CN100415801C - Polyethylene glycol amino acid N-internal ring carbonyl anhydride active derivatives, and medicinal bonding compound and gel thereof - Google Patents
Polyethylene glycol amino acid N-internal ring carbonyl anhydride active derivatives, and medicinal bonding compound and gel thereof Download PDFInfo
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- CN100415801C CN100415801C CNB2003101016884A CN200310101688A CN100415801C CN 100415801 C CN100415801 C CN 100415801C CN B2003101016884 A CNB2003101016884 A CN B2003101016884A CN 200310101688 A CN200310101688 A CN 200310101688A CN 100415801 C CN100415801 C CN 100415801C
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Abstract
The present invention relates to a polyethylene glycol amino acid N-internal ring carbonyl anhydride active derivative of a general formula I, wherein n and m represent integral numbers from 1 to 6; j represents an integral number from 1 to 20; X represents a linking group; Y represents one self hydroxyl of PEG, or the end of the Y is sealed by C1 to 12 alkoxyl, cycloalkoyl, or aralkoxyl. The present invention also provides a derivative of the general formula I and matter containing free amino such as protein, polypeptide, a synthetic polymer and bonding matter formed from a therapeutic medicament. The bonding matter has enhanced biological availability, physiological half-life period and water solubility. The present invention also provides gel which is obtained by the self polymerization of the active derivative, or on the premise of the active derivative and other polymers, or the copolymerization of the active derivative and other small molecular amino acid compounds, and a method for preparing the active derivative and a medical purpose of the gel.
Description
Technical field
The present invention relates to a kind of novel polyethylene glycol omega-amino acid reactive derivative, especially relate to ring carbonyl acid anhydride reactive derivative in a kind of polyethylene glycol omega-amino acid N-, its medicine key compound, and by the gel of this reactive derivative preparation.
Background technology
Protein in the natural drug activeconstituents, polypeptide, terpene, steroidal, alkaloid, flavones, anthraquinone, the plain phenols of phenylpropyl alcohol etc. all show various effective performances on physiologically active, obtained using widely in medicine.Their glucoside, ucleosides, polypeptide analog derivative also have suitable application.As active skull cap components, it is fast that they have a biological degradation, basic noresidue, advantage such as toxic side effect is little.But also there is corresponding problem to have disadvantages such as the biological example utilization ratio is low, physiology transformation period weak point, poorly water-soluble, initiation immunity of organism simultaneously.
Head it off uses polyoxyethylene glycol (PEG) derivative widely, and it is combined with protein, peptide or other treatment medicine, reducing biological degradation, the physiology transformation period of prolong drug, reduces its immunogenicity and toxicity.In clinical use, PEG and derivative thereof have obtained using widely in a lot of commercial medicines as the carrier of making pharmaceutical preparation.And the trial that PEG is bonded to drug molecule has also been obtained significant progress in last decade.As PEG-
, the key compound of a kind of alpha-interferon and polyoxyethylene glycol has just shown longer circulating half-life and better result of treatment.The key compound of taxol and polyoxyethylene glycol has also reduced toxicity accordingly and has prolonged biological activity.Polyoxyethylene glycol is quite clear in the intravital metabolic process of people, is a kind of safe, the drug modified agent that has no side effect.
Polyoxyethylene glycol can be used for being connected with a lot of medicines.When combining with medicine, commonly used to a kind of technology that is called as Pegylation (PEGylation), be to have a suitable functional group after one of the polyoxyethylene glycol two ends or two end groups are chemically activated, this functional group has activity to wanting at least one functional group in the bonded medicine, can form chemical bond with it.The key compound that forms can discharge activeconstituents under the suitable in vivo situation.
Polyoxyethylene glycol (PEG) reactive derivative all has report in a lot of documents.Propionic acid and butyric acid and their N-maloyl imines ester that No. 5672662 United States Patent (USP) described to prepare linear PEG.No. 5643575 United States Patent (USP) described a kind of PEG derivative of U-shaped structure.In the reactive derivative of PEG, the functional group of normal use is N-maloyl imines (NHS) ester, N-maloyl imido-carbonic ester and maleimide etc.
The purpose of this invention is to provide a kind of novel polyethylene glycol omega-amino acid reactive derivative, said reactive derivative need have higher reactive behavior to albumen, polypeptide or other drug molecule etc., and the key compound of said reactive derivative and albumen, polypeptide or other drug molecule has higher bioavailability, physiology transformation period and water-soluble.
For this reason, the polyoxyethylene glycol among the present invention (PEG) active function groups is a kind of interior ring of amino acid-N-carbonyl acid anhydride of special construction.It by to amino acid acid group and its amino in addition cyclisation realize.This structure has very high reactive behavior to the material that contains free amino group, and such as protein, polypeptide etc., therefore they can react and form stable covalent linkage connection.In reaction, a free amino group has caused the open loop generation amido linkage of ring texture, forms a new amino simultaneously.The positive charge that disappears during reaction is protected.Protecting this positive charge is very important keeping aspect proteinic physiologically active, stability and the membrane permeability sometimes.
This polyethylene active derivatives can also form gel under suitable condition.
Summary of the invention
The invention provides a kind of novel polyethylene glycol omega-amino acid reactive derivative, it includes ring carbonyl acid anhydride at least one amino acid whose N-at the end of the chain of PEG, and wherein, the molecular weight of polyoxyethylene glycol is 150～60,000, said amino acid can be α or beta amino acids.
Therefore, according to an aspect of the present invention, provide a kind of interior ring of polyethylene glycol omega-amino acid N-carbonyl acid anhydride reactive derivative of general formula I:
Wherein:
PEG is the polyethylene glycol polymer of straight chain, side chain, star or tree structure;
N and m are the integers of 1-6;
J is the integer of 1-20;
X is a linking group, is preferably amide group, carbonyl, hydrazide group, ester group, ether or thioether group;
Y is a hydroxyl or active function groups F of PEG itself.
In a preferred embodiment of the invention, the molecular weight of described polyoxyethylene glycol is 150～60,000.
When Y was hydroxyl of PEG itself, described derivative was the compound of following general formula I a:
And when Y was active group F, described derivative was the compound of following general formula I b,
Wherein, F is an active function groups, is selected from by C
1-C
12The group of the group that alkoxyl group, cycloalkyloxy and aralkoxy are formed, preferably methoxyl group, oxyethyl group or benzyl.
In a preferred embodiment of the invention, derivative of the present invention is:
Polyoxyethylene glycol amide group glutamic acid N-ring inner-acid anhydride (1);
Methoxy poly (ethylene glycol) amide group glutamic acid N-ring inner-acid anhydride (2);
Polyoxyethylene glycol ester group glutamic acid N-ring inner-acid anhydride (3);
Polyoxyethylene glycol acyl-lysine N-encircles inner-acid anhydride (4); Or
Methoxy poly (ethylene glycol) acyl-lysine N-encircles inner-acid anhydride (5).
According to another aspect of the present invention, the interior ring of the polyethylene glycol omega-amino acid N-carbonyl acid anhydride reactive derivative of general formula I and the key compound of the material formation that contains free radical amino are provided, shown in general formula I I:
Wherein, PEG, n, m, j, X and Y have identical definition with general formula (I), SUB is the material that a class contains free amino group, be selected from the group of forming by protein, enzyme, polypeptide, nucleosides, carbohydrate, organic acid, glucoside, flavonoid, quinones, terpene, the plain phenols of phenylpropyl alcohol, steroidal and glucoside thereof, alkaloid, perhaps be selected from Cinobufagin, glycyrrhetinic acid, scopolactone, taxol, camptothecine, Etoposide or their derivative; And in preferred embodiments, described protein is erythropoietin (EPO) or Interferon, rabbit.
In a preferred embodiment, key compound of the present invention is the key compound of methoxy poly (ethylene glycol) acyl-lysine N-ring inner-acid anhydride and alpha-interferon.
Studies show that the key compound of said reactive derivative and albumen, polypeptide or other drug molecule has higher bioavailability, physiology transformation period and water-soluble.
According to a further aspect of the invention, this polyethylene active derivatives of the present invention forms gel under suitable condition.
Described gel is resulting by ring carbonyl acid anhydride reactive derivative itself in the described polyethylene glycol omega-amino acid N-of polymerization, as the gel by the own polymerization preparation of polyoxyethylene glycol amide group glutamic acid N-ring inner-acid anhydride (1), polyoxyethylene glycol ester group glutamic acid N-ring inner-acid anhydride (3) or polyoxyethylene glycol acyl-lysine N-ring inner-acid anhydride (4).
Described gel also can be by resultant with ring carbonyl acid anhydride reactive derivative and other polymer precursor copolymerization in the described polyethylene glycol omega-amino acid N-, as encircle by polyoxyethylene glycol amide group glutamic acid N-ring inner-acid anhydride (1), polyoxyethylene glycol ester group glutamic acid N-ring inner-acid anhydride (3) or polyoxyethylene glycol acyl-lysine N-inner-acid anhydride (4) respectively with the gel of polyoxamide copolymerization.
Described gel can also be by resulting with ring carbonyl acid anhydride reactive derivative and other small molecules aminocompound copolymerization in the described polyethylene glycol omega-amino acid N-, as encircle by polyoxyethylene glycol amide group glutamic acid N-ring inner-acid anhydride (1), polyoxyethylene glycol ester group glutamic acid N-ring inner-acid anhydride (3) or polyoxyethylene glycol acyl-lysine N-inner-acid anhydride (4) respectively with the gel of Methionin copolymerization.
Described gel can be applied in the biological medicine.Gel according to the present invention can improve drug absorption when pharmaceutical compositions, prolong action time, heightens the effect of a treatment, and reduces dosage and avoids some toxic side effect.
Described gel can be applied in the surgical operation aspect, and the preparation of gel or prevention postoperative intestinal adhesion is sewed up in effect operation back, and therefore, the present invention also provides the pharmaceutical carrier that contains above-mentioned gel, and the preparation of gel or prevention postoperative intestinal adhesion is sewed up in the operation back.
According to a further aspect of the invention, a kind of method for preparing ring carbonyl acid anhydride reactive derivative in the polyethylene glycol omega-amino acid N-of the present invention is provided, this method comprises PEG and amino acid reaction, carry out the structure cyclisation by phosgene or phosgene analogue then, wherein, described phosgene analogue is triphosgene or trichloromethylchloroformate.
Embodiment
Used polyoxyethylene glycol can be other hydrophilic polymer in polyethylene glycol omega-amino acid reactive derivative of the present invention, as the multipolymer of polypropylene glycol, polyvinyl alcohol, polypropylene morpholine or they and polyoxyethylene glycol.These hydrophilic polymers are by the modification to free hydroxy-terminal, acidic-groups such as amino acid are attached on the parent of this polymkeric substance, make this polymkeric substance that tie point with drug molecule can be provided, thus with protein, polypeptide or other natural drug activeconstituentss in free amine group, hydroxyl etc. link together.
Polyoxyethylene glycol (PEG), its general structure is shown in III:
Wherein:
R is H or C
1-12Alkyl,
L is any integer, characterizes its polymerization degree.
When R was low alkyl group, R can be any low alkyl group that contains 1-6 carbon atom, as methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, n-pentyl or n-hexyl.When R was cycloalkyl, R was preferably the cycloalkyl that contains 3-7 carbon atom, as cyclopropyl, cyclobutyl and cyclohexyl.Preferred cycloalkyl is a cyclohexyl.Its exemplary compounds is methoxy poly (ethylene glycol) (mPEG).The similar thing group of other polyoxyethylene glycol ethylene glycol copolymer also can be used for this invention to be used, as polypropylene glycol, polyvinyl alcohol, polypropylene morpholine etc.
For polyoxyethylene glycol, generally adopt molecular weight to be represented, be 300～60000 dalton as long as make the molecular weight of the polyoxyethylene glycol that forms binding substances, this is equivalent to l is about 6～1300.More preferably, l is 28,112 and 450, and this is 1325,5000 and 20000 corresponding to molecular weight respectively.Owing to, preferably use the molecular weight characterization polyethylene glycol polymer, rather than represent the unit of repetition certainly in the PEG polymkeric substance with integer l usually by its molecular-weight average but not repeat the potential unhomogeneity of the initial PEG compound that the unit limits certainly.The initial PEG compound of various molecular weight can or can obtain from commercial source by the preparation of the currently known methods in this area.
All containing functional groups such as amino, carboxyl, hydroxyl in use many medicines, the especially natural medicinal ingredients at present; they all combine with compositions such as monose, polysaccharide, nucleosides, polymerized nucleoside, phosphoryls in vivo usually, to be formed on activated pharmacology structure in the organism.
If free hydroxyl group is arranged on the hydrophilic polymer, then this free hydroxyl group can be used C
1-12Alkoxyl group, cycloalkyloxy or aralkoxy end-blocking, preferably methoxyl group, oxyethyl group, isopropoxy, ring propoxy-, cyclobutoxy group, cyclohexyloxy and benzyloxy.
In addition, on this hydrophilic polymer, also can connect targeted molecular, as antibody etc., so that directed transhipment key compound of the present invention.
Can use suitable drug molecule formation drug moiety wherein in the key compound of the present invention, it comprises amino acid, protein, enzyme, nucleosides, carbohydrate, organic acid, glucoside, flavonoid, quinones, terpene, the plain phenols of phenylpropyl alcohol, steroidal and glucoside, alkaloid etc., and their derivative that contains amino etc.
Key compound of the present invention can the pure compound form or the appropriate drug composition carry out administration, the reagent that can adopt any acceptable administering mode or be used for similar purposes carries out.Composition can comprise conventional pharmaceutical carrier or vehicle and as the key compound of the present invention of activeconstituents (one or more), in addition, also can comprise other medicament, carrier, assistant agent etc.
Studies show that key compound of the present invention has well water-soluble and long physiology transformation period, the toxic side effect of reduction.
Polyethylene active derivatives of the present invention forms gel under suitable condition.Described gel of many uses in biological medicine can be used as pharmaceutical carrier, improves drug absorption, prolongs action time, heightens the effect of a treatment, and reduces dosage and avoids some toxic side effect.In addition, gel of the present invention also can be used on the surgical operation, and the preparation of gel and prevention postoperative intestinal adhesion is sewed up in the back that operates.
Below in conjunction with case description polyethylene glycol omega-amino acid reactive derivative of the present invention and preparation method thereof, it does not limit the present invention, and scope of the present invention is defined by the claims.
Embodiment 1-5
For the situation of detailed embodiment of the present invention is described, it is as follows to present in diagrammatic form:
Table 1
Embodiment 1
The preparation of polyoxyethylene glycol amide group glutamic acid N-ring inner-acid anhydride (1)
10 gram polyethylene glycol diamines (molecular weight is 5000) and 1.5 gram N-tertbutyloxycarbonyl L-glutamic acid trimethyl carbinol esters are dissolved in 100 milliliters of anhydrous methylene chlorides, add 1.15 gram dicyclohexylcarbodiimide and 1 gram dimethyl aminopyridine, stir under the room temperature and spend the night.Remove by filter the solid that reaction produces, decompression concentrated solution adds 100 milliliters of Virahols.Filter collecting precipitation vacuum-drying, productive rate: 9.6 grams (96%).
9 gram polyoxyethylene glycol amino N-tertbutyloxycarbonyl L-glutamic acid trimethyl carbinol esters (molecular weight is 5000, by last step make) are dissolved in 30 milliliters of chloroforms, add 30 milliliters of trifluoroacetic acids, and stirring is 5 hours under the room temperature.Decompression concentrated solution adds 100 milliliters of Virahols.Filter collecting precipitation vacuum-drying, productive rate: 8.1 grams (90%).
The amino L-glutamic acid of 8 gram polyoxyethylene glycol (molecular weight is 5000, by last step make) are dissolved in 100 milliliters of toluene, and heating steams 70 milliliters, and solution is cooled to 35 ℃ and adds 30 milliliters of anhydrous tetrahydro furans, adds 1 gram solid triphosgene again, and 60 ℃ are stirred down and spend the night.Decompression concentrated solution adds 100 milliliters of ether.Filter collecting precipitation, ether washing vacuum-drying, productive rate: 7.0 grams (88%).
