ES2209527T3 - "44- y 5-alquiniloxindolels y 4- y 5-alqueniloxindones. - Google Patents
"44- y 5-alquiniloxindolels y 4- y 5-alqueniloxindones.Info
- Publication number
- ES2209527T3 ES2209527T3 ES99957341T ES99957341T ES2209527T3 ES 2209527 T3 ES2209527 T3 ES 2209527T3 ES 99957341 T ES99957341 T ES 99957341T ES 99957341 T ES99957341 T ES 99957341T ES 2209527 T3 ES2209527 T3 ES 2209527T3
- Authority
- ES
- Spain
- Prior art keywords
- dihydro
- indole
- methylene
- methoxy
- pyrrol
- 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
- 206010039073 rheumatoid arthritis Diseases 0.000 claims abstract description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 149
- 150000001875 compounds Chemical class 0.000 claims description 114
- 125000000623 heterocyclic group Chemical group 0.000 claims description 111
- 230000015572 biosynthetic process Effects 0.000 claims description 104
- 238000003786 synthesis reaction Methods 0.000 claims description 103
- -1 rac - (Z) -1,3-Dihydro-4- [3-hydroxy-3- (3-hydroxyphenyl) -1 -propyl] -3 - [(3-methoxy-1H-pyrrol-2-yl) methylene] -2H-indole-2-one Chemical compound 0.000 claims description 78
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 74
- 229910052736 halogen Inorganic materials 0.000 claims description 51
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 50
- 125000003118 aryl group Chemical group 0.000 claims description 49
- 150000002367 halogens Chemical class 0.000 claims description 45
- 125000001072 heteroaryl group Chemical group 0.000 claims description 43
- 239000002253 acid Substances 0.000 claims description 41
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 34
- 229910052739 hydrogen Inorganic materials 0.000 claims description 34
- 238000002360 preparation method Methods 0.000 claims description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 26
- 125000005010 perfluoroalkyl group Chemical group 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 17
- YLQAQZFUXVPZGQ-LCYFTJDESA-N (3z)-5-ethynyl-3-(1h-pyrrol-2-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=C(C#C)C=C2\C1=C\C1=CC=CN1 YLQAQZFUXVPZGQ-LCYFTJDESA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
- 125000004429 atom Chemical group 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 13
- BXIUQXIGICXFHK-UYRXBGFRSA-N (3Z)-1-ethynyl-5-(4-hydroxyphenyl)-3-(1H-pyrrol-2-ylmethylidene)indol-2-one Chemical compound OC1=CC=C(C=C1)C=1C=C2/C(/C(N(C2=CC1)C#C)=O)=C/C=1NC=CC1 BXIUQXIGICXFHK-UYRXBGFRSA-N 0.000 claims description 12
- KPCZJLGGXRGYIE-UHFFFAOYSA-N [C]1=CC=CN=C1 Chemical group [C]1=CC=CN=C1 KPCZJLGGXRGYIE-UHFFFAOYSA-N 0.000 claims description 11
- 239000000651 prodrug Substances 0.000 claims description 11
- 229940002612 prodrug Drugs 0.000 claims description 11
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 10
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 10
- 125000004104 aryloxy group Chemical group 0.000 claims description 9
