DE69733008T2 - Chinazolinderivate als antitumormittel - Google Patents
Chinazolinderivate als antitumormittel Download PDFInfo
- Publication number
- DE69733008T2 DE69733008T2 DE69733008T DE69733008T DE69733008T2 DE 69733008 T2 DE69733008 T2 DE 69733008T2 DE 69733008 T DE69733008 T DE 69733008T DE 69733008 T DE69733008 T DE 69733008T DE 69733008 T2 DE69733008 T2 DE 69733008T2
- Authority
- DE
- Germany
- Prior art keywords
- alkyl
- alkoxy
- alkylamino
- amino
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 125000001424 substituent group Chemical group 0.000 claims abstract description 59
- 150000003839 salts Chemical class 0.000 claims abstract description 50
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 42
- 239000001257 hydrogen Substances 0.000 claims abstract description 33
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 33
- 238000000034 method Methods 0.000 claims abstract description 29
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 27
- 238000002360 preparation method Methods 0.000 claims abstract description 20
- 125000005843 halogen group Chemical group 0.000 claims abstract description 11
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims abstract description 8
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 8
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 6
- 229910002091 carbon monoxide Inorganic materials 0.000 claims abstract description 6
- 125000002618 bicyclic heterocycle group Chemical group 0.000 claims abstract description 5
- 230000008569 process Effects 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- -1 hydroxy, amino Chemical group 0.000 claims description 305
- 125000000217 alkyl group Chemical group 0.000 claims description 93
- 150000001875 compounds Chemical class 0.000 claims description 84
- 125000003545 alkoxy group Chemical group 0.000 claims description 62
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 52
- 125000003282 alkyl amino group Chemical group 0.000 claims description 49
- 229910052757 nitrogen Inorganic materials 0.000 claims description 40
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 40
- 229910052736 halogen Inorganic materials 0.000 claims description 34
- 150000002367 halogens Chemical class 0.000 claims description 31
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- 239000002253 acid Substances 0.000 claims description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 241000282414 Homo sapiens Species 0.000 claims description 16
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 16
- 230000001028 anti-proliverative effect Effects 0.000 claims description 15
- 229910052717 sulfur Chemical group 0.000 claims description 15
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 14
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- SQQWBSBBCSFQGC-JLHYYAGUSA-N ubiquinone-2 Chemical compound COC1=C(OC)C(=O)C(C\C=C(/C)CCC=C(C)C)=C(C)C1=O SQQWBSBBCSFQGC-JLHYYAGUSA-N 0.000 claims description 14
- 241001465754 Metazoa Species 0.000 claims description 13
- 150000002431 hydrogen Chemical class 0.000 claims description 13
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 12
- 125000005605 benzo group Chemical group 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 11
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 239000011593 sulfur Chemical group 0.000 claims description 11
- 239000000460 chlorine Substances 0.000 claims description 10
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 9
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims description 9
- 125000001246 bromo group Chemical group Br* 0.000 claims description 9
- 229910052801 chlorine Inorganic materials 0.000 claims description 9
- 125000000623 heterocyclic group Chemical group 0.000 claims description 9
- 239000003446 ligand Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 9
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 9
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 8
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims description 8
- 229910052796 boron Inorganic materials 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 7
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 239000011737 fluorine Substances 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- 125000006533 methyl amino methyl group Chemical group [H]N(C([H])([H])[H])C([H])([H])* 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 6
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052794 bromium Inorganic materials 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 5
- 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 5
- 239000003153 chemical reaction reagent Substances 0.000 claims description 5
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
- 125000006264 diethylaminomethyl group Chemical group [H]C([H])([H])C([H])([H])N(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 5
