SK12112001A3 - 4-amino-chinazolínové a chinolínové deriváty, spôsob ich prípravy, farmaceutický prostriedok s ich obsahom a ich použitie - Google Patents
4-amino-chinazolínové a chinolínové deriváty, spôsob ich prípravy, farmaceutický prostriedok s ich obsahom a ich použitie Download PDFInfo
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- SK12112001A3 SK12112001A3 SK1211-2001A SK12112001A SK12112001A3 SK 12112001 A3 SK12112001 A3 SK 12112001A3 SK 12112001 A SK12112001 A SK 12112001A SK 12112001 A3 SK12112001 A3 SK 12112001A3
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- Prior art keywords
- alkyl
- group
- substituted
- oxo
- amino
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- 229940027991 antiseptic and disinfectant quinoline derivative Drugs 0.000 title claims description 22
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical compound C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 title claims description 22
- 150000005011 4-aminoquinolines Chemical class 0.000 title claims description 17
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 title abstract description 10
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 title abstract description 10
- 230000002401 inhibitory effect Effects 0.000 title abstract description 8
- 230000001404 mediated effect Effects 0.000 title abstract description 6
- 230000019491 signal transduction Effects 0.000 title abstract description 4
- 238000002360 preparation method Methods 0.000 claims abstract description 42
- 150000003839 salts Chemical class 0.000 claims abstract description 39
- -1 trifluoromethylsulfenyl Chemical group 0.000 claims description 719
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 413
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 357
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 250
- 125000000217 alkyl group Chemical group 0.000 claims description 206
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 158
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 111
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 107
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 101
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 93
- 125000004432 carbon atom Chemical group C* 0.000 claims description 84
- 125000002947 alkylene group Chemical group 0.000 claims description 76
- 229910052799 carbon Inorganic materials 0.000 claims description 74
- 150000001875 compounds Chemical class 0.000 claims description 74
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 66
- 125000003386 piperidinyl group Chemical group 0.000 claims description 66
- 150000001721 carbon Chemical group 0.000 claims description 58
- 238000006243 chemical reaction Methods 0.000 claims description 58
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 58
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 58
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 56
- 125000004634 hexahydroazepinyl group Chemical group N1(CCCCCC1)* 0.000 claims description 55
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 54
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 52
- 229910052757 nitrogen Inorganic materials 0.000 claims description 52
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 46
- 229910052760 oxygen Inorganic materials 0.000 claims description 44
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 43
- 239000001301 oxygen Substances 0.000 claims description 43
- 229910052717 sulfur Inorganic materials 0.000 claims description 43
- 125000004434 sulfur atom Chemical group 0.000 claims description 43
- 125000003118 aryl group Chemical group 0.000 claims description 42
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 42
