NO325672B1 - Kinazolinderivater, medikamenter inneholdende disse forbindelser, deres anvendelse for fremstilling av legemidler og fremgangsmate for fremstilling derav - Google Patents
Kinazolinderivater, medikamenter inneholdende disse forbindelser, deres anvendelse for fremstilling av legemidler og fremgangsmate for fremstilling derav Download PDFInfo
- Publication number
- NO325672B1 NO325672B1 NO20032726A NO20032726A NO325672B1 NO 325672 B1 NO325672 B1 NO 325672B1 NO 20032726 A NO20032726 A NO 20032726A NO 20032726 A NO20032726 A NO 20032726A NO 325672 B1 NO325672 B1 NO 325672B1
- Authority
- NO
- Norway
- Prior art keywords
- amino
- tetrahydrofuran
- general formula
- chloro
- fluorophenyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 51
- 238000004519 manufacturing process Methods 0.000 title claims description 15
- 238000000034 method Methods 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title description 7
- 239000003814 drug Substances 0.000 title description 5
- 229940079593 drug Drugs 0.000 title description 3
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title 1
- -1 3-chloro-4-fluorophenyl group Chemical group 0.000 claims description 37
- 150000003839 salts Chemical class 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 10
- ULXXDDBFHOBEHA-INIZCTEOSA-N N-[4-(3-chloro-4-fluoroanilino)-7-[[(3S)-3-oxolanyl]oxy]-6-quinazolinyl]-4-(dimethylamino)-2-butenamide Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)C=CCN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-INIZCTEOSA-N 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 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 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 150000007522 mineralic acids Chemical class 0.000 claims description 3
- KERNOJLDNITGPO-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(oxan-4-yloxy)quinazolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N1=CN=C2C=C(OC3CCOCC3)C(NC(=O)C=CCN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 KERNOJLDNITGPO-UHFFFAOYSA-N 0.000 claims description 3
- UIJGHCUIUFFXJL-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(oxolan-2-ylmethoxy)quinazolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N1=CN=C2C=C(OCC3OCCC3)C(NC(=O)C=CCN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 UIJGHCUIUFFXJL-UHFFFAOYSA-N 0.000 claims description 3
- UIJGHCUIUFFXJL-KRWDZBQOSA-N n-[4-(3-chloro-4-fluoroanilino)-7-[[(2s)-oxolan-2-yl]methoxy]quinazolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N1=CN=C2C=C(OC[C@H]3OCCC3)C(NC(=O)C=CCN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 UIJGHCUIUFFXJL-KRWDZBQOSA-N 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 235000005985 organic acids Nutrition 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- IHBCFOYKPRGZLY-ONEGZZNKSA-N (e)-n-[4-(3-chloro-4-fluoroanilino)-7-(oxolan-3-ylmethoxy)quinazolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N1=CN=C2C=C(OCC3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 IHBCFOYKPRGZLY-ONEGZZNKSA-N 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 239000000969 carrier Substances 0.000 claims description 2
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims description 2
- 230000001681 protective effect Effects 0.000 claims description 2
- 150000003246 quinazolines Chemical class 0.000 claims description 2
- 229940126601 medicinal product Drugs 0.000 claims 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 70
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 39
- 238000001819 mass spectrum Methods 0.000 description 35
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 30
- 239000000741 silica gel Substances 0.000 description 30
- 229910002027 silica gel Inorganic materials 0.000 description 30
- 229960000583 acetic acid Drugs 0.000 description 24
- 239000013543 active substance Substances 0.000 description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 239000000243 solution Substances 0.000 description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000002775 capsule Substances 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 239000003826 tablet Substances 0.000 description 9
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 8
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 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
- 150000007530 organic bases Chemical class 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 6
- 102000001301 EGF receptor Human genes 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 5
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 5
- 238000003776 cleavage reaction Methods 0.000 description 5
- 229910052739 hydrogen Inorganic materials 0.000 description 5
