CN108250185B - 6- (2- (o-toluidine amino) acetamido) quinazoline compound, preparation and application thereof - Google Patents
6- (2- (o-toluidine amino) acetamido) quinazoline compound, preparation and application thereof Download PDFInfo
- Publication number
- CN108250185B CN108250185B CN201810069794.5A CN201810069794A CN108250185B CN 108250185 B CN108250185 B CN 108250185B CN 201810069794 A CN201810069794 A CN 201810069794A CN 108250185 B CN108250185 B CN 108250185B
- Authority
- CN
- China
- Prior art keywords
- formula
- organic solvent
- compound shown
- concentrate
- ethyl acetate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- RNVCVTLRINQCPJ-UHFFFAOYSA-N ortho-methyl aniline Natural products CC1=CC=CC=C1N RNVCVTLRINQCPJ-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 44
- -1 quinazoline compound Chemical class 0.000 title claims abstract description 38
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 title abstract description 10
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 21
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 21
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 255
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 148
- 150000001875 compounds Chemical class 0.000 claims description 122
- 239000000243 solution Substances 0.000 claims description 80
- 239000000203 mixture Substances 0.000 claims description 74
- 239000003208 petroleum Substances 0.000 claims description 71
- 239000012141 concentrate Substances 0.000 claims description 69
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 68
- 239000000741 silica gel Substances 0.000 claims description 68
- 229910002027 silica gel Inorganic materials 0.000 claims description 68
- 239000002904 solvent Substances 0.000 claims description 64
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 54
- 239000003960 organic solvent Substances 0.000 claims description 53
- 238000002156 mixing Methods 0.000 claims description 48
- 238000004440 column chromatography Methods 0.000 claims description 44
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 42
- 238000001704 evaporation Methods 0.000 claims description 42
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 41
- 239000003480 eluent Substances 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- 238000001035 drying Methods 0.000 claims description 37
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 33
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 30
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 26
- 239000003054 catalyst Substances 0.000 claims description 26
- 239000011259 mixed solution Substances 0.000 claims description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 24
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 24
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 22
- 238000011049 filling Methods 0.000 claims description 21
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 20
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 18
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 18
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 15
- 239000012295 chemical reaction liquid Substances 0.000 claims description 13
- 239000003638 chemical reducing agent Substances 0.000 claims description 13
- 239000000706 filtrate Substances 0.000 claims description 13
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- 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 claims description 12
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 12
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 11
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 claims description 9
- 238000001914 filtration Methods 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 9
- PNVPNXKRAUBJGW-UHFFFAOYSA-N (2-chloroacetyl) 2-chloroacetate Chemical compound ClCC(=O)OC(=O)CCl PNVPNXKRAUBJGW-UHFFFAOYSA-N 0.000 claims description 8
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 8
- RGUKYNXWOWSRET-UHFFFAOYSA-N 4-pyrrolidin-1-ylpyridine Chemical compound C1CCCN1C1=CC=NC=C1 RGUKYNXWOWSRET-UHFFFAOYSA-N 0.000 claims description 7
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 3
- 238000011321 prophylaxis Methods 0.000 claims 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 abstract description 18
- 201000005202 lung cancer Diseases 0.000 abstract description 18
- 208000020816 lung neoplasm Diseases 0.000 abstract description 18
- 206010008342 Cervix carcinoma Diseases 0.000 abstract description 15
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 abstract description 15
- 201000010881 cervical cancer Diseases 0.000 abstract description 15
- 101000573199 Homo sapiens Protein PML Proteins 0.000 abstract description 12
- 102000054896 human PML Human genes 0.000 abstract description 12
- 208000032839 leukemia Diseases 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 2
- 210000004027 cell Anatomy 0.000 description 87
- 238000001514 detection method Methods 0.000 description 42
- CJVAHWKJGXCAMC-UHFFFAOYSA-N 2-chloro-N-quinazolin-2-ylacetamide Chemical compound ClCC(=O)NC1=NC2=CC=CC=C2C=N1 CJVAHWKJGXCAMC-UHFFFAOYSA-N 0.000 description 36
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 36
- 238000012360 testing method Methods 0.000 description 31
- 239000003795 chemical substances by application Substances 0.000 description 30
- 150000003246 quinazolines Chemical class 0.000 description 30
- RPTKRGHYKSBDJL-UHFFFAOYSA-N 6-nitroquinazoline Chemical compound N1=CN=CC2=CC([N+](=O)[O-])=CC=C21 RPTKRGHYKSBDJL-UHFFFAOYSA-N 0.000 description 28
- 238000002844 melting Methods 0.000 description 22
- 230000008018 melting Effects 0.000 description 22
- 230000001093 anti-cancer Effects 0.000 description 20
- 230000005764 inhibitory process Effects 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 238000003756 stirring Methods 0.000 description 17
- LZOSFEDULGODDH-UHFFFAOYSA-N 4-chloro-6-nitroquinazoline Chemical compound N1=CN=C(Cl)C2=CC([N+](=O)[O-])=CC=C21 LZOSFEDULGODDH-UHFFFAOYSA-N 0.000 description 16
- 239000001963 growth medium Substances 0.000 description 16
- 239000002609 medium Substances 0.000 description 16
- 239000012265 solid product Substances 0.000 description 15
- 230000004071 biological effect Effects 0.000 description 14
- XFGPXURFKAUHQR-UHFFFAOYSA-N quinazolin-6-amine Chemical class N1=CN=CC2=CC(N)=CC=C21 XFGPXURFKAUHQR-UHFFFAOYSA-N 0.000 description 14
- 230000005907 cancer growth Effects 0.000 description 13
- 239000007788 liquid Substances 0.000 description 12
- 210000004881 tumor cell Anatomy 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 9
- 238000012258 culturing Methods 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- DOLQYFPDPKPQSS-UHFFFAOYSA-N 3,4-dimethylaniline Chemical group CC1=CC=C(N)C=C1C DOLQYFPDPKPQSS-UHFFFAOYSA-N 0.000 description 8
- 238000004113 cell culture Methods 0.000 description 8
- 238000002474 experimental method Methods 0.000 description 8
- 230000012010 growth Effects 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 8
- 239000007787 solid Substances 0.000 description 7
- 238000012512 characterization method Methods 0.000 description 5
- 238000011068 loading method Methods 0.000 description 5
- 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 4
- LGDHZCLREKIGKJ-UHFFFAOYSA-N 3,4-dimethoxyaniline Chemical group COC1=CC=C(N)C=C1OC LGDHZCLREKIGKJ-UHFFFAOYSA-N 0.000 description 4
- RUQIUASLAXJZIE-UHFFFAOYSA-N 3-methoxybenzoyl chloride Chemical compound COC1=CC=CC(C(Cl)=O)=C1 RUQIUASLAXJZIE-UHFFFAOYSA-N 0.000 description 4
- GVRRXASZZAKBMN-UHFFFAOYSA-N 4-chloroquinazoline Chemical compound C1=CC=C2C(Cl)=NC=NC2=C1 GVRRXASZZAKBMN-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 229930182555 Penicillin Natural products 0.000 description 4
- 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 4
- WEHWNAOGRSTTBQ-UHFFFAOYSA-N dipropylamine Chemical group CCCNCCC WEHWNAOGRSTTBQ-UHFFFAOYSA-N 0.000 description 4
- 239000012091 fetal bovine serum Substances 0.000 description 4
- 238000011081 inoculation Methods 0.000 description 4
- 238000012544 monitoring process Methods 0.000 description 4
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 4
- 229940055695 pancreatin Drugs 0.000 description 4
- 229940049954 penicillin Drugs 0.000 description 4
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 4
- 229960005322 streptomycin Drugs 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- 125000003831 tetrazolyl group Chemical group 0.000 description 4
- 230000004565 tumor cell growth Effects 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- NJAKCIUOTIPYED-UHFFFAOYSA-N 4-iodobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(I)C=C1 NJAKCIUOTIPYED-UHFFFAOYSA-N 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
- 229960001433 erlotinib Drugs 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
- 229960002584 gefitinib Drugs 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
- 229960004891 lapatinib Drugs 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
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 125000003368 amide group Chemical group 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
- 230000009286 beneficial effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 230000009982 effect on human Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000017066 negative regulation of growth Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a 6- (2- (o-toluidine) acetamido) quinazoline compound, and a preparation method and application thereof. The 6- (2- (o-toluidine) acetamido) quinazoline compound provided by the invention has obvious inhibitory activity on human breast cancer cell strain MCF-7, human lung cancer cell strain A-549, human promyelocytic leukemia cell strain HL-60 and human cervical cancer cell strain Siha, and is expected to be applied to preparation of medicines for preventing or treating human breast cancer, human lung cancer, human leukemia and human cervical cancer. The invention provides a preparation method of the 6- (2- (o-toluidine) acetamido) quinazoline compound, which is simple, easy to operate, easy to obtain raw materials, low in production cost and suitable for practical use.
Description
(I) technical field
The invention relates to a quinazoline compound and application thereof, in particular to a 6- (2- (o-toluidine) acetamido) quinazoline compound and a preparation method thereof, and application of the compound in preparation of a medicament for preventing or treating tumor diseases.
(II) background of the invention
The quinazoline compounds have a plurality of good biological activities and are widely applied in the field of medicine, particularly, some quinazoline derivatives with special structures have obvious antiviral activity, antibacterial activity, antitumor activity and the like, and the quinazoline compounds are marketed as antitumor drugs. For example, Gefitinib (Gefitinib) and Erlotinib (Erlotinib) are marketed for the treatment of lung cancer, and Lapatinib (Lapatinib) is marketed for the treatment of breast cancer, both of which belong to the quinazoline class of compounds. Novel quinazoline compounds and their biological activities are also commonly reported in the literature (see y. -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, chemed chem 2013,8, 136-148; a.garofalo, a.farce, s.ravez, a.lemoine, p.six, p.vachatte, l.gos, p.depenux, j.chem. 1204, d. chem. 1189). Of course most quinazoline compounds do not have anti-tumor activity.
Disclosure of the invention
The invention aims to provide a novel quinazoline compound with anticancer activity, namely a 6- (2- (o-toluidine) acetamido) quinazoline compound, and a preparation method and application thereof, wherein the compound has a good inhibition effect on a human lung cancer cell strain A-549, a human breast cancer cell strain MCF-7, a human promyelocytic leukemia cell strain HL-60 or a human cervical cancer cell strain Siha under a certain dosage; and the preparation method of the compound is simple and convenient, easy to operate, easy to obtain raw materials, low in production cost and suitable for industrial application.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the invention provides a 6- (2- (o-toluidino) acetamido) quinazoline compound shown as a formula (I),
in a second aspect, the present invention provides a method for preparing a 6- (2- (o-toluylamino) acetamido) quinazoline compound represented by formula (i), wherein the method comprises: (1) mixing a compound shown as a formula (II) and a compound shown as a formula (III), reacting at 25-120 ℃ in an organic solvent A under the action of a basic catalyst B (TLC tracking monitoring is carried out, a developing agent is ethyl acetate/petroleum ether which is 1: 3(v/v), and preferably 40-100 ℃ for 0.5-12 h), and after the reaction is completed, separating and purifying a reaction solution to obtain a compound shown as a formula (IV); the organic solvent A is selected from one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the basic catalyst B is selected from one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate (preferably pyridine, diethylamine, triethylamine, NN-dimethylaniline or 4-dimethylaminopyridine);
(2) completely reacting a compound shown in a formula (IV) in an organic solvent D under the action of a reducing agent E at 25-100 ℃ (TLC tracking monitoring, a developing agent is ethyl acetate/petroleum ether which is 1: 1(v/v), and preferably reacting for 0.5-12 h at 40-80 ℃), filtering a reaction solution, concentrating a filtrate under reduced pressure, and drying a concentrate (preferably drying at 25 ℃ in vacuum) to obtain a compound shown in a formula (V); the organic solvent D is one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the reducing agent E is one of the following: iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium on carbon/ammonium formate or palladium on carbon/hydrazine hydrate; the iron powder/concentrated hydrochloric acid refers to the mixing of iron powder and concentrated hydrochloric acid in any proportion, the iron powder/acetic acid refers to the mixing of iron powder and acetic acid in any proportion, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate in any proportion, and the palladium carbon/hydrazine hydrate refers to the mixing of palladium carbon and hydrazine hydrate in any proportion;
(3) mixing a compound shown as a formula (V) with chloroacetyl chloride or chloroacetic anhydride, completely reacting at-10-50 ℃ in an organic solvent G under the action of an alkaline catalyst F (tracking and monitoring by TLC, wherein a developing agent is ethyl acetate/petroleum ether (1: 1(v/v), preferably reacting at-10-50 ℃ for 3-12 h), and carrying out aftertreatment A on a reaction solution to obtain a compound shown as a formula (VI); the alkaline catalyst F is one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate; the organic solvent G is one of the following: tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, diethyl ether, acetonitrile, toluene or benzene;
(4) mixing a compound shown as a formula (VI) with o-toluidine, reacting at 25-120 ℃ in an organic solvent J under the action of a basic catalyst K (TLC tracking monitoring is carried out, a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v), preferably 40-100 ℃ for 0.5-36 h), and after the reaction is completed, carrying out aftertreatment B on a reaction liquid to obtain a compound shown as a formula (I); the organic solvent J is selected from one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the basic catalyst K is selected from one of the following: pyridine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate (preferably pyridine, quinoline, triethylamine, N-dimethylaniline or 4-dimethylaminopyridine);
further, in the step (1), the ratio of the amount of the compound represented by the formula (III) to the amount of the compound represented by the formula (II) and the amount of the substance charged as the basic catalyst B is 1.0: 0.8 to 1.2: 1.0 to 8.0.
Further, in the step (1), the amount of the organic solvent A is 10-50 mL/g based on the mass of the compound represented by the formula (III).
Further, the method for separating and purifying the reaction solution in the step (1) of the present invention comprises: after the reaction is completed, evaporating the solvent from the reaction solution, dissolving the concentrate with an organic solvent C to obtain a dissolved solution, adding column chromatography silica gel of which the weight is 1.0-2.0 times that of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture with the organic solvent C in a volume ratio of 1: taking a mixed solution of petroleum ether and ethyl acetate of 0.1-10 as an eluent, collecting an effluent containing a target component (preferably, ethyl acetate/petroleum ether is 1: 3(v/v) is taken as a developing agent for tracking detection, collecting the target component, preferably, collecting a component with an Rf value of 0.5), concentrating under reduced pressure, and drying (preferably, drying at 50 ℃) to obtain a compound shown in a formula (IV); the organic solvent C is one of the following solvents: ethanol, chloroform, tetrahydrofuran or ethyl acetate. The organic solvent C is used in an amount capable of dissolving the residue.
Further, in the step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, the charging mass ratio of the compound represented by the formula (iv) to the iron powder, concentrated hydrochloric acid or acetic acid in the reducing agent E is 1.0: 1.0 to 3.0: 0.2 to 1.0. In the invention, the mass concentration of the concentrated hydrochloric acid is 36-38%, and the acetic acid is glacial acetic acid.
Further, in the step (2), when the reducing agent E is palladium on carbon/ammonium formate or palladium on carbon/hydrazine hydrate, the feeding mass ratio of the compound represented by the formula (iv) to palladium on carbon, ammonium formate or hydrazine hydrate in the reducing agent E is 1.0: 0.1 to 0.5: 1.0 to 3.0. The mass loading amount of palladium in the palladium-carbon applicable to the invention is 2-10%, preferably 5%, and the mass concentration of hydrazine hydrate is 40-80%, preferably 80%.
Further, in the step (2), the amount of the organic solvent D is 10-50 mL/g based on the mass of the compound represented by the formula (IV).
In the step (3), the ratio of the compound of the formula (v) to the amount of chloroacetyl chloride or chloroacetic anhydride and the basic catalyst F to be fed is 1: 1.0 to 8.0: 1.0 to 3.0.
Further, in the step (3), the amount of the organic solvent G is 11 to 100mL/G based on the mass of the compound represented by the formula (V).
Further, the specific recommended step (3) of the present invention is performed as follows: dropwise adding chloroacetyl chloride or chloroacetic anhydride organic solvent G solution into the compound shown in the formula (V) and the organic solvent G solution of the basic catalyst F at-10 ℃ or the compound shown in the formula (V) and the basic catalyst F, reacting for 3-12 hours at-10-50 ℃, and carrying out aftertreatment on the obtained reaction solution A to obtain the compound shown in the formula (VI); the volume consumption of the organic solvent for dissolving the chloroacetyl chloride or the chloroacetic anhydride does not influence the invention, and the total consumption of the organic solvent G is 11-100 mL/G based on the mass of the compound shown in the formula (V). The total amount of the organic solvent G is the total volume of the organic solvent G in which the basic catalyst F and the compound represented by the formula (V) are dissolved and the organic solvent G in which chloroacetyl chloride or chloroacetic anhydride is dissolved.
Further, the method for post-treating the reaction solution A in the step (3) of the present invention comprises: after the reaction is completed, filtering the reaction solution, evaporating the solvent from the filtrate, dissolving the concentrate with an organic solvent H to obtain a dissolved solution, adding column chromatography silica gel of which the weight is 1.0-2.0 times that of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture with the organic solvent H according to a volume ratio of 1: taking a mixed solution of petroleum ether and ethyl acetate of 0.1-10 as an eluent, collecting an effluent containing a target component (preferably, ethyl acetate/petroleum ether is 1: 1(v/v) is taken as a developing agent for tracking detection, collecting the target component, preferably, collecting a component with an Rf value of 0.5), concentrating under reduced pressure, and drying (preferably, drying at 50 ℃) to obtain a compound shown in a formula (VI); the organic solvent H is one of the following: ethanol, chloroform, tetrahydrofuran or ethyl acetate. The organic solvent H is used in an amount capable of dissolving the residue.
Further, in the step (4), the ratio of the amount of the compound represented by the formula (vi) to the amounts of the o-toluidine and the basic catalyst K to be charged is 1.0: 0.8 to 8.0: 1.0 to 8.0.