Embodiment 2
The preparation of methoxy poly (ethylene glycol) amide group glutamic acid N-ring inner-acid anhydride (2)
20 gram methoxy poly (ethylene glycol) amine (CH
3O-PEG-OCH
2CH
2-NH
2. molecular weight is 10000) and 0.8 gram N-tertbutyloxycarbonyl L-glutamic acid trimethyl carbinol ester, be dissolved in 100 milliliters of anhydrous methylene chlorides, add 0.6 gram dicyclohexylcarbodiimide and 0.5 gram dimethyl aminopyridine, stirring under the room temperature spends the night removes by filter the solid that reaction produces, decompression concentrated solution adds 100 milliliters of Virahols.Filter collecting precipitation vacuum-drying, productive rate: 19 grams (95%).
18 gram methoxy poly (ethylene glycol) amino N-tertbutyloxycarbonyl L-glutamic acid trimethyl carbinol esters (molecular weight is 10000, by last step make) are dissolved in 40 milliliters of chloroforms, add 30 milliliters of trifluoroacetic acids, stirring at room 5 hours.Decompression concentrated solution adds 100 milliliters of Virahols.Filter collecting precipitation vacuum-drying, productive rate: 16.5 grams (91%).
The amino L-glutamic acid of 15 gram methoxy poly (ethylene glycol)s (molecular weight is 5000, by last step make) are dissolved in 100 milliliters of toluene, heating steams 70 milliliters, solution is cooled to 35 ℃ and adds 30 milliliters of anhydrous tetrahydro furans, adds 0.45 gram solid triphosgene again, and 60 ℃ of following stirrings are spent the night.Decompression concentrated solution adds 100 milliliters of ether.Filter collecting precipitation, ether washing vacuum-drying, productive rate: 13.5 grams (90%).
Embodiment 3
The preparation of polyoxyethylene glycol ester group glutamic acid N-ring inner-acid anhydride (3)
10 gram polyoxyethylene glycol (HO-PEG-OH, molecular weight is 5000) and .1.5 gram N-tertbutyloxycarbonyl L-glutamic acid trimethyl carbinol ester, be dissolved in 100 milliliters of anhydrous methylene chlorides, add 1.15 gram dicyclohexylcarbodiimide and 1 gram dimethyl aminopyridine, stir under the room temperature and spend the night, remove by filter the solid that reaction produces, decompression concentrated solution adds 100 milliliters of Virahols.Filter collecting precipitation vacuum-drying, productive rate: 9 grams (90%).
8 gram N-tertbutyloxycarbonyl-r-trimethyl carbinol ester L-glutamic acid macrogol esters (molecular weight is 5000, by last step make) are dissolved in 30 milliliters of chloroforms, add 30 milliliters of trifluoroacetic acids, stirring at room 5 hours.Decompression concentrated solution adds 100 milliliters of Virahols.Filter collecting precipitation vacuum-drying, productive rate: 7.5 grams (92%).
7 gram L-glutamic acid macrogol esters (molecular weight is 5000, by last step make) are dissolved in 100 milliliters of toluene, and heating steams 70 milliliters, and solution is cooled to 35 ℃ and adds 30 milliliters of anhydrous tetrahydro furans, adds 0.5 gram solid triphosgene again, and 60 ℃ are stirred down and spend the night.Decompression concentrated solution adds 100 milliliters of ether.Filter collecting precipitation, ether washing vacuum-drying, productive rate: 6 grams (87%).
Embodiment 4
The preparation of polyoxyethylene glycol acyl-lysine N-ring inner-acid anhydride (4)
10 gram polyoxyethylene glycol acetate N-maloyl imines ester (NHS-OC-CH
2O-PEG-OCH
2CO-NHS, molecular weight are 5000) and 1.2 gram N-tertbutyloxycarbonyl Methionin trimethyl carbinol esters, be dissolved in 100 milliliters of anhydrous methylene chlorides, add 1 milliliter of triethylamine, stir under the room temperature and spend the night, remove by filter the solid that reaction produces, decompression concentrated solution adds 100 milliliters of Virahols.Filter collecting precipitation vacuum-drying, productive rate: 9.6 grams (96%).
8 gram polyoxyethylene glycol acetate N-tertbutyloxycarbonyl Methionin acid amides (molecular weight is 5000, by last step make) are dissolved in 30 milliliters of chloroforms, add 15 milliliters of trifluoroacetic acids, stirring at room 5 hours.Decompression concentrated solution adds 100 milliliters of Virahols.Filter collecting precipitation vacuum-drying, productive rate: 8.5 grams (95%).
(molecular weight is 5000 to 8 gram polyoxyethylene glycol acetate Methionin acid amides, made by the last step) (molecular weight is 5000, made by the last step), be dissolved in 100 milliliters of toluene, heating steams 70 milliliters, solution is cooled to 35 ℃ and adds 30 milliliters of anhydrous tetrahydro furans, adds 0.5 gram solid triphosgene again, and 60 ℃ of following stirrings are spent the night.Decompression concentrated solution adds 100 milliliters of ether.Filter collecting precipitation, ether washing vacuum-drying, productive rate: 7.2 grams (90%).
Embodiment 5
The preparation of methoxy poly (ethylene glycol) acyl-lysine N-ring inner-acid anhydride (5)
40 gram methoxy poly (ethylene glycol) acetate N-maloyl imines ester (CH
3O-PEG-OCH
2CO-NHS, molecular weight are 10000) and 1.2 gram N-tertbutyloxycarbonyl Methionin trimethyl carbinol esters, be dissolved in 150 milliliters of anhydrous methylene chlorides, add 1 milliliter of triethylamine, stir under the room temperature and spend the night, remove by filter the solid that reaction produces, decompression concentrated solution adds 200 milliliters of Virahols.Filter collecting precipitation vacuum-drying, productive rate: 38 grams (95%).
35 gram methoxy poly (ethylene glycol) acetate N-tertbutyloxycarbonyl Methionin acid amides (molecular weight is 10000, by last step make) are dissolved in 80 milliliters of chloroforms, add 40 milliliters of trifluoroacetic acids, stirring at room 5 hours.Decompression concentrated solution adds 100 milliliters of Virahols.Filter collecting precipitation vacuum-drying, productive rate: 33 grams (95%).
20 gram methoxy poly (ethylene glycol) acetate Methionin acid amides (molecular weight is 10000, by last step make) are dissolved in 150 milliliters of toluene, heating steams 110 milliliters, solution is cooled to 35 ℃ and adds 40 milliliters of anhydrous tetrahydro furans, adds 0.6 gram solid triphosgene again, and 60 ℃ of following stirrings are spent the night.Decompression concentrated solution adds 150 milliliters of ether.Filter collecting precipitation, ether washing vacuum-drying, productive rate: 18 grams (90%).
Embodiment 6
The key compound of methoxy poly (ethylene glycol) acyl-lysine N-ring inner-acid anhydride (5) and IL-2
10 milligrams of methoxy poly (ethylene glycol) acyl-lysine N-ring inner-acid anhydrides (molecular weight is 10000, by embodiment 5 preparations) are dissolved in the PBS buffer salt solution of 1 milliliter (pH=7), wherein contain 1 mg/ml IL-2.Slowly jolt 6 hours in room temperature.Add 0.2 milliliter Tris alkali buffered soln (pH7.0,0.1M), by sepherose gel ion exchange resins purifying, collect singly replace, disubstituted composition.Final product shows wherein there is not the free alpha-interferon with SDS-PAGE, and GPC shows does not have free PEG molecule.
Embodiment 7
Prepare gel by regulating the pH value by the polymerization of N-ring inner-acid anhydride
200 milligrams of polyoxyethylene glycol ester group amino acid N-ring inner-acid anhydrides (molecular weight is 5000, by embodiment 1,3 and 4 preparations), be dissolved in 1 milliliter acetate buffer solution (10mM, pH5.0) in, add 0.5 milliliter of phosphate buffer soln (0.2M, pH7.4), solution jolts gently until forming gel.
