CN105906568A - Cyclopropane diamide compound with antitumor activity and preparation method and application thereof - Google Patents

Cyclopropane diamide compound with antitumor activity and preparation method and application thereof Download PDF

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Publication number
CN105906568A
CN105906568A CN201610278878.0A CN201610278878A CN105906568A CN 105906568 A CN105906568 A CN 105906568A CN 201610278878 A CN201610278878 A CN 201610278878A CN 105906568 A CN105906568 A CN 105906568A
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amine
indazole
ring
tumor activity
aminophenyl
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贺浪冲
张�杰
潘晓艳
王金凤
苏萍
卢闻
王嗣岑
张涛
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Xian Jiaotong University
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Xian Jiaotong University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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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Abstract

The invention provides a cyclopropane diamide compound with antitumor activity and a preparation method and application thereof. The formula of the compound is as shown in the description, wherein R1 and R2 are halogen groups or R1 and R2 jointly form a structure as shown in the description. The cyclopropane diamide compound has the advantages that the compound is good in inhibitory activity on VEGFR-2 kinase, the signal channel induced by the VEGFR-2 kinase can be blocked by inhibiting the activity of the VEGFR-2 kinase, the proliferation and migration of tumor cells can be inhibited, and accordingly the cyclopropane diamide compound is applicable to the preparation of antitumor medicine. The preparation method of the compound is easy in raw material obtaining, mild in reaction condition, simple in reaction process operation and cheap in used reagent.

Description

A kind of ring malonamide compounds with anti-tumor activity and its preparation method and application
Technical field
The invention belongs to biomedicine technical field, relate to a kind of antineoplastic compound, particularly to one, there is anti-tumor activity Ring malonamide compounds and its preparation method and application.
Background technology
Malignant tumor, 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 tumor 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 tumor, has had huge development and progress at nearly 30 years, Obtain large quantities of clinical antitumor agents with different mechanism of action.But antineoplastic agent there is also many untoward reaction, such as Alopecia, vomiting, produce bone marrow depression, quickly produce drug resistance etc., these result in chemicals and are unable to reach intended treatment Effect.The research and development of the newest antitumor drug 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 malonamide compounds with anti-tumor activity and its preparation method and application, should Compound embodies good anti-tumor activity in vitro, it is possible to be applied to the preparation of antitumor drug.
For reaching above-mentioned purpose, the present invention by the following technical solutions:
A kind of ring malonamide compounds with anti-tumor activity, its chemical structural formula is as follows:
Wherein, R1、R2For halogen group, or 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 malonamide compounds with anti-tumor activity, comprises the following steps:
1) 2-fluoro-6-iodobenzene formonitrile HCN reacts with hydrazine hydrate and obtains 4-iodo-1H-indazole-3-amine；
2) 4-iodo-1H-indazole-3-amine reacts preparation 4-(4-aminophenyl)-1H-Yin with p-aminophenyl borate hydrochlorate by Suzuki Azoles-3-amine；Or 4-iodo-1H-indazole-3-amine reacts preparation 4-(3-aminophenyl)-1H-indazole with Resocinol-phenol formaldehyde resin by Suzuki -3-amine；
3) 1,1-cyclopropane dicarboxylic acid with prepare anilinocarbonyl cyclopropane-carboxylic acid containing disubstituted aniline by condensation reaction；
4) 4-(4-aminophenyl)-1H-indazole-3-amine or 4-(3-aminophenyl)-1H-indazole-3-amine and anilinocarbonyl cyclopropane-carboxylic acid Be there is the ring malonamide compounds of anti-tumor activity by condensation reaction preparation.
Described step 1) concrete operations be: fluoro-for 2-6-iodobenzene formonitrile HCN is dissolved in dehydrated alcohol, adds hydrazine hydrate and NaHCO3, Back flow reaction, reaction is cooled to room temperature after terminating, and adds water and separates out to solid, then stirring, sucking filtration in reactant liquor, and filter cake is i.e. For 4-iodo-1H-indazole-3-amine.
