CN102558530B - Selenium-containing curcumin polymer and its preparation method and application - Google Patents

Selenium-containing curcumin polymer and its preparation method and application Download PDF

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CN102558530B
CN102558530B CN2011102958632A CN201110295863A CN102558530B CN 102558530 B CN102558530 B CN 102558530B CN 2011102958632 A CN2011102958632 A CN 2011102958632A CN 201110295863 A CN201110295863 A CN 201110295863A CN 102558530 B CN102558530 B CN 102558530B
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selenium
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curcumine
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CN102558530A (en
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唐华东
李小年
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Guangdong Gaohang Intellectual Property Operation Co ltd
Zhejiang Etonpolymer Co ltd
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Zhejiang University of Technology ZJUT
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Abstract

The invention discloses a selenium-containing curcumin polymer and its preparation method and application. The selenium-containing curcumin polymer has a structure as represented by formula (I). The polymer has the advantages of good stability, water-solubility and biocompatibility, low toxic and side effects, high bioavailability, easy injection and administration, obvious curative effects on inhibiting hepatic fibrosis, fatty liver and cirrhosis and a striking clinical application value.

Description

Containing selenium curcumin polymer and its preparation method and application
(1) technical field
The technical field of the invention be medicine synthetic with application, relate to curcumin derivate and be combined form water-soluble with cyclopentane tetracarboxylic acid dianhydride, polyoxyethylene and Se-Methylselenocysteine and contain selenium curcumine high molecular polymer and preparation method thereof and as the application of anti-hepatic fibrosis, anti-fatty liveranti-fatty liver, anti-liver cirrhosis medicine aspect.
(2) technical background
Curcumine is a kind of polyphenolic substance with multiple pharmacologically actives such as anti-inflammatory, anti-oxidant, antimutagenic, anti-ageing, antitumor, reducing blood-fat as extracted the rhizomes such as turmeric, root tuber of aromatic turmeric, curcuma zedoary from the Zingiber curcuma.The curcumine wide material sources, cheap, curative effect is various, be the widely used a kind of foodstuff additive of country in Southeast Asia (wheat Zhenjiang. the Advance on Pharmacological Activities of curcumine. Chinese medicinal materials, 2004, (9): 698).Curcumine has the effect of anti-oxidation stress, can suppress tetracol phenixin, superoxide, D-galactosamine and metal ion as Fe 2+, Cu 2+Damaging action to rat hepatocytes, reduce millet straw, gpt level in serum, remove the hepatic tissue free radical, protection liver cell (KisoY, Suzuki Y, Watanabe N, et al.Anti-hepatotoxic principles of Curcuma longa rhizomes.Planta.Med.1983,49 (3): 185C7; Wan Xiaohua, Luo Xiaoping. copper is on the impact of hepatocyte apoptosis and the provide protection of curcumine. Contemporary Chinese paediatrics magazine 2007,9 (6): 567).Numerous research shows that curcumine can make epoxide hydrolase in liver, Selenoperoxidase, glutathione s-transferase, the activity of superoxide dismutase enzyme increases, lipoid peroxidization resistant is remarkable, can obviously reduce (the Nanji A A of peroxide level in blood plasma and liver, Jokelainen K, Tipoe G L, et al.Curcumin prevents alcohol-induced liver disease in rats by inhibiting the expression of NF-kappa B-dependent genes.Am J Physiol Gastrointest Liver Physiol2003, 284:G321).Curcumine has the effect of anti-inflammatory and anti-fibrosis, thus curcumine can the inflammation-inhibiting factor as the expression of TNF-α, IL-6 and activation performance anti hepatic fibrosis (the Chinese patent CN101019841 of hepatic stellate cell; CN101002911).
Numerous experimentation on animals curcumines are nontoxic or toxic side effect is very weak.Clinical experiment shows that the oral 12g/ of patient days to health (the Cheng A L that has no side effect, Hsu C H, Lin J K, et al.Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-riskorpre-malignantlesions.Anticancer Res.2001,21 (4B): 2895C90).In another clinical second phase test, curcumine does not all show system toxicity (Nam S H, Nam H Y, Joo, J R, Baek S, Park J S Bull.Korean Chem.Soc.2007,28,397) under any intake.But the curcumine molecular polarity is very weak, water-soluble hardly, oral administration biaavailability is very low, curcumine (the Garcea G of the nanogram order of magnitude for example in the patients serum of oral 3.6g curcumine every day, can only be detected, Jones D J, Singh R et al.Detection of curcumin and its metabolites in hepatic tissue and portal blood of patients following oral administration.Br.J.Cancer2004,90:1011).Curcumine is to photaesthesia, unstable under neutrality and alkaline condition, in the PBS solution at pH7.2, curcumine in 10 minutes in degraded 50%(Wang Y J, Pan M H, Cheng A L et al.Stability of curcumin in buffer solutions and characterization of its degradation products J.Pharm.Biomed.Anal.1997,15:1867).Due to water insoluble, curcumine is difficult to directly carry out drug administration by injection, and in blood circulation, eliminate very fast, curcumine detected and have (Ireson C as the glycerol formal solution of curcumine is expelled in Mice Body after half an hour in blood difficulty, Orr S, Jones D J L et al.Characterization of metabolites of the chemopreventive agent curcumin in human and rat hepatocytes and in the rat inVivo, and evaluation of their ability to inhibit phorbol ester-induced prostaglandin E2production.Cancer Res.2001, 61:1058).Extremely low bioavailability has caused curcumine poor reproducibility in therapeutic process, and curative effect is not obvious, can't be in clinical middle practical application.
Curcumine is very restricted for above-mentioned reasons in actual applications, therefore researcher has adopted and curcumine is wrapped in to various nano particles, liposome, vesica, microballoon and the modes such as solid dispersion, polymeric blends, polymer composite that curcumine is made improves the clinical application that the curcumine defect promotes it in recent years.But these methods have, and shortcomings is as low as the curcumine load factor, medicament storage poor stability, emulsifying agent, the solubility promoter usage quantity is large, intravenous injection exists safety issue, complicated process of preparation, with high costs etc.Although had in document by amino-formate bond or peptide bond, curcumine and polyoxyethylene glycol are coupled together and form water-soluble curcumin derivate and, for antineoplastic report, these derivative stability are not high, unstable in blood circulation, remove fast.Derivative (the PBS in neutral environment formed by amino-formate bond as curcumine and Macrogol 2000, pH=7.4) half life of decomposition 60 minutes (Safavy A only, Raisch K P, Mantena S, et al.Designand development of water-soluble curcumin conjugates as potential anticancer agents.J.Med.Chem.2007,50:6284).
Much research in recent years shows, selenium is one of essential trace element of the activity of sustaining life, it is the important component that forms organism antioxidant Selenoperoxidase (GSH – Px), the decline of the shortage of selenium and GSH – Px vigor can cause the illnesss such as hepatitis, hepatic fibrosis, liver cirrhosis to increase the weight of, Different type of Liver Diseases all lack in various degree selenium or blood selenium level low (Wang Zhixin. the clinical meaning that Patients with Viral Hepatitis blood selenium, lipid peroxide and glutathione peroxidase activity are measured. Chinese transmissible disease magazine, 1990,8 (4): 209).Selenium passes through the selenoenzyme class as removing free radicals such as GSH – Px; protection stellate cells, inner cell, liver cell etc. avoid the effect of the damage generation anti-fibrosis of free radical; peroxidatic reaction of lipid with Green Tea Extract and initiation thereof; the effect that appropriate supplement selenium can play prevention hepatitis, hepatic fibrosis, liver cirrhosis (accords with cold; water is auspicious. and selenium is prevented hepatic progress. trace elements and health research; 2005,22 (3): 64).
(3) summary of the invention
The primary technical problem that the present invention will solve is to provide a kind of containing the selenium curcumin polymer, good, the water-soluble height of this polymer stabilizing, be easy to drug administration by injection, bioavailability is high, retained curcumine self good biocompatibility simultaneously, toxic side effect is low and can anti-hepatic fibrosis, the advantage of fatty liver, liver cirrhosis, clinical value is outstanding.
Research Thinking of the present invention is: at first curcumine and cyclopentane tetracarboxylic acid dianhydride are coupled together to the curcumine high molecular polymer that generates two carboxyls of each repeating unit band by polycondensation, one of each unit carboxyl of this polymer chain is wetting ability mono methoxy PEO chain of grafting and make this polymkeric substance can be water-soluble again, finally make again to introduce Se-Methylselenocysteine in a small amount of unit on main chain, obtain the curcumine water-soluble polymers containing selenium.In this polymkeric substance, hydrophobic curcumine is positioned on main chain, water-soluble rear hydrophilic polyoxyethylene chain extends and is wrapped in curcumine main chain skin, form Comblike polymers protection curcumine molecule, it is stable under neutrallty condition and in blood circulation to make it, and fast decoupled discharges curcumine under the effect of liver middle and high concentration esterase, be accumulated in liver organization and reach rapidly the treatment effective concentration, play anti-inflammatory, antiperoxide, anti-fibrosis, the blood ester falls, liver-protective effect, and Se also can improve the GSH-Px activity after being absorbed in vivo, play auxiliary anti-oxidant, anti-fibrosis, the effect of anti-liver cirrhosis.
Of the present invention containing the selenium curcumin polymer, its structure as shown in the formula (I):
Figure GDA00003463082000041
In formula (I), x, y are number of repeat unit, the x value in 4～200, y value 1～10;
Figure GDA00003463082000042
For the group that structure forms suc as formula the mono methoxy polyoxyethylene (PEO) shown in (VI), the polyoxyethylated number-average molecular weight of described mono methoxy is 200～5000Da,
Figure GDA00003463082000043
R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9Be selected from independently of one another one of following: hydrogen atom, hydroxyl, phenyl, straight or branched alkyl, straight or branched alkoxyl group, amido, alkyl amine group, halogen, haloalkyl.
In the present invention, the total number-average molecular weight that contains the selenium curcumin polymer is controlled at 5000～300000Da, wherein containing the number-average molecular weight of Se-Methylselenocysteine part, controls about 1500～15000Da.
Further, the carbon atom number of described straight or branched alkyl is preferably 1～12, the carbon atom number of described straight or branched alkoxyl group is preferably 1～12, and the carbon atom number of described alkyl amine group is preferably 1～12, and the carbon atom number of described haloalkyl is preferably 1～12.
Further, R 1, R 5Be selected from independently of one another the straight or branched alkoxyl group; R 2, R 3, R 4, R 6, R 7, R 8, R 9Be selected from independently of one another one of following: hydrogen, straight or branched alkyl.
Further, R 1, R 5Be selected from independently of one another the carbon atom number for the straight or branched alkoxyl group containing 1～12 carbon atom; R 2, R 3, R 4, R 6, R 7, R 8, R 9Be selected from independently of one another one of following: hydrogen, containing the straight or branched alkyl of 1～12 carbon atom.
Further again, preferred R 1, R 5Be methoxyl group; Preferred R 2, R 3, R 4, R 6, R 7, R 8, R 9Be hydrogen.
Further, the x value is preferably 30～100, and more preferably 40～80.
Further, the y value is preferably 1～5, and more preferably 1～2.
Further, the number-average molecular weight of PEO is preferably 500～2000Da, more preferably 800～1000Da.
Second technical problem that the present invention will solve is to provide that a kind of preparation technology is simple, the preparation method containing the selenium curcumin polymer of low production cost, and described preparation method is: the Se-Methylselenocysteine generation condensation reaction shown in the part carboxyl on the macromolecular chain of the Comblike polymers polymkeric substance shown in formula (III) and formula (VII) obtains containing the selenium curcumin polymer shown in formula (I);
Figure GDA00003463082000051
In formula (III), n=x+y, x, y,
Figure GDA00003463082000052
R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9Definition cotype (I).
The present invention recommends above-mentioned preparation method specifically according to following enforcement: by the Comblike polymers polymer dissolution shown in formula (III) in dry solvent, according to the curcumine contained in the Comblike polymers polymkeric substance or curcumin derivate group: N, the mol ratio of N-dicyclohexylcarbodiimide=1:0.005～0.05 adds N, the N-dicyclohexylcarbodiimide, the curcumine contained according to the Comblike polymers polymkeric substance again after stirring or curcumin derivate group: the mol ratio of Se-Methylselenocysteine: triethylamine: DMAP=1:0.005～0.05:0.005～0.05:0.01 adds Se-Methylselenocysteine, triethylamine and DMAP, stir and spend the night under room temperature, add ether, the centrifugal resolution of precipitate obtained is in tetrahydrofuran (THF), with the classification of ether redeposition, finally obtain shown in formula (I) containing the selenium curcumin polymer.
Further, described solvent is tetrahydrofuran (THF), acetone, dioxane, DMF, dimethyl sulfoxide (DMSO) or N-Methyl pyrrolidone, is preferably tetrahydrofuran (THF).
Comblike polymers polymkeric substance shown in formula of the present invention (III) can be prepared as follows:
1) 1,2,3,4 – cyclopentane tetracarboxylic acid dianhydrides shown in the curcumine shown in formula (IV) or curcumin derivate and formula V are through the polycondensation product shown in polycondensation production (II);
Figure GDA00003463082000061
2) carboxyl on the macromolecular chain of the polycondensation product shown in formula (II) again with the mono methoxy polyoxyethylene (PEO) shown in formula (VI) on hydroxyl reaction obtain the Comblike polymers polymkeric substance shown in formula (III);
Figure GDA00003463082000062
In formula (II), formula (III) or formula (IV), n, R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9Definition the same, the definition of PEO is also the same.
Below above-mentioned preparation process is done and illustrated.
Described step 1) is specifically according to following enforcement: by 1,2,3,4 – cyclopentane tetracarboxylic acid dianhydrides and curcumine or curcumin derivate add in solvent with the 1:1 mixed in molar ratio, under 40～60 ° of C, stir 15～30 hours, then add ether, collecting precipitation, obtain the polycondensation product shown in formula (II) after drying.
Further, the solvent described in step 1) is dry acetone, dioxane, DMF, dimethyl sulfoxide (DMSO) or N-Methyl pyrrolidone, and preferred solvent is dioxane.
Described step 2) specifically according to following enforcement: the polycondensation product that step 1) is obtained, the mono methoxy polyoxyethylene, N, N-dicyclohexylcarbodiimide and DMAP are according to the curcumine contained in polycondensation product or curcumin derivate group: mono methoxy polyoxyethylene: N, the mol ratio of N-dicyclohexylcarbodiimide: DMAP=1:1:1.05:0.05 is dissolved in dry solvent, 20～50 ° of C stir 15～30 hours, add ether, the centrifugal resolution of precipitate obtained is in tetrahydrofuran (THF), with the classification of ether redeposition, obtain making Comblike polymers polymkeric substance as shown in the formula (III) after thick solid vacuum-drying.
Further, step 2) described solvent is acetone, DMF, dimethyl sulfoxide (DMSO) or N-Methyl pyrrolidone etc., is preferably dimethyl sulfoxide (DMSO).
The 3rd technical problem that the present invention will solve is to provide described containing the application of selenium curcumin polymer in preparing anti-hepatic fibrosis, anti-fatty liveranti-fatty liver or anti-liver cirrhosis medicine.
Of the present inventionly can pharmaceutically can accept carrier with it containing the selenium curcumin polymer and be combined and form pharmaceutical composition.
In the present invention, " pharmaceutically acceptable carrier " refers to that various weighting agents, buffer reagent, stablizer, thinner, protective material, sanitas, lapping and other pharmaceutical adjunct of solid-state, the semi-solid state of pharmaceutically having no side effect, liquid even gaseous state are as cyclodextrin, chitosan, glucose, starch, physiological saline etc.
According to therapeutic purpose, route of administration, use public technology in this area, this polymkeric substance and pharmaceutical composition can be made to various formulations, as injection, pill, tablet, film, pulvis, patch, drops, syrup, granule, aerosol etc.Be preferably injection in the present invention, more preferably intravenous injection.
Polymkeric substance in the present invention and pharmaceutical composition are used for the treatment of various disease symptoms, curative effect have anti-inflammatory, anti-oxidant, radioprotective, antimutagenic, anti-ageing, atherosclerosis, anti-senile dementia, anti HIV-1 virus, anticancer, antitumor, blood ester, anti-hepatic fibrosis, anti-fatty liveranti-fatty liver, anti-liver cirrhosis etc. fall, be particularly useful for the treatment of anti-hepatic fibrosis, anti-fatty liveranti-fatty liver, anti-liver cirrhosis.In clinical application, according to therapeutic purpose and pharmaceutical dosage form, one of ordinary skill in the art can use various route of administration administrations, as oral, injection, instillation, transdermal, hypogloeeis, nasal cavity, lung, rectum, vagina etc., be preferably the gi tract external administration as injection, instillation, more preferably intravenous injection.Dosage has the doctor to be determined as age of patient, body weight, sex, the state of an illness, patient's condition etc. according to patient's practical situation.Generally, grownup's dosage is calculated as 10ng～10g/kg body weight with the polymkeric substance shown in formula 1, is preferably 1ug～1g/kg body weight, more preferably 1mg～50mg/kg body weight.
Compared with prior art, beneficial effect of the present invention is: of the present invention containing selenium curcumin polymer good stability, and water-soluble height, be easy to drug administration by injection, bioavailability is high, and anti-hepatic fibrosis, fatty liver, liver cirrhosis curative effect are obvious, have remarkable clinical value.In addition, preparation technology is simple for this polymkeric substance, low production cost.
(4) accompanying drawing explanation
Fig. 1 is the GPC spectrogram containing the selenium curcumin polymer that embodiment 3 makes.
Fig. 2 be embodiment 3 make containing selenium curcumine high molecular polymer anti-hepatic fibrosis and liver cirrhosis design sketch (X100), wherein, A is normal group, B is that model is after 4 weeks, C is for after treating 4 weeks containing the selenium curcumin polymer, D is PBS randomized controlled treatment after 4 weeks, and E is for containing selenium curcumin polymer treatment X100 after 8 weeks, and F is 8 weeks rear X100 of PBS randomized controlled treatment.
Fig. 3 be embodiment 3 make containing selenium curcumine high molecular polymer anti-fatty liveranti-fatty liver design sketch (X100), wherein, A is normal group, B is model group, C is for containing selenium curcumin polymer treatment group, D is the PBS control group.
(5) embodiment
For ease of understanding, below will be elaborated with specific embodiment, but these embodiment just are used for explaining better content of the present invention, do not form limitation of the scope of the invention.Scientific research technician in this area can make correction miscellaneous and improvement within the scope of the invention according to content of the present invention, and these corrections and improvement are also included in scope of the present invention.
If the pharmaceutical chemicals used in embodiment, solvent, equipment etc. are Aldrich company product without specified otherwise, or can buy by other company on market, if pharmaceutical chemicals and solvent are and guarantee pure or analytical pure without specified otherwise purity.Those skilled in that art can be according to " solvent handbook (Chemical Industry Press commonly used in this area, Beijing, 2010) and " organic synthesis laboratory handbook (Chemical Industry Press, Beijing, 2010) etc. in the basic skills described in handbook and technical ability and this paper reference, listed method is implemented following these cases.
Embodiment 1: the polycondensation product shown in formula (II) synthetic
By 3.68g curcumine (Fluka, high-purity) and 2.10g1,2,3,4 – cyclopentane tetracarboxylic acid dianhydrides are dissolved in the anhydrous dioxane of 60mL, stir 36h under 60 ° of C after reaction solution be cooled to room temperature, add the 50mL ether, centrifugal collecting precipitation, precipitation obtains the curcumine polycondensation product shown in 5.4g formula (II), yield 93% with vacuum-drying under room temperature after the ether washing.
Embodiment 2: the pectination curcumine high molecular polymer shown in formula (III) synthetic
By the polycondensation product shown in 5.0g formula (II), 6.9g mono methoxy polyoxyethylene (Mn=800), 1.9g N, the N-dicyclohexylcarbodiimide, the 0.05g4-Dimethylamino pyridine is dissolved in the anhydrous DMSO of 80mL, add the 150mL ether after stirring 18h under room temperature, centrifugal collecting precipitation, resolution of precipitate is in tetrahydrofuran (THF) and use ether sedimentation again, obtains the at room temperature vacuum-drying of thick solid, make the high molecular polymer shown in 10.2g formula (III), yield 87%.
Embodiment 3: the synthesizing containing selenium curcumine high molecular polymer shown in formula (I)
High molecular polymer shown in 6.8g formula (III) is dissolved in the 50mL anhydrous tetrahydro furan, add 5.5mg N, the N-dicyclohexylcarbodiimide, add the 2.5mg triethylamine, the 4.5mg Se-Methylselenocysteine after stirring 15min, 3.0mg4-Dimethylamino pyridine, add the 100mL ether after stirring 12h under room temperature, centrifugal collecting precipitation, resolution of precipitate also adds ether sedimentation in tetrahydrofuran (THF) again, obtain shown in 6.5g formula 1 containing selenium curcumine high molecular polymer, yield 96% under room temperature after vacuum-drying.
Embodiment 4: the sign containing the selenium curcumin polymer shown in formula (I)
This polymkeric substance is at room temperature orange to the soft solid of brown color, the water-soluble 20mg/mL that is greater than, and under room temperature, storage is stable half a year.Detect the molecular weight (Waters, Styragel HR4, HR24.6mm * 300mm chromatographic column, light scattering detector, tetrahydrofuran (THF) moving phase) of polymkeric substance with gel permeation chromatography (GPC), result as shown in Figure 1.Fig. 1 shows that this polymericular weight is distribution as unimodal, and GPC calculation result is number-average molecular weight 6.1 * 10 4, x=45, weight-average molecular weight 9.8 * 10 4.Measuring Se content in polymkeric substance with icp ms (ICP-MS, PerkinElmer ELAN DRC-e) is 262ppm, y=2.Take deuterochloroform as solvent, this compound by hydrogen nuclear magnetic resonance spectrometer (1H-NMR, Bruker Advance DRX-400) detected result is: 7.6ppm (d), 7.1ppm (m), 6.6ppm (d), 5.8ppm (b), 3.9ppm (s), 3.7ppm (s), 3.3ppm (m), 2.9ppm (m), 2.6ppm (m), 2.2ppm (m).
Embodiment 5: shown in formula (I) containing selenium curcumin polymer anti-hepatic fibrosis and liver cirrhosis effect
SD rat (body weight 200～250g), male, be divided at random two groups (n=15), with tetracol phenixin (CCl 4) subcutaneous injection 40%CCl 4: paraffin oil solution, dosage is 2ml/kg, 2 times weekly, first dose doubles, modeling totally 12 weeks.From the 5th week, the dosage that treatment group is pressed 50mg/kg is the PBS solution (pH=7.4,12.5mg/mL) containing the selenium curcumin polymer from injection every day of tail vein, and control group is injected PBS every day.Process respectively rat in treatment after 4 weeks and 8 weeks, hepatic tissue is through HE dyeing demonstration, and result as shown in Figure 2.
Fig. 2 shows: curcumin polymer improves obviously the rat liver fibrosis pathology, alleviates the hyperplasia of hepatic necrosis, inhibition Hepatic Stellate Cell Activation and fibrous tissue, significantly delays hepatic fibrosis and the hepatic fibrosis process to liver cirrhosis.
Embodiment 6: shown in formula (I) containing selenium curcumin polymer anti-fatty liveranti-fatty liver curative effect
SD rat (body weight 200～250g), male, reference literature standard method (Sun Dayu, the progress of fatty liver model, China's digestion magazine, 2002,22 (5), 305-306), make Models of Fatty Liver with high fat diet and tetracol phenixin mixture, be divided at random normal group, model group, treatment group and four groups of PBS control groups (n=15), modeling, after 6 weeks, is processed normal group and model group; And treatment group and PBS control group stop CCl 4Modeling, continue high fat diet, the dosage that treatment group is pressed 50mg/kg contains the PBS solution (pH=7.4 of selenium curcumin polymer from injection every day of tail vein, 12.5mg/mL) treat 2 weeks, the PBS control group is injected PBS lasting 2 weeks every day, process respectively rat, hepatic tissue shows through HE dyeing, as a result shown in Fig. 3:
As can be seen from Figure 3, the curcumin polymer group can be improved the lipid metabolism by high fat diet and tetracol phenixin fatty liver that mixture is made effectively, obviously improve the variation of hepatopathy Neo-Confucianism, this polymkeric substance can reduce the accumulation of lipid in liver greatly than control group, obviously suppress the process of hepatic fibrosis, experimental fatty liver is had to obvious drug effect.

Claims (10)

1. containing the selenium curcumin polymer, its structure as shown in the formula (I):
Figure FDA00003463081900011
In formula (I), x, y are number of repeat unit, the x value in 30～100, y value 1～10;
Figure FDA00003463081900012
For the group that structure forms suc as formula the mono methoxy polyoxyethylene shown in (VI), the polyoxyethylated number-average molecular weight of described mono methoxy is 200～5000Da,
Figure FDA00003463081900013
R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9Be selected from independently of one another one of following: hydrogen atom, hydroxyl, phenyl, straight or branched alkyl, straight or branched alkoxyl group, amido, alkyl amine group, halogen, haloalkyl.
2. as claimed in claim 1 containing the selenium curcumin polymer, it is characterized in that: the carbon atom number of described straight or branched alkyl is 1～12, the carbon atom number of described straight or branched alkoxyl group is 1～12, the carbon atom number of described alkyl amine group is 1～12, and the carbon atom number of described haloalkyl is 1～12.
3. as claimed in claim 1 containing the selenium curcumin polymer, it is characterized in that: R 1, R 5Be selected from independently of one another the straight or branched alkoxyl group; R 2, R 3, R 4, R 6, R 7, R 8, R 9Be selected from independently of one another one of following: hydrogen, straight or branched alkyl.
4. as claimed in claim 1 containing the selenium curcumin polymer, it is characterized in that: R 1, R 5Be methoxyl group; R 2, R 3, R 4, R 6, R 7, R 8, R 9Be hydrogen.
5. as described as one of claim 1～4 containing the selenium curcumin polymer, it is characterized in that: the x value in 30～100, y value 1～5.
6. as described as one of claim 1～4 containing the selenium curcumin polymer, it is characterized in that: the x value in 40～80, y value 1～2.
7. as described as one of claim 1～4 containing the selenium curcumin polymer, it is characterized in that: the polyoxyethylated number-average molecular weight of mono methoxy is 500～2000Da.
8. the preparation method containing the selenium curcumin polymer as claimed in claim 1 is characterized in that described preparation method is: the Se-Methylselenocysteine generation condensation reaction shown in the part carboxyl on the macromolecular chain of the Comblike polymers polymkeric substance shown in formula (III) and formula (VII) obtains containing the selenium curcumin polymer shown in formula (I);
Figure FDA00003463081900021
In formula (III), n=x+y, x, y,
Figure FDA00003463081900022
R 1, R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9Definition cotype (I).
9. the preparation method containing the selenium curcumin polymer as claimed in claim 8, it is characterized in that described preparation method is specifically according to following enforcement: by the Comblike polymers polymer dissolution shown in formula (III) in dry solvent, according to the curcumine contained in the Comblike polymers polymkeric substance or curcumin derivate group: N, the mol ratio of N-dicyclohexylcarbodiimide=1:0.005～0.05 adds N, the N-dicyclohexylcarbodiimide, the curcumine contained according to the Comblike polymers polymkeric substance again after stirring or curcumin derivate group: the mol ratio of Se-Methylselenocysteine: triethylamine: 4-dimethylaminopyridine=1:0.005～0.05:0.005～0.05:0.01 adds Se-Methylselenocysteine, triethylamine and 4-dimethylaminopyridine, stir and spend the night under room temperature, add ether, the centrifugal resolution of precipitate obtained is in tetrahydrofuran (THF), with the classification of ether redeposition, finally obtain shown in formula (I) containing the selenium curcumin polymer.
10. as claimed in claim 1 containing the application of selenium curcumin polymer in preparing anti-hepatic fibrosis, anti-fatty liveranti-fatty liver or anti-liver cirrhosis medicine.
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