PE115999A1 - Secretagogos de la hormona del crecimiento - Google Patents

Secretagogos de la hormona del crecimiento

Info

Publication number
PE115999A1
PE115999A1 PE1998000748A PE00074898A PE115999A1 PE 115999 A1 PE115999 A1 PE 115999A1 PE 1998000748 A PE1998000748 A PE 1998000748A PE 00074898 A PE00074898 A PE 00074898A PE 115999 A1 PE115999 A1 PE 115999A1
Authority
PE
Peru
Prior art keywords
alkyl
aryl
growth hormone
secretagogos
formula
Prior art date
Application number
PE1998000748A
Other languages
English (en)
Inventor
Charles Arthur Alt
Roger Lewis Robey
Kennan Joseph Fahey
Alan David Palkowitz
Kenneth Lee Hauser
Jeffrey Daniel Cohen
William Harlan Gritton
Joseph Henry Kennedy
David Edward Seyler
Iii Charles Willis Lugar
Jeffrey Alan Dodge
Henry Uhlman Bryant
Brian Stephen Muehl
Mark Louis Heiman
William George Trankle
Timothy Alan Shepherd
Andrew Michael Ratz
Louis Nickolaus Jungheim
James Densmore Copp
Scott Alan Jones
Kenneth Jeff Thrasher
Gary Anthony Rhodes
Original Assignee
Lilly Co Eli
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 Lilly Co Eli filed Critical Lilly Co Eli
Publication of PE115999A1 publication Critical patent/PE115999A1/es

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36Oxygen or sulfur atoms
    • C07D207/402,5-Pyrrolidine-diones
    • C07D207/4162,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06008Dipeptides with the first amino acid being neutral
    • C07K5/06017Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P5/00Drugs for disorders of the endocrine system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/02Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/02Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • A61P5/04Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin for decreasing, blocking or antagonising the activity of the hypothalamic hormones
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/42Nitro radicals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D231/00Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38Nitrogen atoms
    • C07D231/40Acylated on said nitrogen atom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D233/00Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/88Nitrogen atoms, e.g. allantoin
    • 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
    • C07D401/06Heterocyclic 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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D403/06Heterocyclic 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 carbon chain containing only aliphatic carbon atoms
    • 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
    • C07D403/12Heterocyclic 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K5/00Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06Dipeptides
    • C07K5/06008Dipeptides with the first amino acid being neutral
    • C07K5/06017Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/0606Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Endocrinology (AREA)
  • Diabetes (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)
  • Steroid Compounds (AREA)

Abstract

SE REFIERE A UN COMPUESTO DE FORMULA I, DONDE A ES ALQUILO C1-C6, ARILO, (ALQUIL C1-C6)ARILO, ENTRE OTROS; B ES NH2, NHR1, (ALQUIL C1-C6)NH2, ENTRE OTROS; R1 ES H, ALQUILO C1-C6, (ALQUIL C1-C6)OH o ALQUILIDENIL C1-C6)(OH)R2; R2 ES ALQUILO C1-C6, ALQUENILO C1-C6, (ALQUIL C1-C6)(O)(ALQUILO C1-C6), CO-O-ALQUILO C1-C6, ARILO o (ALQUIL C1-C6)ARILO; X ES UN ENLACE, ALQUILIDENILO C1-C6, O, S, NH o N(ALQUILO C1-C6); V ES UN GRUPO DE FORMULA (a, b, c, d); W ES S, O, NH, o CH2; "Y" Y Z SON N o CH; Y` ES N, S, CH2, O; Z' ES N, CH2; R4 Y R5 SON H, ALQUILO C1-C6, ARILO, (ALQUIL C1-C6)COR7, ENTRE OTROS; R7 ES H, ALQUILO C1-C6, PIRROLIDINILO, PIPERIDINILO, HOMOPROLINA O PROLINA; D ES C(O)R6, (ALQUIL C1-C6)OH, (ALQUIL C1-C6)C(O)R6, ENTRE OTROS; R6 ES H, ALQUILO C1-C6, ARILO, ENTRE OTROS; E ES H, ALQUILO C1-C6, C(O)ALQUILO C1-C6, ENTRE OTROS; G ES H, ALQUILO C1-C6, ARILO, (ALQUIL C1-C6)ARILO, ALQUENILO C1-C6; J ES H, ALQUILO, ARILO o (ALQUIL C1-C6)ARILO; L ES H, ALQUILO C1-C6, ARILO, ENTRE OTROS. TAMBIEN SE REFIERE A COMPUESTOS DE FORMULA IA, IB. EL COMPUESTO I ES UN SECRETAGOGO DE LA HORMONA DE CRECIMIENTO
PE1998000748A 1997-08-19 1998-08-19 Secretagogos de la hormona del crecimiento PE115999A1 (es)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US5614297P 1997-08-19 1997-08-19

Publications (1)

Publication Number Publication Date
PE115999A1 true PE115999A1 (es) 1999-11-26

Family

ID=22002443

Family Applications (1)

Application Number Title Priority Date Filing Date
PE1998000748A PE115999A1 (es) 1997-08-19 1998-08-19 Secretagogos de la hormona del crecimiento

Country Status (24)

Country Link
EP (1) EP0933365A3 (es)
JP (1) JP2001515046A (es)
KR (1) KR20010027947A (es)
CN (1) CN1243567C (es)
AR (1) AR018010A1 (es)
AU (1) AU738204B2 (es)
BR (1) BR9811948A (es)
CA (1) CA2302467A1 (es)
CO (1) CO5121066A1 (es)
EA (1) EA002746B1 (es)
HR (1) HRP20000090A2 (es)
HU (1) HUP0002392A3 (es)
ID (1) ID25000A (es)
IL (1) IL134596A0 (es)
MY (1) MY138258A (es)
NO (1) NO20000823L (es)
NZ (1) NZ502947A (es)
PE (1) PE115999A1 (es)
PL (1) PL338883A1 (es)
TR (1) TR200000930T2 (es)
TW (1) TW577879B (es)
UA (1) UA58472C2 (es)
WO (1) WO1999008699A1 (es)
ZA (1) ZA987385B (es)

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US6639076B1 (en) 1998-08-18 2003-10-28 Eli Lilly And Company Growth hormone secretagogues
AU2686899A (en) * 1998-08-18 2000-03-14 Eli Lilly And Company Growth hormone secretagogues
CO5160260A1 (es) * 1999-02-19 2002-05-30 Lilly Co Eli Secretagogos de la hormona del crecimiento derivados de imi- dazol 1,4- substituido
US6828331B1 (en) 1999-02-19 2004-12-07 Eli Lilly And Company Growth hormone secretagogues
US6417397B1 (en) * 1999-10-04 2002-07-09 The Regents Of The University Of California, San Diego N-substituted alkylamino acids for use as amino-protecting groups
AU2001264977B2 (en) 2000-05-30 2005-04-14 Merck & Co., Inc. Melanocortin receptor agonists
US6756385B2 (en) * 2000-07-31 2004-06-29 Pfizer Inc. Imidazole derivatives
GT200100147A (es) * 2000-07-31 2002-06-25 Derivados de imidazol
US20040106665A1 (en) * 2000-10-13 2004-06-03 Kress Thomas Joseph Resolution process for preparation of substantially pure (r) and (s) enantiomers of 2-(4-nitroimidazolyl)-4-methodxyphenylpropionic acid and salts thereof
US7125840B2 (en) 2001-10-09 2006-10-24 Eli Lilly And Company Substituted dipeptides as growth hormone secretagogues
ES2271557T3 (es) 2002-04-09 2007-04-16 Eli Lilly And Company Secretagogos dipeptidicos de la hormona del crecimiento.
KR20050085673A (ko) * 2002-12-18 2005-08-29 에프엠씨 코포레이션 N-(치환된 아릴메틸)-4-(이치환된 메틸)피페리딘 및피페라진
BRPI0509069B8 (pt) 2004-03-23 2021-05-25 Pfizer Prod Inc compostos de imidazol e composição farmacêutica que os compreende para o tratamento de distúrbios neurodegenerativos
RS20080139A (en) 2005-09-22 2009-05-06 Pfizer Products Inc., Imidazole coumpounds for the treatment of neurological disorders
US7601844B2 (en) 2006-01-27 2009-10-13 Bristol-Myers Squibb Company Piperidinyl derivatives as modulators of chemokine receptor activity
US7615556B2 (en) 2006-01-27 2009-11-10 Bristol-Myers Squibb Company Piperazinyl derivatives as modulators of chemokine receptor activity
AU2008241532A1 (en) 2007-02-09 2008-10-30 Tranzyme Pharma, Inc. Macrocyclic ghrelin receptor modulators and methods of using the same
TWI433838B (zh) 2008-06-25 2014-04-11 必治妥美雅史谷比公司 作為趨化因子受體活性調節劑之六氫吡啶衍生物
US8642622B2 (en) 2010-06-16 2014-02-04 Bristol-Myers Squibb Company Piperidinyl compound as a modulator of chemokine receptor activity
AR086554A1 (es) 2011-05-27 2014-01-08 Novartis Ag Derivados de la piperidina 3-espirociclica como agonistas de receptores de la ghrelina
CA2867043A1 (en) 2012-05-03 2013-11-07 Novartis Ag L-malate salt of 2,7-diaza-spiro[4.5]dec-7-yle derivatives and crystalline forms thereof as ghrelin receptor agonists
JP6424219B2 (ja) 2013-07-18 2018-11-14 ノバルティス アーゲー 複素芳香環−ベンジル−アミド−サイクルコアを含むオートタキシン阻害剤
US9119832B2 (en) 2014-02-05 2015-09-01 The Regents Of The University Of California Methods of treating mild brain injury
RU2692774C2 (ru) * 2014-08-29 2019-06-27 Дайсел Корпорэйшн Имидазольное соединение, жидкость для обработки металлической поверхности, способ обработки металлической поверхности и способ изготовления ламината
WO2017075535A1 (en) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Methods of treating neurodegenerative conditions
CN107286041A (zh) * 2016-04-01 2017-10-24 成都川科化工有限公司 一种n,n-二乙基甲酰胺的制备方法
CN108299218A (zh) * 2017-01-12 2018-07-20 南京红杉生物科技有限公司 一种4-溴-d-苯丙氨酸的合成方法
CN110128285B (zh) * 2019-06-24 2022-03-01 华北制药股份有限公司 D-苯甘氨酸甲酯盐酸盐/d-二氢苯基甘氨酸甲酯盐酸盐的制备方法

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Also Published As

Publication number Publication date
CA2302467A1 (en) 1999-02-25
JP2001515046A (ja) 2001-09-18
NO20000823L (no) 2000-04-12
CO5121066A1 (es) 2002-01-30
EA200000239A1 (ru) 2000-10-30
AU738204B2 (en) 2001-09-13
TR200000930T2 (tr) 2000-11-21
ZA987385B (en) 2000-04-18
HUP0002392A2 (hu) 2000-10-28
EA002746B1 (ru) 2002-08-29
KR20010027947A (ko) 2001-04-06
HRP20000090A2 (en) 2001-04-30
BR9811948A (pt) 2000-08-22
TW577879B (en) 2004-03-01
AR018010A1 (es) 2001-10-31
MY138258A (en) 2009-05-29
EP0933365A3 (en) 2003-03-19
ID25000A (id) 2000-09-07
NO20000823D0 (no) 2000-02-18
HUP0002392A3 (en) 2000-11-28
AU9025698A (en) 1999-03-08
PL338883A1 (en) 2000-11-20
UA58472C2 (uk) 2003-08-15
CN1243567C (zh) 2006-03-01
NZ502947A (en) 2001-11-30
EP0933365A2 (en) 1999-08-04
CN1276727A (zh) 2000-12-13
IL134596A0 (en) 2001-04-30
WO1999008699A1 (en) 1999-02-25

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