- 239000001257 hydrogen Substances 0.000 description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
- 230000007017 scission Effects 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
- 235000019359 magnesium stearate Nutrition 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 238000002844 melting Methods 0.000 description 4
- 230000008018 melting Effects 0.000 description 4
- DXPHSNWRSQLXHE-UHFFFAOYSA-N n-[4-(3-chloro-4-fluoroanilino)-7-(oxan-4-ylmethoxy)quinazolin-6-yl]-4-(dimethylamino)but-2-enamide Chemical compound N1=CN=C2C=C(OCC3CCOCC3)C(NC(=O)C=CCN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 DXPHSNWRSQLXHE-UHFFFAOYSA-N 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 239000000829 suppository Substances 0.000 description 4
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- 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 3
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- 229920002261 Corn starch Polymers 0.000 description 3
- 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
- 108060006698 EGF receptor Proteins 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 235000011114 ammonium hydroxide Nutrition 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 239000008298 dragée Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- 230000019491 signal transduction Effects 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000758 substrate Substances 0.000 description 3
- 239000011975 tartaric acid Substances 0.000 description 3
- 235000002906 tartaric acid Nutrition 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- NOOLISFMXDJSKH-KXUCPTDWSA-N (-)-Menthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O NOOLISFMXDJSKH-KXUCPTDWSA-N 0.000 description 2
- YKIKDQYYTAOTPL-IHWYPQMZSA-N (z)-2-bromobut-2-enoic acid Chemical class C\C=C(/Br)C(O)=O YKIKDQYYTAOTPL-IHWYPQMZSA-N 0.000 description 2
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 101000851176 Homo sapiens Pro-epidermal growth factor Proteins 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- NKANXQFJJICGDU-QPLCGJKRSA-N Tamoxifen Chemical compound C=1C=CC=CC=1C(/CC)=C(C=1C=CC(OCCN(C)C)=CC=1)/C1=CC=CC=C1 NKANXQFJJICGDU-QPLCGJKRSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 239000012362 glacial acetic acid Substances 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 125000005843 halogen group Chemical group 0.000 description 2
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000012280 lithium aluminium hydride Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- UZYGKNSWZCNBJN-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-6-nitro-7-(oxan-4-ylmethoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCC3CCOCC3)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 UZYGKNSWZCNBJN-UHFFFAOYSA-N 0.000 description 2
- GVUGOAYIVIDWIO-UFWWTJHBSA-N nepidermin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C(C)C)C(C)C)C1=CC=C(O)C=C1 GVUGOAYIVIDWIO-UFWWTJHBSA-N 0.000 description 2
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N p-hydroxybenzoic acid propyl ester Natural products CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000011877 solvent mixture Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 2
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 2
- 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 2
- 229940075966 (+)- menthol Drugs 0.000 description 1
- NOOLISFMXDJSKH-AEJSXWLSSA-N (+)-menthol Chemical compound CC(C)[C@H]1CC[C@H](C)C[C@@H]1O NOOLISFMXDJSKH-AEJSXWLSSA-N 0.000 description 1
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- AJQOHMKOYHIBCK-LBPRGKRZSA-N (2s)-n-benzyl-n-methyloxolane-2-carboxamide Chemical compound O=C([C@H]1OCCC1)N(C)CC1=CC=CC=C1 AJQOHMKOYHIBCK-LBPRGKRZSA-N 0.000 description 1
- XDPCNPCKDGQBAN-SCSAIBSYSA-N (3r)-oxolan-3-ol Chemical compound O[C@@H]1CCOC1 XDPCNPCKDGQBAN-SCSAIBSYSA-N 0.000 description 1
- AAWZDTNXLSGCEK-LNVDRNJUSA-N (3r,5r)-1,3,4,5-tetrahydroxycyclohexane-1-carboxylic acid Chemical compound O[C@@H]1CC(O)(C(O)=O)C[C@@H](O)C1O AAWZDTNXLSGCEK-LNVDRNJUSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- YJARZGCHYQHUFV-IHWYPQMZSA-N (z)-2-bromobut-2-enoyl chloride Chemical compound C\C=C(/Br)C(Cl)=O YJARZGCHYQHUFV-IHWYPQMZSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- LNSCNEJNLACZPA-UHFFFAOYSA-N 2,3-dihydroxy-2,3-bis(2-methylphenyl)butanedioic acid Chemical compound CC1=CC=CC=C1C(O)(C(O)=O)C(O)(C(O)=O)C1=CC=CC=C1C LNSCNEJNLACZPA-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- KMGUEILFFWDGFV-UHFFFAOYSA-N 2-benzoyl-2-benzoyloxy-3-hydroxybutanedioic acid Chemical compound C=1C=CC=CC=1C(=O)C(C(C(O)=O)O)(C(O)=O)OC(=O)C1=CC=CC=C1 KMGUEILFFWDGFV-UHFFFAOYSA-N 0.000 description 1
