AU2001282318A1 - Fused pyrazole derivatives being protein kinase inhibitors - Google Patents
Fused pyrazole derivatives being protein kinase inhibitorsInfo
- Publication number
- AU2001282318A1 AU2001282318A1 AU2001282318A AU8231801A AU2001282318A1 AU 2001282318 A1 AU2001282318 A1 AU 2001282318A1 AU 2001282318 A AU2001282318 A AU 2001282318A AU 8231801 A AU8231801 A AU 8231801A AU 2001282318 A1 AU2001282318 A1 AU 2001282318A1
- Authority
- AU
- Australia
- Prior art keywords
- alkyl
- formula
- compound
- fluorophenyl
- pyrazolo
- 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.)
- Abandoned
Links
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title description 3
- 239000003909 protein kinase inhibitor Substances 0.000 title description 3
- 150000003217 pyrazoles Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims description 394
- -1 C3_ι2cycloalkyl Chemical group 0.000 claims description 84
- 238000000034 method Methods 0.000 claims description 83
- 150000003839 salts Chemical class 0.000 claims description 59
- 102000002574 p38 Mitogen-Activated Protein Kinases Human genes 0.000 claims description 51
- 108010068338 p38 Mitogen-Activated Protein Kinases Proteins 0.000 claims description 51
- 229910052739 hydrogen Inorganic materials 0.000 claims description 49
- 239000012453 solvate Substances 0.000 claims description 49
- 125000000623 heterocyclic group Chemical group 0.000 claims description 43
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 40
- 230000000694 effects Effects 0.000 claims description 40
- 230000001404 mediated effect Effects 0.000 claims description 40
- 102000002569 MAP Kinase Kinase 4 Human genes 0.000 claims description 39
- 108010068304 MAP Kinase Kinase 4 Proteins 0.000 claims description 39
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- 150000002367 halogens Chemical group 0.000 claims description 37
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 34
- 238000011282 treatment Methods 0.000 claims description 31
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 30
- 239000001257 hydrogen Substances 0.000 claims description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 27
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 201000010099 disease Diseases 0.000 claims description 26
- 125000001072 heteroaryl group Chemical group 0.000 claims description 25
- 102000004127 Cytokines Human genes 0.000 claims description 24
- 108090000695 Cytokines Proteins 0.000 claims description 24
- 125000004043 oxo group Chemical group O=* 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 23
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 23
- 125000001424 substituent group Chemical group 0.000 claims description 22
- 229910052757 nitrogen Inorganic materials 0.000 claims description 20
- 238000002360 preparation method Methods 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 150000002431 hydrogen Chemical group 0.000 claims description 17
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 14
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- 238000006467 substitution reaction Methods 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical group C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical group [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- JIIWFBWSAHKMIA-UHFFFAOYSA-N 3-[[4-[2-(4-fluorophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-yl]amino]propan-1-ol Chemical compound OCCCNC1=NC=CC(C2=C3C=CC(=CN3N=C2C=2C=CC(F)=CC=2)C(F)(F)F)=N1 JIIWFBWSAHKMIA-UHFFFAOYSA-N 0.000 claims 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 165
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- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 105
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 97
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- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 69
- 238000006243 chemical reaction Methods 0.000 description 65
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- 239000002904 solvent Substances 0.000 description 60
- 235000002639 sodium chloride Nutrition 0.000 description 53
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 51
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
- 238000001914 filtration Methods 0.000 description 46
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 43
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 42
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 40
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 36
- 235000019439 ethyl acetate Nutrition 0.000 description 36
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- 230000002829 reductive effect Effects 0.000 description 28
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 28
- RAHZWNYVWXNFOC-UHFFFAOYSA-N sulfur dioxide Inorganic materials O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 229940093499 ethyl acetate Drugs 0.000 description 23
- 239000011541 reaction mixture Substances 0.000 description 23
- 238000010992 reflux Methods 0.000 description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 22
- 239000003795 chemical substances by application Substances 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 21
- 150000002500 ions Chemical class 0.000 description 21
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 19
- 150000001412 amines Chemical class 0.000 description 19
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 18
- 239000002244 precipitate Substances 0.000 description 18
- 229960001340 histamine Drugs 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
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- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 16
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 16
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- 238000007792 addition Methods 0.000 description 15
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 229910000027 potassium carbonate Inorganic materials 0.000 description 13
- PBKONEOXTCPAFI-UHFFFAOYSA-N 1,2,4-trichlorobenzene Chemical compound ClC1=CC=C(Cl)C(Cl)=C1 PBKONEOXTCPAFI-UHFFFAOYSA-N 0.000 description 12
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- MLHIFZMHFONVGG-UHFFFAOYSA-N 2-(3-chlorophenyl)-3-(2-methylsulfonylpyrimidin-4-yl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridine Chemical compound CS(=O)(=O)C1=NC=CC(C2=C3C=CC(=CN3N=C2C=2C=C(Cl)C=CC=2)C(F)(F)F)=N1 MLHIFZMHFONVGG-UHFFFAOYSA-N 0.000 description 11
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- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 11
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- BZFGKBQHQJVAHS-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(C(F)(F)F)=C1 BZFGKBQHQJVAHS-UHFFFAOYSA-N 0.000 description 10
- LJLMSFANGMHCBJ-UHFFFAOYSA-N 3-(2-methylsulfonylpyrimidin-4-yl)-6-(trifluoromethyl)-2-[4-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyridine Chemical compound CS(=O)(=O)C1=NC=CC(C2=C3C=CC(=CN3N=C2C=2C=CC(=CC=2)C(F)(F)F)C(F)(F)F)=N1 LJLMSFANGMHCBJ-UHFFFAOYSA-N 0.000 description 10
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- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-N sodium;2-hydroxybenzoic acid Chemical compound [Na+].OC(=O)C1=CC=CC=C1O ABBQHOQBGMUPJH-UHFFFAOYSA-N 0.000 description 1
- AGHLUVOCTHWMJV-UHFFFAOYSA-J sodium;gold(3+);2-sulfanylbutanedioate Chemical compound [Na+].[Au+3].[O-]C(=O)CC(S)C([O-])=O.[O-]C(=O)CC(S)C([O-])=O AGHLUVOCTHWMJV-UHFFFAOYSA-J 0.000 description 1
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- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- RAOIDOHSFRTOEL-UHFFFAOYSA-N tetrahydrothiophene Chemical compound C1CCSC1 RAOIDOHSFRTOEL-UHFFFAOYSA-N 0.000 description 1
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- 150000003536 tetrazoles Chemical class 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
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- LGQXXHMEBUOXRP-UHFFFAOYSA-N tributyl borate Chemical compound CCCCOB(OCCCC)OCCCC LGQXXHMEBUOXRP-UHFFFAOYSA-N 0.000 description 1
- WTFFOOAJSDVASL-UHFFFAOYSA-N tributyl(pyrimidin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=NC=CC=N1 WTFFOOAJSDVASL-UHFFFAOYSA-N 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 description 1
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- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
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- 230000001228 trophic effect Effects 0.000 description 1
- 229940046728 tumor necrosis factor alpha inhibitor Drugs 0.000 description 1
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- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
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- JABYJIQOLGWMQW-UHFFFAOYSA-N undec-4-ene Chemical compound CCCCCCC=CCCC JABYJIQOLGWMQW-UHFFFAOYSA-N 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
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- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical compound [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Landscapes
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Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0020576.7 | 2000-08-22 | ||
| GB0020576A GB0020576D0 (en) | 2000-08-22 | 2000-08-22 | Fused pyrazole derivatives |
| GB0020556 | 2000-08-22 | ||
| GBGB0020556.7A GB0020556D0 (en) | 2000-08-22 | 2000-08-22 | Fused pyrazole derivatives |
| PCT/GB2001/003783 WO2002016359A1 (en) | 2000-08-22 | 2001-08-22 | Fused pyrazole derivatives being protein kinase inhibitors |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| AU2001282318A1 true AU2001282318A1 (en) | 2002-03-04 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU2001282318A Abandoned AU2001282318A1 (en) | 2000-08-22 | 2001-08-22 | Fused pyrazole derivatives being protein kinase inhibitors |
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| WO2002048148A2 (en) | 2000-12-15 | 2002-06-20 | Glaxo Group Limited | Pyrazolopyridine derivatives |
| WO2002048147A2 (en) * | 2000-12-15 | 2002-06-20 | Glaxo Group Limited | Pyrazolopyridines |
| DE60201074T2 (de) * | 2001-03-08 | 2005-09-15 | Smithkline Beecham Corp. | Pyrazolopyridinderivate |
| JP4237497B2 (ja) | 2001-03-30 | 2009-03-11 | スミスクライン ビーチャム コーポレーション | ピラゾロピリジン類、その調製方法及びその治療用化合物としての使用 |
| GB0108770D0 (en) | 2001-04-06 | 2001-05-30 | Eisai London Res Lab Ltd | Inhibitors |
| ES2266487T3 (es) * | 2001-04-10 | 2007-03-01 | Smithkline Beecham Corporation | Compuestos de pirazolopirina antivirales. |
| US6962914B2 (en) | 2001-04-27 | 2005-11-08 | Smithkline Beecham Corporation | Pyrazolopyridinyl pyridine and pyrimidine therapeutic compounds |
| WO2002094833A1 (en) | 2001-05-24 | 2002-11-28 | Eli Lilly And Company | Novel pyrrole derivatives as pharmaceutical agents |
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| US20040235794A1 (en) * | 2001-09-04 | 2004-11-25 | Shinji Nakade | Remedies for respiratory diseases comprising sphingosine-1-phosphate receptor controller |
| EP1432712B1 (en) | 2001-10-05 | 2006-05-17 | SmithKline Beecham Corporation | Imidazo-pyridine derivatives for use in the treatment of herpes viral infection |
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| AU2003207298B2 (en) * | 2002-02-12 | 2009-09-03 | Glaxosmithkline Llc | Nicotinamide derivates useful as p38 inhibitors |
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| DE60331219D1 (de) | 2002-03-28 | 2010-03-25 | Eisai R&D Man Co Ltd | Azaindole als hemmstoffe von c-jun n-terminalen kinasen |
| AR039241A1 (es) | 2002-04-04 | 2005-02-16 | Biogen Inc | Heteroarilos trisustituidos y metodos para su produccion y uso de los mismos |
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| WO2003095455A2 (en) | 2002-05-10 | 2003-11-20 | Smithkline Beecham Corporation | Substituted pyrazolopyrimidines |
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| UA80295C2 (en) * | 2002-09-06 | 2007-09-10 | Biogen Inc | Pyrazolopyridines and using the same |
| BR0314286A (pt) | 2002-09-18 | 2005-08-02 | Pfizer Prod Inc | Compostos de isotiazol e isoxazol como inibidores do fator de crescimento transformante (tgf) |
| DE60330362D1 (de) | 2002-09-18 | 2010-01-14 | Pfizer Prod Inc | Neue pyrazol-verbindungen als hemmer des transformierenden wachstumsfaktors (tgf) |
| PL375980A1 (en) | 2002-09-18 | 2005-12-12 | Pfizer Products Inc. | Novel imidazole compounds as transforming growth factor (tgf) inhibitors |
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- 2001-08-22 WO PCT/GB2001/003783 patent/WO2002016359A1/en active IP Right Grant
- 2001-08-22 CA CA002420024A patent/CA2420024A1/en not_active Abandoned
- 2001-08-22 IL IL15440201A patent/IL154402A0/xx unknown
- 2001-08-22 AR ARP010104007A patent/AR034261A1/es unknown
- 2001-08-22 PL PL36213001A patent/PL362130A1/xx not_active Application Discontinuation
- 2001-08-22 US US10/362,146 patent/US7166597B2/en not_active Expired - Fee Related
- 2001-08-22 BR BR0113448-5A patent/BR0113448A/pt not_active Application Discontinuation
- 2001-08-22 AU AU2001282318A patent/AU2001282318A1/en not_active Abandoned
- 2001-08-22 MX MXPA03001593A patent/MXPA03001593A/es unknown
- 2001-08-22 AT AT01960928T patent/ATE318814T1/de not_active IP Right Cessation
- 2001-08-22 DE DE60117568T patent/DE60117568T2/de not_active Expired - Fee Related
- 2001-08-22 EP EP01960928A patent/EP1311507B1/en not_active Expired - Lifetime
- 2001-08-22 ES ES01960928T patent/ES2259331T3/es not_active Expired - Lifetime
- 2001-08-22 UY UY26899A patent/UY26899A1/es unknown
-
2003
- 2003-02-19 NO NO20030779A patent/NO20030779L/no not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| JP2004506736A (ja) | 2004-03-04 |
| EP1311507B1 (en) | 2006-03-01 |
| US20040053942A1 (en) | 2004-03-18 |
| EP1311507A1 (en) | 2003-05-21 |
| UY26899A1 (es) | 2002-03-22 |
| CA2420024A1 (en) | 2002-02-28 |
| BR0113448A (pt) | 2003-06-17 |
| KR20030040419A (ko) | 2003-05-22 |
| NO20030779D0 (no) | 2003-02-19 |
| DE60117568T2 (de) | 2006-08-24 |
| NO20030779L (no) | 2003-04-07 |
| HUP0400757A2 (hu) | 2004-07-28 |
| US7166597B2 (en) | 2007-01-23 |
| DE60117568D1 (de) | 2006-04-27 |
| PE20020506A1 (es) | 2002-07-09 |
| WO2002016359A1 (en) | 2002-02-28 |
| MXPA03001593A (es) | 2003-06-04 |
| IL154402A0 (en) | 2003-09-17 |
| AR034261A1 (es) | 2004-02-18 |
| ES2259331T3 (es) | 2006-10-01 |
| PL362130A1 (en) | 2004-10-18 |
| ATE318814T1 (de) | 2006-03-15 |
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