CN106187919A - Quinazoline derivant containing hydroxamic acid side chain and preparation and application - Google Patents

Quinazoline derivant containing hydroxamic acid side chain and preparation and application Download PDF

Info

Publication number
CN106187919A
CN106187919A CN201610533023.8A CN201610533023A CN106187919A CN 106187919 A CN106187919 A CN 106187919A CN 201610533023 A CN201610533023 A CN 201610533023A CN 106187919 A CN106187919 A CN 106187919A
Authority
CN
China
Prior art keywords
quinazoline
base
epoxide
acrylamido
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN201610533023.8A
Other languages
Chinese (zh)
Inventor
黄卫
陈文腾
邵加安
俞永平
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang University ZJU
Original Assignee
Zhejiang University ZJU
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang University ZJU filed Critical Zhejiang University ZJU
Priority to CN201610533023.8A priority Critical patent/CN106187919A/en
Publication of CN106187919A publication Critical patent/CN106187919A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention provides a kind of quinazoline derivant containing hydroxamic acid side chain, with 4 aryl amine quinazolines as parent nucleus, is condensed by azanol one step of specific linker with THP protection and follow-up deprotection obtains target compound.Experiment proves, on a cellular level the tumor cell (the people epidermal carcinoma cell strain A431 of EGFR process LAN, human lung adenocarcinoma cell line H1975 to Gefitinib drug resistance) relevant to EGFR tyrosine kinase activity had significant inhibited proliferation, particularly drug-resistant cell strain H1975 there is preferable inhibition, the tumor cells such as Hela, HepG2 also there are is preferable inhibition simultaneously, corresponding antitumor cell medicine can be prepared.General structure is as follows:

Description

Quinazoline derivant containing hydroxamic acid side chain and preparation and application
Technical field
The invention belongs to pharmaceutical field, be specifically related to a kind of quinazoline derivant containing hydroxamic acid side chain, preparation method, Intermediate and application thereof.
Background technology
Epidermal growth factor recipient tyrosine kinase (epidermal growth factor receptor is called for short EGFR) It it is an important target spot of current oncotherapy.EGFR is the expression product of proto-oncogene ErbB-1 (Her-1), and proto-oncogene Activation be typically to cause one of tumorigenic reason.Antitumor drug currently for the exploitation of EGFR target spot has been subjected to three For inhibitor.First generation EGFR inhibitor based on gefitinib and Erlotinib can be effectively for EGFR somatic mutation L858R and delE746_A750.But, due to the generation of acquired drug-resistance, the secondary sudden change headed by T790M becomes pulmonary carcinoma and controls The major obstacles treated.To this end, it has been developed that second filial generation EGFR inhibitor, wherein, Afatinib has the most listed and has faced Important effect has been given play on bed.Second filial generation inhibitor generally introduces on the basis of reversible EGFR inhibitor structure can be with There is alkylating functional group in the amino acid residue (Cys-797 or Cys-784) of ATP location proximate.Due to covalently bound work With, the usual plasma half-life of this kind of inhibitor is long, and the highest blood drug level is low, is the long-acting EGFR inhibitor of a class.
Histon deacetylase (HDAC) (HDAC) inhibitor can the enzymatic activity of inhibition of histone deacetylase so that There is acetylation in HDACs, thus with acetylation of histone transferring enzyme (HAT) antagonism to maintain intracellular acetylation of histone Dynamic equilibrium.But occur all to there is HDAC overexpression during development at Several Kinds of Malignancy, this makes HDAC Become the important target spot of oncotherapy.Correlational study report display, the double target spot inhibitor of EGFR/HDAC is a kind of promising anti- Tumor strategy, is particularly of great importance to the drug resistance overcoming tumor.
Summary of the invention
It is an object of the invention to provide a kind of quinazoline derivant containing hydroxamic acid side chain, there is following structural formula I:
Wherein:
R1For replacing or unsubstituted C6～C10Aryl or substituted or unsubstituted C3～C12Heteroaryl, described replacement For by C1～C6Alkyl, halogen, hydroxyl, amino, C2～C6Alkynyl, C2～C6Thiazolinyl, C1～C6Alkyl oxy, cyano group, nitro, three Methyl fluoride, C3～C6Cycloalkyl and C3～C6One or more in Heterocyclylalkyl are replaced；
N=3,4,5.
Of the present invention is as follows containing hydroxamic acid side chain quinazoline derivant or its corresponding isomer (compound I) Arbitrary compound:
4-(6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7-base) epoxide-N-maloyl group amine (H- 1),
4-(6-acrylamido-4-(3-bromoanilino) quinazoline-7-base) epoxide-N-maloyl group amine (H-2),
4-(6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7-base) epoxide-N-hydroxyl hexanamide (H- 3),
4-(6-acrylamido-4-(3-bromoanilino) quinazoline-7-base) epoxide-N-hydroxyvaleramide (H-4),
4-(6-acrylamido-4-(3-bromoanilino) quinazoline-7-base) epoxide-N-hydroxyl hexanamide (H-5),
4-(6-acrylamido-4-(4-fluoroanilino) quinazoline-7-base) epoxide-N-maloyl group amine (H-6),
4-(6-acrylamido-4-(4-fluoroanilino) quinazoline-7-base) epoxide-N-hydroxyl hexanamide (H-7),
4-(6-acrylamido-4-(4-fluoroanilino) quinazoline-7-base) epoxide-N-hydroxyvaleramide (H-8),
4-(6-acrylamido-4-(3-methylphenylamino) quinazoline-7-base) epoxide-N-maloyl group amine (H-9),
4-(6-acrylamido-4-(3-methylphenylamino) quinazoline-7-base) epoxide-N-hydroxyvaleramide (H-10),
4-(6-acrylamido-4-(3-methylphenylamino) quinazoline-7-base) epoxide-N-hydroxyl hexanamide (H-11),
4-(6-acrylamido-4-(3-trifluoromethyl phenylamino) quinazoline-7-base) epoxide-N-hydroxyvaleramide (H- 12)。
It is a further object to provide the preparation method of described compound I, realized by following steps:
With 2-amino-4-fluobenzoic acid 1 as initiation material, and formamidine acetate refluxes in glycol monoethyl ether and generates 7-fluorine Quinazolinone 2, compound 2 obtains nitration product 6-nitro-7-Fluquinconazole quinoline ketone 3 under the effect of fuming nitric aicd and concentrated sulphuric acid, Compound 3 generates 4-chloro-6-nitro-7-Fluquinconazole quinoline 4, various substituted arylamine and above-mentionedization with the new thionyl chloride effect steamed Compound 4 reaction obtains 4-aryl amine-6-nitro-7-Fluquinconazole quinoline 5, and compound 5 replaces fluorine atom by hydroxyl and obtains compound 6, compound 6 and bromo fatty-acid ethyl ester occur SNAr to replace to obtain compound 7, and compound 7 generates compound 8 through ferrum reduction, changes The acryloyl chloride protection of the amino of compound 8 generates compound 9, and compound 9 becomes corresponding acid (compound through lithium hydrate 10), compound 10 generates compound 11 with THP protection azanol condensation, and compound 11 deprotection in acid condition obtains whole product Compounds I.Reaction equation:
Wherein, described in all the same structural formula I of the definition of each group.
Raw material involved in the present invention or intermediate, can directly buy, or the literature method mentioned according to embodiment part Preparation.
Compound of formula I described in preparation method of the present invention, can be with organic synthesis and medicinal chemistry art and technology people Prepared by the multiple method known to Yuan, it is possible to use method described above prepares the compound of the present invention, it will be appreciated that When providing typical or preferred process condition (i.e. reaction temperature, time, the mol ratio of reactant, solvent, pressure etc. Deng), it is also possible to use other process conditions, except as otherwise noted.Optimum reaction condition can be with concrete reaction used Thing or solvent and change, but these conditions can be determined by routine optimization process by those skilled in the art.Generally, Reaction scheme as above and technique can be used to prepare the compounds of this invention, but the reagent being not limited in reaction condition and Solvent.
It is also another object of the present invention to provide the new quinazoline derivant of a class answering in preparing antitumor drug The people epidermal carcinoma cell strain A431 of process LAN EGFR, thin to the human lung adenocarcinoma of Gefitinib drug resistance is referred to, described tumor cell Born of the same parents strain H1975, human cervical carcinoma cell Hela and human liver cancer cell HepG2.
A kind of quinazoline derivant containing hydroxamic acid side chain that the present invention provides, by principle of hybridization in second filial generation EGFR The key pharmacophore of hdac inhibitor is introduced to reach the double synergistic mould of target spot of EGFR/HDAC on the basis of inhibitor Formula, to further enhancing the overriding resistance effect to EGFR inhibitor, prevents the desensitization of second filial generation EGFR inhibitor simultaneously.External Antiproliferative Inhibition test result show, designed compound shows medium to good suppression in kinds of tumor cells and lives Property, particularly double to L858R/T790M mutant clone H1975 also have good inhibition.
Detailed description of the invention
Further illustrate the present invention below by the mode of embodiment, but the most therefore limit the present invention to described reality Execute among example scope, the experimental technique of unreceipted actual conditions in the following example, conventionally and condition, or according to business Product description selects.
Embodiment 1 4-(6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7-base) epoxide-N-hydroxyl fourth Amide；
Step:
Raw material 1:4-(3-chloro-4-fluoroanilino)-6-nitro-7-hydroxyquinazoline is according to document CN201210411352.7 Method prepare.
The preparation of raw material 2:4-(4-(3-chloro-4-fluoroanilino)-6-nitro-quinazoline-7-base) epoxide ethyl n-butyrate.:
By 4-(3-chloro-4-fluoroanilino)-6-nitro-7-hydroxyquinazoline (1.1g, 3.3mmol) and 4-bromobutyrate (3.3mmol) it is dissolved in 10mL DMF, in mixed system, adds potassium carbonate (0.45g, 3.3mmol), reaction is stirred at room temperature 36 hours, after question response completes, added water a large amount of solids of precipitation, collected by suction product, column chromatography purified product.
1H NMR (500MHz, DMSO) δ 9.58 (s, 1H), 8.93 (s, 1H), 8.54 (s, 1H), 8.14 (d, J=4.8Hz, 1H), 7.91 7.65 (m, 1H), 7.43 (t, J=9.0Hz, 1H), 7.28 (s, 1H), 4.26 (t, J=6.0Hz, 2H), 4.08 (q, J=7.0Hz, 2H), 2.59 (t, J=7.2Hz, 2H), 2.18 1.99 (m, 2H), 1.18 (t, J=7.1Hz, 3H) .HRMS (ESI)m/z calcd for C20H18ClFN4O5[M+H]+:449.1028.Found:449.1033。
The preparation of raw material 3:4-(4-(chloro-4 fluoroanilino of 3-)-6-amido quinazoline-7-base) epoxide ethyl n-butyrate.
By 4-(4-(chloro-4 fluoroanilino of 3-)-6-nitro-quinazoline-7-base) epoxide ethyl n-butyrate. (1.2g, 2.67mmol) It is dissolved in 20ml THF and 20ml H2In the mixed solvent of 0, then in solution, it is separately added into 0.74g reduced iron powder and 0.71g chlorination Ammonium, 65 degree of stirrings are reacted about 3 hours.After having reacted, it is cooled to room temperature, with diatomaceous Suction filtration device sucking filtration, collects Filtrate, decompression is spin-dried for, and obtains solid.The product that silica gel column chromatography isolated is pure.
1H NMR(500MHz,DMSO)δ9.83(s,1H),9.58(s,1H),8.93(s,1H),8.54(s,1H),8.14 (d, J=4.8Hz, 1H), 7.91 7.65 (m, 1H), 7.43 (t, J=9.0Hz, 1H), 7.28 (s, 1H), 6.26 (brs, 2H), 4.26 (t, J=6.0Hz, 2H), 4.08 (q, J=7.0Hz, 2H), 2.59 (t, J=7.2Hz, 2H), 2.18 1.99 (m, 2H), 1.18 (t, J=7.1Hz, 3H) .HRMS (ESI) m/z calcd for C20H20ClFN4O3[M+H]+:419.1286.Found: 419.1289。
The system of raw material 4:4-(6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7-base) epoxide ethyl n-butyrate. Standby
