WO2003076417A3 - Oxo-azabicyclic compounds - Google Patents

Oxo-azabicyclic compounds Download PDF

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Publication number
WO2003076417A3
WO2003076417A3 PCT/EP2003/002277 EP0302277W WO03076417A3 WO 2003076417 A3 WO2003076417 A3 WO 2003076417A3 EP 0302277 W EP0302277 W EP 0302277W WO 03076417 A3 WO03076417 A3 WO 03076417A3
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WO
WIPO (PCT)
Prior art keywords
description
inclusive
integer
formula
group
Prior art date
Application number
PCT/EP2003/002277
Other languages
French (fr)
Other versions
WO2003076417A2 (en
Inventor
Bernard Gaudilliere
Henry Jacobelli
Catherine Kostlan
Jack Li
Wen-Song Yue
Original Assignee
Warner Lambert Co
Bernard Gaudilliere
Henry Jacobelli
Catherine Kostlan
Jack Li
Wen-Song Yue
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 to MXPA04008681A priority Critical patent/MXPA04008681A/en
Priority to EP03708181A priority patent/EP1492775A2/en
Priority to IL16381803A priority patent/IL163818A0/en
Priority to KR10-2004-7013994A priority patent/KR20040095270A/en
Priority to CA002478706A priority patent/CA2478706A1/en
Priority to UY27700A priority patent/UY27700A1/en
Priority to BR0308280-6A priority patent/BR0308280A/en
Priority to AU2003212307A priority patent/AU2003212307A1/en
Application filed by Warner Lambert Co, Bernard Gaudilliere, Henry Jacobelli, Catherine Kostlan, Jack Li, Wen-Song Yue filed Critical Warner Lambert Co
Priority to JP2003574636A priority patent/JP2005526070A/en
Priority to EA200401053A priority patent/EA200401053A1/en
Priority to APAP/P/2004/003125A priority patent/AP2004003125A0/en
Priority to US10/417,073 priority patent/US6747147B2/en
Publication of WO2003076417A2 publication Critical patent/WO2003076417A2/en
Publication of WO2003076417A3 publication Critical patent/WO2003076417A3/en
Priority to IS7414A priority patent/IS7414A/en
Priority to TNP2004000169A priority patent/TNSN04169A1/en
Priority to NO20044041A priority patent/NO20044041L/en

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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
    • C07D471/04Ortho-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
    • 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
    • A61P1/02Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • 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
    • 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
    • A61P17/06Antipsoriatics
    • 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
    • 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
    • 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
    • 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
    • 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D239/00Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72Quinazolines; Hydrogenated quinazolines
    • C07D239/86Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88Oxygen atoms
    • C07D239/91Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • 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
    • C07D401/12Heterocyclic 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

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Cardiology (AREA)
  • Rheumatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pulmonology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Dermatology (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Neurology (AREA)
  • Vascular Medicine (AREA)
  • Hospice & Palliative Care (AREA)
  • Neurosurgery (AREA)
  • Immunology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

A compound selected from those of formula (I) wherein: X1, X2, and X3, represent N or -CR3 in which R3 is as described in the description, G1 represents a group selected from those of formulae (i/a) and (i/b) in which R4, R5, and R6 are as defined in the description, G2 represents a group selected from carbon-carbon triple bond, -CH=C=CH-, C=O, C=S, S(O)n1 in which nl represents an integer from 0 to 2 inclusive, or a group of formula (i/c) in which Y1 represents O, S, -NH or -Nalkyl, and Y2 represents O, S, -NH or -Nalkyl, n is an integer from 0 to 6 inclusive, and m is an integer from 0 to 7 inclusive, Z1 represents -CR9R10,wherein R9 and R10 are as defined in the description, A represents a ring system, R1 represents a group selected from H, alkyl, alkenyl, alkynyl, optionally substituted and the group of formula (i/d) in which p, Z2, B, q and G3 are as defined in the description and optionally, its optical isomers, N-oxide, and addition salts thereof with a pharmaceutically-acceptable acid or base, and medicinal products containing the same are useful as specific inhibitors of type-13 matrix mettaloprotease.
PCT/EP2003/002277 2002-03-08 2003-03-06 Oxo-azabicyclic compounds WO2003076417A2 (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
JP2003574636A JP2005526070A (en) 2002-03-08 2003-03-06 Oxo-azabicyclic compounds
EP03708181A EP1492775A2 (en) 2002-03-08 2003-03-06 Oxo-azabicyclic compounds
EA200401053A EA200401053A1 (en) 2002-03-08 2003-03-06 OXO-ABABYCLIC COMPOUNDS
CA002478706A CA2478706A1 (en) 2002-03-08 2003-03-06 Oxo-azabicyclic compounds
UY27700A UY27700A1 (en) 2002-03-08 2003-03-06 OXO COMPOUNDS - AZABYCLES.
BR0308280-6A BR0308280A (en) 2002-03-08 2003-03-06 Oxo-azabicyclic compounds
AU2003212307A AU2003212307A1 (en) 2002-03-08 2003-03-06 Oxo-azabicyclic compounds
MXPA04008681A MXPA04008681A (en) 2002-03-08 2003-03-06 Oxo-azabicyclic compounds.
IL16381803A IL163818A0 (en) 2002-03-08 2003-03-06 Oxo-azabicyclic compounds
KR10-2004-7013994A KR20040095270A (en) 2002-03-08 2003-03-06 Oxo-Azabicyclic Compounds
APAP/P/2004/003125A AP2004003125A0 (en) 2002-03-08 2003-03-06 Oxo-azabicyclic compounds
US10/417,073 US6747147B2 (en) 2002-03-08 2003-04-16 Oxo-azabicyclic compounds
IS7414A IS7414A (en) 2002-03-08 2004-08-19 Oxo-azabicyclic compounds
TNP2004000169A TNSN04169A1 (en) 2002-03-08 2004-09-03 OXO-AZABICYCLIC COMPOUNDS
NO20044041A NO20044041L (en) 2002-03-08 2004-09-24 Oxo-azabicyclic compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/EP2002/003240 WO2003076416A1 (en) 2002-03-08 2002-03-08 Oxo azabicyclic compounds
EPPCT/EP02/03240 2002-03-08

Publications (2)

Publication Number Publication Date
WO2003076417A2 WO2003076417A2 (en) 2003-09-18
WO2003076417A3 true WO2003076417A3 (en) 2003-11-13

Family

ID=27798761

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP2002/003240 WO2003076416A1 (en) 2002-03-08 2002-03-08 Oxo azabicyclic compounds
PCT/EP2003/002277 WO2003076417A2 (en) 2002-03-08 2003-03-06 Oxo-azabicyclic compounds

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/EP2002/003240 WO2003076416A1 (en) 2002-03-08 2002-03-08 Oxo azabicyclic compounds

Country Status (25)

Country Link
EP (1) EP1492775A2 (en)
JP (1) JP2005526070A (en)
KR (1) KR20040095270A (en)
CN (1) CN1738806A (en)
AP (1) AP2004003125A0 (en)
AR (1) AR039562A1 (en)
AU (2) AU2002249275A1 (en)
BR (1) BR0308280A (en)
CA (1) CA2478706A1 (en)
CO (1) CO5601020A2 (en)
EA (1) EA200401053A1 (en)
EC (1) ECSP045278A (en)
IL (1) IL163818A0 (en)
IS (1) IS7414A (en)
MA (1) MA27183A1 (en)
MX (1) MXPA04008681A (en)
NO (1) NO20044041L (en)
OA (1) OA12782A (en)
PA (1) PA8568501A1 (en)
PE (1) PE20031018A1 (en)
PL (1) PL372622A1 (en)
SV (1) SV2003001495A (en)
TN (1) TNSN04169A1 (en)
UY (1) UY27700A1 (en)
WO (2) WO2003076416A1 (en)

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
PA8539501A1 (en) 2001-02-14 2002-09-30 Warner Lambert Co TRIAZOLO COMPOUNDS AS MMP INHIBITORS
US6962922B2 (en) 2001-10-12 2005-11-08 Warner-Lambert Company Llc Alkynylated quinazoline compounds
US6894057B2 (en) 2002-03-08 2005-05-17 Warner-Lambert Company Oxo-azabicyclic compounds
AU2003253150A1 (en) 2002-08-13 2004-02-25 Warner-Lambert Company Llc Chromone derivatives as matrix metalloproteinase inhibitors
JP2006501215A (en) 2002-08-13 2006-01-12 ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー Monocyclic derivatives as matrix metalloproteinase inhibitors
WO2004014378A1 (en) 2002-08-13 2004-02-19 Warner-Lambert Company Llc 3-isoquinolinone derivatives as matrix metalloproteinase inhiitors
WO2004014375A2 (en) 2002-08-13 2004-02-19 Warner-Lambert Company Llc Fused bicyclic metalloproteinase inhibitors
PA8578101A1 (en) 2002-08-13 2004-05-07 Warner Lambert Co HETEROBIARILO DERIVATIVES AS METALOPROTEINASE IN MATRIX INHIBITORS
AU2003250470A1 (en) 2002-08-13 2004-02-25 Warner-Lambert Company Llc Pyrimidinone fused bicyclic metalloproteinase inhibitors
WO2004014384A2 (en) * 2002-08-13 2004-02-19 Warner-Lambert Company Llc Cyclic compounds containing zinc binding groups as matrix metalloproteinase inhibitors
AU2003250471A1 (en) 2002-08-13 2004-02-25 Warner-Lambert Company Llc Pyrimidine-2,4-dione derivatives as matrix metalloproteinase inhibitors
AU2003253186A1 (en) 2002-08-13 2004-02-25 Warner-Lambert Company Llc Fused tetrahydropyridine derivatives as matrix metalloproteinase inhibitors
BR0313724A (en) 2002-08-13 2005-06-28 Warner Lambert Co Azaisoquinoline derivatives as matrix metalloproteinase inhibitors
WO2005016926A1 (en) * 2003-08-19 2005-02-24 Warner-Lambert Company Llc Pyrido [3,4-d] pyrimidine derivatives as matrix metalloproteinase-13 inhibitors
DE10360835A1 (en) * 2003-12-23 2005-07-21 Boehringer Ingelheim Pharma Gmbh & Co. Kg New bicyclic imidazole derivatives are dipeptidylpeptidase-IV inhibitors useful to treat e.g. arthritis, obesity, allograft transplantation and calcitonin-induced osteoporosis
MXPA06012333A (en) * 2004-04-30 2007-01-17 Takeda Pharmaceutical Heterocyclic amide compound and use thereof as an mmp-13 inhibitor.
CN101001845A (en) * 2004-06-15 2007-07-18 阿斯利康(瑞典)有限公司 Substituted quinazolones as anti-cancer agents.
RU2009112397A (en) 2006-10-05 2010-10-10 Си Ви ТЕРАПЬЮТИКС, ИНК (US) BICYCLIC NITROGEN-CONTAINING HETEROCYCLIC COMPOUNDS FOR USE AS STEAROIL COA DESATURASES INHIBITORS
WO2012052451A1 (en) 2010-10-18 2012-04-26 Merz Pharma Gmbh & Co. Kgaa Metabotropic glutamate receptor modulators
CN103524431B (en) * 2013-09-24 2016-01-13 西安交通大学 3-benzyl-4-quianzolinones and synthetic method thereof and application
JO3512B1 (en) 2014-03-26 2020-07-05 Astex Therapeutics Ltd Quinoxaline derivatives useful as fgfr kinase modulators
CN108137546B (en) 2015-09-23 2021-07-27 詹森药业有限公司 Bis-heteroaryl substituted 1, 4-benzodiazepine compounds and their use for the treatment of cancer
JP6898919B2 (en) 2015-09-23 2021-07-07 ヤンセン ファーマシューティカ エヌ.ベー. New compound
FR3046793B1 (en) * 2016-01-14 2018-01-05 Les Laboratoires Servier NOVEL PHOSPHINAN DERIVATIVES AND AZAPHOSPHINANES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

Citations (3)

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WO2002064572A1 (en) * 2001-02-14 2002-08-22 Warner-Lambert Company Llc Quinazolines as mmp-13 inhibitors
WO2002064080A2 (en) * 2001-02-14 2002-08-22 Warner-Lambert Company Lcc Matrix metalloproteinase inhibitors

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WO1998026664A1 (en) * 1996-12-17 1998-06-25 E.I. Du Pont De Nemours And Company Fungicidal quinazolinones
WO2002064572A1 (en) * 2001-02-14 2002-08-22 Warner-Lambert Company Llc Quinazolines as mmp-13 inhibitors
WO2002064080A2 (en) * 2001-02-14 2002-08-22 Warner-Lambert Company Lcc Matrix metalloproteinase inhibitors

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LIVERTON N J ET AL: "Nonpeptide glycoprotein IIb/IIIa inhibitors: substituted quinazolinediones and quinazolinones as potent fibrinogen receptor antagonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 8, no. 5, 3 March 1998 (1998-03-03), pages 483 - 486, XP004136889, ISSN: 0960-894X *
REITER L A ET AL: "Inhibition of MMP-1 and MMP-13 with phosphinic acids that exploit binding in the S2 pocket", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, OXFORD, GB, vol. 9, no. 2, 18 January 1999 (1999-01-18), pages 127 - 132, XP004152585, ISSN: 0960-894X *

Also Published As

Publication number Publication date
CO5601020A2 (en) 2006-01-31
TNSN04169A1 (en) 2007-03-12
AU2003212307A1 (en) 2003-09-22
JP2005526070A (en) 2005-09-02
CN1738806A (en) 2006-02-22
CA2478706A1 (en) 2003-09-18
EP1492775A2 (en) 2005-01-05
AP2004003125A0 (en) 2004-09-30
SV2003001495A (en) 2003-11-04
PA8568501A1 (en) 2003-12-19
EA200401053A1 (en) 2005-04-28
MXPA04008681A (en) 2004-12-06
AR039562A1 (en) 2005-02-23
WO2003076417A2 (en) 2003-09-18
OA12782A (en) 2006-07-10
NO20044041L (en) 2004-10-07
PL372622A1 (en) 2005-07-25
BR0308280A (en) 2004-12-28
ECSP045278A (en) 2004-10-26
UY27700A1 (en) 2003-10-31
IL163818A0 (en) 2005-12-18
MA27183A1 (en) 2005-01-03
AU2002249275A1 (en) 2003-09-22
IS7414A (en) 2004-08-19
PE20031018A1 (en) 2004-01-09
KR20040095270A (en) 2004-11-12
WO2003076416A1 (en) 2003-09-18

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