CN108143736A - Application of butyrylaminobenzo [ d ] aza-based quinazoline in preparation of drugs for treating lung cancer - Google Patents
Application of butyrylaminobenzo [ d ] aza-based quinazoline in preparation of drugs for treating lung cancer Download PDFInfo
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- CN108143736A CN108143736A CN201810070293.9A CN201810070293A CN108143736A CN 108143736 A CN108143736 A CN 108143736A CN 201810070293 A CN201810070293 A CN 201810070293A CN 108143736 A CN108143736 A CN 108143736A
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- solvent
- ethyl acetate
- quinazoline
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- 206010058467 Lung neoplasm malignant Diseases 0.000 title claims abstract description 25
- 201000005202 lung cancer Diseases 0.000 title claims abstract description 23
- 208000020816 lung neoplasm Diseases 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 title claims abstract description 13
- 229940079593 drug Drugs 0.000 title claims description 8
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 title description 59
- 238000002360 preparation method Methods 0.000 title description 20
- JDAWODWFENGUBC-UHFFFAOYSA-N C(CCC)(=O)NC1=CNC=CC2=C1C=CC=C2 Chemical compound C(CCC)(=O)NC1=CNC=CC2=C1C=CC=C2 JDAWODWFENGUBC-UHFFFAOYSA-N 0.000 claims description 10
- 230000002265 prevention Effects 0.000 claims description 5
- 230000005764 inhibitory process Effects 0.000 claims description 2
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 claims 1
- -1 quinazoline compound Chemical class 0.000 abstract description 14
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 155
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 96
- 239000002904 solvent Substances 0.000 description 57
- 150000001875 compounds Chemical class 0.000 description 54
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 45
- 238000001514 detection method Methods 0.000 description 39
- 239000000741 silica gel Substances 0.000 description 37
- 229910002027 silica gel Inorganic materials 0.000 description 37
- 239000003208 petroleum Substances 0.000 description 32
- 239000012141 concentrate Substances 0.000 description 31
- 235000008504 concentrate Nutrition 0.000 description 31
- 239000000203 mixture Substances 0.000 description 31
- 239000003480 eluent Substances 0.000 description 30
- 239000006166 lysate Substances 0.000 description 27
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 25
- 238000004440 column chromatography Methods 0.000 description 24
- 239000003960 organic solvent Substances 0.000 description 23
- 210000004027 cell Anatomy 0.000 description 22
- 150000003246 quinazolines Chemical class 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 238000000034 method Methods 0.000 description 21
- 239000000243 solution Substances 0.000 description 21
- 238000002156 mixing Methods 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 14
- YGLDQFWPUCURIP-UHFFFAOYSA-N 3h-3-benzazepine Chemical class C1=CNC=CC2=CC=CC=C21 YGLDQFWPUCURIP-UHFFFAOYSA-N 0.000 description 13
- 239000003054 catalyst Substances 0.000 description 13
- VFWCMGCRMGJXDK-UHFFFAOYSA-N 1-chlorobutane Chemical compound CCCCCl VFWCMGCRMGJXDK-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- 239000000706 filtrate Substances 0.000 description 12
- 239000011259 mixed solution Substances 0.000 description 12
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 11
- ANKQEENVDGQKJQ-UHFFFAOYSA-N 3h-3-benzazepin-5-amine Chemical compound NC1=CNC=CC2=CC=CC=C12 ANKQEENVDGQKJQ-UHFFFAOYSA-N 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 10
- 238000010828 elution Methods 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 9
- 229960000583 acetic acid Drugs 0.000 description 9
- 239000012265 solid product Substances 0.000 description 9
- FORUABSETQEFHP-UHFFFAOYSA-N 2-chloro-6-nitroquinazoline Chemical class ClC1=NC2=CC=C(C=C2C=N1)[N+](=O)[O-] FORUABSETQEFHP-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 6
- YHASWHZGWUONAO-UHFFFAOYSA-N butanoyl butanoate Chemical compound CCCC(=O)OC(=O)CCC YHASWHZGWUONAO-UHFFFAOYSA-N 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 6
- 238000010025 steaming Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 230000001093 anti-cancer Effects 0.000 description 5
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WYTRUYFIBXUCNZ-UHFFFAOYSA-N [N+](=O)([O-])C1=CNC=CC2=C1C=CC=C2 Chemical compound [N+](=O)([O-])C1=CNC=CC2=C1C=CC=C2 WYTRUYFIBXUCNZ-UHFFFAOYSA-N 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 239000004575 stone Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- GVRRXASZZAKBMN-UHFFFAOYSA-N 4-chloroquinazoline Chemical class C1=CC=C2C(Cl)=NC=NC2=C1 GVRRXASZZAKBMN-UHFFFAOYSA-N 0.000 description 2
- 206010013786 Dry skin Diseases 0.000 description 2
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 2
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- 235000014666 liquid concentrate Nutrition 0.000 description 2
- 201000005296 lung carcinoma Diseases 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003222 pyridines Chemical class 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- WOGITNXCNOTRLK-VOTSOKGWSA-N (e)-3-phenylprop-2-enoyl chloride Chemical compound ClC(=O)\C=C\C1=CC=CC=C1 WOGITNXCNOTRLK-VOTSOKGWSA-N 0.000 description 1
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 1
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 1
- RUQIUASLAXJZIE-UHFFFAOYSA-N 3-methoxybenzoyl chloride Chemical class COC1=CC=CC(C(Cl)=O)=C1 RUQIUASLAXJZIE-UHFFFAOYSA-N 0.000 description 1
- NJAKCIUOTIPYED-UHFFFAOYSA-N 4-iodobenzoyl chloride Chemical class ClC(=O)C1=CC=C(I)C=C1 NJAKCIUOTIPYED-UHFFFAOYSA-N 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- AJUOROCLPCICAC-UHFFFAOYSA-N Cc(c(CCN(CC1c(cc2)ccc2OC)c2ncnc3ccccc23)c1cc1OC)c1OC Chemical compound Cc(c(CCN(CC1c(cc2)ccc2OC)c2ncnc3ccccc23)c1cc1OC)c1OC AJUOROCLPCICAC-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 108010019160 Pancreatin Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical group N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 206010057362 Underdose Diseases 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- XYOVOXDWRFGKEX-UHFFFAOYSA-N azepine Chemical compound N1C=CC=CC=C1 XYOVOXDWRFGKEX-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- KVSLPQXJQYNHIK-UHFFFAOYSA-N c1ccc2ncncc2c1.Cc1ccc(cc1)S(O)(=O)=O.Cc1ccc(cc1)S(O)(=O)=O Chemical compound c1ccc2ncncc2c1.Cc1ccc(cc1)S(O)(=O)=O.Cc1ccc(cc1)S(O)(=O)=O KVSLPQXJQYNHIK-UHFFFAOYSA-N 0.000 description 1
- 239000003560 cancer drug Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- UHANVDZCDNSILX-UHFFFAOYSA-N n-phenylbutanamide Chemical compound CCCC(=O)NC1=CC=CC=C1 UHANVDZCDNSILX-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229940055695 pancreatin Drugs 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 1
- UBZJXAQDXUGXIZ-UHFFFAOYSA-N quinazoline;quinoline Chemical class N1=CC=CC2=CC=CC=C21.N1=CN=CC2=CC=CC=C21 UBZJXAQDXUGXIZ-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229940120982 tarceva Drugs 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses butyrylaminobenzo [ d]Aza derivatives
Description
(1) technical field
The present invention relates to a kind of butyrylamino benzo [d] azepinesBase quinazoline compounds are preparing prevention or treatment people
Application in the drug of lung cancer disease.
(2) background technology
Quinazoline compounds have many preferable bioactivity, have a wide range of applications in field of medicaments, and especially one
The quinazoline derivative of a little special constructions has apparent antiviral activity, antibacterial activity, antitumor activity etc., quinazoline ditosylate salt
Compound has had listed some kinds as antitumor drug.Such as the Gefitinib for being used to treat lung cancer of listing
(Gefitinib) and Tarceva (Erlotinib) and for treating the Lapatinib of breast cancer (Lapatinib), they
Belong to quinazoline compounds.Also common document report (refers to Y.- for novel quinazoline compounds and its bioactivity
Y.Ke,H.-Y.Shiao,Y.C.Hsu,C.-Y.Chu,W.-C.Wang,Y.-C.Lee,W.-H.Lin,C.-H.Chen,
J.T.A.Hsu,C.-W.Chang,C.-W.Lin,T.-K.Yeh,Y.-S.Chao,M.S.Coumar,H.-P.Hsieh,
ChemMedChem 2013,8,136-148；A.Garofalo,A.Farce,S.Ravez,A.Lemoine,P.Six,
P.Chavatte,L.Goossens,P.Depreux,J.Med.Chem.2012,55,1189-1204).Certainly majority quinazoline
Class compound does not simultaneously have antitumor activity.
(3) invention content
The purpose of the present invention is to provide a kind of novel quinazoline quinoline class compound-butyrylamino benzo [d] azepinesBase quinoline
Application of the oxazoline compound in prevention or treatment lung-cancer medicament is prepared, such compound are thin to human lung cancer under doses
Born of the same parents' strain A-549 has significant inhibiting rate；And such compounds process for production thereof is easy, easily operated, raw material is easy to get, and is produced into
This is relatively low, suitable for industrial applications.
For achieving the above object, the present invention adopts the following technical scheme that：
The present invention provides butyrylamino benzo [d] azepines shown in a kind of formula (I)Base quinazoline compounds are being made
It is standby to prevent or treat the application in tumor disease drug, the particularly application in prevention or treatment human lung cancer drug is prepared；
Preferably, the drug is with the drug for inhibiting human lung cancer cell lines A-549 activity.