By molten for 4-(4-(chloro-4 fluoroanilino of 3-)-6-amido quinazoline-7-base) epoxide ethyl n-butyrate. 0.6g (1.4mmol) Solution, in 15ml dichloromethane, adds 200 μ l (1.4mmol) triethylamines and is cooled to 0 DEG C, then drips acryloyl in solution Chlorine 116 μ l (1.4mmol), continues low-temp reaction about 2 hours.After question response, add dichloromethane, and wash with water 3 times, Collecting organic facies, decompression is spin-dried for solvent, and silica gel column chromatography separates (flowing is mutually for DCM:MeOH=50:1) and obtains gray solid, produces Rate is 49%.
1H NMR(500MHz,DMSO)δ9.83(s,1H),9.58(s,1H),8.93(s,1H),8.54(s,1H),8.14 (d, J=4.8Hz, 1H), 7.91 7.65 (m, 1H), 7.43 (t, J=9.0Hz, 1H), 7.28 (s, 1H), 6.75 (dd, J= 16.7,10.3Hz, 1H), 6.34 (d, J=17.0Hz, 1H), 5.84 (d, J=10.4Hz, 1H), 4.26 (t, J=6.0Hz, 2H), 4.08 (q, J=7.0Hz, 2H), 2.59 (t, J=7.2Hz, 2H), 2.18 1.99 (m, 2H), 1.18 (t, J=7.1Hz, 3H).HRMS(ESI)m/z calcd for C23H22ClFN4O4[M+H]+:473.1392.Found:473.1389。
The preparation of raw material 5:4-((6-acrylamido-4-(3-chloro-4-fluoroanilino)) quinazoline-7-base) epoxide butanoic acid
By 4-(6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7-base) epoxide ethyl n-butyrate. 0.2g (0.4mmol) it is dissolved in the mixed solvent of 4ml oxolane and 4ml water, is cooled to 0 DEG C, in solution, then add 0.1g (4mmol) Lithium hydrate, 0 DEG C of stirring is reacted about 1 hour.After question response completes, decompression is spin-dried for oxolane, and then regulation PH is extremely Faintly acid, a large amount of yellow solids separate out, and collected by suction solid product, productivity is 90%.
1H-NMR(500MHz,DMSO)δ12.20(s,1H),9.85(s,1H),9.54(s,1H),8.95(s,1H),8.55 (s, 1H), 8.14 (dd, J=6.8,2.3Hz, 1H), 7.83 7.78 (m, 1H), 7.43 (t, J=9.1Hz, 1H), 7.28 (s, 1H), 6.76 (dd, J=17.0,10.2Hz, 1H), 6.34 (dd, J=17.0,1.8Hz, 1H), 5.84 (dd, J=10.2, 1.7Hz, 1H), 4.26 (t, J=6.3Hz, 2H), 2.51 (m, 2H), 2.08 (m, J=6.8Hz, 2H) .HRMS (ESI) m/z calcd for C21H18ClFN4O4[M+H]+:445.1079.Found:445.1080。
Raw material 6:4-((6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7-base) epoxide)-N-((tetrahydrochysene- 2H-pyrans-2-base) epoxide) preparation of butyramide
By 4-((6-acrylamido-4-(3-chloro-4-fluoroanilino)) quinazoline-7-base) epoxide butanoic acid 0.444g (1mmol) it is dissolved into is dissolved in 4mL dichloromethane and 4mL with O-(tetrahydrochysene-2H-pyrans-2-base) azanol 0.14g (1.2mmol) In N,N-dimethylformamide mixed solution.EDC hydrochlorate 0.248g (1.3mmol), HOBt 0.175g is added in reactant liquor (1.3mmol) and 362 μ l (2.6mmol) triethylamines.40 degree of stirrings are reacted about 3 hours, and TLC detects after completion of the reaction, Xiang Ti 30mL water in system, then extract three times with 20mL dichloromethane, collect organic facies, decompression is spin-dried for, and through column chromatography for separation, (flowing is mutually DCM/MeOH=100:1) obtaining the solid of yellow, productivity is 67.4%.
m.p.:136-138℃；1H-NMR(500MHz,DMSO)δ11.09(s,1H),9.84(s,1H),9.35(s,1H), 9.06 (s, 1H), 8.53 (s, 1H), 8.12 (dd, J=6.8,2.5Hz, 1H), 7.80 (ddd, J=8.9,4.2,2.7Hz, 1H), 7.42 (t, J=9.1Hz, 1H), 7.25 (s, 1H), 6.88 (dd, J=17.0,10.2Hz, 1H), 6.35 (dd, J=17.0, 1.6Hz, 1H), 5.84 (dd, J=10.2,1.6Hz, 1H), 4.81 (s, 1H), 4.28 4.18 (m, 2H), 3.88 (m, 1H), 3.46 (d, J=10.9Hz, 1H), 2.28 (t, J=6.7Hz, 2H), 2.16 2.07 (m, 2H), 1.68 1.43 (m, 6H) .HRMS (ESI)m/z calcd for C26H27ClFN5O5[M+H]+:544.1763.Found:544.1756。
The system of 4-(6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7-base) epoxide-N-maloyl group amine Standby；
By 4-((6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7-base) epoxide)-N-((tetrahydrochysene-2H- Pyrans-2-base) epoxide) butyramide (1mmol) joins in 25mL round-bottomed flask, and adds the dichloromethane of 10mL.Ice bath bar Ether (4.4mL) solution of 1M hydrogen chloride, low-temp reaction about 1.5 hours is instilled under part.Solid is had to separate out after completion of the reaction, sucking filtration Obtain yellow solid.Productivity is 89.2%.
m.p.:167-170℃；1H-NMR(500MHz,DMSO)δ11.44(s,1H),10.63(s,1H),9.71(s, 1H), 9.28 (s, 1H), 8.90 (s, 1H), 7.96 (dd, J=6.8,2.6Hz, 1H), 7.66 (ddd, J=8.9,4.3,2.6Hz, 1H), 7.55 (t, J=9.0Hz, 1H), 7.48 (s, 1H), 6.99 (dd, J=17.0,10.2Hz, 1H), 6.37 (dd, J= 17.0,1.7Hz, 1H), 5.87 (dd, J=10.2,1.7Hz, 1H), 4.27 (t, J=5.8Hz, 2H), 2.28 (t, J=6.7Hz, 2H),2.15(m,2H).HRMS(ESI)m/z calcd for C21H19ClFN5O4[M+H]+:460.1188.Found: 460.1179。
According to embodiment 1 same procedure, use different material, prepare following compound.
Embodiment 2 4-(6-acrylamido-4-(3-bromoanilino) quinazoline-7-base) epoxide-N-maloyl group amine
With reference to the method for embodiment 1, simply by 4-((6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7- Base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) butyramide replaces to 4-((6-acrylamido-4-(3-bromaniline Base) quinazoline-7-base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) butyramide, productivity is 88.3%.m.p.:200- 202℃；1H-NMR(500MHz,DMSO)δ11.34(s,1H),10.60(s,1H),9.69(s,1H),9.28(s,1H),8.90 (s, 1H), 7.96 (t, J=1.9Hz, 1H), 7.71 7.68 (m, 1H), 7.53 7.49 (m, 1H), 7.45 (m, 2H), 6.97 (dd, J=17.0,10.2Hz, 1H), 6.37 (dd, J=17.0,1.7Hz, 1H), 5.87 (dd, J=10.2,1.7Hz, 1H), 4.27 (t, J=5.8Hz, 2H), 2.27 (t, J=6.7Hz, 2H), 2.18 2.11 (m, 2H) .HRMS (ESI) m/z calcd for C21H20BrN5O4[M+H]+:484.0872.Found:484.0873。
Embodiment 3 4-(6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7-base) epoxide-N-hydroxyl is own Amide
