ES2290479T3 - Diamino-pirimidinas y su uso como inhibidores de la angiogenesis. - Google Patents
Diamino-pirimidinas y su uso como inhibidores de la angiogenesis. Download PDFInfo
- Publication number
- ES2290479T3 ES2290479T3 ES03743709T ES03743709T ES2290479T3 ES 2290479 T3 ES2290479 T3 ES 2290479T3 ES 03743709 T ES03743709 T ES 03743709T ES 03743709 T ES03743709 T ES 03743709T ES 2290479 T3 ES2290479 T3 ES 2290479T3
- Authority
- ES
- Spain
- Prior art keywords
- methyl
- amino
- benzimidazol
- pyrimidinyl
- phenyl
- 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
- 230000033115 angiogenesis Effects 0.000 title claims description 28
- 239000003112 inhibitor Substances 0.000 title description 9
- 229940058936 antimalarials diaminopyrimidines Drugs 0.000 title description 2
- 101000753291 Homo sapiens Angiopoietin-1 receptor Proteins 0.000 claims abstract description 32
- 238000011282 treatment Methods 0.000 claims abstract description 32
- 102100022014 Angiopoietin-1 receptor Human genes 0.000 claims abstract description 31
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 31
- 229940091171 VEGFR-2 tyrosine kinase inhibitor Drugs 0.000 claims abstract description 4
- -1 -NR 8 R 9 Chemical group 0.000 claims description 443
- 150000001875 compounds Chemical class 0.000 claims description 402
- 125000000217 alkyl group Chemical group 0.000 claims description 120
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 94
- 229910052739 hydrogen Inorganic materials 0.000 claims description 92
- 239000001257 hydrogen Substances 0.000 claims description 91
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 77
- 150000002431 hydrogen Chemical group 0.000 claims description 67
- 150000003839 salts Chemical class 0.000 claims description 51
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 49
- 125000003118 aryl group Chemical group 0.000 claims description 42
- 239000012453 solvate Substances 0.000 claims description 39
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 30
- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 230000000694 effects Effects 0.000 claims description 29
- 206010028980 Neoplasm Diseases 0.000 claims description 28
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 claims description 27
- 239000008194 pharmaceutical composition Substances 0.000 claims description 27
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 26
- 239000000460 chlorine Chemical group 0.000 claims description 25
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 claims description 24
- 125000001188 haloalkyl group Chemical group 0.000 claims description 23
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims description 22
- 201000011510 cancer Diseases 0.000 claims description 21
- 239000003814 drug Substances 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 18
- 238000002360 preparation method Methods 0.000 claims description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 17
- 229910052801 chlorine Inorganic materials 0.000 claims description 17
- OWCDMRFUFMERMZ-UHFFFAOYSA-N benzenesulfonamide;hydrochloride Chemical compound Cl.NS(=O)(=O)C1=CC=CC=C1 OWCDMRFUFMERMZ-UHFFFAOYSA-N 0.000 claims description 16
- 230000012010 growth Effects 0.000 claims description 16
- 102000005962 receptors Human genes 0.000 claims description 16
- 108020003175 receptors Proteins 0.000 claims description 16
- 239000003981 vehicle Substances 0.000 claims description 15
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims description 14
- 125000002252 acyl group Chemical group 0.000 claims description 13
- 125000004104 aryloxy group Chemical group 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 11
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- 108091008605 VEGF receptors Proteins 0.000 claims description 9
- 241000124008 Mammalia Species 0.000 claims description 8
- 125000003435 aroyl group Chemical group 0.000 claims description 8
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 8
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 102000009465 Growth Factor Receptors Human genes 0.000 claims description 7