- YLKNMPLAFZNWGM-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-6-[5-(2-morpholin-4-ylethyl)thiophen-2-yl]quinazolin-4-amine Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC=C(C=3SC(CCN4CCOCC4)=CC=3)C=C12 YLKNMPLAFZNWGM-UHFFFAOYSA-N 0.000 claims description 5
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000006319 alkynyl amino group Chemical group 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 239000003814 drug Substances 0.000 claims description 4
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 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 4
- XKNOJJQLAKJXRG-UHFFFAOYSA-N 6-[4-(aminomethyl)phenyl]-n-(3-chloro-4-fluorophenyl)quinazolin-4-amine Chemical compound C1=CC(CN)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(F)=CC=3)C2=C1 XKNOJJQLAKJXRG-UHFFFAOYSA-N 0.000 claims description 3
- SVCDOBRLHLLOCR-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-6-(furan-3-yl)quinazolin-4-amine Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC=C(C3=COC=C3)C=C12 SVCDOBRLHLLOCR-UHFFFAOYSA-N 0.000 claims description 3
- KDLQMDDZCDMRPO-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-6-[5-(morpholin-4-ylmethyl)thiophen-3-yl]quinazolin-4-amine Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC=C(C=3C=C(CN4CCOCC4)SC=3)C=C12 KDLQMDDZCDMRPO-UHFFFAOYSA-N 0.000 claims description 3
- FRNUTEVSVDASOK-UHFFFAOYSA-N n-(3-methylphenyl)-6-phenylquinazolin-4-amine Chemical compound CC1=CC=CC(NC=2C3=CC(=CC=C3N=CN=2)C=2C=CC=CC=2)=C1 FRNUTEVSVDASOK-UHFFFAOYSA-N 0.000 claims description 3
- 230000002829 reductive effect Effects 0.000 claims description 3
- 125000004434 sulfur atom Chemical group 0.000 claims description 3
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 2
- 125000001359 1,2,3-triazol-4-yl group Chemical group [H]N1N=NC([*])=C1[H] 0.000 claims description 2
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 2
- KDDQRKBRJSGMQE-UHFFFAOYSA-N 4-thiazolyl Chemical group [C]1=CSC=N1 KDDQRKBRJSGMQE-UHFFFAOYSA-N 0.000 claims description 2
- 125000005133 alkynyloxy group Chemical group 0.000 claims description 2
- 125000003790 chinazolinyl group Chemical group 0.000 claims description 2
- HGPCQTKICSNBHK-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-6-thiophen-2-ylquinazolin-4-amine Chemical compound C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC=C(C=3SC=CC=3)C=C12 HGPCQTKICSNBHK-UHFFFAOYSA-N 0.000 claims description 2
- 150000003246 quinazolines Chemical class 0.000 claims 15
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 abstract description 50
- 102000027426 receptor tyrosine kinases Human genes 0.000 abstract description 35
- 108091008598 receptor tyrosine kinases Proteins 0.000 abstract description 35
- 206010028980 Neoplasm Diseases 0.000 abstract description 28
- 230000002401 inhibitory effect Effects 0.000 abstract description 19
- 238000011282 treatment Methods 0.000 abstract description 15
- 201000011510 cancer Diseases 0.000 abstract description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 12
- 201000010099 disease Diseases 0.000 abstract description 10
- 230000002062 proliferating effect Effects 0.000 abstract description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 176
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 135
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 117
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 54
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 52
- 239000000243 solution Substances 0.000 description 52
- 238000003756 stirring Methods 0.000 description 51
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 46
- 238000000921 elemental analysis Methods 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 38
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- 238000012360 testing method Methods 0.000 description 32
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 27
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- 210000004027 cell Anatomy 0.000 description 24
- 238000004440 column chromatography Methods 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 239000003480 eluent Substances 0.000 description 20
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(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]([C@@H](C)O)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](CCCNC(N)=N)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)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)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=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 19
- 101800003838 Epidermal growth factor Proteins 0.000 description 18
- 229940116977 epidermal growth factor Drugs 0.000 description 18
- 239000007858 starting material Substances 0.000 description 18
- 102400001368 Epidermal growth factor Human genes 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 17
- 239000000126 substance Substances 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 15
