SK283175B6 - Deriváty chinazolínu, spôsoby ich prípravy, farmaceutický prostriedok, ktorý ich obsahuje, a ich použitie - Google Patents
Deriváty chinazolínu, spôsoby ich prípravy, farmaceutický prostriedok, ktorý ich obsahuje, a ich použitie Download PDFInfo
- Publication number
- SK283175B6 SK283175B6 SK389-99A SK38999A SK283175B6 SK 283175 B6 SK283175 B6 SK 283175B6 SK 38999 A SK38999 A SK 38999A SK 283175 B6 SK283175 B6 SK 283175B6
- Authority
- SK
- Slovakia
- Prior art keywords
- alkyl
- group
- carbon atoms
- moiety
- alkoxy
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims abstract description 62
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 6
- -1 methoxy, amino Chemical group 0.000 claims abstract description 366
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 356
- 150000001875 compounds Chemical class 0.000 claims abstract description 184
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 119
- 150000003839 salts Chemical class 0.000 claims abstract description 91
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 85
- 239000001257 hydrogen Substances 0.000 claims abstract description 81
- 238000000034 method Methods 0.000 claims abstract description 77
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 53
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 49
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 47
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 35
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 30
- 230000000694 effects Effects 0.000 claims abstract description 28
- 125000005843 halogen group Chemical group 0.000 claims abstract description 24
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 23
- 230000008569 process Effects 0.000 claims abstract description 22
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims abstract description 21
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 18
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims abstract description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 9
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims abstract description 4
- 239000004480 active ingredient Substances 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 435
- 125000004432 carbon atom Chemical group C* 0.000 claims description 392
- 229910052757 nitrogen Inorganic materials 0.000 claims description 153
- 125000001424 substituent group Chemical group 0.000 claims description 152
- 125000003545 alkoxy group Chemical group 0.000 claims description 126
- 125000004043 oxo group Chemical group O=* 0.000 claims description 96
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 83
- 229910052736 halogen Inorganic materials 0.000 claims description 78
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 76
- 150000002367 halogens Chemical class 0.000 claims description 75
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 53
- 229910052717 sulfur Inorganic materials 0.000 claims description 48
- 229910052760 oxygen Inorganic materials 0.000 claims description 46
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 38
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 36
- 229910052799 carbon Inorganic materials 0.000 claims description 35
- 125000006699 (C1-C3) hydroxyalkyl group Chemical group 0.000 claims description 33
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 33
- 150000003246 quinazolines Chemical class 0.000 claims description 30
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 28
- 125000002252 acyl group Chemical group 0.000 claims description 28
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 27
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 26
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 25
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 22
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 20
- 125000004848 alkoxyethyl group Chemical group 0.000 claims description 19
- 150000001721 carbon Chemical group 0.000 claims description 19
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 19
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 18
- 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 17
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 17
- 125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 16
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 15
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 12
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
- 230000008728 vascular permeability Effects 0.000 claims description 11
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
- 125000005117 dialkylcarbamoyl group Chemical group 0.000 claims description 10
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
