ZA200207004B - Novel aryl fructose-1,6-bisphosphatase inhibitors. - Google Patents
Novel aryl fructose-1,6-bisphosphatase inhibitors. Download PDFInfo
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- ZA200207004B ZA200207004B ZA200207004A ZA200207004A ZA200207004B ZA 200207004 B ZA200207004 B ZA 200207004B ZA 200207004 A ZA200207004 A ZA 200207004A ZA 200207004 A ZA200207004 A ZA 200207004A ZA 200207004 B ZA200207004 B ZA 200207004B
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- South Africa
- Prior art keywords
- group
- aryl
- substituted
- atoms
- alkyl
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- 125000003118 aryl group Chemical group 0.000 title claims description 298
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- 150000001875 compounds Chemical class 0.000 claims description 93
- 229910052799 carbon Inorganic materials 0.000 claims description 86
- 229910052757 nitrogen Inorganic materials 0.000 claims description 84
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se)
- C07F9/3804—Phosphonic acids RP(=O)(OH)2; Thiophosphonic acids, i.e. RP(=X)(XH)2 (X = S, Se) not used, see subgroups
- C07F9/3826—Acyclic unsaturated acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6536—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and sulfur atoms with or without oxygen atoms, as the only ring hetero atoms
- C07F9/6539—Five-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
- C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65586—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system at least one of the hetero rings does not contain nitrogen as ring hetero atom
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| WO1998039344A1 (en) * | 1997-03-07 | 1998-09-11 | Metabasis Therapeutics, Inc. | Novel purine inhibitors of fructose-1,6-bisphosphatase |
| AU761267C (en) | 1998-09-09 | 2007-08-09 | Metabasis Therapeutics, Inc. | Novel heteroaromatic inhibitors of fructose 1,6-bisphosphatase |
| US6756360B1 (en) * | 1998-12-24 | 2004-06-29 | Metabasis Therapeutics, Inc. | Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes |
| SK8892002A3 (en) * | 1999-12-22 | 2003-04-01 | Metabasis Therapeutics Inc | Novel bisamidate phosphonate prodrugs, process for their preparation and use thereof |
| ATE350385T1 (de) * | 2000-03-08 | 2007-01-15 | Metabasis Therapeutics Inc | Neue aryl fructose-1,6-bisphosphatase inhibitoren |
| US7563774B2 (en) * | 2000-06-29 | 2009-07-21 | Metabasis Therapeutics, Inc. | Combination of FBPase inhibitors and antidiabetic agents useful for the treatment of diabetes |
| WO2004009118A1 (ja) * | 2002-07-23 | 2004-01-29 | Sankyo Company, Limited | 糖尿病の発症予防薬 |
| FR2846327B1 (fr) * | 2002-10-25 | 2006-03-24 | Merck Sante Sas | Derives de n-benzodioxolyl, n-benzodioxanyl et n-benzodioxepinyl arylcarboxamides utilisables dans le traitement de dyslipidemies et compositions pharmaceutiques les contenant. |
| US7129049B2 (en) * | 2003-12-22 | 2006-10-31 | Regents Of The University Of Minnesota | Method of detecting equine glycogen storage disease IV |
| US20070225259A1 (en) * | 2004-08-18 | 2007-09-27 | Qun Dang | Novel Thiazole Inhibitors of Fructose 1,6-Bishosphatase |
| EP1857118A1 (en) * | 2004-12-13 | 2007-11-21 | Daiichi Sankyo Company, Limited | Medicinal composition for treating diabetes |
| TW200633702A (en) * | 2004-12-15 | 2006-10-01 | Sankyo Co | Medicinal composition containing fbpase inhibitor |
| EP1752450A1 (en) | 2005-08-01 | 2007-02-14 | Merck Sante | Imidazole derivatives as fructose-1,6-bisphosphatase inhibitors and pharmaceutical compositions containing them |