- KOHBEDRJXKOYHL-UHFFFAOYSA-N 2-methoxy-n-methylethanamine Chemical compound CNCCOC KOHBEDRJXKOYHL-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 1
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 0.000 description 1
- LKHNQAXOAXIXGM-UHFFFAOYSA-N 4-n-(3-chloro-4-fluorophenyl)-7-(cyclopropylmethoxy)quinazoline-4,6-diamine Chemical compound N1=CN=C2C=C(OCC3CC3)C(N)=CC2=C1NC1=CC=C(F)C(Cl)=C1 LKHNQAXOAXIXGM-UHFFFAOYSA-N 0.000 description 1
- HYXXXCXETVEKHD-UHFFFAOYSA-N 4-n-(3-chloro-4-fluorophenyl)-7-(oxan-4-yloxy)quinazoline-4,6-diamine Chemical compound N1=CN=C2C=C(OC3CCOCC3)C(N)=CC2=C1NC1=CC=C(F)C(Cl)=C1 HYXXXCXETVEKHD-UHFFFAOYSA-N 0.000 description 1
- PFEZMJFVNMXKOY-UHFFFAOYSA-N 4-n-(3-chloro-4-fluorophenyl)-7-(oxolan-3-ylmethoxy)quinazoline-4,6-diamine Chemical compound N1=CN=C2C=C(OCC3COCC3)C(N)=CC2=C1NC1=CC=C(F)C(Cl)=C1 PFEZMJFVNMXKOY-UHFFFAOYSA-N 0.000 description 1
- BIQABKFYKJRXII-NSHDSACASA-N 4-n-(3-chloro-4-fluorophenyl)-7-[(3s)-oxolan-3-yl]oxyquinazoline-4,6-diamine Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(N)=CC2=C1NC1=CC=C(F)C(Cl)=C1 BIQABKFYKJRXII-NSHDSACASA-N 0.000 description 1
- NMYUQRVTMBHNKE-LBPRGKRZSA-N 4-n-(3-chloro-4-fluorophenyl)-7-[[(2s)-oxolan-2-yl]methoxy]quinazoline-4,6-diamine Chemical compound N1=CN=C2C=C(OC[C@H]3OCCC3)C(N)=CC2=C1NC1=CC=C(F)C(Cl)=C1 NMYUQRVTMBHNKE-LBPRGKRZSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- AAWZDTNXLSGCEK-UHFFFAOYSA-N Cordycepinsaeure Natural products OC1CC(O)(C(O)=O)CC(O)C1O AAWZDTNXLSGCEK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- 206010029113 Neovascularisation Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 102000003992 Peroxidases Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- AAWZDTNXLSGCEK-ZHQZDSKASA-N Quinic acid Natural products O[C@H]1CC(O)(C(O)=O)C[C@H](O)C1O AAWZDTNXLSGCEK-ZHQZDSKASA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 108091005682 Receptor kinases Proteins 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 108010090804 Streptavidin Proteins 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 241000251539 Vertebrata <Metazoa> Species 0.000 description 1
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 229940009456 adriamycin Drugs 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- FKFYSAGKTJGORY-UHFFFAOYSA-N benzyl n-(oxolan-3-yl)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1CCOC1 FKFYSAGKTJGORY-UHFFFAOYSA-N 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- MIOPJNTWMNEORI-UHFFFAOYSA-N camphorsulfonic acid Chemical compound C1CC2(CS(O)(=O)=O)C(=O)CC1C2(C)C MIOPJNTWMNEORI-UHFFFAOYSA-N 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229950005499 carbon tetrachloride Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 229940105329 carboxymethylcellulose Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- LDHQCZJRKDOVOX-NSCUHMNNSA-N crotonic acid Chemical class C\C=C\C(O)=O LDHQCZJRKDOVOX-NSCUHMNNSA-N 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 239000003534 dna topoisomerase inhibitor Substances 0.000 description 1
- 238000006911 enzymatic reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 229960005420 etoposide Drugs 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229940116364 hard fat Drugs 0.000 description 1
- 235000012907 honey Nutrition 0.000 description 1
- 239000003667 hormone antagonist Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 229940041682 inhalant solution Drugs 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960004873 levomenthol Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- UEGPKNKPLBYCNK-UHFFFAOYSA-L magnesium acetate Chemical compound [Mg+2].CC([O-])=O.CC([O-])=O UEGPKNKPLBYCNK-UHFFFAOYSA-L 0.000 description 1
- 239000011654 magnesium acetate Substances 0.000 description 1
- 235000011285 magnesium acetate Nutrition 0.000 description 1
- 229940069446 magnesium acetate Drugs 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000005948 methanesulfonyloxy group Chemical group 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- NETMTRFHSWETRT-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-6-nitro-7-(oxan-4-yloxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OC3CCOCC3)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 NETMTRFHSWETRT-UHFFFAOYSA-N 0.000 description 1
- FCXWQECJRGXOTR-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-6-nitro-7-(oxolan-2-ylmethoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCC3OCCC3)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 FCXWQECJRGXOTR-UHFFFAOYSA-N 0.000 description 1
- QJXUSYDXSPFWJY-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-6-nitro-7-(oxolan-3-ylmethoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCC3COCC3)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 QJXUSYDXSPFWJY-UHFFFAOYSA-N 0.000 description 1