Described step 2) concrete operations be: by iodo-for 4-1H-indazole-3-amine, p-aminophenyl borate hydrochlorate or Resocinol-phenol formaldehyde resin, Natrium carbonicum calcinatum, catalyst Pd (PPh3)4It is dissolved in the mixed solution of Isosorbide-5-Nitrae-dioxane and water, the lower reaction of nitrogen protection, reaction It is cooled to room temperature after end, reactant liquor is carried out sucking filtration, be spin-dried for obtaining crude product by filtrate, with chromatographic column separation crude product, obtain 4-(4- Aminophenyl)-1H-indazole-3-amine or 4-(3-aminophenyl)-1H-indazole-3-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: by 4-(4-aminophenyl)-1H-indazole-3-amine or 4-(3-aminophenyl)-1H-indazole-3- Amine, and anilinocarbonyl cyclopropane-carboxylic acid joins in the anhydrous methylene chloride solution in ice bath, is subsequently adding condensing agent HATU, Stir, then drip the dichloromethane solution of anhydrous triethylamine wherein, remove ice bath, react under room temperature, after reaction terminates, Reactant liquor decompression scrubbed, dried boils off solvent, obtains crude product, with chromatographic column separation crude product, obtains the ring with anti-tumor activity Malonamide compounds.
The described ring malonamide compounds with anti-tumor activity answering in the medicine of preparation suppression VEGFR-2 kinase activity With.
The described ring malonamide compounds with anti-tumor activity is preparing the antitumor drug with VEGFR-2 kinases as target spot In application.
Compared with prior art, the method have the advantages that
The ring malonamide compounds with anti-tumor activity that the present invention provides, is a kind of novel chemical combination with anti-tumor activity Thing, it has good inhibitory activity to VEGFR-2 kinases, can be used for the preparation of antitumor drug.Concrete, the present invention provides The ring malonamide compounds with anti-tumor activity, it is possible to suppression the kinase whose activity of VEGFR-2.And angiogenesis and tumor Generation, develop and migrated substantial connection, the formation of suppression new vessels can effectively suppress growth and the migration of tumor, Many somatomedin regulation and control new vesselses generate, and wherein VEGFR-2 is the strongest known positive regulatory factor.Therefore the present invention carries The ring malonamide compounds with anti-tumor activity of confession, by the suppression kinase whose activity of VEGFR-2, blocks the signal of its induction Path, the hypertrophy of suppression tumor cell and migration, thus can be applicable to the preparation of antitumor drug, especially swash with VEGFR-2 Enzyme is antitumor drug and the medicine of suppression VEGFR-2 kinase activity of target spot.
The preparation method of the ring malonamide compounds with anti-tumor activity that the present invention provides, by 2-fluoro-6-iodobenzene formonitrile HCN with Hydrazine hydrate reaction obtains 4-iodo-1H-indazole-3-amine, more anti-with p-aminophenyl borate hydrochlorate or Resocinol-phenol formaldehyde resin Suzuki coupling 4-(4-aminophenyl)-1H-indazole-3-amine or 4-(3-aminophenyl)-1H-indazole-3-amine should be obtained, and by 1,1-cyclopropane dicarboxylic acid Obtain anilinocarbonyl cyclopropane-carboxylic acid with reacting containing disubstituted aniline condensation, the substituent group in aniline is incorporated into anilino- On the phenyl ring of carbonyl cyclopropane-carboxylic acid, then 4-(4-aminophenyl)-1H-indazole-3-amine or 4-(3-aminophenyl)-1H-indazole-3-amine Again with 7-(4-aminophenyl) quinazoline-2-amine condensation reaction, i.e. obtain the ring malonamide compounds with anti-tumor activity, the party 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 malonamide compounds with anti-tumor activity that Fig. 1 provides for the present invention；
Wherein, compound 1 is 2-fluoro-6-iodobenzene formonitrile HCN, and compound 2 is 4-iodo-1H-indazole-3-amine, and compound 3 is to amino Phenylboric acid hydrochlorate, compound 4 is 4-(4-aminophenyl)-1H-indazole-3-amine, and compound is 5 for Resocinol-phenol formaldehyde resin, chemical combination Thing 6 is 4-(3-aminophenyl)-1H-indazole-3-amine, and compound 7 is 1,1-cyclopropane dicarboxylic acid, and compound 8 is containing disubstituted The aniline of base, compound 9 is anilinocarbonyl cyclopropane-carboxylic acid, and compound T1, T4, T6, T9, S1-S10 are anti-swollen for having The ring malonamide compounds of tumor activity.
