CN101870769A - PEG (Polyethylene Glycol), mPEG (Methoxy Polyethylene Glycol) chemical modifier and method thereof for preparing water-soluble resveratrol prodrug - Google Patents
PEG (Polyethylene Glycol), mPEG (Methoxy Polyethylene Glycol) chemical modifier and method thereof for preparing water-soluble resveratrol prodrug Download PDFInfo
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Abstract
The invention discloses a PEG (Polyethylene Glycol)/mPEG (Methoxy Polyethylene Glycol) chemical modifier and a method thereof for preparing a water-soluble resveratrol prodrug. In the PEG/mPEG chemical modifier, PEG or mPEG is used as a vector, and the chemical modifier is prepared through reacting succinic anhydride, bromoacetate or isobutyl bromoacetate with amino acid. The preparation conditions and steps of the chemical modifier are simple. The chemical modifier is used for modifying the resveratrol to prepare the resveratrol prodrug, can change the water solubility and the stability of the resveratrol, is convenient to use and improves the bioactivity. When the prodrug is decomposed in vivo, amino acid required by the human body is also released while the resveratrol is released, thus the application scope of the prodrug is wider than that of the resveratrol.
Description
Technical field
The invention belongs to compound and pharmacy field, relate in particular to a kind of PEG, mPEG chemical modifier and preparation method, and make modifier with it and modify the method that trans-resveratrol prepares the water-soluble resveratrol prodrug.
Background technology
Trans-resveratrol (resveratrol, RES) chemistry by name 3,4 ', 5-trihydroxy-toluylene, it is a kind of modal diphenylethylene compounds, extensively exist in many plants such as grape, giant knotweed and black false hellebore, have antitumor, antibiotic, anti-inflammatory, antianaphylaxis, reducing blood-fat and various pharmacological activities such as anti-oxidant.But because trans-resveratrol comprises the toluylene mother nucleus structure, water-soluble is very poor, is insoluble in water, uses inconvenience, has limited its use range.In addition, trans-resveratrol character instability, oxidation easily, under UV-irradiation, change cis-configuration easily into, cause its bioactive reduction, therefore, improve the water solubility of trans-resveratrol, strengthening its stability is the key that improves its bioavailability and health-care effect.
The application of biocompatibility macromolecule polymkeric substance in natural drug is subjected to extensive concern in recent years, and wherein polyoxyethylene glycol and derivative thereof have obtained widespread use as the carrier of making pharmaceutical preparation in many commercial medicines.Polyoxyethylene glycol (being called for short PEG) has the wetting ability of height, bigger ydrodynamics volume is arranged in the aqueous solution, and there is not immunogenicity, when it is connected to drug molecule or medical surfaces, can the character that it is good give drug molecule, change their biologies in the aqueous solution and distribute behavior and solvability, increase the water solubility of medicine.For avoiding in modification, taking place crosslinked and reunite, also can adopt the synthesis material of mono methoxy polyethylene glycol (mPEG) as modifier.
Chinese invention patent application 2009100710372, a kind of " hydrophilic polymer---resveratrol conjugate and preparation method " disclosed, utilize mono methoxy polyethylene glycol (mPEG), mono methoxy polypropylene glycol exactly successively behind carboxylation reaction, acyl chloride reaction, again with trans-resveratrol prepared in reaction wetting ability resveratrol conjugate, that this product is compared with original trans-resveratrol is just water-soluble, stability is improved.
Summary of the invention
One object of the present invention, aim to provide a kind of amino acid whose PEG, mPEG chemical modifier and preparation method thereof of being connected with, the preparation method of this modifier is simple, can be used for modified compound molecule (comprising drug molecule), with to change water-soluble and stable by modifier, and make it when decomposing, to discharge the amino acid of needed by human body, and modifying the back compound functions increases, and range of application is more extensive.
Another object of the present invention has provided a kind of purposes of above-mentioned PEG, mPEG chemical modifier, promptly is used to modify trans-resveratrol and prepares the trans-resveratrol prodrug.Its preparation method is simple, and made prodrug is compared with trans-resveratrol has good water-solubility, and its stability improves, biological activity improves, and is easy to use, and prodrug discharges the amino acid of needed by human when discharging trans-resveratrol, the prodrug function is increased, and its range of application is more extensive.
The present invention will realize above-mentioned goal of the invention, and the technical scheme that is adopted is:
A kind of PEG, mPEG chemical modifier, molecular structural formula is as follows:
Wherein
The preparation method of described PEG, mPEG chemical modifier is a carrier with water-soluble PEG or mPEG, with Succinic anhydried, ethyl bromoacetate or bromide isobutyl acetate reaction, obtains PEG or mPEG carboxylic acid derivative, is connected with amino acid to be prepared from again.
The preparation method of above-mentioned PEG or mPEG carboxylic acid derivative is divided into two classes, and wherein: the preparation method who is undertaken by water-soluble carrier and Succinic anhydried prepared in reaction carries out according to the following steps order:
1. be solvent reaction with the chloroform with exsiccant carrier, Succinic anhydried, add pyridine, reflux;
2. boil off solvent, add saturated NaHCO
3Solution, ethyl acetate extraction, dilute hydrochloric acid is transferred pH2～3;
3. dichloromethane extraction, drying, concentrating under reduced pressure adds anhydrous diethyl ether, filter, vacuum-drying, the carboxylic end have PEG or the mPPEG or the mPEG carboxylic acid derivative of base.
The second class preparation method of PEG or mPEG carboxylic acid derivative is to be reacted by water-soluble carrier and ethyl bromoacetate or bromide isobutyl acetate to carry out, and its preparation method carries out according to the following steps order:
1. with carrier (PEG or mPEG) in toluene, boil off part toluene.(purpose of this step is that the water in the system is removed, and probably steams general 1/5th of toluene total amount and gets final product)
2. put to room temperature, ice bath adds NaH down and stirs 10--20min;
3. add ethyl bromoacetate or bromide isobutyl acetate, back flow reaction 20--28h;
4. reaction finishes, and filters, and the filtrate decompression steaming removes toluene, and resistates dissolves with methylene dichloride, concentrates, and stirs down and slowly pours ether into, separates out white solid, suction filtration, and vacuum-drying gets PEG or mPEG carboxylicesters;
5. the hydrolysis in NaOH solution of above-mentioned carboxylicesters is stirred down in room temperature reaction 3-5h;
6. under the frozen water cooling, regulate pH2～3 with hydrochloric acid soln, use dichloromethane extraction, merge organic layer, wash with water, anhydrous sodium sulfate drying spends the night, and removes methylene dichloride under reduced pressure, and residue Virahol recrystallization gets PEG or mPEG carboxylic acid derivative.
As qualification of the present invention, among the preparation method of PEG, mPEG chemical modifier, described amino acid is a kind of in glycine, L-Ala, Xie Ansuan, leucine, Isoleucine, phenylalanine, tryptophane or the proline(Pro).
Among the preparation method of described PEG, mPEG chemical modifier, being connected according to the following steps order between PEG or mPEG carboxylic acid derivative and amino acid carried out:
1. prepare corresponding PEG active ester or mPEG active ester
PEG or mPEG carboxylic acid derivative are dissolved in methylene dichloride, after the dissolving, temperature is reduced to 0～5 ℃, adds dicyclohexylcarbodiimide and N-hydroxy-succinamide, rise to room temperature, reaction finishes, the dicyclohexylurea (DCU) that generates in the elimination reaction, concentrating under reduced pressure, add anhydrous diethyl ether, filter, vacuum-drying gets PEG or mPEG active ester;
2. prepare target product PEG, mPEG chemical modifier
PEG or mPEG active ester are dissolved among the DMF, stir and make its dissolving, temperature is reduced to 0～5 ℃, drips amino acid whose NaHCO
3Solution rises to room temperature, stirring reaction, reaction finishes, and filters, and filtrate decompression is removed and desolvated, the resistates dissolve with hydrochloric acid solution is used dichloromethane extraction, merges organic layer, wash with water, anhydrous sodium sulfate drying spends the night, concentrating under reduced pressure, add anhydrous diethyl ether, filter vacuum-drying, must be connected with amino acid whose PEG, mPEG chemical modifier, i.e. target product PEG, mPEG chemical modifier.
The present invention also provides a kind of purposes of above-mentioned PEG, mPEG chemical modifier, is used for linking to each other by ester bond with trans-resveratrol, and preparation water-soluble resveratrol prodrug, its molecular structure is as follows:
Its preparation method carries out according to the following steps order:
1. PEG, mPEG chemical modifier are dissolved in the methylene dichloride, stir and make its dissolving;
2. temperature is reduced to 0～5 ℃, adds trans-resveratrol, dicyclohexylcarbodiimide, Dimethylamino pyridine, rises to room temperature, stirring reaction;
3. reaction finishes, and adds the dicyclohexylcarbodiimide of the THF solution of HAc with decomposing excessive;
4. with the dilute hydrochloric acid washing, dichloromethane extraction merges organic layer, wash with water, and anhydrous sodium sulfate drying, concentrating under reduced pressure is used the Virahol recrystallization, gets the trans-resveratrol prodrug.
As optimization of the present invention, the aforementioned molecular weight for preparing PEG related in the method for trans-resveratrol prodrug, mPEG is 2000～20000.Molecular weight to PEG, mPEG limits, and PEG, the mPEG chemical modifier of expression low-molecular-weight polymeric and high molecular polymerization all are suitable for preparing the trans-resveratrol prodrug.
Compared with prior art, the obtained technical progress of the present invention is:
Amino acid whose PEG of connection provided by the present invention or mPEG chemical modifier, has good chemical property, its preparation method is simple, product is water-soluble high with stability, can be used for modified compound molecule (comprising drug molecule) as trans-resveratrol, have the compound of alcoholic extract hydroxyl group or phenolic hydroxyl group etc., thereby improve the water-soluble and stable of them, so that these materials conveniently use, improve biological activity, when the extracorporeal releasing test proof is being decomposed, observe and discharged amino acid, this characteristic has increased the use properties of material, makes its range of application more extensive.
PEG provided by the present invention or mPEG chemical modifier are used to modify the purposes that trans-resveratrol prepares the trans-resveratrol prodrug, the experiment proved that solubleness improves in the water of trans-resveratrol, stability strengthens, biological activity improves, easy to use when making prodrug as medicine, this prodrug also is proved to be when carrying out extracorporeal releasing test when decomposing and observes the amino acid that has discharged needed by human body, and this characteristic increases the use properties of prodrug, makes its range of application more extensive than trans-resveratrol.
The present invention is described in further detail below in conjunction with specific embodiment.
Embodiment
Following examples only are used to illustrate the present invention, are not qualification of the present invention.
Embodiment 1 prepares the PEG chemical modifier with PEG6000, further this modifier is used to modify trans-resveratrol with preparation water-soluble resveratrol prodrug
Present embodiment may further comprise the steps:
(1) preparation of PEG6000 carboxylic acid derivative
Reaction formula is as follows:
Specific operation process: get dry PEG (polyoxyethylene glycol) 30g (0.005mol), be dissolved in the 200mL chloroformic solution, add Succinic anhydried 1.5g (0.015mol), stir, add the 2ml pyridine, reflux; Reaction 48h, reaction finishes and boils off solvent, the resistates saturated NaHCO of 100mL
3The solution dissolving, 30mL ethyl acetate extraction 3 times is transferred pH2～3 with the water of gained with dilute hydrochloric acid; Use dichloromethane extraction again, merge organic phase, washing is neutral, drying, and concentrating under reduced pressure adds anhydrous diethyl ether, separates out white solid PEG6000 carboxylic acid derivative;
(2) the PEG6000 active ester is synthetic
Reaction formula is as follows:
Concrete operations: get 5g (0.0008mol) PEG6000 carboxylic acid derivative, after the dissolving of 50mL methylene dichloride, temperature is reduced to 0～5 ℃, adds 0.33g (0.0016mol) DCC and N-hydroxy-succinamide (NHS) 0.18g (0.0016mol) that is dissolved in 10mLDFM, rise to room temperature, reaction finishes, the dicyclohexylurea (DCU) that generates in the elimination reaction, concentrating under reduced pressure, add anhydrous diethyl ether, filter, vacuum-drying gets the PEG6000 active ester.
(3) be connected with PEG6000 chemical modifier synthetic of glycine
Reaction formula is as follows:
Concrete operations: get PEG or mPEG active ester 3g (0.0005mol), be dissolved among the 15mLDMF, stirring makes its dissolving, temperature reduce to 0～5 ℃, drips the NaHCO of 0.14g (0.0018mol) glycine
3Solution 5ml rises to room temperature, stirring reaction, reaction finishes, and filters, and filtrate decompression is removed and desolvated, resistates 5% dissolving with hydrochloric acid is used dichloromethane extraction, merges organic layer, wash with water, anhydrous sodium sulfate drying spends the night, concentrating under reduced pressure, add anhydrous diethyl ether, filter, vacuum-drying must be connected with the PEG6000 chemical modifier of glycine.
(4) prepare the trans-resveratrol prodrug with the PEG6000 chemical modifier that is connected with glycine
Reaction formula is as follows:
Concrete operations: get the PEG6000 chemical modifier 0.5g (0.078mmol) that is connected with glycine and be dissolved in the methylene dichloride, stirring makes its dissolving, temperature is reduced to 0～5 ℃, add trans-resveratrol 0.005g (0.24mmol), 0.06g (0.27mmol) DDC, DMAP 0.03g (0.27mmol), rise to room temperature, stirring reaction, reaction finishes, the DCC of the THF solution decomposing excessive of the HAc of adding 10%, wash with 2% dilute hydrochloric acid, dichloromethane extraction merges organic layer, washes with water, anhydrous sodium sulfate drying, concentrating under reduced pressure is used the Virahol recrystallization, gets the trans-resveratrol prodrug.
Experimental results show that: the PEG6000 chemical modifier that is connected with glycine has good water-solubility and stability; The trans-resveratrol prodrug has good water-solubility, and is easy to use, and biological activity improves, and also discharges glycine when discharging trans-resveratrol.
Embodiment 2 prepares the PEG chemical modifier with PEG5000, further this modifier is used to modify trans-resveratrol with preparation water-soluble resveratrol prodrug
(1) preparation of PEG5000 carboxylic acid derivative
Reaction formula is as follows:
Concrete operations: get PEG5000 30g (0.006mol), be dissolved in the 150mL toluene, boil off 30mL toluene, be chilled to room temperature, ice bath adds NaH 0.43g (0.018mol) solution down, stirs 15min, be added dropwise to bromoethyl acetate 11g (0.066mol), back flow reaction 24h filters, and filtrate decompression is steamed and removed toluene, resistates dissolves with methylene dichloride, stir down and slowly pour ether into, separate out white solid, suction filtration, vacuum-drying, getting PEG or mPEG carboxylicesters, is the NaOH solution hydrolysis of 1mol/L in 120mL concentration, stirs down in room temperature reaction 4h.Under the frozen water cooling, make pH=3 with the adjusting of 2mol/L hydrochloric acid, use dichloromethane extraction, merge organic layer, wash with water, anhydrous sodium sulfate drying spends the night, and removes methylene dichloride under reduced pressure, and residue Virahol recrystallization gets the PEG5000 carboxylic acid derivative.
(2) the PEG5000 active ester is synthetic
Reaction formula is as follows:
Concrete operations: get 5g PEG5000 carboxylic acid derivative (0.001mol), after the dissolving of 50mL methylene dichloride, temperature is reduced to 0～5 ℃, adds 0.41g (0.002mol) DCC and N-hydroxy-succinamide (NHS) 0.23g (0.02mol) that is dissolved in 10mLDFM, rise to room temperature, reaction finishes, the dicyclohexylurea (DCU) that generates in the elimination reaction, concentrating under reduced pressure, add anhydrous diethyl ether, filter, vacuum-drying gets the PEG5000 active ester.
(3) be connected with PEG5000 chemical modifier synthetic of proline(Pro)
Reaction formula is as follows:
Concrete operations: with PEG5000 active ester 3g (0.0006mol), be dissolved among the 15mLDMF, stirring makes its dissolving, temperature reduce to 0～5 ℃, drips the NaHCO of 0.24g (0.0021mol) proline(Pro)
3Solution 5ml rises to room temperature, stirring reaction, reaction finishes, and filters, and filtrate decompression is removed and desolvated, resistates 5% dissolving with hydrochloric acid is used dichloromethane extraction, merges organic layer, wash with water, anhydrous sodium sulfate drying spends the night, concentrating under reduced pressure, add anhydrous diethyl ether, filter, vacuum-drying must be connected with the PEG5000 chemical modifier of proline(Pro).
(4) modify trans-resveratrol with the PEG5000 chemical modifier that is connected with proline(Pro), preparation trans-resveratrol prodrug
Reaction formula is as follows:
Concrete operations: get the PEG5000 chemical modifier 0.5g (0.098mmol) that is connected with proline(Pro), be dissolved in the methylene dichloride, stirring makes its dissolving, temperature is reduced to 0～5 ℃, add trans-resveratrol 0.06g (0.29mmol), DDC0.07g (0.34mmol), DMAP 0.04g (0.34mmol) rises to room temperature, stirring reaction, reaction finishes, the DCC of the THF solution decomposing excessive of the HAc of adding 10% is with the washing of 2% dilute hydrochloric acid, dichloromethane extraction, merge organic layer, wash anhydrous sodium sulfate drying, concentrating under reduced pressure with water, use the Virahol recrystallization, get the trans-resveratrol prodrug.
Experimental results show that: the PEG5000 chemical modifier that is connected with proline(Pro) has good water-solubility and stability; The trans-resveratrol prodrug has good water-solubility, and is easy to use, and biological activity improves, and has also discharged proline(Pro) when discharging trans-resveratrol.
Embodiment 3 prepares the PEG chemical modifier with mPEG4000, further this modifier is used to modify trans-resveratrol with preparation water-soluble resveratrol prodrug
(1) preparation of mPEG4000 carboxylic acid derivative
Reaction formula is as follows:
Concrete operations: get mPEG4000 30g (0.0075mol), be dissolved in the 150mL toluene, boil off 30mL toluene, be chilled to room temperature, ice bath adds 0.27g (0.011mol) solution down, stirs 20min, be added dropwise to monobromo-acetic acid isopropyl ester 8.5g (0.045mol), back flow reaction 20h filters, and filtrate decompression is steamed and removed toluene, resistates dissolves with methylene dichloride, stir down and slowly pour ether into, separate out white solid, suction filtration, vacuum-drying, getting PEG or mPEG carboxylicesters, is the NaOH solution hydrolysis of 1mol/L in 120mL concentration, stirs down in room temperature reaction 3h.Under the frozen water cooling, make pH=3 with the adjusting of 2mol/L hydrochloric acid, use dichloromethane extraction, merge organic layer, wash with water, anhydrous sodium sulfate drying spends the night, and removes methylene dichloride under reduced pressure, and residue gets the mPEG4000 carboxylic acid derivative with the Virahol recrystallization;
(2) the mPEG4000 active ester is synthetic
Reaction formula is as follows:
Concrete operations: will get 5g (0.0012mol) mPEG4000 carboxylic acid derivative, with after the 50mL methylene dichloride dissolving, temperature is reduced to 0～5 ℃, adds 0.25g (0.0012mol) DCC, is dissolved in N-hydroxy-succinamide (NHS) 0.14g (0.0012mol) of 10mLDFM, rise to room temperature, reaction finishes, the dicyclohexylurea (DCU) that generates in the elimination reaction, concentrating under reduced pressure, add anhydrous diethyl ether, filter, vacuum-drying gets the mPEG4000 active ester.
(3) be connected with mPEG4000 chemical modifier synthetic of L-Ala
Reaction formula is as follows:
Concrete operations: get 3g (0.0007mol) mPEG4000 active ester, be dissolved among the 15mLDMF, stirring makes its dissolving, temperature reduce to 0～5 ℃, drips the NaHCO of 0.12g (0.0014mol) L-Ala
3Solution 5ml rises to room temperature, stirring reaction, reaction finishes, and filters, and filtrate decompression is removed and desolvated, resistates 5% dissolving with hydrochloric acid is used dichloromethane extraction, merges organic layer, wash with water, anhydrous sodium sulfate drying spends the night, concentrating under reduced pressure, add anhydrous diethyl ether, filter, vacuum-drying must be connected with the mPEG4000 chemical modifier of L-Ala.
(4) the mPEG4000 chemical modifier that is connected with L-Ala is modified trans-resveratrol, preparation trans-resveratrol prodrug
Reaction formula is as follows:
Concrete operations: get the mPEG4000 chemical modifier 0.5g (0.12mmol) that is connected with L-Ala, be dissolved in the methylene dichloride, stirring makes its dissolving, temperature is reduced to 0～5 ℃, add trans-resveratrol 0.005g (0.24mmol), DDC0.05g (0.24mmol), DMAP 0.03g (0.24mmol) rises to room temperature, stirring reaction, reaction finishes, the DCC of the THF solution decomposing excessive of the HAc of adding 10% is with the washing of 2% dilute hydrochloric acid, dichloromethane extraction, merge organic layer, wash anhydrous sodium sulfate drying, concentrating under reduced pressure with water, use the Virahol recrystallization, get the trans-resveratrol prodrug.
Experimental results show that: the mPEG4000 chemical modifier that is connected with L-Ala has good water-solubility and stability; The trans-resveratrol prodrug has good water-solubility, and is easy to use, and biological activity improves, and has also discharged L-Ala when discharging trans-resveratrol.
Embodiment 4 prepares the PEG chemical modifier with mPEG4000, further this modifier is used to modify trans-resveratrol with preparation water-soluble resveratrol prodrug
(3) preparation of mPEG4000 carboxylic acid derivative
Reaction formula is as follows:
Concrete operations: get mPEG4000 30g (0.0075mol), be dissolved in the 150mL toluene, boil off 30mL toluene, be chilled to room temperature, ice bath adds 0.27g (0.011mol) solution down, stirs 10min, be added dropwise to monobromo-acetic acid isopropyl ester 8.5g (0.045mol), back flow reaction 28h filters, and filtrate decompression is steamed and removed toluene, resistates dissolves with methylene dichloride, stir down and slowly pour ether into, separate out white solid, suction filtration, vacuum-drying, getting PEG or mPEG carboxylicesters, is the NaOH solution hydrolysis of 1mol/L in 120mL concentration, stirs down in room temperature reaction 5h.Under the frozen water cooling, make pH=3 with the adjusting of 2mol/L hydrochloric acid, use dichloromethane extraction, merge organic layer, wash with water, anhydrous sodium sulfate drying spends the night, and removes methylene dichloride under reduced pressure, and residue gets the mPEG4000 carboxylic acid derivative with the Virahol recrystallization;
(4) the mPEG4000 active ester is synthetic
Reaction formula is as follows:
Concrete operations: get mPEG4000 carboxylic acid derivative 5g (0.0012mol), with after the 50mL methylene dichloride dissolving, temperature is reduced to 0～5 ℃, adds 0.25g (0.0012mol) DCC, is dissolved in N-hydroxy-succinamide (NHS) 0.14g (0.0012mol) of 10mLDFM, rise to room temperature, reaction finishes, the dicyclohexylurea (DCU) that generates in the elimination reaction, concentrating under reduced pressure, add anhydrous diethyl ether, filter, vacuum-drying gets the mPEG4000 active ester.
(3) be connected with mPEG4000 chemical modifier synthetic of L-Ala
Reaction formula is as follows:
Concrete operations: get mPEG4000 active ester 3g (0.0007mol), be dissolved among the 15mLDMF, stirring makes its dissolving, temperature reduce to 0～5 ℃, drips the NaHCO of 0.12g (0.0014mol) L-Ala
3Solution 5ml rises to room temperature, stirring reaction, reaction finishes, and filters, and filtrate decompression is removed and desolvated, resistates 5% dissolving with hydrochloric acid is used dichloromethane extraction, merges organic layer, wash with water, anhydrous sodium sulfate drying spends the night, concentrating under reduced pressure, add anhydrous diethyl ether, filter, vacuum-drying must be connected with the mPEG4000 chemical modifier of L-Ala.
(4) the mPEG4000 chemical modifier that is connected with L-Ala is modified trans-resveratrol, preparation trans-resveratrol prodrug
Reaction formula is as follows:
Concrete operations: get the mPEG4000 chemical modifier 0.5g (0.12mmol) that is connected with L-Ala, be dissolved in the methylene dichloride, stirring makes its dissolving, temperature is reduced to 0～5 ℃, add trans-resveratrol 0.005g (0.24mmol), DDC0.05g (0.24mmol), DMAP 0.03g (0.24mmol) rises to room temperature, stirring reaction, reaction finishes, the DCC of the THF solution decomposing excessive of the HAc of adding 10% is with the washing of 2% dilute hydrochloric acid, dichloromethane extraction, merge organic layer, wash anhydrous sodium sulfate drying, concentrating under reduced pressure with water, use the Virahol recrystallization, get the trans-resveratrol prodrug.
Experimental results show that: the mPEG4000 chemical modifier that is connected with L-Ala has good water-solubility and stability; The trans-resveratrol prodrug has good water-solubility, and is easy to use, and biological activity improves, and has also discharged L-Ala when discharging trans-resveratrol.
Certainly, the specific embodiment of the present invention is not limited to above several specific embodiments, the equivalent transformation that various ways can be arranged between its various features, various feature can be selected one as amino acid whose kind and select between glycine, L-Ala, Xie Ansuan, leucine, Isoleucine, phenylalanine, tryptophane and proline(Pro); The molecular weight of PEG and mPEG can be adjusted between 2000-20000; The concrete numerical value of the control condition among the preparation method is adjusted in the restricted portion etc. in the claims.In every case be the PEG chemical modifier that spirit realized that do not break away from claim of the present invention, its preparation method, purposes, prepare the method for water-soluble resveratrol prodrug as modifier, all think to fall within protection scope of the present invention with it.
Claims (9)
1. a PEG, mPEG chemical modifier, it is characterized in that: its molecular structural formula is as follows:
Wherein
2. method for preparing PEG as claimed in claim 1, mPEG chemical modifier, it is characterized in that: described PEG, mPEG chemical modifier are carrier with water-soluble PEG or mPEG, with Succinic anhydried, ethyl bromoacetate or bromide isobutyl acetate reaction, obtain PEG or mPEG carboxylic acid derivative, be connected with amino acid again and be prepared from.
3. the preparation method of 2 described PEG, mPEG chemical modifier as requested, it is characterized in that: described PEG or mPEG carboxylic acid derivative are to be made by water-soluble carrier PEG, mPEG and Succinic anhydried reaction, and its preparation method carries out according to the following steps order:
1. be solvent reaction with the chloroform with exsiccant carrier, Succinic anhydried, add pyridine, reflux;
2. boil off solvent, add saturated NaHCO
3Solution, ethyl acetate extraction, dilute hydrochloric acid is transferred pH2～3;
3. dichloromethane extraction, drying, concentrating under reduced pressure adds anhydrous diethyl ether, filter, vacuum-drying, PEG or mPEG carboxylic acid derivative.
4. the preparation method of PEG according to claim 2, mPEG chemical modifier, it is characterized in that: described PEG or mPEG carboxylic acid derivative, be to be reacted by water-soluble carrier PEG, mPEG and ethyl bromoacetate or bromide isobutyl acetate to prepare, its preparation method carries out according to the following steps order:
1. carrier is dissolved in the toluene, boils off part toluene;
2. put to room temperature, ice bath adds NaH down and stirs 10--20min;
3. add ethyl bromoacetate or bromide isobutyl acetate, back flow reaction 20--28h;
4. reaction finishes, and filters, and the filtrate decompression steaming removes toluene, and resistates dissolves with methylene dichloride, concentrates, and stirs down and slowly pours ether into, separates out white solid, suction filtration, and vacuum-drying gets PEG or mPEG carboxylicesters;
5. the hydrolysis in NaOH solution of above-mentioned carboxylicesters is stirred down in room temperature reaction 3-5h;
6. under the frozen water cooling, regulate pH2～3 with hydrochloric acid soln, use dichloromethane extraction, merge organic layer, wash with water, anhydrous sodium sulfate drying spends the night, and removes methylene dichloride under reduced pressure, and residue Virahol recrystallization gets PEG or mPEG carboxylic acid derivative.
5. as the preparation method of each described PEG, mPEG chemical modifier among the claim 2-4, it is characterized in that: described amino acid is a kind of in glycine, L-Ala, Xie Ansuan, leucine, Isoleucine, phenylalanine, tryptophane or the proline(Pro).
6. according to the preparation method of each described PEG, mPEG chemical modifier among the claim 2-4, it is characterized in that: the preparation method who is connected the described PEG of preparation, mPEG chemical modifier by PEG or mPEG carboxylic acid derivative with amino acid carries out according to the following steps order:
1. prepare corresponding PEG active ester or mPEG active ester
PEG or mPEG carboxylic acid derivative are dissolved in methylene dichloride, after the dissolving, temperature is reduced to 0～5 ℃, adds dicyclohexylcarbodiimide and N-hydroxy-succinamide, rise to room temperature, reaction finishes, the dicyclohexylurea (DCU) that generates in the elimination reaction, concentrating under reduced pressure, add anhydrous diethyl ether, filter, vacuum-drying gets PEG or mPEG active ester;
2. prepare target product PEG, mPEG chemical modifier
PEG or mPEG active ester are dissolved among the DMF, stir and make its dissolving, temperature is reduced to 0～5 ℃, drips amino acid whose NaHCO
3Solution rises to room temperature, stirring reaction, reaction finishes, and filters, and filtrate decompression is removed and desolvated, the resistates dissolve with hydrochloric acid solution is used dichloromethane extraction, merges organic layer, wash with water, anhydrous sodium sulfate drying spends the night, concentrating under reduced pressure, add anhydrous diethyl ether, filter vacuum-drying, must be connected with amino acid whose PEG chemical modifier, i.e. target product PEG, mPEG chemical modifier.
7. the preparation method of PEG according to claim 5, mPEG chemical modifier is characterized in that: the preparation method who is connected the described PEG of preparation, mPEG chemical modifier by PEG or mPEG carboxylic acid derivative with amino acid carries out according to the following steps order:
1. prepare corresponding PEG active ester or mPEG active ester
PEG or mPEG carboxylic acid derivative are dissolved in methylene dichloride, after the dissolving, temperature is reduced to 0～5 ℃, adds dicyclohexylcarbodiimide and N-hydroxy-succinamide, rise to room temperature, reaction finishes, the dicyclohexylurea (DCU) that generates in the elimination reaction, concentrating under reduced pressure, add anhydrous diethyl ether, filter, vacuum-drying gets PEG or mPEG active ester;
2. prepare target product PEG, mPEG chemical modifier
PEG or mPEG active ester are dissolved among the DMF, stir and make its dissolving, temperature is reduced to 0～5 ℃, drips amino acid whose NaHCO
3Solution rises to room temperature, stirring reaction, reaction finishes, and filters, and filtrate decompression is removed and desolvated, the resistates dissolve with hydrochloric acid solution is used dichloromethane extraction, merges organic layer, wash with water, anhydrous sodium sulfate drying spends the night, concentrating under reduced pressure, add anhydrous diethyl ether, filter vacuum-drying, must be connected with amino acid whose PEG chemical modifier, i.e. target product PEG, mPEG chemical modifier.
8. the preparation method of a water-soluble resveratrol prodrug is characterized in that: PEG, mPEG chemical modifier linked to each other by ester bond with trans-resveratrol, and preparation water-soluble resveratrol prodrug, its molecular structure is as follows:
Its preparation method carries out according to the following steps order:
1. PEG, mPEG chemical modifier are dissolved in the methylene dichloride, stir and make its dissolving;
2. temperature is reduced to 0～5 ℃, adds trans-resveratrol, dicyclohexylcarbodiimide, Dimethylamino pyridine, rises to room temperature, stirring reaction;
3. reaction finishes, and adds the dicyclohexylcarbodiimide of the THF solution of HAc with decomposing excessive;
4. with the dilute hydrochloric acid washing, dichloromethane extraction merges organic layer, wash with water, and anhydrous sodium sulfate drying, concentrating under reduced pressure is used the Virahol recrystallization, gets the trans-resveratrol prodrug.
9. the preparation method of water-soluble resveratrol prodrug according to claim 8 is characterized in that: the molecular weight of described PEG, mPEG is 2000～20000.
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