CN105924387A - Diarylurea compound with antitumor activity, and preparation method and application thereof - Google Patents

Diarylurea compound with antitumor activity, and preparation method and application thereof Download PDF

Info

Publication number
CN105924387A
CN105924387A CN201610280781.3A CN201610280781A CN105924387A CN 105924387 A CN105924387 A CN 105924387A CN 201610280781 A CN201610280781 A CN 201610280781A CN 105924387 A CN105924387 A CN 105924387A
Authority
CN
China
Prior art keywords
antitumor activity
compounds
aryl ureas
preparation
reaction
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
CN201610280781.3A
Other languages
Chinese (zh)
Inventor
张�杰
卢闻
王金凤
潘晓艳
苏萍
贺怀贞
张琳
王嗣岑
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.)
Xian Jiaotong University
Original Assignee
Xian Jiaotong University
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 Xian Jiaotong University filed Critical Xian Jiaotong University
Priority to CN201610280781.3A priority Critical patent/CN105924387A/en
Publication of CN105924387A publication Critical patent/CN105924387A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates

Abstract

The invention provides a diarylurea compound with antitumor activity, and a preparation method and application thereof. The compound has a structural formula as described in the specification. In the structural formula, R1 and R2 are selected from the group consisting of hydrogen, alkane groups or halogen groups. The compound provided by the invention has good inhibitory activity to VEGFR-2 kinase, so a signal channel induced by the VEGFR-2 kinase can be blocked through inhibition of the activity of the VEGFR-2 kinase, and proliferation and migration of tumor cells are inhibited; thus, the compound can be applied in preparation of antitumor drugs. Meanwhile, the preparation method for the compound has the following advantages: raw materials are easily available; reaction conditions are mild; the process of reaction is simple to operate; and used reagents are cheap.