In figure mark particularly as follows:
a:EtOH,NaHCO3,NH2NH2,H2O；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 malonamide compounds with anti-tumor activity, this ring malonamide compounds has in vitro Anti-tumor activity, can be applicable to the preparation of antitumor drug.
The chemical structural formula of the ring malonamide compounds with anti-tumor 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 para-position 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 malonamide compounds of tumor activity and method for screening active ingredients.
Embodiment 1
This has in the structural formula of ring malonamide compounds of anti-tumor activity, R1For trifluoromethyl, R2For bromine, by following Step is prepared (seeing Fig. 1):
1) 4-iodo-1H-indazole-3-amine (compound 2) is prepared by 2-fluoro-6-iodobenzene formonitrile HCN (compound 1)
Fluoro-for 10g 2-6-iodobenzene formonitrile HCN is dissolved in 70mL dehydrated alcohol, adds 12.5mL hydrazine hydrate and 5.2g NaHCO3, 90 DEG C 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, under room temperature Stirring 2h, sucking filtration, the filter cake of gained is 4-iodo-1H-indazole-3-amine, about 8g, productivity 77%；
2) even by Suzuki by 4-iodo-1H-indazole-3-amine (compound 2) and p-aminophenyl borate hydrochlorate (compound 3) Connection reaction preparation 4-(4-aminophenyl)-1H-indazole-3-amine (compound 4)
By 7.5g (28.9mmol) 4-iodo-1H-indazole-3-amine, 5g (28.9mmol) p-aminophenyl borate hydrochlorate, 9.2g (86.7mmol) Natrium carbonicum calcinatum and 3.3g (2.89mmol) catalyst Pd (PPh3)4It is dissolved in 150mL 1,4-dioxane and the mixed solution of 50mL water In, under nitrogen protection, in 100 DEG C of reactions overnight, reaction is cooled to room temperature after terminating, sucking 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 4-(4-aminophenyl)-1H-indazole-3-amine 3.2g, productivity about 45%；
3) 1,1-cyclopropane dicarboxylic acid (compound 7) and 5-bromo-3-5-trifluoromethylaniline (compound 8) are prepared by condensation reaction 1-({ [5-bromo-2-(trifluoromethyl) phenyl] amino } carbonyl) cyclopropane-carboxylic acid (compound 9)
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, stir after dropping Mix 2h, in reactant liquor, continue the dichloromethane solution of dropping 3.6g (15.4mmol) 5-bromo-3-5-trifluoromethylaniline, drip complete Rear continuation stirs 2h.After reaction terminates, reactant liquor 2mol/L NaOH solution is regulated pH to 10, evaporated under reduced pressure, adds Suitable quantity of water carries out ultrasonic, is then extracted with ethyl acetate once, retains water layer, then with 2mol/L HCl, water layer regulates pH to 2, Being extracted with ethyl acetate three times, decompression rotation, except organic solvent, i.e. obtains 1-({ [5-bromo-2-(trifluoromethyl) phenyl] amino } carbonyl) again Cyclopropane-carboxylic acid, about 0.8g, productivity 37%；
4) by 4-(4-aminophenyl)-1H-indazole-3-amine (compound 4) and 1-({ [5-bromo-2-(trifluoromethyl) phenyl] amino } carbonyl) Cyclopropane-carboxylic acid (compound 9) obtains the ring malonamide compounds with anti-tumor activity by condensation reaction
By 0.38g (0.7mmol) 4-(4-aminophenyl)-1H-indazole-3-amine and 0.24g (0.7mmol) 1-({ [the bromo-2-of 5-(trifluoromethyl) Phenyl] amino } carbonyl) cyclopropane-carboxylic acid joins in the anhydrous methylene chloride solution in ice bath, adds 0.48g (1.26mmol) contracting Mixture HATU, continuation stirring 30min, more slowly drip the dichloromethane solution of 0.1mL anhydrous triethylamine, remove ice bath, room 8h is reacted under temperature.After reaction terminates, by reactant liquor successively with saturated sodium bicarbonate solution and saturated aqueous common salt washing, anhydrous slufuric acid Sodium is dried, and is then spin-dried for obtaining residue, with chromatographic column separating residual thing, obtains the ring Malondiamide chemical combination with anti-tumor activity Thing 0.12g, productivity 20%.
