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ATE284886T1 - Benzimidazolderivate, ihre herstellung und therapeutische verwendung - Google Patents

Benzimidazolderivate, ihre herstellung und therapeutische verwendung

Info

Publication number
ATE284886T1
ATE284886T1 AT01960871T AT01960871T ATE284886T1 AT E284886 T1 ATE284886 T1 AT E284886T1 AT 01960871 T AT01960871 T AT 01960871T AT 01960871 T AT01960871 T AT 01960871T AT E284886 T1 ATE284886 T1 AT E284886T1
Authority
AT
Austria
Prior art keywords
preparation
therapeutic use
benzimidazole derivatives
benzimidazole
derivatives
Prior art date
Application number
AT01960871T
Other languages
English (en)
Inventor
Francis Barth
Daniel Bichon
Frank Bolkenius
Dorsselaer Viviane Van
Original Assignee
Sanofi Aventis
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 FR0010419A external-priority patent/FR2812878B1/fr
Priority claimed from FR0014696A external-priority patent/FR2816619B1/fr
Application filed by Sanofi Aventis filed Critical Sanofi Aventis
Application granted granted Critical
Publication of ATE284886T1 publication Critical patent/ATE284886T1/de

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06Peri-condensed systems
    • 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
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • 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
    • 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
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16Anti-Parkinson drugs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/28Drugs 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
    • 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
    • A61P31/12Antivirals
    • 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
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/04Antineoplastic agents specific for metastasis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • 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
    • A61P9/04Inotropic 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/14Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic 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
    • C07D487/06Peri-condensed systems

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)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Diabetes (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Oncology (AREA)
  • Psychology (AREA)
  • Virology (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Endocrinology (AREA)
  • AIDS & HIV (AREA)
  • Communicable Diseases (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Emergency Medicine (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Transplantation (AREA)
  • Obesity (AREA)
AT01960871T 2000-08-08 2001-08-06 Benzimidazolderivate, ihre herstellung und therapeutische verwendung ATE284886T1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0010419A FR2812878B1 (fr) 2000-08-08 2000-08-08 Derives de benzimidazole, leur preparation et leur application en therapeutique
FR0014696A FR2816619B1 (fr) 2000-11-15 2000-11-15 Derives de benzimidazole, leur preparation et leur application en therapeutique
PCT/FR2001/002556 WO2002012239A1 (fr) 2000-08-08 2001-08-06 Derives de benzimidazole, leur preparation et leur application en therapeutique

Publications (1)

Publication Number Publication Date
ATE284886T1 true ATE284886T1 (de) 2005-01-15

Family

ID=26212570

Family Applications (1)

Application Number Title Priority Date Filing Date
AT01960871T ATE284886T1 (de) 2000-08-08 2001-08-06 Benzimidazolderivate, ihre herstellung und therapeutische verwendung

Country Status (28)

Country Link
US (2) US6794382B2 (de)
EP (1) EP1309594B1 (de)
JP (1) JP2004505975A (de)
KR (1) KR20030020450A (de)
CN (1) CN1446218A (de)
AR (1) AR030121A1 (de)
AT (1) ATE284886T1 (de)
AU (1) AU2001282267A1 (de)
BG (1) BG107460A (de)
BR (1) BR0113046A (de)
CA (1) CA2412368A1 (de)
CZ (1) CZ294493B6 (de)
DE (1) DE60107859T2 (de)
EA (1) EA005950B1 (de)
EE (1) EE200300048A (de)
ES (1) ES2233671T3 (de)
HK (1) HK1053118A1 (de)
HR (1) HRP20030081A2 (de)
HU (1) HUP0301514A2 (de)
IL (1) IL153708A0 (de)
IS (1) IS6661A (de)
MX (1) MXPA03000753A (de)
NO (1) NO20030596L (de)
PL (1) PL365080A1 (de)
PT (1) PT1309594E (de)
SK (1) SK1582003A3 (de)
WO (1) WO2002012239A1 (de)
YU (1) YU7203A (de)