- UXAZURVGMXJLSO-NSHDSACASA-N n-(3-chloro-4-fluorophenyl)-6-nitro-7-[(3s)-oxolan-3-yl]oxyquinazolin-4-amine Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 UXAZURVGMXJLSO-NSHDSACASA-N 0.000 description 1
- FCXWQECJRGXOTR-LBPRGKRZSA-N n-(3-chloro-4-fluorophenyl)-6-nitro-7-[[(2s)-oxolan-2-yl]methoxy]quinazolin-4-amine Chemical compound N1=CN=C2C=C(OC[C@H]3OCCC3)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 FCXWQECJRGXOTR-LBPRGKRZSA-N 0.000 description 1
- CJOJDNRJDBWZKM-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine Chemical compound N1=CN=C2C=C(F)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 CJOJDNRJDBWZKM-UHFFFAOYSA-N 0.000 description 1
- GIKKJKPWTFGDJD-UHFFFAOYSA-N n-benzyl-n-methyl-1-(oxan-4-yl)methanamine Chemical compound C=1C=CC=CC=1CN(C)CC1CCOCC1 GIKKJKPWTFGDJD-UHFFFAOYSA-N 0.000 description 1
- MSNNNMGVEOWGQJ-ZDUSSCGKSA-N n-benzyl-n-methyl-1-[(2s)-oxolan-2-yl]methanamine Chemical compound C=1C=CC=CC=1CN(C)C[C@@H]1CCCO1 MSNNNMGVEOWGQJ-ZDUSSCGKSA-N 0.000 description 1
- UFSVFSMUZQIGIE-UHFFFAOYSA-N n-benzyl-n-methyloxane-4-carboxamide Chemical compound C1COCCC1C(=O)N(C)CC1=CC=CC=C1 UFSVFSMUZQIGIE-UHFFFAOYSA-N 0.000 description 1
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 description 1
- WMBCUXKYKVTJRF-UHFFFAOYSA-N n-methyl-1-(oxan-4-yl)methanamine Chemical compound CNCC1CCOCC1 WMBCUXKYKVTJRF-UHFFFAOYSA-N 0.000 description 1
- VJUDVVHGQMPPEI-LURJTMIESA-N n-methyl-1-[(2s)-oxolan-2-yl]methanamine Chemical compound CNC[C@@H]1CCCO1 VJUDVVHGQMPPEI-LURJTMIESA-N 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- LQVZUXUQGFIYEK-UHFFFAOYSA-N n-methyloxolan-3-amine Chemical compound CNC1CCOC1 LQVZUXUQGFIYEK-UHFFFAOYSA-N 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- BOTREHHXSQGWTR-UHFFFAOYSA-N oxolane-3-carboxylic acid Chemical compound OC(=O)C1CCOC1 BOTREHHXSQGWTR-UHFFFAOYSA-N 0.000 description 1
- 230000035778 pathophysiological process Effects 0.000 description 1
- 108040007629 peroxidase activity proteins Proteins 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000011833 salt mixture Substances 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000010802 sludge Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 238000013022 venting Methods 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
Classifications
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/16—Otologicals
-
- 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]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Oncology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Dermatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Medicinal Preparation (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE10063435A DE10063435A1 (de) | 2000-12-20 | 2000-12-20 | Chinazolinderviate,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
| PCT/EP2001/014569 WO2002050043A1 (fr) | 2000-12-20 | 2001-12-12 | Derives de la quinazoline, medicaments contenant ces composes, leur utilisation et leur procede de fabrication |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO20032726L NO20032726L (no) | 2003-06-16 |
| NO20032726D0 NO20032726D0 (no) | 2003-06-16 |
| NO325672B1 true NO325672B1 (no) | 2008-07-07 |
Family
ID=7667887
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20032726A NO325672B1 (no) | 2000-12-20 | 2003-06-16 | Kinazolinderivater, medikamenter inneholdende disse forbindelser, deres anvendelse for fremstilling av legemidler og fremgangsmate for fremstilling derav |
| NO2014003C NO2014003I2 (no) | 2000-12-20 | 2014-02-11 | Afatinib - tautomerer, stereoisomerer og salter derav, fysiologisk akseptable salter med uorganiske eller organiske syrer eller baser, fortrinnsvis et maleatsalt derav, mer fortrinnsvis et dimaletsalt derav (patentkravene 3, 4 og 5) |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO2014003C NO2014003I2 (no) | 2000-12-20 | 2014-02-11 | Afatinib - tautomerer, stereoisomerer og salter derav, fysiologisk akseptable salter med uorganiske eller organiske syrer eller baser, fortrinnsvis et maleatsalt derav, mer fortrinnsvis et dimaletsalt derav (patentkravene 3, 4 og 5) |
Country Status (40)
| Country | Link |
|---|---|
| EP (2) | EP2112140A1 (fr) |
| JP (1) | JP3827641B2 (fr) |
| KR (1) | KR100852102B1 (fr) |
| CN (1) | CN1277822C (fr) |
| AR (1) | AR040524A1 (fr) |
| AT (1) | ATE430136T1 (fr) |
| AU (2) | AU1917402A (fr) |
| BE (1) | BE2014C009I2 (fr) |
| BG (1) | BG66139B1 (fr) |
| BR (1) | BRPI0116266B8 (fr) |
| CA (1) | CA2432428C (fr) |
| CY (2) | CY1109290T1 (fr) |
| CZ (1) | CZ302721B6 (fr) |
| DE (2) | DE10063435A1 (fr) |
