TWI240723B - Substituted naphthyl benzofuran derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) - Google Patents
Substituted naphthyl benzofuran derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1) Download PDFInfo
- Publication number
- TWI240723B TWI240723B TW091112529A TW91112529A TWI240723B TW I240723 B TWI240723 B TW I240723B TW 091112529 A TW091112529 A TW 091112529A TW 91112529 A TW91112529 A TW 91112529A TW I240723 B TWI240723 B TW I240723B
- Authority
- TW
- Taiwan
- Prior art keywords
- benzofuran
- naphthyl
- scope
- patent application
- pharmaceutically acceptable
- Prior art date
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- -1 naphthyl benzofuran derivatives Chemical class 0.000 title claims abstract description 168
- 108010022233 Plasminogen Activator Inhibitor 1 Proteins 0.000 title claims abstract description 31
- 102000012335 Plasminogen Activator Inhibitor 1 Human genes 0.000 title claims abstract description 30
- 239000003112 inhibitor Substances 0.000 title claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 192
- 150000003839 salts Chemical class 0.000 claims abstract description 53
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 36
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 35
- 125000003118 aryl group Chemical group 0.000 claims abstract description 30
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 16
- 239000002253 acid Substances 0.000 claims abstract description 15
- 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 12
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 10
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims abstract description 9
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 8
- 208000005069 pulmonary fibrosis Diseases 0.000 claims abstract description 6
- 125000005024 alkenyl aryl group Chemical group 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 125000002877 alkyl aryl group Chemical group 0.000 claims abstract description 4
- 239000003527 fibrinolytic agent Substances 0.000 claims abstract description 4
- 230000003480 fibrinolytic effect Effects 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 108
- 150000002148 esters Chemical group 0.000 claims description 54
- 239000000203 mixture Substances 0.000 claims description 47
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 14
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims description 12
- NIHNNTQXNPWCJQ-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2CC3=CC=CC=C3C2=C1 NIHNNTQXNPWCJQ-UHFFFAOYSA-N 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 208000005189 Embolism Diseases 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 9
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 230000015271 coagulation Effects 0.000 claims description 6
- 238000005345 coagulation Methods 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 5
- 210000003462 vein Anatomy 0.000 claims description 5
- 125000003277 amino group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- 230000015556 catabolic process Effects 0.000 claims description 4
- 230000002107 myocardial effect Effects 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 102000009123 Fibrin Human genes 0.000 claims description 3
- 108010073385 Fibrin Proteins 0.000 claims description 3
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 claims description 3
- 230000003143 atherosclerotic effect Effects 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229950003499 fibrin Drugs 0.000 claims description 3
- 230000002093 peripheral effect Effects 0.000 claims description 3
- KJUGUADJHNHALS-UHFFFAOYSA-N 1H-tetrazole Chemical compound C=1N=NNN=1 KJUGUADJHNHALS-UHFFFAOYSA-N 0.000 claims description 2
- RCLVYHIXCSLQDS-UHFFFAOYSA-N 2-[6-(3-pentyl-1-benzofuran-2-yl)naphthalen-2-yl]oxyacetic acid Chemical compound C1=C(OCC(O)=O)C=CC2=CC(C3=C(C4=CC=CC=C4O3)CCCCC)=CC=C21 RCLVYHIXCSLQDS-UHFFFAOYSA-N 0.000 claims description 2
- 208000031104 Arterial Occlusive disease Diseases 0.000 claims description 2
- 206010008088 Cerebral artery embolism Diseases 0.000 claims description 2
- 102000001938 Plasminogen Activators Human genes 0.000 claims description 2
- 108010001014 Plasminogen Activators Proteins 0.000 claims description 2
- 208000007502 anemia Diseases 0.000 claims description 2
- 208000021328 arterial occlusion Diseases 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 201000010849 intracranial embolism Diseases 0.000 claims description 2
- 230000003902 lesion Effects 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 229940127126 plasminogen activator Drugs 0.000 claims description 2
- 208000011580 syndromic disease Diseases 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 208000003663 ventricular fibrillation Diseases 0.000 claims description 2
- QAJLAJGOUHWOEW-UHFFFAOYSA-N 5-[[6-(3-pentyl-1-benzofuran-2-yl)naphthalen-2-yl]oxymethyl]-2h-tetrazole Chemical compound O1C2=CC=CC=C2C(CCCCC)=C1C(C=C1C=C2)=CC=C1C=C2OCC1=NN=NN1 QAJLAJGOUHWOEW-UHFFFAOYSA-N 0.000 claims 2
- GAYZBHFSLMXJGY-UHFFFAOYSA-N 1-[2-[5-bromo-6-(2h-tetrazol-5-ylmethoxy)naphthalen-2-yl]-5-chloro-1-benzofuran-3-yl]pentan-1-one Chemical compound O1C2=CC=C(Cl)C=C2C(C(=O)CCCC)=C1C(C=C1C=C2)=CC=C1C(Br)=C2OCC1=NN=NN1 GAYZBHFSLMXJGY-UHFFFAOYSA-N 0.000 claims 1
- 206010053567 Coagulopathies Diseases 0.000 claims 1
- 208000015294 blood coagulation disease Diseases 0.000 claims 1
- 125000001246 bromo group Chemical group Br* 0.000 claims 1
- PGRHXDWITVMQBC-UHFFFAOYSA-N dehydroacetic acid Natural products CC(=O)C1C(=O)OC(C)=CC1=O PGRHXDWITVMQBC-UHFFFAOYSA-N 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
- PEQJBOMPGWYIRO-UHFFFAOYSA-N n-ethyl-3,4-dimethoxyaniline Chemical compound CCNC1=CC=C(OC)C(OC)=C1 PEQJBOMPGWYIRO-UHFFFAOYSA-N 0.000 claims 1
- 125000002080 perylenyl group Chemical group C1(=CC=C2C=CC=C3C4=CC=CC5=CC=CC(C1=C23)=C45)* 0.000 claims 1
- CSHWQDPOILHKBI-UHFFFAOYSA-N peryrene Natural products C1=CC(C2=CC=CC=3C2=C2C=CC=3)=C3C2=CC=CC3=C1 CSHWQDPOILHKBI-UHFFFAOYSA-N 0.000 claims 1
- 238000001356 surgical procedure Methods 0.000 claims 1
- 239000000052 vinegar Chemical group 0.000 claims 1
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- 238000000034 method Methods 0.000 abstract description 131
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- 206010047249 Venous thrombosis Diseases 0.000 abstract 1
- 125000001589 carboacyl group Chemical group 0.000 abstract 1
- 125000004185 ester group Chemical group 0.000 abstract 1
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 abstract 1
- 230000003278 mimic effect Effects 0.000 abstract 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 250
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 206
- WEVYAHXRMPXWCK-UHFFFAOYSA-N methyl cyanide Natural products CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 128
- 239000007787 solid Substances 0.000 description 107
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 105
- 229910001868 water Inorganic materials 0.000 description 97
- 235000019439 ethyl acetate Nutrition 0.000 description 90
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 76
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 75
- 238000001819 mass spectrum Methods 0.000 description 65
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 64
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 61
- 238000000921 elemental analysis Methods 0.000 description 59
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
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- 230000008569 process Effects 0.000 description 45
- 238000003818 flash chromatography Methods 0.000 description 43
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- 229960000583 acetic acid Drugs 0.000 description 38
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 36
- 239000003480 eluent Substances 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 31
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 27
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- 239000012267 brine Substances 0.000 description 20
