JP2006514099A5 - - Google Patents
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- Publication number
- JP2006514099A5 JP2006514099A5 JP2005501423A JP2005501423A JP2006514099A5 JP 2006514099 A5 JP2006514099 A5 JP 2006514099A5 JP 2005501423 A JP2005501423 A JP 2005501423A JP 2005501423 A JP2005501423 A JP 2005501423A JP 2006514099 A5 JP2006514099 A5 JP 2006514099A5
- Authority
- JP
- Japan
- Prior art keywords
- compound
- substituted
- phosphonate
- alkyl
- following structure
- Prior art date
- Legal status (The legal status 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 status listed.)
- Pending
Links
- 0 *c1c(*)c(*)nc(*)c1* Chemical compound *c1c(*)c(*)nc(*)c1* 0.000 description 41
- PBWVYZYNSCGBQV-UHFFFAOYSA-N CC(C)(C)OC(NC(C1)CN1C(Oc(c1c2nccc1)c(CN(Cc(cc1)ccc1F)C1=O)c1c2OC(c1ccccc1)c1ccccc1)=O)=O Chemical compound CC(C)(C)OC(NC(C1)CN1C(Oc(c1c2nccc1)c(CN(Cc(cc1)ccc1F)C1=O)c1c2OC(c1ccccc1)c1ccccc1)=O)=O PBWVYZYNSCGBQV-UHFFFAOYSA-N 0.000 description 1
- LKXSEJODFICBQQ-UHFFFAOYSA-N CC(c(c1c(c2c3cccn2)O)c3OC)N(Cc(cc2)ccc2F)C1=O Chemical compound CC(c(c1c(c2c3cccn2)O)c3OC)N(Cc(cc2)ccc2F)C1=O LKXSEJODFICBQQ-UHFFFAOYSA-N 0.000 description 1
- ZDKGMGOVBBVDPK-UHFFFAOYSA-N COCOc(c(nccc1)c1c(O)c1C(N2Cc(cc3)ccc3F)=O)c1C2=O Chemical compound COCOc(c(nccc1)c1c(O)c1C(N2Cc(cc3)ccc3F)=O)c1C2=O ZDKGMGOVBBVDPK-UHFFFAOYSA-N 0.000 description 1
- HDOLDXSQPDJGIJ-UHFFFAOYSA-N COCOc(c(nccc1)c1c(OCc1ccccc1)c1C(N2Cc(cc3)ccc3F)=O)c1C2=O Chemical compound COCOc(c(nccc1)c1c(OCc1ccccc1)c1C(N2Cc(cc3)ccc3F)=O)c1C2=O HDOLDXSQPDJGIJ-UHFFFAOYSA-N 0.000 description 1
- NRIFOPWNLUHYCG-UHFFFAOYSA-N COc(c1c2nccc1)c(C(N(Cc(cc1)ccc1F)C1=O)=C)c1c2O Chemical compound COc(c1c2nccc1)c(C(N(Cc(cc1)ccc1F)C1=O)=C)c1c2O NRIFOPWNLUHYCG-UHFFFAOYSA-N 0.000 description 1
- OOIDSMJGMNNWKG-UHFFFAOYSA-N C[O](C1)C1c(c1c2nccc1)c(C(N(Cc(cc1)ccc1F)C1=O)O)c1c2OC(c1ccccc1)c1ccccc1 Chemical compound C[O](C1)C1c(c1c2nccc1)c(C(N(Cc(cc1)ccc1F)C1=O)O)c1c2OC(c1ccccc1)c1ccccc1 OOIDSMJGMNNWKG-UHFFFAOYSA-N 0.000 description 1
- CPHVXWJDDJENTJ-UHFFFAOYSA-N C[Si](C)(C)CCOc(c1c2nccc1)c(CN(Cc(cc1)ccc1F)C1=O)c1c2OC(c1ccccc1)c1ccccc1 Chemical compound C[Si](C)(C)CCOc(c1c2nccc1)c(CN(Cc(cc1)ccc1F)C1=O)c1c2OC(c1ccccc1)c1ccccc1 CPHVXWJDDJENTJ-UHFFFAOYSA-N 0.000 description 1
- MEOUBBLFVJNUAF-UHFFFAOYSA-N C[n]1cnc(S(Cl)(=C)=O)c1 Chemical compound C[n]1cnc(S(Cl)(=C)=O)c1 MEOUBBLFVJNUAF-UHFFFAOYSA-N 0.000 description 1
- AVKNGPAMCBSNSO-UHFFFAOYSA-N NCC1CCCCC1 Chemical compound NCC1CCCCC1 AVKNGPAMCBSNSO-UHFFFAOYSA-N 0.000 description 1
- RSBUIZHXCPXOPI-UHFFFAOYSA-N O=C(CC1)N(B[AlH2])C1=O Chemical compound O=C(CC1)N(B[AlH2])C1=O RSBUIZHXCPXOPI-UHFFFAOYSA-N 0.000 description 1
- NEJCULBWOMKEQW-UHFFFAOYSA-N O=C(c(c1c2nccc1)c(CN(Cc(cc1)ccc1F)C1=O)c1c2OC(c1ccccc1)c1ccccc1)N1CCOCC1 Chemical compound O=C(c(c1c2nccc1)c(CN(Cc(cc1)ccc1F)C1=O)c1c2OC(c1ccccc1)c1ccccc1)N1CCOCC1 NEJCULBWOMKEQW-UHFFFAOYSA-N 0.000 description 1
- GHASJZKLEOZSIG-UHFFFAOYSA-N OCCCCCC(CCC1)CCN1C(Oc(c(CN1Cc(cc2)ccc2F)c2C1=O)c(cccn1)c1c2O)=O Chemical compound OCCCCCC(CCC1)CCN1C(Oc(c(CN1Cc(cc2)ccc2F)c2C1=O)c(cccn1)c1c2O)=O GHASJZKLEOZSIG-UHFFFAOYSA-N 0.000 description 1
- AWHRLSWFNXNGCA-UHFFFAOYSA-N Oc(c(nccc1)c1c(C(N1CCOCC1)=O)c1CN2Cc(cc3)ccc3F)c1C2=O Chemical compound Oc(c(nccc1)c1c(C(N1CCOCC1)=O)c1CN2Cc(cc3)ccc3F)c1C2=O AWHRLSWFNXNGCA-UHFFFAOYSA-N 0.000 description 1
- POHHXIQQPHVHOE-UHFFFAOYSA-N Oc(c(nccc1)c1c(C(NCI)=O)c1CN2Cc(cc3)ccc3F)c1C2=O Chemical compound Oc(c(nccc1)c1c(C(NCI)=O)c1CN2Cc(cc3)ccc3F)c1C2=O POHHXIQQPHVHOE-UHFFFAOYSA-N 0.000 description 1
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US41896302P | 2002-10-16 | 2002-10-16 | |
| US47878303P | 2003-06-16 | 2003-06-16 | |
| PCT/US2003/032666 WO2004035576A2 (en) | 2002-10-16 | 2003-10-16 | Pre-organized tricyclic integrase inhibitor compounds |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2006514099A JP2006514099A (ja) | 2006-04-27 |
| JP2006514099A5 true JP2006514099A5 (https=) | 2007-01-25 |
Family
ID=32110203
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2005501423A Pending JP2006514099A (ja) | 2002-10-16 | 2003-10-16 | 組織化前の三環系インテグラーゼインヒビター化合物 |
Country Status (19)
| Country | Link |
|---|---|
| US (3) | US20040157804A1 (https=) |
| EP (1) | EP1558613A2 (https=) |
| JP (1) | JP2006514099A (https=) |
| KR (1) | KR20050087787A (https=) |
| CN (1) | CN100374438C (https=) |
| AP (1) | AP1858A (https=) |
| AU (2) | AU2003301439A1 (https=) |
| BR (1) | BR0315405A (https=) |
| CA (1) | CA2501881A1 (https=) |
| EA (1) | EA011399B1 (https=) |
| HR (1) | HRP20050431A2 (https=) |
| IS (1) | IS7845A (https=) |
| MX (1) | MXPA05003950A (https=) |
| NO (1) | NO20052378L (https=) |
| NZ (1) | NZ539264A (https=) |
| OA (1) | OA13079A (https=) |
| PL (1) | PL377966A1 (https=) |
| UA (1) | UA79830C2 (https=) |
| WO (2) | WO2004035577A2 (https=) |
Families Citing this family (50)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000071102A2 (en) * | 1999-05-19 | 2000-11-30 | Neurosearch A/S | Inhibitors of proton-gated cation channels and their use in the treatment of ischaemic disorders |
| KR20060006047A (ko) * | 2003-04-28 | 2006-01-18 | 티보텍 파마슈티칼즈 리미티드 | Hiv 인테그레이즈 저해제 |
| US20070185007A1 (en) | 2003-09-19 | 2007-08-09 | Haolun Jin | Aza-quinolinol phosphonate integrase inhibitor compounds |
| WO2005056613A2 (en) * | 2003-12-08 | 2005-06-23 | The Research Foundation Of State University Of New York | Site selectively tagged and templated molecularly imprinted polymers for sensor applications |