- 229910052801 chlorine Inorganic materials 0.000 claims description 42
- 229910052731 fluorine Inorganic materials 0.000 claims description 42
- 239000001257 hydrogen Substances 0.000 claims description 41
- 229910052739 hydrogen Inorganic materials 0.000 claims description 41
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 40
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 39
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 39
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 38
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 38
- 239000011737 fluorine Substances 0.000 claims description 38
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 38
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 38
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 34
- 239000000460 chlorine Substances 0.000 claims description 33
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 32
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 30
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 29
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 29
- 239000000126 substance Substances 0.000 claims description 29
- 125000003277 amino group Chemical group 0.000 claims description 26
- 125000003545 alkoxy group Chemical group 0.000 claims description 24
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 24
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 24
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 24
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 23
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 23
- 125000004122 cyclic group Chemical group 0.000 claims description 22
- 229910052740 iodine Inorganic materials 0.000 claims description 22
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 22
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 21
- 229910052794 bromium Inorganic materials 0.000 claims description 21
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 21
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 21
- 125000001072 heteroaryl group Chemical group 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 15
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- 239000002585 base Substances 0.000 claims description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 11
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 125000005199 aryl carbonyloxy group Chemical group 0.000 claims description 10
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 9
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 9
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 9
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 9
- 125000005002 aryl methyl group Chemical group 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 7
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 claims description 7
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 6
- FOUZISDNESEYLX-UHFFFAOYSA-N 2-(2-hydroxyethylazaniumyl)acetate Chemical class OCCNCC(O)=O FOUZISDNESEYLX-UHFFFAOYSA-N 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 6
- 125000002883 imidazolyl group Chemical group 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 230000029936 alkylation Effects 0.000 claims description 5
- 238000005804 alkylation reaction Methods 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 5
- 238000003402 intramolecular cyclocondensation reaction Methods 0.000 claims description 5
- 150000003248 quinolines Chemical class 0.000 claims description 5
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 4
- 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- 125000003342 alkenyl group Chemical group 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 4