Further, in the step (4), the amount of the organic solvent J is 10-60 mL/g based on the mass of the compound represented by the formula (VI).
Further, the method for post-treating the reaction solution B in the step (4) of the present invention comprises: after the reaction is completed, evaporating the solvent from the reaction solution, dissolving the concentrate with an organic solvent M to obtain a dissolved solution, adding column chromatography silica gel of which the weight is 1.0-2.0 times that of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture with the organic solvent M in a volume ratio of 1: taking a mixed solution of petroleum ether and ethyl acetate of 0.1-10 as an eluent, collecting an effluent containing a target component (preferably, ethyl acetate/petroleum ether is 1: 1(v/v) is taken as a developing agent for tracking detection, collecting the target component, preferably, collecting a component with an Rf value of 0.5), concentrating under reduced pressure, and drying (preferably, drying at 50 ℃) to obtain the compound shown in the formula (I); the organic solvent M is one of the following: ethanol, chloroform, tetrahydrofuran or ethyl acetate. The organic solvent M is used in an amount capable of dissolving the residue.
In a third aspect, the invention also relates to an application of the 6- (2- (o-toluidine) acetamido) quinazoline compound shown in the formula (I) in preparing a medicament for preventing or treating tumors, in particular to an application in preparing a medicament for preventing or treating human breast cancer.
Preferably, the medicament is a medicament for inhibiting the activity of the human breast cancer cell line MCF-7. The compound (I) provided by the invention has a good inhibition effect on human breast cancer cell strain MCF-7.
The 6- (2- (o-toluidine) acetamido) quinazoline compound shown in the formula (I) also has a remarkable inhibiting effect on a human lung cancer cell strain A-549, a human promyelocytic leukemia cell strain HL-60 or a human cervical cancer cell strain Siha, and can be applied to preparation of medicines for preventing or treating human lung cancer, human leukemia or human cervical cancer.
The organic solvents A, C, D, G, H, J and M are organic solvents, so that the organic solvents used for distinguishing different steps are named for convenience, and letters have no meanings; the catalyst B, the reducing agent E, the catalyst F and the catalyst K are all catalysts, so that the catalysts used in different steps are named for convenience of distinguishing, and letters have no meanings; the post-treatment A and the post-treatment B are both post-treatments, so that the post-treatments used for distinguishing different steps are named for convenience, and the letters have no meanings.
The invention has the following beneficial effects: (1) the 6- (2- (o-toluidino) acetamido) quinazoline compound (I) has good anticancer activity, and is expected to be applied to the preparation of medicaments for preventing or treating tumor diseases, in particular to the application of medicaments for preventing human breast cancer, human lung cancer, human leukemia or human cervical cancer; (2) the preparation method of the 6- (2- (o-toluidine) acetamido) quinazoline compound (I) provided by the invention is simple and easy to operate, has easily available raw materials and lower production cost, and is suitable for practical use.
(IV) detailed description of the preferred embodiments
The invention is further illustrated by reference to specific examples, which are intended to illustrate the invention, but not to limit it in any way.
The compound (II) can be prepared by the method described in Weinstock, J.et al.J.Med.chem.,1986, 29(11), 2315-2325. Preparation of 4-chloro-6-nitroquinazoline (III) according to the method of Fernandes, C.et al bioorg.Med.chem.,2007,15(12), 3974-3980.
The palladium-carbon (Pd/C) model D5H5A used in the embodiment of the invention is purchased from Shaanxi Rui New Material Co., Ltd.
Example 1: preparation of 6-nitroquinazoline (IV)
1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 2.39 g (6.87mmol) of compound (II), 3.62 g (45.76mmol) of pyridine and 12 ml of chloroform were sequentially added to a 50ml reaction flask, heated to 40 ℃ and subjected to TLC follow-up detection (developing solvent ethyl acetate/petroleum ether: 1: 3(v/v)), and the reaction was stopped after stirring for 10 hours, the solvent was distilled off from the reaction solution, and 10 ml of acetic acid was added to the resulting concentrateDissolving the ethyl ester to obtain a dissolved solution, adding 3.0 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating to remove the solvent to obtain a mixture of a dried concentrate and the silica gel, loading the mixture into a column, and then mixing the mixture according to a volume ratio of 1: eluting with a mixed solution of petroleum ether and ethyl acetate as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 85.1%, and the melting point is 164-166 ℃.1H NMR(500MHz,CDCl3):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。
Example 2: preparation of 6-nitroquinazoline (IV)
Sequentially adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 1.59 g (4.57mmol) of compound (II), 1.67 g (22.83mmol) of diethylamine and 60ml of toluene into a 100ml three-neck flask, heating to 100 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 2 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of ethanol into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 2.5 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography by using a volume ratio of 1: eluting with a petroleum ether/ethyl acetate mixed solution of 5 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 72.6%, and the melting point is 164-166 ℃.1H NMR and IR were performed simultaneouslyExample 1.
Example 3: preparation of 6-nitroquinazoline (IV)
Sequentially adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 1.99 g (5.72mmol) of compound (II), 0.58 g (5.73mmol) of triethylamine and 60ml of ethanol into a 100ml three-neck flask, heating to 60 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 8 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of chloroform into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 2.5 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography by using a volume ratio of 10: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 77.2%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 4: preparation of 6-nitroquinazoline (IV)
Adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 2.20 g (6.32mmol) of compound (II), 1.40 g (11.46mmol) of 4-dimethylaminopyridine and 60ml of isopropanol into a 100ml three-neck flask, stirring at room temperature and 25 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether ═ 1: 3(v/v)), reacting for 12 hours, closing the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of tetrahydrofuran into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 4.0 g of column chromatography silica gel (300-400 mesh silica gel) into the dissolved solution, mixing uniformly, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography on the mixture in a volume ratio of 5: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, detecting by TLC (developing solvent ethyl acetate/petroleum ether is 1: 3(v/v)), collecting eluate containing compound shown in formula (IV) (Rf value is 0.5) according to TLC detection, concentrating the collected solution, and drying at 50 deg.C to obtain light yellow solid shown in formula (IV)The yield of the product is 80.2%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 5: preparation of 6-nitroquinazoline (IV)
Adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 1.79 g (5.15mmol) of compound (II), 1.04 g (8.58mmol) of N, N-dimethylaniline and 12 ml of N, N-dimethylformamide into a 50ml reaction bottle, heating to 120 ℃, performing TLC tracking detection (ethyl acetate/petroleum ether is 1: 3(v/v)) and stirring for 0.5 hour, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of tetrahydrofuran into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 5.0 g of silica gel (300-400 mesh silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then filling the mixture into the column according to the volume ratio of 1: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 3(v/v)), collecting an eluent containing the compound shown in the formula (IV) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 89.6%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 6: preparation of 6-nitroquinazoline (IV)
Adding 1.20 g (5.73mmol) of 4-chloro-6-nitroquinazoline (III) and 2.39 g (6.87mmol) of compound (II), 3.62 g (45.76mmol) of pyridine and 20 ml of propanol into a 50ml reaction bottle, heating to 40 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 3(v/v)), stirring for 10 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of ethyl acetate into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 3.5 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography by using a volume ratio of 1: eluting with petroleum ether/ethyl acetate mixed solution of 1 as eluent, detecting by TLC (developing solvent ethyl acetate/petroleum ether is 1: 3(v/v)), and collecting the compound containing formula (IV) according to TLC detectionAnd (3) eluting the eluent (the Rf value is 0.5), concentrating the collected solution, and drying at 50 ℃ to obtain a light yellow solid product shown in the formula (IV), wherein the yield is 78.3%, and the melting point is 164-166 ℃.1H NMR and IR were the same as in example 1.
Example 7: preparation of 6-aminoquinazolines (V)
0.40 g (0.77mmol) of 6-nitroquinazoline (IV), 0.40 g (6.34mmol) of ammonium formate, 0.04 g of 5% Pd/C and 4.0 ml of chloroform prepared in the method of example 1 are sequentially added into a reaction bottle, stirred at the room temperature of 25 ℃, subjected to TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), reacted for 12 hours, filtered, concentrated, and dried in vacuum at the temperature of 25 ℃ to obtain a light yellow solid product, namely 6-aminoquinazoline (V), with the yield of 98.2% and the melting point of 122-126 ℃.1H NMR(500MHz,CDCl3):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。
Example 8: preparation of 6-aminoquinazolines (V)
0.40 g (0.77mmol) of 6-nitroquinazoline (IV), 1.20 g (19.18mmol) of 80 wt% hydrazine hydrate, 0.20 g of 5% Pd/C and 20.0 ml of toluene prepared by the method in example 2 are sequentially added into a 50ml reaction bottle, heated to 100 ℃, subjected to TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirred for 0.5 hour, cooled and filtered, the filtrate is concentrated, and vacuum-dried at 25 ℃ to obtain a light yellow solid product, namely 6-aminoquinazoline (V), with the yield of 100.0% and the melting point of 122-126 ℃.1H NMR and IR were the same as in example 7.
Example 9: preparation of 6-aminoquinazolines (V)
0.40 g (0.77mmol) of 6-nitroquinazoline (IV), 0.08 g of concentrated hydrochloric acid (mass concentration is 36-38%), 0.40 g of iron powder and 20.0 ml of methanol prepared in the method of example 3 are sequentially added into a 50ml reaction bottle, heated to 40 ℃, subjected to TLC tracking detection (ethyl acetate/petroleum ether is used as a developing agent: 1(v/v)), and stirred for reactionCooling and filtering the mixture for 8 hours, concentrating the filtrate, and drying the filtrate in vacuum at 25 ℃ to obtain a light yellow solid product 6-aminoquinazoline (V), wherein the yield is 94.1 percent, and the melting point is 122-126 ℃.1H NMR and IR were the same as in example 7.
Example 10: preparation of 6-aminoquinazolines (V)
0.40 g (0.77mmol) of 6-nitroquinazoline (IV), 0.40 g of acetic acid, 1.20 g of iron powder and 20.0 ml of isopropanol prepared in the method of example 4 are sequentially added into a 50ml reaction bottle, heated to 80 ℃, subjected to TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirred for reaction for 3 hours, cooled and filtered, and concentrated and dried in vacuum at 25 ℃ to obtain a light yellow solid product, namely 6-aminoquinazoline (V), wherein the yield is 97.5% and the melting point is 122-126 ℃.1H NMR and IR were the same as in example 7.
Example 11: preparation of chloroacetamidoquinazoline (VI)
Adding 0.27 g (0.55mmol) of 6-aminoquinazoline (V), 0.13 g (1.64mmol) of pyridine and 3 ml of tetrahydrofuran prepared in the method of example 7 into a reaction bottle, dropwise adding 0.497 g (4.40mmol) of chloroacetyl chloride under the condition of stirring at-10 ℃, after dropwise adding, performing TLC tracking detection (the developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 12 hours at-10 ℃, filtering, evaporating the filtrate to remove the solvent, adding 10 ml of ethyl acetate into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.60 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating to remove the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography on the mixture in a volume ratio of 1: eluting by using a petroleum ether/ethyl acetate mixed solution of 10 as an eluent, tracking and detecting by TLC (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (VI) according to TLC detection (the Rf value is 0.5), concentrating the collected liquid, and drying at 50 ℃ to obtain the chloracetyl amido quinazoline yellow solid shown in the formula (VI), wherein the yield is 95.6%, and the melting point is 255-258 ℃.1H NMR(500MHz,CDCl3):3.26-3.33(m,1H),3.54(dt,J=3.7,15.4Hz,1H),3.74(s,3H),3.81-3.82(m,7H),3.95-4.05(m,2H),4.28(s,2H),4.64(dd,J=8.2,14.4Hz,1H),5.24(t,J=8.8Hz,1H).6.64(s,1H),6.88(d,J=8.8Hz,2H),7.07(d,J=8.7Hz,2H),7.53(dd,J=2.3,9.0Hz,1H),7.83(d,J=9.0Hz,1H),8.54(s,1H),8.60(s,1H),8.69(d,J=2.2Hz,1H)。IR(KBr,cm-1)ν:3396,2998,2937,2835,1694,1557,1525,1510,1489,1463,1349,1249,1179,1036,840。
Example 12: preparation of chloroacetamidoquinazoline (VI)
Adding 0.27 g (0.55mmol) of 6-aminoquinazoline (V), 0.04 g (0.55mmol) of diethylamine and 10.0 ml of chloroform prepared in the method of example 8 into a 50ml reaction bottle, dropwise adding a mixed solution of 0.07 g (0.55mmol) of chloroacetyl chloride and 5.0 ml of chloroform under the condition of stirring at 10 ℃, after dropwise adding, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether ═ 1: 1(v/v)), reacting for 8 hours at 10 ℃, filtering, evaporating the solvent from the filtrate, adding 20 ml of ethanol into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.26 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, mixing uniformly, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then filling the mixture into the column at a volume ratio of 1: and (3) eluting by using a petroleum ether/ethyl acetate mixed solution of 5 as an eluent, tracking and detecting by TLC (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent (the Rf value is 0.5) containing the compound shown in the formula (VI) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a chloroacetylamidoquinazoline yellow solid shown in the formula (VI), wherein the yield is 83.4%, and the melting point is 255-258 ℃.1H NMR and IR were the same as in example 11.
Example 13: preparation of chloroacetamidoquinazoline (VI)
Adding 0.27 g (0.55mmol) of 6-aminoquinazoline (V), 0.111 g (1.10mmol) of triethylamine and 10.0 ml of ethyl acetate prepared in the method of example 9 into a 50ml reaction bottle, dropwise adding 0.14 g (1.09mmol) of chloroacetyl chloride and 5.0 ml of ethyl acetate solution under the condition of stirring at 0 ℃, after dropwise adding, performing TLC tracking detection (the developing agent is ethyl acetate/petroleum ether is 1: 1), reacting for 6 hours at 25 ℃, filtering, evaporating the filtrate to remove the solvent, adding 20 ml of chloroform into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.30 g of silica gel (300-400 mesh silica gel) into the dissolved solution, mixing uniformly, evaporating to remove the solvent to obtain a mixture of dried concentrate and silica gel, and mixing the mixture to obtain a mixture of the dried concentrate and the silica gel, and performing column chromatography on the mixture to obtain a mixtureLoading the column, and then mixing the column with the volume ratio of 10: eluting by using a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (VI) according to TLC detection (the Rf value is 0.5), concentrating the collected liquid, and drying at 50 ℃ to obtain a chloroacetylamidoquinazoline yellow solid shown in the formula (VI), wherein the yield is 70.5%, and the melting point is 255-258 ℃.1H NMR and IR were the same as in example 11.
Example 14: preparation of chloroacetamidoquinazoline (VI)
0.27 g (0.55mmol) of 6-aminoquinazoline (v), 0.067 g (0.55mmol) of 4-dimethylaminopyridine and 20.0 ml of toluene prepared in example 10 are sequentially added to a 50ml reaction flask, a solution of 0.376 g (2.20mmol) of chloroacetic anhydride and 7.0 ml of toluene is added dropwise under stirring at 5 ℃, the mixture is heated to 50 ℃, TLC tracking detection is carried out (the developing agent is ethyl acetate/petroleum ether is 1: 1), the mixture reacts for 3 hours, the filtrate is filtered, the solvent is distilled off, the concentrate is dissolved by adding 20 ml of tetrahydrofuran to obtain a dissolved solution, 0.40 g of silica gel (300-400 mesh column chromatography silica gel) is added to the dissolved solution, the mixture is uniformly mixed, the solvent is distilled off to obtain a mixture of dried concentrate and silica gel, the mixture is filled into a column, and then the volume ratio of the mixture is 5: eluting by using a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (VI) according to TLC detection (the Rf value is 0.5), concentrating the collected liquid, and drying at 50 ℃ to obtain a chloroacetylamidoquinazoline yellow solid shown in the formula (VI), wherein the yield is 85.3%, and the melting point is 255-258 ℃.1H NMR and IR were the same as in example 11.
Example 15: preparation of chloroacetamidoquinazoline (VI)
0.27 g (0.55mmol) of 6-aminoquinazoline (V), 0.213 g (1.65mmol) of quinoline and 15.0 ml of benzene prepared in example 7 are added in sequence to a 50ml reaction flask, a solution of 0.28 g (2.19mmol) of chloroacetyl chloride and 5.0 ml of benzene are added dropwise with stirring at-10 ℃ after the dropwise addition, followed by TLC detection (the developing solvent is ethyl acetate/petroleum ether ═ 1: 1), the reaction is carried out at-10 ℃ for 12 hours, the filtrate is filtered, the solvent is distilled off, and concentratedAnd (2) adding 20 ml of tetrahydrofuran into the condensate to dissolve the condensate to obtain a dissolved solution, adding 0.40 g of column chromatography silica gel (300-400-mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture according to a volume ratio of 1: eluting by using a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (VI) according to TLC detection (the Rf value is 0.5), concentrating the collected liquid, and drying at 50 ℃ to obtain a chloroacetylamidoquinazoline yellow solid shown in the formula (VI), wherein the yield is 82.1%, and the melting point is 255-258 ℃.1H NMR and IR were the same as in example 11.
Example 16: preparation of chloroacetamidoquinazoline (VI)
Adding 0.27 g (0.55mmol) of 6-aminoquinazoline (V), 0.164 g (1.10mmol) of 4-pyrrolidinylpyridine and 15.0 ml of dichloromethane prepared in the method of example 7 into a 50ml reaction bottle, dropwise adding 00.14 g (1.09mmol) of chloroacetyl chloride and 5.0 ml of dichloromethane solution under the condition of stirring at 10 ℃, after dropwise adding, performing TLC tracking detection (ethyl acetate/petroleum ether is used as a developing agent, 1: 1), reacting for 8 hours at 10 ℃, filtering, evaporating the solvent from the filtrate, adding 20 ml of ethanol into the concentrate to dissolve the concentrate to obtain a dissolved solution, adding 0.50 g of silica gel (300-400 mesh silica gel) into the dissolved solution for column chromatography, mixing uniformly, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then filling the mixture into the column at a volume ratio of 10: eluting by using a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (VI) according to TLC detection (the Rf value is 0.5), concentrating the collected liquid, and drying at 50 ℃ to obtain a chloroacetylamidoquinazoline yellow solid shown in the formula (VI), wherein the yield is 90.2%, and the melting point is 255-258 ℃.1H NMR and IR were the same as in example 11.