| WO2005061519A1 (en) | 2003-12-19 | 2005-07-07 | Takeda San Diego, Inc. | Kinase inhibitors |
| US7598087B2 (en) * | 2004-01-07 | 2009-10-06 | The Research Foundation Of State University Of New York | Protein imprinted polymers with integrated emission sites |
| EP1742642B1 (en) * | 2004-04-14 | 2008-10-15 | Gilead Sciences, Inc. | Phosphonate analogs of hiv integrase inhibitor compounds |
| ES2529038T3 (es) * | 2004-05-07 | 2015-02-16 | Merck Sharp & Dohme Corp. | Inhibidores de la integrasa de VIH |
| US7476666B2 (en) | 2004-06-09 | 2009-01-13 | Merck & Co., Inc. | HIV integrase inhibitors |
| EP1778669A2 (en) | 2004-08-18 | 2007-05-02 | Takeda San Diego, Inc. | Kinase inhibitors |
| US7745459B2 (en) | 2004-09-21 | 2010-06-29 | Japan Tobacco Inc. | Quinolizinone compound and use thereof as HIV integrase inhibitor |
| ATE479687T1 (de) | 2004-10-15 | 2010-09-15 | Takeda Pharmaceutical | Kinaseinhibitoren |
| TW200716632A (en) * | 2005-05-16 | 2007-05-01 | Gilead Sciences Inc | Integrase inhibitor compounds |
| US8013159B2 (en) | 2005-05-19 | 2011-09-06 | Merck Canada Inc. | Quinoline derivatives as EP4 antagonists |
| CA2616314A1 (en) * | 2005-07-27 | 2007-02-01 | Gilead Sciences, Inc. | Antiviral phosphonate conjugates for inhibition of hiv |
| WO2007019130A2 (en) * | 2005-08-04 | 2007-02-15 | Smithkline Beecham Corporation | Hiv integrase inhibitors |
| US8119655B2 (en) | 2005-10-07 | 2012-02-21 | Takeda Pharmaceutical Company Limited | Kinase inhibitors |
| WO2007076005A2 (en) * | 2005-12-21 | 2007-07-05 | Gilead Sciences, Inc. | Processes and intermediates useful for preparing integrase inhibitor compounds |
| JP4676536B2 (ja) * | 2005-12-30 | 2011-04-27 | ギリアド サイエンシズ, インコーポレイテッド | Hivインテグラーゼ阻害剤の薬物動態の改善方法 |
| US20090233964A1 (en) * | 2005-12-30 | 2009-09-17 | Gilead Sciences, Inc. | Methods for improving the pharmacokinetics of hiv integrase inhibitors |
| NZ572367A (en) * | 2006-05-16 | 2011-09-30 | Gilead Sciences Inc | Fused cyclic compounds as integrase inhibitors |
| SG158147A1 (en) | 2006-10-09 | 2010-01-29 | Takeda Pharmaceutical | Kinase inhibitors |
| US20090291921A1 (en) * | 2007-11-20 | 2009-11-26 | Gilead Sciences, Inc. | Integrase inhibitors |
| EP2254582B1 (en) | 2008-01-25 | 2016-01-20 | Chimerix, Inc. | Methods of treating viral infections |
| EP2320909B8 (en) | 2008-07-25 | 2016-03-30 | VIIV Healthcare Company | Chemical compounds |
| RU2530899C2 (ru) * | 2008-07-28 | 2014-10-20 | Селлсьютикс Корпорейшн | Противомалярийные соединения |
| KR101682058B1 (ko) | 2008-12-11 | 2016-12-02 | 비이브 헬쓰케어 컴퍼니 | 카르바모일피리돈 hiv 인테그라제 억제제를 위한 제조방법 및 중간체 |
| CA2744019C (en) | 2008-12-11 | 2017-03-14 | Shionogi & Co., Ltd. | Synthesis of carbamoylpyridone hiv integrase inhibitors and intermediates |