Embodiment 8
By N-ring inner-acid anhydride and polyoxamide copolymerization gel
(molecular weight is 5000 to 200 milligrams of polyoxyethylene glycol ester group amino acid N-ring inner-acid anhydrides, by embodiment 1,3 and 4 preparations), be dissolved in 1 milliliter acetate buffer solution (10mM, pH5.0) in, add 1 milliliter of phosphate buffer soln (0.2M, pH7.4), wherein contain 50 milligrams of polyoxamides, solution jolts gently until forming gel.
Embodiment 9
By N-ring inner-acid anhydride and small molecule amine copolymerization gel
(molecular weight is 5000 to 200 milligrams of polyoxyethylene glycol ester group amino acid N-ring inner-acid anhydrides, by embodiment 1,3 and 4 preparations), be dissolved in 1 milliliter of (10mM, pH5.0) in the acetate buffer solution, add 1 milliliter of phosphate buffer soln (0.2M, pH7.4), wherein contain 5 milligrams of Methionins, solution jolts gently until forming gel.
Claims (20)
1. encircle carbonyl acid anhydride reactive derivative in the polyethylene glycol omega-amino acid N-of general formula I:
Wherein:
PEG is the polyethylene glycol polymer of straight chain, side chain, star or tree structure;
N and m are the integers of 1-6;
J is the integer of 1-20;
X is a linking group, is selected from amide group, carbonyl, hydrazide group, ester group, ether or thioether group;
Y is a hydroxyl or active function groups F of PEG itself, and active function groups F is selected from C
1-C
12Alkoxyl group, cycloalkyloxy or aralkoxy.
2. derivative as claimed in claim 1, wherein, the molecular weight of described polyoxyethylene glycol is 150～60,000.
3. derivative as claimed in claim 1, wherein, described derivative is the compound of following general formula I a
4. derivative as claimed in claim 1, wherein, described active function groups F is selected from methoxyl group, oxyethyl group or benzyl.
5. derivative as claimed in claim 1, wherein, described derivative is:
Polyoxyethylene glycol amide group glutamic acid N-ring inner-acid anhydride (1);
Methoxy poly (ethylene glycol) amide group glutamic acid N-ring inner-acid anhydride (2);
Polyoxyethylene glycol ester group glutamic acid N-ring inner-acid anhydride (3);
Polyoxyethylene glycol acyl-lysine N-encircles inner-acid anhydride (4); Or
Methoxy poly (ethylene glycol) acyl-lysine N-encircles inner-acid anhydride (5).
6. key compound that forms as ring carbonyl acid anhydride reactive derivative in the described polyethylene glycol omega-amino acid N-of one of claim 1-5 and the material that contains free amino group:
Wherein, PEG, n, m, j, X and Y have identical definition with general formula (I), and SUB is the material that a class contains free amino group.
7. key compound as claimed in claim 6, wherein, the described material that contains free amino group is selected from protein, enzyme, polypeptide, nucleosides, carbohydrate, organic acid, glucoside, flavonoid, quinones, terpene, the plain phenols of phenylpropyl alcohol, steroidal and glucoside or alkaloid.
8. key compound as claimed in claim 7, wherein, described protein is erythropoietin or Interferon, rabbit.
9. key compound as claimed in claim 6, wherein, the described material that contains free amino group is selected from Cinobufagin, glycyrrhetinic acid, scopolactone, taxol, camptothecine, Etoposide or their derivative.
10. key compound as claimed in claim 6, wherein, described key compound is the key compound of methoxy poly (ethylene glycol) acyl-lysine N-ring inner-acid anhydride (5) and alpha-interferon.
11. a gel, described gel are resulting by ring carbonyl acid anhydride reactive derivative itself in the polyethylene glycol omega-amino acid N-of one of polymerization such as claim 1-5.
12. a gel, described gel are by will be resulting as ring carbonyl acid anhydride reactive derivative and other polymer precursor copolymerization in the polyethylene glycol omega-amino acid N-of one of claim 1-5.
13. gel as claimed in claim 12, wherein, described other polymer precursors are polyoxamides.
14. a gel, described gel are by will be resulting as ring carbonyl acid anhydride reactive derivative and other small molecules aminocompound copolymerization in the polyethylene glycol omega-amino acid N-of one of claim 1-5.
