CA2437989A1 - Terminally-branched polymeric linkers and polymeric conjugates containing the same - Google Patents
Terminally-branched polymeric linkers and polymeric conjugates containing the same Download PDFInfo
- Publication number
- CA2437989A1 CA2437989A1 CA002437989A CA2437989A CA2437989A1 CA 2437989 A1 CA2437989 A1 CA 2437989A1 CA 002437989 A CA002437989 A CA 002437989A CA 2437989 A CA2437989 A CA 2437989A CA 2437989 A1 CA2437989 A1 CA 2437989A1
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- CA
- Canada
- Prior art keywords
- substituted
- compound
- alkyls
- group
- independently
- 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.)
- Abandoned
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- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 238000000034 method Methods 0.000 claims abstract description 28
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 241000124008 Mammalia Species 0.000 claims abstract description 13
- 229920001223 polyethylene glycol Polymers 0.000 claims description 45
- 229920000642 polymer Polymers 0.000 claims description 43
- 239000002202 Polyethylene glycol Substances 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 229910052760 oxygen Inorganic materials 0.000 claims description 28
- 229910052717 sulfur Inorganic materials 0.000 claims description 27
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 239000003814 drug Substances 0.000 claims description 21
- 229940079593 drug Drugs 0.000 claims description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 16
- 239000001257 hydrogen Substances 0.000 claims description 16
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 16
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 16
- 150000001412 amines Chemical class 0.000 claims description 15
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 15
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 15
- 125000003107 substituted aryl group Chemical group 0.000 claims description 15
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- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 claims description 14
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- 125000006716 (C1-C6) heteroalkyl group Chemical group 0.000 claims 14
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract description 3
- 238000011068 loading method Methods 0.000 abstract description 2
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- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 17
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 125000004404 heteroalkyl group Chemical group 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
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- 238000001727 in vivo Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 13
- 230000007062 hydrolysis Effects 0.000 description 13
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
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- 125000003545 alkoxy group Chemical group 0.000 description 11
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 11
- 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 description 10
- 230000001225 therapeutic effect Effects 0.000 description 10
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
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- 238000006243 chemical reaction Methods 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 9
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 8
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 8
- 229940123237 Taxane Drugs 0.000 description 8
- PFYXSUNOLOJMDX-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)ON1C(=O)CCC1=O PFYXSUNOLOJMDX-UHFFFAOYSA-N 0.000 description 8
- 238000002835 absorbance Methods 0.000 description 7
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
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- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 6
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- 229910010271 silicon carbide Inorganic materials 0.000 description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 241000699670 Mus sp. Species 0.000 description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 5
- NPOMSUOUAZCMBL-UHFFFAOYSA-N dichloromethane;ethoxyethane Chemical compound ClCCl.CCOCC NPOMSUOUAZCMBL-UHFFFAOYSA-N 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
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Classifications
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
- C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
- C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
- C08G65/329—Polymers modified by chemical after-treatment with organic compounds
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L2203/00—Applications
- C08L2203/02—Applications for biomedical use
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
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- Organic Chemistry (AREA)
- Public Health (AREA)
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- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Polymers & Plastics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Other Resins Obtained By Reactions Not Involving Carbon-To-Carbon Unsaturated Bonds (AREA)
- Polyethers (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Graft Or Block Polymers (AREA)
- Cosmetics (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
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| US27000901P | 2001-02-20 | 2001-02-20 | |
| US60/270,009 | 2001-02-20 | ||
| PCT/US2002/004781 WO2002065988A2 (en) | 2001-02-20 | 2002-02-19 | Terminally-branched polymeric linkers and polymeric conjugates containing the same |
Publications (1)
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| CA2437989A1 true CA2437989A1 (en) | 2002-08-29 |
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| CA002437989A Abandoned CA2437989A1 (en) | 2001-02-20 | 2002-02-19 | Terminally-branched polymeric linkers and polymeric conjugates containing the same |
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|---|---|
| US (1) | US20020183259A1 (OSRAM) |
| EP (1) | EP1362053B1 (OSRAM) |
| JP (1) | JP2004532289A (OSRAM) |
| AT (1) | ATE378342T1 (OSRAM) |
| AU (1) | AU2002251988A1 (OSRAM) |
| CA (1) | CA2437989A1 (OSRAM) |
| DE (1) | DE60223499T2 (OSRAM) |
| DK (1) | DK1362053T3 (OSRAM) |
| MX (1) | MXPA03007392A (OSRAM) |
| WO (1) | WO2002065988A2 (OSRAM) |
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| US6624142B2 (en) * | 1997-12-30 | 2003-09-23 | Enzon, Inc. | Trimethyl lock based tetrapartate prodrugs |
| EP2236161A1 (en) | 2001-10-18 | 2010-10-06 | Nektar Therapeutics | Polymer conjugates of opioid antagonists |
| US7332164B2 (en) * | 2003-03-21 | 2008-02-19 | Enzon Pharmaceuticals, Inc. | Heterobifunctional polymeric bioconjugates |
| MXPA05011022A (es) * | 2003-04-13 | 2006-04-27 | Enzon Pharmaceuticals Inc | Profarmacos oligonucleotidos polimericos. |
| EP1626983B8 (en) * | 2003-05-12 | 2010-12-22 | Affymax, Inc. | Novel poly (ethylene glycol) modified erythropoietin agonists and uses thereof |
| JP2007500218A (ja) | 2003-05-12 | 2007-01-11 | アフィーマックス・インコーポレイテッド | ポリ（エチレングリコール）修飾ペプチド系化合物の新規スペーサー部分 |
| ES2395413T3 (es) | 2003-05-12 | 2013-02-12 | Affymax, Inc. | Péptidos que se unen al receptor de eritropoyetina |
| DE602004020610D1 (de) | 2003-05-12 | 2009-05-28 | Affymax Inc | Neue, an den erythropoietinrezeptor bindende peptide |
| US20060182692A1 (en) | 2003-12-16 | 2006-08-17 | Fishburn C S | Chemically modified small molecules |
| HRP20140361T1 (hr) * | 2003-12-16 | 2014-05-23 | Nektar Therapeutics | Monodisperzne smjese pegiliranog naloksola |
| BRPI0515573A (pt) * | 2004-09-22 | 2008-07-29 | Nippon Kayaku Kk | copolìmero por blocos, preparação de micela e agente anticáncer contendo a mesma como o ingrediente ativo |
| BRPI0609095A2 (pt) * | 2005-05-11 | 2010-02-17 | Nippon Kayaku Kk | derivado polimérico de antagonista metabólico de citidina, agente antitumor e antiviral e método para produzir o referido derivado |
| US7550433B2 (en) | 2005-06-03 | 2009-06-23 | Affymax, Inc. | Erythropoietin receptor peptide formulations and uses |
| PT2279758E (pt) | 2005-06-16 | 2015-05-27 | Nektar Therapeutics | Conjugados possuindo uma ligação degradável e reagentes poliméricos úteis na preparação de tais conjugados |
| JP5249016B2 (ja) | 2006-03-28 | 2013-07-31 | 日本化薬株式会社 | タキサン類の高分子結合体 |
| CA2652656A1 (en) | 2006-05-18 | 2007-11-29 | Nippon Kayaku Kabushiki Kaisha | High-molecular weight conjugate of podophyllotoxins |
| WO2008010463A1 (en) * | 2006-07-19 | 2008-01-24 | Nippon Kayaku Kabushiki Kaisha | Polymer conjugate of combretastatin |
| EP2073820A4 (en) * | 2006-09-15 | 2014-07-16 | Belrose Pharma Inc | TARGETED POLYMER PRODRUGS WITH MULTIFUNCTIONAL CONNECTORS |
| WO2008041610A1 (fr) * | 2006-10-03 | 2008-04-10 | Nippon Kayaku Kabushiki Kaisha | Mélange d'un dérivé de résorcinol avec un polymère |
| EP2080779B1 (en) | 2006-11-06 | 2016-05-18 | Nippon Kayaku Kabushiki Kaisha | Polymeric derivative of nucleic acid metabolic antagonist |
| EP2090607B1 (en) * | 2006-11-08 | 2015-05-20 | Nippon Kayaku Kabushiki Kaisha | Polymeric derivative of nucleic acid metabolic antagonist |
| CA2676820A1 (en) | 2007-01-31 | 2008-08-07 | Affymax, Inc. | Nitrogen-based linkers for attaching modifying groups to polypeptides and other macromolecules |
| USRE46190E1 (en) | 2007-09-28 | 2016-11-01 | Nippon Kayaku Kabushiki Kaisha | High-molecular weight conjugate of steroids |
| JP5687899B2 (ja) * | 2008-03-18 | 2015-03-25 | 日本化薬株式会社 | 生理活性物質の高分子結合体 |
| 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 |
| EP2431403B1 (en) | 2009-05-15 | 2016-09-28 | Nipponkayaku Kabushikikaisha | Polymer conjugate of bioactive substance having hydroxy group |
| PE20140636A1 (es) | 2010-09-30 | 2014-06-18 | Astrazeneca Ab | Conjugado de naloxol-peg cristalino |
| WO2012067138A1 (ja) | 2010-11-17 | 2012-05-24 | 日本化薬株式会社 | 新規なシチジン系代謝拮抗剤の高分子誘導体 |
| EP2741778A1 (en) * | 2011-08-12 | 2014-06-18 | Ascendis Pharma A/S | Polymeric hyperbranched carrier-linked prodrugs |
| ES2635117T3 (es) | 2011-09-11 | 2017-10-02 | Nippon Kayaku Kabushiki Kaisha | Método para la fabricación de un copolímero de bloques |
| EP3820879B1 (en) | 2018-06-29 | 2024-11-06 | Changchun Changcheng Pharmaceutical Technology Co., LTD | Phosphorus-containing prodrugs of gemcitabine |
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| US4179337A (en) * | 1973-07-20 | 1979-12-18 | Davis Frank F | Non-immunogenic polypeptides |
| IL83966A (en) * | 1986-09-26 | 1992-03-29 | Schering Ag | Amides of aminopolycarboxylic acids and pharmaceutical compositions containing them |
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-
2002
- 2002-02-19 MX MXPA03007392A patent/MXPA03007392A/es unknown
- 2002-02-19 JP JP2002565549A patent/JP2004532289A/ja active Pending
- 2002-02-19 AT AT02721033T patent/ATE378342T1/de not_active IP Right Cessation
- 2002-02-19 US US10/078,730 patent/US20020183259A1/en not_active Abandoned
- 2002-02-19 DK DK02721033T patent/DK1362053T3/da active
- 2002-02-19 EP EP02721033A patent/EP1362053B1/en not_active Expired - Lifetime
- 2002-02-19 CA CA002437989A patent/CA2437989A1/en not_active Abandoned
- 2002-02-19 WO PCT/US2002/004781 patent/WO2002065988A2/en not_active Ceased
- 2002-02-19 DE DE60223499T patent/DE60223499T2/de not_active Expired - Lifetime
- 2002-02-19 AU AU2002251988A patent/AU2002251988A1/en not_active Abandoned
Also Published As
| Publication number | Publication date |
|---|---|
| WO2002065988A2 (en) | 2002-08-29 |
| AU2002251988A1 (en) | 2002-09-04 |
| DE60223499T2 (de) | 2008-10-16 |
| JP2004532289A (ja) | 2004-10-21 |
| MXPA03007392A (es) | 2003-12-04 |
| DE60223499D1 (de) | 2007-12-27 |
| EP1362053A2 (en) | 2003-11-19 |
| EP1362053B1 (en) | 2007-11-14 |
| US20020183259A1 (en) | 2002-12-05 |
| EP1362053A4 (en) | 2005-01-19 |
| DK1362053T3 (da) | 2008-03-10 |
| WO2002065988A3 (en) | 2003-04-10 |
| ATE378342T1 (de) | 2007-11-15 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |