CN103936631A - Oximido diphenyl urea compound as well as preparation method and application thereof - Google Patents

Oximido diphenyl urea compound as well as preparation method and application thereof Download PDF

Info

Publication number
CN103936631A
CN103936631A CN201410148844.0A CN201410148844A CN103936631A CN 103936631 A CN103936631 A CN 103936631A CN 201410148844 A CN201410148844 A CN 201410148844A CN 103936631 A CN103936631 A CN 103936631A
Authority
CN
China
Prior art keywords
biphenyl
compound
oximido
dimethoxy
biphenyl carbamide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201410148844.0A
Other languages
Chinese (zh)
Other versions
CN103936631B (en
Inventor
张�杰
贺浪冲
张彦民
高洪平
王琛
潘晓艳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xian Jiaotong University
Original Assignee
Xian Jiaotong University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Xian Jiaotong University filed Critical Xian Jiaotong University
Priority to CN201410148844.0A priority Critical patent/CN103936631B/en
Publication of CN103936631A publication Critical patent/CN103936631A/en
Application granted granted Critical
Publication of CN103936631B publication Critical patent/CN103936631B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Abstract

The invention discloses an oximido diphenyl urea compound as well as a preparation method and an application thereof. The oximido diphenyl urea compound is a novel compound with the antitumor activity, which has the good inhibitory activity to VEGFR-2 (Vascular Endothelial Growth Factor Receptor 2) kinases and can be used for preparing antitumor medicines. According to the oximido diphenyl urea compound, each oximido and each hydroxyl are adjacent so as to form an intramolecular hydrogen bond, so that the affinity and the inhibitory activity of the compound and the VEGFR-2 are enhanced; and meanwhile, the physicochemical properties such as the water solubility and the like of the compound are improved by leading the hydroxyls into the compound, so that the medicine likeness of the compound is improved.

Description

A kind of biphenyl carbamide compound that contains oximido and its preparation method and application
Technical field
The invention belongs to biological medicine technology field, relate to a kind of antineoplastic compound, particularly a kind of biphenyl carbamide compound that contains oximido and its preparation method and application.
Background technology
Malignant tumour is as one of larger public health problem in the whole world, the greatly health of harm humans, and will become the first killer of the new millennium mankind.Malignant tumour is the serious disease of advanced industrial country no longer just, and developing country is faced with larger disease burden.Chemotherapy, as treating one of important means of tumour, has had huge development and progress at nearly 30 years, has obtained large quantities of clinical antitumor drugs with different mechanism of action.But antitumour drug also exists many untoward reactions, such as alopecia, vomiting, produces bone marrow depression, produces fast resistance etc., and these all cause chemicals cannot reach the result for the treatment of of expection.Therefore the research and development of new antitumor drug are one of the focus of current pharmaceutical field and difficulties.
Summary of the invention
The problem that the present invention solves is to provide a kind of biphenyl carbamide compound that contains oximido and preparation method thereof, and this biphenyl carbamide compound embodies good anti-tumor activity in vitro, can be applied to the preparation of antitumor drug.
The present invention is achieved through the following technical solutions:
A biphenyl carbamide compound that contains oximido, its chemical structural formula is as follows:
Wherein, R 1for hydrogen, methyl or halogen, R 2the alkoxyl group that the carbonatoms being replaced by tertiary amine groups for end is 1～4, is connected in contraposition or a position of urea by O atom.
In described tertiary amine groups, N atom is the N atom in the heterocycle of 5～6 yuan, and in tertiary amine groups, carbonatoms is 2～5.
In described heterocycle, also comprise O atom, N atom is adjacent with O atom or relative.
What in described tertiary amine groups, be connected with N atom is one or more in straight chained alkyl, cycloalkyl, epoxy alkyl.
Described tertiary amine groups is dimethylamino, diethylin, morpholinyl, piperidyl or piperazinyl.
The preparation method of the described biphenyl carbamide compound that contains oximido, comprises the following steps:
1) then react 3-benzyloxy-4-acetylbenzene pinacol borate and 3 by Suzuki, the connection of 4-dimethoxy-5-bromaniline obtains biphenyl compound 1-(5 '-amino-2 ', 3 '-dimethoxy-3-benzyloxy-[1,1 '-biphenyl]-4-yl) ethyl ketone;
2) 1-(5 '-amino-2 ', 3 '-dimethoxy-3-benzyloxy-[1,1 '-biphenyl]-4-yl) ethyl ketone and two (trichloromethyl) carbonate reactions formation isocyanic ester, then obtain biphenyl carbamide compounds with the aniline condensation formation ureas that contains tertiary amine side chain;
R in biphenyl carbamide compound 1introduced R by the substituting group on phenyl ring in aniline 2be linked on the phenyl ring of aniline R by Williamson's etherification reaction 1, R 2in step 2) reaction before introducing;
3) biphenyl carbamide compounds is reduced to the biphenyl carbamide compounds that contains phenolic hydroxyl group under the catalysis of palladium carbon through debenzylation reaction with hydrogen;
4) the biphenyl carbamide compounds that contains phenolic hydroxyl group is reacted ethanoyl is generated to acetyl oximido with oxammonium hydrochloride, generate the biphenyl carbamide compounds that contains oximido.
The preparation method of the described biphenyl carbamide compound that contains oximido, comprises the following steps:
1) Vanillin is under the katalysis of iron powder, react with bromine and obtain 3-methoxyl group-4-hydroxyl-5-bromobenzaldehyde, then 3-methoxyl group-4-hydroxyl-5-bromobenzaldehyde is obtained to 3-methoxyl group-4-hydroxyl-5-bromobenzylcyanide by reacting with oxammonium sulfate;
2) 3-methoxyl group-4-hydroxyl-5-bromobenzylcyanide is obtained to 3,4-dimethoxy-5-bromobenzylcyanide with methyl-sulfate protection hydroxyl;
3) with ethanol-sodium hydroxide binary hydrolyzation system, the hydrolysis of 3,4-dimethoxy-5-bromobenzylcyanide is obtained to 3,4-dimethoxy-5-brombenzamide;
4), by hoffman degradation reaction, in sodium hypobromite solution, 3,4-dimethoxy-5-brombenzamide is reset and obtained 3,4-dimethoxy-5-bromaniline;
5) between general, bromophenol obtains 3-acetobrom phenol by acetylization reaction, utilizes Fris to reset under Louis acid catalysis, and bromophenol between acetyl is reset and obtained 2-ethanoyl-5-bromophenol;
6) 2-ethanoyl-5-bromophenol is obtained to 1-(the bromo-phenyl of 2-benzyloxy-4-)-ethyl ketone with Benzyl Chloride protection phenolic hydroxyl group;
7) under the catalysis of palladium carbon, 1-(the bromo-phenyl of 2-benzyloxy-4-)-ethyl ketone reacts and obtains 3-benzyloxy-4-acetylbenzene pinacol borate with two (pinacol ester) two boron, then react and 3 by Suzuki, the connection of 4-dimethoxy-5-bromaniline obtains biphenyl compound 1-(5 '-amino-2 ', 3 '-dimethoxy-3-benzyloxy-[1,1 '-biphenyl]-4-yl) ethyl ketone;
8) 1-(5 '-amino-2 ', 3 '-dimethoxy-3-benzyloxy-[1,1 '-biphenyl]-4-yl) ethyl ketone and two (trichloromethyl) carbonate reactions formation isocyanic ester, then obtain biphenyl carbamide compounds with the aniline condensation formation ureas that contains tertiary amine side chain;
R in biphenyl carbamide compound 1introduced R by the substituting group on phenyl ring in aniline 2be linked on the phenyl ring of aniline R by Williamson's etherification reaction 1, R 2before step 8) reaction, introduce;
9) biphenyl carbamide compounds is reduced to the biphenyl carbamide compounds that contains phenolic hydroxyl group under the catalysis of palladium carbon through debenzylation reaction with hydrogen;
10) the biphenyl carbamide compounds that contains phenolic hydroxyl group is reacted ethanoyl is generated to acetyl oximido with oxammonium hydrochloride, generate the biphenyl carbamide compounds that contains oximido.
The application of the described biphenyl carbamide compound that contains oximido in the medicine of preparation inhibition VEGFR-2 kinase activity.
The described biphenyl carbamide compound that contains oximido is in the application of preparing in antitumor drug.
Described antitumor drug is the medicine taking VEGFR-2 kinases as target spot, comprises anti-cancer of the stomach, leukemia, anti-neural cancer, the medicine of inhibitor against colon carcinoma cells, anti-breast cancer, anti-lung cancer, anti-cervical cancer and anti-carcinoma of the pancreas.
Compared with prior art, the present invention has following useful technique effect:
The biphenyl carbamide compound that contains oximido provided by the invention, is a kind of novel compound with anti-tumor activity, and it has good inhibition active to VEGFR-2 kinases, can be used for the preparation of antitumor drug.
