DE60012888T2 - Mevinolinderivate - Google Patents
Mevinolinderivate Download PDFInfo
- Publication number
- DE60012888T2 DE60012888T2 DE60012888T DE60012888T DE60012888T2 DE 60012888 T2 DE60012888 T2 DE 60012888T2 DE 60012888 T DE60012888 T DE 60012888T DE 60012888 T DE60012888 T DE 60012888T DE 60012888 T2 DE60012888 T2 DE 60012888T2
- Authority
- DE
- Germany
- Prior art keywords
- alkyl
- alkoxy
- aryl
- hydroxy
- heteroaryl
- 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 - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 claims description 104
- -1 morpholino, pyridyl Chemical group 0.000 claims description 23
- 150000003839 salts Chemical class 0.000 claims description 21
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 150000003951 lactams Chemical class 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000001424 substituent group Chemical group 0.000 claims description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- WLAMNBDJUVNPJU-BYPYZUCNSA-N (S)-2-methylbutyric acid Chemical compound CC[C@H](C)C(O)=O WLAMNBDJUVNPJU-BYPYZUCNSA-N 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 7
- 125000004122 cyclic group Chemical group 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 7
- 230000002519 immonomodulatory effect Effects 0.000 claims description 7
- 230000001506 immunosuppresive effect Effects 0.000 claims description 7
- 125000005936 piperidyl group Chemical class 0.000 claims description 7
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 claims description 4
- 235000008206 alpha-amino acids Nutrition 0.000 claims description 4
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 4
- 229940124599 anti-inflammatory drug Drugs 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 3
- 229940124622 immune-modulator drug Drugs 0.000 claims description 3
- 229940124589 immunosuppressive drug Drugs 0.000 claims description 3
- 125000005493 quinolyl group Chemical group 0.000 claims description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 125000005223 heteroarylcarbonyl group Chemical group 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 1
- 125000000623 heterocyclic group Chemical group 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 37
- 238000000034 method Methods 0.000 description 30
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 19
- 238000006243 chemical reaction Methods 0.000 description 18
- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical class C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- PCZOHLXUXFIOCF-UHFFFAOYSA-N Monacolin X Natural products C12C(OC(=O)C(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 PCZOHLXUXFIOCF-UHFFFAOYSA-N 0.000 description 15
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
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- 239000000203 mixture Substances 0.000 description 10
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- 239000007858 starting material Substances 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
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- 238000002360 preparation method Methods 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
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- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 7
- 229930105110 Cyclosporin A Natural products 0.000 description 7
- 108010036949 Cyclosporine Proteins 0.000 description 7
- AJLFOPYRIVGYMJ-UHFFFAOYSA-N SJ000287055 Natural products C12C(OC(=O)C(C)CC)CCC=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 AJLFOPYRIVGYMJ-UHFFFAOYSA-N 0.000 description 7
- 239000004480 active ingredient Substances 0.000 description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 7
- 229960001265 ciclosporin Drugs 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 7
- 210000002216 heart Anatomy 0.000 description 7
- AJLFOPYRIVGYMJ-INTXDZFKSA-N mevastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=CCC[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 AJLFOPYRIVGYMJ-INTXDZFKSA-N 0.000 description 7
- BOZILQFLQYBIIY-UHFFFAOYSA-N mevastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CCC=C21 BOZILQFLQYBIIY-UHFFFAOYSA-N 0.000 description 7
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 206010012442 Dermatitis contact Diseases 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 208000002029 allergic contact dermatitis Diseases 0.000 description 6
- 239000012131 assay buffer Substances 0.000 description 6
- 230000002354 daily effect Effects 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 6
- 229960002930 sirolimus Drugs 0.000 description 6
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- DIVNUTGTTIRPQA-UHFFFAOYSA-N (3,4-dimethoxyphenyl)methanamine Chemical compound COC1=CC=C(CN)C=C1OC DIVNUTGTTIRPQA-UHFFFAOYSA-N 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N N,N′-Dicyclohexylcarbodiimide Substances C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
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- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
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- 229920006395 saturated elastomer Polymers 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 5
- 208000023275 Autoimmune disease Diseases 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 150000001412 amines Chemical class 0.000 description 4
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- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 4
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| PCT/EP2000/001191 WO2000048989A1 (en) | 1999-02-16 | 2000-02-14 | Mevinolin derivatives |
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| DE60012888D1 DE60012888D1 (de) | 2004-09-16 |
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| US6110922A (en) | 1998-12-29 | 2000-08-29 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds |
| US6867203B2 (en) | 1998-12-29 | 2005-03-15 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds |
| US6878700B1 (en) | 1998-12-29 | 2005-04-12 | Abbott Laboratories | Cell adhesion-inhibiting antiinflammatory and immune-suppressive compounds |
| NZ523445A (en) | 2000-06-29 | 2004-10-29 | Abbott Lab | Aryl phenylheterocyclyl sulfide derivatives and their use as cell adhesion-inhibiting anti-inflammatory and immune-suppressive agents |
| US20020156122A1 (en) * | 2000-09-19 | 2002-10-24 | Novlmmune S.A. | Statins (HMG-CoA reductase inhibitors) as a novel type of immunomodulator, immunosuppressor and anti-inflammatory agent |
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| ATE551339T1 (de) | 2003-11-05 | 2012-04-15 | Sarcode Bioscience Inc | Modulatoren der zellulären adhäsion |
| US7884116B2 (en) * | 2003-12-26 | 2011-02-08 | Nippon Shinyaku Co., Ltd. | Octahydronaphthalene derivative and medicine |
| JP2008507592A (ja) * | 2004-06-09 | 2008-03-13 | ジェネンテック・インコーポレーテッド | 環状肉芽腫又はサルコイドの治療法 |
| EP2583678A3 (en) | 2004-06-24 | 2013-11-13 | Novartis Vaccines and Diagnostics, Inc. | Small molecule immunopotentiators and assays for their detection |
| TW200616634A (en) | 2004-10-01 | 2006-06-01 | Bristol Myers Squibb Co | Crystalline forms and process for preparing spiro-hydantoin compounds |
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| CN102617533B (zh) * | 2011-02-01 | 2014-08-27 | 北京北大维信生物科技有限公司 | 一种从红曲中分离的化合物、其制备方法及用途 |
| WO2016161085A1 (en) | 2015-04-01 | 2016-10-06 | Cedars-Sinai Medical Center | Anti-methanogenic lovastatin analogs or derivatives and uses thereof |
| WO2017038650A1 (ja) * | 2015-08-28 | 2017-03-09 | 積水メディカル株式会社 | ベンジル化合物 |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4678806A (en) | 1986-09-02 | 1987-07-07 | Merck & Co., Inc. | Prodrugs of antihypercholesterolemic compounds |
| US4820850A (en) | 1987-07-10 | 1989-04-11 | Merck & Co., Inc. | Process for α-C-alkylation of the 8-acyl group on mevinolin and analogs thereof |
| US5021451A (en) * | 1988-11-14 | 1991-06-04 | Hoffman-La Roche Inc. | Method for inhibiting hyperproliferative diseases |
| EP0415488B1 (en) * | 1989-08-31 | 1994-04-20 | Merck & Co. Inc. | 7-Substituted HMG-COA reductase inhibitors |
| NZ250609A (en) * | 1992-12-28 | 1995-07-26 | Sankyo Co | Hexahydronaphthalene esters and ring closed lactones; preparation and medicaments |
| US5393893A (en) | 1993-11-08 | 1995-02-28 | Apotex, Inc. | Process for producing simvastatin and analogs thereof |
| AU720853B2 (en) * | 1995-11-02 | 2000-06-15 | Warner-Lambert Company | Method and pharmaceutical composition for regulating lipid concentration |
| US5763653A (en) | 1997-03-13 | 1998-06-09 | Ranbaxy Laboratories, Ltd. | Key intermediates in the manufacture of simvastatin |
| US5763646A (en) | 1997-03-13 | 1998-06-09 | Ranbaxy Laboratories, Ltd. | Process for manufacturing simvastatin from lovastatin or mevinolinic acid |
| ES2197465T3 (es) | 1997-01-28 | 2004-01-01 | Plus Chemicals B.V. | Proceso para la produccion de estatinas semisinteticas a traves de nuevos intermedios. |
| PT1007033E (pt) * | 1997-08-28 | 2008-07-22 | Novartis Ag | Antagonistas do antigénio-1 da função de linfócitos |
-
2000
- 2000-02-09 CO CO00008363A patent/CO5140104A1/es unknown
- 2000-02-14 ES ES00916832T patent/ES2226802T3/es not_active Expired - Lifetime
- 2000-02-14 AR ARP000100626A patent/AR022588A1/es unknown
- 2000-02-14 PE PE2000000114A patent/PE20001495A1/es not_active Application Discontinuation
- 2000-02-14 SI SI200030511T patent/SI1154988T1/xx unknown
- 2000-02-14 EP EP00916832A patent/EP1154988B1/en not_active Expired - Lifetime
- 2000-02-14 DE DE60012888T patent/DE60012888T2/de not_active Expired - Fee Related
- 2000-02-14 CN CNB008038171A patent/CN1229335C/zh not_active Expired - Fee Related
- 2000-02-14 PT PT00916832T patent/PT1154988E/pt unknown
- 2000-02-14 JP JP2000599730A patent/JP4167806B2/ja not_active Expired - Fee Related
- 2000-02-14 DK DK00916832T patent/DK1154988T3/da active
- 2000-02-14 AT AT00916832T patent/ATE273272T1/de not_active IP Right Cessation
- 2000-02-14 AU AU38040/00A patent/AU763357B2/en not_active Ceased
- 2000-02-14 BR BR0008292-9A patent/BR0008292A/pt not_active Application Discontinuation
- 2000-02-14 WO PCT/EP2000/001191 patent/WO2000048989A1/en not_active Ceased
- 2000-02-14 CA CA002361841A patent/CA2361841C/en not_active Expired - Fee Related
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2001
- 2001-08-13 US US09/928,593 patent/US20020037895A1/en not_active Abandoned
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2002
- 2002-07-11 US US10/192,888 patent/US6818638B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| US6818638B2 (en) | 2004-11-16 |
| JP2002537284A (ja) | 2002-11-05 |
| CO5140104A1 (es) | 2002-03-22 |
| BR0008292A (pt) | 2001-11-06 |
| CN1340044A (zh) | 2002-03-13 |
| AU763357B2 (en) | 2003-07-17 |
| PT1154988E (pt) | 2004-12-31 |
| US20020037895A1 (en) | 2002-03-28 |
| DK1154988T3 (da) | 2004-11-22 |
| ATE273272T1 (de) | 2004-08-15 |
| EP1154988A1 (en) | 2001-11-21 |
| WO2000048989A1 (en) | 2000-08-24 |
| CA2361841C (en) | 2008-12-02 |
| AU3804000A (en) | 2000-09-04 |
| ES2226802T3 (es) | 2005-04-01 |
| PE20001495A1 (es) | 2001-01-12 |
| AR022588A1 (es) | 2002-09-04 |
| US20030087903A1 (en) | 2003-05-08 |
| CN1229335C (zh) | 2005-11-30 |
| EP1154988B1 (en) | 2004-08-11 |
| JP4167806B2 (ja) | 2008-10-22 |
| SI1154988T1 (en) | 2005-02-28 |
| DE60012888D1 (de) | 2004-09-16 |
| CA2361841A1 (en) | 2000-08-24 |
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