HUP0401431A3 - Cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine structure and cathepsin k inhibitory activity, process for producing them and pharmaceutical compositions containing them - Google Patents

Cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine structure and cathepsin k inhibitory activity, process for producing them and pharmaceutical compositions containing them

Info

Publication number
HUP0401431A3
HUP0401431A3 HU0401431A HUP0401431A HUP0401431A3 HU P0401431 A3 HUP0401431 A3 HU P0401431A3 HU 0401431 A HU0401431 A HU 0401431A HU P0401431 A HUP0401431 A HU P0401431A HU P0401431 A3 HUP0401431 A3 HU P0401431A3
Authority
HU
Hungary
Prior art keywords
cathepsin
cyano
amino
producing
pharmaceutical compositions
Prior art date
Application number
HU0401431A
Other languages
English (en)
Hungarian (hu)
Original Assignee
Novartis Ag
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 GBGB0121026.9A external-priority patent/GB0121026D0/en
Priority claimed from GB0121024A external-priority patent/GB0121024D0/en
Application filed by Novartis Ag filed Critical Novartis Ag
Publication of HUP0401431A2 publication Critical patent/HUP0401431A2/hu
Publication of HUP0401431A3 publication Critical patent/HUP0401431A3/hu

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic 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
    • C07D401/02—Heterocyclic 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
    • C07D401/12—Heterocyclic 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 linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • 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
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A61P33/12—Schistosomicides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61P37/02—Immunomodulators
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic 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
    • C07D403/12—Heterocyclic 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 linked by a chain containing hetero atoms as chain links

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Rheumatology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Vascular Medicine (AREA)
  • Pulmonology (AREA)
  • Neurology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
HU0401431A 2001-08-30 2002-08-29 Cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine structure and cathepsin k inhibitory activity, process for producing them and pharmaceutical compositions containing them HUP0401431A3 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB0121026.9A GB0121026D0 (en) 2001-08-30 2001-08-30 Organic compounds
GB0121024A GB0121024D0 (en) 2001-08-30 2001-08-30 Organic compounds
PCT/EP2002/009661 WO2003020278A1 (en) 2001-08-30 2002-08-29 Cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine structure and cathepsin k inhibitory activity for the treatment of inflammations and other diseases

Publications (2)

Publication Number Publication Date
HUP0401431A2 HUP0401431A2 (hu) 2004-10-28
HUP0401431A3 true HUP0401431A3 (en) 2004-11-29

Family

ID=26246490

Family Applications (1)

Application Number Title Priority Date Filing Date
HU0401431A HUP0401431A3 (en) 2001-08-30 2002-08-29 Cysteine protease inhibitors with 2-cyano-4-amino-pyrimidine structure and cathepsin k inhibitory activity, process for producing them and pharmaceutical compositions containing them

Country Status (22)

Country Link
US (2) US7112589B2 (enExample)
EP (1) EP1423121B1 (enExample)
JP (1) JP4131701B2 (enExample)
KR (1) KR100629834B1 (enExample)
CN (1) CN1549717B (enExample)
AR (1) AR036375A1 (enExample)
AT (1) ATE345136T1 (enExample)
AU (1) AU2002333758B2 (enExample)
BR (1) BR0212141A (enExample)
CA (1) CA2456127C (enExample)
CO (1) CO5560576A2 (enExample)
DE (1) DE60216122T2 (enExample)
ES (1) ES2275946T3 (enExample)
HU (1) HUP0401431A3 (enExample)
IL (1) IL160295A0 (enExample)
MX (1) MXPA04001930A (enExample)
NZ (1) NZ531287A (enExample)
PE (1) PE20030772A1 (enExample)
PL (1) PL208280B1 (enExample)
PT (1) PT1423121E (enExample)
RU (1) RU2326119C2 (enExample)
WO (1) WO2003020278A1 (enExample)

Families Citing this family (47)

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SE0201980D0 (sv) 2002-06-24 2002-06-24 Astrazeneca Ab Novel compounds
SE0201976D0 (sv) 2002-06-24 2002-06-24 Astrazeneca Ab Novel compounds
GB0220187D0 (en) 2002-08-30 2002-10-09 Novartis Ag Organic compounds
US20060281714A1 (en) * 2003-07-21 2006-12-14 Johann Zimmermann Combinations of a cathepsin k inhibitor and a bisphosphonate in the treatment of bone metastasis, tumor growth and tumor-induced bone loss
WO2005011703A1 (en) * 2003-08-04 2005-02-10 Akzo Nobel N.V. 2-cyano-1,3,5-triazine-4,6-diamine derivatives
US20060281803A1 (en) * 2003-09-23 2006-12-14 Lindsley Craig W Pyrazole modulators of metabotropic glutamate receptors
EP1686995A1 (en) * 2003-11-19 2006-08-09 Novartis AG Use of cathepsin k inhibitors for treating of severe bone loss diseases
WO2005103012A1 (ja) * 2004-04-21 2005-11-03 Ono Pharmaceutical Co., Ltd. ヒドラジノ複素環ニトリル化合物およびその用途
TW200614993A (en) * 2004-06-11 2006-05-16 Akzo Nobel Nv 4-phenyl-pyrimidine-2-carbonitrile derivatives
AR050858A1 (es) * 2004-09-07 2006-11-29 Glaxo Group Ltd Compuesto de heteroaril-nitrilo sustituido, su uso para la fabricacion de un medicamento, composicion farmaceutica que lo comprende y procedimiento para la preparacion del mismo
WO2006040300A1 (en) * 2004-10-12 2006-04-20 N.V. Organon 4-cycloalkyl-pyrimidine-2-carbonitrile derivatives
IL164942A0 (en) * 2004-10-31 2005-12-18 Yeda Res & Dev The use of a protease or a protease inhibitor for the manufacture of medicaments
GB0514684D0 (en) * 2005-07-18 2005-08-24 Novartis Ag Organic compounds
RU2424234C2 (ru) * 2005-08-05 2011-07-20 Ибриженикс Са Новые ингибиторы цистеиновых протеаз и их терапевтическое применение
AR057110A1 (es) * 2005-09-02 2007-11-14 Glaxo Group Ltd DERIVADOS DE HETEROARIL-NITRILOS SUSTITUíDOS QUE SON INHIBIDORES DE PROTEASAS
TW200745055A (en) * 2005-09-23 2007-12-16 Organon Nv 4-Phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives
US7326715B2 (en) 2005-09-23 2008-02-05 N.V. Organon 4-Phenyl-6-substituted-pyrimidine-2-carbonitrile derivatives
US7687515B2 (en) 2006-01-17 2010-03-30 N.V. Organon 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives
WO2007137149A2 (en) * 2006-05-22 2007-11-29 Velcura Therapeutics, Inc. Use of cathepsin k antagonists in bone production
CN101479269A (zh) * 2006-06-23 2009-07-08 阿斯利康(瑞典)有限公司 蝶啶衍生物及其作为组织蛋白酶抑制剂的用途
EP1947091A1 (en) * 2007-01-16 2008-07-23 Glaxo Group Limited Pyrimidyl nitrile derivatives as cysteine protease inhibitors
US7932251B2 (en) 2007-07-16 2011-04-26 N.V. Organon 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives
CN101945853B (zh) 2007-12-21 2014-08-20 配体药物公司 选择性雄激素受体调节剂(sarm)及其应用
JP5587790B2 (ja) 2008-01-09 2014-09-10 アミュラ セラピューティクス リミティド 化合物
US8026236B2 (en) 2009-01-16 2011-09-27 N.V. Organon 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives
TW201035094A (en) 2009-01-16 2010-10-01 Organon Nv 6-phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile derivatives
EP2316820A1 (en) * 2009-10-28 2011-05-04 Dompe S.p.A. 2-aryl-propionamide derivatives useful as bradykinin receptor antagonists and pharmaceutical compositions containing them
EP2523954B1 (en) 2010-01-15 2014-04-16 Merck Sharp & Dohme B.V. 1h-[1,2,3]triazolo[4,5-c]pyridine-4- carbonitrile derivatives as cathepsin s inhibitors
ES2562274T3 (es) 2010-10-06 2016-03-03 Fundació Institut De Recerca Biomèdica (Irb Barcelona) Procedimiento para el diagnóstico, pronóstico y tratamiento de metástasis de cáncer de mama
US8524710B2 (en) * 2010-11-05 2013-09-03 Hoffmann-La Roche Inc. Pyrrolidine derivatives
EP2650682A1 (en) 2012-04-09 2013-10-16 Fundació Privada Institut de Recerca Biomèdica Method for the prognosis and treatment of cancer metastasis
EP3467124A1 (en) 2012-06-06 2019-04-10 Fundació Institut de Recerca Biomèdica IRB (Barcelona) Method for the diagnosis, prognosis and treatment of lung cancer metastasis
CA2888122A1 (en) 2012-10-12 2014-04-17 Inbiomotion S.L. Method for the diagnosis, prognosis and treatment of prostate cancer metastasis using c-maf
US10119171B2 (en) 2012-10-12 2018-11-06 Inbiomotion S.L. Method for the diagnosis, prognosis and treatment of prostate cancer metastasis
US20160032400A1 (en) 2013-03-15 2016-02-04 Fundació Institut De Recerca Biomèdica (Irb Barcelona) Method for the prognosis and treatment of cancer metastasis
US20160032399A1 (en) 2013-03-15 2016-02-04 Inbiomotion S.L. Method for the Prognosis and Treatment of Renal Cell Carcinoma Metastasis
EP3524698A1 (en) 2013-10-09 2019-08-14 Fundació Institut de Recerca Biomèdica IRB (Barcelona) Method for the prognosis and treatment of cancer metastasis
EP3613418A1 (en) 2014-01-17 2020-02-26 Ligand Pharmaceuticals, Inc. Methods and compositions for modulating hormone levels
KR20170093182A (ko) 2014-12-11 2017-08-14 인바이오모션 에스.엘. 인간 c-maf에 대한 결합 구성원
CA3025264A1 (en) 2016-05-25 2017-11-30 Inbiomotion S.L. Therapeutic treatment of breast cancer based on c-maf status
KR20190112009A (ko) * 2017-01-27 2019-10-02 장피트 Ror감마 조절제 및 이의 용도
CN108586356B (zh) * 2017-03-16 2021-02-19 杭州科巢生物科技有限公司 瑞博西尼新中间体及其制备瑞博西尼的合成方法
CA3082728A1 (en) 2017-11-22 2019-05-31 Inbiomotion S.L. Therapeutic treatment of breast cancer based on c-maf status
CN109467536B (zh) * 2018-12-23 2020-06-05 沧州普瑞东方科技有限公司 2-氯/羟基嘧啶-5-羧酸的合成方法
AU2020250933A1 (en) 2019-04-05 2021-10-28 Centre Hospitalier Régional Et Universitaire De Brest Protease-activated receptor-2 inhibitors for the treatment of sensory neuropathy induced by a marine neurotoxic poisoning
AU2020257397B2 (en) 2019-04-19 2026-02-26 Ligand Pharmaceuticals Inc. Crystalline forms and methods of producing crystalline forms of a compound

