CN105924403B - A kind of ring propane diamide compound with anti-tumor activity and its preparation method and application - Google Patents
A kind of ring propane diamide compound with anti-tumor activity and its preparation method and application Download PDFInfo
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- CN105924403B CN105924403B CN201610280871.2A CN201610280871A CN105924403B CN 105924403 B CN105924403 B CN 105924403B CN 201610280871 A CN201610280871 A CN 201610280871A CN 105924403 B CN105924403 B CN 105924403B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
- C07D239/84—Nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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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- C—CHEMISTRY; METALLURGY
- 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
Abstract
The present invention provides a kind of ring propane diamide compounds with anti-tumor activity and its preparation method and application, and the structural formula of the compound isWherein R1For halogen group, R2For halogen group orOr R1、R2It is collectively formed
Description
Technical field
The invention belongs to biomedicine technical fields, are related to a kind of antitumor compound, more particularly to a kind of with anti-
Ring propane diamide compound of tumor promotion and its preparation method and application.
Background technology
The malignant tumour public health problem one of larger as the whole world, greatly endangers the health of the mankind, and will become
The first killer of the new century mankind.Malignant tumour has no longer been the serious disease of advanced industrial country, and developing country faces
The Disease Spectrum of bigger.Chemotherapy had huge as one of the important means for the treatment of tumour at nearly 30 years
Big development and progress has obtained large quantities of clinical antitumor agents with different role mechanism.But antineoplastic is also deposited
In many adverse reactions, such as alopecia, vomiting generates bone marrow suppression, quickly generates drug resistance etc., these result in chemical drugs
Object is unable to reach expected therapeutic effect.Therefore new antitumor drug research and development be current pharmaceutical field hot spot and
One of difficulties.
Invention content
The purpose of the present invention is to provide a kind of ring propane diamide compound with anti-tumor activity and its preparation sides
Method and application, the compound embody good antitumor activity in vitro, can be applied to the preparation of antitumor drug.
In order to achieve the above objectives, the present invention uses following technical scheme：
A kind of ring propane diamide compound with anti-tumor activity, chemical structural formula are as follows：
Wherein, R1For halogen group, R2For halogen group orOr R1、R2It is collectively formed
The halogen group is fluorine atom, chlorine atom, bromine atom, trifluoromethyl or trifluoromethoxy.
The preparation method of the ring propane diamide compound with anti-tumor activity, includes the following steps：
1) 7- bromine quinazoline -2- amine is obtained by the reaction with guanidine carbonate in the fluoro- 5- bromobenzaldehydes of 2-；
2) 7- bromines quinazoline -2- amine prepares 7- (4- amino with p-aminophenyl boric acid hydrochloride by Suzuki coupling reactions
Phenyl) quinazoline -2- amine；
3) 1,1- cyclopropane dicarboxylic acids with containing disubstituted aniline anilinocarbonyl ring third is prepared by condensation reaction
Alkane carboxylic acid；
4) 7- (4- aminophenyls) quinazoline -2- amine has with anilinocarbonyl cyclopropane-carboxylic acid by condensation reaction preparation
The ring propane diamide compound of antitumor activity.
The concrete operations of the step 1) are：The fluoro- 5- bromobenzaldehydes of 2- and guanidine carbonate are dissolved in DMAC N,N' dimethyl acetamide
In solution, back flow reaction is cooled to room temperature after reaction, and water to solid is added into reaction solution and is precipitated, then filters, filter cake
As 7- bromines quinazoline -2- amine.
The concrete operations of the step 2) are：By 7- bromine quinazoline -2- amine, p-aminophenyl boric acid hydrochloride, Carbon Dioxide
Sodium and catalyst Pd (PPh3)4It is dissolved in the mixed solution of Isosorbide-5-Nitrae-dioxane and water, is reacted under nitrogen protection, after reaction
It is cooled to room temperature, reaction solution is filtered, filtrate is spin-dried for obtain crude product, with chromatography post separation crude product, obtain 7- (4- amino
Phenyl) quinazoline -2- amine.
