ZA200507896B - Fluoro-and trifluoroalkyl-containing heterocylclic sulfonamide inhibitors of beta amyloid production and derivatives thereof - Google Patents
Fluoro-and trifluoroalkyl-containing heterocylclic sulfonamide inhibitors of beta amyloid production and derivatives thereof Download PDFInfo
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- ZA200507896B ZA200507896B ZA200507896A ZA200507896A ZA200507896B ZA 200507896 B ZA200507896 B ZA 200507896B ZA 200507896 A ZA200507896 A ZA 200507896A ZA 200507896 A ZA200507896 A ZA 200507896A ZA 200507896 B ZA200507896 B ZA 200507896B
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- ZA
- South Africa
- Prior art keywords
- sulfonamide
- trifluoro
- thiophene
- chloro
- compound according
- Prior art date
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- 102000013455 Amyloid beta-Peptides Human genes 0.000 title claims description 25
- 108010090849 Amyloid beta-Peptides Proteins 0.000 title claims description 25
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- 238000004519 manufacturing process Methods 0.000 title claims description 10
- 125000004950 trifluoroalkyl group Chemical group 0.000 title description 10
- 239000003112 inhibitor Substances 0.000 title description 6
- 125000003709 fluoroalkyl group Chemical group 0.000 title description 2
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- 238000000034 method Methods 0.000 claims description 56
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- -1 CFs Chemical group 0.000 claims description 49
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
- C07D333/62—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes 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 carbon atoms of the hetero ring
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic 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
- C07D231/14—Heterocyclic 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
- C07D231/18—One oxygen or sulfur atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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
- C07D333/30—Hetero atoms other than halogen
- C07D333/34—Sulfur atoms
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US45922803P | 2003-03-31 | 2003-03-31 |
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ZA200507896B true ZA200507896B (en) | 2007-03-28 |
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ZA200507896A ZA200507896B (en) | 2003-03-31 | 2005-09-29 | Fluoro-and trifluoroalkyl-containing heterocylclic sulfonamide inhibitors of beta amyloid production and derivatives thereof |
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Families Citing this family (35)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002057252A2 (en) * | 2000-12-13 | 2002-07-25 | Wyeth | Heterocyclic sulfonamide inhibitors of beta amyloid production |
MXPA04005927A (es) * | 2001-12-20 | 2004-11-01 | Squibb Bristol Myers Co | Derivados de alfa-(n-sulfonamido)acetamida como inhibidores del peptido beta-amiloideo. |
RU2321394C2 (ru) * | 2002-06-11 | 2008-04-10 | Уайт | Замещенные фенилсульфонамидные ингибиторы продуцирования бета-амилоида |
CL2004000647A1 (es) * | 2003-03-31 | 2005-02-04 | Wyeth Corp | Compuestos derivados de heterociclicos de sulfonamida que contienen fluoro y trifluoro alquilo; composicion farmaceutica; kit farmaceutico; procedimiento de preparacion; y su uso como inhibidores de beta amiloides para tratar alzheimer, angiopatia am |