The present invention provides butyrylamino benzo [d] azepine shown in a kind of formula (I)The preparation of base quinazoline compounds
Method, the method are：(1) compound shown in formula (II) is mixed with compound shown in formula (III), in organic solvent A,
Under the action of basic catalyst B, 25~120 DEG C reacted (TLC tracking and monitorings, solvent for ethyl acetate/petroleum ether=
1：3 (v/v), preferably 40~100 DEG C 0.5~12h of reaction), after the reaction was complete, reaction solution is isolated and purified, formula (IV) institute is made
Show compound；The organic solvent A is selected from one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N, N-
Dimethylformamide；The basic catalyst B is selected from one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylbenzene
Amine, 4-dimethylaminopyridine, 4- pyrollidinopyridines or sodium carbonate (preferably pyridine, diethylamine, triethylamine, N, N- dimethylanilines
Or 4-dimethylaminopyridine)；
(2) formula (IV) compound represented obtained by step (1) is dissolved in organic solvent D, under reducing agent E effects,
The reaction was complete at 25~100 DEG C, and (TLC tracking and monitorings, solvent are ethyl acetate/petroleum ether=1：1 (v/v), preferably 40~80
DEG C 0.5~12h of reaction), reaction solution filtering, the concentrate drying (preferably 25 DEG C vacuum drying) after filtrate decompression concentration is made
Formula (V) compound represented；The organic solvent D is one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, second
Nitrile or N,N-dimethylformamide；The reducing agent E is one of following：Iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium carbon/ammonium formate
Or palladium carbon/hydrazine hydrate；Iron powder/the concentrated hydrochloric acid refers to that the mixing of iron powder and concentrated hydrochloric acid arbitrary proportion, iron powder/acetic acid refer to iron powder
With the mixing of acetic acid arbitrary proportion, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate arbitrary proportion, the palladium carbon/
Hydrazine hydrate is the mixture of palladium carbon and hydrazine hydrate arbitrary proportion；
(3) compound shown in formula (V) obtained by step (2) with butyl chloride or butyric anhydride is mixed, made in basic catalyst F
Under, in organic solvent G, -10~50 DEG C the reaction was complete, and (TLC tracking and monitorings, solvent are ethyl acetate/petroleum ether=1：1
(v/v), preferably -10~50 DEG C 3~12h of reaction), reaction solution is post-treated, and formula (I) compound represented is made；It is described organic
Solvent G is one of following：Tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, ether, acetonitrile, toluene or benzene；The alkalinity
Catalyst F is one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4-dimethylaminopyridine, 4- pyrroles
Alkyl pyridine or sodium carbonate；
Further, in step (1), compound shown in compound shown in the formula (III) and formula (II), basic catalyst B
The ratio between the amount of substance of feeding intake is 1.0 ﹕, 0.8~1.2 ﹕ 1.0~8.0.
Further, in step (1), the dosage of the organic solvent A is calculated as 10 with the quality of compound shown in formula (III)~
50mL/g。
Further, the method that reaction solution isolates and purifies described in step (1) of the present invention is：After the reaction was complete, by reaction solution
Solvent is evaporated off, concentrate is taken to be dissolved with organic solvent C, obtain lysate, then into lysate add in concentrate 1.0~
The column chromatography silica gel (preferably 300~400 mesh gross porosity (zcx.II) type column chromatography silica gels) of 2.0 times of weight after mixing, is evaporated off molten
Agent, it is dry, the mixture of concentrate and silica gel is obtained, mixture is filled into column, then using volume ratio as 1：0.1~10 petroleum ether
It is eluant, eluent with ethyl acetate mixture, collects the efflux containing target components (preferably with ethyl acetate/petroleum ether=1：3
(v/v) it is solvent tracing detection, collects target components, preferably collect the component that Rf values are 0.5), it is concentrated under reduced pressure, drying is (excellent
Select 50 DEG C of dryings), obtain formula (IV) compound represented；The organic solvent C is one of following：Ethyl alcohol, chloroform, tetrahydrofuran
Or ethyl acetate.The organic solvent C dosages are with being capable of dissolution residual substance.
Further, in step (2), the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, shown in formula (IV)
The mass ratio that feeds intake of iron powder, concentrated hydrochloric acid or acetic acid in compound and reducing agent E is 1.0 ﹕, 1.0~3.0 ﹕ 0.2~1.0.This hair
Concentrated hydrochloric acid mass concentration described in bright is 36%~38%, and the acetic acid is glacial acetic acid.
Further, in step (2), the reducing agent E is palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate, shown in formula (IV)
The mass ratio that feeds intake of palladium carbon, ammonium formate or hydrazine hydrate in compound and reducing agent E is 1.0 ﹕, 0.1~0.5 ﹕ 1.0~3.0.This
The mass loading amount of palladium is 2~10%, preferably 5% in the palladium carbon being applicable in invention, and hydrazine hydrate mass concentration is 40~80%, excellent
Select 80%.
Further, in step (2), the dosage of the organic solvent D is calculated as 10 with the quality of formula (IV) compound represented
~50mL/g.
Further, in step (3), compound shown in the formula (V) and butyl chloride or butyric anhydride, basic catalyst F
The ratio between the amount of substance of feeding intake is 1 ﹕, 1.0~8.0 ﹕ 1.0~3.0.
Further, in step (3), the dosage of the organic solvent G is calculated as 11 with the quality of compound shown in formula (V)~
100mL/g。
Further, step (3) carries out as follows：Under the conditions of -10~10 DEG C, toward compound shown in formula (V) and
Be added dropwise in the organic solvent G solution of basic catalyst F or into compound shown in formula (V) and basic catalyst F butyl chloride or
The organic solvent G solution of butyric anhydride, drop finish, and -10~50 DEG C are reacted 3~12 hours, and gained reaction solution is post-treated to be obtained
Compound shown in formula (I)；Dissolving the organic solvent volume dosage of butyl chloride or butyric anhydride does not influence the present invention, described organic molten
Total dosage of agent G is calculated as 11~100mL/g with the quality of compound shown in formula (V).Total dosage of organic solvent G refers to dissolve
The totality of the organic solvent G of compound and dissolving butyl chloride or butyric anhydride organic solvent G shown in basic catalyst F and formula (V)
Product.
Further, the post-processing approach of step (3) the of the present invention reaction solution is：Reaction solution is filtered, filtrate is evaporated off molten
Agent takes concentrate to be dissolved with organic solvent H, obtains lysate, and 1.0~2.0 times of concentrate is then added in into lysate
After mixing, solvent is evaporated off in the column chromatography silica gel (preferably 300~400 mesh gross porosity (zcx.II) type column chromatography silica gels) of weight, does
It is dry, the mixture of concentrate and silica gel is obtained, mixture is filled into column, then using volume ratio as 1：0.1~10 petroleum ether and second
Acetoacetic ester mixed solution is eluant, eluent, collects the efflux containing target components (preferably with ethyl acetate/petroleum ether=1：1(v/v)
For solvent tracing detections, target components are collected, preferably collect the component that Rf values are 0.5), it is concentrated under reduced pressure, it is (preferably 50 DEG C dry
It is dry), obtain formula (I) compound represented；The organic solvent H is one of following：Ethyl alcohol, chloroform, tetrahydrofuran or acetic acid
Ethyl ester.The organic solvent H dosages are with being capable of dissolution residual substance.
Organic solvent A of the present invention, C, D, G and H are organic solvent, organic used in different step for the ease of distinguishing
Solvent is different and names, and letter itself does not have meaning；The catalyst B, reducing agent E and catalyst F are catalyst, in order to just
It is named in differentiation different step used catalyst difference, letter itself does not have meaning.
The beneficial effects are mainly as follows：Provide a kind of novel quinazoline compounds prepare prevention or
The application in the drug of human lung cancer is treated, which has significant inhibitory activity to human lung cancer cell lines A-549.
(4) specific embodiment
The present invention be further described in conjunction with specific embodiments, following embodiment illustrate the present invention rather than
It limit the invention in any way.
Compound (II) prepare reference literature (Weinstock, J.et al.J.Med.Chem., 1986,29 (11),
Method 2315-2325) is prepared.The chloro- 6- nitro-quinazolines (III) of 4- prepare reference literature (Fernandes, C.et
Al.Bioorg.Med.Chem., 2007,15 (12), 3974-3980) method be prepared.
Palladium carbon (Pd/C) model that the embodiment of the present invention uses：D5H5A, manufacturer：The auspicious section's new material share in Shaanxi has
Limit company
Embodiment 1：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.39 grams of (6.87mmol) compounds
(II), 3.62 grams of (45.76mmol) pyridines, 12 milliliters of chloroforms are added in 50 milliliters of reaction bulb, are heated to 40 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is stirred to react 10 hours, closes reaction, reaction solution is evaporated off molten
Agent adds in 10 milliliters of ethyl acetate in obtained concentrate and is dissolved, obtains lysate, 3.0 grams of columns are added in into lysate
Chromatographic silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixture of dry concentrate and silica gel,
Mixture is filled into column, then using volume ratio as 1：10 petrol ether/ethyl acetate mixed solution is eluant, eluent, is eluted, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values are 0.5), the eluent concentration of collection, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), receive
Rate 85.1%, 164~166 DEG C of fusing point.1H NMR(500MHz,CDCl3)δ:3.32-3.38 (m, 1H), 3.63 (dt, J=3.4,
15.5Hz, 1H), 3.75 (s, 3H), 3.82 (s, 6H), 3.91 (dd, J=8.1,14.3Hz, 1H), 4.03 (td, J=4.1,
11.7Hz, 1H), 4.15 (d, J=11.5Hz, 1H), 4.72 (dd, J=8.3,14.2Hz, 1H), 5.14 (t, J=8.9Hz,
1H), 6.60 (s, 1H), 6.90 (d, J=8.7Hz, 2H), 7.08 (d, J=8.6Hz, 2H), 7.93 (d, J=9.1Hz, 1H),
8.48 (dd, J=2.4,9.2Hz, 1H), 8.71 (s, 1H), 8.96 (d, J=2.4Hz, 1H).IR(KBr,cm-1)ν:2917,
2848,1616,1580,1510,1463,1355,1327,1249,1038,847。
Embodiment 2：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.59 grams of (4.57mmol) compounds
(II), 1.67 grams of (22.83mmol) diethylamine, 60 milliliters of toluene are added in 100 milliliters of three-necked flask, are heated to 100 DEG C,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it is stirred to react 2 hours, closes reaction, reaction solution
Solvent is evaporated off, 20 milliliters of ethyl alcohol are added in obtained concentrate and are dissolved, obtain lysate, 2.5 grams are added in into lysate
Column chromatography silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixing of dry concentrate and silica gel
Mixture is filled column, then using volume ratio as 1 by object：5 petrol ether/ethyl acetate mixed solution be eluant, eluent, elution, TLC with
(solvent is ethyl acetate/petroleum ether=1 for track detection：3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values be 0.5), the eluent concentration of collection, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV),
Yield 72.6%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 3：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.99 grams of (5.72mmol) compounds
(II), 0.58 gram of (5.73mmol) triethylamine, 60 milliliters of ethyl alcohol are added in 100 milliliters of three-necked flask, are heated to 60 DEG C, TLC
(solvent is ethyl acetate/petroleum ether=1 to tracing detection：3 (v/v)), it is stirred to react 8 hours, closes reaction, reaction solution is evaporated off
Solvent adds in 20 milliliters of chloroforms in obtained concentrate and is dissolved, obtains lysate, 2.5 grams of column layers are added in into lysate
Silica gel (300~400 mesh column chromatography silica gel) is analysed, after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, it will
Mixture fills column, then using volume ratio as 10：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, TLC, which is tracked, to be examined
(solvent is ethyl acetate/petroleum ether=1 for survey：3 (v/v)), it is detected according to TLC and collects washing for (IV) compound represented Han formula
De- liquid (Rf values are 0.5), the eluent concentration of collection, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), yield
77.2%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 4：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.20 grams of (6.32mmol) compounds
(II), 1.40 grams of (11.46mmol) 4-dimethylaminopyridine, 60 milliliters of isopropanols are added in 100 milliliters of three-necked flask, room temperature
25 DEG C of stirrings, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it reacts 12 hours, closes reaction,
Solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, lysate are obtained, into lysate
4.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in, after mixing, solvent is evaporated off, obtains dry concentrate and silicon
Mixture is filled column, then using volume ratio as 5 by the mixture of glue：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, is washed
De-, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it is collected according to TLC detections containing shown in formula (IV)
Compound eluent (Rf values be 0.5), the eluent concentration of collection, 50 DEG C are dried to obtain the pale yellow colored solid shown in formula (IV)
Body product, yield 80.2%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 5：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 1.79 grams of (5.15mmol) compounds
(II), 1.04 grams of (8.58mmol) N, N- dimethylanilines, 12 milliliters of n,N-Dimethylformamide are added in 50 milliliters of reaction bulb,
120 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it is stirred to react 0.5 hour, closes
Reaction is closed, solvent is evaporated off in reaction solution, and 20 milliliters of tetrahydrofurans are added in obtained concentrate and are dissolved, obtain lysate, to
5.0 grams of column chromatography silica gels (300~400 mesh column chromatography silica gel) are added in lysate, after mixing, solvent is evaporated off, are obtained dry dense
Mixture is filled column, then using volume ratio as 1 by the mixture of contracting object and silica gel：1 petrol ether/ethyl acetate mixed solution is
Eluant, eluent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：3 (v/v)), it is collected and contained according to TLC detections
The eluent (Rf values are 0.5) of formula (IV) compound represented, the eluent concentration of collection, 50 DEG C are dried to obtain shown in formula (IV)
Faint yellow solid product, yield 89.6%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 6：Nitro benzo [d] azepineThe preparation of base quinazoline (IV)
Successively by the chloro- 6- nitro-quinazolines (III) of 1.20 grams of (5.73mmol) 4- and 2.39 grams of (6.87mmol) compounds
(II), 3.62 grams of (45.76mmol) pyridines, 20 milliliters of propyl alcohol are added in 50 milliliters of reaction bulb, are heated to 40 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is stirred to react 10 hours, closes reaction, reaction solution is evaporated off molten
Agent adds in 20 milliliters of ethyl acetate in obtained concentrate and is dissolved, obtains lysate, 3.5 grams of columns are added in into lysate
Chromatographic silica gel (300~400 mesh column chromatography silica gel) after mixing, is evaporated off solvent, obtains the mixture of dry concentrate and silica gel,
Mixture is filled into column, then using volume ratio as 1：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, is eluted, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：3 (v/v)), it is collected according to TLC detections containing formula (IV) compound represented
Eluent (Rf values are 0.5), the eluent concentration of collection, 50 DEG C are dried to obtain the faint yellow solid product shown in formula (IV), receive
Rate 78.3%, 164~166 DEG C of fusing point.1H NMR and IR is the same as embodiment 1.
Embodiment 7：Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 1 method of embodimentBase quinazoline (IV),
0.40 gram of (6.34mmol) ammonium formate, 0.04 gram of 5%Pd/C, 4.0 milliliters of chloroforms are added in reaction bulb, 25 DEG C of stirrings of room temperature,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it reacts 12 hours, filtering, filtrate concentration, 25 DEG C
Vacuum drying obtains faint yellow solid product amino benzo [d] azepineBase quinazoline (V), yield 98.2%, fusing point 122~
126℃。1H NMR(500MHz,CDCl3)δ:3.40-3.48(m,2H),3.71(s,3H),3.82(s,3H),3.83(s,3H),
3.87-3.98 (m, 5H), 4.45 (dd, J=6.3,13.8Hz, 1H), 4.95 (dd, J=6.5,9.2Hz, 1H), 6.47 (s,
1H), 6.90 (d, J=8.7Hz, 2H), 6.95 (d, J=2.5Hz, 1H), 7.11 (d, J=8.6Hz, 2H), 7.15 (dd, J=
8.9,2.5Hz, 1H), 7.69 (d, J=8.9Hz, 1H), 8.50 (s, 1H).IR(KBr,cm-1)ν:3368,3215,2932,
2825,1628,1566,1512,1487,1353,1248,1036,834。
Embodiment 8：Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 2 method of embodimentBase quinazoline (IV),
1.20 grams of (19.18mmol) 80wt% hydrazine hydrates, 0.20 gram of 5%Pd/C, 20.0 milliliters of toluene are added to 50 milliliters of reaction bulb
In, 100 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is small to be stirred to react 0.5
When, cold filtration, filtrate concentrates, and 25 DEG C of vacuum drying obtain faint yellow solid product amino benzo [d] azepineBase quinazoline
(V), yield 100.0%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 9：Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 3 method of embodimentBase quinazoline (IV),
0.08 gram of concentrated hydrochloric acid (mass concentration 36~38%), 0.40 gram of iron powder, 20.0 ml methanols are added in 50 milliliters of reaction bulb,
40 DEG C are heated to, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 8 hours, cools down
Filtering, filtrate concentration, 25 DEG C of vacuum drying obtain faint yellow solid product amino benzo [d] azepineBase quinazoline (V) is received
Rate 94.1%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 10：Amino benzo [d] azepineThe preparation of base quinazoline (V)
0.40 gram of (0.77mmol) nitro benzo [d] azepine successively prepared by 4 method of embodimentBase quinazoline (IV),
0.40 gram of acetic acid, 1.20 grams of iron powders, 20.0 milliliters of isopropanols are added in 50 milliliters of reaction bulb, are heated to 80 DEG C, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：1 (v/v)), it is stirred to react 3 hours, cold filtration, filtrate concentration, 25 DEG C
Vacuum drying obtains faint yellow solid product amino benzo [d] azepineBase quinazoline (V), yield 97.5%, fusing point 122~
126℃。1H NMR and IR is the same as embodiment 7.
Embodiment 11：Butyrylamino benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 7 method of embodimentBase quinazoline (V),
0.13 gram of (1.64mmol) pyridine, 3 milliliters of tetrahydrofurans are added in reaction bulb, and 0.469 gram is added dropwise under -10 DEG C of stirring conditions
(4.40mmol) butyl chloride, drop finish, and (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1) it is, anti-under the conditions of -10 DEG C
It answers 12 hours, filters, filtrate steaming removal solvent, concentrate adds in 10 milliliters of ethyl acetate and dissolved, and lysate is obtained, to dissolving
0.60 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in liquid, after mixing, solvent is evaporated off, obtains dry concentrate
With the mixture of silica gel, mixture is filled into column, then using volume ratio as 1：10 petrol ether/ethyl acetate mixed solution is elution
Agent, elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is detected according to TLC and collects (I) containing formula
The eluent (Rf values are 0.5) of compound represented, collection liquid concentration, 50 DEG C are dried to obtain the butyrylamino benzene shown in formula (I)
And [d] azepineBase quinazoline pale solid, yield 47.2%, 216~217 DEG C of fusing point.1H NMR(500MHz,CDCl3)
δ:1.02 (t, J=7.4Hz, 3H)；1.76-1.83(m,2H)；2.41-2.51(m,2H)；3.24-3.30(m,1H),3.54
(dt, J=3.6,15.1Hz, 1H), 3.74 (s, 3H), 3.81-3.82 (m, 7H), 3.98-4.09 (m, 2H), 4.66 (dd, J=
8.3,14.2Hz, 1H), 5.27 (t, J=8.8Hz, 1H) .6.67 (s, 1H), 6.88 (d, J=8.8Hz, 2H), 7.07 (d, J=
8.7Hz, 2H), 7.61 (dd, J=2.0,9.0Hz, 1H), 7.80 (d, J=8.9Hz, 1H), 8.40 (s, 1H), 8.53 (s, 1H),
8.85 (d, J=1.8Hz, 1H).HRMS-ESI m/z:561.2265[M+H]+。IR(KBr,cm-1)ν:2960,2933,2870,
2835,1692,1562,1523,1511,1488,1463,1349,1250,1035,836。
Embodiment 12：Butyrylamino benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 8 method of embodimentBase quinazoline (V),
0.04 gram of (0.55mmol) diethylamine, 10.0 milliliters of chloroforms are added in 50 milliliters of reaction bulb, are added dropwise under 10 DEG C of stirring conditions
0.059 gram of (0.55mmol) butyl chloride and 5.0 milliliters of chloroform mixed solutions, drop finish, and (solvent is acetic acid second to TLC tracing detections
Ester/petroleum ether=1：1 (v/v)), it reacts 8 hours under the conditions of 10 DEG C, filters, filtrate steaming removal solvent, concentrate adds in 20 milliliters of second
Alcohol is dissolved, and obtains lysate, and 0.26 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in into lysate, is mixed
After even, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then using volume ratio as 1：5 stone
Oily ether/ethyl acetate mixture is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1
(v/v)) eluent (Rf values are 0.5) containing formula (I) compound represented, is collected according to TLC detections, collection liquid concentrates, 50 DEG C
It is dried to obtain butyrylamino benzo [d] azepine shown in formula (I)Base quinazoline pale solid, yield 32.9%, fusing point 216
~217 DEG C.1H NMR and IR is the same as embodiment 11.
Embodiment 13：Butyrylamino benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 9 method of embodimentBase quinazoline (V),
0.111 gram of (1.10mmol) triethylamine, 10.0 milliliters of ethyl acetate are added in 50 milliliters of reaction bulb, under 0 DEG C of stirring condition
0.117 gram of (1.10mmol) butyl chloride and 5.0 milliliters of ethyl acetate solutions are added dropwise, drop finishes, and (solvent is second to TLC tracing detections
Acetoacetic ester/petroleum ether=1：1) it, reacts 6 hours under the conditions of 25 DEG C, filters, filtrate steaming removal solvent, concentrate adds in 20 milliliters of chlorine
It is imitative to be dissolved, lysate is obtained, 0.30 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in into lysate, is mixed
After even, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then using volume ratio as 10：1
Petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1
(v/v)) eluent (Rf values are 0.5) containing formula (I) compound represented, is collected according to TLC detections, collection liquid concentrates, 50 DEG C
It is dried to obtain butyrylamino benzo [d] azepine shown in formula (I)Base quinazoline pale solid, yield 46.6%, fusing point 216
~217 DEG C.1H NMR and IR is the same as embodiment 11.
Embodiment 14：Butyrylamino benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 10 method of embodimentBase quinazoline
(V), 0.067 gram of (0.55mmol) 4-dimethylaminopyridine, 20.0 milliliters of toluene are added in 50 milliliters of reaction bulb, and 5 DEG C are stirred
The solution of 0.348 gram of (2.20mmol) butyric anhydride and 7.0 milliliters of toluene is added dropwise under the conditions of mixing, drop finishes, and is heated to 50 DEG C, TLC with
(solvent is ethyl acetate/petroleum ether=1 for track detection：1) it, reacts 3 hours, filtering, filtrate steaming removal solvent, concentrate adds in 20
Milliliter tetrahydrofuran is dissolved, and obtains lysate, and 0.40 gram of column chromatography silica gel (300~400 mesh column layer is added in into lysate
Analyse silica gel), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then with volume
Than being 5：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/stone to TLC tracing detections
Oily ether=1：1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented, collection liquid are collected according to TLC detections
Concentration, 50 DEG C of butyrylamino benzo [d] azepines being dried to obtain shown in formula (I)Base quinazoline pale solid, yield
50.7%, 216~217 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 15：Butyrylamino benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 7 method of embodimentBase quinazoline (V),
0.213 gram of (1.65mmol) quinoline, 15.0 milliliters of benzene are added in 50 milliliters of reaction bulb, are added dropwise under -10 DEG C of stirring conditions
The solution of 0.234 gram of (2.20mmol) butyl chloride and 5.0 milliliters of benzene, drop finish, and (solvent is ethyl acetate/stone to TLC tracing detections
Oily ether=1：1) it, reacts 12 hours under the conditions of -10 DEG C, filters, filtrate steaming removal solvent, concentrate adds in 20 milliliters of tetrahydrofurans will
It is dissolved, and obtains lysate, and 0.40 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel), mixing are added in into lysate
Afterwards, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then using volume ratio as 1：1 oil
Ether/ethyl acetate mixture is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1(v/
V)), the eluent (Rf values are 0.5) containing formula (I) compound represented, collection liquid concentration, 50 DEG C of dryings are collected according to TLC detections
Obtain butyrylamino benzo [d] azepine shown in formula (I)Base quinazoline pale solid, yield 51.4%, fusing point 216~
217℃。1H NMR and IR is the same as embodiment 11.
Embodiment 16：Butyrylamino benzo [d] azepineThe preparation of base quinazoline (I)
0.27 gram of (0.55mmol) amino benzo [d] azepine successively prepared by 7 method of embodimentBase quinazoline (V),
0.164 gram of (1.10mmol) 4- pyrollidinopyridine, 15.0 milliliters of dichloromethane are added in 50 milliliters of reaction bulb, and 10 DEG C are stirred
0.117 gram of (1.10mmol) butyl chloride and 5.0 milliliters of dichloromethane solutions are added dropwise under the conditions of mixing, drop finishes, (the exhibition of TLC tracing detections
Agent is opened as ethyl acetate/petroleum ether=1：1) it, reacts 8 hours under the conditions of 10 DEG C, filters, filtrate steaming removal solvent, concentrate adds in
20 milliliters of ethyl alcohol are dissolved, and obtain lysate, and 0.50 gram of column chromatography silica gel (300~400 mesh column chromatography is added in into lysate
Silica gel), after mixing, solvent is evaporated off, obtains the mixture of dry concentrate and silica gel, mixture is filled into column, then with volume ratio
It is 10：1 petrol ether/ethyl acetate mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/stone to TLC tracing detections
Oily ether=1：1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented, collection liquid are collected according to TLC detections
Concentration, 50 DEG C of butyrylamino benzo [d] azepines being dried to obtain shown in formula (I)Base quinazoline pale solid, yield
43.7%, 216~217 DEG C of fusing point.1H NMR and IR is the same as embodiment 11.
Embodiment 17：Active anticancer testing in vitro
(1) compound obtained (I) and (IV) human lung cancer cell lines A-549 biological activity test has been subjected to.
Test method：Tetrazolium reduction method (mtt assay).
Cell strain：Human lung cancer cell lines A-549.Above-mentioned tumor cell line is thin purchased from Chinese Academy of Sciences's Shanghai school of life and health sciences
Born of the same parents library.
Experimental procedure is as follows：
(a) preparation of sample：For solvable sample, dissolved per 1mg with 40 μ LDMSO, take 2 μ L dilute with 1000 μ L culture mediums
It releases, makes a concentration of 100 μ g/mL, then concentration is extremely used with culture solution serial dilution.
(b) culture of cell
1. the preparation of culture medium:Containing 800,000 units of Penicillin, 1.0g strepto-s in per 1000mL DMEM culture mediums (Gibco)
Element, 10% inactivated fetal bovine serum.
2. the culture of cell：By tumor cell inoculation in culture medium, 37 DEG C are put, 5%CO2It is cultivated in incubator, 3~5d
Passage.
3. determination sample is to the inhibiting effect of growth of tumour cell
2nd generation cell EDTA- pancreatin digestive juice is digested, and be diluted to 1 × 10 with culture medium6It is thin to be added to 96 holes by/mL
In born of the same parents' culture plate, per 100 μ L of hole, 37 DEG C are put, 5%CO2It is cultivated in incubator.After inoculation for 24 hours, it is separately added into and is diluted with culture medium
100 μ g/mL, 10 μ g/mL and 1 μ g/mL samples, per 100 μ L of hole, each concentration adds 3 holes, puts 37 DEG C, 5%CO2In incubator
It cultivates, adds in the MTT of 5mg/mL after 72h in cell culture well, per 10 μ L of hole, put 37 DEG C of incubation 3h, add in DMSO, every hole
150 μ L, are vibrated with oscillator, and Shi Jia Za is completely dissolved, with microplate reader under 570nm wavelength colorimetric.To be free of under similarity condition
Sample, the cell of the medium culture containing similary concentration DMSO calculate IC of the sample to growth of tumour cell as control50。
The results are shown in Table 1 for test：
The inhibiting effect that 1. compound of table (I) and (IV) grow cancer cell line A-549
(2) according to embodiment 11, butyl chloride is used into 4- iodobenzoyl chlorides, 3- methoxy benzoyl chlorides or cinnamoyl chloride respectively
Instead of other operations have been respectively synthesized quinazoline compounds (a), (b) and (c), structure are as follows with embodiment 11：
According to the above method by quinazoline compounds (a) obtained, (b) and (c) has carried out human lung cancer cell lines A-549
Biological activity test, test result show quinazoline compounds (a), and (b) and (c) inhibits to imitate to human lung cancer cell lines A-549
The equal unobvious of fruit, compound (a), (b) and (c) can not show a candle to the active anticancer of human lung cancer cell lines A-549 compound (I).Tool
The results are shown in Table 2 for body：
The inhibiting effect that 2. compound (a) of table, (b) and (c) grow cancer cell line A-549
Above-mentioned active anticancer testing in vitro experiment shows：The similar compound (a) of other 3 structures, (b) and (c) is to people
The equal unobvious of inhibiting effect of lung cancer cell line A-549 growths.The inhibition that compound (I) grows human lung cancer cell lines A-549
Effect is notable, hence it is evident that better than compound (a), (b) and (c).
(3) method of reference literature (Rao, G.-W.et al.ChemMedChem, 2013,8 (6), 928-933) is prepared into
To 4- chloro-quinazolines, further according to embodiment 1, the chloro- 6- nitro-quinazolines of 4- are replaced with 4- chloro-quinazolines, other operations are the same as implementation
Example 1, has synthesized quinazoline compounds (d), and structure is as follows：
Quinazoline compounds (d) obtained have been carried out by human lung cancer cell lines A-549 bioactivity according to the above method
Test, test result show that quinazoline compounds (d) can not show a candle to compound to the active anticancer of human lung cancer cell lines A-549
(Ⅰ).Concrete outcome is as shown in table 3：
The inhibiting effect that 3. compound (d) of table grows cancer cell line A-549
(4) according to embodiment 11, butyl chloride is replaced respectively with chlorobenzoyl chloride, propionyl chloride, chloracetyl chloride or isobutyryl chloride,
Other operations have been respectively synthesized quinazoline compounds (e), (f), (g) and (h), structure is as follows with embodiment 11：
Quinazoline compounds (e) obtained, (f), (g) and (h) have been carried out by human lung carcinoma cell line according to the above method
A-549 biological activity tests, test result show quinazoline compounds (e), (f), (g) with (h) to human lung carcinoma cell line A-
549 active anticancer is not so good as compound (I).Concrete outcome is as shown in table 4：
The inhibiting effect that 4. compound (e) of table, (f), (g) and (h) grow cancer cell line A-549
Claims (2)
1. a kind of butyrylamino benzo [d] azepine shown in formula (I)Base quinazoline compounds are preparing prevention or treatment people
Application in lung-cancer medicament；
2. application as described in claim 1, it is characterised in that：The drug is to live with inhibition human lung cancer cell lines A-549
The drug of property.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
| WO1995023141A1 (en) * | 1994-02-23 | 1995-08-31 | Pfizer Inc. | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents |
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2018
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1061411A (en) * | 1990-11-06 | 1992-05-27 | 美国辉瑞有限公司 | Be used to strengthen the active quinazoline derivant of antineoplastic agent |
| WO1995023141A1 (en) * | 1994-02-23 | 1995-08-31 | Pfizer Inc. | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents |
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