NO328159B1 - Substituerte kinazolinderivater, fremgangsmate for fremstilling av slike, farmasoytiske preparater inneholdende slike samt anvendelse av slike forbindelser for fremstilling av medikamenter for behandling av sykdom. - Google Patents

Info

Publication number

NO328159B1

NO328159B1 NO20043158A NO20043158A NO328159B1 NO 328159 B1 NO328159 B1 NO 328159B1 NO 20043158 A NO20043158 A NO 20043158A NO 20043158 A NO20043158 A NO 20043158A NO 328159 B1 NO328159 B1 NO 328159B1

Authority

NO

Norway

Prior art keywords

amino

propoxy

pyrazol

acetamide

methoxyquinazolin

Prior art date

2001-12-24

Links

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• 150000001875 compounds Chemical class 0.000 title claims description 260
• 238000002360 preparation method Methods 0.000 title claims description 170
• 238000011282 treatment Methods 0.000 title claims description 19
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 17
• 201000010099 disease Diseases 0.000 title claims description 16
• 239000003814 drug Substances 0.000 title claims description 10
• 238000004519 manufacturing process Methods 0.000 title claims description 5
• 238000000034 method Methods 0.000 title description 32
• 230000008569 process Effects 0.000 title description 2
• 239000008194 pharmaceutical composition Substances 0.000 title 1
• 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title 1
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 404
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 307
• -1 alkyl R 32 Chemical compound 0.000 claims description 218
• 238000006243 chemical reaction Methods 0.000 claims description 180
• 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 105
• 125000000217 alkyl group Chemical group 0.000 claims description 53
• 150000003839 salts Chemical class 0.000 claims description 53
• 239000001257 hydrogen Substances 0.000 claims description 52
• 229910052739 hydrogen Inorganic materials 0.000 claims description 52
• 150000002148 esters Chemical class 0.000 claims description 51
• 229910052736 halogen Inorganic materials 0.000 claims description 42
• 150000002367 halogens Chemical class 0.000 claims description 42
• 238000001727 in vivo Methods 0.000 claims description 42
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 34
• 125000001424 substituent group Chemical group 0.000 claims description 31
• 229910052757 nitrogen Inorganic materials 0.000 claims description 30
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
• 150000002431 hydrogen Chemical class 0.000 claims description 24
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
• 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 23
• 125000000623 heterocyclic group Chemical group 0.000 claims description 22
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 20
• 229910052799 carbon Inorganic materials 0.000 claims description 19
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 19
• 125000005842 heteroatom Chemical group 0.000 claims description 18
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 17
• 206010028980 Neoplasm Diseases 0.000 claims description 17
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 16
• 125000004546 quinazolin-4-yl group Chemical group N1=CN=C(C2=CC=CC=C12)* 0.000 claims description 16
• 125000004432 carbon atom Chemical group C* 0.000 claims description 14
• 229910052760 oxygen Inorganic materials 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 14
• 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 13
• 125000003545 alkoxy group Chemical group 0.000 claims description 13
• 125000003118 aryl group Chemical group 0.000 claims description 13
• 229910052717 sulfur Inorganic materials 0.000 claims description 13
• 239000002243 precursor Substances 0.000 claims description 11
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 10
• 125000002853 C1-C4 hydroxyalkyl group Chemical group 0.000 claims description 10
• 201000011510 cancer Diseases 0.000 claims description 10
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 10
• 125000004043 oxo group Chemical group O=* 0.000 claims description 9
• 230000002062 proliferating effect Effects 0.000 claims description 9
• 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 8
• 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 8
• 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 8
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 7
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 7
• 238000012986 modification Methods 0.000 claims description 7
• 230000004048 modification Effects 0.000 claims description 7
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 7
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 6
• 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 6
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
• 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 6
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 5
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 4
• 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 4
• 230000009466 transformation Effects 0.000 claims description 4
• 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 3
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 3
• 125000004122 cyclic group Chemical group 0.000 claims description 3
• RWTNPBWLLIMQHL-UHFFFAOYSA-N fexofenadine Chemical compound C1=CC(C(C)(C(O)=O)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 RWTNPBWLLIMQHL-UHFFFAOYSA-N 0.000 claims description 3
• 125000001624 naphthyl group Chemical group 0.000 claims description 3
• 229920006395 saturated elastomer Polymers 0.000 claims description 3
• FABBCJXQMLKZOQ-UHFFFAOYSA-N 2-[3-[[5,7-bis(2-methoxyethoxy)quinazolin-4-yl]amino]-1h-pyrazol-5-yl]-n-(2,3-difluorophenyl)acetamide Chemical compound N=1C=NC2=CC(OCCOC)=CC(OCCOC)=C2C=1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1F FABBCJXQMLKZOQ-UHFFFAOYSA-N 0.000 claims description 2
• HLQLFPGYUIPDHN-UHFFFAOYSA-N 2-[3-[[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino]-1h-pyrazol-5-yl]-n-phenylacetamide Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1NC(=NN1)C=C1CC(=O)NC1=CC=CC=C1 HLQLFPGYUIPDHN-UHFFFAOYSA-N 0.000 claims description 2
• IXWYSFLPFVYVIZ-UHFFFAOYSA-N 2-[3-[[7-[3-[2,2-dimethylpropyl(2-hydroxyethyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]-1h-pyrazol-5-yl]-n-(3-fluorophenyl)acetamide Chemical compound N1=CN=C2C=C(OCCCN(CCO)CC(C)(C)C)C(OC)=CC2=C1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 IXWYSFLPFVYVIZ-UHFFFAOYSA-N 0.000 claims description 2
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 2
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
• 125000006577 C1-C6 hydroxyalkyl group Chemical group 0.000 claims description 2
• 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 2
• 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
• 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 claims description 2
• 239000003937 drug carrier Substances 0.000 claims description 2
• 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
• AQYSYJUIMQTRMV-UHFFFAOYSA-N hypofluorous acid Chemical compound FO AQYSYJUIMQTRMV-UHFFFAOYSA-N 0.000 claims description 2
• 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 2
• YHRGIXFOAKICCF-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[3-[[7-[3-[2-hydroxyethyl(prop-2-ynyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]-1h-pyrazol-5-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCN(CCO)CC#C)C(OC)=CC2=C1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1F YHRGIXFOAKICCF-UHFFFAOYSA-N 0.000 claims description 2
• YRWLZRYGIWCIDI-UHFFFAOYSA-N n-(2,3-difluorophenyl)-3-[[7-[3-[2-hydroxyethyl(2-methylpropyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]-1h-pyrazole-5-carboxamide Chemical compound N1=CN=C2C=C(OCCCN(CCO)CC(C)C)C(OC)=CC2=C1NC(=NN1)C=C1C(=O)NC1=CC=CC(F)=C1F YRWLZRYGIWCIDI-UHFFFAOYSA-N 0.000 claims description 2
• VRDJRQVQAHDGSI-UHFFFAOYSA-N n-(3,5-difluorophenyl)-2-[3-[[7-[3-(2-hydroxybutylamino)propoxy]-6-methoxyquinazolin-4-yl]amino]-1h-pyrazol-5-yl]acetamide Chemical compound C=12C=C(OC)C(OCCCNCC(O)CC)=CC2=NC=NC=1NC(=NN1)C=C1CC(=O)NC1=CC(F)=CC(F)=C1 VRDJRQVQAHDGSI-UHFFFAOYSA-N 0.000 claims description 2
• DBVUTJCHFFMXJE-UHFFFAOYSA-N n-(3,5-difluorophenyl)-2-[3-[[7-[3-[4-(2-hydroxyethyl)piperidin-1-yl]propoxy]-6-methoxyquinazolin-4-yl]amino]-1h-pyrazol-5-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCN3CCC(CCO)CC3)C(OC)=CC2=C1NC(=NN1)C=C1CC(=O)NC1=CC(F)=CC(F)=C1 DBVUTJCHFFMXJE-UHFFFAOYSA-N 0.000 claims description 2
• ZANANFGGIFKOPP-UHFFFAOYSA-N n-(3-fluorophenyl)-2-[3-[[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-yl]amino]-1h-pyrazol-5-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCN3CCCC3)C(OC)=CC2=C1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 ZANANFGGIFKOPP-UHFFFAOYSA-N 0.000 claims description 2
• RJUAMPYMPLZWLC-UHFFFAOYSA-N n-(3-fluorophenyl)-2-[3-[[7-(2-methoxyethoxy)-5-propan-2-yloxyquinazolin-4-yl]amino]-1h-pyrazol-5-yl]acetamide Chemical compound N=1C=NC2=CC(OCCOC)=CC(OC(C)C)=C2C=1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 RJUAMPYMPLZWLC-UHFFFAOYSA-N 0.000 claims description 2
• VJOZGUMSAJGDMW-UHFFFAOYSA-N n-(3-fluorophenyl)-2-[3-[[7-[3-(3-hydroxypiperidin-1-yl)propoxy]-6-methoxyquinazolin-4-yl]amino]-1h-pyrazol-5-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCN3CC(O)CCC3)C(OC)=CC2=C1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 VJOZGUMSAJGDMW-UHFFFAOYSA-N 0.000 claims description 2
• STSWYZWXFYOWAA-UHFFFAOYSA-N n-(3-fluorophenyl)-2-[3-[[7-[3-(4-hydroxypiperidin-1-yl)propoxy]-6-methoxyquinazolin-4-yl]amino]-1h-pyrazol-5-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCN3CCC(O)CC3)C(OC)=CC2=C1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 STSWYZWXFYOWAA-UHFFFAOYSA-N 0.000 claims description 2
• 125000004193 piperazinyl group Chemical group 0.000 claims description 2
• 125000003386 piperidinyl group Chemical group 0.000 claims description 2
• UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical group OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 2
• 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims 2
• YBOAQTBEDYEWGB-UHFFFAOYSA-N 2-[3-[[7-[3-[2,2-dimethoxyethyl(2-hydroxyethyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]-1h-pyrazol-5-yl]-n-(3-fluorophenyl)acetamide Chemical compound C=12C=C(OC)C(OCCCN(CCO)CC(OC)OC)=CC2=NC=NC=1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 YBOAQTBEDYEWGB-UHFFFAOYSA-N 0.000 claims 1
• 125000006316 iso-butyl amino group Chemical group [H]N(*)C([H])([H])C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
• CSSKIQUMIWCMJR-UHFFFAOYSA-N n-(1h-pyrazol-5-yl)acetamide Chemical compound CC(=O)NC1=CC=NN1 CSSKIQUMIWCMJR-UHFFFAOYSA-N 0.000 claims 1
• ARQPPPCSTGSCQR-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[3-[[7-[3-[2-hydroxyethyl(propyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]-1h-pyrazol-5-yl]acetamide Chemical compound C=12C=C(OC)C(OCCCN(CCO)CCC)=CC2=NC=NC=1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1F ARQPPPCSTGSCQR-UHFFFAOYSA-N 0.000 claims 1
• CNWZWPQCJCOBHA-UHFFFAOYSA-N n-(2,3-difluorophenyl)-2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]quinazolin-4-yl]amino]-1h-pyrazol-5-yl]acetamide Chemical compound N=1C=NC2=CC(OCCCN(CCO)CC)=CC=C2C=1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1F CNWZWPQCJCOBHA-UHFFFAOYSA-N 0.000 claims 1
• WRJDGSVSNRGUPN-UHFFFAOYSA-N n-(3,5-difluorophenyl)-2-[3-[[7-[3-[(3-hydroxy-2,2-dimethylpropyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]-1h-pyrazol-5-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCNCC(C)(C)CO)C(OC)=CC2=C1NC(=NN1)C=C1CC(=O)NC1=CC(F)=CC(F)=C1 WRJDGSVSNRGUPN-UHFFFAOYSA-N 0.000 claims 1
• IMPLWHLTFYDQKW-UHFFFAOYSA-N n-(3,5-difluorophenyl)-2-[3-[[7-[3-[2-(2-hydroxyethyl)piperidin-1-yl]propoxy]-6-methoxyquinazolin-4-yl]amino]-1h-pyrazol-5-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCN3C(CCCC3)CCO)C(OC)=CC2=C1NC(=NN1)C=C1CC(=O)NC1=CC(F)=CC(F)=C1 IMPLWHLTFYDQKW-UHFFFAOYSA-N 0.000 claims 1
• HPVBFZIYQCVIDN-UHFFFAOYSA-N n-(3,5-difluorophenyl)-2-[3-[[7-[3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy]-6-methoxyquinazolin-4-yl]amino]-1h-pyrazol-5-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCN3CCN(CCO)CC3)C(OC)=CC2=C1NC(=NN1)C=C1CC(=O)NC1=CC(F)=CC(F)=C1 HPVBFZIYQCVIDN-UHFFFAOYSA-N 0.000 claims 1
• VIJQSQLREUKHMY-UHFFFAOYSA-N n-(3-fluorophenyl)-2-[3-[[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-yl]amino]-1h-pyrazol-5-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCN3CCCCC3)C(OC)=CC2=C1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 VIJQSQLREUKHMY-UHFFFAOYSA-N 0.000 claims 1
• HUGSWQRLDPDCTK-HSZRJFAPSA-N n-(3-fluorophenyl)-2-[3-[[6-methoxy-7-[[(2r)-1-[2-[(2-methylpropan-2-yl)oxy]ethyl]pyrrolidin-2-yl]methoxy]quinazolin-4-yl]amino]-1h-pyrazol-5-yl]acetamide Chemical compound N1=CN=C2C=C(OC[C@@H]3N(CCC3)CCOC(C)(C)C)C(OC)=CC2=C1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 HUGSWQRLDPDCTK-HSZRJFAPSA-N 0.000 claims 1
• RGCULYFIEIGHSJ-UHFFFAOYSA-N n-(3-fluorophenyl)-2-[3-[[7-[3-[2-hydroxyethyl(methyl)amino]propoxy]-6-methoxyquinazolin-4-yl]amino]-1h-pyrazol-5-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCN(C)CCO)C(OC)=CC2=C1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 RGCULYFIEIGHSJ-UHFFFAOYSA-N 0.000 claims 1
• QFAOWMHMXHMJCM-UHFFFAOYSA-N n-(3-fluorophenyl)-2-[3-[[7-[3-[4-(2-hydroxyethyl)piperazin-1-yl]propoxy]-6-methoxyquinazolin-4-yl]amino]-1h-pyrazol-5-yl]acetamide Chemical compound N1=CN=C2C=C(OCCCN3CCN(CCO)CC3)C(OC)=CC2=C1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 QFAOWMHMXHMJCM-UHFFFAOYSA-N 0.000 claims 1
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 452
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 288
• 238000005160 1H NMR spectroscopy Methods 0.000 description 198
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