EP1347980A4 - RECEPTOR SPECIFIC COMPOUNDS OF ADENOSINE-A1, -A2A, AND-A3 AND USES THEREOF - Google Patents

RECEPTOR SPECIFIC COMPOUNDS OF ADENOSINE-A1, -A2A, AND-A3 AND USES THEREOF

Info

Publication number
EP1347980A4
EP1347980A4 EP01997029A EP01997029A EP1347980A4 EP 1347980 A4 EP1347980 A4 EP 1347980A4 EP 01997029 A EP01997029 A EP 01997029A EP 01997029 A EP01997029 A EP 01997029A EP 1347980 A4 EP1347980 A4 EP 1347980A4
Authority
EP
European Patent Office
Prior art keywords
adenosine
receptor
compounds specific
compounds
specific
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
EP01997029A
Other languages
German (de)
English (en)
French (fr)
Other versions
EP1347980A1 (en
Inventor
Arlindo L Castelhano
Bryan Mckibben
David J Witter
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.)
OSI Pharmaceuticals LLC
Original Assignee
OSI Pharmaceuticals 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
Priority claimed from US09/728,616 external-priority patent/US7160890B2/en
Priority claimed from US09/728,607 external-priority patent/US6664252B2/en
Priority claimed from US09/728,316 external-priority patent/US6680322B2/en
Application filed by OSI Pharmaceuticals LLC filed Critical OSI Pharmaceuticals LLC
Publication of EP1347980A1 publication Critical patent/EP1347980A1/en
Publication of EP1347980A4 publication Critical patent/EP1347980A4/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • A61P39/06—Free radical scavengers or antioxidants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/46—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of glucocorticosteroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Pulmonology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Ophthalmology & Optometry (AREA)
  • Diabetes (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Rheumatology (AREA)
  • Hematology (AREA)
  • Anesthesiology (AREA)
  • Otolaryngology (AREA)
  • Endocrinology (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Medicinal Preparation (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP01997029A 2000-12-01 2001-11-30 RECEPTOR SPECIFIC COMPOUNDS OF ADENOSINE-A1, -A2A, AND-A3 AND USES THEREOF Ceased EP1347980A4 (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US09/728,616 US7160890B2 (en) 1999-12-02 2000-12-01 Compounds specific to adenosine A3 receptor and uses thereof
US09/728,607 US6664252B2 (en) 1999-12-02 2000-12-01 4-aminopyrrolo[2,3-d]pyrimidine compounds specific to adenosine A2a receptor and uses thereof
US09/728,316 US6680322B2 (en) 1999-12-02 2000-12-01 Compounds specific to adenosine A1 receptors and uses thereof
US728607 2000-12-01
US728316 2000-12-01
US728616 2000-12-01
PCT/US2001/045280 WO2002057267A1 (en) 2000-12-01 2001-11-30 Compounds specific to adenosine a1, a2a, and a3 receptor and uses thereof

Publications (2)

Publication Number Publication Date
EP1347980A1 EP1347980A1 (en) 2003-10-01
EP1347980A4 true EP1347980A4 (en) 2005-02-09

Family

ID=27419112

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01997029A Ceased EP1347980A4 (en) 2000-12-01 2001-11-30 RECEPTOR SPECIFIC COMPOUNDS OF ADENOSINE-A1, -A2A, AND-A3 AND USES THEREOF

Country Status (20)

Country Link
EP (1) EP1347980A4 (hu)
JP (1) JP4579497B2 (hu)
CN (1) CN1263757C (hu)
AP (1) AP1893A (hu)
AU (1) AU2002248151B2 (hu)
BR (1) BR0115847A (hu)
CA (1) CA2430577A1 (hu)
CZ (1) CZ20031831A3 (hu)
EA (1) EA007254B1 (hu)
HU (1) HUP0400692A3 (hu)
IL (1) IL155962A0 (hu)
ME (1) MEP35308A (hu)
MX (1) MXPA03004717A (hu)
NO (1) NO327207B1 (hu)
NZ (1) NZ525885A (hu)
OA (1) OA13295A (hu)
PL (1) PL363245A1 (hu)
WO (1) WO2002057267A1 (hu)
YU (1) YU42703A (hu)
ZA (1) ZA200303729B (hu)

Families Citing this family (39)