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- PAXRLLNPFPVNOW-WJDWOHSUSA-N (3z)-1-ethynyl-3-(1h-pyrrol-2-ylmethylidene)-5-trimethylsilylindol-2-one Chemical compound C12=CC([Si](C)(C)C)=CC=C2N(C#C)C(=O)\C1=C/C1=CC=CN1 PAXRLLNPFPVNOW-WJDWOHSUSA-N 0.000 claims description 6
- 125000000389 2-pyrrolyl group Chemical group [H]N1C([*])=C([H])C([H])=C1[H] 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 6
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 claims description 6
- 239000001301 oxygen Substances 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000003107 substituted aryl group Chemical group 0.000 claims description 6
- CIBQBCXWQYRSFJ-SDXDJHTJSA-N (3z)-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-4-(3-phenoxyprop-1-ynyl)-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CCOC=4C=CC=CC=4)C=CC=C3NC\2=O)=C1OC CIBQBCXWQYRSFJ-SDXDJHTJSA-N 0.000 claims description 5
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 5
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 5
- IUKAFMMNZXWTHT-UHFFFAOYSA-N COC1=C(NC=C1)C=C1/C(N(C2=CC=C(C=C12)[Si](C)(C)C)C#C)=O Chemical compound COC1=C(NC=C1)C=C1/C(N(C2=CC=C(C=C12)[Si](C)(C)C)C#C)=O IUKAFMMNZXWTHT-UHFFFAOYSA-N 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 5
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 5
- HZVOKZDLKRWNNT-AQTBWJFISA-N (3Z)-1-ethynyl-5-(2-nitrophenyl)-3-(1H-pyrrol-2-ylmethylidene)indol-2-one Chemical compound [N+](=O)([O-])C1=C(C=CC=C1)C=1C=C2/C(/C(N(C2=CC1)C#C)=O)=C/C=1NC=CC1 HZVOKZDLKRWNNT-AQTBWJFISA-N 0.000 claims description 4
- JONAZLREQPKWMB-UYRXBGFRSA-N (3Z)-1-ethynyl-5-(4-nitrophenyl)-3-(1H-pyrrol-2-ylmethylidene)indol-2-one Chemical compound [N+](=O)([O-])C1=CC=C(C=C1)C=1C=C2/C(/C(N(C2=CC1)C#C)=O)=C/C=1NC=CC1 JONAZLREQPKWMB-UYRXBGFRSA-N 0.000 claims description 4
- SOQYSQMXYLSISO-SSZFMOIBSA-N (3z)-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-4-(2-pyridin-2-ylethynyl)-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC=4N=CC=CC=4)C=CC=C3NC\2=O)=C1OC SOQYSQMXYLSISO-SSZFMOIBSA-N 0.000 claims description 4
- LBRHIACYAJUKFX-VBKFSLOCSA-N (3z)-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-4-(2-pyridin-3-ylethynyl)-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC=4C=NC=CC=4)C=CC=C3NC\2=O)=C1OC LBRHIACYAJUKFX-VBKFSLOCSA-N 0.000 claims description 4
- RGVWLPQHWJEXQI-OWBHPGMISA-N (3z)-4-(3-hydroxy-3-thiophen-2-ylprop-1-ynyl)-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC(O)C=4SC=CC=4)C=CC=C3NC\2=O)=C1OC RGVWLPQHWJEXQI-OWBHPGMISA-N 0.000 claims description 4
- JIZBUYBBALMSAD-OWBHPGMISA-N (3z)-4-[3-(furan-2-yl)-3-hydroxyprop-1-ynyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC(O)C=4OC=CC=4)C=CC=C3NC\2=O)=C1OC JIZBUYBBALMSAD-OWBHPGMISA-N 0.000 claims description 4
- FLUWNHUCLAWPKG-ATVHPVEESA-N (3z)-4-[3-hydroxy-3-(2,4,5-trimethoxyphenyl)prop-1-ynyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC(O)C=4C(=CC(OC)=C(OC)C=4)OC)C=CC=C3NC\2=O)=C1OC FLUWNHUCLAWPKG-ATVHPVEESA-N 0.000 claims description 4
- SENKVSSHGZDFNW-LGMDPLHJSA-N (3z)-4-[3-hydroxy-3-(3-nitrophenyl)prop-1-ynyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC(O)C=4C=C(C=CC=4)[N+]([O-])=O)C=CC=C3NC\2=O)=C1OC SENKVSSHGZDFNW-LGMDPLHJSA-N 0.000 claims description 4
- NSIKGWYDIJARHZ-VBKFSLOCSA-N (3z)-4-[3-hydroxy-3-(7-methoxy-1,3-benzodioxol-5-yl)prop-1-ynyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC(O)C=4C=C(OC)C=5OCOC=5C=4)C=CC=C3NC\2=O)=C1OC NSIKGWYDIJARHZ-VBKFSLOCSA-N 0.000 claims description 4
- GHRIUISNTDKVTN-QOCHGBHMSA-N (3z)-4-[3-hydroxy-3-[3-methoxy-4-(2-morpholin-4-ylethoxy)phenyl]prop-1-ynyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC(O)C=4C=C(OC)C(OCCN5CCOCC5)=CC=4)C=CC=C3NC\2=O)=C1OC GHRIUISNTDKVTN-QOCHGBHMSA-N 0.000 claims description 4
- UJYFDCHHAWEECC-GXTSIBQPSA-N (3z)-4-[3-hydroxy-3-[3-methoxy-4-(2-morpholin-4-ylethoxy)phenyl]prop-1-ynyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one;hydrochloride Chemical compound Cl.C1=CNC(\C=C/2C3=C(C#CC(O)C=4C=C(OC)C(OCCN5CCOCC5)=CC=4)C=CC=C3NC\2=O)=C1OC UJYFDCHHAWEECC-GXTSIBQPSA-N 0.000 claims description 4
- DTBCCPGQXHCCJH-RGEXLXHISA-N (3z)-5-(2-phenylethynyl)-3-(1h-pyrrol-2-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=C(C#CC=3C=CC=CC=3)C=C2\C1=C\C1=CC=CN1 DTBCCPGQXHCCJH-RGEXLXHISA-N 0.000 claims description 4
- SDORKXKUPWJUFE-YFHOEESVSA-N (3z)-5-bromo-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=CC(Br)=CC=C3NC\2=O)=C1OC SDORKXKUPWJUFE-YFHOEESVSA-N 0.000 claims description 4
- ATVKSANJAPEZRZ-YHYXMXQVSA-N (3z)-5-bromo-3-[(5-methyl-1h-imidazol-4-yl)methylidene]-1h-indol-2-one Chemical compound N1=CNC(\C=C/2C3=CC(Br)=CC=C3NC\2=O)=C1C ATVKSANJAPEZRZ-YHYXMXQVSA-N 0.000 claims description 4
- GZSXMGUALNRWHL-XFXZXTDPSA-N (3z)-5-ethynyl-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=CC(=CC=C3NC\2=O)C#C)=C1OC GZSXMGUALNRWHL-XFXZXTDPSA-N 0.000 claims description 4
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 claims description 4
- QBVALIXKYOFQGQ-UHFFFAOYSA-N CC=1N=CNC1C=C1/C(N(C2=CC=C(C=C12)[Si](C)(C)C)C#C)=O Chemical compound CC=1N=CNC1C=C1/C(N(C2=CC=C(C=C12)[Si](C)(C)C)C#C)=O QBVALIXKYOFQGQ-UHFFFAOYSA-N 0.000 claims description 4
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Natural products COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 claims description 4
- PTXMJHSJWXPRSV-UHFFFAOYSA-N N1C(=CC=C1)C=C1/C(N(C2=CC=C(C=C12)C=1SC=CC1)C#C)=O Chemical compound N1C(=CC=C1)C=C1/C(N(C2=CC=C(C=C12)C=1SC=CC1)C#C)=O PTXMJHSJWXPRSV-UHFFFAOYSA-N 0.000 claims description 4
- 239000002207 metabolite Substances 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- PVZQFACHIBRALC-UYRXBGFRSA-N (3Z)-1-ethynyl-5-(3-hydroxyphenyl)-3-(1H-pyrrol-2-ylmethylidene)indol-2-one Chemical compound OC=1C=C(C=CC1)C=1C=C2/C(/C(N(C2=CC1)C#C)=O)=C/C=1NC=CC1 PVZQFACHIBRALC-UYRXBGFRSA-N 0.000 claims description 3
- QZKVAZAVEPWSMG-UYRXBGFRSA-N (3Z)-1-ethynyl-5-(3-nitrophenyl)-3-(1H-pyrrol-2-ylmethylidene)indol-2-one Chemical compound [N+](=O)([O-])C=1C=C(C=CC1)C=1C=C2/C(/C(N(C2=CC1)C#C)=O)=C/C=1NC=CC1 QZKVAZAVEPWSMG-UYRXBGFRSA-N 0.000 claims description 3
- XJTVTRHINXLJJY-ZHZULCJRSA-N (3Z)-1-ethynyl-5-(4-methoxyphenyl)-3-(1H-pyrrol-2-ylmethylidene)indol-2-one Chemical compound COC1=CC=C(C=C1)C=1C=C2/C(/C(N(C2=CC1)C#C)=O)=C/C=1NC=CC1 XJTVTRHINXLJJY-ZHZULCJRSA-N 0.000 claims description 3
- XKJWZNUOYVREGV-UYRXBGFRSA-N (3Z)-5-(4-aminophenyl)-1-ethynyl-3-(1H-pyrrol-2-ylmethylidene)indol-2-one Chemical compound NC1=CC=C(C=C1)C=1C=C2/C(/C(N(C2=CC1)C#C)=O)=C/C=1NC=CC1 XKJWZNUOYVREGV-UYRXBGFRSA-N 0.000 claims description 3
- YOXOAFPXWNTVIV-AQTBWJFISA-N (3z)-1-ethynyl-5-(4-hydroxyphenyl)-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]indol-2-one Chemical compound C1=CNC(\C=C/2C3=CC(=CC=C3N(C#C)C\2=O)C=2C=CC(O)=CC=2)=C1OC YOXOAFPXWNTVIV-AQTBWJFISA-N 0.000 claims description 3
- LFSKVYQOHAAGQB-VKAVYKQESA-N (3z)-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-4-(2-phenylethynyl)-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC=4C=CC=CC=4)C=CC=C3NC\2=O)=C1OC LFSKVYQOHAAGQB-VKAVYKQESA-N 0.000 claims description 3
- SOYFKPDKCDIHMW-SSZFMOIBSA-N (3z)-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-4-(2-pyridin-4-ylethynyl)-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC=4C=CN=CC=4)C=CC=C3NC\2=O)=C1OC SOYFKPDKCDIHMW-SSZFMOIBSA-N 0.000 claims description 3
- IZXHJFBVDXOSDL-VKAVYKQESA-N (3z)-4-(3-hydroxy-3-phenylprop-1-ynyl)-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC(O)C=4C=CC=CC=4)C=CC=C3NC\2=O)=C1OC IZXHJFBVDXOSDL-VKAVYKQESA-N 0.000 claims description 3
- PXCCQARRVLKNIM-SQFISAMPSA-N (3z)-4-(3-hydroxy-3-pyridin-2-ylprop-1-ynyl)-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC(O)C=4N=CC=CC=4)C=CC=C3NC\2=O)=C1OC PXCCQARRVLKNIM-SQFISAMPSA-N 0.000 claims description 3
- GIGNTIVPOROLOI-VBKFSLOCSA-N (3z)-4-(3-hydroxy-3-pyridin-3-ylprop-1-ynyl)-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC(O)C=4C=NC=CC=4)C=CC=C3NC\2=O)=C1OC GIGNTIVPOROLOI-VBKFSLOCSA-N 0.000 claims description 3
- DTCDOONGFRBLDF-PAAQWSFZSA-N (3z)-4-[(e)-2-(4-methoxyphenyl)ethenyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(\C=C\C=4C=CC(OC)=CC=4)C=CC=C3NC\2=O)=C1OC DTCDOONGFRBLDF-PAAQWSFZSA-N 0.000 claims description 3
- COGFBJXZPOJDJS-JXAWBTAJSA-N (3z)-4-[2-(4-methoxyphenyl)ethynyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC=4C=CC(OC)=CC=4)C=CC=C3NC\2=O)=C1OC COGFBJXZPOJDJS-JXAWBTAJSA-N 0.000 claims description 3
- WXWYYUPZZCUBKY-PYCFMQQDSA-N (3z)-4-[3-[4-[3-(dimethylamino)propoxy]phenyl]-3-hydroxyprop-1-ynyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC(O)C=4C=CC(OCCCN(C)C)=CC=4)C=CC=C3NC\2=O)=C1OC WXWYYUPZZCUBKY-PYCFMQQDSA-N 0.000 claims description 3
- YRXDNKVXUTYODU-SQFISAMPSA-N (3z)-4-[3-hydroxy-3-(1-methylpyrrol-2-yl)prop-1-ynyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC(O)C=4N(C=CC=4)C)C=CC=C3NC\2=O)=C1OC YRXDNKVXUTYODU-SQFISAMPSA-N 0.000 claims description 3