- 239000002244 precipitate Substances 0.000 description 15
- 230000009467 reduction Effects 0.000 description 15
- 238000006722 reduction reaction Methods 0.000 description 15
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 14
- 229910052751 metal Inorganic materials 0.000 description 14
- 239000002184 metal Substances 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 14
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 14
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 13
- 238000001704 evaporation Methods 0.000 description 13
- 230000008020 evaporation Effects 0.000 description 13
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 12
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- 239000003638 chemical reducing agent Substances 0.000 description 11
- VLIQZNRGFUZCIP-UHFFFAOYSA-N 6-bromo-n-(3-chloro-4-fluorophenyl)quinazolin-4-amine;hydrochloride Chemical compound Cl.C1=C(Cl)C(F)=CC=C1NC1=NC=NC2=CC=C(Br)C=C12 VLIQZNRGFUZCIP-UHFFFAOYSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000003701 inert diluent Substances 0.000 description 9
- 239000012442 inert solvent Substances 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 238000000746 purification Methods 0.000 description 9
- 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 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 230000012010 growth Effects 0.000 description 8
- 239000008101 lactose Substances 0.000 description 8
- 239000012280 lithium aluminium hydride Substances 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
- 239000007787 solid Substances 0.000 description 8
- NHDIQVFFNDKAQU-UHFFFAOYSA-N tripropan-2-yl borate Chemical compound CC(C)OB(OC(C)C)OC(C)C NHDIQVFFNDKAQU-UHFFFAOYSA-N 0.000 description 8
- HJAGRTPTIMMQPY-UHFFFAOYSA-N 4-n-(3-chloro-4-fluorophenyl)quinazoline-4,6-diamine Chemical compound C12=CC(N)=CC=C2N=CN=C1NC1=CC=C(F)C(Cl)=C1 HJAGRTPTIMMQPY-UHFFFAOYSA-N 0.000 description 7
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 7
- 238000005481 NMR spectroscopy Methods 0.000 description 7
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 7
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- 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
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9603095 | 1996-02-14 | ||
| GBGB9603095.2A GB9603095D0 (en) | 1996-02-14 | 1996-02-14 | Quinazoline derivatives |
| PCT/GB1997/000344 WO1997030034A1 (en) | 1996-02-14 | 1997-02-10 | Quinazoline derivatives as antitumor agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69733008D1 DE69733008D1 (de) | 2005-05-19 |
| DE69733008T2 true DE69733008T2 (de) | 2006-02-16 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| DE69733008T Expired - Lifetime DE69733008T2 (de) | 1996-02-14 | 1997-02-10 | Chinazolinderivate als antitumormittel |
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| EP (1) | EP0880507B1 (2) |
| JP (1) | JP4074342B2 (2) |
| KR (1) | KR100494824B1 (2) |
| CN (1) | CN1142919C (2) |
| AT (1) | ATE293103T1 (2) |
| AU (1) | AU707339B2 (2) |
| DE (1) | DE69733008T2 (2) |
| ES (1) | ES2239351T3 (2) |
| GB (1) | GB9603095D0 (2) |
| IL (1) | IL125685A (2) |
| MY (1) | MY119992A (2) |
| NO (1) | NO311936B1 (2) |
| NZ (1) | NZ330816A (2) |
| PT (1) | PT880507E (2) |
| WO (1) | WO1997030034A1 (2) |
| ZA (1) | ZA971231B (2) |
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| US7772432B2 (en) * | 1991-09-19 | 2010-08-10 | Astrazeneca Ab | Amidobenzamide derivatives which are useful as cytokine inhibitors |
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| US7060808B1 (en) * | 1995-06-07 | 2006-06-13 | Imclone Systems Incorporated | Humanized anti-EGF receptor monoclonal antibody |
| DE69720965T2 (de) | 1996-02-13 | 2004-02-05 | Astrazeneca Ab | Chinazolinderivate und deren verwendung als vegf hemmer |
| GB9603095D0 (en) * | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline derivatives |
| NZ331191A (en) | 1996-03-05 | 2000-03-27 | Zeneca Ltd | 4-anilinoquinazoline derivatives and pharmaceutical compositions thereof |
| EA001595B1 (ru) | 1996-04-12 | 2001-06-25 | Варнер-Ламберт Компани | Необратимые ингибиторы тирозинкиназ |
| GB9707800D0 (en) | 1996-05-06 | 1997-06-04 | Zeneca Ltd | Chemical compounds |
| AR007857A1 (es) | 1996-07-13 | 1999-11-24 | Glaxo Group Ltd | Compuestos heterociclicos fusionados como inhibidores de proteina tirosina quinasa, sus metodos de preparacion, intermediarios uso en medicina ycomposiciones farmaceuticas que los contienen. |
| GB9718972D0 (en) | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
| US6225318B1 (en) | 1996-10-17 | 2001-05-01 | Pfizer Inc | 4-aminoquinazolone derivatives |
| AR012634A1 (es) * | 1997-05-02 | 2000-11-08 | Sugen Inc | Compuesto basado en quinazolina, composicion famaceutica que lo comprende, metodo para sintetizarlo, su uso, metodos de modulacion de la funcion deserina/treonina proteinaquinasa con dicho compuesto y metodo in vitro para identificar compuestos que modulan dicha funcion |