- 125000004312 morpholin-2-yl group Chemical group [H]N1C([H])([H])C([H])([H])OC([H])(*)C1([H])[H] 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
- 125000004574 piperidin-2-yl group Chemical group N1C(CCCC1)* 0.000 claims description 10
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 9
- 230000001772 anti-angiogenic effect Effects 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 125000004572 morpholin-3-yl group Chemical group N1C(COCC1)* 0.000 claims description 9
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 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 8
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 8
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 7
- 125000004429 atom Chemical group 0.000 claims description 7
- 239000000460 chlorine Chemical group 0.000 claims description 7
- 125000001153 fluoro group Chemical group F* 0.000 claims description 7
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 5
- 230000002137 anti-vascular effect Effects 0.000 claims description 5
- 239000011737 fluorine Substances 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 4
- 239000002168 alkylating agent Substances 0.000 claims description 4
- 229940100198 alkylating agent Drugs 0.000 claims description 4
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- ZTECKKZKKXHFNQ-UHFFFAOYSA-N n-(4-chloro-2-fluorophenyl)-6-methoxy-7-(2-thiomorpholin-4-ylethoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCN3CCSCC3)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F ZTECKKZKKXHFNQ-UHFFFAOYSA-N 0.000 claims description 4
- KYTFODVCZWKCLN-UHFFFAOYSA-N n-(4-chloro-2-fluorophenyl)-6-methoxy-7-(3-methylsulfonylpropoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCCS(C)(=O)=O)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F KYTFODVCZWKCLN-UHFFFAOYSA-N 0.000 claims description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 230000001939 inductive effect Effects 0.000 claims description 3
- VMFPOLWHGLQSAO-CYBMUJFWSA-N n-(4-chloro-2-fluorophenyl)-2,6-dimethoxy-7-[(3s)-1-methylpiperidin-3-yl]quinazolin-4-amine Chemical compound C=12C=C(OC)C([C@H]3CN(C)CCC3)=CC2=NC(OC)=NC=1NC1=CC=C(Cl)C=C1F VMFPOLWHGLQSAO-CYBMUJFWSA-N 0.000 claims description 3
- OMPULNWENFCTGO-UHFFFAOYSA-N n-(4-chloro-2-fluorophenyl)-7-(1,3-dioxolan-2-ylmethoxy)-6-methoxyquinazolin-4-amine Chemical compound N1=CN=C2C=C(OCC3OCCO3)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F OMPULNWENFCTGO-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- PPRJXYIAPVSGRX-IBGZPJMESA-N (2s)-1-[3-[4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypropyl]pyrrolidine-2-carboxamide Chemical compound N1=CN=C2C=C(OCCCN3[C@@H](CCC3)C(N)=O)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F PPRJXYIAPVSGRX-IBGZPJMESA-N 0.000 claims description 2
- SHLGEKGJWKDGRO-UHFFFAOYSA-N 1-[3-[4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypropyl]pyrrolidin-2-one Chemical compound N1=CN=C2C=C(OCCCN3C(CCC3)=O)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F SHLGEKGJWKDGRO-UHFFFAOYSA-N 0.000 claims description 2
- JQHWOLMSBYBMIF-UHFFFAOYSA-N 4-[2-[4-(4-bromo-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxyethyl]morpholin-3-one Chemical compound N1=CN=C2C=C(OCCN3C(COCC3)=O)C(OC)=CC2=C1NC1=CC=C(Br)C=C1F JQHWOLMSBYBMIF-UHFFFAOYSA-N 0.000 claims description 2
- UPIWNRZVGHSLKP-UHFFFAOYSA-N 4-[2-[4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxyethyl]morpholin-3-one Chemical compound N1=CN=C2C=C(OCCN3C(COCC3)=O)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F UPIWNRZVGHSLKP-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- QJQYPZZUKLQGGT-UHFFFAOYSA-N methyl hypobromite Chemical group COBr QJQYPZZUKLQGGT-UHFFFAOYSA-N 0.000 claims description 2
- QXUKSGOUVJIOKA-UHFFFAOYSA-N n-(4-chloro-2-fluorophenyl)-6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]quinazolin-4-amine Chemical compound C=12C=C(OC)C(OCCOCCOC)=CC2=NC=NC=1NC1=CC=C(Cl)C=C1F QXUKSGOUVJIOKA-UHFFFAOYSA-N 0.000 claims description 2
- BBSONACIKKJKMB-UHFFFAOYSA-N n-(4-chloro-2-fluorophenyl)-6-methoxy-7-[2-[2-(4-methylpiperazin-1-yl)ethoxy]ethoxy]quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCOCCN3CCN(C)CC3)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F BBSONACIKKJKMB-UHFFFAOYSA-N 0.000 claims description 2
- OZVUSEVFXCWUBV-CQSZACIVSA-N n-(4-chloro-2-fluorophenyl)-6-methoxy-7-[[(3r)-1-methylpiperidin-3-yl]methoxy]quinazolin-4-amine Chemical compound N1=CN=C2C=C(OC[C@H]3CN(C)CCC3)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F OZVUSEVFXCWUBV-CQSZACIVSA-N 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims 5
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical group [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 2
- GSMCDXGKZOUAET-UHFFFAOYSA-N (z)-pent-2-ene Chemical group C[CH]C=CC GSMCDXGKZOUAET-UHFFFAOYSA-N 0.000 claims 1