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BR6915234D0 (pt) 1969-05-22 1973-06-07 American Cyanamid Co Novos derivados de melamina e processo para sua preparaca
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US6313127B1 (en) 1996-02-02 2001-11-06 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
DE19817459A1 (de) 1998-04-20 1999-10-21 Basf Ag Neue heterozyklische substituierte Amide, Herstellung und Anwendung
HUP0302380A2 (hu) * 1999-09-13 2004-03-01 Boehringer Ingelheim Pharmaceuticals, Inc. Cisztein-proteázok reverzibilis inhibitoraiként alkalmazható új spiroheterociklusos vegyületek, eljárás az előállításukra és ezeket tartalmazó gyógyszerkészítmények
CA2383466C (en) * 1999-09-16 2009-08-25 Tanabe Seiyaku Co., Ltd. Aromatic nitrogen-containing 6-membered cyclic compounds
KR100711042B1 (ko) 2000-04-28 2007-04-24 다나베 세이야꾸 가부시키가이샤 환상 화합물
GB0013383D0 (en) 2000-06-01 2000-07-26 Glaxo Group Ltd Therapeutic benzamide derivatives
AR036375A1 (es) * 2001-08-30 2004-09-01 Novartis Ag Compuestos pirrolo [2,3-d] pirimidina -2- carbonitrilo, un proceso para su preparacion, una composicion farmaceutica y el uso de dichos compuestos para la preparacion de medicamentos
SE0201980D0 (sv) 2002-06-24 2002-06-24 Astrazeneca Ab Novel compounds
SE0201976D0 (sv) 2002-06-24 2002-06-24 Astrazeneca Ab Novel compounds

Also Published As

Publication number Publication date
ATE345136T1 (de) 2006-12-15
AU2002333758B2 (en) 2006-01-19
PE20030772A1 (es) 2003-10-02
KR20040029101A (ko) 2004-04-03
ES2275946T3 (es) 2007-06-16
PL367821A1 (en) 2005-03-07
KR100629834B1 (ko) 2006-09-29
IL160295A0 (en) 2004-07-25
PT1423121E (pt) 2007-02-28
EP1423121B1 (en) 2006-11-15
WO2003020278A1 (en) 2003-03-13
US20040249153A1 (en) 2004-12-09
PL208280B1 (pl) 2011-04-29
CN1549717B (zh) 2011-08-17
CO5560576A2 (es) 2005-09-30
US7112589B2 (en) 2006-09-26
MXPA04001930A (es) 2004-06-15
US20060074092A1 (en) 2006-04-06
DE60216122T2 (de) 2007-09-06
JP2005505550A (ja) 2005-02-24
EP1423121A1 (en) 2004-06-02
RU2004109812A (ru) 2005-10-20
RU2326119C2 (ru) 2008-06-10
BR0212141A (pt) 2004-08-24
CA2456127A1 (en) 2003-03-13
CN1549717A (zh) 2004-11-24
JP4131701B2 (ja) 2008-08-13
HUP0401431A2 (hu) 2004-10-28
CA2456127C (en) 2009-10-20
NZ531287A (en) 2005-12-23
AR036375A1 (es) 2004-09-01
DE60216122D1 (de) 2006-12-28

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