KR20060058705A - 혈관형성 억제제로서의 퀴나졸린 유도체 - Google Patents
혈관형성 억제제로서의 퀴나졸린 유도체 Download PDFInfo
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- KR20060058705A KR20060058705A KR1020067002540A KR20067002540A KR20060058705A KR 20060058705 A KR20060058705 A KR 20060058705A KR 1020067002540 A KR1020067002540 A KR 1020067002540A KR 20067002540 A KR20067002540 A KR 20067002540A KR 20060058705 A KR20060058705 A KR 20060058705A
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- South Korea
- Prior art keywords
- alkyl
- group
- alkoxy
- ring
- amino
- Prior art date
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- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical class N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 title claims description 14
- 239000004037 angiogenesis inhibitor Substances 0.000 title description 4
- 229940121369 angiogenesis inhibitor Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 220
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 148
- 150000003839 salts Chemical class 0.000 claims abstract description 92
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 82
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 80
- 238000000034 method Methods 0.000 claims abstract description 67
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 48
- 125000002619 bicyclic group Chemical group 0.000 claims abstract description 35
- 241001465754 Metazoa Species 0.000 claims abstract description 20
- 230000033115 angiogenesis Effects 0.000 claims abstract description 20
- 230000008728 vascular permeability Effects 0.000 claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 14
- 125000003118 aryl group Chemical group 0.000 claims abstract description 12
- 230000005764 inhibitory process Effects 0.000 claims abstract description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 948
- -1 R 46 Chemical compound 0.000 claims description 392
- 125000001424 substituent group Chemical group 0.000 claims description 179
- 125000003545 alkoxy group Chemical group 0.000 claims description 176
- 229910052739 hydrogen Inorganic materials 0.000 claims description 158
- 239000001257 hydrogen Substances 0.000 claims description 158
- 125000000623 heterocyclic group Chemical group 0.000 claims description 129
- 125000001589 carboacyl group Chemical group 0.000 claims description 122
- 150000002431 hydrogen Chemical class 0.000 claims description 113
- 125000005843 halogen group Chemical group 0.000 claims description 104
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 102
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 98
- 229910052717 sulfur Inorganic materials 0.000 claims description 78
- 125000004043 oxo group Chemical group O=* 0.000 claims description 69
- 125000003282 alkyl amino group Chemical group 0.000 claims description 68
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 60
- 125000000304 alkynyl group Chemical group 0.000 claims description 55
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 55
- 125000003342 alkenyl group Chemical group 0.000 claims description 54
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 47
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 45
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 45
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 43
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 42
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 35
- 229910052799 carbon Inorganic materials 0.000 claims description 30
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 29
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 28
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 26
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 26
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 claims description 24
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 24
- 125000003386 piperidinyl group Chemical group 0.000 claims description 23
- 125000004193 piperazinyl group Chemical group 0.000 claims description 22
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 19
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
- 125000004739 (C1-C6) alkylsulfonyl group Chemical group 0.000 claims description 18
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 18
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 17
- 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 17
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 17
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 16
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 16
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 15
- 125000001153 fluoro group Chemical group F* 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 241000282412 Homo Species 0.000 claims description 12
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 12
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 12
- 239000002253 acid Substances 0.000 claims description 9
- 150000001721 carbon Chemical group 0.000 claims description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 9
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 7
- 125000001246 bromo group Chemical group Br* 0.000 claims description 7
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 6
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 6
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 6
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 6
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 6
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 5
- KIDITLRMHHRNNQ-UHFFFAOYSA-N 1-[4-[2-[6-methoxy-4-[(2-methyl-1h-indol-5-yl)oxy]quinazolin-7-yl]oxyethyl]piperazin-1-yl]propan-2-one Chemical compound COC1=CC2=C(OC=3C=C4C=C(C)NC4=CC=3)N=CN=C2C=C1OCCN1CCN(CC(C)=O)CC1 KIDITLRMHHRNNQ-UHFFFAOYSA-N 0.000 claims description 5
- HRVVCEOIDNXSIV-UHFFFAOYSA-N 5-[2-[4-[(4-fluoro-2-methyl-1h-indol-5-yl)oxy]-6-methoxyquinazolin-7-yl]oxyethyl]-3a,4,6,6a-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole Chemical compound C1=C2NC(C)=CC2=C(F)C(OC2=C3C=C(C(=CC3=NC=N2)OCCN2CC3OCOC3C2)OC)=C1 HRVVCEOIDNXSIV-UHFFFAOYSA-N 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 5
- QEMQZTUAJCGRIH-UHFFFAOYSA-N 1-[4-[2-[4-[(4-fluoro-2-methyl-1h-indol-5-yl)oxy]-6-methoxyquinazolin-7-yl]oxyethyl]piperazin-1-yl]propan-2-one Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCN1CCN(CC(C)=O)CC1 QEMQZTUAJCGRIH-UHFFFAOYSA-N 0.000 claims description 4
- IELFRTCUXMQWBP-UHFFFAOYSA-N 1-[4-[2-[6-methoxy-4-[(3-methyl-1h-indol-5-yl)oxy]quinazolin-7-yl]oxyethyl]piperazin-1-yl]propan-2-one Chemical compound COC1=CC2=C(OC=3C=C4C(C)=CNC4=CC=3)N=CN=C2C=C1OCCN1CCN(CC(C)=O)CC1 IELFRTCUXMQWBP-UHFFFAOYSA-N 0.000 claims description 4
- 125000004423 acyloxy group Chemical group 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 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 4
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 3
- UAQNJPXMOZCSEZ-UHFFFAOYSA-N 1-[4-[2-[6-methoxy-4-[(2-methyl-1h-indol-5-yl)oxy]quinazolin-7-yl]oxyethyl]piperazin-1-yl]-2-pyrrolidin-1-ylethanone Chemical compound COC1=CC2=C(OC=3C=C4C=C(C)NC4=CC=3)N=CN=C2C=C1OCCN(CC1)CCN1C(=O)CN1CCCC1 UAQNJPXMOZCSEZ-UHFFFAOYSA-N 0.000 claims description 3
- RHKWHQSLWYKYCM-UHFFFAOYSA-N 1-[4-[[6-methoxy-4-[(3-methyl-1h-indol-5-yl)oxy]quinazolin-7-yl]oxymethyl]piperidin-1-yl]propan-2-one Chemical compound COC1=CC2=C(OC=3C=C4C(C)=CNC4=CC=3)N=CN=C2C=C1OCC1CCN(CC(C)=O)CC1 RHKWHQSLWYKYCM-UHFFFAOYSA-N 0.000 claims description 3
- SMUZSLBRTYLRAN-UHFFFAOYSA-N 5-[2-[6-methoxy-4-[(2-methyl-1h-indol-5-yl)oxy]quinazolin-7-yl]oxyethyl]-3a,4,6,6a-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole Chemical compound C1=C2NC(C)=CC2=CC(OC2=C3C=C(C(=CC3=NC=N2)OCCN2CC3OCOC3C2)OC)=C1 SMUZSLBRTYLRAN-UHFFFAOYSA-N 0.000 claims description 3
- IOHSSFHJTGVTOZ-UHFFFAOYSA-N 5-[2-[6-methoxy-4-[(3-methyl-1h-indol-5-yl)oxy]quinazolin-7-yl]oxyethyl]-3a,4,6,6a-tetrahydro-[1,3]dioxolo[4,5-c]pyrrole Chemical compound C1=C2NC=C(C)C2=CC(OC2=C3C=C(C(=CC3=NC=N2)OCCN2CC3OCOC3C2)OC)=C1 IOHSSFHJTGVTOZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- UDNVOJWOIXRDLF-UHFFFAOYSA-N 1-[4-[4-[(4-fluoro-2-methyl-1h-indol-5-yl)oxy]-6-methoxyquinazolin-7-yl]oxypiperidin-1-yl]propan-2-one Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OC1CCN(CC(C)=O)CC1 UDNVOJWOIXRDLF-UHFFFAOYSA-N 0.000 claims description 2
- JIDBTFNSOGJOPT-UHFFFAOYSA-N 1-[4-[6-methoxy-4-[(2-methyl-1h-indol-5-yl)oxy]quinazolin-7-yl]oxypiperidin-1-yl]propan-2-one Chemical compound COC1=CC2=C(OC=3C=C4C=C(C)NC4=CC=3)N=CN=C2C=C1OC1CCN(CC(C)=O)CC1 JIDBTFNSOGJOPT-UHFFFAOYSA-N 0.000 claims description 2
- HWFNODHJXDEFNM-UHFFFAOYSA-N 1-[4-[6-methoxy-4-[(2-methyl-1h-indol-6-yl)oxy]quinazolin-7-yl]oxypiperidin-1-yl]propan-2-one Chemical compound COC1=CC2=C(OC=3C=C4NC(C)=CC4=CC=3)N=CN=C2C=C1OC1CCN(CC(C)=O)CC1 HWFNODHJXDEFNM-UHFFFAOYSA-N 0.000 claims description 2
- SDCNZLCBPPVHFM-UHFFFAOYSA-N 1-[4-[[6-methoxy-4-[(2-methyl-1h-indol-5-yl)oxy]quinazolin-7-yl]oxymethyl]piperidin-1-yl]propan-2-one Chemical compound COC1=CC2=C(OC=3C=C4C=C(C)NC4=CC=3)N=CN=C2C=C1OCC1CCN(CC(C)=O)CC1 SDCNZLCBPPVHFM-UHFFFAOYSA-N 0.000 claims description 2
- RZQRGWIRKGAYAD-UHFFFAOYSA-N 1-[4-[[6-methoxy-4-[(2-methyl-1h-indol-6-yl)oxy]quinazolin-7-yl]oxymethyl]piperidin-1-yl]propan-2-one Chemical compound COC1=CC2=C(OC=3C=C4NC(C)=CC4=CC=3)N=CN=C2C=C1OCC1CCN(CC(C)=O)CC1 RZQRGWIRKGAYAD-UHFFFAOYSA-N 0.000 claims description 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- 206010041349 Somnolence Diseases 0.000 claims description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000014759 maintenance of location Effects 0.000 claims description 2
- 230000014399 negative regulation of angiogenesis Effects 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 230000000717 retained effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 28
- 238000011282 treatment Methods 0.000 abstract description 24
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 abstract description 22
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 abstract description 22
- 206010028980 Neoplasm Diseases 0.000 abstract description 20
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 14
- 201000010099 disease Diseases 0.000 abstract description 13
- 201000011510 cancer Diseases 0.000 abstract description 9
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 99
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 71
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 60
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 52
- 239000000203 mixture Substances 0.000 description 48
- 239000007787 solid Substances 0.000 description 47
- 239000002904 solvent Substances 0.000 description 43
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 42
- 238000001819 mass spectrum Methods 0.000 description 41
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 40
- 229910001868 water Inorganic materials 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 35
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 34
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 33
- 239000000243 solution Substances 0.000 description 29
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 26
- 238000000746 purification Methods 0.000 description 25
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 22
- 238000001914 filtration Methods 0.000 description 22
- 238000012360 testing method Methods 0.000 description 22
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 21
- 239000007858 starting material Substances 0.000 description 21
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 18
- 229910000027 potassium carbonate Inorganic materials 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 238000003556 assay Methods 0.000 description 14
- 238000000921 elemental analysis Methods 0.000 description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 13
- 238000001704 evaporation Methods 0.000 description 13
- 230000008020 evaporation Effects 0.000 description 13
- 239000000377 silicon dioxide Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 11
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 11
- 239000002585 base Substances 0.000 description 11
- 238000010626 work up procedure Methods 0.000 description 11
- 102000004190 Enzymes Human genes 0.000 description 10
- 108090000790 Enzymes Proteins 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 150000001408 amides Chemical class 0.000 description 10
- 150000002148 esters Chemical class 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 10
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 10
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 10
- 0 CCC(NC(C)(CCCCC1)CC*1(C)C(C)COC)=C(C=CC(C)(C)C=C1*2C(CC3)C3C2)C1=C(C)C Chemical compound CCC(NC(C)(CCCCC1)CC*1(C)C(C)COC)=C(C=CC(C)(C)C=C1*2C(CC3)C3C2)C1=C(C)C 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000013459 approach Methods 0.000 description 9
- 239000012267 brine Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 238000004440 column chromatography Methods 0.000 description 9
- 229940088598 enzyme Drugs 0.000 description 9
- 239000003102 growth factor Substances 0.000 description 9
- 239000003701 inert diluent Substances 0.000 description 9
- 239000012442 inert solvent Substances 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 238000007363 ring formation reaction Methods 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 8
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 8
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 8
- 125000001041 indolyl group Chemical group 0.000 description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 8
- 235000019341 magnesium sulphate Nutrition 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 125000004848 alkoxyethyl group Chemical group 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 238000001727 in vivo Methods 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 7
- 239000002798 polar solvent Substances 0.000 description 7
- 102000005962 receptors Human genes 0.000 description 7
- 108020003175 receptors Proteins 0.000 description 7
- NPHFOFOYWYLBTF-UHFFFAOYSA-N 3-methyl-1h-indol-5-ol Chemical compound C1=C(O)C=C2C(C)=CNC2=C1 NPHFOFOYWYLBTF-UHFFFAOYSA-N 0.000 description 6
- VRDGPSDTYIITKT-UHFFFAOYSA-N 4,5,6,6a-tetrahydro-3ah-[1,3]dioxolo[4,5-c]pyrrole;hydrochloride Chemical compound Cl.O1COC2CNCC21 VRDGPSDTYIITKT-UHFFFAOYSA-N 0.000 description 6
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Classifications
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- 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
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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
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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
Landscapes
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- Physical Education & Sports Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
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| GB0318422.3 | 2003-08-06 | ||
| GBGB0318422.3A GB0318422D0 (en) | 2003-08-06 | 2003-08-06 | Chemical compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20060058705A true KR20060058705A (ko) | 2006-05-30 |
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| US (2) | US7989460B2 (enExample) |
| EP (1) | EP1658280A1 (enExample) |