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 208000023504 respiratory system disease Diseases 0.000 claims description 4
- 125000004760 (C1-C4) alkylsulfonylamino group Chemical group 0.000 claims description 3
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 3
- 208000019693 Lung disease Diseases 0.000 claims description 3
- 208000037062 Polyps Diseases 0.000 claims description 3
- 230000010933 acylation Effects 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 claims description 3
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- AMHKPXOWCSHZAD-UHFFFAOYSA-N ethyl 2-[3-[4-(3-bromoanilino)-6-(prop-2-enoylamino)quinazolin-7-yl]oxypropyl-methylamino]acetate Chemical compound C=12C=C(NC(=O)C=C)C(OCCCN(C)CC(=O)OCC)=CC2=NC=NC=1NC1=CC=CC(Br)=C1 AMHKPXOWCSHZAD-UHFFFAOYSA-N 0.000 claims description 3
- FFIXXGYSMLZUIC-UHFFFAOYSA-N ethyl 2-[4-[4-(3-bromoanilino)-6-(prop-2-enoylamino)quinazolin-7-yl]oxypiperidin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCC1OC1=CC2=NC=NC(NC=3C=C(Br)C=CC=3)=C2C=C1NC(=O)C=C FFIXXGYSMLZUIC-UHFFFAOYSA-N 0.000 claims description 3
- PQFBMYDNUKQCCE-UHFFFAOYSA-N ethyl 2-[[4-[[4-(3-bromoanilino)quinazolin-6-yl]amino]-4-oxobut-2-enyl]-methylamino]acetate Chemical compound C12=CC(NC(=O)C=CCN(C)CC(=O)OCC)=CC=C2N=CN=C1NC1=CC=CC(Br)=C1 PQFBMYDNUKQCCE-UHFFFAOYSA-N 0.000 claims description 3
- 150000002466 imines Chemical class 0.000 claims description 3
- NRNNQOZJUUDVME-UHFFFAOYSA-N n-[4-(3-bromoanilino)-7-methoxyquinazolin-6-yl]-4-[diethoxyphosphorylmethyl(methyl)amino]but-2-enamide Chemical compound N1=CN=C2C=C(OC)C(NC(=O)C=CCN(C)CP(=O)(OCC)OCC)=CC2=C1NC1=CC=CC(Br)=C1 NRNNQOZJUUDVME-UHFFFAOYSA-N 0.000 claims description 3
- 230000008569 process Effects 0.000 claims description 3
- 238000005932 reductive alkylation reaction Methods 0.000 claims description 3
- 230000006103 sulfonylation Effects 0.000 claims description 3
- 238000005694 sulfonylation reaction Methods 0.000 claims description 3
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 2
- ILFIRBGRMCGNOO-UHFFFAOYSA-N 1,1-bis($l^{1}-oxidanyl)ethene Chemical group [O]C([O])=C ILFIRBGRMCGNOO-UHFFFAOYSA-N 0.000 claims description 2
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 2
- PCURDZQUZDFDLH-UHFFFAOYSA-N 5-methylmorpholin-2-one Chemical compound CC1COC(=O)CN1 PCURDZQUZDFDLH-UHFFFAOYSA-N 0.000 claims description 2
- 101150065749 Churc1 gene Proteins 0.000 claims description 2
- 102100038239 Protein Churchill Human genes 0.000 claims description 2
- 125000004442 acylamino group Chemical group 0.000 claims description 2
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 2
- UPNOBGDLKMEMDK-UHFFFAOYSA-N ethyl 2-[[4-[[4-(3-bromoanilino)-3-cyanoquinolin-6-yl]amino]-4-oxobut-2-enyl]-methylamino]acetate Chemical compound C12=CC(NC(=O)C=CCN(C)CC(=O)OCC)=CC=C2N=CC(C#N)=C1NC1=CC=CC(Br)=C1 UPNOBGDLKMEMDK-UHFFFAOYSA-N 0.000 claims description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 2
- 208000020694 gallbladder disease Diseases 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 230000000241 respiratory effect Effects 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims 5
- KAKZBPTYRLMSJV-UHFFFAOYSA-N Butadiene Chemical compound C=CC=C KAKZBPTYRLMSJV-UHFFFAOYSA-N 0.000 claims 2
- 125000000304 alkynyl group Chemical group 0.000 claims 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims 1
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims 1
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 claims 1
- XTFIVUDBNACUBN-UHFFFAOYSA-N 1,3,5-trinitro-1,3,5-triazinane Chemical compound [O-][N+](=O)N1CN([N+]([O-])=O)CN([N+]([O-])=O)C1 XTFIVUDBNACUBN-UHFFFAOYSA-N 0.000 claims 1
- ZQXCQTAELHSNAT-UHFFFAOYSA-N 1-chloro-3-nitro-5-(trifluoromethyl)benzene Chemical group [O-][N+](=O)C1=CC(Cl)=CC(C(F)(F)F)=C1 ZQXCQTAELHSNAT-UHFFFAOYSA-N 0.000 claims 1
- 150000005015 5-aminoquinolines Chemical class 0.000 claims 1
- 208000017283 Bile Duct disease Diseases 0.000 claims 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims 1
- 125000005196 alkyl carbonyloxy group Chemical group 0.000 claims 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims 1
- 125000005133 alkynyloxy group Chemical group 0.000 claims 1
- 210000000013 bile duct Anatomy 0.000 claims 1
- 125000005112 cycloalkylalkoxy group Chemical group 0.000 claims 1
- KTRMJZKBFCFXLV-UHFFFAOYSA-N ethyl 2-[4-[3-[4-(3-bromoanilino)-6-(prop-2-enoylamino)quinazolin-7-yl]oxypropyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CCCOC1=CC2=NC=NC(NC=3C=C(Br)C=CC=3)=C2C=C1NC(=O)C=C KTRMJZKBFCFXLV-UHFFFAOYSA-N 0.000 claims 1
- BPNFWFBXWNYDBI-UHFFFAOYSA-N ethyl 2-[4-[4-[[4-(3-chloro-4-fluoroanilino)-7-(2-cyclopropylethoxy)quinazolin-6-yl]amino]-4-oxobut-2-enyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CC=CC(=O)NC(C(=CC1=NC=N2)OCCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 BPNFWFBXWNYDBI-UHFFFAOYSA-N 0.000 claims 1
- JJSCHBLJDPABAO-UHFFFAOYSA-N ethyl 2-[4-[4-[[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]amino]-4-oxobut-2-enyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CC=CC(=O)NC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 JJSCHBLJDPABAO-UHFFFAOYSA-N 0.000 claims 1
- DGRIZWGJPVGWFU-GOSISDBHSA-N ethyl 2-[[4-[[7-methoxy-4-[[(1R)-1-phenylethyl]amino]quinazolin-6-yl]amino]-4-oxobut-2-enyl]-methylamino]acetate Chemical compound C1(=CC=CC=C1)[C@@H](C)NC1=NC=NC2=CC(=C(C=C12)NC(C=CCN(C)CC(=O)OCC)=O)OC DGRIZWGJPVGWFU-GOSISDBHSA-N 0.000 claims 1
- JOJZPSWIPNOVGD-UHFFFAOYSA-N ethyl 4-[4-[3-[4-(3-bromoanilino)-6-(prop-2-enoylamino)quinazolin-7-yl]oxypropyl]piperazin-1-yl]butanoate Chemical compound C1CN(CCCC(=O)OCC)CCN1CCCOC1=CC2=NC=NC(NC=3C=C(Br)C=CC=3)=C2C=C1NC(=O)C=C JOJZPSWIPNOVGD-UHFFFAOYSA-N 0.000 claims 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims 1
- 210000003734 kidney Anatomy 0.000 claims 1
- SCEZDJMDGXKLLA-DEOSSOPVSA-N methyl (2s)-1-[4-[[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]amino]-4-oxobut-2-enyl]pyrrolidine-2-carboxylate Chemical compound COC(=O)[C@@H]1CCCN1CC=CC(=O)NC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 SCEZDJMDGXKLLA-DEOSSOPVSA-N 0.000 claims 1
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 claims 1
- PJUPDYXOPGQSMN-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]-4-(2-oxomorpholin-4-yl)but-2-enamide Chemical compound C1=C(Cl)C(F)=CC=C1NC(C1=C2)=NC=NC1=CC(OCC1CC1)=C2NC(=O)C=CCN1CC(=O)OCC1 PJUPDYXOPGQSMN-UHFFFAOYSA-N 0.000 claims 1
- ZOOUDMWPZJXWEZ-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]-4-(5,5-dimethyl-2-oxomorpholin-4-yl)but-2-enamide Chemical compound CC1(C)COC(=O)CN1CC=CC(=O)NC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 ZOOUDMWPZJXWEZ-UHFFFAOYSA-N 0.000 claims 1
- 230000001681 protective effect Effects 0.000 claims 1
- KWHDQPVGKVPPPS-UHFFFAOYSA-N quinazolin-5-amine Chemical compound C1=NC=C2C(N)=CC=CC2=N1 KWHDQPVGKVPPPS-UHFFFAOYSA-N 0.000 claims 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 claims 1
- 201000010099 disease Diseases 0.000 abstract description 9
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- 150000007522 mineralic acids Chemical class 0.000 abstract description 3
- 150000007524 organic acids Chemical class 0.000 abstract description 3
- 235000005985 organic acids Nutrition 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract description 3
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- 125000002618 bicyclic heterocycle group Chemical group 0.000 abstract 1
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- 230000001173 tumoral effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 366
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 360
- 238000001819 mass spectrum Methods 0.000 description 230
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 228
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 125
- 239000000741 silica gel Substances 0.000 description 123
- 229910002027 silica gel Inorganic materials 0.000 description 123
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 98
- 238000002844 melting Methods 0.000 description 92
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- VHILCGLWRNUWCX-UHFFFAOYSA-N ethyl 2-[2-[[4-[[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]amino]-4-oxobut-2-enoyl]amino]ethyl-methylamino]acetate Chemical compound N1=CN=C2C=C(OCC3CC3)C(NC(=O)C=CC(=O)NCCN(C)CC(=O)OCC)=CC2=C1NC1=CC=C(F)C(Cl)=C1 VHILCGLWRNUWCX-UHFFFAOYSA-N 0.000 description 1
- JVRHHCMBBVUBBU-UHFFFAOYSA-N ethyl 2-[2-acetylsulfanylethyl-[4-[[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]amino]-4-oxobut-2-enyl]amino]acetate Chemical compound N1=CN=C2C=C(OCC3CC3)C(NC(=O)C=CCN(CCSC(C)=O)CC(=O)OCC)=CC2=C1NC1=CC=C(F)C(Cl)=C1 JVRHHCMBBVUBBU-UHFFFAOYSA-N 0.000 description 1
- RYPRJVDSCQDQDD-UHFFFAOYSA-N ethyl 2-[2-aminoethyl(methyl)amino]acetate;dihydrochloride Chemical compound Cl.Cl.CCOC(=O)CN(C)CCN RYPRJVDSCQDQDD-UHFFFAOYSA-N 0.000 description 1
- JEJOFKNLFXKXOK-UHFFFAOYSA-N ethyl 2-[3-[[4-[[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]amino]-4-oxobut-2-enoyl]amino]propyl-methylamino]acetate Chemical compound N1=CN=C2C=C(OCC3CC3)C(NC(=O)C=CC(=O)NCCCN(C)CC(=O)OCC)=CC2=C1NC1=CC=C(F)C(Cl)=C1 JEJOFKNLFXKXOK-UHFFFAOYSA-N 0.000 description 1
- PKRHKOHFXJRGKG-UHFFFAOYSA-N ethyl 2-[3-aminopropyl(methyl)amino]acetate Chemical compound CCOC(=O)CN(C)CCCN PKRHKOHFXJRGKG-UHFFFAOYSA-N 0.000 description 1
- LKNFTQFQVQSQEO-UHFFFAOYSA-N ethyl 2-[3-aminopropyl(methyl)amino]acetate;hydrochloride Chemical compound Cl.CCOC(=O)CN(C)CCCN LKNFTQFQVQSQEO-UHFFFAOYSA-N 0.000 description 1
- YMPDDUHUROBCDR-UHFFFAOYSA-N ethyl 2-[4-[2-[4-(3-bromoanilino)-6-(prop-2-enoylamino)quinazolin-7-yl]oxyethyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CCOC1=CC2=NC=NC(NC=3C=C(Br)C=CC=3)=C2C=C1NC(=O)C=C YMPDDUHUROBCDR-UHFFFAOYSA-N 0.000 description 1
- ZNXQYJSAMGQEGB-UHFFFAOYSA-N ethyl 2-[4-[2-[4-(3-bromoanilino)-6-(prop-2-enoylamino)quinazolin-7-yl]oxyethyl]piperidin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCC1CCOC1=CC2=NC=NC(NC=3C=C(Br)C=CC=3)=C2C=C1NC(=O)C=C ZNXQYJSAMGQEGB-UHFFFAOYSA-N 0.000 description 1
- KCCAWYZBBXTJQB-UHFFFAOYSA-N ethyl 2-[4-[3-[4-(3-bromoanilino)-6-(prop-2-enoylamino)quinazolin-7-yl]oxypropyl]piperidin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCC1CCCOC1=CC2=NC=NC(NC=3C=C(Br)C=CC=3)=C2C=C1NC(=O)C=C KCCAWYZBBXTJQB-UHFFFAOYSA-N 0.000 description 1
- ZLZMJYPHTIAXPJ-UHFFFAOYSA-N ethyl 2-[4-[3-[4-(3-bromoanilino)-6-nitroquinazolin-7-yl]oxypropyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CCCOC1=CC2=NC=NC(NC=3C=C(Br)C=CC=3)=C2C=C1[N+]([O-])=O ZLZMJYPHTIAXPJ-UHFFFAOYSA-N 0.000 description 1
- RWDMVHRLMZSUAE-UHFFFAOYSA-N ethyl 2-[4-[3-[4-(3-bromoanilino)-6-nitroquinazolin-7-yl]oxypropyl]piperidin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCC1CCCOC1=CC2=NC=NC(NC=3C=C(Br)C=CC=3)=C2C=C1[N+]([O-])=O RWDMVHRLMZSUAE-UHFFFAOYSA-N 0.000 description 1
- DULYCHNMGDEOJZ-UHFFFAOYSA-N ethyl 2-[4-[3-[6-amino-4-(3-bromoanilino)quinazolin-7-yl]oxypropyl]piperidin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCC1CCCOC1=CC2=NC=NC(NC=3C=C(Br)C=CC=3)=C2C=C1N DULYCHNMGDEOJZ-UHFFFAOYSA-N 0.000 description 1