Example 17: preparation of 6- (2- (o-toluidino) acetamido) quinazoline (I)
3.25 g (5.73mmol) of the chloroacetamidoquinazoline (VI) prepared in example 11 were combined in succession with 0.736 g (6.87mmol) of o-toluidine, 3.626 gAdding (45.84mmol) pyridine and 32.5 ml methanol into a 50ml reaction bottle, heating to 40 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirring for 10 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 10 ml ethyl acetate into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 1.5 g column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of a dried concentrate and the silica gel, loading the mixture into a column, and then performing column chromatography by using a volume ratio of 1: eluting with a mixed solution of petroleum ether and ethyl acetate as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (I) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a yellow solid product shown in the formula (I), wherein the yield is 53.4%, and the melting point is 179-181 ℃.1H NMR(500MHz,CDCl3):2.32(s,3H),3.26-3.32(m,1H),3.55(dt,J=3.5,15.3Hz,1H),3.76(s,3H),3.81-3.82(m,7H),4.00-4.06(m,4H),4.33(t,J=5.3Hz,1H),4.65(dd,J=8.2,14.3Hz,1H),5.29(t,J=8.8Hz,1H),6.62(d,J=8.2Hz,1H),6.68(s,1H),6.84(t,J=7.3Hz,1H),6.88(d,J=8.7Hz,2H),7.09(d,J=8.7Hz,2H),7.15-7.18(m,2H),7.37(dd,J=2.2,9.0Hz,1H),7.75(d,J=8.9Hz,1H),8.57(s,1H),8.79(s,2H)。HRMS-ESI m/z:638.2527[M+H]+。13C NMR(125MHz,CDCl3):17.6,28.8,49.7,50.0,51.1,54.4,55.3,56.0,60.5,110.9,113.9,114.2,114.4,116.1,120.0,123.0,125.3,127.6,128.0,128.1,128.7,128.8,130.7,133.6,135.0,137.5,144.0,145.0,149.0,152.2,153.3,158.4,163.7,169.1。IR(KBr,cm-1)ν:2934,2831,1695,1562,1512,1487,1453,1349,1248,1036,837。
Example 18: preparation of 6- (2- (o-toluidino) acetamido) quinazoline (I)
Sequentially adding 3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared in example 12, 0.490 g (4.57mmol) of o-toluidine, 2.95 g (22.84mmol) of quinoline and 80 ml of toluene into a 100ml three-neck flask, heating to 100 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirring for 2 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of ethanol into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 2.5 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, loading the mixture into a column, and then mixing in a volume ratio of 1: eluting with a mixed solution of petroleum ether and ethyl acetate as eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting eluent containing the compound shown in the formula (I) (the Rf value is 0.5) according to TLC detection, concentrating the collected liquid, and drying at 50 ℃ to obtain a yellow solid product shown in the formula (I), wherein the yield is 52.8%, and the melting point is 179-181 ℃. The characterization was the same as example 17.
Example 19: preparation of 6- (2- (o-toluidino) acetamido) quinazoline (I)
Sequentially adding 3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared in example 13, 0.614 g (5.73mmol) of o-toluidine, 0.58 g (5.73mmol) of triethylamine and 80 ml of ethanol into a 100ml three-neck flask, heating to 60 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirring for 8 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of chloroform into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 2.5 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, loading the mixture into a column, and then performing column chromatography on the mixture according to a volume ratio of 10: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (I) (the Rf value is 0.5) according to TLC detection, concentrating a collected solution, and drying at 50 ℃ to obtain a yellow solid product shown in the formula (I), wherein the yield is 47.6%, and the melting point is 179-181 ℃. The characterization was the same as example 17.
Example 20: preparation of 6- (2- (o-toluidino) acetamido) quinazoline (I)
3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared by the method of example 14, 2.456 g (22.92mmol) of o-toluidine, 1.40 g (11.46mmol) of 4-dimethylaminopyridine and 60ml of isopropanol are sequentially added into a 100ml three-neck flask, stirred at room temperature of 25 ℃, subjected to TLC tracing detection (ethyl acetate/petroleum ether ═ 1: 1(v/v)) and reacted for 36 hours, the reaction is stopped, the solvent is distilled off from the reaction solution, 20 ml of tetrahydrofuran is added into the obtained concentrate to be dissolved to obtain a dissolved solution, 3.0 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) is added into the dissolved solution, after uniform mixing, the solvent is distilled off to obtain a mixture of dried concentrate and silica gel, the mixture is packed into a column, and then the volume ratio of the mixture is 5: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (I) (the Rf value is 0.5) according to TLC detection, concentrating a collected solution, and drying at 50 ℃ to obtain a yellow solid product shown in the formula (I), wherein the yield is 62.2%, and the melting point is 179-181 ℃. The characterization was the same as example 17.
Example 21: preparation of 6- (2- (o-toluidino) acetamido) quinazoline (I)
Sequentially adding 3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared in example 15, 0.552 g (5.15mmol) of o-toluidine, 1.04 g (8.58mmol) of N, N-xylidine and 33 ml of N, N-dimethylformamide into a 50ml reaction bottle, heating to 120 ℃, performing TLC tracking detection (ethyl acetate/petroleum ether is 1: 1(v/v)) and stirring for reaction for 0.5 hour, stopping the reaction, evaporating the reaction solution to remove the solvent, adding 20 ml of tetrahydrofuran into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 4.0 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, mixing uniformly, evaporating the solvent to obtain a mixture of a dried concentrate and the silica gel, filling the mixture into a column, and then filling the mixture into the column at a volume ratio of 1: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (I) (the Rf value is 0.5) according to TLC detection, concentrating a collected solution, and drying at 50 ℃ to obtain a yellow solid product shown in the formula (I), wherein the yield is 58.1%, and the melting point is 179-181 ℃. The characterization was the same as example 17.
Example 22: preparation of 6- (2- (o-toluidino) acetamido) quinazoline (I)
Sequentially adding 3.25 g (5.73mmol) of chloroacetamidoquinazoline (VI) prepared in example 16, 4.912 g (45.84mmol) of o-toluidine, 3.626 g (45.84mmol) of pyridine and 195 ml of propanol into a 500 ml reaction bottle, heating to 40 ℃, performing TLC tracking detection (a developing agent is ethyl acetate/petroleum ether is 1: 1(v/v)), stirring for 10 hours, stopping the reaction, evaporating the reaction liquid to remove the solvent, adding 20 ml of ethyl acetate into the obtained concentrate to dissolve the concentrate to obtain a dissolved solution, adding 6.0 g of column chromatography silica gel (300-400 mesh column chromatography silica gel) into the dissolved solution, uniformly mixing, evaporating the solvent to obtain a mixture of dried concentrate and silica gel, filling the mixture into a column, and then performing column chromatography by using a volume ratio of 1: eluting with a petroleum ether/ethyl acetate mixed solution of 1 as an eluent, tracking and detecting by TLC (the developing solvent is ethyl acetate/petroleum ether is 1: 1(v/v)), collecting an eluent containing the compound shown in the formula (I) (the Rf value is 0.5) according to TLC detection, concentrating a collected solution, and drying at 50 ℃ to obtain a yellow solid product shown in the formula (I), wherein the yield is 65.3%, and the melting point is 179-181 ℃. The characterization was the same as example 17.
Example 23: in vitro test for anti-cancer Activity
(1) The prepared compound (I) is subjected to a human breast cancer cell line MCF-7 bioactivity test.
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: human breast cancer cell strain MCF-7. The tumor cell strain is purchased from cell banks of Shanghai Life sciences of Chinese academy of sciences.
The experimental procedure was as follows:
(a) preparation of samples: for soluble samples, each 1mg was dissolved in 40. mu.L DMSO, 2. mu.L was diluted with 1000. mu.L of medium to a concentration of 100. mu.g/mL, and then serially diluted with the culture medium to the use concentration.
(b) Culture of cells
Preparation of culture medium, each 1000mL of DMEM culture medium (Gibco) contains 80 ten thousand units of penicillin, 1.0g of streptomycin and 10% inactivated fetal bovine serum.
② cultivation of cells, inoculating tumor cells into culture medium, standing at 37 deg.C and 5% CO2Culturing in an incubator, and carrying out passage for 3-5 days.
Measuring the inhibition of the sample on the growth of tumor cells
The 10 th generation cells were digested with EDTA-pancreatin digest and diluted to 1 × 10 with medium6Perml, 100. mu.L/well in 96-well cell culture plates, 37 ℃ 5% CO2Culturing in an incubator. After 24h of inoculation, 100. mu.L of 100. mu.L/well, 10. mu.g/mL and 1. mu.g/mL samples diluted with medium were added to each well at 3 concentrations, and the mixture was incubated at 37 ℃ with 5% CO2The culture was performed in an incubator, 5mg/mL MTT was added to the cell culture wells after 72h, 10. mu.L per well, incubated at 37 ℃ for 3h, DMSO was added, 150. mu.L per well, shaken with a shaker, and formazan was completely solubilized and colorimetric with a microplate reader at a wavelength of 570 nm. Using cells cultured in the same DMSO concentration medium without the sample under the same conditions as a control, the IC of the sample on tumor cell growth was calculated50。
The results of the test are shown in table 1:
TABLE 1 inhibitory Effect of Compound (I) on the growth of cancer cell line MCF-7
(2) Quinazoline compounds (a), (b) and (c) were synthesized according to example 11 by substituting chloroacetyl chloride with 4-iodobenzoyl chloride, 3-methoxybenzoyl chloride or cinnamoyl chloride, respectively, and following the following structures:
the prepared quinazoline compounds (a), (b) and (c) are subjected to a biological activity test on a human breast cancer cell line MCF-7 according to the method, and the test results show that the quinazoline compounds (a), (b) and (c) have no obvious inhibition effect on the human breast cancer cell line MCF-7, and the compounds (a), (b) and (c) have far lower anticancer activity on the human breast cancer cell line MCF-7 than the compound (I). The specific results are shown in table 2:
TABLE 2 inhibitory Effect of Compounds (a), (b) and (c) on the growth of cancer cell line MCF-7
The anti-cancer activity in vitro test experiment shows that: the other 3 compounds (a), (b) and (c) with similar structures have no obvious inhibition effect on the growth of the human breast cancer cell strain MCF-7. The compound (I) has obvious inhibition effect on the growth of human breast cancer cell strains MCF-7, and is obviously superior to the compounds (a), (b) and (c).
(3) Quinazoline compounds (d), (e) and (f) were synthesized in the same manner as in example 17 except that o-toluidine was replaced with 3, 4-dimethylaniline, 3, 4-dimethoxyaniline or di-n-propylamine, respectively, according to example 17, and the structures thereof were as follows:
the prepared quinazoline compounds (d), (e) and (f) are subjected to a biological activity test of a human breast cancer cell line MCF-7 according to the method, and the results show that the quinazoline compounds (d), (e) and (f) have far lower anticancer activity than the compound (I) on the human breast cancer cell line MCF-7. Specific results are shown in table 3:
TABLE 3 inhibitory Effect of Compounds (d), (e) and (f) on the growth of cancer cell line MCF-7
(4) Referring to the literature (Rao, G. -W.et al. ChemMedChem,2013,8(6),928-933), 4-chloroquinazoline was prepared, 4-chloro-6-nitroquinazoline was substituted with 4-chloroquinazoline according to example 1, and the other operations were the same as in example 1 to synthesize a quinazoline compound (g) having the following structure:
the prepared quinazoline compound (g) is subjected to a biological activity test of a human breast cancer cell line MCF-7 according to the method, and the test result shows that the quinazoline compound (g) has far lower anticancer activity on the human breast cancer cell line MCF-7 than the compound (I). Specific results are shown in table 4:
TABLE 4 inhibitory Effect of Compound (g) on the growth of cancer cell line MCF-7
Example 24: in vitro test for anti-cancer Activity
(1) The prepared compounds (I), (IV) and (VI) are tested for the biological activity of a human lung cancer cell strain A-549.
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: human lung cancer cell strain A-549. The tumor cell strain is purchased from cell banks of Shanghai Life sciences of Chinese academy of sciences.
The experimental procedure was as follows:
(a) preparation of samples: for soluble samples, each 1mg was dissolved in 40. mu.L DMSO, 2. mu.L was diluted with 1000. mu.L of medium to a concentration of 100. mu.g/mL, and then serially diluted with the culture medium to the use concentration.
(b) Culture of cells
Preparation of culture medium, each 1000mL of DMEM culture medium (Gibco) contains 80 ten thousand units of penicillin, 1.0g of streptomycin and 10% inactivated fetal bovine serum.
② cultivation of cells, inoculating tumor cells into culture medium, standing at 37 deg.C and 5% CO2Culturing in an incubator, and carrying out passage for 3-5 days.
Measuring the inhibition of the sample on the growth of tumor cells
The 2 nd generation cells were digested with EDTA-pancreatin digest and diluted to 1 × 10 with medium6Perml, 100. mu.L/well in 96-well cell culture plates, 37 ℃ 5% CO2Culturing in an incubator. After 24h of inoculation, 100. mu.L of 100. mu.L/well, 10. mu.g/mL and 1. mu.g/mL samples diluted with medium were added to each well at 3 concentrations, and the mixture was incubated at 37 ℃ with 5% CO2Culturing in incubator, adding 5mg/mL MTT into cell culture well after 72 hr, placing 10 μ L MTT into each well, and standing at 37 deg.CIncubate for 3h, add DMSO, 150 μ L per well, shake with a shaker, fully solubilize the formazan, and color compare with a microplate reader at a wavelength of 570 nm. Using cells cultured in the same DMSO concentration medium without sample under the same conditions as a control, the IC of the sample on tumor cell growth was calculated50。
The results of the test are shown in table 5:
TABLE 5 inhibitory Effect of Compounds (I), (IV) and (VI) on the growth of cancer cell line A-549
(2) Quinazoline compounds (a), (b) and (c) were synthesized according to example 11 by substituting chloroacetyl chloride with 4-iodobenzoyl chloride, 3-methoxybenzoyl chloride or cinnamoyl chloride, respectively, and following the following structures:
the prepared quinazoline compounds (a), (b) and (c) are subjected to a biological activity test of a human lung cancer cell strain A-549 according to the method, and test results show that the quinazoline compounds (a), (b) and (c) have no obvious inhibition effect on the human lung cancer cell strain A-549, and the compounds (a), (b) and (c) have far lower anti-cancer activity than the compound (I) on the human lung cancer cell strain A-549. Specific results are shown in table 6:
TABLE 6 inhibitory Effect of Compounds (a), (b) and (c) on the growth of cancer cell line A-549
The anti-cancer activity in vitro test experiment shows that: the other 3 compounds (a), (b) and (c) with similar structures have no obvious inhibition effect on the growth of the human lung cancer cell strain A-549. The compound (I) has obvious inhibition effect on the growth of a human lung cancer cell strain A-549, and is obviously superior to the compounds (a), (b) and (c).
(3) Quinazoline compounds (d), (e) and (f) were synthesized in the same manner as in example 17 except that o-toluidine was replaced with 3, 4-dimethylaniline, 3, 4-dimethoxyaniline or di-n-propylamine, respectively, according to example 17, and the structures thereof were as follows:
the prepared quinazoline compounds (d), (e) and (f) are subjected to a biological activity test of a human lung cancer cell strain A-549 according to the method, and the results show that the anticancer activity of the quinazoline compounds (d), (e) and (f) on the human lung cancer cell strain A-549 is far lower than that of the compound (I). Specific results are shown in table 7:
TABLE 7 inhibitory Effect of Compounds (d), (e) and (f) on the growth of cancer cell line A-549
(4) Referring to the literature (Rao, G. -W.et al. ChemMedChem,2013,8(6),928-933), 4-chloroquinazoline was prepared, 4-chloro-6-nitroquinazoline was substituted with 4-chloroquinazoline according to example 1, and the other operations were the same as in example 1 to synthesize a quinazoline compound (g) having the following structure:
the prepared quinazoline compound (g) is subjected to a biological activity test of a human lung cancer cell strain A-549 according to the method, and a test result shows that the anticancer activity of the quinazoline compound (g) on the human lung cancer cell strain A-549 is far lower than that of the compound (I). Specific results are shown in table 8:
TABLE 8 inhibitory Effect of Compound (g) on the growth of cancer cell line A-549
Example 25: in vitro test for anti-cancer Activity
(1) The prepared compound (I) is subjected to biological activity test of a human promyelocytic leukemia cell strain HL-60.
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: human promyelocytic leukemia cell line HL-60. The tumor cell strain is purchased from cell banks of Shanghai Life sciences of Chinese academy of sciences.
The experimental procedure was as follows:
(a) preparation of samples: for soluble samples, each 1mg was dissolved in 40. mu.L DMSO, 2. mu.L was diluted with 1000. mu.L of medium to a concentration of 100. mu.g/mL, and then serially diluted with the culture medium to the use concentration.
(b) Culture of cells
Preparation of culture medium, each 1000mL of DMEM culture medium (Gibco) contains 80 ten thousand units of penicillin, 1.0g of streptomycin and 10% inactivated fetal bovine serum.
② cultivation of cells, inoculating tumor cells into culture medium, standing at 37 deg.C and 5% CO2Culturing in an incubator, and carrying out passage for 3-5 days.