- RRCHGUVCSGQAPF-LGMDPLHJSA-N (3z)-4-[3-hydroxy-3-(4-hydroxyphenyl)prop-1-ynyl]-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-1h-indol-2-one Chemical compound C1=CNC(\C=C/2C3=C(C#CC(O)C=4C=CC(O)=CC=4)C=CC=C3NC\2=O)=C1OC RRCHGUVCSGQAPF-LGMDPLHJSA-N 0.000 claims description 3
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 3
- 150000005840 aryl radicals Chemical class 0.000 claims description 3
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- RZTFYTLJOXSQKQ-PAAQWSFZSA-N methyl 4-[(e)-2-[(3z)-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-2-oxo-1h-indol-4-yl]ethenyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1\C=C\C1=CC=CC(NC\2=O)=C1C/2=C/C1=C(OC)C=CN1 RZTFYTLJOXSQKQ-PAAQWSFZSA-N 0.000 claims description 3
- WNPUJTJJHQVVHZ-RGEXLXHISA-N n-[4-[1-hydroxy-3-[(3z)-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-2-oxo-1h-indol-4-yl]prop-2-ynyl]phenyl]acetamide Chemical compound C1=CNC(\C=C/2C3=C(C#CC(O)C=4C=CC(NC(C)=O)=CC=4)C=CC=C3NC\2=O)=C1OC WNPUJTJJHQVVHZ-RGEXLXHISA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- STIWOYHKYURXLZ-LGMDPLHJSA-N (3Z)-1-ethynyl-5-pyridin-2-yl-3-(1H-pyrrol-2-ylmethylidene)indol-2-one Chemical compound N1=C(C=CC=C1)C=1C=C2/C(/C(N(C2=CC1)C#C)=O)=C/C=1NC=CC1 STIWOYHKYURXLZ-LGMDPLHJSA-N 0.000 claims description 2
- RNBIKCQNFKTTBX-PDGQHHTCSA-N (3Z)-1-ethynyl-5-pyridin-3-yl-3-(1H-pyrrol-2-ylmethylidene)indol-2-one Chemical compound N1=CC(=CC=C1)C=1C=C2/C(/C(N(C2=CC1)C#C)=O)=C/C=1NC=CC1 RNBIKCQNFKTTBX-PDGQHHTCSA-N 0.000 claims description 2
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- 235000011090 malic acid Nutrition 0.000 description 1
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- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 1
- RWMOHADUIRDVJN-UHFFFAOYSA-N methyl 4-(1-hydroxyprop-2-ynyl)benzoate Chemical compound COC(=O)C1=CC=C(C(O)C#C)C=C1 RWMOHADUIRDVJN-UHFFFAOYSA-N 0.000 description 1
- JYQHZYNJTJQVKS-JXAWBTAJSA-N methyl 4-[1-hydroxy-3-[(3z)-3-[(3-methoxy-1h-pyrrol-2-yl)methylidene]-2-oxo-1h-indol-4-yl]prop-2-ynyl]benzoate Chemical compound C1=CC(C(=O)OC)=CC=C1C(O)C#CC1=CC=CC(NC\2=O)=C1C/2=C/C1=C(OC)C=CN1 JYQHZYNJTJQVKS-JXAWBTAJSA-N 0.000 description 1
- FEIOASZZURHTHB-UHFFFAOYSA-N methyl 4-formylbenzoate Chemical compound COC(=O)C1=CC=C(C=O)C=C1 FEIOASZZURHTHB-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 238000002156 mixing Methods 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 229940105132 myristate Drugs 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 230000027405 negative regulation of phosphorylation Effects 0.000 description 1
- 230000004770 neurodegeneration Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 201000008968 osteosarcoma Diseases 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 150000005623 oxindoles Chemical class 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- SEVSMVUOKAMPDO-UHFFFAOYSA-N para-Acetoxybenzaldehyde Natural products CC(=O)OC1=CC=C(C=O)C=C1 SEVSMVUOKAMPDO-UHFFFAOYSA-N 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
