CN104418883A - Curcumin phosphate compound and preparation method and application thereof - Google Patents
Curcumin phosphate compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a curcumin phosphate compound, a preparation method and an application thereof. The compound is obtained by a phosphorylation reaction with curcumin as a starting material. In vitro experiment research shows that the compound has good anti-tumor, anti-inflammatory and anti-Alzheimer's disease effects, and has good application prospects in the medicine field.
Description
Technical field
The present invention relates to a kind of curcumine phosphate compounds and preparation method thereof, belong to medicinal chemistry art.
Background technology
Curcumine (Curcumin, 1,7-bis-(4-hydroxy-3-methoxy) phenyl-1,6-heptadiene-3,5-diketone) be the effective constituent extracted from the rhizome of Zingiber curcuma turmeric, curcuma zedoary and root tuber of aromatic turmeric etc., for orange-yellow crystalline powder, water insoluble and ether, be dissolved in ethanol, acetone, Glacial acetic acid and ethylene glycol, in light yellow under acidity and neutrallty condition, in the basic conditions in sorrel, can with many kinds of metal ions chelating and variable color, its structural formula is as follows:
Turmeric is the medicinal herbs most in use simply in traditional Chinese medicine, is mainly used in brokenly blood gas, inducing meastruation to relieve menalgia.Recent study shows, curcumine has reducing blood-fat, antitumor, anti-inflammatory, cholagogic and the effect such as anti-oxidant, and wherein, its antitumor action is especially noticeable.First the Kuttan of India in 1985 proposes the possibility that curcumine has antitumor action, and later countries in the world scholar has conducted intensive studies the antitumor action of curcumine and mechanism.Multiple in vitro and in vivo research shows: curcumine effectively can suppress the tumour at multiple positions such as mammary gland, gi tract, liver, pancreas, colon, bladder, kidney, prostate gland, uterus, ovary, lung, oral cavity and skin.In addition, curcumine also shows good restraining effect to hematological system tumors such as leukemia, lymphoma and multiple myelomas.It is generally acknowledged the P4501A1 of curcumine by T suppression cell cytochrome p 450 enzyme system, suppress tyrosine kinase activity, suppress vascular endothelial growth factor (VEDGF), suppress Prostatropin (b-FGF), suppress telomerase activity, reduce the expression of MMP-2 (MMP-2), improve the expression of tissue inhibitor of metalloproteinase (TIMP-I), block the growth of the number of ways inhibition tumor cells such as the activity of nf-KB and transcription factor AP-1, national cancer institute has been classified as third generation cancer chemoprevention medicine, and entered III phase clinical trial.
Except having good antitumor action, curcumine also has the effect of prevention and therapy Alzheimer's disease.Modern study is verified, and in brain, amyloid beta gathers in a large number is the one of the main reasons that Alzheimer's disease is fallen ill.The experimentation on animals display of Duke Univ USA, the curcumine in curry can not only make the IC amyloid beta of experimental mouse decompose, and can also prevent the generation of this albumen.This achievement in research is that the research of anti-Alzheimer disease drug provides new thinking, the focus simultaneously also making the research of curcumine become new.
Although curcumine has multiple biological activity, curcumine character is unstable, poorly water-soluble, and internal metabolism speed is fast, thus causes its bioavailability low, limits it in clinical application.In order to find, biological activity is good, toxic side effect is low, pharmacokinetic property more reasonably compound, comprehensive and systematic structure of modification has been carried out to curcumine in countries in the world, mainly comprise change the replacement kind of phenyl ring and position, reduction unsaturated double-bond, change in the middle of unsaturated conjugated chain length, beta-diketon changed into single ketones or form imines and oxime, 4 active methylene group replacements etc.Although synthesized large quantization compound, but still there is no satisfied result.Although the biological activity of some compound increases, but toxic side effect also increases thereupon, consider security and validity, also do not find the compound being better than curcumine, therefore finding new decorating site and synthesizing new curcumin derivate simultaneously, also should consider to carry out texture improvement by new thinking to curcumine.
Prodrug refers to that non-activity own or activity are very low, discharges former medicine in vivo and produce bioactive compound after activation.Prodrug design is carrier molecule on the optimum moiety of former medicine, and this bonding process requires easy and efficient synthesis, can discharge former medicine fast in vivo, require that carrier can not have any toxic side effect in prodrug design through hydrolysis or enzymic catalytic reaction.Phosphate is present in human body in a large number as the integral part of nucleic acid, is a kind of harmless endogenous material, and when medicine becomes after ester with phosphate, the fat-soluble medicine that is conducive to improving medicine is entered in cell by cytolemma.
Summary of the invention
In view of the defect that above-mentioned prior art exists, first object of the present invention is to provide a kind of curcumine phosphate compounds, and this object is achieved through the following technical solutions.
A kind of curcumine phosphate compounds, its structure is as shown in formula I:
；
Wherein, R is selected from H
+, Na
+, K
+, NH
4 +, Li
+, phenyl, furyl, thienyl, pyrryl, pyridyl, there is the straight-chain paraffin base of 1 ~ 20 carbon atom, there is the branched alkane alkyl of 1 ~ 20 carbon atom, the group that there is the hydrogen on the straight-chain paraffin base of 1 ~ 20 carbon atom and formed is replaced by phenyl ring or naphthalene nucleus, the group that there is the hydrogen on the branched alkane alkyl of 1 ~ 20 carbon atom and formed is replaced by phenyl ring or naphthalene nucleus, by five yuan or hexa-atomic fragrant heterocyclic substituted, there is the group that the hydrogen on the straight-chain paraffin base of 1 ~ 20 carbon atom formed, by five yuan or hexa-atomic fragrant heterocyclic substituted, there is the group that the hydrogen on the branched alkane alkyl of 1 ~ 20 carbon atom formed.
Preferably, described R is selected from has 1, the straight-chain paraffin base of 2 ~ 16 carbon atoms, have 1, the branched alkane alkyl of 2 ~ 16 carbon atoms, the group that there is the hydrogen on the straight-chain paraffin base of 1 ~ 10 carbon atom and formed is replaced by phenyl ring or naphthalene nucleus, the group that there is the hydrogen on the branched alkane alkyl of 1 ~ 10 carbon atom and formed is replaced by phenyl ring or naphthalene nucleus, by five yuan or hexa-atomic fragrant heterocyclic substituted, there is the group that the hydrogen on the straight-chain paraffin base of 1 ~ 10 carbon atom formed, by five yuan or hexa-atomic fragrant heterocyclic substituted, there is the group that the hydrogen on the branched alkane alkyl of 1 ~ 10 carbon atom formed.