The structural formula of the ring malonamide compounds with anti-tumor activity that embodiment 1 prepares is as follows:
Physicochemical property: mp:186～188 DEG C
Hydrogen spectrum nuclear magnetic resonance data is:1H NMR(400MHz,CDCl3) δ 8.32 (d, J=8.3Hz, 2H), 7.55 (m, 1H), 7.33 7.14 (m, 4H), 7.11 (d, J=8.5Hz, 1H), 6.85 (m, 2H), 4.54 (d, J=4.9Hz, 2H), 1.73 1.58 (m, 4H).
Embodiment 2
This has in the structural formula of ring malonamide compounds of anti-tumor activity, R1、R2It is connected to amide respectively by O atom The meta of group and the alkoxyl of para-position.
Step 1)～2) with the step 1 of embodiment 1)～2) identical, i.e. prepared 4-by 2-fluoro-6-iodobenzene formonitrile HCN (compound 1) Iodo-1H-indazole-3-amine (compound 2), then (changed by 4-iodo-1H-indazole-3-amine (compound 2) and p-aminophenyl borate hydrochlorate Compound 3) prepare 4-(4-aminophenyl)-1H-indazole-3-amine (compound 4).
3) 1,1-cyclopropane dicarboxylic acid (compound 7) and pepper amine (compound 8) prepare N1-1,3 benzo two by condensation reaction Oxa-ring amyl-5-cyclopropyl-1,1-diformamide (compound 9)
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, after dropping stir 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, use second Acetoacetic ester extracts once, retains water layer, then with the HCl of 2mol/L, water layer regulates pH to 2, then is 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 40% except organic solvent；
4) by 4-(4-aminophenyl)-1H-indazole-3-amine (compound 4) and N1-1,3 benzo dioxane amyl-5-cyclopropyl-1,1- Diformamide (compound 9) obtains the ring malonamide compounds with anti-tumor activity by condensation reaction
By 0.5g (0.92mmol) 4-(4-aminophenyl)-1H-indazole-3-amine and 0.23g (0.92mmol) N1-1,3 benzo dioxane penta -5-cyclopropyl-1,1-diformamide 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.After reaction terminates, being washed with saturated sodium bicarbonate solution and saturated aqueous common salt successively by reactant liquor, anhydrous sodium sulfate is done Dry, then it is spin-dried for obtaining residue, with chromatographic column separating residual thing, obtains the ring malonamide compounds with anti-tumor activity 0.1g, productivity 20%.
The structural formula of the ring malonamide compounds with anti-tumor activity that embodiment 2 prepares is as follows:
Physicochemical property: mp:116～118 DEG C
Hydrogen spectrum nuclear magnetic resonance data is:1H NMR(400MHz,CDCl3) δ 8.28 (d, J=7.4Hz, 1H), 8.08 (s, 1H), 7.47 (t, J=7.8Hz, 1H), 7.24 (d, J=8.2Hz, 2H), 7.15 (d, J=7.1Hz, 2H), 6.79 (d, J=8.2Hz, 2H), 6.70 (d, J=11.8Hz, 1H), 5.90 (s, 2H), 4.39 (s, 2H), 1.67 (s, 2H), 1.60 (s, 2H).
Embodiment 3
This has in the structural formula of ring malonamide compounds of anti-tumor activity, R1、R2It is trifluoromethoxy and bromine respectively, logical Cross following steps to prepare (seeing Fig. 1):
1) 4-iodo-1H-indazole-3-amine (compound 2) is prepared by 2-fluoro-6-iodobenzene formonitrile HCN (compound 1)
Fluoro-for 10g 2-6-iodobenzene formonitrile HCN is dissolved in 70mL dehydrated alcohol, adds 12.5mL hydrazine hydrate and 5.2g NaHCO3, 90 DEG C 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, under room temperature Stirring 2h, sucking filtration, the filter cake of gained is 4-iodo-1H-indazole-3-amine, about 8g, productivity 77%；
2) Suzuki coupling reaction is passed through by 4-iodo-1H-indazole-3-amine (compound 2) and Resocinol-phenol formaldehyde resin (compound 5) Preparation 4-(3-aminophenyl)-1H-indazole-3-amine (compound 6)
By 7.6g (36.5mmol) 4-iodo-1H-indazole-3-amine, 4g (36.5mmol) Resocinol-phenol formaldehyde resin, 9.3g (87.6mmol) anhydrous carbon Acid sodium and 3.4g (3.65mmol) catalyst Pd (PPh3)4It is dissolved in the mixed solution of 150mL Isosorbide-5-Nitrae-dioxane and 50mL water, nitrogen Under gas shielded, in 100 DEG C of reactions overnight, reaction is cooled to room temperature, sucking filtration after terminating, with Isosorbide-5-Nitrae-dioxane washing filter cake, receive Collection filtrate, is spin-dried for obtaining residue, and residue separates (eluting solvent is petroleum ether: ethyl acetate=3:1, volume ratio) through chromatographic column, Obtain 4-(3-aminophenyl)-1H-indazole-3-amine 2.9g, productivity about 40%；
3) 1,1-cyclopropane dicarboxylic acid (compound 7) and 5-bromo-2-trifluoro-methoxyaniline (compound 8) are by condensation reaction system Standby 1-({ [5-bromo-2-(trifluoromethoxy) phenyl] amino } carbonyl) cyclopropane-carboxylic acid (compound 9)
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, stir after dropping Mix 2h, in reactant liquor, continue the dichloromethane solution of dropping 3.5g (13.9mmol) 5-bromo-2-trifluoro-methoxyaniline, drip Stirring 2h is continued after Biing.After reaction terminates, reactant liquor 2mol/L NaOH solution is regulated pH to 10, evaporated under reduced pressure, adds Enter suitable quantity of water and carry out ultrasonic, be then extracted with ethyl acetate once, retain water layer, then with 2mol/L HCl, water layer is regulated pH To 2, then being extracted with ethyl acetate three times, decompression rotation, except organic solvent, i.e. obtains 1-({ [5-bromo-2-(trifluoromethoxy) phenyl] amino } Carbonyl) cyclopropane-carboxylic acid, about 0.8g, productivity 35%；
4) by 4-(3-aminophenyl)-1H-indazole-3-amine (compound 6) and 1-({ [5-bromo-2-(trifluoromethoxy) phenyl] amino } carbonyl Base) cyclopropane-carboxylic acid (compound 9) obtains the ring malonamide compounds with anti-tumor activity by condensation reaction
By 0.5g (0.92mmol) 4-(3-aminophenyl)-1H-indazole-3-amine and 0.34g (0.92mmol) 1-({ [5-bromo-2-(trifluoro methoxy Base) phenyl] amino } carbonyl) 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.After reaction terminates, by reactant liquor successively with saturated sodium bicarbonate solution and saturated aqueous common salt washing, anhydrous slufuric acid Sodium is dried, and is then spin-dried for obtaining residue, with chromatographic column separating residual thing, obtains the ring Malondiamide chemical combination with anti-tumor activity Thing 0.12g, productivity 25%.
The structural formula of the ring malonamide compounds with anti-tumor activity that embodiment 3 prepares is as follows:
Physicochemical property: mp:173～174 DEG C
Hydrogen spectrum nuclear magnetic resonance data is:1H NMR(400MHz,CDCl3) δ 8.62 (s, 1H), 8.61 (d, J=2.3Hz, 1H), 8.41 (d, J=8.1Hz, 1H), 7.60 7.55 (m, 1H), 7.31 7.26 (m, 1H), 7.22 (d, J=6.9Hz, 1H), 7.04 (m, 1H), 6.79 (m, 2H), 6.74 (d, J=1.7Hz, 1H), 4.38 (s, 2H), 1.73 (s, 4H).
Embodiment 4
This has in the structural formula of ring malonamide compounds of anti-tumor activity, R1、R2For chlorine:
Step 1)～2) with the step 1 of embodiment 1)～2) identical, i.e. prepared 4-by 2-fluoro-6-iodobenzene formonitrile HCN (compound 1) Iodo-1H-indazole-3-amine (compound 2), then (changed by 4-iodo-1H-indazole-3-amine (compound 2) and p-aminophenyl borate hydrochlorate Compound 3) prepare 4-(4-aminophenyl)-1H-indazole-3-amine (compound 4).
3) 1,1-cyclopropane dicarboxylic acid (compound 7) and 3,4-dichloroaniline (compound 8) prepare 1-({ 3,4-by condensation reaction Dichloroaniline amino } carbonyl) cyclopropane-carboxylic acid (compound 9)
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, stir after dropping Mix 2h, in reactant liquor, continue the dichloromethane solution of dropping 4.5g (27.7mmol) 3,4-DCA, drip and stir complete follow-up continuing Mix 2h.Then reactant liquor 2mol/L NaOH solution 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 2mol/L HCl, water layer regulated pH to 2, then be extracted with ethyl acetate three Secondary, decompression rotation, except organic solvent, i.e. obtains 1-({ 3,4-DCA amino } carbonyl) cyclopropane-carboxylic acid, about 2g, productivity 40%；
4) by 4-(4-aminophenyl)-1H-indazole-3-amine (compound 4) and 1-({ 3,4-dichloroaniline amino } carbonyl) cyclopropane carboxylic acid Acid (compound 9) obtains the ring malonamide compounds with anti-tumor activity by condensation reaction
By 0.5g (0.92mmol) 4-(4-aminophenyl)-1H-indazole-3-amine and 0.25g (0.92mmol) 1-({ 3,4-dichloroaniline amino } Carbonyl) 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, under room temperature, react 8h. After reaction terminates, being washed with saturated sodium bicarbonate solution and saturated aqueous common salt successively by reactant liquor, anhydrous sodium sulfate is dried, and then revolves Dry obtain residue, with chromatographic column separating residual thing, obtain the ring malonamide compounds 0.12g with anti-tumor activity, productivity 22%.
The structural formula of the ring malonamide compounds with anti-tumor activity that embodiment 4 prepares is as follows:
Physicochemical property: mp:103～104 DEG C
Hydrogen spectrum nuclear magnetic resonance data is:1H NMR (400MHz, DMSO) δ 9.95 (s, 1H), 8.26 (d, J=8.1Hz, 1H), 7.91 (s, 1H), 7.59 7.54 (m, 1H), 7.49 (s, 2H), 7.12 (d, J=8.2Hz, 3H), 6.73 (d, J=8.4Hz, 2H), 5.12(s,2H),1.53(m,2H),1.46(m,2H).
Embodiment 5
This has in the structural formula of ring malonamide compounds of anti-tumor activity, R1、R2For chlorine:
Step 1)～2) with the step 1 of embodiment 3)～2) identical, i.e. prepared 4-by 2-fluoro-6-iodobenzene formonitrile HCN (compound 1) Iodo-1H-indazole-3-amine (compound 2), then by 4-iodo-1H-indazole-3-amine (compound 2) and Resocinol-phenol formaldehyde resin (compound 5) Preparation 4-(3-aminophenyl)-1H-indazole-3-amine (compound 6).
3) 1,1-cyclopropane dicarboxylic acid (compound 7) and 2,4 dichloro aniline (compound 8) prepare 1-({ 2,4-by condensation reaction Dichloroaniline amino } carbonyl) cyclopropane-carboxylic acid (compound 9)
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, stir after dropping Mix 2h, in reactant liquor, continue dropping 4.5g (27.7mmol) 2, the dichloromethane solution of 4-dichloroaniline, drip and stir complete follow-up continuing Mix 2h.Then reactant liquor 2mol/L NaOH solution 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 2mol/L HCl, water layer regulated pH to 2, then be extracted with ethyl acetate three Secondary, decompression rotation, except organic solvent, i.e. obtains 1-({ 2,4-dichloroaniline amino } carbonyl) cyclopropane-carboxylic acid, about 2g, productivity 40%；
4) by 4-(3-aminophenyl)-1H-indazole-3-amine (compound 6) and 1-({ 2,4 dichloro aniline amino } carbonyl) cyclopropane carboxylic acid Acid (compound 9) obtains the ring malonamide compounds with anti-tumor activity by condensation reaction
By 0.5g (0.92mmol) 4-(3-aminophenyl)-1H-indazole-3-amine and 0.25g (0.92mmol) 1-({ 2,4 dichloro aniline amino } Carbonyl) 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, under room temperature, react 8h. After reaction terminates, being washed with saturated sodium bicarbonate solution and saturated aqueous common salt successively by reactant liquor, anhydrous sodium sulfate is dried, and then revolves Dry obtain residue, with chromatographic column separating residual thing, obtain the ring malonamide compounds 0.12g with anti-tumor activity, productivity 20%.
The structural formula of the ring malonamide compounds with anti-tumor activity that embodiment 5 prepares is as follows:
Physicochemical property: mp:109～111 DEG C
Hydrogen spectrum nuclear magnetic resonance data is:1H NMR(400MHz,CDCl3) δ 8.43 (d, J=8.3Hz, 1H), 8.38 (s, 1H), 8.22 (d, J=8.8Hz, 1H), 7.59 (t, J=7.8Hz, 1H), 7.30 7.28 (m, 3H), 7.25 7.20 (m, 2H), 6.82 (d, J =7.6Hz, 1H), 6.77 (d, J=9.7Hz, 1H), 4.37 (s, 2H), 1.72 (s, 2H), 1.69 (s, 2H).
The ring malonamide compounds with anti-tumor activity prepared the present invention below carries out the kinase whose inhibitory activity of VEGFR-2 Screening.
Kinases VEGFR-2 and substrate A bltide, purchased from Signal-Chem company, select the ADP-of Promega company The ring malonamide compounds with anti-tumor activity that the GlobTM Kinase Assays detection kit detection present invention provides Inhibiting enzyme activity, operational approach illustrates to carry out according to test kit.By ATP (10mM) with buffer (2 ×) (Tris 80mM, MgCl220mM, BSA 0.2mg/mL, DTT 2mM) dilute 40 times of buffer (2 ×) solution being configured to ATP (250 μMs)； The ATP solution of 250 μMs and Abltide liquor capacity 1:1 are hybridly prepared into the mixing of ATP (125 μMs)-Abltide (0.5 μ g/ μ l) Solution for standby；VEGFR-2 kinase solution buffer (1 ×) (Tris 40mM, MgCl2 10mM,BSA 0.1mg/mL,DTT 1mM) Dilute 66 times of buffer (1 ×) solution for standby being configured to VEGFR-2 (1.5ng/ μ l)；By target compound and positive control drug (Sorafinib) 6 × 10 it are configured to 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 Concentraton gradient, on 384 orifice plates, every hole is sequentially added into 2 μ L ATP-Abltide Mixed solution, 1 μ L sample solution, 2 μ L enzymatic solution；The mixing that blank well adds 3 μ L buffer and 2 μ LATP-Abltide is molten Liquid；Control wells adds the mixed solution of 2 μ L ATP-Abltide, 1 μ L buffer, 2 μ L enzymatic solution, finishes, hatches 60min at 30 DEG C； Add ADP-Glo reagent 5 μ L, at 25 DEG C, hatch 40min；Add Kinase detection reagent 10 μ L, at 25 DEG C Hatch 30min.The chemiluminescence module using the multi-functional microplate reader of PerkinElmer measures the luminous value in every hole, calculates the present invention The ring malonamide compounds with anti-tumor activity provided is to the suppression ratio of VEGFR-2 and IC50。
Inhibitory activity kinase whose to the VEGFR result of the ring malonamide compounds with anti-tumor activity that the present invention provides is concrete As shown in table 1:
Table 1 ring malonamide compounds IC kinase whose to VEGFR50
As can be seen from Table 1, what prepared by the present invention has the ring malonamide compounds of anti-tumor activity to VEGFR-2 kinases tool 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 Antitumor drug.
The structure of above-claimed cpd is the most as shown in table 2:
The concrete structure formula of the ring malonamide compounds with anti-tumor activity that table 2 present invention provides

Claims (9)

1. a ring malonamide compounds with anti-tumor activity, it is characterised in that its chemical structural formula is as follows:
Wherein, R1、R2For halogen group, or R1、R2It is collectively forming
There is the ring malonamide compounds of anti-tumor activity the most as claimed in claim 1, it is characterised in that described halogen Group is fluorine atom, chlorine atom, bromine atoms, trifluoromethyl or trifluoromethoxy.
3. the preparation method of the ring malonamide compounds with anti-tumor activity described in claim 1 or 2, it is characterised in that Comprise the following steps:
1) 2-fluoro-6-iodobenzene formonitrile HCN reacts with hydrazine hydrate and obtains 4-iodo-1H-indazole-3-amine；
2) 4-iodo-1H-indazole-3-amine reacts preparation 4-(4-aminophenyl)-1H-Yin with p-aminophenyl borate hydrochlorate by Suzuki Azoles-3-amine；Or 4-iodo-1H-indazole-3-amine reacts preparation 4-(3-aminophenyl)-1H-indazole with Resocinol-phenol formaldehyde resin by Suzuki -3-amine；
3) 1,1-cyclopropane dicarboxylic acid with prepare anilinocarbonyl cyclopropane-carboxylic acid containing disubstituted aniline by condensation reaction；
4) 4-(4-aminophenyl)-1H-indazole-3-amine or 4-(3-aminophenyl)-1H-indazole-3-amine and anilinocarbonyl cyclopropane-carboxylic acid Be there is the ring malonamide compounds of anti-tumor activity by condensation reaction preparation.
The preparation method of the ring malonamide compounds with anti-tumor activity the most according to claim 3, it is characterised in that: Described step 1) concrete operations be: fluoro-for 2-6-iodobenzene formonitrile HCN is dissolved in dehydrated alcohol, adds hydrazine hydrate and NaHCO3, return Stream reaction, reaction is cooled to room temperature after terminating, and adds water and separates out to solid, then stirring, sucking filtration in reactant liquor, and filter cake is 4-iodo-1H-indazole-3-amine.
The preparation method of the ring malonamide compounds with anti-tumor activity the most according to claim 3, it is characterised in that: Described step 2) concrete operations be: by iodo-for 4-1H-indazole-3-amine, p-aminophenyl borate hydrochlorate or Resocinol-phenol formaldehyde resin, nothing Aqueous sodium carbonate, catalyst Pd (PPh3)4It is dissolved in the mixed solution of Isosorbide-5-Nitrae-dioxane and water, the lower reaction of nitrogen protection, reaction knot It is cooled to room temperature after bundle, reactant liquor is carried out sucking filtration, be spin-dried for obtaining crude product by filtrate, with chromatographic column separation crude product, obtain 4-(4- Aminophenyl)-1H-indazole-3-amine or 4-(3-aminophenyl)-1H-indazole-3-amine.
The preparation method of the ring malonamide compounds with anti-tumor activity the most according to claim 3, it is characterised in that: Described step 3) concrete operations be: under nitrogen protection, anhydrous triethylamine is added drop-wise to 1, the dichloromethane of 1-ring propane dicarboxylic acid In solution, stir under condition of ice bath, then drip SOCl wherein2Dichloromethane solution, after dropping stirring reaction, Continue the dropping dichloromethane solution containing disubstituted aniline the most wherein, drip complete follow-up continuous stirring reaction, reaction knot Shu Hou, the pH value of regulation reactant liquor, it is extracted with ethyl acetate, then vacuum rotary steam removes organic solvent, i.e. obtains anilinocarbonyl Cyclopropane-carboxylic acid.
The preparation method of the ring malonamide compounds with anti-tumor activity the most according to claim 3, it is characterised in that: Described step 4) concrete operations be: by 4-(4-aminophenyl)-1H-indazole-3-amine or 4-(3-aminophenyl)-1H-indazole-3-amine, And anilinocarbonyl cyclopropane-carboxylic acid joins in the anhydrous methylene chloride solution in ice bath, it is subsequently adding condensing agent HATU, stirs Mix uniformly, then drip the dichloromethane solution of anhydrous triethylamine wherein, remove ice bath, react under room temperature, after reaction terminates, instead Answer liquid decompression scrubbed, dried to boil off solvent, obtain crude product, with chromatographic column separation crude product, obtain the ring third with anti-tumor activity Diamide compound.
8. the ring malonamide compounds with anti-tumor activity described in claim 1 or 2 swashs at preparation suppression VEGFR-2 Application in the medicine of enzymatic activity.
9. the ring malonamide compounds with anti-tumor activity described in claim 1 or 2 is being prepared with VEGFR-2 kinases For the application in the antitumor drug of target spot.
CN201610278878.0A 2016-04-28 2016-04-28 Cyclopropane diamide compound with antitumor activity and preparation method and application thereof Pending CN105906568A (en)

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