • the present invention provides a process for preparing optically active cetirizine or its salt.
  • the present invention also provides a compound useful as an intermediate for preparation of optically active cetirizine or its salt.
  • a process for preparing optically active cetirizine or its salt including: (a) reacting an optically active compound represented by formula 1 below with a base to prepare an optically active compound represented by formula 2a below; and (b) hydrolyzing the compound of the formula 2a:
  • R 1 is alkyl of C -C and R 2 is an amino protecting group.
  • the amino protecting group may be a common amino protecting group, for example, phenylsulfonyl, unsubstituted or substituted by lower alkyl of C -C ; sulfonyl 1 4 substituted by lower alkyl of C -C ; acetyl; ethoxycarbonyl; t-butoxycarbonyl; benzy- 1 4 loxycarbonyl; benzoyl; nicotinoyl; phthaloyl; or the like.
  • the amino protecting group may be phenylsulfonyl or (4-methylphenyl)sulfonyl.
  • the base that can be used in operation (a) is a common organic or inorganic base.
  • the base include sodium hydrogen carbonate, sodium carbonate, potassium hydrogen carbonate, potassium carbonate, sodium hydroxide, and potassium hydroxide.
  • Operation (a) may be performed in a mixed solvent of a non-polar organic solvent and water, preferably a mixed solvent of methylene chloride and water or a mixed solvent of ethyl acetate and water.
  • the mixture ratio of the non-polar organic solvent to water is about 1 to 1 (v/v).
  • the optically active compound of the formula 2a can be separated using a common method, for example, by extraction of an organic layer followed by washing (if necessary), drying, and concentration.
  • amino protecting group-containing glutamic acids can be reused after recovery. That is, amino protecting group-containing glutamic acids obtained in operation (a) are mobilized to a water layer. The water layer is adjusted to pH 3 or less by addition of hydrochloric acid (HC1) and extracted with an organic solvent such as ethyl acetate. A combined organic layer is dried, filtered, and washed by common methods. An organic phase is concentrated, crystallized in an organic solvent such as diisopropylether, and filtered, to recover the amino protecting group-containing glutamic acids (yield: about 82 %) for reuse.
  • HC1 hydrochloric acid
  • an organic solvent such as ethyl acetate
  • a combined organic layer is dried, filtered, and washed by common methods.
  • An organic phase is concentrated, crystallized in an organic solvent such as diisopropylether, and filtered, to recover the amino protecting group-containing glutamic acids (yield: about 82 %) for reuse.
  • the hydrolysis reaction of operation (b) may be performed in an acidic or basic condition.
  • a basic condition is preferable.
  • Hydrolysis reaction in a basic condition may be performed using 1-2 equivalents of sodium hydroxide or potassium hydroxide.
  • the hydrolysis reaction may be performed in alcohol such as methanol, ethanol, and isopropanol, or a mixed solvent of alcohol and water, preferably in a mixed solvent of methanol and water.
  • the ratio (v/v) of alcohol to water may be about 4 to 6.
  • the hydrolysis reaction may be performed at 0 °C to reflux temperature, preferably 20 to 40 °C .
  • a reaction solution may be purified by washing with ethyl acetate.
  • a washed aqueous solution may be adjusted to pH 4-5 by addition of HC1 and extracted with methylene chloride.
  • Organic phases are combined and dried by a common method.
  • a hydrolysate obtained in operation (b) may react with HC1 in the presence of an organic solvent such as acetone to prepare optically active cetirizine hydrochloride.
  • optically active compound of the formula 1 used as a starting material in the preparation process of the present invention may be prepared by reacting a racemic compound represented by formula 2b below with an optically active compound represented by formula 3 below:
  • the compound of the formula 2b may be easily prepared by a preparation process disclosed in European Patent No. EP 58146 or by esterification of cetirizine dihydrochloride in alcohol in the presence of acid catalyst.
  • the compound of the formula 3 is commercially available or may be prepared by reacting glutamic acid with a common amino protecting group.
  • the amino protecting group may be phenylsulfonyl, unsubstituted or substituted by lower alkyl of C -C ; sulfonyl substituted by lower alkyl of C -C ; acetyl; ethoxycarbonyl; t-butoxycarbonyl; benzyloxycarbonyl; benzoyl; nicotinoyl; phthaloyl; or the like.
  • the amino protecting group may be phenylsulfonyl or (4-methylphenyl)sulfonyl.
