CA2470427C - Compositions and methods for treating heart failure - Google Patents
Compositions and methods for treating heart failure Download PDFInfo
- Publication number
- CA2470427C CA2470427C CA2470427A CA2470427A CA2470427C CA 2470427 C CA2470427 C CA 2470427C CA 2470427 A CA2470427 A CA 2470427A CA 2470427 A CA2470427 A CA 2470427A CA 2470427 C CA2470427 C CA 2470427C
- Authority
- CA
- Canada
- Prior art keywords
- pyridin
- phenyl
- fluoro
- yloxy
- cndot
- 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.)
- Expired - Lifetime
Links
- 206010019280 Heart failures Diseases 0.000 title claims abstract description 29
- 239000000203 mixture Substances 0.000 title claims description 42
- 238000000034 method Methods 0.000 title description 41
- 150000001875 compounds Chemical class 0.000 claims description 129
- -1 pyridin-yl Chemical group 0.000 claims description 94
- 125000001072 heteroaryl group Chemical group 0.000 claims description 74
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 39
- 125000005843 halogen group Chemical group 0.000 claims description 36
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 33
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 26
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 26
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 25
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 239000001257 hydrogen Chemical group 0.000 claims description 23
- 125000001153 fluoro group Chemical group F* 0.000 claims description 22
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Chemical group C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 17
- 125000004076 pyridyl group Chemical group 0.000 claims description 16
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 14
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 13
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 12
- MIIQJAUWHSUTIT-UHFFFAOYSA-N 1,2-oxazole-5-carboxylic acid Chemical compound OC(=O)C1=CC=NO1 MIIQJAUWHSUTIT-UHFFFAOYSA-N 0.000 claims description 11
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
- 238000002360 preparation method Methods 0.000 claims description 11
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 10
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 10
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 9
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 9
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 8
- 125000005518 carboxamido group Chemical group 0.000 claims description 8
- 239000003814 drug Substances 0.000 claims description 8
- JIWOQJSUFBYTQZ-UHFFFAOYSA-N 4-fluoro-n-(3-pyridin-2-yl-5-pyridin-3-yloxyphenyl)benzamide Chemical compound C1=CC(F)=CC=C1C(=O)NC1=CC(OC=2C=NC=CC=2)=CC(C=2N=CC=CC=2)=C1 JIWOQJSUFBYTQZ-UHFFFAOYSA-N 0.000 claims description 7
- 125000004499 isoxazol-5-yl group Chemical group O1N=CC=C1* 0.000 claims description 7
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 7
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- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 claims description 7
- 125000001544 thienyl group Chemical group 0.000 claims description 7
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 6
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- KQTKQVOTCPHKGP-UHFFFAOYSA-N 4-fluoro-n-(3-nitro-5-pyridin-2-yloxyphenyl)benzamide Chemical compound C=1C(OC=2N=CC=CC=2)=CC([N+](=O)[O-])=CC=1NC(=O)C1=CC=C(F)C=C1 KQTKQVOTCPHKGP-UHFFFAOYSA-N 0.000 claims description 5
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- 206010071436 Systolic dysfunction Diseases 0.000 claims description 5
- XROWCUJOXCTJHT-UHFFFAOYSA-N ethyl 3-[(4-fluorobenzoyl)amino]-5-pyridin-3-yloxybenzoate Chemical compound C=1C(OC=2C=NC=CC=2)=CC(C(=O)OCC)=CC=1NC(=O)C1=CC=C(F)C=C1 XROWCUJOXCTJHT-UHFFFAOYSA-N 0.000 claims description 5
- FFMJZGQEJFSZQJ-UHFFFAOYSA-N n-(3-fluoro-5-pyridin-3-yloxyphenyl)-3-hydroxybenzamide Chemical compound OC1=CC=CC(C(=O)NC=2C=C(OC=3C=NC=CC=3)C=C(F)C=2)=C1 FFMJZGQEJFSZQJ-UHFFFAOYSA-N 0.000 claims description 5
- ZUHYXIFIFNZDOT-UHFFFAOYSA-N n-(3-fluoro-5-pyridin-3-yloxyphenyl)-4-hydroxybenzamide Chemical compound C1=CC(O)=CC=C1C(=O)NC1=CC(F)=CC(OC=2C=NC=CC=2)=C1 ZUHYXIFIFNZDOT-UHFFFAOYSA-N 0.000 claims description 5
- APXPHJKKKDJVLH-UHFFFAOYSA-N n-(3-fluoro-5-pyridin-3-yloxyphenyl)pyridine-3-carboxamide Chemical compound C=1C(OC=2C=NC=CC=2)=CC(F)=CC=1NC(=O)C1=CC=CN=C1 APXPHJKKKDJVLH-UHFFFAOYSA-N 0.000 claims description 5
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- AEMOBTAPCIDTGO-UHFFFAOYSA-N 4-fluoro-n-(3-pyrazin-2-yl-5-pyridin-3-yloxyphenyl)benzamide Chemical compound C1=CC(F)=CC=C1C(=O)NC1=CC(OC=2C=NC=CC=2)=CC(C=2N=CC=NC=2)=C1 AEMOBTAPCIDTGO-UHFFFAOYSA-N 0.000 claims description 4
- ISELKUFHSCAZAC-UHFFFAOYSA-N 4-fluoro-n-(3-pyridin-3-yloxyphenyl)benzamide Chemical compound C1=CC(F)=CC=C1C(=O)NC1=CC=CC(OC=2C=NC=CC=2)=C1 ISELKUFHSCAZAC-UHFFFAOYSA-N 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
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- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 7
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 5
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims 5
- 150000002431 hydrogen Chemical group 0.000 claims 5
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- 230000000747 cardiac effect Effects 0.000 abstract description 29
- 206010007559 Cardiac failure congestive Diseases 0.000 abstract description 24
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- 208000008253 Systolic Heart Failure Diseases 0.000 abstract description 3
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- 125000003107 substituted aryl group Chemical group 0.000 description 29
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- 125000003118 aryl group Chemical group 0.000 description 22
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 17
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- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- 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
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/65—One oxygen atom attached in position 3 or 5
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
-
- 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
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Pyridine Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US34308801P | 2001-12-21 | 2001-12-21 | |
| US60/343,088 | 2001-12-21 | ||
| PCT/US2002/040996 WO2003059258A2 (en) | 2001-12-21 | 2002-12-20 | Compositions and methods for treating heart failure |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2470427A1 CA2470427A1 (en) | 2003-07-24 |
| CA2470427C true CA2470427C (en) | 2012-07-10 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2470427A Expired - Lifetime CA2470427C (en) | 2001-12-21 | 2002-12-20 | Compositions and methods for treating heart failure |
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| Country | Link |
|---|---|
| US (3) | US6908923B2 (enExample) |
| EP (1) | EP1503986B1 (enExample) |
| JP (2) | JP4361800B2 (enExample) |
| AU (1) | AU2002367023A1 (enExample) |
| CA (1) | CA2470427C (enExample) |
| WO (1) | WO2003059258A2 (enExample) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6495337B1 (en) * | 2000-03-29 | 2002-12-17 | Cytokinetics, Inc. | High throughput sarcomeric assay |
| EP1503986B1 (en) | 2001-12-21 | 2015-09-30 | Cytokinetics, Inc. | Compositions and methods for treating heart failure |
| KR20050100615A (ko) * | 2003-01-14 | 2005-10-19 | 싸이토키네틱스, 인코포레이티드 | 화합물, 조성물 및 방법 |
| CA2570999C (en) | 2004-06-17 | 2014-01-07 | Cytokinetics, Inc. | Compounds, compositions and methods |
| KR20150002863A (ko) | 2004-09-02 | 2015-01-07 | 제넨테크, 인크. | 헤지호그 신호전달에 대한 피리딜 억제제 |
| WO2006040056A1 (en) * | 2004-10-13 | 2006-04-20 | Merck Patent Gmbh | Heterocyclic substituted bisarylurea derivatives as kinase inhibitors |
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-
2002
- 2002-12-20 EP EP02806491.3A patent/EP1503986B1/en not_active Expired - Lifetime
- 2002-12-20 CA CA2470427A patent/CA2470427C/en not_active Expired - Lifetime
- 2002-12-20 AU AU2002367023A patent/AU2002367023A1/en not_active Abandoned
- 2002-12-20 JP JP2003559423A patent/JP4361800B2/ja not_active Expired - Lifetime
- 2002-12-20 US US10/327,219 patent/US6908923B2/en not_active Expired - Lifetime
- 2002-12-20 WO PCT/US2002/040996 patent/WO2003059258A2/en not_active Ceased
-
2004
- 2004-11-08 JP JP2004324438A patent/JP2005068160A/ja not_active Withdrawn
-
2005
- 2005-01-20 US US11/040,478 patent/US7053094B2/en not_active Expired - Lifetime
-
2006
- 2006-02-14 US US11/353,252 patent/US7605164B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003059258A3 (en) | 2004-11-11 |
| US20050148638A1 (en) | 2005-07-07 |
| JP2005068160A (ja) | 2005-03-17 |
| AU2002367023A1 (en) | 2003-07-30 |
| AU2002367023A8 (en) | 2003-07-30 |
| US6908923B2 (en) | 2005-06-21 |
| EP1503986A2 (en) | 2005-02-09 |
| US7605164B2 (en) | 2009-10-20 |
| US20030158233A1 (en) | 2003-08-21 |
| US7053094B2 (en) | 2006-05-30 |
| JP2005514432A (ja) | 2005-05-19 |
| EP1503986B1 (en) | 2015-09-30 |
| US20060173024A1 (en) | 2006-08-03 |
| EP1503986A4 (en) | 2005-11-30 |
| CA2470427A1 (en) | 2003-07-24 |
| WO2003059258A2 (en) | 2003-07-24 |
| JP4361800B2 (ja) | 2009-11-11 |
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