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 20
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- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 18
- 244000166102 Eucalyptus leucoxylon Species 0.000 description 17
- 235000004694 Eucalyptus leucoxylon Nutrition 0.000 description 17
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 17
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 15
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- 238000006243 chemical reaction Methods 0.000 description 12
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 11
- 208000024891 symptom Diseases 0.000 description 11
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- 238000010168 coupling process Methods 0.000 description 10
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- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- CWYNVVGOOAEACU-UHFFFAOYSA-N Fe2+ Chemical compound [Fe+2] CWYNVVGOOAEACU-UHFFFAOYSA-N 0.000 description 9
- 229910052778 Plutonium Inorganic materials 0.000 description 9
- 229910021627 Tin(IV) chloride Inorganic materials 0.000 description 9
- 108090000373 Tissue Plasminogen Activator Proteins 0.000 description 9
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- 238000004364 calculation method Methods 0.000 description 9
- 238000005859 coupling reaction Methods 0.000 description 9
- RMBPEFMHABBEKP-UHFFFAOYSA-N fluorene Chemical compound C1=CC=C2C3=C[CH]C=CC3=CC2=C1 RMBPEFMHABBEKP-UHFFFAOYSA-N 0.000 description 9
- OYEHPCDNVJXUIW-UHFFFAOYSA-N plutonium atom Chemical compound [Pu] OYEHPCDNVJXUIW-UHFFFAOYSA-N 0.000 description 9
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 9
- 229960000187 tissue plasminogen activator Drugs 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
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- 125000004244 benzofuran-2-yl group Chemical group [H]C1=C(*)OC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 8
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- 238000002360 preparation method Methods 0.000 description 8
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- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 7
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 7
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- HECLRDQVFMWTQS-HORUIINNSA-N bis[cyclopentadiene] Chemical compound C1C2[C@H]3CC=C[C@H]3C1C=C2 HECLRDQVFMWTQS-HORUIINNSA-N 0.000 description 7
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 7
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- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 7
- PHFJAODRBDSBPX-UHFFFAOYSA-N 2-(6-methoxynaphthalen-2-yl)-1-benzofuran Chemical compound C1=CC=C2OC(C3=CC4=CC=C(C=C4C=C3)OC)=CC2=C1 PHFJAODRBDSBPX-UHFFFAOYSA-N 0.000 description 6
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- 239000000284 extract Substances 0.000 description 4
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Classifications
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Landscapes
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Applications Claiming Priority (1)
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| US29970201P | 2001-06-20 | 2001-06-20 |
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| US7291639B2 (en) * | 2001-06-20 | 2007-11-06 | Wyeth | Aryloxy-acetic acid compounds useful as inhibitors of plasminogen activator inhibitor-1 (PAI-1) |
| ES2290318T3 (es) * | 2001-06-20 | 2008-02-16 | Wyeth | Derivados sustituidos de acido indolico como inhibidores del inhibidor del activador del plasminogeno-1 (pai-1). |
| TWI224101B (en) * | 2001-06-20 | 2004-11-21 | Wyeth Corp | Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1) |
| ES2314289T3 (es) * | 2002-12-10 | 2009-03-16 | Wyeth | Derivados del acido 1h-indol-3-il glioxilico sustituidos con arilo, ariloxi y alquloxi como inhibidores del inhibidor del activador del plasminogeno-1(pai-1). |
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| AU2006279496A1 (en) * | 2005-08-17 | 2007-02-22 | Wyeth | Substituted indoles and use thereof |
| AR059629A1 (es) * | 2006-02-27 | 2008-04-16 | Wyeth Corp | Inhibidores del inhibidor del activador de plasminogeno (pai- 1) para el tratamiento de trastornos musculares |
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| US8044236B2 (en) | 2006-10-12 | 2011-10-25 | Institute Of Medicinal Molecular Design, Inc. | Carboxilic acid derivatives |
| JP5470046B2 (ja) | 2007-10-23 | 2014-04-16 | 株式会社医薬分子設計研究所 | Ｐａｉ−１産生抑制剤 |
| RU2010145916A (ru) | 2008-04-11 | 2012-05-20 | Инститьют Оф Медисинал Молекьюлар Дизайн, Инк. (Jp) | Ингибитор pai-1 |
| US8633245B2 (en) * | 2008-04-11 | 2014-01-21 | Institute Of Medicinal Molecular Design, Inc. | PAI-1 inhibitor |
| EP2361093A2 (en) | 2008-11-26 | 2011-08-31 | Five Prime Therapeutics, Inc. | Compositions and methods for regulating collagen and smooth muscle actin expression by serpine2 |
| EP2427057B1 (en) | 2009-05-05 | 2015-08-12 | Sloan-Kettering Institute for Cancer Research | Benzofuran-4,5-diones as selective peptide deformylase inhibitors |
| CN102850451B (zh) * | 2011-06-29 | 2014-05-07 | 辽宁诺康生物制药有限责任公司 | 具有抑制纤溶酶活性的重组textilinin-1及其制备方法和应用 |
| CN108778307A (zh) | 2015-12-18 | 2018-11-09 | 泰伦基国际有限公司 | 一种预防和治疗糖尿病肾病的方法 |
| CN106890324A (zh) * | 2015-12-18 | 2017-06-27 | 深圳瑞健生命科学研究院有限公司 | 一种预防和治疗糖尿病肾病的方法 |
| TWI669130B (zh) | 2016-12-15 | 2019-08-21 | 深圳瑞健生命科學硏究院有限公司 | 纖溶酶原在製備用於治療糖尿病的藥物上的用途 |
| CN114957176A (zh) * | 2022-07-01 | 2022-08-30 | 河南中医药大学第一附属医院 | 人血管紧张素转化酶抑制剂化合物和合成方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB1464242A (en) * | 1974-04-18 | 1977-02-09 | Smithkline Corp | Benzoyl benzofurans and compositions comprising them |
| US4024273A (en) | 1974-06-20 | 1977-05-17 | Smithkline Corporation | Coronary vasodilator and anti-anginal compositions comprising substituted benzofurans and benzothiophenes and methods of producing coronary vasodilation and anti-anginal activity |
| ZA825413B (en) | 1981-08-26 | 1983-06-29 | Pfizer | Thromboxane synthetase inhibitors, processes for their production, and pharmaceutical compositions comprising them |
| ZA928276B (en) * | 1991-10-31 | 1993-05-06 | Daiichi Seiyaku Co | Aromatic amidine derivates and salts thereof. |
| US6756388B1 (en) | 1993-10-12 | 2004-06-29 | Pfizer Inc. | Benzothiophenes and related compounds as estrogen agonists |
| CA2134192A1 (en) | 1993-11-12 | 1995-05-13 | Michael L. Denney | 5, 6-bicyclic glycoprotein iib/iiia antagonists |
| CA2207141A1 (en) * | 1996-07-15 | 1998-01-15 | David Thompson Berg | Benzothiophene compounds, and uses and formulations thereof |
| US6110963A (en) | 1998-05-12 | 2000-08-29 | American Home Products Corporation | Aryl-oxo-acetic acids useful in the treatment of insulin resistance and hyperglycemia |
-
2002
- 2002-06-10 TW TW091112529A patent/TWI240723B/zh not_active IP Right Cessation
- 2002-06-18 CA CA002449844A patent/CA2449844A1/en not_active Abandoned
- 2002-06-18 JP JP2003507076A patent/JP4476624B2/ja not_active Expired - Lifetime
- 2002-06-18 WO PCT/US2002/019231 patent/WO2003000671A1/en not_active Ceased
- 2002-06-18 US US10/174,166 patent/US6599925B2/en not_active Expired - Fee Related
- 2002-06-18 CN CNB028161874A patent/CN1308320C/zh not_active Expired - Fee Related
- 2002-06-18 BR BR0210532-2A patent/BR0210532A/pt not_active IP Right Cessation
- 2002-06-18 EP EP02747904A patent/EP1401822A1/en not_active Withdrawn
- 2002-06-18 MX MXPA03011400A patent/MXPA03011400A/es active IP Right Grant
- 2002-06-20 AR ARP020102314A patent/AR036100A1/es unknown
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|---|---|
| WO2003000671A1 (en) | 2003-01-03 |
| BR0210532A (pt) | 2004-06-22 |
| JP2004534824A (ja) | 2004-11-18 |
| AR036100A1 (es) | 2004-08-11 |
| CN1543456A (zh) | 2004-11-03 |
| CN1308320C (zh) | 2007-04-04 |
| EP1401822A1 (en) | 2004-03-31 |
| JP4476624B2 (ja) | 2010-06-09 |
| CA2449844A1 (en) | 2003-01-03 |
| US6599925B2 (en) | 2003-07-29 |
| US20030018067A1 (en) | 2003-01-23 |
| MXPA03011400A (es) | 2004-04-05 |
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