CA2552558A1 (en) * | 2004-01-16 | 2005-08-11 | Wyeth | Heterocyclic sulfonamide inhibitors of beta amyloid production containing an azole |
AU2007217966A1 (en) * | 2006-02-17 | 2007-08-30 | Wyeth | Selective N-sulfonylation of 2-amino trifluoroalkyl substituted alcohols |
JP2009528281A (ja) | 2006-02-17 | 2009-08-06 | ワイス | スルホンアミド置換アルコールおよびその中間体の調製方法 |
US7550629B2 (en) * | 2006-04-21 | 2009-06-23 | Wyeth | Trifluoromethyl-containing phenylsulfonamide beta amyloid inhibitors |
US7476762B2 (en) | 2006-04-21 | 2009-01-13 | Wyeth | Methods for preparing sulfonamide compounds |
BRPI0710470A2 (pt) | 2006-04-21 | 2011-08-16 | Wyeth Corp | métodos para preparar seletivamente um aminoálcool quiral e uma sulfonamida quiral |
JP2010509235A (ja) * | 2006-11-03 | 2010-03-25 | ノースウェスタン ユニバーシティ | 多発性硬化症の治療 |
US20090023903A1 (en) * | 2007-07-16 | 2009-01-22 | Wyeth | Process for the preparation of trifluoroalkyl-phenyl and heterocyclic sulfonamides |
PE20090810A1 (es) * | 2007-07-16 | 2009-07-20 | Wyeth Corp | Procesos e intermediarios para la preparacion de compuestos de sulfonamida heterociclica |
CA2693959A1 (en) * | 2007-07-16 | 2009-01-22 | Wyeth | Inhibitors of beta amyloid production |
US8093276B2 (en) * | 2007-10-31 | 2012-01-10 | Bristol-Myers Squibb Company | Alpha-(N-sulfonamido)acetamide compound as an inhibitor of beta amyloid peptide production |
US8084477B2 (en) * | 2007-10-31 | 2011-12-27 | Bristol-Myers Squibb Company | Alpha-(N-sulfonamido)acetamide compound as an inhibitor of beta amyloid peptide production |
WO2009089237A1 (en) * | 2008-01-11 | 2009-07-16 | Wyeth | Compositions containing o-sulfate and o-phosphate containing aryl sulfonamide derivatives useful as beta-amyloid inhibitors |
EP2278878A4 (en) * | 2008-05-08 | 2014-08-27 | Bristol Myers Squibb Co | 2-ARYL-GYCINAMID DERIVATIVES |
CN102143928A (zh) * | 2008-09-05 | 2011-08-03 | 马克斯普朗克科学促进协会 | 利用两个连续的结晶步骤对化合物形成的手性体系进行对映体拆分的方法 |
US8044077B2 (en) * | 2009-03-19 | 2011-10-25 | Bristol-Myers Squibb Company | Alpha-(N-sulfonamido)acetamide compounds incorporating deuterium as inhibitors of beta amyloid peptide production |
US7977362B2 (en) * | 2009-03-20 | 2011-07-12 | Bristol-Myers Squibb Company | Alpha-(N-benzenesulfonamido)cycloalkyl derivatives |
US20110071199A1 (en) * | 2009-03-20 | 2011-03-24 | Bristol-Myers Squibb Company | Thiophenyl Sulfonamides for the Treatment of Alzheimer's Disease |
TW201043269A (en) * | 2009-04-14 | 2010-12-16 | Bristol Myers Squibb Co | Bioavailable compositions of amorphous alpha-(N-sulfonamido)acetamide compound |
US8252821B2 (en) * | 2009-04-14 | 2012-08-28 | Bristol-Myers Squibb Company | Bioavailable capsule compositions of amorphous alpha-(N-sulfonamido)acetamide compound |
WO2010126002A1 (ja) * | 2009-04-28 | 2010-11-04 | 塩野義製薬株式会社 | ヘテロ環スルホンアミド化合物を含有する医薬 |
WO2011084503A1 (en) * | 2009-12-16 | 2011-07-14 | North Carolina Central University | Phenoxy thiophene sulfonamides and their use in the treatment of neurodegenerative diseases |
US9223209B2 (en) * | 2010-02-19 | 2015-12-29 | International Business Machines Corporation | Sulfonamide-containing photoresist compositions and methods of use |
US9223217B2 (en) * | 2010-02-19 | 2015-12-29 | International Business Machines Corporation | Sulfonamide-containing topcoat and photoresist additive compositions and methods of use |
US9617239B2 (en) | 2010-03-10 | 2017-04-11 | North Carolina Central University | Phenoxy thiophene sulfonamides and their use as inhibitors of glucuronidase |
JP2015527398A (ja) | 2012-09-07 | 2015-09-17 | マサチューセッツ アイ アンド イヤー インファーマリー | 聴覚喪失治療 |
JP6319912B2 (ja) | 2013-04-19 | 2018-05-09 | 国立大学法人 岡山大学 | アミロイドβ蛋白質により誘発される認知障害の治療剤およびアルツハイマー病治療薬、ならびにこれらに関連する治療方法および病態解析方法 |
EP3212773B1 (en) | 2014-10-29 | 2021-09-15 | Massachusetts Eye and Ear Infirmary | Efficient delivery of therapeutic molecules to cells of the inner ear |
KR102362222B1 (ko) | 2016-05-16 | 2022-02-11 | 더 제너럴 하스피탈 코포레이션 | 폐 상피 공학에서 인간 기도 줄기 세포 |
WO2019148067A1 (en) | 2018-01-26 | 2019-08-01 | Massachusetts Eye And Ear Infirmary | Treatment of hearing loss |
EP4299062A1 (en) | 2022-06-30 | 2024-01-03 | Vilnius University | Inhibition of protein amyloid aggregation using fluorinated benzenesulfonamides |
Family Cites Families (43)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5464853A (en) | 1993-05-20 | 1995-11-07 | Immunopharmaceutics, Inc. | N-(5-isoxazolyl)biphenylsulfonamides, N-(3-isoxazolyl)biphenylsulfonamides and derivatives thereof that modulate the activity of endothelin |
US5594021A (en) | 1993-05-20 | 1997-01-14 | Texas Biotechnology Corporation | Thienyl-, furyl- and pyrrolyl sulfonamides and derivatives thereof that modulate the activity of endothelin |
US5591761A (en) | 1993-05-20 | 1997-01-07 | Texas Biotechnology Corporation | Thiophenyl-, furyl-and pyrrolyl-sulfonamides and derivatives thereof that modulate the activity of endothelin |
US5514691A (en) | 1993-05-20 | 1996-05-07 | Immunopharmaceutics, Inc. | N-(4-halo-isoxazolyl)-sulfonamides and derivatives thereof that modulate the activity of endothelin |
US5571821A (en) | 1993-05-20 | 1996-11-05 | Texas Biotechnology Corporation | Sulfonamides and derivatives thereof that modulate the activity of endothelin |
EP0510700A3 (en) | 1991-04-26 | 1992-12-16 | Takeda Chemical Industries, Ltd. | Azole compounds, their production and use |
GB9110722D0 (en) | 1991-05-17 | 1991-07-10 | Fujisawa Pharmaceutical Co | Amine derivatives |
US5766846A (en) | 1992-07-10 | 1998-06-16 | Athena Neurosciences | Methods of screening for compounds which inhibit soluble β-amyloid peptide production |
US5968942A (en) | 1992-08-25 | 1999-10-19 | G. D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
US6376523B1 (en) | 1994-05-20 | 2002-04-23 | Texas Biotechnology Corporation | Benzenesulfonamides and the use thereof to modulate the activity of endothelin |
ZA945719B (en) | 1993-08-09 | 1996-02-01 | Lilly Co Eli | Identification and use of protease inhibitors |
US5519040A (en) | 1994-04-29 | 1996-05-21 | Allergan | Substituted thiazole sulfonamides as antiglaucoma agents |
US5624937A (en) | 1995-03-02 | 1997-04-29 | Eli Lilly And Company | Chemical compounds as inhibitors of amyloid beta protein production |
ATE377006T1 (de) | 1995-11-28 | 2007-11-15 | Cephalon Inc | Aus d-aminosäuren abgeleitete cystein- und serinproteasehemmer |
KR20000067964A (ko) | 1996-07-22 | 2000-11-25 | 죤 에이치. 뷰센 | 티올 술폰아미드 메탈로프로테아제 저해제 |
US5703129A (en) | 1996-09-30 | 1997-12-30 | Bristol-Myers Squibb Company | 5-amino-6-cyclohexyl-4-hydroxy-hexanamide derivatives as inhibitors of β-amyloid protein production |
US5985930A (en) | 1996-11-21 | 1999-11-16 | Pasinetti; Giulio M. | Treatment of neurodegenerative conditions with nimesulide |
IL129477A0 (en) | 1996-11-22 | 2000-02-29 | Elan Pharm Inc | N-(aryl/heteroaryl)amino acid derivatives pharmaceutical compositions comprising same and methods for inhibiting beta-amyloid peptide release and/or its synthesis by use of such compounds |
DE19650196A1 (de) | 1996-12-04 | 1998-06-10 | Bayer Ag | Thienylsulfonylamino(thio)carbonylverbindungen |
JPH11343279A (ja) | 1998-03-16 | 1999-12-14 | Shionogi & Co Ltd | スルホンアミド誘導体およびそれらを含有するTNF―α産生抑制剤 |
US5981168A (en) | 1998-05-15 | 1999-11-09 | The University Of British Columbia | Method and composition for modulating amyloidosis |
US7410995B1 (en) | 1998-08-14 | 2008-08-12 | Gpi Nil Holdings Inc. | N-linked sulfonamide of heterocyclic thioesters for vision and memory disorders |
NZ514453A (en) | 1999-02-26 | 2003-04-29 | Merck & Co Inc | Novel sulfonamide compounds and uses thereof |
EP1172361A4 (en) | 1999-04-19 | 2002-05-08 | Shionogi & Co | SULFONAMIDE DERIVATIVES HAVING OXADIAZOLE CORES |
EP1088815A1 (en) | 1999-09-28 | 2001-04-04 | Applied Research Systems ARS Holding N.V. | Pharmaceutically active sulfonyl amino acid derivatives |
EP1088821A1 (en) | 1999-09-28 | 2001-04-04 | Applied Research Systems ARS Holding N.V. | Pharmaceutically active sulfonamide derivatives |
CA2387493A1 (en) | 1999-10-08 | 2001-04-19 | Lorin Andrew Thompson | Amino lactam sulfonamides as inhibitors of a.beta. protein production |
DE60124684T2 (de) | 2000-03-20 | 2007-09-13 | Merck Sharp & Dohme Ltd., Hoddesdon | Sulfonamido-substituierte verbrückte bicycloalkylderivative |
WO2002057252A2 (en) | 2000-12-13 | 2002-07-25 | Wyeth | Heterocyclic sulfonamide inhibitors of beta amyloid production |
US6657070B2 (en) | 2000-12-13 | 2003-12-02 | Wyeth | Production of chirally pure α-amino acids and N-sulfonyl α-amino acids |
CA2470111A1 (en) | 2001-12-11 | 2003-06-19 | Wyeth | Production of chirally pure .alpha.-amino acids and n-sulfonyl .alpha.-amino acids |
BR0214863A (pt) | 2001-12-11 | 2004-12-14 | Wyeth Corp | Processo para a sìntese de beta-aminoálcoois quiralmente puros |
RU2321394C2 (ru) | 2002-06-11 | 2008-04-10 | Уайт | Замещенные фенилсульфонамидные ингибиторы продуцирования бета-амилоида |
CL2004000647A1 (es) * | 2003-03-31 | 2005-02-04 | Wyeth Corp | Compuestos derivados de heterociclicos de sulfonamida que contienen fluoro y trifluoro alquilo; composicion farmaceutica; kit farmaceutico; procedimiento de preparacion; y su uso como inhibidores de beta amiloides para tratar alzheimer, angiopatia am |
CA2552558A1 (en) * | 2004-01-16 | 2005-08-11 | Wyeth | Heterocyclic sulfonamide inhibitors of beta amyloid production containing an azole |
JP2009528281A (ja) * | 2006-02-17 | 2009-08-06 | ワイス | スルホンアミド置換アルコールおよびその中間体の調製方法 |
AU2007217966A1 (en) * | 2006-02-17 | 2007-08-30 | Wyeth | Selective N-sulfonylation of 2-amino trifluoroalkyl substituted alcohols |
US7550629B2 (en) * | 2006-04-21 | 2009-06-23 | Wyeth | Trifluoromethyl-containing phenylsulfonamide beta amyloid inhibitors |
BRPI0710470A2 (pt) * | 2006-04-21 | 2011-08-16 | Wyeth Corp | métodos para preparar seletivamente um aminoálcool quiral e uma sulfonamida quiral |
US7476762B2 (en) * | 2006-04-21 | 2009-01-13 | Wyeth | Methods for preparing sulfonamide compounds |
PE20090810A1 (es) * | 2007-07-16 | 2009-07-20 | Wyeth Corp | Procesos e intermediarios para la preparacion de compuestos de sulfonamida heterociclica |