| DK (1) | DK1345910T3 (fr) |
| EA (1) | EA006317B1 (fr) |
| EE (1) | EE05244B1 (fr) |
| ES (1) | ES2326617T3 (fr) |
| FR (1) | FR14C0009I2 (fr) |
| HK (1) | HK1060571A1 (fr) |
| HR (1) | HRP20030504B1 (fr) |
| HU (2) | HU228874B1 (fr) |
| IL (2) | IL156277A0 (fr) |
| LT (1) | LTC1345910I2 (fr) |
| LU (1) | LU92370I2 (fr) |
| ME (1) | ME02777B (fr) |
| MX (1) | MXPA03005559A (fr) |
| MY (1) | MY136086A (fr) |
| NO (2) | NO325672B1 (fr) |
| NZ (1) | NZ526918A (fr) |
| PL (1) | PL214798B1 (fr) |
| PT (1) | PT1345910E (fr) |
| RS (1) | RS50860B (fr) |
| SI (1) | SI1345910T1 (fr) |
| SK (1) | SK287573B6 (fr) |
| TW (1) | TWI295992B (fr) |
| UA (1) | UA74614C2 (fr) |
| UY (1) | UY27078A1 (fr) |
| WO (1) | WO2002050043A1 (fr) |
| ZA (1) | ZA200304141B (fr) |
Families Citing this family (86)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SK287010B6 (sk) | 1999-06-21 | 2009-09-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Bicyklické heterocyklické zlúčeniny, spôsob ich prípravy, farmaceutický prostriedok s ich obsahom a ich použitie |
| US7019012B2 (en) | 2000-12-20 | 2006-03-28 | Boehringer Ingelheim International Pharma Gmbh & Co. Kg | Quinazoline derivatives and pharmaceutical compositions containing them |
| DE10204462A1 (de) * | 2002-02-05 | 2003-08-07 | Boehringer Ingelheim Pharma | Verwendung von Tyrosinkinase-Inhibitoren zur Behandlung inflammatorischer Prozesse |
| US6924285B2 (en) | 2002-03-30 | 2005-08-02 | Boehringer Ingelheim Pharma Gmbh & Co. | Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them |
| US20040044014A1 (en) | 2002-04-19 | 2004-03-04 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for the preparation thereof |
| DE10221018A1 (de) | 2002-05-11 | 2003-11-27 | Boehringer Ingelheim Pharma | Verwendung von Hemmern der EGFR-vermittelten Signaltransduktion zur Behandlung von gutartiger Prostatahyperplasie (BPH)/Prostatahypertrophie |
| PE20040945A1 (es) * | 2003-02-05 | 2004-12-14 | Warner Lambert Co | Preparacion de quinazolinas substituidas |
| DE10307165A1 (de) * | 2003-02-20 | 2004-09-02 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, ihre Verwendung und Verfahren zu ihrer Herstellung |
| US7223749B2 (en) | 2003-02-20 | 2007-05-29 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for preparing them |
| US20050043233A1 (en) * | 2003-04-29 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Combinations for the treatment of diseases involving cell proliferation, migration or apoptosis of myeloma cells or angiogenesis |
| DE10334226A1 (de) * | 2003-07-28 | 2005-02-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von Tyrosinkinase-Inhibitoren zur Behandlung inflammatorischer Prozesse |
| GB0317665D0 (en) | 2003-07-29 | 2003-09-03 | Astrazeneca Ab | Qinazoline derivatives |
| US7456189B2 (en) | 2003-09-30 | 2008-11-25 | Boehringer Ingelheim International Gmbh | Bicyclic heterocycles, medicaments containing these compounds, their use and processes for their preparation |
| DE10349113A1 (de) * | 2003-10-17 | 2005-05-12 | Boehringer Ingelheim Pharma | Verfahren zur Herstellung von Aminocrotonylverbindungen |
| JP4205757B2 (ja) * | 2004-05-06 | 2009-01-07 | ワーナー−ランバート カンパニー リミテッド ライアビリティー カンパニー | ４−フェニルアミノ−キナゾリン−６−イル−アミド |
| US20060035893A1 (en) | 2004-08-07 | 2006-02-16 | Boehringer Ingelheim International Gmbh | Pharmaceutical compositions for treatment of respiratory and gastrointestinal disorders |
| PE20060777A1 (es) | 2004-12-24 | 2006-10-06 | Boehringer Ingelheim Int | Derivados de indolinona para el tratamiento o la prevencion de enfermedades fibroticas |
| WO2006081741A1 (fr) * | 2005-02-05 | 2006-08-10 | Piaoyang Sun | Dérivés de quinazoline ou leurs sels de qualité pharmaceutique, synthèse et applications médicales desdites substances |
| KR100832594B1 (ko) * | 2005-11-08 | 2008-05-27 | 한미약품 주식회사 | 다중저해제로서의 퀴나졸린 유도체 및 이의 제조방법 |
| WO2007054550A1 (fr) * | 2005-11-11 | 2007-05-18 | Boehringer Ingelheim International Gmbh | Derives de quinazoline pour le traitement des affections cancereuses |
| PL1948180T3 (pl) | 2005-11-11 | 2013-09-30 | Boehringer Ingelheim Int | Terapia skojarzona raka polegająca na podawaniu inhibitorów EGFR/HER2 |
| CA2639936C (fr) * | 2006-01-26 | 2014-06-17 | Boehringer Ingelheim International Gmbh | Procede de preparation de derives quinazoline a substitution aminocrotonylamino |
| BRPI0717586A2 (pt) | 2006-09-18 | 2013-10-29 | Boehringer Ingelheim Int | Método para tratar câncer apresentando mutações do egfr |
| EP1921070A1 (fr) | 2006-11-10 | 2008-05-14 | Boehringer Ingelheim Pharma GmbH & Co. KG | heterocycles bicycliques, medicaments á base de ces composes, leur usage et procédé pour leur preparation |
