CN106748991B - Diaryl urea compound with anti-tumor activity and preparation method and application thereof - Google Patents
Diaryl urea compound with anti-tumor activity and preparation method and application thereof Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention provides a diaryl urea compound with anti-tumor activity, a preparation method and application thereof, wherein the structural formula of the compound is
Wherein R is1Is hydrogen or halogen radical, R2Is an alkane group or a halogen group. The compound has good inhibitory activity on VEGFR-2 kinase, can block a signal path induced by VEGFR-2 kinase through inhibiting the activity of VEGFR-2 kinase, and inhibits the proliferation and migration of tumor cells, so that the compound can be applied to the preparation of antitumor drugs. The preparation method of the compound has the advantages of easily obtained raw materials, mild reaction conditions, simple reaction process operation and cheap used reagents.
Description
Technical Field
The invention belongs to the technical field of biological medicines, relates to an anti-tumor compound, and particularly relates to a diaryl urea compound with anti-tumor activity, and a preparation method and application thereof.
Background
Malignant tumors, one of the major public health problems worldwide, greatly endanger human health and will become the first killer of humans in the new century. Malignant tumors are no longer only serious diseases in developed industrial countries, and developing countries face a greater burden of diseases. As one of the important means for treating tumors, chemical drug therapy has been developed and advanced greatly in the last thirty years, and a large number of clinical antitumor drugs with different action mechanisms are obtained. However, antineoplastic drugs also have many adverse reactions, such as alopecia, vomiting, myelosuppression, rapid drug resistance, etc., which result in failure of the desired therapeutic effect of the drugs. Therefore, research and development of new antitumor drugs are one of the hot and difficult problems in the pharmaceutical field at present.
Disclosure of Invention
The invention aims to provide a diaryl urea compound with anti-tumor activity, a preparation method and application thereof.
In order to achieve the purpose, the invention adopts the technical scheme that:
a biaryl urea compound with anti-tumor activity has the following chemical structural formula:
wherein R is1Is hydrogen or halogen radical, R2Is an alkane group or a halogen group.
The halogen group is fluorine atom, chlorine atom, trifluoromethyl or trifluoromethoxy; the alkyl group is methyl or isobutyl.
The preparation method of the diaryl urea compound with the antitumor activity comprises the following steps:
1) aniline with mono-substituent or di-substituent reacts with bis (trichloromethyl) carbonate to form isocyanate, and then the isocyanate and 4-aminophenylboronic acid pinacol ester are subjected to condensation reaction to obtain urea compounds with mono-substituent or di-substituent;
2) under the catalysis of a tetrakis (triphenylphosphine) palladium reaction, carrying out a Suzuki reaction on a urea compound with a single substituent or a double substituent and 2-amino-6-bromopyridine to obtain a diaryl urea compound intermediate;
3) and (3) carrying out acylation reaction on the intermediate of the diaryl urea compound and acryloyl chloride to obtain the diaryl urea compound with anti-tumor activity.
The specific operation of the step 1) is as follows: under the ice bath condition, redistilling dichloromethane to dissolve bis (trichloromethyl) carbonate and uniformly stirring, dropwise adding dichloromethane solution of aniline with mono-substituent or bis-substituent into the mixture, uniformly stirring after dropwise adding, then continuously dropwise adding dichloromethane solution of triethylamine into the mixture, continuously uniformly stirring after dropwise adding, dropwise adding dichloromethane solution of triethylamine and 4-aminophenylboronic acid pinacol ester into the mixture, stirring and reacting after dropwise adding, washing and drying reaction liquid after the reaction is finished, evaporating the solvent under reduced pressure to obtain a crude product, and separating the crude product by using a chromatographic column to obtain the urea compound with mono-substituent or bis-substituent.
The specific operation of the step 2) is as follows: dissolving urea compounds with single substituent or double substituent, 2-amino-6-bromopyridine, anhydrous potassium carbonate and tetrakis (triphenylphosphine) palladium in a mixed solution of acetonitrile and water, reacting at 90 ℃ overnight under the protection of nitrogen, cooling to room temperature after the reaction is finished, extracting with ethyl acetate, washing and drying an extracted organic phase, decompressing and steaming to remove the solvent to obtain a crude product, and separating the crude product by using a chromatographic column to obtain a diaryl urea compound intermediate.
The specific operation of the step 3) is as follows: under the condition of ice bath, dissolving the intermediate of the diaryl urea compound in anhydrous tetrahydrofuran, dropwise adding anhydrous triethylamine, stirring uniformly, dropwise adding acryloyl chloride, removing the ice bath after dropwise adding, stirring at room temperature for reaction, after the reaction is finished, evaporating the solvent from the reaction liquid under reduced pressure to obtain a crude product, and separating the crude product by using a chromatographic column to obtain the diaryl urea compound with the antitumor activity.
The diaryl urea compound with anti-tumor activity is applied to the preparation of the medicine for inhibiting the VEGFR-2 kinase activity.
The diaryl urea compound with anti-tumor activity is applied to preparing anti-tumor drugs taking VEGFR-2 kinase as a target spot.
Compared with the prior art, the invention has the beneficial effects that:
the diaryl urea compound with anti-tumor activity provided by the invention is a novel compound with anti-tumor activity, has good inhibitory activity on VEGFR-2 kinase, and can be used for preparing drugs for inhibiting the VEGFR-2 kinase activity and anti-tumor drugs taking the VEGFR-2 kinase as a target spot. Specifically, the diaryl urea compound with anti-tumor activity provided by the invention can inhibit the activity of VEGFR-2 kinase. Angiogenesis has a close relationship with the generation, development and migration of tumors, the inhibition of the formation of new blood vessels can effectively inhibit the growth and migration of tumors, and a plurality of growth factors regulate the new blood vessel generation, wherein VEGFR-2 is the strongest known positive regulation factor. Therefore, the diaryl urea compound with anti-tumor activity provided by the invention can inhibit the activity of VEGFR-2 kinase, block the induced signal path, and inhibit the proliferation and migration of tumor cells, thereby being applicable to the preparation of anti-tumor drugs.
The preparation method of the diaryl urea compound with the anti-tumor activity provided by the invention comprises the steps of forming isocyanate by aniline with substituent and bis (trichloromethyl) carbonate, carrying out condensation reaction with 4-aminobenzene pinacol ester to obtain a urea compound with substituent, introducing the substituent in the aniline onto the urea compound, carrying out Suzuki reaction on the urea compound and 2-amino-6-bromopyridine to obtain a diaryl urea compound intermediate, and carrying out acylation reaction with acryloyl chloride to obtain the diaryl urea compound with the anti-tumor activity.
Drawings
FIG. 1 is a scheme showing the synthesis scheme of bisarylurea compounds having antitumor activity according to the present invention;
wherein the compound 1 is 4-aminophenylboronic acid pinacol ester, the compound 2 is a urea compound with a single substituent or a double substituent, and the compound 3 is 2-amino-6-bromopyridine; the compound 4 is a diaryl urea compound intermediate, namely 1- (4- (6-aminopyridine-2-yl) phenyl) diaryl urea, and the compound 5 is a target compound, namely a diaryl urea compound with anti-tumor activity.
The specific notations in the figures are:
a.R-NH2,BTC,Et3N,DCM,rt；b.Pd(PPh3)4,K2CO3,H2O,CH3CN,90℃；c.Acryloylchloride,Et3N,THF,0℃to rt.
Detailed Description
The present invention will now be described in further detail with reference to specific examples, which are intended to be illustrative, but not limiting, of the invention.
The invention provides a diaryl urea compound with anti-tumor activity, which has the anti-tumor activity in vitro and can be applied to the preparation of anti-tumor drugs, and the chemical structural formula is as follows:
wherein R is1Is hydrogen or halogen radical, R2Is an alkane group or a halogen group. The halogen group is fluorine atom, chlorine atom, trifluoromethyl or trifluoromethoxy; the alkane group is methyl or isobutyl. In addition, the bisaryl urea compound with the anti-tumor activity is connected with an acrylamide structure on a pyridine ring.
The preparation and activity screening method of the bisarylurea compound as an antitumor candidate drug of the present invention will be described in detail below with reference to the synthetic route and specific synthetic examples shown in FIG. 1.