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- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 230000000865 phosphorylative effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 229940081310 piperonal Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- VYXXMAGSIYIYGD-NWAYQTQBSA-N propan-2-yl 2-[[[(2R)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(pyrimidine-4-carbonylamino)phosphoryl]amino]-2-methylpropanoate Chemical compound CC(C)OC(=O)C(C)(C)NP(=O)(CO[C@H](C)Cn1cnc2c(N)ncnc12)NC(=O)c1ccncn1 VYXXMAGSIYIYGD-NWAYQTQBSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
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- 239000011877 solvent mixture Substances 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- TUNFSRHWOTWDNC-UHFFFAOYSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000011144 upstream manufacturing Methods 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
- C07D401/14—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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]
-
- 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
- C07D403/06—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 carbon chain containing only aliphatic carbon atoms
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Rheumatology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Indole Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US11258998P | 1998-12-17 | 1998-12-17 | |
| US112589P | 1998-12-17 | ||
| US14148299P | 1999-06-29 | 1999-06-29 | |
| US141482P | 2008-12-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2209527T3 true ES2209527T3 (es) | 2004-06-16 |
Family
ID=26810125
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES99957341T Expired - Lifetime ES2209527T3 (es) | 1998-12-17 | 1999-12-07 | "44- y 5-alquiniloxindolels y 4- y 5-alqueniloxindones. |
Country Status (14)
| Country | Link |
|---|---|
| EP (1) | EP1149092B1 (enExample) |
| JP (1) | JP2002532490A (enExample) |
| KR (1) | KR20010087421A (enExample) |
| CN (1) | CN1147486C (enExample) |
| AT (1) | ATE253062T1 (enExample) |
| AU (1) | AU771599B2 (enExample) |
| BR (1) | BR9916272A (enExample) |
| CA (1) | CA2354510A1 (enExample) |
| DE (1) | DE69912479T2 (enExample) |
| DK (1) | DK1149092T3 (enExample) |
| ES (1) | ES2209527T3 (enExample) |
| PT (1) | PT1149092E (enExample) |
| TR (1) | TR200101747T2 (enExample) |
| WO (1) | WO2000035906A2 (enExample) |
Families Citing this family (28)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6569868B2 (en) | 1998-04-16 | 2003-05-27 | Sugen, Inc. | 2-indolinone derivatives as modulators of protein kinase activity |
| MY128450A (en) | 2000-05-24 | 2007-02-28 | Upjohn Co | 1-(pyrrolidin-1-ylmethyl)-3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives |
| EP1294688A2 (en) | 2000-06-02 | 2003-03-26 | Sugen, Inc. | Indolinone derivatives as protein kinase/phosphatase inhibitors |
| CA2414468A1 (en) * | 2000-06-30 | 2002-01-10 | Sugen, Inc. | 4-heteroaryl-3-heteroarylidenyl-2-indolinones and their use as protein kinase inhibitors |
| AU2002255263B2 (en) | 2001-04-16 | 2006-12-14 | Eisai R&D Management Co., Ltd. | Novel 1H-indazole compound |
| US7018999B2 (en) | 2001-05-16 | 2006-03-28 | Cephalon, Inc. | Methods for the treatment and prevention of pain |
| US6599902B2 (en) | 2001-05-30 | 2003-07-29 | Sugen, Inc. | 5-aralkysufonyl-3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives as kinase inhibitors |
| ATE419247T1 (de) | 2001-07-23 | 2009-01-15 | Serono Lab | Arylsulfonamidderivate als hemmer c-jun- terminaler kinasen (jnk) |
| MXPA04002537A (es) * | 2001-10-12 | 2004-05-31 | Warner Lambert Co | Alquinos como inhibidores de metaloproteinasa de matriz. |
| US6962922B2 (en) | 2001-10-12 | 2005-11-08 | Warner-Lambert Company Llc | Alkynylated quinazoline compounds |
| DE60332215D1 (de) | 2002-02-28 | 2010-06-02 | Eisai R&D Man Co Ltd | Neue indazolverbindungen mit kondensiertem ring |
| US6747147B2 (en) | 2002-03-08 | 2004-06-08 | Warner-Lambert Company | Oxo-azabicyclic compounds |
| US6894057B2 (en) | 2002-03-08 | 2005-05-17 | Warner-Lambert Company | Oxo-azabicyclic compounds |
| IL164209A0 (en) | 2002-05-31 | 2005-12-18 | Eisai Co Ltd | Pyrazole derivatives and pharmaceutical compositions containing the same |
| CA2487948A1 (en) | 2002-06-14 | 2003-12-24 | Applied Research Systems Ars Holding N.V. | Azole methylidene cyanide derivatives and their use as protein kinase modulators |
| BRPI0415773A (pt) | 2003-10-24 | 2006-12-26 | Schering Ag | derivados de indolinona e sua aplicação no tratamento de estados de doença tais como cáncer |
| DE102004012070A1 (de) * | 2004-03-12 | 2005-09-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue cycloalkyl-haltige 5-Acylindolinone, deren Herstellung und deren Verwendung als Arzneimittel |
| US7803824B2 (en) | 2004-10-29 | 2010-09-28 | Alcon, Inc. | Use of inhibitors of Jun N-terminal kinases to treat glaucoma |
| US20060094753A1 (en) | 2004-10-29 | 2006-05-04 | Alcon, Inc. | Use of inhibitors of Jun N-terminal kinases for the treatment of glaucomatous retinopathy and ocular diseases |
| WO2006090698A1 (ja) * | 2005-02-22 | 2006-08-31 | Ono Pharmaceutical Co., Ltd. | キナーゼ阻害薬およびその用途 |
| KR20080044836A (ko) | 2005-07-15 | 2008-05-21 | 라보라뚜와르 세로노 에스. 에이. | 자궁내막증 치료용 jnk 억제제 |
| BRPI0613042A2 (pt) | 2005-07-15 | 2010-12-14 | Serono Lab | inibidores de jnk para o tratamento de endometriose |
| CN1939922B (zh) * | 2005-09-27 | 2010-10-13 | 天津和美生物技术有限公司 | 可抑制细胞释放肿瘤坏死因子的5H-噻吩[3,4-c]吡咯-4,6-二酮衍生物 |
| US7968572B2 (en) | 2005-10-03 | 2011-06-28 | Ono Pharmaceuticals Co., Ltd. | Nitrogen-containing heterocyclic compound and pharmaceutical application thereof |
| FR2962733B1 (fr) | 2010-07-13 | 2012-08-17 | Michelin Soc Tech | Polymere greffe par des molecules associatives azotees. |