| EP2118075A1 (fr) | 2007-02-06 | 2009-11-18 | Boehringer Ingelheim International GmbH | Hétérocycles bicycliques, agents pharmaceutiques contenant ces composés, leur utilisation et leur procédé de préparation |
| EA019709B1 (ru) | 2008-02-07 | 2014-05-30 | Бёрингер Ингельхайм Интернациональ Гмбх | Спирогетероциклы и их применение в качестве лекарственных средств |
| EA019183B1 (ru) | 2008-05-13 | 2014-01-30 | Астразенека Аб | Фумаратная соль 4-(3-хлор-2-фторанилино)-7-метокси-6-{[1-(n-метилкарбамоилметил)пиперидин-4-ил]окси}хиназолина |
| PE20100252A1 (es) | 2008-06-06 | 2010-04-12 | Boehringer Ingelheim Int | Nuevas formulaciones farmaceuticas solidas que comprenden dimaleato de 4-[(3-cloro-4-fluorofenil) amino]-6-{[4-(n,n-dimetilamino)-1-oxo-2-buten-1-il] amino}-7-((s)-tetrahidrofuran-3-iloxi)-quinazolina |
| US8426430B2 (en) | 2008-06-30 | 2013-04-23 | Hutchison Medipharma Enterprises Limited | Quinazoline derivatives |
| WO2010015522A1 (fr) | 2008-08-08 | 2010-02-11 | Boehringer Ingelheim International Gmbh | Hétérocycles à substitution cyclohexyloxy, médicaments contenant ces composés, leur utilisation et procédés pour les préparer |
| JP5781934B2 (ja) * | 2008-11-10 | 2015-09-24 | ナショナル ヘルス リサーチ インスティテューツ | チロシンキナーゼ阻害剤としての融合２環および３環ピリミジン化合物 |
| WO2010081817A1 (fr) | 2009-01-14 | 2010-07-22 | Boehringer Ingelheim International Gmbh | Méthode de traitement d'un cancer colorectal |
| WO2010130757A1 (fr) | 2009-05-14 | 2010-11-18 | Boehringer Ingelheim International Gmbh | Nouvelle polytherapie destinee a traiter les maladies oncologiques et fibrotiques |
| EP2429527A1 (fr) * | 2009-05-14 | 2012-03-21 | Boehringer Ingelheim International GmbH | Nouvelle thérapie en combinaison dans le traitement du cancer et de maladies fibreuses |
| WO2011003853A2 (fr) | 2009-07-06 | 2011-01-13 | Boehringer Ingelheim International Gmbh | Procédé de séchage du bibw2992, de ses sels et des préparations pharmaceutiques solides contenant ce principe actif |
| JP2013512882A (ja) | 2009-12-07 | 2013-04-18 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | トリプルネガティブ乳癌の治療に使用するｂｉｂｗ２９９２ |
| US8735409B2 (en) * | 2009-12-21 | 2014-05-27 | Qiang Zhang | Quinazoline derivatives |
| US20120107304A1 (en) | 2010-04-27 | 2012-05-03 | Boehringer Ingelheim International Gmbh | Combination therapy in treatment of oncological and fibrotic diseases |
| PL2608792T3 (pl) | 2010-08-26 | 2018-03-30 | Boehringer Ingelheim International Gmbh | Sposoby podawania inhibitora EGFR |
| JP5808818B2 (ja) * | 2010-11-25 | 2015-11-10 | ラツィオファーム・ゲーエムベーハー | アファチニブの新規塩及び多形形態 |
| KR20210043016A (ko) | 2011-03-04 | 2021-04-20 | 뉴젠 세러퓨틱스 인코포레이티드 | 알킨 치환된 퀴나졸린 화합물 및 그것의 사용 방법 |
| US8828391B2 (en) | 2011-05-17 | 2014-09-09 | Boehringer Ingelheim International Gmbh | Method for EGFR directed combination treatment of non-small cell lung cancer |
| CN102918029B (zh) | 2011-05-17 | 2015-06-17 | 江苏康缘药业股份有限公司 | 4-苯胺-6-丁烯酰胺-7-烷醚喹唑啉衍生物及其制备方法和用途 |
| CN102838590B (zh) * | 2011-06-21 | 2014-07-09 | 苏州迈泰生物技术有限公司 | 氨基喹唑啉衍生物及其在制备抗恶性肿瘤药物中的用途 |
| US20150232457A1 (en) | 2011-10-06 | 2015-08-20 | Ratiopharm Gmbh | Crystalline forms of afatinib di-maleate |
| CN103073539B (zh) * | 2011-10-26 | 2016-05-11 | 齐鲁制药有限公司 | 4-(取代苯氨基)喹唑啉衍生物及其制备方法、药物组合物和用途 |
| EP2805940B1 (fr) | 2012-01-17 | 2016-11-23 | Astellas Pharma Inc. | Composé pyrazine carboxamide |
| CN103772380A (zh) * | 2012-10-23 | 2014-05-07 | 杨子娇 | 一类治疗房角狭窄的化合物及其用途 |
| JP2016511754A (ja) | 2013-02-01 | 2016-04-21 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 放射性標識キナゾリン誘導体 |
| US20140303098A1 (en) | 2013-04-05 | 2014-10-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US11813275B2 (en) | 2013-04-05 | 2023-11-14 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| US20140303097A1 (en) | 2013-04-05 | 2014-10-09 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| AU2014255727B2 (en) | 2013-04-18 | 2019-07-25 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| CN103254182A (zh) * | 2013-05-10 | 2013-08-21 | 苏州明锐医药科技有限公司 | 一种阿法替尼的制备方法 |
| CN103254183B (zh) * | 2013-05-10 | 2015-11-11 | 苏州明锐医药科技有限公司 | 阿法替尼的制备方法 |
| WO2014180271A1 (fr) * | 2013-05-10 | 2014-11-13 | 苏州明锐医药科技有限公司 | Procédé de préparation de l'afatinib et intermédiaire associé |
| WO2014183560A1 (fr) * | 2013-05-16 | 2014-11-20 | 苏州明锐医药科技有限公司 | Afatinib et procédé de préparation d'un intermédiaire de celui-ci |
| CN103242303B (zh) * | 2013-05-16 | 2015-03-25 | 苏州明锐医药科技有限公司 | 阿法替尼的制备方法 |
| CN104513229A (zh) * | 2013-09-28 | 2015-04-15 | 正大天晴药业集团股份有限公司 | 喹唑啉衍生物及其制备方法 |
| CN103755688B (zh) * | 2013-12-24 | 2015-11-18 | 江苏奥赛康药业股份有限公司 | 一种阿法替尼化合物的制备方法 |
| US9242965B2 (en) * | 2013-12-31 | 2016-01-26 | Boehringer Ingelheim International Gmbh | Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors |
| WO2015103456A1 (fr) | 2014-01-02 | 2015-07-09 | Teva Pharmaceuticals International Gmbh | Formes cristallines de di-maléate d'afatinib |
| CN105315263B (zh) * | 2014-07-30 | 2018-11-27 | 正大天晴药业集团股份有限公司 | 阿法替尼中间体的合成方法 |
| EP3023421A1 (fr) | 2014-11-21 | 2016-05-25 | Sandoz Ag | Formes cristallines de dimaléate d'afatinib |
| CN105801568B (zh) | 2015-01-15 | 2019-07-30 | 杭州普晒医药科技有限公司 | 阿法替尼一马来酸盐晶型及其制备方法和药物组合物 |
| CN107406430B (zh) * | 2015-03-20 | 2019-04-26 | 正大天晴药业集团股份有限公司 | 喹唑啉衍生物的盐及其制备方法 |
| CN105175400B (zh) * | 2015-09-29 | 2018-04-10 | 河北神威药业有限公司 | 一种阿法替尼中间体的制备方法 |
| WO2017141271A1 (fr) * | 2016-02-17 | 2017-08-24 | Sun Pharmaceutical Industries Ltd. | Composition pharmaceutique stable d'afatinib |
| CN106442793B (zh) * | 2016-10-21 | 2019-05-24 | 河北神威药业有限公司 | 一种制备阿法替尼的中间体及其对映异构体的检测方法 |
| TWI808958B (zh) | 2017-01-25 | 2023-07-21 | 美商特普醫葯公司 | 涉及二芳基巨環化合物之組合療法 |
| WO2019126136A2 (fr) | 2017-12-18 | 2019-06-27 | Sterngreene, Inc. | Composés de pyrimidine utiles en tant qu'inhibiteurs de tyrosine kinase |
| CN110437163A (zh) * | 2018-05-03 | 2019-11-12 | 斯特恩格林公司 | 作为酪氨酸激酶抑制剂的嘧啶类化合物 |
| KR20210137422A (ko) | 2018-09-25 | 2021-11-17 | 블랙 다이아몬드 테라퓨틱스, 인코포레이티드 | 티로신 키나아제 억제제로서의 퀴나졸린 유도체, 조성물, 이들의 제조 방법 및 이들의 용도 |
| CN109265449B (zh) * | 2018-11-07 | 2021-11-23 | 沈阳工业大学 | Egfr和her2双靶点酪氨酸激酶抑制剂及制备方法和用途 |
| EP3903828A4 (fr) | 2018-12-21 | 2022-10-05 | Daiichi Sankyo Company, Limited | Combinaison d'un conjugué anticorps-médicament et d'un inhibiteur de kinase |
| CN109824657A (zh) * | 2019-03-26 | 2019-05-31 | 石药集团中奇制药技术（石家庄）有限公司 | 一种二马来酸阿法替尼新晶型及其制备方法和应用 |
| CN110590682A (zh) * | 2019-10-14 | 2019-12-20 | 重庆医科大学 | 一种制备阿法替尼杂质的方法以及制备的杂质 |
| US20210161897A1 (en) | 2019-11-12 | 2021-06-03 | Astrazeneca Ab | Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of cancer |
| KR20220130190A (ko) | 2020-01-20 | 2022-09-26 | 아스트라제네카 아베 | 암 치료를 위한 표피성장인자 수용체 티로신 키나제 억제제 |
| US20210369709A1 (en) | 2020-05-27 | 2021-12-02 | Astrazeneca Ab | EGFR TKIs FOR USE IN THE TREATMENT OF NON-SMALL CELL LUNG CANCER |
| WO2023187037A1 (fr) | 2022-03-31 | 2023-10-05 | Astrazeneca Ab | Inhibiteurs de tyrosine kinase du récepteur du facteur de croissance épidermique (egfr) en combinaison avec un inhibiteur d'akt pour le traitement du cancer |
| US20240116926A1 (en) | 2022-04-28 | 2024-04-11 | Astrazeneca Ab | Heteroaromatic compounds |
| WO2023209088A1 (fr) | 2022-04-28 | 2023-11-02 | Astrazeneca Ab | Composés hétéroaromatiques bicycliques et leur utilisation dans le traitement du cancer |
| WO2023209084A1 (fr) | 2022-04-28 | 2023-11-02 | Astrazeneca Ab | Composés hétéroaromatiques bicycliques condensés et leur utilisation dans le traitement du cancer |
| WO2023209090A1 (fr) | 2022-04-28 | 2023-11-02 | Astrazeneca Ab | Composés hétéroaromatiques bicycliques et leur application dans le traitement du cancer |
| WO2024002938A1 (fr) | 2022-06-27 | 2024-01-04 | Astrazeneca Ab | Combinaisons impliquant des inhibiteurs de tyrosine kinase du récepteur du facteur de croissance épidermique pour traiter le cancer |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK0892789T4 (da) * | 1996-04-12 | 2010-04-06 | Warner Lambert Co | Irreversible inhibitorer af tyrosin kinaser |
| ZA986729B (en) * | 1997-07-29 | 1999-02-02 | Warner Lambert Co | Irreversible inhibitors of tyrosine kinases |
| ZA986732B (en) * | 1997-07-29 | 1999-02-02 | Warner Lambert Co | Irreversible inhibitiors of tyrosine kinases |
| DE19911366A1 (de) * | 1999-03-15 | 2000-09-21 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
| TR200102505T2 (tr) * | 1999-02-27 | 2003-01-21 | Boehringer Ingelheim Pharma Kg | 4-amino-kinazolin ve kinolin türevleri. |
| DE19908567A1 (de) * | 1999-02-27 | 2000-08-31 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
| DE19911509A1 (de) * | 1999-03-15 | 2000-09-21 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
| SK287010B6 (sk) * | 1999-06-21 | 2009-09-07 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Bicyklické heterocyklické zlúčeniny, spôsob ich prípravy, farmaceutický prostriedok s ich obsahom a ich použitie |
| ES2280375T3 (es) * | 2000-04-08 | 2007-09-16 | BOEHRINGER INGELHEIM PHARMA GMBH & CO.KG | Heterociclos biciclicos, medicamentos que contienen estos compuestos, su uso y procedimiento para su preparacion. |
-
2000
- 2000-12-20 DE DE10063435A patent/DE10063435A1/de not_active Withdrawn
-
2001
- 2001-12-12 AT AT01271363T patent/ATE430136T1/de active
- 2001-12-12 NZ NZ526918A patent/NZ526918A/en not_active IP Right Cessation
- 2001-12-12 CN CNB018208665A patent/CN1277822C/zh not_active Expired - Lifetime
- 2001-12-12 AU AU1917402A patent/AU1917402A/xx active Pending
- 2001-12-12 EA EA200300671A patent/EA006317B1/ru not_active IP Right Cessation
- 2001-12-12 EE EEP200300300A patent/EE05244B1/xx active Protection Beyond IP Right Term
- 2001-12-12 BR BRPI0116266A patent/BRPI0116266B8/pt not_active IP Right Cessation
- 2001-12-12 EP EP09158964A patent/EP2112140A1/fr not_active Withdrawn
- 2001-12-12 SK SK771-2003A patent/SK287573B6/sk not_active IP Right Cessation
- 2001-12-12 SI SI200130916T patent/SI1345910T1/sl unknown
- 2001-12-12 HU HU0301852A patent/HU228874B1/hu active Protection Beyond IP Right Term
- 2001-12-12 WO PCT/EP2001/014569 patent/WO2002050043A1/fr active Application Filing
- 2001-12-12 UA UA2003076821A patent/UA74614C2/uk unknown
- 2001-12-12 RS YUP-496/03A patent/RS50860B/sr unknown
- 2001-12-12 CZ CZ20031930A patent/CZ302721B6/cs not_active IP Right Cessation
- 2001-12-12 AU AU2002219174A patent/AU2002219174B2/en active Active
- 2001-12-12 EP EP01271363.2A patent/EP1345910B9/fr not_active Expired - Lifetime
- 2001-12-12 ME MEP-2008-595A patent/ME02777B/fr unknown
- 2001-12-12 DK DK01271363T patent/DK1345910T3/da active
- 2001-12-12 KR KR1020037008246A patent/KR100852102B1/ko active Protection Beyond IP Right Term
- 2001-12-12 CA CA002432428A patent/CA2432428C/fr not_active Expired - Lifetime
- 2001-12-12 MX MXPA03005559A patent/MXPA03005559A/es active IP Right Grant
- 2001-12-12 PT PT01271363T patent/PT1345910E/pt unknown
- 2001-12-12 PL PL361798A patent/PL214798B1/pl unknown
- 2001-12-12 DE DE50114874T patent/DE50114874D1/de not_active Expired - Lifetime
- 2001-12-12 JP JP2002551540A patent/JP3827641B2/ja not_active Expired - Lifetime
- 2001-12-12 IL IL15627701A patent/IL156277A0/xx unknown
- 2001-12-12 ES ES01271363T patent/ES2326617T3/es not_active Expired - Lifetime
- 2001-12-17 UY UY27078A patent/UY27078A1/es not_active Application Discontinuation
- 2001-12-19 AR AR20010105883A patent/AR040524A1/es active Pending
- 2001-12-19 MY MYPI20015767A patent/MY136086A/en unknown
- 2001-12-19 TW TW090131520A patent/TWI295992B/zh active
-
2003
- 2003-05-28 ZA ZA200304141A patent/ZA200304141B/en unknown
- 2003-06-03 IL IL156277A patent/IL156277A/en active Protection Beyond IP Right Term
- 2003-06-16 NO NO20032726A patent/NO325672B1/no active Protection Beyond IP Right Term
- 2003-06-18 HR HR20030504A patent/HRP20030504B1/xx not_active IP Right Cessation
- 2003-06-19 BG BG107929A patent/BG66139B1/bg active Active
-
2004
- 2004-05-20 HK HK04103590A patent/HK1060571A1/xx not_active IP Right Cessation
-
2009
- 2009-07-23 CY CY20091100793T patent/CY1109290T1/el unknown
-
2014
- 2014-01-30 FR FR14C0009C patent/FR14C0009I2/fr active Active
- 2014-01-31 LU LU92370C patent/LU92370I2/fr unknown
- 2014-02-06 LT LTPA2014005C patent/LTC1345910I2/lt unknown
- 2014-02-11 NO NO2014003C patent/NO2014003I2/no not_active IP Right Cessation
- 2014-02-12 HU HUS1400005C patent/HUS1400005I1/hu unknown
- 2014-02-12 CY CY2014008C patent/CY2014008I2/el unknown
- 2014-02-18 BE BE2014C009C patent/BE2014C009I2/fr unknown
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NO325672B1 (no) | Kinazolinderivater, medikamenter inneholdende disse forbindelser, deres anvendelse for fremstilling av legemidler og fremgangsmate for fremstilling derav | |
| US8586608B2 (en) | Quinazoline derivatives and pharmaceutical compositions containing them | |
| US7863281B2 (en) | Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for the preparation thereof | |
| NO322094B1 (no) | Bicykliske heterocykler, medikamenter inneholdende disse forbindelser, deres anvendelse og fremgangsmate for fremstilling av dem. | |
| CA2484395C (fr) | Heterocycles bicycliques, medicaments contenant ces composes, leur utilisation et leur procede de production | |
| EP1597240B1 (fr) | Heterocycles bicycliques, medicaments les contenant, leur utilisation et leurs procedes de production | |
| WO2007068552A1 (fr) | Heterocycles bicycliques, medicaments contenant ces composes, utilisation et procede de fabrication de ceux-ci | |
| DE10326186A1 (de) | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung | |
| JP2009529511A (ja) | 二環式複素環化合物、これらの化合物を含む医薬組成物、その使用方法及び製造方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| SPCG | Granted supplementary protection certificate |
Free format text: PRODUCT NAME: GIOTRIT; REG.NO/DATE: EU/1/13/879/001-012 2013.10.16; FIRST REG.NO/DATE: EU/1/13/879/001-012 2013.09.25 Spc suppl protection certif: 2014003 Filing date: 20140211 Extension date: 20261212 |
|
| MK1K | Patent expired | ||
| SPCF | Filing of supplementary protection certificate |
Free format text: PRODUCT NAME: AFATINIB - TAUTOMERS STEREOISOMERS OG SALTS THEREOF - FORLENGELSE SPC; REG. NO/DATE: EU/1/13/879/001-012 20131016 Spc suppl protection certif: 2022028 Filing date: 20220701 |