NO326515B1 - Kinazolinderivater, anvendelse og fremstilling derav, samt farmasoytisk preparat - Google Patents

Info

Publication number

NO326515B1

NO326515B1 NO20030795A NO20030795A NO326515B1 NO 326515 B1 NO326515 B1 NO 326515B1 NO 20030795 A NO20030795 A NO 20030795A NO 20030795 A NO20030795 A NO 20030795A NO 326515 B1 NO326515 B1 NO 326515B1

Authority

NO

Norway

Prior art keywords

group

ethoxy

piperidin

alkyl

pyrrolidin

Prior art date

2000-08-21

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• 238000002360 preparation method Methods 0.000 title claims description 46
• 239000000825 pharmaceutical preparation Substances 0.000 title claims description 7
• 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title description 4
• -1 hydroxy, amino Chemical group 0.000 claims description 448
• 125000000217 alkyl group Chemical group 0.000 claims description 127
• 150000001875 compounds Chemical class 0.000 claims description 123
• 125000001424 substituent group Chemical group 0.000 claims description 97
• 150000003839 salts Chemical class 0.000 claims description 74
• 238000000034 method Methods 0.000 claims description 66
• 150000003246 quinazolines Chemical class 0.000 claims description 59
• 125000003545 alkoxy group Chemical group 0.000 claims description 51
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 47
• 238000006243 chemical reaction Methods 0.000 claims description 47
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 43
• 125000000623 heterocyclic group Chemical group 0.000 claims description 36
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 27
• 125000006239 protecting group Chemical group 0.000 claims description 27
• 239000000460 chlorine Substances 0.000 claims description 25
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 24
• 229910052801 chlorine Inorganic materials 0.000 claims description 24
• 206010028980 Neoplasm Diseases 0.000 claims description 23
• 239000002253 acid Substances 0.000 claims description 22
• 125000003282 alkyl amino group Chemical group 0.000 claims description 22
• 229910052739 hydrogen Inorganic materials 0.000 claims description 22
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 21
• 239000001257 hydrogen Substances 0.000 claims description 21
• 229910052736 halogen Inorganic materials 0.000 claims description 20
• 150000002367 halogens Chemical class 0.000 claims description 20
• 125000001072 heteroaryl group Chemical group 0.000 claims description 20
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 20
• 125000004432 carbon atom Chemical group C* 0.000 claims description 19
• JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 18
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
• 238000011282 treatment Methods 0.000 claims description 17
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 15
• 238000003776 cleavage reaction Methods 0.000 claims description 15
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 15
• 239000011737 fluorine Substances 0.000 claims description 15
• 229910052731 fluorine Inorganic materials 0.000 claims description 15
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 14
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 13
• 125000000524 functional group Chemical group 0.000 claims description 13
• 238000003780 insertion Methods 0.000 claims description 13
• 230000037431 insertion Effects 0.000 claims description 13
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 12
• 125000003342 alkenyl group Chemical group 0.000 claims description 11
• 125000002947 alkylene group Chemical group 0.000 claims description 11
• 150000001412 amines Chemical class 0.000 claims description 11
• 125000003118 aryl group Chemical group 0.000 claims description 11
• 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 11
• 230000007017 scission Effects 0.000 claims description 11
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 10
• 229910052760 oxygen Inorganic materials 0.000 claims description 10
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
• 241001465754 Metazoa Species 0.000 claims description 9
• 125000000304 alkynyl group Chemical group 0.000 claims description 9
• 238000007796 conventional method Methods 0.000 claims description 9
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 8
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 8
• 239000003795 chemical substances by application Substances 0.000 claims description 8
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 8
• 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 7
• 125000003006 2-dimethylaminoethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 7
• 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 7
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 7
• 125000004423 acyloxy group Chemical group 0.000 claims description 7
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
• 229910052794 bromium Inorganic materials 0.000 claims description 7
• 125000001589 carboacyl group Chemical group 0.000 claims description 7
• 125000002883 imidazolyl group Chemical group 0.000 claims description 7
• WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims description 7
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 7
• 125000001425 triazolyl group Chemical group 0.000 claims description 7
• 125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 6
• 230000001740 anti-invasion Effects 0.000 claims description 6
• 229910052757 nitrogen Inorganic materials 0.000 claims description 6
• 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 6
• 125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 6
• 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 6
• 125000004076 pyridyl group Chemical group 0.000 claims description 6
• 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 5
• 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 5
• 125000003302 alkenyloxy group Chemical group 0.000 claims description 5
• 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 5
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 5
• 125000004414 alkyl thio group Chemical group 0.000 claims description 5
• 230000029936 alkylation Effects 0.000 claims description 5
• 238000005804 alkylation reaction Methods 0.000 claims description 5
• 125000005133 alkynyloxy group Chemical group 0.000 claims description 5
• HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 5
• 125000003277 amino group Chemical group 0.000 claims description 5
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
• 239000003814 drug Substances 0.000 claims description 5
• 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 5
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
• 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 5
• 239000003085 diluting agent Substances 0.000 claims description 4
• 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 4
• 125000002757 morpholinyl group Chemical group 0.000 claims description 4
• 125000004193 piperazinyl group Chemical group 0.000 claims description 4
• 125000003386 piperidinyl group Chemical group 0.000 claims description 4
• 230000008569 process Effects 0.000 claims description 4
• 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
• 125000000547 substituted alkyl group Chemical group 0.000 claims description 4
• 125000003718 tetrahydrofuranyl group Chemical group 0.000 claims description 4
• 125000001412 tetrahydropyranyl group Chemical group 0.000 claims description 4
• 238000002560 therapeutic procedure Methods 0.000 claims description 4
• 125000005153 alkyl sulfamoyl group Chemical group 0.000 claims description 3
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 3
• 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 3
• 229940079593 drug Drugs 0.000 claims description 3
• MWCIFBSDQJFWIE-UHFFFAOYSA-N n-(5-bromo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-amine Chemical compound COC1=CC2=C(NC=3C(=CC=C4OCOC4=3)Br)N=CN=C2C=C1OCCCN1CCCCC1 MWCIFBSDQJFWIE-UHFFFAOYSA-N 0.000 claims description 3
• 125000000466 oxiranyl group Chemical group 0.000 claims description 3
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 3
• 229920002554 vinyl polymer Polymers 0.000 claims description 3
• QCEYSUFQHXTGTC-UHFFFAOYSA-N 1-[4-(1,3-benzodioxol-4-ylamino)-6-methoxyquinazolin-7-yl]oxy-3-[methyl(propan-2-yl)amino]propan-2-ol Chemical compound N1=CN=C2C=C(OCC(O)CN(C)C(C)C)C(OC)=CC2=C1NC1=CC=CC2=C1OCO2 QCEYSUFQHXTGTC-UHFFFAOYSA-N 0.000 claims description 2
• GDKVKFPZULERFV-UHFFFAOYSA-N 1-[4-(1,3-benzodioxol-4-ylamino)-6-methoxyquinazolin-7-yl]oxy-3-pyrrolidin-1-ylpropan-2-ol Chemical compound COC1=CC2=C(NC=3C=4OCOC=4C=CC=3)N=CN=C2C=C1OCC(O)CN1CCCC1 GDKVKFPZULERFV-UHFFFAOYSA-N 0.000 claims description 2
• QTDVHHYSYHHNBA-UHFFFAOYSA-N 2-[4-[3-[4-[(5-chloro-1,3-benzodioxol-4-yl)amino]-6-methoxyquinazolin-7-yl]oxypropyl]piperazin-1-yl]acetonitrile Chemical compound COC1=CC2=C(NC=3C(=CC=C4OCOC4=3)Cl)N=CN=C2C=C1OCCCN1CCN(CC#N)CC1 QTDVHHYSYHHNBA-UHFFFAOYSA-N 0.000 claims description 2
• DLSRIJJGQIAZHW-UHFFFAOYSA-N 4-[[4-[(5-chloro-1,3-benzodioxol-4-yl)amino]-6-methoxyquinazolin-7-yl]oxymethyl]pyridine-2-carbonitrile Chemical compound COC1=CC2=C(NC=3C(=CC=C4OCOC4=3)Cl)N=CN=C2C=C1OCC1=CC=NC(C#N)=C1 DLSRIJJGQIAZHW-UHFFFAOYSA-N 0.000 claims description 2
• DNWPHHNJIJAHJZ-UHFFFAOYSA-N n-(1,3-benzodioxol-4-yl)-6-methoxy-7-(2-pyridin-4-yloxyethoxy)quinazolin-4-amine Chemical compound COC1=CC2=C(NC=3C=4OCOC=4C=CC=3)N=CN=C2C=C1OCCOC1=CC=NC=C1 DNWPHHNJIJAHJZ-UHFFFAOYSA-N 0.000 claims description 2
• FQYJMIYZRDNWFL-UHFFFAOYSA-N n-(1,3-benzodioxol-4-yl)-6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-amine Chemical compound COC1=CC2=C(NC=3C=4OCOC=4C=CC=3)N=CN=C2C=C1OCCCN1CCCCC1 FQYJMIYZRDNWFL-UHFFFAOYSA-N 0.000 claims description 2
• ZRIFTMSDRYXGNF-UHFFFAOYSA-N n-(1,3-benzodioxol-4-yl)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazolin-4-amine Chemical compound COC1=CC2=C(NC=3C=4OCOC=4C=CC=3)N=CN=C2C=C1OCCCN1CCCC1 ZRIFTMSDRYXGNF-UHFFFAOYSA-N 0.000 claims description 2
• IFKVYXZTVIFTQM-UHFFFAOYSA-N n-(1,3-benzodioxol-4-yl)-6-methoxy-7-[2-(1-methylpiperidin-4-yl)ethoxy]quinazolin-4-amine Chemical compound COC1=CC2=C(NC=3C=4OCOC=4C=CC=3)N=CN=C2C=C1OCCC1CCN(C)CC1 IFKVYXZTVIFTQM-UHFFFAOYSA-N 0.000 claims description 2
• UYKYCBACTCRLLP-UHFFFAOYSA-N n-(5-chloro-1,3-benzodioxol-4-yl)-6-methoxy-7-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine Chemical compound COC1=CC2=C(NC=3C(=CC=C4OCOC4=3)Cl)N=CN=C2C=C1OCC1CCN(C)CC1 UYKYCBACTCRLLP-UHFFFAOYSA-N 0.000 claims description 2
• 230000008878 coupling Effects 0.000 claims 1
• 238000010168 coupling process Methods 0.000 claims 1
• 238000005859 coupling reaction Methods 0.000 claims 1
• 125000001153 fluoro group Chemical group F* 0.000 claims 1
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 417
• 239000000203 mixture Substances 0.000 description 363
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 297
• 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 226
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 180
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 171
• 239000000243 solution Substances 0.000 description 144
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 134
• 238000001819 mass spectrum Methods 0.000 description 130
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 119
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 112
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 100
• 239000007858 starting material Substances 0.000 description 96
• 239000000047 product Substances 0.000 description 90
• 239000007787 solid Substances 0.000 description 80
• 239000000463 material Substances 0.000 description 78
• 238000004440 column chromatography Methods 0.000 description 68
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 67
• 239000000377 silicon dioxide Substances 0.000 description 65
• 239000003480 eluent Substances 0.000 description 63
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 60
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 56
• 235000019341 magnesium sulphate Nutrition 0.000 description 56
• 239000011541 reaction mixture Substances 0.000 description 53
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 52
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
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• 239000012267 brine Substances 0.000 description 47
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 47
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• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 38
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• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 35
• 239000000706 filtrate Substances 0.000 description 35
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
• 238000010992 reflux Methods 0.000 description 34
• 235000011114 ammonium hydroxide Nutrition 0.000 description 33
• 239000012074 organic phase Substances 0.000 description 30
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• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 30
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• 235000011181 potassium carbonates Nutrition 0.000 description 25
• 238000012360 testing method Methods 0.000 description 25
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• 238000001914 filtration Methods 0.000 description 22
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