CN102875481A - 4-[2-(substituted benzylidene) hydrazino]-5, 6, 7-trialkoxy quinazoline compound and preparation method and application - Google Patents

Abstract

The invention discloses a 4-[2-(substituted benzylidene) hydrazino]-5, 6, 7-trialkoxy quinazoline compound and a preparation method and application thereof. 4-[2-(substituted benzylidene) hydrazino]-5, 6, 7-trialkoxy quinazoline compound has the structure shown as the following general form (I). According to the preparation method, 2, 3, 4-trihydroxybenzoic acid, dimethyl sulfate, diethyl sulfate, carbinol, sulfuric acid, nitric acid, hydrogen, formamide, phosphorus oxychloride, 80% of hydrazine hydrate and aromatic aldehyde are adopted as raw materials, and synthesized to obtain a series of novel 4-[2-(substituted benzylidene) hydrazino]-5, 6, 7-trialkoxy quinazoline compounds through eight steps; and such compounds have excellent antitumous effects and high effects on restraining the fungi of plant, and can be applied to preparing anti-cancer drugs and anti-plant fungal pesticides.

Description

4-[2-(substituted benzene methylene radical) diazanyl]-5,6,7-tri-alkoxy quinazoline compounds and preparation method and application

Technical field

The present invention relates to have 4-[2-(substituted benzene methylene radical) diazanyl of antitumous effect and anti-plant pathogen]-5,6,7-tri-alkoxy quinazoline compounds preparation method and application.

Background technology

Quinazoline compounds shows good biological activity, becomes one of focus that region of chemistry and the biological scholars of educational circles study.Aspect agricultural chemicals, quinazoline compounds has antibiotic, and is antiviral, kills the biological activitys such as mite.Wherein sterilant fluquinconazole (Fluquinconazole) is a kind of systemic fungicide of wide spectrum, and the biosynthesizing of ergosterol is had good restraining effect.Aspect medical, since the specific inhibitor of the discovery 4-anilinoquinazolines (PD 153035) such as Fry in 1994 as the EGFR Tyrosylprotein kinase, quinazoline compounds has developed the cancer therapy drug take EGFR as target of the first-generation and the s-generation.First-generation EGFR reversible inhibitor Gefitinib ZD1839 (Iressa) and erlotinib OSI-774 (Tarceva) etc. are because of its commercialization of good antitumour activity.Yet they only produce inhibition to growth of cancer cells, can't effectively kill cancer cells, and life-time service can lead oncogenic resistance, so their effects clinically are restricted, and this has just impelled the research and development of s-generation EGFR irreversible inhibitor.At present, the s-generation has the medicine of irreversible inhibition to EGFR, and also oneself enters the clinical trial stage, BIBW2992 such as Boehringer Ingelheim exploitation has entered the clinical II phase, and can combine with the other treatment method and carry out combined therapy, and effect is better.

(Shalaby, the A. A. such as Shalaby in 2000; El-Khamry, A. M. A.; Shiba, S. A. Synthesis and antifungal activity of some new quinazoline and benzoxazinone derivatives [ J]. Arch der Pharmazie, 2000,333:365-372.) reported novel quinazoline quinoline compound, biological activity test shows: onion white root disease and stem rot are had better inhibition, and inhibiting rate can reach 68-88% under 15 μ g/mL drug concentrations.

Bright military grade of fourth in 2004 (Ding Mingwu, Chen Yun peak, Yang Shangjun. the synthetic and fungicidal activity of 2-alkoxyl group-3H-quinazoline-4-one [ J]. organic chemistry, 2004,24 (8): 923-926.) having reported novel quinazoline quinoline ketone compound, shown preferably bacteriostatic activity, when 50 mg/ L concentration, is 89%. to the inhibiting rate of Rhizoctonia solani (Pellicularia sasakii)

(Xu, the G. F. such as Xu in 2007; Song, B. A.; Bhadury P. S.; Yang S.; Zhang P. Q.; JIn L. H.; Xue W.; Hu D. Y. and Lu P. Synthesis and antifungal activity of novel s-substituted 6-fluoro-4-alkya (aryl) thiopuinazoline derivatives[ J]. Bioorganic Medicinal Chemistry, 2007,15:3768-3774.) reported series of new 4-sulfydryl quinazoline compound, wherein 3 compounds have good bacteriostatic activity.Be under the 500 μ g/mL at drug concentration, inhibiting rate to fusarium graminearum is 100%, inhibiting rate to the capsicum wilt bacterium is respectively 92.3%, 98.5%, 89.3%, and the inhibiting rate of Valsa mali is respectively 96.9%, 100%, 94.8%, all is higher than the contrast medicament and dislikes mould spirit.Preliminary supposition target compound is to suppress the activity of chitinase in the mycelium to the mode of action of the withered mycelia of capsicum, and then affect reducing sugar content in the thalline, chitosan content, thereby destroy the composition and decomposition balance of hyphal cell cell walls, affect the growth of mycelia.

2008 high promotes culture etc. (height is promoted culture, Cai Xuejian, and Yan Kai, the Koryo is beautiful, Wang Heying, Chen Zhuo, Song Baoan. 4-( 3HSynthetic and the activity of resisting tobacco mosaic virus of)-quinazolinones Schiff alkali [ J]. organic chemistry, 2008,28 (10): 1785-1791.) reported the novel 4-of a class ( 3H)-quinazolinones Schiff alkali.This compounds live body to TMV when the mass concentration of medicament is 500 mg/L all has higher therapeutic action, and its inhibiting rate is suitable with contrast medicament Ningnanmycin.Part of compounds is carried out the Biochemical Research of anti-TMV, and the result shows that the relevant enzyme such as its PAL enzyme, POD enzyme, SOD enzyme, chlorophyll content and regulation and control substance all have dependency within the regular hour; This compounds has the effect of inducing PR-5 genetic expression to raise simultaneously, thereby improves the ability of Resistance In Tobacco virus, stops the system of TMV virus to infect and remote invasion and attack.

(Vicentini, the C. such as Vicentini in 2003; Festuccia, C.; Gravina, G. L.; Angelucci, A.; Marronaro, A.; Bologna, M. Prostate cancer cell proliferation is strongly reduced by the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in vitroon human cell lines and primary cultures[ J]. JOurnal of cancer reserch and clinical oncology. 2003,129,165-174.) studied EGFR tyrosine kinase inhibitor ZD1839 (Gefitinib) to the external prostate cancer cell (PC3 that comprises non-Androgen-dependent type, DU145, the ND1 of TSU-Pr1 cancer cells and Androgen-dependent type, LNCaP, the LALVA-31 cancer cells) impact of proliferation activity, the IC50 value scope that discovery ZD1839 suppresses the EGFR autophosphorylation of above-mentioned tumour cell is 0.46-0.97 μ mol/L, the IC that on cell proliferation suppresses ₅₀The value scope is 0.37-1.03 μ mol/L.During greater than 1 μ mol/L, ZD1839 can induce the apoptosis of PC3 cell at dosage.Result of study shows that this type of EGFR tyrosine kinase inhibitor may just can block growth and the propagation of Human Prostate Cancer Cells in early days.

Hennequin in 2005 and Halsall (Hennequin, L. F. A.; Halsall, C. T. Quinazoline derivatives as tyrosine kinase inhibitors[ P]. WO2005026150,2005.) in patent, reported the series of quinazoline compound, compare with OSI-774, mainly be that fixedly quinazoline ring 6-position is methoxy substitution, the 7-position then transform the alkoxyl group that contains amide group morpholine structure as and replaces, this series compound has preferably inhibition activity, IC to human oral cavity epithelial cancer (KB) cell EGFR ₅₀The value scope is 0.001-5 μ mol/L, and live test shows that suitable oral dosage is 1-200 mg/kg/day, has the potentiality of the cancer treatment drugs of being developed further into.

(Bradbury, the R. H. such as Bradbury in 2005; Hennequin, L. F. A.; Barlaam, B. C. Quinazoline derivatives[ P] .WO2005028469,2005.) in patent, reported the series of quinazoline compound, this series compound quinazoline ring 7-position still is methoxyl group, the 6-position then is that the piperidines oxygen base that contains amide group replaces, to the IC of KB cell EGFR ₅₀The value scope is 0.001-10 μ mol/L, and live test shows that suitable oral dosage is 1-200 mg/kg/day, has the potentiality of the cancer treatment drugs of being developed further into.

(Barlaam, the B. C. such as Barlaam in 2005; Halsall, C. T.; Hennequin, L. F. A. Quinazoline derivatives as antiproliferative agents[ P]. WO2005030765,2005) in patent, reported series of quinazoline compound 3, compared with aforesaid compound 2 that its constitutional features mainly is 6, introduce the heterocyclic groups such as thiazole, isoxzzole, pyridine in the amide group piperidines oxygen base of 7-position, wherein compound 3a-f suppresses the IC of EGFR ₅₀Value is respectively 17,16, and 47,87,30,17 nmol/L are to the IC of Tyrosylprotein kinase protein phosphorylation ₅₀Value is respectively＜and 1,14,15,43,＜1,＜1 nmol/L possesses good potentiality to be exploited.

(Kiguchi, the K. such as Kiguchi in 2005; Ruffino, L.; Kawamoto, T.; Ajiki, T.; DiGiovanni, J. Chemopreventive and Therapeutic Efficacy of Orally ActiveTyrosine Kinase Inhibitors in a TransgenicMouse Model of Gallbladder Carcinoma[ J] .Clinical cancer reserch. 2005,11,5572-5580.) reported Gefitinib as oral property EGFR tyrosine kinase inhibitor to turning chemoprophylaxis and the result for the treatment of of Human gallbladder carcinoma (BTC) dna murine.In the diet of mouse, add 400 ppm Gefitinib every day, the mouse that turns Human gallbladder carcinoma (BTC) had good chemoprophylaxis and therapeutic action, research also confirms simultaneously to play an important role in the development of activation to BTC of EGFR, and may be the effective way for the treatment of carcinoma of gallbladder take EGFR as target.

