CN1100540C - 具有选择性抑制her-2自磷酸化性质的蛋白质酪氨酸激酶芳基和杂芳基喹唑啉化合物 - Google Patents
具有选择性抑制her-2自磷酸化性质的蛋白质酪氨酸激酶芳基和杂芳基喹唑啉化合物 Download PDFInfo
- Publication number
- CN1100540C CN1100540C CN96194512A CN96194512A CN1100540C CN 1100540 C CN1100540 C CN 1100540C CN 96194512 A CN96194512 A CN 96194512A CN 96194512 A CN96194512 A CN 96194512A CN 1100540 C CN1100540 C CN 1100540C
- Authority
- CN
- China
- Prior art keywords
- dimethoxyquinazoline
- hydrogen
- pharmaceutically acceptable
- chemical compound
- acceptable salt
- 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 - Fee Related
Links
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 title claims abstract description 26
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 title claims abstract description 26
- -1 heteroaryl quinazoline compounds Chemical class 0.000 title claims description 53
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 title description 15
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 title description 15
- 230000035578 autophosphorylation Effects 0.000 title description 10
- 125000003118 aryl group Chemical group 0.000 title description 9
- 230000005764 inhibitory process Effects 0.000 title description 6
- 238000000034 method Methods 0.000 claims abstract description 18
- 230000000694 effects Effects 0.000 claims abstract description 14
- 230000010261 cell growth Effects 0.000 claims abstract description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 5
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 64
- 150000003839 salts Chemical class 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 24
- 229910052739 hydrogen Inorganic materials 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 14
- 125000001624 naphthyl group Chemical group 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 239000000203 mixture Substances 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 230000004069 differentiation Effects 0.000 claims description 7
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical group C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 claims description 6
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 125000004122 cyclic group Chemical group 0.000 claims description 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000002541 furyl group Chemical group 0.000 claims description 6
- 125000001188 haloalkyl group Chemical group 0.000 claims description 6
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 6
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 claims description 6
- 125000004193 piperazinyl group Chemical group 0.000 claims description 6
- 125000005936 piperidyl group Chemical group 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 6
- 125000005493 quinolyl group Chemical group 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000004104 aryloxy group Chemical group 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- ZUPRNGKVHHRCEZ-UHFFFAOYSA-N 4-(1-benzylindol-3-yl)-6,7-dimethoxyquinazoline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1C(C1=CC=CC=C11)=CN1CC1=CC=CC=C1 ZUPRNGKVHHRCEZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
- 239000000460 chlorine Substances 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- 125000004442 acylamino group Chemical group 0.000 claims description 3
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 claims description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 150000005171 halobenzenes Chemical class 0.000 claims description 3
- 125000004415 heterocyclylalkyl group Chemical group 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 3
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 3
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000002757 morpholinyl group Chemical group 0.000 claims description 3
- 125000002971 oxazolyl group Chemical group 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 3
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 3
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- NAUXREJEKXHHLT-UHFFFAOYSA-N 4-(3,4-dihydro-2h-quinolin-1-yl)-6,7-dimethoxyquinazoline Chemical compound C1CCC2=CC=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 NAUXREJEKXHHLT-UHFFFAOYSA-N 0.000 claims description 2
- PSEFPQZGWLHPGF-UHFFFAOYSA-N 4-[4-(3-chlorophenyl)piperazin-1-yl]-6,7-dimethoxyquinazoline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1N(CC1)CCN1C1=CC=CC(Cl)=C1 PSEFPQZGWLHPGF-UHFFFAOYSA-N 0.000 claims description 2
- FYNYWPMPAKYSKW-UHFFFAOYSA-N 6,7-dimethoxy-4-(1-methylindol-3-yl)quinazoline Chemical compound C1=CC=C2C(C=3N=CN=C4C=C(C(=CC4=3)OC)OC)=CN(C)C2=C1 FYNYWPMPAKYSKW-UHFFFAOYSA-N 0.000 claims description 2
- UWAQQRRVNFYNQW-UHFFFAOYSA-N 6,7-dimethoxy-4-naphthalen-1-ylquinazoline Chemical compound C1=CC=C2C(C=3N=CN=C4C=C(C(=CC4=3)OC)OC)=CC=CC2=C1 UWAQQRRVNFYNQW-UHFFFAOYSA-N 0.000 claims description 2
- UYWRXDKESNBMJB-UHFFFAOYSA-N C1(CCCCC1)C1=C(C=CC=C1)C(=O)NC1=NC=NC2=CC(=C(C=C12)OC)OC Chemical compound C1(CCCCC1)C1=C(C=CC=C1)C(=O)NC1=NC=NC2=CC(=C(C=C12)OC)OC UYWRXDKESNBMJB-UHFFFAOYSA-N 0.000 claims description 2
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 2
- 125000004639 dihydroindenyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims 3
- 230000024245 cell differentiation Effects 0.000 abstract description 3
- 230000001105 regulatory effect Effects 0.000 abstract description 2
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 43
- 238000002360 preparation method Methods 0.000 description 19
- 238000000354 decomposition reaction Methods 0.000 description 17
- 239000002585 base Substances 0.000 description 12
- 239000000463 material Substances 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 10
- 238000006366 phosphorylation reaction Methods 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
- 239000003513 alkali Substances 0.000 description 9
- 239000001963 growth medium Substances 0.000 description 9
- 230000026731 phosphorylation Effects 0.000 description 9
- 230000004663 cell proliferation Effects 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 239000002253 acid Substances 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 229910000080 stannane Inorganic materials 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000002775 capsule Substances 0.000 description 5
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 5
- 239000006185 dispersion Substances 0.000 description 5
- 239000013067 intermediate product Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000002953 phosphate buffered saline Substances 0.000 description 5
- 238000001890 transfection Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 102000009465 Growth Factor Receptors Human genes 0.000 description 4
- 108010009202 Growth Factor Receptors Proteins 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 102000013275 Somatomedins Human genes 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 125000005842 heteroatom Chemical group 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical compound [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- OTDNCSDKIMJHAS-UHFFFAOYSA-N 1H-indol-2-ylstannane Chemical compound C1=CC=C2NC([SnH3])=CC2=C1 OTDNCSDKIMJHAS-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 229920001817 Agar Polymers 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 3
- 101150054472 HER2 gene Proteins 0.000 description 3
- 101000852815 Homo sapiens Insulin receptor Proteins 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 3
- 108090001061 Insulin Proteins 0.000 description 3
- 102100036721 Insulin receptor Human genes 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- 108700020796 Oncogene Proteins 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 239000000872 buffer Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- 238000006555 catalytic reaction Methods 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 239000013553 cell monolayer Substances 0.000 description 3
- 230000001413 cellular effect Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 108700020302 erbB-2 Genes Proteins 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 229940102223 injectable solution Drugs 0.000 description 3
- 229940125396 insulin Drugs 0.000 description 3
- 201000001117 malignant triton tumor Diseases 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 230000002018 overexpression Effects 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 3
- 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 3
- 125000005871 1,3-benzodioxolyl group Chemical group 0.000 description 2
- 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 2
- XDUSWBSGDKRQAF-UHFFFAOYSA-N 4-(3-chlorophenoxy)-6,7-dimethoxyquinazoline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC1=CC=CC(Cl)=C1 XDUSWBSGDKRQAF-UHFFFAOYSA-N 0.000 description 2
- XXLFLUJXWKXUGS-UHFFFAOYSA-N 6-methoxyquinoline-4-carboxylic acid Chemical compound N1=CC=C(C(O)=O)C2=CC(OC)=CC=C21 XXLFLUJXWKXUGS-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 101800003838 Epidermal growth factor Proteins 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 108010001336 Horseradish Peroxidase Proteins 0.000 description 2