| JP5572549B2 (ja) * | 2007-08-13 | 2014-08-13 | リガンド・ファーマシューティカルズ・インコーポレイテッド | グルコキナーゼの新規な活性化剤 |
| EP2058308A1 (fr) | 2007-11-12 | 2009-05-13 | Merck Sante | Dérivés de benzimidazoledihydrothiadiazinone comme inhibiteurs de fructose-1,6-biphosphatase et compositions pharmaceutiques les contenant. |
| EP2805951B1 (en) | 2009-03-20 | 2018-03-14 | Metabasis Therapeutics, Inc. | Inhibitors of diacylglycerol o-acyltransferase 1 (DGAT-1) and uses thereof |
| US9006568B2 (en) | 2012-02-15 | 2015-04-14 | Phillips 66 Company | Synthesis of photovoltaic conjugated polymers |
| US10125126B2 (en) * | 2012-04-20 | 2018-11-13 | Bayer Cropscience Ag | N-cycloalkyl-N-[(heterocyclylphenyl)methylene]-(thio)carboxamide derivatives |
| CN103665043B (zh) | 2012-08-30 | 2017-11-10 | 江苏豪森药业集团有限公司 | 一种替诺福韦前药及其在医药上的应用 |
| WO2014088795A1 (en) | 2012-12-03 | 2014-06-12 | Phillips 66 Company | Benzo [1,2-b:4,5-b'] dithiophene-thienothiophene based conjugated polymers |
| EP3078378B1 (en) | 2015-04-08 | 2020-06-24 | Vaiomer | Use of factor xa inhibitors for regulating glycemia |
| US9911919B2 (en) | 2015-10-01 | 2018-03-06 | Phillips 66 Company | Process of manufacturing an electron transport material |
| US10312448B2 (en) | 2015-10-01 | 2019-06-04 | Phillips 66 Company | Process of manufacturing an electron transport material |
| US10418555B2 (en) | 2015-10-01 | 2019-09-17 | Phillips 66 Company | Formation of films for organic photovoltaics |
| US9905769B2 (en) | 2015-10-01 | 2018-02-27 | Phillips 66 Company | Process of manufacturing an electron transport material |
| WO2017058406A1 (en) | 2015-10-01 | 2017-04-06 | Phillips 66 Company | Formation of films for organic photovoltaics |
| JP7072557B2 (ja) | 2016-07-22 | 2022-05-20 | ブリストル－マイヤーズ スクイブ カンパニー | グルコキナーゼ活性化剤およびその使用方法 |
| CN111116647B (zh) * | 2019-12-02 | 2021-08-24 | 西安电子科技大学 | 一种具有hdac抑制活性的磷酸类化合物及其制备方法与用途 |
Family Cites Families (40)
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|---|---|---|---|---|
| NL72851C (pt) * | 1950-10-31 | 1900-01-01 | ||
| US2683168A (en) * | 1950-12-22 | 1954-07-06 | California Research Corp | Preparation of organo phosphonyl chlorides |
| US3524846A (en) | 1967-06-02 | 1970-08-18 | Syntex Corp | Process for the didealkylation of phosphonate esters |
| GB2043073B (en) * | 1979-02-13 | 1983-05-11 | Symphar Sa | Mono-and diphosphonate compounds |
| US4640701A (en) * | 1984-04-17 | 1987-02-03 | Ciba-Geigy Corporation | Herbicidal phosphonic acid and phosphinic acid derivatives |
| US4746653A (en) * | 1986-02-28 | 1988-05-24 | Ciba-Geigy Corporation | Certain hetero phosphonic acid derivatives of 2-piperidine or 2-tetrahydropyridinecarboxylates and esters thereof which are useful for the treatment of disorders responsive to blockade of the NMDA receptor in mammals |
| US4968788A (en) | 1986-04-04 | 1990-11-06 | Board Of Regents, The University Of Texas System | Biologically reversible phosphate and phosphonate protective gruops |
| DE3770982D1 (de) * | 1986-04-24 | 1991-08-01 | Fujisawa Pharmaceutical Co | Diphosphonsaeure-verbindungen, verfahren zu deren herstellung und sie enthaltende arzneimittel. |
| US5091552A (en) | 1986-06-30 | 1992-02-25 | Board Of Regents, The University Of Texas System | Novel antitumor aldophosphamide analogs |
| US5045557A (en) * | 1987-03-20 | 1991-09-03 | Schering Agrochemicals Ltd. | Imidazable fungicides and use thereof |
| US4943629A (en) | 1988-08-12 | 1990-07-24 | American Cyanamid Company | Antidiabetic alpha-substituted phosphonates |
| US4968790A (en) | 1988-08-12 | 1990-11-06 | American Cyanamid Company | Antidiabetic phosphates |
| US5658889A (en) | 1989-01-24 | 1997-08-19 | Gensia Pharmaceuticals, Inc. | Method and compounds for aica riboside delivery and for lowering blood glucose |
| CA2008325A1 (en) | 1989-01-24 | 1990-07-24 | Harry E. Gruber | Method and compounds for aica riboside delivery and for lowering blood glucose |
| DK0533833T3 (da) | 1990-06-13 | 1996-04-22 | Arnold Glazier | Phosphorprolægemidler |
| US5157027A (en) | 1991-05-13 | 1992-10-20 | E. R. Squibb & Sons, Inc. | Bisphosphonate squalene synthetase inhibitors and method |
| US5208235A (en) * | 1992-03-10 | 1993-05-04 | E. R. Squibb & Sons, Inc. | Indole- and benzimidazole-substituted imidazole derivatives |
| US5278153A (en) * | 1992-05-18 | 1994-01-11 | E. R. Squibb & Sons, Inc. | Aryl and heteroaryl (phosphinylmethyl)phosphonate squalene synthetase inhibitors and method |
| CA2145640C (en) * | 1992-09-28 | 2001-01-30 | Banavara L. Mylari | Substituted pyrimidines for control of diabetic complications |
| DE69426904T2 (de) | 1993-06-29 | 2001-10-11 | Mitsubishi Chem Corp | Phosphonat-Nukleotid Ester-Derivate |
| WO1995007920A1 (en) | 1993-09-17 | 1995-03-23 | Gilead Sciences, Inc. | Nucleotide analogs |
| US6011049A (en) | 1997-02-19 | 2000-01-04 | Warner-Lambert Company | Combinations for diabetes |
| US6110903A (en) * | 1997-03-07 | 2000-08-29 | Sankyo Company Ltd. | Benzimidazole inhibitors of fructose 1,6-bisphosphatase |
| WO1998039344A1 (en) * | 1997-03-07 | 1998-09-11 | Metabasis Therapeutics, Inc. | Novel purine inhibitors of fructose-1,6-bisphosphatase |
| AU6691798A (en) * | 1997-03-07 | 1998-09-22 | Metabasis Therapeutics, Inc. | Novel indole and azaindole inhibitors of fructose-1,6-bisphosphatase |
| AU767599B2 (en) | 1998-03-06 | 2003-11-20 | Metabasis Therapeutics, Inc. | Novel prodrugs for phosphorus-containing compounds |
| US6312662B1 (en) * | 1998-03-06 | 2001-11-06 | Metabasis Therapeutics, Inc. | Prodrugs phosphorus-containing compounds |
| AU3087099A (en) | 1998-03-16 | 1999-10-11 | Ontogen Corporation | Piperazines as inhibitors of fructose-1,6-bisphosphatase (FBPase) |
| AU761267C (en) * | 1998-09-09 | 2007-08-09 | Metabasis Therapeutics, Inc. | Novel heteroaromatic inhibitors of fructose 1,6-bisphosphatase |
| DE19843383A1 (de) * | 1998-09-22 | 2000-03-30 | Hassan Jomaa | Phosphororganische Verbindungen und ihre Verwendung |
| DE69926400T2 (de) | 1998-12-24 | 2006-05-24 | Metabasis Therapeutics Inc., San Diego | Zusammensetzung enthaltend insulin-sensibilisierenden wirkstoffe und inhibitoren der fruktose-1,6-bisphosphatase (fbpase) zur behandlung von diabetes |
| US6756360B1 (en) * | 1998-12-24 | 2004-06-29 | Metabasis Therapeutics, Inc. | Combination of FBPase inhibitors and insulin sensitizers for the treatment of diabetes |
| HUP0200260A3 (en) | 1999-03-05 | 2002-11-28 | Metabasis Therapeutics Inc San | Novel phosphorus-containing prodrugs, their preparation and their use |
| SK8892002A3 (en) * | 1999-12-22 | 2003-04-01 | Metabasis Therapeutics Inc | Novel bisamidate phosphonate prodrugs, process for their preparation and use thereof |
| DK1248604T4 (da) | 2000-01-21 | 2012-05-21 | Novartis Ag | Kombinationer indeholdende dipeptidylpeptidase-IV-inhibitorer og antidiabetiske midler |
| ATE350385T1 (de) | 2000-03-08 | 2007-01-15 | Metabasis Therapeutics Inc | Neue aryl fructose-1,6-bisphosphatase inhibitoren |
| CY2010012I2 (el) * | 2000-05-25 | 2020-05-29 | Novartis Ag | Μιμητικα θρομβοποιητινης |
| US7563774B2 (en) * | 2000-06-29 | 2009-07-21 | Metabasis Therapeutics, Inc. | Combination of FBPase inhibitors and antidiabetic agents useful for the treatment of diabetes |
| CN101301294A (zh) | 2000-07-06 | 2008-11-12 | 症变治疗公司 | Fbp酶抑制剂与抗糖尿病药联合用于治疗糖尿病 |
| US20070225259A1 (en) | 2004-08-18 | 2007-09-27 | Qun Dang | Novel Thiazole Inhibitors of Fructose 1,6-Bishosphatase |
-
2001
- 2001-03-07 AT AT01918456T patent/ATE350385T1/de not_active IP Right Cessation
- 2001-03-07 EP EP01918456A patent/EP1265907B9/en not_active Expired - Lifetime
- 2001-03-07 BR BR0109062-3A patent/BR0109062A/pt not_active Application Discontinuation
- 2001-03-07 CN CNA018090214A patent/CN1516705A/zh active Pending
- 2001-03-07 HU HU0300344A patent/HUP0300344A3/hu unknown
- 2001-03-07 CA CA002401706A patent/CA2401706A1/en not_active Abandoned
- 2001-03-07 JP JP2001565369A patent/JP2003525944A/ja not_active Withdrawn
- 2001-03-07 CZ CZ20023018A patent/CZ20023018A3/cs unknown
- 2001-03-07 KR KR1020027011737A patent/KR20020079988A/ko not_active Application Discontinuation
- 2001-03-07 MX MXPA02008722A patent/MXPA02008722A/es active IP Right Grant
- 2001-03-07 RU RU2002126616/04A patent/RU2002126616A/ru unknown
- 2001-03-07 WO PCT/US2001/007452 patent/WO2001066553A2/en active IP Right Grant
- 2001-03-07 AU AU2001245532A patent/AU2001245532B2/en not_active Ceased
- 2001-03-07 SK SK1272-2002A patent/SK12722002A3/sk unknown
- 2001-03-07 CN CNA2005100720821A patent/CN1699383A/zh active Pending
- 2001-03-07 DE DE60125734T patent/DE60125734T2/de not_active Expired - Fee Related
- 2001-03-07 EP EP05015039A patent/EP1607401A1/en not_active Withdrawn
- 2001-03-07 IL IL15124801A patent/IL151248A0/xx active IP Right Grant
- 2001-03-07 AU AU4553201A patent/AU4553201A/xx active Pending
- 2001-03-07 US US09/801,933 patent/US6919322B2/en not_active Expired - Lifetime
- 2001-03-07 PL PL01357251A patent/PL357251A1/xx not_active Application Discontinuation
-
2002
- 2002-08-14 IL IL151248A patent/IL151248A/en not_active IP Right Cessation
- 2002-08-30 ZA ZA200207004A patent/ZA200207004B/en unknown
- 2002-09-05 NO NO20024240A patent/NO20024240L/no not_active Application Discontinuation
-
2003
- 2003-06-10 HK HK03104075A patent/HK1051865A1/xx not_active IP Right Cessation
-
2005
- 2005-01-25 US US11/043,859 patent/US7371739B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| ATE350385T1 (de) | 2007-01-15 |
| BR0109062A (pt) | 2002-11-26 |
| US20050176684A1 (en) | 2005-08-11 |
| EP1265907B9 (en) | 2007-05-09 |
| CN1516705A (zh) | 2004-07-28 |
| US7371739B2 (en) | 2008-05-13 |
| NO20024240L (no) | 2002-11-08 |
| CZ20023018A3 (cs) | 2003-01-15 |
| SK12722002A3 (sk) | 2003-04-01 |
| AU2001245532B2 (en) | 2005-08-11 |
| RU2002126616A (ru) | 2004-03-20 |
| PL357251A1 (en) | 2004-07-26 |
| NO20024240D0 (no) | 2002-09-05 |
| AU4553201A (en) | 2001-09-17 |
| EP1607401A1 (en) | 2005-12-21 |
| HK1051865A1 (en) | 2003-08-22 |
| WO2001066553A2 (en) | 2001-09-13 |
| MXPA02008722A (es) | 2004-05-05 |
| CN1699383A (zh) | 2005-11-23 |
| EP1265907B1 (en) | 2007-01-03 |
| JP2003525944A (ja) | 2003-09-02 |
| US6919322B2 (en) | 2005-07-19 |
| HUP0300344A3 (en) | 2007-05-29 |
| IL151248A (en) | 2007-06-17 |
| KR20020079988A (ko) | 2002-10-21 |
| WO2001066553A3 (en) | 2002-03-14 |
| DE60125734D1 (en) | 2007-02-15 |
| DE60125734T2 (de) | 2007-10-25 |
| US20020040014A1 (en) | 2002-04-04 |
| EP1265907A2 (en) | 2002-12-18 |
| CA2401706A1 (en) | 2001-09-13 |
| IL151248A0 (en) | 2003-04-10 |
| HUP0300344A2 (hu) | 2003-06-28 |
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