(Lee, the K.-O. such as Lee in 2008; Cha, M.-Y.; Kim, M.-R.; JUng, Y.-H.; Lee, C.-G.; Kim, S.-Y.; Bang, K.; Park, B.-W.; Choi, B.-I.; Chae, Y.- J.; Ko, M.-Y.; Kim, H.-K.; Ahn, Y.-G; Kim, M.-S.; Lee, G.-S. Novel amide derivatives for inhibiting the growth of cancer cells[ P]. WO2008150118,2008.) synthesized the series of quinazoline compound, biological activity test shows the cancer cells that the EGFR overexpression of this compounds energy establishment EGFR and sudden change is induced.This series compound all has the activity of good inhibition A431 and SK-Br3 cell, active two best compounds wherein, its IC ₅₀Value is 0.3 μ mol/L, obviously is better than control drug Gefitinib (to the IC of A431 and SK-Br3 Growth of Cells ₅₀Value is respectively 28 μ mol/L and 206 μ mol/L).

(Schettino, the C. such as Schettino in 2008; Bareschino, M. A.; Ricci, V.; Ciardiello, F.Erlotinib:an EGF receptor tyrosine kinase inhibitor innon-small-cell lung cancer treatment[ J]. Expert reviews of Respiratory Medicine. 2008,2 (2), 167-178.) summed up Erlotinib as the application of EGFR receptor tyrosine kinase inhibitors in the lung cancer in non-cellule type treatment.Erlotinib is used for the treatment of patient's terminal cancer in the one-phase clinical trial, its curative effect is similar to Gefitinib, efficiently when oral dosage is 150 mg/day reaches 46%.When using separately in the two-stage clinical trial its efficient be 31.3%; Also attempt in the two-stage clinical trial Erlotinib and rhuMAb-VEGF medicine (Bevacizumab, trade(brand)name Avastin, a kind of human monoclonal lgG1 antibody of restructuring, work by the biologic activity that suppresses human vascular endothelial growth factor) carry out combined therapy, efficiently reach 54%.Carried out the combined therapy tests such as Erlotinib and taxol, carboplatin in the clinical trial of three stages, found that combination does not manifest clear superiority.

(Cai, the X. such as Cai in 2009 and Qian; Qian, C.-G; Zhai, H.-X.Tartrate salts or complexes of quinazoline based EGFR inhibitors containing a zinc binding moiety[ J]. WO2009035718,2009.) reported that in Patents the moieties end is the quinazoline compound of N-oxyamide in the alkoxyl group of a series of 6-position, active best compound suppresses the IC of mammary cancer (MCF-7, MDAMB468), lung cancer (H-292) and pancreatic cancer cell (BXPC3) ₅₀Value is all less than 0.1 μ mol/L; And have the activity of inducing colon cancer cell and Apoptosis of Breast Cancer, Erlotinib is lower than 20 μ mol/L in concentration can inactivation, and this compound is lower than 0.17 μ mol/L in concentration and just understands inactivation.Show that this compound also has better inhibition active to the chemical sproof cancer cells of Erlotinib.In addition, the venous toxicity test shows that this compound can not cause to the body weight of mouse large change under 200 mg/kg dosage.

(Chandregowda, the V. such as Chandregowda in 2009; Kush, A. K.; Reddy, G. C. Synthesis and in vitro antitumor activities of novel 4-anilinoquinazoline derivatives[ J] .European journal medicinal chemisty. 2009,44,3046-3055.) reported that series of quinazoline compounds, biological activity test result show that wherein three compound activities are better, suppress the IC of A431 cell proliferation and MCF-7 cell proliferation ₅₀Value is respectively 3.51,3.00,4.05 and 38.83,32.65,35.90 μ mol/L, the molecular docking result shows that active best compound and Gefitinib binding mode are similar, all with the EGFR tyrosine kinase domain in amino-acid residue Val702, Ala719, Ser696, and Lys721 interacts.

[El-Azab, the A. S. such as El-Azab in 2010; Al-Omar, M. A.; Abdel-Aziz, A. A.-M.; Abdel-Aziz, N. I.; El-Sayed, M. A.-A.; Aleisa, A. M.; Sayed-Ahmed, M. M.; Abdel-Hamide, S. G. Design, synthesis and biological evaluation of novel quinazoline derivatives as potential antitumor agents:Molecular docking study[ J].

European JOurnal of Medicinal Chemistry. 2010,45,4188-4198.] reported quinazolinone or the quinazoline compounds of 2-phenyl substituted, biological activity test shows that this compounds suppresses the IC of human breast carcinoma (MCF-7) cell proliferation ₅₀The value scope is 3.35-6.81 μ g/mL, and wherein part of compounds shows the inhibition activity of wide spectrum, suppresses the IC of the cell proliferations such as people's liver cancer (HEPG2), human breast carcinoma (MCF-7) and human cervical carcinoma (HELA) ₅₀The value scope is 3.35-5.59 μ g/mL.Compound is carried out the molecular docking experiment, and the result shows CN base and the NO in the compound ₂Base forms hydrogen bond with the Lys-721 of EGFR, thereby the inhibition that has strengthened compound is active.

(Garofalo, the A. such as Garofalo in 2011; Goossens, L.; Lemoine, A.; Ravez, S.; Six, P.; Howsam, M.; Farce, A.; Depreux, P. [4-(6,7-Disubstituted quinazolin-4-yl amino) phenyl] carbamic acid esters:a novel series of dual EGFR/VEGFR-2 tyrosine kinase inhibitors[ J]. Medicinal chemistry communion. 2011,2,65-72.) reported the series of new quinazoline compound, have the dual-use function that suppresses EGFR and VEGFR.Such as activity two compounds preferably, suppress the IC of EGFR ₅₀Value is respectively 1.0 μ mol/L and 0.9 μ mol/L, suppresses the IC of VEGFR ₅₀Value is respectively 0.5 μ mol/L and 0.85 μ mol/L, with the control drug ZD6476 (IC that suppresses EGFR and VEGFR ₅₀Value is respectively 0.8 μ mol/L and 0.1 μ mol/L) active quite.Further the 6-position on the quinazoline ring or 7-position are modified, found quinazoline ring 6, introduce the replacement of amido alkyl on the 7-position and can improve the anticancer proliferation activity, active best compound suppresses HT29, the IC of MCF-7 and EAHY926 ₅₀Value is respectively 2.5 μ mol/L, 7.1 μ mol/L and 2.8 μ mol/L, and the inhibition activity of HT29 and EAHY926 is better than contrasting medicament ZD6476, and (Vandetanib suppresses the IC of HT29 and EAHY926 ₅₀Value is respectively 4.2 μ mol/L, 5.1 μ mol/L).

From background technology as can be known, quinazoline (ketone) analog derivative has the biological activity of desinsection preferably, the aspect such as antibiotic, anticancer, but about 4-[2-(substituted benzene methylene radical) diazanyl]-5,6,7-tri-alkoxy quinazoline compounds there is no at present the people and synthesized, and, also fewer about the research report of this compounds anti-plant pathogenic fungi and antitumour activity both at home and abroad.

Summary of the invention

What the object of the invention was to design synthetic a series of novel structures contains 4-[2-(substituted benzene methylene radical) diazanyl]-5,6,7-tri-alkoxy quinazoline derivative, this compounds uses quinazoline structure as skeleton, the diazanyl that connects the α-tolylene replacement in the 4-position carries out the active group splicing, and this series compound has been carried out synthetic method and anti-plant pathogenic fungi and Anticancer Activities.The compound structure general formula ( I) as follows:

( I)

R wherein ₁Be methyl, ethyl, propyl group, sec.-propyl, butyl;

R ₂For adjacent on the phenyl ring,, contain one or more substituting groups in the contraposition, substituting group is hydroxyl, methyl, ethyl, n-propyl, sec.-propyl, butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, butoxy, allyl group, acrylamido, trifluoromethyl, trifluoromethoxy, amido, substituted amido, nitro and halogen atom, and halogen atom is fluorine, chlorine, bromine, iodine;

In the content of the present invention, this compounds is to gibberella saubinetii, the capsicum Fusarium oxysporum, the apple decay bacterium, botrytis cinerea, potato late blight bacterium, the phytopathogens such as Rhizoctonia solani have preferably bacteriostatic activity, this compounds has Human Prostate Cancer Cells (PC3) simultaneously, people's malignant melanoma cell (A375), human breast cancer cell (BGC823), people's gastric adenocarcinoma cells (MGC803), and the good anti-tumor activity of human breast cancer cell (Bcap-37), its purposes is the application in preparation anti-plant pathogenic fungi agricultural chemicals and preparation cancer therapy drug.

General formula of the present invention ( I) preparation method of compound is with 2,3,4-trihydroxybenzoic acid, methyl-sulfate, ethyl sulfate, methyl alcohol, sulfuric acid, nitric acid, hydrogen, methane amide, phosphorus oxychloride, 80% hydrazine hydrate, aromatic aldehyde are raw material, through etherificate, esterification, nitrated, reduction, closed loop, chloro, diazanyl, become eight steps of hydrazone reaction synthetic, its synthetic route is:

Eight step synthetic methods are:

The first step: the benzoic preparation of 2,3,4-tri-alkoxy

With a small amount of 2,3,4-trihydroxybenzoic acid and water stir in bottle.Drip sodium hydroxide solution and methyl-sulfate (or ethyl sulfate).Reflux, TLC follows the tracks of reaction process, after raw material point disappears, stopped reaction, it is neutral transferring pH value with hydrochloric acid, has the reddish-brown solid to separate out, suction filtration is dried to get thick product, filtrate gets thick product with the chloroform extraction precipitation, merges thick product and uses column chromatography the purification of target compound, gets white (or yellow) solid.