The concrete operations of the step 3) are：Under nitrogen protection, anhydrous triethylamine is added drop-wise to 1,1- ring propane dicarboxylic acids
Dichloromethane solution in, stirred evenly under condition of ice bath, then SOCl is added dropwise thereto2Dichloromethane solution, be added dropwise
After be stirred to react, then continue thereto be added dropwise containing disubstituted aniline dichloromethane solution, continue after being added dropwise
It is stirred to react, after reaction, adjusts the pH value of reaction solution, be extracted with ethyl acetate, then vacuum rotary steam removes organic solvent, i.e.,
Obtain anilinocarbonyl cyclopropane-carboxylic acid.
The concrete operations of the step 4) are：By 7- (4- aminophenyls) quinazoline -2- amine and anilinocarbonyl cyclopropane
Carboxylic acid is added in the anhydrous methylene chloride solution in ice bath, and condensing agent HATU is then added, stirs evenly, then be added dropwise thereto
The dichloromethane solution of anhydrous triethylamine removes ice bath, reacts at room temperature, after reaction, reaction solution is washed, it is dry after subtract
Pressure boils off solvent, obtains crude product, with chromatography post separation crude product, obtains ring propane diamide compound with anti-tumor activity.
The ring propane diamide compound with anti-tumor activity inhibits the medicine of VEGFR-2 kinase activities preparing
Application in object.
The ring propane diamide compound with anti-tumor activity is being prepared using VEGFR-2 kinases as the anti-of target spot
Application in tumour medicine.
Compared with prior art, the invention has the advantages that：
Ring propane diamide compound with anti-tumor activity provided by the invention, be it is a kind of it is novel have it is antitumor
Active compound has good inhibitory activity to VEGFR-2 kinases, can be used for the preparation of antitumor drug.Specifically, this
The ring propane diamide compound with anti-tumor activity provided is provided, the activity of VEGFR-2 kinases can be inhibited.And blood vessel
It generates and the generation of tumour, development and migration has substantial connection, inhibit the formation of new vessels that can effectively inhibit tumour
Growth and migration, many growth factors regulation and control new vessels generate, wherein VEGFR-2 be known strongest positive regulation and control because
Son.Therefore the work that ring propane diamide compound with anti-tumor activity provided by the invention passes through inhibition VEGFR-2 kinases
Property, the signal path for blocking it to induce inhibits hyperplasia and the migration of tumour cell, so as to the system applied to antitumor drug
It is standby, especially using VEGFR-2 kinases as the antitumor drug of target spot and the drug of inhibition VEGFR-2 kinase activities.
The preparation method of ring propane diamide compound with anti-tumor activity provided by the invention, passes through the fluoro- 5- of 2-
Bromobenzaldehyde and guanidine carbonate are obtained by the reaction 7- bromine quinazoline -2- amine, then with p-aminophenyl boric acid hydrochloride Suzuki coupling reactions
7- (4- aminophenyls) quinazoline -2- amine is obtained, and by 1,1- cyclopropane dicarboxylic acids and contains disubstituted aniline condensation
Anilinocarbonyl cyclopropane-carboxylic acid is obtained by the reaction, the substituent group in aniline is introduced into the phenyl ring of anilinocarbonyl cyclopropane-carboxylic acid
On, then anilinocarbonyl cyclopropane-carboxylic acid is again with 7- (4- aminophenyls) quinazoline -2- amine condensation reactions to get to anti-
The ring propane diamide compound of tumor promotion, this method are easy to get with raw material, and reaction condition is mild, reaction process operation letter
It is single, the cheap advantage of agents useful for same.
Description of the drawings
Fig. 1 is the synthetic route chart of ring propane diamide compound with anti-tumor activity provided by the invention；
Wherein, compound 1 is the fluoro- 5- bromobenzaldehydes of 2-, and compound 2 is 7- bromine quinazoline -2- amine, and compound 3 is to ammonia
Base phenyl boric acid hydrochloride, compound 4 are 7- (4- aminophenyls) quinazoline -2- amine, and it is 1,1- cyclopropane dicarboxyls that compound, which is 5,
Acid, compound 6 are containing disubstituted aniline, and compound 7 is anilinocarbonyl cyclopropane-carboxylic acid, and compound A1-A11 is tool
There is the ring propane diamide compound of antitumor activity.
Mark in figure is specially：
a:guanidine carbonate,DMA,140℃；b:Pd(PPh3)4,Na2CO3,H2O,dioxane；c:
SOCl2,Et3N, DCM；d:HATU,Et3N,DCM,0℃to rt.
Specific implementation mode
The present invention is described in further detail with specific embodiment below in conjunction with the accompanying drawings, and described is to the present invention
It explains rather than limits.
The present invention provides a kind of ring propane diamide compound with anti-tumor activity, the ring Malonamides chemical combination
Object has antitumor activity in vitro, can be applied to the preparation of antitumor drug.
The chemical structural formula of ring propane diamide compound with anti-tumor activity provided by the invention is specific as follows：
Wherein, R1For trifluoromethyl, trifluoromethoxy or halogen, R2For trifluoromethyl, trifluoromethoxy, halogen or alcoxyl
Base is connected to meta position and the contraposition of amide group by O atom.
Carry out the tool that the present invention will be described in detail provides with reference to synthetic route shown in Fig. 1 and specific synthetic example
There are preparation and the method for screening active ingredients of the drug candidate ring propane diamide compound of antitumor activity.
Embodiment 1
In the structural formula of the ring propane diamide compound with anti-tumor activity, R1For CF3, R2For Br, by following
Step is prepared (referring to Fig. 1)：
1) 7- bromine quinazoline -2- amine (compound 2) is prepared by the fluoro- 5- bromobenzaldehydes (compound 1) of 2-
The fluoro- 5- bromobenzaldehydes of 10g (49.2mmol) 2- and 13.3g (74mmol) guanidine carbonate are dissolved in N, N- dimethylacetamides
In amine aqueous solution, 140 DEG C of back flow reaction 5h wait for that reaction solution is cooled to room temperature after reaction, and 120mL water is added, and have a large amount of solid
Body is precipitated, and filters, the filter cake of gained is 7- bromine quinazoline -2- amine, about 5g, yield 60%；
2) Suzuki idols are passed through by 7- bromine quinazoline -2- amine (compound 2) and p-aminophenyl boric acid hydrochloride (compound 3)
Connection reaction prepares 7- (4- aminophenyls) quinazoline -2- amine (compound 4)
By 2g (8.9mmol) 7- bromine quinazoline -2- amine, 1.54g (8.9mmol) p-aminophenyl boric acid hydrochloride, 2.8g
(26.7mmol) natrium carbonicum calcinatum and 1.03g (0.89mmol) catalyst Pd (PPh3)4Be dissolved in 120mL 1,4- dioxane and
In the mixed solution of 40mL water, under nitrogen protection, overnight in 100 DEG C of reactions, it is cooled to room temperature, filters after reaction, with 1,
4- dioxane washs filter cake, collects filtrate, is spin-dried for obtaining residue, (eluting solvent is oil to residue by chromatography post separation
Ether:Ethyl acetate=3:1, volume ratio), obtain 7- (4- aminophenyls) quinazoline -2- amine 0.8g, yield about 28%；
3) 1,1- cyclopropane dicarboxylic acids (compound 5) and the bromo- 3- 5-trifluoromethylanilines (compound 6) of 5- pass through condensation reaction
Prepare 1- { [(3,5- 3,5-dimethylphenyls) amino] carbonyl } cyclopropane-carboxylic acid (compound 7)
Under the conditions of nitrogen protection, 2.2mL anhydrous triethylamines are added drop-wise to 2g (15.4mmol) 1,1- ring propane dicarboxylic acids
In dichloromethane solution, 30min is stirred under condition of ice bath, then 1.2mL SOCl are slowly added dropwise2Dichloromethane solution, drip
Finish stirring 2h, the dichloromethane for then continuing to be added dropwise the bromo- 3- 5-trifluoromethylanilines of 3.6g (15.4mmol) 5- into reaction solution is molten
Liquid continues to stir 2h after being added dropwise.Then the reaction solution NaOH solution of 2mol/L is adjusted into pH to 10, evaporated under reduced pressure adds
Enter suitable quantity of water and carry out ultrasound, primary, reservation water layer is extracted with ethyl acetate, then water layer is adjusted into pH to 2 with the HCl of 2mol/L,
It is extracted with ethyl acetate again three times, decompression rotation obtains 1- { [(3,5- 3,5-dimethylphenyl) amino] carbonyl } ring third except organic solvent
Alkane carboxylic acid, about 0.8g, yield 37%；
4) by 7- (4- aminophenyls) quinazoline -2- amine (compound 4) and 1- { [(3,5- 3,5-dimethylphenyls) amino] carbonyls
Base } cyclopropane-carboxylic acid (compound 7) obtains ring propane diamide compound (chemical combination with anti-tumor activity by condensation reaction
Object 8)
By 0.38g (0.7mmol) 7- (4- aminophenyls) quinazoline -2- amine and 0.24g (0.7mmol) 1- { [(3,5- bis-
Aminomethyl phenyl) amino] carbonyl } cyclopropane-carboxylic acid is added in the anhydrous methylene chloride solution in ice bath, add 0.48g
(1.26mmol) condensing agent HATU continues to stir 30min, then the dichloromethane solution of 0.1mL anhydrous triethylamines is slowly added dropwise, and removes
Ice bath is removed, 8h is reacted at room temperature.Then reaction solution is used into saturated sodium bicarbonate solution and saturated common salt water washing, anhydrous slufuric acid successively
Sodium is dried, then is spin-dried for obtaining residue, with chromatographic column separating residual object, obtains ring Malonamides with anti-tumor activity
Close object 0.12g, yield 20%.
The structural formula of ring propane diamide compound with anti-tumor activity made from embodiment 1 is as follows：
Physicochemical property:mp:234~236 DEG C
Hydrogen composes nuclear magnetic resonance data：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
In the structural formula of the ring propane diamide compound with anti-tumor activity, R1、R2For chlorine.
Step 1)~2 of step 1)~step 2) and embodiment 1) it is identical, i.e., by the fluoro- 5- bromobenzaldehydes (compound 1) of 2-
7- bromine quinazoline -2- amine (compound 2) is prepared, then by 7- bromine quinazoline -2- amine (compound 2) and p-aminophenyl boric acid hydrochloride
(compound 3) prepares 7- (4- aminophenyls) quinazoline -2- amine (compound 4) by Suzuki coupling reactions.
3) 1,1- cyclopropane dicarboxylic acids (compound 5) and 3,4- dichloroanilines (compound 6) prepare 1- by condensation reaction
({ 3,4- dichloroanilines amino } carbonyl) cyclopropane-carboxylic acid (compound 7)
Under the conditions of nitrogen protection, 12.9mL anhydrous triethylamines are added drop-wise to 4g (30.8mmol) 1,1- ring propane dicarboxylic acids
In dichloromethane solution, 30min is stirred under condition of ice bath, then 2.3mL SOCl are slowly added dropwise2Dichloromethane solution, drip
Finish stirring 2h, then continues the dichloromethane solution that 4.5g (27.7mmol) 3,4-DCA is added dropwise into reaction solution, be added dropwise
After continue stir 2h.Then the reaction solution NaOH solution of 2mol/L is adjusted into pH to 10, suitable quantity of water is added in evaporated under reduced pressure
Ultrasound is carried out, primary, reservation water layer is extracted with ethyl acetate, then water layer is adjusted into pH to 2 with the HCl of 2mol/L, then use acetic acid
Ethyl ester extracts three times, and decompression rotation obtains 1- ({ 3,4-DCA amino } carbonyl) cyclopropane-carboxylic acid, about 2g except organic solvent,
Yield 40%；
4) by 7- (4- aminophenyls) quinazoline -2- amine (compound 4) and 1- ({ 3,4- dichloroanilines amino } carbonyl) ring
Propanecarboxylic acid's (compound 7) obtains ring propane diamide compound (compound 8) with anti-tumor activity by condensation reaction
By 0.5g (0.92mmol) 7- (4- aminophenyls) quinazoline -2- amine and 0.23g (0.92mmol) 1- ({ 3,4- bis-
Chloroaniline amino } carbonyl) cyclopropane-carboxylic acid is added in the anhydrous methylene chloride solution in ice bath, add 0.63g
(1.66mmol) condensing agent HATU continues to stir 30min, then the dichloromethane solution of 0.13mL anhydrous triethylamines is slowly added dropwise,
Ice bath is removed, 8h is reacted at room temperature.Then reaction solution is used into saturated sodium bicarbonate solution and saturated common salt water washing, anhydrous sulphur successively
Sour sodium drying, then be spin-dried for obtaining residue, with chromatographic column separating residual object, obtain ring Malonamides with anti-tumor activity
Compound 0.1g, yield 20%.