| TWI518084B (zh) | 2009-03-26 | 2016-01-21 | 鹽野義製藥股份有限公司 | 哌喃酮與吡啶酮衍生物之製造方法 |
| EP2270021A1 (en) * | 2009-06-18 | 2011-01-05 | Centre National de la Recherche Scientifique | Phosphonates synthons for the synthesis of phosphonates derivatives showing better bioavailability |
| WO2011011483A1 (en) * | 2009-07-22 | 2011-01-27 | Glaxosmithkline Llc | Chemical compounds |
| WO2011045330A1 (en) | 2009-10-13 | 2011-04-21 | Tibotec Pharmaceuticals | Macrocyclic integrase inhibitors |
| US8283366B2 (en) | 2010-01-22 | 2012-10-09 | Ambrilia Biopharma, Inc. | Derivatives of pyridoxine for inhibiting HIV integrase |
| JP5745869B2 (ja) * | 2010-01-22 | 2015-07-08 | 富山化学工業株式会社 | アルアルキル基を有する複素環化合物 |
| US9006218B2 (en) | 2010-02-12 | 2015-04-14 | Chimerix Inc. | Nucleoside phosphonate salts |
| TWI582097B (zh) | 2010-03-23 | 2017-05-11 | Viiv醫療保健公司 | 製備胺甲醯吡啶酮衍生物及中間體之方法 |
| TWI503323B (zh) * | 2010-03-29 | 2015-10-11 | Oncotherapy Science Inc | 三環化合物以及含此化合物之pbk抑制劑 |
| RU2567385C2 (ru) | 2010-04-02 | 2015-11-10 | ЯНССЕН Ар ЭНД Ди АЙРЛЭНД | Макроциклические ингибиторы интегразы |
| EP2691393B1 (en) | 2011-03-31 | 2016-09-14 | Pfizer Inc | Novel bicyclic pyridinones |
| EP4556010A3 (en) | 2011-11-30 | 2025-07-23 | Emory University | Jak inhibitors for use in the prevention or treatment of a viral disease caused by a coronaviridae |
| KR101365849B1 (ko) * | 2012-03-28 | 2014-02-24 | 경동제약 주식회사 | 솔리페나신 또는 그의 염의 제조방법 및 이에 사용되는 신규 중간체 |
| UA110688C2 (uk) | 2012-09-21 | 2016-01-25 | Пфайзер Інк. | Біциклічні піридинони |
| US10260089B2 (en) | 2012-10-29 | 2019-04-16 | The Research Foundation Of The State University Of New York | Compositions and methods for recognition of RNA using triple helical peptide nucleic acids |
| DK3236972T3 (en) | 2014-12-26 | 2021-10-04 | Univ Emory | Antivirale N4-hydroxycytidin-derivativer |
| MX368391B (es) | 2015-02-03 | 2019-09-30 | Pfizer | Ciclopropabenzofuranil-piridopirazindionas novedosas. |
| CN104803905B (zh) * | 2015-04-17 | 2017-10-10 | 复旦大学 | 一种合成异吲哚啉‑1‑酮衍生物的方法 |
| CN107709288A (zh) * | 2016-02-03 | 2018-02-16 | 四川海思科制药有限公司 | 一种磷酰胺衍生物及制备方法和用途 |
| CN109305989B (zh) * | 2017-07-28 | 2021-02-26 | 四川海思科制药有限公司 | 一种磷酰胺衍生物及制备方法和用途 |
| CN109305990B (zh) * | 2017-07-28 | 2021-02-26 | 四川海思科制药有限公司 | 一种磷酸衍生物及制备方法和用途 |
| JP6804790B1 (ja) | 2017-12-07 | 2020-12-23 | エモリー ユニバーシティー | N4−ヒドロキシシチジンおよび誘導体ならびにそれらに関連する抗ウイルス用途 |
Family Cites Families (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH385846A (de) * | 1960-03-31 | 1964-12-31 | Geigy Ag J R | Verfahren zur Herstellung von neuen 7-Acyl-8-hydroxy-chinolinen und ihre Verwendung als Fungizide und Bakterizide im Pflanzen- und Materialschutz |