Second step: the preparation of 2,3,4-tri-alkoxy methyl benzoate

With a small amount of 2,3,4-front three (or second) aminobenzoic acid and methanol mixed stir, add a small amount of vitriol oil, reflux, TLC follows the tracks of reaction process, after raw material point disappears, stopped reaction, solution precipitation after will reacting adds water, the chloroform extraction precipitation, the column chromatographic isolation and purification target compound gets colorless oil.

The 3rd step: 6-nitro-2,3, the preparation of 4-tri-alkoxy methyl benzoate

With a small amount of 2,3,4-front three (or second) aminobenzoic acid methyl esters adds in the nitric acid, pours frozen water into, and TLC follows the tracks of reaction process, and after the disappearance of raw material point, stopped reaction is used the chloroform extraction precipitation, and the column chromatographic isolation and purification target compound gets yellow solid or oily matter.

The 4th step: 6-amino-2,3, the preparation of 4-tri-alkoxy methyl benzoate

Pass into hydrogen, with a small amount of 6-nitro-2,3,4-front three (or second) aminobenzoic acid methyl esters and a small amount of palladium carbon catalyst and methanol mixed stir, and TLC follows the tracks of reaction process, and after raw material point disappeared, stopped reaction, precipitation got the red-brown solid.The column chromatographic isolation and purification target compound gets the brown color solid.

The 5th step: 5,6,7-tri-alkoxy quinazoline-4-( 3HThe preparation of)-ketone

With a small amount of 6-amino-2,3,4-tri-alkoxy methyl benzoate, methane amide, phosphorus oxychloride and toluene are mixed thermal backflow, after reaction for some time, separate out a large amount of solids, TLC follows the tracks of reaction process, after raw material point disappears, stopped reaction, precipitation get the red-brown solid, add that to transfer pH value with ammoniacal liquor behind the water be neutral, separate out the tawny precipitation, the chloroform extraction precipitation, the column chromatographic isolation and purification target compound obtains white solid.

The 6th step: 4-chloro-5,6, the preparation of 7-tri-alkoxy quinazoline

With a small amount of quinazolinone, phosphorus oxychloride, triethylamine and toluene mix and blend, TLC follows the tracks of reaction process, after raw material point disappears, stopped reaction, precipitation adds water, and it is neutral transferring pH value with ammoniacal liquor, the chloroform extraction precipitation, the column chromatographic isolation and purification target compound obtains the pistac solid.

The 7th step: 4-diazanyl-5,6, the preparation of 7-tri-alkoxy quinazoline

With a small amount of 4-chloro-5,6,7-tri-alkoxy quinazoline, 80% hydrazine hydrate and ethanol mix, heated and stirred, and TLC follows the tracks of reaction process, after raw material point disappears, stopped reaction, precipitation gets pale solid, a large amount of frozen water washings, purifying obtains white solid.

The 8th step: 4-[2-(substituted benzene methylene radical) diazanyl]-5,6, the preparation of 7-tri-alkoxy quinazoline

With a small amount of 4-diazanyl-5,6,7-tri-alkoxy quinazoline, substituted benzaldehyde, tosic acid and ethanol Hybrid Heating stir, and TLC follows the tracks of reaction process, after raw material point disappears, and stopped reaction, precipitation, the thin layer chromatography purifying gets the class yellow solid.

This step is applicable to all above-mentioned target compound 4-[2-(substituted benzene methylene radical) diazanyls]-5,6,7-tri-alkoxy quinazoline compound synthetic.

Synthetic and proof has the compound of bacteriostatic action and antitumous effect as follows according to invention route and preparation method:

Compound a:

(E))-2-(4-oil of mirbane methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound b:

(E)-2-(4-(N, N dimethylamine base) α-tolylene)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound c:

(E)-2-(2,3-dimethoxy α-tolylene)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound d:

(E)-2-(2-hydroxy-5-methyl oxygen base α-tolylene)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Verbindung:

(E)-2-(2-anisole methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound f:

(E)-2-(2,4 dichloro benzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound g:

(Z)-2-(2,6-dichlorobenzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound h:

(E)-2-(2,6-dichlorobenzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound i:

(E)-2-(2-chlorobenzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound j:

(E)-2-(2,4-dihydroxy-benzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound k:

(E)-2-(4-isobutyl-benzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound l:

(E)-2-(3,4-dihydroxy-benzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound m:

(E)-2-(2-chlorobenzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound n:

(E)-2-(4-isobutyl-benzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound o:

(E)-2-(2,4 dichloro benzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound p:

(E)-2-(4-oil of mirbane methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound q:

(E)-2-(3,4-dimethoxy α-tolylene)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound r:

(E)-2-(2-hydroxy-5-methyl base α-tolylene)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound s:

(E)-2-(2,3-dihydroxy-benzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound t:

(E)-2-(2,4-dihydroxy-benzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound u:

(E)-2-(2-anisole methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound v:

(Z)-2-(2,6-dichlorobenzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound w:

(E)-2-(2,6-dichlorobenzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound x:

(E)-2-(3,4-dihydroxy-benzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound y:

(E)-2-(4-(N, N dimethylamine base) α-tolylene)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound z:

(E)-2-(2-hydroxy-5-methyl oxygen base α-tolylene)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Embodiment

Embodiment one, (E))-2-(4-oil of mirbane methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

(compound number is a) synthetic

(1) 2,3,4 trimethoxybenzoic acid is synthetic

With 5.0 g 2,3,4-trihydroxybenzoic acid and 20 mL water stir in bottle, drip 25 mL sodium hydroxide solutions (4mol/L) and 20 g methyl-sulfates under the normal temperature water-bath.Dropwise post-heating 6 h that reflux, stopped reaction, it is neutral transferring pH value with hydrochloric acid, have brown solid to separate out, suction filtration is dried to get thick product, and filtrate gets thick product with the chloroform extraction precipitation, merge thick product and use column chromatography the purification of target compound, get white solid 4.2 g, yield 67.3%.

(2) the 2,3,4 trimethoxybenzoic acid methyl esters is synthetic

With 1.2 g 2,3,4-trimethoxybenzoic acid and 5 mL methanol mixed stir, and add the 0.5 mL amount vitriol oil, reflux 10 h, stopped reaction, solution precipitation after will reacting adds water 20 mL, the chloroform extraction precipitation, the column chromatographic isolation and purification target compound gets colorless oil 1.0 g, yield 78.1%.

(3) 6-nitro-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

1.2 g 2,3,4 trimethoxybenzoic acid methyl esters add in the concentrated nitric acid under the ice bath, pour 50 mL frozen water into and stir 2 h, and stopped reaction is used the chloroform extraction precipitation, and column chromatographic isolation and purification gets 1.0 g gray solid, yield rate 69.4%.

(4) 6-amino-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Pass into hydrogen, with 1.3 g 6-nitro-2,3,4 trimethoxybenzoic acid methyl esters and 0.12 g palladium carbon catalyst and 5 mL methanol mixed, stirring at normal temperature 24 h react complete, stopped reaction, and precipitation gets brown solid.Column chromatographic isolation and purification gets yellow solid 0.9 g, yield 77.6%.

(5) 5,6,7-trimethoxy quinazoline-4-( 3HSynthesizing of)-ketone

With 5.0 g 6-amino-2,3,4-tri-methoxybenzoate, 10 mL methane amides, 3 mL phosphorus oxychloride and 25 mL toluene are mixed thermal backflow, after reaction for some time, separate out a large amount of solids, stopped reaction behind 5 h, precipitation gets brown solid, adds that to transfer pH value with ammoniacal liquor behind the water be neutral, separate out the tawny precipitation, chloroform extraction precipitation, column chromatographic isolation and purification obtain white cotton-shaped solid 3.9 g, yield 79.6%.

(6) the 4-chloro-5,6,7-trimethoxy quinazoline synthetic

With 0.5 g 5,6,7-trimethoxy quinazoline-4-( 3H)-ketone, 1 mL phosphorus oxychloride, 3 mL triethylamines and 8 mL toluene mix and blends, reflux 5 h, stopped reaction, precipitation adds 20 mL water, and it is neutral transferring pH value with ammoniacal liquor, the chloroform extraction precipitation, column chromatographic isolation and purification obtains pistac solid 0.44 g, yield 81.5%.

(7) 4-diazanyl-5,6,7-trimethoxy quinazoline synthetic

With 0.7 g 4-chloro-5,6,7-trimethoxy quinazoline, 80% hydrazine hydrate, 2 mL and 5 mL ethanol mix, and reflux stirs 8 h, react complete, stopped reaction, precipitation gets pale solid, a large amount of frozen water washings, purifying gets white solid 0.5 g, yield 72.5%.

(8) (E)-2-(4-oil of mirbane methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine synthetic

With 0.08 g 4-diazanyl-5,6,7-trimethoxy quinazoline, 0.06 g 4-nitrobenzaldehyde, 0.2g tosic acid and 8 mL ethanol Hybrid Heating return stirrings, 6 h, stopped reaction, precipitation, thin layer chromatography purifying get yellow solid 0.061 g, yield 50.1%.

(4-(N, N dimethylamine base) α-tolylene)-(compound number is hydrazine 1-(5,6,7-trimethoxy quinazoline-4-yl) for embodiment two, compound (E)-2- b) synthetic

(1) 2,3,4 trimethoxybenzoic acid is synthetic

Synthetic such as embodiment one (1) condition and method

(2) the 2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (2) condition and method

(3) 6-nitro-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (3) condition and method

(4) 6-amino-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (4) condition and method

(5) 5,6,7-trimethoxy quinazoline-4-(3H)-ketone synthetic

Synthetic such as embodiment one (5) condition and method

(6) the 4-chloro-5,6,7-trimethoxy quinazoline synthetic

Synthetic such as embodiment one (6) condition and method

(7) 4-diazanyl-5,6,7-trimethoxy quinazoline synthetic

Synthetic such as embodiment one (7) condition and method

(8) (E)-2-(4-(N, N dimethylamine base) α-tolylene)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine synthetic

Synthetic such as embodiment one (8) condition and method, difference is to add 0.06 g 4-(N, N dimethylamine base) phenyl aldehyde, gets yellow solid 0.073 g.

Embodiment three, compound (E)-2-(2,3-dimethoxy α-tolylene)-(compound number is hydrazine 1-(5,6,7-trimethoxy quinazoline-4-yl) c) synthetic

(1) 2,3,4 trimethoxybenzoic acid is synthetic

Synthetic such as embodiment one (1) condition and method

(2) the 2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (2) condition and method

(3) 6-nitro-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (3) condition and method

(4) 6-amino-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (4) condition and method

(5) 5,6,7-trimethoxy quinazoline-4-(3H)-ketone synthetic

Synthetic such as embodiment one (5) condition and method

(6) the 4-chloro-5,6,7-trimethoxy quinazoline synthetic

Synthetic such as embodiment one (6) condition and method

(7) 4-diazanyl-5,6,7-trimethoxy quinazoline synthetic

Synthetic such as embodiment one (7) condition and method

(8) (E)-2-(2,3-dimethoxy α-tolylene)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine synthetic

Synthetic such as embodiment one (8) condition and method, difference is to add 0.06 g 2, and the 3-dimethoxy benzaldehyde gets yellow solid 0.067 g.

(2-hydroxy-5-methyl oxygen base α-tolylene)-(compound number is hydrazine 1-(5,6,7-trimethoxy quinazoline-4-yl) for embodiment four, compound (E)-2- d) synthetic

(1) 2,3,4 trimethoxybenzoic acid is synthetic

Synthetic such as embodiment one (1) condition and method

(2) the 2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (2) condition and method

(3) 6-nitro-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (3) condition and method

(4) 6-amino-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (4) condition and method

(5) 5,6,7-trimethoxy quinazoline-4-(3H)-ketone synthetic

Synthetic such as embodiment one (5) condition and method

(6) the 4-chloro-5,6,7-trimethoxy quinazoline synthetic

Synthetic such as embodiment one (6) condition and method

(7) 4-diazanyl-5,6,7-trimethoxy quinazoline synthetic

Synthetic such as embodiment one (7) condition and method

(8) (E)-2-(2-hydroxy-5-methyl oxygen base α-tolylene)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine synthetic

Synthetic such as embodiment one (8) condition and method, difference is to add 0.05 g 2-hydroxy-5-methyl oxygen benzaldehyde, and ethyl alcohol recrystallization gets yellow solid 0.062 g.

Embodiment five, (compound number is hydrazine compound (E)-2-(2,4 dichloro benzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) f) synthetic

(1) 2,3,4 trimethoxybenzoic acid is synthetic

Synthetic such as embodiment one (1) condition and method

(2) the 2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (2) condition and method

(3) 6-nitro-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (3) condition and method

(4) 6-amino-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (4) condition and method

(5) 5,6,7-trimethoxy quinazoline-4-(3H)-ketone synthetic

Synthetic such as embodiment one (5) condition and method

(6) the 4-chloro-5,6,7-trimethoxy quinazoline synthetic

Synthetic such as embodiment one (6) condition and method

(7) 4-diazanyl-5,6,7-trimethoxy quinazoline synthetic

Synthetic such as embodiment one (7) condition and method

(8) (E)-2-(2,4 dichloro benzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine synthetic

Synthetic such as embodiment one (8) condition and method, difference is to add 0.07 g 2,4 dichloro benzene formaldehyde, gets light yellow solid 0.071 g.

Embodiment six, compound (Z)-2-(2,6-dichlorobenzene methylene radical)-(compound number is hydrazine 1-(5,6,7-trimethoxy quinazoline-4-yl) g) synthetic

(1) 2,3,4 trimethoxybenzoic acid is synthetic

Synthetic such as embodiment one (1) condition and method

(2) the 2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (2) condition and method

(3) 6-nitro-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (3) condition and method

(4) 6-amino-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (4) condition and method

(5) 5,6,7-trimethoxy quinazoline-4-(3H)-ketone synthetic

Synthetic such as embodiment one (5) condition and method

(6) the 4-chloro-5,6,7-trimethoxy quinazoline synthetic

Synthetic such as embodiment one (6) condition and method

(7) 4-diazanyl-5,6,7-trimethoxy quinazoline synthetic

Synthetic such as embodiment one (7) condition and method

(8) (Z)-2-(2,6-dichlorobenzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine synthetic

Synthetic such as embodiment one (8) condition and method, difference is to add 0.07 g 2, and the 6-dichlorobenzaldehyde gets yellow solid 0.041g.

Embodiment seven, compound (E)-2-(2,6-dichlorobenzene methylene radical)-(compound number is hydrazine 1-(5,6,7-trimethoxy quinazoline-4-yl) h) synthetic

(1) 2,3,4 trimethoxybenzoic acid is synthetic

Synthetic such as embodiment one (1) condition and method

(2) the 2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (2) condition and method

(3) 6-nitro-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (3) condition and method

(4) 6-amino-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (4) condition and method

(5) 5,6,7-trimethoxy quinazoline-4-(3H)-ketone synthetic

Synthetic such as embodiment one (5) condition and method

(6) the 4-chloro-5,6,7-trimethoxy quinazoline synthetic

Synthetic such as embodiment one (6) condition and method

(7) 4-diazanyl-5,6,7-trimethoxy quinazoline synthetic

Synthetic such as embodiment one (7) condition and method

(8) (E)-2-(2,6-dichlorobenzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine synthetic

Synthetic such as embodiment one (8) condition and method, difference is to add 0.07g 2, and the 6-dichlorobenzaldehyde gets light yellow solid 0.040 g.

Embodiment eight, compound (E)-2-(2,4-dihydroxy-benzene methylene radical)-(compound number is hydrazine 1-(5,6,7-trimethoxy quinazoline-4-yl) j) synthetic

(1) 2,3,4 trimethoxybenzoic acid is synthetic

Synthetic such as embodiment one (1) condition and method

(2) the 2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (2) condition and method

(3) 6-nitro-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (3) condition and method

(4) 6-amino-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (4) condition and method

(5) 5,6,7-trimethoxy quinazoline-4-(3H)-ketone synthetic

Synthetic such as embodiment one (5) condition and method

(6) the 4-chloro-5,6,7-trimethoxy quinazoline synthetic

Synthetic such as embodiment one (6) condition and method

(7) 4-diazanyl-5,6,7-trimethoxy quinazoline synthetic

Synthetic such as embodiment one (7) condition and method

(8) (E)-2-(2,4-dihydroxy-benzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine synthetic

Synthetic such as embodiment one (8) condition and method, difference is to add 0.06 g 2, and the 4-Dihydroxy benzaldehyde gets yellow solid 0.106 g.

Embodiment nine, compound (E)-2-(4-isobutyl-benzene methylene radical)-(compound number is hydrazine 1-(5,6,7-trimethoxy quinazoline-4-yl) k) synthetic

(1) 2,3,4 trimethoxybenzoic acid is synthetic

Synthetic such as embodiment one (1) condition and method

(2) the 2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (2) condition and method

(3) 6-nitro-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (3) condition and method

(4) 6-amino-2,3,4 trimethoxybenzoic acid methyl esters is synthetic

Synthetic such as embodiment one (4) condition and method

(5) 5,6,7-trimethoxy quinazoline-4-(3H)-ketone synthetic

Synthetic such as embodiment one (5) condition and method

(6) the 4-chloro-5,6,7-trimethoxy quinazoline synthetic

Synthetic such as embodiment one (6) condition and method

(7) 4-diazanyl-5,6,7-trimethoxy quinazoline synthetic

Synthetic such as embodiment one (7) condition and method

(8) (E)-2-(4-isobutyl-benzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine synthetic

Synthetic such as embodiment one (8) condition and method, difference is to add 0.07 g 4-isobutyl-benzene formaldehyde, gets light yellow solid 0.101 g.

Synthesizing of embodiment ten, compound (E)-2-(2-hydroxy-5-methyl base α-tolylene)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine (compound number is r)

(1) 2,3,4-triethoxy is benzoic synthetic

Synthetic such as embodiment one (1) condition and method, difference is to add 21.5 g ethyl sulfates, gets 2,3,4-triethoxy phenylformic acid, 4.0 g, productive rate 53.5 %.

(2) 2,3,4-triethoxy methyl benzoate synthetic

Synthetic such as embodiment one (2) condition and method, difference be 2,3,4-triethoxy methyl benzoate 0.9 g, productive rate 53.5 %.

(3) 6-nitro-2,3,4-triethoxy methyl benzoate synthetic

Synthetic such as embodiment one (3) condition and method, difference is to get 6-nitro-2,3,4-triethoxy methyl benzoate yellow oil 0.9 g, productive rate 62.9 %.

(4) 6-is amino-2,3,4-triethoxy methyl benzoate synthetic

Synthetic such as embodiment one (4) condition and method, difference is to get 6-amino-2,3,4-triethoxy methyl benzoate 0.8 g, productive rate 67.8 %.

(5) 5,6,7-triethoxy quinazoline-4-( 3HSynthesizing of)-ketone

Synthetic such as embodiment one (5) condition and method, difference be 5,6,7-triethoxy quinazoline-4-( 3H)-ketone 3.3 g, productive rate 67.3 %.

(6) the 4-chloro-5,6,7-triethoxy quinazoline synthetic

Synthetic such as embodiment one (6) condition and method, difference is to get 4-chloro-5,6,7-triethoxy quinazoline 0.4 g, productive rate 75.5 %.

(7) 4-diazanyl-5,6,7-triethoxy quinazoline synthetic

Synthetic such as embodiment one (7) condition and method, difference is to get 4-diazanyl-5,6,7-triethoxy quinazoline 0.45 g, productive rate 65.2%.

(8) (E)-2-(2-hydroxy-5-methyl base α-tolylene)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine synthetic

Synthetic such as embodiment one (8) condition and method, difference is to add 0.06 g 2-hydroxy-5-methyl benzaldehyde, gets brown color solid 0.066 g.

Institute's composite part structural formula of compound is as follows:

Table 1Composite part contains 4-[2-(substituted benzene methylene radical) diazanyl]-5,6,7-tri-alkoxy quinazoline ditosylate salt

Synthetic part 4-[2-(substituted benzene methylene radical) diazanyl]-5,6, the spectral data of 7-tri-alkoxy quinazoline compounds descends:

(E)-2-(4-oil of mirbane methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine (compound a)

Yellow solid, yield 50.1%, 199 ~ 202 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃, CD ₃The OD mixed solvent) δ: 7.86,7.94,8.13 (3s, 9H, 3OCH ₃), 10.96 (s, 1H, H-8 of quinazoline), 12.17 (s, 1H, H-2 of quinazoline), 11.99-12.00 (d, 2H, H-2,6 of Ar-H, J=5.00 Hz), 12.19-12.20 (d, 2H, H-3,5 of Ar-H, J=5.00 Hz), 12.16 (s, 1H, N=CH). ESI-MS M/z: (M+H) ⁺384.2.

(E)-2-(4-(N, N dimethylamine base) α-tolylene)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine (compound b)

Yellow solid, yield 59.6%, 95 ~ 98 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃, CD ₃The OD mixed solvent) δ: 5.15 (s, 1H, N=CH), 7.86,7.94,8.13 (3s, 9H, 3OCH ₃), 10.96 (s, 1H, H-8 of quinazoline), 11.99-12.00 (d, 2H, H-2,6 of Ar-H, J=5.00 Hz), 12.19-12.20 (d, 2H, H-3,5 of Ar-H, J=5.00 Hz), 12.16 (s, 1H, H-2 of quinazoline), 12.17 (s, 1H, NH). ESI-MS M/z: (M+H) ⁺382.2.

(E)-2-(2,3-dimethoxy α-tolylene)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine (compound c)

Yellow oil, yield 52.5%. ¹HNMR (500 MHz, CD ₃OD) δ: 3.86,3.88 (2s, 6H, 2OCH ₃Of Ar-H), 3.91,3.98,4.17 (3s, 9H, 3OCH ₃), 6.98 (s, 1H, H-8 of quinazoline), 7.06-7.09 (m, 2H, H-4,5 of Ar-H), 7.81-7.83 (d, 1H, H-6 of Ar-H, J=10.00 Hz), 8.37 (s, 1H, N=CH), 8.56 (s, 1H, H-2 of quinazoline), 12.16 (s, 1H, NH). ESI-MS M/z: (M+H) ⁺399.2.

(E)-2-(2-hydroxy-5-methyl oxygen base α-tolylene)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine (compound d)

Yellow solid, yield 50.2%, 192 ~ 195 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃) δ: 3.79 (s, 3H, OCH ₃Of Ar-H), 3.94,3.99,4.18 (3s, 9H, 3OCH ₃), 6.76 (s, 1H, H-6 of Ar-H), 6.89-6.91 (d, 1H, H-4 of Ar-H, J=10.00 Hz), 6.97-6.99 (d, 1H, H-3 of Ar-H, J=10.00 Hz), 7.07 (s, 1H, H-8 of quinazoline), 8.12 (s, 1H, N=CH), 8.66 (s, 1H, H-2 of quinazoline), 10.76 (s, 1H, OH), 11.22 (s, 1H, NH). ESI-MS M/z: (M+H) ⁺385.2.

(E)-2-(2-anisole methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine (Verbindung)

Yellow solid, yield 79.6%, 167 ~ 169 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃) δ: 3.89 (s, 3H, OCH ₃Of Ar-H), 3.94,3.98,4.16 (3s, 9H, 3OCH ₃), 6.90-6.92 (d, 1H, H-3 of Ar-H, J=10.00 Hz), 6.99-7.02 (t, 1H, H-5 of Ar-H, J=7.50 Hz), 7.07 (s, 1H, H-8 of quinazoline), 7.34-7.36 (t, 1H, H-4 of Ar-H, J=5.00 Hz), 8.20-8.22 (d, 1H, H-6 of Ar-H, J=10.00 Hz), 8.47 (s, 1H, N=CH), 8.67 (s, 1H, H-2 of quinazoline), 10.95 (s, 1H, NH). ESI-MS M/z: (M+H) ⁺369.2.

(E)-2-(2,4 dichloro benzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine (compound f)

Light yellow solid, yield 55.0%, 197 ~ 199 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃) δ: 8.23 (s, 1H, N=CH), 3.94,3.98,4.17 (3s, 9H, 3OCH ₃), 7.08 (s, 1H, H-8 of quinazoline), 8.67 (s, 1H, H-2 of quinazoline), 7.19-7.22 (t, 1H, H-4 of Ar-H, J=7.50 Hz), 7.34-7.37 (d, 2H, H-3,5 of Ar-H, J=20.00 Hz), 11.09 (s, 1H, NH). ESI-MS M/z: (M+H) ⁺407.2.

(Z)-2-(2,6-dichlorobenzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine (compound g)

Yellow solid, yield 31.5%, 182 ~ 185 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃) δ: 3.95,4.00,4.18 (3s, 9H, 3OCH ₃), 7.41 (s, 1H, H-3 of Ar-H), 7.30-7.31 (d, 1H, H-5 of Ar-H, J=5.00 Hz), 8.24-8.26 (d, 1H, H-6 of Ar-H, J=10.00 Hz), 7.11 (s, 1H, H-8 of quinazoline), 8.40 (s, 1H, N=CH), 8.70 (s, 1H, H-2 of quinazoline), 11.12 (s, 1H, NH). ESI-MS M/z: (M+H) ⁺407.2.

(E)-2-(2,6-dichlorobenzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine (compound h)

Light yellow solid, yield 31.5%, 219 ~ 222 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃) δ: 7.67 (s, 1H, N=CH), 3.53,3.81,3.96 (3s, 9H, 3OCH ₃), 7.05 (s, 1H, H-8 of quinazoline), 8.69 (s, 1H, H-2 of quinazoline), 7.41-7.45 (t, 1H, H-4 of Ar-H, J=10.00 Hz), 7.49-7.50 (d, 2H, H-3,5 of Ar-H, J=5.00 Hz), 10.76 (s, 1H, NH). ESI-MS M/z: (M+H) ⁺407.2.

(E)-2-(2-chlorobenzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine (compound i)

Yellow solid, yield 53.8%, 168 ~ 170 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃) δ: 3.95,4.00,4.18 (3s, 9H, 3OCH ₃), 7.30-7.32 (m, 2H, H-4,5 of Ar-H), 7.37-7.39 (m, 1H, H-3 of Ar-H), (8.29-8.31 m, 1H, H-6 of Ar-H), 7.13 (s, 1H, H-8 of quinazoline), 8.48 (s, 1H, N=CH), 8.69 (s, 1H, H-2 of quinazoline), (11.10 s, 1H, NH). ESI-MS M/z: (M+H) ⁺373.1.

(E)-2-(2,4-dihydroxy-benzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine (compound j)

Yellow solid, yield 89.2%, m.p.〉250 ℃; ¹HNMR (500 MHz, DMSO-d ₆) δ: 3.83,3.95,4.08 (3s, 9H, 3OCH ₃), 6.35-6.37 (dd, 1H, H-5 of Ar-H, J=10.00 Hz), 7.40-7.42 (d, 1H, H-6 of Ar-H, J=10.00 Hz), 6.31 (s, 1H, H-3 of Ar-H), 7.03 (s, 1H, H-8 of quinazoline), 8.46 (s, 1H, N=CH), 8.71 (s, 1H, H-2 of quinazoline), 10.02 (s, 1H, NH). and ESI-MS M/z: (M+H) ⁺371.2.

(E)-2-(4-isobutyl-benzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine (compound k)

Light yellow solid, yield 80.4%, 90 ~ 92 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃) δ: 1.32 (s, 9H, 4-tert-butyl of Ar), 3.92,3.97,4.14 (3s, 9H, 3OCH ₃), 7.40-7.42 (d, 2H, H-3,5 of Ar-H, J=10.00 Hz), 7.74-7.76 (d, 2H, H-2,6 of Ar-H, J=10.00 Hz), 7.05 (s, 1H, H-8 of quinazoline), 8.03 (s, 1H, N=CH), 8.66 (s, 1H, H-2 of quinazoline), 10.91 (s, 1H, NH). ESI-MS M/z: (M+H) ⁺395.2.

