JP2002527436A - キナゾリン誘導体 - Google Patents
キナゾリン誘導体Info
- Publication number
- JP2002527436A JP2002527436A JP2000575861A JP2000575861A JP2002527436A JP 2002527436 A JP2002527436 A JP 2002527436A JP 2000575861 A JP2000575861 A JP 2000575861A JP 2000575861 A JP2000575861 A JP 2000575861A JP 2002527436 A JP2002527436 A JP 2002527436A
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- methoxy
- alkoxy
- compound
- ethoxy
- 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.)
- Withdrawn
Links
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title description 13
- -1 cyano, amino Chemical group 0.000 claims abstract description 292
- 150000001875 compounds Chemical class 0.000 claims abstract description 205
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 169
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 109
- 239000001257 hydrogen Substances 0.000 claims abstract description 109
- 150000003839 salts Chemical class 0.000 claims abstract description 92
- 125000005843 halogen group Chemical group 0.000 claims abstract description 67
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 66
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 56
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 55
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 41
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 32
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 30
- 230000000694 effects Effects 0.000 claims abstract description 26
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 23
- 230000008728 vascular permeability Effects 0.000 claims abstract description 23
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 21
- 241001465754 Metazoa Species 0.000 claims abstract description 20
- 238000004519 manufacturing process Methods 0.000 claims abstract description 19
- 230000001772 anti-angiogenic effect Effects 0.000 claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 17
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 16
- 238000011282 treatment Methods 0.000 claims abstract description 16
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 12
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 10
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical group O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 claims abstract description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 8
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims abstract description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims abstract description 5
- 239000004480 active ingredient Substances 0.000 claims abstract description 4
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims abstract description 3
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 79
- 238000000034 method Methods 0.000 claims description 75
- 125000001424 substituent group Chemical group 0.000 claims description 67
- 229910052757 nitrogen Inorganic materials 0.000 claims description 61
- 238000006243 chemical reaction Methods 0.000 claims description 37
- 229910052760 oxygen Inorganic materials 0.000 claims description 29
- 125000004043 oxo group Chemical group O=* 0.000 claims description 28
- 229910052717 sulfur Inorganic materials 0.000 claims description 28
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 229910052799 carbon Inorganic materials 0.000 claims description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 14
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 230000002401 inhibitory effect Effects 0.000 claims description 14
- 125000004848 alkoxyethyl group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 12
- 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 11
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
- 229920006395 saturated elastomer Polymers 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000003386 piperidinyl group Chemical group 0.000 claims description 10
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 9
- 150000001721 carbon Chemical group 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 9
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 8
- 125000004122 cyclic group Chemical group 0.000 claims description 8
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
- 241000282412 Homo Species 0.000 claims description 7
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 7