15. gel as claimed in claim 14, wherein, described other small molecules aminocompounds are Methionin.
16. pharmaceutical carrier that comprises the gel of one of claim 11-15.
17. sew up gel after the operation of a gel that comprises one of claim 11-15.
18. the preparation of the prevention postoperative intestinal adhesion of a gel that comprises one of claim 11-15.
19. a method for preparing as ring carbonyl acid anhydride reactive derivative in one of claim 1-5 polyethylene glycol omega-amino acid N-comprises PEG and amino acid reaction, carries out the structure cyclisation by phosgene or phosgene analogue then.
20. method as claimed in claim 19, wherein, described phosgene analogue is triphosgene or trichloromethylchloroformate.
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| CN101108895B (en) * | 2006-07-19 | 2011-10-26 | 北京键凯科技有限公司 | Polyglycol ethanal derivant and combo of medicament and the same |
| CN101176791B (en) * | 2006-11-07 | 2013-01-09 | 中国药科大学 | Amino acid communicating with polyglycol as well as manufacturing method and usage thereof |
| CN102827365B (en) * | 2006-11-07 | 2014-08-20 | 中国药科大学 | Amino acid connected with polyethylene glycol and preparation method and application for amino acid |
| JP2013234207A (en) * | 2010-08-31 | 2013-11-21 | Jsr Corp | New polymer and new n-carboxyamino acid anhydride, and method for producing them |
| WO2014114262A1 (en) * | 2013-01-28 | 2014-07-31 | 天津键凯科技有限公司 | Water soluble polymer-amino acid oligopeptide-medicine combination, preparation method therefore, and use thereof |
| US9700633B2 (en) | 2013-01-28 | 2017-07-11 | Jenkem Technology Co., Ltd., Tianjin Branch | Conjugates of water soluble polymer-amino acid oligopeptide-drug, preparation method and use thereof |
| TWI647253B (en) * | 2016-12-29 | 2019-01-11 | 大東樹脂化學股份有限公司 | Method for producing amides or polyamides by using aromatic carbamates by way of isocyanates as precursors through catalyzed thermal processes and method for producing aromatic carbamate precursors from aromatic amines |
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| WO2002009766A1 (en) * | 2000-07-29 | 2002-02-07 | Park Myung Ok | Highly reactive branched polymer and proteins or peptides conjugated with the polymer |
| US20020044921A1 (en) * | 2000-09-29 | 2002-04-18 | Seoju Lee | Pegylated interleukin-10 |
| WO2002043663A2 (en) * | 2000-12-01 | 2002-06-06 | Enzon, Inc. | Tetrapartate prodrugs |
| US6602498B2 (en) * | 2000-02-22 | 2003-08-05 | Shearwater Corporation | N-maleimidyl polymer derivatives |
| CN1440995A (en) * | 2003-03-28 | 2003-09-10 | 中国科学院长春应用化学研究所 | Ternary polyglycol-aliphatic polyester-polyamino acid block copolymer and its prepn |
| CN1125097C (en) * | 2000-07-05 | 2003-10-22 | 天津大学 | Precursor of polyglycol carried taxusol or polyene taxusol |
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2003
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| US6602498B2 (en) * | 2000-02-22 | 2003-08-05 | Shearwater Corporation | N-maleimidyl polymer derivatives |
| CN1125097C (en) * | 2000-07-05 | 2003-10-22 | 天津大学 | Precursor of polyglycol carried taxusol or polyene taxusol |
| WO2002009766A1 (en) * | 2000-07-29 | 2002-02-07 | Park Myung Ok | Highly reactive branched polymer and proteins or peptides conjugated with the polymer |
| US20020044921A1 (en) * | 2000-09-29 | 2002-04-18 | Seoju Lee | Pegylated interleukin-10 |
| WO2002043663A2 (en) * | 2000-12-01 | 2002-06-06 | Enzon, Inc. | Tetrapartate prodrugs |
| CN1440995A (en) * | 2003-03-28 | 2003-09-10 | 中国科学院长春应用化学研究所 | Ternary polyglycol-aliphatic polyester-polyamino acid block copolymer and its prepn |
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| CN1611524A (en) | 2005-05-04 |
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