CN1995094A - Multiple-arm polyethylene glycol with functional group at long chain end, its preparation method and uses - Google Patents
Multiple-arm polyethylene glycol with functional group at long chain end, its preparation method and uses Download PDFInfo
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- CN1995094A CN1995094A CNA2006101476716A CN200610147671A CN1995094A CN 1995094 A CN1995094 A CN 1995094A CN A2006101476716 A CNA2006101476716 A CN A2006101476716A CN 200610147671 A CN200610147671 A CN 200610147671A CN 1995094 A CN1995094 A CN 1995094A
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Abstract
The invention discloses a new multiple-arm carbowax and making method and application in the macromolecular material technical domain, which is characterized by the following: possessing active functional group on one end of arm; fitting for decorating micromolecular drug, protein and peptide drug; modifying the solubility, stability and immunity of drug; lengthening the half-life of drug.
Description
Technical field
The invention belongs to technical field of polymer materials, be specifically related to a kind of activity functional groups in the multi-arm polyethylene glycol of long-chain end and preparation method thereof and the application in medication preparation.
Background technology
At present, antitumor drug of a great variety divided with regard to its molecular weight size, and generally can be divided into two big classes: the molecule amount is lower, usually below 1000, the overwhelming majority is common chemical synthetic drugs and some natural drugs, as mustargen, cis-platinum, 5 FU 5 fluorouracil, taxol etc. all belong to these row; Another kind of then molecular weight is bigger, and most protein and polypeptide drugs of being produced by genetically engineered then belong to second class.But no matter small-molecule drug or macromolecular drug, shortcoming such as it is big all to exist toxicity, poorly soluble, and the transformation period is short.Concerning protein and polypeptide drugs, also there is the problem of an immunity.
The polymkeric substance binding medicine that will have biocompatibility is an approach of dealing with problems.Caliceti, T. etc. have reported the reaction of modifying superoxide-dismutase with Polyvinylpyrolidone (PVP) at J.Bioactive Compatible Polym.10:103-120 (1995); Uren, J.R. etc. are at Cancer Res.39, and 1927-1933 (1981) has then reported the modification reaction of poly DL-L-Ala to the altheine enzyme.What report was maximum in document and the patent then is the modification reaction that various medicines is carried out with various activated polyglycol (PEG).As Nandini, K is at Eur.Pat.87304703.9, and Mike.A has described the reaction of tumour necrosis factor (TNF) and PEG at PCT/US98/00683 etc.; Gilbert, C.W. etc. are in U.S. Pat 5951974, and US5981709 and US6042822 have reported the modification reaction of PEG to interferon-' alpha '.Similarly reaction as interleukin-2 (Rrakash, R.K., US6251866) and PEG; The granular leukocyte macrophage colony factor (GM-CSF) and PEG (Knusli, C etc., Br.J.Haematl, 82 (4), 654-663 (1992); Malik, E etc., Exp.Hemaol, 20 (8), 1028-1035 (1992)); Tethelin and PEG etc. can find in numerous documents and patent.
In the modification reaction of PEG, maximum active group of usefulness is by the ester group of succinimide, aldehyde radical, trifluoro sulfonate group, p-nitrophenyl carbonate group and benzotriazole carbonate group etc.And PEG commonly used has a line style and two kinds of two arm branch types, and its molecular weight is between 2,000～60,000, and an end wherein is by alkylation (Monfardini, C.et al.BioconjugateChem.6:62-69 (1995)).
As everyone knows, the structure of performance behind the medicine high molecular and used macromolecular material, molecular weight, molecular weight distribution and high molecular configuration are relevant.Same structure, the polymer of different molecular weight can produce different character behind modified medicaments; Same structure, the same molecular amount, but the different polymer of configuration also can produce very big difference behind modified medicaments.The several problems that exist when protein or other medicines are carried out Pegylation made the advantage of binding substances of prepared polyoxyethylene glycol/protein or medicine be difficult to realize in the past.The first and protein-coupled multi-arm polyethylene glycol active function groups are positioned at the junction of arm, like this with protein-coupled sterically hindered bigger, are unfavorable for that reaction carries out.It is two because coupled reaction lacks selectivity, and the activity of proteins position is probably reacted, thereby loses biological activity.It three is for the protein that a plurality of reflecting points are arranged, and the position of the better controlled reaction is difficulty relatively in general, and this makes the quality of binding substances be difficult to control.
Summary of the invention
The purpose of this invention is to provide a kind of activity functional groups in the multi-arm PEG of long-chain end and preparation method thereof and the application in medicine.Compare with the line style and the two arm PEG of same molecular amount, the static viscosity of the type multi-arm PEG is little, and hydrodynamic volume is big, can produce more efficiently physiological action to pharmaceutical grade protein.Multi-arm fork type PEG in the arm junction compares with activity functional groups, and its active end group is at the end of long-chain, and is sterically hindered less, is more conducive to the coupled reaction with drug molecule.
The activity functional groups that the present invention proposes is at the multi-arm PEG of long-chain end, is PEG is combined and to obtain through chemical reaction by the trifunctional micromolecular compound.The multi-arm PEG of this functionalization is designated as (R-PEG)
z-X-PEG-F, wherein R is the following straight-chain paraffins of 10 carbon, sec.-propyl or benzyl; Z represents the arm number, is the integer of 1-8; X is a point of contact, i.e. the trifunctional micromolecular compound; PEG is a polyoxyethylene glycol, and F represents activity functional groups, for example is terminal functionality etc.;
PEG is connected with covalent linkage with the trifunctional micromolecular compound, and linking group is selected from amide group, inferior amide group, carbamate, ester group, epoxy group(ing), carboxyl, hydroxyl, sulfydryl or carbohydrate, or several combinations a kind of wherein; The structural formula of used trifunctional micromolecular compound is a kind of of following A, B, C, D, E and F:
Here, n is 1～9 integer, and m is 0～6 integer;
For example, when trifunctional micromolecular compound X wherein be H
2N (CH
2)
nCH (NH
2) CO
2H (n is the integer of 1-9) when linking group is amide group or carbamate, is the eight arm polyoxyethylene glycol ((R-PEG) of active end group at the long-chain end
8-X-PEG-F), its structural formula is as follows:
Here, R is the following straight-chain paraffins of 10 carbon, and sec.-propyl or benzyl are preferentially selected methyl;
N is 1～9 integer;
K is 0～6 integer;
S, t, o, p are 10～2,000 integer;
W is one of O, S or NH;
F is one of following functional group:
H，OH，NH
2，
The active PEG of the fork type of other arm numbers has and above-mentioned (R-PEG)
8The similar structure of-X-PEG-F, concrete structure will be according to concrete arm numbers and are different.For example, in the structure of seven arm PEG, replace one two arm configuration in the eight arm PEG structures with having a strand PEG, and in the structure of six arm PEG, then contain six strand PEG, the rest may be inferred.Wherein, the molecular weight of every arm PEG is 400～80,000.
The preparation method of above-mentioned multi-arm polyethylene glycol is as follows: earlier by strand polyoxyethylene glycol and the reaction of trifunctional micromolecular compound, and then all have the PEG reaction of active group by two ends, promptly obtain active group and gather di-alcohol at the multi-arm of long-chain end.
Among the present invention, the active group of described trifunctional micromolecular compound (X) is carboxyl and two amino, perhaps is carboxyl and two carboxyls.Be specifically as follows aforementioned structural formula (A), (B), (C), (D), (E) and (F) a kind of.
Among the present invention, the molecular weight of every arm PEG is 400-80000.By the control reaction, on the basis of the active PEG for preparing single armed or both arms, prepare the polyoxyethylene glycol of active group respectively at 3 arms, 4 arms, 5 arms, 6 arms, 7 arms or 8 arms of long-chain end.
The synthetic method of two arm fork type PEG is existing in the art to be described, for example, and Yamsuki etc., Agric.Bio.Chem.1998,52,2185-2196; Monfardini etc., Bioconjugate Chem.1995，6，62-69。In the present invention, these documents all are introduced into as a reference.
Active end group is similar in the preparation method of the multi-arm PEG of long-chain end, and when X is Methionin (Lysine), W is NH, and n is 4, and k is 0, and F is NH
2The time, can prepare active end group NH by following reaction scheme
2Three arm fork type PEG ((R-PEG) at the PEG end
3-Lys-PEG-NH
2), the active PEG of wherein used single armed and both arms can prepare according to people's such as above-mentioned Monfardini method.
Come activated carboxyl by the p-nitrophenyl phenolic ester in the above-mentioned route, also can come carboxyl is activated, as succinimide ester with the method that generates other active ester.
Obviously,, only need in preparation process, as required reaction conditions suitably to be controlled, just can prepare the multi-arm PEG of active end group with comparalive ease at the long-chain end according to top route.In conjunction with of the present invention open, this point will be conspicuous for the person skilled in the art of this area.
Active end group provided by the invention can be used for the preparation of medicine at the multi-arm PEG of long-chain end.As being widely used in the modification of small-molecule drug, protein and polypeptide drugs, promptly the activity functional groups by the long-chain end combines with small-molecule drug, polypeptide or pharmaceutical grade protein.Here Chlorambucil, Shun , 5-fluor-uracil, taxol, Zorubicin or the Rheumatrex in small-molecule drug such as the antitumor drug; Pharmaceutical grade protein such as Interferon, rabbit, interleukin, tumour necrosis factor, somatomedin, G CFS, erythropoietin or superoxide-dismutase.The concrete operations of modifying can be with reference to the method for strand PEG, and this is existing the description in this area.As:Greenwald etc., Bioorg.Med.Chem.Lett.1994,4,2465; Caliceti etc., IL Farmaco, 1993,48,919; Zalipsky and Lee, " polyoxyethylene glycol chemistry:biotechnology and biomedical applications ", J.M.Harris compiles, Plenum Press, N.Y., 1992.At this that these documents are open, all be incorporated herein by reference.Use the medicine of macromolecular material modification of the present invention, can improve solvability, stability and the immunogenicity of medicine,, improve curative effect with the transformation period of prolong drug.
Actual tests shows that the present invention has following advantage: one because the activity functional groups of multi-arm PEG of preparation is positioned at the end of long-chain, increased with drug molecule on the probability of collision of reactive group, improved reaction efficiency.They are two years old, because active end group is big at the hydrodynamic volume of the multi-arm PEG of long-chain end, when it with after certain position on the protein combines, owing to sterically hindered effect, other positions just are difficult to the reaction with another multi-arm PEG, thereby have improved the selectivity to combining site.Its three, can control its hydrodynamic volume by arm number and the molecular weight of control multi-arm PEG, make its inaccessibility activity of proteins position, the polyoxyethylene glycol/protein conjugate of gained can keep higher biological activity like this.They are four years old, because the existence of multi-arm structure, make multi-arm PEG more effectively to stop macromole or cell, thereby further improve binding substances round-robin time in vivo, reduce immunoreactive generation than linear PEG or two arm bifurcated PEG near protein surface.
Embodiment
The present invention obtains further instruction in following embodiment.These embodiment are for illustrative purposes, rather than are used for limiting the scope of the invention.For convenience of explanation, in following embodiment, the R base is a methyl, and mPEG refers to mono methoxy PEG, and wherein characterizing method GPC refers to gel permeation chromatography, and MALDI is substance assistant laser desorpted/ionization massspectrum.
Embodiment one
The mPEG of different brachiums
3-Lys-PEG-NH
2Preparation (p-nitrophenyl phenolic ester activation method)
With Methionin (439mg, 3mmol) being dissolved in the 20mlpH value is in 8.0～8.3 the water, then in 3 hours to wherein add mPEG in batches
2-Lys-CO
2PhNO
2(wherein an arm is 7000 for two arm mPEG p-nitrophenyl phenolic esters, molecular weight 10000, and another arm is 3000,10g, and 1mmol), the NaOH with 0.2mol/L comes the pH value of maintenance system 8.3 simultaneously.After stirred overnight at room temperature, reactant is cooled to 0 ℃, and the pH value of system is adjusted to 3 with the hydrochloric acid of 2mol/L.Now extract impurity with ether from water, extract three times continuously with chloroform, extracting solution is added dropwise in the anhydrous diethyl ether after concentrating, and obtains white precipitate, and gained precipitates behind twice recrystallization of ethanol, obtains mPEG
2Mono-substituted Methionin (mPEG
2-mono-Lysine).Product is through amino titration, and GPC and MALDI characterize, and its purity reaches 99%.
(9g in anhydrous methylene chloride 0.9mmol) (30mL), adds triethylamine (TEA) and reaches 8 until the pH value to being dissolved with the said products.MPEG-Lys-CO
2PhNO
2(5.025g 1.05mmol) added within three hours in the reaction solution in batches for single armed mPEG p-nitrophenyl phenolic ester, molecular weight 5000, used the pH value of TEA maintenance system simultaneously about 8.Reactant was cooled off by room temperature after refluxing 72 hours, after concentrating, filtered, and used ether sedimentation, used the small amount of ethanol recrystallization then.Excessive mPEGCO
2PhNO
2At PH 9～10 Na
2CO
3Stir in the buffered soln and be hydrolyzed after spending the night, solution is chilled to 0 ℃, and is adjusted to 3 with the pH value of the hydrochloric acid system of 2mol/L.Then by the p-NP in the ether extraction solution.Extract three times continuously with chloroform, the extracting solution drying concentrates the back with the anhydrous diethyl ether precipitation, uses the dehydrated alcohol recrystallization then again.Products therefrom is further purified with QAESephadexA50 post (5 * 80cm, the borate buffer solution of leacheate: pH=8.9), obtains mPEG
3-Lys-CO
2H, its functional end-group are carboxyl.Product is through the carboxyl titration, and GPC and MALDI characterize, and purity reaches 99%.
At 0 ℃, to being dissolved with above-mentioned mPEG
3-Lys-CO
2H (three arm mPEG carboxylic acid derivative 9g, 0.6mmol) anhydrous methylene chloride (20mL) in add p-NP (0.167g, 1.2mmol) and DCC (0.48g, 1.2mmol), after the stirred overnight at room temperature, filter, precipitate with anhydrous diethyl ether after the concentrating filter liquor, through re-crystallizing in ethyl acetate, obtain carboxyl end group again by p-nitrophenyl phenolic ester activatory three arm PEG (mPEG
3-Lys-CO
2PhNO
2).Product is measured the uv-absorbing of para-nitrophenoxide anion under alkaline condition after hydrolysis, show that active ester content reaches more than 98%.With two ends is NH
2(molecular weight 2,000,5g 2.5mmol) are dissolved in the anhydrous methylene chloride (20mL) PEG of group, and regulating the pH value with triethylamine is 8.In this solution, add mPEG in batches
3-Lys-CO
2PhNO
2(7.55g 0.5mmol), adds in two hours and finishes, simultaneously with the pH value of TEA maintenance system about 8.After reactant refluxed 72 hours, the room temperature cooling after concentrating, was filtered, and uses ether sedimentation, uses the small amount of ethanol recrystallization then.Products therefrom is further purified with QAESephadexA50 post (5 * 80cm, the borate buffer solution of leacheate: pH=8.9), obtains mPEG
3-Lys-PEG-NH
2Product is through amino titration, and GPC and MALDI characterize, and purity reaches 99%.
Embodiment 2
The mPEG of different brachiums
3-Lys-PEG-NH
2Preparation (N-hydroxy-succinamide ester activation method)
The N-hydroxy-succinamide that p-NP in the foregoing description 1 is changed into equivalent gets final product.
Embodiment 3
The mPEG of different brachiums
4-Lys-PEG-NH
2Preparation (p-nitrophenyl phenolic ester activation method)
To being dissolved with product mPEG described in the embodiment 1
2(molecular weight 10000,9g in anhydrous methylene chloride 0.9mmol) (20mL), add triethylamine (TEA) and reach at 8 o'clock until pH value-mono-Lysine.MPEG
2CO
2PhNO
2(molecular weight 10000, wherein an arm is 6000, and another arm is 4000, and 10.5g 1.05mmol) added in three hours in the reaction solution in batches, and the pH value of using the TEA maintenance system simultaneously is about 8.Reactant was cooled to room temperature after refluxing 72 hours, after concentrating, filtered, and used ether sedimentation, used the small amount of ethanol recrystallization then.Excessive mPEG
2-CO
2PhNO
2Stir in the buffered soln of pH value 9-10 and be hydrolyzed after spending the night, solution is chilled to 0 ℃, and is adjusted to 3 with the pH value of the hydrochloric acid system of 2mol/L.Then by the p-NP in the ether extraction solution.Extract three times continuously with chloroform, the extracting solution drying concentrates the back with the anhydrous diethyl ether precipitation, uses the dehydrated alcohol recrystallization then again.Products therefrom obtains very pure mPEG after separating with QAESephadexA50 post (5 * 80cm, the borate buffer solution of leacheate: PH=8.9)
4-Lys-CO
2H, its functional end-group are carboxyl.Product is through the carboxyl titration, and GPC and MALDI characterize, and purity is 98.5%.
At 0 ℃, to being dissolved with above-mentioned mPEG
4-Lys-CO
2H (12g, 0.6mmol) anhydrous methylene chloride (25mL) in add p-NP (0.167g, 1.2mmol) and DCC (0.48g, 1.2mmol), after stirring is spent the night under the room temperature, filter, precipitate with anhydrous diethyl ether after the concentrating filter liquor, through re-crystallizing in ethyl acetate, obtain carboxyl end group again by p-nitrophenyl phenolic ester activatory four arm PEG (mPEG
4-Lys-CO
2PhNO
2), purity 98%.With two ends is NH
2(molecular weight 2,000,5g 2.5mmol) are dissolved in the anhydrous methylene chloride (20mL) PEG of group, and regulating the pH value with triethylamine is 8.In this solution, add mPEG in batches
4-Lys-CO
2PhNO
2(10.05g 0.5mmol), adds in two hours and finishes, simultaneously with the pH value of TEA maintenance system about 8.After reactant refluxed 72 hours, the room temperature cooling after concentrating, was filtered, and uses ether sedimentation, uses the small amount of ethanol recrystallization then.Products therefrom is further purified with QAESephadexA50 post (5 * 80cm, the borate buffer solution of leacheate: pH=8.9), obtains mPEG
4-Lys-PEG-NH
2Product is through amino titration, and GPC and MALDI characterize, and purity reaches 99%.
Embodiment 4
The mPEG of different brachiums
4-Lys-PEG-NH
2Preparation (N-hydroxy-succinamide ester activation method)
The N-hydroxy-succinamide that p-NP in the foregoing description 3 is changed into equivalent gets final product.
Embodiment 5
Identical brachium mPEG
4-Lys-PEG-NH
2Preparation
(365mg 2mmol) is dissolved in the 100mLPH value in 8 borax buffer solution, then to wherein adding mPEG with lysine hydrochloride
2-Lys-CO
2Su (every arm molecular weight is 10,000 for two arm mPEG succinimide esters, molecular weight 20,000,80g, and 4mmol), the NaOH with 0.2mol/L comes the pH value of maintenance system 8 simultaneously., will react useless deionized water and be diluted to 400mL after 24 hours in stirring at room, regulate pH value of filtrate to 3 with oxalic acid, extract three times continuously with methylene dichloride then, extracting solution is added drop-wise in the anhydrous diethyl ether after concentrating, and gets white precipitate, the gained precipitation obtains mPEG behind twice recrystallization of ethanol
4-Lys-CO
2The crude product of H.Crude product gets pure mPEG after DEAE Sephadex FF post separates
4-Lys-CO
2H, productive rate are 92%.Product structure is through nucleus magnetic resonance, and GPC and MALDI mass spectrum confirm.
With above-mentioned mPEG
4-Lys-CO
2H (24g, 0.6mmol) be dissolved in the anhydrous methylene chloride (20mL), be cooled to 0 ℃, to wherein add N-hydroxy-succinamide (0.138g, 1.2mmol) and DCC (0.48g, 1.2mmol), after the stirred overnight at room temperature, filter, precipitate with anhydrous diethyl ether after the concentrating filter liquor, through re-crystallizing in ethyl acetate, get pure product mPEG again
4-Lys-CO
2Su.Active ester content is measured through ultraviolet spectroscopy in the product, is 96%.
With two ends is NH
2(molecular weight 2,000,5g 2.5mmol) are dissolved in the anhydrous methylene chloride (20mL) PEG of group, and regulating the pH value with triethylamine is 8.In this solution, add mPEG in batches
4-Lys-CO
2Su (20g 0.5mmol), adds in two hours and finishes, simultaneously with the pH value of TEA maintenance system about 8.After reactant refluxed 72 hours, the room temperature cooling after concentrating, was filtered, and uses ether sedimentation, uses the small amount of ethanol recrystallization then.Products therefrom is further purified with QAESephadexA50 post (5 * 80cm, the borate buffer solution of leacheate: pH=8.9), obtains mPEG
4-Lys-PEG-NH
2Product is through amino titration, and GPC and MALDI characterize, and purity reaches 99%.
Embodiment 6
Identical brachium mPEG
8-Lys-PEG-NH
2Preparation
With reference to the method for embodiment 5, with mPEG
4CO
2Su is a raw material, makes mPEG
8CO
2Su is amino PEG reaction with two ends again, obtains the mPEG of identical brachium
8-Lys-PEG-NH
2, overall yield is 85%.
In following examples, if raw material adopts the multi-arm function PEG of unequal arm, then product is a unequal arm; If raw material adopts the multi-arm function PEG of equiarm, then product is an equiarm.
Embodiment 7
MPEG
5-Lys-PEG-NH
2Preparation
With reference to the method for embodiment 1, successively with mPEG
3-Lys-CO
2PhNO
2And mPEG
2-Lys-CO
2PhNO
2Be raw material, can make mPEG
5-Lys-CO
2PhNO
2, overall yield is 90%.With reference to the method for embodiment 2, can make mPEG
5-Lys-CO
2Su, overall yield is 91%.Be amino PEG reaction with two ends again, obtain corresponding mPEG
5-Lys-PEG-NH
2
Embodiment 8
MPEG
6-Lys-PEG-NH
2Preparation
With reference to the method for embodiment 1, with mPEG
3-Lys-CO
2PhNO
2Be raw material, can make mPEG
6-Lys-CO
2PhNO
2, overall yield is 89%, perhaps successively with mPEG
2-Lys-CO
2PhNO
2And mPEG
4-Lys-CO
2Su is a raw material, can make mPEG
6-Lys-CO
2PhNO
2, overall yield is 92%.With reference to the method for embodiment 2, can make mPEG
6-Lys-CO
2Su, overall yield is 88%.Be amino PEG reaction with two ends again, obtain corresponding mPEG
6-Lys-PEG-NH
2
Embodiment 9
MPEG
7-Lys-PEG-NH
2Preparation
With reference to the method for embodiment 1, successively with mPEG
3-Lys-CO
2PhNO
2And mPEG
4-Lys-CO
2Su is a raw material, can make mPEG
7-Lys-CO
2PhNO
2, overall yield is 86%.With reference to the method for embodiment 2, can make mPEG
7-Lys-CO
2Su, overall yield is 87%.Be amino PEG reaction with two ends again, obtain corresponding mPEG
6-Lys-PEG-NH
2
Embodiment 10
MPEG
8-Lys-PEG-NH
2Preparation
With reference to the method for embodiment 1, successively with mPEG
3-Lys-CO
2PhNO
2And mPEG
5-Lys-CO
2Su is a raw material, can make mPEG
8-Lys-CO
2PhNO
2, overall yield is 80%.With reference to the method for embodiment 2, can make mPEG
8-Lys-CO
2Su, overall yield is 78%.Be amino PEG reaction with two ends again, obtain corresponding mPEG
6-Lys-PEG-NH
2
Embodiment 11
With the same method of embodiment 1-10, we have prepared 3 arms of active group aldehyde radical at the long-chain end, 4 arms, 5 arms, 6 arms, 7 arms and 8 arm polyoxyethylene glycol.
Embodiment 12
With the same method of embodiment 1-10, we have prepared 3 arms of active group carboxyl at the long-chain end, 4 arms, 5 arms, 6 arms, 7 arms and 8 arm polyoxyethylene glycol.
Embodiment 13
With the same method of embodiment 1-10, we have prepared 3 arms of active group hydroxyl at the long-chain end, 4 arms, 5 arms, 6 arms, 7 arms and 8 arm polyoxyethylene glycol.
Embodiment 14
With the same method of embodiment 1-10, we have prepared 3 arms of active group maleimide at the long-chain end, 4 arms, 5 arms, 6 arms, 7 arms and 8 arm polyoxyethylene glycol.
Claims (10)
1, a kind of active group is at the multi-arm polyethylene glycol of long-chain end, it is characterized in that being combined and forming through chemical reaction and PEG by the trifunctional micromolecular compound, is designated as (R-PEG)
z-X-PEG-F, wherein, R is the following straight-chain paraffins of 10 carbon, sec.-propyl or benzyl; Z represents the arm number, is the integer of 1-8; X is a point of contact, i.e. the trifunctional micromolecular compound; F represents the movable function group, PEG is a polyoxyethylene glycol, PEG is connected with covalent linkage with the trifunctional micromolecular compound, and linking group is selected from amide group, inferior amide group, carbamate, ester group, epoxy group(ing), carboxyl, hydroxyl, sulfydryl or carbohydrate, or several combinations a kind of wherein; The structural formula of used trifunctional micromolecular compound is following a kind of:
Here, n is 1～9 integer, and m is 0～6 integer.
2,, it is characterized in that array structure under trifunctional micromolecular compound X is according to the multi-arm polyethylene glycol of the described active group of claim 1 at the long-chain end:
Wherein, n is 1～9 integer, when being connected to amide group or carbamate, is eight arms tree power type functional polyethylene glycol (R-PEG)
8-X-PEG-F, its structural formula is as follows:
Wherein
R is the following straight-chain paraffins of 10 carbon, sec.-propyl or benzyl;
N is 1～9 integer;
K is 1～6 integer;
S, t, o, p are 10～2,000 integer;
W is one of O, S or NH;
F is one of following functional group:
3, a kind of active group as claimed in claim 1 is in the preparation method of the multi-arm polyethylene glycol of long-chain end, it is characterized in that by strand polyoxyethylene glycol and the reaction of trifunctional micromolecular compound, and then all have the PEG reaction of active group with two ends, obtain the multi-arm polyethylene glycol of active group at the long-chain end.
4, active group according to claim 3 is in the preparation method of the multi-arm polyethylene glycol of long-chain end, and the active group that it is characterized in that the trifunctional micromolecular compound is carboxyl and two amino or carboxyl and two hydroxyls.
5, active group according to claim 3 is characterized in that in the preparation method of the multi-arm polyethylene glycol of long-chain end the trifunctional micromolecular compound is one of following array structure:
Wherein, n is 1～9 integer, and m is 0～6 integer.
6, active group according to claim 3 is in the preparation method of the multi-arm polyethylene glycol of long-chain end, it is characterized in that by strand PEG and the reaction of trifunctional micromolecular compound, the molecular weight of its every arm is 400～80,000, by the control reaction, prepare 3 arms of active group respectively at the long-chain end, 4 arms, 5 arms, 6 arms, 7 arms and 8 arm polyoxyethylene glycol.
7, active group according to claim 3 is in the preparation method of the multi-arm polyethylene glycol of long-chain end, it is characterized in that PEG is connected with the trifunctional micromolecular compound, linking group is amide group, inferior amide group, carbamate, ester group, epoxy group(ing), carboxyl, hydroxyl, sulfydryl or carbohydrate, or several combinations a kind of wherein.
8, the active group of stating as claim 1 is characterized in that in the application of multi-arm polyethylene glycol in medication preparation of long-chain end its activity functional groups that passes through the long-chain end combines with small-molecule drug, polypeptide and pharmaceutical grade protein.
9, active group according to claim 8 is characterized in that in the application of the multi-arm polyethylene glycol of long-chain end described small-molecule drug is Chlorambucil, cis-platinum, 5-fluor-uracil, taxol, Zorubicin or Rheumatrex.
10, active group according to claim 8 is characterized in that in the application of the multi-arm polyethylene glycol of long-chain end described pharmaceutical grade protein is Interferon, rabbit, interleukin, tumour necrosis factor, somatomedin, G CFS, erythropoietin or superoxide-dismutase.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010060260A1 (en) * | 2008-11-03 | 2010-06-03 | 北京键凯科技有限公司 | Novel multi-arm polyethylene glycol, preparation method and uses thereof |
| CN102100915A (en) * | 2011-01-05 | 2011-06-22 | 武汉理工大学 | Chlorambucil multi-targeting medicine carrying system and preparation method and application thereof |
| WO2017129046A1 (en) * | 2016-01-29 | 2017-08-03 | 北京键凯科技股份有限公司 | Pegylated opioid with low addictive effect |
| WO2017210963A1 (en) * | 2016-06-07 | 2017-12-14 | 北京键凯科技有限公司 | Peg linker and ligand drug conjugate |
| CN109608633A (en) * | 2018-11-09 | 2019-04-12 | 北京诺康达医药科技股份有限公司 | A kind of novel specific multi-arm polyethylene glycol derivative and preparation method thereof |
| CN110591079A (en) * | 2018-06-13 | 2019-12-20 | 厦门赛诺邦格生物科技股份有限公司 | Preparation method of monofunctional nonlinear polyethylene glycol |
| US11564990B2 (en) * | 2017-03-29 | 2023-01-31 | Jenkem Technology Co., Ltd. (Beijing) | Multi-drug-loading-site, high drug-loading capacity ligand-drug conjugate |
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Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010060260A1 (en) * | 2008-11-03 | 2010-06-03 | 北京键凯科技有限公司 | Novel multi-arm polyethylene glycol, preparation method and uses thereof |
| US11208530B2 (en) | 2008-11-03 | 2021-12-28 | Xuan Zhao | Multi-arm polyethylene glycol, preparation method and uses thereof |
| CN102100915A (en) * | 2011-01-05 | 2011-06-22 | 武汉理工大学 | Chlorambucil multi-targeting medicine carrying system and preparation method and application thereof |
| CN102100915B (en) * | 2011-01-05 | 2013-11-20 | 武汉理工大学 | Chlorambucil multi-targeting medicine carrying system and preparation method and application thereof |
| WO2017129046A1 (en) * | 2016-01-29 | 2017-08-03 | 北京键凯科技股份有限公司 | Pegylated opioid with low addictive effect |
| WO2017210963A1 (en) * | 2016-06-07 | 2017-12-14 | 北京键凯科技有限公司 | Peg linker and ligand drug conjugate |
| CN107469089A (en) * | 2016-06-07 | 2017-12-15 | 北京键凯科技股份有限公司 | A kind of PEG connexons and aglucon drug conjugates |
| CN107469089B (en) * | 2016-06-07 | 2022-01-07 | 北京键凯科技股份有限公司 | PEG connector and aglucon drug conjugate |
| US11759528B2 (en) | 2016-06-07 | 2023-09-19 | Jenkem Technology Co., Ltd. (Beijing) | Peg linker and ligand drug conjugate |
| US11564990B2 (en) * | 2017-03-29 | 2023-01-31 | Jenkem Technology Co., Ltd. (Beijing) | Multi-drug-loading-site, high drug-loading capacity ligand-drug conjugate |
| CN110591079A (en) * | 2018-06-13 | 2019-12-20 | 厦门赛诺邦格生物科技股份有限公司 | Preparation method of monofunctional nonlinear polyethylene glycol |
| CN109608633A (en) * | 2018-11-09 | 2019-04-12 | 北京诺康达医药科技股份有限公司 | A kind of novel specific multi-arm polyethylene glycol derivative and preparation method thereof |
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