| JP (1) | JP4890249B2 (enExample) |
| KR (1) | KR20060058705A (enExample) |
| CN (1) | CN1863794B (enExample) |
| AU (1) | AU2004263360A1 (enExample) |
| BR (1) | BRPI0413284A (enExample) |
| CA (1) | CA2534811A1 (enExample) |
| GB (1) | GB0318422D0 (enExample) |
| IL (1) | IL173484A0 (enExample) |
| MX (1) | MXPA06001395A (enExample) |
| NO (1) | NO20060650L (enExample) |
| WO (1) | WO2005014582A1 (enExample) |
| ZA (1) | ZA200601025B (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR20150119361A (ko) * | 2013-02-20 | 2015-10-23 | 칼라 파마슈티컬스, 인크. | 치료 화합물 및 그의 용도 |
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| EE05345B1 (et) | 1999-02-10 | 2010-10-15 | Astrazeneca Ab | Kinasoliini derivaadid angiogeneesi inhibiitoritena |
| PE20021011A1 (es) * | 2001-03-23 | 2003-02-01 | Bayer Corp | Derivados quinazolinicos como inhibidores de la rho-quinasa |
| MXPA04007459A (es) * | 2002-02-01 | 2005-09-08 | Astrazeneca Ab | Compuestos de quinazolina. |
| MX2007004403A (es) | 2004-10-12 | 2007-04-27 | Astrazeneca Ab | Derivados de quinazolina. |
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| US7851623B2 (en) * | 2006-11-02 | 2010-12-14 | Astrazeneca Ab | Chemical process |
| CA2701594C (en) * | 2007-10-24 | 2014-02-18 | Merck Sharp & Dohme Corp. | Heterocycle phenyl amide t-type calcium channel antagonists |
| US8211911B2 (en) * | 2008-08-19 | 2012-07-03 | Guoqing Paul Chen | Compounds as kinase inhibitors |
| US8759362B2 (en) * | 2008-10-24 | 2014-06-24 | Purdue Pharma L.P. | Bicycloheteroaryl compounds and their use as TRPV1 ligands |
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| AU2002347336A1 (en) * | 2001-12-05 | 2003-06-17 | Astrazeneca Ab | Quinoline derivatives |
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2003
- 2003-08-06 GB GBGB0318422.3A patent/GB0318422D0/en not_active Ceased
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2004
- 2004-08-05 EP EP04743664A patent/EP1658280A1/en not_active Withdrawn
- 2004-08-05 MX MXPA06001395A patent/MXPA06001395A/es unknown
- 2004-08-05 BR BRPI0413284-0A patent/BRPI0413284A/pt not_active IP Right Cessation
- 2004-08-05 CA CA002534811A patent/CA2534811A1/en not_active Abandoned
- 2004-08-05 WO PCT/GB2004/003376 patent/WO2005014582A1/en not_active Ceased
- 2004-08-05 AU AU2004263360A patent/AU2004263360A1/en not_active Abandoned
- 2004-08-05 CN CN2004800290795A patent/CN1863794B/zh not_active Expired - Fee Related
- 2004-08-05 US US10/566,842 patent/US7989460B2/en not_active Expired - Fee Related
- 2004-08-05 KR KR1020067002540A patent/KR20060058705A/ko not_active Withdrawn
- 2004-08-05 JP JP2006522400A patent/JP4890249B2/ja not_active Expired - Fee Related
-
2006
- 2006-01-31 IL IL173484A patent/IL173484A0/en unknown
- 2006-02-03 ZA ZA200601025A patent/ZA200601025B/en unknown
- 2006-02-09 NO NO20060650A patent/NO20060650L/no not_active Application Discontinuation
-
2011
- 2011-06-20 US US13/164,310 patent/US20120046300A1/en not_active Abandoned
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20150119361A (ko) * | 2013-02-20 | 2015-10-23 | 칼라 파마슈티컬스, 인크. | 치료 화합물 및 그의 용도 |
Also Published As
| Publication number | Publication date |
|---|---|
| NO20060650L (no) | 2006-04-24 |
| CA2534811A1 (en) | 2005-02-17 |
| ZA200601025B (en) | 2007-05-30 |
| US20080058342A1 (en) | 2008-03-06 |
| WO2005014582A1 (en) | 2005-02-17 |
| CN1863794A (zh) | 2006-11-15 |
| JP2007501210A (ja) | 2007-01-25 |
| US20120046300A1 (en) | 2012-02-23 |
| IL173484A0 (en) | 2006-06-11 |
| JP4890249B2 (ja) | 2012-03-07 |
| US7989460B2 (en) | 2011-08-02 |
| BRPI0413284A (pt) | 2006-10-10 |
| EP1658280A1 (en) | 2006-05-24 |
| GB0318422D0 (en) | 2003-09-10 |
| MXPA06001395A (es) | 2006-05-19 |
| AU2004263360A1 (en) | 2005-02-17 |
| CN1863794B (zh) | 2012-04-25 |
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