CN102060875A - Novel quinazoline derivative, and preparation method and application thereof - Google Patents
Novel quinazoline derivative, and preparation method and application thereof Download PDFInfo
- Publication number
- CN102060875A CN102060875A CN 200910228308 CN200910228308A CN102060875A CN 102060875 A CN102060875 A CN 102060875A CN 200910228308 CN200910228308 CN 200910228308 CN 200910228308 A CN200910228308 A CN 200910228308A CN 102060875 A CN102060875 A CN 102060875A
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- alkyl
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- hydroxyl
- compound according
- hydrogen
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- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 16
- 125000000217 alkyl group Chemical group 0.000 claims description 16
- -1 nitro, methyl Chemical group 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 239000001257 hydrogen Substances 0.000 claims description 10
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 10
- 241001597008 Nomeidae Species 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 229910019142 PO4 Inorganic materials 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 239000010452 phosphate Substances 0.000 claims description 6
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 6
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 150000003973 alkyl amines Chemical class 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 125000000392 cycloalkenyl group Chemical group 0.000 claims description 4
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- 125000005843 halogen group Chemical group 0.000 claims description 3
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 claims description 2
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- 125000004122 cyclic group Chemical group 0.000 claims description 2
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- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.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](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.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](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940127072 targeted antineoplastic agent Drugs 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
Abstract
The invention belongs to the technical field of pharmaceutical chemistry and relates to a quinazoline derivative which is shown as a general formula (1). In the general formula (1), R1, R2, R3, A, X, m and n have meanings defined in the specifications respectively. The invention also relates to a preparation method of the derivative, physiologically acceptable salt which is prepared from the derivative, inorganic or organic acid or alkali and a medicinal composition which comprises the derivative and the physiologically acceptable salt. A compound has a valuable pharmacological property, and particularly plays a role in suppressing signal transduction caused by tyrosine kinase. The invention also relates to the application of the derivative to the treatment of diseases, particularly tumor disease and the preparation method of the derivative.
Description
Technical field
The present invention relates to novel quinazoline quinoline derivant or its pharmacy acceptable salt, these compounds have anti-tumor activity.The invention still further relates to method, the pharmaceutical composition that contains these derivatives and their application in antitumor drug of the described quinazoline derivant of preparation.
Background technology
Tumour is a series of with abnormal cells hyperplasia out of control and the disease that is diffused as feature, it is the major disease of serious threat human life health, according to statistics, about more than 790 ten thousand people of annual global tumor mortality sum, China dies from tumour person more than 160 ten thousand people every year, and increase gradually, become first cause of the death of urban population.In recent years, continuous development along with molecular biotechnology, medically verified, the cell function activity is subjected to the regulation and control of complicated signal transduction pathway (signaling pathway), the signal transduction of meticulous adjusting is the prerequisite of normal activities, and signal transduction can cause pathologic process unusually.For example, a large amount of evidences show that the generation of numerous disease is relevant with the signal transduction pathway obstacle of the growth of control cell, hyperplasia and death.Along with the research of molecular target medicine is day by day goed deep into, the breakthrough achievement in research of some of cell signalling and apoptosis, make the exploitation of specificity PTS become possibility, many kinds of this type of medicine have entered clinical study and have obtained gratifying curative effect, and cell signalling (signal transduction) has become one of important focus of biomedical sector research.
Present many synthetic compounds have the activity of inhibition epidermal growth factor recipient tyrosine kinase (EGFR-PTK), especially the most deep with quinazoline compounds research, wherein ZD1839 was used for the treatment of nonsmall-cell lung cancer (Ranson in 2003 by FDA approval listing, M.Epideraml growth factor receptor tyrosine kinase inhibitors.British J.Caneer 2004,90,2250-2255.).ZD6474 had both had the activity that suppresses EGFR, has the activity that suppresses VEGFR simultaneously, declared listing (Alessandro in 2009, M.Vandetanib (ZD6474), a Dual Inhibitor of Vascular Endothelial Growth Factor Receptor (VEGFR) and Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase:Current Status and Future DirectionsThe Oneologist2009,14,378-390.).
By to before ZD6474 clinical and the analysis and the contrast of clinical data, patent situation etc., we establish with it is lead compound, then according to reporting compound and biological activity test data, utilize the means of computer aided design (CAD), autotelic structure to ZD6474 designs, synthetic and screening, in the hope of finding novel structure, high special, active better novel targeted antineoplastic compound.
Summary of the invention
The purpose of this invention is to provide a class novel quinazoline quinoline derivant, and this compounds in antitumor drug as the purposes of activeconstituents.
The present invention be quinazoline derivant shown in general formula (I):
Wherein:
R
1Expression: hydrogen, trifluoromethyl, nitro, methyl, cyano group, C
1-4Alkyl, C
1-4Alkoxyl group, N-(C
1-4) alkylamine, halogen, hydroxyl, N, N-phenodiazine (C
1-4) alkylamine, C
1-4Alkyl sulfide, C
1-4Alkyl sulphonyl; R
1Preferably from hydrogen, trifluoromethyl, nitro, methyl, cyano group, halogen, particularly fluorine atom and bromine atoms.
R
2Expression: hydrogen, hydroxyl, C
1-4Alkyl, halo (C
1-4) alkyl, hydroxyl (C
1-4) alkyl, C
1-4Alkoxyl group, C
1-4Phosphamide, C
1-4Phosphate-based and salt; R
2Preferably from hydroxyl (C
1-4) alkyl, C
1-4Alkoxyl group, C
1-4Phosphamide, C
1-4Phosphate-based and salt.
R
3Expression: hydrogen, hydroxyl, amino, nitro, (C
1-6) amide group, (C
1-6) alkoxyl group; X represents: SO, SO
2, CON, SO
2N, CH
2OR
2R
3Preferably from hydrogen, methoxyl group.X is preferably from CON, SO
2N, CH
2OR
2
A represents: (C
3-7) cycloalkyl, (C
3-7) cycloalkyl-(C
1-6) alkyl, (C
3-7) cycloalkenyl group, (C
3-7) cycloalkenyl group-(C
1-6) alkyl, heterocyclic radical or cyclic group-(C
1-6) alkyl, wherein any alkyl or alkenyl can connect one or more halogens or (C
1-6) alkyl substituent or connect a substituting group that is selected from: hydroxyl, cyano group, amino, carboxyl, formamyl, (C
1-6) alkyl, (C
1-6) alkoxyl group, haloalkyl; A is preferably from C
6Heterocyclic radical is especially preferably from piperidyl.
M represents: 1, or 2, or 3;
N represents: 0, or 1, or 2.
Below be the preparation method of The compounds of this invention, wherein initial compounds (II) can be purchased.
Compound (II) prepares compound 2 with sulfur oxychloride through chlorination reaction, and compound 2 obtains compound 3 with the aromatic primary amine of different replacements through the azane glycosylation reaction; Compound 3 debenzylation under the catalytic hydrogenation condition obtains 4, and compound 4 obtains formula (I) target compound with the halohydrocarbon amination that different substituents is rolled into a ball again.
R wherein
1, R
2, R
3, A, X, m and n are as defined above.
The pharmacy acceptable salt of formula of the present invention (I) compound, can contain carboxyl or amido according to different derivatives, carboxyl can react with alkaline matter (as oxyhydroxide, carbonate and the supercarbonate of basic metal or alkaline-earth metal), they include, but are not limited to: sodium hydroxide, potassium hydroxide, calcium hydroxide, yellow soda ash etc. form pharmacy acceptable salt, as corresponding sodium salts, and sylvite or calcium salt or the like.Also can adopt nontoxic organic bases such as methylamine, triethylamine, meglumine etc. to generate salt; Amido can react with acidic substance (example hydrochloric acid, Hydrogen bromide, sulfuric acid etc.), and they include, but are not limited to: hydrochloric acid, and Hydrogen bromide, sulfuric acid, phosphoric acid etc. form pharmacy acceptable salt, also can adopt organic acid such as acetate, oxalic acid, citric acid etc. to generate salt.The compound of formula (I) and the form of salt thereof have anti-tumor activity,
Formula of the present invention (I) compound or its pharmacy acceptable salt can be made pharmaceutical composition jointly with one or more pharmaceutically acceptable carriers, vehicle or thinner.This pharmaceutical composition can be made formulations such as solid orally ingestible, liquid oral medicine, injection.
Described solid and liquid oral medicine comprise: tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, syrup, granule, oral solution.Can adopt lactose or starch carrier as described solid orally ingestible; Use gelatin, methylcellulose gum, hypromellose, polyvinylpyrrolidone, starch slurry etc. are as tackiness agent; Use starch, Xylo-Mucine, carboxymethylstach sodium, low-substituted hydroxypropyl methylcellulose, polyvinylpolypyrrolidone, Microcrystalline Cellulose as disintegrating agent; Use talcum powder, little part of silica gel, stearin, calcium stearate or magnesium etc. are as antiadhesives and lubricant.The preparation method of described solid orally ingestible may further comprise the steps: with activeconstituents and carrier and optionally with a disintegration additive composition mixture, make the aqueous solution of this mixture and tackiness agent then, alcohol or aqueous alcohol solution carry out wet method or dry granulation in suitable device, dried particles, the disintegrating agent, lubricant and the antisticking agent that add other are subsequently made appropriate formulations.
Described injection comprises: little pin, freeze-dried powder and infusion solutions etc.The preparation method of described injection may further comprise the steps: get water for injection, the auxiliary material that takes by weighing recipe quantity stirs and makes dissolving, adds the sample stirring and dissolving, adjust pH is to proper range, after adding the charcoal absorption certain hour of 0.1%-0.5%, decarburization, filtration, packing or freeze-drying again.
The present invention shows by external tetrazolium reduction method (mtt assay) test: the quinazoline derivant with general formula I structure is tied rectal adenocarcinoma cell (Colo205), Human Prostate Cancer Cells (PC-3), Proliferation of Human Ovarian Cell (SKOV-3), human breast cancer cell (MCF-7), human leukemia cell (HL-60) etc. to Human umbilical vein endothelial cells (HUVEC), human lung adenocarcinoma cell (A-549), people's marrow shape thyroid cell (TT), people and is had very strong cell inhibitory effect effect.
Embodiment
The following examples can make those skilled in the art more fully understand the present invention, but do not limit the present invention in any way.
The preparation of embodiment 1 (4-((4-(4-bromo-2-fluoroanilino) quinazoline-7-base oxygen base) methyl) piperidines-1-yl) methyl di-isopropyl phosphoric acid ester
The first step: (5.0g 0.018mol) is dissolved among the DMF (20mL), drips thionyl chloride, reflux 3h with 7-benzyloxy-6-methoxyl group quinazoline-4-one.Steaming desolventizes, and re-crystallizing in ethyl acetate obtains white solid 7-benzyloxy-4-chloro-6-methoxyl group quinazoline (4.8g, 90.2%), m.p.247 ℃;
1H NMR (400MHz, DMSO): δ 3.84 (s, 3H, CH
3O), 5.26 (s, 2H, CH
2O), 7.23 (s, 1H, ArH), 7.41-7.55 (m, 6H, ArH), 7.99 (s, 1H, Ar) .ESI-MS:m/z 301[M+H]
+.
Second step: (4.8g, 0.016mol) (3.0g 0.016mol) is dissolved in the Virahol (100mL) reflux 2h with 2-bromo-4-fluoroaniline with 7-benzyloxy-4-chloro-6-methoxyl group quinazoline.After the solution cooling, filter, Virahol and ether are washed, dry 7-benzyloxy-N-(2-bromo-4-fluorophenyl)-6-methoxyl group quinazoline-4-amine (6.9g, 95.8%), m.p.231-233 ℃ of getting;
1H NMR (400MHz, DMSO): δ 3.99 (s, 3H, CH
3O), 5.26 (s, 2H, CH
2O), 7.38-7.50 (m, 9H, ArH), 8.13 (s, 1H, Ar), 8.77 (s, 1H, Ar) .ESI-MS:m/z 455[M+H]
+.
The 3rd step: (6.9g 0.015mol) is dissolved in the three fluoro acetic acid of 50mL reflux 1h with 7-benzyloxy-N-(4-bromo-2-fluorophenyl)-6-methoxyl group quinazoline-4-amine.
After the cooling, mixture is poured in the trash ice, filters, and solid is dissolved in the methyl alcohol, regulating pH with ammoniacal liquor is 11, concentrates after-filtration, and ether is washed, vacuum-drying, obtain white solid 4-(4-bromo-2-fluoroaniline)-6-methoxyl group quinazoline-7-phenol (4.9g, 88.6%), m.p.145-147 ℃;
1H NMR (400MHz, DMSO): δ 3.94 (s, 3H, CH
3O), 7.33-7.55 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar) .ES I-MS:m/z364[M+H]
+.
The 4th step: with 4-(4-bromo-2-fluoroaniline)-6-methoxyl group quinazoline-7-phenol (4.9g, 0.013mol), (4-(chloromethyl) piperidines-1-yl) methyl di-isopropyl phosphoric acid ester (5.3g, 0.013mol), salt of wormwood (3.7g, 0.026mol) and 100mL DMF be heated to 60 ℃ the reaction 10h.Solvent evaporated, crude product column chromatography (ethyl acetate: sherwood oil=4: 1) obtain white solid (4-((4-(4-bromo-2-fluoroanilino) quinazoline-7-base oxygen base) methyl) piperidines-1-yl) methyl di-isopropyl phosphoric acid ester (I-1) 5.0g, yield 71.0%, m.p.169-171 ℃;
1H NMR (400MHz, DMSO): δ 1.22-1.65 (m, 4H, 2 * CH
2), 1.98 (m, 1H, CH), 2.38-2.55 (m, 4H, 2 * CH
2), 3.99 (s, 2H, CH
2O), 4.71-4.79 (m, 2H, 2 * CH), 7.31-7.51 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar) .ESI-MS:m/z625[M+H]
+
Embodiment 2-8
With reference to the operation of embodiment 1, difference is to obtain the compound of following formula I with (4-(chloromethyl) piperidines-1-yl) the methyl acid phosphate ester derivative of different structure and 4-(4-bromo-2-fluoroaniline)-quinazoline derivant reaction.
(4-((4-(4-bromo-2-fluoroanilino) quinazoline-7-base oxygen base) methyl) piperidines-1-yl) methyl dihydrogen phosphoric acid ester, m.p.211-212 ℃;
1H NMR (400MHz, DMSO): δ 1.21-1.37 (m, 12H, 4 * CH
3), 1.32-1.61 (m, 4H, 2 * CH
2), 2.34-2.45 (m, 4H, 2 * CH
2), 2.81-2.89 (m, 2H, CH
2), 4.71-4.79 (m, 2H, 2 * CH), 5.07-5.11 (m, 2H, CH
2O), 7.31-7.51 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar), 11.96 (2 * s, 2H, 2 * OH) .ESI-MS:m/z541[M+H]
+
(4-((4-(4-bromo-2-fluoroanilino) quinazoline-7-base oxygen base) methyl) piperidines-1-yl) methyl disodium phosphoric acid ester, m.p.211-212 ℃;
1H NMR (400MHz, DMSO): δ 1.32-1.61 (m, 4H, 2 * CH
2), 2.34-2.45 (m, 4H, 2 * CH
2), 2.81-2.89 (m, 2H, CH
2), 4.71-4.79 (m, 2H, 2 * CH), 5.07-5.11 (m, 2H, CH
2O), 7.31-7.51 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar) .ESI-MS:m/z585[M+H]
+
(4-((4-(4-bromo-2-fluoroanilino)-6-methoxyl group quinazoline-7-base oxygen base) methyl) piperidines-1-yl) methyl di-isopropyl phosphoric acid ester, m.p.198-199 ℃;
1H NMR (400MHz, DMSO): δ 1.21-1.37 (m, 12H, 4 * CH
3), 1.42-1.65 (m, 4H, 2 * CH
2), 1.98 (m, 1H, CH), 2.38-2.55 (m, 4H, 2 * CH
2), 2.81-2.89 (m, 2H, CH
2), 3.94 (s, 3H, CH
3O), 4.71-4.79 (m, 2H, 2 * CH), 5.10-5.21 (m, 2H, CH
2O), 7.31-7.51 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar) .ESI-MS:m/z655[M+H]
+
(4-((4-(4-bromo-2-fluoroanilino)-6-methoxyl group quinazoline-7-base oxygen base) methyl) piperidines-1-yl) methyl dihydrogen phosphoric acid ester, m.p.211-212 ℃;
1H NMR (400MHz, DMSO): δ 1.32-1.61 (m, 4H, 2 * CH
2), 2.34-2.45 (m, 4H, 2 * CH
2), 2.81-2.89 (m, 2H, CH
2), 3.94 (s, 3H, CH
3O), 4.71-4.79 (m, 2H, 2 * CH), 5.07-5.11 (m, 2H, CH
2O), 7.31-7.51 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar), 11.96 (2 * s, 2H, 2 * OH) .ES I-MS:m/z571[M+H]
+
(4-((4-(4-bromo-2-fluoroanilino)-6-methoxyl group quinazoline-7-base oxygen base) methyl) piperidines-1-yl) methyl disodium phosphoric acid ester, m.p.211-212 ℃;
1H NMR (400MHz, DMSO): δ 1.32-1.61 (m, 4H, 2 * CH
2), 2.34-2.45 (m, 4H, 2 * CH
2), 2.81-2.89 (m, 2H, CH
2), 3.94 (s, 3H, CH
3O), 4.71-4.79 (m, 2H, 2 * CH), 5.07-5.11 (m, 2H, CH
2O), 7.31-7.51 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar) .ESI-MS:m/z 615[M+H]
+
4-((4-(4-bromo-2-fluoroanilino)-6-methoxyl group quinazoline-7-base oxygen base) methyl) piperidines-1-methane amide, m.p.154-155 ℃;
1H NMR (400MHz, DMSO): δ 1.22-1.65 (m, 4H, 2 * CH
2), 1.98 (m, 1H, CH), 2.38-2.55 (m, 4H, 2 * CH
2), 3.94 (s, 2H, CH
2O), 3.99 (s, 3H, CH
3O), 6.01 (s, 2H, NH
2), 7.31-7.51 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar) .ES I-MS:m/z 504[M+H]
+
4-((4-(4-bromo-2-fluoroanilino)-6-methoxyl group quinazoline-7-base oxygen base) methyl) piperidines-1 Toluidrin, m.p.161-162 ℃;
1H NMR (400MHz, DMSO): δ 1.22-1.65 (2 * CH 2 for m, 4H), 1.98 (m, 1H, CH), 2.38-2.55 (m, 4H, 2 * CH
2), 2.91 (s, 3H, CH
3), 3.94 (s, 2H, CH
2O), 3.99 (s, 3H, CH
3O), 6.31 (s, 2H, NH
2), 7.31-7.51 (m, 4H, ArH), 8.11 (s, 1H, Ar), 8.67 (s, 1H, Ar) .ESI-MS:m/z 540[M+H]+.
Embodiment 9
Method for preparing tablet thereof is as follows:
Technology: the activeconstituents auxiliary material is crossed 100 mesh sieves respectively; take by weighing the main ingredient and auxiliary material (half sodium starch glycolate) thorough mixing of recipe quantity; add the polyvinylpyrrolidone aqueous solution and make softwood in right amount; cross 24 mesh sieves; make wet granular in 50-60 ℃ of baking oven dry about 2-3 hour, will remain sodium starch glycolate and Magnesium Stearate and particle and mix, whole; measure intermediate content, with the shallow stamping of Φ 8mm.
Embodiment 10
The preparation of injection liquid
Technology: get water for injection 50ml, the citric acid, SODIUM PHOSPHATE, MONOBASIC that take by weighing recipe quantity stir and make dissolving, add the sample stirring and dissolving, are 4.0-5.0 with hydrochloric acid or the sodium hydroxide adjust pH of 0.1mol/L, the charcoal absorption of adding 0.1% 20 minutes.Filter with 0.45 μ m filter membrane earlier, again with the smart filter of 0.22 μ m.Press 5 milliliters of cans of per ampoule, 105 ℃ of high-temperature sterilizations promptly got injection liquid in 30 minutes.
The anti tumor activity in vitro test of Compound I
(1) material
Cell strain: Human umbilical vein endothelial cells (HUVEC), human lung adenocarcinoma cell (A-549), people's marrow shape thyroid cell (TT), people tie rectal adenocarcinoma cell (Colo205), Human Prostate Cancer Cells (PC-3), Proliferation of Human Ovarian Cell (SKOV-3), human breast cancer cell (MCF-7), human leukemia cell (HL-60).Tianjin Inst. of Materia Medica medicine Innovation Research Center is frozen.
Reagent: MTT, Amresco company; DMEM, DMEM/F12 substratum, Gibco company; Calf serum, Lanzhou people's marine life; Trypsinase, Amresco company.
Instrument: Bechtop, Suzhou Decontamination Equipment Plant; The CO2 incubator, Thermo company, model: HERA Cell150; Inverted microscope, Carl Zeiss company, model: Axiovert 200; Enzyme-linked immunosorbent assay instrument, TECAN company, model: Sunrise; Whizzer, Kerdro company, model: Heraeus.
(2) method
Cell cultures: cell inoculation is containing 10% calf serum, in the DMEM of 100IU/ml penicillin G sodium salt and 100ug/ml Vetstrep or the DMEM/F12 complete culture solution, put 37 ℃, 100% relative humidity, contain in the incubator of 5%C02, it is standby after 3 times to go down to posterity.
The MTT colorimetry detects: the cell in the vegetative period of taking the logarithm, behind 0.25% tryptic digestion (suspension cell need not digest), be suspended in the nutrient solution that contains 10% calf serum, blow and beat into single cell suspension gently, microscopically blood cell counts plate numeration viable cell with the glass dropper.(cell concn is 3-6 * 10 to the every hole of 96 well culture plates inoculating cell suspension 90 μ l
4Individual/mL), put incubator 24h after, every hole adds 10 μ l soups.In addition, each concentration is established negative control (isoconcentration DMSO) and blank background (not adding cell), and each group is all established 6 multiple holes.Cultured continuously 48h again, every then hole adds the MTT solution of 10 μ l 5mg/mL, and after continuing to cultivate 4h, the careful suction removed supernatant liquor.Every hole adds 100 μ l DMSO, puts micro oscillator concussion 5mi n so that crystallization is dissolved fully, in the single wavelength colorimetric of microplate reader 492nm, measures the OD value, and test-results sees Table 1.
Inhibiting rate (%)=[1-(experimental group OD average-blank group OD average)/(control group OD average-blank group OD average)] * 100%.The Bliss method is calculated test-compound IC
50Value.
(3) result
The IC of table 1. pair cultured cell in vitro growth
50(μ g/ml)
Claims (8)
1. general formula (I) quinazoline derivant or its pharmacy acceptable salt:
Wherein:
R
1Expression: hydrogen, trifluoromethyl, nitro, methyl, cyano group, C
1-4Alkyl, C
1-4Alkoxyl group, N-(C
1-4) alkylamine, halogen, hydroxyl, N, N-phenodiazine (C
1-4) alkylamine, C
1-4Alkyl sulfide, C
1-4Alkyl sulphonyl;
R
2Expression: hydrogen, hydroxyl, C
1-4Alkyl, halo (C
1-4) alkyl, hydroxyl (C
1-4) alkyl, C
1-4Alkoxyl group, C
1-4Phosphamide, C
1-4Phosphate-based and salt;
R
3Expression: hydrogen, hydroxyl, amino, nitro, (C
1-6) amide group, (C
1-6) alkoxyl group; X represents: SO, SO
2, CON, SO
2N, CH
2OR
2
A represents: (C
3-7) cycloalkyl, (C
3-7) cycloalkyl-(C
1-6) alkyl, (C
3-7) cycloalkenyl group, (C
3-7) cycloalkenyl group-(C
1-6) alkyl, heterocyclic radical or cyclic group-(C
1-6) alkyl, wherein any alkyl or alkenyl can connect one or more halogens or (C
1-6) alkyl substituent or connect a substituting group that is selected from: hydroxyl, cyano group, amino, carboxyl, formamyl, (C
1-6) alkyl, (C
1-6) alkoxyl group, haloalkyl;
M represents: 1, or 2, or 3;
N represents: 0, or 1, or 2.
2. compound according to claim 1 is characterized in that R
1Preferably from hydrogen, trifluoromethyl, nitro, methyl, cyano group, halogen, particularly fluorine atom and bromine atoms.
3. compound according to claim 1 is characterized in that R
2Preferably from hydroxyl (C
1-4) alkyl, C
1-4Alkoxyl group, C
1-4Phosphamide, C
1-4Phosphate-based and salt.
4. compound according to claim 1 is characterized in that R
3Preferably from hydrogen, methoxyl group.
5. compound according to claim 1 is characterized in that X is preferably from CON, SO
2N, CH
2OR
2
6. compound according to claim 1 is characterized in that A is preferably from C
6Heterocyclic radical is especially preferably from piperidyl.
7. compound according to claim 1 is characterized in that its corresponding medicinal salt is: formula 1 compound H
qX, X represents halogen, sulfate radical, nitrate radical, phosphate radical, q are 1, or 2, or 3.
8. as the application of the described arbitrary compound of claim 1-5 in preparation antitumor drug or antineoplastic pharmaceutical compositions.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103554091A (en) * | 2013-11-05 | 2014-02-05 | 沈阳工业大学 | Quinazoline derivative as well as preparation method and use thereof |
| CN103804308A (en) * | 2012-11-06 | 2014-05-21 | 天津药物研究院 | 7-substituted cyclohexyl quinazoline derivatives and preparing method and uses thereof |
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| AU779695B2 (en) * | 2000-04-07 | 2005-02-10 | Astrazeneca Ab | Quinazoline compounds |
| GB0207323D0 (en) * | 2002-03-28 | 2002-05-08 | Astrazeneca Ab | Compounds |
| ES2279441T3 (en) * | 2003-09-19 | 2007-08-16 | Astrazeneca Ab | DERIVATIVES OF QUINAZOLINA. |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103804308A (en) * | 2012-11-06 | 2014-05-21 | 天津药物研究院 | 7-substituted cyclohexyl quinazoline derivatives and preparing method and uses thereof |
| CN103554091A (en) * | 2013-11-05 | 2014-02-05 | 沈阳工业大学 | Quinazoline derivative as well as preparation method and use thereof |
| CN103554091B (en) * | 2013-11-05 | 2016-05-18 | 沈阳工业大学 | Quinazoline derivant and its production and use |
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