With reference to the method for embodiment 1, simply by 4-((6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7- Base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) butyramide replaces to 4-((6-acrylamido-4-(3-chloro-4-fluorine Anilino-) quinazoline-7-base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pentanamide, productivity is 91.3%.
m.p.:174-176℃；1H-NMR(500MHz,DMSO)δ11.49(s,1H),10.58(s,1H),9.93(s, 1H), 9.21 (s, 1H), 8.91 (s, 1H), 7.96 (dd, J=6.8,2.6Hz, 1H), 7.67 (ddd, J=8.9,4.3,2.6Hz, 1H), 7.55 (m, 2H), 6.85 (dd, J=17.0,10.2Hz, 1H), 6.36 (dd, J=17.0,1.8Hz, 1H), 5.87 (dd, J =10.3,1.7Hz, 1H), 4.27 (t, J=6.3Hz, 2H), 2.09 (t, J=7.2Hz, 2H), 1.94 1.81 (m, 2H), 1.78–1.68(m,2H).HRMS(ESI)m/z calcd for C22H21ClFN5O4[M+H]+:472.1439.Found: 472.1435。
Embodiment 4 4-(6-acrylamido-4-(3-bromoanilino) quinazoline-7-base) epoxide-N-hydroxyvaleramide
With reference to the method for embodiment 1, simply by 4-((6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7- Base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) butyramide replaces to 4-((6-acrylamido-4-(3-bromaniline Base) quinazoline-7-base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pentanamide, productivity is 87.2%.
m.p.:177-180℃；1H-NMR(500MHz,DMSO)δ11.43(s,1H),10.51(s,1H),9.91(s, 1H), 9.22 (s, 1H), 8.92 (s, 1H), 7.96 (t, J=1.8Hz, 1H), 7.70 (d, J=8.0Hz, 1H), 7.52 (d, J= 6.5Hz, 2H), 7.45 (t, J=8.0Hz, 1H), 6.85 (dd, J=17.0,10.2Hz, 1H), 6.36 (dd, J=17.0, 1.7Hz, 1H), 5.90 5.84 (m, 1H), 4.28 (t, J=6.1Hz, 2H), 2.09 (t, J=7.1Hz, 2H), 1.87 (m, 2H), 1.74(m,,2H).HRMS(ESI)m/z calcd for C21H19ClFN5O4[M+H]+:498.1028.Found:498.1030。
Embodiment 5 4-(6-acrylamido-4-(3-bromoanilino) quinazoline-7-base) epoxide-N-hydroxyl hexanamide
With reference to the method for embodiment 1, simply by 4-((6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7- Base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) butyramide replaces to 4-((6-acrylamido-4-(3-bromaniline Base) quinazoline-7-base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) caproamide, productivity is 85.4%.
m.p.:175-178℃；1H-NMR(500MHz,DMSO)δ11.37(s,1H),10.45(s,1H),10.30(s, 1H), 9.87 (s, 1H), 9.19 (s, 1H), 8.92 (s, 1H), 7.98 (m, 1H), 7.71 (ddd, J=8.0,1.8,1.0Hz, 1H), 7.54 7.50 (m, 2H), 7.46 (t, J=8.0Hz, 1H), 6.80 (dd, J=16.9,6.7Hz, 1H), 6.36 (dd, J= 17.0,1.6Hz, 1H), 5.92 5.78 (m, 1H), 4.27 (t, J=6.3Hz, 2H), 2.02 (t, J=7.3Hz, 2H), 1.93 1.84(m,2H),1.61(m,2H),1.48(m,2H).HRMS(ESI)m/z calcd for C23H24BrN5O4[M+H]+: 512.1185.Found:512.1186。
Embodiment 6 4-(6-acrylamido-4-(4-fluoroanilino) quinazoline-7-base) epoxide-N-maloyl group amine
With reference to the method for embodiment 1, simply by 4-((6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7- Base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) butyramide replaces to 4-((6-acrylamido-4-(4-fluoroaniline Base) quinazoline-7-base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) butyramide, productivity is 84.9%.
m.p.:186-188℃；1H-NMR(500MHz,DMSO)δ11.43(s,1H),10.63(s,1H),9.72(s, 1H), 9.28 (s, 1H), 8.84 (s, 1H), 7.67 (dd, J=8.9,5.0Hz, 2H), 7.49 (s, 1H), 7.33 (t, J= 8.7Hz, 2H), 6.98 (dd, J=17.0,10.2Hz, 1H), 6.37 (d, J=17.1Hz, 1H), 5.87 (d, J=10.6Hz, 1H), 4.26 (t, J=5.4Hz, 2H), 2.28 (t, J=6.6Hz, 2H), 2.18 2.10 (m, 2H) .HRMS (ESI) m/z calcd for C21H20FN5O4[M+H]+:424.1673.Found:424.1674。
Embodiment 7 4-(6-acrylamido-4-(4-fluoroanilino) quinazoline-7-base) epoxide-N-hydroxyl hexanamide
With reference to the method for embodiment 1, simply by 4-((6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7- Base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) butyramide replaces to 4-((6-acrylamido-4-(4-fluoroaniline Base) quinazoline-7-base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) caproamide, productivity is 88.5%.
m.p.:163-165℃；1H-NMR(500MHz,DMSO)δ11.44(s,1H),10.46(s,1H),10.31(s, 1H), 9.88 (s, 1H), 9.17 (s, 1H), 8.85 (s, 1H), 7.67 (dd, J=8.5,5.1Hz, 2H), 7.52 (d, J= 6.9Hz, 1H), 7.33 (t, J=8.7Hz, 2H), 6.81 (dd, J=17.0,10.2Hz, 1H), 6.35 (d, J=17.0Hz, 1H), 5.87 (d, J=10.5Hz, 1H), 4.25 (t, J=6.3Hz, 2H), 2.01 (t, J=7.3Hz, 2H), 1.93 1.85 (m, 2H),1.64–1.56(m,2H),1.52–1.40(m,2H).HRMS(ESI)m/z calcd for C23H24FN5O4[M+H]+: 452.1986.Found:452.1988。
Embodiment 8 4-(6-acrylamido-4-(4-fluoroanilino) quinazoline-7-base) epoxide-N-hydroxyvaleramide
With reference to the method for embodiment 1, simply by 4-((6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7- Base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) butyramide replaces to 4-((6-acrylamido-4-(4-fluoroaniline Base) quinazoline-7-base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pentanamide, productivity is 87%.
m.p.:184-186℃；1H NMR(500MHz,DMSO)δ11.44(s,1H),9.92(s,1H),9.20(s,1H), 8.84 (s, 1H), 7.66 (dd, J=8.7,5.1Hz, 2H), 7.53 (s, 1H), 7.33 (t, J=8.7Hz, 2H), 6.84 (dd, J =17.0,10.2Hz, 1H), 6.35 (d, J=17.1Hz, 1H), 5.86 (d, J=10.7Hz, 1H), 4.26 (t, J=6.1Hz, 2H), 2.08 (t, J=7.1Hz, 2H), 1.86 (m, 2H), 1.73 (m, 2H) .HRMS (ESI) m/z calcd for C22H22FN5O4[M+H]+:438.1829.Found:438.1830。
Embodiment 9 4-(6-acrylamido-4-(3-methylphenylamino) quinazoline-7-base) epoxide-N-maloyl group amine
With reference to the method for embodiment 1, simply by 4-((6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7- Base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) butyramide replaces to 4-((6-acrylamido-4-(3-methylbenzene Amido) quinazoline-7-base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) butyramide, productivity is 84%.