Measuring the inhibition of the sample on the growth of tumor cells
The 2 nd generation cells were digested with EDTA-pancreatin digest and diluted to 1 × 10 with medium6Perml, 100. mu.L/well in 96-well cell culture plates, 37 ℃ 5% CO2Culturing in an incubator. After 24h of inoculation, 100. mu.L of 100. mu.L/well, 10. mu.g/mL and 1. mu.g/mL samples diluted with medium were added to each well at 3 concentrations, and the mixture was incubated at 37 ℃ with 5% CO2The culture was performed in an incubator, 5mg/mL MTT was added to the cell culture wells after 72h, 10. mu.L per well, incubated at 37 ℃ for 3h, DMSO was added, 150. mu.L per well, shaken with a shaker, and formazan was completely solubilized and colorimetric with a microplate reader at a wavelength of 570 nm. Using cells cultured in the same DMSO concentration medium without sample under the same conditions as a control, the IC of the sample on tumor cell growth was calculated50。
The results of the testing are shown in table 9:
TABLE 9 inhibitory Effect of Compound (I) on the growth of cancer cell line HL-60
(2) Quinazoline compounds (b) and (c) were synthesized according to example 11 by substituting chloroacetyl chloride with 3-methoxybenzoyl chloride or cinnamoyl chloride, respectively, and following structures as shown in the following, in the same manner as in example 11:
the prepared quinazoline compounds (b) and (c) are subjected to a biological activity test of a human promyelocytic leukemia cell line HL-60 according to the method, and test results show that the quinazoline compounds (b) and (c) have no obvious inhibition effect on the human promyelocytic leukemia cell line HL-60, and the anticancer activities of the compounds (b) and (c) on the human promyelocytic leukemia cell line HL-60 are far lower than that of the compound (I). Specific results are shown in table 10:
TABLE 10 inhibitory Effect of Compounds (b) and (c) on the growth of cancer cell line HL-60
The anti-cancer activity in vitro test experiment shows that: the other 2 compounds (b) and (c) with similar structures have no obvious inhibition effect on the growth of the human promyelocytic leukemia cell line HL-60. The compound (I) has obvious inhibition effect on the growth of human promyelocytic leukemia cell strain HL-60, and is obviously superior to the compounds (b) and (c).
(3) Quinazoline compounds (d), (e) and (f) were synthesized in the same manner as in example 17 except that o-toluidine was replaced with 3, 4-dimethylaniline, 3, 4-dimethoxyaniline or di-n-propylamine, respectively, according to example 17, and the structures thereof were as follows:
the biological activity of the quinazoline compounds (d), (e) and (f) prepared by the method in a human promyelocytic leukemia cell line HL-60 test proves that the anticancer activity of the quinazoline compounds (d), (e) and (f) in the human promyelocytic leukemia cell line HL-60 is far lower than that of the compound (I). Specific results are shown in table 11:
TABLE 11 inhibitory Effect of Compounds (d), (e) and (f) on the growth of cancer cell line HL-60
Example 26: in vitro test for anti-cancer Activity
(1) The prepared compound (I) is subjected to a biological activity test of a human cervical cancer cell strain Siha.
The test method comprises the following steps: tetrazolium salt reduction (MTT process).
Cell lines: human cervical cancer cell line Siha. The tumor cell strain is purchased from cell banks of Shanghai Life sciences of Chinese academy of sciences.
The experimental procedure was as follows:
(a) preparation of samples: for soluble samples, each 1mg was dissolved in 40. mu.L DMSO, 2. mu.L was diluted with 1000. mu.L of medium to a concentration of 100. mu.g/mL, and then serially diluted with the culture medium to the use concentration.
(b) Culture of cells
Preparation of culture medium, each 1000mL of DMEM culture medium (Gibco) contains 80 ten thousand units of penicillin, 1.0g of streptomycin and 10% inactivated fetal bovine serum.
② cultivation of cells, inoculating tumor cells into culture medium, standing at 37 deg.C and 5% CO2Culturing in an incubator, and carrying out passage for 3-5 days.
Measuring the inhibition of the sample on the growth of tumor cells
The 2 nd generation cells were digested with EDTA-pancreatin digest and diluted to 1 × 10 with medium6Perml, 100. mu.L/well in 96-well cell culture plates, 37 ℃ 5% CO2Culturing in an incubator. After 24h of inoculation, 100. mu.g of each diluted medium was addedsamples/mL, 10. mu.g/mL and 1. mu.g/mL, 100. mu.L per well, 3 wells per concentration, 37 ℃ 5% CO2The culture was performed in an incubator, 5mg/mL MTT was added to the cell culture wells after 72h, 10. mu.L per well, incubated at 37 ℃ for 3h, DMSO was added, 150. mu.L per well, shaken with a shaker, and formazan was completely solubilized and colorimetric with a microplate reader at a wavelength of 570 nm. Using cells cultured in the same DMSO concentration medium without sample under the same conditions as a control, the IC of the sample on tumor cell growth was calculated50. The results of the testing are shown in table 12:
TABLE 12 inhibition of growth of cancer cell lines Siha by Compound (I)
(2) Quinazoline compounds (b) and (c) were synthesized according to example 11 by substituting chloroacetyl chloride with 3-methoxybenzoyl chloride or cinnamoyl chloride, respectively, and following structures as shown in the following, in the same manner as in example 11:
the prepared quinazoline compounds (b) and (c) are subjected to a human cervical cancer cell line Siha bioactivity test according to the method, and test results show that the quinazoline compounds (b) and (c) have no obvious inhibition effect on the human cervical cancer cell line Siha, and the anticancer activities of the compounds (b) and (c) on the human cervical cancer cell line Siha are far lower than that of the compound (I). Specific results are shown in table 13:
TABLE 13 inhibitory Effect of Compounds (b) and (c) on growth of cancer cell lines Siha
The anti-cancer activity in vitro test experiment shows that: the other 2 compounds (b) and (c) with similar structures have no obvious inhibition effect on the growth of the human cervical cancer cell strain Siha. The compound (I) has obvious inhibition effect on the growth of human cervical cancer cell strains Siha, and is obviously superior to the compounds (b) and (c).
(3) Quinazoline compounds (d), (e) and (f) were synthesized in the same manner as in example 17 except that o-toluidine was replaced with 3, 4-dimethylaniline, 3, 4-dimethoxyaniline or di-n-propylamine, respectively, according to example 17, and the structures thereof were as follows:
the prepared quinazoline compounds (d), (e) and (f) are subjected to a biological activity test on human cervical cancer cell lines Siha according to the method, and the results show that the anticancer activity of the quinazoline compounds (d), (e) and (f) on the human cervical cancer cell lines Siha is far lower than that of the compound (I). Specific results are shown in table 14:
TABLE 14 inhibitory Effect of Compounds (d), (e) and (f) on growth of cancer cell line Siha
Claims (10)
2. a process for the preparation of a 6- (2- (o-toluylamino) acetamido) quinazoline compound of the formula (i) as defined in claim 1, which comprises:
(1) mixing a compound shown as a formula (II) and a compound shown as a formula (III), reacting in an organic solvent A at 25-120 ℃ under the action of a basic catalyst B, and after the reaction is completed, separating and purifying a reaction liquid to obtain a compound shown as a formula (IV); the organic solvent A is selected from one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the basic catalyst B is selected from one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate;
(2) completely reacting a compound shown in a formula (IV) in an organic solvent D under the action of a reducing agent E at 25-100 ℃, filtering a reaction solution, and drying a concentrate obtained by concentrating a filtrate under reduced pressure to obtain a compound shown in a formula (V); the organic solvent D is one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the reducing agent E is one of the following: iron powder/concentrated hydrochloric acid, iron powder/acetic acid, palladium on carbon/ammonium formate or palladium on carbon/hydrazine hydrate; the iron powder/concentrated hydrochloric acid refers to the mixing of iron powder and concentrated hydrochloric acid in any proportion, the iron powder/acetic acid refers to the mixing of iron powder and acetic acid in any proportion, the palladium carbon/ammonium formate refers to the mixing of palladium carbon and ammonium formate in any proportion, and the palladium carbon/hydrazine hydrate refers to the mixing of palladium carbon and hydrazine hydrate in any proportion;
(3) mixing a compound shown in a formula (V) with chloroacetyl chloride or chloroacetic anhydride, completely reacting in an organic solvent G at-10-50 ℃ under the action of an alkaline catalyst F, and carrying out post-treatment on a reaction solution A to obtain a compound shown in a formula (VI); the alkaline catalyst F is one of the following: pyridine, diethylamine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate; the organic solvent G is one of the following: tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, diethyl ether, acetonitrile, toluene or benzene;
(4) mixing a compound shown as a formula (VI) with o-toluidine, reacting in an organic solvent J at 25-120 ℃ under the action of a basic catalyst K, and after the reaction is completed, carrying out post-treatment B on a reaction liquid to obtain a compound shown as a formula (I); the organic solvent J is selected from one of the following: chloroform, toluene, methanol, ethanol, propanol, isopropanol, acetonitrile or N, N-dimethylformamide; the basic catalyst K is selected from one of the following: pyridine, triethylamine, quinoline, N-dimethylaniline, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine or sodium carbonate.
3. The method of claim 2, wherein: the ratio of the compound represented by the formula (III) to the compound represented by the formula (II) and the amount of the charged substance of the basic catalyst B in the step (1) is 1.0: 0.8 to 1.2: 1.0 to 8.0; the dosage of the organic solvent A is 10-50 mL/g based on the mass of the compound shown in the formula (III).
4. The method of claim 2, wherein: the method for separating and purifying the reaction liquid in the step (1) comprises the following steps: after the reaction is completed, evaporating the solvent from the reaction solution, dissolving the concentrate with an organic solvent C to obtain a dissolved solution, adding column chromatography silica gel of which the weight is 1.0-2.0 times that of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture with the organic solvent C in a volume ratio of 1: taking a mixed solution of petroleum ether and ethyl acetate of 0.1-10 as an eluent, collecting an effluent containing a target component, concentrating under reduced pressure, and drying to obtain a compound shown as a formula (IV); the organic solvent C is one of the following solvents: ethanol, chloroform, tetrahydrofuran or ethyl acetate.
5. The method of claim 2, wherein: in the step (2), when the reducing agent E is iron powder/concentrated hydrochloric acid or iron powder/acetic acid, the feeding mass ratio of the compound shown in the formula (IV) to the iron powder, concentrated hydrochloric acid or acetic acid in the reducing agent E is 1.0: 1.0-3.0: 0.2-1.0; when the reducing agent E is palladium carbon/ammonium formate or palladium carbon/hydrazine hydrate, the feeding mass ratio of the compound shown in the formula (IV) to the palladium carbon, ammonium formate or hydrazine hydrate in the reducing agent E is 1.0: 0.1-0.5: 1.0-3.0.
6. The method of claim 2, wherein: the ratio of the compound of the formula (V) to chloroacetyl chloride or chloroacetic anhydride and the basic catalyst F in the feeding substances in the step (3) is 1: 1.0-8.0: 1.0-3.0; the dosage of the organic solvent G is 11-100 mL/G based on the mass of the compound shown in the formula (V).
7. The method of claim 2, wherein: the method for post-treating the reaction solution A in the step (3) comprises the following steps: filtering the reaction solution, evaporating the solvent from the filtrate, dissolving the concentrate with an organic solvent H to obtain a dissolved solution, adding column chromatography silica gel of which the weight is 1.0-2.0 times that of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture with the silica gel in a volume ratio of 1: taking a mixed solution of petroleum ether and ethyl acetate of 0.1-10 as an eluent, collecting an effluent containing a target component, concentrating under reduced pressure, and drying to obtain a compound shown in a formula (I); the organic solvent H is one of the following: ethanol, chloroform, tetrahydrofuran or ethyl acetate.
8. The method of claim 2, wherein: in the step (4), the ratio of the compound represented by the formula (VI) to the amounts of the o-toluidine and the basic catalyst K fed is 1.0: 0.8 to 8.0: 1.0 to 8.0; the dosage of the organic solvent J is 10-60 mL/g based on the mass of the compound shown in the formula (VI);
the method for post-treating the reaction solution B comprises the following steps: after the reaction is completed, evaporating the solvent from the reaction solution, dissolving the concentrate with an organic solvent M to obtain a dissolved solution, adding column chromatography silica gel of which the weight is 1.0-2.0 times that of the concentrate into the dissolved solution, uniformly mixing, evaporating the solvent, drying to obtain a mixture of the concentrate and the silica gel, filling the mixture into a column, and then mixing the mixture with the organic solvent M in a volume ratio of 1: taking a mixed solution of petroleum ether and ethyl acetate of 0.1-10 as an eluent, collecting an effluent containing a target component, concentrating under reduced pressure, and drying to obtain a compound shown in a formula (I); the organic solvent M is one of the following: ethanol, chloroform, tetrahydrofuran or ethyl acetate.
9. The use of a 6- (2- (o-toluylamino) acetamido) quinazoline compound of the formula (i) as defined in claim 1 in the manufacture of a medicament for the prophylaxis or treatment of human breast cancer.
10. The use according to claim 9, wherein the medicament is a medicament having the activity of inhibiting the activity of human breast cancer cell line MCF-7.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810069794.5A CN108250185B (en) | 2018-01-24 | 2018-01-24 | 6- (2- (o-toluidine amino) acetamido) quinazoline compound, preparation and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810069794.5A CN108250185B (en) | 2018-01-24 | 2018-01-24 | 6- (2- (o-toluidine amino) acetamido) quinazoline compound, preparation and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN108250185A CN108250185A (en) | 2018-07-06 |
CN108250185B true CN108250185B (en) | 2020-08-21 |
Family
ID=62742182
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810069794.5A Active CN108250185B (en) | 2018-01-24 | 2018-01-24 | 6- (2- (o-toluidine amino) acetamido) quinazoline compound, preparation and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108250185B (en) |
Citations (3)
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 |
CN1141633A (en) * | 1994-02-23 | 1997-01-29 | 辉瑞大药厂 | 4-heterocyclyl-substituted Quinazoline derivatives, method for prepn. of same and the use as anti-cancer agent |
CN101678019A (en) * | 2007-06-08 | 2010-03-24 | 詹森药业有限公司 | piperidine/piperazine derivatives |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9508565D0 (en) * | 1995-04-27 | 1995-06-14 | Zeneca Ltd | Quiazoline derivative |
-
2018
- 2018-01-24 CN CN201810069794.5A patent/CN108250185B/en active Active
Patent Citations (3)
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 |
CN1141633A (en) * | 1994-02-23 | 1997-01-29 | 辉瑞大药厂 | 4-heterocyclyl-substituted Quinazoline derivatives, method for prepn. of same and the use as anti-cancer agent |
CN101678019A (en) * | 2007-06-08 | 2010-03-24 | 詹森药业有限公司 | piperidine/piperazine derivatives |
Also Published As
Publication number | Publication date |
---|---|
CN108250185A (en) | 2018-07-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN108017621B (en) | Morpholinyl acetamido dimethoxy benzo [ d ] aza-based quinazoline compound and preparation and application thereof | |
CN108078994B (en) | Application of 6- (2-morpholinyl acetamido) quinazoline compound in preparation of medicine for treating lung cancer | |
CN108125961B (en) | Application of morpholinyl acetamido methoxyphenyl benzazepinyl quinazoline compound in preparation of drugs for treating leukemia | |
CN108042546B (en) | Application of morpholinyl acetamidobenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating cervical cancer | |
CN108014113B (en) | Application of butyrylamidodimethoxybenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating cervical cancer | |
CN109251196B (en) | Aminobenzo [ d ] aza-quinazoline compound and preparation method and application thereof | |
CN108324719B (en) | Application of o-toluidino-acetamido-methoxy-phenyl benzazepinyl-quinazoline compound in preparation of cervical cancer treatment drug | |
CN108014112B (en) | Application of o-toluidine amino acetamido benzo [ d ] aza-based quinazoline compound in preparation of drugs for treating lung cancer | |
CN108324717B (en) | Application of pivaloylchlorobenzo [ d ] aza-quinazoline compound in preparation of drugs for treating cervical cancer | |
CN108309984B (en) | Application of propionyl aminoquinazoline compound in preparation of medicine for treating cervical cancer | |
CN108329299B (en) | Butyrylamino chloro benzo [ d ] aza-based quinazoline compound, preparation and application thereof | |
CN108324718B (en) | Application of cyclohexyl methoxy formyl amino chloro benzo aza group quinazoline compound in leukemia treatment drug | |
CN108129461B (en) | Benzoylaminobenzo [ d ] aza-quinazoline compound, preparation and application thereof | |
CN108117542B (en) | Propionyl amino methoxyphenyl benzo [ d ] nitrogen hetero-pinyl quinazoline compound, preparation and application | |
CN108125962B (en) | Application of benzo [ d ] aza-quinazoline compound in preparation of drugs for treating lung cancer | |
CN108295076B (en) | Application of propionyl-amino-dimethoxy-benzo [ d ] aza-quinazoline in preparation of drugs for treating lung cancer | |
CN108276384B (en) | acetaminobenzo [ d ] azepinyl quinazoline compound and preparation and application thereof | |
CN108250185B (en) | 6- (2- (o-toluidine amino) acetamido) quinazoline compound, preparation and application thereof | |
CN108329300B (en) | Nitrobenzo [ d ] aza-quinazoline compound and preparation method and application thereof | |
CN108125958B (en) | Application of o-toluidine amino acetamido chloro benzazepine radical quinazoline compound in preparing medicament for treating leukemia | |
CN108245521B (en) | Application of dipropylaminoacetamidobenzazepinyl quinazoline compound in preparation of drugs for treating leukemia | |
CN108125959B (en) | Application of dimethoxy phenylamino acetamido quinazoline compound in preparation of drugs for treating leukemia | |
CN108078992B (en) | Application of pivaloyl-amino-dimethoxy-benzo [ d ] aza-quinazoline compound in preparation of drugs for treating leukemia | |
CN108014114B (en) | Application of chloroacetylamidoquinazoline compounds in preparation of drugs for treating lung cancer | |
CN108276386B (en) | Cyclohexyl methoxy formyl amino quinazoline compound and preparation and application thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |