NO311427B1 - 4-anilino-kinazolin-derivater, fremgangsmåte for fremstilling og anvendelse derav samt farmasöytisk preparat - Google Patents

Info

Publication number

NO311427B1

NO311427B1 NO19984085A NO984085A NO311427B1 NO 311427 B1 NO311427 B1 NO 311427B1 NO 19984085 A NO19984085 A NO 19984085A NO 984085 A NO984085 A NO 984085A NO 311427 B1 NO311427 B1 NO 311427B1

Authority

NO

Norway

Prior art keywords

formula

methoxy

compound

quinazoline

mmol

Prior art date

1996-03-05

Links

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• Global Dossier
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• 238000000034 method Methods 0.000 title claims abstract description 38
• 238000002360 preparation method Methods 0.000 title claims abstract description 18
• 230000008569 process Effects 0.000 title claims abstract description 18
• 239000000825 pharmaceutical preparation Substances 0.000 title claims description 5
• MTSNDBYBIZSILH-UHFFFAOYSA-N n-phenylquinazolin-4-amine Chemical class N=1C=NC2=CC=CC=C2C=1NC1=CC=CC=C1 MTSNDBYBIZSILH-UHFFFAOYSA-N 0.000 title 1
• 150000001875 compounds Chemical class 0.000 claims abstract description 169
• -1 methoxy, ethoxy, 2-methoxyethoxy, 3-methoxypropoxy, 2-ethoxyethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-(N,N-dimethylamino)ethoxy Chemical group 0.000 claims abstract description 134
• 150000003839 salts Chemical class 0.000 claims abstract description 77
• 230000000694 effects Effects 0.000 claims abstract description 26
• 239000001257 hydrogen Substances 0.000 claims abstract description 13
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 7
• 239000004480 active ingredient Substances 0.000 claims abstract description 5
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 4
• 125000004215 2,4-difluorophenyl group Chemical group [H]C1=C([H])C(*)=C(F)C([H])=C1F 0.000 claims abstract description 3
• 238000006243 chemical reaction Methods 0.000 claims description 45
• 150000003246 quinazolines Chemical class 0.000 claims description 22
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
• 239000002253 acid Substances 0.000 claims description 11
• 241001465754 Metazoa Species 0.000 claims description 9
• 238000010511 deprotection reaction Methods 0.000 claims description 9
• 125000003545 alkoxy group Chemical group 0.000 claims description 8
• 230000001772 anti-angiogenic effect Effects 0.000 claims description 7
• 239000003814 drug Substances 0.000 claims description 7
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
• 230000002137 anti-vascular effect Effects 0.000 claims description 4
• 229940079593 drug Drugs 0.000 claims description 4
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
• 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 3
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 3
• QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 3
• 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 3
• 239000000654 additive Substances 0.000 claims description 3
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• 230000000996 additive effect Effects 0.000 claims description 2
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• SELCESISHFJQIV-UHFFFAOYSA-N n-(4-bromo-2-fluorophenyl)-6-methoxy-7-(2-methoxyethoxy)quinazolin-4-amine Chemical group C=12C=C(OC)C(OCCOC)=CC2=NC=NC=1NC1=CC=C(Br)C=C1F SELCESISHFJQIV-UHFFFAOYSA-N 0.000 claims description 2
• JOVAHIJBMPYDFT-UHFFFAOYSA-N n-(4-bromo-2-fluorophenyl)-6-methoxy-7-(2-morpholin-4-ylethoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCN3CCOCC3)C(OC)=CC2=C1NC1=CC=C(Br)C=C1F JOVAHIJBMPYDFT-UHFFFAOYSA-N 0.000 claims description 2
• SWIHGAFGYUTAOY-UHFFFAOYSA-N n-(4-chloro-2-fluorophenyl)-6-methoxy-7-(2-methoxyethoxy)quinazolin-4-amine Chemical group C=12C=C(OC)C(OCCOC)=CC2=NC=NC=1NC1=CC=C(Cl)C=C1F SWIHGAFGYUTAOY-UHFFFAOYSA-N 0.000 claims description 2
• WOSBEBRTYHKLTR-UHFFFAOYSA-N n-(4-chloro-2-fluorophenyl)-6-methoxy-7-(2-morpholin-4-ylethoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCN3CCOCC3)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F WOSBEBRTYHKLTR-UHFFFAOYSA-N 0.000 claims description 2
• JNAHSSCHKKAPHI-UHFFFAOYSA-N n-(4-chloro-2-fluorophenyl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F JNAHSSCHKKAPHI-UHFFFAOYSA-N 0.000 claims description 2
• GSFNVLNOUTVLFC-UHFFFAOYSA-N n-(4-chloro-2-fluorophenyl)-6-methoxy-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCN3CCN(C)CC3)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F GSFNVLNOUTVLFC-UHFFFAOYSA-N 0.000 claims description 2
• GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims 1
• CPLJHWLUSQOSQK-UHFFFAOYSA-N n-(4-bromo-2-fluorophenyl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1NC1=CC=C(Br)C=C1F CPLJHWLUSQOSQK-UHFFFAOYSA-N 0.000 claims 1
• YPIGRTXUACJGMP-UHFFFAOYSA-N n-(4-bromo-2-fluorophenyl)-6-methoxy-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCN3CCN(C)CC3)C(OC)=CC2=C1NC1=CC=C(Br)C=C1F YPIGRTXUACJGMP-UHFFFAOYSA-N 0.000 claims 1
• 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 abstract description 23
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• 206010028980 Neoplasm Diseases 0.000 abstract description 11
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• 201000010099 disease Diseases 0.000 abstract description 8
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• 201000011510 cancer Diseases 0.000 abstract description 7
• 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 abstract description 4
• 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 4
• 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 1
• 239000008194 pharmaceutical composition Substances 0.000 abstract 1
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• 238000001704 evaporation Methods 0.000 description 124
• 230000008020 evaporation Effects 0.000 description 124
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 114
• 239000000203 mixture Substances 0.000 description 113
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
• 238000001914 filtration Methods 0.000 description 79
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 78
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 63
• 239000007787 solid Substances 0.000 description 63
• 239000002904 solvent Substances 0.000 description 53
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 51
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• 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 49
• 239000000243 solution Substances 0.000 description 47
• 229910001868 water Inorganic materials 0.000 description 47
• 239000007858 starting material Substances 0.000 description 41
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 34
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
• 238000010992 reflux Methods 0.000 description 30
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 27
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 26
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 25
• 239000002244 precipitate Substances 0.000 description 25
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 24
• 238000012360 testing method Methods 0.000 description 24
• 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 22
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• 239000000706 filtrate Substances 0.000 description 18
• 239000003039 volatile agent Substances 0.000 description 17
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• 239000003102 growth factor Substances 0.000 description 13
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• XGZKSSTZBKFZMF-UHFFFAOYSA-N 4-(4-chloro-2-fluoroanilino)-6-methoxyquinazolin-7-ol Chemical compound N1=CN=C2C=C(O)C(OC)=CC2=C1NC1=CC=C(Cl)C=C1F XGZKSSTZBKFZMF-UHFFFAOYSA-N 0.000 description 11
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• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
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• ZKHQWZAMYRWXGA-KQYNXXCUSA-N Adenosine triphosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-N 0.000 description 9
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