m.p.:194-196℃；1H-NMR(500MHz,DMSO)δ11.38(s,1H),10.65(s,1H),10.34(s, 1H), 9.73 (s, 1H), 9.27 (s, 1H), 8.83 (s, 1H), 7.49 (s, 1H), 7.44 (d, J=6.5Hz, 2H), 7.37 (t, J =7.7Hz, 1H), 7.15 (d, J=7.5Hz, 1H), 6.98 (dd, J=16.9,10.3Hz, 1H), 6.36 (d, J=17.0Hz, 1H), 5.86 (d, J=10.2Hz, 1H), 4.25 (m, 2H), 2.36 (s, 3H), 2.28 (t, J=6.5Hz, 2H), 2.18 2.10 (m,2H).HRMS(ESI)m/z calcd for C22H23N5O4[M+H]+:422.1828.Found:422.1831。
Embodiment 10 4-(6-acrylamido-4-(3-methylphenylamino) quinazoline-7-base) epoxide-N-hydroxypentanoyl Amine
With reference to the method for embodiment 1, simply by 4-((6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7- Base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) butyramide replaces to 4-((6-acrylamido-4-(3-methylbenzene Amido) quinazoline-7-base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pentanamide, productivity is 86.8%.
m.p.:204-206℃；1H-NMR(500MHz,DMSO)δ11.34(s,1H),10.50(s,1H),10.27(s, 1H), 9.89 (s, 1H), 9.21 (s, 1H), 8.84 (s, 1H), 7.44 (m, 3H), 7.37 (t, J=8.0Hz, 1H), 7.15 (d, J =7.5Hz, 1H), 6.83 (dd, J=17.0,10.2Hz, 1H), 6.35 (d, J=17.2Hz, 1H), 5.86 (d, J=10.9Hz, 1H), 4.27 (t, J=5.9Hz, 2H), 2.36 (s, 3H), 2.08 (t, J=7.1Hz, 2H), 1.93 1.83 (m, 2H), 1.74 (m,2H).HRMS(ESI)m/z calcd for C23H25N5O4[M+H]+:436.1985.Found:436.1986。
Embodiment 11 4-(6-acrylamido-4-(3-methylphenylamino) quinazoline-7-base) epoxide-N-hydroxyl hexanoyl Amine
With reference to the method for embodiment 1, simply by 4-((6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7- Base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) butyramide replaces to 4-((6-acrylamido-4-(3-methylbenzene Amido) quinazoline-7-base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) caproamide, productivity is 92.3%.
m.p.:199-200℃；1H-NMR(500MHz,DMSO)δ11.32(s,1H),10.45(s,1H),9.87(s, 1H), 9.17 (s, 1H), 8.84 (s, 1H), 7.50 (s, 1H), 7.44 (d, J=6.1Hz, 2H), 7.39 7.34 (m, 1H), 7.14 (d, J=7.5Hz, 1H), 6.80 (dd, J=17.0,10.2Hz, 1H), 6.35 (dd, J=17.0,1.8Hz, 1H), 5.86 (dd, J=10.2,1.8Hz, 1H), 4.25 (t, J=6.5Hz, 2H), 2.01 (t, J=7.3Hz, 2H), 1.93 1.84 (m, 2H), 1.64 1.54 (m, 2H), 1.46 (dt, J=15.1,7.5Hz, 2H) .HRMS (ESI) m/z calcd for C24H27N5O4[M+ H]+:450.2141.Found:450.2144。
Embodiment 12 4-(6-acrylamido-4-(3-trifluoromethyl phenylamino) quinazoline-7-base) epoxide-N-hydroxyl Pentanamide (H-12)
With reference to the method for embodiment 1, simply by 4-((6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7- Base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) butyramide replaces to 4-((6-acrylamido-4-(3-fluoroform Base anilino-) quinazoline-7-base) epoxide)-N-((tetrahydrochysene-2H-pyrans-2-base) epoxide) pentanamide, productivity is 85.9%. m.p.:195-197℃；1H-NMR(500MHz,DMSO)δ11.53(s,1H),10.53(s,1H),9.94(s,1H),9.23(s, 1H), 8.92 (s, 1H), 8.06 (s, 1H), 8.00 (d, J=8.1Hz, 1H), 7.72 (t, J=7.9Hz, 1H), 7.67 (d, J= 7.8Hz, 1H), 7.50 (s, 1H), 6.84 (dd, J=17.0,10.2Hz, 1H), 6.34 (dd, J=17.0,1.7Hz, 1H), 5.88 5.83 (m, 1H), 4.26 (t, J=6.2Hz, 2H), 2.06 (t, J=7.1Hz, 2H), 1.89 1.82 (m, 2H), 1.72 (m,2H).HRMS(ESI)m/z calcd for C23H22F3N5O4[M+H]+:490.1702.Found:490.1706。
Embodiment 13 compound is to A431, H1975, Hela and HepG2 cell inhibitory effect determination of activity
It is thin for EGFR wild type overexpression cell line A431, T790M point mutation that this example is used for measuring the compounds of this invention Born of the same parents strain H1975, human cervical carcinoma cell Hela and the proliferation inhibition activity of HepG2 cell lines, compound on intracellular The inhibitory activity half-inhibition concentration IC of propagation50Represent.Testing program is as follows: four class cells are all purchased from ATCC, with suitably Cell concentration (A431:20000 cell/ml culture medium；H1975:15000 cell/ml culture medium；Hela:25000 Cell/ml culture medium；HepG2:20000 cell/ml culture medium) cell is inoculated in 96 well culture plates of White-opalescent On；Afterwards cell is positioned over 37 DEG C, 5%CO2Environment in cultivate, after 24 hours, to cultivate cell culture medium in Add the medicine of a series of Concentraton gradient, be typically chosen 6 concentration, afterwards cell is put back to continuation cultivation 48 in former culture environment Hour, afterwards according to the method for MTT Assay, measure the test-compound impact on tumor cell proliferation, and calculate different dense The inhibitory activity of the compound on intracellular propagation of degree.Afterwards tumor cell proliferation inhibition activity under the compound of variable concentrations is entered Row matching, the IC50 data of test-compound of the present invention are shown in Table 1.
Table 1
Conclusion: have novelty in the compounds of this invention structure, is the double target of the novel non-reversible EGFR/HDAC proposed first Point covalency inhibitor, Bioactivity evaluation result shows simultaneously, the compound of present invention people's epidermis to process LAN EGFR JEG-3 A431, human lung adenocarcinoma cell line H1975, human cervical carcinoma cell Hela and people liver to Gefitinib drug resistance JEG-3 HepG2 has obvious Inhibit proliferaton activity.

Claims (4)

1. the quinazoline derivant containing hydroxamic acid side chain, it is characterised in that general structure I is as follows:
Wherein:
R1For replacing or unsubstituted C6～C10Aryl or substituted or unsubstituted C3～C12Heteroaryl, described be substituted by by C1～C6Alkyl, halogen, hydroxyl, amino, C2～C6Alkynyl, C2～C6Thiazolinyl, C1～C6Alkyl oxy, cyano group, nitro, fluoroform Base, C3～C6Cycloalkyl and C3～C6One or more in Heterocyclylalkyl are replaced；
N=3,4,5.
Quinazoline derivant containing hydroxamic acid side chain the most according to claim 1, it is characterised in that described compound I is following arbitrary compound:
4-(6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7-base) epoxide-N-maloyl group amine (H-1),
4-(6-acrylamido-4-(3-bromoanilino) quinazoline-7-base) epoxide-N-maloyl group amine (H-2),
4-(6-acrylamido-4-(3-chloro-4-fluoroanilino) quinazoline-7-base) epoxide-N-hydroxyl hexanamide (H-3),
4-(6-acrylamido-4-(3-bromoanilino) quinazoline-7-base) epoxide-N-hydroxyvaleramide (H-4),
4-(6-acrylamido-4-(3-bromoanilino) quinazoline-7-base) epoxide-N-hydroxyl hexanamide (H-5),
4-(6-acrylamido-4-(4-fluoroanilino) quinazoline-7-base) epoxide-N-maloyl group amine (H-6),
4-(6-acrylamido-4-(4-fluoroanilino) quinazoline-7-base) epoxide-N-hydroxyl hexanamide (H-7),
4-(6-acrylamido-4-(4-fluoroanilino) quinazoline-7-base) epoxide-N-hydroxyvaleramide (H-8),
4-(6-acrylamido-4-(3-methylphenylamino) quinazoline-7-base) epoxide-N-maloyl group amine (H-9),
4-(6-acrylamido-4-(3-methylphenylamino) quinazoline-7-base) epoxide-N-hydroxyvaleramide (H-10),
4-(6-acrylamido-4-(3-methylphenylamino) quinazoline-7-base) epoxide-N-hydroxyl hexanamide (H-11),
4-(6-acrylamido-4-(3-trifluoromethyl phenylamino) quinazoline-7-base) epoxide-N-hydroxyvaleramide (H-12).
The preparation method of the quinazoline derivant containing hydroxamic acid side chain the most according to claim 1 and 2, its feature exists In, realized by following steps:
With 2-amino-4-fluobenzoic acid 1 as initiation material, and formamidine acetate refluxes in glycol monoethyl ether and generates 7-Fluquinconazole Quinoline ketone 2,7-Fluquinconazole quinoline ketone 2 obtains nitration product 6-nitro-7-Fluquinconazole quinoline ketone under the effect of fuming nitric aicd and concentrated sulphuric acid 3,6-nitro-7-Fluquinconazole quinoline ketone 3 generate 4-chloro-6-nitro-7-Fluquinconazole quinoline 4 with the new thionyl chloride effect steamed, substituted Arylamine obtains 4-aryl amine-6-nitro-7-Fluquinconazole quinoline 5 with compound 4 reaction, and compound 5 replaces fluorine atom by hydroxyl and obtains To compound 6, compound 6 and bromo fatty-acid ethyl ester occur SN to replace to obtain intermediate 7, and intermediate 7 generates chemical combination through ferrum reduction Thing 8, the acryloyl chloride protection of the amino of compound 8 generates compound 9, and compound 9 becomes corresponding chemical combination through lithium hydrate Thing 10, compound 10 generates compound 11 with THP protection azanol condensation, and compound 11 deprotection in acid condition obtains chemical combination Thing I；Reaction equation is as follows:
Wherein the definition of substituent group is with claim 1.
Quinazoline derivant containing hydroxamic acid side chain the most according to claim 1 and 2 is preparing answering of antitumor cell With, it is characterised in that described tumor cell refers to the people epidermal carcinoma cell strain A431 of process LAN EGFR, to Gefitinib drug resistance Human lung adenocarcinoma cell line H1975, human cervical carcinoma cell Hela and human liver cancer cell HepG2.
CN201610533023.8A 2016-06-30 2016-06-30 Quinazoline derivant containing hydroxamic acid side chain and preparation and application Pending CN106187919A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610533023.8A CN106187919A (en) 2016-06-30 2016-06-30 Quinazoline derivant containing hydroxamic acid side chain and preparation and application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610533023.8A CN106187919A (en) 2016-06-30 2016-06-30 Quinazoline derivant containing hydroxamic acid side chain and preparation and application

Publications (1)

Publication Number Publication Date
CN106187919A true CN106187919A (en) 2016-12-07

Family

ID=57472808

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610533023.8A Pending CN106187919A (en) 2016-06-30 2016-06-30 Quinazoline derivant containing hydroxamic acid side chain and preparation and application

Country Status (1)

Country Link
CN (1) CN106187919A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018108083A1 (en) * 2016-12-12 2018-06-21 杭州英创医药科技有限公司 Heterocyclic compound as syk inhibitor and/or syk-hdac dual inhibitor

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102898386A (en) * 2011-07-27 2013-01-30 上海医药集团股份有限公司 Quinazoline derivative, preparation method, intermediate, composition and application
CN103896860A (en) * 2012-12-25 2014-07-02 通化济达医药有限公司 Zinc binding group-containing irreversible EGFR inhibitors
CN103965120A (en) * 2013-01-25 2014-08-06 上海医药集团股份有限公司 Quinoline and quinazoline derivative, preparation method, intermediate, composition and application
CN104761507A (en) * 2014-01-06 2015-07-08 广东东阳光药业有限公司 Aminoquinazoline derivatives and use thereof in drugs

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102898386A (en) * 2011-07-27 2013-01-30 上海医药集团股份有限公司 Quinazoline derivative, preparation method, intermediate, composition and application
CN103896860A (en) * 2012-12-25 2014-07-02 通化济达医药有限公司 Zinc binding group-containing irreversible EGFR inhibitors
CN103965120A (en) * 2013-01-25 2014-08-06 上海医药集团股份有限公司 Quinoline and quinazoline derivative, preparation method, intermediate, composition and application
CN104761507A (en) * 2014-01-06 2015-07-08 广东东阳光药业有限公司 Aminoquinazoline derivatives and use thereof in drugs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
齐维兴: "克服耐药的非可逆EGFR抑制剂的设计合成和生物活性筛选", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018108083A1 (en) * 2016-12-12 2018-06-21 杭州英创医药科技有限公司 Heterocyclic compound as syk inhibitor and/or syk-hdac dual inhibitor

Similar Documents

Publication Publication Date Title
Graffner-Nordberg et al. Design, Synthesis, Computational Prediction, and Biological Evaluation of Ester Soft Drugs as Inhibitors of Dihydrofolate Reductase from Pneumocystis c arinii
CN103965120B (en) Quinoline and quinazoline derivant, preparation method, intermediate, compositions and application
CN105646454B (en) The 2- aryl amine pyridine derivatives of the fragment containing hydroxamic acid and preparation and application
CN107709320A (en) A kind of pyrido nitrogen heterocyclic and its production and use
CN108239083B (en) Aromatic hydrocarbon receptor modulators
CN107383004B (en) 2-amino imidazopyridine derivative and preparation and application thereof
Tu et al. Design, synthesis, and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors
Liao et al. Design and biological evaluation of novel 4-(2-fluorophenoxy) quinoline derivatives bearing an imidazolone moiety as c-Met kinase inhibitors
Zhou et al. Design, synthesis and pharmacological evaluation of 6, 7-disubstituted-4-phenoxyquinoline derivatives as potential antitumor agents
CN110330484B (en) Substituted phenyl pyrimidine derivative as JAK kinase inhibitor or pharmaceutically acceptable salt thereof, preparation method and application
Tang et al. Synthesis and antiproliferative activity of 6, 7-disubstituted-4-phenoxyquinoline derivatives bearing the 2-oxo-4-chloro-1, 2-dihydroquinoline-3-carboxamide moiety
Qin et al. Design, synthesis and biological evaluation of 2, 3-dihydro-[1, 4] dioxino [2, 3-f] quinazoline derivatives as EGFR inhibitors
Chen et al. Bioisosterism-based design and enantiomeric profiling of chiral hydroxyl-substituted biphenyl-diarylpyrimidine nonnucleoside HIV-1 reverse transcriptase inhibitors
Reiersølmoen et al. Potent and selective EGFR inhibitors based on 5-aryl-7H-pyrrolopyrimidin-4-amines
Balakumar et al. Design, microwave-assisted synthesis and in silico docking studies of new 4H-pyrimido [2, 1-b] benzothiazole-2-arylamino-3-cyano-4-ones as possible adenosine A2B receptor antagonists
CN106243044A (en) Pyridine derivatives containing halo acrylamide side chain and preparation and application
CN105646371B (en) The 2,4- diaryl-amine yl pyrimidines analog derivative of the segment containing hydroxamic acid and preparation and application
CN106187919A (en) Quinazoline derivant containing hydroxamic acid side chain and preparation and application
CN115477639B (en) Polysubstituted pyrimidine compound with FGFR1 as target point, and preparation method and application thereof
CN115141197B (en) 3-aromatic heterocycle substituted phenyl derivative and preparation method and application thereof
CN113956234B (en) N-phenyl substituted 1H-indazole-3-amine compound, preparation thereof and application of antitumor activity
CN114835640B (en) Fibroblast growth factor receptor inhibitor, preparation method and application
CN106045980A (en) Quinazoline derivative and preparation method thereof
EP3426635B1 (en) 3-oxa-8-azabicyclo[3.2.1]octane derivatives and their use in the treatment of cancer and hemoglobinopathies
CN109053594A (en) 1- (3,5- Dimethoxyphenyl) -3- (substituted pyrimidines -4- base) carbamide compounds and its preparation and application

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
WD01 Invention patent application deemed withdrawn after publication
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20161207