| FR2962729B1 (fr) | 2010-07-13 | 2012-09-21 | Arkema France | Molecules porteuses de groupes associatifs |
| WO2012178015A2 (en) * | 2011-06-24 | 2012-12-27 | Zenobia Therapeutics, Inc. | Lrrk2 inhibitors |
| JP7270590B2 (ja) | 2019-11-27 | 2023-05-10 | 財團法人工業技術研究院 | 自己発電式検出送信装置 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9501567D0 (en) * | 1995-01-26 | 1995-03-15 | Pharmacia Spa | Hydrosoluble 3-arylidene-2-oxindole derivatives as tyrosine kinase inhibitors |
| GB9507298D0 (en) * | 1995-04-07 | 1995-05-31 | Pharmacia Spa | Substituted indolylmethylene-oxindale analogues as tyrosine kinase inhibitors |
| US5880141A (en) * | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
| GB9610964D0 (en) * | 1996-05-24 | 1996-07-31 | Pharmacia & Upjohn Spa | Substituted tetralylmethylen-oxindole analogues as tyrosine kinase inhibitors |
| ATE308520T1 (de) * | 1996-08-23 | 2005-11-15 | Sugen Inc | Kombinatorische bibliotheken von indolinone und verwandte produkte und verfahren zur behandlung von krankheiten |
| EP0984930B1 (en) * | 1997-05-07 | 2005-04-06 | Sugen, Inc. | 2-indolinone derivatives as modulators of protein kinase activity |
-
1999
- 1999-12-07 DE DE69912479T patent/DE69912479T2/de not_active Expired - Fee Related
- 1999-12-07 WO PCT/EP1999/009578 patent/WO2000035906A2/en not_active Ceased
- 1999-12-07 CA CA002354510A patent/CA2354510A1/en not_active Abandoned
- 1999-12-07 BR BR9916272-5A patent/BR9916272A/pt not_active IP Right Cessation
- 1999-12-07 EP EP99957341A patent/EP1149092B1/en not_active Expired - Lifetime
- 1999-12-07 AT AT99957341T patent/ATE253062T1/de not_active IP Right Cessation
- 1999-12-07 JP JP2000588166A patent/JP2002532490A/ja active Pending
- 1999-12-07 KR KR1020017007552A patent/KR20010087421A/ko not_active Ceased
- 1999-12-07 CN CNB998146994A patent/CN1147486C/zh not_active Expired - Fee Related
- 1999-12-07 PT PT99957341T patent/PT1149092E/pt unknown
- 1999-12-07 AU AU15076/00A patent/AU771599B2/en not_active Ceased
- 1999-12-07 DK DK99957341T patent/DK1149092T3/da active
- 1999-12-07 ES ES99957341T patent/ES2209527T3/es not_active Expired - Lifetime
- 1999-12-07 TR TR2001/01747T patent/TR200101747T2/xx unknown
Also Published As
| Publication number | Publication date |
|---|---|
| WO2000035906A2 (en) | 2000-06-22 |
| EP1149092B1 (en) | 2003-10-29 |
| WO2000035906A3 (en) | 2000-11-09 |
| CN1147486C (zh) | 2004-04-28 |
| CN1331689A (zh) | 2002-01-16 |
| DK1149092T3 (da) | 2004-02-23 |
| EP1149092A2 (en) | 2001-10-31 |
| BR9916272A (pt) | 2001-09-04 |
| DE69912479T2 (de) | 2004-07-22 |
| AU771599B2 (en) | 2004-03-25 |
| KR20010087421A (ko) | 2001-09-15 |
| CA2354510A1 (en) | 2000-06-22 |
| DE69912479D1 (de) | 2003-12-04 |
| TR200101747T2 (tr) | 2001-11-21 |
| JP2002532490A (ja) | 2002-10-02 |
| AU1507600A (en) | 2000-07-03 |
| ATE253062T1 (de) | 2003-11-15 |
| PT1149092E (pt) | 2004-03-31 |
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