CN108245519A - Application of butyrylaminoquinazoline compound in preparation of drugs for treating leukemia - Google Patents
Application of butyrylaminoquinazoline compound in preparation of drugs for treating leukemia Download PDFInfo
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- CN108245519A CN108245519A CN201810069144.0A CN201810069144A CN108245519A CN 108245519 A CN108245519 A CN 108245519A CN 201810069144 A CN201810069144 A CN 201810069144A CN 108245519 A CN108245519 A CN 108245519A
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- ethyl acetate
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- 239000003814 drug Substances 0.000 title claims abstract description 14
- 229940079593 drug Drugs 0.000 title claims abstract description 11
- 208000032839 leukemia Diseases 0.000 title claims abstract description 9
- 238000002360 preparation method Methods 0.000 title abstract description 21
- -1 butyrylaminoquinazoline compound Chemical class 0.000 title description 8
- KDKUGCMUJITHRJ-UHFFFAOYSA-N N-quinazolin-2-ylbutanamide Chemical class C(CCC)(=O)NC1=NC2=CC=CC=C2C=N1 KDKUGCMUJITHRJ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 230000000694 effects Effects 0.000 claims abstract description 7
- 230000002265 prevention Effects 0.000 claims description 6
- 230000005764 inhibitory process Effects 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 9
- 101000573199 Homo sapiens Protein PML Proteins 0.000 abstract description 2
- 102000054896 human PML Human genes 0.000 abstract description 2
- 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 59
- 150000001875 compounds Chemical class 0.000 description 53
- 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 36
- RPTKRGHYKSBDJL-UHFFFAOYSA-N 6-nitroquinazoline Chemical compound N1=CN=CC2=CC([N+](=O)[O-])=CC=C21 RPTKRGHYKSBDJL-UHFFFAOYSA-N 0.000 description 34
- 239000000203 mixture Substances 0.000 description 32
- 239000012141 concentrate Substances 0.000 description 30
- 235000008504 concentrate Nutrition 0.000 description 30
- 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 25
- 239000003960 organic solvent Substances 0.000 description 22
- 239000000243 solution Substances 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 18
- 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 16
- 150000003246 quinazolines Chemical class 0.000 description 16
- 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-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
- 239000000706 filtrate Substances 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 11
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 11
- 239000011259 mixed solution Substances 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 10
- 238000010828 elution 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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-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
- 229960000583 acetic acid Drugs 0.000 description 9
- 239000012265 solid product Substances 0.000 description 9
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- 235000019441 ethanol Nutrition 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 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 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 7
- 239000003638 chemical reducing agent Substances 0.000 description 7
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-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
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-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
- 239000003795 chemical substances by application Substances 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
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical class CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 230000012010 growth Effects 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 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
- QCCWVNLOJADEAV-UHFFFAOYSA-N n,n-dimethyl-1h-pyrrol-3-amine Chemical class CN(C)C=1C=CNC=1 QCCWVNLOJADEAV-UHFFFAOYSA-N 0.000 description 2
- 239000003921 oil Substances 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
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 description 1
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-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
- 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
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 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
- 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
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004113 cell culture Methods 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
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 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
- 238000010438 heat treatment Methods 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
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 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
- AUGVANPBWQRQIN-UHFFFAOYSA-N n-quinolin-2-ylbutanamide Chemical compound C1=CC=CC2=NC(NC(=O)CCC)=CC=C21 AUGVANPBWQRQIN-UHFFFAOYSA-N 0.000 description 1
- 150000002825 nitriles Chemical class 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
- 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
- 238000013207 serial dilution Methods 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000004575 stone 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 application of butyrylaminoquinazoline compounds in preparation of drugs for preventing or treating human leukemia, which has a remarkable effect of inhibiting the activity of human promyelocytic leukemia cell strain H L-60.
Description
(1) technical field
The present invention relates to a kind of butyrylamino quinazoline compounds in the drug for preparing prevention or treatment human leukemia
Application.
(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 quinazoline compounds to exist
The application in the drug of prevention or treatment human leukemia is prepared, such compound is thin to human promyelocytic leukemia under doses
Born of the same parents' strain HL-60 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 the butyrylamino quinazoline compounds shown in a kind of formula (I) to prepare prevention or treatment tumour
Application in disease medicament, the particularly application in the drug for preparing prevention or treatment human leukemia：
Preferably, the drug is with the drug for inhibiting people in loop strain HL-60 activity.
The present invention provides a kind of preparation method of the butyrylamino quinazoline compounds shown in formula (I), the method
For：(1) compound shown in formula (II) is mixed with compound shown in formula (III), in organic solvent A, in basic catalyst B's
Under effect, 25~120 DEG C reacted (TLC tracking and monitorings, solvent be ethyl acetate/petroleum ether=1：3 (v/v), preferably 40
~100 DEG C of 0.5~12h of reaction), after the reaction was complete, reaction solution is isolated and purified, compound shown in formula (IV) is made；It is described to have
Solvent A is selected from one of following：Chloroform, toluene, methanol, ethyl alcohol, propyl alcohol, isopropanol, acetonitrile or N,N-dimethylformamide；Institute
The basic catalyst B stated is selected from one of following：Pyridine, diethylamine, triethylamine, quinoline, N, N- dimethylanilines, 4- dimethylamino pyrroles
Pyridine, 4- pyrollidinopyridines or sodium carbonate (preferably pyridine, diethylamine, triethylamine, N, N- dimethylanilines or 4- dimethylamino pyrroles
Pyridine)；
(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 leukemia is treated, which has people in loop strain HL-60 significant inhibit
Activity.
(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：The preparation of 6- nitro-quinazolines (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：The preparation of 6- nitro-quinazolines (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：The preparation of 6- nitro-quinazolines (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：The preparation of 6- nitro-quinazolines (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：The preparation of 6- nitro-quinazolines (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：The preparation of 6- nitro-quinazolines (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：The preparation of 6- amido quinazolines (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 1 method of embodiment, 0.40 gram
(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, TLC tracking
(solvent is ethyl acetate/petroleum ether=1 for detection：1 (v/v)), it reacts 12 hours, filtering, filtrate concentration, 25 DEG C of vacuum drying
Obtain faint yellow solid product 6- amido quinazolines (V), yield 98.2%, 122~126 DEG C of fusing point.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：The preparation of 6- amido quinazolines (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 2 method of embodiment, 1.20 grams
(19.18mmol) 80wt% hydrazine hydrates, 0.20 gram of 5%Pd/C, 20.0 milliliters of toluene are added in 50 milliliters of reaction bulb, heating
To 100 DEG C, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 0.5 hour, it is cooled
Filter, filtrate concentration, 25 DEG C of vacuum drying obtain faint yellow solid product 6- amido quinazolines (V), yield 100.0%, fusing point
122~126 DEG C.1H NMR and IR is the same as embodiment 7.
Embodiment 9：The preparation of 6- amido quinazolines (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 3 method of embodiment, 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, are heated to 40 DEG C,
(solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), it is stirred to react 8 hours, cold filtration, filtrate is dense
Contracting, 25 DEG C of vacuum drying obtain faint yellow solid product 6- amido quinazolines (V), yield 94.1%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 10：The preparation of 6- amido quinazolines (V)
0.40 gram of (0.77mmol) the 6- nitro-quinazoline (IV) successively prepared by 4 method of embodiment, 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 tracing detection (solvents
For ethyl acetate/petroleum ether=1：1 (v/v)), it is stirred to react 3 hours, cold filtration, filtrate concentration, 25 DEG C of vacuum drying obtain
Faint yellow solid product 6- amido quinazolines (V), yield 97.5%, 122~126 DEG C of fusing point.1H NMR and IR is the same as embodiment 7.
Embodiment 11：The preparation of butyrylamino quinazoline (I)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 7 method of embodiment, 0.13 gram
(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 quinoline shown in formula (I)
Oxazoline 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：The preparation of butyrylamino quinazoline (I)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 8 method of embodiment, 0.04 gram
(0.55mmol) diethylamine, 10.0 milliliters of chloroforms are added in 50 milliliters of reaction bulb, and 0.059 gram is added dropwise under 10 DEG C of stirring conditions
(0.55mmol) butyl chloride and 5.0 milliliters of chloroform mixed solutions, drop finish, and (solvent is ethyl acetate/oil to TLC tracing detections
Ether=1：1 (v/v)), react 8 hours under the conditions of 10 DEG C, filter, filtrate steaming removal solvent, concentrate add in 20 milliliters of ethyl alcohol by its
Dissolving obtains lysate, 0.26 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) of addition into lysate, after mixing,
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 petroleum ether/
Ethyl acetate mixture is eluant, eluent, elution, and (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 concentration, 50 DEG C are dried to obtain
Butyrylamino quinazoline pale solid shown in formula (I), yield 32.9%, 216~217 DEG C of fusing point.1H NMR and IR are the same as real
Apply example 11.
Embodiment 13：The preparation of butyrylamino quinazoline (I)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 9 method of embodiment, 0.111 gram
(1.10mmol) triethylamine, 10.0 milliliters of ethyl acetate are added in 50 milliliters of reaction bulb, are added dropwise under 0 DEG C of stirring condition
0.117 gram of (1.10mmol) butyl chloride and 5.0 milliliters of ethyl acetate solutions, drop finish, and (solvent is acetic acid second to TLC tracing detections
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 chloroforms will
It is dissolved, and obtains lysate, and 0.30 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 10：1 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 the butyrylamino quinazoline pale solid shown in formula (I), yield 46.6%, 216~217 DEG C of fusing point.1H NMR
With IR with embodiment 11.
Embodiment 14：The preparation of butyrylamino quinazoline (I)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 10 method of embodiment, 0.067 gram
(0.55mmol) 4-dimethylaminopyridine, 20.0 milliliters of toluene are added in 50 milliliters of reaction bulb, are added dropwise under 5 DEG C of stirring conditions
The solution of 0.348 gram of (2.20mmol) butyric anhydride and 7.0 milliliters of toluene, drop finish, and are heated to 50 DEG C, TLC tracing detection (solvents
For ethyl acetate/petroleum ether=1：1) it, reacts 3 hours, filtering, filtrate steaming removal solvent, concentrate adds in 20 milliliters of tetrahydrofurans
It is dissolved, obtains lysate, 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 5：1 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 the butyrylamino quinazoline pale solid shown in formula (I), yield 50.7%, 216~217 DEG C of fusing point.1H NMR and IR
With embodiment 11.
Embodiment 15：The preparation of butyrylamino quinazoline (I)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 7 method of embodiment, 0.213 gram
(1.65mmol) quinoline, 15.0 milliliters of benzene are added in 50 milliliters of reaction bulb, and 0.234 gram is added dropwise under -10 DEG C of stirring conditions
The solution of (2.20mmol) butyl chloride and 5.0 milliliters of benzene, drop finish, TLC tracing detections (solvent for ethyl acetate/petroleum 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, and its is molten
Solution obtains lysate, 0.40 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) of addition into lysate, after mixing, steams
Except solvent, the mixture of dry concentrate and silica gel is obtained, mixture is filled into column, then using volume ratio as 1：1 petroleum ether/second
Acetoacetic ester mixed solution is eluant, eluent, and elution, (solvent is ethyl acetate/petroleum ether=1 to TLC tracing detections：1 (v/v)), root
The eluent (Rf values are 0.5) containing formula (I) compound represented is collected according to TLC detections, collection liquid concentration, 50 DEG C are dried to obtain formula
(I) the butyrylamino quinazoline pale solid shown in, yield 51.4%, 216~217 DEG C of fusing point.1H NMR and IR are the same as implementation
Example 11.
Embodiment 16：The preparation of butyrylamino quinazoline (I)
0.27 gram of (0.55mmol) the 6- amido quinazoline (V) successively prepared by 7 method of embodiment, 0.164 gram
(1.10mmol) 4- pyrollidinopyridines, 15.0 milliliters of dichloromethane are added in 50 milliliters of reaction bulb, 10 DEG C of stirring conditions
Lower dropwise addition 0.117 gram of (1.10mmol) butyl chloride and 5.0 milliliters of dichloromethane solutions, drop finish, and (solvent is TLC tracing detections
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
Ethyl alcohol is dissolved, and obtains lysate, and 0.50 gram of column chromatography silica gel (300~400 mesh column chromatography silica gel) is added in into lysate,
After mixing, 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 for eluant, eluent, elution, TLC tracing detections (solvent for ethyl acetate/petroleum ether=
1：1 (v/v)), the eluent (Rf values are 0.5) containing formula (I) compound represented is collected according to TLC detections, collection liquid concentrates, and 50
DEG C it is dried to obtain the butyrylamino quinazoline pale solid shown in formula (I), 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) people in loop strain HL-60 biological activity tests have been subjected to.
Test method：Tetrazolium reduction method (mtt assay).
Cell strain：People in loop strain HL-60.Above-mentioned tumor cell line is purchased from Chinese Academy of Sciences's Shanghai life
Academy of sciences's cell bank.
Experimental procedure is as follows：
(a) preparation of sample：For solvable sample, dissolved per 1mg with 40 μ L DMSO, 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
10th generation cell EDTA- pancreatin digestive juice is digested, and be diluted to 1 × 10 with culture medium6/ mL is added to 96 holes
In tissue 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 dilute with culture medium
100 μ g/mL, the 10 μ g/mL and 1 μ g/mL samples released, per 100 μ L of hole, each concentration adds 3 holes, puts 37 DEG C, 5%CO2Incubator
Middle culture adds in the MTT of 5mg/mL after 72h in cell culture well, per 10 μ L of hole, puts 37 DEG C of incubation 3h, DMSO is added in, per 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) grows cancer cell line HL-60
(2) according to embodiment 11, butyl chloride is replaced respectively with 3- methoxy benzoyl chlorides or cinnamoyl chloride, other operations
With embodiment 11, quinazoline compounds (b) and (c) are respectively synthesized, structure is as follows：
Quinazoline compounds (b) obtained and (c) have been carried out by people in loop strain according to the above method
HL-60 biological activity tests, test result show quinazoline compounds (b) and (c) to people in loop strain HL-
The equal unobvious of 60 inhibitions, compound (b) and (c) can not show a candle to the active anticancer of people in loop strain HL-60
Compound (I).Concrete outcome is as shown in table 2：
The inhibiting effect that 2. compound (b) of table and (c) grow cancer cell line HL-60
Above-mentioned active anticancer testing in vitro experiment shows：The similar compound (b) of other 2 structures and (c) are early young to people
The equal unobvious of inhibiting effect of grain leukemia cell line HL-60 growth.Compound (I) is to people in loop strain HL-
The inhibiting effect of 60 growths is notable, hence it is evident that better than compound (b) and (c).
(3) according to embodiment 11, butyl chloride is replaced respectively with propionyl chloride or pivaloyl chloride, other operate same embodiment
11, quinazoline compounds (f) and (j) are respectively synthesized, structure is as follows：
Quinazoline compounds (f) obtained and (j) have been carried out by people in loop strain according to the above method
HL-60 biological activity tests, test result show quinazoline compounds (f) and (j) to people in loop strain HL-
60 active anticancer is not so good as compound (I).Concrete outcome is as shown in table 3：
The inhibiting effect that 3. compound (f) of table and (j) grow cancer cell line HL-60
Claims (2)
1. the butyrylamino quinazoline compounds shown in a kind of formula (I) are in the drug for preparing prevention or treatment human leukemia
Using：
2. application as described in claim 1, it is characterised in that：The drug is with inhibition people in loop strain
The drug of HL-60 activity.
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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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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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