The biphenyl carbamide compound that contains oximido provided by the invention, wherein oximido and hydroxyl are ortho position, thereby make hydroxyl and oximido form intramolecular hydrogen bond, strengthen the avidity of compound and VEGFR-2 and suppress active, the simultaneously introducing of hydroxyl can improve the physico-chemical property such as water-soluble of compound, improves its quasi-medicated property.Screening active ingredients result also signify hydroxy compound has raising in various degree with corresponding methoxyl group and oximido adjacent compound phase specific activity.
The biphenyl carbamide compound that contains oximido provided by the invention, has raw material and is easy to get, reaction conditions gentleness, and reaction process is simple to operate, the advantage that agents useful for same is cheap.Wherein, in order to form oximido and the hydroxyl at ortho position, adopt Benzyl Chloride protection phenolic hydroxyl group in follow-up reaction, to obtain hydroxy derivatives through debenzylation reaction again, and the methyl of methoxyl group is difficult to remove.
The biphenyl carbamide compound that contains oximido provided by the invention, can suppress the kinase whose activity of VEGFR-2.And the generation of vasculogenesis and tumour, development and migration have substantial connection, the formation that suppresses new vessel can effectively suppress growth and the migration of tumour, and many somatomedin regulation and control new vesseles generate, and wherein VEGFR-2 is the strongest known positive regulatory factor.Biphenyl carbamide compound provided by the invention like this, by suppressing VEGFR-2 kinase whose activity, is blocked the signal path of its induction, the hyperplasia of inhibition tumor cell and migration, thus can be applicable to the preparation of antitumor drug.
The biphenyl carbamide compound that contains oximido provided by the invention, can be to comprising stomach cancer cell (SGC-7901), chronic myeloid leukemia cell (K562), neural hybridoma (SY5Y), breast cancer cell (MDA-MB-231), human colon cancer cell (LOVO), breast cancer cell (SK-BR-3), Non-small cell lung carcinoma cell (A549), liver cancer cell (SMCC-7721), cervical cancer cell (HeLa) cell, at its cell-proliferation activity of interior inhibiting tumour cells, can be applicable to the preparation of antitumor drug.
Brief description of the drawings
Fig. 1 is the biphenyl carbamide compound synthetic route chart that contains oximido with anti-tumor activity;
Wherein compound 1 is Vanillin, and compound 2 is 3-methoxyl group-4-hydroxyl-5-bromobenzaldehyde, and compound 3 is 3-methoxyl group-4-hydroxyl-5-bromobenzylcyanide, and compound 4 is 3,4-dimethoxy-5-bromobenzylcyanide; Compound is 5 to be 3,4-dimethoxy-5-brombenzamide, compound 6 is 3,4-dimethoxy-5-bromaniline, compound 7 be between bromophenol, compound 8 is 3-acetobrom phenol, and compound 9 is 2-ethanoyl-5-bromophenol, and compound 10 is 1-(the bromo-phenyl of 2-benzyloxy-4-)-ethyl ketone; Compound 11 is 3-benzyloxy-4-acetylbenzene pinacol borate, and compound 12 is 1-(5 '-amino-2 ', 3 '-dimethoxy-3-benzyloxy-[1,1 '-biphenyl]-4-yl) ethyl ketone; The biphenyl carbamide compounds of compound 13 for containing various tertiary amine fragments; The biphenyl carbamide compounds of compound 14 for containing phenolic hydroxyl group; The biphenyl carbamide compounds of compound 15 for containing oximido.
What in figure, mark is specially:
a:Br 2,AcOH,AcONa,Fe,rt;b:HCOOH,HCOONa,(NH 4OH) 2SO 4,90℃;c:(CH 3) 2SO 4,K 2CO 3,Me 2CO,50℃;d:H 2O 2,NaOH,EtOH,60℃;e:Br 2,NaOH;f:Py,Ac 2O,rt;g:AlCl 3,160℃;h:BnCl,K 2CO 3,100℃;i:B 2O 4(CH) 4(CH 3) 8,dioxane,Pd(pddf)Cl 2,KOAc,100℃;j:Na 2CO 3,H 2O,dioxane,100℃;k:BTC,Et 3N,DCM,rt;l:Pd/C,H 2,CH 3OH;m:NH 2OH·HCl,EtOH。
Embodiment
Below in conjunction with specific embodiment, the present invention is described in further detail, and the explanation of the invention is not limited.
The invention provides a kind of biphenyl carbamide compound that contains oximido with anti-tumor activity, this biphenyl carbamide compound has anti-tumor activity in vitro, can be applicable to the preparation of antitumor drug.
Below in conjunction with drawings and Examples, the present invention is described in detail, the explanation of the invention is not limited.
The biphenyl carbamide compound that contains oximido with anti-tumor activity provided by the invention, its chemical structural formula is:
Wherein, R1 is hydrogen, methyl or halogen, and R2 is the alkoxyl group that carbonatoms that end is replaced by tertiary amine groups is 1～4, is connected in contraposition or a position of urea by O atom.
Further, in described tertiary amine groups, N atom is the N atom in the heterocycle of 5～6 yuan.And in described heterocycle, also comprising O atom, N atom is adjacent with O atom or relative.
In described tertiary amine groups, carbonatoms is 2～5, and what in tertiary amine groups, be connected with N atom is one or more in straight chained alkyl, cycloalkyl, epoxy alkyl.Concrete described tertiary amine groups is dimethylamino, diethylin, morpholinyl, piperidyl or piperazinyl.
Describe preparation and the method for screening active ingredients with antitumor drug candidate biphenyl carbamide compound in detail below in conjunction with the synthetic route shown in Fig. 1 and concrete synthesis example.
Embodiment 1
In the structural formula of this compound, R 1for hydrogen, R 2for the alkoxyl group that carbonatoms is 2, end is replaced by diethylin, prepares (referring to Fig. 1) by following steps:
1) Vanillin (1) is prepared compound 3-methoxyl group-4-hydroxyl-5-bromobenzaldehyde (2) by bromination reaction
The iron powder of 20.0g (132mmol) Vanillin (1), 21.59g (263mmol) sodium acetate and 0.68g (12mmol) is placed in to 500mL three-necked bottle, add 120mL glacial acetic acid, stirring at room temperature 30min; After stirring completes, control temperature under the condition of 23～25 DEG C, drip the solution in advance 7.0mL (140mmol) bromine and 30mL Glacial acetic acid being hybridly prepared into, drip off 23～25 DEG C of rear temperature controls and continue stirring 3h;
Then add 250mL frozen water, stir 1h; Filter, solid drying, ethyl alcohol recrystallization, obtains canescence 3-methoxyl group-4-hydroxyl-5-bromobenzaldehyde (2) 24.70g, productive rate 82%;
Its physico-chemical property is: mp:159～160 DEG C, MS (EI) [M] +: m/z=230.
Proton nmr spectra data: 1h NMR (400MHz, CDCl 3) δ ppm:9.80 (s, 1H), 7.66 (s, 1H), 7.38 (s, 1H), 6.62 (s, 1H), 4.00 (s, 3H).
2) change the aldehyde radical of 3-methoxyl group-4-hydroxyl-5-bromobenzaldehyde into itrile group and prepare compound 3-methoxyl group-4-hydroxyl-5-bromobenzylcyanide (3)
5-bromine Vanillin 20.70g (90mmol) is suspended in 150mL formic acid, then add sodium formiate 26.46g (300mmol), be heated to 90 DEG C of stirring and dissolving, in 30 minutes, add oxammonium sulfate 8.88g (180mmol) in batches, then continue reaction 5h.
To be cooledly to room temperature, reaction suspension is poured in 450mL saturated aqueous common salt, stirring at room temperature 10 minutes, suction filtration is collected filter cake, and is neutral with frozen water washing leaching cake to filtrate, dry cake obtains pink solid 3-methoxyl group-4-hydroxyl-5-bromobenzylcyanide crude product 18g, productive rate 86%;
Physico-chemical property: mp:142～144 DEG C, MS (EI) [M] +: m/z=227.
Hydrogen spectrum nuclear magnetic resonance data: 1h NMR (400MHz, CDCl 3) δ ppm:7.49 (s, 1H), 7.07 (s, 1H), 6.42 (s, 1H), 3.98 (s, 3H).
3) 3-methoxyl group-4-hydroxyl-5-bromobenzylcyanide (3) is by preparation 3, the 4-dimethoxy-5-bromobenzylcyanide (4) that methylates
3-methoxyl group-4-hydroxyl-5-bromobenzylcyanide 13.5g (60mmol) is dissolved in 150mL anhydrous propanone, under stirring, add Anhydrous potassium carbonate 24.9g (180mmol), be warming up to 50 DEG C, stir the lower methyl-sulfate 6.6mL of dropping (66mmol), continue to stir 1h, stopped reaction.Question response liquid is put to room temperature, adds 2mol/LNaOH solution stirring 1h, and reaction suspension is poured in cold water, and suction filtration obtains white solid, washes 3 times, is dried to obtain white solid 13.5g, productive rate 94.1%;
Physico-chemical property: mp:122～123 DEG C .MS (EI) [M] +: m/z=243.
Hydrogen spectrum nuclear magnetic resonance data: 1h NMR (400MHz, CDCl 3) δ ppm:7.50 (s, 1H), 7.12 (s, 1H), 3.94 (s, 3H), 3.92 (s, 3H).
4) 3,4-dimethoxy-5-bromobenzylcyanide (4) hydrolysis preparation 3,4-dimethoxy-5-brombenzamide (5)
By compound 3, in 4-dimethoxy-5-bromobenzylcyanide (4) 8g (33mmol) suspension 150mL ethanol solution, be heated to 60 DEG C of dissolvings, then add 1.6g (40mmol) NaOH, stir 10min, then drip 17mL30%H 2o 2solution, controls temperature at 60 DEG C in dropping process, dropwise rear continuation and stir 20min, and dropping HCl solution regulates pH to neutral, is spin-dried for ethanol and obtains white 3,4-dimethoxy-5-brombenzamide crude product, is dried to obtain 7.7g, productive rate 89.5%;
Physico-chemical property: mp:156～157 DEG C, MS (EI) [M] +: m/z=259.
Hydrogen spectrum nuclear magnetic resonance data: 1h NMR (400MHz, CDCl 3) δ ppm:7.53 (s, 1H), 7.45 (s, 1H), 3.95 (s, 3H), 3.93 (s, 3H).
5) compound 3,4-dimethoxy-5-brombenzamide (5) is prepared 3,4-dimethoxy-5-bromaniline (6)
In the NaOH solution of 27mL10% (67.5mmol), drip 0.9mL (17.4mmol) bromine water in-10 DEG C, and stir 20min, in above-mentioned pale yellow solution, add 3.6g (13.9mmol) compound (5) in batches, after adding, continue to stir 30min and rise to room temperature, then at 35 DEG C, continue to stir 1h, be down to after room temperature, in above-mentioned solution, add water, with ethyl acetate solution extraction (50mL × 3), with pressure reducing and steaming solution after anhydrous sodium sulfate drying, resistates separates (eluent is sherwood oil: ethyl acetate=1:1 by volume) with chromatography column and obtains yellow solid 3, 4-dimethoxy-5-bromaniline 1.92g (6), productive rate 60%,
Physico-chemical property: mp:90～91 DEG C, MS (EI) [M] +: m/z=233.
Hydrogen spectrum nuclear magnetic resonance data: 1h NMR (400MHz, CDCl 3) δ ppm:6.48 (s, 1H), 6.23 (s, 1H), 3.83 (s, 3H), 3.79 (s, 3H).
6) between compound, bromophenol (7) is prepared 3-acetobrom phenol (8) through esterification
Under condition of ice bath, bromophenol between 10g (58mmol) is dissolved in 40ml pyridine, slowly drips acetic anhydride 8.3ml (88mmol), continue to stir 2h, detection reaction is complete.In reaction solution, add 200ml frozen water, with concentrated hydrochloric acid adjusting Ph to 7, ethyl acetate extraction (50ml × 3), merges dry organic phase, is spin-dried for and obtains yellow oil 10g(8), productive rate 74%.
7) compound 3-acetobrom phenol (8) is reset and is obtained compound 2-ethanoyl-5-bromophenol (9) through Fris
To being heated to add aluminum trichloride (anhydrous) 6.9g (51.4mmol) in 5.5g (25.7mmol) compound (8) of 160 DEG C, stir 2h, to the hydrochloric acid that adds 100mL2mol/L in reactant, stir 1h, with ethyl acetate solution extraction (100mL × 3), with pressure reducing and steaming solution after anhydrous sodium sulfate drying, resistates separates (eluent is sherwood oil: ethyl acetate=30:1 by volume) with chromatography column and obtains white product 3.85g, productive rate 70%;
Physico-chemical property: mp:36～38 DEG C, MS (EI) [M] +: m/z=213.
Hydrogen spectrum nuclear magnetic resonance data: 1h NMR (400MHz, CDCl 3) δ ppm:7.60 (d, 8Hz, 2H), 7.20 (s, 1H), 7.07 (d, 8Hz, 2H), 2.63 (s, 3H).
8) 2-ethanoyl-5-bromophenol (9) is prepared 1-(the bromo-phenyl of 2-benzyloxy-4-)-ethyl ketone (10) with Benzyl Chloride protection phenolic hydroxyl group
2-ethanoyl-5-bromophenol (9) 2.15g (10mmol) is dissolved in 50mLDMF solution, under stirring, add Anhydrous potassium carbonate 4.14g (30mmol), then slowly drip Benzyl Chloride 1.26mL (11mmol), nitrogen protection, be warming up to 100 DEG C of reaction 1h, cooling reaction solution is to room temperature, reaction solution is poured in 250ml frozen water and stirred and obtain white solid, frozen water washs and is dried and to obtain 1-(the bromo-phenyl of 2-benzyloxy-4-)-ethyl ketone (10) 2.60g, productive rate 85%;
Physico-chemical property: mp:78～79 DEG C, MS (EI) [M] +: m/z=304.0.
Hydrogen spectrum nuclear magnetic resonance data: 1h NMR (400MHz, (CD 3) 2sO) δ ppm:7.55 (d, J=4Hz, 1H), 7.52 (d, J=2Hz, 3H), 7.43 (t, J=8Hz, 2H), 7.37 (t, J=8Hz, 1H), 7.25 (d, J=4Hz, 1H), 5.28 (s, 2H), 2.49 (s, 3H).
9) 1-(the bromo-phenyl of 2-benzyloxy-4-)-ethyl ketone (10) is prepared compound 3-benzyloxy-4-acetylbenzene pinacol borate (11)
1-(the bromo-phenyl of 2-benzyloxy-4-)-ethyl ketone (10) 3g (10mmol) is dissolved in to 20mL1, in 4-dioxane, adds connection pinacol borate 2.74g (11mmol), catalyst P d (pddf) Cl 20.72g (1mmol) and Potassium ethanoate 3.86g (40mmol), under nitrogen protection, in 100 DEG C of reaction 5h, be cooled to room temperature and obtain product (11) under nitrogen protection, solution is not treated carries out next step operation.
10) compound 3; 4-dimethoxy-5-bromaniline (6) is prepared 1-(5 '-amino-2 ' with 3-benzyloxy-4-acetylbenzene pinacol borate (11) by Suzuki linked reaction; 3 '-dimethoxy-3-benzyloxy-[1,1 '-biphenyl]-4-yl) ethyl ketone (12)
In above-mentioned solution, add anhydrous sodium carbonate 1.95g (25mmol), compound (6) 1.70g (10mmol) and 9.8mL H 2o, spends the night in 100 DEG C of reactions under nitrogen protection.Be cooled to room temperature, suction filtration, Isosorbide-5-Nitrae-dioxane washing leaching cake, collects filtrate, is spin-dried for to obtain black residue, separates (eluting solvent is by sherwood oil: ethyl acetate=5:1) obtain yellow solid 1.66g, productive rate 60% through chromatography column;
Physico-chemical property: mp:103～105 DEG C, MS (EI) [M] +: m/z=377.2.
Hydrogen spectrum nuclear magnetic resonance data: 1h NMR (400MHz, (CD 3) 2sO) δ ppm:7.66 (d, J=4Hz, 1H), 7.53 (d, J=4Hz, 2H), 7.43 (t, J=6Hz, 2H), 7.36 (d, J=4Hz, 1H), 7.31 (s, 1H), 7.09 (d, J=4Hz, 1H), 6.35 (s, 1H), 6.15 (s, 1H), 5.28 (s, 2H), 3.76 (s, 3H), 3.37 (s, 3H), 2.55 (s, 3H).
11) compound 1-(5 '-amino-2 '; 3 '-dimethoxy-3-benzyloxy-[1; 1 '-biphenyl]-4-yl) ethyl ketone (12) and 4-(2-(N; N dimethylamine base) oxyethyl group) aniline prepares 1-(4'-ethanoyl-5 by condensation reaction; 6-dimethoxy-3'-benzyloxy-[1,1'-biphenyl]-3-yl)-3-(4-(2-(diethylin) ethyl) phenyl) urea (13)
Under condition of ice bath, heavily steaming methylene dichloride with 15mL dissolves two 0.26g (0.9mmol) (trichloromethyl) carbonic ether (BTC) and stirs 5min, slowly drip again 0.74g (2mmol) 1-(5 '-amino-2 ', 3 '-dimethoxy-3-benzyloxy-[1, 1 '-biphenyl]-4-yl) dichloromethane solution of ethyl ketone, dropwise and stir 15min, to the dichloromethane solution 10mL that continues to drip 0.27mL (1.98mmol) triethylamine in turbid solution, dropwise rear continuation and stir 15min, then in reaction soln, drip 0.51g (2mmol) 4-(2-(N, N dimethylamine base) oxyethyl group) the dichloromethane solution 10mL of aniline and 0.27mL (1.98mmol) triethylamine, dropwise rear continuation and stir 20min, reaction solution is used to saturated sodium bicarbonate solution successively, saturated common salt water washing, anhydrous sodium sulfate drying, be spin-dried for and obtain red residue, separate and obtain light yellow solid 0.46g with chromatography column, productive rate 42.2%.
12) 1-(4'-ethanoyl-5; 6-dimethoxy-3'-benzyloxy-[1; 1'-biphenyl]-3-yl)-3-(4-(2-(diethylin) ethyl) phenyl) urea (13) prepares 1-(4'-ethanoyl-5 through debenzylation reaction; 6-dimethoxy-3'-hydroxyl-[1,1'-biphenyl]-3-yl)-3-(4-(2-(diethylin) ethyl) phenyl) urea (14)
With 20ml methyl alcohol by 1-(4'-ethanoyl-5; 6-dimethoxy-3'-benzyloxy-[1; 1'-biphenyl]-3-yl)-3-(4-(2-(diethylin) ethyl) phenyl) urea (13) 0.61g (1mmol) dissolving; add 0.03g palladium carbon; hydrogen balloon passes into hydrogen normal-temperature reaction 24 hours; filter paper filtering; filtrate evaporate to dryness is obtained to 1-(4'-ethanoyl-5; 6-dimethoxy-3'-hydroxyl-[1; 1'-biphenyl]-3-yl)-3-(4-(2-(diethylin) ethyl) phenyl) urea (14) crude product 0.42g, productive rate 80%
13) 1-(4'-ethanoyl-5; 6-dimethoxy-3'-hydroxyl-[1; 1'-biphenyl]-3-yl)-3-(4-(2-(diethylin) ethyl) phenyl) urea (14) prepares 1-(4'(-1-(oxyimino) ethyl)-3'; 5; 6-trimethoxy-[1,1'-biphenyl]-3-yl)-3-(4-(2-(diethylin) ethyl) phenyl) urea (15)
With 20ml dehydrated alcohol by 0.52g (1mmol) 1-(4'-ethanoyl-5, 6-dimethoxy-3'-hydroxyl-[1, 1'-biphenyl]-3-yl) dissolving of-3-(4-(2-(diethylin) ethyl) phenyl) urea (14), be warming up to 50 DEG C, add the aqueous solution 2ml of 0.72g (10mmol) oxammonium hydrochloride, after reaction 1h, reaction solution is cooled to room temperature, in reaction solution, add saturated sodium carbonate solution to regulate reaction solution to pH=8, extract with chloroform (20mL × 3), merge organic phase, with anhydrous sodium sulfate drying, obtain crude product 0.47g, productive rate is 85%.
Gained compound structure is as follows:
Physico-chemical property: mp:117～119 DEG C, MS (ESI) [M+H] +: m/z=536.1.
Hydrogen spectrum nuclear magnetic resonance data is: 1h NMR (400MHz, (CD 3) 2sO) δ ppm:7.54 (d, J=4Hz, 1H), 7.34 (d, J=4Hz, 2H), 7.25 (s, 1H), 7.01 (d, J=4Hz, 1H), 6.98 (s, 1H), 6.95 (s, 1H), 7.06 (d, J=4Hz, 2H), 3.97 (t, J=6Hz, 2H), 3.83 (s, 3H), 3.50 (s, 3H), 2.76 (t, J=6Hz, 2H), 2.56 (t, J=8Hz, 4H), 2.30 (s, 3H), 0.98 (t, J=6Hz, 6H).
Embodiment 2
Wherein R 1for methyl, R 2for the alkoxyl group that carbonatoms is 3, end is replaced by dimethylamino, is positioned at the contraposition of urea.
Step 1～8 are identical with step in example 1; prepare compound 1-(4'-ethanoyl-5 by initial compounds Vanillin (1); 6-dimethoxy-3'-hydroxyl-[1; 1'-biphenyl]-3-yl)-3-(4-(2-(dimethylamino) propyl group) phenyl) urea; then change ethanoyl into oximido, concrete operation steps is:
With 20mL dehydrated alcohol by 0.51g (1mmol) 1-(4'-ethanoyl-5; 6-dimethoxy-3'-hydroxyl-[1; 1'-biphenyl]-3-yl) dissolving of-3-(4-(2-(dimethylamino) propyl group) phenyl) urea; be heated to 50 DEG C; add the aqueous solution 2mL of 0.72g (10mmol) oxammonium hydrochloride; after reaction 1h; reaction solution is cooled to room temperature; in reaction solution, add saturated sodium carbonate solution to regulate reaction solution to pH=8; with chloroform (20mL × 3) extraction, merge organic phase, with anhydrous sodium sulfate drying; obtain crude product 0.47g, productive rate is 88%.Gained compound is 1-(4'(-1-(oxyimino) ethyl)-5,6-dimethoxy-3'-hydroxyl-[1,1'-biphenyl]-3-yl)-3-(2-methyl-4-(2-(dimethylamino) propyl group) phenyl) urea.
Gained compound structure is as follows:
Physico-chemical property: mp:148～150 DEG C, MS (ESI) [M+H] +: m/z=522.0.
Hydrogen spectrum nuclear magnetic resonance data is: 1h NMR (400MHz, (CD 3) 2sO) δ ppm:7.53 (d, J=4Hz, 1H), 7.49 (d, J=4Hz, 1H), 7.34 (s, 1H), 7.00 (d, J=4Hz, 1H), 6.97 (s, 2H), 6.76 (s, 1H), 6.69 (d, J=4Hz, 1H), 3.94 (t, J=6Hz, 2H), 3.81 (s, 3H), 3.49 (s, 3H), 2.34 (t, J=8Hz, 2H), 2.29 (s, 3H), 2.22 (s, 3H), 2.14 (s, 6H), 1.82 (m, J=10Hz, 2H).
Embodiment 3
Wherein R 1for methyl, R 2middle tertiary amine groups is the compound of morpholinyl, n=3, be positioned at urea between position.
Step 1～8 are identical with step in example 1; prepare compound 1-(4'-ethanoyl-5 by initial compounds Vanillin (1); 6-dimethoxy-3'-hydroxyl-[1; 1'-biphenyl]-3-yl)-3-(2-methyl-5-(2-morpholine propyl group) phenyl) urea; then change ethanoyl into oximido, concrete operation steps is:
With 20mL dehydrated alcohol by 0.56g (1mmol) 1-(4'-ethanoyl-5; 6-dimethoxy-3'-hydroxyl-[1; 1'-biphenyl]-3-yl) dissolving of-3-(2-methyl-5-(2-morpholine propyl group) phenyl) urea; be heated to 50 DEG C; add the aqueous solution 2mL of 0.72g (10mmol) oxammonium hydrochloride; after reaction 1h; reaction solution is cooled to room temperature; in reaction solution, add saturated sodium carbonate solution to regulate reaction solution to pH=8; with chloroform (20mL × 3) extraction, merge organic phase, with anhydrous sodium sulfate drying; obtain crude product 0.50g, productive rate is 87.3%.Gained compound is 1-(4'(-1-(oxyimino) ethyl)-5,6-dimethoxy-3'-hydroxyl-[1,1'-biphenyl]-3-yl)-3-(2-methyl-4-(2-morpholine propyl group) phenyl) urea.
Gained compound structure is as follows:
Physico-chemical property: mp:202～203 DEG C, MS (ESI) [M+H] +: m/z=578.3.
Hydrogen spectrum nuclear magnetic resonance data is: 1h NMR (400MHz, (CD 3) 2sO) δ ppm:7.87 (d, J=4Hz, 1H), 7.59 (d, J=4Hz, 1H), 7.46 (d, J=4Hz, 1H), 7.40 (d, J=4Hz, 1H), 7.23 (s, 1H), 7.03 (s, 1H), 6.98 (s, 1H), 6.50 (s, 1H), 3.93 (t, J=6Hz, 2H), 3.84 (s, 3H), 3.70 (t, J=6Hz, 2H), 3.57 (t, J=8Hz, 4H), 3.49 (s, 3H), 2.38 (t, J=10Hz, 4H), 2.16 (s, 3H), 2.08 (s, 3H), 1.83 (m, J=14Hz, 2H).
Embodiment 4
Wherein R 1for fluorine, n=2, R 2for the alkoxyl group that carbonatoms is 2, end is replaced by diethylin.
Step 1～8 are identical with step in example 1; prepare compound 1-(4'-ethanoyl-5 by initial compounds Vanillin (1); 6-dimethoxy-3'-hydroxyl-[1; 1'-biphenyl]-3-yl)-3-(the fluoro-4-of 2-(2-(diethylin) ethyl) phenyl) urea; then change ethanoyl into oximido, concrete operation steps is:
With 20mL dehydrated alcohol by 0.54g (1mmol) 1-(4'-ethanoyl-5, 6-dimethoxy-3'-hydroxyl-[1, 1'-biphenyl]-3-yl) dissolving of-3-(the fluoro-4-of 2-(2-(diethylin) ethyl) phenyl) urea, be heated to 50 DEG C, add the aqueous solution 2mL of 0.72g (10mmol) oxammonium hydrochloride, after reaction 1h, reaction solution is cooled to room temperature, in reaction solution, add saturated sodium carbonate solution to regulate reaction solution to pH=8, extract with chloroform (20mL × 3), merge organic phase, with anhydrous sodium sulfate drying, obtain crude product 0.48g, productive rate is 86.9%.Gained compound is 1-(4'(-1-(oxyimino) ethyl)-3', 5,6-trimethoxy-[1,1'-biphenyl]-3-yl)-3-(the fluoro-4-of 2-(2-(diethylin) ethyl) phenyl) urea.
Gained compound is as follows
Physico-chemical property: mp:163～165 DEG C, MS (ESI) [M+H] +: m/z=554.2.
Hydrogen spectrum nuclear magnetic resonance data is: 1h NMR (400MHz, (CD 3) 2sO) δ ppm:7.54 (d, J=4Hz, 1H), 7.47 (d, J=6Hz, 1H), 7.27 (s, 1H), 7.08 (d, J=4Hz, 2H), 7.01 (d, J=4Hz, 1H), 6.98 (s, 1H), 6.97 (s, 1H), 4.03 (t, J=6Hz, 2H), 3.83 (s, 3H), 3.50 (s, 3H), 2.76 (t, J=6Hz, 2H), 2.55 (m, J=12Hz, 4H), 2.30 (s, 3H), 0.97 (t, J=8Hz, 6H).
Embodiment 5
Wherein R 1for chlorine, n=2, R 2for the compound of morpholinyl, be positioned at the contraposition of urea.
Rapid 1～8 is identical with step in example 1 step by step; prepare compound 1-(4'-ethanoyl-5 by initial compounds Vanillin (1); 6-dimethoxy-3'-hydroxyl-[1; 1'-biphenyl]-3-yl)-3-(the chloro-4-of 2-(2-morpholine ethyl) phenyl) urea; then change ethanoyl into oximido, concrete operation steps is:
With 20mL dehydrated alcohol by 0.55g (1mmol) 1-(4'-ethanoyl-5; 6-dimethoxy-3'-hydroxyl-[1; 1'-biphenyl]-3-yl) dissolving of-3-(the chloro-4-of 2-(2-morpholine ethyl) phenyl) urea; be heated to 50 DEG C; add the aqueous solution 2mL of 0.72g (10mmol) oxammonium hydrochloride; after reaction 1h; reaction solution is cooled to room temperature; in reaction solution, add saturated sodium carbonate solution to regulate reaction solution to pH=8; with chloroform (20mL × 3) extraction, merge organic phase, with anhydrous sodium sulfate drying; obtain crude product 0.51g, productive rate is 88.6%.Gained compound is 1-(4'(-1-(oxyimino) ethyl)-3', 5,6-trimethoxy-[1,1'-biphenyl]-3-yl)-3-(the chloro-4-of 2-(2-morpholine ethyl) phenyl) urea
Gained compound is as follows
Physico-chemical property: mp:122～124 DEG C, MS (ESI) [M+H] +: m/z=584.1.
Hydrogen spectrum nuclear magnetic resonance data is: 1h NMR (400MHz, (CD 3) 2sO) δ ppm:7.54 (d, J=4Hz, 1H), 7.35 (d, J=6Hz, 1H), 7.26 (s, 1H), 7.10 (d, J=4Hz, 2H), 7.02 (d, J=6Hz, 1H), 6.96 (s, 1H), 6.87 (d, J=4Hz, 1H), 4.12 (t, J=4Hz, 1H), 4.02 (t, J=4Hz, 1H), 3.83 (s, 3H), 3.58 (t, J=4Hz, 4H), 3.50 (s, 3H), 2.71 (t, J=4Hz, 1H), 2.67 (t, J=4Hz, 1H), 2.51 (s, 4H), 2.30 (s, 3H).
Embodiment 6
The biphenyl carbamide compounds that contains oximido is to the kinase whose inhibition screening active ingredients of VEGFR-2
Inhibition activity with HTRF KinEASE kit measurement compound to VEGFR-2: adopt the inhibition activity of Lance experiment detection compound to VEGFR-2, working method is carried out according to test kit explanation.The substrate of 2 μ L kinases and 2 μ L is added in 384 orifice plates, and VEGFR-2 concentration is 0.09ng/ μ L, and concentration of substrate is 180nM.Then add substrate polypeptide and the 4 μ L testing compounds of different concns, add 2 μ L ATP to start reaction, at 37 DEG C, react after 30min, add EDTA termination reaction.Reaction finishes to add respectively Eu in backward reaction solution 3+the antibody of-kryptofix 222 mark and streptavidin-XL665, at room temperature hatch 1h, adopts Perkin-Elmer Victor5 to measure respectively absorbancy, A665/A615 for kinase activity × 10 under 665nm and 615nm wavelength 4characterize inhibiting rate and the IC of computerized compound to VEGFR-2 50.
The result of the novel biphenyl carbamide compound that contains oximido to VEGFR-2 kinase inhibitor activity, as shown in table 1:
It is active that the VEGFR-2 of the biphenyl carbamide compounds that table 1 contains oximido suppresses
The generation of vasculogenesis and tumour, development and migration have substantial connection, and the formation that suppresses new vessel can effectively suppress the growth of tumour.Many somatomedin regulation and control new vesseles generate, and wherein VEGFR-2 is the strongest known positive regulatory factor.By suppressing the kinase whose activity of VEGFR-2, block the signal path of its induction, the hyperplasia of inhibition tumor cell and migration, and then reach the object for the treatment of tumour.
The antitumor activity screening of the biphenyl carbamide compound that embodiment 7 contains oximido
Adopt the growth inhibitory activity of the mtt assay inspection biphenyl carbamide compounds that contains oximido to be measured to tumour cell:
The biphenyl carbamide compound that contains oximido provided by the invention has antitumor action, tumour cell is had to vitro inhibition proliferation activity, at lung carcinoma cell (A549), breast cancer cell (MCF7), endotheliocyte (ECV304), breast cancer cell (MDA-MB-431s), human lung carcinoma cell (NCI-H1299), breast cancer cell (MDA-MB-231), melanoma cell (A375), colon cancer cell (HT29), liver cancer cell (SMCC-7721), in Non-small cell lung carcinoma cell (H460) clone, there is the proliferation activity of inhibition tumor cell, can be for the treatment to these cancers, compared with positive drug Sutent, individual compound has shown higher inhibition tumor cell proliferation activity.
By the lung carcinoma cell in logarithmic phase (A549), breast cancer cell (MCF7), endotheliocyte (ECV304), breast cancer cell (MDA-MB-431s), human lung carcinoma cell (NCI-H1299), breast cancer cell (MDA-MB-231), melanoma cell (A375), colon cancer cell (HT29), liver cancer cell (SMCC-7721), Non-small cell lung carcinoma cell (H460), the trysinization with 0.25% 3～5 minutes, after piping and druming evenly, being diluted to concentration is 1 × 10 4～2 × 10 4the single cell suspension of individual/mL, parallel being inoculated in 96 well culture plates, every hole inoculation volume is 200 μ L; In 37 DEG C, 5%CO 2in incubator, cultivate 24 hours;
With the negative contrast of the aqueous solution containing 0.25%DMSO (N, N-dimethyl sulfoxide (DMSO)), with the positive contrast of Sutent, testing sample adds the biphenyl urea derivatives (1 × 10 of 4 different concns -7mol/L; 1 × 10 -6mol/L; 1 × 10 -5mol/L; 5 × 10 -5mol/L), each concentration is established 5 multiple holes, continues to cultivate 48 hours;
Then every hole adds the MTT working fluid 10 μ L of 5mg/mL, mix, 37 DEG C of incubators are hatched after 4 hours and are taken out, careful suction abandoned nutrient solution, every hole adds 150 μ L DMSO, vibration 10min, and euzymelinked immunosorbent assay (ELISA) detector is measured 490nm place, each hole ultraviolet absorption value (OD value), then calculate cell inhibitory rate, and obtain IC according to inhibiting rate 50value; The calculation formula of cell inhibitory rate is:
Inhibiting rate %=(positive controls OD value-medication group OD value)/negative control cell OD value × 100%
Detected result shows: compared with negative control group, the biphenyl carbamide compound that contains oximido has In-vitro Inhibitory Effect in various degree to above-mentioned 9 kinds of tumour cells.
Anti tumor activity in vitro (the IC of the biphenyl carbamide compound that table 2. contains oximido 50, μ M)
The inhibition of result display section compound to tumour cell is suitable with positive control drug Sutent, even has some activity will be higher than positive control.Illustrate that the novel biphenyl carbamide compounds that contains oximido is obvious to the proliferation inhibiting effect of tumour cell.
Above-claimed cpd structure:

Claims (10)

1. a biphenyl carbamide compound that contains oximido, is characterized in that, its chemical structural formula is as follows:
Wherein, R 1for hydrogen, methyl or halogen, R 2the alkoxyl group that the carbonatoms being replaced by tertiary amine groups for end is 1～4, is connected in contraposition or a position of urea by O atom.
2. the biphenyl carbamide compound that contains oximido as claimed in claim 1, is characterized in that, in described tertiary amine groups, N atom is the N atom in the heterocycle of 5～6 yuan, and in tertiary amine groups, carbonatoms is 2～5.
3. the biphenyl carbamide compound that contains oximido with anti-tumor activity as claimed in claim 2, is characterized in that, in described heterocycle, also comprise O atom, N atom is adjacent with O atom or relative.
4. the biphenyl carbamide compound that contains oximido with anti-tumor activity as claimed in claim 1, is characterized in that, what in described tertiary amine groups, be connected with N atom is one or more in straight chained alkyl, cycloalkyl, epoxy alkyl.
5. the biphenyl carbamide compound that contains oximido with anti-tumor activity as claimed in claim 1, is characterized in that, described tertiary amine groups is dimethylamino, diethylin, morpholinyl, piperidyl or piperazinyl.
6. the preparation method of the biphenyl carbamide compound that contains oximido claimed in claim 1, is characterized in that, comprises the following steps:
1) then react 3-benzyloxy-4-acetylbenzene pinacol borate and 3 by Suzuki, the connection of 4-dimethoxy-5-bromaniline obtains biphenyl compound 1-(5 '-amino-2 ', 3 '-dimethoxy-3-benzyloxy-[1,1 '-biphenyl]-4-yl) ethyl ketone;
2) 1-(5 '-amino-2 ', 3 '-dimethoxy-3-benzyloxy-[1,1 '-biphenyl]-4-yl) ethyl ketone and two (trichloromethyl) carbonate reactions formation isocyanic ester, then form ureas with the aniline condensation that contains tertiary amine side chain, obtain biphenyl carbamide compounds;
R in biphenyl carbamide compound 1introduced R by the substituting group on phenyl ring in aniline 2be linked on the phenyl ring of aniline R by Williamson's etherification reaction 1, R 2in step 2) reaction before introducing;
3) biphenyl carbamide compounds is reduced to the biphenyl carbamide compounds that contains phenolic hydroxyl group under the catalysis of palladium carbon through debenzylation reaction with hydrogen;
4) the biphenyl carbamide compounds that contains phenolic hydroxyl group is reacted ethanoyl is generated to acetyl oximido with oxammonium hydrochloride, generate the biphenyl carbamide compounds that contains oximido.
7. the preparation method of the biphenyl carbamide compound that contains oximido claimed in claim 1, is characterized in that, comprises the following steps:
1) Vanillin is under the katalysis of iron powder, react with bromine and obtain 3-methoxyl group-4-hydroxyl-5-bromobenzaldehyde, then 3-methoxyl group-4-hydroxyl-5-bromobenzaldehyde is obtained to 3-methoxyl group-4-hydroxyl-5-bromobenzylcyanide by reacting with oxammonium sulfate;
2) 3-methoxyl group-4-hydroxyl-5-bromobenzylcyanide is obtained to 3,4-dimethoxy-5-bromobenzylcyanide with methyl-sulfate protection hydroxyl;
3) with ethanol-sodium hydroxide binary hydrolyzation system, the hydrolysis of 3,4-dimethoxy-5-bromobenzylcyanide is obtained to 3,4-dimethoxy-5-brombenzamide;
4), by hoffman degradation reaction, in sodium hypobromite solution, 3,4-dimethoxy-5-brombenzamide is reset and obtained 3,4-dimethoxy-5-bromaniline;
5) between general, bromophenol obtains 3-acetobrom phenol by acetylization reaction, utilizes Fris to reset under Louis acid catalysis, and bromophenol between acetyl is reset and obtained 2-ethanoyl-5-bromophenol;
6) 2-ethanoyl-5-bromophenol is obtained to 1-(the bromo-phenyl of 2-benzyloxy-4-)-ethyl ketone with Benzyl Chloride protection phenolic hydroxyl group;
7) under the catalysis of palladium carbon, 1-(the bromo-phenyl of 2-benzyloxy-4-)-ethyl ketone reacts and obtains 3-benzyloxy-4-acetylbenzene pinacol borate with two (pinacol ester) two boron, then react and 3 by Suzuki, the connection of 4-dimethoxy-5-bromaniline obtains biphenyl compound 1-(5 '-amino-2 ', 3 '-dimethoxy-3-benzyloxy-[1,1 '-biphenyl]-4-yl) ethyl ketone;
8) 1-(5 '-amino-2 ', 3 '-dimethoxy-3-benzyloxy-[1,1 '-biphenyl]-4-yl) ethyl ketone and two (trichloromethyl) carbonate reactions formation isocyanic ester, then obtain biphenyl carbamide compounds with the aniline condensation formation ureas that contains tertiary amine side chain;
R in biphenyl carbamide compound 1introduced R by the substituting group on phenyl ring in aniline 2be linked on the phenyl ring of aniline R by Williamson's etherification reaction 1, R 2before step 8) reaction, introduce;
9) biphenyl carbamide compounds is reduced to the biphenyl carbamide compounds that contains phenolic hydroxyl group under the catalysis of palladium carbon through debenzylation reaction with hydrogen;
10) the biphenyl carbamide compounds that contains phenolic hydroxyl group is reacted ethanoyl is generated to acetyl oximido with oxammonium hydrochloride, generate the biphenyl carbamide compounds that contains oximido.
8. the application of the biphenyl carbamide compound that contains oximido claimed in claim 1 in the medicine of preparation inhibition VEGFR-2 kinase activity.
9. the biphenyl carbamide compound that contains oximido claimed in claim 1 is in the application of preparing in antitumor drug.
10. antitumor drug as claimed in claim 9, is characterized in that, described antitumor drug is the medicine taking VEGFR-2 kinases as target spot, comprise anti-cancer of the stomach, leukemia, anti-neural cancer, the medicine of inhibitor against colon carcinoma cells, anti-breast cancer, anti-lung cancer, anti-cervical cancer and anti-carcinoma of the pancreas.
CN201410148844.0A 2014-04-14 2014-04-14 A kind of Biphenyl carbamide compound containing oximido and its preparation method and application Active CN103936631B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201410148844.0A CN103936631B (en) 2014-04-14 2014-04-14 A kind of Biphenyl carbamide compound containing oximido and its preparation method and application

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201410148844.0A CN103936631B (en) 2014-04-14 2014-04-14 A kind of Biphenyl carbamide compound containing oximido and its preparation method and application

Publications (2)

Publication Number Publication Date
CN103936631A true CN103936631A (en) 2014-07-23
CN103936631B CN103936631B (en) 2015-08-05

Family

ID=51184550

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201410148844.0A Active CN103936631B (en) 2014-04-14 2014-04-14 A kind of Biphenyl carbamide compound containing oximido and its preparation method and application

Country Status (1)

Country Link
CN (1) CN103936631B (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104725319A (en) * 2015-03-11 2015-06-24 西安交通大学 1H-indazole-3-aminobphenyl urea compound with anti-tumor activity as well as preparation method and application of 1H-indazole-3-aminobphenyl urea compound
CN104744350A (en) * 2015-03-11 2015-07-01 西安交通大学 Pyridine-substituted diarylurea compound and preparation method and application thereof
CN104817493A (en) * 2015-03-11 2015-08-05 西安交通大学 Aromatic heterocyclic amide substituted diarylurea compound, preparation method and application thereof
CN112961081A (en) * 2021-02-05 2021-06-15 山东第一医科大学(山东省医学科学院) Bibenzamide urea compound and preparation method and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103288684A (en) * 2013-05-03 2013-09-11 西安交通大学 Biphenyl carbamide compound with antineoplastic activity and preparation method thereof
WO2013175483A1 (en) * 2012-05-23 2013-11-28 Shilpa Medicare Limited Process for preparing crystalline sorafenib tosylate

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013175483A1 (en) * 2012-05-23 2013-11-28 Shilpa Medicare Limited Process for preparing crystalline sorafenib tosylate
CN103288684A (en) * 2013-05-03 2013-09-11 西安交通大学 Biphenyl carbamide compound with antineoplastic activity and preparation method thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEN WANG,ET AL: "Design, synthesis and biological evaluation of biphenyl urea derivatives as novel VEGFR-2 inhibitors", 《MED.CHEM.COMMUN》, vol. 4, 21 August 2013 (2013-08-21), pages 2 - 1 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104725319A (en) * 2015-03-11 2015-06-24 西安交通大学 1H-indazole-3-aminobphenyl urea compound with anti-tumor activity as well as preparation method and application of 1H-indazole-3-aminobphenyl urea compound
CN104744350A (en) * 2015-03-11 2015-07-01 西安交通大学 Pyridine-substituted diarylurea compound and preparation method and application thereof
CN104817493A (en) * 2015-03-11 2015-08-05 西安交通大学 Aromatic heterocyclic amide substituted diarylurea compound, preparation method and application thereof
CN112961081A (en) * 2021-02-05 2021-06-15 山东第一医科大学(山东省医学科学院) Bibenzamide urea compound and preparation method and application thereof
CN112961081B (en) * 2021-02-05 2022-09-13 山东第一医科大学(山东省医学科学院) Bibenzamide urea compound and preparation method and application thereof

Also Published As

Publication number Publication date
CN103936631B (en) 2015-08-05

Similar Documents

Publication Publication Date Title
CN103288684B (en) Biphenyl carbamide compound with antineoplastic activity and preparation method thereof
You et al. A new tetraphenylethylene‐derived fluorescent probe for nitroreductase detection and hypoxic‐tumor‐cell imaging
CN103936631B (en) A kind of Biphenyl carbamide compound containing oximido and its preparation method and application
CN106243031A (en) A kind of Ah handkerchief is for the preparation method of Buddhist nun
Abbas et al. Ternary Eu (iii) and Tb (iii) β-diketonate complexes containing chalcones: photophysical studies and biological outlook
CN108101926B (en) Pyrimido five-membered heterocyclic compound containing quinolinone, preparation method and application thereof
CN104817493A (en) Aromatic heterocyclic amide substituted diarylurea compound, preparation method and application thereof
CN104211632A (en) 2-Indolone derivative with tyrosine kinase inhibition activity, and preparation method and application thereof
CN102827087B (en) Synthetic method of erlotinib
CN106749097B (en) A kind of chloro- 2- aminobenzothiazole analog derivative of 6- and its preparation method and application
CN104725319A (en) 1H-indazole-3-aminobphenyl urea compound with anti-tumor activity as well as preparation method and application of 1H-indazole-3-aminobphenyl urea compound
CN105153026A (en) Biaryl amide structure containing sorafenib derivative as well as preparation method and applications thereof
CN105503744A (en) Diphenyl urea compound containing quinazolinone and preparation method and application of diphenyl urea compound
CN103070868B (en) A kind of IDO inhibitor containing NH-1,2,3-triazole and preparation method thereof
CN104744350A (en) Pyridine-substituted diarylurea compound and preparation method and application thereof
CN111454254B (en) Preparation and application of benzimidazole derivative with fluorine-containing substituent
CN102010347B (en) Biphenyl compound serving as antitumor medicament and preparation method thereof
CN110128343A (en) A kind of hydrazide kind compound
Wang et al. Synthesis, characterization and anticancer properties: A series of highly selective palladium (II) substituted-terpyridine complexes
CN106045980A (en) Quinazoline derivative and preparation method thereof
CN103360423B (en) Benzyltin aromatic aldehyde condensed arylamine Schiff base complex and its preparation method and application thereof
CN112174958B (en) Pyrido [2,3-d ] pyrimidine compound and preparation method and application thereof
CN104817489B (en) A kind of heterocycle biphenyl aryl urea compounds with antitumor activity and its preparation method and application
CN106083740A (en) A kind of 4 anilinoquinazoline derivatives containing 1,2,3 triazoles and preparation method
CN103724260A (en) Benzamide derivative and preparation method and application thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant