JP2005539014A - 高眼圧および緑内障処置用のプロスタグランジン類似体の９，１１−シクロエンドペルオキシドプロドラッグ - Google Patents
高眼圧および緑内障処置用のプロスタグランジン類似体の９，１１−シクロエンドペルオキシドプロドラッグ Download PDFInfo
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- JP2005539014A JP2005539014A JP2004526380A JP2004526380A JP2005539014A JP 2005539014 A JP2005539014 A JP 2005539014A JP 2004526380 A JP2004526380 A JP 2004526380A JP 2004526380 A JP2004526380 A JP 2004526380A JP 2005539014 A JP2005539014 A JP 2005539014A
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- 239000000651 prodrug Substances 0.000 title claims abstract description 22
- 229940002612 prodrug Drugs 0.000 title claims abstract description 22
- 150000003180 prostaglandins Chemical class 0.000 title abstract description 24
- 208000010412 Glaucoma Diseases 0.000 title description 5
- 206010030043 Ocular hypertension Diseases 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 93
- 238000000034 method Methods 0.000 claims description 44
- 125000004432 carbon atom Chemical group C* 0.000 claims description 35
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 24
- -1 unsaturated acyclic hydrocarbon Chemical class 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- 125000001931 aliphatic group Chemical group 0.000 claims description 16
- 125000003118 aryl group Chemical group 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 239000004215 Carbon black (E152) Substances 0.000 claims description 9
- 229930195733 hydrocarbon Natural products 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 229920006395 saturated elastomer Polymers 0.000 claims description 9
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 8
- 229910052717 sulfur Inorganic materials 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 230000004410 intraocular pressure Effects 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 239000007787 solid Substances 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims 6
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
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- AQOKCDNYWBIDND-FTOWTWDKSA-N bimatoprost Chemical compound CCNC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)CCC1=CC=CC=C1 AQOKCDNYWBIDND-FTOWTWDKSA-N 0.000 abstract description 11
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- 239000000126 substance Substances 0.000 abstract description 8
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- MKPLKVHSHYCHOC-AHTXBMBWSA-N travoprost Chemical compound CC(C)OC(=O)CCC\C=C/C[C@H]1[C@@H](O)C[C@@H](O)[C@@H]1\C=C\[C@@H](O)COC1=CC=CC(C(F)(F)F)=C1 MKPLKVHSHYCHOC-AHTXBMBWSA-N 0.000 abstract description 8
- TVHAZVBUYQMHBC-SNHXEXRGSA-N unoprostone Chemical compound CCCCCCCC(=O)CC[C@H]1[C@H](O)C[C@H](O)[C@@H]1C\C=C/CCCC(O)=O TVHAZVBUYQMHBC-SNHXEXRGSA-N 0.000 abstract description 8
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 13
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 12
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
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- LGEQQWMQCRIYKG-DOFZRALJSA-N anandamide Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCO LGEQQWMQCRIYKG-DOFZRALJSA-N 0.000 description 11
- LGEQQWMQCRIYKG-UHFFFAOYSA-N arachidonic acid ethanolamide Natural products CCCCCC=CCC=CCC=CCC=CCCCC(=O)NCCO LGEQQWMQCRIYKG-UHFFFAOYSA-N 0.000 description 11
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- 108010065942 Prostaglandin-F synthase Proteins 0.000 description 9
- 238000006911 enzymatic reaction Methods 0.000 description 9
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- YZXBAPSDXZZRGB-DOFZRALJSA-N arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 8
- 239000012267 brine Substances 0.000 description 8
- 229940125898 compound 5 Drugs 0.000 description 8
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 8
- 150000003815 prostacyclins Chemical class 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
- 125000003342 alkenyl group Chemical group 0.000 description 6
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- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
- 150000003163 prostaglandin D2 derivatives Chemical class 0.000 description 6
- 150000003591 thromboxane A2 derivatives Chemical class 0.000 description 6
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- 235000019439 ethyl acetate Nutrition 0.000 description 5
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- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 description 4
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- 125000000304 alkynyl group Chemical group 0.000 description 3
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 3
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D317/02—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 2
- C07D317/06—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 2 condensed with carbocyclic rings or ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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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
- A61P9/12—Antihypertensives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
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- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Hematology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
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| US10/212,437 US6864282B2 (en) | 2002-08-05 | 2002-08-05 | 9,11-cycloendoperoxide pro-drugs of prostaglandin analogues for treatment of ocular hypertension and glaucoma |
| PCT/US2003/024305 WO2004013119A1 (en) | 2002-08-05 | 2003-08-04 | The 9, 11-cycloendoperoxide pro-drugs of prostaglandin analogues for treatment of ocular hypertension and glaucoma |
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| JP2005539014A true JP2005539014A (ja) | 2005-12-22 |
| JP2005539014A5 JP2005539014A5 (enExample) | 2006-09-28 |
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| Country | Link |
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| US (1) | US6864282B2 (enExample) |
| EP (2) | EP1527063B1 (enExample) |
| JP (1) | JP2005539014A (enExample) |
| AT (1) | ATE334123T1 (enExample) |
| AU (1) | AU2003261352A1 (enExample) |
| CA (1) | CA2494146A1 (enExample) |
| DE (1) | DE60307106T2 (enExample) |
| ES (1) | ES2268433T3 (enExample) |
| WO (1) | WO2004013119A1 (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2015036382A (ja) * | 2013-08-15 | 2015-02-23 | チャイロゲート インターナショナル インク．Ｃｈｉｒｏｇａｔｅ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｉｎｃ． | 異性体を含まないプロスタグランジンを製造するための方法及び中間体 |
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| US7070768B2 (en) * | 2003-09-25 | 2006-07-04 | Allergan, Inc. | Method for imparting artificial tan to human skin |
| GB0501192D0 (en) * | 2005-01-20 | 2005-03-02 | Resolution Chemicals Ltd | Stable prostaglandin-containing compositions |
| WO2010102078A1 (en) | 2009-03-04 | 2010-09-10 | Allergan, Inc. | Enhanced bimatoprost ophthalmic solution |
| US7851504B2 (en) * | 2005-03-16 | 2010-12-14 | Allergan, Inc. | Enhanced bimatoprost ophthalmic solution |
| EP1916002B1 (en) | 2005-08-02 | 2014-03-05 | Santen Pharmaceutical Co., Ltd. | Method for prevention of degradation of thermally unstable substance |
| WO2007111806A2 (en) | 2006-03-23 | 2007-10-04 | Massachusetts Eye And Ear Infirmary | Cyclopentane heptanoic acid compounds for reducing body fat |
| US20110293549A1 (en) | 2009-02-03 | 2011-12-01 | Athena Cosmetics, Inc. | Composition, method and kit for enhancing hair |
| US9522153B2 (en) | 2009-12-22 | 2016-12-20 | Allergan, Inc. | Compositions and methods for lowering intraocular pressure |
| ES2687494T3 (es) | 2011-01-19 | 2018-10-25 | Topokine Therapeutics, Inc. | Métodos y composiciones para reducir la grasa corporal |
| US8426471B1 (en) | 2011-12-19 | 2013-04-23 | Topokine Therapeutics, Inc. | Methods and compositions for reducing body fat and adipocytes |
| CA2869676C (en) | 2012-11-21 | 2015-06-23 | Topokine Therapeutics, Inc. | Uses and compositions comprising a thiazolidinedione and oleic acid for locally increasing subcutaneous fat |
| NO2753788T3 (enExample) | 2013-05-10 | 2018-06-16 | ||
| WO2014186504A1 (en) | 2013-05-15 | 2014-11-20 | Topokine Therapeutics, Inc. | Methods and compositions for topical delivery of prostaglandins to subcutaneous fat |
| US10188661B2 (en) | 2014-06-27 | 2019-01-29 | Topokine Therapeutics, Inc. | Topical dosage regimen |
| EP3675866B1 (en) | 2017-09-01 | 2023-08-02 | East Carolina University | Ex vivo methods for activating immune cells |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS591418A (ja) * | 1982-05-03 | 1984-01-06 | ザ・トラステイ−ズ・オブ・コロンビア・ユニヴア−シテイ・イン・ザ・シテイ・オブ・ニユ−・ヨ−ク | 眼圧亢進及び緑内障の治療用エイコサノイド及びその誘導体 |
| US4867915A (en) * | 1986-05-21 | 1989-09-19 | Syntex (U.S.A.) Inc. | 16-Substituted polyunsaturated hexadecanoic fatty acids |
| JPH07165703A (ja) * | 1993-08-03 | 1995-06-27 | Alcon Lab Inc | 緑内障及び高眼圧治療用局所眼薬組成物 |
| JPH08501310A (ja) * | 1992-09-21 | 1996-02-13 | アラーガン、インコーポレイテッド | 医薬としての非酸性シクロペンタンヘプタン酸，２−シクロアルキルまたはアリールアルキル誘導体 |
| US6329426B1 (en) * | 1997-10-13 | 2001-12-11 | R-Tech Ueno, Ltd. | Method for treating ocular hypertension of glaucoma |
| WO2002012445A1 (en) * | 2000-08-07 | 2002-02-14 | Vanderbilt University | Detection of cox-2 activity and anandamide metabolites |
Family Cites Families (4)
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|---|---|---|---|---|
| ES2213504T1 (es) | 1988-09-06 | 2004-09-01 | Pfizer Health Ab | Derivados de prostaglandina para el tratamiento del glaucoma o hipertension ocular. |
| US5767154A (en) | 1991-02-07 | 1998-06-16 | Allergan | 5-trans-prostaglandins of the F series and their use as ocular hypotensives |
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2002
- 2002-08-05 US US10/212,437 patent/US6864282B2/en not_active Expired - Fee Related
-
2003
- 2003-08-04 CA CA002494146A patent/CA2494146A1/en not_active Abandoned
- 2003-08-04 DE DE60307106T patent/DE60307106T2/de not_active Expired - Fee Related
- 2003-08-04 AU AU2003261352A patent/AU2003261352A1/en not_active Abandoned
- 2003-08-04 WO PCT/US2003/024305 patent/WO2004013119A1/en not_active Ceased
- 2003-08-04 EP EP03767129A patent/EP1527063B1/en not_active Expired - Lifetime
- 2003-08-04 JP JP2004526380A patent/JP2005539014A/ja active Pending
- 2003-08-04 ES ES03767129T patent/ES2268433T3/es not_active Expired - Lifetime
- 2003-08-04 AT AT03767129T patent/ATE334123T1/de not_active IP Right Cessation
- 2003-08-04 EP EP06011653A patent/EP1731516A3/en not_active Withdrawn
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| JP2015036382A (ja) * | 2013-08-15 | 2015-02-23 | チャイロゲート インターナショナル インク．Ｃｈｉｒｏｇａｔｅ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｉｎｃ． | 異性体を含まないプロスタグランジンを製造するための方法及び中間体 |
| US9464028B2 (en) | 2013-08-15 | 2016-10-11 | Chirogate International Inc. | Processes and intermediates for the preparations of isomer free prostaglandins |
| JP2016193930A (ja) * | 2013-08-15 | 2016-11-17 | チャイロゲート インターナショナル インク．Ｃｈｉｒｏｇａｔｅ Ｉｎｔｅｒｎａｔｉｏｎａｌ Ｉｎｃ． | 異性体を含まないプロスタグランジンを製造するための方法及び中間体 |
| US9540311B2 (en) | 2013-08-15 | 2017-01-10 | Chirogate International Inc. | Processes and intermediates for the preparations of isomer free prostaglandins |
| US9828356B2 (en) | 2013-08-15 | 2017-11-28 | Chirogate International Inc. | Processes and intermediates for the preparations of isomer free prostaglandis |
| US9890135B1 (en) | 2013-08-15 | 2018-02-13 | Chirogate International Inc. | Processes and intermediates for the preparations of isomer free prostaglandins |
| US9994543B2 (en) | 2013-08-15 | 2018-06-12 | Chirogate International Inc. | Processes and intermediates for the preparations of isomer free prostaglandins |
Also Published As
| Publication number | Publication date |
|---|---|
| US20040023954A1 (en) | 2004-02-05 |
| EP1527063B1 (en) | 2006-07-26 |
| ES2268433T3 (es) | 2007-03-16 |
| DE60307106T2 (de) | 2007-02-22 |
| DE60307106D1 (de) | 2006-09-07 |
| ATE334123T1 (de) | 2006-08-15 |
| US6864282B2 (en) | 2005-03-08 |
| EP1731516A3 (en) | 2007-01-03 |
| AU2003261352A1 (en) | 2004-02-23 |
| EP1527063A1 (en) | 2005-05-04 |
| EP1731516A2 (en) | 2006-12-13 |
| CA2494146A1 (en) | 2004-02-12 |
| WO2004013119B1 (en) | 2004-05-06 |
| WO2004013119A1 (en) | 2004-02-12 |
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