Example 1
In the structural formula of the diaryl urea compound with anti-tumor activity, R1Is Cl, R2Is CF3Prepared by the following steps (see fig. 1):
1) preparation of compound 1- (4-chloro-3-trifluoromethyl) phenyl) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) urea (compound 2) from 4-aminophenylboronic acid pinacol ester (compound 1) and 4-chloro-3-trifluoromethylaniline
Under the ice bath condition, dissolving 0.80g (2.74mmol) of bis (trichloromethyl) carbonate (BTC) by using 20mL of redistilled dichloromethane and stirring for 5min, slowly dropwise adding 1.10g (6.85mmol) of dichloromethane solution of 4-chloro-3-trifluoromethylaniline, stirring for 15min after dropwise adding, continuously dropwise adding 10mL of dichloromethane solution of 1.1mL (8.22mmol) of triethylamine into the turbid solution, continuously stirring for 15min after dropwise adding, then dropwise adding 1.50g (6.85mmol) of 4-aminobenzeneboronic acid pinacol ester (compound 1) and 10mL of dichloromethane solution of 1.1mL (8.22mmol) of triethylamine into the reaction solution, continuously stirring for 20min after dropwise adding, sequentially using saturated sodium bicarbonate solution, saturated common salt water for washing, drying by anhydrous sodium sulfate to obtain red residue, separating by using a chromatographic column to obtain a white solid 1- (4-chloro-3-trifluoromethyl) phenyl) -3- (4-trifluoromethyl) phenyl-3-propionic acid 1.77g of (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) urea (compound 2), yield 63.7%;
2) preparation of 1- (4- (6-aminopyridin-3-yl) phenyl) -2- (4-chloro-3-trifluoromethyl) phenyl) urea (compound 4) from 1- (4-chloro-3-trifluoromethyl) phenyl) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) urea (compound 2) and 2-amino-6-bromopyridine (compound 3) by a Suzuki coupling reaction
1- (4-chloro-3-trifluoromethyl) phenyl) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) phenyl) urea (compound 2)1.20g (2.72mmol), 2-amino-6-bromopyridine (compound 3)0.71g (4.08mmol), anhydrous potassium carbonate 1.12g (8.16mmol), tetrakis (triphenylphosphine) palladium 0.31g (0.27mmol) were dissolved in a mixed solution of 60mL acetonitrile and 40mL water and reacted overnight at 90 ℃ under nitrogen protection. After the reaction, the reaction mixture was cooled to room temperature, extracted with ethyl acetate 3 to 4 times, and the extracted organic phase was washed successively with a saturated sodium bicarbonate solution, a saturated sodium chloride solution, dried over anhydrous sodium sulfate, spun-dried, and separated by a column chromatography to obtain 0.50g of 1- (4- (6-aminopyridin-3-yl) phenyl) -2- (4-chloro-3-trifluoromethyl) phenyl) urea (compound 4) as a white solid in a yield of 45.5%.
3)1- (4- (6-aminopyridin-3-yl) phenyl) -2- (4-chloro-3-trifluoromethyl) phenyl) urea (compound 4) and acryloyl chloride are subjected to acylation reaction to prepare a target compound
Under the ice bath condition, 0.30g (0.85mmol) of 1- (4- (6-aminopyridin-3-yl) phenyl) -2- (4-chloro-3-trifluoromethyl) phenyl) urea (compound 4) is dissolved in 20mL of anhydrous tetrahydrofuran, 0.47mL (3.40mmol) of anhydrous triethylamine is slowly dripped, the mixture is stirred for reaction for 30min, then 0.15mL (2.04mmol) of acryloyl chloride is slowly dripped, after the dripping is finished, the ice bath is removed, the reaction is carried out for 45min at room temperature, after the reaction is finished, the reaction solution is decompressed and evaporated to dryness to obtain a crude product, and the crude product is separated by column chromatography to obtain 0.21g of a white target compound, wherein the yield is 55.3%;
the structure of the obtained target compound is as follows:
physical and chemical properties: mp is 165-167 ℃.
The hydrogen spectrum nuclear magnetic resonance data is as follows:1H NMR(400MHz,DMSO)δ10.69(s,1H),9.24(s,1H),9.06(s,1H),8.15(d,J＝2.2Hz,1H),8.12(d,J＝8.2Hz,1H),8.05(d,J＝8.8Hz,2H),7.86(t,J＝8.0Hz,1H),7.65(d,J＝1.8Hz,2H),7.63(d,J＝4.4Hz,1H),7.60(s,1H),6.70(m,J＝17.0,10.2Hz,1H),6.34(m,J＝17.0,1.9Hz,1H),5.81(m,J＝10.2,1.9Hz,1H).
the carbon spectrum nuclear magnetic resonance data are as follows:13C NMR(101MHz,DMSO)δ164.26,155.01,152.76,152.11,140.76,139.72,139.62,132.49,132.12,128.18,127.66,127.35,127.04,123.62,122.91,118.82,117.32,115.70,112.37.
example 2
In the structural formula of the diaryl urea compound with anti-tumor activity, R1Is hydrogen, R2Is chlorine.
Steps 1) to 2) are the same as steps 1) to 2) in example 1, i.e., 1- (3-chlorophenyl) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) urea (compound 2) is prepared from the starting compound 4-aminobenzeneboronic acid pinacol ester (compound 1) and m-chloroaniline, and 1- (4- (6-aminopyridin-3-yl) phenyl) -2- (3-chlorophenyl) urea (compound 4) is prepared by Suzuki coupling reaction with 2-amino-6-bromopyridine (compound 3).
3) The target compound is prepared from 1- (4- (6-aminopyridin-3-yl) phenyl) -2- (3- (trichlorophenyl) urea (compound 4) and acryloyl chloride through acylation reaction, and the specific operation steps are as follows:
under the ice bath condition, 0.28g (0.83mmol) of 1- (4- (6-aminopyridin-3-yl) phenyl) -2- (3- (trichlorophenyl) urea (compound 4) is dissolved in 20mL of anhydrous tetrahydrofuran, 0.46mL (3.32mmol) of anhydrous triethylamine is slowly dripped, the mixture is stirred and reacted for 30min, then 0.18mL (1.98mmol) of acryloyl chloride is slowly dripped, after the dripping is finished, the ice bath is removed, the reaction is carried out for 45min at room temperature, after the reaction is finished, the reaction solution is decompressed and evaporated to dryness to obtain a crude product, and the crude product is separated by column chromatography to obtain 0.23g of a milky target compound with the yield of 69.7%;
the structure of the obtained target compound is as follows:
physical and chemical properties: mp is 214-216 ℃.
The hydrogen spectrum nuclear magnetic resonance data is as follows:1H NMR(400MHz,DMSO)δ10.68(s,1H),8.98(s,2H),8.12(d,J＝8.2Hz,1H),8.04(d,J＝8.7Hz,2H),7.86(t,J＝8.0Hz,1H),7.76(s,1H),7.64(d,J＝7.6Hz,1H),7.60(d,J＝8.8Hz,2H),7.33(d,J＝8.1Hz,1H),7.30(d,J＝1.5Hz,1H),7.04(m,J＝7.3,1.8Hz,1H),6.70(m,J＝17.0,10.2Hz,1H),6.34(m,J＝17.0,1.8Hz,1H),5.81(m,J＝10.2,1.8Hz,1H).
the carbon spectrum nuclear magnetic resonance data are as follows:13C NMR(101MHz,DMSO)δ164.26,155.05,152.74,152.10,141.62,140.98,139.61,133.69,132.29,132.13,130.88,128.17,127.67,122.05,118.60,118.12,117.20,115.65,112.31.
example 3
In the structural formula of the diaryl urea compound with anti-tumor activity, R1Is hydrogen, R2Is fluorine.
Steps 1) to 2) are the same as steps 1) to 2) in example 1, namely, 1- (2-fluorophenyl) -3- (4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) urea (compound 2) is prepared from the starting compound 4-aminobenzeneboronic acid pinacol ester (compound 1) and o-fluoroaniline, and then 1- (4- (6-aminopyridin-3-yl) phenyl) -2- (2-fluorophenyl) urea (compound 4) is prepared by Suzuki coupling reaction with 2-amino-6-bromopyridine (compound 3).
3) The target compound is prepared by acylation reaction of 1- (4- (6-aminopyridine-3-yl) phenyl) -2- (2-fluorophenyl) urea (compound 4) and acryloyl chloride, and the specific operation steps are as follows:
under the ice bath condition, 0.30g (0.93mmol) of 1- (4- (6-aminopyridin-3-yl) phenyl) -2- (2-fluorophenyl) urea (compound 4) is dissolved in 20mL of anhydrous tetrahydrofuran, 0.52mL (3.72mmol) of anhydrous triethylamine is slowly dripped, the mixture is stirred and reacted for 30min, then 0.18mL (2.23mmol) of acryloyl chloride is slowly dripped, after the dripping is finished, the ice bath is removed, the reaction is carried out for 45min at room temperature, after the reaction is finished, the reaction solution is decompressed and evaporated to dryness to obtain a crude product, and the crude product is separated by column chromatography to obtain 0.23g of a white target compound, wherein the yield is 65.7%;
the structure of the obtained target compound is as follows:
physical and chemical properties: mp is 214-216 ℃.
The hydrogen spectrum nuclear magnetic resonance data is as follows:1H NMR(400MHz,DMSO)δ10.69(s,1H),9.27(s,1H),8.63(d,J＝2.3Hz,1H),8.18(td,J＝8.2,1.4Hz,1H),8.12(d,J＝8.2Hz,1H),8.05(d,J＝8.7Hz,2H),7.86(t,J＝8.0Hz,1H),7.64(d,J＝7.7Hz,1H),7.59(d,J＝8.7Hz,2H),7.30–7.22(m,1H),7.16(t,J＝7.7Hz,1H),7.08–6.98(m,1H),6.70(m,J＝17.0,10.2Hz,1H),6.34(m,J＝17.0,1.8Hz,1H),5.81(m,J＝10.2,1.8Hz,1H).
the carbon spectrum nuclear magnetic resonance data are as follows:13C NMR(101MHz,DMSO)δ164.26,155.05,153.73,152.54,152.10,151.34,140.97,139.62,132.28,132.13,128.18,127.75,125.00,123.06,121.09,118.35,115.66,115.38,112.32.
the medicinal activity of the bisarylurea compounds having antitumor activity prepared by the present invention is screened and described below.
Screening of inhibitory Activity of Bisarylurea Compounds having antitumor Activity on VEGFR-2 kinase:
VEGFR-2 inhibitory activity of diarylurea compounds with anti-tumor activity was determined using HTRF KinEASE kit: the inhibition activity of the diaryl urea compound with the anti-tumor activity on VEGFR-2 is detected by Lance experiment, and the operation method is carried out according to the instruction of the kit. mu.L of kinase and 2. mu.L of substrate were added to 384 well plates at a VEGFR-2 concentration of 0.09 ng/. mu.L and a substrate concentration of 180 nM. Then adding substrate polypeptide and 4 μ L test compound at different concentrations, adding 2 μ L ATP to start reaction, and heating at 37 deg.CAfter 30min of reaction, EDTA was added to terminate the reaction. Respectively adding Eu into the reaction solution after the reaction is finished3+Cryptate-labeled antibody and streptavidin-XL 665, incubated for 1h at room temperature, the absorbance measured at 665nm and 615nm respectively using Perkin-Elmer Victor 5, the kinase activity measured A665/A615X 104Characterization, calculating the inhibition rate and IC of the prepared diaryl urea compound with anti-tumor activity on VEGFR-250。
The results of the activity of the biaryl urea compounds with antitumor activity prepared by the present invention on VEGFR-2 kinase inhibitors are shown in table 1:
TABLE 1 VEGFR-2 inhibitory Activity of Bisarylurea Compounds
The diaryl urea compounds with the anti-tumor activity prepared by the invention are Q1-Q5, and as can be seen from Table 1, the diaryl urea compounds with the anti-tumor activity prepared by the invention have inhibitory activity on VEGFR-2 kinase, wherein the inhibitory activity of Q4 and Q5 on VEGFR-2 kinase is far higher than that of a positive control medicament Soraninib, so that the diaryl urea compounds with the anti-tumor activity prepared by the invention can be used for preparing medicaments for inhibiting the activity of VEGFR-2 kinase.
In addition, because angiogenesis is closely related to the generation, development and migration of tumors, the inhibition of the formation of new blood vessels can effectively inhibit the growth and migration of tumors, and a plurality of growth factors regulate the new blood vessels, wherein VEGFR-2 is the strongest known positive regulation factor. Therefore, the diaryl urea compound with anti-tumor activity provided by the invention can inhibit the activity of VEGFR-2 kinase, block the induced signal path, and inhibit the proliferation and migration of tumor cells, thereby being applicable to the preparation of anti-tumor drugs taking VEGFR-2 kinase as a target.
The above description is only a preferred embodiment of the present invention, and is not intended to limit the present invention, and all simple modifications, changes and equivalent structural changes made to the above embodiment according to the technical spirit of the present invention still fall within the protection scope of the technical solution of the present invention.
Claims (3)
1. A bisaryl urea compound having an antitumor activity, characterized by having the following chemical structural formula:
wherein R is1Is 4-Cl, R2Is 3-CF3Or R is1Is 3-Cl, R2Is 4-CH3Or R is1Is H, R2Is 4-C (CH)3)3。
2. Use of the biaryl urea compounds with anti-tumor activity according to claim 1 for the preparation of a medicament for inhibiting VEGFR-2 kinase activity.
3. The use of the bisaryl urea compound having anti-tumor activity according to claim 1 for preparing an anti-tumor medicament targeting VEGFR-2 kinase.
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