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 108010058765 Oncogene Protein pp60(v-src) Proteins 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 229930182555 Penicillin Natural products 0.000 description 2
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 2
- 239000013504 Triton X-100 Substances 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 238000001378 electrochemiluminescence detection Methods 0.000 description 2
- 229940116977 epidermal growth factor Drugs 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000003599 food sweetener Nutrition 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- BRZYSWJRSDMWLG-CAXSIQPQSA-N geneticin Chemical compound O1C[C@@](O)(C)[C@H](NC)[C@@H](O)[C@H]1O[C@@H]1[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](C(C)O)O2)N)[C@@H](N)C[C@H]1N BRZYSWJRSDMWLG-CAXSIQPQSA-N 0.000 description 2
- 239000003102 growth factor Substances 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007937 lozenge Substances 0.000 description 2
- 239000012139 lysis buffer Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000012528 membrane Substances 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
- 230000000813 microbial effect Effects 0.000 description 2
- 210000003470 mitochondria Anatomy 0.000 description 2
- 239000010413 mother solution Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229940049954 penicillin Drugs 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 2
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 2
- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 2
- 229940023488 pill Drugs 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 210000000664 rectum Anatomy 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000011593 sulfur Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000003765 sweetening agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- WMPTYRGXBUYONY-UHFFFAOYSA-N 2-chloroquinazoline Chemical compound C1=CC=CC2=NC(Cl)=NC=C21 WMPTYRGXBUYONY-UHFFFAOYSA-N 0.000 description 1
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- HORNXRXVQWOLPJ-UHFFFAOYSA-N 3-chlorophenol Chemical compound OC1=CC=CC(Cl)=C1 HORNXRXVQWOLPJ-UHFFFAOYSA-N 0.000 description 1
- TVMABLXKYCZLQT-UHFFFAOYSA-N 4-(1h-indol-3-yl)-6,7-dimethoxyquinazoline Chemical compound C1=CC=C2C(C=3N=CN=C4C=C(C(=CC4=3)OC)OC)=CNC2=C1 TVMABLXKYCZLQT-UHFFFAOYSA-N 0.000 description 1
- VFCGGDJQUYSDNZ-UHFFFAOYSA-N 4-(3-chlorophenyl)sulfanyl-6,7-dimethylquinazoline Chemical compound C=12C=C(C)C(C)=CC2=NC=NC=1SC1=CC=CC(Cl)=C1 VFCGGDJQUYSDNZ-UHFFFAOYSA-N 0.000 description 1
- JEDZCSQOMABHIL-UHFFFAOYSA-N 4-(3-fluoro-4-methoxyphenyl)-6,7-dimethoxyquinazoline Chemical compound C1=C(F)C(OC)=CC=C1C1=NC=NC2=CC(OC)=C(OC)C=C12 JEDZCSQOMABHIL-UHFFFAOYSA-N 0.000 description 1
- FPBDLXOPYMEJEU-UHFFFAOYSA-N 4-(6,7-dimethoxyquinazolin-4-yl)phenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1C1=CC=C(O)C=C1 FPBDLXOPYMEJEU-UHFFFAOYSA-N 0.000 description 1
- JIMDFIJSVLWCJL-UHFFFAOYSA-N 4-benzyl-6,7-dimethoxyquinazoline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1CC1=CC=CC=C1 JIMDFIJSVLWCJL-UHFFFAOYSA-N 0.000 description 1
- LLLHRNQLGUOJHP-UHFFFAOYSA-N 4-chloro-6,7-dimethoxyquinazoline Chemical compound C1=NC(Cl)=C2C=C(OC)C(OC)=CC2=N1 LLLHRNQLGUOJHP-UHFFFAOYSA-N 0.000 description 1
- JZPZNNWLQTURQT-UHFFFAOYSA-N 4-indol-1-yl-6,7-dimethoxyquinazoline Chemical compound C1=CC2=CC=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 JZPZNNWLQTURQT-UHFFFAOYSA-N 0.000 description 1
- UAUAGTWGPRTDGV-UHFFFAOYSA-N 6,7-dimethoxy-4-(1-methylsulfonylindol-3-yl)quinazoline Chemical compound C1=CC=C2C(C=3N=CN=C4C=C(C(=CC4=3)OC)OC)=CN(S(C)(=O)=O)C2=C1 UAUAGTWGPRTDGV-UHFFFAOYSA-N 0.000 description 1
- CBHGEWAKLVNPCO-UHFFFAOYSA-N 6,7-dimethoxy-4-(4-phenylpiperidin-1-yl)quinazoline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1N(CC1)CCC1C1=CC=CC=C1 CBHGEWAKLVNPCO-UHFFFAOYSA-N 0.000 description 1
- OOSROWLVMZGPNU-UHFFFAOYSA-N 6,7-dimethoxy-4-(6-methoxypyridin-3-yl)quinazoline Chemical compound C1=NC(OC)=CC=C1C1=NC=NC2=CC(OC)=C(OC)C=C12 OOSROWLVMZGPNU-UHFFFAOYSA-N 0.000 description 1
- AXILPVOKGYMDFU-UHFFFAOYSA-N 6,7-dimethoxy-4-naphthalen-1-ylsulfanylquinazoline Chemical compound C1=CC=C2C(SC=3N=CN=C4C=C(C(=CC4=3)OC)OC)=CC=CC2=C1 AXILPVOKGYMDFU-UHFFFAOYSA-N 0.000 description 1
- OBHRKFNHNKJLME-UHFFFAOYSA-N 6,7-dimethoxy-4-naphthalen-2-ylquinazoline Chemical compound C1=CC=CC2=CC(C=3N=CN=C4C=C(C(=CC4=3)OC)OC)=CC=C21 OBHRKFNHNKJLME-UHFFFAOYSA-N 0.000 description 1
- GBBRLTRKZKVEGX-UHFFFAOYSA-N 6,7-dimethyl-4-[7-(trifluoromethyl)-3,4-dihydro-2h-quinolin-1-yl]quinazoline Chemical compound C1CCC2=CC=C(C(F)(F)F)C=C2N1C1=C(C=C(C(C)=C2)C)C2=NC=N1 GBBRLTRKZKVEGX-UHFFFAOYSA-N 0.000 description 1
- KSGXTSVNEOZOHU-UHFFFAOYSA-N 6,7-dimethyl-4-naphthalen-1-ylsulfanylquinazoline Chemical compound C1=CC=C2C(SC=3N=CN=C4C=C(C(=CC4=3)C)C)=CC=CC2=C1 KSGXTSVNEOZOHU-UHFFFAOYSA-N 0.000 description 1
- ZDXANTCHDQIHQK-UHFFFAOYSA-N 6,7-dimethyl-n-naphthalen-1-ylquinazolin-4-amine Chemical compound C1=CC=C2C(NC=3N=CN=C4C=C(C(=CC4=3)C)C)=CC=CC2=C1 ZDXANTCHDQIHQK-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- WGPYEKRKOGJHER-UHFFFAOYSA-N C1(=CC=CC=2CCCCC12)C1=NC(=NC2=CC(=C(C=C12)OC)OC)N Chemical compound C1(=CC=CC=2CCCCC12)C1=NC(=NC2=CC(=C(C=C12)OC)OC)N WGPYEKRKOGJHER-UHFFFAOYSA-N 0.000 description 1
- HCFZZIUGQJOGOY-UHFFFAOYSA-N CC=1C=C(C=C(C1)C)C(=O)NC1=NC=NC2=CC(=C(C=C12)C)C Chemical compound CC=1C=C(C=C(C1)C)C(=O)NC1=NC=NC2=CC(=C(C=C12)C)C HCFZZIUGQJOGOY-UHFFFAOYSA-N 0.000 description 1
- JQTQNPCIHRAKHP-UHFFFAOYSA-N CN(C(=O)C1=CC(=C(C(=C1)OC)OC)OC)C1=NC=NC2=CC(=C(C=C12)OC)OC Chemical compound CN(C(=O)C1=CC(=C(C(=C1)OC)OC)OC)C1=NC=NC2=CC(=C(C=C12)OC)OC JQTQNPCIHRAKHP-UHFFFAOYSA-N 0.000 description 1
- AKFFIFJVQYKUCR-UHFFFAOYSA-N CN(C(=O)C1=CC=C(C=C1)OC)C1=NC=NC2=CC(=C(C=C12)OC)OC Chemical compound CN(C(=O)C1=CC=C(C=C1)OC)C1=NC=NC2=CC(=C(C=C12)OC)OC AKFFIFJVQYKUCR-UHFFFAOYSA-N 0.000 description 1
- DYXAAJDUNNCUJQ-UHFFFAOYSA-N COC1=C(SC=C1OC)C1=NC=NC2=CC=CC=C12 Chemical compound COC1=C(SC=C1OC)C1=NC=NC2=CC=CC=C12 DYXAAJDUNNCUJQ-UHFFFAOYSA-N 0.000 description 1
- XNKIZOHRIIKKSX-UHFFFAOYSA-N COC=1C=C(C=C(C1OC)OC)C(=O)NC1=NC=NC2=CC(=C(C=C12)OC)OC Chemical compound COC=1C=C(C=C(C1OC)OC)C(=O)NC1=NC=NC2=CC(=C(C=C12)OC)OC XNKIZOHRIIKKSX-UHFFFAOYSA-N 0.000 description 1
- AQEXORBPAPGPOX-UHFFFAOYSA-N COC=1C=C2C(=NC=NC2=CC1OC)N(CC)C1=CC2=CC=CC=C2C=C1 Chemical compound COC=1C=C2C(=NC=NC2=CC1OC)N(CC)C1=CC2=CC=CC=C2C=C1 AQEXORBPAPGPOX-UHFFFAOYSA-N 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 108010035563 Chloramphenicol O-acetyltransferase Proteins 0.000 description 1
- 235000001258 Cinchona calisaya Nutrition 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000009024 Epidermal Growth Factor Human genes 0.000 description 1
- 208000035126 Facies Diseases 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 102100029974 GTPase HRas Human genes 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 101000584633 Homo sapiens GTPase HRas Proteins 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108060003951 Immunoglobulin Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 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 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 102000000422 Matrix Metalloproteinase 3 Human genes 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- 102000016979 Other receptors Human genes 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 102000009097 Phosphorylases Human genes 0.000 description 1
- 108010073135 Phosphorylases Proteins 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- 101710089165 Protein white Proteins 0.000 description 1
- 201000004681 Psoriasis Diseases 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 101001010820 Rattus norvegicus Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 239000012722 SDS sample buffer Substances 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- 102000004584 Somatomedin Receptors Human genes 0.000 description 1
- 108010017622 Somatomedin Receptors Proteins 0.000 description 1
- QTENRWWVYAAPBI-YZTFXSNBSA-N Streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@H]1[C@H](N=C(N)N)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@H]1[C@H](N=C(N)N)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]1O QTENRWWVYAAPBI-YZTFXSNBSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 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 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 102100023935 Transmembrane glycoprotein NMB Human genes 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- ZKHQWZAMYRWXGA-KNYAHOBESA-N [[(2r,3s,4r,5r)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] dihydroxyphosphoryl hydrogen phosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)O[32P](O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KNYAHOBESA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical class NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001502 aryl halides Chemical class 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 229940046011 buccal tablet Drugs 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- DKVNPHBNOWQYFE-UHFFFAOYSA-N carbamodithioic acid Chemical compound NC(S)=S DKVNPHBNOWQYFE-UHFFFAOYSA-N 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000013592 cell lysate Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000005757 colony formation Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- HCAJEUSONLESMK-UHFFFAOYSA-N cyclohexylsulfamic acid Chemical compound OS(=O)(=O)NC1CCCCC1 HCAJEUSONLESMK-UHFFFAOYSA-N 0.000 description 1
- 230000002559 cytogenic effect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- UGMCXQCYOVCMTB-UHFFFAOYSA-K dihydroxy(stearato)aluminium Chemical compound CCCCCCCCCCCCCCCCCC(=O)O[Al](O)O UGMCXQCYOVCMTB-UHFFFAOYSA-K 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 108700021358 erbB-1 Genes Proteins 0.000 description 1
- 229950007655 esilate Drugs 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-N ethanesulfonic acid Chemical compound CCS(O)(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 238000005194 fractionation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000011544 gradient gel Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 235000003642 hunger Nutrition 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 1
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 229950004152 insulin human Drugs 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007951 isotonicity adjuster Substances 0.000 description 1
- 238000002372 labelling Methods 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
- 239000010410 layer Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 210000005075 mammary gland Anatomy 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- HJAAVYKVKNFYNJ-UHFFFAOYSA-N n-(3-chlorophenyl)-6,7-dimethoxy-n-methylquinazolin-4-amine;hydrochloride Chemical compound Cl.C=12C=C(OC)C(OC)=CC2=NC=NC=1N(C)C1=CC=CC(Cl)=C1 HJAAVYKVKNFYNJ-UHFFFAOYSA-N 0.000 description 1
- ALKGLGQPIJKSCS-UHFFFAOYSA-N n-(3-chlorophenyl)-6,7-dimethylquinazolin-4-amine Chemical compound C=12C=C(C)C(C)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1 ALKGLGQPIJKSCS-UHFFFAOYSA-N 0.000 description 1
- QEKVMLIDJJUYJN-UHFFFAOYSA-N n-(3-chlorophenyl)-n-ethyl-6,7-dimethoxyquinazolin-4-amine Chemical compound N=1C=NC2=CC(OC)=C(OC)C=C2C=1N(CC)C1=CC=CC(Cl)=C1 QEKVMLIDJJUYJN-UHFFFAOYSA-N 0.000 description 1
- KSYPLPLNXJJFNG-UHFFFAOYSA-N n-(3-chlorophenyl)-n-methylquinazolin-4-amine Chemical compound N=1C=NC2=CC=CC=C2C=1N(C)C1=CC=CC(Cl)=C1 KSYPLPLNXJJFNG-UHFFFAOYSA-N 0.000 description 1
- PKOUZZXESDCMFW-UHFFFAOYSA-N n-(4-chlorophenyl)-6,7-dimethoxy-n-methylquinazolin-4-amine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1N(C)C1=CC=C(Cl)C=C1 PKOUZZXESDCMFW-UHFFFAOYSA-N 0.000 description 1
- LNIYPQOICFDONW-UHFFFAOYSA-N n-ethyl-6,7-dimethoxy-n-phenylquinazolin-4-amine Chemical compound N=1C=NC2=CC(OC)=C(OC)C=C2C=1N(CC)C1=CC=CC=C1 LNIYPQOICFDONW-UHFFFAOYSA-N 0.000 description 1
- YQXKCMLAWNXNNN-UHFFFAOYSA-N n-methyl-n-phenylquinazolin-4-amine;hydrochloride Chemical compound Cl.N=1C=NC2=CC=CC=C2C=1N(C)C1=CC=CC=C1 YQXKCMLAWNXNNN-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 229910052756 noble gas Inorganic materials 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 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
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 238000010837 poor prognosis Methods 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 229960000948 quinine Drugs 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 239000012723 sample buffer Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 230000037351 starvation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 229940041022 streptomycins Drugs 0.000 description 1
- 108091007196 stromelysin Proteins 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 150000005846 sugar alcohols Polymers 0.000 description 1
- IIACRCGMVDHOTQ-UHFFFAOYSA-M sulfamate Chemical compound NS([O-])(=O)=O IIACRCGMVDHOTQ-UHFFFAOYSA-M 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 210000001258 synovial membrane Anatomy 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate 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
- 210000003684 theca cell Anatomy 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- CCRMAATUKBYMPA-UHFFFAOYSA-N trimethyltin Chemical compound C[Sn](C)C.C[Sn](C)C CCRMAATUKBYMPA-UHFFFAOYSA-N 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
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 235000012431 wafers Nutrition 0.000 description 1
- 210000004885 white matter Anatomy 0.000 description 1
- 239000009637 wintergreen oil Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring
- C07C43/2055—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring containing more than one ether bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/50—Pyridazines; Hydrogenated pyridazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/225—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
-
- 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
- C07D213/28—Radicals substituted by singly-bound oxygen or sulphur atoms
- C07D213/30—Oxygen atoms
-
- 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
- C07D213/60—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/18—Halogen atoms or nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
- C07D215/22—Oxygen atoms attached in position 2 or 4
- C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
-
- 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
- C07D239/74—Quinazolines; Hydrogenated quinazolines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to ring carbon atoms of the hetero ring
-
- 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
- C07D239/88—Oxygen atoms
-
- 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
- C07D239/88—Oxygen atoms
- C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
-
- 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
- C07D239/93—Sulfur atoms
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/50—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to ring nitrogen atoms
- C07D241/52—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/20—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 4
- C07D265/22—Oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
- C07D277/62—Benzothiazoles
- C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D405/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Heart & Thoracic Surgery (AREA)
- Virology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Urology & Nephrology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及用于选择性治疗以人表皮生长因子受体2型(HER2)的活性为特征的细胞生长和分化的方法。更具体地说,本发明涉及取代的或未取代的单-环或双-环芳基、杂芳基、环烷基或杂环烷基化合物在选择性地调节细胞生长中的用途。本发明也描述了用于选择性治疗细胞生长和分化的药物组合物。
Description
发明背景
本申请是PCT国际申请PCT/US94/14180(其国际申请日为1994年12月8日,指定美国)、美国08/166,199号申请(其申请日是1993年12月10日,它是1992年12月10日提出申请的美国07/988,515号申请的部分继续申请,后者是1991年5月年10日提出申请的美国07/698,420号申请的部分继续申请)以及PCT国际申请PCT/US92/03736(1992年5月6日提出申请,指定美国,已导致获得美国专利5,409,930)的部分继续申请。
发明所属技术领域
本发明涉及用于选择性治疗以人表皮生长因子受体2型(HER2)的活性为特征的细胞生长和分化的方法。更具体地说,本发明涉及取代的或未取代的单-环或双-环芳基、杂芳基、环烷基或杂环烷基化合物在选择性地调节细胞生长中的用途。
正常的细胞复制被认为由细胞底物与一种或多种生长因子的接触触发,生长因子的例子是胰岛素、表皮生长因子(EGF)和血小板来源的生长因子(PDGF)。这样的生长因子受体嵌镶于细胞膜中并穿过细胞膜。当生长因子结合到细胞膜外表面的相应受体上时就认为细胞复制开始发生。该生长因子-受体结合改变了受体(存在于细胞内部,作为催化胞内底物或受体自身磷酸化的酶起作用,后者称为自磷酸化)的结合部分的化学特征。这样的磷酸化酶的例子包括酪氨酸激酶,该酪氨酸激酶催化底物蛋白质的酪氨酸残基的磷酸化。
许多疾病状态的特征在于细胞不受控制的复制。这些疾病状态包括各种细胞类型并包括这样一些病症,如白血病、癌、牛皮癣、炎症性疾病、骨疾病、动脉粥样硬化和血管形成术后的再狭窄。酪氨酸激酶的抑制被认为具有控制不受控制的细胞复制(即细胞增殖病症)的效用。
胞内底物宿主(host)的自磷酸化(即生长因子受体自身的磷酸化)和磷酸化的起始是一些生物化学事件,这些事件包括介质释放导致有丝分裂和细胞增殖。胰岛素受体的自磷酸化以及通过其它受体的底物蛋白质的磷酸化是最早可鉴别的生物化学激素反应。
通过细胞遗传物质(负责胰岛素和EGF的产生)的定点诱变除去胰岛素受体和表皮生长因子(EGF)受体的蛋白质酪氨酸激酶(PTK)活性导致受体生物学活性的完全消除。这不是很合乎需要,因为身体还需要胰岛素完成与细胞增殖无关的其它生物学功能。因此,以小于抑制胰岛素受体的PTK部分所需浓度的浓度抑制EGF和/或PDGF受体的PTK部分的化合物可提供用于选择性地治疗细胞增殖病症的有价值的药剂。
已报道的进展
人们普遍接受这样一种观点,即与生长因子受体有关的蛋白质酪氨酸激酶(PTK)活性对配体诱导的生物学反应(如细胞生长和分化)是必需的。J.M.Bishop(1985)细胞,42:23-38和T.Hunter(1987)细胞50:823-829报道了通过酪氨酸磷酸化的异常细胞生长和形态转变的证据,生长因子受体代表了bonafide致癌基因族。这些致癌基因产物中是人表皮生长因子受体2型(HER2;c-erbB-2)。Carpenter等(1987)生物化学年评,56:881-和Gill等(1987)Mol.Cell.Endocrinol.,51:169-报道了c-erbB-1基因编码170kDa的跨膜糖蛋白。HER2基因是大鼠原癌基因neu的人同系物,这由C.I.Bargmann,M.C.Hung和R.A.Weinberg(1986)自然,319:226-229报导,其产物是185-kDa跨膜细胞表面糖蛋白,称为p185HER2,这由Coussens等(1985)科学230:1132-1139和Yamamoto等(1986)自然319:230-234报导。该受体具有内在的酪氨酸-特异性激酶活性(通过把其同源配体结合在受体胞外结构域上,它能够催化自磷酸化反应并介导内源底物磷酸化)。
发现了未改变的HER2基因在各种人肿瘤上扩增。此外,在患几种癌症类型的患者中建立了高水平P185HER2表达和不良预后或短暂存活时间之间的相关性。因为使用抗p185HER2产生的抗体(它封闭受体功能)导致肿瘤细胞系的生长停止和小鼠中抗肿瘤作用,化学-设计的试剂选择性地抑制p185HER2-有关的PTK的策略在癌症治疗中有价值。现在大量文献显示已系统地评价了许多天然产生的和合成的PTK抑制剂的潜在抗肿瘤功效,如由C.Workman,V.G.Brunton和D.J.Robins(1992)在“癌症生物学研论会”,3:369-381以及C.Wasylyk,A.Gutman,R.Nicholson和B.Wasylyk(1991)EMBO杂志,10:1127-1134中报道的。
在本文中申请人描述了一系列喹唑啉衍生物(它们是p185HER2选择性的酪氨酸激酶抑制剂)的鉴别和定性方法。尤其是,申请人证明了保持由p185HER2超量表达诱导的转化的细胞表型,需要与HER2基因产物有关的酪氨酸激酶活性。
发明概述
本发明提供了用于选择性治疗以人表皮生长因子受体2型(HER2)的活性为特征的细胞生长和分化的方法,该方法包括对需要这样治疗的患者施用HER2受体抑制有效量的、在本发明中所描述的喹唑啉化合物。
本发明的另一个方面涉及用于选择性地治疗以人表皮生长因子受体2型(HER2)的活性为特征的细胞生长和分化的药物组合物,该药物组合物包含与药学上可接受的载体混合的、治疗有效量的前述类型的化合物。
本发明的另一个方面还包括用于实施本发明的方法的新化合物。
就本发明的各方面而言,由以下式I描述的化合物或其药学上可接受的盐组成了一类前述的、用于实施本发明的喹唑啉化合物:其中
A是大约5至12个原子的取代的或未取代的单-环或双-环芳基、杂芳基、环烷基或杂环烷基环状系统,其中的取代基可位于环状系统的任何适当的位置,并由R代表;
X是化学键、O、S、SO、SO2、OCH2、CR4=CR4、C≡C、NR4或NR4CH2;
R独立地包括氢、烷基、苯基、卤苯基、芳烷基、羟基、烷氧基、芳氧基、酰氧基、卤素、卤代烷基、氨基、一-和二-烷基氨基、酰基氨基、羧基、酰氨基、一-和二-烷基酰氨基、烷硫基、烷亚硫酰基以及烷磺酰基。
R4是氢、烷基或芳烷基;
R5,R6,R7和R8独立地是氢、烷氧基或芳烷氧基。
详述描述及优选的实施方案
除非特别指出,上面与本说明书全文使用的下列术语应理解为具有下列含义:
“单环芳基”或“单环杂芳基”指碳环或杂环芳环。优选的环包括苯基、吡咯基、噻吩基、呋喃基、噻唑基、咪唑基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、异噻唑基、异噁唑基和噁唑基。
“双环芳基”或“双环杂芳基”指由两个稠和的环(其中至少之一是碳环或杂环芳环)组成的双环环状系统。优选的环包括取代的和未取代的萘基、1,2,3,4-四氢萘基、1,2,3,4-四氢喹啉基、苯并呋喃基、苯并噻吩基、吲哚基、二氢吲哚基、1,3-苯并间二氧杂环戊烯基、苯并二噁烷基、喹啉基、四氢喹啉基、异喹啉基、喹唑啉基和喹喔啉基。
“单环环烷基”指包含大约四至七个碳原子的脂族环,如取代的和未取代的环戊基、环己基和环庚基。
“双环环烷基”指包含大约8至12个碳原子的、由包含两个稠和的脂族环组成的饱和双环环状系统,如取代的和未取代的十氢萘基。
“单环杂环烷基”指包含大约四至七个原子的饱和环状的脂族环,它包含选自N、O和S的1-2个杂原子(假如所说的杂原子不在氧和/或硫附近),如取代和未取代的哌啶基、哌嗪基和吗啉基。
“双环杂环烷基”指包含大约8至12个原子的两个稠和的脂族环的饱和双环环状系统,它包含选自N、O和S的1-3个杂原子(假如所说的杂原子不在氧和/或硫附近),如取代和未取代的十氢喹啉基。
“烷基”指饱和的支链或直链脂族烃。优选的烷基是具有大约1至6个碳原子的“低级烷基”。烷基的例子包括甲基、乙基、正丙基、异丙基、丁基、仲丁基、叔丁基、戊基和己基。
“烷氧基”指烷基-O-基团。优选的烷氧基包括甲氧基、乙氧基、丙氧基和丁氧基。
“芳氧基”指芳基-O-基团。优选的芳氧基是苯氧基。
“芳烷基”指由芳基取代的烷基基团。优选的芳烷基是苯基或苯乙基。
优选的芳烷氧基基团是苄氧基和苯乙氧基。
优选的酰氧基基团是乙酰氧基和苄氧基;
“卤素”指卤素。优选的卤素包括氯、溴和氟。
优选的卤代烷基基团是单-、二-和三氟甲基。
更具体地说,优选的A单环芳基或杂芳基环包括取代的或未取代的苯基、吡咯基、噻吩基、呋喃基、噻唑基、咪唑基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、异噻唑基、异噁唑基和噁唑基。
优选的A双环芳基或杂芳基环包括取代的或未取代的萘基、1,2,3,4-四氢萘基、1,2,3,4-四氢喹啉基、苯并呋喃基、苯并噻吩基、吲哚基、二氢吲哚基、1,3-苯并间二氧杂环戊烯基、苯并二噁烷基、喹啉基、四氢喹啉基、异喹啉基、喹唑啉基和喹喔啉基。
优选的A单环环烷基或杂环烷基环包括取代的或未取代的环戊基、环己基、环庚基、十氢萘基、哌啶基、哌嗪基、吗啉基或十氢喹啉基。
优选的A双环环烷基或杂环烷基环包括取代的或未取代的十氢萘基或十氢喹啉基。
更优选的化合物如下:
A是取代和未取代的苯基、吡啶基、噻吩基、呋喃基、吡唑基、萘基、1,2,3,4-四氢萘基,1,2,3,4-四氢喹啉基、吲哚基、二氢吲哚基、喹啉基、四氢喹啉基、环己基、哌啶基或哌嗪基;
X是化学键、O、S或NR4;
R是氢、烷基、烷氧基、卤素、卤代烷基、烷硫基、烷亚硫酰基、烷磺酰基、苯基和芳烷基;
R4是氢、烷基或芳烷基;
R5,R6,R7和R8独立地是氢或烷氧基。
最优选的化合物如下:
A是取代的和未取代的苯基、萘基或吲哚基;
X是化学键;
R是氢、甲氧基、乙氧基、氯、三氟甲基、甲磺酰基、苯基和苄基;
R4是氢、甲基或苄基;
R5,R6,R7和R8独立地是氢或甲氧基。
在本发明范围之内的化合物是人表皮生长因子受体2型(HER2)的选择性酪氨酸激酶抑制剂。治疗有用的PTK抑制化合物被认为对能够催化自身磷酸化的酪氨酸激酶活性特异。此外,这些化合物应抑制生长因子诱导的细胞增殖。达到此标准的化合物具有重要的价值,在实施本发明时尤其有用。本文描述了表现出对上述受体有选择性的化合物。
本发明的化合物可以以游离碱的形式、盐的形式和以水合物的形式使用。所有形式都在本发明的范围之内。可以形成酸加成盐,这是简单的、更方便的使用形式;在实施中,盐形式的使用本质上相当于碱形式的使用。可以用于制备酸加成盐的酸优选地包括这样的酸,该酸在与游离碱结合时产生药学上可接受的盐(即其阴离子在该盐的药剂量下对动物有机体无毒的盐)以使在游离碱中本质上有益性质不受阴离子的副作用的损害。尽管所说的碱性化合物的药学上可接受的盐是优选的,但所有的酸加成盐可用作游离碱形式的来源(既使上述特定的盐仅需要作为中间产物,例如,在当仅为了纯化和鉴别目的形成盐时,或当通过离子交换方法制备药学上可接受的盐中其作为中间产物时)。
在本发明的范围之内的药学上可接受的盐包括来源于下列酸的盐:无机酸如盐酸、硫酸、磷酸的和氨磺酸;有机酸如乙酸、柠檬酸、乳酸、酒石酸、丙二酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环己基氨基磺酸、奎宁酸等。
相应的酸加成盐分别包括下列盐:盐酸盐、硫酸盐、磷酸盐、氨基磺酸盐、醋酸盐、柠檬酸盐、乳酸盐、酒石酸盐、甲磺酸盐、乙磺酸盐、苯磺酸盐、对甲苯磺酸盐、环己基氨基磺酸盐和奎宁酸盐。
可以通过把游离碱溶解在包含适当酸的水或水-醇溶液中或其它适合溶剂中并通过蒸发溶液分离所述盐,或者通过游离碱与酸在有机溶剂中反应(在这种情况下,直接分离所述盐或通过溶液浓缩获得)制备本发明化合物的酸加成盐。
可以通过使用文献中已知的方法从已知化合物或易于制备的中间产物开始制备本发明的化合物。一般型方法举例说明如下。
一般可以通过钯催化的芳基或杂芳基锡烷与芳基或杂芳基卤化物或三氟甲磺酸酯的偶联反应制备用于选择性治疗以人表皮生长因子受体2型的活性为特征的细胞生长和分化方法的化合物。
式中Y是卤素或三氟甲磺酸酯,Z是三烷基锡烷,R如前所述。
以经典方法制备4-卤喹唑啉起始物质:使用邻氨基苯甲酸衍生物和甲酰胺回流产生中间产物喹唑啉。随后在大约110℃下用POCl3处理大约两小时产生了氯喹唑啉。通过与适当的苯胺衍生物在极性溶剂(如乙醇中)缩合制备最终产物。在苯氧基或噻吩氧基衍生物的情况下,制备金属盐(优选的是钠盐)并与适当的卤喹唑啉在溶剂(如THF)中回流几个小时。
当然,这些产物也可以以相反的方式利用芳基或杂芳基卤化物和相应的锡烷制备。
喹唑啉锡烷中间产物可以如在Chem Pharm RUll 1982,30,1731-1737中描述的通过三甲基锡钠作用于芳基卤化物制备。
在本发明中有用的化合物的制备在申请人的共同未决申请PCT/US94/14180(其国际申请日为1994年12月8日,指定美国作为合同国)、美国08/166,199(在1993年12月10日提出申请)和美国08/229,886(在1994年4月19日提出申请)中描述,本申请对所有这些要求优先权。本文引入PCT/US94/14180、U.S.08/166,199和U.S.08/229,886作为参考。
此外,下列实施例是用于合成本发明的化合物的方法的代表。
可按照下列实施例和PCT/US94/14180和U.S.08/166,199中描述的实施例制备任一本发明所需的化合物。可以制备的化合物的代表性例子显示如下。
实施例14-(3-氯苯氧基)-6,7-二甲氧喹唑啉
在室温下把THF(5ml)和NaH(在油中的60%分散体,大约28mg)添加到惰性气体下保持的干燥烧瓶中。加入3-氯苯酚(0.09g)的THF(1ml)溶液。持续搅拌直到溶液变得澄清。一次添加所有4-氯-6,7-二甲氧基喹唑啉(固体),在RT下持续搅拌过夜。使溶液在CH2Cl2和5%NaOH之间分配。以盐水洗涤有机层,干燥(Na2SO4)并浓缩。快速柱层析(40%EtOAc/Hex)给出纯化合物。通过重结晶从EtOAc/Hex获得分析样品,得4-(3-氯苯氧基)-6,7-二甲氧基喹唑啉(0.05g),白色针状,熔点152-153℃。
实施例24-(1-甲磺酰吲哚-3-基)-6,7-二甲氧基喹唑啉
步骤A N-甲磺酰基-3-三甲基甲锡烷基吲哚
以氮充分冲洗5g(15.57mmol)六甲基二锡、5.1g(15.57mmol)N-甲磺酰基-3-碘吲哚和0.89g(0.78mmol)Pd(PPh3)4在75ml干燥甲苯中的溶液,加热至90℃并保持4小时。然后使混合物蒸发并在硅胶上层析(先用己烷,然后用10%乙酸乙酯/己烷洗脱)产生在下一步直接使用的N-甲磺酰基-3-三甲基甲锡烷基吲哚。
步骤B 4-(1-甲磺酰吲哚-3-基)-6,7-二甲氧基喹唑啉
以氮充分冲洗1.33g(4.01mmol)的N-甲磺酰基-3-三甲基甲锡烷基吲哚、750mg(3.34mmol)的4-氯-6,7-二甲氧基喹唑啉和0.19g(5mol%0.16mmol)的Pd(PPh3)4在10ml干燥的N,N-二甲基甲酰胺中的溶液,加热至90℃并保持12小时。以二氯甲烷稀释反应混合物,并用10%氢氧化铵洗涤,剧烈搅拌,然后用水洗涤,用盐水洗涤合并的有机相(75ml),干燥(MgSO4)并蒸发至干。从乙酸乙酯中重结晶产生4-(1-甲磺酰吲哚-3-基)-6,7-二甲氧基喹唑啉(熔点>220℃)。
可以按照上述实施例制备任何本发明所需的化合物。可以制备的化合物的代表性例子列于以下。
6,7-二甲氧基-4-萘-2-基乙炔基喹唑啉,熔点158-161℃
4-(4-羟苯基)-6,7-二甲氧基喹唑啉盐酸盐,熔点>270℃(分解)
4-(萘-1-基)-6,7-二甲氧基喹唑啉,熔点144-147℃
4-(萘-2-基)-6,7-二甲氧基喹唑啉,熔点115-118℃
4-苯乙炔基-6,7-二甲氧基喹唑啉,熔点146-148℃
4-(3-氟-4-甲氧基苯基)-6,7-二甲氧基喹唑啉,熔点207-210℃
4-(3-苯基苯基)-6,7-二甲氧基喹唑啉,熔点160-163℃
4-(2-苯乙烯基)-6,7-二甲氧基喹唑啉,熔点168-169℃
4-(2-甲氧基吡啶-5-基)-6,7-二甲氧基喹唑啉,熔点175-176℃
4-(1-苄基吲哚-3-基)-6,7-二甲氧基喹唑啉,熔点148-150℃
4-(吲哚-3-基)-6,7-二甲氧基喹唑啉,熔点>240℃(分解)
4-(1-甲基吲哚-3-基)-6,7-二甲氧基喹唑啉盐酸盐,熔点>230℃(分解)
4-(1-甲磺酰基吲哚-3-基)-6,7-二甲氧喹唑啉,熔点>220℃(分解)
4-(4-苯基哌啶-1-基)-6,7-二甲氧基喹唑啉,熔点150-151℃
4-[4-(3-氯苯基)哌嗪-l-基]-6,7-二甲氧基喹唑啉,熔点155-156℃
4-(N-甲基-3,4,5-三甲氧基苯胺基)-6,7-二甲氧基喹唑啉,熔点149-151℃
(+-)-4-(2-甲基-1,2,3,4-四氢喹啉-1-基)-6,7-二甲氧基喹唑啉盐酸盐,熔点198-201℃(分解)
4-(1,2,3,4-四氢喹啉-1-基)-6,7-二甲氧基喹唑啉盐酸盐,熔点195-197℃(分解)
4-(5,6,7,8-四氢化萘-1-基)氨基-6,7-二甲氧基喹唑啉盐酸盐,熔点219-222℃
4-(3,6-二噁烷苯胺基)-6,7-二甲氧基喹唑啉,熔点267-269℃(分解)
4-苯乙炔基-6,7-二甲氧基喹唑啉,熔点146-148℃
4-(吲哚-1-基)-6,7-二甲氧基喹唑啉,熔点166-167℃
4-(N-甲基-4-甲氧基苯胺基)-6,7-二甲氧基喹唑啉盐酸盐,熔点202-205℃
4-(N-甲基-4-氯苯胺基)-6,7-二甲氧基喹唑啉盐酸盐,熔点220-222℃
4-(2,3-二氢吲哚-1-基)-6,7-二甲氧基喹唑啉盐酸盐,熔点226-229℃(分解)
N-(6,7-二甲氧基喹唑啉-4-基)-N-甲基-N-(3-三氟甲基苯基)胺盐酸盐,熔点240-243℃
N-(3-氯苯基)-N-(6,7-二甲氧基喹唑啉-4-基)-N-甲基胺盐酸盐,熔点235-237℃
N-(3-氯苯基)-N-(喹唑啉-4-基)-N-甲基-胺盐酸盐,熔点233-235℃
6,7-二甲氧基-4-萘-1-基-乙炔基喹唑啉,熔点175-177℃
4-(噻吩-3-基)-6,7-二甲氧基喹唑啉,熔点148.5-151.5℃
4-苄基-6,7-二甲氧基喹唑啉,熔点122.5-125℃
(6,7-二甲氧基喹唑啉-4-基)-5-吲唑基胺盐酸盐,熔点261-263℃(分解)
N-(6,7-二甲氧基喹唑啉-4-基)-N-苯基-N-乙基胺盐酸盐,熔点227-230℃(分解)
N-苄基-N-(6,7-二甲氧基喹唑啉-4-基)-N-苯基胺盐酸盐,熔点269-271℃
N-(6-氯喹唑啉-4-基)-N-甲基-N-苯基胺,熔点106-108℃
N-(3-氯-苯基)-N-(6,7-二甲氧基喹唑啉-4-基)-N-乙基胺盐酸盐,熔点261-263℃
N-(6,7-二甲氧基喹唑啉-4-基)-N-甲基-N-对甲苯基胺盐酸盐,熔点230-234℃(分解)
N-苄基-N-(6,7-二甲氧基喹唑啉-4-基)胺,熔点220-225℃
N-(4-甲氧苄基)-N-(6,7-二甲氧基喹唑啉-4-基)胺,熔点194-198℃
N-(3,5-二甲氧苄基)-N-(6,7-二甲氧基喹唑啉-4-基)胺盐酸盐,熔点265-269℃
4-(3,4,5-三甲氧基苯氧基)-6,7-二甲氧基喹唑啉,熔点228-232℃
N-(喹唑啉-4-基)-N-苯基-N-甲基胺盐酸盐,熔点242-246℃(分解)
N-(6,7-二甲氧基喹唑啉-4-基)-N-(4-吗啉-4-基苯基)胺盐酸盐,熔点231-235℃(分解)
4-(3-甲氧基噻吩氧基)-6,7-二甲氧基喹唑啉,熔点139.5-141.5℃
4-[N-(5-二氢茚基)氨基)-6,7-二甲氧基喹唑啉盐酸盐,熔点244-246℃(分解)
4-(3-氯噻吩氧基)-6,7-二甲氧基喹唑啉,熔点152-153.5℃
4-(3-氨基吡唑基)-6,7-二甲氧基喹唑啉盐酸盐,熔点262-264℃(分解)
4-(1,4-苯并二噁烷-6-基氨基)-6,7-二甲氧基喹唑啉盐酸盐,熔点267-269℃(分解)
6,7-二甲氧基-4-(α-萘氨基)喹唑啉盐酸盐,熔点>250℃
6,7-二甲氧基-4-(β-萘氨基)喹唑啉盐酸盐,熔点>250℃
4-(环己基苯胺基)-6,7-二甲氧基喹唑啉,熔点239-244℃
4-(3,4,5-三甲氧基苯胺基)-6,7-二甲氧喹唑啉盐酸盐,熔点260-265℃
6,7-二甲氧基-4-(N-甲基苯胺基)喹唑啉盐酸盐,熔点>230℃
4-(3-氯苯氧基)-6,7-二甲氧基喹唑啉,熔点152-153℃
6,7-二甲氧-4-(1-萘硫基)-喹唑啉,熔点174.5-176.5℃
6,7-二甲氧基-4-(2-萘硫基)-喹唑啉,熔点178-179℃
6,7-二甲氧基-4-(1-萘氧基)-喹唑啉,熔点214-215.5℃
6,7-二甲氧基-4-(2-萘氧基)-喹唑啉,熔点169-170℃
N-(6,7-二甲氧基-喹唑啉-4-基)-N-(萘-2-基)-N-乙基胺盐酸盐,熔点236-239℃(分解)
6,7-二甲氧基-4-(萘-2-亚硫酰基)喹唑啉,熔点182.5-185℃
6,7-二甲氧基-4-(萘-2-磺酰基)喹唑啉
4-(3-氯苯胺基)-6,7-二甲基喹唑啉盐酸盐,熔点271-274℃
4-(3,5-二甲基苯胺基)-6,7-二甲基喹唑啉盐酸盐,熔点>275℃
4-(N-甲基-4-甲基苯胺基)-6,7-二甲基喹唑啉盐酸盐,熔点235-238℃
6,7-二甲基-4-(1-萘氨基)喹唑啉盐酸盐,熔点244-247℃
6,7-二甲基-4-(7-三氟甲基-3,4-二氢-2H-喹啉-1-基)喹唑啉盐酸盐,熔点240℃
4-(N-甲基-3-甲基苯胺基)-6,7-二甲基喹唑啉盐酸盐,熔点205-207℃
4-(3-氯苯硫基)-6,7-二甲基喹唑啉盐酸盐,熔点197-202℃
4-(1-萘硫基)-6,7-二甲基喹唑啉盐酸盐,熔点204-209℃
4-(3,4-二甲氧基苯硫基)喹唑啉,熔点115-117℃
药物组合物的制备与药理学试验部分
为了确定本发明的化合物的效能,使用了如下描述的药理学实验,该实验在本领域可以被接受并被认为与在哺乳动物中的药理活性相关。对本发明范围内的化合物进行了各种实验,获得的结果被认为与有用地抑制生长因子-诱导的细胞增殖相关。下面描述的实验可用于测定本发明的化合物的抑制作用。
实验方法
材料:把实验材料在实验即时溶解在DMSO中以制作母液,随后以培养基稀释该母液以达到所需的化合物的浓度(0.1%的载体最终浓度)。所利用的材料如下:Dulbecco’s改进Eagle培养基(DMEM),RPMI 1640,胎牛血清(FCS),青霉素-链霉素溶液(10,000IU/ml青霉素和10,000μg/ml链霉素)从GIBCO BPL购得。3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四唑鎓溴化物(MTT)和遗传霉素购自Sigma。放射性标记的[γ-32P]ATP(cat#NEG002H;3,000Ci/mmol)购自NEN。抗-c neu抗体(Ab-5;cat#OP39)来源于Oncogene Science。小鼠单克隆抗磷酸酪氨酸抗体(单克隆IgG2bk)得自UBI,辣根过氧化物酶缀合的兔抗小鼠IgG得自北欧免疫学实验室。按照C.Wasylyk,A.Gutman,R.Nicholson和B.Wasylyk,(1991)EMBO杂志,10:A127-A134的方法,制备溶基质素启动子片段-1100/+8控制的溶基质素-CAT质粒DNA构建体(由氯霉素乙酰转移酶cDNA组成)。所有其它化学药品是可得到的最好质量的药品。
细胞系和细胞培养:小鼠胚胎成纤维细胞(NIH3T3)、人表皮样瘤(A431)癌细胞系以及胸部(SK-BR-3)和卵巢(SK-OV-3)腺癌细胞系、人肺脏(A549)和乳腺(BT474和BT20)癌细胞系从ATCC购得。按照R.M.Hudziak,J.Schlessinger和A.Ulirich(1987)美国科学院学报,84:7159-7163的方法制备用HER2构建体转染的超量表达p185HER2的NIH3T3细胞,NIH/HER2。通过按照I.Barlat,F.Schweighoffer,M.C.Chevalier-Multon,M.Duchesne,I.Faith,D.Landais,M.Jacquet和B.Tocqué(1993)癌基因8:215-218的方法用Val2Ha-ras转化NIH3T3细胞建立NIH/Ha-Ras细胞系。用包含突变Y527F的活化的v-src(NIH/v-Src)转染的NIH3T3细胞得自Dr.B.Wasylyk。HIR3.5(NIH/IR)细胞系代表超量表达人胰岛素受体的NIH3T3细胞,它由Dr.J.Whitaker提供。所有细胞系于37℃下的CO2恒温箱(5%CO2/95%的湿空气)中在补加有10%FCS和1%青霉素链霉素溶液的培养基中培养。除非特别指出,培养基每隔一天换一次。