- FPCRAFGYNVALNS-UHFFFAOYSA-N 1-[2-[4-(4-bromo-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxyethyl]pyrrolidin-2-one Chemical compound N1=CN=C2C=C(OCCN3C(CCC3)=O)C(OC)=CC2=C1NC1=CC=C(Br)C=C1F FPCRAFGYNVALNS-UHFFFAOYSA-N 0.000 claims 1
- JIPCXHMOZHGMNH-UHFFFAOYSA-N 1-[2-[4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxyethyl]pyrrolidin-2-one Chemical compound N1=CN=C2C=C(OCCN3C(CCC3)=O)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F JIPCXHMOZHGMNH-UHFFFAOYSA-N 0.000 claims 1
- JKVBSIJOTHGKEE-UHFFFAOYSA-N 1-[3-[4-(4-bromo-2-fluoroanilino)-6-methoxyquinazolin-7-yl]oxypropyl]pyrrolidin-2-one Chemical compound N1=CN=C2C=C(OCCCN3C(CCC3)=O)C(OC)=CC2=C1NC1=CC=C(Br)C=C1F JKVBSIJOTHGKEE-UHFFFAOYSA-N 0.000 claims 1
- GZELITDCOZGUPD-UHFFFAOYSA-N 6,7-dimethoxy-n-(3-methyl-2h-indazol-6-yl)quinazolin-4-amine Chemical compound C1=C2C(C)=NNC2=CC(NC=2N=CN=C3C=C(C(=CC3=2)OC)OC)=C1 GZELITDCOZGUPD-UHFFFAOYSA-N 0.000 claims 1
- LCLIFQFGSVSLJD-UHFFFAOYSA-N n-(4-chloro-2-fluorophenyl)-6-methoxy-7-(4-morpholin-4-ylbut-2-ynoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCC#CCN3CCOCC3)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F LCLIFQFGSVSLJD-UHFFFAOYSA-N 0.000 claims 1
- BMEKKWWFQMYXPU-SNAWJCMRSA-N n-(4-chloro-2-fluorophenyl)-6-methoxy-7-[(e)-4-pyrrolidin-1-ylbut-2-enoxy]quinazolin-4-amine Chemical compound N1=CN=C2C=C(OC\C=C\CN3CCCC3)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F BMEKKWWFQMYXPU-SNAWJCMRSA-N 0.000 claims 1
- SPRJHDMLXZXXRJ-UHFFFAOYSA-N n-(4-chloro-2-fluorophenyl)-6-methoxy-7-[2-(2-morpholin-4-ylethoxy)ethoxy]quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCOCCN3CCOCC3)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F SPRJHDMLXZXXRJ-UHFFFAOYSA-N 0.000 claims 1
- 239000008096 xylene Substances 0.000 claims 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 abstract description 31
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 abstract description 31
- 206010028980 Neoplasm Diseases 0.000 abstract description 13
- 238000011282 treatment Methods 0.000 abstract description 13
- 201000010099 disease Diseases 0.000 abstract description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
- 201000011510 cancer Diseases 0.000 abstract description 6
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 4
- 125000005647 linker group Chemical group 0.000 abstract description 2
- 125000002837 carbocyclic group Chemical group 0.000 abstract 2
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 261
- 239000000203 mixture Substances 0.000 description 213
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 188
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 171
- 239000000243 solution Substances 0.000 description 116
- 238000001704 evaporation Methods 0.000 description 111
- 230000008020 evaporation Effects 0.000 description 111
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 81
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 81
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 78
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 76
- 239000007858 starting material Substances 0.000 description 72
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 66
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 61
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 61
- 239000002904 solvent Substances 0.000 description 60
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 57
- 238000000921 elemental analysis Methods 0.000 description 56
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 53
- 238000004440 column chromatography Methods 0.000 description 50
- 239000003039 volatile agent Substances 0.000 description 50
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 48
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 48
- 239000002244 precipitate Substances 0.000 description 42
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 39
- 239000012264 purified product Substances 0.000 description 39
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 38
- 239000012267 brine Substances 0.000 description 35
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 35
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 34
- 239000011541 reaction mixture Substances 0.000 description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 32
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 30
- 238000006243 chemical reaction Methods 0.000 description 29
- 239000007787 solid Substances 0.000 description 29
- XGZKSSTZBKFZMF-UHFFFAOYSA-N 4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-ol Chemical compound N1=CN=C2C=C(O)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F XGZKSSTZBKFZMF-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 27
- FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 27
- 239000000706 filtrate Substances 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 25
- 239000000284 extract Substances 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 20
- 229910000027 potassium carbonate Inorganic materials 0.000 description 19
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 17
- 235000019341 magnesium sulphate Nutrition 0.000 description 17
- 238000010992 reflux Methods 0.000 description 17
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 16
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- 235000011114 ammonium hydroxide Nutrition 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 description 15
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 15
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 13
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Classifications
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- C07—ORGANIC CHEMISTRY
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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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
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- A61F13/00—Bandages or dressings; Absorbent pads
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- A61F13/023—Adhesive bandages or dressings wound covering film layers without a fluid retention layer
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- A61K31/33—Heterocyclic compounds
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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EP96402033 | 1996-09-25 | ||
EP97401042 | 1997-05-09 | ||
PCT/GB1997/002588 WO1998013354A1 (en) | 1996-09-25 | 1997-09-23 | Quinazoline derivatives and pharmaceutical compositions containing them |
Publications (2)
Publication Number | Publication Date |
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SK38999A3 SK38999A3 (en) | 1999-10-08 |
SK283175B6 true SK283175B6 (sk) | 2003-03-04 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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SK389-99A SK283175B6 (sk) | 1996-09-25 | 1997-09-23 | Deriváty chinazolínu, spôsoby ich prípravy, farmaceutický prostriedok, ktorý ich obsahuje, a ich použitie |
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US (6) | US6414148B1 (zh) |
EP (1) | EP0929530B1 (zh) |
JP (3) | JP3438818B2 (zh) |
KR (1) | KR100618065B1 (zh) |
CN (1) | CN1142920C (zh) |
AT (1) | ATE228114T1 (zh) |
AU (1) | AU729968C (zh) |
BR (1) | BR9711302B1 (zh) |
CA (1) | CA2263319C (zh) |
CH (1) | CH0929530H1 (zh) |
CL (1) | CL2004001178A1 (zh) |
CY (1) | CY2453B1 (zh) |
CZ (1) | CZ296962B6 (zh) |
DE (1) | DE69717294C5 (zh) |
DK (1) | DK0929530T3 (zh) |
ES (1) | ES2185999T3 (zh) |
GB (1) | GB9718972D0 (zh) |
HK (1) | HK1019332A1 (zh) |
HU (1) | HU228176B1 (zh) |
IL (1) | IL129038A (zh) |
MY (1) | MY129540A (zh) |
NO (1) | NO313138B1 (zh) |
NZ (1) | NZ334014A (zh) |
PL (1) | PL190326B1 (zh) |
PT (1) | PT929530E (zh) |
RU (1) | RU2198879C2 (zh) |
SI (1) | SI0929530T1 (zh) |
SK (1) | SK283175B6 (zh) |
TR (1) | TR199900674T2 (zh) |
TW (1) | TW520364B (zh) |
UA (1) | UA57752C2 (zh) |
WO (1) | WO1998013354A1 (zh) |
ZA (1) | ZA978553B (zh) |
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- 1997-09-23 CH CH97943954T patent/CH0929530H1/de unknown
- 1997-09-23 US US12/170,027 patent/USRE42353E1/en not_active Expired - Lifetime
- 1997-09-23 EP EP97943954A patent/EP0929530B1/en not_active Expired - Lifetime
- 1997-09-23 HU HU9902850A patent/HU228176B1/hu unknown
- 1997-09-24 MY MYPI97004436A patent/MY129540A/en unknown
- 1997-09-24 TW TW086113896A patent/TW520364B/zh not_active IP Right Cessation
-
1999
- 1999-03-24 NO NO991422A patent/NO313138B1/no not_active IP Right Cessation
- 1999-09-22 HK HK99104114A patent/HK1019332A1/xx not_active IP Right Cessation
-
2002
- 2002-02-25 US US10/080,716 patent/US6673803B2/en not_active Expired - Lifetime
-
2003
- 2003-03-20 JP JP2003079216A patent/JP2003238539A/ja active Pending
- 2003-03-20 JP JP2003120734A patent/JP2004002406A/ja not_active Withdrawn
- 2003-11-03 US US10/698,388 patent/US6897210B2/en not_active Expired - Lifetime
-
2004
- 2004-05-17 CY CY0400038A patent/CY2453B1/xx unknown
- 2004-05-20 CL CL200401178A patent/CL2004001178A1/es unknown
- 2004-12-30 US US11/024,840 patent/US20050239777A1/en not_active Abandoned
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2010
- 2010-04-23 US US12/766,106 patent/US20110071144A1/en not_active Abandoned
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Owner name: GENZYME CORPORATION, CAMBRIDGE, MA, US Free format text: FORMER OWNER: ASTRAZENECA UK LIMITED, LONDON, GB Effective date: 20160920 |
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