Families Citing this family (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050119251A1 (en) * 2001-12-21 2005-06-02 Jian-Min Fu Nicotinamide derivatives and their use as therapeutic agents
US20040014744A1 (en) * 2002-04-05 2004-01-22 Fortuna Haviv Substituted pyridines having antiangiogenic activity
WO2003104233A1 (en) * 2002-06-07 2003-12-18 Altana Pharma Ag 4,5-dihydro-imidazo (4,5,1-ij) quinolin-6-ones derivatives and their use as poly (adp-ribosyl) transferase (parp) inhibitors
WO2003103666A2 (en) * 2002-06-07 2003-12-18 Altana Pharma Ag Novel 4,5-dihydro-imidazo[4,5,1-ij]quinolin-6-ones
WO2004108723A1 (en) * 2003-06-04 2004-12-16 Altana Pharma Ag 4,5-dihydro-imidazo[4,5,1-ii]quinolin-6-ones as parp inhibitors
GB0317466D0 (en) * 2003-07-25 2003-08-27 Univ Sheffield Use
DK1684736T3 (da) 2003-12-01 2011-11-21 Kudos Pharm Ltd Inhibitorer af DNA-skadereparation til behandling af cancer
AR051294A1 (es) * 2004-09-20 2007-01-03 Xenon Pharmaceuticals Inc Derivados heterociclicos y su uso como inhibidores de la estearoil-coa desaturasa
TW200626139A (en) * 2004-09-20 2006-08-01 Xenon Pharmaceuticals Inc Heterocyclic derivatives and their use as therapeutic agents
CN101083982A (zh) 2004-09-20 2007-12-05 泽农医药公司 用于治疗硬脂酰CoA去饱和酶介导的疾病的杂环衍生物
AU2005286728A1 (en) * 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as mediators of stearoyl-CoA desaturase
WO2006034440A2 (en) 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors
US7829712B2 (en) * 2004-09-20 2010-11-09 Xenon Pharmaceuticals Inc. Pyridazine derivatives for inhibiting human stearoyl-CoA-desaturase
CN101084211A (zh) * 2004-09-20 2007-12-05 泽农医药公司 杂环衍生物及其作为治疗剂的用途
CA2580860A1 (en) * 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Pyridine derivatives for inhibiting human stearoyl-coa-desaturase
WO2006034441A1 (en) * 2004-09-20 2006-03-30 Xenon Pharmaceuticals Inc. Heterocyclic derivatives and their use as stearoyl-coa desaturase inhibitors
JP2008526815A (ja) * 2005-01-11 2008-07-24 ノイロサーチ アクティーゼルスカブ 低コンダクタンスのカルシウム依存性カリウムチャネルのモジュレーターとしての新規2−アミノベンゾイミダゾール誘導体及びそれらの使用
EP2029138A1 (de) * 2005-06-03 2009-03-04 Xenon Pharmaceuticals Inc. Aminothiazolderivate als humane stearoyl-coa desaturasehemmer
BRPI0614168A2 (pt) * 2005-08-05 2017-07-25 Astrazeneca Ab Composto ou um sal, hidrato, solvato, isoforma, tautômero, isômero óptico farmaceuticamente aceitável ou uma combinação dos mesmos, composição farmacêutica, método para o tratamento ou prevenção de distúrbios neurológicos e psquiátricos, uso de um composto, e, processo para a preparação de um composto
US20090239880A1 (en) * 2006-07-03 2009-09-24 Ulrik Svane Sorensen Combinations of monoamine reuptake inhibitors and potassium channel activators
GB0716532D0 (en) 2007-08-24 2007-10-03 Angeletti P Ist Richerche Bio Therapeutic compounds
GB201220157D0 (en) * 2012-11-08 2012-12-26 Selvita Sa Substitute tricyclic benzimidazoles as kinase inhibitors
CN103923088B (zh) * 2013-01-11 2016-09-07 上海汇伦生命科技有限公司 2,5-二氮杂双环[2.2.1]庚烷类化合物和制备方法、其药用组合物及其在医药上的应用
EP3581576B1 (de) 2013-03-15 2022-01-26 Incyte Holdings Corporation Trizyklische heterozyklen als bet-proteininhibitoren zur behandlung einer proliferativen erkrankung in kombination mit einem janus-kinaseinhibitor
CN104230896A (zh) * 2013-06-17 2014-12-24 上海汇伦生命科技有限公司 苯并咪唑-2-哌嗪杂环类化合物、其药物组合物及其制备方法和用途
WO2015095492A1 (en) 2013-12-19 2015-06-25 Incyte Corporation Tricyclic heterocycles as bet protein inhibitors
TWI735002B (zh) 2014-04-23 2021-08-01 美商英塞特公司 作為BET蛋白抑制劑之1H-吡咯并[2,3-c]吡啶-7(6H)-酮及吡唑并[3,4-c]吡啶-7(6H)-酮
US10494380B2 (en) * 2015-05-29 2019-12-03 Shionogi & Co., Ltd. Nitrogen-containing tricyclic derivatives having HIV replication inhibitory activity
TWI786050B (zh) 2016-06-20 2022-12-11 美商英塞特公司 Bet抑制劑之結晶固體形式
CN110661676B (zh) * 2018-06-29 2022-06-28 大唐移动通信设备有限公司 一种带宽部分的测量方法、配置方法、终端及网络设备
CN111349094B (zh) * 2020-04-23 2021-02-02 杭州师范大学 一种6H-咪唑[4,5,1-ij]并喹诺酮及其合成方法和应用
US11833155B2 (en) 2020-06-03 2023-12-05 Incyte Corporation Combination therapy for treatment of myeloproliferative neoplasms