- 125000004193 piperazinyl group Chemical group 0.000 claims description 7
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 6
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 5
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 5
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- XRAIRKLUFOYIFQ-UHFFFAOYSA-N 4-[3-[4-[[5-(4-chlorophenyl)-1h-pyrazol-3-yl]oxy]-6-methoxyquinazolin-7-yl]oxypropyl]morpholine Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1OC(=NN1)C=C1C1=CC=C(Cl)C=C1 XRAIRKLUFOYIFQ-UHFFFAOYSA-N 0.000 claims description 4
- LYLCWAABWMSIJZ-UHFFFAOYSA-N 6-methoxy-7-(2-methoxyethoxy)-4-[[5-(4-methoxyphenyl)-1h-pyrazol-3-yl]oxy]quinazoline Chemical compound C=12C=C(OC)C(OCCOC)=CC2=NC=NC=1OC(=NN1)C=C1C1=CC=C(OC)C=C1 LYLCWAABWMSIJZ-UHFFFAOYSA-N 0.000 claims description 4
- DQTUPVSQFVNKJO-UHFFFAOYSA-N 6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]-4-[(5-phenyl-1h-pyrazol-3-yl)oxy]quinazoline Chemical compound N1=CN=C2C=C(OCCCN3CCN(C)CC3)C(OC)=CC2=C1OC(=NN1)C=C1C1=CC=CC=C1 DQTUPVSQFVNKJO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002168 alkylating agent Substances 0.000 claims description 4
- 229940100198 alkylating agent Drugs 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 230000003647 oxidation Effects 0.000 claims description 4
- 238000007254 oxidation reaction Methods 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- LDRQIAPESKISGW-UHFFFAOYSA-N 4-[3-[4-[[5-(2-fluorophenyl)-1h-pyrazol-3-yl]oxy]-6-methoxyquinazolin-7-yl]oxypropyl]morpholine Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1OC(=NN1)C=C1C1=CC=CC=C1F LDRQIAPESKISGW-UHFFFAOYSA-N 0.000 claims description 3
- GJNOSEZQSAEDBT-UHFFFAOYSA-N 4-[3-[4-[[5-(furan-3-yl)-1h-pyrazol-3-yl]oxy]-6-methoxyquinazolin-7-yl]oxypropyl]morpholine Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1OC(=NN1)C=C1C=1C=COC=1 GJNOSEZQSAEDBT-UHFFFAOYSA-N 0.000 claims description 3
- DOQOAOBWHHEXSW-UHFFFAOYSA-N 4-[3-[6-methoxy-4-[(5-phenyl-1h-pyrazol-3-yl)oxy]quinazolin-7-yl]oxypropyl]morpholine Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1OC(=NN1)C=C1C1=CC=CC=C1 DOQOAOBWHHEXSW-UHFFFAOYSA-N 0.000 claims description 3
- ZMOXRVVUBDCFRG-UHFFFAOYSA-N 4-[3-[6-methoxy-4-[(5-pyridin-4-yl-1h-pyrazol-3-yl)oxy]quinazolin-7-yl]oxypropyl]morpholine Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1OC(=NN1)C=C1C1=CC=NC=C1 ZMOXRVVUBDCFRG-UHFFFAOYSA-N 0.000 claims description 3
- TUFSFBAIBGKNLQ-UHFFFAOYSA-N 4-[3-[6-methoxy-4-[[5-(3-nitrophenyl)-1h-pyrazol-3-yl]oxy]quinazolin-7-yl]oxypropyl]morpholine Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1OC(=NN1)C=C1C1=CC=CC([N+]([O-])=O)=C1 TUFSFBAIBGKNLQ-UHFFFAOYSA-N 0.000 claims description 3
- PHEVGILJEFELHN-UHFFFAOYSA-N 4-[3-[6-methoxy-4-[[5-(4-nitrophenyl)-1h-pyrazol-3-yl]oxy]quinazolin-7-yl]oxypropyl]morpholine Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1OC(=NN1)C=C1C1=CC=C([N+]([O-])=O)C=C1 PHEVGILJEFELHN-UHFFFAOYSA-N 0.000 claims description 3
- MDBVRWFEYLAMBA-UHFFFAOYSA-N 6-methoxy-4-[[5-(4-methoxyphenyl)-1h-pyrazol-3-yl]oxy]-7-[(1-methylpiperidin-4-yl)methoxy]quinazoline Chemical compound C1=CC(OC)=CC=C1C1=CC(OC=2C3=CC(OC)=C(OCC4CCN(C)CC4)C=C3N=CN=2)=NN1 MDBVRWFEYLAMBA-UHFFFAOYSA-N 0.000 claims description 3
- VXGFRTSSUJBKEZ-UHFFFAOYSA-N 6-methoxy-4-[[5-(4-methoxyphenyl)-1h-pyrazol-3-yl]oxy]-7-[2-(triazol-1-yl)ethoxy]quinazoline Chemical compound C1=CC(OC)=CC=C1C1=CC(OC=2C3=CC(OC)=C(OCCN4N=NC=C4)C=C3N=CN=2)=NN1 VXGFRTSSUJBKEZ-UHFFFAOYSA-N 0.000 claims description 3
- XQXJCZQAVUTNBQ-UHFFFAOYSA-N 6-methoxy-4-[[5-(4-methoxyphenyl)-1h-pyrazol-3-yl]oxy]-7-[[1-(2-methylsulfonylethyl)piperidin-4-yl]methoxy]quinazoline Chemical compound C1=CC(OC)=CC=C1C1=CC(OC=2C3=CC(OC)=C(OCC4CCN(CCS(C)(=O)=O)CC4)C=C3N=CN=2)=NN1 XQXJCZQAVUTNBQ-UHFFFAOYSA-N 0.000 claims description 3
- CNDJEHZZDXTJAD-UHFFFAOYSA-N 6-methoxy-7-[2-(2-methoxyethoxy)ethoxy]-4-[(5-phenyl-1h-pyrazol-3-yl)oxy]quinazoline Chemical compound C=12C=C(OC)C(OCCOCCOC)=CC2=NC=NC=1OC(=NN1)C=C1C1=CC=CC=C1 CNDJEHZZDXTJAD-UHFFFAOYSA-N 0.000 claims description 3
- TWYLGVCHEXWXMH-UHFFFAOYSA-N 7-(2-methoxyethoxy)-4-[(5-phenyl-1h-pyrazol-3-yl)oxy]quinazoline Chemical compound N=1C=NC2=CC(OCCOC)=CC=C2C=1OC(=NN1)C=C1C1=CC=CC=C1 TWYLGVCHEXWXMH-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 3
- 230000001052 transient effect Effects 0.000 claims description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 2
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 2
- 125000001246 bromo group Chemical group Br* 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 229940079593 drug Drugs 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims 2
- 230000001629 suppression Effects 0.000 claims 2
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims 1
- JYNXVUZDAIUVRF-UHFFFAOYSA-N 6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]-n-(5-phenyl-1h-pyrazol-3-yl)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCC3CCN(C)CC3)C(OC)=CC2=C1NC(=NN1)C=C1C1=CC=CC=C1 JYNXVUZDAIUVRF-UHFFFAOYSA-N 0.000 claims 1
- LATNIDZFEFGNMI-UHFFFAOYSA-N 7-(2-imidazol-1-ylethoxy)-6-methoxy-4-[(5-phenyl-1h-pyrazol-3-yl)oxy]quinazoline Chemical compound N1=CN=C2C=C(OCCN3C=NC=C3)C(OC)=CC2=C1OC(=NN1)C=C1C1=CC=CC=C1 LATNIDZFEFGNMI-UHFFFAOYSA-N 0.000 claims 1
- 235000018936 Vitellaria paradoxa Nutrition 0.000 claims 1
- 125000004103 aminoalkyl group Chemical group 0.000 claims 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims 1
- 239000006187 pill Substances 0.000 claims 1
- 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims 1
- 125000005023 xylyl group Chemical group 0.000 claims 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 abstract description 14
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 abstract description 14
- 206010028980 Neoplasm Diseases 0.000 abstract description 11
- 201000011510 cancer Diseases 0.000 abstract description 8
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 4
- 230000009471 action Effects 0.000 abstract description 3
- 125000005647 linker group Chemical group 0.000 abstract description 3
- 125000004183 alkoxy alkyl group Chemical group 0.000 abstract 1
- 125000004849 alkoxymethyl group Chemical group 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 159
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 138
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 102
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 73
- 238000001704 evaporation Methods 0.000 description 64
- 230000008020 evaporation Effects 0.000 description 64
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 63
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 61
- 239000007858 starting material Substances 0.000 description 59
- 238000001914 filtration Methods 0.000 description 54
- 239000000243 solution Substances 0.000 description 54
- 239000007787 solid Substances 0.000 description 49
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 36
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 30
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000012044 organic layer Substances 0.000 description 23
- 239000012267 brine Substances 0.000 description 22
- 238000001816 cooling Methods 0.000 description 22
- 238000000921 elemental analysis Methods 0.000 description 22
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
- 238000003756 stirring Methods 0.000 description 22
- OUJRTEVIUYGUQY-UHFFFAOYSA-N 4-[3-(4-chloro-6-methoxyquinazolin-7-yl)oxypropyl]morpholine Chemical compound COC1=CC2=C(Cl)N=CN=C2C=C1OCCCN1CCOCC1 OUJRTEVIUYGUQY-UHFFFAOYSA-N 0.000 description 21
- 239000002244 precipitate Substances 0.000 description 19
- 239000002904 solvent Substances 0.000 description 19
- 239000003039 volatile agent Substances 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- 239000000725 suspension Substances 0.000 description 18
- 150000001408 amides Chemical class 0.000 description 17
- 150000002148 esters Chemical class 0.000 description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 16
- 238000010992 reflux Methods 0.000 description 16
- 239000012312 sodium hydride Substances 0.000 description 16
- 229910000104 sodium hydride Inorganic materials 0.000 description 16
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 14
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 14
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- 235000017557 sodium bicarbonate Nutrition 0.000 description 14
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 14
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 13
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 13
- 229940002612 prodrug Drugs 0.000 description 13
- 239000000651 prodrug Substances 0.000 description 13
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 12
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- 238000004440 column chromatography Methods 0.000 description 11
- 239000012442 inert solvent Substances 0.000 description 11
- DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 11
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 10
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- 238000003556 assay Methods 0.000 description 10
- 239000003701 inert diluent Substances 0.000 description 10
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 9
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 9
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- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- 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
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- 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
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- 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
- C07D403/14—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 three or more hetero rings
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- 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
- C07D405/14—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 three or more hetero rings
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Reproductive Health (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| EP98402496 | 1998-10-08 | ||
| EP98402496.8 | 1998-10-08 | ||
| PCT/GB1999/003295 WO2000021955A1 (en) | 1998-10-08 | 1999-10-05 | Quinazoline derivatives |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| JP2011006012A Division JP2011126888A (ja) | 1998-10-08 | 2011-01-14 | キナゾリン誘導体 |
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| JP2002527436A true JP2002527436A (ja) | 2002-08-27 |
| JP2002527436A5 JP2002527436A5 (https=) | 2006-11-30 |
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| JP2011006012A Pending JP2011126888A (ja) | 1998-10-08 | 2011-01-14 | キナゾリン誘導体 |
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| JP2011006012A Pending JP2011126888A (ja) | 1998-10-08 | 2011-01-14 | キナゾリン誘導体 |
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| US (1) | US7262201B1 (https=) |
| EP (1) | EP1119567B1 (https=) |
| JP (2) | JP2002527436A (https=) |
| KR (1) | KR100860295B1 (https=) |
| CN (1) | CN1161352C (https=) |
| AT (1) | ATE294796T1 (https=) |
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| BR (1) | BR9914326A (https=) |
| CA (1) | CA2344290C (https=) |
| DE (1) | DE69925141T2 (https=) |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007326862A (ja) * | 2002-12-24 | 2007-12-20 | Astrazeneca Ab | ホスホノオキシキナゾリン誘導体及びその医薬用途 |
| JP2016510000A (ja) * | 2013-02-20 | 2016-04-04 | カラ ファーマシューティカルズ インコーポレイテッド | 治療用化合物およびその使用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100881105B1 (ko) | 1999-11-05 | 2009-02-02 | 아스트라제네카 아베 | Ｖｅｇｆ 억제제로서의 퀴나졸린 유도체 |
| AU2001235804A1 (en) | 2000-03-06 | 2001-09-17 | Astrazeneca Ab | Therapy |
| ES2267748T3 (es) | 2000-04-07 | 2007-03-16 | Astrazeneca Ab | Compuestos de quinazolina. |
| UA73993C2 (uk) | 2000-06-06 | 2005-10-17 | Астразенека Аб | Хіназолінові похідні для лікування пухлин та фармацевтична композиція |
| EP1292591B1 (en) | 2000-06-22 | 2005-02-02 | Pfizer Products Inc. | Substituted bicyclic derivatives for the treatment of abnormal cell growth |
| IL153246A0 (en) * | 2000-06-28 | 2003-07-06 | Astrazeneca Ab | Substituted quinazoline derivatives and their use as inhibitors |
| WO2002016352A1 (en) | 2000-08-21 | 2002-02-28 | Astrazeneca Ab | Quinazoline derivatives |
| US7473691B2 (en) | 2000-09-15 | 2009-01-06 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
| WO2002022605A1 (en) | 2000-09-15 | 2002-03-21 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
| RU2340611C2 (ru) * | 2000-09-15 | 2008-12-10 | Вертекс Фармасьютикалз Инкорпорейтед | Производные пиразола, используемые в качестве ингибиторов протеинкиназы |
| US6610677B2 (en) | 2000-09-15 | 2003-08-26 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
| US6660731B2 (en) | 2000-09-15 | 2003-12-09 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
| SI1318997T1 (sl) | 2000-09-15 | 2006-12-31 | Vertex Pharma | Pirazolne spojine, uporabne kot inhibitorji protein-kinaze |
| JP4564713B2 (ja) | 2000-11-01 | 2010-10-20 | ミレニアム・ファーマシューティカルズ・インコーポレイテッド | 窒素性複素環式化合物、ならびに窒素性複素環式化合物およびその中間体を作製するための方法 |