Described five yuan or hexa-atomic fragrant heterocycles are furan nucleus, thiphene ring, pyrrole ring or pyridine ring.
Preferred further, described R is selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, n-pentyl, isopentyl, neo-pentyl, hexyl, heptyl, octyl group, Ren Ji, decyl, dodecyl, hexadecyl, eicosyl, phenmethyl, styroyl, hydrocinnamyl, benzene butyl, furfuryl, furylethyl, furans propyl group, furans butyl, furans amyl group, thenyl, thienylethyl, thiophene propyl group, thiophene butyl, thiophene amyl group, pyrrolylmethyl, pyrrolylethyl, pyrroles's propyl group, pyrroles's butyl, pyrroles's amyl group, picolyl, pyridine ethyl, pyridylpropyl, pyridine butyl.
Above-mentioned curcumine phosphate compounds, is specifically selected from compound shown in following structural formula cur-1, cur-2, cur-3, cur-4, cur-5, cur-6, cur-7, cur-8, cur-9, cur-10:
Chemical name: two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane diene-1-in heptan-1,6-base)-2-methoxyphenyl) phosphoric acid ester;
Chemical name: two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane diene-1-in heptan-1,6-base)-2-methoxyphenyl) sodium phosphate;
Chemical name: two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane diene-1-in heptan-1,6-base)-2-methoxyphenyl)-1-ethyl phosphonic acid ester;
Chemical name: two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane diene-1-in heptan-1,6-base)-2-methoxyphenyl)-2-propyl phosphate;
Chemical name: two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane diene-1-in heptan-1,6-base)-2-methoxyphenyl)-1-pentyl;
Chemical name: two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane diene-1-in heptan-1,6-base)-2-methoxyphenyl)-1-decylphosphonic acid ester;
Chemical name: two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane diene-1-in heptan-1,6-base)-2-methoxyphenyl)-1-dodecyl base phosphoric acid ester;
Chemical name: two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane diene-1-in heptan-1,6-base)-2-methoxyphenyl)-1-hexadecyl base phosphoric acid ester;
Chemical name: two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane diene-1-in heptan-1,6-base)-2-methoxyphenyl) styroyl phosphoric acid ester;
Chemical name: 3-(furans-3-base) propyl group-two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane diene-1-in heptan-1,6-base)-2-methoxyphenyl) phosphoric acid ester.
Second object of the present invention is the preparation method providing above-mentioned curcumine phosphate compounds, adopts following technical scheme:
The preparation method of above-mentioned curcumine phosphate compounds, is characterized in that comprising the steps:
A () phosphorus oxychloride and alcohol are obtained by reacting either dichlorophosphate:
Solvent for use is ether or tetrahydrofuran (THF), and adds alkali in solvent, and described alkali is triethylamine or diisopropyl ethyl amine, and alkali is 1 ~ 4: 1 with the amount of substance ratio of alcohol, and temperature of reaction is 0 DEG C ~ 30 DEG C;
B () either dichlorophosphate and curcumine obtain described curcumine phosphate compounds through acylation reaction:
Solvent for use is methylene dichloride or trichloromethane, and adds alkali in solvent, and described alkali is triethylamine or diisopropyl ethyl amine, and alkali is 1 ~ 4: 1 with the amount of substance ratio of either dichlorophosphate, and temperature of reaction is 0 DEG C ~ 50 DEG C;
In above-mentioned (a) (b), R is not H
+, Na
+, K
+, NH
4 +and Li
+;
When R is H
+, Na
+, K
+, NH
4 +, Li
+a period of time is that raw material obtains through above-mentioned (a) (b) with methyl alcohol:
Then the two curcumin ester of phosphoric acid is obtained with bromotrimethylsilane demethylation; React with sodium hydroxide, potassium hydroxide, ammoniacal liquor and lithium hydroxide again and namely obtain respective objects compound.
Or the another kind of preparation method of above-mentioned curcumine phosphate compounds, is characterized in that comprising the steps:
A () alcohol and phosphorus trichloride are obtained by reacting phosphorodichloridites:
Solvent for use is ether or tetrahydrofuran (THF), and adds alkali in solvent, and described alkali is triethylamine or diisopropyl ethyl amine, and alkali is 1 ~ 4: 1 with the amount of substance ratio of alcohol, and temperature of reaction is-50 DEG C ~ 30 DEG C;
B () phosphorodichloridites and curcumine are obtained by reacting curcumine phosphorous acid ester:
Solvent for use is methylene dichloride or trichloromethane, and adds alkali in solvent, and described alkali is triethylamine or diisopropyl ethyl amine, and alkali is 1 ~ 4: 1 with the amount of substance ratio of phosphorodichloridites, and temperature of reaction is 0 DEG C ~ 50 DEG C;
C () curcumine phosphorous acid ester obtains curcumine phosphate compounds through metachloroperbenzoic acid oxidation:
The temperature of reaction is-20 DEG C ~ 10 DEG C, and the amount of substance of metachloroperbenzoic acid is 1 ~ 4 times of phosphorodichloridites;
In above-mentioned (a) (b) (c), R is not H
+, Na
+, K
+, NH
4 +and Li
+;
When R is H
+, Na
+, K
+, NH
4 +, Li
+a period of time is that raw material obtains through above-mentioned (a) (b) (c) with methyl alcohol:
Then the two curcumin ester of phosphoric acid is obtained with bromotrimethylsilane demethylation; React with sodium hydroxide, potassium hydroxide, ammoniacal liquor and lithium hydroxide again and namely obtain respective objects compound.
3rd object of the present invention is to provide above-mentioned curcumine phosphate compounds preparing the application in anti-breast cancer, anti-lung cancer, inhibitor against colon carcinoma cells, anti-liver cancer, anti-inflammatory, anti-Alzheimer disease medicine.Above-claimed cpd has obvious anti-breast cancer, anti-lung cancer, inhibitor against colon carcinoma cells, anti-liver cancer, anti-inflammatory, anti-Alzheimer disease effect, may be used for preparing anti-breast cancer, anti-lung cancer, inhibitor against colon carcinoma cells, anti-liver cancer, anti-inflammatory, anti-Alzheimer disease medicine.
Anticancer experiment in vitro shows, curcumine phosphate compounds of the present invention is to human liver cancer cell HepG2, human breast cancer cell line Bcap-37, human colon cancer cell HCT-116, human lung cancer cell A549 all shows obvious restraining effect, wherein, two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3, 5-dicarbapentaborane heptan-1, 6-diene-1-base)-2-methoxyphenyl) phosphoric acid ester (cur-1), two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3, 5-dicarbapentaborane heptan-1, 6-diene-1-base)-2-methoxyphenyl) sodium phosphate (cur-2), two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3, 5-dicarbapentaborane heptan-1, 6-diene-1-base)-2-methoxyphenyl)-1-pentyl (cur-5) shows stronger restraining effect to human hepatoma cell HepG2,
Two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane diene-1-in heptan-1,6-base)-2-methoxyphenyl)-2-propyl phosphate (cur-4) is suitable with cis-platinum with curcumine to the restraining effect of Human Lung Cancer cell A549; Two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane diene-1-in heptan-1,6-base)-2-methoxyphenyl)-1-pentyl (cur-5) is to the level of the restraining effect of human breast cancer cell MCF-7 close to cis-platinum; And two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane heptan-1,6-diene-1-base)-2-methoxyphenyl) phosphoric acid ester (cur-1), two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane heptan-1,6-diene-1-base)-2-methoxyphenyl) sodium phosphate (cur-2), two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane diene-1-in heptan-1,6-base)-2-methoxyphenyl)-1-decylphosphonic acid ester (cur-6),
Two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane heptan-1,6-diene-1-base)-2-methoxyphenyl)-1-1-isobutyl-3,5-dimethylhexylphosphoric acid (cur-7) and two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3,5-dicarbapentaborane heptan-1,6-diene-1-base)-2-methoxyphenyl)-1-hexadecanyl phosphate (cur-8) shows very high inhibition effect to human colon cancer cell HCT-116, to be better than or suitable with cis-platinum.
In vitro in anti-inflammatory activity evaluation test, the mice ear that curcumine phosphate compounds p-Xylol of the present invention causes show with curcumine quite or stronger anti-inflammatory activity, wherein, two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3, 5-dicarbapentaborane heptan-1, 6-diene-1-base)-2-methoxyphenyl) phosphoric acid ester (cur-1), two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3, 5-dicarbapentaborane heptan-1, 6-diene-1-base)-2-methoxyphenyl) sodium phosphate (cur-2), two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3, 5-dicarbapentaborane heptan-1, 6-diene-1-base)-2-methoxyphenyl) styroyl phosphoric acid ester (cur-9) and two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3, 5-dicarbapentaborane heptan-1, 6-diene-1-base)-2-methoxyphenyl)-1-decylphosphonic acid ester (cur-6) shows very strong anti-inflammatory activity, there is the value of exploitation further.
Anti-acetylcholinesterase induction A β (1-40) is assembled in Inhibition test in vitro, curcumine phosphate compounds of the present invention demonstrates obviously stronger than curcumine restraining effect to A β (1-40) gathering that AchE induces, wherein two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3, 5-dicarbapentaborane heptan-1, 6-diene-1-base)-2-methoxyphenyl) styroyl phosphoric acid ester (cur-9), two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3, 5-dicarbapentaborane heptan-1, 6-diene-1-base)-2-methoxyphenyl)-1-decylphosphonic acid ester (cur-6) and 3-(furans-3-base) propyl group-two (4-((1E, 6E)-7-(4-hydroxyl-3-methoxyphenyl)-3, 5-dicarbapentaborane heptan-1, 6-diene-1-base)-2-methoxyphenyl) phosphoric acid ester (cur-10) to the restraining effect of acetylcholinesterase close to the single-minded inhibitor propidium iodide acting on acetylcholinesterase, illustrate that this kind of compound has good potential applicability in clinical practice in advance.
In sum, curcumine phosphate compounds of the present invention has the effect of good antitumor, anti-inflammatory and anti-Alzheimer disease, compared with the antitumor of current Clinical practice and other corresponding medicines, curcumine has low-down toxicity, in early stage toxicity test, have no overt toxicity to SD Oral Administration in Rats curcumine 5g/kg; In the clinical experiment of I phase, 25 experimenter's administration every day 8g curcumines have no the report of toxic side effect, and therefore curcumine is that a class biological activity is good, and the compound that toxic side effect is low has good application and development prospect.
Embodiment
Below by the synthesis of following curcumine phosphate compounds and biological assessment, the invention will be further described, but following embodiment should not be construed as limitation of the present invention.
In following examples, fusing point adopts Fisher-John micro-meldometer to measure (temperature is not calibrated); NMR (Nuclear Magnetic Resonance) spectrum adopts Bruker Avance 400 nmr determination, TMS(tetramethylsilane) be interior mark; LC-MS(liquid chromatograph-mass spectrometer) data acquisition Varian MS 500 measures, GC-MS(gas chromatograph-mass spectrometer) data acquisition Thermo Fisher DSQ-GC MS measures, uv-absorbing adopts NanoDrop 2000/2000c ultraviolet-visible spectrophotometer to measure, fluorescent absorption adopts Lumina fluorescent spectrophotometer measuring, and agents useful for same is analytical reagent.
the synthesis of embodiment 1 cur-1
Adopt document (Journal of Fluorine Chemistry, 2001,109,103-111) described method to prepare dichloro methyl orthophosphoric acid, concrete grammar is as follows:
By methyl alcohol 8g(0.25mol) and triethylamine 25.3g(0.25mol) be dissolved in 250mL tetrahydrofuran (THF) and obtain mixing solutions, mixing solutions is under agitation dropwise added phosphorus oxychloride 58g(0.38mol in 0 DEG C ~ 5 DEG C) tetrahydrofuran solution in, dropwise, rise to 25 DEG C of reaction 15h gradually; React complete, crossed by product and filter precipitation, filtrate reduced in volume obtains crude product, and crude product underpressure distillation obtains pale yellowish oil liquid 26.5g, yield 71.6%.
1H NMR(400MHz, CDCl
3) δ：4.212(s, 3H)；GC-MS m/z：148(M
+)。
By curcumine 0.74g(0.02mol) and triethylamine 4g(0.04mol) be dissolved in the CHCl of 100mL
3in obtain mixing solutions, mixing solutions is dropwise added dichloro methyl orthophosphoric acid 1.49g(0.01mol at 0 DEG C ~ 5 DEG C) CHCl
3in solution, slowly rise to 25 DEG C of reaction 20h, stopped reaction, washing, anhydrous Na
2sO
4dry; Cross and filter Na
2sO
4, filtrate reduced in volume obtains yellow powder, and yellow powder obtains yellow powdery solid 5.85g through column chromatography (sherwood oil: ethyl acetate=20: 1, volume ratio), and yield is 72.1%.m.p:90～92℃；
1H NMR(400MHz, CDCl
3) δ：7.611(t, 2H), 7.330 (d, 1H), 7.141-7.069(m, 4H), 6.941(d, 1H), 6.526(t, 2H), 5.845(s, 1H), 4.225(t, 4H), 3.966(s, 3H), 3.927(s,3H), 1.421(t, 6H)；MS（ESI）m/z：813（M+H）。
By two curcumine methyl orthophosphoric acid 1.624g(2mmol) be dissolved in 15mL dioxane, bromotrimethylsilane 0.918g(6mmol is dropwise added) under stirring, dropwise and react 4h under room temperature, stopped reaction, solvent evaporate to dryness is obtained yellow powdery solid 1.532g by decompression, yield 96.1%, structural formula is as shown in aforementioned cur-1.m.p:198-200℃；
1H NMR(400MHz, CDCl
3) δ：7.611(t, 2H), 7.330 (d, 1H), 7.141-7.069(m, 4H), 6.941(d, 1H), 6.526(t, 2H), 5.845(s, 1H), 3.966(s, 3H), 3.927(s,3H)；MS（ESI）m/z：799（M+H）。
the synthesis of embodiment 2 cur-2
Cur-11.99g(2.5mmol by embodiment 1 prepares) to be dissolved in the methanol solution obtaining cur-1 in 20mL anhydrous methanol and to be down to 0 DEG C, by 0.1g(2.5mmol) NaOH is dissolved in 1mL water and obtains the NaOH aqueous solution, the NaOH aqueous solution to be dropwise added dropwise in the methanol solution of cur-1 in 0-5 DEG C and to obtain product in this thermotonus 30min, product at reduced pressure solvent evaporated is obtained yellow powdery solid 1.91g, yield is 93.2%, structural formula as shown in aforementioned cur-2, m.p>250 DEG C.
the synthesis of embodiment 3 cur-3
By ethanol 4.6g(0.1mol) and diisopropyl ethyl amine 12.9g(0.1mol) be dissolved in 50mL ether and obtain mixing solutions 1, by phosphorus trichloride 9ml(0.1mmol) add 50mL ether and obtain the diethyl ether solution of phosphorus trichloride and be cooled to-40 DEG C,-40 DEG C are kept will to be slowly added dropwise to the diethyl ether solution of phosphorus trichloride in mixing solutions 1, dropwise in-40 DEG C of reaction 15min, then be slowly warming up to 30 DEG C, and continuation reaction 30min obtains product; By the solvent under reduced pressure evaporate to dryness in product, then underpressure distillation obtains dichloro phosphorous acid ethyl ester 13.5g, and yield is 84%.
1H NMR(400MHz, CDCl
3) δ：4.443（t, 2H）, 1.382 (t,3H)；GC-MS m/z：147(M
+)。
By dichloro phosphorous acid ethyl ester 3.67g(0.025mol) and triethylamine 10.1g(0.1mol) be dissolved in 50mL CH
2cl
2in obtain mixing solutions 2, and be down to 0 DEG C; By curcumine 23g(0.063mol) be dissolved in the CH of 100mL
2cl
2in obtain the CH of curcumine
2cl
2solution, at 0 DEG C ~ 5 DEG C dropwise by the CH of curcumine
2cl
2in solution instillation mixing solutions 2, dropwise in 0 DEG C ~ 5 DEG C reaction 6h, obtain mixing solutions 3; Cool the temperature to-20 DEG C, m-chloroperoxybenzoic acid 0.1mol added in mixing solutions 3 in batches, and in-20 DEG C continue reaction 1h, stopped reaction, reaction solution 10%(mass percent) Na
2s
2o
3solution washing, then uses anhydrous Na
2sO
4dried overnight; Finally cross and filter anhydrous Na
2sO
4, concentrating under reduced pressure obtains yellow oil, and yellow oil obtains yellow powdery solid 14.6g through column chromatography (sherwood oil: ethyl acetate=30: 1, volume ratio), and yield 64.5%, structural formula is as shown in aforementioned cur-3.m.p:105~106℃；
1H NMR(400MHz, CDCl
3) δ：7.594(t, 4H), 7.327(d, 2H), 7.114-7.041(m,8H), 6.905(d, 2H), 6.545-6.476(m, 4H), 5.832(s, 2H), 4.364(t, 2H), 3.935(s, 6H), 3.879(s, 6H), 1.251(t, 3H)；MS（ESI）m/z：827 (M+H)。。
the synthesis of embodiment 4 cur-4
Adopt document (Journal of Organic Chemistry, 2011,76 (10), 3782-3790) described method to prepare dichloro p isopropylbenzoic acid ester, concrete grammar is as follows:
By Virahol 24g(0.4mol) and diisopropyl ethyl amine 206g(1.6mol) be dissolved in 500mL anhydrous diethyl ether and obtain mixing solutions 1, mixing solutions 1 is under agitation dropwise added phosphorus oxychloride 91.8g(0.6mol in 0 DEG C ~ 5 DEG C) diethyl ether solution in, dropwise, be warming up to 30 DEG C of reaction 14h gradually, react complete, crossed by the product obtained and filter precipitation, filtrate concentrates to obtain crude product, crude product underpressure distillation obtains dichloro p isopropylbenzoic acid ester 43g, yield 61.4%.
1H NMR(400MHz, CDCl
3) δ：5.041(t, 1H)，1.493(d, 6H)；GC-MS m/z：177(M
+)。
By curcumine 18.4g(0.05mol) and diisopropyl ethyl amine 2.58g(0.02mol) be dissolved in the CHCl of 200mL
3in obtain mixing solutions 2, mixing solutions 2 is dropwise added dichloro p isopropylbenzoic acid ester 3.54g(0.02mol at 0 DEG C ~ 5 DEG C) CHCl
3in solution, dropwise, be warming up to 50 DEG C of reaction 10h gradually, obtain product to filter, removing precipitation, filtrate decompression evaporate to dryness obtains yellow oily liquid, yellow oily liquid is through column chromatography (sherwood oil: ethyl acetate=10: 1, volume ratio) obtain yellow powdery solid 8.1g, yield 46.2%, structural formula is as shown in aforementioned cur-4.m.p:116~118℃；
1H NMR(400MHz, CDCl
3) δ：7.618(t, 4H), 7.338(d, 2H), 7.116-7.029(m,8H), 6.912(d, 2H), 6.55-6.476(m, 4H), 5.035(t, 1H), 3.898(s, 6H), 3.869(s, 6H), 1.482(d, 6H)；MS（ESI）m/z：841(M+H)。
the synthesis of embodiment 5 cur-5
By Pentyl alcohol 35.2g(0.4mol) and triethylamine 60.6g(0.6mol) be dissolved in 500mL anhydrous diethyl ether and obtain mixing solutions 1, mixing solutions 1 is stirred down and dropwise adds phosphorus oxychloride 91.8g(0.6mol in 0 DEG C ~ 5 DEG C) diethyl ether solution in, dropwise, rise to 20 DEG C of reaction 18h gradually, react complete, the product obtained is filtered, removing precipitation, filtrate concentrates to obtain crude product, and crude product underpressure distillation obtains dichloro phosphoric acid pentyl ester 55.9g, yield 68.2%.
1H NMR(400MHz, CDCl
3) δ：4.452(t, 2H)，1.563(m,2H),1.352（m,2H），1.321（m,2H），0.911（t,3H）；GC-MS m/z：205(M
+)。
Curcumine 18.4g(0.05mol) and triethylamine 4.04g(0.04mol) be dissolved in the CH of 200mL
2cl
2in obtain mixing solutions 2, mixing solutions 2 is dropwise added dichloro phosphoric acid pentyl ester 4.1g(0.02mol at 0 DEG C ~ 5 DEG C) CH
2cl
2in solution, dropwise, rise to room temperature gradually and in room temperature reaction 13h, the product obtained filters, removing precipitation, and filtrate decompression evaporate to dryness obtains yellow oily liquid, yellow oily liquid is through column chromatography (sherwood oil: ethyl acetate=10: 1, volume ratio) obtain yellow powdery solid 9.1g, yield is 52.4%, and structural formula is as shown in aforementioned cur-5.m.p:124～126℃；
1H NMR(400MHz, CDCl
3) δ：7.624 (t, 4H), 7.344 (d, 2H), 7.118-7.043(m,8H), 6.914(d, 2H), 6.546-6.479(m, 4H), 4.446(t, 2H), 3.935(s, 6H), 3.879(s, 6H), 1.543(m,2H),1.356(m, 2H),1.323(m,2H), 0.910 (t,3H)；MS（ESI）m/z：869(M+H)。
the synthesis of embodiment 6 cur-6, cur-7 and cur-8
By nonylcarbinol 31.6g(0.2mol) and triethylamine 30.3g(0.3mol) be dissolved in 400mL anhydrous diethyl ether, obtain mixing solutions 1, mixing solutions 1 is under agitation dropwise added phosphorus oxychloride 46g(0.3mol in 0 DEG C ~ 5 DEG C) diethyl ether solution in, dropwise, rise to gradually 28 DEG C reaction 24h, react complete, filtered by the product obtained, removing precipitation, filtrate concentrates to obtain crude product, crude product underpressure distillation obtains dichloro phosphoric acid ester in last of the ten Heavenly stems 55.9g, and yield is 68.2%.
1H NMR(400MHz, CDCl
3) δ：4.457(t, 2H)，1.563-1.262(m, 16H), 0.891（t,3H）；GC-MS m/z：275(M
+)。
By curcumine 0.03mol and triethylamine 1.01g(0.02mol) be dissolved in the CH of 100mL
2cl
2in, obtain mixing solutions 2, mixing solutions 2 dropwise added dichloro phosphoric acid ester in last of the ten Heavenly stems 5.5g(0.01mol at 0 DEG C ~ 5 DEG C) CH
2cl
2in solution, dropwise, be warming up to 40 DEG C of reaction 20h gradually, the product obtained filters, removing precipitation, and filtrate decompression evaporate to dryness obtains yellow oily liquid, yellow oily liquid is through column chromatography (sherwood oil: ethyl acetate=15: 1, volume ratio) obtain yellow powdery solid 6.53g, yield is 34.8%, and structural formula is as shown in aforementioned cur-6.m.p:141~143℃；
1H NMR(400MHz, CDCl
3) δ：7.615-7.568(m, 4H), 7.336(d, 2H), 7.085-7.003(m,8H), 6.925(d, 2H), 6.525(t, 4H), 5.810(s, 2H), 4.348(t, 2H), 3.925(s, 6H), 3.876(s, 6H), 1.545-1.271(m,16H), 0.894 (t,3H)；MS（ESI）m/z：962(M+Na)。
Nonylcarbinol is changed into dodecyl alcohol same method and can obtain aforementioned cur-7, yield is 33.5%; Nonylcarbinol is changed into n-hexadecyl alcohol same method and can obtain aforementioned cur-8, yield is 32.1%.
The experimental data of cur-7 is as follows:
m.p:132~133℃；
1H NMR(400MHz, CDCl
3) δ：7.649-7.593(m, 4H), 7.356(d, 2H), 7.145-7.076(m,8H), 6.959(d, 2H), 6.584-60499(m, 4H), 5.850(s,2H), 4.363(t, 2H), 3.975(s, 6H), 3.894(s, 6H), 1.768(t, 2H), 1.392(t, 2H), 1.325-1.271(m,16H), 0.892 (t,3H)；MS（ESI）m/z：967(M+1)。
The experimental data of cur-8 is as follows:
m.p:148~150℃；
1H NMR(400MHz, CDCl
3) δ：7.598-7.521(m, 4H), 7.315 (d, 2H), 7.085-7.007(m,8H), 6.870(d, 2H), 6.483(t, 4H), 5.810(s,2H), 4.357(t, 2H), 3.898(s, 6H), 3.858(s, 6H), 1.759（t, 2H）, 1.382(t, 2H), 1.296-1.257(m, 24H), 0.881 (t,3H)；MS（ESI）m/z：1046(M+Na)。
the synthesis of embodiment 7 cur-9
By phenylethyl alcohol 24.4g(0.2mol) and triethylamine 50.5g(0.5mol) be dissolved in 400mL anhydrous diethyl ether, obtain mixing solutions 1, mixing solutions 1 is under agitation dropwise added phosphorus oxychloride 46g(0.3mol in 0 DEG C ~ 5 DEG C) diethyl ether solution in, dropwise, rise to room temperature gradually and react 20h under room temperature, react complete, filter, removing precipitation, filtrate concentrates to obtain crude product, crude product underpressure distillation obtains dichloro phosphoric acid phenylglycollic ester 55.9g, and yield is 70.1%.
1H NMR(400MHz, CDCl
3) δ：7.491（s,5H）4.854(t, 2H)，2.845(t, 2H)；GC-MS m/z：239(M
+)。
By curcumine 14.72g(0.04mol) and triethylamine 2.02g(0.02mol) be dissolved in the CH of 100mL
2cl
2in obtain mixing solutions 2, mixing solutions 2 is dropwise added dichloro phosphoric acid phenylglycollic ester 2.39g(0.01mol at 0 DEG C ~ 5 DEG C) CH
2cl
2solution, dropwise, be warming up to 30 DEG C of reaction 20h gradually, the product obtained filters, removing precipitation, and filtrate decompression evaporate to dryness obtains yellow oily liquid, yellow oily liquid is through column chromatography (sherwood oil: ethyl acetate=18:1, volume ratio) obtain yellow powdery solid 4.07g, yield is 45.2%, and structural formula is as shown in aforementioned cur-9.m.p:185～186℃；
1H NMR(400MHz, CDCl
3) δ：7.622(t, 4H), 7.424-7.285(m, 7H), 7.148-7.043(m,8H), 6.908(d, 2H), 6.546-6.479(m, 4H), 4.782(t, 2H), 2.796(t, 2H)；MS（ESI）m/z：925(M+Na) 。
the synthesis of embodiment 8 cur-10
By 3-furans propyl alcohol 31.5g(0.25mol) and diisopropyl ethyl amine 32.3g(0.25mol) be dissolved in 400mL anhydrous tetrahydro furan and obtain mixing solutions 1, by phosphorus trichloride 22.5mL(0.25mmol) add 50mL tetrahydrofuran (THF) and obtain the tetrahydrofuran solution of phosphorus trichloride and be cooled to-50 DEG C, keep-50 DEG C of tetrahydrofuran solutions being slowly added dropwise to phosphorus trichloride in mixing solutions 1, dropwise in-50 DEG C of reaction 15min, then be slowly warming up to 25 DEG C, and continuation reaction 1h obtains product; By the solvent under reduced pressure evaporate to dryness in product, then underpressure distillation obtains dichloro phosphorous acid furans propyl ester 47.6g, and yield is 84%.
1H NMR(400MHz, CDCl
3) δ：7.412(m, 2H), 6.379(d, 1H)，4.052 (t, 2H)，2.647(m, 2H),1.7 82(t, 2H)；GC-MS m/z：227(M
+)。
By dichloro phosphorous acid furans propyl ester 5.67g(0.025mol) and diisopropyl ethyl amine 3.23g(0.025mol) be dissolved in the CHCl of 50mL
3in obtain mixing solutions 2, and be down to 0 DEG C; By curcumine 23g(0.063mol) be dissolved in the CHCl of 100mL
3in obtain the CHCl of curcumine
3solution, at 0 DEG C ~ 5 DEG C dropwise by the CHCl of curcumine
3in solution instillation mixing solutions 2, dropwise in 50 DEG C of reaction 6h, obtain mixing solutions 3; Temperature is adjusted to 10 DEG C, m-chloroperoxybenzoic acid 0.025mol is added in mixing solutions 3 at 10 DEG C in batches, and in 10 DEG C continue reaction 1h, stopped reaction, reaction solution 10%(mass percent) Na
2s
2o
3solution washing, then uses anhydrous Na
2sO
4dried overnight; Finally cross and filter anhydrous Na
2sO
4, concentrating under reduced pressure obtains yellow oil, and yellow oil is through column chromatography (sherwood oil: ethyl acetate=30: 1) obtain yellow powdery solid 14.6g, yield is 64.5%, and structural formula is as shown in aforementioned cur-10.m.p: 205℃～207℃；
1H NMR (400MHz, CDCl
3) δ：7.604-7.592(d, 4H), 7.111-7.099(d, 2H), 7.031-6.913(m, 2H), 6.804-6.791(m, 1H), 6.401-6.382(m, 2H), 6.355-6.422(d, 1H), 5.852(s, 1H), 4.410(t, 2H), 3.932(s, 6H), 3.862(s, 6H), 2.521（m,2H）,1.425(t, 3H)；MS（ESI）m/z：929（M+Na）。
embodiment 9: antitumor activity
The curcumine phosphate compounds cur-1 ~ cur-10 obtained to embodiment 1 ~ 8 has carried out anti tumor activity in vitro screening respectively, screened tumor cell line has: human hepatoma cell HepG2, human breast cancer cell MCF-7, Human Lung Cancer cell A549 and human colon cancer cell HCT-116, curcumine and cis-platinum is selected to be positive control, anti tumor activity in vitro screening experiment adopts CCK-8 RNA isolation kit, concrete operations are as follows: be inoculated on 96 orifice plates by the tumor cell line nutrient solution (100 microlitre 5000 cell) of screening, adding 10 μ L test-compound 4 ‰ (amount of substance permillage) DMSO(dimethyl sulfoxide (DMSO) simultaneously) (Test compound concentrations is followed successively by 0.1 μ g/ml to the aqueous solution respectively, 0.4 μ g/ml, 2 μ g/ml, 10 μ g/ml and 50 μ g/ml) carry out 37 DEG C of constant temperature culture 48h, then every hole adds the CCK-8 solution of 10 μ L, continues to cultivate 4h, obtain nutrient solution in cell culture incubator.Measure nutrient solution absorbancy with ultraviolet spectrophotometer at 450nm wavelength place, and calculate test-compound IC
50value, test result is in table 1.
Experimental result shows: curcumine phosphate compounds of the present invention shows certain restraining effect to four kinds of tumor models, and wherein, cur-1, cur-2 and cur-5 show stronger restraining effect to human hepatoma cell HepG2; Cur-4 is suitable with cis-platinum with curcumine to the restraining effect of Human Lung Cancer cell A549; Cur-5 is to the level of the restraining effect of human breast cancer cell MCF-7 close to cis-platinum; And cur-1, cur-2, cur-6, cur-7 and cur-8 show very high inhibition effect to human colon cancer cell HCT-116, to be better than or suitable with the restraining effect of cis-platinum.
embodiment 10: anti-inflammatory activity research
Curcumine phosphate compounds cur-1 ~ cur-10 that curcumine and embodiment 1 ~ 8 are synthesized is used 0.5% mass concentration CMC(Xylo-Mucine respectively) liquid is mixed with the curcumine suspension of 0.2% substance withdrawl syndrome and the curcumine phosphate compounds suspension of 0.2% substance withdrawl syndrome, with the curcumine suspension of 0.2% substance withdrawl syndrome, the aspirin solution of 0.5% mass concentration CMC liquid and 0.75% mass concentration as a control group, the curcumine phosphate compounds suspension of 0.2% substance withdrawl syndrome is as experimental group, get Kunming mouse 66 and be only divided into 11 groups at random by body weight, often organize 6, male and female half and half, each group of mouse, daily (i.e. test-compound) once, successive administration 6 days, 30min after last administration, smear every mouse auris dextra with dimethylbenzene 0.05mL/ mouse and cause inflammation, left ear compares, cause scorching after 30min take off cervical vertebra and put to death mouse.Take off the left and right auricle of ear edge with 7mm diameter punch tool, use scales/electronic balance weighing respectively, represent swelling with right, left auricle weight difference, between organizing, significance difference compares, and experimental result is in table 2.
Experimental result shows: curcumine phosphate compounds has and curcumine quite or better anti-inflammatory activity, and wherein compound cur-1, cur-2, cur-6 and cur-9 shows very strong anti-inflammatory activity, has the value of exploitation further.
embodiment 11:
anti-beta amyloid focusing experiment is studied
A major pathologic features of Alzheimer's disease is the generation of amyloid beta (A β), gathering and precipitation, finally forms amyloid plaque, so suppress the gathering of amyloid beta can delay the process of disease.And the gathering of amyloid beta is associated with the expression of acetylcholinesterase (AChE), acetylcholinesterase can induce its formation amyloid state to cause the gathering of 4 amyloid in conjunction with non-starch sample albumen (A β (1-40)).Therefore the combination of blockage of acetylcholine esterase and non-starch sample amyloid proteins can suppress the generation of amyloid beta.Acetylcholine esterase inhibition induction A β (1-40) focusing experiment of curcumine phosphate compounds cur-1 ~ cur-10 that the present invention is synthesized by embodiment 1 ~ 8 examines or check the activity of its anti-Alzheimer disease, and specific experiment method is as follows:
In 100 μ L centrifuge tubes, add the DMSO solution of the A β (1-40) of 2 μ L, 16 μ L acetylcholine ester enzyme solution (the phosphate buffer solution preparation with 0.215mol/L pH=8.0) and 2 μ L curcumine phosphate compounds solution (the phosphate buffer solution preparation with 0.215mol/L pH=8.0) successively, form buffer system; In buffer system, the final concentration of A β (1-40) is 230 μm of ol/L, and acetylcholinesterase final concentration is 2.3 μm of ol/L, (A β (1-40): AChE substance withdrawl syndrome=100: 1); Curcumine and propidium iodide are positive control, and the final concentration of curcumine and propidium iodide and curcumine phosphate compounds is 50 or 100 μm of ol/L.Buffer system at room temperature hatches 48h, then in buffer system, add the ThT(thioflavin T containing 1.5 μm of ol/L) glycine-NaOH solution (wherein, concentration 50 μm of ol/L of glycine) make volume be 2mL, on spectrophotofluorometer, survey the fluorescent emission intensity of 2mL solution at 490nm place with fixing excitation wavelength 446nm.Not add compound and not add acetylcholine ester enzyme solution for blank; 8 ~ 10 times of independent A β (1-40) value can be reached as standard using the fluorescent value of AchE+ A β (1-40).
Inhibiting rate (%)=100-(If of A β
i/ If
o) × 100
Wherein, If
iand If
obe respectively the difference that there is fluorescence intensity under inhibitor (i.e. curcumine, propidium iodide and curcumine phosphate compounds) and unrestraint agent and blank fluorescence intensity.Experimental result is in table 3.
Experimental result shows: curcumine phosphate compounds has and curcumine quite or better anti-inflammatory activity, and wherein compound cur-1, cur-2, cur-6 and cur-9 shows very strong anti-inflammatory activity, has the value of exploitation further.
embodiment 11:
anti-beta amyloid focusing experiment is studied
A major pathologic features of Alzheimer's disease is the generation of amyloid beta (A β), gathering and precipitation, finally forms amyloid plaque, so suppress the gathering of amyloid beta can delay the process of disease.And the gathering of amyloid beta is associated with the expression of acetylcholinesterase (AChE), acetylcholinesterase can induce its formation amyloid state to cause the gathering of 4 amyloid in conjunction with non-starch sample albumen (A β (1-40)).Therefore the combination of blockage of acetylcholine esterase and non-starch sample amyloid proteins can suppress the generation of amyloid beta.Acetylcholine esterase inhibition induction A β (1-40) focusing experiment of curcumine phosphate compounds cur-1 ~ cur-10 that the present invention is synthesized by embodiment 1 ~ 8 examines or check the activity of its anti-Alzheimer disease, and specific experiment method is as follows:
In 100 μ L centrifuge tubes, add the DMSO solution of the A β (1-40) of 2 μ L, 16 μ L acetylcholine ester enzyme solution (the phosphate buffer solution preparation with 0.215mol/L pH=8.0) and 2 μ L curcumine phosphate compounds solution (the phosphate buffer solution preparation with 0.215mol/L pH=8.0) successively, form buffer system; In buffer system, the final concentration of A β (1-40) is 230 μm of ol/L, and acetylcholinesterase final concentration is 2.3 μm of ol/L, (A β (1-40): AChE substance withdrawl syndrome=100: 1); Curcumine and propidium iodide are positive control, and the final concentration of curcumine and propidium iodide and curcumine phosphate compounds is 50 or 100 μm of ol/L.Buffer system at room temperature hatches 48h, then in buffer system, add the ThT(thioflavin T containing 1.5 μm of ol/L) glycine-NaOH solution (wherein, concentration 50 μm of ol/L of glycine) make volume be 2mL, on spectrophotofluorometer, survey the fluorescent emission intensity of 2mL solution at 490nm place with fixing excitation wavelength 446nm.Not add compound and not add acetylcholine ester enzyme solution for blank; 8 ~ 10 times of independent A β (1-40) value can be reached as standard using the fluorescent value of AchE+ A β (1-40).
Inhibiting rate (%)=100-(If of A β
i/ If
o) × 100
Wherein, If
iand If
obe respectively the difference that there is fluorescence intensity under inhibitor (i.e. curcumine, propidium iodide and curcumine phosphate compounds) and unrestraint agent and blank fluorescence intensity.Experimental result is in table 3.
Test-results shows, when tested Test compound concentrations is 50 μm of ol/L, gained A beta peptide aggregation inhibiting rate is all not obvious.When concentration rises to 100 μm of ol/L, Comparison of experiment results is obvious.Curcumine phosphate compounds demonstrates obviously stronger than curcumine restraining effect to A β (1-40) gathering that AchE induces, wherein cur-6, cur-9 and cur-10 are to the restraining effect of acetylcholinesterase close to the single-minded inhibitor propidium iodide acting on acetylcholinesterase, illustrate that this kind of compound has good potential applicability in clinical practice in advance.
Claims (8)
1. a curcumine phosphate compounds, its structure is as shown in formula I:
；
Wherein, R is selected from H
+, Na
+, K
+, NH
4 +, Li
+, phenyl, furyl, thienyl, pyrryl, pyridyl, there is the straight-chain paraffin base of 1 ~ 20 carbon atom, there is the branched alkane alkyl of 1 ~ 20 carbon atom, the group that there is the hydrogen on the straight-chain paraffin base of 1 ~ 20 carbon atom and formed is replaced by phenyl ring or naphthalene nucleus, the group that there is the hydrogen on the branched alkane alkyl of 1 ~ 20 carbon atom and formed is replaced by phenyl ring or naphthalene nucleus, by five yuan or hexa-atomic fragrant heterocyclic substituted, there is the group that the hydrogen on the straight-chain paraffin base of 1 ~ 20 carbon atom formed, by five yuan or hexa-atomic fragrant heterocyclic substituted, there is the group that the hydrogen on the branched alkane alkyl of 1 ~ 20 carbon atom formed.
2. curcumine phosphate compounds as claimed in claim 1, it is characterized in that, described R is selected from has 1, the straight-chain paraffin base of 2 ~ 16 carbon atoms, have 1, the branched alkane alkyl of 2 ~ 16 carbon atoms, the group that there is the hydrogen on the straight-chain paraffin base of 1 ~ 10 carbon atom and formed is replaced by phenyl ring or naphthalene nucleus, the group that there is the hydrogen on the branched alkane alkyl of 1 ~ 10 carbon atom and formed is replaced by phenyl ring or naphthalene nucleus, by five yuan or hexa-atomic fragrant heterocyclic substituted, there is the group that the hydrogen on the straight-chain paraffin base of 1 ~ 10 carbon atom formed, by five yuan or hexa-atomic fragrant heterocyclic substituted, there is the group that the hydrogen on the branched alkane alkyl of 1 ~ 10 carbon atom formed.
3. curcumine phosphate compounds as claimed in claim 2, it is characterized in that, described five yuan or hexa-atomic fragrant heterocycles are furan nucleus, thiphene ring, pyrrole ring or pyridine ring.
4. curcumine phosphate compounds as claimed in claim 1, it is characterized in that, described R is selected from methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, n-pentyl, isopentyl, neo-pentyl, hexyl, heptyl, octyl group, Ren Ji, decyl, dodecyl, hexadecyl, eicosyl, phenmethyl, styroyl, hydrocinnamyl, benzene butyl, furfuryl, furylethyl, furans propyl group, furans butyl, furans amyl group, thenyl, thienylethyl, thiophene propyl group, thiophene butyl, thiophene amyl group, pyrrolylmethyl, pyrrolylethyl, pyrroles's propyl group, pyrroles's butyl, pyrroles's amyl group, picolyl, pyridine ethyl, pyridylpropyl, pyridine butyl.
5. curcumine phosphate compounds as claimed in claim 1, is characterized in that this compound is selected from compound shown in structural formula cur-1, cur-2, cur-3, cur-4, cur-5, cur-6, cur-7, cur-8, cur-9, cur-10:
。
6. a preparation method for the curcumine phosphate compounds as described in claim 1,2,3,4 or 5, is characterized in that comprising the steps:
A () phosphorus oxychloride and alcohol are obtained by reacting either dichlorophosphate:
Solvent for use is ether or tetrahydrofuran (THF), and adds alkali in solvent, and described alkali is triethylamine or diisopropyl ethyl amine, and alkali is 1 ~ 4: 1 with the amount of substance ratio of alcohol, and temperature of reaction is 0 DEG C ~ 30 DEG C;
B () either dichlorophosphate and curcumine obtain described curcumine phosphate compounds through acylation reaction:
Solvent for use is methylene dichloride or trichloromethane, and adds alkali in solvent, and described alkali is triethylamine or diisopropyl ethyl amine, and alkali is 1 ~ 4: 1 with the amount of substance ratio of either dichlorophosphate, and temperature of reaction is 0 DEG C ~ 50 DEG C;
In above-mentioned (a) (b), R is not H
+, Na
+, K
+, NH
4 +and Li
+;
When R is H
+, Na
+, K
+, NH
4 +, Li
+a period of time is that raw material obtains through above-mentioned (a) (b) with methyl alcohol:
Then the two curcumin ester of phosphoric acid is obtained with bromotrimethylsilane demethylation; React with sodium hydroxide, potassium hydroxide, ammoniacal liquor and lithium hydroxide again and namely obtain respective objects compound.
7. a preparation method for the curcumine phosphate compounds as described in claim 1,2,3,4 or 5, is characterized in that comprising the steps:
A () alcohol and phosphorus trichloride are obtained by reacting phosphorodichloridites:
Solvent for use is ether or tetrahydrofuran (THF), and adds alkali in solvent, and described alkali is triethylamine or diisopropyl ethyl amine, and alkali is 1 ~ 4: 1 with the amount of substance ratio of alcohol, and temperature of reaction is-50 DEG C ~ 30 DEG C;
B () phosphorodichloridites and curcumine are obtained by reacting curcumine phosphorous acid ester:
Solvent for use is methylene dichloride or trichloromethane, and adds alkali in solvent, and described alkali is triethylamine or diisopropyl ethyl amine, and alkali is 1 ~ 4: 1 with the amount of substance ratio of phosphorodichloridites, and temperature of reaction is 0 DEG C ~ 50 DEG C;
C () curcumine phosphorous acid ester obtains curcumine phosphate compounds through metachloroperbenzoic acid oxidation:
The temperature of reaction is-20 DEG C ~ 10 DEG C, and the amount of substance of metachloroperbenzoic acid is 1 ~ 4 times of phosphorodichloridites;
In above-mentioned (a) (b) (c), R is not H
+, Na
+, K
+, NH
4 +and Li
+;
When R is H
+, Na
+, K
+, NH
4 +, Li
+a period of time is that raw material obtains through above-mentioned (a) (b) (c) with methyl alcohol:
Then the two curcumin ester of phosphoric acid is obtained with bromotrimethylsilane demethylation; React with sodium hydroxide, potassium hydroxide, ammoniacal liquor and lithium hydroxide again and namely obtain respective objects compound.
8. the curcumine phosphate compounds as described in claim 1,2,3,4 or 5 is preparing the application in anti-breast cancer, anti-lung cancer, inhibitor against colon carcinoma cells, anti-liver cancer, anti-inflammatory, anti-Alzheimer disease medicine.
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