FI111631B - Menetelmä terapeuttisesti käyttökelpoisten 4-anilinokinatsoliinijohdannaisten valmistamiseksi - Google Patents

Info

Publication number

FI111631B

FI111631B FI930208A FI930208A FI111631B FI 111631 B FI111631 B FI 111631B FI 930208 A FI930208 A FI 930208A FI 930208 A FI930208 A FI 930208A FI 111631 B FI111631 B FI 111631B

Authority

FI

Finland

Prior art keywords

alkyl

alkoxy

amino

mixture

quinazoline

Prior art date

1992-01-20

Links

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• 238000000034 method Methods 0.000 title claims abstract description 68
• 238000002360 preparation method Methods 0.000 title claims abstract description 25
• 230000008569 process Effects 0.000 title claims abstract description 13
• 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 claims description 4
• -1 hydroxy, amino, carboxy, carbamoyl Chemical group 0.000 claims abstract description 330
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 198
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 169
• 150000001875 compounds Chemical class 0.000 claims abstract description 90
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 58
• 150000003839 salts Chemical class 0.000 claims abstract description 39
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 28
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 27
• 239000001257 hydrogen Substances 0.000 claims abstract description 22
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 22
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 18
• 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract description 17
• 125000005115 alkyl carbamoyl group Chemical group 0.000 claims abstract description 16
• 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 12
• 125000005530 alkylenedioxy group Chemical group 0.000 claims abstract description 11
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 11
• 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims abstract description 5
• 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims abstract description 5
• 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 claims abstract description 4
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 6
• 125000003282 alkyl amino group Chemical group 0.000 claims description 100
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 59
• 150000003246 quinazolines Chemical class 0.000 claims description 59
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
• 150000002367 halogens Chemical class 0.000 claims description 30
• 229910052736 halogen Inorganic materials 0.000 claims description 29
• 125000004414 alkyl thio group Chemical group 0.000 claims description 22
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 20
• JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 20
• 239000002253 acid Substances 0.000 claims description 18
• 125000004423 acyloxy group Chemical group 0.000 claims description 16
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 16
• 125000001424 substituent group Chemical group 0.000 claims description 12
• 230000002829 reductive effect Effects 0.000 claims description 10
• 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
• GBJXFMREUNFKRX-UHFFFAOYSA-N 4-n-(4-aminophenyl)quinazoline-4,6-diamine Chemical compound C1=CC(N)=CC=C1NC1=NC=NC2=CC=C(N)C=C12 GBJXFMREUNFKRX-UHFFFAOYSA-N 0.000 claims description 6
• 150000001412 amines Chemical class 0.000 claims description 5
• XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 2
• VOPNWXZDJKCCRE-UHFFFAOYSA-N n-(3-chloro-4-fluorophenyl)-6,7-dimethoxyquinazolin-4-amine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 VOPNWXZDJKCCRE-UHFFFAOYSA-N 0.000 claims description 2
• 150000003573 thiols Chemical class 0.000 claims description 2
• BYBQXGBBLHNCIR-UHFFFAOYSA-N 4-(4-chloroanilino)quinazolin-8-ol Chemical compound N1=CN=C2C(O)=CC=CC2=C1NC1=CC=C(Cl)C=C1 BYBQXGBBLHNCIR-UHFFFAOYSA-N 0.000 claims 1
• 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims 1
• 206010028980 Neoplasm Diseases 0.000 abstract description 22
• 102000027426 receptor tyrosine kinases Human genes 0.000 abstract description 12
• 108091008598 receptor tyrosine kinases Proteins 0.000 abstract description 12
• 201000011510 cancer Diseases 0.000 abstract description 11
• 238000011282 treatment Methods 0.000 abstract description 10
• 230000002401 inhibitory effect Effects 0.000 abstract description 8
• 125000005843 halogen group Chemical group 0.000 abstract description 6
• 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 abstract description 4
• 125000000033 alkoxyamino group Chemical group 0.000 abstract description 3
• 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
• 239000000203 mixture Substances 0.000 description 287
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 206
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 135
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 115
• 238000000921 elemental analysis Methods 0.000 description 85
• 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 83
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 77
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 61
• 239000000243 solution Substances 0.000 description 57
• 239000003480 eluent Substances 0.000 description 56
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 55
• 238000004440 column chromatography Methods 0.000 description 54
• ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 47
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
• 125000004356 hydroxy functional group Chemical group O* 0.000 description 44
• 239000007858 starting material Substances 0.000 description 43
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 39
• 235000019439 ethyl acetate Nutrition 0.000 description 39
• ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 36
• IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 35
• 229910000041 hydrogen chloride Inorganic materials 0.000 description 35
• 239000000047 product Substances 0.000 description 33
• 239000002244 precipitate Substances 0.000 description 27
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 26
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 23
• 229910052757 nitrogen Inorganic materials 0.000 description 23
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 22
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
• 239000012258 stirred mixture Substances 0.000 description 21
• 239000000463 material Substances 0.000 description 20
• 239000012074 organic phase Substances 0.000 description 20
• JJYPMNFTHPTTDI-UHFFFAOYSA-N 3-methylaniline Chemical compound CC1=CC=CC(N)=C1 JJYPMNFTHPTTDI-UHFFFAOYSA-N 0.000 description 18
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 18
• QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 17
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
• 210000004027 cell Anatomy 0.000 description 16
• 239000011541 reaction mixture Substances 0.000 description 16
• 239000007787 solid Substances 0.000 description 16
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 15
• ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 14
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
• NFBCSWGEYDCCDW-UHFFFAOYSA-N 4-n-(3-methylphenyl)quinazoline-4,6-diamine Chemical compound CC1=CC=CC(NC=2C3=CC(N)=CC=C3N=CN=2)=C1 NFBCSWGEYDCCDW-UHFFFAOYSA-N 0.000 description 13
• 241000282414 Homo sapiens Species 0.000 description 13
• 238000010992 reflux Methods 0.000 description 13
• 238000012360 testing method Methods 0.000 description 13
• PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
• YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 12
• 229960004592 isopropanol Drugs 0.000 description 12
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 12
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 11
• 230000001093 anti-cancer Effects 0.000 description 11
• 238000006243 chemical reaction Methods 0.000 description 11
• 239000012071 phase Substances 0.000 description 11
• 229910000027 potassium carbonate Inorganic materials 0.000 description 11
• 125000004390 alkyl sulfonyl group Chemical group 0.000 description 10
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
• 230000002441 reversible effect Effects 0.000 description 10
• 239000000126 substance Substances 0.000 description 10
• 241001465754 Metazoa Species 0.000 description 9
• 238000003556 assay Methods 0.000 description 9
• 239000002585 base Substances 0.000 description 9
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 9
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 9
• 239000003921 oil Substances 0.000 description 9
• 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 8
• JFDWMFYUKLPRSP-UHFFFAOYSA-N 6-methyl-n-phenylquinazolin-4-amine Chemical compound C12=CC(C)=CC=C2N=CN=C1NC1=CC=CC=C1 JFDWMFYUKLPRSP-UHFFFAOYSA-N 0.000 description 8
• KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 8
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
• PQLVXDKIJBQVDF-UHFFFAOYSA-N acetic acid;hydrate Chemical compound O.CC(O)=O PQLVXDKIJBQVDF-UHFFFAOYSA-N 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
• 239000012044 organic layer Substances 0.000 description 8
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 8
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 8
• CMYBAHRLNADCKS-UHFFFAOYSA-N 6-(bromomethyl)-n-(3-methylphenyl)quinazolin-4-amine Chemical compound CC1=CC=CC(NC=2C3=CC(CBr)=CC=C3N=CN=2)=C1 CMYBAHRLNADCKS-UHFFFAOYSA-N 0.000 description 7
• 102400001368 Epidermal growth factor Human genes 0.000 description 7
• 101800003838 Epidermal growth factor Proteins 0.000 description 7
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 7
• 229960000583 acetic acid Drugs 0.000 description 7
• 125000004644 alkyl sulfinyl group Chemical group 0.000 description 7
• 230000000694 effects Effects 0.000 description 7
• 229940116977 epidermal growth factor Drugs 0.000 description 7
• 238000002474 experimental method Methods 0.000 description 7
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• 230000012010 growth Effects 0.000 description 7
• 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 7
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 7
• 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 7
• VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 7
• MTEZLAATISORQK-UHFFFAOYSA-N 2-methoxyacetamide Chemical compound COCC(N)=O MTEZLAATISORQK-UHFFFAOYSA-N 0.000 description 6
• MJKCGAHOCZLYDG-UHFFFAOYSA-N 6,7-dimethoxy-n-phenylquinazolin-4-amine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC=CC=C1 MJKCGAHOCZLYDG-UHFFFAOYSA-N 0.000 description 6
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• 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 6
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• 239000000460 chlorine Substances 0.000 description 6
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• 238000000746 purification Methods 0.000 description 5
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• QJDUDPQVDAASMV-UHFFFAOYSA-M sodium;ethanethiolate Chemical compound [Na+].CC[S-] QJDUDPQVDAASMV-UHFFFAOYSA-M 0.000 description 5
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• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
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• JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
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