| US4816570A (en) * | 1982-11-30 | 1989-03-28 | The Board Of Regents Of The University Of Texas System | Biologically reversible phosphate and phosphonate protective groups |
| US4968788A (en) * | 1986-04-04 | 1990-11-06 | Board Of Regents, The University Of Texas System | Biologically reversible phosphate and phosphonate protective gruops |
| ATE131825T1 (de) | 1990-06-13 | 1996-01-15 | Arnold Glazier | Phosphorylierte prodrugs |
| EP0481214B1 (en) * | 1990-09-14 | 1998-06-24 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
| EP0498722B1 (fr) * | 1991-02-07 | 1997-07-30 | Roussel Uclaf | Dérivés bicycliques azotés, leur procédé de préparation, les intermédiaires obtenus, leur application comme médicaments et les compositions pharmaceutiques les renfermant |
| EP0520573A1 (en) * | 1991-06-27 | 1992-12-30 | Glaxo Inc. | Cyclic imide derivatives |
| US5639881A (en) * | 1991-11-08 | 1997-06-17 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Synthesis and elucidation of pyrimido (4,5-Q) quinazoline derivatives |
| TW304945B (https=) * | 1992-06-27 | 1997-05-11 | Hoechst Ag | |
| US5798340A (en) * | 1993-09-17 | 1998-08-25 | Gilead Sciences, Inc. | Nucleotide analogs |
| US5538988A (en) * | 1994-04-26 | 1996-07-23 | Martinez; Gregory R. | Benzocycloalkylazolethione derivatives |
| US5854275A (en) * | 1996-05-16 | 1998-12-29 | Pfizer Inc. | Cyclic imide derivatives |
| EP0927164A1 (en) * | 1996-09-10 | 1999-07-07 | PHARMACIA & UPJOHN COMPANY | 8-hydroxy-7-substituted quinolines as anti-viral agents |
| US6329375B1 (en) * | 1997-08-05 | 2001-12-11 | Sugen, Inc. | Tricyclic quinoxaline derivatives as protein tyrosine kinase inhibitors |
| US6312662B1 (en) * | 1998-03-06 | 2001-11-06 | Metabasis Therapeutics, Inc. | Prodrugs phosphorus-containing compounds |
| WO1999062520A1 (en) | 1998-06-03 | 1999-12-09 | Merck & Co., Inc. | Hiv integrase inhibitors |
| WO1999062513A1 (en) | 1998-06-03 | 1999-12-09 | Merck & Co., Inc. | Hiv integrase inhibitors |
| IL139254A0 (en) * | 1998-06-10 | 2001-11-25 | Arena Pharm Inc | Acetylcholine enhancers |
| US6187907B1 (en) * | 1998-08-31 | 2001-02-13 | James Chen | Triple helix coil template having a biologically active ligand |
| AU3118200A (en) | 1998-12-14 | 2000-07-03 | Merck & Co., Inc. | Hiv integrase inhibitors |
| JP3929244B2 (ja) | 1998-12-25 | 2007-06-13 | 塩野義製薬株式会社 | Hivインテグラーゼ阻害活性を有する芳香族ヘテロ環誘導体 |
| KR100423781B1 (ko) | 1999-06-02 | 2004-03-22 | 시오노기세이야쿠가부시키가이샤 | 신규 치환 프로페논 유도체의 제조방법 |
| JP2003503386A (ja) | 1999-06-25 | 2003-01-28 | メルク エンド カムパニー インコーポレーテッド | 1−(芳香族またはヘテロ芳香族置換)−3−(ヘテロ芳香族置換)−1,3−プロパンジオン類およびそれの使用 |
| US6245806B1 (en) | 1999-08-03 | 2001-06-12 | Merck & Co., Inc. | HIV integrase inhibitors |
| WO2001027309A1 (en) * | 1999-10-13 | 2001-04-19 | Merck & Co., Inc. | Hiv integrase inhibitors |