- 108010009202 Growth Factor Receptors Proteins 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 6
- 229910052760 oxygen Inorganic materials 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 125000001769 aryl amino group Chemical group 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- CHKFOGJYAICJSR-UHFFFAOYSA-N benzenesulfonamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.NS(=O)(=O)C1=CC=CC=C1 CHKFOGJYAICJSR-UHFFFAOYSA-N 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 5
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 claims description 4
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 claims description 4
- XLZLNCSZYWPDRJ-UHFFFAOYSA-N ethanesulfonamide;hydrochloride Chemical compound Cl.CCS(N)(=O)=O XLZLNCSZYWPDRJ-UHFFFAOYSA-N 0.000 claims description 4
- 230000001404 mediated effect Effects 0.000 claims description 4
- NYHUWXNDQAZDPK-UHFFFAOYSA-N 2-[4-[[4-[[2-[(3-fluorophenyl)methylamino]-1-methylbenzimidazol-5-yl]-methylamino]pyrimidin-2-yl]amino]phenyl]-n-methylethanesulfonamide;hydrochloride Chemical compound Cl.C1=CC(CCS(=O)(=O)NC)=CC=C1NC1=NC=CC(N(C)C=2C=C3N=C(NCC=4C=C(F)C=CC=4)N(C)C3=CC=2)=N1 NYHUWXNDQAZDPK-UHFFFAOYSA-N 0.000 claims description 3
- IYECZNNMBACPSD-UHFFFAOYSA-N 2-[4-[[4-[[2-[(4-chlorophenyl)methylamino]-1-methylbenzimidazol-5-yl]-methylamino]pyrimidin-2-yl]amino]phenyl]-n-methylethanesulfonamide;hydrochloride Chemical compound Cl.C1=CC(CCS(=O)(=O)NC)=CC=C1NC1=NC=CC(N(C)C=2C=C3N=C(NCC=4C=CC(Cl)=CC=4)N(C)C3=CC=2)=N1 IYECZNNMBACPSD-UHFFFAOYSA-N 0.000 claims description 3
- JPCFCNOWHUSYDM-UHFFFAOYSA-N 2-[4-[[4-[[2-[(4-fluorophenyl)methylamino]-1-methylbenzimidazol-5-yl]-methylamino]pyrimidin-2-yl]amino]phenyl]-n-methylethanesulfonamide;hydrochloride Chemical compound Cl.C1=CC(CCS(=O)(=O)NC)=CC=C1NC1=NC=CC(N(C)C=2C=C3N=C(NCC=4C=CC(F)=CC=4)N(C)C3=CC=2)=N1 JPCFCNOWHUSYDM-UHFFFAOYSA-N 0.000 claims description 3
- MIBFTLBYFXKULA-UHFFFAOYSA-N 2-cyclohexyl-5-N,1-dimethyl-5-N-[2-[4-(methylsulfonylmethyl)anilino]pyrimidin-4-yl]-3H-benzimidazole-2,5-diamine Chemical compound C1(CCCCC1)C1(NC2=C(N1C)C=CC(=C2)N(C)C1=NC(=NC=C1)NC1=CC=C(C=C1)CS(=O)(=O)C)N MIBFTLBYFXKULA-UHFFFAOYSA-N 0.000 claims description 3
- MMXUAMZMIXZKFR-UHFFFAOYSA-N 5-[[4-[[2-(4-tert-butylanilino)-1-methylbenzimidazol-5-yl]-methylamino]pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide;hydrochloride Chemical compound Cl.C=1C=NC(NC=2C=C(C(C)=CC=2)S(N)(=O)=O)=NC=1N(C)C(C=C1N=2)=CC=C1N(C)C=2NC1=CC=C(C(C)(C)C)C=C1 MMXUAMZMIXZKFR-UHFFFAOYSA-N 0.000 claims description 3
- HLNHVGLYGBHAAZ-UHFFFAOYSA-N 5-[[4-[[2-(cyclohexylamino)-1-methylbenzimidazol-5-yl]-methylamino]pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide;hydrochloride Chemical compound Cl.C=1C=NC(NC=2C=C(C(C)=CC=2)S(N)(=O)=O)=NC=1N(C)C(C=C1N=2)=CC=C1N(C)C=2NC1CCCCC1 HLNHVGLYGBHAAZ-UHFFFAOYSA-N 0.000 claims description 3
- RAJZBUQASUJFSW-UHFFFAOYSA-N CC1(NC2=C(N1C)C=CC(=C2)N(C2=NC(=NC=C2)NC2=CC(=CC=C2)CS(=O)(=O)C)C)N Chemical compound CC1(NC2=C(N1C)C=CC(=C2)N(C2=NC(=NC=C2)NC2=CC(=CC=C2)CS(=O)(=O)C)C)N RAJZBUQASUJFSW-UHFFFAOYSA-N 0.000 claims description 3
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- UQEQLFFYFWTDQY-UHFFFAOYSA-N N-[4-[[4-[[2-[(3-fluorophenyl)methylamino]-1-methylbenzimidazol-5-yl]-methylamino]pyrimidin-2-yl]amino]phenyl]methanesulfonamide hydrochloride Chemical compound Cl.CN(c1ccc2n(C)c(NCc3cccc(F)c3)nc2c1)c1ccnc(Nc2ccc(NS(C)(=O)=O)cc2)n1 UQEQLFFYFWTDQY-UHFFFAOYSA-N 0.000 claims description 3
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- LJBVEPZIIJXOJC-UHFFFAOYSA-N 2-[4-[[4-[[2-(benzylamino)-1-ethylbenzimidazol-5-yl]-methylamino]pyrimidin-2-yl]amino]phenyl]-n-methylethanesulfonamide;hydrochloride Chemical compound Cl.N=1C2=CC(N(C)C=3N=C(NC=4C=CC(CCS(=O)(=O)NC)=CC=4)N=CC=3)=CC=C2N(CC)C=1NCC1=CC=CC=C1 LJBVEPZIIJXOJC-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001475 halogen functional group Chemical group 0.000 claims 10
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Classifications
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- 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
- C07D401/14—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 three or more hetero rings