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2710915B1 (fr) 1993-10-04 1995-11-24 Synthelabo Dérivés de pipéridine, leur préparation et leur utilisation en thérapeutique.
FR2731708B1 (fr) * 1995-03-13 1997-04-30 Synthelabo Derives de piperidine, leur procede de preparation et leur application en therapeutique
EP1133477B1 (de) * 1998-11-27 2004-02-18 Abbott GmbH & Co. KG Substituierte benzimidazole und ihre verwendung als parp inhibitoren

Also Published As

Publication number Publication date
MXPA03000753A (es) 2003-10-15
HRP20030081A2 (en) 2005-02-28
KR20030020450A (ko) 2003-03-08
NO20030596L (no) 2003-04-01
YU7203A (sh) 2006-01-16
SK1582003A3 (en) 2003-08-05
HK1053118A1 (en) 2003-10-10
US20030203893A1 (en) 2003-10-30
US20050032779A1 (en) 2005-02-10
ES2233671T3 (es) 2005-06-16
PL365080A1 (en) 2004-12-27
BR0113046A (pt) 2003-07-01
DE60107859D1 (de) 2005-01-20
AU2001282267A1 (en) 2002-02-18
EP1309594A1 (de) 2003-05-14
JP2004505975A (ja) 2004-02-26
EA005950B1 (ru) 2005-08-25
CN1446218A (zh) 2003-10-01
EE200300048A (et) 2004-12-15
WO2002012239A1 (fr) 2002-02-14
DE60107859T2 (de) 2005-12-22
CZ294493B6 (cs) 2005-01-12
CZ2003354A3 (cs) 2003-05-14
BG107460A (bg) 2003-09-30
US6794382B2 (en) 2004-09-21
IL153708A0 (en) 2003-07-06
HUP0301514A2 (hu) 2003-09-29
PT1309594E (pt) 2005-04-29
IS6661A (is) 2002-12-19
EP1309594B1 (de) 2004-12-15
AR030121A1 (es) 2003-08-13
NO20030596D0 (no) 2003-02-06
EA200201259A1 (ru) 2003-06-26
CA2412368A1 (fr) 2002-02-14

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