Description

A kind of double aryl ureas compounds with antitumor activity and its preparation method and application
Technical field
The invention belongs to biomedicine technical field, relate to a kind of antineoplastic compound, particularly to one, there is antitumor activity Double aryl ureas compounds and its preparation method and application.
Background technology
Malignant tumour, as one of bigger public health problem in the whole world, greatly endangers the health of the mankind, and will become new century people First killer of class.Malignant tumour is the most no longer the serious disease of advanced industrial country, and developing country is faced with bigger disease Burden.Chemotherapy, as one of important means treating tumour, has had huge development and progress at nearly 30 years, Obtain large quantities of clinical antitumor agents with different mechanism of action.But antineoplastic there is also many bad reactions, such as Alopecia, vomiting, produce bone marrow suppression, quickly produce drug resistance etc., these result in chemicals and are unable to reach intended treatment Effect.The research and development of the newest antineoplastic are one of focus and difficulties of current pharmaceutical field.
Summary of the invention
It is an object of the invention to provide a kind of double aryl ureas compounds with antitumor activity and its preparation method and application, this change Compound embodies good antitumor activity in vitro, it is possible to be applied to the preparation of antineoplastic.
For reaching above-mentioned purpose, the present invention by the following technical solutions:
A kind of double aryl ureas compounds with antitumor activity, its chemical structural formula is as follows:
Wherein, R1、R2For hydrogen, alkane group or halogen group.
Described halogen group is fluorine atom, chlorine atom, trifluoromethyl or trifluoromethoxy.
Described alkane group is-CH3、-CH2CH2N(CH3)2Or-C (CH3)3。
The preparation method of described double aryl ureas compounds with antitumor activity, comprises the following steps:
1) 4-aminobenzene borate hydrochlorate reacts with pinacol under magnesium sulfate is catalyzed and obtains 4-aminobenzene pinacol borate；
2) monosubstituted or disubstituted aniline and double (trichloromethyl) carbonic esters form isocyanates, then with 4-aminobenzene boric acid frequency which Alcohol ester condensation reaction obtains the substituted carbamide compounds of aniline；Wherein the substituent in the substituted carbamide compounds of aniline is by benzene in aniline Substituent on ring introduces；
3) 2-amino-5-bromopyridine and ring the third formyl chloride prepare N-(5-bromo-2-pyridyl base) cyclopropane carboxamide by acylation reaction；
4) under the catalytic action of tetrakis triphenylphosphine palladium, the substituted carbamide compounds of aniline and N-(5-bromo-2-pyridyl base) cyclopropane Formamide obtains double aryl ureas compounds with antitumor activity by Suzuki reaction.
Described step 1) concrete operations be: 4-aminobenzene borate hydrochlorate, pinacol, anhydrous magnesium sulfate are joined in flask, Add oxolane, under room temperature stirring reaction, reaction terminate rear filtering reacting liquid, organic phase is scrubbed, be dried, be spin-dried for after obtain Filemot crude product 4-aminobenzene pinacol borate.
Described step 2) concrete operations be: under condition of ice bath, with heavily steaming dichloromethane, double (trichloromethyl) carbonic esters are dissolved And stir, then drip the dichloromethane solution of monosubstituted or disubstituted aniline wherein, stir after dropping, continue The continuous dichloromethane solution dripping triethylamine wherein, drips and stirs complete follow-up continuing, dropping 4-aminobenzene the most wherein Pinacol borate and the dichloromethane solution of triethylamine, drip and stir complete follow-up continuing, by the reactant liquor washing obtained, do After dry, decompression boils off solvent, obtains crude product, then with chromatographic column separation crude product, obtains the substituted carbamide compounds of aniline.
Described step 3) concrete operations be: 2-amino-5-bromopyridine is dissolved in anhydrous methylene chloride, add anhydrous triethylamine, Stirring reaction under condition of ice bath, then drip the anhydrous methylene chloride solution of ring the third formyl chloride wherein, after dropping, remove ice bath, Reacting under room temperature, after reaction terminates, extract with dichloromethane, the decompression scrubbed, dried of the organic phase of extraction boils off solvent, Crude product, i.e. obtains N-(5-bromo-2-pyridyl base) cyclopropane carboxamide with chromatographic column separation crude product.
Described step 4) concrete operations be: by substituted for aniline carbamide compounds, N-(5-bromo-2-pyridyl base) cyclopropane carboxamide, Anhydrous potassium carbonate, tetrakis triphenylphosphine palladium are dissolved in the mixed solvent of Isosorbide-5-Nitrae-dioxane and water, react under nitrogen protection, reaction Being cooled to room temperature after end, be extracted with ethyl acetate, the decompression scrubbed, dried of the organic phase of extraction boils off solvent, obtains crude product, Double aryl ureas compounds with antitumor activity are i.e. obtained with chromatographic column separation crude product.
Described double aryl ureas compounds with antitumor activity answering in the medicine of preparation suppression VEGFR-2 kinase activity With.
Described double aryl ureas compounds with antitumor activity are in preparing the antineoplastic with VEGFR-2 kinases as target spot Application.
Compared with prior art, the method have the advantages that
Double aryl ureas compounds with antitumor activity that the present invention provides, are a kind of novel chemical combination with antitumor activity Thing, it has good inhibitory activity to VEGFR-2 kinases, can be used for the preparation of antineoplastic.Concrete, the present invention provides Double aryl ureas compounds with antitumor activity, it is possible to suppression the kinase whose activity of VEGFR-2.And Angiogenesis and tumour Occurring, develop and migrated substantial connection, the formation of suppression new vessels can effectively suppress growth and the migration of tumour, is permitted Many growth factors regulation and control new vessels generates, and wherein VEGFR-2 is the strongest known positive regulatory factor.Therefore the present invention provides Double aryl ureas compounds with antitumor activity by suppression the kinase whose activity of VEGFR-2, block its induction signal path, The hyperplasia of suppression tumour cell and migration, thus can be applicable to the preparation of antineoplastic, especially with VEGFR-2 kinases as target The antineoplastic of point and the medicine of suppression VEGFR-2 kinase activity.
The preparation method of double aryl ureas compounds with antitumor activity that the present invention provides, by the aniline with substituent with double (trichloromethyl) carbonic ester forms isocyanates, then obtains the substituted ureas of aniline with 4-aminobenzene pinacol borate condensation reaction Compound, is incorporated into the substituent in aniline on the substituted carbamide compounds of aniline, then the substituted carbamide compounds of aniline again with by It is anti-that N-(the 5-bromo-2-pyridyl base) cyclopropane carboxamide that 2-amino-5-bromopyridine and ring the third formyl chloride acylation reaction prepare carries out Suzuki Should, i.e. obtaining double aryl ureas compounds with antitumor activity, the method has raw material and is easy to get, and reaction condition is gentle, reacts Journey is simple to operate, the advantage that agents useful for same is cheap.
Accompanying drawing explanation
The synthetic route chart of double aryl ureas compounds with antitumor activity that Fig. 1 provides for the present invention；
Wherein, compound 1 is 4-aminobenzene borate hydrochlorate, and compound 2 is 4-aminobenzene pinacol borate, compound 3 For the substituted carbamide compounds of aniline, compound 4 is 2-amino-5-bromopyridine, and compound is 5 for N-(5-bromo-2-pyridyl base) ring Cyclopropane carboxamide, compound 6 is double aryl ureas compounds with antitumor activity.
Mark in figure particularly as follows:
a.Pinacol,MgSO4,Et3N,THF；b.R-NH2,BTC,Et3N,DCM,rt；c.Cyclopropane-carbonyl chloride,Et3N,DCM,rt；d.Pd(PPh3)4,K2CO3,H2O,dioxane,100℃。
Detailed description of the invention
The present invention is described in further detail with specific embodiment below in conjunction with the accompanying drawings, described in be explanation of the invention and not It is to limit.
The invention provides a kind of double aryl ureas compounds with antitumor activity, this pair of aryl ureas compound has anti-swollen in vitro Tumor activity, can be applicable to the preparation of antineoplastic.This has in the structural formula of double aryl ureas compounds of antitumor activity, pyridine Connecting on ring and have ring propyl formamide structure, its chemical structural formula is specific as follows:
Wherein, R1、R2For hydrogen, alkane group or halogen group.Described halogen group is fluorine atom, chlorine atom, fluoroform Base, trifluoromethoxy.
Having of present invention offer is described in detail anti-swollen below in conjunction with the synthetic route shown in Fig. 1 and concrete synthetic example The preparation of the double aryl ureas compound of the drug candidate of tumor activity and method for screening active ingredients.
Embodiment 1
This has in the structural formula of double aryl ureas compounds of antitumor activity, R1For hydrogen, R2For CF3, by following steps system Standby (seeing Fig. 1):
1) 4-aminobenzene borate hydrochlorate (compound 1) and pinacol react preparation 4-aminobenzene pinacol borate (compound 2)
20g 4-aminobenzene borate hydrochlorate, 19.2g pinacol, 46.6g anhydrous magnesium sulfate are joined in 500ml round-bottomed flask, Add 250ml oxolane, stirring reaction 5 hours under room temperature, react and filter after terminating, organic phase saturated sodium-chloride washs two Secondary, then be dried with anhydrous sodium sulfate, finally it is spin-dried for, i.e. obtains white solid 4-aminobenzene pinacol borate 21.5g, productivity 76%.
2) 4-aminobenzene pinacol borate (compound 2) and 3-Aminotrifluorotoluene prepare compound 1-(3 trifluoromethyl) benzene Base)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base) phenyl) urea (compound 3)
Under condition of ice bath, heavily steam dichloromethane with 20mL by molten to double for 0.80g (2.74mmol) (trichloromethyl) carbonic ester (BTC) Solve and stir 5min, then be slowly added dropwise the dichloromethane solution of 1.10g (6.85.mmol) 3-Aminotrifluorotoluene wherein, drip Stir 15min after Biing, continue the dichloromethane solution 10mL of dropping 1.1mL (8.22mmol) triethylamine wherein, after dropping Continue stirring 15min, drip 1.50g (6.85mmol) 4-aminobenzene pinacol borate and 1.1mL (8.22mmol) the most wherein The dichloromethane solution 10mL of triethylamine, drips complete follow-up continuous stirring 20min, then reactant liquor is used unsaturated carbonate hydrogen successively Sodium solution and saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and is finally spin-dried for obtaining red residue, then uses chromatographic column isolated White solid 1-(3 trifluoromethyl) phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-bases) phenyl) urea 1.77g, productivity 63.7%.
3) 2-amino-5-bromopyridine (compound 4) and ring the third formyl chloride are by acylated preparation N-(5-bromo-2-pyridyl base) cyclopropane first Acid amides (compound 5)
Under condition of ice bath, 1.0g (5.78mmol) 2-amino-5-bromopyridine is dissolved in 20ml anhydrous methylene chloride, delays wherein Slowly drip 1.4ml (10.37mmol) anhydrous triethylamine, stirring reaction 30min, then be slowly added dropwise 1.1ml (11.56mmol) wherein The anhydrous methylene chloride solution of ring the third formyl chloride, after dropping, removes and reacts overnight under ice bath, room temperature, after reaction terminates, uses Dichloromethane extracts 2-3 time, and the organic phase of extraction is successively with saturated sodium bicarbonate solution and saturated aqueous common salt washing, anhydrous sodium sulfate It is dried, is finally spin-dried for, obtains faint yellow solid N-(5-bromo-2-pyridyl base) cyclopropane carboxamide 1.43g, productivity 100%.
4) 1-(3 trifluoromethyl) phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base) phenyl) urea (compound 3) with N-(5-bromo-2-pyridyl base) cyclopropane carboxamide (compound 5) prepares (2-cyclopropanecarbonyl amido) pyrrole by Suzuki coupling reaction Pyridine)-3-(3-(trifluoromethyl) phenyl) urea (compound 6)
By 1.60g (3.94mmol) 1-(3 trifluoromethyl) phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base) phenyl) Urea, 0.89g (3.94mmol) N-(5-bromo-2-pyridyl base) cyclopropane carboxamide, 1.63g (11.82mmol) potassium carbonate and 0.45g (0.39mmol), during tetrakis triphenylphosphine palladium is dissolved in the mixed solution of 120mL Isosorbide-5-Nitrae-dioxane and 40ml water, protect at nitrogen Under in 100 DEG C reaction overnight, reaction terminate after be cooled to room temperature, be extracted with ethyl acetate 3-4 time, the organic phase of extraction is used successively Saturated sodium bicarbonate solution and saturated aqueous common salt washing, anhydrous sodium sulfate is dried, and is then spin-dried for, whiter through chromatographic column isolated Look solid (2-cyclopropanecarbonyl amido) pyridine radicals)-3-(3-(trifluoromethyl) phenyl) urea 0.19g, productivity 13.0%.
The structure of double aryl ureas compounds with antitumor activity of gained is as follows:
Physicochemical property: mp:270～272 DEG C.
Hydrogen spectrum nuclear magnetic resonance data is:1H NMR(400MHz,DMSO)δ10.87(s,1H),9.21(s,1H),8.99(s,1H), 8.63 (d, J=2.2Hz, 1H), 8.14 (d, J=8.7Hz, 2H), 8.04 (m, J=8.7,2.4Hz, 1H), 7.65 (t, J=8.3Hz, 4H), 7.58 (d, J=8.7Hz, 2H), 2.03 (t, J=12.3,8.6,4.8Hz, 1H), 0.92 0.71 (m, 4H).
Carbon spectrum nuclear magnetic resonance data is:13C NMR(101MHz,DMSO)δ173.01,152.91,151.41,145.65,141.00, 139.51,135.96,131.04,130.98,130.40,130.15,129.84,127.15,126.04,123.34,122.36,119.35, 118.58,114.65,114.61,113.69,14.69,8.15.
Embodiment 2
This has in the structural formula of double aryl ureas compounds of antitumor activity, R1、R2It is fluorine.
Step 1)～3) with step 1 in embodiment 1)～3) identical, i.e. by 4-aminobenzene borate hydrochlorate (compound 1) with Pinacol reaction preparation 4-aminobenzene pinacol borate (compound 2), 4-aminobenzene pinacol borate (compound 2) with 3,4-difluoroaniline prepares 1-(3,4-difluoro) phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base) phenyl) urea (chemical combination Thing 3), 2-amino-5-bromopyridine (compound 4) and ring the third formyl chloride prepare N-(5-bromo-2-pyridyl base) cyclopropane carboxamide (chemical combination Thing 5).
4) 1-(3,4-difluoro) phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base) phenyl) urea (compound 3) with N-(5-bromo-2-pyridyl base) cyclopropane carboxamide (compound 5) prepares (2-cyclopropanecarbonyl amido) pyrrole by Suzuki coupling reaction Pyridine)-3-(3,4-difluoro) phenyl) urea (compound 6), concrete operating procedure is:
By 1.10g (2.94mmol) 1-(3,4-difluoro) phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base) phenyl) Urea, 0.67g (2.94mmol) N-(5-bromo-2-pyridyl base) cyclopropane carboxamide, 1.22g (8.82mmol) potassium carbonate and 0.35g (0.30mmol) during tetrakis triphenylphosphine palladium is dissolved in the mixed solution of 90mL Isosorbide-5-Nitrae-dioxane and 30ml water, under nitrogen protection In 100 DEG C of reactions overnight, reaction is cooled to room temperature after terminating, and is extracted with ethyl acetate 3-4 time, and the organic phase of extraction is successively with full Washing with sodium bicarbonate solution and saturated aqueous common salt, anhydrous sodium sulfate is dried, and is then spin-dried for, then through chromatographic column isolated white Solid (2-cyclopropanecarbonyl amido) pyridine radicals)-3-(3,4-difluoro) phenyl) urea 0.4g, productivity 27.2%.
The structure of double aryl ureas compounds with antitumor activity of gained is as follows:
Physicochemical property: mp:280～282 DEG C.
Hydrogen spectrum nuclear magnetic resonance data is:1H NMR(400MHz,DMSO)δ10.87(s,1H),8.94(s,1H),8.89(s,1H), 8.62 (d, J=2.1Hz, 1H), 8.14 (d, J=8.7Hz, 1H), 8.04 (m, J=8.7,2.3Hz, 1H), 7.72 7.62 (m, 2H), 7.56 (d, J=8.6Hz, 2H), 7.35 (m, J=19.6,9.3Hz, 1H), 7.14 (d, J=9.0Hz, 1H), 2.09 1.98 (m, 1H), 0.82 (m, J=14.9,6.4Hz, 4H).
Carbon spectrum nuclear magnetic resonance data is:13C NMR(101MHz,DMSO)δ173.01,152.85,151.40,150.87,150.74, 148.46,148.33,146.21,146.09,145.62,143.83,143.70,139.56,137.31,137.29,137.22,137.20, 135.90,131.06,130.92,127.13,119.28,117.88,117.70,114.88,114.85,114.82,114.79,113.71, 107.78,107.57,14.71,8.13.
Embodiment 3
This has in the structural formula of double aryl ureas compounds of antitumor activity, R1For hydrogen, R2For OCF3。
Step 1)～3) with step 1 in embodiment 1)～3) identical, i.e. by 4-aminobenzene borate hydrochlorate (compound 1) with Pinacol reaction preparation 4-aminobenzene pinacol borate (compound 2), 4-aminobenzene pinacol borate (compound 2) is with right Trifluoro-methoxyaniline prepares 1-(4-trifluoromethoxy) phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base) phenyl) Urea (compound 3), 2-amino-5-bromopyridine (compound 4) and ring the third formyl chloride prepare N-(5-bromo-2-pyridyl base) cyclopropanecarbonyl Amine (compound 5).
4) 1-(4-trifluoromethoxy) phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base) phenyl) urea (compound 3) (2-cyclopropanecarbonyl amido) is prepared by Suzuki coupling reaction with N-(5-bromo-2-pyridyl base) cyclopropane carboxamide (compound 5) Pyridine)-3-(4-trifluoromethoxy) phenyl) urea (compound 6), concrete operating procedure is:
By 0.87g (2.06mmol) 1-(4-trifluoromethoxy) phenyl)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxy boron penta ring-2-base) Phenyl) urea, 0.47g (2.06mmol) N-(5-bromo-2-pyridyl base) cyclopropane carboxamide, 0.85g (6.18mmol) potassium carbonate and 0.24g (0.21mmol) during tetrakis triphenylphosphine palladium is dissolved in the mixed solution of 90mL Isosorbide-5-Nitrae-dioxane and 30ml water, under nitrogen protection In 100 DEG C of reactions overnight, reaction is cooled to room temperature after terminating, and is extracted with ethyl acetate 3-4 time, and the organic phase of extraction is successively with full Washing with sodium bicarbonate solution and saturated aqueous common salt, anhydrous sodium sulfate is dried, and is then spin-dried for, then through chromatographic column isolated white Solid (2-cyclopropanecarbonyl amido) pyridine radicals)-3-(4-trifluoromethoxy) phenyl) urea 0.14g, productivity 14.89%.
The structure of double aryl ureas compounds with antitumor activity of gained is as follows:
Physicochemical property: mp:236～238 DEG C.
Hydrogen spectrum nuclear magnetic resonance data is:1H NMR(400MHz,DMSO)δ10.93(s,1H),8.96(s,3H),8.93(s,1H), 7.72 (d, J=8.7Hz, 2H), 7.67 7.45 (m, 4H), 7.31 (d, J=8.6Hz, 2H), 2.24 2.11 (m, 1H), 0.91 0.77(m,4H).
Carbon spectrum nuclear magnetic resonance data is:13C NMR(101MHz,DMSO)δ172.24,156.76,155.91,155.73,152.87, 143.12,140.28,139.37,128.33,127.75,127.22,126.13,122.21,121.93,119.96,119.87,119.39, 119.22,14.79,8.47.
The double aryl ureas compounds with antitumor activity prepared the present invention below carry out VEGFR-2 kinase whose inhibitory activity sieve Choosing.
The double aryl ureas compounds pair with antitumor activity prepared by the HTRF KinEASE kit measurement present invention The inhibitory activity of VEGFR-2: use the Lance double aryl ureas compound inhibitory activity to VEGFR-2 of experiment detection, operation side Method illustrates to carry out according to kit.Adding in 384 orifice plates by the substrate of 2 μ L kinases and 2 μ L, VEGFR-2 concentration is 0.09ng/ μ L, concentration of substrate is 180nM.It is subsequently adding substrate polypeptide and the 4 μ L testing compounds of variable concentrations, adds 2 μ L ATP starts reaction, after reacting 30min, adds EDTA and terminates reaction at 37 DEG C.Reaction terminates to divide in backward reactant liquor Do not add Eu3+The antibody of-cryptate mark and streptavidin-XL665, at room temperature hatch 1h, uses Perkin-Elmer Victor 5 measures absorbance, kinase activity A665/A615 × 10 under 665nm and 615nm wavelength respectively4 Characterizing, calculate the present invention has double aryl ureas compounds of antitumor activity to the inhibiting rate of VEGFR-2 and IC50。
Double aryl ureas compounds inhibitory activity kinase whose to VEGFR-2 result such as table 1 with antitumor activity that the present invention provides Shown in:
The VEGFR-2 inhibitory activity of 1 pair of aryl ureas compound of table
As can be seen from Table 1, VEGFR-2 kinases is had by double aryl ureas compounds of what prepared by the present invention have antitumor activity Inhibitory activity, can be used for medicine and preparation the resisting with VEGFR-2 kinases as target spot of preparation suppression VEGFR-2 kinase activity Tumour medicine.
Aryl ureas chemical combination the most double to VEGFR-2 kinase inhibitory effect in above-mentioned double aryl ureas compounds with antitumor activity The concrete structure of thing is as shown in table 2.
The structural formula of 2 pairs of aryl ureas compounds of table

Claims (10)

1. double aryl ureas compounds with antitumor activity, it is characterised in that its chemical structural formula is as follows:
Wherein, R1、R2For hydrogen, alkane group or halogen group.
There are double aryl ureas compounds of antitumor activity the most as claimed in claim 1, it is characterised in that described halogen radical Group is fluorine atom, chlorine atom, trifluoromethyl or trifluoromethoxy.
There are double aryl ureas compounds of antitumor activity the most as claimed in claim 1, it is characterised in that described alkyl Group is-CH3、-CH2CH2N(CH3)2Or-C (CH3)3。
4. the preparation method of double aryl ureas compounds with antitumor activity described in any one in claim 1-3, it is special Levy and be, comprise the following steps:
1) 4-aminobenzene borate hydrochlorate reacts with pinacol under magnesium sulfate is catalyzed and obtains 4-aminobenzene pinacol borate；
2) monosubstituted or disubstituted aniline and double (trichloromethyl) carbonic esters form isocyanates, then with 4-aminobenzene boric acid frequency which Alcohol ester condensation reaction obtains the substituted carbamide compounds of aniline；Wherein the substituent in the substituted carbamide compounds of aniline is by benzene in aniline Substituent on ring introduces；
3) 2-amino-5-bromopyridine and ring the third formyl chloride prepare N-(5-bromo-2-pyridyl base) cyclopropane carboxamide by acylation reaction；
4) under the catalytic action of tetrakis triphenylphosphine palladium, the substituted carbamide compounds of aniline and N-(5-bromo-2-pyridyl base) cyclopropane Formamide obtains double aryl ureas compounds with antitumor activity by Suzuki reaction.
The preparation method of double aryl ureas compounds with antitumor activity the most according to claim 4, it is characterised in that: Described step 1) concrete operations be: 4-aminobenzene borate hydrochlorate, pinacol, anhydrous magnesium sulfate are joined in flask, add Enter oxolane, under room temperature stirring reaction, reaction terminate rear filtering reacting liquid, organic phase is scrubbed, be dried, be spin-dried for after obtain Huang The crude product 4-aminobenzene pinacol borate of brown.
The preparation method of double aryl ureas compounds with antitumor activity the most according to claim 4, it is characterised in that: Described step 2) concrete operations be: under condition of ice bath, with heavily steaming dichloromethane, double (trichloromethyl) carbonic esters are dissolved and stir Mix uniformly, then drip the dichloromethane solution of monosubstituted or disubstituted aniline wherein, stir after dropping, continue to Wherein drip the dichloromethane solution of triethylamine, drip and stir complete follow-up continuing, dropping 4-aminobenzene boric acid the most wherein Pinacol ester and the dichloromethane solution of triethylamine, drip and stir complete follow-up continuing, by the reactant liquor washing obtained, after drying Decompression boils off solvent, obtains crude product, then with chromatographic column separation crude product, obtains the substituted carbamide compounds of aniline.
The preparation method of double aryl ureas compounds with antitumor activity the most according to claim 4, it is characterised in that: Described step 3) concrete operations be: 2-amino-5-bromopyridine is dissolved in anhydrous methylene chloride, add anhydrous triethylamine, ice bath Under the conditions of stirring reaction, more wherein drip ring the third formyl chloride anhydrous methylene chloride solution, after dropping, remove ice bath, room The lower reaction of temperature, after reaction terminates, extracts with dichloromethane, and the decompression scrubbed, dried of the organic phase of extraction boils off solvent, obtains slightly Product, i.e. obtain N-(5-bromo-2-pyridyl base) cyclopropane carboxamide with chromatographic column separation crude product.
The preparation method of double aryl ureas compounds with antitumor activity the most according to claim 4, it is characterised in that: Described step 4) concrete operations be: by substituted for aniline carbamide compounds, N-(5-bromo-2-pyridyl base) cyclopropane carboxamide, nothing Aqueous carbonate potassium, tetrakis triphenylphosphine palladium are dissolved in the mixed solvent of Isosorbide-5-Nitrae-dioxane and water, react under nitrogen protection, reaction knot Being cooled to room temperature after bundle, be extracted with ethyl acetate, the decompression scrubbed, dried of the organic phase of extraction boils off solvent, obtains crude product, uses Chromatographic column separation crude product i.e. obtains double aryl ureas compounds with antitumor activity.
9. in claim 1-3 double aryl ureas compounds with antitumor activity described in any one in preparation suppression Application in the medicine of VEGFR-2 kinase activity.
10. in claim 1-3 double aryl ureas compounds with antitumor activity described in any one in preparation with VEGFR-2 Kinases is the application in the antineoplastic of target spot.
CN201610280781.3A 2016-04-28 2016-04-28 Diarylurea compound with antitumor activity, and preparation method and application thereof Pending CN105924387A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201610280781.3A CN105924387A (en) 2016-04-28 2016-04-28 Diarylurea compound with antitumor activity, and preparation method and application thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201610280781.3A CN105924387A (en) 2016-04-28 2016-04-28 Diarylurea compound with antitumor activity, and preparation method and application thereof

Publications (1)

Publication Number Publication Date
CN105924387A true CN105924387A (en) 2016-09-07

Family

ID=56837749

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201610280781.3A Pending CN105924387A (en) 2016-04-28 2016-04-28 Diarylurea compound with antitumor activity, and preparation method and application thereof

Country Status (1)

Country Link
CN (1) CN105924387A (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106748990A (en) * 2016-11-14 2017-05-31 西安交通大学 A kind of substituted bisarylurea compound with antitumor activity and its preparation method and application
CN106748989A (en) * 2016-11-14 2017-05-31 西安交通大学 A kind of diaryl urea compound with antitumor activity and its preparation method and application
CN106748991A (en) * 2016-11-14 2017-05-31 西安交通大学 A kind of double aryl carbamide compounds with antitumor activity and its preparation method and application
WO2021092262A1 (en) * 2019-11-05 2021-05-14 Dermira, Inc. Mrgprx2 antagonists and uses thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012047017A2 (en) * 2010-10-05 2012-04-12 크리스탈지노믹스(주) 2,3-dihydro-isoindol-1-one derivative and a composition comprising the same
CN104817493A (en) * 2015-03-11 2015-08-05 西安交通大学 Aromatic heterocyclic amide substituted diarylurea compound, preparation method and application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012047017A2 (en) * 2010-10-05 2012-04-12 크리스탈지노믹스(주) 2,3-dihydro-isoindol-1-one derivative and a composition comprising the same
CN104817493A (en) * 2015-03-11 2015-08-05 西安交通大学 Aromatic heterocyclic amide substituted diarylurea compound, preparation method and application thereof

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
XIAOLONG JIANG，ET AL.: "Discovery and SAR study of c-Met kinase inhibitors bearing an 3-amino-benzo[d]isoxazole or 3-aminoindazole scaffold", 《BIOORGANIC & MEDICINAL CHEMISTRY》 *
YUANYUAN SHAN，ET AL.: "Discovery of novel VEGFR-2 inhibitors. Part5: Exploration of diverse hinge-binding fragments via core-refining approach", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106748990A (en) * 2016-11-14 2017-05-31 西安交通大学 A kind of substituted bisarylurea compound with antitumor activity and its preparation method and application
CN106748989A (en) * 2016-11-14 2017-05-31 西安交通大学 A kind of diaryl urea compound with antitumor activity and its preparation method and application
CN106748991A (en) * 2016-11-14 2017-05-31 西安交通大学 A kind of double aryl carbamide compounds with antitumor activity and its preparation method and application
CN106748991B (en) * 2016-11-14 2020-03-17 西安交通大学 Diaryl urea compound with anti-tumor activity and preparation method and application thereof
CN106748989B (en) * 2016-11-14 2020-03-17 西安交通大学 Diaryl urea compound with anti-tumor activity and preparation method and application thereof
WO2021092262A1 (en) * 2019-11-05 2021-05-14 Dermira, Inc. Mrgprx2 antagonists and uses thereof

Similar Documents

Publication Publication Date Title
JP7026196B2 (en) RET inhibitor
CN105461695B (en) Pyrimidine or pyrrolotriazine derivatives and its production and use
CN112239469B (en) Targeted protein degradation c-Met degradation agent and preparation method and application thereof
KR101104666B1 (en) Heteroaryl derivatives as protein kinase inhibitors
CA2971872C (en) Mutant idh1 inhibitors useful for treating cancer
RU2497808C2 (en) 5,6-bisaryl-2-pyridine carboxamide derivatives, method for preparing and using them in therapy as receptor antagonists
CA2793594C (en) Method and process for preparation and production of deuterated .omega.-diphenylurea
JP6950897B2 (en) Bruton's tyrosine kinase inhibitor
TW200417546A (en) New compounds
CN105924387A (en) Diarylurea compound with antitumor activity, and preparation method and application thereof
JP2008525409A (en) Pyrazine and pyridine and their derivatives as therapeutic compounds
CN107474011A (en) A kind of the stibazole class LSD1 inhibitor of 2 phenyl 4, its preparation method and application
CN108069929A (en) 3- substituted cumarins analog derivative and the agonist of application and GPR35 receptors
Zhan et al. Design, synthesis and antitumor activities of novel bis-aryl ureas derivatives as Raf kinase inhibitors
CN107501169A (en) A kind of trans diarylethene LSD1 inhibitor, its preparation method and application
US20190169163A1 (en) Quinoline derivative and use thereof
Lu et al. Design, synthesis and evaluation of novel diaryl urea derivatives as potential antitumor agents
CN106748989B (en) Diaryl urea compound with anti-tumor activity and preparation method and application thereof
CN102558172B (en) 5,8-bis-replaces-1,6-naphthyridine-7-amidocarbonylation compound and dimer compound thereof, Preparation Method And The Use
CN104163794A (en) 2-amino aromatic ring vascular endothelial growth factor receptor (VEGFR) inhibitor, preparation method and use thereof
CN107163028B (en) A kind of benzamides Hedgehog inhibitor and its preparation method and application
KR20130106186A (en) Azaindole derivatives, trk inhibitoring composition and pharmaceutical compositions for prevention and treatment of diseases linked to trk comprising the same
JP2019520359A (en) Biaryl urea derivatives or salts thereof and methods for their preparation and use
CN108530337A (en) A kind of alternative indole amides class compound for inhibiting stomach cancer cell
CN105906568A (en) Cyclopropane diamide compound with antitumor activity and preparation method and application thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20160907