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| GB9800575D0 (en) * | 1998-01-12 | 1998-03-11 | Glaxo Group Ltd | Heterocyclic compounds |
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| ATE232205T1 (de) * | 1998-10-01 | 2003-02-15 | Astrazeneca Ab | Chinolin- und chinazolin derivate und ihre verwendung als inhibitoren von krankheiten, bei denen cytokine beteiligt wird |
| JP3270834B2 (ja) * | 1999-01-27 | 2002-04-02 | ファイザー・プロダクツ・インク | 抗がん剤として有用なヘテロ芳香族二環式誘導体 |
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| CZ20014083A3 (cs) * | 1999-05-14 | 2002-08-14 | Imclone Systems Incorporated | Léčivo pro indikaci růstu refrakterních nádorů |
| HK1044769B (zh) * | 1999-06-21 | 2005-02-25 | 贝林格尔英格海姆法玛两合公司 | 雙環雜環化合物,含有該化合物的藥物組合物,該化合物的用途及其製備方法 |
| JP2003504363A (ja) | 1999-07-09 | 2003-02-04 | グラクソ グループ リミテッド | プロテインチロシンキナーゼ阻害剤としてのアニリノキナゾリン類 |
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| CA2384282A1 (en) * | 1999-09-21 | 2001-03-29 | Astrazeneca Ab | Quinazoline compounds and pharmaceutical compositions containing them |
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| US6521618B2 (en) | 2000-03-28 | 2003-02-18 | Wyeth | 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors |
| ES2267748T3 (es) | 2000-04-07 | 2007-03-16 | Astrazeneca Ab | Compuestos de quinazolina. |
| US6627634B2 (en) * | 2000-04-08 | 2003-09-30 | Boehringer Ingelheim Pharma Kg | Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them |
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| DE10042058A1 (de) * | 2000-08-26 | 2002-03-07 | Boehringer Ingelheim Pharma | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
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| GB0206215D0 (en) | 2002-03-15 | 2002-05-01 | Novartis Ag | Organic compounds |
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| JP4776882B2 (ja) * | 2002-03-30 | 2011-09-21 | ベーリンガー インゲルハイム ファルマ ゲゼルシャフト ミット ベシュレンクテル ハフツング ウント コンパニー コマンディトゲゼルシャフト | 二環式複素環化合物、これらの化合物を含む医薬組成物、それらの使用及びそれらの調製方法 |
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| 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 |
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-
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- 1996-02-14 GB GBGB9603095.2A patent/GB9603095D0/en active Pending
-
1997
- 1997-02-10 EP EP97902496A patent/EP0880507B1/en not_active Expired - Lifetime
- 1997-02-10 WO PCT/GB1997/000344 patent/WO1997030034A1/en not_active Ceased
- 1997-02-10 NZ NZ330816A patent/NZ330816A/xx not_active IP Right Cessation
- 1997-02-10 IL IL12568597A patent/IL125685A/en not_active IP Right Cessation
- 1997-02-10 ES ES97902496T patent/ES2239351T3/es not_active Expired - Lifetime
- 1997-02-10 KR KR10-1998-0706321A patent/KR100494824B1/ko not_active Expired - Fee Related
- 1997-02-10 AT AT97902496T patent/ATE293103T1/de active
- 1997-02-10 JP JP52907397A patent/JP4074342B2/ja not_active Expired - Fee Related
- 1997-02-10 CN CNB97192242XA patent/CN1142919C/zh not_active Expired - Fee Related
- 1997-02-10 PT PT97902496T patent/PT880507E/pt unknown
- 1997-02-10 DE DE69733008T patent/DE69733008T2/de not_active Expired - Lifetime
- 1997-02-10 AU AU16126/97A patent/AU707339B2/en not_active Ceased
- 1997-02-12 MY MYPI97000500A patent/MY119992A/en unknown
- 1997-02-13 US US08/796,483 patent/US5866572A/en not_active Expired - Lifetime
- 1997-02-13 ZA ZA9701231A patent/ZA971231B/xx unknown
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1998
- 1998-08-13 NO NO19983707A patent/NO311936B1/no not_active IP Right Cessation
- 1998-09-11 US US09/152,070 patent/US6399602B1/en not_active Expired - Fee Related
-
2002
- 2002-05-02 US US10/136,276 patent/US6897214B2/en not_active Expired - Fee Related
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| ATE293103T1 (de) | 2005-04-15 |
| AU707339B2 (en) | 1999-07-08 |
| EP0880507A1 (en) | 1998-12-02 |
| GB9603095D0 (en) | 1996-04-10 |
| IL125685A0 (en) | 1999-04-11 |
| EP0880507B1 (en) | 2005-04-13 |
| US5866572A (en) | 1999-02-02 |
| KR19990082583A (ko) | 1999-11-25 |
| JP2000504713A (ja) | 2000-04-18 |
| IL125685A (en) | 2002-11-10 |
| WO1997030034A1 (en) | 1997-08-21 |
| AU1612697A (en) | 1997-09-02 |
| KR100494824B1 (ko) | 2005-11-23 |
| CN1142919C (zh) | 2004-03-24 |
| CN1211240A (zh) | 1999-03-17 |
| JP4074342B2 (ja) | 2008-04-09 |
| US6897214B2 (en) | 2005-05-24 |
| US6399602B1 (en) | 2002-06-04 |
| NO983707L (no) | 1998-10-13 |
| MY119992A (en) | 2005-08-30 |
| ZA971231B (en) | 1997-08-14 |
| NO311936B1 (no) | 2002-02-18 |
| PT880507E (pt) | 2005-07-29 |
| DE69733008D1 (de) | 2005-05-19 |
| NO983707D0 (no) | 1998-08-13 |
| US20030018029A1 (en) | 2003-01-23 |
| NZ330816A (en) | 2000-05-26 |
| ES2239351T3 (es) | 2005-09-16 |
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