NO315469B1 - Camptothecinderivater, fremgangsmåter for fremstilling derav, farmasöytiskepreparater som omfatter disse, og anvendelse av derivatene tilfremstilling avpreparater for profylakse eller behandliing av tumor - Google Patents
Camptothecinderivater, fremgangsmåter for fremstilling derav, farmasöytiskepreparater som omfatter disse, og anvendelse av derivatene tilfremstilling avpreparater for profylakse eller behandliing av tumor Download PDFInfo
- Publication number
- NO315469B1 NO315469B1 NO19963214A NO963214A NO315469B1 NO 315469 B1 NO315469 B1 NO 315469B1 NO 19963214 A NO19963214 A NO 19963214A NO 963214 A NO963214 A NO 963214A NO 315469 B1 NO315469 B1 NO 315469B1
- Authority
- NO
- Norway
- Prior art keywords
- group
- compound
- camptothecin
- formula
- peptide
- Prior art date
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- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title claims abstract description 145
- 238000002360 preparation method Methods 0.000 title claims description 134
- 238000000034 method Methods 0.000 title claims description 18
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- 238000011282 treatment Methods 0.000 title claims 2
- 239000008194 pharmaceutical composition Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 155
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract description 76
- 150000001413 amino acids Chemical class 0.000 claims abstract description 61
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 56
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 52
- 239000005017 polysaccharide Substances 0.000 claims abstract description 52
- 150000003839 salts Chemical class 0.000 claims abstract description 49
- 125000004430 oxygen atom Chemical group O* 0.000 claims abstract description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 17
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 15
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- 150000004676 glycans Chemical group 0.000 claims abstract 15
- 229940127093 camptothecin Drugs 0.000 claims description 210
- -1 3-aminopropyloxy group Chemical group 0.000 claims description 84
- 239000000203 mixture Substances 0.000 claims description 71
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 42
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 31
- 125000003277 amino group Chemical group 0.000 claims description 29
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- 210000004899 c-terminal region Anatomy 0.000 claims description 5
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- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP19739195 | 1995-08-02 | ||
| JP34061995 | 1995-12-27 | ||
| JP17337296 | 1996-07-03 |
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| NO963214D0 NO963214D0 (no) | 1996-08-01 |
| NO963214L NO963214L (no) | 1997-02-03 |
| NO315469B1 true NO315469B1 (no) | 2003-09-08 |
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| Application Number | Title | Priority Date | Filing Date |
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| NO19963214A NO315469B1 (no) | 1995-08-02 | 1996-08-01 | Camptothecinderivater, fremgangsmåter for fremstilling derav, farmasöytiskepreparater som omfatter disse, og anvendelse av derivatene tilfremstilling avpreparater for profylakse eller behandliing av tumor |
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| Country | Link |
|---|---|
| US (1) | US5837673A (es) |
| EP (1) | EP0757049B1 (es) |
| KR (1) | KR100387191B1 (es) |
| CN (2) | CN1143859C (es) |
| AT (1) | ATE178067T1 (es) |
| AU (1) | AU717653B2 (es) |
| BG (1) | BG63342B1 (es) |
| CA (1) | CA2182244C (es) |
| DE (1) | DE69601841T2 (es) |
| DK (1) | DK0757049T3 (es) |
| ES (1) | ES2131913T3 (es) |
| GR (1) | GR3029796T3 (es) |
| HK (1) | HK1005545A1 (es) |
| HU (1) | HUP9602122A3 (es) |
| IL (1) | IL118957A (es) |
| MY (1) | MY116665A (es) |
| NO (1) | NO315469B1 (es) |
| RU (1) | RU2138503C1 (es) |
| SG (1) | SG50747A1 (es) |
| TW (1) | TW466242B (es) |
Families Citing this family (70)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2192725C (en) | 1995-12-28 | 2004-04-20 | Kenji Tsujihara | Camptothecin derivatives |
| US6096336A (en) * | 1996-01-30 | 2000-08-01 | The Stehlin Foundation For Cancer Research | Liposomal prodrugs comprising derivatives of camptothecin and methods of treating cancer using these prodrugs |
| US6441025B2 (en) * | 1996-03-12 | 2002-08-27 | Pg-Txl Company, L.P. | Water soluble paclitaxel derivatives |
| TW409058B (en) | 1996-06-06 | 2000-10-21 | Daiichi Seiyaku Co | Method for preparation of a drug complex |
| TW527183B (en) | 1996-06-06 | 2003-04-11 | Daiichi Seiyaku Co | Drug complex |
| DE19640207A1 (de) * | 1996-09-30 | 1998-04-02 | Bayer Ag | Glycokonjugate von modifizierten Camptothecin-Derivaten (A- oder B-Ring-Verknüpfung) |
| DK0934329T3 (da) * | 1996-09-30 | 2002-04-08 | Bayer Ag | Glycokonjugater af modificerede camptothecinderivater (20-O-binding) |
| SG88737A1 (en) | 1996-10-30 | 2002-05-21 | Tanabe Seiyaku Co | S type 2-substituted hydroxy-2-indolidinylbutyric ester compounds and process for preparation thereof |
| US6361938B1 (en) * | 1996-11-08 | 2002-03-26 | Elan Corporation, Plc | Peptides which enhance transport across tissues and methods of identifying and using the same |
| ID23424A (id) * | 1997-05-14 | 2000-04-20 | Bayer Ag | Glikokonjugat dari 20(s)-kamptotesin |
| US6011042A (en) * | 1997-10-10 | 2000-01-04 | Enzon, Inc. | Acyl polymeric derivatives of aromatic hydroxyl-containing compounds |
| US6352996B1 (en) | 1999-08-03 | 2002-03-05 | The Stehlin Foundation For Cancer Research | Liposomal prodrugs comprising derivatives of camptothecin and methods of treating cancer using these prodrugs |
| US6228855B1 (en) | 1999-08-03 | 2001-05-08 | The Stehlin Foundation For Cancer Research | Aromatic esters of camptothecins and methods to treat cancers |
| AU775373B2 (en) | 1999-10-01 | 2004-07-29 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
| US20030054977A1 (en) * | 1999-10-12 | 2003-03-20 | Cell Therapeutics, Inc. | Manufacture of polyglutamate-therapeutic agent conjugates |
| US20040009229A1 (en) * | 2000-01-05 | 2004-01-15 | Unger Evan Charles | Stabilized nanoparticle formulations of camptotheca derivatives |
| US20020077290A1 (en) * | 2000-03-17 | 2002-06-20 | Rama Bhatt | Polyglutamic acid-camptothecin conjugates and methods of preparation |
| CA2412582A1 (en) * | 2000-06-29 | 2002-01-03 | Daiichi Pharmaceutical Co., Ltd. | Dds compound and process for the preparation thereof |
| CA2427467C (en) | 2000-11-09 | 2010-01-12 | Neopharm, Inc. | Sn-38 lipid complexes and methods of use |
| WO2003030864A1 (en) | 2001-05-29 | 2003-04-17 | Neopharm, Inc. | Liposomal formulation of irinotecan |
| US20030092608A1 (en) * | 2001-08-21 | 2003-05-15 | Takayuki Kawaguchi | Pharmaceutical composition for inhibiting the metastasis or preventing the recurrence of malignant tumor |
| TWI313609B (en) * | 2001-08-21 | 2009-08-21 | Mitsubishi Tanabe Pharma Corp | Pharmaceutical composition for inhibiting the metastasis or preventing the recurrence of malignant tumor |
| WO2003033525A1 (en) * | 2001-10-12 | 2003-04-24 | Debio Recherche Pharmacuetique S.A. | Amino-substituted camptothecin polymer derivatives and use of the same for the manufacture of a medicament |
| TW200306314A (en) * | 2002-04-16 | 2003-11-16 | Tanabe Seiyaku Co | Liquid preparation comprising camptothecin derivative and pharmaceutical composition producible by lyophilizing the preparation |
| US7495099B2 (en) * | 2002-10-31 | 2009-02-24 | Nippon Kayaku Kabushiki Kaisha | High-molecular weight derivatives of camptothecins |
| WO2004092205A1 (en) * | 2003-04-16 | 2004-10-28 | Debio Recherche Pharmacuetique S.A. | Hydroxy-substituted-20-acyloxy-camptothecin polymer derivatives and use of the same for the manufacture of a medicament |
| US20040247624A1 (en) * | 2003-06-05 | 2004-12-09 | Unger Evan Charles | Methods of making pharmaceutical formulations for the delivery of drugs having low aqueous solubility |
| CN102172405B (zh) * | 2003-09-17 | 2014-11-12 | 耐科塔医药公司 | 多支链聚合物的药物前体 |
| US8394365B2 (en) | 2003-09-17 | 2013-03-12 | Nektar Therapeutics | Multi-arm polymer prodrugs |
| JP4433918B2 (ja) * | 2004-07-15 | 2010-03-17 | コニカミノルタエムジー株式会社 | 画像形成方法 |
| KR101203475B1 (ko) | 2004-09-22 | 2012-11-21 | 니폰 가야꾸 가부시끼가이샤 | 신규 블록 공중합체, 미셀 제제물 및 이를 유효성분으로함유하는 항암제 |
| KR100651728B1 (ko) * | 2004-11-10 | 2006-12-06 | 한국전자통신연구원 | 정착기를 갖는 전자 소자용 화합물 및 이를 포함하는 전자소자와 이들의 제조 방법 |
| TWI375678B (en) | 2005-06-09 | 2012-11-01 | Yakult Honsha Kk | A method of preparation of a tricyclic ketone |
| ITFI20050246A1 (it) * | 2005-12-02 | 2007-06-03 | Menarini Internat Operations Luxembourg Sa | Uso di un composto comprendente un derivato della camptotecina per la preparazione di formulazioni farmaceutiche utili nel trattamento del melanoma |
| US7462627B2 (en) | 2006-02-09 | 2008-12-09 | Enzon Pharmaceuticals, Inc. | Multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamptothecin for treatment of breast, colorectal, pancreatic, ovarian and lung cancers |
| US7671067B2 (en) | 2006-02-09 | 2010-03-02 | Enzon Pharmaceuticals, Inc. | Treatment of non-hodgkin's lymphomas with multi-arm polymeric conjugates of 7-ethyl-10-hydroxycamtothecin |
| KR20080106254A (ko) | 2006-03-28 | 2008-12-04 | 니폰 가야꾸 가부시끼가이샤 | 탁산류의 고분자 결합체 |
| US8940332B2 (en) | 2006-05-18 | 2015-01-27 | Nippon Kayaku Kabushiki Kaisha | High-molecular weight conjugate of podophyllotoxins |
| EP2080779B1 (en) | 2006-11-06 | 2016-05-18 | Nippon Kayaku Kabushiki Kaisha | Polymeric derivative of nucleic acid metabolic antagonist |
| JP5548365B2 (ja) | 2006-11-08 | 2014-07-16 | 日本化薬株式会社 | 核酸系代謝拮抗剤の高分子誘導体 |
| US8354549B2 (en) | 2006-11-30 | 2013-01-15 | Nektar Therapeutics | Method for preparing a polymer conjugate |
| MX2009008549A (es) | 2007-02-09 | 2009-08-18 | Enzon Pharmaceuticals Inc | Tratamiento de canceres resistentes o refractarios con conjugados polimericos de brazos multiples de 7-etil-10-hidroxicamptotecina. |
| JP5349318B2 (ja) | 2007-09-28 | 2013-11-20 | 日本化薬株式会社 | ステロイド類の高分子結合体 |
| EP2258397B1 (en) | 2008-03-18 | 2017-10-11 | Nippon Kayaku Kabushiki Kaisha | Polymer conjugate of physiologically active substance |
| US8236319B2 (en) | 2008-04-30 | 2012-08-07 | Immunogen, Inc. | Cross-linkers and their uses |
| WO2009136572A1 (ja) | 2008-05-08 | 2009-11-12 | 日本化薬株式会社 | 葉酸若しくは葉酸誘導体の高分子結合体 |
| JP5588983B2 (ja) | 2008-08-11 | 2014-09-10 | ウェルズ ファーゴ バンク ナショナル アソシエイション | マルチアームポリマーアルカノエートコンジュゲート |
| EP2349346B1 (en) | 2008-09-23 | 2019-08-28 | Nektar Therapeutics | Method of metronomic dosing with camptothecin prodrugs (e.g. peg-irinotecan) |
| CN102421827B (zh) | 2009-05-15 | 2014-07-30 | 日本化药株式会社 | 具有羟基的生理活性物质的高分子结合体 |
| EP2641605B1 (en) | 2010-11-17 | 2018-03-07 | Nippon Kayaku Kabushiki Kaisha | Polymer derivative of cytidine metabolism antagonist |
| US10894087B2 (en) | 2010-12-22 | 2021-01-19 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of cabazitaxel-based compounds |
| US20130331443A1 (en) | 2010-12-22 | 2013-12-12 | Nektar Therapeutics | Multi-arm polymeric prodrug conjugates of taxane-based compounds |
| ES2556985T3 (es) | 2011-01-11 | 2016-01-21 | Capsugel Belgium Nv | Nuevas cápsulas duras que comprenden pululano |
| EP2754682B1 (en) | 2011-09-11 | 2017-06-07 | Nippon Kayaku Kabushiki Kaisha | Method for manufacturing block copolymer |
| CN115960111A (zh) | 2012-10-11 | 2023-04-14 | 第一三共株式会社 | 抗体－药物偶联物 |
| US9872924B2 (en) | 2012-10-19 | 2018-01-23 | Daiichi Sankyo Company, Limited | Antibody-drug conjugate produced by binding through linker having hydrophilic structure |
| KR102088169B1 (ko) | 2013-12-25 | 2020-03-12 | 다이이찌 산쿄 가부시키가이샤 | 항 trop2 항체-약물 컨쥬게이트 |
| JP5998289B2 (ja) | 2014-01-31 | 2016-09-28 | 第一三共株式会社 | 抗ｈｅｒ２抗体−薬物コンジュゲート |
| JP6612738B2 (ja) | 2014-04-10 | 2019-11-27 | 第一三共株式会社 | 抗ｈｅｒ２抗体−薬物コンジュゲート |
| WO2015155998A1 (en) | 2014-04-10 | 2015-10-15 | Daiichi Sankyo Company, Limited | Anti-her3 antibody-drug conjugate |
| JP6787890B2 (ja) | 2015-06-29 | 2020-11-18 | 第一三共株式会社 | 抗体−薬物コンジュゲートの選択的製造方法 |
| JPWO2018110515A1 (ja) | 2016-12-12 | 2019-10-24 | 第一三共株式会社 | 抗体−薬物コンジュゲートと免疫チェックポイント阻害剤の組み合わせ |
| WO2018135501A1 (ja) | 2017-01-17 | 2018-07-26 | 第一三共株式会社 | 抗ｇｐｒ２０抗体及び抗ｇｐｒ２０抗体－薬物コンジュゲート |
| CA3059527A1 (en) | 2017-04-14 | 2018-10-18 | Capsugel Belgium Nv | Pullulan capsules |
| BR112019021396A2 (pt) | 2017-04-14 | 2020-04-28 | Capsugel Belgium Nv | processo para fabricação de pululano |
| TWI794230B (zh) | 2017-05-15 | 2023-03-01 | 日商第一三共股份有限公司 | 抗ｃｄｈ６抗體及抗ｃｄｈ６抗體-藥物結合物、以及其製造方法 |
| AU2018327170B2 (en) | 2017-08-31 | 2021-03-11 | Daiichi Sankyo Company, Limited | Novel method for producing antibody-drug conjugate |
| KR20200041993A (ko) | 2017-08-31 | 2020-04-22 | 다이이찌 산쿄 가부시키가이샤 | 항체-약물 콘주게이트의 개량 제조 방법 |
| SG11202010496WA (en) | 2018-05-18 | 2020-12-30 | Daiichi Sankyo Co Ltd | Anti-muc1 antibody-drug conjugate |
| WO2024020734A1 (en) * | 2022-07-25 | 2024-02-01 | Immunogen, Inc. | Novel processes for preparing camptothecin derivatives |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0220601B1 (en) | 1985-10-21 | 1991-12-11 | Daiichi Seiyaku Co., Ltd. | Pyranoindolizine derivatives and preparation process thereof |
| US4981968A (en) * | 1987-03-31 | 1991-01-01 | Research Triangle Institute | Synthesis of camptothecin and analogs thereof |
| US5244903A (en) * | 1987-03-31 | 1993-09-14 | Research Triangle Institute | Camptothecin analogs as potent inhibitors of topoisomerase I |
| US5049668A (en) * | 1989-09-15 | 1991-09-17 | Research Triangle Institute | 10,11-methylenedioxy-20(RS)-camptothecin analogs |
| US4939255A (en) * | 1987-06-24 | 1990-07-03 | Daiichi Pharmaceutical Co., Ltd. | Hexa-cyclic camptothecin derivatives |
| JP2540357B2 (ja) * | 1987-06-24 | 1996-10-02 | 第一製薬株式会社 | 六環性化合物 |
| EP0418099B1 (en) * | 1989-09-15 | 2001-12-19 | Research Triangle Institute | Process of preparation of 10, 11-Methylenedioxy-20 (RS) camptothecin and 10, 11-methylenedioxy-20 (S) - camptothecin analog |
| WO1991004260A2 (en) * | 1989-09-15 | 1991-04-04 | Research Triangle Institute | 10,11-methylenedioxy-20(rs)-camptothecin and 10,11-methylenedioxy-20(s)-camptothecin analogs |
| US5140010A (en) * | 1989-09-28 | 1992-08-18 | Immunobiology Research Institute | Stabilized aqueous formulations of thymopentin |
| DK0544000T3 (da) * | 1990-08-17 | 1997-11-03 | Drug Delivery System Inst Ltd | N-acetylcarboxymethylchitosanderivater og fremgangsmåde til fremstilling deraf. |
| EP0540099B1 (en) * | 1991-10-29 | 1996-04-17 | Glaxo Wellcome Inc. | Water soluble camptothecin derivatives |
| CA2087898A1 (en) * | 1992-01-24 | 1993-07-25 | Hiroshi Akimoto | Condensed heterocyclic compounds, their production and use |
| JPH06228141A (ja) * | 1992-01-24 | 1994-08-16 | Takeda Chem Ind Ltd | 縮合複素環誘導体、その塩、その製造法および用途 |
| AU3611093A (en) * | 1992-02-21 | 1993-09-13 | Smithkline Beecham Corporation | Substituted furo(3',4':6,7)indolizino(1,2-b)quinolinones |
| JP3359955B2 (ja) * | 1992-07-16 | 2002-12-24 | 第一製薬株式会社 | 抗腫瘍剤 |
| DE4236237A1 (de) * | 1992-10-27 | 1994-04-28 | Behringwerke Ag | Prodrugs, ihre Herstellung und Verwendung als Arzneimittel |
| ES2149867T3 (es) * | 1993-02-26 | 2000-11-16 | Drug Delivery System Inst Ltd | Derivados de polisacaridos y soportes para farmacos. |
| GB9320781D0 (en) | 1993-10-08 | 1993-12-01 | Erba Carlo Spa | Polymer-bound camptothecin derivatives |
-
1996
- 1996-07-24 SG SG1996010359A patent/SG50747A1/en unknown
- 1996-07-25 IL IL11895796A patent/IL118957A/xx not_active IP Right Cessation
- 1996-07-25 AU AU60698/96A patent/AU717653B2/en not_active Ceased
- 1996-07-29 CA CA002182244A patent/CA2182244C/en not_active Expired - Fee Related
- 1996-07-30 DK DK96305579T patent/DK0757049T3/da active
- 1996-07-30 US US08/689,018 patent/US5837673A/en not_active Expired - Lifetime
- 1996-07-30 DE DE69601841T patent/DE69601841T2/de not_active Expired - Fee Related
- 1996-07-30 EP EP96305579A patent/EP0757049B1/en not_active Expired - Lifetime
- 1996-07-30 AT AT96305579T patent/ATE178067T1/de not_active IP Right Cessation
- 1996-07-30 ES ES96305579T patent/ES2131913T3/es not_active Expired - Lifetime
- 1996-07-31 BG BG100758A patent/BG63342B1/bg unknown
- 1996-08-01 MY MYPI96003153A patent/MY116665A/en unknown
- 1996-08-01 HU HU9602122A patent/HUP9602122A3/hu unknown
- 1996-08-01 RU RU96115394A patent/RU2138503C1/ru not_active IP Right Cessation
- 1996-08-01 NO NO19963214A patent/NO315469B1/no not_active IP Right Cessation
- 1996-08-02 KR KR1019960032296A patent/KR100387191B1/ko not_active IP Right Cessation
- 1996-08-02 CN CNB001326619A patent/CN1143859C/zh not_active Expired - Fee Related
- 1996-08-02 TW TW085109331A patent/TW466242B/zh not_active IP Right Cessation
- 1996-08-02 CN CN96106979A patent/CN1075501C/zh not_active Expired - Fee Related
-
1998
- 1998-05-29 HK HK98104671A patent/HK1005545A1/xx not_active IP Right Cessation
-
1999
- 1999-03-26 GR GR990400802T patent/GR3029796T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU6069896A (en) | 1997-02-06 |
| HU9602122D0 (en) | 1996-09-30 |
| HUP9602122A3 (en) | 1998-07-28 |
| DE69601841T2 (de) | 1999-08-05 |
| CA2182244C (en) | 2004-02-03 |
| IL118957A (en) | 2000-11-21 |
| HUP9602122A2 (en) | 1997-11-28 |
| EP0757049B1 (en) | 1999-03-24 |
| IL118957A0 (en) | 1996-10-31 |
| SG50747A1 (en) | 1998-07-20 |
| US5837673A (en) | 1998-11-17 |
| CN1145365A (zh) | 1997-03-19 |
| CA2182244A1 (en) | 1997-02-03 |
| NO963214D0 (no) | 1996-08-01 |
| CN1075501C (zh) | 2001-11-28 |
| RU2138503C1 (ru) | 1999-09-27 |
| EP0757049A1 (en) | 1997-02-05 |
| DK0757049T3 (da) | 1999-06-23 |
| MY116665A (en) | 2004-03-31 |
| BG63342B1 (bg) | 2001-10-31 |
| CN1308078A (zh) | 2001-08-15 |
| KR100387191B1 (ko) | 2003-10-04 |
| DE69601841D1 (de) | 1999-04-29 |
| TW466242B (en) | 2001-12-01 |
| CN1143859C (zh) | 2004-03-31 |
| ATE178067T1 (de) | 1999-04-15 |
| NO963214L (no) | 1997-02-03 |
| ES2131913T3 (es) | 1999-08-01 |
| GR3029796T3 (en) | 1999-06-30 |
| HK1005545A1 (en) | 1999-01-15 |
| BG100758A (bg) | 1997-02-28 |
| AU717653B2 (en) | 2000-03-30 |
| KR19980013708A (ko) | 1998-05-15 |
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