CN106748990A - A kind of substituted bisarylurea compound with antitumor activity and its preparation method and application - Google Patents
A kind of substituted bisarylurea compound with antitumor activity and its preparation method and application Download PDFInfo
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- CN106748990A CN106748990A CN201611001517.8A CN201611001517A CN106748990A CN 106748990 A CN106748990 A CN 106748990A CN 201611001517 A CN201611001517 A CN 201611001517A CN 106748990 A CN106748990 A CN 106748990A
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- 0 **1C=CC(NC(Nc(cc2)ccc2-c2ccc(NC(C=C)=O)nc2)=O)=C*(*)C=C1 Chemical compound **1C=CC(NC(Nc(cc2)ccc2-c2ccc(NC(C=C)=O)nc2)=O)=C*(*)C=C1 0.000 description 1
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- 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 kind of substituted bisarylurea compound with antitumor activity and its preparation method and application, the structural formula of the compound isWherein R1It is hydrogen, R2It is isopropyl or halogen group.The compound has good inhibitory activity to the kinases of VEGFR 2, can block the signal path of its induction by suppressing the activity of the kinases of VEGFR 2, suppresses hyperplasia and the migration of tumour cell, so as to can be applied to the preparation of antineoplastic.And there is the preparation method of the compound raw material to be easy to get, reaction condition is gentle, and course of reaction is simple to operate, the cheap advantage of agents useful for same.
Description
Technical field
The invention belongs to biomedicine technical field, it is related to a kind of antineoplastic compound, it is more particularly to a kind of with anti-
Substituted bisarylurea compound of tumor promotion and its preparation method and application.
Background technology
Malignant tumour greatly endangers the health of the mankind as one of larger public health problem in the whole world, and will turn into
First killer of the new century mankind.Malignant tumour has no longer been the serious disease of advanced industrial country, and developing country faces
Bigger Disease Spectrum.Chemotherapy had huge as one of important means for treating tumour at nearly 30 years
Big development and progress, has obtained large quantities of clinical antitumor agents with different mechanism of action.But antineoplastic is also deposited
In many adverse reactions, such as alopecia, vomiting produces bone marrow suppression, and quick to produce drug resistance etc., these result in chemical drugs
Thing is unable to reach expected therapeutic effect.Therefore the research and development of new antineoplastic be current pharmaceutical field focus and
One of difficulties.
The content of the invention
It is an object of the invention to provide a kind of substituted bisarylurea compound with antitumor activity and preparation method thereof
And application, the compound embodies good antitumor activity, can be applied to the preparation of antineoplastic in vitro.
To reach above-mentioned purpose, the technical solution adopted by the present invention is:
A kind of substituted bisarylurea compound with antitumor activity, its chemical structural formula is as follows:
Wherein, R1It is hydrogen, R2It is isopropyl or halogen group.
Described halogen group is fluorine atom, chlorine atom, trifluoromethyl or trifluoromethoxy.
The preparation method of the described substituted bisarylurea compound with antitumor activity, comprises the following steps:
1) isocyanates is formed with double (trichloromethyl) carbonate reactions with monosubstituted base or disubstituted aniline, then
Monosubstituted base or disubstituted carbamide compounds are obtained with 4- aminobenzene pinacol borate condensation reactions;
2) under tetrakis triphenylphosphine palladium catalytic reaction, monosubstituted base or disubstituted carbamide compounds and 2- will be carried
Amino -5- bromopyridines are reacted by Suzuki and obtain substituted bisarylurea compound intermediate;
3) substituted bisarylurea compound intermediate obtains double with antitumor activity with acryloyl chloride by acylation reaction
Aryl urea compounds.
The step 1) concrete operations be:Under condition of ice bath, will double (trichloromethyl) carbonic acid with dichloromethane is steamed again
Ester dissolves and stirs, and the dichloromethane solution with monosubstituted base or disubstituted aniline is added dropwise thereto, drips
Stirred after finishing, then continue that the dichloromethane solution of triethylamine is added dropwise thereto, continue to stir after completion of dropping, then
The dichloromethane solution and 4- aminobenzene pinacol borates of triethylamine, stirring reaction after completion of dropping, reaction are added dropwise thereto
After end, by reaction solution washing, dry after decompression boil off solvent afforded crude material, obtained with monosubstituted base with chromatography post separation crude product
Or disubstituted carbamide compounds.
The step 2) concrete operations be:Monosubstituted base or disubstituted carbamide compounds, 2- amino -5- will be carried
Bromopyridine, Carbon Dioxide caesium, tetrakis triphenylphosphine palladium are dissolved in the mixed solution of Isosorbide-5-Nitrae dioxane and water, under nitrogen protection
In 100 DEG C of reactions overnight, after reaction terminates, room temperature is cooled to, is extracted with ethyl acetate, the organic phase of extraction is scrubbed, dry
Decompression afterwards boils off solvent afforded crude material, and substituted bisarylurea compound intermediate is obtained with chromatography post separation crude product.
The step 3) concrete operations be:Under condition of ice bath, substituted bisarylurea compound intermediate is dissolved in anhydrous
In tetrahydrofuran, anhydrous triethylamine is added dropwise thereto, stirs, then acryloyl chloride is added dropwise thereto, after completion of dropping, remove
Ice bath, at room temperature stirring is reacted, and after reaction terminates, reaction solution decompression is boiled off into solvent and obtains crude product, with chromatography post separation
Crude product obtains the substituted bisarylurea compound with antitumor activity.
The described substituted bisarylurea compound with antitumor activity suppresses the medicine of VEGFR-2 kinase activities preparing
In application.
The described substituted bisarylurea compound with antitumor activity is anti-swollen with VEGFR-2 kinases as target spot in preparation
Application in tumor medicine.
Relative to prior art, beneficial effects of the present invention are:
The substituted bisarylurea compound with antitumor activity that the present invention is provided, is a kind of new with antitumor work
Property compound, it has good inhibitory activity to VEGFR-2 kinases, can be used for prepare suppress VEGFR-2 kinase activities medicine
Thing and the antineoplastic with VEGFR-2 kinases as target spot.Specifically, the double aryl with antitumor activity that the present invention is provided
Carbamide compounds, can suppress the activity of VEGFR-2 kinases.And generation, development and the migration of angiogenesis and tumour have close
Relation is cut, suppressing the formation of new vessels can effectively suppress the growth and migration of tumour, and many growth factor regulation and control are newborn
Angiogenesis, wherein VEGFR-2 are known most strong positive regulatory factors.Therefore the present invention provide with antitumor activity
Substituted bisarylurea compound blocks the signal path of its induction by suppressing the activity of VEGFR-2 kinases, suppresses tumour cell
Hyperplasia and migration, so as to can be applied to the preparation of antineoplastic.
The preparation method of the substituted bisarylurea compound with antitumor activity that the present invention is provided, by the substituted base of band
Aniline and double (trichloromethyl) carbonic esters form isocyanates, then obtain band with 4- aminobenzene pinacol borate condensation reactions
The carbamide compounds of substituted base, the substitution base in aniline are incorporated on carbamide compounds, then the carbamide compounds and 2-
Amino -5- bromopyridines are reacted by Suzuki and obtain substituted bisarylurea compound intermediate, then with acryloyl chloride by acylated anti-
Should be to obtain the substituted bisarylurea compound with antitumor activity, be easy to get with raw material, reaction condition is gentle, course of reaction behaviour
Make simple, the cheap advantage of agents useful for same.
Brief description of the drawings
The synthetic route chart of the substituted bisarylurea compound with antitumor activity that Fig. 1 is provided for the present invention;
Wherein compound 1 is 4- aminobenzene pinacol borates, and compound 2 is with monosubstituted base or disubstituted urea
Class compound, compound 3 is 2- amino -5- bromopyridines;Compound is substituted bisarylurea compound intermediate, i.e. 1- (4- for 4
(6- aminopyridine -3- bases) phenyl) double aryl ureas, compound 5 is target compound, i.e., the double aryl ureas with antitumor activity
Class compound.
What is marked in figure is specially:
a.R-NH2,BTC,Et3N,DCM,rt;b.Pd(PPh3)4,CS2CO3,H2O,dioxane,100℃;c.Acryloyl
chloride,Et3N,THF,0℃to rt.
Specific embodiment
With reference to specific embodiment, the present invention is described in further detail, it is described be explanation of the invention and
It is not to limit.
The invention provides a kind of substituted bisarylurea compound with antitumor activity, the substituted bisarylurea compound exists
There is antitumor activity in vitro, the preparation of antineoplastic is can be applied to, its chemical structural formula is:
Wherein, R1It is hydrogen, R2It is isopropyl or halogen group.Described halogen group is fluorine atom, chlorine atom, fluoroform
Base, trifluoromethoxy.And connected on the pyridine ring of the substituted bisarylurea compound with antitumor activity of present invention offer
There is acrylamide structure.
Described in detail with reference to the synthetic route shown in Fig. 1 and specific synthetic example with of the invention anti-
The preparation of tumor candidate medicine substituted bisarylurea compound and method for screening active ingredients.
Embodiment 1
This has in the structural formula of substituted bisarylurea compound of antitumor activity, R1It is hydrogen, R2It is CF3, by following step
Suddenly prepare (referring to Fig. 1):
1) 4- aminobenzenes pinacol borate (compound 1) and 3-Aminotrifluorotoluene prepare compound 1- (3- fluoroforms
Base) phenyl) -3- (4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) phenyl) urea (compound 2)
Under condition of ice bath, dichloromethane is steamed again with 20mL by double (trichloromethyl) carbonic esters of 0.80g (2.74mmol)
(BTC) dissolve and stir 5min, then be slowly added dropwise the dichloromethane solution of 1.10g (6.85.mmol) 3-Aminotrifluorotoluene, drop
Add and stir 15min after finishing, to the dichloromethane solution 10mL for continuing dropwise addition 1.1mL (8.22mmol) triethylamine in turbid solution,
Continue to stir 15min after completion of dropping, then to dropwise addition 1.50g (6.85mmol) 4- amino phenyl boric acid pinacols in reaction solution
The dichloromethane solution 10mL of ester (compound 1) and 1.1mL (8.22mmol) triethylamine, continues to stir 20min after completion of dropping,
Reaction solution is used into saturated sodium bicarbonate solution successively, saturated common salt water washing, anhydrous sodium sulfate drying is spin-dried for obtaining red residual
Thing, with chromatographic column isolated white solid 1- (3- trifluoromethyls) phenyl -3- (4- (4,4,5,5- tetramethyl -1,3,2- dioxies
Ring -2- the bases of boron penta) phenyl) urea (compound 2) 1.77g, yield 63.7%;
2) 1- (3- trifluoromethyls) phenyl) -3- (4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) benzene
Base) urea (compound 2) and 2- amino -5- bromopyridines (compound 3) prepare 1- (4- (6- amino pyrroles by Suzuki coupling reactions
Pyridine -3- bases) phenyl) -3- (3- (trifluoromethyl) phenyl) urea (compound 4)
By 1- (3- trifluoromethyls) phenyl) -3- (4- (ring -2- bases of 4,4,5,5- tetramethyl -1,3,2- dioxies boron penta) benzene
Base) urea (compound 2) 2.00g (5.10mmol), 2- amino -5- bromopyridine (compound 3) 1.32g (7.65mmol), anhydrous carbon
Sour caesium 3.32g (10.20mmol), tetrakis triphenylphosphine palladium 0.59g (0.51mmol) is dissolved in 90mL1,4 dioxane and 40mL water
Mixed solution in, under nitrogen protection in 100 DEG C reaction overnight.Reaction is cooled to room temperature after terminating, and is extracted with ethyl acetate
3-4 times, the organic phase of extraction uses saturated sodium bicarbonate solution successively, and saturated common salt water washing, anhydrous sodium sulfate drying is spin-dried for,
By the isolated white solid 1- of chromatographic column (4- (6- aminopyridine -3- bases) phenyl) -3- (3- (trifluoromethyl) phenyl) urea
(compound 4) 0.57g, yield 30.0%.
3) 1- (4- (6- aminopyridine -3- bases) phenyl) -3- (3- (trifluoromethyl) phenyl) ureas (compound 4) and acryloyl
Chlorine prepares target compound by acylation reaction
Under condition of ice bath, 1- (4- (6- aminopyridine -3- bases) phenyl) -3- (3- (trifluoromethyl) phenyl) urea (is changed
Compound 4) 0.28g (0.75mmol) is dissolved in 20mL anhydrous tetrahydro furans, is slowly added dropwise anhydrous three second of 0.42mL (3.0mmol)
Amine, stirring reaction 30min, then 0.15mL (1.80mmol) acryloyl chloride is slowly added dropwise, after completion of dropping, remove ice bath, room temperature
Reaction 45min, after reaction terminates, obtains crude product, through the isolated white object compound of post level by reaction solution evaporated under reduced pressure
0.17g, yield 53.1%;
Gained target compound structure is as follows:
Physicochemical property:mp:193~195 DEG C.
Hydrogen composes nuclear magnetic resonance data:1H NMR(400MHz,DMSO)δ10.82(s,1H),9.12(s,1H),8.97(s,
1H), 8.67 (d, J=2.1Hz, 1H), 8.28 (d, J=8.7Hz, 1H), 8.10 (m, J=8.7,2.4Hz, 1H), 8.04 (s,
1H), 7.68 (d, J=8.7Hz, 2H), 7.60 (d, J=7.4Hz, 2H), 7.59 (s, 1H), 7.53 (t, J=7.9Hz, 1H),
7.33 (d, J=7.6Hz, 1H), 6.65 (m, J=17.0,10.2Hz, 1H), 6.34 (m, J=17.0,1.8Hz, 1H), 5.80
(m, J=10.2,1.8Hz, 1H)
Carbon composes nuclear magnetic resonance data:13C NMR(101MHz,DMSO)δ164.10,152.92,151.27,145.85,
141.01,139.63,136.04,132.01,131.53,130.88,130.39,130.16,129.85,128.19,127.23,
122.37,119.36,118.58,114.66,114.07.
Embodiment 2
This has in the structural formula of substituted bisarylurea compound of antitumor activity, R1It is hydrogen, R2It is fluorine.
Step 1)~2) with step 1 in embodiment 1)~it is 2) identical, i.e., by initial compounds 4- amino phenyl boric acid pinacols
Ester (compound 1) and m-fluoroaniline prepare compound 1- (3- fluorophenyls) -3- (4- (4,4,5,5- tetramethyl -1,3,2- dioxy boron
Penta ring -2- bases) phenyl) urea (compound 2), then prepared by Suzuki coupling reactions with 2- amino -5- bromopyridines (compound 3)
1- (4- (6- aminopyridine -3- bases) phenyl) -3- (3- fluorophenyls) urea (compound 4).
3) (3- (trifluorophenyl) urea (compound 4) leads to 1- (4- (6- aminopyridine -3- bases) phenyl) -3- with acryloyl chloride
Cross acylation reaction and prepare target compound, specific operating procedure is:
Under condition of ice bath, by 1- (4- (6- aminopyridine -3- bases) phenyl) -3- (3- (trifluorophenyl) ureas (compound 4)
0.27g (0.84mmol) is dissolved in 20mL anhydrous tetrahydro furans, is slowly added dropwise 0.47mL (3.36mmol) anhydrous triethylamine, stirring
Reaction 30min, then 0.16mL (2.01mmol) acryloyl chloride is slowly added dropwise, after completion of dropping, remove ice bath, room temperature reaction
45min, after reaction terminates, obtains crude product, through the isolated white object compound of post level by reaction solution evaporated under reduced pressure
0.11g, yield 34.4%;
Gained target compound structure is as follows:
Physicochemical property:mp:199~201 DEG C.
Hydrogen composes nuclear magnetic resonance data:1H NMR(400MHz,DMSO)δ10.82(s,1H),8.99(s,1H),8.93(s,
1H), 8.66 (d, J=2.1Hz, 1H), 8.28 (d, J=8.7Hz, 1H), 8.10 (m, J=8.7,2.4Hz, 1H), 7.68 (d, J
=8.7Hz, 2H), 7.58 (d, J=8.7Hz, 2H), 7.55-7.49 (m, 1H), 7.32 (m, J=15.2,8.1Hz, 1H), 7.15
(d, J=8.1Hz, 1H), 6.80 (m, J=8.4,2.1Hz, 1H), 6.65 (m, J=17.0,10.2Hz, 1H), 6.34 (m, J=
17.0,1.8Hz, 1H), 5.80 (m, J=10.2,1.8Hz, 1H)
Carbon composes nuclear magnetic resonance data:13C NMR(101MHz,DMSO)δ164.10,161.68,152.80,151.26,
145.84,141.96,139.71,136.02,132.02,131.55,130.78,128.18,127.23,119.25,114.46,
114.08,108.55,105.51,105.25.
Embodiment 3
This has in the structural formula of substituted bisarylurea compound of antitumor activity, R1It is hydrogen, R2It is OCF3。
Step 1)~2) with step 1 in embodiment 1)~it is 2) identical, i.e., by initial compounds 4- amino phenyl boric acid pinacols
Ester (compound 1) with to trifluoro-methoxyaniline prepare compound 1- (4- trifluoromethoxies) phenyl) -3- (4- (4,4,5,5- tetra-
Methyl isophthalic acid, the ring -2- bases of 3,2- dioxy boron penta) phenyl) urea (compound 2), then pass through with 2- amino -5- bromopyridines (compound 3)
Suzuki coupling reactions prepare 1- (4- (6- aminopyridine -3- bases) phenyl) -3- (4- trifluoromethoxies) phenyl) urea (compound
4)。
3) 1- (4- (6- aminopyridine -3- bases) phenyl) -3- (4- trifluoromethoxies) phenyl) urea (compound 4) and propylene
Acyl chlorides prepares target compound by acylation reaction, and specific operating procedure is:
Under condition of ice bath, by 1- (4- (6- aminopyridine -3- bases) phenyl) -3- (4- trifluoromethoxies) phenyl) urea (change
Compound 4) 0.30g (0.77mmol) is dissolved in 20mL anhydrous tetrahydro furans, is slowly added dropwise anhydrous three second of 0.43mL (3.08mmol)
Amine, stirring reaction 30min, then 0.15mL (1.85mmol) acryloyl chloride is slowly added dropwise, after completion of dropping, remove ice bath, room temperature
Reaction 45min, after reaction terminates, obtains crude product, through the isolated white object compound of post level by reaction solution evaporated under reduced pressure
0.11g, yield 26.5%;
Gained target compound structure is as follows:
Physicochemical property:mp:220~222 DEG C.
Hydrogen composes nuclear magnetic resonance data:1H NMR(400MHz,DMSO)δ10.81(s,1H),8.94(s,1H),8.89(s,
1H), 8.66 (d, J=2.1Hz, 1H), 8.27 (d, J=8.7Hz, 1H), 8.10 (m, J=8.7,2.4Hz, 1H), 7.68 (d, J
=8.7Hz, 2H), 7.58 (d, J=8.8Hz, 4H), 7.30 (d, J=8.6Hz, 2H), 6.65 (m, J=17.0,10.2Hz,
1H), 6.34 (m, J=17.0,1.8Hz, 1H), 5.80 (m, J=10.2,1.8Hz, 1H)
Carbon composes nuclear magnetic resonance data:13C NMR(101MHz,DMSO)δ164.09,152.88,151.25,145.83,
143.10,139.79,139.42,136.01,132.02,131.56,130.72,128.18,127.23,122.20,119.93,
119.40,119.21,114.07.
The medical active to the substituted bisarylurea compound with antitumor activity obtained in the present invention is screened below
And be explained.
Substituted bisarylurea compound with antitumor activity is screened to the inhibitory activity of VEGFR-2 kinases:
There is suppression of the substituted bisarylurea compound of antitumor activity to VEGFR-2 with HTRF KinEASE kit measurements
System activity:There is the substituted bisarylurea compound of antitumor activity to the inhibitory activity of VEGFR-2 using Lance experiment detections,
Operating method is carried out according to kit explanation.By in substrate 384 orifice plates of addition of 2 μ L kinases and 2 μ L, VEGFR-2 concentration is
0.09ng/ μ L, concentration of substrate is 180nM.The substrate polypeptide and 4 μ L testing compounds of various concentrations are subsequently adding, 2 μ are added
LATP starts reaction, after reacting 30min at 37 DEG C, adds EDTA terminating reactions.Reaction terminates to add respectively in backward reaction solution
Enter Eu3+The antibody and streptavidin-XL665 of-cryptate mark, are incubated 1h, using Perkin- at room temperature
Elmer Victor 5 distinguish mensuration absorbance, kinase activity A665/A615 × 10 under 665nm and 615nm wavelength4Table
Levy, calculate inhibiting rate and IC of the obtained substituted bisarylurea compound with antitumor activity of the present invention to VEGFR-250。
Substituted bisarylurea compound with antitumor activity prepared by the present invention is to VEGFR-2 kinase inhibitory activities
As a result, as shown in table 1:
The VEGFR-2 inhibitory activity of the substituted bisarylurea compound of table 1
Wherein H1, H2, H3 are the substituted bisarylurea compounds with antitumor activity prepared by the present invention, can be with by table 1
Find out, the substituted bisarylurea compound with antitumor activity prepared by the present invention has inhibitory activity to VEGFR-2 kinases, its
Middle H1 and H2 is significantly larger than positive control drug Soranifib to the inhibitory activity of VEGFR-2 kinases, illustrates the tool of present invention preparation
The substituted bisarylurea compound for having antitumor activity can be used to prepare the medicine for suppressing VEGFR-2 kinase activities.
Further, since and the generation of angiogenesis and tumour, development and migration have a substantial connection, suppress new vessels
Formation can effectively suppress the growth and migration of tumour, and many growth factor regulation and control new vesselses are generated, and wherein VEGFR-2 is
Known most strong positive regulatory factor.Therefore the substituted bisarylurea compound with antitumor activity that the present invention is provided is by suppression
The activity of VEGFR-2 kinases processed, blocks the signal path of its induction, suppresses hyperplasia and the migration of tumour cell, so as to can apply
In the preparation of the antineoplastic with VEGFR-2 kinases as target spot.
The above, is only presently preferred embodiments of the present invention, and not the present invention is imposed any restrictions, every according to the present invention
Any simple modification, change and equivalent structure transformation that technical spirit is made to above example, still fall within skill of the present invention
In the protection domain of art scheme.
Claims (8)
1. a kind of substituted bisarylurea compound with antitumor activity, it is characterised in that its chemical structural formula is as follows:
Wherein, R1It is hydrogen, R2It is isopropyl or halogen group.
2. the substituted bisarylurea compound with antitumor activity according to claim 1, it is characterised in that:Described halogen
Plain group is fluorine atom, chlorine atom, trifluoromethyl or trifluoromethoxy.
3. the preparation method of the substituted bisarylurea compound with antitumor activity described in claim 1 or 2, its feature exists
In comprising the following steps:
1) form isocyanates with monosubstituted base or disubstituted aniline and double (trichloromethyl) carbonate reactions, then with 4-
Aminobenzene pinacol borate condensation reaction is obtained with monosubstituted base or disubstituted carbamide compounds;
2) under tetrakis triphenylphosphine palladium catalytic reaction, by with monosubstituted base or disubstituted carbamide compounds and 2- ammonia
Base -5- bromopyridines are reacted by Suzuki and obtain substituted bisarylurea compound intermediate;
3) substituted bisarylurea compound intermediate obtains the double aryl with antitumor activity by acylation reaction with acryloyl chloride
Carbamide compounds.
4. the preparation method of the substituted bisarylurea compound with antitumor activity according to right wants 3, it is characterised in that:
The step 1) concrete operations be:Under condition of ice bath, double (trichloromethyl) carbonic esters are dissolved simultaneously with dichloromethane is steamed again
Stir, the dichloromethane solution with monosubstituted base or disubstituted aniline is added dropwise thereto, stirred after completion of dropping
Uniformly, the dichloromethane solution of dropwise addition triethylamine is then continued thereto, continues to stir after completion of dropping, then drip thereto
Plus the dichloromethane solution and 4- aminobenzene pinacol borates of triethylamine, stirring reaction after completion of dropping, after reaction terminates, will
Reaction solution washing, dry after decompression boil off solvent afforded crude material, obtained with monosubstituted base or disubstituted with chromatography post separation crude product
The carbamide compounds of base.
5. the preparation method of the substituted bisarylurea compound with antitumor activity according to right wants 3, it is characterised in that:
The step 2) concrete operations be:Will with monosubstituted base or disubstituted carbamide compounds, 2- amino -5- bromopyridines,
Carbon Dioxide caesium, tetrakis triphenylphosphine palladium are dissolved in the mixed solution of Isosorbide-5-Nitrae dioxane and water, under nitrogen protection in 100 DEG C
Reaction overnight, after reaction terminates, is cooled to room temperature, is extracted with ethyl acetate, the organic phase of extraction is scrubbed, dry after depressurize and steam
Solvent afforded crude material is removed, substituted bisarylurea compound intermediate is obtained with chromatography post separation crude product.
6. the preparation method of the substituted bisarylurea compound with antitumor activity according to right wants 3, it is characterised in that:
The step 3) concrete operations be:Under condition of ice bath, substituted bisarylurea compound intermediate is dissolved in anhydrous tetrahydro furan
In, anhydrous triethylamine is added dropwise thereto, stir, then acryloyl chloride is added dropwise thereto, after completion of dropping, remove ice bath, room
The lower stirring of temperature is reacted, and after reaction terminates, reaction solution decompression is boiled off into solvent and obtains crude product, is obtained with chromatography post separation crude product
Substituted bisarylurea compound with antitumor activity.
7. the substituted bisarylurea compound with antitumor activity described in claim 1 is preparing suppression VEGFR-2 kinases work
Application in the medicine of property.
8. the substituted bisarylurea compound with antitumor activity described in claim 1 is being prepared with VEGFR-2 kinases as target
Application in the antineoplastic of point.
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