NO327747B1 - Bisykliske heterosykler, fremgangsmater for fremstilling av disse, fysiologisk akseptable salter av disse forbindelsene, farmasoytiske blandinger inneholdende disse forbindelsene samt anvendelse av disse forbindelsene for fremstilling av farmasoytiske preparater for behandling og forebygging av sykdom - Google Patents
Bisykliske heterosykler, fremgangsmater for fremstilling av disse, fysiologisk akseptable salter av disse forbindelsene, farmasoytiske blandinger inneholdende disse forbindelsene samt anvendelse av disse forbindelsene for fremstilling av farmasoytiske preparater for behandling og forebygging av sykdom Download PDFInfo
- Publication number
- NO327747B1 NO327747B1 NO20014487A NO20014487A NO327747B1 NO 327747 B1 NO327747 B1 NO 327747B1 NO 20014487 A NO20014487 A NO 20014487A NO 20014487 A NO20014487 A NO 20014487A NO 327747 B1 NO327747 B1 NO 327747B1
- Authority
- NO
- Norway
- Prior art keywords
- group
- methyl
- substituted
- alkyl
- amino
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 105
- 150000003839 salts Chemical class 0.000 title claims description 26
- 238000000034 method Methods 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title description 14
- 125000002618 bicyclic heterocycle group Chemical group 0.000 title description 3
- 239000008194 pharmaceutical composition Substances 0.000 title 2
- 230000006806 disease prevention Effects 0.000 title 1
- -1 methoxy, ethynyl Chemical group 0.000 claims description 125
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 66
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 62
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 42
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 41
- 125000000217 alkyl group Chemical group 0.000 claims description 41
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 28
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 20
- 238000004519 manufacturing process Methods 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 238000006243 chemical reaction Methods 0.000 claims description 18
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 18
- 125000002947 alkylene group Chemical group 0.000 claims description 16
- 125000004432 carbon atom Chemical group C* 0.000 claims description 15
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 14
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 14
- 239000000460 chlorine Substances 0.000 claims description 14
- 229910052801 chlorine Inorganic materials 0.000 claims description 14
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 14
- 125000003386 piperidinyl group Chemical group 0.000 claims description 14
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 14
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 13
- 125000002619 bicyclic group Chemical group 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 201000010099 disease Diseases 0.000 claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 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 10
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- 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 8
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- OTZSBBDSVSPPKW-UHFFFAOYSA-N ethyl 2-[4-[2-[4-(3-bromoanilino)-7-methoxyquinazolin-6-yl]oxyethyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CCOC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(Br)=C1 OTZSBBDSVSPPKW-UHFFFAOYSA-N 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 125000004634 hexahydroazepinyl group Chemical group N1(CCCCCC1)* 0.000 claims description 8
- 210000001035 gastrointestinal tract Anatomy 0.000 claims description 7
- 125000006239 protecting group Chemical group 0.000 claims description 7
- FOUZISDNESEYLX-UHFFFAOYSA-N 2-(2-hydroxyethylazaniumyl)acetate Chemical class OCCNCC(O)=O FOUZISDNESEYLX-UHFFFAOYSA-N 0.000 claims description 6
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 6
- 150000007513 acids Chemical class 0.000 claims description 5
- SWPBXPQKXQIJCP-UHFFFAOYSA-N ethyl 2-[4-[3-[4-(3-bromoanilino)-7-methoxyquinazolin-6-yl]oxy-2-hydroxypropyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CC(O)COC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(Br)=C1 SWPBXPQKXQIJCP-UHFFFAOYSA-N 0.000 claims description 5
- SUDPDYLEQCSMEC-UHFFFAOYSA-N methyl 2-[4-[3-[4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypropyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OC)CCN1CCCOC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=C(F)C(Cl)=C1 SUDPDYLEQCSMEC-UHFFFAOYSA-N 0.000 claims description 5
- 210000002345 respiratory system Anatomy 0.000 claims description 5
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 4
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 4
- 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 4
- 208000037062 Polyps Diseases 0.000 claims description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000002993 cycloalkylene group Chemical group 0.000 claims description 4
- 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 4
- 125000002933 cyclohexyloxy group Chemical group C1(CCCCC1)O* 0.000 claims description 4
- 125000004851 cyclopentylmethyl group Chemical group C1(CCCC1)C* 0.000 claims description 4
- 125000001887 cyclopentyloxy group Chemical group C1(CCCC1)O* 0.000 claims description 4
- 150000002148 esters Chemical class 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 229910052701 rubidium Inorganic materials 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 201000011510 cancer Diseases 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 3