| JP2004513134A (ja) | 2000-10-12 | 2004-04-30 | メルク エンド カムパニー インコーポレーテッド | Hivインテグラーゼ阻害薬として有用なアザ−およびポリアザ−ナフタレニルケトン類 |
| JP2004517860A (ja) | 2000-10-12 | 2004-06-17 | メルク エンド カムパニー インコーポレーテッド | Hivインテグラーゼ阻害薬として有用なアザ−およびポリアザ−ナフタレニルカルボキサミド類 |
| CA2425440C (en) * | 2000-10-12 | 2010-04-13 | Merck & Co., Inc. | Aza- and polyaza-naphthalenyl carboxamides useful as hiv integrase inhibitors |
| US6919351B2 (en) * | 2000-10-12 | 2005-07-19 | Merck & Co., Inc. | Aza-and polyaza-naphthalenyl-carboxamides useful as HIV integrase inhibitors |
| AU2002215018A1 (en) * | 2000-10-13 | 2002-04-22 | Bayer Aktiengesellschaft | Human histone deacetylase gene |
| US6518767B1 (en) * | 2000-10-19 | 2003-02-11 | Schweitzer Engineering Laboratories, Inc. | Line differential protection system for a power transmission line |
| EP1742642B1 (en) * | 2004-04-14 | 2008-10-15 | Gilead Sciences, Inc. | Phosphonate analogs of hiv integrase inhibitor compounds |
-
2003
- 2003-10-15 US US10/687,374 patent/US20040157804A1/en not_active Abandoned
- 2003-10-15 WO PCT/US2003/032866 patent/WO2004035577A2/en not_active Ceased
- 2003-10-15 AU AU2003301439A patent/AU2003301439A1/en not_active Abandoned
- 2003-10-16 EP EP03809030A patent/EP1558613A2/en not_active Withdrawn
- 2003-10-16 CA CA002501881A patent/CA2501881A1/en not_active Abandoned
- 2003-10-16 US US10/687,373 patent/US7253180B2/en not_active Expired - Fee Related
- 2003-10-16 HR HR20050431A patent/HRP20050431A2/hr not_active Application Discontinuation
- 2003-10-16 CN CNB2003801061816A patent/CN100374438C/zh not_active Expired - Fee Related
- 2003-10-16 EA EA200500660A patent/EA011399B1/ru not_active IP Right Cessation
- 2003-10-16 OA OA1200500108A patent/OA13079A/en unknown
- 2003-10-16 BR BR0315405-0A patent/BR0315405A/pt not_active IP Right Cessation
- 2003-10-16 NZ NZ539264A patent/NZ539264A/en not_active IP Right Cessation
- 2003-10-16 UA UAA200504480A patent/UA79830C2/uk unknown
- 2003-10-16 AP AP2005003279A patent/AP1858A/xx active
- 2003-10-16 KR KR1020057006668A patent/KR20050087787A/ko not_active Ceased
- 2003-10-16 WO PCT/US2003/032666 patent/WO2004035576A2/en not_active Ceased
- 2003-10-16 MX MXPA05003950A patent/MXPA05003950A/es active IP Right Grant
- 2003-10-16 PL PL377966A patent/PL377966A1/pl not_active Application Discontinuation
- 2003-10-16 JP JP2005501423A patent/JP2006514099A/ja active Pending
- 2003-10-16 AU AU2003301306A patent/AU2003301306A1/en not_active Abandoned
-
2005
- 2005-05-13 NO NO20052378A patent/NO20052378L/no not_active Application Discontinuation
- 2005-05-13 IS IS7845A patent/IS7845A/is unknown
-
2007
- 2007-05-25 US US11/807,303 patent/US20090029939A1/en not_active Abandoned
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