- OJUDLLJABZXMPR-UHFFFAOYSA-N ethyl 2-[4-[4-(3-bromoanilino)-6-nitroquinazolin-7-yl]oxypiperidin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCC1OC1=CC2=NC=NC(NC=3C=C(Br)C=CC=3)=C2C=C1[N+]([O-])=O OJUDLLJABZXMPR-UHFFFAOYSA-N 0.000 description 1
- IXMHOHPRRMXREX-UHFFFAOYSA-N ethyl 2-[4-[4-[[4-(3-chloro-4-fluoroanilino)-7-cyclobutyloxyquinazolin-6-yl]amino]-4-oxobut-2-enyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CC=CC(=O)NC(C(=CC1=NC=N2)OC3CCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 IXMHOHPRRMXREX-UHFFFAOYSA-N 0.000 description 1
- HJPONFOAJXWWKY-UHFFFAOYSA-N ethyl 2-[4-[4-[[4-(3-chloro-4-fluoroanilino)-7-cyclohexyloxyquinazolin-6-yl]amino]-4-oxobut-2-enyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CC=CC(=O)NC(C(=CC1=NC=N2)OC3CCCCC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 HJPONFOAJXWWKY-UHFFFAOYSA-N 0.000 description 1
- XGNGUAWIHWAMJK-UHFFFAOYSA-N ethyl 2-[4-[4-[[4-(benzylamino)-7-(cyclopropylmethoxy)quinazolin-6-yl]amino]-4-oxobut-2-enyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CC=CC(=O)NC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NCC1=CC=CC=C1 XGNGUAWIHWAMJK-UHFFFAOYSA-N 0.000 description 1
- JPNGMAALPMWHET-HSZRJFAPSA-N ethyl 2-[4-[4-[[7-cyclobutyloxy-4-[[(1R)-1-phenylethyl]amino]quinazolin-6-yl]amino]-4-oxobut-2-enyl]piperazin-1-yl]acetate Chemical compound C1(=CC=CC=C1)[C@@H](C)NC1=NC=NC2=CC(=C(C=C12)NC(C=CCN1CCN(CC1)CC(=O)OCC)=O)OC1CCC1 JPNGMAALPMWHET-HSZRJFAPSA-N 0.000 description 1
- XWMPORAIHQIJSL-XMMPIXPASA-N ethyl 2-[4-[4-[[7-cyclopentyloxy-4-[[(1r)-1-phenylethyl]amino]quinazolin-6-yl]amino]-4-oxobut-2-enyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CC=CC(=O)NC(C(=CC1=NC=N2)OC3CCCC3)=CC1=C2N[C@H](C)C1=CC=CC=C1 XWMPORAIHQIJSL-XMMPIXPASA-N 0.000 description 1
- KHTSJLGRAJHXIZ-UHFFFAOYSA-N ethyl 2-[4-[5-[[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]amino]-2-methyl-5-oxopent-3-en-2-yl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1C(C)(C)C=CC(=O)NC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 KHTSJLGRAJHXIZ-UHFFFAOYSA-N 0.000 description 1
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- LGDDMCQQGKGJOQ-UHFFFAOYSA-N ethyl 2-[4-[[4-(3-bromoanilino)-6-nitroquinazolin-7-yl]oxymethyl]piperidin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCC1COC1=CC2=NC=NC(NC=3C=C(Br)C=CC=3)=C2C=C1[N+]([O-])=O LGDDMCQQGKGJOQ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- 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
- C07D401/02—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 two hetero rings
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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- 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
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- 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
- C07D405/02—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 two hetero rings
- C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Urology & Nephrology (AREA)
- Gastroenterology & Hepatology (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE1999108567 DE19908567A1 (de) | 1999-02-27 | 1999-02-27 | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
DE1999111366 DE19911366A1 (de) | 1999-03-15 | 1999-03-15 | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
DE1999128306 DE19928306A1 (de) | 1999-06-21 | 1999-06-21 | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
US14932999P | 1999-08-17 | 1999-08-17 | |
DE19954816A DE19954816A1 (de) | 1999-11-13 | 1999-11-13 | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
PCT/EP2000/001496 WO2000051991A1 (en) | 1999-02-27 | 2000-02-24 | 4-AMINO-QUINAZOLINE AND QUINOLINE DERIVATIVES HAVING AN INHIBITORY EFFECT ON SIGNAL TRANsSDUCTION MEDIATED BY TYROSINE KINASES |
Publications (1)
Publication Number | Publication Date |
---|---|
SK12112001A3 true SK12112001A3 (sk) | 2001-12-03 |
Family
ID=27512681
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SK1211-2001A SK12112001A3 (sk) | 1999-02-27 | 2000-02-24 | 4-amino-chinazolínové a chinolínové deriváty, spôsob ich prípravy, farmaceutický prostriedok s ich obsahom a ich použitie |
Country Status (21)
Country | Link |
---|---|
US (1) | US6972288B1 (cs) |
EP (2) | EP2298746A1 (cs) |
JP (1) | JP3751201B2 (cs) |
KR (1) | KR20020068261A (cs) |
CN (1) | CN1341104A (cs) |
AU (1) | AU3281600A (cs) |
BG (1) | BG105765A (cs) |
BR (1) | BR0008524A (cs) |
CA (1) | CA2361174C (cs) |
CZ (1) | CZ20013079A3 (cs) |
EE (1) | EE200100449A (cs) |
HR (1) | HRP20010617A2 (cs) |
HU (1) | HUP0301132A3 (cs) |
ID (1) | ID29800A (cs) |
IL (1) | IL144143A0 (cs) |
NO (1) | NO20014114L (cs) |
NZ (1) | NZ513802A (cs) |
PL (1) | PL351619A1 (cs) |
SK (1) | SK12112001A3 (cs) |
TR (1) | TR200102505T2 (cs) |
WO (1) | WO2000051991A1 (cs) |
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2000
- 2000-02-24 BR BR0008524-3A patent/BR0008524A/pt not_active Expired - Fee Related
- 2000-02-24 US US09/914,323 patent/US6972288B1/en not_active Expired - Lifetime
- 2000-02-24 SK SK1211-2001A patent/SK12112001A3/sk unknown
- 2000-02-24 ID IDW00200101847A patent/ID29800A/id unknown
- 2000-02-24 CN CN00804215A patent/CN1341104A/zh active Pending
- 2000-02-24 EE EEP200100449A patent/EE200100449A/xx unknown
- 2000-02-24 PL PL00351619A patent/PL351619A1/xx not_active Application Discontinuation
- 2000-02-24 EP EP10181231A patent/EP2298746A1/en not_active Withdrawn
- 2000-02-24 KR KR1020017010981A patent/KR20020068261A/ko not_active Application Discontinuation
- 2000-02-24 HU HU0301132A patent/HUP0301132A3/hu unknown
- 2000-02-24 AU AU32816/00A patent/AU3281600A/en not_active Abandoned
- 2000-02-24 TR TR2001/02505T patent/TR200102505T2/xx unknown
- 2000-02-24 NZ NZ513802A patent/NZ513802A/xx not_active Application Discontinuation
- 2000-02-24 JP JP2000602218A patent/JP3751201B2/ja not_active Expired - Fee Related
- 2000-02-24 WO PCT/EP2000/001496 patent/WO2000051991A1/en not_active Application Discontinuation
- 2000-02-24 CA CA002361174A patent/CA2361174C/en not_active Expired - Lifetime
- 2000-02-24 CZ CZ20013079A patent/CZ20013079A3/cs unknown
- 2000-02-24 IL IL14414300A patent/IL144143A0/xx unknown
- 2000-02-24 EP EP00910695A patent/EP1157011A1/en not_active Withdrawn
-
2001
- 2001-08-01 BG BG105765A patent/BG105765A/xx active Pending
- 2001-08-23 HR HR20010617A patent/HRP20010617A2/hr not_active Application Discontinuation
- 2001-08-24 NO NO20014114A patent/NO20014114L/no not_active Application Discontinuation
Also Published As
Publication number | Publication date |
---|---|
PL351619A1 (en) | 2003-05-19 |
EE200100449A (et) | 2002-12-16 |
KR20020068261A (ko) | 2002-08-27 |
EP2298746A1 (en) | 2011-03-23 |
JP3751201B2 (ja) | 2006-03-01 |
NO20014114D0 (no) | 2001-08-24 |
HUP0301132A3 (en) | 2004-03-29 |
IL144143A0 (en) | 2002-05-23 |
WO2000051991A1 (en) | 2000-09-08 |
CN1341104A (zh) | 2002-03-20 |
HUP0301132A2 (hu) | 2003-12-29 |
CA2361174C (en) | 2009-10-27 |
NO20014114L (no) | 2001-10-15 |
AU3281600A (en) | 2000-09-21 |
BR0008524A (pt) | 2001-12-18 |
CA2361174A1 (en) | 2000-09-08 |
US6972288B1 (en) | 2005-12-06 |
TR200102505T2 (tr) | 2003-01-21 |
EP1157011A1 (en) | 2001-11-28 |
NZ513802A (en) | 2001-09-28 |
BG105765A (en) | 2002-03-29 |
JP2002538145A (ja) | 2002-11-12 |
HRP20010617A2 (en) | 2002-10-31 |
ID29800A (id) | 2001-10-11 |
CZ20013079A3 (cs) | 2001-11-14 |
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