体外p185HER2自磷酸化测定:ER22或A431以及NIH/HER2细胞系用作p185Her2的来源。在4℃下于包含1%Triton X-100和1mM PMSF的HNEG(HNEG:50mM Hepes缓冲液,pH7.5,150mM NaCl,1mMEDTA和10%甘油)缓冲液中裂解半丰细胞单层10分钟。然后用包含0.1%Triton X-100和1%BSA的HNEG缓冲液(裂解缓冲液)稀释细胞裂解物,通过在12,000.g下离心5分钟使细胞提取物澄清。自磷酸化测定如S.M.Smyth,I.Stefanova,F.Hartman,I.D.Horak,N.Osherov,A.Levitzki和T.R.Burke(1993)医学化学杂志36:3010-3014所述进行。简言之,在37℃下用10μg/ml浓度的100μl山羊抗小鼠免疫球蛋白(Biosys)涂覆96孔U形底塑料平板2小时。用包含0.05%Tween的PBS洗涤后,将100μl的抗c-neu抗体在37℃下温育2小时(两种抗体都以1μg/ml使用)。通过在37℃下和在PBS中的2%BSA温育1小时封闭未结合的结合位点。细胞裂解物于4℃下在包被的孔中温育1小时。在用裂解缓冲液洗涤几次后,于室温下在申请人的化合物不存在或存在的情况下,自磷酸化测定直接在孔中在包含2mM MnCl2、0.1%Triton和5μCi[γ-32P]ATP的25mM Hepes缓冲液(pH7.4)中进行20分钟。通过添加按照U.K.Laemmli(1970)(自然,225:680-685)制备的Laemmli’s样品缓冲液终止磷酸化反应,通过SDS-PAGE在4-12%聚丙烯酰胺梯度凝胶上分析[32P]-标记的受体。磷酸化强度通过在Instant Imager(Packard)上扫描干燥的凝胶估计。
完整细胞酪氨酸磷酸化:汇生细胞单层在血清饥饿过夜后用指定的化合物浓度培养2小时。然后抽吸培养基,通过直接把Laemmli’s SDS样品缓冲液添加到细胞单层上灭活细胞。然后在试验包含磷酸酪氨酸的蛋白质前,在100℃下处理样品5分钟。通过SDS-PAGE在4-20%聚丙烯酰胺梯度凝胶上使蛋白质分级分离,其后使蛋白质电泳转移到聚偏二氟乙烯膜(PVDF膜,PolyScreen,NEN)上。利用小鼠单克隆抗磷酸酪氨酸抗体进行包含磷酸酪氨酸的蛋白质的免疫检测。通过增强化学发光法(ECL,NEN)使用辣根过氧化酶缀合的兔抗小鼠IgG显示印迹。
细胞增殖:把细胞以大约20,000细胞/孔接种于24孔细胞培养平板上。使细胞在1ml培养基中对塑料粘附8小时,其后在各种浓度的化合物存在下培养细胞72-96小时。按照表明的培养时间,估计了每孔的细胞数目。作为相对生存的细胞数目的测定,按照M.C.Alley,D.A.Scudiero,A.Monks,M.L.Hursey,M.J.Czerwinski,D.L.Fine,B.J.Abbot,J.G.Mayo,R.H.Shoemaker和M.R.Boyd(1988)癌症研究48:589-601的方法使用了MTT的线粒体还原。简言之,向每个孔添加100μl在磷酸盐缓冲盐水中的MTT的5mg/ml溶液,平板于37℃下在CO2恒温箱中培养4小时。然后,为了溶解在活细胞的线粒体中形成的甲的黑紫色晶体,除去650μl的培养基并以750μl的异丙醇/HCl(1N)溶液(25∶1)代替。随搅拌在室温下培养5-10分钟后,从每个孔中把200μl等分试样转移到96孔细胞培养平板上,由于所获得的蓝色程度与细胞数量直接成比例,就可以在微滴定板自动读数仪上于590nm通过分光光度测定该值。
不依赖贴壁细胞的生长:通过检查悬浮在软琼脂中的所说的细胞的菌落形成能力研究不依赖贴壁细胞的生长。利用50mm直径的细胞培养皿进行实验。4ml无细胞饲养底层由补加有10%FCS和指定浓度的化合物的培养基中的0.5%琼脂组成。4ml上层包含在补加有10%FCS和相应浓度的化合物的培养基内的0.3%琼脂中的大约10,000个细胞。于37℃下培养2周后,测定菌落数目。
细胞转染和CAT测定:使用脂转染胺试剂通过转染把溶基质素-CAT质粒DNA构建体(STRM-CAT)导入细胞。简言之,使细胞的50-70%铺满培养皿(3.5cm)于37℃下接触在1ml无血清的DMEM中的1μg质粒DNA和10μg脂转染胺试剂4小时。然后使细胞在37℃下和补加有0.5%FCS和指定浓度的化合物的DMEM培养36小时。细胞通过与包含3mM EDTA的PBS培养从平板上分离下来,通过在1,500rpm下离心5分钟沉淀。把细胞重新悬浮在0.25M Tris/HCl缓冲液pH 7.8中并进行重复冷冻-解冻循环。把细胞提取物加热到65℃并保持15分钟;冷却后,在14,000rpm下微离心15分钟。按照J.R.Neumann,C.A.Morency和K.O.Russian(1987)生物技术,5:444-447的方法测定上清液中CAT活性。
在本发明范围之内的化合物显示了作为蛋白质酪氨酸激酶抑制剂的明显的特异性活性,并具有抑制生长因子诱导的细胞增殖的治疗价值。本发明的化合物还是人表皮生长因子受体2型的特异性抑制剂,因此可用于治疗细胞生长和分化。
下表显示了本发明的代表性化合物的例子及其通过上述人表皮生长因子受体2型的抑制测定的试验结果。通过上述实验方法获得的结果证明了在本发明范围内的化合物的有用的HER2受体蛋白质酪氨酸激酶抑制性质,并在异常细胞生长的调节中具有治疗价值。 X R5 R6 R7 R8 HER-2 化学键 H OCH3 OCH3 H 20%,5μM 化学键 H OCH3 OCH3 H 10%,5μM化学键 H OCH3 OCH3 H 0.5-1μM 化学键 H OCH3 OCH3 H 10%,5μM
可以以各种适用于所选择的给药途径的方式(即口服或肠胃外)对哺乳动物宿主施用本发明的化合物。在这方面肠胃外施用包括通过下列途径施用:静脉内、肌肉内、皮下、眼内、滑膜内、经上皮(包括经皮、眼、舌下和颊);局部施用(包括通过吹入剂与气雾剂的经眼、皮、眼内、直肠和鼻吸入)与直肠全身施用。
活性化合物可以,例如,与惰性稀释剂或与可同化的可食载体口服,或者可以把它装入硬或软壳的明胶胶囊中,或者把它压缩成片剂,或者把它直接与饮食掺合施用。对于口服治疗施用,活性化合物可以与赋形剂掺合并以可消化的片剂、口腔片、锭剂、胶囊、酏剂、悬浮液、糖浆剂、糯米纸囊剂等形式使用。这样的组合物和制剂应包含至少0.1%的活性化合物。当然,组合物与制剂的百分比可以不同,可以方便地在单位重量的大约2至大约6%之间。在这样的治疗用的组合物中的活性化合物的量是可以获得适合剂量的量。制备了本发明优选的组合物或制剂以使口服剂量单位形式包含大约1至1000mg之间的活性化合物。
片剂、锭剂、丸剂、胶囊等也可以包含下列物质:粘合剂如黄蓍胶、阿拉伯胶、玉米淀粉或明胶;赋形剂如磷酸二钙;崩解剂如玉米淀粉、马铃薯淀粉、海藻酸等;润滑剂如硬脂酸镁;可以添加增甜剂如蔗糖、乳糖或糖精或增香剂如薄荷、冬青油或樱桃调味料。当剂量单位形式是胶囊时,除了上述类型的物质外它还可以包含液态载体。可以有各种其它物质如包衣剂,或以其它方式修改剂量单位外形的物质。例如,片剂、丸剂或胶囊可以用紫胶片、食糖或两者包衣。糖浆或酏剂可以包含活性化合物、作为增甜剂的蔗糖,作为防腐剂的对羟基苯甲酸甲酯和对羟基苯甲酸丙酯,染料和调味料如樱桃或桔子调味香料。当然,在制备任何剂量单位形式时使用的物质以所使用的量应该是药学纯度的和实质上无毒的。此外,活性化合物可以制成缓释剂和制剂。
也可以肠胃外或腹膜内施用活性化合物。可以在与表面活性剂(如羟丙基纤维素)适当混合的水中制备作为游离碱或药学可接受的盐的活性化合物的溶液。也可以在甘油、液态聚乙二醇及其混合物、油中制备分散体。在保存和使用的普通条件下,这些制剂包含防腐剂以防止微生物的生长。
适合于可注射用途的药剂形式包括无菌水溶液或分散体以及用于临时制备无菌可注射溶液或分散体的无菌粉剂。在所有情况下制剂必须是无菌的,并且必须是达到易于注射的程度的液体。它在制造和存储条件下可以是稳定的,而且必须受到保护以抗有污染作用的微生物(如细菌和真菌)。载体可以是包含,例如,水、乙醇、多元醇(例如,甘油、丙二醇和液态聚乙二醇等)及其适合的混合物以及植物油的溶剂或分散介质。例如,可以通过利用包衣剂(如卵磷脂)、通过分散情况下保持适当的所需的粒子大小、通过利用表面活性剂保持适当的流动性。可以通过各种杀细菌剂和杀真菌剂(例如,羟苯甲酸甲酯、氯丁醇、酚、山梨酸、乙基汞硫代水杨酸钠等)防止微生物作用。在许多情况下,优选地包括等渗剂(例如,糖或氯化钠)。可以通过使用延缓吸收剂(例如,单硬脂酸铝和明胶)延长可注射组合物的吸收。
通过把活性化合物以所需的量掺入具有上述各种其它成分的适当的溶剂中(如果需要,在其后进行过滤灭菌)制备无菌的可注射溶液。通常,通过把各种灭菌的活性组分掺入无菌载体中制备分散体,在该载体中包含基本的分散介质和所需的上述其它成分。在用于制备无菌可注射溶液的无菌粉剂的情况下,优选的制备方法是真空干燥和冷冻干燥技术,该方法产生活性成分加上前述灭菌过滤溶液中所需任何其它成分的粉剂。
本发明的治疗化合物可以单独或与药学上可接受的载体结合对哺乳动物给药,如上所述,其比例决定于化合物的溶解性和化学性质、选择的给药途径和标准的药学实践。
最适合于预防或治疗的本发明的治疗剂的剂量随给药方式、所选择的特定化合物和治疗的病人的特定的生理特征而变化。通常,最初使用小剂量,如果必要,小量增加,直到达到所述状况下的最佳效果。基于大鼠的生理研究,治疗性人剂量通常是每天从大约0.01mg至大约100mg/kg体重,或从大约0.4mg至大约10g或更高(尽管该剂量可以以一天一次到几次的不同剂量单位施用)。口服需要较高的剂量。
Claims (20)
A是5至12个原子的取代的或未取代的单-环或双-环芳基、杂芳基、环烷基或杂环烷基环状系统,其中的取代基可位于环状系统的任何适当的位置,并由R表示;
X是化学键、O、S、SO、SO2、OCH2、CR4=CR4、C≡C、NR4或NR4CH2;
R独立地包括氢、烷基、苯基、卤苯基、芳烷基、羟基、烷氧基、芳氧基、酰氧基、卤素、卤代烷基、氨基、一-和二-烷基氨基、酰基氨基、羧基、酰氨基、一-和二-烷基酰氨基、烷硫基、烷亚硫酰基以及烷磺酰基;
R4是氢、烷基或芳烷基;和
R5,R6,R7和R8独立地是氢、烷氧基或芳烷氧基。
2.按照权利要求1的应用,其中:
A是选自苯基、吡咯基、噻吩基、呋喃基、噻唑基、咪唑基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、异噻唑基、异噁唑基和噁唑基的取代的或未取代的单环芳基或杂芳基环。
3.按照权利要求1的应用,其中:
A是选自萘基、1,2,3,4-四氢萘基、1,2,3,4-四氢喹啉基、苯并呋喃基、苯并噻吩基、二氢茚基、吲哚基、二氢吲哚基、1,3-苯并间二氧杂环戊烯基、苯并二噁烷基、喹啉基、四氢喹啉基、异喹啉基、喹唑啉基和喹喔啉基的取代的或未取代的双环芳基或杂芳基环。
4.按照权利要求1的应用,其中:
A是选自环戊基、环己基、环庚基、十氢萘基、哌啶基、哌嗪基、吗啉基或十氢喹啉基的取代的或未取代的单环环烷基或杂环烷基环。
5.按照权利要求1的应用,其中:
A是选自十氢萘基或十氢喹啉基的取代的或未取代的双环环烷基或杂环烷基环。
6.按照权利要求1的应用,其中:
A是取代的和未取代的苯基、吡啶基、噻吩基、呋喃基、吡唑基、萘基、1,2,3,4-四氢萘基,1,2,3,4-四氢喹啉基、二氢茚基、吲哚基、二氢吲哚基、喹啉基、四氢喹啉基、环己基、哌啶基或哌嗪基;
X是化学键、O、S或NR4;
R是氢、烷基、烷氧基、卤素、卤代烷基、烷硫基、烷亚硫酰基、烷磺酰基、苯基和芳烷基;
R4是氢、烷基或芳烷基;
R5,R6,R7和R8独立地是氢或烷氧基。
7.按照权利要求6的方法,其中:
A是取代的和未取代的苯基、萘基或吲哚基;
X是化学键;
R是氢、甲氧基、乙氧基、氯、三氟甲基、甲磺酰基、苯基和苄基;
R4是氢、甲基或苄基;
R5,R6,R7和R8独立地是氢或甲氧基。
8.按照权利要求2的应用,其中所施用的化合物是4-(2-苯乙烯基)-6,7-二甲氧基喹唑啉或其药学上可接受的盐。
9.按照权利要求3的应用,其中所施用的化合物是6,7-二甲氧基-4-萘-1-基-乙炔基喹唑啉或其药学上可接受的盐。
10.按照权利要求6的应用,其中所施用的化合物选自:4-(2-甲氧吡啶-5-基)-6,7-二甲氧基喹唑啉,4-(4-苯哌啶-1-基)-6,7-二甲氧基喹唑啉,4-[4-(3-氯苯基)哌嗪-1-基]-6,7-二甲氧基喹唑啉,和4-(1,2,3,4-四氢喹啉-1-基)-6,7-二甲氧基喹唑啉或它们的药学上可接受的盐。
11.按照权利要求6的应用,其中所施用的化合物选自:6,7-二甲氧基-4-(β-萘氨基)喹唑啉,4-[N-(5-二氢茚基)氨基]-6,7-二甲氧基喹唑啉,N-苄基-N-(6,7-二甲氧基喹唑啉-4-基)-N-苯基胺,6,7-二甲氧基-4-(N-甲基苯胺基)喹唑啉,N-(3-氯苯基)-N-(6,7-二甲氧基喹唑啉-4-基)-N-甲基胺,4-(3-氨基吡唑基)-6,7-二甲氧基喹唑啉,和4-(环己基苯胺基)-6,7-二甲氧基喹唑啉,或它们的药学上可接受的盐。
12.按照权利要求6的应用,其中所施用的化合物是6,7-二甲氧基-4-(α-萘氨基)喹唑啉或其药学上可接受的盐。
13.按照权利要求7的应用,其中所施用的化合物选自:4-(萘-1-基)-6,7-二甲氧基喹唑啉,4-(萘-2-基)-6,7-二甲氧基喹唑啉,4-(3-苯基苯基)-6,7-二甲氧基喹唑啉,4-(吲哚-3-基)-6,7-二甲氧基喹唑啉,和4-(1-甲基吲哚-3-基)-6,7-二甲氧基喹唑啉,或它们的药学上可接受的盐。
14.按照权利要求7的应用,其中所施用的化合物是4-(1-苄基吲哚-3-基)-6,7-二甲氧基喹唑啉或其药学上可接受的盐。
15.一种用于选择性治疗以人表皮生长因子受体2型(HER2)的活性为特征的细胞生长和分化的药物组合物,该药物组合物包含与药学上可接受的载体混合的HER2受体抑制有效量的下式的化合物或其药学上可接受的盐:其中
A是大约5至12个原子的取代的或未取代的单-环或双-环芳基、杂芳基、环烷基或杂环烷基环状系统,其中的取代基可位于环状系统的任何适当的位置,并由R代表;
X是化学键、O、S、SO、SO2、OCH2、CR4=CR4、C≡C、NR4或NR4CH2;
R独立地包括氢、烷基、苯基、卤苯基、芳烷基、羟基、烷氧基、芳氧基、酰氧基、卤素、卤代烷基、氨基、一-和二-烷基氨基、酰基氨基、羧基、酰氨基、一-和二-烷基酰氨基、烷硫基、烷亚硫酰基以及烷磺酰基;
R4是氢、烷基或芳烷基;和
R5,R6,R7和R8独立地是氢、烷氧基或芳烷氧基。
16.按照权利要求15的组合物,其中:
A是取代的和未取代的苯基、吡啶基、噻吩基、呋喃基、吡唑基、萘基、1,2,3,4-四氢萘基,1,2,3,4-四氢喹啉基、二氢茚基、吲哚基、二氢吲哚基、喹啉基、四氢喹啉基、环己基、哌啶基或哌嗪基;
X是化学键、O、S或NR4;
R是氢、烷基、烷氧基、卤素、卤代烷基、烷硫基、烷亚硫酰基、烷磺酰基、苯基和芳烷基;
R4是氢、烷基或芳烷基;和
R5,R6,R7和R8独立地是氢或烷氧基。
17.按照权利要求16的化合物,其中所说的化合物是6,7-二甲氧基-4-(α-萘氨基)喹唑啉或其药学上可接受的盐。
18.按照权利要求16的化合物,其中所说的化合物是4-(1-苄基吲哚-3-基)-6,7-二甲氧基喹唑啉或其药学上可接受的盐。
19. 6,7-二甲氧基-4-(α-萘氨基)喹唑啉或其药学上可接受的盐。
20. 4-(1-苄基吲哚-3-基)-6,7-二甲氧基喹唑啉或其药学上可接受的盐。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/469,147 US5721237A (en) | 1991-05-10 | 1995-06-06 | Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties |
US08/469,147 | 1995-06-06 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1187129A CN1187129A (zh) | 1998-07-08 |
CN1100540C true CN1100540C (zh) | 2003-02-05 |
Family
ID=23862606
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN96194512A Expired - Fee Related CN1100540C (zh) | 1995-06-06 | 1996-06-06 | 具有选择性抑制her-2自磷酸化性质的蛋白质酪氨酸激酶芳基和杂芳基喹唑啉化合物 |
Country Status (14)
Country | Link |
---|---|
US (1) | US5721237A (zh) |
EP (1) | EP0831831A4 (zh) |
JP (1) | JPH11507355A (zh) |
KR (1) | KR19990022533A (zh) |
CN (1) | CN1100540C (zh) |
AU (1) | AU696456B2 (zh) |
BR (1) | BR9608638A (zh) |
CA (1) | CA2223016C (zh) |
CZ (1) | CZ289338B6 (zh) |
EA (1) | EA000840B1 (zh) |
HU (1) | HUP9802702A3 (zh) |
SI (1) | SI9620092A (zh) |
SK (1) | SK284475B6 (zh) |
WO (1) | WO1996039145A1 (zh) |
Families Citing this family (191)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5480883A (en) * | 1991-05-10 | 1996-01-02 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
TW321649B (zh) * | 1994-11-12 | 1997-12-01 | Zeneca Ltd | |
GB9424233D0 (en) * | 1994-11-30 | 1995-01-18 | Zeneca Ltd | Quinazoline derivatives |
GB9508565D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quiazoline derivative |
GB9508535D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivative |
GB9508537D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
GB9508538D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quinazoline derivatives |
AU5343096A (en) * | 1995-04-27 | 1996-11-18 | Zeneca Limited | Quinazoline derivatives |
DE69618587T2 (de) * | 1995-06-07 | 2002-08-29 | Sugen, Inc. | Chinazoline und pharmazeutische zusammensetzungen |
GB9624482D0 (en) * | 1995-12-18 | 1997-01-15 | Zeneca Phaema S A | Chemical compounds |
IL125686A (en) | 1996-02-13 | 2002-11-10 | Zeneca Ltd | Quinazoline derivatives, processes for their preparation, pharmaceutical preparations containing them and their use in the manufacture of a drug with an anti-angiogenic effect and / or an effect of reducing vascular permeability |
GB9603095D0 (en) * | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline derivatives |
GB9603097D0 (en) * | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline compounds |
WO1997032856A1 (en) | 1996-03-05 | 1997-09-12 | Zeneca Limited | 4-anilinoquinazoline derivatives |
DK0892789T4 (da) | 1996-04-12 | 2010-04-06 | Warner Lambert Co | Irreversible inhibitorer af tyrosin kinaser |
GB9607729D0 (en) * | 1996-04-13 | 1996-06-19 | Zeneca Ltd | Quinazoline derivatives |
GB9707800D0 (en) | 1996-05-06 | 1997-06-04 | Zeneca Ltd | Chemical compounds |
GB9718972D0 (en) | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
US6987113B2 (en) | 1997-06-11 | 2006-01-17 | Sugen, Inc. | Tyrosine kinase inhibitors |
ES2289791T3 (es) | 1997-08-22 | 2008-02-01 | Astrazeneca Ab | Derivados de oxindolilquinazolina como inhibidores de la angiogenesis. |
BR9815200A (pt) * | 1997-10-27 | 2001-10-16 | Agouron Pharma | Composto, composição farmacêutica e método de tratamento de uma doença ou distúrbio mediado pela inibição de cdk4 ou um complexo de cdk4/ciclina |
EP1215208B1 (en) * | 1997-10-27 | 2006-07-12 | Agouron Pharmaceuticals, Inc. | 4-Aminothiazole derivatives, their preparation and their use as inhibitors of cyclin-dependent kinases |
SG74717A1 (en) | 1998-04-10 | 2000-08-22 | Japan Tobacco Inc | Amidine compound |
AU4317399A (en) * | 1998-05-28 | 1999-12-13 | Parker Hughes Institute | Quinazolines for treating brain tumor |
AR020590A1 (es) | 1998-06-02 | 2002-05-22 | Cadus Pharmaceutical Corp | 7-diazapurina-n-6 sustituida, un metodo para su preparacion, composiciones farmaceuticas que la comprenden |
US6686366B1 (en) | 1998-06-02 | 2004-02-03 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A3 receptor and uses thereof |
US6878716B1 (en) | 1998-06-02 | 2005-04-12 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A1 receptor and uses thereof |
US6184226B1 (en) * | 1998-08-28 | 2001-02-06 | Scios Inc. | Quinazoline derivatives as inhibitors of P-38 α |
ATE294796T1 (de) * | 1998-10-08 | 2005-05-15 | Astrazeneca Ab | Chinazolin derivate |
US8124630B2 (en) * | 1999-01-13 | 2012-02-28 | Bayer Healthcare Llc | ω-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors |
EP2298311B1 (en) * | 1999-01-13 | 2012-05-09 | Bayer HealthCare LLC | w-Carboxy aryl substituted diphenyl ureas as p38 kinase inhibitors |
EP1144404A1 (en) * | 1999-01-20 | 2001-10-17 | Smithkline Beecham Plc | Piperidinylquinolines as protein tyrosine kinase inhibitors |
CZ303692B6 (cs) | 1999-02-10 | 2013-03-13 | Astrazeneca Ab | Chinazolinové deriváty jako inhibitory angiogeneze |
DE60037938T2 (de) * | 1999-02-26 | 2009-01-29 | The University Of British Columbia, Vancouver | Antisense-therapie für trpm-2 |
US6258820B1 (en) * | 1999-03-19 | 2001-07-10 | Parker Hughes Institute | Synthesis and anti-tumor activity of 6,7-dialkoxy-4-phenylamino-quinazolines |
GB9914486D0 (en) | 1999-06-21 | 1999-08-18 | Smithkline Beecham Plc | Medicaments |
GB9917406D0 (en) | 1999-07-23 | 1999-09-22 | Smithkline Beecham Plc | Compounds |
GB9917408D0 (en) | 1999-07-23 | 1999-09-22 | Smithkline Beecham Plc | Compounds |
GB9922171D0 (en) * | 1999-09-21 | 1999-11-17 | Zeneca Ltd | Chemical compounds |
IL149034A0 (en) | 1999-11-05 | 2002-11-10 | Astrazeneca Ab | Quinazoline derivatives as vegf inhibitors |
JP2003514803A (ja) * | 1999-11-15 | 2003-04-22 | パーカー ヒューズ インスティテュート | 結直腸ガンの発達を防止するための4−(4’−ヒドロキシフェニル)アミノ−6,7−ジメトキシキナゾリン |
US6482828B1 (en) | 1999-11-15 | 2002-11-19 | Parker Hughes Institute | 4-(4′-hydroxyphenyl) amino-6,7-dimethoxyquinazoline to prevent development of colorectal cancer |
US7160890B2 (en) * | 1999-12-02 | 2007-01-09 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A3 receptor and uses thereof |
US6664252B2 (en) | 1999-12-02 | 2003-12-16 | Osi Pharmaceuticals, Inc. | 4-aminopyrrolo[2,3-d]pyrimidine compounds specific to adenosine A2a receptor and uses thereof |
US6680322B2 (en) | 1999-12-02 | 2004-01-20 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A1 receptors and uses thereof |
US7569551B2 (en) | 2000-02-25 | 2009-08-04 | The University Of British Columbia | Chemo- and radiation-sensitization of cancer by antisense TRPM-2 oligodeoxynucleotides |
KR100858069B1 (ko) * | 2000-04-07 | 2008-09-22 | 아스트라제네카 아베 | 퀴나졸린 화합물류 |
UA73993C2 (uk) | 2000-06-06 | 2005-10-17 | Астразенека Аб | Хіназолінові похідні для лікування пухлин та фармацевтична композиція |
PL202812B1 (pl) | 2000-08-21 | 2009-07-31 | Astrazeneca Ab | Pochodna chinazoliny, jej kompozycja famaceutyczna oraz jej zastosowanie |
WO2002030926A1 (en) | 2000-10-13 | 2002-04-18 | Astrazeneca Ab | Quinazoline derivatives |
AU2001292138A1 (en) | 2000-10-13 | 2002-04-22 | Astrazeneca Ab | Quinazoline derivatives with anti-tumour activity |
HU230302B1 (hu) | 2000-10-20 | 2015-12-28 | Eisai R&D Management Co., Ltd. | Nitrogéntartalmú aromás származékok és ezeket tartalmazó gyógyászati készítmények |
US6680324B2 (en) | 2000-12-01 | 2004-01-20 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A1 receptors and uses thereof |
US6673802B2 (en) | 2000-12-01 | 2004-01-06 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine A3 receptor and uses thereof |
GB0031088D0 (en) * | 2000-12-20 | 2001-01-31 | Smithkline Beecham Plc | Medicaments |
GB0031086D0 (en) * | 2000-12-20 | 2001-01-31 | Smithkline Beecham Plc | Medicaments |
ATE325795T1 (de) * | 2001-03-23 | 2006-06-15 | Bayer Corp | Rho-kinase inhibitoren |
JP4320705B2 (ja) * | 2001-03-23 | 2009-08-26 | バイエル コーポレイション | Rhoキナーゼ阻害剤 |
EP1381599B1 (en) | 2001-04-19 | 2008-09-24 | Astrazeneca AB | Quinazoline derivatives |
US7371763B2 (en) * | 2001-04-20 | 2008-05-13 | Bayer Pharmaceuticals Corporation | Inhibition of raf kinase using quinolyl, isoquinolyl or pyridyl ureas |
WO2002087619A1 (fr) * | 2001-04-27 | 2002-11-07 | Takeda Chemical Industries, Ltd. | Methode de prevention et de traitement du cancer |
WO2002087618A1 (fr) * | 2001-04-27 | 2002-11-07 | Takeda Chemical Industries, Ltd. | Methode de prevention et de traitement du cancer |
GB0126433D0 (en) * | 2001-11-03 | 2002-01-02 | Astrazeneca Ab | Compounds |
ES2320980T3 (es) * | 2001-11-03 | 2009-06-01 | Astrazeneca Ab | Derivados de quinazolina como agentes antitumorales. |
GB0128108D0 (en) * | 2001-11-23 | 2002-01-16 | Astrazeneca Ab | Therapeutic use |
CA2468673C (en) * | 2001-11-30 | 2011-01-25 | Osi Pharmaceuticals, Inc. | Compounds specific to adenosine a1 and a3 receptors and uses thereof |
WO2003047582A1 (en) * | 2001-12-05 | 2003-06-12 | Astrazeneca Ab | Quinoline derivatives as antitumour agents |
BR0214499A (pt) * | 2001-12-12 | 2005-05-10 | Pfizer Prod Inc | Derivados de quinazolina para o tratamento do crescimento anormal das células |
US20030229067A1 (en) * | 2001-12-20 | 2003-12-11 | Arlindo Castelhano | Pyrrolopyrimidine A2b selective antagonist compounds, their synthesis and use |
KR20040068317A (ko) | 2001-12-20 | 2004-07-30 | 오에스아이 파마슈티컬스, 인코포레이티드 | 피리미딘 a₂b 선택성 길항 화합물, 그의 합성 방법 및용도 |
MXPA04006260A (es) | 2001-12-24 | 2005-03-31 | Astrazeneca Ab | Derivados de quinazolina sustituidos como inhibidores de cinasas aurora. |
NZ533126A (en) * | 2002-01-17 | 2006-04-28 | Univ British Columbia | Bispecific antisense oligonucleotides that inhibit IGFBP-2 and IGFBP-5 and methods of using same |
US7268230B2 (en) * | 2002-02-01 | 2007-09-11 | Astrazeneca Ab | Quinazoline compounds |
WO2003068228A1 (en) * | 2002-02-11 | 2003-08-21 | Bayer Pharmaceuticals Corporation | Aryl ureas with angiogenesis inhibiting activity |
TWI324597B (en) * | 2002-03-28 | 2010-05-11 | Astrazeneca Ab | Quinazoline derivatives |
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 |
WO2004004732A1 (en) * | 2002-07-09 | 2004-01-15 | Astrazeneca Ab | Quinazoline derivatives for use in the treatment of cancer |
US20050239852A1 (en) | 2002-08-02 | 2005-10-27 | Ab Science | 2-(3-aminoaryl)amino-4-aryl-thiazoles and their use as c-kit inhibitors |
US8450302B2 (en) * | 2002-08-02 | 2013-05-28 | Ab Science | 2-(3-aminoaryl) amino-4-aryl-thiazoles and their use as c-kit inhibitors |
EP1548008A4 (en) | 2002-08-23 | 2008-08-06 | Kirin Pharma Kk | COMPOUND HAVING BETA-TRANSFORMING GROWTH FACTOR INHIBITORY ACTIVITY AND DRUG CONTAINING COMPOSITION |
US7223776B2 (en) | 2002-10-10 | 2007-05-29 | Morphochem Ag | Compounds with anti-bacterial activity |
EP1562955B1 (en) | 2002-11-04 | 2008-02-27 | Astrazeneca AB | Quinazoline derivatives as src tyrosine kinase inhibitors |
ATE438644T1 (de) | 2002-12-24 | 2009-08-15 | Astrazeneca Ab | Chinazolinderivate |
US7318437B2 (en) * | 2003-02-21 | 2008-01-15 | Resmed Limited | Nasal assembly |
UY28213A1 (es) * | 2003-02-28 | 2004-09-30 | Bayer Pharmaceuticals Corp | Nuevos derivados de cianopiridina útiles en el tratamiento de cáncer y otros trastornos. |
GB0309009D0 (en) * | 2003-04-22 | 2003-05-28 | Astrazeneca Ab | Quinazoline derivatives |
GB0309850D0 (en) * | 2003-04-30 | 2003-06-04 | Astrazeneca Ab | Quinazoline derivatives |
EP1636585B2 (en) * | 2003-05-20 | 2012-06-13 | Bayer HealthCare LLC | Diaryl ureas with kinase inhibiting activity |
JO2785B1 (en) | 2003-05-27 | 2014-03-15 | شركة جانسين فارماسوتيكا ان. في | Quinazoline derivatives |
US7439241B2 (en) * | 2003-05-27 | 2008-10-21 | Galderma Laboratories, Inc. | Compounds, formulations, and methods for treating or preventing rosacea |
US8410102B2 (en) | 2003-05-27 | 2013-04-02 | Galderma Laboratories Inc. | Methods and compositions for treating or preventing erythema |
WO2004108710A1 (en) * | 2003-06-05 | 2004-12-16 | Astrazeneca Ab | 4-pyrimidinyl quinazoline derivatives for use in the treatment of tumours |
WO2004108707A1 (en) * | 2003-06-05 | 2004-12-16 | Astrazeneca Ab | Pyridazinil quinazoline derivatives for use in the treatment of tumours |
US8309562B2 (en) * | 2003-07-03 | 2012-11-13 | Myrexis, Inc. | Compounds and therapeutical use thereof |
NZ544472A (en) * | 2003-07-03 | 2009-04-30 | Myriad Genetics Inc | Compounds and therapeutical use thereof |
ME00294B (me) | 2003-07-23 | 2011-05-10 | Bayer Pharmaceuticals Corp | Fluoro supstituisana omega-karaboksiaril difenil urea za liječenje i prevenciju bolesti i stanja bolesti |
GB0321648D0 (en) * | 2003-09-16 | 2003-10-15 | Astrazeneca Ab | Quinazoline derivatives |
SI1667991T1 (sl) | 2003-09-16 | 2008-10-31 | Astrazeneca Ab | Kinazolinski derivati kot inhibitorji tirozin kinaze |
CA2539022A1 (en) * | 2003-09-16 | 2005-03-24 | Astrazeneca Ab | Quinazoline derivatives as tyrosine kinase inhibitors |
US20070037837A1 (en) * | 2003-09-19 | 2007-02-15 | Hennequin Laurent Francois A | Quinazoline derivatives |
US8318752B2 (en) * | 2003-09-19 | 2012-11-27 | Astrazeneca Ab | 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-{[1-(N-methylcarbamoyl-methyl)piperidin-4-yl]oxy}quinazoline, its pharmaceutically acceptable salts, and pharmaceutical compositions comprising the same |
US20070043010A1 (en) * | 2003-09-25 | 2007-02-22 | Astrazeneca Uk Limited | Quinazoline derivatives |
GB0322409D0 (en) | 2003-09-25 | 2003-10-29 | Astrazeneca Ab | Quinazoline derivatives |
US7232824B2 (en) * | 2003-09-30 | 2007-06-19 | Scios, Inc. | Quinazoline derivatives as medicaments |
NZ546645A (en) * | 2003-10-23 | 2010-02-26 | Ab Science | 2-Aminoaryloxazole compounds as tyrosine kinase inhibitors |
CN101337930B (zh) | 2003-11-11 | 2010-09-08 | 卫材R&D管理有限公司 | 脲衍生物的制备方法 |
GB0326459D0 (en) * | 2003-11-13 | 2003-12-17 | Astrazeneca Ab | Quinazoline derivatives |
CA2545711A1 (en) | 2003-11-13 | 2005-06-02 | Ambit Biosciences Corporation | Urea derivatives as kinase modulators |
DE602004012891T2 (de) | 2003-12-18 | 2009-04-09 | Janssen Pharmaceutica N.V. | Pyrido- und pyrimidopyrimidinderivate als anti-proliferative mittel |
GB0330002D0 (en) | 2003-12-24 | 2004-01-28 | Astrazeneca Ab | Quinazoline derivatives |
BRPI0400869B8 (pt) * | 2004-03-02 | 2021-05-25 | Univ Estadual Campinas Unicamp | novos compostos derivados de 4-anilinoquinazolinas com propriedade inibidora de adenosinacinases |
ES2315834T3 (es) | 2004-02-03 | 2009-04-01 | Astrazeneca Ab | Derivados de quinazolina. |
ES2554330T3 (es) * | 2004-02-19 | 2015-12-18 | Rexahn Pharmaceuticals, Inc. | Derivados de quinazolina y uso terapéutico de los mismos |
WO2005115145A2 (en) * | 2004-05-20 | 2005-12-08 | Wyeth | Quinone substituted quinazoline and quinoline kinase inhibitors |
MXPA06014125A (es) * | 2004-06-04 | 2007-01-31 | Astrazeneca Ab | Derivados de quinazolina en la forma de cinasas de tirosina de receptor erbb. |
US20060019975A1 (en) * | 2004-07-23 | 2006-01-26 | Pfizer Inc | Novel piperidyl derivatives of quinazoline and isoquinoline |
ATE428421T1 (de) | 2004-09-17 | 2009-05-15 | Eisai R&D Man Co Ltd | Medizinische zusammensetzung mit verbesserter stabilität und reduzierten gelierungseigenschaften |
NZ554017A (en) | 2004-10-12 | 2010-06-25 | Astrazeneca Ab | [(Quinazolin-4-yloxy)phenyl]acetamide derivatives |
JP4980919B2 (ja) * | 2004-11-23 | 2012-07-18 | ザ ユニバーシティー オブ ブリティッシュ コロンビア ユニバーシティー−インダストリー リエゾン オフィス | Efgシグナル伝達経路を混乱させる薬剤とクラステリンレベルを減少させるオリゴヌクレオチドとの併用による癌の治療 |
JO3088B1 (ar) * | 2004-12-08 | 2017-03-15 | Janssen Pharmaceutica Nv | مشتقات كوينازولين كبيرة الحلقات و استعمالها بصفتها موانع كينيز متعددة الاهداف |
NI200700147A (es) | 2004-12-08 | 2019-05-10 | Janssen Pharmaceutica Nv | Derivados de quinazolina inhibidores de cinasas dirigidos a multip |
WO2006064196A1 (en) | 2004-12-14 | 2006-06-22 | Astrazeneca Ab | Pyrazolopyrimidine compounds as antitumor agents |
US20060183763A1 (en) * | 2004-12-31 | 2006-08-17 | Pfizer Inc | Novel pyrrolidyl derivatives of heteroaromatic compounds |
CA2592900A1 (en) | 2005-01-03 | 2006-07-13 | Myriad Genetics Inc. | Nitrogen containing bicyclic compounds and therapeutical use thereof |
US8258145B2 (en) * | 2005-01-03 | 2012-09-04 | Myrexis, Inc. | Method of treating brain cancer |
EP1846396A2 (de) * | 2005-02-11 | 2007-10-24 | Freie Universität Berlin | Substituierte 4-(indol-3-yl)chinazoline und ihre verwendung |
GT200600078A (es) | 2005-02-17 | 2007-04-12 | Derivados de indol, benzotiofeno, benzofurano e indeno cicloalquil condensados | |
EP1856095B1 (en) * | 2005-02-26 | 2011-08-24 | AstraZeneca AB | Quinazoline derivatives as tyrosine kinase inhibitors |
GB0504474D0 (en) * | 2005-03-04 | 2005-04-13 | Astrazeneca Ab | Chemical compounds |
CA2603826C (en) | 2005-04-04 | 2013-03-12 | Ab Science | Substituted oxazole derivatives and their use as tyrosine kinase inhibitors |
GB0508717D0 (en) * | 2005-04-29 | 2005-06-08 | Astrazeneca Ab | Chemical compounds |
GB0508715D0 (en) * | 2005-04-29 | 2005-06-08 | Astrazeneca Ab | Chemical compounds |
WO2007015578A1 (ja) | 2005-08-02 | 2007-02-08 | Eisai R & D Management Co., Ltd. | 血管新生阻害物質の効果を検定する方法 |
JP2009508917A (ja) * | 2005-09-20 | 2009-03-05 | アストラゼネカ アクチボラグ | 抗癌剤としてのキナゾリン誘導体 |
JP2009508918A (ja) * | 2005-09-20 | 2009-03-05 | アストラゼネカ アクチボラグ | 癌治療のためのerbB受容体チロシンキナーゼ阻害剤としての4−(1H−インダゾール−5−イル]アミノ)キナゾリン化合物 |
CN101321739A (zh) * | 2005-12-02 | 2008-12-10 | 阿斯利康(瑞典)有限公司 | 用作erbB酪氨酸激酶抑制剂的喹唑啉衍生物 |
JP2009517450A (ja) * | 2005-12-02 | 2009-04-30 | アストラゼネカ アクチボラグ | チロシンキナーゼ阻害薬としての4−アニリノ置換キナゾリン誘導体 |
US20090099175A1 (en) * | 2006-03-01 | 2009-04-16 | Arrington Mark P | Phosphodiesterase 10 inhibitors |
UY30183A1 (es) | 2006-03-02 | 2007-10-31 | Astrazeneca Ab | Derivados de quinolina |
RU2448708C3 (ru) | 2006-05-18 | 2017-09-28 | Эйсай Ар Энд Ди Менеджмент Ко., Лтд. | Противоопухолевое средство против рака щитовидной железы |
BRPI0714211B8 (pt) * | 2006-07-13 | 2021-05-25 | Janssen Pharmaceutica Nv | derivados de mtki quinazolina, sua utilização e composição farmacêutica que os compreende |
US8246966B2 (en) * | 2006-08-07 | 2012-08-21 | University Of Georgia Research Foundation, Inc. | Trypanosome microsome system and uses thereof |
KR101472600B1 (ko) | 2006-08-28 | 2014-12-15 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 미분화형 위암에 대한 항종양제 |
EP1921070A1 (de) * | 2006-11-10 | 2008-05-14 | Boehringer Ingelheim Pharma GmbH & Co. KG | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstelllung |
EP2088863A2 (en) * | 2006-11-22 | 2009-08-19 | University Of Georgia Research Foundation, Inc. | Tyrosine kinase inhibitors as anti-kinetolastid and anti-apicomplexan agents |
WO2008093855A1 (ja) | 2007-01-29 | 2008-08-07 | Eisai R & D Management Co., Ltd. | 未分化型胃癌治療用組成物 |
EP2118075A1 (de) * | 2007-02-06 | 2009-11-18 | Boehringer Ingelheim International GmbH | Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
US20080190689A1 (en) * | 2007-02-12 | 2008-08-14 | Ballard Ebbin C | Inserts for engine exhaust systems |
JP5536647B2 (ja) | 2007-07-27 | 2014-07-02 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | ピロロピリミジン |
WO2009060945A1 (ja) | 2007-11-09 | 2009-05-14 | Eisai R & D Management Co., Ltd. | 血管新生阻害物質と抗腫瘍性白金錯体との併用 |
US8193182B2 (en) | 2008-01-04 | 2012-06-05 | Intellikine, Inc. | Substituted isoquinolin-1(2H)-ones, and methods of use thereof |
CN104926815B (zh) | 2008-01-04 | 2017-11-03 | 英特利凯恩有限责任公司 | 某些化学实体、组合物和方法 |
EA019709B1 (ru) * | 2008-02-07 | 2014-05-30 | Бёрингер Ингельхайм Интернациональ Гмбх | Спирогетероциклы и их применение в качестве лекарственных средств |
DE102008009609A1 (de) | 2008-02-18 | 2009-08-20 | Freie Universität Berlin | Substituierte 4-(Indol-3-yl)chinazoline und deren Verwendung und Herstellung |
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 |
WO2010015522A1 (de) * | 2008-08-08 | 2010-02-11 | Boehringer Ingelheim International Gmbh | Cyclohexyloxy-substituierte heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung |
EP2329849B1 (en) | 2009-11-18 | 2015-04-29 | Galderma Research & Development | Combination of alpha-2 adrenergic receptor agonist and non-steroidal anti-inflammatory agent for treating or preventing an inflammatory skin disorder |
US8394800B2 (en) | 2009-11-19 | 2013-03-12 | Galderma Laboratories, L.P. | Method for treating psoriasis |
CN102146076B (zh) * | 2010-02-05 | 2013-12-25 | 陕西师范大学 | 苯胺喹唑啉衍生物及其制备方法 |
HUE033143T2 (en) | 2010-03-26 | 2017-11-28 | Galderma Res & Dev | Preparations containing brimonidine for the treatment of erythema |
JP5747392B2 (ja) | 2010-03-26 | 2015-07-15 | ガルデルマ・リサーチ・アンド・デヴェロップメント | 毛細血管拡張症の安全かつ有効な治療のための改善された方法および組成物 |
WO2011153049A1 (en) * | 2010-06-02 | 2011-12-08 | The Trustees Of The University Of Pennsylvania | Methods and use of compounds that bind to her2/neu receptor complex |
BR112012032462A2 (pt) | 2010-06-25 | 2016-11-08 | Eisai R&D Man Co Ltd | agente antitumoral empregando compostos que, em combinação, têm efeito inibidor de quinase. |
US8053427B1 (en) | 2010-10-21 | 2011-11-08 | Galderma R&D SNC | Brimonidine gel composition |
RU2571277C2 (ru) | 2010-10-21 | 2015-12-20 | Галдерма С.А. | Композиции геля с бримонидином и способы применения |
CN102558160B (zh) * | 2010-12-20 | 2015-09-23 | 天津药物研究院 | 4-取代对甲磺酰胺苯胺基-喹唑啉衍生物及其制备方法和用途 |
BR112013017670B1 (pt) | 2011-01-10 | 2022-07-19 | Infinity Pharmaceuticals, Inc | Processos de preparação de isoquinolinonas e formas sólidas de isoquinolinonas |
KR20210043016A (ko) | 2011-03-04 | 2021-04-20 | 뉴젠 세러퓨틱스 인코포레이티드 | 알킨 치환된 퀴나졸린 화합물 및 그것의 사용 방법 |
CN103402519B (zh) | 2011-04-18 | 2015-11-25 | 卫材R&D管理有限公司 | 肿瘤治疗剂 |
JP6038128B2 (ja) | 2011-06-03 | 2016-12-07 | エーザイ・アール・アンド・ディー・マネジメント株式会社 | レンバチニブ化合物に対する甲状腺癌対象及び腎臓癌対象の反応性を予測及び評価するためのバイオマーカー |
CN102786512A (zh) | 2012-05-31 | 2012-11-21 | 中国人民解放军军事医学科学院毒物药物研究所 | N-芳基不饱和稠环叔胺类化合物及其制备方法和抗肿瘤应用 |
US8828998B2 (en) | 2012-06-25 | 2014-09-09 | Infinity Pharmaceuticals, Inc. | Treatment of lupus, fibrotic conditions, and inflammatory myopathies and other disorders using PI3 kinase inhibitors |
CN102942529B (zh) * | 2012-11-09 | 2015-06-24 | 贵州大学 | 4-(4-取代哌嗪)-5,6,7-三烷氧基喹唑啉类化合物及其制备方法和应用 |
CN104755463A (zh) | 2012-12-21 | 2015-07-01 | 卫材R&D管理有限公司 | 非晶态形式的喹啉衍生物及其生产方法 |
JP2016507537A (ja) * | 2013-02-07 | 2016-03-10 | メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツングMerck Patent Gesellschaft mit beschraenkter Haftung | 置換アセチレン誘導体およびmGluR4の正のアロステリックモジュレーターとしてのそれらの使用 |
MX368099B (es) | 2013-05-14 | 2019-09-19 | Eisai R&D Man Co Ltd | Biomarcadores para predecir y evaluar el grado de respuesta de sujetos con cancer de endometrio a compuestos de tipo lenvatinib. |
PT3046584T (pt) | 2013-09-16 | 2017-09-18 | Astrazeneca Ab | Nanopartículas poliméricas terapêuticas e métodos para fabrico e uso das mesmas |
US9771333B2 (en) * | 2013-11-20 | 2017-09-26 | Signalchem Lifesciences Corp. | Quinazoline derivatives as TAM family kinase inhibitors |
US9815797B2 (en) | 2013-12-09 | 2017-11-14 | Ucb Biopharma Sprl | Fused bicyclic heteroaromatic derivatives as modulators of TNF activity |
WO2015160975A2 (en) | 2014-04-16 | 2015-10-22 | Infinity Pharmaceuticals, Inc. | Combination therapies |
KR102329681B1 (ko) | 2014-08-28 | 2021-11-23 | 에자이 알앤드디 매니지먼트 가부시키가이샤 | 고순도의 퀴놀린 유도체 및 이를 제조하는 방법 |
BR112017017428A2 (pt) | 2015-02-25 | 2018-04-03 | Eisai R&D Management Co., Ltd. | ?método para supressão do amargor de derivado de quinolina? |
CA2978226A1 (en) | 2015-03-04 | 2016-09-09 | Merck Sharpe & Dohme Corp. | Combination of a pd-1 antagonist and a vegfr/fgfr/ret tyrosine kinase inhibitor for treating cancer |
BR112017027227B1 (pt) | 2015-06-16 | 2023-12-12 | Eisai R&D Management Co., Ltd | Agente anti-câncer |
JP6740354B2 (ja) | 2015-10-05 | 2020-08-12 | ザ トラスティーズ オブ コロンビア ユニバーシティー イン ザ シティー オブ ニューヨーク | オートファジーの流れ及びホスホリパーゼd及びタウを含むタンパク質凝集体のクリアランスの活性化剤ならびにタンパク質症の治療方法 |
MX2018016227A (es) | 2016-06-24 | 2019-07-08 | Infinity Pharmaceuticals Inc | Terapias de combinacion. |
RU2626403C1 (ru) * | 2016-07-18 | 2017-07-27 | Федеральное государственное бюджетное учреждение науки Институт органического синтеза им. И.Я. Постовского Уральского отделения Российской академии наук (ИОС УрО РАН) | Способ получения (2-гидроксинафталин-1-ил)азина |
DK3658552T3 (da) | 2017-07-28 | 2023-11-20 | Yuhan Corp | Fremgangsmåde til fremstilling af n-(5-((4-(4-((dimethylamino)methyl)-3-phenyl-1h-pyrazol-1-yl)pyrimidin-2-yl)amino)-4-methoxy-2-morpholinophenyl)acrylamid ved reaktion af den tilsvarende amin med et 3-halogen-propionylchlorid |
JP2022501344A (ja) * | 2018-09-21 | 2022-01-06 | スペクトラム ファーマシューティカルズ インコーポレイテッド | 新規キナゾリンegfr阻害剤 |
CN112300082B (zh) * | 2019-07-26 | 2022-04-26 | 暨南大学 | 一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、制法与用途 |
CN111087391A (zh) * | 2020-01-06 | 2020-05-01 | 郑州大学 | 4-吲哚喹唑啉类化合物及其制备方法和应用 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5480883A (en) * | 1991-05-10 | 1996-01-02 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
NL6816241A (zh) * | 1967-12-01 | 1969-06-03 | ||
US3718743A (en) * | 1970-11-19 | 1973-02-27 | Merck & Co Inc | 5-phenyl-2-piperidones and 5-phenyl-2-thiopiperidones in compositions and methods for treating pain, fever and inflammation |
US3985749A (en) * | 1975-12-22 | 1976-10-12 | Eastman Kodak Company | Process for preparation of 4-aminoquinazoline |
GB1543560A (en) * | 1976-04-27 | 1979-04-04 | Shell Int Research | Herbicidal compositions containing phenylquinoxaline compounds |
JPS5538325A (en) * | 1978-09-11 | 1980-03-17 | Sankyo Co Ltd | 4-anilinoquinazoline derivative and its preparation |
US4465686A (en) * | 1981-09-08 | 1984-08-14 | Sterling Drug Inc. | 5-(Hydroxy- and/or amino-phenyl)-6-(lower-alkyl)-2-(1H)-pyridinones, their cardiotonic use and preparation |
US4599423A (en) * | 1982-04-26 | 1986-07-08 | Sterling Drug Inc. | Preparation of 5-(hydroxy- and/or aminophenyl-6-lower-alkyl)-2(1H)-pyridinones |
US4661499A (en) * | 1985-06-18 | 1987-04-28 | Merck Frosst Canada, Inc. | 2-[(substituted)-phenoxymethyl]quinolines |
US5710158A (en) * | 1991-05-10 | 1998-01-20 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
CA2102780C (en) * | 1991-05-10 | 2007-01-09 | Alfred P. Spada | Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase |
NZ243082A (en) * | 1991-06-28 | 1995-02-24 | Ici Plc | 4-anilino-quinazoline derivatives; pharmaceutical compositions, preparatory processes, and use thereof |
GB9300059D0 (en) * | 1992-01-20 | 1993-03-03 | Zeneca Ltd | Quinazoline derivatives |
-
1995
- 1995-06-06 US US08/469,147 patent/US5721237A/en not_active Expired - Lifetime
-
1996
- 1996-06-06 HU HU9802702A patent/HUP9802702A3/hu unknown
- 1996-06-06 AU AU61044/96A patent/AU696456B2/en not_active Ceased
- 1996-06-06 JP JP9501889A patent/JPH11507355A/ja not_active Ceased
- 1996-06-06 KR KR1019970709014A patent/KR19990022533A/ko not_active Application Discontinuation
- 1996-06-06 SK SK1663-97A patent/SK284475B6/sk not_active IP Right Cessation
- 1996-06-06 CZ CZ19973503A patent/CZ289338B6/cs not_active IP Right Cessation
- 1996-06-06 CN CN96194512A patent/CN1100540C/zh not_active Expired - Fee Related
- 1996-06-06 EA EA199800020A patent/EA000840B1/ru not_active IP Right Cessation
- 1996-06-06 SI SI9620092A patent/SI9620092A/sl not_active IP Right Cessation
- 1996-06-06 CA CA002223016A patent/CA2223016C/en not_active Expired - Fee Related
- 1996-06-06 BR BR9608638A patent/BR9608638A/pt not_active Application Discontinuation
- 1996-06-06 EP EP96918362A patent/EP0831831A4/en not_active Ceased
- 1996-06-06 WO PCT/US1996/009606 patent/WO1996039145A1/en not_active Application Discontinuation
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5480883A (en) * | 1991-05-10 | 1996-01-02 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Bis mono- and bicyclic aryl and heteroaryl compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
Also Published As
Publication number | Publication date |
---|---|
MX9709430A (es) | 1998-10-31 |
EP0831831A1 (en) | 1998-04-01 |
CN1187129A (zh) | 1998-07-08 |
CA2223016A1 (en) | 1996-12-12 |
SK166397A3 (en) | 1998-06-03 |
HUP9802702A2 (hu) | 1999-03-29 |
AU6104496A (en) | 1996-12-24 |
BR9608638A (pt) | 1999-06-29 |
HUP9802702A3 (en) | 2001-11-28 |
CZ289338B6 (cs) | 2002-01-16 |
AU696456B2 (en) | 1998-09-10 |
CA2223016C (en) | 2003-05-20 |
EA199800020A1 (ru) | 1998-06-25 |
CZ350397A3 (cs) | 1998-03-18 |
EA000840B1 (ru) | 2000-04-24 |
SK284475B6 (sk) | 2005-04-01 |
US5721237A (en) | 1998-02-24 |
EP0831831A4 (en) | 1998-05-27 |
WO1996039145A1 (en) | 1996-12-12 |
SI9620092A (sl) | 1998-08-31 |
KR19990022533A (ko) | 1999-03-25 |
JPH11507355A (ja) | 1999-06-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1100540C (zh) | 具有选择性抑制her-2自磷酸化性质的蛋白质酪氨酸激酶芳基和杂芳基喹唑啉化合物 | |
CN1177833C (zh) | 取代的间二氮杂萘衍生物 | |
CN1160338C (zh) | N-[4-(3-氯-4-氟-苯基氨基)-7-(3-吗啉-4-基-丙氧基)-喹唑啉-6-基]-丙烯酰胺,不可逆的酪氨酸激酶抑制剂 | |
CN1101391C (zh) | 抑制法呢基转移酶的2-喹诺酮衍生物 | |
CN1264840C (zh) | 8-甲氧基-(1,2,4)三唑并(1,5-a)吡啶衍生物及其作为腺苷受体配体的应用 | |
CN1200114A (zh) | 作为gnrh拮抗剂的喹啉衍生物 | |
CN100349888C (zh) | 药物化合物 | |
CN1311773A (zh) | 神经肽y5受体拮抗剂 | |
CN1264381A (zh) | 4-氨基吡咯并(3,2-d)嘧啶作为神经肽Y受体拮抗药 | |
CN105541836A (zh) | 激酶抑制剂的前药形式及其在治疗中的用途 | |
CN1646500A (zh) | 芳基取代的嘧啶及其用途 | |
CN103626742A (zh) | 激酶的联-芳基间-嘧啶抑制剂 | |
CN1233177A (zh) | Vegf相关疾病的治疗 | |
JPH11228447A (ja) | 組み合わせ療法 | |
CN1215066C (zh) | 新吲哚衍生物及其作为药物的用途 | |
JP2022538493A (ja) | 2-アミノピリミジン化合物及びその使用 | |
CN1665792A (zh) | 芳基羰基哌嗪和杂芳基羰基哌嗪及其治疗良性和恶性肿瘤疾病的用途 | |
CN1891701A (zh) | 杂芳环缩氨基硫脲类化合物及其衍生物和它们在制备抗肿瘤药物中的应用 | |
MXPA04010539A (es) | Derivados de quinazolina y medicamentos que los contienen. | |
JPH04247080A (ja) | 3−アリール−4(3h)キナゾリノンcckアンタゴニストおよびそれを含有する医薬製剤 | |
TW202128666A (zh) | 氨基嘧啶類化合物甲磺酸鹽的晶型a及其製備方法和應用 | |
TWI774780B (zh) | 化合物 | |
CN1277607A (zh) | 2-取代的1,2-苯并异噻唑衍生物及其作为血清素拮抗剂(5-ht1a,5-ht1b和5-ht1d)的应用 | |
CN1058397A (zh) | 1-二苯甲基哌嗪的新颖衍生物,其制备方法及其医药用途 | |
CN1181062C (zh) | 2-苯氧基嘧啶衍生物及其治疗用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1036773 Country of ref document: HK |
|
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20030205 |