CN105924403A - Cyclomalonamide compound with antitumor activity, and preparation method and application thereof - Google Patents
Cyclomalonamide compound with antitumor activity, and preparation method and application thereof Download PDFInfo
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- CN105924403A CN105924403A CN201610280871.2A CN201610280871A CN105924403A CN 105924403 A CN105924403 A CN 105924403A CN 201610280871 A CN201610280871 A CN 201610280871A CN 105924403 A CN105924403 A CN 105924403A
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- 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
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/84—Nitrogen atoms
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- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention provides a cyclomalonamide 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 is a halogen group; and R2 is a halogen group or a group as described in the specification, or a group formed by R1 and R2 together. 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
Technical field
The invention belongs to biomedicine technical field, relate to a kind of antineoplastic compound, particularly to one, there is antitumor activity
Ring propane diamide compound 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 ring propane diamide compound with antitumor activity and its preparation method and application,
This 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 ring propane diamide compound with antitumor activity, its chemical structural formula is as follows:
Wherein, R1For halogen group, R2For halogen group orOr R1、R2It is collectively forming
Described halogen group is fluorine atom, chlorine atom, bromine atoms, trifluoromethyl or trifluoromethoxy.
The preparation method of the described ring propane diamide compound with antitumor activity, comprises the following steps:
1) 2-fluoro-5-bromobenzaldehyde reacts with guanidine carbonate and obtains 7-bromine quinazoline-2-amine；
2) 7-bromine quinazoline-2-amine and p-aminophenyl borate hydrochlorate prepare 7-(4-aminophenyl) quinoline azoles by Suzuki coupling reaction
Quinoline-2-amine；
3) 1,1-cyclopropane dicarboxylic acid with prepare anilinocarbonyl cyclopropane-carboxylic acid containing disubstituted aniline by condensation reaction；
4) 7-(4-aminophenyl) quinazoline-2-amine has antitumor activity with anilinocarbonyl cyclopropane-carboxylic acid by condensation reaction preparation
Ring propane diamide compound.
Described step 1) concrete operations be: fluoro-for 2-5-bromobenzaldehyde and guanidine carbonate are dissolved in DMA solution,
Back flow reaction, reaction is cooled to room temperature after terminating, and adds water and separate out to solid in reactant liquor, and then suction filtration, filter cake is 7-
Bromine quinazoline-2-amine.
Described step 2) concrete operations be: by 7-bromine quinazoline-2-amine, p-aminophenyl borate hydrochlorate, natrium carbonicum calcinatum with urge
Agent Pd (PPh3)4Being dissolved in the mixed solution of Isosorbide-5-Nitrae-dioxane and water, the lower reaction of nitrogen protection, reaction is cooled to room after terminating
Temperature, carries out suction filtration to reactant liquor, is spin-dried for obtaining crude product by filtrate, with chromatographic column separation crude product, obtains 7-(4-aminophenyl) quinoline azoles
Quinoline-2-amine.
Described step 3) concrete operations be: under nitrogen protection, anhydrous triethylamine is added drop-wise to 1, the dichloro of 1-ring propane dicarboxylic acid
In dichloromethane, stir under condition of ice bath, then drip SOCl wherein2Dichloromethane solution, after dropping, stirring is anti-
Should, continue the dropping dichloromethane solution containing disubstituted aniline the most wherein, drip complete follow-up continuous stirring reaction, instead
After should terminating, the pH value of regulation reactant liquor, it is extracted with ethyl acetate, then vacuum rotary steam removes organic solvent, i.e. obtains anilino-
Carbonyl cyclopropane-carboxylic acid.
Described step 4) concrete operations be: 7-(4-aminophenyl) quinazoline-2-amine and anilinocarbonyl cyclopropane-carboxylic acid are added
In anhydrous methylene chloride solution in ice bath, it is subsequently adding condensing agent HATU, stirs, then drip anhydrous three second wherein
The dichloromethane solution of amine, removes ice bath, reacts under room temperature, and after reaction terminates, reactant liquor decompression scrubbed, dried boils off molten
Agent, obtains crude product, with chromatographic column separation crude product, obtains the ring propane diamide compound with antitumor activity.
The described ring propane diamide compound with antitumor activity is in the medicine of preparation suppression VEGFR-2 kinase activity
Application.
The described ring propane diamide compound with antitumor activity is preparing the antineoplastic with VEGFR-2 kinases as target spot
Application in thing.
Compared with prior art, the method have the advantages that
The ring propane diamide compound with antitumor activity that the present invention provides, is a kind of novel change with antitumor activity
Compound, it has good inhibitory activity to VEGFR-2 kinases, can be used for the preparation of antineoplastic.Concrete, the present invention carries
The ring propane diamide compound with antitumor activity of confession, it is possible to the suppression kinase whose activity of VEGFR-2.And Angiogenesis with
The generation of tumour, developing and migrated substantial connection, the formation of suppression new vessels can effectively suppress the growth of tumour and move
Moving, many growth factor regulation and control new vesselses generate, and wherein VEGFR-2 is the strongest known positive regulatory factor.Therefore this
The ring propane diamide compound with antitumor activity of bright offer, by the suppression kinase whose activity of VEGFR-2, blocks its induction
Signal path, the suppression hyperplasia of tumour cell and migration, thus can be applicable to the preparation of antineoplastic, especially with
VEGFR-2 kinases is antineoplastic and the medicine of suppression VEGFR-2 kinase activity of target spot.
The preparation method of the ring propane diamide compound with antitumor activity that the present invention provides, by 2-fluoro-5-bromobenzaldehyde
React with guanidine carbonate and obtain 7-bromine quinazoline-2-amine, then obtain 7-(4-amino with p-aminophenyl borate hydrochlorate Suzuki coupling reaction
Phenyl) quinazoline-2-amine, and by 1,1-cyclopropane dicarboxylic acid obtains anilinocarbonyl with reacting containing disubstituted aniline condensation
Cyclopropane-carboxylic acid, is incorporated into the substituent in aniline on the phenyl ring of anilinocarbonyl cyclopropane-carboxylic acid, then anilinocarbonyl ring third
Alkane carboxylic acid again with the-2-amine condensation reaction of 7-(4-aminophenyl) quinazoline, i.e. obtain the ring Malonamides chemical combination with antitumor activity
Thing, the method has raw material and is easy to get, and reaction condition is gentle, and course of reaction is simple to operate, the advantage that agents useful for same is cheap.
Accompanying drawing explanation
The synthetic route chart of the ring propane diamide compound with antitumor activity that Fig. 1 provides for the present invention；
Wherein, compound 1 is 2-fluoro-5-bromobenzaldehyde, and compound 2 is 7-bromine quinazoline-2-amine, and compound 3 is p-aminophenyl
Borate hydrochlorate, compound 4 is 7-(4-aminophenyl) quinazoline-2-amine, and compound is 5 to be 1,1-cyclopropane dicarboxylic acid, chemical combination
Thing 6 is containing disubstituted aniline, and compound 7 is anilinocarbonyl cyclopropane-carboxylic acid, and compound A1-A11 is anti-swollen for having
The ring propane diamide compound of tumor activity.
Mark in figure particularly as follows:
a:guanidine carbonate,DMA,140℃；b:Pd(PPh3)4,Na2CO3,H2O,dioxane；c:SOCl2,Et3N,
DCM；d:HATU,Et3N,DCM,0℃to rt.
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 ring propane diamide compound with antitumor activity, this ring propane diamide compound is in vitro
There is antitumor activity, can be applicable to the preparation of antineoplastic.
The chemical structural formula of the ring propane diamide compound with antitumor activity that the present invention provides is specific as follows:
Wherein, R1For trifluoromethyl, trifluoromethoxy or halogen, R2For trifluoromethyl, trifluoromethoxy, halogen or alkoxyl,
Meta and the contraposition of amide group it is connected to by O atom.
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 drug candidate ring propane diamide compound of tumor activity and method for screening active ingredients.
Embodiment 1
This has in the structural formula of ring propane diamide compound of antitumor activity, R1For CF3, R2For Br, by following step
Rapid preparation (seeing Fig. 1):
1) 7-bromine quinazoline-2-amine (compound 2) is prepared by 2-fluoro-5-bromobenzaldehyde (compound 1)
10g (49.2mmol) 2-fluoro-5-bromobenzaldehyde and 13.3g (74mmol) guanidine carbonate are dissolved in DMA solution,
140 DEG C of back flow reaction 5h, after reaction terminates, question response liquid is cooled to room temperature, adds 120mL water, has a large amount of solid to separate out,
Suction filtration, the filter cake of gained is 7-bromine quinazoline-2-amine, about 5g, productivity 60%；
2) Suzuki coupling is passed through by 7-bromine quinazoline-2-amine (compound 2) and p-aminophenyl borate hydrochlorate (compound 3)
Reaction preparation 7-(4-aminophenyl) quinazoline-2-amine (compound 4)
By 2g (8.9mmol) 7-bromine quinazoline-2-amine, 1.54g (8.9mmol) p-aminophenyl borate hydrochlorate, 2.8g (26.7mmol) nothing
Aqueous sodium carbonate and 1.03g (0.89mmol) catalyst Pd (PPh3)4It is dissolved in 120mL 1,4-dioxane and the mixed solution of 40mL water
In, under nitrogen protection, in 100 DEG C of reactions overnight, reaction is cooled to room temperature after terminating, suction filtration, with Isosorbide-5-Nitrae-dioxane washing filter
Cake, collect filtrate, be spin-dried for obtaining residue, residue through chromatographic column separate (eluting solvent is petroleum ether: ethyl acetate=3:1,
Volume ratio), obtain 7-(4-aminophenyl) quinazoline-2-amine 0.8g, productivity about 28%；
3) 1,1-cyclopropane dicarboxylic acid (compound 5) and 5-bromo-3-5-trifluoromethylaniline (compound 6) are prepared by condensation reaction
1-{ [(3,5-3,5-dimethylphenyl) amino] carbonyl } cyclopropane-carboxylic acid (compound 7)
Under nitrogen protective condition, 2.2mL anhydrous triethylamine is added drop-wise to 2g (15.4mmol) 1, the dichloromethane of 1-ring propane dicarboxylic acid
In alkane solution, stir 30min under condition of ice bath, then be slowly added dropwise 1.2mL SOCl2Dichloromethane solution, drip complete stirring
2h, then continues the dichloromethane solution of dropping 3.6g (15.4mmol) 5-bromo-3-5-trifluoromethylaniline in reactant liquor, drips complete
Rear continuation stirs 2h.Then the NaOH solution of reactant liquor 2mol/L is regulated pH to 10, evaporated under reduced pressure, adds suitable quantity of water
Carry out ultrasonic, be extracted with ethyl acetate once, retain water layer, then with the HCl of 2mol/L, water layer regulated pH to 2, then use second
Acetoacetic ester extracts three times, and decompression rotation i.e. obtains 1-{ [(3,5-3,5-dimethylphenyl) amino] carbonyl except organic solvent } cyclopropane-carboxylic acid, about
0.8g, productivity 37%；
4) by 7-(4-aminophenyl) quinazoline-2-amine (compound 4) and 1-{ [(3,5-3,5-dimethylphenyl) amino] carbonyl } cyclopropane carboxylic acid
Acid (compound 7) obtains the ring propane diamide compound (compound 8) with antitumor activity by condensation reaction
By 0.38g (0.7mmol) 7-(4-aminophenyl) quinazoline-2-amine and 0.24g (0.7mmol) 1-{ [(3,5-3,5-dimethylphenyl) amino]
Carbonyl } cyclopropane-carboxylic acid joins in the anhydrous methylene chloride solution in ice bath, adds 0.48g (1.26mmol) condensing agent HATU,
Continuation stirring 30min, more slowly drip the dichloromethane solution of 0.1mL anhydrous triethylamine, remove ice bath, room temperature reaction 8h.
Then being washed with saturated sodium bicarbonate solution and saturated aqueous common salt successively by reactant liquor, anhydrous sodium sulfate is dried, then is spin-dried for being remained
Thing, with chromatographic column separating residual thing, obtains the ring propane diamide compound 0.12g with antitumor activity, productivity 20%.
The structural formula of the ring propane diamide compound with antitumor activity that embodiment 1 prepares is as follows:
Physicochemical property: mp:234～236 DEG C
Hydrogen spectrum nuclear magnetic resonance data is:1H NMR(400MHz,DMSO)δ11.49(s,1H),9.74(s,1H),9.16(s,1H),
8.44 (s, 1H), 8.12 (d, J=2.0Hz, 1H), 8.05 (m, 1H), 7.76 (d, J=8.8Hz, 2H), 7.72 (d, J=8.8Hz,
2H), 7.50 (d, J=8.8Hz, 1H), 7.43 (s, 2H), 6.90 (s, 2H), 1.76 (m, 2H), 1.63 (m, 2H).
Embodiment 2
This has in the structural formula of ring propane diamide compound of antitumor activity, R1、R2For chlorine.
Step 1)～step 2) with the step 1 of embodiment 1)～2) identical, i.e. by 2-fluoro-5-bromobenzaldehyde (compound 1) make
Standby 7-bromine quinazoline-2-amine (compound 2), then (changed by 7-bromine quinazoline-2-amine (compound 2) and p-aminophenyl borate hydrochlorate
Compound 3) prepare 7-(4-aminophenyl) quinazoline-2-amine (compound 4) by Suzuki coupling reaction.
3) 1,1-cyclopropane dicarboxylic acid (compound 5) and 3,4-dichloroaniline (compound 6) prepare 1-({ 3,4-by condensation reaction
Dichloroaniline amino } carbonyl) cyclopropane-carboxylic acid (compound 7)
Under nitrogen protective condition, 12.9mL anhydrous triethylamine is added drop-wise to 4g (30.8mmol) 1, the dichloromethane of 1-ring propane dicarboxylic acid
In alkane solution, stir 30min under condition of ice bath, then be slowly added dropwise 2.3mL SOCl2Dichloromethane solution, drip complete stirring
2h, then continues the dichloromethane solution of dropping 4.5g (27.7mmol) 3,4-DCA in reactant liquor, drips complete follow-up continuous
Stirring 2h.Then the NaOH solution of reactant liquor 2mol/L is regulated pH to 10, evaporated under reduced pressure, adds suitable quantity of water and surpass
Sound, is extracted with ethyl acetate once, retains water layer, then with the HCl of 2mol/L, water layer regulates pH to 2, then uses ethyl acetate
Extracting three times, decompression rotation i.e. obtains 1-({ 3,4-DCA amino } carbonyl) cyclopropane-carboxylic acid, about 2g, productivity 40% except organic solvent；
4) by 7-(4-aminophenyl) quinazoline-2-amine (compound 4) and 1-({ 3,4-dichloroaniline amino } carbonyl) cyclopropane-carboxylic acid
(compound 7) obtains the ring propane diamide compound (compound 8) with antitumor activity by condensation reaction
By 0.5g (0.92mmol) 7-(4-aminophenyl) quinazoline-2-amine and 0.23g (0.92mmol) 1-({ 3,4-dichloroaniline amino } carbonyl
Base) cyclopropane-carboxylic acid joins in the anhydrous methylene chloride solution in ice bath, adds 0.63g (1.66mmol) condensing agent HATU,
Continuation stirring 30min, more slowly drip the dichloromethane solution of 0.13mL anhydrous triethylamine, remove ice bath, room temperature reaction 8h.
Then being washed with saturated sodium bicarbonate solution and saturated aqueous common salt successively by reactant liquor, anhydrous sodium sulfate is dried, then is spin-dried for being remained
Thing, with chromatographic column separating residual thing, obtains the ring propane diamide compound 0.1g with antitumor activity, productivity 20%.
The structural formula of the ring propane diamide compound with antitumor activity that embodiment 2 prepares is as follows:
Physicochemical property: mp:253～254 DEG C
Hydrogen spectrum nuclear magnetic resonance data is:1H NMR(400MHz,DMSO)δ10.32(s,1H),10.11(s,1H),9.17(s,1H),
8.09 (d, J=2.0Hz, 1H), 8.06 (d, J=2.1Hz, 1H), 8.03 (m, 1H), 7.77 (d, J=8.8Hz, 2H), 7.71 (d, J=
8.8Hz, 2H), 7.60 (m, 1H), 7.56 (d, J=8.8Hz, 1H), 7.49 (d, J=8.8Hz, 1H), 6.90 (s, 2H), 1.52 (d, J
=10.2Hz, 2H), 1.48 (d, J=10.1Hz, 2H).
Embodiment 3
This has in the structural formula of ring propane diamide compound of antitumor activity, R1、R2For chlorine.
Step 1)～step 2) with the step 1 of embodiment 1)～2) identical, i.e. by 2-fluoro-5-bromobenzaldehyde (compound 1) make
Standby 7-bromine quinazoline-2-amine (compound 2), then (changed by 7-bromine quinazoline-2-amine (compound 2) and p-aminophenyl borate hydrochlorate
Compound 3) prepare 7-(4-aminophenyl) quinazoline-2-amine (compound 4) by Suzuki coupling reaction.
3) 1,1-cyclopropane dicarboxylic acid (compound 5) and 2,4 dichloro aniline (compound 6) prepare 1-({ 2,4-by condensation reaction
Dichloroaniline amino } carbonyl) cyclopropane-carboxylic acid (compound 7)
Under nitrogen protective condition, 12.9mL anhydrous triethylamine is added drop-wise to 4g (30.8mmol) 1, the dichloromethane of 1-ring propane dicarboxylic acid
In alkane solution, stir 30min under condition of ice bath, then be slowly added dropwise 2.3mL SOCl2Dichloromethane solution, drip complete stirring
2h, then continues dropping 4.5g (27.7mmol) 2, the dichloromethane solution of 4-dichloroaniline in reactant liquor, drips complete follow-up continuous
Stirring 2h.Then the NaOH solution of reactant liquor 2mol/L is regulated pH to 10, evaporated under reduced pressure, adds suitable quantity of water and surpass
Sound, is extracted with ethyl acetate once, retains water layer, then with the HCl of 2mol/L, water layer regulates pH to 2, then uses ethyl acetate
Extracting three times, decompression rotation i.e. obtains 1-({ 2,4-dichloroaniline amino } carbonyl) cyclopropane-carboxylic acid, about 2g, productivity 40% except organic solvent；
4) by 7-(4-aminophenyl) quinazoline-2-amine (compound 4) and 1-({ 2,4 dichloro aniline amino } carbonyl) cyclopropane-carboxylic acid
(compound 7) obtains the ring propane diamide compound (compound 8) with antitumor activity by condensation reaction
By 0.5g (0.92mmol) 7-(4-aminophenyl) quinazoline-2-amine and 0.23g (0.92mmol) 1-({ 2,4 dichloro aniline amino } carbonyl
Base) cyclopropane-carboxylic acid joins in the anhydrous methylene chloride solution in ice bath, adds 0.63g (1.66mmol) condensing agent HATU,
Continuation stirring 30min, more slowly drip the dichloromethane solution of 0.13mL anhydrous triethylamine, remove ice bath, room temperature reaction 8h.
Then being washed with saturated sodium bicarbonate solution and saturated aqueous common salt successively by reactant liquor, anhydrous sodium sulfate is dried, then is spin-dried for being remained
Thing, with chromatographic column separating residual thing, obtains the ring propane diamide compound 0.1g with antitumor activity, productivity 20%.
The structural formula of the ring propane diamide compound with antitumor activity that embodiment 3 prepares is as follows:
Physicochemical property: mp:261～263 DEG C
Hydrogen spectrum nuclear magnetic resonance data is:1H NMR(400MHz,DMSO)δ10.99(s,1H),9.93(s,1H),9.17(s,1H),
8.09 (d, J=8.7Hz, 2H), 8.04 (d, J=8.8Hz, 1H), 7.74 (t, J=7.1Hz, 4H), 7.70 7.68 (m, 1H), 7.50
(d, J=8.7Hz, 1H), 7.44 (m, 1H), 6.90 (s, 2H), 1.71 (s, 2H), 1.64 (s, 2H).
Embodiment 4
This has in the structural formula of ring propane diamide compound of antitumor activity, R1、R2It is respectively trifluoromethoxy and bromine.
Step 1)～step 2) with the step 1 of embodiment 1)～2) identical, i.e. by 2-fluoro-5-bromobenzaldehyde (compound 1) make
Standby 7-bromine quinazoline-2-amine (compound 2), then (changed by 7-bromine quinazoline-2-amine (compound 2) and p-aminophenyl borate hydrochlorate
Compound 3) prepare 7-(4-aminophenyl) quinazoline-2-amine (compound 4) by Suzuki coupling reaction.
3) 1,1-cyclopropane dicarboxylic acid (compound 5) and 5-bromo-2-trifluoro-methoxyaniline (compound 6) are by condensation reaction system
Standby 1-({ [5-bromo-2-(trifluoromethoxy) phenyl] amino } carbonyl) cyclopropane-carboxylic acid (compound 7)
Under nitrogen protective condition, 2.2mL anhydrous triethylamine is added drop-wise to 2g (15.4mmol) 1, the dichloromethane of 1-ring propane dicarboxylic acid
In solution, stir 30min under condition of ice bath, then be slowly added dropwise 1.2mL SOCl2Dichloromethane solution, drip complete stirring
2h, then continues the dichloromethane solution of dropping 3.5g (13.9mmol) 5-bromo-2-trifluoro-methoxyaniline in reactant liquor, drips
Stirring 2h is continued after Biing.Then the NaOH solution of reactant liquor 2mol/L is regulated pH to 10, evaporated under reduced pressure, adds appropriate
Water carries out ultrasonic, is extracted with ethyl acetate once, retains water layer, then with the HCl of 2mol/L, water layer regulates pH to 2, then uses
Ethyl acetate extracts three times, and decompression rotation i.e. obtains 1-({ [5-bromo-2-(trifluoromethoxy) phenyl] amino } carbonyl) cyclopropane except organic solvent
Carboxylic acid, about 0.8g, productivity 35%；
4) by 7-(4-aminophenyl) quinazoline-2-amine (compound 4) and 1-({ [5-bromo-2-(trifluoromethoxy) phenyl] amino } carbonyl)
Cyclopropane-carboxylic acid (compound 7) obtains the ring propane diamide compound (compound 8) with antitumor activity by condensation reaction
By 0.45g (1.91mmol) 7-(4-aminophenyl) quinazoline-2-amine and 0.7g (1.91mmol) 1-({ [the bromo-2-of 5-(trifluoromethoxy)
Phenyl] amino } carbonyl) cyclopropane-carboxylic acid joins in the anhydrous methylene chloride solution in ice bath, adds 1.31g (3.44mmol) contracting
Mixture HATU, continuation stirring 30min, more slowly drip the dichloromethane solution of 0.8mL anhydrous triethylamine, remove ice bath, room
Temperature reaction 8h.Then being washed with saturated sodium bicarbonate solution and saturated aqueous common salt successively by reactant liquor, anhydrous sodium sulfate is dried, then
It is spin-dried for obtaining residue, with chromatographic column separating residual thing, obtains the ring propane diamide compound 0.12g with antitumor activity,
Productivity 20%.
The structural formula of the ring propane diamide compound with antitumor activity that embodiment 4 prepares is as follows:
Physicochemical property: mp:239～240 DEG C
Hydrogen spectrum nuclear magnetic resonance data is:1H NMR(400MHz,DMSO)δ11.48(s,1H),9.74(s,1H),9.16(s,1H),
8.44 (d, J=0.8Hz, 1H), 8.12 (d, J=2.0Hz, 1H), 8.05 (m, 1H), 7.76 (d, J=8.9Hz, 2H), 7.72 (d, J=
8.9Hz, 2H), 7.50 (d, J=8.8Hz, 1H), 7.44 (s, 2H), 6.90 (s, 2H), 1.76 (m, 2H), 1.63 (m, 2H).
Embodiment 5
This has in the structural formula of ring propane diamide compound of antitumor activity, R1、R2It is respectively and is connected to by O atom
The meta of amide group and the alkoxyl of contraposition.
Step 1)～step 2) with the step 1 of embodiment 1)～2) identical, i.e. by 2-fluoro-5-bromobenzaldehyde (compound 1) make
Standby 7-bromine quinazoline-2-amine (compound 2), then (changed by 7-bromine quinazoline-2-amine (compound 2) and p-aminophenyl borate hydrochlorate
Compound 3) prepare 7-(4-aminophenyl) quinazoline-2-amine (compound 4) by Suzuki coupling reaction.
3) 1,1-cyclopropane dicarboxylic acid (compound 5) and pepper amine (compound 6) prepare N1-1,3 benzo two by condensation reaction
Oxa-ring amyl-5-cyclopropyl-1,1-diformamide (compound 7)
Under nitrogen protective condition, 2.2mL anhydrous triethylamine is added drop-wise to 2g (15.4mmol) 1, the dichloromethane of 1-ring propane dicarboxylic acid
In solution, stir 30min under condition of ice bath, then be slowly added dropwise 1.2mL SOCl2Dichloromethane solution, drip complete stirring
2h, then continues the dichloromethane solution of dropping 1.9g (15.4mmol) pepper amine in reactant liquor, drips complete follow-up continuous stirring
2h.Then the NaOH solution of reactant liquor 2mol/L is regulated pH to 10, evaporated under reduced pressure, adds suitable quantity of water and carry out ultrasonic,
It is extracted with ethyl acetate once, retains water layer, then with the HCl of 2mol/L, water layer regulated pH to 2, then be extracted with ethyl acetate
Three times, decompression rotation i.e. obtains N1-1,3 benzo dioxane amyl-5-cyclopropyl-1,1-diformamide, about 1g, productivity except organic solvent
35%；
4) by 7-(4-aminophenyl) quinazoline-2-amine (compound 4) and N1-1,3 benzo dioxane amyl-5-cyclopropyl-1,1-two
Formamide (compound 7) obtains the ring propane diamide compound (compound 8) with antitumor activity by condensation reaction
By 0.3g (1.27mmol) 7-(4-aminophenyl) quinazoline-2-amine and 0.35g (1.4mmol) the N1-1,3 amyl-5-of benzo dioxane
Cyclopropyl-1,1-diformamide joins in the anhydrous methylene chloride solution in ice bath, adds 0.87g (2.29mmol) condensing agent
HATU, continuation stirring 30min, more slowly drip the dichloromethane solution of 0.53mL anhydrous triethylamine, remove ice bath, room temperature
Reaction 8h.Then being washed with saturated sodium bicarbonate solution and saturated aqueous common salt successively by reactant liquor, anhydrous sodium sulfate is dried, then revolves
Dry obtain residue, with chromatographic column separating residual thing, obtain the ring propane diamide compound 0.12g with antitumor activity, produce
Rate 20%.
The structural formula of the ring propane diamide compound with antitumor activity that embodiment 5 prepares is as follows:
Physicochemical property: mp:283～285 DEG C
Hydrogen spectrum nuclear magnetic resonance data is:1H NMR(400MHz,DMSO)δ10.21(s,1H),9.91(s,1H),9.17(s,1H),
8.09 (d, J=1.8Hz, 1H), 8.03 (m, 1H), 7.76 (d, J=8.8Hz, 2H), 7.72 (d, J=8.8Hz, 2H), 7.49 (d, J=
8.8Hz, 1H), 7.32 (d, J=1.5Hz, 1H), 7.02 (m, 1H), 6.90 (s, 2H), 6.86 (d, J=8.4Hz, 1H), 6.00 (s,
2H),1.49(s,4H).
The ring propane diamide compound with antitumor activity prepared the present invention below carries out the kinase whose suppression of VEGFR-2 and lives
Property screening.
Kinases VEGFR-2 and substrate A bltide, purchased from Signal-Chem company, select the ADP-GlobTM of Promega company
The enzyme that presses down of the ring propane diamide compound with antitumor activity that the Kinase Assays detection kit detection present invention provides is lived
Property, method of operating illustrates to carry out according to kit.By ATP (10mM) buffer (2 ×) (Tris 80mM, MgCl2 20mM,BSA
0.2mg/mL, DTT 2mM) dilute 40 times of buffer (2 ×) solution being configured to ATP (250 μMs)；By the ATP solution of 250 μMs
The mixed solution being hybridly prepared into ATP (125 μMs)-Abltide (0.5 μ g/ μ l) with Abltide liquor capacity 1:1 is standby；VEGFR-2
Kinase solution buffer (1 ×) (Tris 40mM, MgCl210mM, BSA0.1mg/mL, DTT 1mM) dilute 66 times and be configured to
Buffer (1 ×) solution for standby of VEGFR-2 (1.5ng/ μ l)；By target compound and positive control drug (Sorafinib) buffer (1 ×)
It is configured to 6 × 10 respectively-5Mol/L, 6 × 10-6Mol/L, 6 × 10-7Mol/L, 6 × 10-8Mol/L, 6 × 10-9Mol/L, 6 × 10-10mol/L
The sample solution of concentration gradient, on 384 orifice plates, every hole is sequentially added into the mixed solution of 2 μ L ATP-Abltide, and 1 μ L sample is molten
Liquid, 2 μ L enzyme solutions；Blank well adds 3 μ L buffer solutions and the mixed solution of 2 μ LATP-Abltide；Control wells adds 2 μ L ATP-Abltide
Mixed solution, 1 μ L buffer solution, 2 μ L enzyme solutions, finish, at 30 DEG C, hatch 60min；Add ADP-Glo reagent 5 μ L,
40min is hatched at 25 DEG C；Add Kinase detection reagent 10 μ L, at 25 DEG C, hatch 30min.Use PerkinElmer
The chemiluminescence module of multi-functional ELIASA measures the luminous value in every hole, calculates the ring with antitumor activity that the present invention provides the third two
Amides compound is to the inhibiting rate of VEGFR-2 and IC50。
Inhibitory activity kinase whose to the VEGFR-2 result such as table 1 of the ring propane diamide compound with antitumor activity of the present invention
Shown in:
Table 1 ring propane diamide compound IC kinase whose to VEGFR50
As can be seen from Table 1, what prepared by the present invention has the ring propane diamide compound of antitumor activity to VEGFR-2 kinases
There is inhibitory activity, can be used for the medicine of preparation suppression VEGFR-2 kinase activity and prepare with VEGFR-2 kinases as target spot
Antineoplastic.
The structure of above-claimed cpd is the most as shown in table 2:
The structural formula of the ring propane diamide compound with antitumor activity that table 2 present invention provides
Claims (9)
1. a ring propane diamide compound with antitumor activity, it is characterised in that its chemical structural formula is as follows:
Wherein, R1For halogen group, R2For halogen group orOr R1、R2It is collectively forming
There is the ring propane diamide compound of antitumor activity the most as claimed in claim 1, it is characterised in that described halogen
Element group is fluorine atom, chlorine atom, bromine atoms, trifluoromethyl or trifluoromethoxy.
3. the preparation method of the ring propane diamide compound with antitumor activity described in claim 1 or 2, its feature exists
In, comprise the following steps:
1) 2-fluoro-5-bromobenzaldehyde reacts with guanidine carbonate and obtains 7-bromine quinazoline-2-amine；
2) 7-bromine quinazoline-2-amine and p-aminophenyl borate hydrochlorate prepare 7-(4-aminophenyl) quinoline azoles by Suzuki coupling reaction
Quinoline-2-amine；
3) 1,1-cyclopropane dicarboxylic acid with prepare anilinocarbonyl cyclopropane-carboxylic acid containing disubstituted aniline by condensation reaction；
4) 7-(4-aminophenyl) quinazoline-2-amine has antitumor activity with anilinocarbonyl cyclopropane-carboxylic acid by condensation reaction preparation
Ring propane diamide compound.
The preparation method of the ring propane diamide compound with antitumor activity the most according to claim 3, its feature exists
In described step 1) concrete operations be: fluoro-for 2-5-bromobenzaldehyde and guanidine carbonate be dissolved in DMA solution,
Back flow reaction, reaction is cooled to room temperature after terminating, and adds water and separate out to solid in reactant liquor, and then suction filtration, filter cake is 7-
Bromine quinazoline-2-amine.
The preparation method of the ring propane diamide compound with antitumor activity the most according to claim 3, its feature exists
In described step 2) concrete operations be: by 7-bromine quinazoline-2-amine, p-aminophenyl borate hydrochlorate, natrium carbonicum calcinatum with urge
Agent Pd (PPh3)4Being dissolved in the mixed solution of Isosorbide-5-Nitrae-dioxane and water, the lower reaction of nitrogen protection, reaction is cooled to room after terminating
Temperature, carries out suction filtration to reactant liquor, is spin-dried for obtaining crude product by filtrate, with chromatographic column separation crude product, obtains 7-(4-aminophenyl) quinoline azoles
Quinoline-2-amine.
The preparation method of the ring propane diamide compound with antitumor activity the most according to claim 3, its feature exists
In described step 3) concrete operations be: under nitrogen protection, anhydrous triethylamine is added drop-wise to 1, the dichloro of 1-ring propane dicarboxylic acid
In dichloromethane, stir under condition of ice bath, then drip SOCl wherein2Dichloromethane solution, after dropping, stirring is anti-
Should, continue the dropping dichloromethane solution containing disubstituted aniline the most wherein, drip complete follow-up continuous stirring reaction, instead
After should terminating, the pH value of regulation reactant liquor, it is extracted with ethyl acetate, then vacuum rotary steam removes organic solvent, i.e. obtains anilino-
Carbonyl cyclopropane-carboxylic acid.
The preparation method of the ring propane diamide compound with antitumor activity the most according to claim 3, its feature exists
In described step 4) concrete operations be: 7-(4-aminophenyl) quinazoline-2-amine and anilinocarbonyl cyclopropane-carboxylic acid are added
In anhydrous methylene chloride solution in ice bath, it is subsequently adding condensing agent HATU, stirs, then drip anhydrous three second wherein
The dichloromethane solution of amine, removes ice bath, reacts under room temperature, and after reaction terminates, reactant liquor decompression scrubbed, dried boils off molten
Agent, obtains crude product, with chromatographic column separation crude product, obtains the ring propane diamide compound with antitumor activity.
8. the ring propane diamide compound with antitumor activity described in claim 1 or 2 is at preparation suppression VEGFR-2
Application in the medicine of kinase activity.
9. the ring propane diamide compound with antitumor activity described in claim 1 or 2 swashs with VEGFR-2 in preparation
Enzyme is the application in the antineoplastic of target spot.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107879946A (en) * | 2017-04-25 | 2018-04-06 | 湖南比德生化科技股份有限公司 | A kind of method for preparing ring malonamic acid |
| CN109761785A (en) * | 2019-02-16 | 2019-05-17 | 安徽诺全药业有限公司 | The synthetic method of one kind (1R, 2R) -2- (3,4- difluorophenyl) cyclopropane-carboxylic acid |
| CN114605391A (en) * | 2022-02-21 | 2022-06-10 | 广州六顺生物科技股份有限公司 | Quinoxaline derivative and preparation method and application thereof |
Citations (2)
| 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 |
| CN105175351A (en) * | 2014-05-30 | 2015-12-23 | 中国科学院上海药物研究所 | 3-amino-benzo five-membered heterocyclic compounds and preparation method and applications thereof |
-
2016
- 2016-04-28 CN CN201610280871.2A patent/CN105924403B/en active Active
Patent Citations (2)
| 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 |
| CN105175351A (en) * | 2014-05-30 | 2015-12-23 | 中国科学院上海药物研究所 | 3-amino-benzo five-membered heterocyclic compounds and preparation method and applications thereof |
Non-Patent Citations (2)
| 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 (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107879946A (en) * | 2017-04-25 | 2018-04-06 | 湖南比德生化科技股份有限公司 | A kind of method for preparing ring malonamic acid |
| CN109761785A (en) * | 2019-02-16 | 2019-05-17 | 安徽诺全药业有限公司 | The synthetic method of one kind (1R, 2R) -2- (3,4- difluorophenyl) cyclopropane-carboxylic acid |
| CN114605391A (en) * | 2022-02-21 | 2022-06-10 | 广州六顺生物科技股份有限公司 | Quinoxaline derivative and preparation method and application thereof |
| CN114605391B (en) * | 2022-02-21 | 2024-01-26 | 广州六顺生物科技股份有限公司 | Quinoxaline derivative, preparation method and application thereof |
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