The structural formula of ring propane diamide compound with anti-tumor activity made from embodiment 2 is as follows：
Physicochemical property:mp:253~254 DEG C
Hydrogen composes nuclear magnetic resonance data：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
In the structural formula of the ring propane diamide compound with anti-tumor activity, R1、R2For chlorine.
Step 1)~2 of step 1)~step 2) and embodiment 1) it is identical, i.e., by the fluoro- 5- bromobenzaldehydes (compound 1) of 2-
7- bromine quinazoline -2- amine (compound 2) is prepared, then by 7- bromine quinazoline -2- amine (compound 2) and p-aminophenyl boric acid hydrochloride
(compound 3) prepares 7- (4- aminophenyls) quinazoline -2- amine (compound 4) by Suzuki coupling reactions.
3) 1,1- cyclopropane dicarboxylic acids (compound 5) and 2,4 dichloro aniline (compound 6) prepare 1- by condensation reaction
({ 2,4- dichloroanilines amino } carbonyl) cyclopropane-carboxylic acid (compound 7)
Under the conditions of nitrogen protection, 12.9mL anhydrous triethylamines are added drop-wise to 4g (30.8mmol) 1,1- ring propane dicarboxylic acids
In dichloromethane solution, 30min is stirred under condition of ice bath, then 2.3mL SOCl are slowly added dropwise2Dichloromethane solution, drip
Finish stirring 2h, then continues the dichloromethane solution that 4.5g (27.7mmol) 2,4- dichloroanilines are added dropwise into reaction solution, be added dropwise
After continue stir 2h.Then the reaction solution NaOH solution of 2mol/L is adjusted into pH to 10, suitable quantity of water is added in evaporated under reduced pressure
Ultrasound is carried out, primary, reservation water layer is extracted with ethyl acetate, then water layer is adjusted into pH to 2 with the HCl of 2mol/L, then use acetic acid
Ethyl ester extracts three times, and decompression rotation obtains 1- ({ 2,4- dichloroaniline amino } carbonyl) cyclopropane-carboxylic acid, about 2g except organic solvent,
Yield 40%；
4) by 7- (4- aminophenyls) quinazoline -2- amine (compound 4) and 1- ({ 2,4 dichloro aniline amino } carbonyl) ring
Propanecarboxylic acid's (compound 7) obtains ring propane diamide compound (compound 8) with anti-tumor activity by condensation reaction
By 0.5g (0.92mmol) 7- (4- aminophenyls) quinazoline -2- amine and 0.23g (0.92mmol) 1- ({ 2,4- bis-
Chloroaniline amino } carbonyl) cyclopropane-carboxylic acid is added in the anhydrous methylene chloride solution in ice bath, add 0.63g
(1.66mmol) condensing agent HATU continues to stir 30min, then the dichloromethane solution of 0.13mL anhydrous triethylamines is slowly added dropwise,
Ice bath is removed, 8h is reacted at room temperature.Then reaction solution is used into saturated sodium bicarbonate solution and saturated common salt water washing, anhydrous sulphur successively
Sour sodium drying, then be spin-dried for obtaining residue, with chromatographic column separating residual object, obtain ring Malonamides with anti-tumor activity
Compound 0.1g, yield 20%.
The structural formula of ring propane diamide compound with anti-tumor activity made from embodiment 3 is as follows：
Physicochemical property:mp:261~263 DEG C
Hydrogen composes nuclear magnetic resonance data：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
In the structural formula of the ring propane diamide compound with anti-tumor activity, R1、R2Respectively trifluoromethoxy and
Bromine.
Step 1)~2 of step 1)~step 2) and embodiment 1) it is identical, i.e., by the fluoro- 5- bromobenzaldehydes (compound 1) of 2-
7- bromine quinazoline -2- amine (compound 2) is prepared, then by 7- bromine quinazoline -2- amine (compound 2) and p-aminophenyl boric acid hydrochloride
(compound 3) prepares 7- (4- aminophenyls) quinazoline -2- amine (compound 4) by Suzuki coupling reactions.
3) 1,1- cyclopropane dicarboxylic acids (compound 5) and the bromo- 2- trifluoro-methoxyanilines (compound 6) of 5- are anti-by being condensed
1- ({ [5- bromo- 2- (trifluoromethoxy) phenyl] amino } carbonyl) cyclopropane-carboxylic acid (compound 7) should be prepared
Under the conditions of nitrogen protection, 2.2mL anhydrous triethylamines are added drop-wise to 2g (15.4mmol) 1,1- ring propane dicarboxylic acids
In dichloromethane solution, 30min is stirred under condition of ice bath, then 1.2mL SOCl are slowly added dropwise2Dichloromethane solution, drip
Finish stirring 2h, then continues the dichloromethane that the bromo- 2- trifluoro-methoxyanilines of 3.5g (13.9mmol) 5- are added dropwise into reaction solution
Solution continues to stir 2h after being added dropwise.Then the reaction solution NaOH solution of 2mol/L is adjusted into pH to 10, evaporated under reduced pressure,
Suitable quantity of water is added and carries out ultrasound, is extracted with ethyl acetate primary, retains water layer, then with the HCl of 2mol/L by water layer adjusting pH to
2, then be extracted with ethyl acetate three times, decompression rotation obtains 1- ({ [5- bromo- 2- (trifluoromethoxy) phenyl] ammonia except organic solvent
Base } carbonyl) cyclopropane-carboxylic acid, about 0.8g, yield 35%；
4) by 7- (4- aminophenyls) quinazoline -2- amine (compound 4) and 1- ({ [5- bromo- 2- (trifluoromethoxy) phenyl]
Amino } carbonyl) cyclopropane-carboxylic acid (compound 7) obtains ring Malonamides with anti-tumor activity by condensation reaction
Close object (compound 8)
By 0.45g (1.91mmol) 7- (4- aminophenyls) quinazoline -2- amine and 0.7g (1.91mmol) 1-, ({ [5- is bromo-
2- (trifluoromethoxy) phenyl] amino } carbonyl) cyclopropane-carboxylic acid is added in the anhydrous methylene chloride solution in ice bath, then is added
Enter 1.31g (3.44mmol) condensing agent HATU, continues to stir 30min, then the dichloromethane of 0.8mL anhydrous triethylamines is slowly added dropwise
Solution removes ice bath, reacts at room temperature 8h.Then reaction solution is used into saturated sodium bicarbonate solution and saturated common salt water washing successively,
Anhydrous sodium sulfate is dried, then is spin-dried for obtaining residue, with chromatographic column separating residual object, obtains ring with anti-tumor activity the third two
Amides compound 0.12g, yield 20%.
The structural formula of ring propane diamide compound with anti-tumor activity made from embodiment 4 is as follows：
Physicochemical property:mp:239~240 DEG C
Hydrogen composes nuclear magnetic resonance data：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
In the structural formula of the ring propane diamide compound with anti-tumor activity, R1、R2Respectively connected by O atom
It is connected to the meta position of amide group and the alkoxy of contraposition.
Step 1)~2 of step 1)~step 2) and embodiment 1) it is identical, i.e., by the fluoro- 5- bromobenzaldehydes (compound 1) of 2-
7- bromine quinazoline -2- amine (compound 2) is prepared, then by 7- bromine quinazoline -2- amine (compound 2) and p-aminophenyl boric acid hydrochloride
(compound 3) prepares 7- (4- aminophenyls) quinazoline -2- amine (compound 4) by Suzuki coupling reactions.
3) 1,1- cyclopropane dicarboxylic acids (compound 5) and pepper amine (compound 6) prepare N1-1,3 benzene by condensation reaction
And the amyl- 5- cyclopropyl -1,1- diformamides (compound 7) of dioxane
Under the conditions of nitrogen protection, 2.2mL anhydrous triethylamines are added drop-wise to 2g (15.4mmol) 1,1- ring propane dicarboxylic acids
In dichloromethane solution, 30min is stirred under condition of ice bath, then 1.2mL SOCl are slowly added dropwise2Dichloromethane solution, drip
Finish stirring 2h, then continues the dichloromethane solution that 1.9g (15.4mmol) pepper amine is added dropwise into reaction solution, after being added dropwise
Continue to stir 2h.Then the reaction solution NaOH solution of 2mol/L is adjusted into pH to 10, evaporated under reduced pressure is added suitable quantity of water and carries out
Ultrasound is extracted with ethyl acetate primary, reservation water layer, then water layer is adjusted pH to 2 with the HCl of 2mol/L, then uses ethyl acetate
Three times, decompression rotation is to obtain N1-1 except organic solvent, amyl- 5- cyclopropyl -1, the 1- diformamide of 3 benzo dioxanes, about for extraction
1g, yield 35%；
4) by 7- (4- aminophenyls) quinazoline -2- amine (compound 4) and the amyl- 5- rings of N1-1,3 benzo dioxanes third
Base -1,1- diformamides (compound 7) obtain ring propane diamide compound with anti-tumor activity by condensation reaction and (change
Close object 8)
By 0.3g (1.27mmol) 7- (4- aminophenyls) quinazoline -2- amine and 0.35g (1.4mmol) N1-1,3 benzos two
Amyl- 5- cyclopropyl -1, the 1- diformamide of oxa- ring is added in the anhydrous methylene chloride solution in ice bath, adds 0.87g
(2.29mmol) condensing agent HATU continues to stir 30min, then the dichloromethane solution of 0.53mL anhydrous triethylamines is slowly added dropwise,
Ice bath is removed, 8h is reacted at room temperature.Then reaction solution is used into saturated sodium bicarbonate solution and saturated common salt water washing, anhydrous sulphur successively
Sour sodium drying, then be spin-dried for obtaining residue, with chromatographic column separating residual object, obtain ring Malonamides with anti-tumor activity
Compound 0.12g, yield 20%.
The structural formula of ring propane diamide compound with anti-tumor activity made from embodiment 5 is as follows：
Physicochemical property:mp:283~285 DEG C
Hydrogen composes nuclear magnetic resonance data：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).
VEGFR-2 kinases is carried out to ring propane diamide compound with anti-tumor activity produced by the present invention below
Inhibitory activity is screened.
Kinases VEGFR-2 and substrate A bltide is purchased from Signal-Chem companies, selects the ADP- of Promega companies
GlobTM Kinase Assays detection kits detect ring Malonamides with anti-tumor activity provided by the invention
The Inhibiting enzyme activity of object is closed, operating method illustrates to carry out according to kit.By ATP (10mM) with buffer (2 ×) (Tris 80mM,
MgCl220mM, BSA 0.2mg/mL, DTT 2mM) 40 times of buffer (2 ×) solution for being configured to ATP (250 μM) of dilution；It will
250 μM of ATP solution and Abltide liquor capacities 1:1 is hybridly prepared into the mixed of ATP (125 μM)-Abltide (0.5 μ g/ μ l)
Close solution for standby；VEGFR-2 kinase solutions buffer (1 ×) (Tris 40mM, MgCl2 10mM,BSA0.1mg/mL,DTT
1mM) dilute 66 times of buffer (1 ×) solution for standby for being configured to VEGFR-2 (1.5ng/ μ l)；By target compound and the positive
Comparison medicine (Sorafinib) is configured to 6 × 10 respectively with buffer (1 ×)-5Mol/L, 6 × 10-6Mol/L, 6 × 10-7mol/
L, 6 × 10-8Mol/L, 6 × 10-9Mol/L, 6 × 10-10The sample solution of mol/L concentration gradients, in every Kong Yi on 384 orifice plates
The secondary mixed solution that 2 μ L ATP-Abltide are added, 1 μ L sample solution, 2 μ L enzyme solutions；Blank well adds 3 μ L buffer solutions and 2 μ
The mixed solution of LATP-Abltide；Control wells add the mixed solution of 2 μ L ATP-Abltide, 1 μ L buffer solutions, and 2 μ L enzymes are molten
Liquid finishes, and 60min is incubated at 30 DEG C；5 μ L of ADP-Glo reagents are added, 40min is incubated at 25 DEG C；Kinase is added
10 μ L of detection reagents, 30min is incubated at 25 DEG C.Using the chemiluminescence mould of PerkinElmer multi-function microplate readers
Block measures the luminous value per hole, calculates ring propane diamide compound with anti-tumor activity provided by the invention to VEGFR-
2 inhibiting rate and IC50。
Inhibitory activity result of the ring propane diamide compound with anti-tumor activity of the present invention to VEGFR-2 kinases
As shown in table 1：
IC of the 1 ring propane diamide compound of table to VEGFR kinases50
As can be seen from Table 1, the ring propane diamide compound with anti-tumor activity that prepared by the present invention is to VEGFR-2
Kinases has inhibitory activity, can be used for preparing the drug for inhibiting VEGFR-2 kinase activities and prepares using VEGFR-2 kinases as target
The antitumor drug of point.
The structure of above compound is specifically as shown in table 2：
The structural formula of the ring propane diamide compound with anti-tumor activity provided by the invention of table 2.
Claims (9)
1. a kind of ring propane diamide compound with anti-tumor activity, which is characterized in that its chemical structural formula is as follows：
Wherein, R1For halogen group, R2For halogen group orOr R1、R2It is collectively formed
2. ring propane diamide compound with anti-tumor activity as described in claim 1, which is characterized in that the halogen
Plain group is fluorine atom, chlorine atom or bromine atom.
3. the preparation method of ring propane diamide compound with anti-tumor activity as claimed in claim 1 or 2, feature exist
In including the following steps：
1) 7- bromine quinazoline -2- amine is obtained by the reaction with guanidine carbonate in the fluoro- 5- bromobenzaldehydes of 2-；
2) 7- bromines quinazoline -2- amine prepares 7- (4- aminophenyls) with p-aminophenyl boric acid hydrochloride by Suzuki coupling reactions
Quinazoline -2- amine；
3) 1,1- cyclopropane dicarboxylic acids with containing disubstituted aniline anilinocarbonyl cyclopropane carboxylic acid is prepared by condensation reaction
Acid；
4) 7- (4- aminophenyls) quinazoline -2- amine, which is prepared with anilinocarbonyl cyclopropane-carboxylic acid by condensation reaction, has anti-swell
The ring propane diamide compound of tumor activity.
4. the preparation method of ring propane diamide compound with anti-tumor activity according to claim 3, feature
It is：The concrete operations of the step 1) are：The fluoro- 5- bromobenzaldehydes of 2- and guanidine carbonate are dissolved in DMAC N,N' dimethyl acetamide solution
In, back flow reaction is cooled to room temperature after reaction, and water to solid is added into reaction solution and is precipitated, then filters, filter cake is
7- bromine quinazoline -2- amine.
5. the preparation method of ring propane diamide compound with anti-tumor activity according to claim 3, feature
It is：The concrete operations of the step 2) are：By 7- bromine quinazoline -2- amine, p-aminophenyl boric acid hydrochloride, natrium carbonicum calcinatum and
Catalyst Pd (PPh3)4It is dissolved in the mixed solution of Isosorbide-5-Nitrae-dioxane and water, reacts under nitrogen protection, cool down after reaction
To room temperature, reaction solution is filtered, filtrate is spin-dried for obtain crude product, with chromatography post separation crude product, obtains 7- (4- aminobenzenes
Base) quinazoline -2- amine.
6. the preparation method of ring propane diamide compound with anti-tumor activity according to claim 3, feature
It is：The concrete operations of the step 3) are：Under nitrogen protection, anhydrous triethylamine is added drop-wise to the two of 1,1- ring propane dicarboxylic acids
In chloromethanes solution, stirred evenly under condition of ice bath, then SOCl is added dropwise thereto2Dichloromethane solution, stirred after being added dropwise
Reaction is mixed, then continues that the dichloromethane solution containing disubstituted aniline is added dropwise thereto, continues to stir after being added dropwise
Reaction, after reaction, adjust the pH value of reaction solution, be extracted with ethyl acetate, then vacuum rotary steam remove organic solvent to get to
Anilinocarbonyl cyclopropane-carboxylic acid.
7. the preparation method of ring propane diamide compound with anti-tumor activity according to claim 3, feature
It is：The concrete operations of the step 4) are：By 7- (4- aminophenyls) quinazoline -2- amine and anilinocarbonyl cyclopropane-carboxylic acid
It is added in the anhydrous methylene chloride solution in ice bath, condensing agent HATU is then added, stirs evenly, then be added dropwise thereto anhydrous
The dichloromethane solution of triethylamine removes ice bath, reacts at room temperature, after reaction, reaction solution is washed, it is dry after depressurize and steam
Solvent is removed, crude product is obtained, with chromatography post separation crude product, obtains ring propane diamide compound with anti-tumor activity.
8. ring propane diamide compound with anti-tumor activity as claimed in claim 1 or 2 inhibits VEGFR-2 to swash in preparation
Application in the drug of enzymatic activity.
9. ring propane diamide compound with anti-tumor activity as claimed in claim 1 or 2 is being prepared with VEGFR-2 kinases
For the application in the antitumor drug of target spot.
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