- 125000004981 cycloalkylmethyl group Chemical group 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- GMKYVHLXOZJAPC-UHFFFAOYSA-N dimethyl 2-[4-[2-[4-(3-bromoanilino)-7-methoxyquinazolin-6-yl]oxyethyl]piperazin-1-yl]butanedioate Chemical compound C1CN(C(CC(=O)OC)C(=O)OC)CCN1CCOC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(Br)=C1 GMKYVHLXOZJAPC-UHFFFAOYSA-N 0.000 claims description 3
- 230000032050 esterification Effects 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 3
- 210000004072 lung Anatomy 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 210000000013 bile duct Anatomy 0.000 claims description 2
- 210000000232 gallbladder Anatomy 0.000 claims description 2
- 210000003734 kidney Anatomy 0.000 claims description 2
- 230000002265 prevention Effects 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 238000001149 thermolysis Methods 0.000 claims description 2
- 125000000623 heterocyclic group Chemical group 0.000 claims 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims 3
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims 2
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 2
- 101000983970 Conus catus Alpha-conotoxin CIB Proteins 0.000 claims 1
- 125000000000 cycloalkoxy group Chemical group 0.000 claims 1
- 210000003491 skin Anatomy 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 180
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 126
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 114
- 238000001819 mass spectrum Methods 0.000 description 62
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 58
- 239000000741 silica gel Substances 0.000 description 56
- 229910002027 silica gel Inorganic materials 0.000 description 56
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 48
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 45
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 33
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 33
- 235000011114 ammonium hydroxide Nutrition 0.000 description 33
- 239000002904 solvent Substances 0.000 description 33
- 239000000203 mixture Substances 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- 239000013543 active substance Substances 0.000 description 24
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 22
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 19
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 17
- 238000001704 evaporation Methods 0.000 description 17
- 230000008020 evaporation Effects 0.000 description 17
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 239000003826 tablet Substances 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 15
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 14
- 150000007530 organic bases Chemical group 0.000 description 13
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 12
- 230000008018 melting Effects 0.000 description 11
- 238000002844 melting Methods 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 239000002775 capsule Substances 0.000 description 9
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 9
- 102000001301 EGF receptor Human genes 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 8
- 108060006698 EGF receptor Proteins 0.000 description 7
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 7
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- 238000004587 chromatography analysis Methods 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 150000007529 inorganic bases Chemical class 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 6
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 description 4
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 4
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
- IISUFHXUQWEMSR-UHFFFAOYSA-N ethyl 2-[2-[4-(3-bromoanilino)-7-methoxyquinazolin-6-yl]oxyethyl-(2-hydroxy-2-methylpropyl)amino]acetate Chemical compound N1=CN=C2C=C(OC)C(OCCN(CC(=O)OCC)CC(C)(C)O)=CC2=C1NC1=CC=CC(Br)=C1 IISUFHXUQWEMSR-UHFFFAOYSA-N 0.000 description 4
- SCBFWLYOPNBTDY-UHFFFAOYSA-N ethyl 2-[4-[[4-(3-bromoanilino)-7-methoxyquinazolin-6-yl]oxymethyl]piperidin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCC1COC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(Br)=C1 SCBFWLYOPNBTDY-UHFFFAOYSA-N 0.000 description 4
- 125000001841 imino group Chemical group [H]N=* 0.000 description 4
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- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 4
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 4
- 239000012071 phase Substances 0.000 description 4
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- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
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- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 4
- 230000035755 proliferation Effects 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
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- 230000007306 turnover Effects 0.000 description 4
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 3
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 3
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- 101710098940 Pro-epidermal growth factor Proteins 0.000 description 3
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- RTCZNUNEWQGRMI-UHFFFAOYSA-N ethyl 2-[4-[3-[4-(3-bromoanilino)-7-(2-methoxyethoxy)quinazolin-6-yl]oxypropyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CCCOC(C(=CC1=NC=N2)OCCOC)=CC1=C2NC1=CC=CC(Br)=C1 RTCZNUNEWQGRMI-UHFFFAOYSA-N 0.000 description 2
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- UCEFPGOPICGAOE-UHFFFAOYSA-N ethyl 2-[4-[3-[4-(3-bromoanilino)-7-methoxyquinazolin-6-yl]oxypropyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CCCOC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(Br)=C1 UCEFPGOPICGAOE-UHFFFAOYSA-N 0.000 description 2
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- NWWGBLNXKXYINX-UHFFFAOYSA-N ethyl 2-[4-[3-[4-(3-chloroanilino)-7-methoxyquinazolin-6-yl]oxypropyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CCCOC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(Cl)=C1 NWWGBLNXKXYINX-UHFFFAOYSA-N 0.000 description 2
- WBEPBVLNSBETAK-UHFFFAOYSA-N ethyl 2-[4-[3-[7-methoxy-4-(1-phenylethylamino)quinazolin-6-yl]oxypropyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CCCOC(C(=CC1=NC=N2)OC)=CC1=C2NC(C)C1=CC=CC=C1 WBEPBVLNSBETAK-UHFFFAOYSA-N 0.000 description 2
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- BCYNAOCPBRKUHF-UHFFFAOYSA-N ethyl 2-[4-[2-[4-(3-bromoanilino)-7-cyclohexyloxyquinazolin-6-yl]oxyethyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CCOC(C(=CC1=NC=N2)OC3CCCCC3)=CC1=C2NC1=CC=CC(Br)=C1 BCYNAOCPBRKUHF-UHFFFAOYSA-N 0.000 description 1
- WDEGCYPHDGCILX-UHFFFAOYSA-N ethyl 2-[4-[2-[4-(3-bromoanilino)-7-cyclopentyloxyquinazolin-6-yl]oxyethyl]piperazin-1-yl]acetate Chemical compound C1CN(CC(=O)OCC)CCN1CCOC(C(=CC1=NC=N2)OC3CCCC3)=CC1=C2NC1=CC=CC(Br)=C1 WDEGCYPHDGCILX-UHFFFAOYSA-N 0.000 description 1
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- 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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- 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
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- 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
- C07D403/12—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 chain containing hetero atoms as chain links
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- 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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DE19911509A DE19911509A1 (de) | 1999-03-15 | 1999-03-15 | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
PCT/EP2000/002228 WO2000055141A1 (en) | 1999-03-15 | 2000-03-14 | Bicyclic heterocycles, pharmaceutical compositions containing these compounds, and processes for preparing them |
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NO20014487L NO20014487L (no) | 2001-09-14 |
NO20014487D0 NO20014487D0 (no) | 2001-09-14 |
NO327747B1 true NO327747B1 (no) | 2009-09-14 |
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NO20014487A NO327747B1 (no) | 1999-03-15 | 2001-09-14 | Bisykliske heterosykler, fremgangsmater for fremstilling av disse, fysiologisk akseptable salter av disse forbindelsene, farmasoytiske blandinger inneholdende disse forbindelsene samt anvendelse av disse forbindelsene for fremstilling av farmasoytiske preparater for behandling og forebygging av sykdom |
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EP (1) | EP1163227B1 (de) |
JP (2) | JP3754617B2 (de) |
KR (1) | KR100749292B1 (de) |
CN (1) | CN1150171C (de) |
AR (1) | AR022939A1 (de) |
AT (1) | ATE305456T1 (de) |
AU (1) | AU772520B2 (de) |
BG (1) | BG65130B1 (de) |
BR (1) | BR0009076A (de) |
CA (1) | CA2368059C (de) |
CO (1) | CO5150216A1 (de) |
CZ (1) | CZ20013326A3 (de) |
DE (2) | DE19911509A1 (de) |
DK (1) | DK1163227T3 (de) |
EA (1) | EA005098B1 (de) |
EC (1) | ECSP034646A (de) |
EE (1) | EE05034B1 (de) |
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IL (1) | IL144626A (de) |
ME (1) | MEP45608A (de) |
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NO (1) | NO327747B1 (de) |
NZ (1) | NZ514706A (de) |
PL (1) | PL205726B1 (de) |
RS (1) | RS50062B (de) |
SK (1) | SK286959B6 (de) |
TR (1) | TR200102782T2 (de) |
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US10253036B2 (en) | 2016-09-08 | 2019-04-09 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
US10392399B2 (en) | 2016-09-08 | 2019-08-27 | Kala Pharmaceuticals, Inc. | Crystalline forms of therapeutic compounds and uses thereof |
MA46852A (fr) | 2016-11-17 | 2019-09-25 | Univ Texas | Composés à activité antitumorale contre des cellules cancéreuses porteuses de mutations egfr ou her2 exon 20 |
CN107513040A (zh) * | 2017-08-02 | 2017-12-26 | 北京师范大学 | 取代苯并嘧啶类化合物的制备及分子靶向肿瘤治疗药物的应用 |
CN108727285A (zh) * | 2018-05-25 | 2018-11-02 | 北京师范大学 | 增加氰基苯胺基取代喹唑啉类化合物的生物活性及其应用 |
CN111499583B (zh) * | 2020-05-22 | 2022-02-15 | 沈阳工业大学 | 喹唑啉衍生物及其作为抗肿瘤药物的应用 |
CN112321814B (zh) * | 2020-12-30 | 2021-03-23 | 广州初曲科技有限公司 | 一种吉非替尼艾地苯醌轭合物的制备及用途 |
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GB8910722D0 (en) * | 1989-05-10 | 1989-06-28 | Smithkline Beckman Intercredit | Compounds |
AU661533B2 (en) * | 1992-01-20 | 1995-07-27 | Astrazeneca Ab | Quinazoline derivatives |
US6184799B1 (en) * | 1995-04-20 | 2001-02-06 | The Nippon Signal Co., Ltd. | Monitoring apparatus and control apparatus for traffic signal lights |
GB9508538D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
US5747498A (en) * | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
NO303045B1 (no) * | 1995-06-16 | 1998-05-25 | Terje Steinar Olsen | Stol med fot/leggst÷tte |
TR199801530T2 (xx) * | 1996-02-13 | 1998-11-23 | Zeneca Limited | VEGF �nhibit�rleri olarak kinazolin t�revleri. |
JP4464466B2 (ja) * | 1996-03-05 | 2010-05-19 | アストラゼネカ・ユーケイ・リミテッド | 4―アニリノキナゾリン誘導体 |
GB9718972D0 (en) * | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
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