CN1139596C - 头孢地尼的胺盐晶体 - Google Patents
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Abstract
头孢地尼与二环己基胺形成的盐，制备此盐的方法以及其在纯化不纯头孢地尼过程中的用途。
Description
本发明涉及头孢地尼，即式I所示的7-(Z)-[2-(2-氨基噻唑-4-基)-2-肟基乙酰氨基]-3-乙烯基-3-头孢烯-4-羧酸纯化过程中的中间体
头孢地尼可以以例如一水合物的形式作为药物例如抗生素来使用；参见例如Y.Inamoto，Toshiyuki Chiba，Toshiaki Kiamimura和Takao Takaya，《抗生素杂志》(J.Antibiotics)，第XLI卷，第6期，829，(1988)。
依据已知的制备方法，可以获得不纯的头孢地尼。现在，令人惊奇地发现，不纯的头孢地尼可以通过形成盐，例如以其结晶形式的盐来纯化。
一方面，本发明提供了式I化合物与二环己基胺形成的盐，例如结晶盐。
式I化合物与二环己基胺形成的盐可通过如下方法制备：
头孢地尼，例如头孢地尼溶剂化物，如头孢地尼水合物，例如不纯形式，例如在头孢地尼制备过程中获得的，例如头孢地尼和杂质的混合物，例如在头孢地尼制备过程中生成的副产物和头孢地尼的混合物；可在溶剂存在下，例如以溶解或悬浮的形式用二环己基胺处理。溶剂包括对头孢地尼或头孢地尼与二环己基胺形成的盐具有惰性的任意溶剂，例如极性有机溶剂，如酰胺，例如二甲基甲酰胺；醇，例如甲醇或乙醇；酮，例如丙酮；例如与水混合以及水。可以使用溶剂体系，例如单个溶剂的混合物，例如上述溶剂的混合物。优选的溶剂体系可以是例如丙酮/水，其比例包括，例如约100∶1，如50∶1，例如20∶1-1∶5；如10∶1-1∶3，如5∶1-2∶1，例如约1∶1。每当量头孢地尼可以使用约1当量或1当量以上如5、3、或2当量的二环己基胺，例如与不纯的头孢地尼在溶剂中的混合物混合。式I化合物与二环己基胺形成的盐可以结晶，例如从反应溶液中结晶，或，例如式I化合物在溶剂中的悬浮液可以转化成式I化合物与二环己基胺形成的盐的结晶悬浮液。可以向反应混合物中加入反溶剂，以例如结晶完全。反溶剂包括这样的溶剂，如果把它们加到式I化合物与二环己基胺形成的盐的溶液或悬浮液中，则式I化合物与二环己基胺形成的盐将不能溶解或只能溶解一小部分，例如非极性溶剂；例如醚，如乙醚，四氢呋喃；或酮，例如丙酮。用例如常规分离方法，如通过过滤、离心，可以把式I化合物与二环己基胺形成的盐从反应混合物中分离出来。
式I化合物与二环己基胺形成的盐能以纯的形式获得，例如纯度为98％以及98％以上，例如99％-100％的纯度；例如，杂质在用于成盐的不纯的头孢地尼中的含量可以减少；例如，杂质的含量可以从在不纯的头孢地尼中的10％或10％以上，降到在头孢地尼与二环己基胺形成的盐中的1％或1％以下，例如0-1％。通过在例如(反)溶剂(体系)，例如上述(反)溶剂(体系)中，如上所述进行再悬浮或再溶解，可以进一步纯化式I化合物与二环己基胺形成的盐。
另一方面，本发明提供了制备式I化合物与二环己基胺形成的盐，例如晶体形式的盐的方法，包括将式I化合物，例如其溶剂化物如水合物，在溶剂中用二环己基胺处理，分离式I化合物与二环己基胺形成的盐，例如晶体形式的盐。
游离形式，例如溶剂化物形式，如水合物形式，例如一水合物形式的头孢地尼，并且就用于形成式I化合物与二环己基胺的盐的不纯头孢地尼而言算是纯的头孢地尼，可通过下述方法从式I化合物与二环己基胺形成的盐中获得：用例如释放盐形式的化合物如胺盐化合物的常规方法，通过例如加入酸性试剂，例如有机酸或无机酸，优选无机酸，例如硫酸来调节例如头孢地尼与二环己基胺形成的盐与溶剂，例如在水存在下，优选在水中的混合物，例如溶液的pH至适当值，例如1.5-4，如2-3。头孢地尼，例如水合物形式，如一水合物形式的头孢地尼，可以结晶并且可以用常规分离方法，例如通过过滤、离心来分离。依据本发明的方法，可以获得式I化合物本身，或溶剂化物形式，例如水合物形式，如一水合物形式的式I化合物。依据本发明的方法获得的式I化合物本身可以转化成溶剂化物形式，如水合物形式，例如一水合物形式的式I化合物，反之亦然。
另一方面，本发明提供了制备式I化合物，例如溶剂化物形式，如水合物形式，例如一水合物形式的式I化合物的方法，包括将式I化合物与二环己基胺形成的盐，例如晶体形式的盐，转化成式I化合物，例如溶剂化物形式的式I化合物，分离式I化合物，例如溶剂化物形式的式I化合物。
另一方面，本发明提供了在式I化合物与杂质的混合物中纯化头孢地尼的方法，包括形成式I化合物与二环己基胺的盐；将式I化合物与二环己基胺形成的盐，例如晶体形式的盐，转化成式I化合物，例如溶剂化物形式的式I化合物，分离式I化合物，例如溶剂化物形式的式I化合物。
式I化合物与二环己基胺形成的盐能用于纯化不纯的头孢地尼。
另一方面，本发明提供了式I化合物与二环己基胺形成的盐例如结晶形式的盐在式I化合物与杂质的混合物纯化过程中的用途。
本发明具有几个令人惊奇的优点：
式I化合物与二环己基胺形成的盐可以是晶体形式；盐形式头孢地尼能以令人惊奇的高纯度获得，例如纯度为98％和98％以上，例如98％-100％的纯度；所述盐的制备过程很简单；从所述盐获得的头孢地尼令人惊奇地纯，例如纯度为98％和98％以上，例如99％-100％的纯度。
令人惊奇的是，头孢地尼在依据本发明成盐的碱性条件下是稳定的，因为从例如Yoshihiko Okamoto等人的《药物科学杂志》(J.ofPharmaceutical Sciences)，第85卷，第9期，976，(1996)中得知，头孢地尼在碱性环境下是不稳定的；例如，发现在类似的条件下，在其它胺例如叔辛基胺存在下，头孢地尼可能会例如严重地降解。
另一方面，本发明提供了式I’所示的7-(Z)-[2-(2-氨基噻唑-4-基)-2-肟基乙酰氨基]-3-乙烯基-3-头孢烯-4-羧酸.二环己基铵盐晶体。
在下述用于更详细地阐述本发明，但决不是限制本发明保护范围的实施例中，所有的温度是摄氏度。所得化合物的纯度是用HPLC测定的。
实施例17-(Z)-[2-(2-氨基噻唑-4-基)-2-肟基乙酰氨基]-3-乙烯基-3-头孢烯-4-羧酸与二环己基胺形成的盐
将在50ml水和50ml丙酮中的10g头孢地尼粗产物，例如在头孢地尼生产过程中获得的头孢地尼在搅拌下用5ml二环己基胺处理。获得了溶液，并且7-(Z)-[2-(2-氨基噻唑-4-基)-2-肟基乙酰氨基]-3-乙烯基-3-头孢烯-4-羧酸与二环己基胺形成的盐结晶出来。向晶体悬浮液中加入250ml丙酮，在室温下搅拌约30分钟。将晶体过滤，用丙酮洗涤并干燥。获得纯度为98.6％的7-(Z)-[2-(2-氨基噻唑-4-基)-2-肟基乙酰氨基]-3-乙烯基-3-头孢烯-4-羧酸与二环己基胺形成的结晶盐。熔点：175℃(分解)。1H-NMR(DMSO-d6)：9.41(d，1H，J＝8.1Hz，NH)；7.12(s，2H，NH2)；6.99(dd，1H，J＝11.4和17.7Hz，CH＝CH2)；6.64(s，1H，噻唑)；5.60(dd，1H，J＝4.8和8.1Hz，H7)；5.15(d，1H J＝17.7Hz，CH＝CH2)；5.04(d，iH，J＝4.8Hz，H6)；4.94(d，1H，J＝11.4Hz，CH＝CH2)；3.52，3.39(AB d，1H，J＝17Hz，H2)；3.21(m，2H)；2.05(m，4H)；1.8(m，4H)；1.6(m，2H)；1.2-1.4(m，10H).
实施例27-(Z)-[2-(2-氨基噻唑-4-基)-2-肟基乙酰氨基]-3-乙烯基-3-头孢烯-4-羧酸一水合物
在大约35-40℃温度下，将10g依据实施例1获得的7-(Z)-[2-(2-氨基噻唑-4-基)-2-肟基乙酰氨基]-3-乙烯基-3-头孢烯-4-羧酸与二环己基胺形成的盐溶在175ml水中，用活性炭处理。滤除活性炭，在约35℃通过加入5ml硫酸将溶液的pH值调至2.5。7-(Z)-[2-(2-氨基噻唑-4-基)-2-肟基乙酰氨基]-3-乙烯基-3-头孢烯-4-羧酸一水合物沉淀出来，过滤，用水洗涤并干燥。获得纯度为99％的7-(Z)-[2-(2-氨基噻唑-4-基)-2-肟基乙酰氨基]-3-乙烯基-3-头孢烯-4-羧酸一水合物。
实施例3制备头孢地尼粗产物
将在400ml二氯甲烷中的40g 7-氨基-3-乙烯基-3-头孢烯-4-羧酸用55.7ml N，O-双三甲基甲硅烷基乙酰胺处理。把获得的混合物在室温下搅拌约2小时，冷却至0℃，用52.2g 2-(Z)-(2-氨基噻唑-4-基)-2-乙酰氧基亚氨基乙酰氯盐酸盐(分成小批量加入)处理。将获得的混合物在0℃搅拌约90分钟，在5℃搅拌条件下加入44.55gNaHCO3、600ml水和100ml二氯甲烷。用饱和NaHCO3水溶液将混合物的pH值调至约7.2-7.3。分离形成的各相。向水相中加入300ml水和28.7g NH4Cl。通过加入10％的K2CO3水溶液将所得混合物的pH值调至8，将混合物搅拌约80分钟。获得了溶液。通过加入5ml硫酸把所得溶液的pH值调至3。7-(Z)-[2-(2-氨基噻唑-4-基)-2-肟基乙酰氨基]-3-乙烯基-3-头孢烯-4-羧酸沉淀出来，过滤，用水洗涤并干燥。获得纯度为94.3％的7-(Z)-[2-(2-氨基噻唑-4-基)-2-肟基乙酰氨基]-3-乙烯基-3-头孢烯-4-羧酸。
Claims (7)
1.一种式I化合物与二环己基胺形成的结晶形盐。
2.一种制备如权利要求1所定义的式I化合物的方法，包括将式I化合物与二环己基胺形成的结晶形盐转化成式I化合物，分离式I化合物。
3.一种在式I化合物与杂质的混合物中纯化如权利要求1所定义的式I化合物的方法，包括形成式I化合物与二环己基胺的盐；分离式I化合物与二环己基胺形成的结晶形盐；将式I化合物与二环己基胺形成的盐转化成式I化合物，分离式I化合物。
4.根据权利要求2-3任一项的方法，包括将式I化合物与二环己基胺形成的结晶形盐转化成溶剂化物形式的式I化合物。
5.根据权利要求2-4任一项的方法，包括分离式I化合物的溶剂化物。
6.权利要求1所述的化合物在式I化合物与杂质的混合物纯化过程中的用途。
7.式I’所示的7-(Z)-[2-(2-氨基噻唑-4-基)-2-肟基乙酰氨基]-3-乙烯基-3-头孢烯-4-羧酸.二环己基铵盐晶体。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AT0057097A AT405283B (de) | 1997-04-04 | 1997-04-04 | Neues kristallines 7-(z)-(2-(2-aminothiazol-4-yl) -2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4- carbonsäure dicyclohexylammoniumsalz und verfahren zu dessen herstellung |
| ATA570/97 | 1997-04-04 | ||
| ATA570/1997 | 1997-04-04 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1251590A CN1251590A (zh) | 2000-04-26 |
| CN1139596C true CN1139596C (zh) | 2004-02-25 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB988038501A Expired - Fee Related CN1139596C (zh) | 1997-04-04 | 1998-04-02 | 头孢地尼的胺盐晶体 |
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| Country | Link |
|---|---|
| US (1) | US6350869B1 (zh) |
| EP (1) | EP0973779B1 (zh) |
| JP (1) | JP3421354B2 (zh) |
| KR (1) | KR100442717B1 (zh) |
| CN (1) | CN1139596C (zh) |
| AT (2) | AT405283B (zh) |
| AU (1) | AU731413B2 (zh) |
| BR (1) | BR9809745A (zh) |
| CA (1) | CA2283718A1 (zh) |
| DE (1) | DE69816056T2 (zh) |
| HU (1) | HUP0002987A3 (zh) |
| ID (1) | ID22536A (zh) |
| IL (1) | IL131755A0 (zh) |
| NO (1) | NO994466L (zh) |
| PL (1) | PL335620A1 (zh) |
| SK (1) | SK134399A3 (zh) |
| TR (1) | TR199902406T2 (zh) |
| WO (1) | WO1998045299A1 (zh) |
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| ITMI20020913A0 (it) * | 2002-04-29 | 2002-04-29 | Acs Dobfar Spa | Nuova forma cristallina del cefdinir |
| EP1842852A1 (en) | 2002-08-13 | 2007-10-10 | Sandoz AG | A cefdinir intermediate |
| ITMI20022076A1 (it) | 2002-10-01 | 2004-04-02 | Antibioticos Spa | Sali di intermedi del cefdinir. |
| AU2003276525A1 (en) * | 2002-11-15 | 2004-06-15 | Orchid Chemicals And Pharmaceuticals Ltd | Novel amorphous hydrate of a cephalosporin antibiotic |
| ITMI20022724A1 (it) * | 2002-12-20 | 2004-06-21 | Antibioticos Spa | Sali cristallini del cefdinir. |
| JPWO2004085443A1 (ja) * | 2003-03-24 | 2006-06-29 | ア・チ・エツセ・ドブフアル・エツセ・ピー・アー | ７−［２−（２−アミノチアゾール−４−イル）−２−ヒドロキシイミノアセトアミド−３−ビニル−３−セフェム−４−カルボン酸（シン異性体）の新規結晶およびその製造方法 |
| WO2004104010A1 (en) * | 2003-05-20 | 2004-12-02 | Ranbaxy Laboratories Limited | Crystalline form of cefdinir |
| US20050137182A1 (en) * | 2003-06-02 | 2005-06-23 | Ramesh Dandala | Novel crystalline form of cefdinir |
| US20040242556A1 (en) * | 2003-06-02 | 2004-12-02 | Ramesh Dandala | Novel crystalline form of cefdinir |
| US20050059819A1 (en) * | 2003-09-12 | 2005-03-17 | Duerst Richard W. | Cefdinir pyridine salt |
| US20050059818A1 (en) * | 2003-09-12 | 2005-03-17 | Duerst Richard W. | Polymorph of a pharmaceutical |
| US20050113355A1 (en) * | 2003-09-12 | 2005-05-26 | Duerst Richard W. | Cefdinir pyridine salt |
| US20060142563A1 (en) * | 2004-03-16 | 2006-06-29 | Devalina Law | Crystalline anhydrous cefdinir and crystalline cefdinir hydrates |
| US20050209211A1 (en) * | 2004-03-16 | 2005-09-22 | Devalina Law | Trihemihydrate, anhydrate and novel hydrate forms of Cefdinir |
| US20060211676A1 (en) * | 2004-03-16 | 2006-09-21 | Devalina Law | Crystalline anhydrous cefdinir and crystalline cefdinir hydrates |
| US20060142261A1 (en) * | 2004-03-16 | 2006-06-29 | Devalina Law | Crystalline anhydrous cefdinir and crystalline cefdinir hydrates |
| WO2005090360A1 (en) * | 2004-03-19 | 2005-09-29 | Orchid Chemicals & Pharmaceuticals Limited | Novel polymorph of cefdinir |
| US20060069079A1 (en) * | 2004-09-27 | 2006-03-30 | Sever Nancy E | Stable amorphous cefdinir |
| US20050245738A1 (en) * | 2004-05-03 | 2005-11-03 | Lupin Ltd | Stable bioavailable crystalline form or cefdinir and a process for the preparation thereof |
| WO2006010978A1 (en) * | 2004-06-30 | 2006-02-02 | Wockhardt Limited | Cefdinir polymorphic forms, and imidazole salt |
| EP1765833A2 (en) | 2004-07-05 | 2007-03-28 | Orchid Chemicals and Pharmaceuticals Limited | News salts in the preparation of cephalosporin antibiotics |
| WO2006018807A1 (en) * | 2004-08-16 | 2006-02-23 | Ranbaxy Laboratories Limited | Crystalline forms of cefdinir |
| ITMI20042231A1 (it) * | 2004-11-19 | 2005-02-19 | Antibioticos Spa | Cefdinir sale d'ammonio in forma cristallina |
| MX2007006018A (es) * | 2004-11-30 | 2007-06-07 | Astellas Pharma Inc | Suspension farmaceutica oral novedosa de cristal de cefdinir. |
| GB2421024A (en) * | 2004-12-07 | 2006-06-14 | Sandoz Ag | Cefdinir crystalline form C |
| WO2006117794A1 (en) * | 2005-05-02 | 2006-11-09 | Hetero Drugs Limited | A novel crystalline form of cefdinir |
| US20080287673A1 (en) * | 2005-06-15 | 2008-11-20 | Parthasaradhi Reddy Bandk | Cefdinir process |
| CN1903860B (zh) * | 2005-07-25 | 2012-01-18 | 四川抗菌素工业研究所有限公司 | 溶媒法制备高纯度头孢他美钠工艺及医药用途 |
| WO2007053722A2 (en) * | 2005-10-31 | 2007-05-10 | Teva Pharmaceutical Industries Ltd. | Crystalline form of cefdinir cesium salt |
| US20070128268A1 (en) * | 2005-12-07 | 2007-06-07 | Herwig Jennewein | Pharmaceutical compositions comprising an antibiotic |
| CN101481383B (zh) * | 2008-12-31 | 2012-01-11 | 杭州奥默医药技术有限公司 | 头孢地尼酸式复盐化合物及制备方法 |
| TR200909784A1 (tr) * | 2009-12-25 | 2011-07-21 | Bi̇lgi̇ç Mahmut | Yeni sefdinir tuzları |
| US8614315B2 (en) | 2009-12-25 | 2013-12-24 | Mahmut Bilgic | Cefdinir and cefixime formulations and uses thereof |
| CN102010427B (zh) * | 2010-11-19 | 2012-09-12 | 苏州中联化学制药有限公司 | 一种头孢地尼的制备方法 |
| CN101974020B (zh) * | 2010-11-19 | 2012-09-12 | 苏州中联化学制药有限公司 | 一种头孢地尼的合成方法 |
| CN103012433B (zh) * | 2012-12-13 | 2015-06-24 | 珠海保税区丽珠合成制药有限公司 | 头孢地尼晶型b的制备方法 |
| CN111039958B (zh) * | 2017-05-31 | 2022-05-20 | 郑州大学第一附属医院 | 头孢地尼的制备方法 |
| CN107286148B (zh) * | 2017-06-20 | 2019-10-15 | 广州市桐晖通医药科技有限公司 | 一种头孢地尼的制备方法及其新的中间体化合物 |
| CN111635419B (zh) * | 2020-07-13 | 2022-05-24 | 广药白云山化学制药(珠海)有限公司 | 一种头孢地尼精制母液的处理方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR5564M (zh) * | 1964-03-14 | 1968-01-02 | ||
| GB8323034D0 (en) | 1983-08-26 | 1983-09-28 | Fujisawo Pharmaceutical Co Ltd | 7-substituted-3-vinyl-3-cephem compounds |
| ZA885709B (en) * | 1987-08-19 | 1989-04-26 | Fujisawa Pharmaceutical Co | Novel crystalline 7-(2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido)-3-vinyl-3-cephem-4-carboxylic acid(syn isomer) |
| JP2825655B2 (ja) * | 1992-02-05 | 1998-11-18 | バイオケミ・ゲゼルシヤフト・エム・ベー・ハー | ３−セフェム−４−カルボン酸誘導体の精製方法 |
| KR960704897A (ko) * | 1994-07-22 | 1996-10-09 | 에밀리오 마우리 | 글루타릴 7-아미노세팔로스포란산 유도체 및 이의 제조 방법 (Glutaryl 7-ACA derivatives and processes for obtaining them) |
| AT403049B (de) * | 1995-08-14 | 1997-10-27 | Biochemie Gmbh | Abreicherung von 7-adca in 3-vinyl-aca |
| EP0874853B1 (en) * | 1995-12-27 | 2002-06-05 | Hanmi Pharmaceutical Co.,Ltd. | Process for preparation of cefdinir |
| AT404251B (de) * | 1996-08-14 | 1998-10-27 | Biochemie Gmbh | Neues kristallines salz von cefixim |
-
1997
- 1997-04-04 AT AT0057097A patent/AT405283B/de active
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1998
- 1998-04-02 CN CNB988038501A patent/CN1139596C/zh not_active Expired - Fee Related
- 1998-04-02 US US09/381,947 patent/US6350869B1/en not_active Expired - Lifetime
- 1998-04-02 CA CA002283718A patent/CA2283718A1/en not_active Abandoned
- 1998-04-02 SK SK1343-99A patent/SK134399A3/sk unknown
- 1998-04-02 AT AT98921425T patent/ATE244249T1/de not_active IP Right Cessation
- 1998-04-02 BR BR9809745-8A patent/BR9809745A/pt not_active IP Right Cessation
- 1998-04-02 JP JP54235898A patent/JP3421354B2/ja not_active Expired - Fee Related
- 1998-04-02 TR TR1999/02406T patent/TR199902406T2/xx unknown
- 1998-04-02 PL PL98335620A patent/PL335620A1/xx unknown
- 1998-04-02 DE DE69816056T patent/DE69816056T2/de not_active Expired - Fee Related
- 1998-04-02 IL IL13175598A patent/IL131755A0/xx unknown
- 1998-04-02 KR KR10-1999-7008984A patent/KR100442717B1/ko not_active IP Right Cessation
- 1998-04-02 ID IDW991137A patent/ID22536A/id unknown
- 1998-04-02 WO PCT/EP1998/001953 patent/WO1998045299A1/en active IP Right Grant
- 1998-04-02 AU AU74288/98A patent/AU731413B2/en not_active Ceased
- 1998-04-02 EP EP98921425A patent/EP0973779B1/en not_active Expired - Lifetime
- 1998-04-02 HU HU0002987A patent/HUP0002987A3/hu unknown
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Also Published As
| Publication number | Publication date |
|---|---|
| JP3421354B2 (ja) | 2003-06-30 |
| ID22536A (id) | 1999-11-04 |
| BR9809745A (pt) | 2000-06-20 |
| DE69816056T2 (de) | 2004-04-15 |
| HUP0002987A2 (hu) | 2001-02-28 |
| IL131755A0 (en) | 2001-03-19 |
| US6350869B1 (en) | 2002-02-26 |
| JP2000514833A (ja) | 2000-11-07 |
| NO994466D0 (no) | 1999-09-15 |
| WO1998045299A1 (en) | 1998-10-15 |
| AU7428898A (en) | 1998-10-30 |
| HUP0002987A3 (en) | 2001-04-28 |
| KR100442717B1 (ko) | 2004-08-02 |
| PL335620A1 (en) | 2000-05-08 |
| KR20010005907A (ko) | 2001-01-15 |
| EP0973779A1 (en) | 2000-01-26 |
| TR199902406T2 (xx) | 2000-02-21 |
| ATA57097A (de) | 1998-11-15 |
| SK134399A3 (en) | 2000-05-16 |
| DE69816056D1 (de) | 2003-08-07 |
| AT405283B (de) | 1999-06-25 |
| AU731413B2 (en) | 2001-03-29 |
| CN1251590A (zh) | 2000-04-26 |
| EP0973779B1 (en) | 2003-07-02 |
| NO994466L (no) | 1999-09-15 |
| CA2283718A1 (en) | 1998-10-15 |
| ATE244249T1 (de) | 2003-07-15 |
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