BG106492A - Хиназолинови производни и приложението им като фармацевтични средства - Google Patents
Хиназолинови производни и приложението им като фармацевтични средства Download PDFInfo
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- BG106492A BG106492A BG106492A BG10649202A BG106492A BG 106492 A BG106492 A BG 106492A BG 106492 A BG106492 A BG 106492A BG 10649202 A BG10649202 A BG 10649202A BG 106492 A BG106492 A BG 106492A
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- Prior art keywords
- alkyl
- group
- defined above
- optionally substituted
- hydrogen
- Prior art date
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- 239000003814 drug Substances 0.000 title claims abstract description 14
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 504
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 216
- 239000001257 hydrogen Substances 0.000 claims abstract description 216
- 238000002360 preparation method Methods 0.000 claims abstract description 209
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 166
- 150000002431 hydrogen Chemical group 0.000 claims abstract description 138
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 82
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 64
- 125000001183 hydrocarbyl group Chemical group 0.000 claims abstract description 50
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 48
- 150000002148 esters Chemical class 0.000 claims abstract description 43
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 40
- 150000003839 salts Chemical class 0.000 claims abstract description 37
- 150000001408 amides Chemical class 0.000 claims abstract description 33
- 108090000461 Aurora Kinase A Proteins 0.000 claims abstract description 26
- 102100032311 Aurora kinase A Human genes 0.000 claims abstract description 24
- 229940002612 prodrug Drugs 0.000 claims abstract description 20
- 239000000651 prodrug Substances 0.000 claims abstract description 20
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 14
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims abstract description 10
- 125000005415 substituted alkoxy group Chemical group 0.000 claims abstract description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 484
- -1 4-methyl-1-piperazinyl Chemical group 0.000 claims description 432
- 125000003545 alkoxy group Chemical group 0.000 claims description 120
- 125000005843 halogen group Chemical group 0.000 claims description 120
- 229910052757 nitrogen Inorganic materials 0.000 claims description 116
- 125000001424 substituent group Chemical group 0.000 claims description 93
- 125000000524 functional group Chemical group 0.000 claims description 92
- 125000003118 aryl group Chemical group 0.000 claims description 83
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 68
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 67
- 125000005842 heteroatom Chemical group 0.000 claims description 61
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 60
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 59
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 58
- 229910052799 carbon Inorganic materials 0.000 claims description 53
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 48
- 125000004122 cyclic group Chemical group 0.000 claims description 47
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 45
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 44
- 125000004043 oxo group Chemical group O=* 0.000 claims description 43
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 41
- 125000000304 alkynyl group Chemical group 0.000 claims description 37
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 33
- 229920006395 saturated elastomer Polymers 0.000 claims description 32
- 125000003342 alkenyl group Chemical group 0.000 claims description 31
- 125000003282 alkyl amino group Chemical group 0.000 claims description 27
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 26
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 25
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical compound FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 24
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 23
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 23
- 125000002947 alkylene group Chemical group 0.000 claims description 20
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 20
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 19
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 18
- 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 18
- 125000001589 carboacyl group Chemical group 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 16
- 150000001721 carbon Chemical group 0.000 claims description 16
- 125000001153 fluoro group Chemical group F* 0.000 claims description 16
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 15
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 15
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 15
- 125000004423 acyloxy group Chemical group 0.000 claims description 14
- 125000004414 alkyl thio group Chemical group 0.000 claims description 14
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 14
- 238000011282 treatment Methods 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 125000004432 carbon atom Chemical group C* 0.000 claims description 12
- 125000005518 carboxamido group Chemical group 0.000 claims description 12
- 238000001727 in vivo Methods 0.000 claims description 12
- 239000001301 oxygen Substances 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 11
- 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 11
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 11
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 10
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 10
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 239000002243 precursor Substances 0.000 claims description 9
- 241001465754 Metazoa Species 0.000 claims description 8
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 8
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 8
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 7
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 7
- 125000004966 cyanoalkyl group Chemical group 0.000 claims description 7
- 125000002632 imidazolidinyl group Chemical group 0.000 claims description 7
- 125000004193 piperazinyl group Chemical group 0.000 claims description 7
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 6
- 125000004450 alkenylene group Chemical group 0.000 claims description 6
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 6
- 125000004419 alkynylene group Chemical group 0.000 claims description 5
- 125000003072 pyrazolidinyl group Chemical group 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 4
- 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 4
- 239000011593 sulfur Substances 0.000 claims description 4
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
- 125000003302 alkenyloxy group Chemical group 0.000 claims description 3
- 125000005907 alkyl ester group Chemical group 0.000 claims description 3
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 3
- 125000005553 heteroaryloxy group Chemical group 0.000 claims description 3
- 125000005646 oximino group Chemical group 0.000 claims description 3
- 229910052698 phosphorus Inorganic materials 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 125000004738 (C1-C6) alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000005083 alkoxyalkoxy group Chemical group 0.000 claims description 2
- 125000004976 cyclobutylene group Chemical group 0.000 claims description 2
- 125000004956 cyclohexylene group Chemical group 0.000 claims description 2
- 125000004979 cyclopentylene group Chemical group 0.000 claims description 2
- 125000004980 cyclopropylene group Chemical group 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
- 125000006413 ring segment Chemical group 0.000 claims description 2
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 35
- 125000004760 (C1-C4) alkylsulfonylamino group Chemical group 0.000 claims 2
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims 1
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims 1
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 claims 1
- 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims 1
- 150000001336 alkenes Chemical class 0.000 claims 1
- GRVDJDISBSALJP-UHFFFAOYSA-N methyloxidanyl Chemical group [O]C GRVDJDISBSALJP-UHFFFAOYSA-N 0.000 claims 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract description 4
- 229910052736 halogen Inorganic materials 0.000 abstract description 3
- 150000002367 halogens Chemical group 0.000 abstract description 3
- 230000005764 inhibitory process Effects 0.000 abstract description 3
- 229910020008 S(O) Inorganic materials 0.000 abstract 6
- 125000000962 organic group Chemical group 0.000 abstract 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 abstract 1
- 101001043818 Mus musculus Interleukin-31 receptor subunit alpha Proteins 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 404
- 239000007787 solid Substances 0.000 description 277
- 238000004949 mass spectrometry Methods 0.000 description 261
- 238000006243 chemical reaction Methods 0.000 description 193
- 238000005160 1H NMR spectroscopy Methods 0.000 description 180
- 239000011541 reaction mixture Substances 0.000 description 65
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 56
- 239000000243 solution Substances 0.000 description 55
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- 239000000203 mixture Substances 0.000 description 41
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- 239000000126 substance Substances 0.000 description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 30
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 29
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
- 239000002904 solvent Substances 0.000 description 27
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 27
- 238000005481 NMR spectroscopy Methods 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 24
- 238000004128 high performance liquid chromatography Methods 0.000 description 24
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 24
- 238000003828 vacuum filtration Methods 0.000 description 23
- 238000001035 drying Methods 0.000 description 22
- 239000002253 acid Substances 0.000 description 20