CA2693959A1 (en) * | 2007-07-16 | 2009-01-22 | Wyeth | Inhibitors of beta amyloid production |
US20090023903A1 (en) * | 2007-07-16 | 2009-01-22 | Wyeth | Process for the preparation of trifluoroalkyl-phenyl and heterocyclic sulfonamides |
-
2004
- 2004-03-26 CL CL200400647A patent/CL2004000647A1/es unknown
- 2004-03-26 US US10/810,517 patent/US7300951B2/en not_active Expired - Fee Related
- 2004-03-26 CA CA002517155A patent/CA2517155A1/en not_active Abandoned
- 2004-03-26 KR KR1020057018637A patent/KR20060002908A/ko not_active Application Discontinuation
- 2004-03-26 EP EP04758978A patent/EP1608638A1/en not_active Withdrawn
- 2004-03-26 CN CN2004800087813A patent/CN1780829B/zh not_active Expired - Fee Related
- 2004-03-26 BR BRPI0408962-6A patent/BRPI0408962A/pt not_active IP Right Cessation
- 2004-03-26 RU RU2005133434/04A patent/RU2342374C2/ru not_active IP Right Cessation
- 2004-03-26 NZ NZ542468A patent/NZ542468A/en not_active IP Right Cessation
- 2004-03-26 WO PCT/US2004/009268 patent/WO2004092155A1/en active Application Filing
- 2004-03-26 AU AU2004230844A patent/AU2004230844B2/en not_active Expired - Fee Related
- 2004-03-26 UA UAA200510177A patent/UA82093C2/uk unknown
- 2004-03-26 CN CNA2008100013400A patent/CN101274926A/zh active Pending
- 2004-03-26 SG SG200708961-8A patent/SG167669A1/en unknown
- 2004-03-26 AR ARP040101022A patent/AR043940A1/es unknown
- 2004-03-26 TW TW093108219A patent/TWI336698B/zh not_active IP Right Cessation
- 2004-03-26 JP JP2006509331A patent/JP2006522126A/ja active Pending
- 2004-03-26 MX MXPA05010368A patent/MXPA05010368A/es active IP Right Grant
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2005
- 2005-08-19 CR CR7951A patent/CR7951A/es unknown
- 2005-09-15 NO NO20054263A patent/NO20054263L/no not_active Application Discontinuation
- 2005-09-29 ZA ZA200507896A patent/ZA200507896B/en unknown
- 2005-10-26 CO CO05109226A patent/CO5640049A2/es not_active Application Discontinuation
- 2005-10-28 EC EC2005006128A patent/ECSP056128A/es unknown
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2007
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- 2009-05-05 US US12/435,442 patent/US7858658B2/en not_active Expired - Fee Related
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NZ542468A (en) | 2009-01-31 |
BRPI0408962A (pt) | 2006-04-04 |
CR7951A (es) | 2008-10-29 |
EP1608638A1 (en) | 2005-12-28 |
KR20060002908A (ko) | 2006-01-09 |
US7547725B2 (en) | 2009-06-16 |
AU2004230844A1 (en) | 2004-10-28 |
NO20054263L (no) | 2005-12-14 |
TW200504047A (en) | 2005-02-01 |
US20040198778A1 (en) | 2004-10-07 |
RU2342374C2 (ru) | 2008-12-27 |
AU2004230844B2 (en) | 2010-12-09 |
CN1780829A (zh) | 2006-05-31 |
TWI336698B (en) | 2011-02-01 |
WO2004092155A1 (en) | 2004-10-28 |
AR043940A1 (es) | 2005-08-17 |
JP2006522126A (ja) | 2006-09-28 |
CL2004000647A1 (es) | 2005-02-04 |
CN101274926A (zh) | 2008-10-01 |
US7300951B2 (en) | 2007-11-27 |
UA82093C2 (uk) | 2008-03-11 |
US20070254929A1 (en) | 2007-11-01 |
RU2005133434A (ru) | 2006-07-10 |
CN1780829B (zh) | 2010-12-29 |
ECSP056128A (es) | 2006-03-01 |
CA2517155A1 (en) | 2004-10-28 |
US7858658B2 (en) | 2010-12-28 |
MXPA05010368A (es) | 2005-11-17 |
US20090227667A1 (en) | 2009-09-10 |
NO20054263D0 (no) | 2005-09-15 |
CO5640049A2 (es) | 2006-05-31 |
SG167669A1 (en) | 2011-01-28 |
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