| US6989385B2 (en) * | 2000-12-21 | 2006-01-24 | Vertex Pharmaceuticals Incorporated | Pyrazole compounds useful as protein kinase inhibitors |
| BR0116452A (pt) | 2000-12-21 | 2003-09-30 | Glaxo Group Ltd | Composto, composição farmacêutica, uso de um composto |
| JP4307843B2 (ja) | 2001-04-19 | 2009-08-05 | アストラゼネカ アクチボラグ | キナゾリン誘導体 |
| RU2332415C2 (ru) * | 2001-04-27 | 2008-08-27 | Вертекс Фармасьютикалз Инкорпорейтед | Производные пиразола, полезные в качестве ингибиторов протеинкиназы |
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| US7576074B2 (en) | 2002-07-15 | 2009-08-18 | Rice Kenneth D | Receptor-type kinase modulators and methods of use |
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| GB0318423D0 (en) * | 2003-08-06 | 2003-09-10 | Astrazeneca Ab | Chemical compounds |
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| US20090099165A1 (en) | 2003-10-14 | 2009-04-16 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Protein Kinase Inhibitors |
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- 1999-10-05 US US09/806,836 patent/US7262201B1/en not_active Expired - Fee Related
- 1999-10-05 PT PT99947758T patent/PT1119567E/pt unknown
- 1999-10-05 KR KR1020017004370A patent/KR100860295B1/ko not_active Expired - Fee Related
- 1999-10-05 BR BR9914326-7A patent/BR9914326A/pt not_active Application Discontinuation
- 1999-10-05 EP EP99947758A patent/EP1119567B1/en not_active Expired - Lifetime
- 1999-10-05 DE DE69925141T patent/DE69925141T2/de not_active Expired - Lifetime
- 1999-10-05 AT AT99947758T patent/ATE294796T1/de active
- 1999-10-05 CN CNB998118613A patent/CN1161352C/zh not_active Expired - Fee Related
- 1999-10-05 CA CA002344290A patent/CA2344290C/en not_active Expired - Fee Related
- 1999-10-05 AU AU61128/99A patent/AU756556B2/en not_active Ceased
- 1999-10-05 HK HK02100744.7A patent/HK1039126B/en not_active IP Right Cessation
- 1999-10-05 DK DK99947758T patent/DK1119567T3/da active
- 1999-10-05 JP JP2000575861A patent/JP2002527436A/ja not_active Withdrawn
- 1999-10-05 ES ES99947758T patent/ES2241324T3/es not_active Expired - Lifetime
- 1999-10-05 WO PCT/GB1999/003295 patent/WO2000021955A1/en not_active Ceased
- 1999-10-05 IL IL14235999A patent/IL142359A0/xx unknown
- 1999-10-05 NZ NZ510434A patent/NZ510434A/en not_active IP Right Cessation
-
2001
- 2001-03-30 ZA ZA200102655A patent/ZA200102655B/en unknown
- 2001-04-01 IL IL142359A patent/IL142359A/en not_active IP Right Cessation
- 2001-04-06 NO NO20011739A patent/NO322644B1/no not_active IP Right Cessation
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2011
- 2011-01-14 JP JP2011006012A patent/JP2011126888A/ja active Pending
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| WO1995015758A1 (en) * | 1993-12-10 | 1995-06-15 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit csf-1r receptor tyrosine kinase |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2007326862A (ja) * | 2002-12-24 | 2007-12-20 | Astrazeneca Ab | ホスホノオキシキナゾリン誘導体及びその医薬用途 |
| JP2016510000A (ja) * | 2013-02-20 | 2016-04-04 | カラ ファーマシューティカルズ インコーポレイテッド | 治療用化合物およびその使用 |
| JP2021006574A (ja) * | 2013-02-20 | 2021-01-21 | カラ ファーマシューティカルズ インコーポレイテッド | 治療用化合物およびその使用 |
Also Published As
| Publication number | Publication date |
|---|---|
| BR9914326A (pt) | 2001-06-26 |
| NO20011739D0 (no) | 2001-04-06 |
| CA2344290C (en) | 2009-06-02 |
| CA2344290A1 (en) | 2000-04-20 |
| AU756556B2 (en) | 2003-01-16 |
| PT1119567E (pt) | 2005-08-31 |
| US7262201B1 (en) | 2007-08-28 |
| DK1119567T3 (da) | 2005-07-25 |
| HK1039126A1 (en) | 2002-04-12 |
| CN1161352C (zh) | 2004-08-11 |
| EP1119567B1 (en) | 2005-05-04 |
| DE69925141T2 (de) | 2006-04-27 |
| KR100860295B1 (ko) | 2008-09-25 |
| JP2011126888A (ja) | 2011-06-30 |
| AU6112899A (en) | 2000-05-01 |
| ATE294796T1 (de) | 2005-05-15 |
| CN1322202A (zh) | 2001-11-14 |
| HK1039126B (en) | 2005-09-30 |
| IL142359A0 (en) | 2002-03-10 |
| KR20010085890A (ko) | 2001-09-07 |
| NO322644B1 (no) | 2006-11-13 |
| EP1119567A1 (en) | 2001-08-01 |
| ES2241324T3 (es) | 2005-10-16 |
| NO20011739L (no) | 2001-06-07 |
| DE69925141D1 (de) | 2005-06-09 |
| NZ510434A (en) | 2003-10-31 |
| ZA200102655B (en) | 2002-09-30 |
| IL142359A (en) | 2008-11-03 |
| WO2000021955A1 (en) | 2000-04-20 |
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