- 206010028980 Neoplasm Diseases 0.000 description 19
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 17
- 238000001704 evaporation Methods 0.000 description 17
- 230000008020 evaporation Effects 0.000 description 17
- 239000007858 starting material Substances 0.000 description 17
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 16
- 239000004480 active ingredient Substances 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 14
- 201000010099 disease Diseases 0.000 description 13
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 13
- 239000000725 suspension Substances 0.000 description 13
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 12
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
- 238000010992 reflux Methods 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 235000017557 sodium bicarbonate Nutrition 0.000 description 12
- 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 11
- FCQHLBNBKHUZIB-UHFFFAOYSA-N 4-n-(6,7-dimethoxyquinazolin-4-yl)benzene-1,4-diamine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=C(N)C=C1 FCQHLBNBKHUZIB-UHFFFAOYSA-N 0.000 description 11
- 201000011510 cancer Diseases 0.000 description 11
- 239000003112 inhibitor Substances 0.000 description 11
- 239000012044 organic layer Substances 0.000 description 11
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 239000012298 atmosphere Substances 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 230000022131 cell cycle Effects 0.000 description 9
- 108090000623 proteins and genes Proteins 0.000 description 9
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 8
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 8
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 8
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 8
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 8
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 230000002062 proliferating effect Effects 0.000 description 7
- IHCCAYCGZOLTEU-UHFFFAOYSA-N 3-furoic acid Chemical compound OC(=O)C=1C=COC=1 IHCCAYCGZOLTEU-UHFFFAOYSA-N 0.000 description 6
- 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 6
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 6
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 6
- JBDSSBMEKXHSJF-UHFFFAOYSA-N cyclopentanecarboxylic acid Chemical compound OC(=O)C1CCCC1 JBDSSBMEKXHSJF-UHFFFAOYSA-N 0.000 description 6
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 6
- 235000019341 magnesium sulphate Nutrition 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 6
- 238000000746 purification Methods 0.000 description 6
- 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 description 5
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 description 5
- XJFJRBLNIFZTPK-UHFFFAOYSA-N 4-n-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]benzene-1,4-diamine Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1NC1=CC=C(N)C=C1 XJFJRBLNIFZTPK-UHFFFAOYSA-N 0.000 description 5
- 108091007914 CDKs Proteins 0.000 description 5
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 5
- 230000009471 action Effects 0.000 description 5
- 125000002102 aryl alkyloxo group Chemical group 0.000 description 5
- 239000007859 condensation product Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000000796 flavoring agent Substances 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- NBDOSEUNJLCDLN-UHFFFAOYSA-N n-(4-amino-2-methylphenyl)benzamide Chemical compound CC1=CC(N)=CC=C1NC(=O)C1=CC=CC=C1 NBDOSEUNJLCDLN-UHFFFAOYSA-N 0.000 description 5
- GTTFJYUWPUKXJH-UHFFFAOYSA-N n-(4-aminophenyl)benzamide Chemical compound C1=CC(N)=CC=C1NC(=O)C1=CC=CC=C1 GTTFJYUWPUKXJH-UHFFFAOYSA-N 0.000 description 5
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- 102000004169 proteins and genes Human genes 0.000 description 5
- 239000003765 sweetening agent Substances 0.000 description 5
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Classifications
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- 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
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- 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
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- 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
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- 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
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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
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- 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
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- 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
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- C07D409/12—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 linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
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Application Number | Priority Date | Filing Date | Title |
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GBGB9922154.1A GB9922154D0 (en) | 1999-09-21 | 1999-09-21 | Chemical compounds |
GBGB9922170.7A GB9922170D0 (en) | 1999-09-21 | 1999-09-21 | Chemical compounds |
PCT/GB2000/003580 WO2001021596A1 (en) | 1999-09-21 | 2000-09-18 | Quinazoline derivatives and their use as pharmaceuticals |
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US (1) | US7709479B1 (cs) |
EP (1) | EP1218354B1 (cs) |
JP (1) | JP4870304B2 (cs) |
KR (1) | KR20020032612A (cs) |
CN (1) | CN1391562A (cs) |
AT (1) | ATE449083T1 (cs) |
AU (1) | AU7301000A (cs) |
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PL78381B2 (cs) * | 1972-08-09 | 1975-06-30 | ||
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 |
AU661533B2 (en) * | 1992-01-20 | 1995-07-27 | Astrazeneca Ab | Quinazoline derivatives |
DE4208254A1 (de) * | 1992-03-14 | 1993-09-16 | Hoechst Ag | Substituierte pyrimidine, verfahren zu ihrer herstellung und ihre verwendung als schaedlingsbekaempfungsmittel und fungizid |
GB9510757D0 (en) | 1994-09-19 | 1995-07-19 | Wellcome Found | Therapeuticaly active compounds |
TW321649B (cs) * | 1994-11-12 | 1997-12-01 | Zeneca Ltd | |
WO1997017329A1 (fr) * | 1995-11-07 | 1997-05-15 | Kirin Beer Kabushiki Kaisha | Derives de quinoline et derives de quinazoline inhibant l'autophosphorylation d'un recepteur de facteur de croissance originaire de plaquettes, et compositions pharmaceutiques les contenant |
GB9624482D0 (en) | 1995-12-18 | 1997-01-15 | Zeneca Phaema S A | Chemical compounds |
CA2239692C (en) * | 1995-12-18 | 2008-12-16 | Sugen, Inc. | Diagnosis and treatment of aur-1 and/or aur-2 related disorders |
BR9707495A (pt) | 1996-02-13 | 1999-07-27 | Zeneca Ltd | Derivado de quinazolina processo para a preparação do mesmo composição farmacêutica e processo para a produç o de um efeito antiangiogênico e/ou de redução de permeabilidade vascular em um animal de sangue quente |
KR100489174B1 (ko) | 1996-03-05 | 2005-09-30 | 제네카-파마 소시에떼아노님 | 4-아닐리노퀴나졸린유도체 |
JPH107657A (ja) * | 1996-06-19 | 1998-01-13 | Sankyo Co Ltd | スルホンアミド化合物 |
GB9718972D0 (en) * | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
US6251912B1 (en) * | 1997-08-01 | 2001-06-26 | American Cyanamid Company | Substituted quinazoline derivatives |
GB9800575D0 (en) | 1998-01-12 | 1998-03-11 | Glaxo Group Ltd | Heterocyclic compounds |
GB9800569D0 (en) | 1998-01-12 | 1998-03-11 | Glaxo Group Ltd | Heterocyclic compounds |
IL142257A0 (en) * | 1998-10-01 | 2002-03-10 | Astrazeneca Ab | Amide derivatives, process for their preparation, compositions containing them and use thereof in the manufacture of a medicament for the treatment of cytokine-mediated diseases |
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2000
- 2000-09-18 WO PCT/GB2000/003580 patent/WO2001021596A1/en not_active Application Discontinuation
- 2000-09-18 EE EEP200200119A patent/EE200200119A/xx unknown
- 2000-09-18 DE DE60043349T patent/DE60043349D1/de not_active Expired - Lifetime
- 2000-09-18 CA CA002384291A patent/CA2384291A1/en not_active Abandoned
- 2000-09-18 AU AU73010/00A patent/AU7301000A/en not_active Abandoned
- 2000-09-18 KR KR1020027003704A patent/KR20020032612A/ko not_active Withdrawn
- 2000-09-18 BR BR0014116-0A patent/BR0014116A/pt not_active IP Right Cessation
- 2000-09-18 CZ CZ20021009A patent/CZ20021009A3/cs unknown
- 2000-09-18 HK HK02108372.9A patent/HK1046686A1/zh unknown
- 2000-09-18 JP JP2001524975A patent/JP4870304B2/ja not_active Expired - Fee Related
- 2000-09-18 EP EP00960840A patent/EP1218354B1/en not_active Expired - Lifetime
- 2000-09-18 IL IL14857600A patent/IL148576A0/xx unknown
- 2000-09-18 CN CN00816011A patent/CN1391562A/zh active Pending
- 2000-09-18 AT AT00960840T patent/ATE449083T1/de not_active IP Right Cessation
- 2000-09-18 US US10/088,814 patent/US7709479B1/en not_active Expired - Fee Related
- 2000-09-18 PL PL00354323A patent/PL354323A1/xx not_active Application Discontinuation
- 2000-09-18 SK SK382-2002A patent/SK3822002A3/sk unknown
- 2000-09-18 ES ES00960840T patent/ES2334879T3/es not_active Expired - Lifetime
- 2000-09-18 HU HU0300059A patent/HUP0300059A3/hu unknown
- 2000-09-18 RU RU2002110461/14A patent/RU2002110461A/ru unknown
- 2000-09-21 CO CO00071837A patent/CO5200785A1/es not_active Application Discontinuation
-
2002
- 2002-03-07 BG BG106492A patent/BG106492A/bg unknown
- 2002-03-18 IS IS6305A patent/IS6305A/is unknown
- 2002-03-20 NO NO20021399A patent/NO20021399L/no unknown
Also Published As
Publication number | Publication date |
---|---|
IL148576A0 (en) | 2002-09-12 |
JP4870304B2 (ja) | 2012-02-08 |
CA2384291A1 (en) | 2001-03-29 |
ES2334879T3 (es) | 2010-03-17 |
KR20020032612A (ko) | 2002-05-03 |
BR0014116A (pt) | 2002-05-21 |
HUP0300059A3 (en) | 2003-08-28 |
AU7301000A (en) | 2001-04-24 |
WO2001021596A1 (en) | 2001-03-29 |
EP1218354B1 (en) | 2009-11-18 |
HUP0300059A2 (hu) | 2003-07-28 |
PL354323A1 (en) | 2004-01-12 |
US7709479B1 (en) | 2010-05-04 |
DE60043349D1 (de) | 2009-12-31 |
NO20021399D0 (no) | 2002-03-20 |
IS6305A (is) | 2002-03-18 |
EE200200119A (et) | 2003-04-15 |
CO5200785A1 (es) | 2002-09-27 |
CZ20021009A3 (cs) | 2002-06-12 |
EP1218354A1 (en) | 2002-07-03 |
ATE449083T1 (de) | 2009-12-15 |
JP2003509499A (ja) | 2003-03-11 |
RU2002110461A (ru) | 2004-03-10 |
HK1046686A1 (zh) | 2003-01-24 |
SK3822002A3 (en) | 2002-10-08 |
CN1391562A (zh) | 2003-01-15 |
NO20021399L (no) | 2002-04-30 |
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