  • the compound of the formula 3 may be prepared by reacting glutamic acid with phenylsulfonyl chloride or (4-methylphenyl)sulfonyl chloride in a mixed solvent of a common organic solvent and water, for example a mixed solvent of tetrahydrofuran and water, in the presence of a base such as triethylamine.
  • the reaction between the compound of the formula 2b and the optically active compound of the formula 3 may be performed in alcohol selected from the group consisting of methanol, ethanol, and isopropanol, or a mixed solvent of alcohol and water, preferably in ethanol, isopropanol, or a mixed solvent of isopropanol and water (95:5, v/v).
  • the compound of the formula 3 may react with the compound of the formula 2b in a mole ratio of 0.4-2.2 to 1, preferably 0.4-1.1 to 1.
  • the reaction between the compound of the formula 2b and the optically active compound of the formula 3 may be performed at 0 °C to reflux temperature, preferably at about 60 to 82 °C (or reflux temperature of a solvent).
  • optically active compound of the formula 1 obtained after the reaction between the compound of the formula 2b and the optically active compound of the formula 3 is recrystallized in alcohol selected from the group consisting of methanol, ethanol, and isopropanol, or a mixed solvent of alcohol and water, to obtain a purer product.
  • the re- crystallization may be performed as follows: a solid obtained by gradual cooling after reflux is filtered at 20 to 40 °C , preferably at 25-30 °C , to obtain a purer product.
  • the thus obtained compound of the formula 1 is an optically active compound. Therefore, the compound of the formula 1 can be used for preparation of optically active cetirizine or its salt. That is, an optically pure compound of the formula 1 may be separated using a common filtration process.
  • the compound of the formula 2b reacts with an L-isomer of the compound of the formula 3 to obtain a dextrorotatory compound of the formula 1 which then reacts with a base followed by hydrolysis and reaction with HC1 to obtain levorotatory cetirizine • dihydrochloride. Also, the compound of the formula 2b reacts with a D-isomer of the compound of the formula 3 to obtain a levorotatory compound of the formula 1 which then reacts with a base followed by hydrolysis and reaction with HC1 to obtain dextrorotatory cetirizine • dihydrochloride.
  • optical purity was measured by high-performance liquid chromatography (HPLC) (CHIRALCELL OD-R column, 250 x 4.6 mm, water (0.5 M NaClO , pH 2 buffer)-acetonitrile, 60:40 (v/v) mixed solvent, flow rate 0.5 ml/min) on a chiral stationary phase.
  • HPLC high-performance liquid chromatography
  • polarity was measured using JASCO P-1030
  • nuclear magnetic resonance (NMR) spectrum was measured using 300 MHz FT-NMR Spectrometer (JEOL JNM-LA300), and a melting point was measured using Buchi B- 545.
  • Example 1 preparation of racemic methyl 2-r2-r4-r(4-chloropheny phenylmethyll - 1-piperazinyllethoxyl acetate
  • the resultant solution was adjusted to pH 3 or less by addition of 33.3 ml (0.2 mole) of a 6 N hydrochloric acid solution and extracted with 150 ml of ethyl acetate continuously three times.
  • a combined organic phase was washed with 100 ml of an aqueous saturated sodium chloride solution.
  • the washed organic phase was dried over anhydrous magnesium sulfate, filtered, washed with ethyl acetate, and concentrated.
  • the concentrate was crystallized by addition of 150 ml of diisopropylether.
  • the resultant solid was filtered and washed with a small quantity of diisopropylether to give 21.79 g of (+)-N-(phenylsulfonyl)-D-glutamic acid as a desired product.
  • Example 3 preparation of (-VN-r(4-methylphenyl)sulfonyll -D-glutamic acid
  • Example 4 preparation of dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyll - 1 -piperazinyll ethoxyl acetate • N- (phenylsulfonyl)-L- glutamate
  • the reaction solution was cooled to room temperature, and the precipitated solid was filtered, washed with a small quantity of a mixed solvent of isopropanol and water, and dried.
  • the dried solid was recrystallized in a mixed solvent (95:5, v/v) of isopropanol and water to give 7.68 g of dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy ] acetate • N- (phenylsulfonyl)-L-glutamate.
  • Example 5 preparation of levorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyll - 1 -piperazinyll ethoxyl acetate • N- (phenylsulfonylVD- lutamate [65] 15.19 g (0.038 mole) of the racemic methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl ]-l-piperazinyl]efhoxy]acetate prepared in Example 1 was dissolved in 150 ml of a mixed solvent (95:5, v/v) of isopropanol and water, heated to 60 °C , and then stirred for one hour after addition of 11.00 g (0.038 mole) of (+)-N- (phenylsulfonyl) -D-glutamic acid prepared in Example 2.