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US5090531A (en) * 1990-01-10 1992-02-25 Lord Corporation Electrophoretic fluid differential
WO1999062518A1 (en) 1998-06-02 1999-12-09 Osi Pharmaceuticals, Inc. PYRROLO[2,3d]PYRIMIDINE COMPOSITIONS AND THEIR USE
US6680324B2 (en) 2000-12-01 2004-01-20 Osi Pharmaceuticals, Inc. Compounds specific to adenosine A1 receptors and uses thereof
DE10148883A1 (de) 2001-10-04 2003-04-10 Merck Patent Gmbh Pyrimidinderivate
EP2050751A1 (en) 2001-11-30 2009-04-22 OSI Pharmaceuticals, Inc. Compounds specific to adenosine A1 and A3 receptors and uses thereof
US20030199526A1 (en) * 2001-12-07 2003-10-23 Deborah Choquette Pyrimidine-based compounds useful as GSK-3 inhibitors
CN1816551A (zh) 2001-12-20 2006-08-09 Osi药物公司 吡咯并嘧啶A2b选择性拮抗剂化合物,它们的合成及用途
KR20040068317A (ko) 2001-12-20 2004-07-30 오에스아이 파마슈티컬스, 인코포레이티드 피리미딘 ａ₂ｂ 선택성 길항 화합물, 그의 합성 방법 및용도
CA2502429A1 (en) * 2002-10-31 2004-05-21 Amgen Inc. Antiinflammation agents
HUP0203976A3 (en) * 2002-11-15 2004-08-30 Sanofi Aventis Adenozine a3 receptors, process for their preparation and pharmaceutical compositions containing them
MY179032A (en) 2004-10-25 2020-10-26 Cancer Research Tech Ltd Ortho-condensed pyridine and pyrimidine derivatives (e.g.purines) as protein kinase inhibitors
UY29177A1 (es) 2004-10-25 2006-05-31 Astex Therapeutics Ltd Derivados sustituidos de purina, purinona y deazapurina, composiciones que los contienen métodos para su preparación y sus usos
EP3719018A1 (en) 2006-04-25 2020-10-07 Astex Therapeutics Ltd Purine and deazapurine derivatives as pharmaceutical compounds
US20070260203A1 (en) * 2006-05-04 2007-11-08 Allergan, Inc. Vasoactive agent intraocular implant
TW200808819A (en) * 2006-06-19 2008-02-16 Solvay Pharm Gmbh Use of adenosine A1 antagonists in radiocontrast media induced nephrophaty
KR101494734B1 (ko) 2007-10-11 2015-02-26 아스트라제네카 아베 단백질 키나제 ｂ 억제제로서 피롤로[2,3-ｄ]피리미딘 유도체
AP2010005347A0 (en) 2008-01-11 2010-08-31 Natco Pharma Ltd Novel pyrazolo [3,4-D] pyrimidine derivatives as anti-cancer agents
AR070127A1 (es) 2008-01-11 2010-03-17 Novartis Ag Pirrolo - pirimidinas y pirrolo -piridinas
MY169449A (en) 2011-04-01 2019-04-11 Astrazeneca Ab Therapeutic treatment
DK2785349T4 (da) 2011-11-30 2023-01-09 Astrazeneca Ab Kombinationsbehandling af cancer
AU2013204533B2 (en) 2012-04-17 2017-02-02 Astrazeneca Ab Crystalline forms
WO2013182580A1 (en) * 2012-06-07 2013-12-12 F. Hoffmann-La Roche Ag Pyrrolopyrimidone and pyrrolopyridone inhibitors of tankyrase
US9662311B2 (en) * 2013-06-21 2017-05-30 Zenith Epigenetics Ltd. Substituted bicyclic compounds as bromodomain inhibitors
SG10201710705UA (en) 2013-06-21 2018-02-27 Zenith Epigenetics Ltd Novel bicyclic bromodomain inhibitors
EP3027604B1 (en) 2013-07-31 2019-02-20 Zenith Epigenetics Ltd. Novel quinazolinones as bromodomain inhibitors
CA2966298A1 (en) 2014-12-01 2016-06-09 Zenith Epigenetics Ltd. Substituted pyridinones as bromodomain inhibitors
US10179125B2 (en) 2014-12-01 2019-01-15 Zenith Epigenetics Ltd. Substituted pyridines as bromodomain inhibitors
CA2966449A1 (en) 2014-12-11 2016-06-16 Zenith Epigenetics Ltd. Substituted heterocycles as bromodomain inhibitors
EP3233846A4 (en) 2014-12-17 2018-07-18 Zenith Epigenetics Ltd. Inhibitors of bromodomains
HUE064003T2 (hu) * 2015-01-20 2024-02-28 Wuxi Fortune Pharmaceutical Co Ltd JAK-gátló
ES2734048T3 (es) 2015-04-29 2019-12-04 Wuxi Fortune Pharmaceutical Co Ltd Inhibidores de Janus cinasas (JAK)
MX2017013797A (es) 2015-05-29 2018-03-21 Wuxi Fortune Pharmaceutical Co Ltd Inhibidor de janus quinasa.
CN105771672B (zh) * 2016-04-18 2018-03-02 天津工业大学 一种抗污染抗菌芳香聚酰胺反渗透复合膜及制备方法
CN108570054B (zh) * 2017-03-07 2021-07-16 广州再极医药科技有限公司 氨基嘧啶并五元杂环化合物、其中间体、制备方法、药物组合物及应用
CN108017584B (zh) * 2017-06-20 2021-03-23 南开大学 A3腺苷受体的小分子拮抗剂
BR112020024700A2 (pt) * 2018-06-04 2021-03-02 Exscientia Ltd compostos de pirazolopirimidina como antagonistas receptores de adenosina
CN110128316B (zh) * 2019-05-22 2021-08-31 北京大学深圳研究生院 5位取代的β-脯氨酸及其衍生物的制备方法
CN110272373B (zh) * 2019-07-02 2022-07-29 天津国际生物医药联合研究院 一种具有选择性的腺苷a1受体拮抗剂及其应用
CN114085178A (zh) * 2021-12-29 2022-02-25 苏州楚凯药业有限公司 一种4-甲基-1-丙基-2-氨基-1h-吡咯-3-腈的制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5780450A (en) * 1995-11-21 1998-07-14 Alcon Laboratories, Inc. Use of adenosine uptake inhibitors for treating retinal or optic nerve head damage
WO1999062518A1 (en) * 1998-06-02 1999-12-09 Osi Pharmaceuticals, Inc. PYRROLO[2,3d]PYRIMIDINE COMPOSITIONS AND THEIR USE
WO2001039777A1 (en) * 1999-12-02 2001-06-07 Osi Pharmaceuticals, Inc. Compounds specific to adenosine a1 a2a, and a3 receptors and uses thereof
WO2003048120A2 (en) * 2001-11-30 2003-06-12 Osi Pharmaceuticals, Inc. 2-aryl pyrrologpyrimidines for a1 and a3 receptors

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR19990067704A (ko) * 1992-12-17 1999-08-25 디. 제이. 우드, 스피겔 알렌 제이 부신피질자극호르몬 유리인자 길항제로서의 피롤로피리미딘을함유하는 약학 조성물

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5780450A (en) * 1995-11-21 1998-07-14 Alcon Laboratories, Inc. Use of adenosine uptake inhibitors for treating retinal or optic nerve head damage
WO1999062518A1 (en) * 1998-06-02 1999-12-09 Osi Pharmaceuticals, Inc. PYRROLO[2,3d]PYRIMIDINE COMPOSITIONS AND THEIR USE
WO2001039777A1 (en) * 1999-12-02 2001-06-07 Osi Pharmaceuticals, Inc. Compounds specific to adenosine a1 a2a, and a3 receptors and uses thereof
WO2003048120A2 (en) * 2001-11-30 2003-06-12 Osi Pharmaceuticals, Inc. 2-aryl pyrrologpyrimidines for a1 and a3 receptors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of WO02057267A1 *

Also Published As

Publication number Publication date
NZ525885A (en) 2005-01-28
JP2004517896A (ja) 2004-06-17
IL155962A0 (en) 2003-12-23
CZ20031831A3 (cs) 2004-05-12
HUP0400692A2 (hu) 2004-07-28
ZA200303729B (en) 2004-05-14
CN1263757C (zh) 2006-07-12
EA200300628A1 (ru) 2003-12-25
NO20032482D0 (no) 2003-06-02
MXPA03004717A (es) 2004-06-30
CN1489590A (zh) 2004-04-14
CA2430577A1 (en) 2002-07-25
EA007254B1 (ru) 2006-08-25
JP4579497B2 (ja) 2010-11-10
YU42703A (sh) 2006-03-03
OA13295A (en) 2007-04-13
MEP35308A (en) 2011-02-10
AP2003002807A0 (en) 2003-06-30
AU2002248151B2 (en) 2008-02-21
NO20032482L (no) 2003-07-28
AP1893A (en) 2008-09-23
PL363245A1 (en) 2004-11-15
BR0115847A (pt) 2004-02-25
HUP0400692A3 (en) 2007-09-28
EP1347980A1 (en) 2003-10-01
NO327207B1 (no) 2009-05-11
WO2002057267A1 (en) 2002-07-25

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