(E)-2-(3,4-dihydroxy-benzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine (compound l)

Yellow solid, yield 68.4%, 245 ~ 248 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃, CD ₃The OD mixed solvent) δ: 7.87,7.98,8.22 (3s, 9H, 3OCH ₃), 11.03 (s, 1H, H-2 of Ar-H), 10.69-10.70 (d, 1H, H-5 of Ar-H, J=5.00 Hz), 11.44-11.45 (d, 1H, H-6 of Ar-H), 11.04 (s, 1H, H-8 of quinazoline), 11.43 (s, 1H, N=CH), 11.49 (s, 1H, H-2 of quinazoline), 12.30 (s, 1H, NH). ESI-MS M/z: (M+H) ⁺371.1.

(E)-2-(2-chlorobenzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine (compound m)

Yellow solid, yield 58.9%, 156 ~ 158 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃) δ: 1.41-1.58 (3t, 9H, 3OCH ₂ CH ₃ ), 4.11-4.49 (m, 6H, 3O CH ₂ CH ₃), 7.29-7.31 (m, 2H, H-4,5 of Ar-H), 7.36-7.37 (m, 1H, H-3 of Ar-H), (8.28-8.31 m, 1H, H-6 of Ar-H), 7.05 (s, 1H, H-8 of quinazoline), 8.48 (s, 1H, N=CH), 8.68 (s, 1H, H-2 of quinazoline), (11.41 s, 1H, NH). ESI-MS M/z: (M+H) ⁺415.2.

(E)-2-(4-isobutyl-benzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine (compound n)

Light yellow solid, yield 50.5%, 161 ~ 163 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃) δ: 1.33 (s, 9H, 4-tert-butyl of Ar), 1.41-1.55 (3t, 9H, 3OCH ₂ CH ₃ ), 4.11-4.45 (m, 6H, 3O CH ₂ CH ₃), 7.41-7.43 (d, 2H, H-3,5 of Ar-H, J=10.00 Hz), 7.75-7.76 (d, 2H, H-2,6 of Ar-H, J=5.00 Hz), 7.04 (s, 1H, H-8 of quinazoline), 8.01 (s, 1H, N=CH), 8.67 (s, 1H, H-2 of quinazoline), 11.18 (s, 1H, NH). ESI-MS M/z: (M+H) ⁺437.3.

(E)-2-(2,4 dichloro benzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine (compound o)

Light yellow solid, yield 69.6%, 193 ~ 195 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃) δ: 1.41-1.57 (3t, 9H, 3OCH ₂ CH ₃ ), 4.11-4.49 (m, 6H, 3O CH ₂ CH ₃), 7.40 (s, 1H, H-3 of Ar-H), 7.28-7.30 (d, 1H, H-5 of Ar-H, J=10.00 Hz), 8.23-8.25 (d, 1H, H-6 of Ar-H, J=10.00 Hz), 7.04 (s, 1H, H-8 of quinazoline), 8.39 (s, 1H, N=CH), 8.68 (s, 1H, H-2 of quinazoline), 11.42 (s, 1H, NH). ESI-MS M/z: (M+H) ⁺449.2.

(E)-2-(4-oil of mirbane methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine (compound p)

Yellow solid, yield 50.1%, 232 ~ 235 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃) δ: 1.40-1.58 (3t, 9H, 3OCH ₂ CH ₃ ), 4.12-4.51 (m, 6H, 3O CH ₂ CH ₃), 8.08 (s, 1H, N=CH), 7.07 (s, 1H, H-8 of quinazoline), 8.72 (s, 1H, H-2 of quinazoline), 7.98-8.00 (d, 2H, H-2,6 of Ar-H, J=10.00 Hz), 8.26-8.27 (d, 2H, H-3,5 of Ar-H, J=5.00 Hz), 11.45 (s, 1H, NH). ESI-MS M/z: (M+H) ⁺426.2.

(E)-2-(3,4-dimethoxy α-tolylene)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine (compound q)

Light yellow solid, yield 66.2%, 159 ~ 161 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃) δ: 3.92,3.99 (2s, 6H, 2OCH ₃Of Ar), 1.40-1.56 (3t, 9H, 3OCH ₂ CH ₃ ), 4.11-4.46 (m, 6H, 3O CH ₂ CH ₃), 7.56 (s, 1H, H-2 of Ar-H), 7.17-7.19 (d, 1H, H-6 of Ar-H, J=10.00 Hz), 6.87-6.88 (d, 1H, H-5 of Ar-H, J=5.00 Hz), 7.03 (s, 1H, H-8 of quinazoline), 7.97 (s, 1H, N=CH), 8.63 (s, 1H, H-2 of quinazoline), 11.14 (s, 1H, NH). ESI-MS M/z: (M+H) ⁺441.2.

(E)-2-(2-hydroxy-5-methyl base α-tolylene)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine (compound r)

The brown color solid, yield 58.8%, 199 ~ 201 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃, CD ₃The OD mixed solvent) δ: 6.20 (s, 3H, CH ₃Of Ar-H), 5.32-5.48 (3t, 9H, 3OCH ₂ CH ₃ ), 8.04-8.41 (3q, 6H, 3O CH ₂ CH ₃), 11.06 (s, 1H, H-6 of Ar-H), 11.01-11.06 (d, 1H, H-4 of Ar-H, J=25.00 Hz), 10.80-10.82 (d, 1H, H-3 of Ar-H, J=10.00 Hz), 10.90 (s, 1H, H-8 of quinazoline), 12.09 (s, 1H, N=CH), 12.41 (s, 1H, H-2 of quinazoline), 11.35 (s, 1H, OH). ESI-MS M/z: (M+H) ⁺411.2.

(E)-2-(2,3-dihydroxy-benzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine (compound s)

Yellow solid, yield 50.4%, 246 ~ 248 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃, CD ₃The OD mixed solvent) δ: 5.33-5.49 (3t, 9H, 3OCH ₂ CH ₃ ), 7.97-8.16 (m, 6H, 3O CH ₂ CH ₃), 10.72-10.73 (t, 1H, H-5 of Ar-H, J=2.50 Hz), 10.80-10.81 (d, 1H, H-4 of Ar-H, J=5.00 Hz), 10.83-10.85 (d, 1H, H-6 of Ar-H, J=10.00 Hz), 10.91 (s, 1H, H-8 of quinazoline), 12.13 (s, 1H, N=CH), 12.40 (s, 1H, H-2 of quinazoline). ESI-MS M/z: (M+H) ⁺413.2.

(E)-2-(2,4-dihydroxy-benzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine (compound t)

Brown color solid, yield 56.7%, m.p.〉250 ℃; ¹HNMR (500 MHz, CD ₃OD, DMSO- d ₆ Mixed solvent) δ: 1.29-1.43 (3t, 9H, 3OCH ₂ CH ₃ ), 4.04-4.48 (m, 6H, 3O CH ₂ CH ₃), 6.34-6.35 (dd, 1H, H-5 of Ar-H, J=5.00 Hz), 7.45-7.46 (d, 1H, H-6 of Ar-H, J=5.00 Hz), 6.29 (s, 1H, H-3 of Ar-H), 6.99 (s, 1H, H-8 of quinazoline), 8.59 (s, 1H, N=CH), 8.60 (s, 1H, H-2 of quinazoline). ESI-MS M/z: (M+H) ⁺413.2.

(E)-2-(2-anisole methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine (compound u)

The brown color solid, yield 50.4%, 145 ~ 148 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃) δ: 3.86 (s, 3H, OCH3 of Ar-H), 1.39-1.54 (3t, 9H, 3OCH ₂ CH ₃ ), 4.09-4.46 (m, 6H, 3O CH ₂ CH ₃), 6.87-6.89 (d, 1H, H-3 of Ar-H, J=10.00 Hz), 6.97-7.00 (t, 1H, H-5 of Ar-H, J=7.50 Hz), 7.07 (s, 1H, H-8 of quinazoline), 7.32-7.36 (t, 1H, H-4 of Ar-H, J=10.00 Hz), 8.22-8.23 (d, 1H, H-6 of Ar-H, J=5.00 Hz), 8.45 (s, 1H, N=CH), 8.64 (s, 1H, H-2 of quinazoline), 11.00 (s, 1H, NH). ESI-MS M/z: (M+H) ⁺411.2.

(Z)-2-(2,6-dichlorobenzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine (compound v)

Yellow solid, yield 20.5%, 96 ~ 99 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃) δ: 8.60 (s, 1H, N=CH), 0.76-1.51 (3t, 9H, 3OCH ₂ CH ₃ ), 3.91-4.18 (m, 6H, 3O CH ₂ CH ₃), 7.17 (s, 1H, H-8 of quinazoline), (8.22 s, 1H, H-2 of quinazoline), 7.19-7.22 (t, 1H, H-4 of Ar-H, J=7.50 Hz), 7.33-7.35 (d, 2H, H-3,5 of Ar-H, J=10.00 Hz), (10.89 s, 1H, NH). ESI-MS M/z: (M+H) ⁺449.2.

(E)-2-(2,6-dichlorobenzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine (compound w)

Light yellow solid, yield 20.5%, 134 ~ 137 ℃ of m.p.; ¹HNMR (500 MHz, CDCl ₃) δ: 0.76-1.51 (3t, 9H, 3OCH ₂ CH ₃ ), 3.91-4.18 (m, 6H, 3O CH ₂ CH ₃), 7.03 (s, 1H, H-8 of quinazoline), 7.39-7.42 (t, 1H, H-4 of Ar-H, J=7.50 Hz), 7.47-7.48 (d, 2H, H-3,5 of Ar-H, J=5.00 Hz), 7.66 (s, 1H, N=CH), 8.68 (s, 1H, H-2 of quinazoline), 10.89 (s, 1H, NH). ESI-MS M/z: (M+H) ⁺449.2.

(E)-2-(3,4-dihydroxy-benzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine (compound x)

Yellow solid, yield 50.2%, 248 ~ 250 ℃ of m.p.; ¹HNMR (500 MHz, CD ₃OD) δ: 1.39-1.54 (m, 9H, 3OCH ₂ CH ₃ ), 4.12-4.58 (m, 6H, 3O CH ₂ CH ₃), 6.78-6.80 (d, 1H, H-5 of Ar-H, J=5.00 Hz), 7.47 (s, 1H, H-2 of Ar-H), 7.14-7.16 (d, 1H, H-6 of Ar-H, J=10.00 Hz), 7.07 (s, 1H, H-8 of quinazoline), 8.16 (s, 1H, N=CH), 8.45 (s, 1H, H-2 of quinazoline). ESI-MS M/z: (M+H) ⁺413.2.

(E)-2-(4-(N, N dimethylamine base) α-tolylene)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine (compound y)

Yellow solid, yield 50.2%, 145 ~ 148 ℃ of m.p.; ¹HNMR (500 MHz, CD ₃OD) δ: 1.38-1.52 (m, 9H, 3OCH ₂ CH ₃ ), 4.08-4.44 (m, 6H, 3O CH ₂ CH ₃), 7.16 (s, 1H, H-8 of quinazoline), 6.65-6.67 (d, 2H, H-2,6 of Ar-H, J=10.00 Hz), 7.67-7.69 (d, 2H, H-3,5 of Ar-H, J=10.00 Hz), 7.89 (s, 1H, N=CH), 8.59 (s, 1H, H-2 of quinazoline). ESI-MS M/z: (M+H) ⁺424.2.

(E)-2-(2-hydroxy-5-methyl oxygen base α-tolylene)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine (compound z)

Yellow solid, yield 50.2%, 231 ~ 233 ℃ of m.p.; 1HNMR (500 MHz, CDCl ₃) δ: 3.76 (s, 3H, OCH ₃Of Ar-H), 1.40-1.56 (m, 9H, 3OCH ₂ CH ₃ ), 4.12-4.49 (m, 6H, 3O CH ₂ CH ₃), 7.11 (s, 1H, H-6 of Ar-H), (6.84-6.86 d, 1H, H-4 of Ar-H, J=10.00 Hz), (6.91-6.93 d, 1H, H-3 of Ar-H, J=10.00 Hz), (6.92 s, 1H, H-8 of quinazoline), 8.02 (s, 1H, N=CH), 8.58 (s, 1H, H-2 of quinazoline), 11.09 (s, 1H, NH) .. ESI-MS M/z: (M+H) ⁺427.2.

Embodiment 11, compound are to the inhibition activity test method of six kind of plant pathogenic fungies

Adopt growth rate method, take fusarium graminearum (G. zeae), capsicum wilt bacterium (F.oxysporum), apple decay bacterium (C. mandshurica) as tested object, the Antifungal Activity in Vitro of target compound is carried out preliminary screening.Main potato dextrose agar (PDA) substratum that adopts, measuring respectively 90 mL substratum, to be divided in the 200 mL triangular flasks sterilization for subsequent use.The preparation of pastille substratum is all carried out under aseptic condition, and every kind of drug concentration is made as 50 μ g/mL.Take by weighing respectively various medicaments in 10 mL volumetric flasks, add the aqua sterilisa that contains 0.1% Tween 20 and be mixed with certain density medicament, add in the 90 mL PDA substratum (40-50 ° of C), fully shake up, be poured in the culture dish after the sterilization of diameter 9 cm, if three times are repeated, take the solvent that adds equivalent as blank.During primary dcreening operation, take fusarium graminearum, capsicum wilt bacterium, apple decay bacterium as the screening object, to grow with punch tool (internal diameter 4 mm), to make some bacterium cakes for subsequent use for the punching of normal bacterium colony, with inoculating needle the bacterium cake is moved and to receive dull and stereotyped central authorities, every ware connects a bacterium cake, place 27 ° of C saturated humidity constant incubators to cultivate, when treating that contrast is covered with, measure colony diameter.Each bacterium colony is measured 2 times by the right-angled intersection method, represents the size of bacterium colony with its mean number, and the calculation formula of bacteriostasis rate is as follows:

I/%＝[(C－T)/(C－0.4)]×100

I is inhibiting rate, and C is blank diameter, and T is for processing diameter

Same method also be applicable to compound to botrytis cinerea pers ( Botrytis cinerea), the late blight of potato Bacterium (Phytophthora infestans), Rhizoctonia solani Kuhn ( Thanatephorus cucumeris (Frank) Donk)The inhibition active testing.

Annotate: "-" expression does not detect it and suppresses active.

As can be seen from Table 2, compound when concentration is 50mg/L f, g, i, m, n, o, rAll have certain inhibition active to botrytis cinerea, inhibiting rate is respectively 57.7%, 61.1%, 55.3%, 58.5%, 54.9%, 50.1%, 58.1%; d, e, k, s, t, xInhibition to botrytis cinerea is better active, and inhibiting rate is respectively 72.6%, 74.0%, 86.2%, 70.6%, 70.0%, 76.8%.Compound mRhizoctonia solani is had certain inhibition activity, and inhibiting rate is 64.6%.

Embodiment 12, compound suppress activity test method to the in-vitro multiplication of five kinds of cancer cells

With the uplink and downlink of 96 orifice plates sterilization intermediate water edge sealing, every hole 200 μ L.The cell in vegetative period of taking the logarithm after the conventional digestion, is resuspended among the RPMI 1640 or DMDM substratum that contains 10% FBS, with 2 * 10 ⁴The final concentration of individual/mL is inoculated in 96 well culture plates, every hole 100 μ L, and the rightmost side one is classified the blank group as, adds acellular serum RPMI 1640 substratum that have.Place 37 ℃, 5% CO ₂The saturated humidity incubator in cultivate 24 h and make cell attachment.Sop up substratum, add the blood serum medium that has that contains different pharmaceutical concentration, every hole 200 μ L notice that the DMSO final concentration can not surpass 0.1% in the substratum, and the every hole of blank group adds 200 μ L perfect mediums.Process respectively the requirement of experiment time, remove supernatant, add the MTT of 100 μ L/well concentration, 0.5 mg/mL.Cultivate 10% the SDS that adds again 100 μ Lwell behind 4 h.37 ℃ of lower 10 h make crystallisate fully dissolve rear taking-up, and 5 min are swung in microseism, place 30 min under the room temperature, at A ₅₉₅Survey the OD value under the wavelength, and calculate cytoactive, inhibiting rate and P value.

Take drug level or treatment time as transverse axis, OD value or inhibiting rate are the longitudinal axis, curve plotting.Every concentration of specimens repeats six holes, and each tests triplicate, averages to be net result.

Experimental result is carried out variance analysis with SPSS software, and p＜0.05 o'clock is significant difference, and p＜0.01 o'clock is that difference is extremely remarkable.The inhibiting rate calculation formula of cell proliferation is as follows:

Table 3 contains 4-[2-(substituted benzene methylene radical) diazanyl]-5,6,7-tri-alkoxy quinazoline derivative is to the inhibiting rate of Bcap-37, MGC803 and PC3 tumour cell

Annotate: it is active that "-" expression does not detect its vitro inhibition.

Table 4 contains 4-[2-(substituted benzene methylene radical) diazanyl]-5,6,7-tri-alkoxy quinazoline derivative to A375,

Annotate: it is active that "-" expression does not detect its vitro inhibition.

As can be seen from Table 3, compound when concentration is 10 μ M d, j, r, s, t, w, zInhibition to human breast cancer cell strain (Bcap-37) cancer cells is better active, and inhibiting rate is 85.2%, 75.1%, 73.5%, 76.4%, 65.2%, 73.8%, 91.5%; Be 1 in concentration μCompound during M j, r, t, zBetter active to the inhibition of human breast cancer cell strain (Bcap-37) cancer cells, inhibiting rate is respectively 66.6%, 77.7%, 57.9%, 86.8%, and it suppresses activity, and all to be much better than control drug Gefitinib (be 10 in concentration μM and 1 μInhibiting rate during M is respectively 27.9% and 16.4%); Be 10 in concentration μCompound during M d, j, m, n, r, s, t, u, w, zInhibition to people's gastric adenocarcinoma cells strain (MGC803) cancer cells is better active, and inhibiting rate is respectively 80.8%, 73.3%, 91.4%, 80.4%, 89.9%, 71.9%, 76.8%, 77.5%, 69.1%, 78.5%, is 1 in concentration μCompound during M d, j, r, s, t, zInhibition to people's gastric adenocarcinoma cells strain (MGC803) cancer cells is better active, inhibiting rate is respectively 79.1%, 74.1%, 81.0%, 73.1%, 68.0%, 66.5%, and it suppresses activity and all is much better than control drug Gefitinib (inhibiting rate when concentration is 10 μ M and 1 μ M is respectively 51.8% and-2.6%); Compound when concentration is 10 μ M d, j, m, r, s, t, w, zInhibition to human prostate cancer cell line (PC3) cancer cells is better active, and inhibiting rate is respectively 90.9%, 83.3%, 70.3%, 84.6%, 71.9%, 70.4%, 88.6%, 84.0%; Compound when concentration is 1 μ M d, j, r, t, zInhibition to human prostate cancer cell line (PC3) cancer cells is better active, inhibiting rate is respectively 60.8%, 64.8%, 66.7%, 56.8%, 75.5%, and it suppresses activity and all is much better than control drug Gefitinib (inhibiting rate when concentration is 10 μ M and 1 μ M is respectively 49.6% and 25.1%).

As can be seen from Table 4, compound when concentration is 10 μ M d, h, j, m, r, s, t, w, zInhibition to people's malignant melanoma cell strain (A375) cancer cells is better active, and inhibiting rate is respectively 98.9%, 94.3%, 98.3%, 81.8%, 91.6%, 91.4%, 91.7%, 95.5%, 96.0%; Compound when concentration is 1 μ M d, j, r, s, t, zInhibition to people's malignant melanoma cell strain (A375) cancer cells is better active, inhibiting rate is respectively 94.0%, 95.3%, 91.1%, 87.6%, 90.9%, 93.9%, and it suppresses activity, and all to be much better than control drug Gefitinib (be 10 μ M and 1 in concentration μInhibiting rate during M is respectively 32.1% and 18.9%); Compound when concentration is 10 μ M d, j, n, r, s, t, w, zInhibition to human stomach cancer cell line (BGC823) cancer cells is better active, and inhibiting rate is respectively 93.5%, 90.5%, 69.7%, 77.0%, 69.9%, 70.6%, 79.5%, 80.5%; Compound when concentration is 1 μ M j, r, s, zInhibition to human stomach cancer cell line (BGC823) cancer cells is better active, inhibiting rate is respectively 60.8%, 73.5%, 52.6%, 64.9%, and it suppresses activity and all is much better than control drug Gefitinib (inhibiting rate when concentration is 10 μ M and 1 μ M is respectively 16.7% and 13.4%).

The embodiment of the invention is aided with explanation technical scheme of the present invention, but the content of embodiment is not limited to this.

Claims (5)

1. 4-[2-(substituted benzene methylene radical) diazanyl]-5,6,7-tri-alkoxy quinazoline compounds, its compound structure general formula is as follows:

( I)

R wherein ₁Be methyl, ethyl, propyl group, sec.-propyl, butyl;

R ₂For adjacent on the phenyl ring,, contain one or more substituting groups in the contraposition, substituting group is hydroxyl, methyl, ethyl, n-propyl, sec.-propyl, butyl, isobutyl-, the tertiary butyl, methoxyl group, oxyethyl group, propoxy-, butoxy, allyl group, acrylamido, trifluoromethyl, trifluoromethoxy, amido, substituted amido, nitro and halogen atom, and halogen atom is fluorine, chlorine, bromine, iodine.

2. compound according to claim 1 is characterized in that described compound is as follows:

Compound a:

(E))-2-(4-oil of mirbane methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound b:

(E)-2-(4-(N, N dimethylamine base) α-tolylene)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound c:

(E)-2-(2,3-dimethoxy α-tolylene)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound d:

(E)-2-(2-hydroxy-5-methyl oxygen base α-tolylene)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Verbindung:

(E)-2-(2-anisole methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound f:

(E)-2-(2,4 dichloro benzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound g:

(Z)-2-(2,6-dichlorobenzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound h:

(E)-2-(2,6-dichlorobenzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound i:

(E)-2-(2-chlorobenzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound j:

(E)-2-(2,4-dihydroxy-benzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound k:

(E)-2-(4-isobutyl-benzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound l:

(E)-2-(3,4-dihydroxy-benzene methylene radical)-1-(5,6,7-trimethoxy quinazoline-4-yl) hydrazine

Compound m:

(E)-2-(2-chlorobenzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound n:

(E)-2-(4-isobutyl-benzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound o:

(E)-2-(2,4 dichloro benzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound p:

(E)-2-(4-oil of mirbane methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound q:

(E)-2-(3,4-dimethoxy α-tolylene)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound r:

(E)-2-(2-hydroxy-5-methyl base α-tolylene)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound s:

(E)-2-(2,3-dihydroxy-benzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound t:

(E)-2-(2,4-dihydroxy-benzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound u:

(E)-2-(2-anisole methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound v:

(Z)-2-(2,6-dichlorobenzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound w:

(E)-2-(2,6-dichlorobenzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound x:

(E)-2-(3,4-dihydroxy-benzene methylene radical)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound y:

(E)-2-(4-(N, N dimethylamine base) α-tolylene)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine

Compound z:

(E)-2-(2-hydroxy-5-methyl oxygen base α-tolylene)-1-(5,6,7-triethoxy quinazoline-4-yl) hydrazine.

3. the application of compound according to claim 1 and 2 in preparation anti-plant pathogen and cancer therapy drug.

4. described 4-[2-(substituted benzene methylene radical) diazanyl according to claim 1]-5,6, the preparation method of 7-tri-alkoxy quinazoline compounds, it is characterized in that general formula ( I) preparation method of compound is with 2,3,4-trihydroxybenzoic acid, methyl-sulfate, ethyl sulfate, methyl alcohol, sulfuric acid, nitric acid, hydrogen, methane amide, phosphorus oxychloride, 80% hydrazine hydrate, aromatic aldehyde are raw material, through etherificate, esterification, nitrated, reduction, closed loop, chloro, diazanyl, become eight steps of hydrazone reaction synthetic, its synthetic route is:

。

5. 4-[2-according to claim 4 (substituted benzene methylene radical) diazanyl]-5,6, the preparation method of 7-tri-alkoxy quinazoline compounds is characterized in that eight steps are synthetic, synthetic method is:

The first step: the benzoic preparation of 2,3,4-tri-alkoxy

With a small amount of 2,3,4-trihydroxybenzoic acid and water stir in bottle, drip sodium hydroxide solution and methyl-sulfate (or ethyl sulfate),

Reflux, TLC follows the tracks of reaction process, after raw material point disappears, stopped reaction is neutral with the hydrochloric acid adjust pH, has the reddish-brown solid to separate out, suction filtration is dried to get thick product, filtrate gets thick product with the chloroform extraction precipitation, merges thick product and uses column chromatography the purification of target compound, gets white (or yellow) solid;

Second step: the preparation of 2,3,4-tri-alkoxy methyl benzoate

With a small amount of 2,3,4-front three (or second) aminobenzoic acid and methanol mixed stir, add a small amount of vitriol oil, reflux, TLC follows the tracks of reaction process, after raw material point disappears, stopped reaction, solution precipitation after will reacting adds water, the chloroform extraction precipitation, the column chromatographic isolation and purification target compound gets colorless oil;

The 3rd step: 6-nitro-2,3, the preparation of 4-tri-alkoxy methyl benzoate

With a small amount of 2,3,4-front three (or second) aminobenzoic acid methyl esters adds in the nitric acid, pours frozen water into, and TLC follows the tracks of reaction process, and after the disappearance of raw material point, stopped reaction is used the chloroform extraction precipitation, and the column chromatographic isolation and purification target compound gets yellow solid or oily matter;

The 4th step: 6-amino-2,3, the preparation of 4-tri-alkoxy methyl benzoate

Pass into hydrogen, with a small amount of 6-nitro-2,3,4-front three (or second) aminobenzoic acid methyl esters and a small amount of palladium carbon catalyst and methanol mixed stir, and TLC follows the tracks of reaction process, and after raw material point disappeared, stopped reaction, precipitation got the red-brown solid,

The column chromatographic isolation and purification target compound gets the brown color solid;

The 5th step: 5,6,7-tri-alkoxy quinazoline-4-( 3HThe preparation of)-ketone

With a small amount of 6-amino-2,3,4-tri-alkoxy methyl benzoate, methane amide, phosphorus oxychloride and toluene are mixed thermal backflow, after reaction for some time, separate out a large amount of solids, TLC follows the tracks of reaction process, after raw material point disappears, stopped reaction, precipitation get the red-brown solid, add that to transfer pH value with ammoniacal liquor behind the water be neutral, separate out the tawny precipitation, the chloroform extraction precipitation, the column chromatographic isolation and purification target compound obtains white solid;

The 6th step: 4-chloro-5,6, the preparation of 7-tri-alkoxy quinazoline

With a small amount of quinazolinone, phosphorus oxychloride, triethylamine and toluene mix and blend, TLC follows the tracks of reaction process, after raw material point disappears, stopped reaction, precipitation adds water, and it is neutral transferring pH value with ammoniacal liquor, the chloroform extraction precipitation, the column chromatographic isolation and purification target compound obtains the pistac solid;

The 7th step: 4-diazanyl-5,6, the preparation of 7-tri-alkoxy quinazoline

With a small amount of 4-chloro-5,6,7-tri-alkoxy quinazoline, 80% hydrazine hydrate and ethanol mix, heated and stirred, and TLC follows the tracks of reaction process, after raw material point disappears, stopped reaction, precipitation gets pale solid, a large amount of frozen water washings, purifying obtains white solid;

The 8th step: 4-[2-(substituted benzene methylene radical) diazanyl]-5,6, the preparation of 7-tri-alkoxy quinazoline

With a small amount of 4-diazanyl-5,6,7-tri-alkoxy quinazoline, substituted benzaldehyde, tosic acid and ethanol Hybrid Heating stir, and TLC follows the tracks of reaction process, after raw material point disappears, and stopped reaction, precipitation, the thin layer chromatography purifying gets the class yellow solid.