CN1283643A - Precursor of polyglycol carried taxusol or polyene taxusol - Google Patents
Precursor of polyglycol carried taxusol or polyene taxusol Download PDFInfo
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- CN1283643A CN1283643A CN00109748A CN00109748A CN1283643A CN 1283643 A CN1283643 A CN 1283643A CN 00109748 A CN00109748 A CN 00109748A CN 00109748 A CN00109748 A CN 00109748A CN 1283643 A CN1283643 A CN 1283643A
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- taxol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/65—Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
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Abstract
A precursor of polyglycol carried taxusol or polyene taxusol features that amino acid or oligopeptide is used to bond the polyglycol with taxusol or polyene taxusol to obtain the derivative compound of taxusol or polyene taxusol. The PEG-[-(X)-CH2C(O)-A-NH-CH(R)-C=O]n radical is bonded to OH at 2' position of the structure formula of taxusol or polyene taxusol to substitute H. Its advantages are high water solubility, and slow releasing.
Description
The present invention relates to a kind of polyglycol supported taxol or the prodrug of Docetaxel.It is the derivative compound that belongs to water-soluble paclitaxel or Docetaxel.
Taxol and Docetaxel treatment tumour have good curative effect by common people's cognition.When they during as a kind of injection therapeutic medicine because their water-soluble extreme difference, be difficult to be absorbed by the body and give full play to its drug effect.Therefore, existing clinical injection liquid all is to stablize taxol by usefulness polyoxyethylenated castor oil and dewatered ethanol with 1: 1 mixed solution, and compound concentration is a 6mg/ml solution, is diluted to final administration volume with physiological saline or 5% glucose again.Such paclitaxel injection, tensio-active agent wherein has comparatively serious hypersensitivity reaction side effect to patient.Therefore, the prodrug of exploitation water-soluble taxol or Docetaxel more and more is subject to people's attention.At present, the derivative of having developed water-soluble paclitaxel comprises amidates, Sulfonates, metal carboxylate, carbonates and phosphoric acid ester.
Purpose of the present invention is to provide a kind of polyglycol supported taxol or the prodrug of Docetaxel.This water-soluble paclitaxel or Docetaxel derivative compound have good water-solubility, and can reach the good slow release purpose by the regulating and controlling effect of human body endoenzyme, and the drug effect phase is long, the curative effect height.
For achieving the above object, the present invention is realized by following technical proposals.Utilize amino acid or oligopeptides water miscible polyoxyethylene glycol and taxol, or polyoxyethylene glycol and Docetaxel keyed jointing be constructed as follows the D51-7059 compound shown in formula 1 and the formula 2, i.e. the prodrug of taxol, and Docetaxel derivative compound, it is the prodrug of Docetaxel
Formula 1
Formula 2
It is characterized in that, in above two structural formulas, be positioned on 2 ' the locational OH base keyed jointing PEG-[(X) CH
2C (O)-A-NH-CH (R)-C=O] the n group, replace H, in the group, X is O, or is OCOCH
2Or be NH, or be NHCOCH
2A is a chemical single bond, or for being selected from (l)-L-Ala, (l)-and leucine, glycine, (l)-Isoleucine, (l)-proline(Pro), (l)-phenylalanine, (d)-phenylalanine, (dl)-phenylalanine, (dl)-a seed amino acid in the methionine(Met), perhaps be oligopeptides; R is amino acid whose residue; N equals 1 or equal 2;
A kind of prodrug of above-mentioned taxol or Docetaxel, its PEG molecular weight is 2000, X is OCOCH
2, A is a chemical single bond, and R is a leucine, and n equals 2;
A kind of prodrug of above-mentioned taxol or Docetaxel, its PEG molecular weight is 6000, X is OCOCH
2, A is a chemical single bond, and R is a leucine, and n equals 2;
A kind of prodrug of above-mentioned taxol or Docetaxel, its PEG molecular weight is 20000, X is OCOCH
2, A is a chemical single bond, and R is a leucine, and n equals 2;
A kind of prodrug of above-mentioned taxol or Docetaxel, its PEG molecular weight is 2000, X is OCOCH
2, A is a chemical single bond, and R is a proline(Pro), and n equals 2;
A kind of prodrug of above-mentioned taxol or Docetaxel, its PEG molecular weight is 6000, X is OCOCH
2, A is a chemical single bond, and R is a proline(Pro), and n equals 2;
A kind of prodrug of above-mentioned taxol or Docetaxel, its PEG molecular weight is 20000, X is OCOCH
2, A is a chemical single bond, and R is a proline(Pro), and n equals 2.
Below the present invention is described in detail.
The present invention utilizes polyoxyethylene glycol to be Zhi Zaiti, and its reason has 2 points, a bit is the further investigation through in recent years, has proved that polyoxyethylene glycol is nontoxic, suitable with biophase, protein repels, the good carrier of FFI and nonantigenic medicine; In addition, it has good water-solubility to reach and other organic good solubility again, helps carrying out the characteristic that chemical reaction is modified.And, can change the triplicity thing at people's body-internal-circulation cycle and release rate by the size of control molecular weight and the connecting arm between medicine and the polymkeric substance.For this reason, the present invention determines that molecular weight polyethylene glycol is advisable between 2000～20000, and wherein 2000,6000,20000 is best; If select excessive molecular weight polyethylene glycol for use, its solution viscosity is bigger, is unfavorable for transfusion, if molecular weight less than 2000, has then strengthened toxicity again, can not use.Synthetic preparation route of the present invention comprises following four steps:
1) the polymkeric substance polyglycol diacid of preparation functionalization, its main process be polyoxyethylene glycol through methylbenzene azeotropic dewaters after and excessive Succinic anhydried in the exsiccant chloroform, back flow reaction made in 48 hours under pyridine catalysis.
2) the active ester of preparation polyglycol diacid.Its main process be polyglycol diacid and maloyl imines in dimethyl formamide, under dicyclohexylcarbodiimide and Dimethylamino pyridine effect, room temperature reaction made in 6～20 hours.
3) polyglycol diacid and amino acid or oligopeptides is connected.Its main process is that the active ester of polyglycol diacid that said process makes is dissolved in dimethyl formamide, is added drop-wise in the sodium bicarbonate aqueous solution of amino acid or oligopeptides, and room temperature reaction made in 24 hours.
4) introducing of drug molecule.Its main process be with above-mentioned be connected with amino acid whose polyoxyethylene glycol and taxol or and Docetaxel, in the exsiccant methylene dichloride, under dicyclohexylcarbodiimide and Dimethylamino pyridine effect, the ice bath reaction is after 3 hours, and room temperature reaction made prodrug in 20 hours again.In the above-mentioned process, main synthetic route is shown below:
With the prepared taxol of above-mentioned steps and operational path or the prodrug of Docetaxel is white powder, and fusing point is between 36～60 ℃.
The external antitumour activity of the prodrug of the present invention's preparation is significantly better than taxol and Docetaxel.PEG for example
2K-SUC-Pro-Taxol and PEG
2K-SUC-Leu-Taxol to human breast cancer cell's (MCF-7) inhibiting rate 10
-11M is 84.7% and 61.1%, and taxol only is 43.1%.
With embodiment the present invention is further specified again below.
Embodiment one:
Polyoxyethylene glycol-2000-diacid-proline(Pro)-taxol (PEG
2K-SUC-Pro-Taxol)
1. polyoxyethylene glycol-2000-diacid (PEG
2K-SUC) synthetic
The polyoxyethylene glycol-2000 that takes by weighing 10.0g (0.005mol) is dissolved in the 50ml toluene and dewaters with the methylbenzene azeotropic distillation, treat that toluene steams 2/3rds backs and add 15ml trichloromethane and prior load weighted 5.0g (0.05mol) Succinic anhydried in reaction system, and add the pyridine of 2ml, 60 ℃ of left and right sides back flow reaction 48 hours.Evaporated under reduced pressure solvent after reaction finishes, the sodium bicarbonate aqueous solution that then in resistates, adds the 0.1M of 20ml, suction filtration again, filtrate is used the hydrochloric acid 20ml acidifying of 0.1N, with concentrated hydrochloric acid the pH value of solution value is transferred to 3-4, then at ethyl acetate washing water layer with 3 * 15ml, combined ethyl acetate solution adds anhydrous sodium sulfate drying, suction filtration solution after one hour with the saturated sodium-chloride water solution washing of 2 * 15ml, solvent in the rotation evaporate to dryness filtrate, the ethyl acetate heating that adds 2ml makes it the resistates dissolving, then adds a large amount of anhydrous diethyl ethers, freezing and crystallizing in ultrasonic concussion in solution, suction filtration, get white solid with a small amount of ether washing leaching cake, vacuum-drying is to constant weight, and 9.8g weighs, productive rate 89%, a fusing point 46.5-47.5 ℃ product need not purifying and is directly used in the next step.
2. polyoxyethylene glycol-2000-diacid-active ester (PEG
2K-SS) synthetic
5.0g polyoxyethylene glycol (2.28mmol)-2000-diacid (PEG
2k-SUC) be dissolved in the 25ml exsiccant methylene dichloride, and after being cooled to 0-5 ℃, the N-maloyl imines (NHS) that adds 1.04g (5.0 mmol) dicyclohexylcarbodiimide (DCC) and 0.58g is dissolved in the solution of 25ml methylene dichloride, and under this temperature stirring reaction 2 hours, reaction is 24 hours under the room temperature.After finishing, reaction,, adds anhydrous sodium sulfate drying with the washing of 30ml saturated nacl aqueous solution with the distilled water wash reaction solution of 30ml.One hour after-filtration, concentrated filtrate makes it dissolving at adding 30ml methylene dichloride and heating, refilter solution, add the heating of 3ml methylene dichloride behind the concentrated filtrate and make it dissolving, in ultrasonic concussion in the impouring 30ml anhydrous diethyl ether, freezing and crystallizing, suction filtration solution, get white solid with a small amount of ether washing leaching cake, vacuum-drying is to constant weight, 5.0g, productive rate 93% is surveyed 36-37 ℃ of fusing point.
3. polyoxyethylene glycol-2000-diacid-proline(Pro) (PEG2K-SUC-Pro) is synthetic
1.0g (0.418mmol) polyoxyethylene glycol-active ester of 2000-diacid (PEG2K-SS) is dissolved in 3ml exsiccant N, in the dinethylformamide (DMF), 0.1000g (1.0mmol) proline(Pro) is dissolved in 4ml 1M NaHCO3 solution, and ultrasonic concussion 10min makes it abundant dissolving, in the DMF of active ester solution, drip amino acid whose sodium hydrogen carbonate solution, reaction solution becomes muddiness and heat release, and stirring reaction is 24 hours under the room temperature.After reaction finishes, water and the N in the reaction system removed in underpressure distillation, dinethylformamide (DMF), resistates after the distillation is emitted a large amount of CO2 gases with the HCl dissolving of 20ml 2%, uses the dichloromethane extraction of 3 * 5ml again, the combining extraction liquid distilled water wash solution of 10ml, the washing of 10ml saturated nacl aqueous solution is used anhydrous sodium sulfate drying to clarification, filters, filtrate concentrates, the ether that adds 30ml, freezing and crystallizing, suction filtration, get white solid with a small amount of ether washing leaching cake, vacuum-drying is to constant weight, and 0.9800g surveys 41.5-42.5 ℃ of fusing point.
4. polyoxyethylene glycol-2000-diacid-proline(Pro)-taxol (PEG
2K-SUC-Pro-Taxol) synthetic
Elder generation is with polyoxyethylene glycol-2000-diacid-proline(Pro) (PEG of 100.0mg (about 0.0418mmol)
2K-SUC-Pro) add in the 50ml flask, the methylene dichloride that adds 10ml again with transfer pipet, in ice-water bath, be stirred to 0 ℃, the taxol (Taxol) that adds 100.0mg (0.1170mmol), 15.0mg (0.1030mmol) to dimethyl aminopyridine (DMAP) and 30.0mg (0.1450mmol) dicyclohexylcarbodiimide (DCC), stirring reaction is warming up to room temperature naturally, continues reaction 24hr.After reaction finishes, in reaction system, drip the HAC/THF solution of 1ml 10%.Add 10ml 0.1N HCl solution washing organic phase after ten minutes, after be washed with distilled water to neutrality, use the water in the saturated nacl aqueous solution flush away organic phase again, add a small amount of anhydrous sodium sulfate drying.A hour after-filtration, and concentrated filtrate add the 15ml dichloromethane solution again, filter with absorbent cotton, reconcentration filtrate, back add 2ml aqueous isopropanol freezing and crystallizing, and filtration under diminished pressure gets white solid, wash solid with ether, vacuum-drying is to constant weight, 0.0796g, fusing point 44-45 ℃.Content of taxol is 22%.
Embodiment two:
Polyoxyethylene glycol-6000-diacid-proline(Pro)-taxol (PEG
6K-SUC-Pro-Taxol)
The preparation therapy is identical with embodiment one, and each step underlying condition is: 1, polyoxyethylene glycol-6000-diacid (PEG
6K-SUC)
The polyoxyethylene glycol-6000 that takes by weighing 60.0g (0.0100mol) is dissolved in the 200ml toluene and dewaters with the methylbenzene azeotropic distillation, treat that toluene steams 2/3rds backs and add 100ml trichloromethane and prior load weighted 5.0g (0.05mol) Succinic anhydried in reaction system, and add the pyridine of 2ml, 60 ℃ of left and right sides back flow reaction 48 hours.Obtain product 52.0g, fusing point 54.0-55.5 ℃.2, polyoxyethylene glycol-6000-diacid-active ester (PEG
6K-SS)
31.0g polyoxyethylene glycol (5mmol)-6000-diacid (PEG-SUC) is dissolved in the 100ml toluene, after azeotropic anhydrates, be cooled to room temperature, add 100ml exsiccant methylene dichloride, and after being cooled to 0-5 ℃, adding is dissolved in 30ml N to the N-maloyl imines (NHS) of the dicyclohexylcarbodiimide of 2.0800g (DCC) and 1.2040g, dinethylformamide (DMF) solution, and under this temperature stirring reaction 2 hours, reaction is 24 hours under the room temperature.Obtain product 26.2g, productive rate 93%, fusing point 52.5-54.0 ℃.3, polyoxyethylene glycol-6000-diacid-proline(Pro) (PEG
6K-SUC-Pro)
With 3.0g (0.4827mmol) polyoxyethylene glycol-active ester (PEG of 6000-diacid
6K-SS) be dissolved in 10ml exsiccant N, in the dinethylformamide (DMF), 0.2000g (1.7mmol) proline(Pro) is dissolved in 4ml 1M NaHCO
3Solution, and ultrasonic concussion 10min makes it abundant dissolving, drips amino acid whose sodium hydrogen carbonate solution in the DMF of active ester solution, reaction solution becomes muddiness and heat release, and stirring reaction is 24 hours under the room temperature.Get product 2.2991g, productive rate 76%, fusing point 41.5-42.5 ℃.4, polyoxyethylene glycol-6000-diacid-proline(Pro)-taxol (PEG
6K-SUC-Pro-Taxol)
Elder generation is with polyoxyethylene glycol-6000-diacid-proline(Pro) (PEG of 0.2500g (about 0.0401mmol)
6K-SUC-Pro) add in the 50ml flask, the methylene dichloride that adds 10ml again with transfer pipet, in ice-water bath, be stirred to 0 ℃, the taxol (Taxol) that adds 100.0mg (0.1170mmol), 15.0mg (0.103mmol) to dimethyl aminopyridine (DMAP) and 30.0mg (0.1450mmol) dicyclohexylcarbodiimide (DCC), stirring reaction is warming up to room temperature naturally, continues reaction 24hr.Get prodrug 0) .2311g, productive rate 81%, content of taxol are 9.1%.
Embodiment three:
Polyoxyethylene glycol-20000-diacid-proline(Pro)-taxol (PERG
20K-SUC-Pro-Taxol)
The preparation method is identical with embodiment one, and each step underlying condition is: 1, polyoxyethylene glycol-20000-diacid (PEG
20K-SUC)
The polyoxyethylene glycol-20000 that takes by weighing 100.0g (0.01mol) is dissolved in the 300ml toluene and dewaters with the methylbenzene azeotropic distillation, treat that toluene steams 2/3rds backs and add 100ml trichloromethane and prior load weighted 5.0g (0.05mol) Succinic anhydried in reaction system, and add the pyridine of 2ml, 60 ℃ of left and right sides back flow reaction 48 hours.Get product 98.1g, fusing point 57.0-58.5 ℃.2, polyoxyethylene glycol-20000-diacid-active ester (PEG
20K-SS)
38.4g polyoxyethylene glycol-20000-diacid (PEG
20K-SUC) be dissolved in the 100ml toluene, after azeotropic anhydrates, be cooled to room temperature, add 100ml exsiccant methylene dichloride, and after being cooled to 0-5 ℃, adding the dicyclohexylcarbodiimide (DCC) of 2.0800g and the N-maloyl imines (NHS) of 1.2040g and be dissolved in 30ml N, dinethylformamide (DMF) solution, and under this temperature stirring reaction 2 hours, reaction is 24 hours under the room temperature.Get product 35.6g, productive rate 95% is surveyed 58.5-59.0 ℃ of fusing point.3, polyoxyethylene glycol-20000-diacid-proline(Pro) (PEG
20K-SUC-Pro)
With 5.0g (0.2473mmol) polyoxyethylene glycol-active ester (PEG of 20000-diacid
20K-SS) be dissolved in 25ml exsiccant N, in the dinethylformamide (DMF), 0.1200g (1.0400mmol) proline(Pro) is dissolved in 4ml 1M NaHCO
3Solution, and ultrasonic concussion 10min makes it abundant dissolving, drips amino acid whose sodium hydrogen carbonate solution in the DMF of active ester solution, reaction solution becomes muddiness and heat release, and stirring reaction is 24 hours under the room temperature.Get product 2.2913g, productive rate 45%.
4, polyoxyethylene glycol-20000-diacid-proline(Pro)-taxol (PEG
20K-SUC-Pro-Taxol)
Elder generation is with polyoxyethylene glycol-20000-diacid-proline(Pro) (PEG of 0.4000g (about 0.0197mmol)
20K-SUC-Pro) add in the 50ml flask, the methylene dichloride that adds 10ml again with transfer pipet, in ice-water bath, be stirred to 0 ℃, the taxol (Taxol) that adds 50.0mg (0.0585mmol), the dicyclohexylcarbodiimide (DCC) of 10mg to dimethyl aminopyridine (DMAP) and 20mg, stirring reaction is warming up to room temperature naturally, continues reaction 24 hours.Get product 0.3366g, productive rate 84%, content of taxol are 3.8%.
Polyglycol supported water-soluble paclitaxel of the present invention or Docetaxel prodrug have good aqueous solubility, by the regulating and controlling effect of enzyme, reach the good slow release purpose in human body, and the curative effect phase is long, the curative effect height, and its preparation route is simple, and cost is lower.
Claims (7)
1, a kind of polyglycol supported taxol or the prodrug of Docetaxel, utilize amino acid or oligopeptides water miscible polyoxyethylene glycol and taxol, or polyoxyethylene glycol and Docetaxel keyed jointing be constructed as follows the D51-7059 compound shown in formula 1 and the formula 2, it is the prodrug of taxol, and Docetaxel derivative compound, it is the prodrug of Docetaxel
Formula 1
Formula 2
It is characterized in that, in above two structural formulas, be positioned on 2 ' the locational OH base keyed jointing PEG-[(X) CH
2C (O)-A-NH-CH (R)-C=O] the n group, replace H, in the group, X is O, or is OCOCH
2Or be NH, or be NHCOCH
2A is a chemical single bond, or for being selected from (l)-L-Ala, (l)-and leucine, glycine, (l)-Isoleucine, (l)-proline(Pro), (l)-phenylalanine, (d)-phenylalanine, (dl)-phenylalanine, (dl)-a seed amino acid in the methionine(Met), perhaps be oligopeptides; R is amino acid whose residue; N equals 1 or equal 2;
2, the polyglycol supported taxol according to claim 1 or the prodrug of Docetaxel, it is characterized in that: its PEG molecular weight is 2000, X is OCOCH
2, A is a chemical single bond, and R is a leucine, and n equals 2;
3, the polyglycol supported taxol according to claim 1 or the prodrug of Docetaxel, it is characterized in that: its PEG molecular weight is 6000, X is OCOCH
2, A is a chemical single bond, and R is a leucine, and n equals 2;
4, the polyglycol supported taxol according to claim 1 or the prodrug of Docetaxel, it is characterized in that: its PEG molecular weight is 20000, X is OCOCH
2, A is a chemical single bond, and R is a leucine, and n equals 2;
5, the polyglycol supported taxol according to claim 1 or the prodrug of Docetaxel, it is characterized in that: its PEG molecular weight is 2000, X is OCOCH
2, A is a chemical single bond, and R is a proline(Pro), and n equals 2;
6, the polyglycol supported taxol according to claim 1 or the prodrug of Docetaxel, it is characterized in that: its PEG molecular weight is 6000, X is OCOCH
2, A is a chemical single bond, and R is a proline(Pro), and n equals 2;
7, the polyglycol supported taxol according to claim 1 or the prodrug of Docetaxel, it is characterized in that: its PEG molecular weight is 20000, X is OCOCH
2, A is a chemical single bond, and R is a proline(Pro), and n equals 2.
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| CN00109748A CN1125097C (en) | 2000-07-05 | 2000-07-05 | Precursor of polyglycol carried taxusol or polyene taxusol |
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| CN00109748A CN1125097C (en) | 2000-07-05 | 2000-07-05 | Precursor of polyglycol carried taxusol or polyene taxusol |
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| CN1125097C CN1125097C (en) | 2003-10-22 |
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| EP1274460A4 (en) * | 2000-04-15 | 2005-06-29 | Kolon Inc | Aqueous-prodrug compound comprising moiety of paclitxel or derivatives thereof, method of preparing same and pharmaceutical composition comprising same |
| WO2005092898A1 (en) * | 2004-03-29 | 2005-10-06 | Beijing Jenkem Technology Co., Ltd. | The conjugates of a hydrophilic polymer-tripterygium's extracts and the pharmaceutical compositions thereof |
| CN100431610C (en) * | 2006-01-24 | 2008-11-12 | 中国科学院长春应用化学研究所 | Amphiphilic tri-block copolymer-paclitaxel bonded drug and preparation method thereof |
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| US8003089B2 (en) | 2002-03-13 | 2011-08-23 | Beijing Jiankai Technology Co., Ltd. | Y shape branched hydrophilic polymer derivatives, their preparation methods, conjugates of the derivatives and drug molecules, and pharmaceutical compositions comprising the conjugates |
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| CN1743337B (en) * | 2004-09-03 | 2012-06-13 | 上海复旦张江生物医药股份有限公司 | Taxol derivative and its pharmaceutical composition |
| CN102614110A (en) * | 2012-04-27 | 2012-08-01 | 北京大学 | Stable polyethylene glycol medicinal micelle composition and preparation method thereof |
| CN101569747B (en) * | 2008-04-30 | 2012-08-22 | 宁波大学 | Preparation method of taxol prodrug using polyethylene glycol as carrier |
| CN101569748B (en) * | 2008-04-30 | 2012-08-22 | 宁波大学 | Water-soluble taxol prodrug prodrug preparation method |
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| CN101028259A (en) * | 1996-03-12 | 2007-09-05 | Pg－Txl有限公司 | Water soluble paclitaxel product |
| CN1164533A (en) * | 1997-01-09 | 1997-11-12 | 云南汉德技术发展有限公司 | Water-soluble anticancer compound-polyamino acid toxol ester |
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