AU3859999A - 1,5-diaryl substituted pyrazoles as p38 kinase inhibitors - Google Patents

1,5-diaryl substituted pyrazoles as p38 kinase inhibitors

Info

Publication number
AU3859999A
AU3859999A AU38599/99A AU3859999A AU3859999A AU 3859999 A AU3859999 A AU 3859999A AU 38599/99 A AU38599/99 A AU 38599/99A AU 3859999 A AU3859999 A AU 3859999A AU 3859999 A AU3859999 A AU 3859999A
Authority
AU
Australia
Prior art keywords
kinase inhibitors
substituted pyrazoles
diaryl substituted
diaryl
pyrazoles
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
Application number
AU38599/99A
Other languages
English (en)
Inventor
Paul W. Collins
Joyce Z. Crich
Shashidhar N. Rao
Richard M. Weier
Xiangdong Xu
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.)
GD Searle LLC
Original Assignee
GD Searle LLC
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 GD Searle LLC filed Critical GD Searle LLC
Publication of AU3859999A publication Critical patent/AU3859999A/en
Abandoned legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00Drugs for disorders of the urinary system
    • A61P13/12Drugs for disorders of the urinary system of the kidneys
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/02Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/08Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00Drugs for disorders of the senses
    • A61P27/02Ophthalmic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04Antibacterial agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/18Antivirals for RNA viruses for HIV
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00Antiparasitic agents
    • A61P33/02Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06Antimalarials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/02Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D401/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Diabetes (AREA)
  • Rheumatology (AREA)
  • Virology (AREA)
  • Dermatology (AREA)
  • Pulmonology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Oncology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Communicable Diseases (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Hospice & Palliative Care (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pain & Pain Management (AREA)
  • Vascular Medicine (AREA)
  • Molecular Biology (AREA)
  • Obesity (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • AIDS & HIV (AREA)
  • Gastroenterology & Hepatology (AREA)
AU38599/99A 1998-05-14 1999-05-12 1,5-diaryl substituted pyrazoles as p38 kinase inhibitors Abandoned AU3859999A (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US8549498P 1998-05-14 1998-05-14
US60085494 1998-05-14
PCT/US1999/007036 WO1999058523A1 (fr) 1998-05-14 1999-05-12 PYRAZOLES A SUBSTITUTION 1,5-DIARYLE COMME INHIBITEURS DE LA PROTEINE p38 KINASE

Publications (1)

Publication Number Publication Date
AU3859999A true AU3859999A (en) 1999-11-29

Family

ID=22191985

Family Applications (1)

Application Number Title Priority Date Filing Date
AU38599/99A Abandoned AU3859999A (en) 1998-05-14 1999-05-12 1,5-diaryl substituted pyrazoles as p38 kinase inhibitors

Country Status (5)

Country Link
EP (1) EP1077971A1 (fr)
JP (1) JP2002514640A (fr)
AU (1) AU3859999A (fr)
CA (1) CA2331878A1 (fr)
WO (1) WO1999058523A1 (fr)

Families Citing this family (48)

* Cited by examiner, † Cited by third party
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US6979686B1 (en) 2001-12-07 2005-12-27 Pharmacia Corporation Substituted pyrazoles as p38 kinase inhibitors
AU7966198A (en) * 1997-06-13 1998-12-30 Smithkline Beecham Corporation Novel pyrazole and pyrazoline substituted compounds
US7301021B2 (en) 1997-07-02 2007-11-27 Smithkline Beecham Corporation Substituted imidazole compounds
JP4632544B2 (ja) 1998-12-25 2011-02-16 あすか製薬株式会社 アミノピラゾール誘導体
KR100697585B1 (ko) 1999-06-03 2007-03-22 아스카 세이야쿠 가부시키가이샤 치환 피라졸 화합물
US7122666B2 (en) 1999-07-21 2006-10-17 Sankyo Company, Limited Heteroaryl-substituted pyrrole derivatives, their preparation and their therapeutic uses
JP2003514899A (ja) 1999-11-23 2003-04-22 スミスクライン・ビーチャム・コーポレイション CSBP/p38キナーゼ阻害剤としての3,4‐ジヒドロ−(1H)−キナゾリン−2−オン化合物
US6569885B1 (en) 1999-12-23 2003-05-27 Icos Corporation Cyclic AMP-specific phosphodiesterase inhibitors
US6403629B2 (en) * 2000-05-02 2002-06-11 J.B. Chemical And Pharmaceuticals Limited Heterocyclic compounds for therapeutic use
PE20020506A1 (es) * 2000-08-22 2002-07-09 Glaxo Group Ltd Derivados de pirazol fusionados como inhibidores de la proteina cinasa
WO2002048148A2 (fr) 2000-12-15 2002-06-20 Glaxo Group Limited Composes therapeutiques
JP2004518651A (ja) 2000-12-15 2004-06-24 グラクソ グループ リミテッド 治療用化合物
GB0102687D0 (en) * 2001-02-02 2001-03-21 Pharmacia & Upjohn Spa Oxazolyl-pyrazole derivatives active as kinase inhibitors,process for their preparation and pharmaceutical compositions comprising them
MY130778A (en) * 2001-02-09 2007-07-31 Vertex Pharma Heterocyclic inhibitiors of erk2 and uses thereof
ES2227451T3 (es) 2001-03-08 2005-04-01 Smithkline Beecham Corporation Derivados de pirazolopiridina.
GB2373245A (en) * 2001-03-12 2002-09-18 Bayer Ag Pyridinyl pyrazoles and their use for the treatment of COPD
WO2002078700A1 (fr) 2001-03-30 2002-10-10 Smithkline Beecham Corporation Pyralopyridines, leur procede de preparation et leur utilisation en tant que composes therapeutiques
JP4219171B2 (ja) 2001-04-10 2009-02-04 スミスクライン ビーチャム コーポレーション 抗ウイルス性ピラゾロピリジン化合物
ES2242028T3 (es) 2001-04-27 2005-11-01 Smithkline Beecham Corporation Derivados de pirazolo(1,5-a)piridina.
US6878729B2 (en) * 2001-05-04 2005-04-12 The Procter & Gamble Company Medicinal uses of dihydropyrazoles
IL158667A0 (en) 2001-06-21 2004-05-12 Smithkline Beecham Corp Imidazo [1,2-a] pyridine derivatives for the prophylaxis and treatment of herpes viral infections
CN1281603C (zh) * 2001-08-30 2006-10-25 霍夫曼-拉罗奇有限公司 作为抗炎药的氨基吡咯化合物
CN1321644C (zh) 2001-09-25 2007-06-20 法玛西雅公司 制备取代的吡唑的方法
US7057049B2 (en) 2001-09-25 2006-06-06 Pharmacia Corporation Process for making substituted pyrazoles
DE60211539T2 (de) 2001-10-05 2006-09-21 Smithkline Beecham Corp. Imidazopyridinderivate zur verwendung bei der behandlung von herpes-vireninfektion
GB0124938D0 (en) 2001-10-17 2001-12-05 Glaxo Group Ltd Chemical compounds
GB0127929D0 (en) 2001-11-21 2002-01-16 Celltech R&D Ltd Chemical compounds
ATE373000T1 (de) * 2001-12-11 2007-09-15 Smithkline Beecham Corp Pyrazolopyridin-derivate als antiherpesmittel
EP1463505A2 (fr) * 2001-12-13 2004-10-06 Abbott Laboratories Derives de la 3-(phenyl-alkoxy)-5-(phenyl)-pyridine et composes similaires avec activite inhibiteur de kinase pour le traitement du cancer.
US20030187026A1 (en) 2001-12-13 2003-10-02 Qun Li Kinase inhibitors
ES2278170T3 (es) 2002-07-09 2007-08-01 BOEHRINGER INGELHEIM PHARMA GMBH & CO.KG Composiciones farmaceuticas de anticolinergicos e inhibidores de la quinasa p38 en el tratamiento de enfermedades respiratorias.
ATE323702T1 (de) 2002-08-06 2006-05-15 Astrazeneca Ab Kondensierte pyridine und pyrimidine mit tie2 (tek) aktivität
WO2004033454A1 (fr) 2002-10-03 2004-04-22 Smithkline Beecham Corporation Composes therapeutiques a base de derives de pyrazolopyridine
AU2003300076C1 (en) 2002-12-30 2010-03-04 Angiotech International Ag Drug delivery from rapid gelling polymer composition
CA2515119A1 (fr) 2003-02-07 2004-08-19 Daiichi Pharmaceutical Co., Ltd. Derive de pyrazole
RU2342365C2 (ru) 2003-05-01 2008-12-27 Бристол-Маерс Сквибб Компани Арилзамещенные пиразоламиды в качестве ингибиторов киназ
GB0402518D0 (en) 2004-02-05 2004-03-10 Astrazeneca Ab Therapeutic agents
US20060035893A1 (en) 2004-08-07 2006-02-16 Boehringer Ingelheim International Gmbh Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders
GB0417910D0 (en) * 2004-08-11 2004-09-15 Novartis Ag Organic compounds
DK1778686T3 (da) 2004-08-12 2009-01-12 Pfizer Triazolopyridinylsulfanylderivater som P38 MAP kinase-inhibitorer
PE20060777A1 (es) 2004-12-24 2006-10-06 Boehringer Ingelheim Int Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas
EP1992344A1 (fr) 2007-05-18 2008-11-19 Institut Curie P38 alpha comme cible therapeutique pour les maladies associées á une mutation de FGFR3
WO2012170931A2 (fr) * 2011-06-10 2012-12-13 Calcimedica, Inc. Composés qui modulent le calcium intracellulaire
US9856240B2 (en) 2011-10-19 2018-01-02 Calcimedica, Inc. Compounds that modulate intracellular calcium
SG11201605559VA (en) 2014-01-06 2016-08-30 Algomedix Inc Trpa1 modulators
US20200179357A1 (en) * 2016-07-06 2020-06-11 Algomedix, Inc. Trpa1 antagonists for treatment of dry eye, ocular pain and inflammation
WO2022195579A1 (fr) 2021-03-15 2022-09-22 Saul Yedgar Dipalmitoyl-phosphatidyl-éthanol-amine conjuguée à l'acide hyaluronique en combinaison avec des médicaments anti-inflammatoires non stéroïdiens (ains) pour traiter ou soulager des maladies inflammatoires
CN114773262B (zh) * 2022-05-19 2024-05-07 兄弟科技股份有限公司 2-氰基-4-吡啶羧酸甲酯的合成方法

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US2833779A (en) * 1956-10-29 1958-05-06 American Cyanamid Co Substituted pyrazoles
US5434178A (en) * 1993-11-30 1995-07-18 G.D. Searle & Co. 1,3,5 trisubstituted pyrazole compounds for treatment of inflammation
AU7966198A (en) * 1997-06-13 1998-12-30 Smithkline Beecham Corporation Novel pyrazole and pyrazoline substituted compounds

Also Published As

Publication number Publication date
EP1077971A1 (fr) 2001-02-28
CA2331878A1 (fr) 1999-11-18
WO1999058523A1 (fr) 1999-11-18
JP2002514640A (ja) 2002-05-21

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