  • reaction solution was cooled to room temperature, and the precipitated solid was filtered, washed with a small quantity of a mixed solvent of isopropanol and water, and dried.
  • the dried solid was recrystallized in a mixed solvent (95:5, v/v) of isopropanol and water to give 8.47 g of levorotatory methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy ] acetate • N-(phenylsulfonyl)-D-glutamate.
  • Example 6 preparation of dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyll - 1 -piperazinyll ethoxyl acetate • N- [(4-methylphenyl)sulfonyll-L-glutamate
  • Example 7 preparation of dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyll - 1 -piperazinyll ethoxyl acetate • N- r(4-methylphenyl)sulfonyll-L-glutamate
  • Example 8 preparation of levorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyll - 1 -piperazinyll ethoxyl acetate • N- [(4-methylphenyl)sulfonyll -D-glutamate
  • the reaction solution was cooled to room temperature, and the precipitated solid was filtered, washed with a small quantity of a mixed solvent of isopropanol and water, and dried.
  • the dried solid was recrystallized in a mixed solvent (95:5, v/v) of isopropanol and water to give 10.10 g of levorotatory methyl 2-[2-[4-[(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy ] acetate • N- [(4-methylphenyl)sulfonyl] -D-glutamate.
  • Example 10 preparation of levorotatory 2-r2-r4-r(4-chloropheny phenylmethyll - 1-piperazinyllethoxyl acetic acid • dihydrochloride (cetirizine • dihydrochloride)
  • Example 11 preparation of levorotatory 2-r2-r4-r(4-chloropheny phenylmethyll - 1-piperazinyllethoxyl acetic acid • dihydrochloride (cetirizine • dihydrochloride [ 104] 1.84 g of levorotatory 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy] acetic acid • dihydrochloride was prepared in the same manner as in Example 10 using 3.25 g (4.62 mmole) of the dextrorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy] acetate • N- [(4-methylphenyl)sulfonyl]-L-glutamate prepared in Example 7.
  • Example 12 preparation of dextrorotatory 2-[2-[4-[(4-chlorophenyl)phenylmethyll -1 -piperazinyll ethoxyl acetic acid • dihydrochloride (cetirizine • dihydrochloride)
  • the concentrate was dissolved in 9.1 ml of methanol and 13.6 ml of a IN aqueous sodium hydroxide solution was gradually added thereto.
  • the reaction mixture was stirred at room temperature for 3 hours and then washed with 91 ml of ethyl acetate after addition of 77.4 ml of water.
  • the aqueous solution phase was adjusted to pH 4-5 by addition of a IN hydrochloric acid solution and extracted with 91 ml of methylene chloride continuously three times.
  • a combined organic phase was dried over anhydrous magnesium sulfate, filtered, washed with methylene chloride, and concentrated.
  • Example 13 preparation of dextrorotatory 2-r2-r4-r(4-chlorophenyl)phenylmethyll -1 -piperazinyll ethoxyl acetic acid • dihydrochloride (cetirizine • dihydrochloride)
  • Example 12 After 91 ml of ethyl acetate was added to 9.10 g (0.013 mole) of the levorotatory methyl 2- [2- [4- [(4-chlorophenyl)phenylmethyl] - 1 -piperazinyl] ethoxy] acetate • N-[(4-methylphenyl)sulfonyl]-D-glutamate prepared in Example 8, 91 ml of a 0.5 M aqueous sodium hydrogen carbonate solution was gradually added and stirred for one hour, and then an organic phase was extracted, a residual aqueous solution of 0.5 M sodium hydrogen carbonate was adjusted to pH 3 or less by addition of 47 ml of IN hydrochloric acid solution and extracted with 50 ml of ethyl acetate continuously three times.
  • optical resolution of racemic cetirizine or its salt using glutamate of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-l-piperazinyl]ethoxy] acetic ester can produce optically active cetirizine or its salt with high yield and purity.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de préparation de cétirizine optiquement active ou de son sel à partir de cétirizine racémique ou de son sel, qui consiste à utiliser du glutamate de 2-[2-[4-[(4-chlorphényl)phénylméthyl]-1-pipérazinyl] éthoxy] ester acétique et du glutamate de 2-[2-[4-[(4-chlorophényl)phénylméthyl]-1-pipérazinyl] éthoxy] ester acétique; celle-ci servant d'intermédiaire dans la préparation de cétirizine optiquement active ou de son sel.
PCT/KR2005/000231 2004-02-02 2005-01-27 Procede de preparation de cetirizine optiquement active ou de son sel Ceased WO2005073207A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP05726293A EP1718627A4 (fr) 2004-02-02 2005-01-27 Procede de preparation de cetirizine optiquement active ou de son sel

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020040006608A KR100503443B1 (ko) 2004-02-02 2004-02-02 광학적으로 활성인 세티리진 또는 그의 염의 제조방법
KR10-2004-0006608 2004-02-02

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WO2005073207A1 true WO2005073207A1 (fr) 2005-08-11

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EP (1) EP1718627A4 (fr)
KR (1) KR100503443B1 (fr)
WO (1) WO2005073207A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101128446B (zh) * 2005-03-03 2010-12-08 Ucb法奇姆股份有限公司 焦谷氨酸盐及其在用于合成右旋西替利嗪和左旋西替利嗪的中间体的光学拆分中的用途

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100954755B1 (ko) * 2007-12-17 2010-04-27 한미약품 주식회사 (ｒ)-(-)-1-[(4-클로로페닐)페닐메틸]피페라진의 제조방법
KR100998067B1 (ko) 2008-09-08 2010-12-03 주식회사 삼오제약 비스(1-[(4-클로로페닐)페닐메틸]피페라진)-2,3-디벤조일 타르타르산 신규 중간체 염 및 이를 이용한 광학 활성적으로 순수한 1-[(4-클로로페닐)페닐메틸]피페라진을 분리하는 분리방법
KR102491445B1 (ko) * 2021-01-05 2023-01-25 (주)분자와물질 광학분할에 의한 새로운 레보세티리진의 제조방법

Citations (6)

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GB2225321A (en) 1988-11-23 1990-05-30 Ucb Sa Process for preparation of a 1-piperazine-ethoxyacetic acid
US5478941A (en) 1993-03-15 1995-12-26 U C B, S.A. Enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl) sulfonyl]piperazine
WO1997037982A1 (fr) * 1996-04-10 1997-10-16 Ucb S.A. Nouveaux [2-(1-piperazinyl)ethoxy]methyle substitues
EP0952153A2 (fr) * 1998-04-23 1999-10-27 Chemagis Ltd. Procédé pour la préparation des esters de l'acide [2-[4-[(4-chlorophényl)phénylméthyl]-1-piperazinyl]-éthoxy]acétique
WO2001012584A2 (fr) * 1999-08-12 2001-02-22 Nicox S.A. Composes pharmaceutiques
WO2001032641A1 (fr) * 1999-10-29 2001-05-10 Salsbury Chemicals, Inc. Procede de preparation de carboxylates aliphatiques a substitution piperazine

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NO155805C (no) * 1981-02-06 1987-06-10 Ucb Sa Analogifremgangsmaate for fremstilling av terapeutisk virksomme 2-(4-(difenylmethyl)-1-piperazinyl)-eddiksyrer og deres amider og ikke-toksiske salter.

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2225321A (en) 1988-11-23 1990-05-30 Ucb Sa Process for preparation of a 1-piperazine-ethoxyacetic acid
US5478941A (en) 1993-03-15 1995-12-26 U C B, S.A. Enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl) sulfonyl]piperazine
WO1997037982A1 (fr) * 1996-04-10 1997-10-16 Ucb S.A. Nouveaux [2-(1-piperazinyl)ethoxy]methyle substitues
EP0952153A2 (fr) * 1998-04-23 1999-10-27 Chemagis Ltd. Procédé pour la préparation des esters de l'acide [2-[4-[(4-chlorophényl)phénylméthyl]-1-piperazinyl]-éthoxy]acétique
WO2001012584A2 (fr) * 1999-08-12 2001-02-22 Nicox S.A. Composes pharmaceutiques
WO2001032641A1 (fr) * 1999-10-29 2001-05-10 Salsbury Chemicals, Inc. Procede de preparation de carboxylates aliphatiques a substitution piperazine

Non-Patent Citations (3)

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Title
COREY ET AL: "Catalytic enantioselective synthesis of the second generation histamine antagonist cetirizine hydrochloride", TETRAHEDRON LETTERS, vol. 37, no. 28, 8 July 1996 (1996-07-08), pages 4837 - 4840, XP004029527 *
PFLUM, D.A. ET AL., ORGANIC PROCESS RESEARCH & DEVELOPMENT, vol. 5, no. 2, March 2001 (2001-03-01), pages 110 - 115
See also references of EP1718627A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101128446B (zh) * 2005-03-03 2010-12-08 Ucb法奇姆股份有限公司 焦谷氨酸盐及其在用于合成右旋西替利嗪和左旋西替利嗪的中间体的光学拆分中的用途

Also Published As

Publication number Publication date
KR100503443B1 (ko) 2005-07-22
EP1718627A1 (fr) 2006-11-08
EP1718627A4 (fr) 2007-04-18

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