JP2003514770A - 抗増殖性医薬の燐脂質プロドラッグ - Google Patents
抗増殖性医薬の燐脂質プロドラッグInfo
- Publication number
- JP2003514770A JP2003514770A JP2001522958A JP2001522958A JP2003514770A JP 2003514770 A JP2003514770 A JP 2003514770A JP 2001522958 A JP2001522958 A JP 2001522958A JP 2001522958 A JP2001522958 A JP 2001522958A JP 2003514770 A JP2003514770 A JP 2003514770A
- Authority
- JP
- Japan
- Prior art keywords
- mtx
- glycero
- stearoyl
- disease
- phosphatidylcholine
- 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
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IL13188799A IL131887A0 (en) | 1999-09-14 | 1999-09-14 | Phospholipid prodrugs of anti-proliferative drugs |
| IL131887 | 1999-09-14 | ||
| PCT/IL2000/000562 WO2001019320A2 (en) | 1999-09-14 | 2000-09-13 | Phospholipid prodrugs of anti-proliferative drugs |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JP2003514770A true JP2003514770A (ja) | 2003-04-22 |
| JP2003514770A5 JP2003514770A5 (OSRAM) | 2007-10-11 |
Family
ID=11073248
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2001522958A Pending JP2003514770A (ja) | 1999-09-14 | 2000-09-13 | 抗増殖性医薬の燐脂質プロドラッグ |
Country Status (9)
| Country | Link |
|---|---|
| US (1) | US6774121B1 (OSRAM) |
| EP (1) | EP1218013A4 (OSRAM) |
| JP (1) | JP2003514770A (OSRAM) |
| AU (1) | AU781507B2 (OSRAM) |
| CA (1) | CA2382633A1 (OSRAM) |
| IL (2) | IL131887A0 (OSRAM) |
| NZ (1) | NZ517522A (OSRAM) |
| WO (1) | WO2001019320A2 (OSRAM) |
| ZA (1) | ZA200201081B (OSRAM) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013525390A (ja) * | 2010-04-30 | 2013-06-20 | テロルメディクス エセアー | リン脂質薬物類似体 |
Families Citing this family (39)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0781138B1 (en) | 1994-08-29 | 2008-05-21 | Wake Forest University | Lipid analogs for treating viral infections |
| US7135584B2 (en) | 1995-08-07 | 2006-11-14 | Wake Forest University | Lipid analogs for treating viral infections |
| US7026469B2 (en) * | 2000-10-19 | 2006-04-11 | Wake Forest University School Of Medicine | Compositions and methods of double-targeting virus infections and cancer cells |
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| US7309696B2 (en) | 2000-10-19 | 2007-12-18 | Wake Forest University | Compositions and methods for targeting cancer cells |
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| EA008775B1 (ru) | 2002-04-26 | 2007-08-31 | Джилид Сайэнс, Инк. | Ингибиторы протеазы вич для лечения инфекции вич и фармацевтическая композиция |
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| WO2005002626A2 (en) | 2003-04-25 | 2005-01-13 | Gilead Sciences, Inc. | Therapeutic phosphonate compounds |
| CA2523083C (en) | 2003-04-25 | 2014-07-08 | Gilead Sciences, Inc. | Antiviral phosphonate analogs |
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| WO2004096285A2 (en) | 2003-04-25 | 2004-11-11 | Gilead Sciences, Inc. | Anti-infective phosphonate conjugates |
| US7470724B2 (en) | 2003-04-25 | 2008-12-30 | Gilead Sciences, Inc. | Phosphonate compounds having immuno-modulatory activity |
| US7432261B2 (en) | 2003-04-25 | 2008-10-07 | Gilead Sciences, Inc. | Anti-inflammatory phosphonate compounds |
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| ATE412897T1 (de) | 2003-05-30 | 2008-11-15 | Purdue Research Foundation | Diagnoseverfahren für atherosklerose |
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| US7432273B2 (en) | 2003-10-24 | 2008-10-07 | Gilead Sciences, Inc. | Phosphonate analogs of antimetabolites |
| US7427624B2 (en) | 2003-10-24 | 2008-09-23 | Gilead Sciences, Inc. | Purine nucleoside phosphorylase inhibitory phosphonate compounds |
| AU2004309418B2 (en) | 2003-12-22 | 2012-01-19 | Gilead Sciences, Inc. | 4'-substituted carbovir-and abacavir-derivatives as well as related compounds with HIV and HCV antiviral activity |
| JP2008508291A (ja) | 2004-07-27 | 2008-03-21 | ギリアード サイエンシーズ, インコーポレイテッド | 抗hiv剤としてのヌクレオシドホスホネート結合体 |
| WO2007006041A2 (en) | 2005-07-05 | 2007-01-11 | Purdue Research Foundation | Imaging and therapeutic method using monocytes |
| DE102006019907A1 (de) * | 2006-04-28 | 2007-10-31 | Müller-Enoch, Dieter, Prof. Dr. | Verwendung von substituierten Glycerinderivaten zur Herstellung einer pharmazeutischen Zubereitung |
| CA2668197A1 (en) | 2006-11-03 | 2008-05-15 | Philip S. Low | Ex vivo flow cytometry method and device |
| JP5869205B2 (ja) | 2007-02-07 | 2016-02-24 | パーデュー・リサーチ・ファウンデーションPurdue Research Foundation | ポジトロン放射断層画像法 |
| US8961926B2 (en) | 2007-05-25 | 2015-02-24 | Purdue Research Foundation | Method of imaging localized infections |
| EP2307435B1 (en) | 2008-07-08 | 2012-06-13 | Gilead Sciences, Inc. | Salts of hiv inhibitor compounds |
| WO2010088924A1 (en) | 2009-02-06 | 2010-08-12 | Telormedix Sa | Pharmaceutical compositions comprising imidazoquinolin(amines) and derivatives thereof suitable for local administration |
| WO2011134669A1 (en) * | 2010-04-30 | 2011-11-03 | Telormedix Sa | Methods for inducing an immune response |
| US20130244982A1 (en) * | 2010-12-02 | 2013-09-19 | Bengurion University Of The Negev Research And Development Authority | Conjugates of a phospholipid and a drug for the treatment of inflammatory bowel disease |
| US9499800B2 (en) | 2013-12-26 | 2016-11-22 | Regents Of The University Of Minnesota | Methods of making and using chemically self assembled-nanorings |
| MX381235B (es) * | 2014-11-17 | 2025-03-12 | Cellectar Biosciences Inc | Análogos de éter fosfolipídico como portadores de fármacos dirigidos a cáncer. |
| EP3661937B1 (en) | 2017-08-01 | 2021-07-28 | Gilead Sciences, Inc. | Crystalline forms of ethyl ((s)-((((2r,5r)-5-(6-amino-9h-purin-9-yl)-4-fluoro-2,5-dihydrofuran-2-yl)oxy)methyl)(phenoxy)phosphoryl)-l-alaninate (gs-9131) for treating viral infections |
| WO2019200043A1 (en) * | 2018-04-11 | 2019-10-17 | New Mexico Tech University Research Park Coporation | Lipid prodrugs for use in drug delivery |
| WO2025202629A1 (en) | 2024-03-26 | 2025-10-02 | Coopervision International Limited | Contact lens loaded with a glycerophospholipid |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61152694A (ja) * | 1984-12-27 | 1986-07-11 | Toyama Chem Co Ltd | 新規な5−フルオロ−2′−デオキシウリジン−5′−ホスフエ−ト誘導体およびその塩 |
| JPS6383093A (ja) * | 1986-09-27 | 1988-04-13 | Toyo Jozo Co Ltd | ヌクレオシド−リン脂質複合体 |
| WO1996039831A1 (en) * | 1995-06-07 | 1996-12-19 | The Regents Of The University Of California | Prodrugs of pharmaceuticals with improved bioavailability |
| WO1998005349A1 (en) * | 1996-08-02 | 1998-02-12 | Smithkline Beecham Corporation | A novel method of detecting and treating cancer |
| WO1999042830A1 (en) * | 1998-02-23 | 1999-08-26 | Diadexus Llc | Methods using pla2 as a marker of metastases and for the diagnosis of selected cancers |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5223263A (en) | 1988-07-07 | 1993-06-29 | Vical, Inc. | Liponucleotide-containing liposomes |
| EP0237051B1 (en) | 1986-03-14 | 1991-05-02 | Fujisawa Pharmaceutical Co., Ltd. | Prodrug compounds, process for the preparation thereof and sustained release preparation comprising the same |
| US5411947A (en) | 1989-06-28 | 1995-05-02 | Vestar, Inc. | Method of converting a drug to an orally available form by covalently bonding a lipid to the drug |
| WO1991016920A1 (en) | 1990-05-07 | 1991-11-14 | Vical, Inc. | Lipid prodrugs of salicylate and nonsteroidal anti-inflammatory drugs |
| US5543389A (en) | 1990-11-01 | 1996-08-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education On Behalf Of The Oregon Health Sciences University, A Non Profit Organization | Covalent polar lipid-peptide conjugates for use in salves |
| US5149794A (en) | 1990-11-01 | 1992-09-22 | State Of Oregon | Covalent lipid-drug conjugates for drug targeting |
| EP0594677A4 (en) | 1991-07-12 | 1997-09-17 | Vical Inc | Antiviral liponucleosides: treatment of hepatitis b |
| IL105244A (en) | 1993-03-31 | 2003-07-31 | Dpharm Ltd | Prodrugs with enhanced penetration into cells |
| US6413949B1 (en) | 1995-06-07 | 2002-07-02 | D-Pharm, Ltd. | Prodrugs with enhanced penetration into cells |
| US6090800A (en) | 1997-05-06 | 2000-07-18 | Imarx Pharmaceutical Corp. | Lipid soluble steroid prodrugs |
-
1999
- 1999-09-14 IL IL13188799A patent/IL131887A0/xx unknown
-
2000
- 2000-09-13 WO PCT/IL2000/000562 patent/WO2001019320A2/en not_active Ceased
- 2000-09-13 EP EP00960946A patent/EP1218013A4/en not_active Withdrawn
- 2000-09-13 NZ NZ517522A patent/NZ517522A/en not_active IP Right Cessation
- 2000-09-13 US US10/088,160 patent/US6774121B1/en not_active Expired - Fee Related
- 2000-09-13 CA CA002382633A patent/CA2382633A1/en not_active Abandoned
- 2000-09-13 JP JP2001522958A patent/JP2003514770A/ja active Pending
- 2000-09-13 AU AU73093/00A patent/AU781507B2/en not_active Ceased
-
2002
- 2002-02-07 ZA ZA200201081A patent/ZA200201081B/en unknown
- 2002-03-07 IL IL148554A patent/IL148554A/en unknown
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS61152694A (ja) * | 1984-12-27 | 1986-07-11 | Toyama Chem Co Ltd | 新規な5−フルオロ−2′−デオキシウリジン−5′−ホスフエ−ト誘導体およびその塩 |
| JPS6383093A (ja) * | 1986-09-27 | 1988-04-13 | Toyo Jozo Co Ltd | ヌクレオシド−リン脂質複合体 |
| WO1996039831A1 (en) * | 1995-06-07 | 1996-12-19 | The Regents Of The University Of California | Prodrugs of pharmaceuticals with improved bioavailability |
| WO1998005349A1 (en) * | 1996-08-02 | 1998-02-12 | Smithkline Beecham Corporation | A novel method of detecting and treating cancer |
| WO1999042830A1 (en) * | 1998-02-23 | 1999-08-26 | Diadexus Llc | Methods using pla2 as a marker of metastases and for the diagnosis of selected cancers |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2013525390A (ja) * | 2010-04-30 | 2013-06-20 | テロルメディクス エセアー | リン脂質薬物類似体 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1218013A4 (en) | 2004-12-15 |
| IL131887A0 (en) | 2001-03-19 |
| WO2001019320A3 (en) | 2001-09-27 |
| CA2382633A1 (en) | 2001-03-22 |
| AU781507B2 (en) | 2005-05-26 |
| AU7309300A (en) | 2001-04-17 |
| US6774121B1 (en) | 2004-08-10 |
| ZA200201081B (en) | 2003-04-30 |
| NZ517522A (en) | 2003-08-29 |
| WO2001019320A2 (en) | 2001-03-22 |
| IL148554A (en) | 2007-10-31 |
| EP1218013A2 (en) | 2002-07-03 |
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