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- A—HUMAN NECESSITIES
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- 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
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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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
- A61P9/10—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
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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
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- 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
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- 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
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
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- Bioinformatics & Cheminformatics (AREA)
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- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Polymers With Sulfur, Phosphorus Or Metals In The Main Chain (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US36074102P | 2002-03-01 | 2002-03-01 | |
| US360741P | 2002-03-01 |
Publications (1)
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|---|---|
| ES2290479T3 true ES2290479T3 (es) | 2008-02-16 |
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Family Applications (1)
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|---|---|---|---|
| ES03743709T Expired - Lifetime ES2290479T3 (es) | 2002-03-01 | 2003-02-28 | Diamino-pirimidinas y su uso como inhibidores de la angiogenesis. |
Country Status (10)
| Country | Link |
|---|---|
| US (1) | US7338959B2 (https=) |
| EP (1) | EP1487824B1 (https=) |
| JP (1) | JP2005524668A (https=) |
| AT (1) | ATE365165T1 (https=) |
| AU (1) | AU2003220970A1 (https=) |
| CA (1) | CA2477505A1 (https=) |
| DE (1) | DE60314500T2 (https=) |
| ES (1) | ES2290479T3 (https=) |
| MX (1) | MXPA04008458A (https=) |
| WO (1) | WO2003074515A1 (https=) |
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| TWI329105B (en) | 2002-02-01 | 2010-08-21 | Rigel Pharmaceuticals Inc | 2,4-pyrimidinediamine compounds and their uses |
| NZ535985A (en) * | 2002-03-29 | 2007-04-27 | Chiron Corp | Substituted benzazoles and use thereof as RAF kinase inhibitors |
| ES2445208T3 (es) | 2002-07-29 | 2014-02-28 | Rigel Pharmaceuticals, Inc. | Compuestos de 2,4-pirimidindiamina para uso en métodos para tratar o prevenir enfermedades autoinmunitarias |
| US20050282814A1 (en) * | 2002-10-03 | 2005-12-22 | Targegen, Inc. | Vasculostatic agents and methods of use thereof |
| US7531553B2 (en) * | 2003-03-21 | 2009-05-12 | Amgen Inc. | Heterocyclic compounds and methods of use |
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| GB9523675D0 (en) | 1995-11-20 | 1996-01-24 | Celltech Therapeutics Ltd | Chemical compounds |
| WO2000012089A1 (en) * | 1998-08-31 | 2000-03-09 | Merck & Co., Inc. | Novel angiogenesis inhibitors |
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2003
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- 2003-02-28 ES ES03743709T patent/ES2290479T3/es not_active Expired - Lifetime
- 2003-02-28 JP JP2003572983A patent/JP2005524668A/ja active Pending
- 2003-02-28 US US10/506,447 patent/US7338959B2/en not_active Expired - Fee Related
- 2003-02-28 CA CA002477505A patent/CA2477505A1/en not_active Abandoned
- 2003-02-28 DE DE60314500T patent/DE60314500T2/de not_active Expired - Fee Related
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- 2003-02-28 EP EP03743709A patent/EP1487824B1/en not_active Expired - Lifetime
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| DE60314500D1 (de) | 2007-08-02 |
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| CA2477505A1 (en) | 2003-09-12 |
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| MXPA04008458A (es) | 2004-12-06 |
| ATE365165T1 (de) | 2007-07-15 |
| EP1487824A1 (en) | 2004-12-22 |
| EP1487824B1 (en) | 2007-06-20 |
| US7338959B2 (en) | 2008-03-04 |
| JP2005524668A (ja) | 2005-08-18 |
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