CN106883277B - A kind of furazan class NO donator type scutellarin derivative with anti-tumor activity and its preparation method and application - Google Patents

A kind of furazan class NO donator type scutellarin derivative with anti-tumor activity and its preparation method and application Download PDF

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CN106883277B
CN106883277B CN201710141498.7A CN201710141498A CN106883277B CN 106883277 B CN106883277 B CN 106883277B CN 201710141498 A CN201710141498 A CN 201710141498A CN 106883277 B CN106883277 B CN 106883277B
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furazan
pharmaceutically acceptable
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donator type
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CN106883277A (en
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李达翃
华会明
李占林
韩通
续繁星
高祥
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Shenyang Pharmaceutical University
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    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
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Abstract

The present invention relates to natural drug and field of medicinal chemistry, and in particular to a kind of furazan class NO donator type scutellarin derivative with anti-tumor activity and its pharmaceutically acceptable salt.More particularly to these scutellarin derivatives that in sugared carboxyl site there is the furazan class NO donor of aliphatic chain linking arm to replace and preparation method thereof and application in preparation of anti-tumor drugs.Shown in furazan class NO donator type scutellarin derivative of the present invention and its following general formula I of pharmaceutically acceptable salt structure, wherein R, R1As described in claims and specification.

Description

A kind of furazan class NO donator type scutellarin derivative with anti-tumor activity and its Preparation method and purposes
Technical field
The present invention relates to field of medicinal chemistry, and in particular to the sugared carboxyl site of scutellarin carries out furazan class NO donor and repairs The derivative of decorations.The scutellarin derivative replaced more particularly to these in sugared carboxyl site furazan class NO donor and its preparation side Method and application in preparation of anti-tumor drugs.
Background technique
The research and development of anti-tumor drug are faced with stern challenge at present, and many anti-tumor drugs on the market are being shown While preferably active, side effect is also more and more, seriously affects the therapeutic effect of disease.Therefore, exploitation high-efficiency low-toxicity is found Anti-tumor drug become particularly important.Natural products is the important sources of drug discovery, in the drug listed, Hen Duocheng The drug of function all directly or indirectly derives from natural products.In nature, it finds and obtains that active more preferable, toxicity is lower, property The more stable antitumor candidate compound of matter becomes most important.
Scutellarin (scutellarin) is from compositae plant Erigeron breviscapus Erigeron breviscapus (Vant.) A kind of isolated flavonoids effective constituent is extracted in the drying herb of Hand-Mazz, is a kind of pale yellow powder.Modern Pharmaceutical research shows that scutellarin has extensive pharmacological activity, including expansion blood vessel, increase blood flow, anticoagulation, inhibition Platelet aggregation inhibits tumor cell proliferation and neurocyte protection isoreactivity.In recent years, about scutellarin in antitumor side The research in face is more and more deep, and correlative study shows that scutellarin has good inhibiting effect to various tumor cell strains.Packet Include breast cancer cell, human leukemia cell, liver cancer cells, colon cancer cell, people's Human Tongue Carcinoma Lines etc..Scutellarin is as a kind of normal The flavone compound seen, from a wealth of sources and have presence in the plant of many daily consumptions, this is research and development high-efficiency low-toxicity Anti-tumor drug have laid a good foundation.
Nitric oxide plays important physiological action as biological courier or effector molecule in vivo, and it is horizontal different in vivo It is often closely related with the occurrence and development of a variety of diseases.Therefore, the research of nitric oxide donator type drug is concerned.Furazan nitrogen Oxygen compound (Furoxan) is a kind of important nitric oxide donors, the oxidation that synthesizes with some drugs molecule coupling labeled The pharmacological activity of drug can be improved in nitrogen donor type drug, and furazan type nitric oxide donors have become research and development new type antineoplastic medicine One of hot spot.
The present invention is using scutellarin as lead compound, and using principle of hybridization, selection can generate the furazan of higher concentration NO Nitrogen oxides is connected on the sugared carboxyl of its molecular structure as NO donor, by it by linking group, has been designed and synthesized logical Formula is the NO donator type scutellarin derivative of I.
Summary of the invention
Technical problems to be solved by the inivention are to find the good NO donator type scutellarin derivative of anti-tumor activity, go forward side by side one Step provides a kind of pharmaceutical composition for treating tumour and Other diseases or illness.
In order to solve the above technical problems, the invention provides the following technical scheme:
General formula I is shown furazan NO donator type scutellarin derivative and its pharmaceutically acceptable salt:
Wherein, R is substituted or unsubstituted C1-C12Alkyl, substituted or unsubstituted benzyl；The substituent group are as follows: C1- C4Alkyl, C1-C4Alkoxy；R1For substituted or unsubstituted C1-C12Alkyl；The substituent group are as follows: C1-C4Alkyl, C1-C4Alkane Oxygroup.
Further, R C1-C6Alkyl, substituted or unsubstituted benzyl；The substituent group is C1-C4Alkyl, C1-C4 Alkoxy；R1For substituted or unsubstituted C1-C6Alkyl；The substituent group are as follows: C1-C4Alkyl, C1-C4Alkoxy.
Preferably, R is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or benzyl；R1For-(CH2)2-、- (CH2)3-、-CH2CH(CH3)-、-(CH2)4-、-CH2CH(CH3)CH2-、-CH2CH2CH(CH3)-or-(CH2)5-。
It is highly preferred that R is methyl or benzyl；R1For-(CH2)2,-(CH2)3Or-CH2CH(CH3)-。
The preferably following compound of the present invention:
The derivative of general formula I of the present invention can be prepared with following method:
Scutellarin (1) is in K2CO3It with halohydrocarbons reaction under the conditions of/DMF, obtains intermediate (2,3), intermediate 2,3 exists Hydrolysis obtains target compound (4,5) under conditions of KOH/MeOH.
Benzenethiol (6) is reacted to obtain to benzene sulphur acetic acid (7) under alkaline condition with monoxone, then through 30%H2O2Oxidation life At benzene sulfonyl acetic acid (8).Compound 8 is in smoke HNO3In the presence of heating cyclization at 3,4- dibenzenesulfonyl furoxan-based NO donors (9), compound 9 generates target compound using THF as reaction dissolvent from different hydramine reactions under conditions of NaH is catalyzed (10a-c)。
The sugared carboxyl site and amido alcohol of compound 4,5, which replace, generates single benzenesulfonyl furoxan-based NO donors class NO donor It closes object 10a-c reaction under conditions of HOBt, EDCI catalysis and is condensed to obtain target compound 11a-c, 12a-c.
Specific embodiment
Embodiment 1
Scutellarin 1 (300mg, 0.65mmol) is taken, DMF (10ml) is dissolved in, in, it is added cylite (0.38ml, 3mmol) With Anhydrous potassium carbonate (414mg, 3mmol), reaction is stirred at room temperature, TCL monitors reaction process, terminates reaction afterwards for 24 hours.By reaction solution It being poured into 20ml mixture of ice and water, ethyl acetate extracts (30ml × 3), and the washing of saturated common salt aqueous solution, anhydrous sodium sulfate is dry, Ethyl acetate is recycled, crude product 2 is obtained, through silicagel column (methylene chloride: methanol=20:1), separation obtains yellow solid 315mg, Yield 67.2%.ESI-MS m/z 733.2[M+H]+。1H NMR(DMSO-d6,400MHz)δ:12.96(s,1H,5-OH), 8.03 (d, 2H, J=9.0Hz, H-2 ', 6 '), 7.55 (d, 2H, Ar-H), 7.48 (d, 2H, Ar-H), 7.36 (m, 9H, Ar-H), 7.25 (d, 2H, Ar-H), 7.20 (d, 2H, J=9.0Hz, H-3 ', 5 '), 7.12 (s, 1H, H-8), 6.95 (s, 1H, H-3), 5.66(d,1H,H-1″),5.57(d,1H,sugar proton),5.43(d,1H,sugar proton),5.37(d,1H, sugarproton),5.24(s,2H,-CH2-),5.17(dd,2H,-CH2-),5.02(dd,2H,-CH2-),4.29(d,1H,H- 5″),3.53-3.40(m,3H,H-2″,3″,4″)。
Embodiment 2
Compound 3 is prepared into referring to the synthetic method of embodiment 1.Yellow powder, yield 41.9%, ESI-MS m/z 505.1[M+H]+。1H NMR(DMSO-d6, 400MHz) and δ: 12.94 (s, 1H, 5-OH), 8.06 (d, 2H, J=9.0Hz, H-2 ', 6 '), 7.15 (d, 2H, J=9.0Hz, H-3 ', 5 '), 7.09 (s, 1H, H-8), 6.96 (s, 1H, H-3), 5.61 (brs, 1H, H- 1″),5.50(d,1H,sugar proton),5.37(d,1H,sugar proton),5.33(d,1H,sugar proton), 4.21(d,1H,H-5″),3.87(s,3H,-OCH3),3.76(s,3H,-OCH3),3.66(s,3H,-OCH3),3.48-3.35 (m,3H,H-2″,3″,4″)。
Embodiment 3
Compound 2 (1g, 1.37mmol) in Example 1, is dissolved in methanol (80ml), is added dropwise sodium methoxide (2-3ml), Room temperature reaction is for 24 hours.Concentration, acid-water washing filter, and drying obtains yellow solid 838mg, yield 95.3%.ESI-MS m/z 643.2 [M+H]+。1H NMR(DMSO-d6, 400MHz) and δ: 12.98 (s, 1H, 5-OH), 8.05 (d, 2H, J=8.5Hz, H-2 ', 6 '), 7.56(d,2H,Ar-H),7.48(d,2H,Ar-H),7.41(t,2H,Ar-H),7.37(q,3H,Ar-H),7.32(t,1H,Ar- ), H 7.21 (d, 2H, J=8.7Hz, H-3 ', 5 '), 7.13 (s, 1H, H-8), 6.95 (s, 1H, H-3), 5.67 (d, 1H, H-1 "), 5.40(d,2H,sugar proton),5.22(s,2H,-CH2-),5.02(dd,2H,-CH2-),4.09(d,1H,H-5″), 3.48-3.42(m,3H,H-2″,3″,4″).
Embodiment 4
Compound 5 is prepared into referring to the synthetic method of embodiment 3.Yellow powder, yield 94.1%, ESI-MS m/z 491.1[M+H]+。1H NMR(DMSO-d6, 400MHz) and δ: 12.94 (s, 1H, 5-OH), 8.06 (d, 2H, J=9.0Hz, H-2 ', 6 '), 7.15 (d, 2H, J=9.0Hz, H-3 ', 5 '), 7.09 (s, 1H, H-8), 6.96 (s, 1H, H-3), 5.61 (brs, 1H, H- 1″),5.50(d,1H,sugar proton),5.37(d,1H,sugar proton),5.33(d,1H,sugar proton), 4.21(d,1H,H-5″),3.87(s,3H,-OCH3),3.76(s,3H,-OCH3),3.66(s,3H,-OCH3),3.48-3.35 (m,3H,H-2″,3″,4″)。
Embodiment 5
By 60g NaOH and 480mL H2The solution that O is made into pours into reaction flask, takes benzenethiol (75mL, 0.63mol), and Monoxone (78g, 0.825mol) is added afterwards, there are a large amount of white precipitates to be precipitated in reaction solution.6N HCl is added, obtains white solid benzene Sulphur acetic acid (7).7 (20g, 0.12mol) are dissolved in 90mL glacial acetic acid, 24.3mL 30%H is added2O2, it is stirred at room temperature.Wait react Completely, HNO is added348mL.Temperature reaction after 4h, there is white needle-like crystals precipitation, filters, dry 3,4- dibenzenesulfonyl Furoxan-based NO donors (9).Compound 9 (366mg, 1mmol) is dissolved in 10mL THF, NaH (24mg, 1.2mmol), ethyl alcohol are taken Amine (1mmol, 60 μ l) it is added in THF, in 0 DEG C of stirring 2h.TLC monitoring reaction stops reaction to fully reacting.By reaction solution It pours into 20ml distilled water, three times with the extraction of 20ml ethyl acetate, saturated common salt washing, then, filtering dry with anhydrous sodium sulfate, Concentration, obtains light yellow oil crude product 10a 235mg, yield: 82.4%.Without being further purified, it is directly used in next Step reaction.
Compound 4 (321mg, 0.5mmol) in embodiment 3 is placed in a reaction flask, is added DMF (5ml), stirring to change It closes object to be completely dissolved, HOBt (66mg, 0.6mmol), EDCI (144mg, 0.75mmol) and 10a (214mg, 0.75mmol) is added 2-3h is reacted at room temperature, TLC monitors reaction process, to which after reaction, reaction solution is poured into the mixture of ice and water of 30ml, uses 30ml ethyl acetate extracts 2-3 times, saturated common salt water washing, and anhydrous sodium sulfate is dry, filtering, is concentrated.Obtain yellowish crude product, warp Silica gel column chromatogram separating purification (methanol: methylene chloride=50:1), obtains buff powder 11a 241mg, yield 53.1%. ESI-MS m/z 910.2[M+H]+。1H NMR(DMSO-d6,400MHz)δ(ppm):12.95(s,1H,5-OH),8.23(t, 1H ,-NH-), 8.02 (d, 2H, J=8.9Hz, H-2 ', 6 '), 7.95 (d, 2H, Ar-H), 7.75 (t, 1H, Ar-H), 7.65 (d, 2H, Ar-H), 7.56 (d, 2H, Ar-H), 7.47 (d, 2H, Ar-H), 7.43-7.31 (m, 6H, Ar-H), 7.17 (d, 2H, J= 8.9Hz,H-3′,5′),7.12(s,1H,H-8),6.95(s,1H,H-3),5.65(brs,1H,H-1″),5.37-5.31(m, 3H,sugar proton),5.21(s,2H,-CH2-),5.10(dd,2H,-CH2-),4.43(t,2H,-CH2-),4.06(d, 1H,H-5″),3.62-3.52(m,3H,H-2″,3″,4″),3.44(t,2H,-CH2-)。
Embodiment 6
Referring to the synthetic method prepare compound 11b of embodiment 5.Yellow powder, yield 45.6%, ESI-MS m/z 924.2[M+H]+。1H NMR(DMSO-d6,400MHz)δ(ppm):12.97(s,1H,5-OH),8.19(t,1H,-NH-),8.05 (d, 2H, J=8.9Hz, H-2 ', 6 '), 7.98 (d, 2H, Ar-H), 7.81 (t, 1H, Ar-H), 7.69 (d, 2H, Ar-H), 7.56 (d, 2H, Ar-H), 7.47 (d, 2H, Ar-H), 7.40-7.35 (m, 6H, Ar-H), 7.18 (d, 2H, J=8.9Hz, H-3 ', 5 '), 7.07(s,1H,H-8),6.95(s,1H,H-3),5.64(brs,1H,H-1″),5.44-5.27(m,3H,sugar proton), 5.21(s,2H,-CH2-),5.02(dd,2H,-CH2-),4.34(t,2H,-CH2-),3.96(d,1H,H-5″),3.53-3.45 (m,3H,H-2″,3″,4″),3.24(dt,2H,-CH2-),1.90(m,2H,-CH2-)。
Embodiment 7
Referring to the synthetic method prepare compound 11c of embodiment 5.Yellow powder, yield 66.3%, ESI-MS m/z 924.1[M+H]+。1H NMR(DMSO-d6,400MHz)δ(ppm):12.96(s,1H,5-OH),8.23(t,1H,-NH-),8.05 (d, 2H, J=8.9Hz, H-2 ', 6 '), 7.97 (d, 2H, Ar-H), 7.77 (t, 1H, Ar-H), 7.68 (d, 2H, Ar-H), 7.57 (d, 2H, Ar-H), 7.48 (d, 2H, Ar-H), 7.43-7.33 (m, 6H, Ar-H), 7.18 (d, 2H, J=8.9Hz, H-3 ', 5 '), 7.06(s,1H,H-8),6.94(s,1H,H-3),5.65(d,1H,H-1″),5.42-5.27(m,3H,sugar proton), 5.21(s,2H,-CH2-),4.96(dd,2H,-CH2-),4.23(m,2H,-CH2-),4.03(d,1H,H-5″),3.61-3.50 (m,3H,H-2″,3″,4″),3.43(dt,2H,-CH2-),1.27(t,2H,-CH2-)。
Embodiment 8
Referring to the synthetic method prepare compound 12a of embodiment 5.Yellow powder, yield 13.2%, ESI-MS m/z 758.1[M+H]+。1H NMR(DMSO-d6,400MHz)δ(ppm):12.92(s,1H,5-OH),8.24(t,1H,-NH-),8.02 (d, 2H, J=9.0Hz, H-2 ', 6 '), 7.95 (d, 2H, Ar-H), 7.82 (t, 1H, Ar-H), 7.69 (d, 2H, Ar-H), 7.09 (d, 2H, J=9.0Hz, H-3 ', 5 '), 7.04 (s, 1H, H-8), 6.93 (s, 1H, H-3), 5.59 (d, 1H, J=5.0Hz, H- 1″),5.35(d,2H,sugar proton),5.30(t,2H,sugar proton),4.43(t,2H,-CH2-),4.02(d, 1H,H-5″),3.85(s,3H,-OCH3),3.76(s,3H,-OCH3),3.57-3.49(m,3H,H-2″,3″,4″),3.40(t, 2H,-CH2-)。
Embodiment 9
Referring to the synthetic method prepare compound 12b of embodiment 5.Yellow powder, yield 15.6%, ESI-MS m/z 772.1[M+H]+。1H NMR(DMSO-d6,400MHz)δ(ppm):12.96(s,1H,5-OH),8.36(t,1H,-NH-),8.05 (d, 2H, J=8.9Hz, H-2 ', 6 '), 7.98 (d, 2H, Ar-H), 7.84 (t, 1H, Ar-H), 7.69 (d, 2H, Ar-H), 7.10 (d, 2H, J=8.9Hz, H-3 ', 5 '), 7.06 (s, 1H, H-8), 6.95 (s, 1H, H-3), 5.70-5.51 (m, 4H, sugar proton),4.35(t,2H,-CH2-),3.94(d,1H,H-5″),3.84(s,3H,-OCH3),3.73(s,3H,-OCH3), 3.52-3.44(m,3H,H-2″,3″,4″),3.26(t,2H,-CH2-),1.90(t,2H,-CH2-)。
Embodiment 10
Referring to the synthetic method prepare compound 12c of embodiment 5.Yellow powder, yield 50.6%, ESI-MS m/z 772.1[M+H]+。1H NMR(DMSO-d6,400MHz)δ(ppm):12.92(s,1H,5-OH),8.23(t,1H,-NH-),8.05 (d, 2H, J=8.9Hz, H-2 ', 6 '), 7.97 (d, 2H, Ar-H), 7.83 (t, 1H, Ar-H), 7.69 (d, 2H, Ar-H), 7.09 (d, 2H, J=8.9Hz, H-3 ', 5 '), 7.03 (s, 1H, H-8), 6.95 (s, 1H, H-3), 5.60 (brs, 1H, sugar proton),5.35-5.51(m,3H,sugar proton),4.97(m,1H,-CH-),4.01(d,1H,H-5″),3.86(s, 3H,-OCH3),3.75(s,3H,-OCH3),3.59-3.50(m,3H,H-2″,3″,4″),3.42(t,2H,-CH2-),1.28(d, 3H,-CH3)。
Embodiment 11
Here is the pharmacological results of part of compounds of the present invention
Experimental facilities and reagent
Instrument superclean bench (safe and sound company, Su Jing group)
Constant incubator (Thermo electron Corporation)
Microplate reader (BIO-RAD company)
Inverted biologic microscope (Chongqing optical instrument factory)
Agent cell culture medium RPMI-1640, DMEM (high sugar) (GIBCO company)
Fetal calf serum (the Hangzhou four seasons clear Co., Ltd)
Methyl thiazoly tetrazolium assay (MTT) (Sigma Products)
DMSO (Sigma company)
Before cell strain human hepatoma cell strain HepG-2, MCF-7 cell strainHJ2mm, people
Column adenocarcinoma cell strain PC-3, human colon cancer cell strain HCT-116
Experimental method
Cell inhibitory activity experimental method
Cell is in 37 DEG C, 5%CO2Routine culture in the incubator of saturated humidity.Culture solution is containing 10% heat inactivation tire ox The RPMI1640 cell culture medium of serum, penicillin 100U/mL and streptomysin 100U/mL.48h replaces culture solution, and cell is adherent Afterwards, it is passed on 0.25% trypsin digestion.Experiment is in logarithmic growth phase with cell, and trypan exclusion stain shows that cell is living Power > 95%.
It takes in good condition one bottle of cell of logarithmic growth phase, digestive juice (0.125% trypsase+0.01% is added EDTA it) digests, counts 2~4 × 104Cell suspension inoculation is made on 96 orifice plates in cell/mL, and constant temperature CO is set in 100 holes μ L/2Training It supports and is cultivated 24 hours in case.Liquid is changed, test medicine is added, 100 holes μ L/ are cultivated 72 hours.MTT is added in 96 orifice plates, 50 μ The hole L/ is incubated for 4 hours in incubator.Supernatant is sucked, adds DMSO, 200 holes μ L/ are shaken 10 minutes on plate shaker.Tested material 7 concentration (50 μM, 25 μM, 12.5 μM, 6.25 μM, 3.13 μM, 1.56,0.78 μM) are investigated, with enzyme linked immunological monitor in wave The absorbance that every hole is measured at a length of 570nm, calculates separately the cell inhibitory rate under each concentration.Inhibiting rate calculation method:
Susceptibility hole is with respect to the absolute absolute OD value of OD value ﹣ blank control wells in OD value=susceptibility hole
Experimental result
IC of 1 embodiment of table to 4 kinds of human cancer cell's strain antiproliferative activities50It is worth (μM)

Claims (13)

1. furazan NO donator type scutellarin derivative and its pharmaceutically acceptable salt shown in general formula I:
Wherein, R is substituted or unsubstituted C1-C12Alkyl, substituted or unsubstituted benzyl, the substituent group are as follows: C1-C4Alkane Base, C1-C4Alkoxy；R1For substituted or unsubstituted C1-C12Alkylidene, the substituent group are as follows: C1-C4Alkyl, C1-C4Alcoxyl Base.
2. furazan NO donator type scutellarin derivative shown in general formula I described in claim 1 and its pharmaceutically acceptable Salt:
Wherein, R is substituted or unsubstituted C1-C6Alkyl, substituted or unsubstituted benzyl, the substituent group are C1-C4Alkyl, C1-C4Alkoxy；R1For substituted or unsubstituted C1-C6Alkylidene, the substituent group are as follows: C1-C4Alkyl, C1-C4Alkoxy.
3. furazan NO donator type scutellarin derivative shown in general formula I of any of claims 1 or 2 and its pharmaceutically acceptable Salt:
Wherein, R is methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group or benzyl.
4. furazan NO donator type scutellarin derivative shown in general formula I as claimed in claim 1 or 2 and its can pharmaceutically connect The salt received:
Wherein, R is methyl or benzyl.
5. furazan NO donator type scutellarin derivative and its pharmacy shown in general formula I described in claim 1-2 any one Upper acceptable salt:
Wherein, R1For-(CH2)2-、-(CH2)3-、-CH2CH(CH3)-、-(CH2)4-、-CH2CH(CH3)CH2-、-CH2CH2CH (CH3)-or-(CH2)5-。
6. furazan NO donator type scutellarin derivative shown in general formula I as claimed in claim 3 and its pharmaceutically acceptable Salt:
Wherein, R1For-(CH2)2-、-(CH2)3-、-CH2CH(CH3)-、-(CH2)4-、-CH2CH(CH3)CH2-、-CH2CH2CH (CH3)-or-(CH2)5-。
7. furazan NO donator type scutellarin derivative shown in general formula I as claimed in claim 4 and its pharmaceutically acceptable Salt:
Wherein, R1For-(CH2)2-、-(CH2)3-、-CH2CH(CH3)-、-(CH2)4-、-CH2CH(CH3)CH2-、-CH2CH2CH (CH3)-or-(CH2)5-。
8. furazan NO donator type scutellarin derivative and its pharmaceutically acceptable salt, are selected from:
9. a kind of pharmaceutical composition, wherein furazan NO donor described in the claim 1-8 any one containing therapeutically effective amount Type scutellarin derivative and its pharmaceutically acceptable salt and pharmaceutically acceptable carrier.
10. the preparation of furazan NO donator type scutellarin derivative as claimed in claim 8 and its pharmaceutically acceptable salt Method, which is characterized in that
Scutellarin 1 is in K2CO3With halohydrocarbons reaction under the conditions of/DMF, intermediate 2,3 is obtained, intermediate 2,3 is KOH/MeOH's Under the conditions of hydrolysis obtain target compound 4,5；
Benzenethiol 6 is reacted to obtain to benzene sulphur acetic acid 7 under alkaline condition with monoxone, then through 30%H2O2Oxidation generates benzene sulfonyl Acetic acid 8, compound 8 is in smoke HNO3In the presence of heating cyclization at 3,4- dibenzenesulfonyl furoxan-based NO donors 9, compound 9 exists Under conditions of NaH catalysis, target compound 10a-c is generated using THF as reaction dissolvent from different hydramine reactions；
The sugared carboxyl site and amido alcohol of compound 4,5, which replace, generates single benzenesulfonyl furoxan-based NO donors class NO compound donator 10a-c reaction under conditions of HOBt, EDCI catalysis is condensed to obtain target compound 11a-c and 12a-c；
11. furazan NO donator type scutellarin derivative described in claim 1-8 any one and its pharmaceutically acceptable Application of the salt in the drug of preparation treatment tumor disease.
12. application of the pharmaceutical composition as claimed in claim 9 in the drug of preparation treatment tumor disease.
13. the application as described in claim 11 or 12, which is characterized in that the tumour is breast cancer, colon cancer, prostate Cancer or liver cancer.
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