CN100475837C - Branched polyglycol-amino acid oligopeptide and active derivative and medicinal composition thereof - Google Patents
Branched polyglycol-amino acid oligopeptide and active derivative and medicinal composition thereof Download PDFInfo
- Publication number
- CN100475837C CN100475837C CNB2004100480166A CN200410048016A CN100475837C CN 100475837 C CN100475837 C CN 100475837C CN B2004100480166 A CNB2004100480166 A CN B2004100480166A CN 200410048016 A CN200410048016 A CN 200410048016A CN 100475837 C CN100475837 C CN 100475837C
- Authority
- CN
- China
- Prior art keywords
- polyoxyethylene glycol
- amino acid
- compound
- group
- oligopeptides
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- 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
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6903—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Surgery (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
Abstract
Each of the branched polyglycol-amino acid oligopeptide and its active derivative of the general expression II has one central molecule with several active groups to form the branches of polyglycol and 3-30 branches. The polymer is non-toxic and can bear several medicine molecules to reach the aims of raising dissolubility, delayed releasing, etc. It has obvious reinforcing effect on medicine, especially taxol, camptothecine, etc. The branched polyglycol-amino acid oligopeptide may form gel together with other molecule and the gel may be used in biomedicine.
Description
Technical field
The present invention relates to a kind of novel many forks ramose polyoxyethylene glycol-amino acid oligopeptides, its reactive derivative, itself and the binding substances of drug molecule, the pharmaceutical composition that comprises this binding substances and their preparation method and their biomedical uses, the especially purposes in the preparation medicine.
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.
Be head it off, use polyethyleneglycol derivative widely, make itself and the combining of protein, peptide or other treatment medicine, with physiology transformation period of prolong drug, reduce 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, in many approval medicines, be widely used, as PEG-
With
The key compound 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, drug modified agent of having no side effect.
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 the end group of polyoxyethylene glycol is chemically activated, this functional group has activity to wanting at least one functional group in the bonded medicine, can form stable key with it.
There is report to show that polyoxyethylene glycol can be used for being connected with a lot of medicines.The the 5824701st and No. 5840900 United States Patent (USP) and Chinese patent CN1283643 have reported this analog derivative and paclitaxel bonded prodrug, in this drug model the polyoxyethylene glycol two ends all a bonding taxol molecule.Polyoxyethylene glycol is a kind of linear polymer, only modifies to be used for the bonding drug molecule in its end group position usually.In order to improve the load factor to drug molecule, No. 6153655 United States Patent (USP) disclosed a kind of end of the chain branch polyethylene glycol structures, and this structure connects by amino at the two ends of polyoxyethylene glycol and generated two functional groups.But introduce the uncertainty that abiotic side chain small molecules has been introduced medicine.The the 5977163rd and No. 6262107 United States Patent (USP) and Chinese patent CN1164533 disclose a kind of polyglutamic acid and have propped up the prodrugs of paclitaxel that carries, taxol is along on the polyglutamic acid skeletal chain pendant carboxylic group that is connected to L-glutamic acid at random in this drug model, and the percent polymerization of broad distributes and to the toxic use that can not knowing property have limited this invention of polyglutamic acid.In the work in earlier stage of this laboratory, a kind of linear polyethylene glycol-amino acid oligopeptides (WO03/074586) is synthetic to be used for multiple drug molecule by success.
Therefore, the object of the present invention is to provide one novel, can load the polyethylene glycol compound of multiple medicines thing more, and the binding substances that forms of this polyethylene glycol compound and drug molecule.
Another object of the present invention is to provide the application of this novel polyethylene glycol compound aspect the preparation gel.
This novel polyethylene glycol compound provided by the invention is many fork ramose polyethylene glycol compounds, and it contains the end group more than two.Compare with the PEG of existing linearity, by can the more drug molecule of load after transforming.Polyoxyethylene glycol based on these type of many fork branched structures the invention provides a kind of novel many forks ramose polyoxyethylene glycol-amino acid oligopeptides and its reactive derivative, and it can obviously improve the load factor to drug molecule.This many fork ramose polyoxyethylene glycol-amino acid oligopeptides reactive derivative can also form gel under suitable condition.
Summary of the invention
One aspect of the present invention provides a kind of many forks ramose polyoxyethylene glycol-amino acid oligopeptides and reactive derivative compound thereof of general formula I:
Wherein:
R
1Be selected from poly-hydroxy structure, polyamino structure or many carboxyl structure;
N is the integer of 3-2000;
M is an integer among the 2-12;
I is an integer among the 3-30;
R
2Be amino acid whose side-chain radical, can be identical or different;
X is a linking group, is selected from but is not limited to: O (CH
2)
kCO, O (CH
2)
kOCO, O (CH
2)
kNHCO, NR (CH
2)
kOCO, NR (CH
2)
kNHCO, NR (CH
2)
kThe group of the group that CO forms, and k is the integer of 0-10;
Y is selected from the group of being made up of hydroxyl, ester group, acyl chlorides, hydrazides, maleimide, pyridine disulphide active group.
Preferably, the invention provides polyoxyethylene glycol-amino acid oligopeptides of a kind of general formula I I:
Wherein:
R
1Be a central element, contain a plurality of end group active groups, pitch ramose polyoxyethylene glycol, R more by final formation of linear polyethylene glycol that these groups derive
1Can be poly-hydroxy molecule, polyamino molecule, many carboxyls molecule;
N is any integer, characterizes its polymerization degree, is selected from 3-2000;
M is an integer among the 2-12;
I is an integer among the 3-30, characterizes the bifurcated number;
R
2Be the side-chain radical of related amino acid, can be identical, can be different;
X is a linking group, connects the end group of many fork ramose polyoxyethylene glycol and the amino of amino acid oligopeptides, is selected from but is not limited to: O (CH
2)
kCO, O (CH
2)
kOCO, O (CH
2)
kNHCO, NR (CH
2)
kOCO, NR (CH
2)
kNHCO, NR (CH
2)
kCO, k are the integer of 0-10.
The compound of a kind of general formula I Ia and general formula I Ib more preferably, is provided:
R
1Be a central element, contain a plurality of end group active groups, pitch ramose polyoxyethylene glycol, R more by final formation of linear polyethylene glycol that these groups derive
1Can be poly-hydroxy molecule, polyamino molecule, many carboxyls molecule;
N is any integer, characterizes its polymerization degree, is selected from 3-2000;
M is an integer among the 2-12;
J is an integer among the 1-4;
I is an integer among the 3-30, characterizes the bifurcated number;
R is the group that is selected from following group: H, C
1-12Alkyl, substituted aryl, aralkyl, assorted alkyl and substituted alkyl;
X is a linking group, connects the end group of many fork ramose polyoxyethylene glycol and the amino of amino acid oligopeptides, is selected from but is not limited to: O (CH
2)
kCO, O (CH
2)
kOCO, O (CH
2)
kNHCO, NR (CH
2)
kOCO, NR (CH
2)
kNHCO, NR (CH
2)
kCO, k are the integer of 0-10.
In embodiments of the invention, described amino acid is natural amino acid and synthesizing amino acid, is preferably L-glutamic acid, glycine, Methionin, Gelucystine, aspartic acid, arginine, tyrosine or Serine.
In embodiments of the invention, described central element R
1Be tetramethylolmethane or glycerine.The many forks ramose polyoxyethylene glycol that derives by tetramethylolmethane is four fork ramose polyoxyethylene glycol, and the many forks ramose polyoxyethylene glycol that derives by glycerine is a trident ramose polyoxyethylene glycol.
Preferably, the invention provides a kind of many forks ramose polyoxyethylene glycol-amino acid oligopeptides reactive derivative of general formula III:
Wherein:
R
1Be a central element, contain a plurality of active groups, pitch ramose polyoxyethylene glycol, R more by final formation of linear polyethylene glycol that these groups derive
1Can be poly-hydroxy molecule, polyamino molecule, many carboxyls molecule;
N is any integer, characterizes its polymerization degree, is selected from 3-2000;
M is an integer among the 2-12;
I is an integer among the 3-30, characterizes the bifurcated number;
R
2Be the side-chain radical of related amino acid, can be identical, can be different;
X is a linking group, connects the end group of many fork ramose polyoxyethylene glycol and the amino of amino acid oligopeptides, is selected from but is not limited to: O (CH
2)
kCO, O (CH
2)
kOCO, O (CH
2)
kNHCO, NR (CH
2)
kOCO, NR (CH
2)
kNHCO, NR (CH
2)
kCO, k are the integer of 0-10;
Z is an active group, is selected from but is not limited in following group: ester group, carbonate group, acyl chlorides, hydrazides, maleimide, pyridine disulphide.
In preferred embodiments, described amino acid is natural amino acid and synthesizing amino acid, is preferably L-glutamic acid, glycine, Methionin, Gelucystine, aspartic acid, arginine, Tyrosine or Serine.
In embodiments of the invention, described R
1Be tetramethylolmethane or glycerine.The many forks ramose polyoxyethylene glycol that derives by tetramethylolmethane is four fork ramose polyoxyethylene glycol, and the many forks ramose polyoxyethylene glycol that derives by glycerine is a trident ramose polyoxyethylene glycol.
Another aspect of the present invention provides the many forks ramose polyoxyethylene glycol-amino acid oligopeptides of a kind of general formula I V and the binding substances of reactive derivative and drug molecule thereof:
Wherein:
P is above-mentioned many forks ramose polyoxyethylene glycol-amino acid oligopeptides or its reactive derivative;
Ii is an integer among the 1-30;
TA is a drug molecule;
TA and P link by key or a stable key of a facile hydrolysis.
In the binding substances of above-mentioned many fork ramose polyoxyethylene glycol-amino acid oligopeptides and drug molecule, the amino acid side chain radicals R
2Can participate in connecting drug molecule TA equally.
Preferably, described drug molecule is selected from the group of being made up of amino acid, protein, enzyme, nucleosides, carbohydrate, organic acid, glucoside, flavonoid, quinones, terpene, the plain phenols of phenylpropyl alcohol, steroidal and glucoside thereof, alkaloid, perhaps, be selected from the group of forming by Cinobufagin, glycyrrhetinic acid, Buxine, scutellarin and scopolactone.Preferably, described drug molecule is the antineoplastic agent that is selected from the group of being made up of taxol (comprise Docetaxel and take off the acetyl taxol), camptothecine (comprising Rinotecan and topotecan), Etoposide, cantharidimide, triptolide and their derivative.
Another aspect of the present invention provides a kind of pharmaceutical composition that comprises above-mentioned binding substances and pharmacology acceptable carrier or vehicle, and described pharmaceutical composition is the formulation of tablet, suppository, pill, soft hard-gelatin capsules, powder, solution, suspensoid or aerosol.
Can improve drug absorption according to binding substances of the present invention, prolong action time, heighten the effect of a treatment, reduce dosage and avoid some toxic side effect.
Another aspect of the present invention provides a kind of by above-mentioned many forks ramose polyoxyethylene glycol-amino acid oligopeptides and the compound of derivative and general formula V thereof
R
3-(Z
1)
l(V)
The gel that forms, wherein,
Z
1Be active group, can form covalently bound with group Y reaction or non covalent bond is connected;
L is an integer among the 2-20;
R
3Be that a class contains a plurality of (2-20) Z
1The molecule of active group; R
3Can be a polymkeric substance or small molecules.
Wherein the gel that is connected to form with covalent linkage can characterize by following formula:
Preferably, described R
3Be selected from polyoxyethylene glycol, polypropylene glycol, polyvinyl alcohol, polypropylene morpholine, polyamino acid, their multipolymer and their derivative; More preferably, described R
3Be selected from polylysine or polyglutamic acid, further, described R
3Be selected from Methionin oligopeptides or Gelucystine oligopeptides.
Another aspect of the present invention provides the purposes of described gel in biological medicine, comprises the operation resistance adhesion agent, surgical operation sealing material or the pharmaceutical carrier that comprise above-mentioned gel.
Gel of the present invention 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.
Embodiment
Polyoxyethylene glycol (PEG), its general structure is as follows:
Wherein:
R is H or C
1-12Alkyl,
N 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).Similar thing of other polyoxyethylene glycol or 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 n is about 6～1300.More preferably, n 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 n usually by its molecular-weight average but not repeat the potential unhomogeneity of the initial PEG compound that the unit limits certainly.
Its general structure of many forks ramose polyoxyethylene glycol used among the present invention is as follows:
R wherein
1Be to be a central element, contain a plurality of end group groups, pitch ramose polyoxyethylene glycol by final formation of linear polyethylene glycol that these groups derive more, n is any integer, characterizes its polymerization degree, and i characterizes the bifurcated number, is an integer among the 3-30.
R
1Can be a poly-hydroxy molecule, pass through ehter bond with linear polyethylene glycol, ester bond connects.
In embodiments of the invention, described R
1Be poly-hydroxy tetramethylolmethane or glycerine.By the four fork ramose polyoxyethylene glycol of many forks ramose polyoxyethylene glycol for connecting by ehter bond that tetramethylolmethane derives, the many forks ramose polyoxyethylene glycol that derives by glycerine is a trident ramose polyoxyethylene glycol.
R
1Also can be a polyamino molecule, pass through the ammonia key with linear polyethylene glycol, amido linkage connects.
R
1Also can be carboxyl molecule more than, pass through ester bond with linear polyethylene glycol, amido linkage connects.
Many forks ramose polyoxyethylene glycol-amino acid oligopeptides used in binding substances of the present invention is attached to amino acid oligopeptides, particularly L-glutamic acid oligopeptides 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.Particularly, can in the ramose of fork more than polyoxyethylene glycol-L-glutamic acid oligopeptides, connect more a plurality of drug molecules, to guarantee higher drug loading rate to micromolecular natural drug activeconstituents.
Be that with the polyglutamic acid difference L-glutamic acid oligopeptides has the pendant carboxylic group that ascertains the number in every oligopeptides chain.Therefore, when bound drug such as taxol divide the period of the day from 11 p.m. to 1 a.m, the load factor of drug molecule will be easy to confirm and repeat.
An advantage of the invention is that the oligopeptides group will provide the POL to drug molecule except remaining with the common solvability of hydrophilic polyglycol or derivatives thereof, non-immunogenic and feature such as nontoxic.
The amino acid oligopeptides, its general structure is as follows:
Wherein:
M is an integer among the 2-12, characterizes its polymerization degree;
R
2It is the side-chain radical of related amino acid.
For example, to Methionin oligopeptides, R
2Be-CH
2CH
2CH
2NH
2To Serine oligopeptides, R
2Be-CH
2OH; To L-glutamic acid oligopeptides, R
2Be-CH
2CH
2COOH.
Amino acid in the oligopeptides can identical (homopolypeptide), can different (different polypeptide).
The amino acid that uses among the present invention comprises all natural amino acids and synthesizing amino acid.Especially preferably L-glutamic acid, glycine, Methionin, aspartic acid and Serine.
Oligopeptides is synthetic can to use protection amino acid with reference to general synthetic way, can obtain the aminoacid polymers of fine productive rate under the effect of dewatering agent.Certainly, as the oligopeptides that uses is homopolypeptide, do not have the structural order problem, therefore can adopt easier way preparation, as mixed anhydride method, active ester method, N-carboxyl inner-acid anhydride (NCA) method etc.
With N-carboxyl inner-acid anhydride (NCA) method is example:
This reaction has following advantage: speed of response is fast, and synthesis cycle is short; Behind the end of synthesis, resulting amino free peptide can separate and to be directly used in second peptide of taking turns synthetic.Side chain can lessly be protected, and except that the side chain of NCA needed protection, amino group had only Methionin and halfcystine to protect.
The L-glutamic acid oligopeptide compounds can or can obtain from commercial source by the preparation of the currently known methods in this area.
Many fork ramose polyoxyethylene glycol of the present invention-amino acid oligopeptides by go by many forks ramose polyoxyethylene glycol and the reaction of amino acid oligopeptides into.
In actual applications, need the end group of many forks ramose polyoxyethylene glycol partly be activated, can be reacted with the amino of oligopeptides or carboxyl and with the two combination to guarantee it.Purposes at needs are realized, can adopt following several method that terminal functionality is carried out modification:
A. amination, the hydrophilic polymer after the amination, the amino bigger by reactive behavior has replaced hydroxyl, is even more important reacting to form in the key compound with a molecule that contains the carboxylic acid group.
B. carboxylated, after hydrophilic polymer is carboxylated, can improve its reactivity, make it and can form key compound with another molecular reaction that contains amino or hydroxyl.
C. other also can suitably adopt as modification mode such as carboxyl ester, carbonic ether, acyl chlorides, hydrazides, maleimide, pyridine disulphide.
This several method all can make the functional group on hydrophilic polymer and the oligopeptides be connected in the mode of chemical bond, so that the premium properties of the two is well brought into play separately.
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.
Therefore, pitch ramose polyoxyethylene glycol-amino acid oligopeptides can be by identical mode and these drug molecule combinations more, substituting biological organic molecule, and overcome drug molecule in vivo the physiology transformation period short, the defective that duration of efficacy is short.
The binding substances of many fork ramose polyoxyethylene glycol of the present invention-amino acid oligopeptides and drug molecule can be represented by following formula:
Wherein:
P is many fork ramose polyoxyethylene glycol-amino acid oligopeptides;
Ii is an integer among the 1-30, characterizes the drug molecule number on polyoxyethylene glycol-amino acid oligopeptides;
TA is a drug molecule;
The key that connects drug molecule TA can be key (as ester bond) or a stable key of a facile hydrolysis.
Many fork ramose polyoxyethylene glycol-paddy amino acid oligopeptides and drug molecule can for example form ester bond by reaction and combine, and this process can be as follows simply:
Ester bond is the key of a facile hydrolysis, can degrade in organism and discharges activeconstituents.
The key of other facile hydrolysiss comprises: carbonic ether, carboxamide key etc.
Can use suitable drug molecule formation drug moiety wherein in binding substances 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.
In binding substances of the present invention, the drug molecule part is preferably by isolating active constituents of medicine in the natural phant, as Cinobufagin, glycyrrhetinic acid, Buxine, scutellarin and scopolactone.This drug molecule part preferably is used for the treatment of the natural medicinal ingredients of tumour, for example taxol, camptothecine, Etoposide, cantharidimide, triptolide and their derivative etc. especially.Wherein, the derivative of camptothecine comprises Rinotecan and topotecan; The derivative of taxol, comprise Docetaxel and take off the acetyl taxol (Tai Suodi, taxotere).
Binding substances 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.Therefore, the administering mode that adopts can be selected in through port, the nose, non-enteron aisle, part, transdermal or rectal, its form is solid, semisolid, lyophilized powder or liquid preparation form administration, for example, tablet, suppository, pill, soft hard-gelatin capsules, powder, solution, suspensoid or aerosol etc., the preferred presented in unit dosage form that adopts the simple administration that is applicable to exact dosage desired.Composition can comprise conventional pharmaceutical carrier or vehicle and as the binding substances of the present invention of activeconstituents (one or more), in addition, also can comprise other medicament, carrier, assistant agent etc.
Usually, according to required administering mode, pharmaceutically acceptable composition will comprise the suitable pharmaceutical excipient of about 1 to about 99 weight % binding substances of the present invention and 99 to 1 weight %.Preferred composition comprises the binding substances of the present invention of about 5 to 75 weight %, and all the other are suitable pharmaceutical excipient.
Can adopt the pharmaceutical composition of liquid form administration for example can dissolve, be scattered in the carrier by the medicinal adjuvant of means such as dissolving, dispersion with binding substances of the present invention (about 0.5 to about 20%) and selectivity existence, the example of carrier is water, salt solution, dextrose hydrate, glycerine, ethanol etc., thereby forms solution or suspensoid.
If necessary, pharmaceutical composition of the present invention also can comprise a spot of auxiliary substance, as wetting agent or emulsifying agent, pH buffer reagent, antioxidant etc., for example: citric acid, Arlacel-20, Emulphor FM, Yoshinox BHT etc.
The actual fabrication method of such formulation is that those skilled in the art is known or conspicuous, for example can be referring to Remington ' s Pharmaceutical Sciences, the 18th edition, (Mack Publishing Company, Easton, Pennsylvania, 1990).In any case according to technology of the present invention, employed composition will contain the binding substances of the present invention for the treatment of significant quantity, to be used for the treatment of corresponding disease.
It is a kind of with gel that many forks ramose polyoxyethylene glycol-the amino acid oligopeptides forms under suitable condition that the present invention also provides.This gel is by many fork ramose polyoxyethylene glycol-amino acid oligopeptides or its reactive derivative and other molecules (comprising another kind of many forks ramose polyoxyethylene glycol-amino acid oligopeptides, polyethylene active derivatives and other small molecules) reaction formation.Gel can be to be connected to form by covalent linkage or non covalent bond.
According to the present invention, the gel that is connected to form with covalent linkage can characterize by following formula:
Wherein:
Z
1Be active group, can form covalently bound with group Z reaction;
L is an integer among the 2-20;
R
3Be that a class contains a plurality of (2-20) Z
1The molecule of active group; R
3Can be a polymkeric substance or small molecules.
Below in conjunction with case description binding substances of the present invention and preparation method thereof, it does not limit the present invention.Embodiments of the present invention are not limited to above-mentioned explanation, also should be considered as protection scope of the present invention not deviating from the improvement carried out on the basis that the invention is intended to and change.
Embodiment
Embodiment 1
The preparation of four fork branch polyoxyethylene glycol-L-glutamic acid dipeptides (1a)
10 grams, four fork branch's polyoxyethylene glycol (molecular weight is 10000) and 2 gram N, N '-two succinimidyl carbonate is dissolved in 100 milliliters of second eyeballs, adds 1 milliliter of anhydrous pyridine again.Reaction mixture is stirred overnight at room temperature under nitrogen protection.Unnecessary solvent is removed by rotary evaporation, product vacuum-drying.Solid product adds in 40 milliliters of anhydrous methylene chlorides, and insolubles is by removing by filter, and (0.1M, pH5.5) washing once with sodium acetate buffer solution for organic phase.Use anhydrous sodium sulfate drying again, concentrate.Product shifts with ether, filters vacuum-drying.Productive rate: 9.5 grams (95%).HNMR (DMSO): 3.5 (br m, the hydrogen among the PEG), 3.24 (s, 3 hydrogen), 4.45 (t, 2 hydrogen), 2.82 (s, 4 hydrogen).
0.6 gram L-glutamic acid dipeptides (Glu-Glu) is dissolved in 20 milliliters of dimethyl formamides (DMF), adds four fork branch's polyoxyethylene glycol-succinimidyl carbonates (molecular weight is 10000) of step prepared in reaction on 4 grams in solution.Stirred 6 hours under the solution room temperature, remove by filter muddy thing.Resistates filters product vacuum-drying with 100 milliliters of isopropanol precipitatings.Product can pass through ion-exchange chromatogram purification.Obtain four fork branch polyoxyethylene glycol-L-glutamic acid dipeptides (1a).Productive rate: 2.5 grams.HNMR (DMSO): 3.5 (brm, the hydrogen among the PEG), 4.41 (t, 2 hydrogen), 2.37 (s, 2 hydrogen), 2.32 (t, 2 hydrogen).
Embodiment 2
The preparation of trident branch polyoxyethylene glycol-L-glutamic acid dipeptides (1b)
10 gram trident branch's polyoxyethylene glycol (molecular weight is 15000) and 1 gram N, N '-two succinimidyl carbonate is dissolved in 100 milliliters of acetonitriles, adds 0.8 milliliter of anhydrous pyridine again.Reaction mixture is stirred overnight at room temperature under nitrogen protection.Unnecessary solvent is removed by rotary evaporation, product vacuum-drying.Solid product adds in 40 milliliters of anhydrous methylene chlorides, and insolubles is by removing by filter, and (0.1M, pH5.5) washing once with sodium acetate buffer solution for organic phase.Use anhydrous sodium sulfate drying again, concentrate.Product shifts with ether, filters vacuum-drying.Productive rate: 9.5 grams (95%).HNMR (DMSO): 3.5 (br m, the hydrogen among the PEG), 3.24 (s, 3 hydrogen), 4.45 (t, 2 hydrogen), 2.82 (s, 4 hydrogen).
0.4 gram L-glutamic acid dipeptides (Glu-Glu) is dissolved in 20 milliliters of dimethyl formamides (DMF), adds the trident branch polyoxyethylene glycol-succinimidyl carbonate (molecular weight is 10000) of step prepared in reaction on 4 grams in solution.Stirred 6 hours under the solution room temperature, remove by filter muddy thing.Resistates filters product vacuum-drying with 100 milliliters of isopropanol precipitatings.Product can pass through ion-exchange chromatogram purification.Obtain trident branch polyoxyethylene glycol-L-glutamic acid dipeptides (1b).Productive rate: 2.5 grams.HNMR (DMSO): 3.5 (brm, the hydrogen among the PEG), 4.41 (t, 2 hydrogen), 2.37 (s, 2 hydrogen), 2.32 (t, 2 hydrogen).
Embodiment 3
The preparation of four fork branch's polyoxyethylene glycol-glycine dipeptidases (2a)
0.3 gram glycine dipeptidase (Glu-Glu) is dissolved in 20 milliliters of dimethyl formamides (DMF), adds four fork branch's polyoxyethylene glycol-succinimidyl carbonates (molecular weight is 10000) of 3 gram embodiment, 1 preparation in solution.Stirred 6 hours under the solution room temperature, remove by filter muddy thing.Resistates filters product vacuum-drying with 100 milliliters of isopropanol precipitatings.Product can pass through ion-exchange chromatogram purification.Obtain four fork branch's polyoxyethylene glycol-glycine dipeptidases (2a).Productive rate: 2.5 grams.HNMR (DMSO): 3.5 (br m, the hydrogen among the PEG), 4.54 (t, 2 hydrogen), 4.91 (s, 2 hydrogen).
Embodiment 4
The preparation of trident branch polyoxyethylene glycol-glycine dipeptidase (2b)
0.2 gram glycine dipeptidase (Glu-Glu) is dissolved in 20 milliliters of dimethyl formamides (DMF), adds the trident branch polyoxyethylene glycol-succinimidyl carbonate (molecular weight is 15000) of 3 gram embodiment, 2 preparations in solution.Stirred 6 hours under the solution room temperature, remove by filter muddy thing.Resistates filters product vacuum-drying with 100 milliliters of isopropanol precipitatings.Product can pass through ion-exchange chromatogram purification.Obtain trident branch polyoxyethylene glycol-glycine dipeptidase (2b).Productive rate: 2.5 grams.HNMR (DMSO): 3.5 (br m, the hydrogen among the PEG), 4.54 (t, 2 hydrogen), 4.91 (s, 2 hydrogen).
Embodiment 5
The preparation of the binding substances of four fork branch's polyoxyethylene glycol-glycine dipeptidases and taxol
1.35 four fork branch's polyoxyethylene glycol-glycine dipeptidases (molecular weight is 10000) that gram is made by embodiment 3,0.5 gram taxol, 0.1 gram 4-dimethylaminopyridine (DMAP) are dissolved in 15 milliliters of anhydrous methylene chlorides, add 0.2 gram dicyclohexylcarbodiimide (DCC) again.Solution under nitrogen protection, the ambient temperature overnight stirring reaction.Unnecessary solvent rotary evaporation is removed, and resistates adds 8 milliliter 1, the dissolving of 4-dioxane.Remove by filter precipitation, solution concentration, resistates adds 30 milliliters of Virahols (IPA), filters product vacuum-drying.Obtain four fork branch polyoxyethylene glycol-glycine dipeptidase-Japanese yew alcohol esters (3).Productive rate: 1.3 grams.Fusing point: 59-62 ℃.
Embodiment 6
The preparation of the binding substances of four fork branch polyoxyethylene glycol-L-glutamic acid dipeptides and camptothecin derivative
0.7 gram camptothecine (Camptothecin) and 0.5 gram N-t-butoxycarbonyl glycine (BOC-gly), be dissolved in 10 milliliters of anhydrous methylene chlorides, add 0.62 gram dicyclohexylcarbodiimide (DCC) and 0.36 gram 4-dimethylaminopyridine (DMAP), stir under the room temperature and spend the night.Remove by filter the solid that reaction produces, decompression concentrated solution adds 50 milliliters of ether.Filter collecting precipitation vacuum-drying.
0.5 gram camptothecine N-t-butoxycarbonyl glycine ester (being made by the last step) is dissolved in 10 milliliters of chloroforms, adds 10 milliliters of trifluoroacetic acids, stirring is 5 hours under the room temperature.Decompression concentrated solution adds 50 milliliters of ether.Filter, collecting precipitation, vacuum-drying makes camptothecin derivative.
0.5 four fork branch's polyoxyethylene glycol L-glutamic acid dipeptides (molecular weight is 10000) that gram is made by embodiment 1,0.3 gram camptothecin derivative (by previous step preparation), 32 milligrams 4-dimethylaminopyridine (DMAP) are dissolved in 30 milliliters of anhydrous methylene chlorides, add 0.2 gram dicyclohexylcarbodiimide (DCC) again.Solution under nitrogen protection, the ambient temperature overnight stirring reaction.Unnecessary solvent rotary evaporation is removed, and resistates adds 50 milliliters of Virahols (IPA), filters product vacuum-drying.Obtain four fork branch polyoxyethylene glycol-L-glutamic acid dipeptides-glycine-camptothecin esters (4).Productive rate: 0.5 gram.Fusing point: 60-63 ℃.
Embodiment 7
The preparation of four fork branch polyoxyethylene glycol-L-glutamic acid dipeptides and Cinobufagin (Cinobufagin) binding substances
0.5 restraining four fork branch's polyoxyethylene glycol L-glutamic acid dipeptides (made by embodiment 1, molecular weight is 10000) is dissolved in 10 milliliters of methylene dichloride.Add 300 milligrams of Cinobufagins, 32 milligrams of 4-dimethylaminopyridines (DMAP) and 200 milligrams of dicyclohexylcarbodiimide (DCC).Solution under nitrogen protection, the ambient temperature overnight stirring reaction.Unnecessary solvent rotary evaporation is removed, and resistates adds 20 milliliter 1, the dissolving of 4-dioxane.Remove by filter precipitation, solution concentration, resistates adds 100 milliliters of Virahols (IPA), filters product vacuum-drying.Obtain four fork branch polyoxyethylene glycol-L-glutamic acid dipeptides-Cinobufagin esters (5).Productive rate: 0.5 gram.Fusing point: 58-60 ℃.
Embodiment 8
The preparation of four fork branch polyoxyethylene glycol-L-glutamic acid dipeptides and scopolactone (Scopoletin) binding substances
1 gram, four fork branch polyoxyethylene glycol L-glutamic acid dipeptides (are made by embodiment 1, molecular weight is 10000) be dissolved in 25 milliliters of methylene dichloride, the scopolactone that adds 0.30 gram again, the dicyclohexylcarbodiimide (DCC) of the 4-dimethylaminopyridine (DMAP) of 0.1 gram and 0.4 gram.The nitrogen protection at room temperature of this solution was stirred 12 hours.Solution decompression steams and removes, and resistates adds 100 milliliters of Virahols (IPA).Filter collecting precipitation again with draining after the ether washing.Merge throw out, vacuum-drying.Obtain four fork branch polyoxyethylene glycol-L-glutamic acid dipeptides-scopolactones (6).Productive rate: 1 gram.Fusing point: 58-61 ℃.
Embodiment 9
The preparation of four fork branch polyoxyethylene glycol-glycine dipeptidase reactive derivatives
2 grams, four fork branch polyoxyethylene glycol-glycine oligopeptides (molecular weight is 10000, by embodiment 3 preparations) are dissolved in 25 milliliters of methylene dichloride, add 90 milligrams N-hydroxy-succinamide (NHS) and 0.2 milligram dicyclohexylcarbodiimide (DCC) again.The nitrogen protection at room temperature of this solution was stirred 12 hours.Solution decompression steams and removes, and resistates adds 100 milliliters of Virahols (IPA).Filter collecting precipitation, again with draining after the ether washing.Vacuum-drying.Obtain four fork branch polyoxyethylene glycol-glycine dipeptidase-N-hydroxy-succinamide esters (7).Productive rate: 1.8 grams.Fusing point: 55-57 ℃.
Embodiment 10
The preparation of four fork branch polyoxyethylene glycol-Methionin tetrapeptides (8)
0.3 gram N-9-fluorenylmethyloxycarbonyl-Methionin tetrapeptide (Fmoc-Lys-Fmoc-Lys-Fmoc-Lys-Fmoc-Lys) is dissolved in 20 milliliters of dimethyl formamides (DMF), in solution, add 3 grams, four fork branch polyoxyethylene glycol-two succinimidyl carbonates (molecular weight is 10000, by embodiment 1 preparation).Stirred 6 hours under the solution room temperature, remove by filter muddy thing.Solution precipitates with 100 milliliters of Virahols, filters.Filtrate is added 100 milliliters of ether sedimentations.Merge throw out, be dissolved in 20 milliliters of chloroforms, add 5 milliliters of piperidines, stirred 3 hours under the room temperature.Decompression concentrated solution adds 50 milliliters of Virahols.Filter collecting precipitation, product vacuum-drying.Obtain four fork branch polyoxyethylene glycol-Methionin tetrapeptides (8).Productive rate: 2.0 grams.Fusing point: 55-57 ℃.
Embodiment 11
Prepare gel by four fork branch polyoxyethylene glycol-glycine dipeptidase reactive derivatives and polyethylene glycol diamines
Polyoxyethylene glycol-(molecular weight is 10000 to glycine oligopeptides reactive derivative in 200 milligram of four fork branch, by embodiment 9 preparations), be dissolved in 2 milliliters acetate buffer solution (10mM, pH5.0) in, add 2 milliliters of phosphate buffer soln (0.1M, pH 7.4), wherein contain 200 milligrams of polyethylene glycol diamines (molecular weight is 5000), solution jolts gently until forming gel.
Embodiment 12
By four fork branch polyoxyethylene glycol-glycine dipeptidase reactive derivatives and small molecule amine (Methionin dipeptides) preparation gel
Polyoxyethylene glycol-(molecular weight is 10000 to the glycine dipeptidase reactive derivative in 200 milligram of four fork branch, by embodiment 9 preparations), be dissolved in 1 milliliter acetate buffer solution (10mM, pH5.0) in, add 1 milliliter of phosphate buffer soln (0.1M, pH7.4), wherein contain 20 milligrams of Methionin dipeptides, solution jolts gently until forming gel.
Embodiment 13
By four fork branch polyoxyethylene glycol-glycine dipeptidase reactive derivatives and
Another four forks branch polyoxyethylene glycol-Methionin tetrapeptide prepares gel
Polyoxyethylene glycol-(molecular weight is 10000 to the glycine dipeptidase reactive derivative in 200 milligram of four fork branch, by embodiment 9 preparations), be dissolved in 2 milliliters acetate buffer solution (10mM, pH5.0) in, add 2 milliliters of phosphate buffer solns (0.1M, pH7.4), wherein contain 100 milligram four the fork branch polyoxyethylene glycol-(molecular weight is 10000 to the Methionin tetrapeptide, by embodiment 10 preparations), solution jolts gently until forming gel.
Embodiment 14
Prepare gel by four fork branch polyoxyethylene glycol-Methionin tetrapeptides and polyglutamic acid
Polyoxyethylene glycol-(molecular weight is 10000 to the Methionin tetrapeptide in 200 milligram of four fork branch, by embodiment 10 preparations), be dissolved in 1 milliliter phosphate buffer soln (0.1M, pH7.4) in, add 1 milliliter of phosphate buffer soln (0.1M, pH7.4), wherein contain 50 milligrams of polyglutamic acids (molecular weight is 10000), solution jolts gently until forming gel.
Embodiment 15
Pharmaceutical composition
Present embodiment illustrates the preparation of drug combination process of representative parenteral administration, and described composition comprises binding substances of the present invention.
Composition
Binding substances 2 grams of embodiment 5
0.9% salt brine solution to 100 milliliter
The binding substances of embodiment 5 is dissolved in 0.9% salt brine solution, obtains 100 milliliters used for intravenous injection solution,, under aseptic condition, pack its membrane filtration filtration of material by 0.2 μ m.
Claims (27)
1, many forks of general formula I ramose polyoxyethylene glycol-amino acid oligopeptides or its reactive derivative compound:
Wherein:
R
1Be selected from poly-hydroxy structure, polyamino structure or many carboxyl structure;
N is the integer of 3-2000;
M is an integer among the 2-12;
I is an integer among the 3-30;
R
2Be amino acid whose side-chain radical, can be identical or different;
X is a linking group, is selected from (the CH by O
2)
kCO, O (CH
2)
kOCO, O (CH
2)
kNHCO, NR (CH
2)
kOCO, NR (CH
2)
kNHCO, NR (CH
2)
kThe group of the group that CO forms, and k is the integer of 0-10;
Y is selected from the group of being made up of hydroxyl, ester group, acyl chlorides, hydrazides, maleimide, pyridine disulphide active group.
2, compound as claimed in claim 1, described compound are the polyoxyethylene glycol monoamino-acid oligopeptides of general formula I I:
3, compound as claimed in claim 2, wherein, described compound is the compound of general formula I Ia:
Wherein, R is for being selected from by H, C
1-12The group of the group that alkyl, substituted aryl, aralkyl, assorted alkyl and substituted alkyl are formed, j is an integer among the 1-4.
4, compound as claimed in claim 2, wherein, described compound is the compound of general formula I Ib:
Wherein, R is for being selected from by H, C
1-12The group of the group that alkyl, substituted aryl, aralkyl, assorted alkyl and substituted alkyl are formed, j is an integer among the 1-4.
5, compound as claimed in claim 1, wherein, described amino acid is natural amino acid and synthesizing amino acid.
6, compound as claimed in claim 5, wherein, described amino acid is L-glutamic acid, glycine, Methionin, Gelucystine, aspartic acid, arginine, tyrosine or Serine.
7, compound as claimed in claim 1, wherein, described R
1Be tetramethylolmethane, methylglucoside, sucrose, glycol ether, propylene glycol, glycerine or Polyglycerine structure.
8, compound as claimed in claim 2, wherein, described polyoxyethylene glycol-amino acid oligopeptides is
Four fork branch polyoxyethylene glycol-L-glutamic acid dipeptides of formula (1a)
The trident branch polyoxyethylene glycol-L-glutamic acid dipeptides of formula (1b)
Four fork branch polyoxyethylene glycol-glycine dipeptidases of formula (2a)
The trident branch polyoxyethylene glycol-glycine dipeptidase of formula (2b)
Four fork branch polyoxyethylene glycol-Methionin tetrapeptides of formula (8)
9, compound as claimed in claim 1, wherein, described compound is the many forks ramose polyoxyethylene glycol-amino acid oligopeptides reactive derivative of general formula III:
Wherein:
Z is selected from the group of being made up of ester group, acyl chlorides, hydrazides, maleimide, pyridine disulphide active group.
10, compound as claimed in claim 9, wherein, described Z is the N-hydroxy-succinamide ester group.
11, compound as claimed in claim 9, wherein, described amino acid is natural amino acid and synthesizing amino acid.
12, compound as claimed in claim 9, wherein, described amino acid is L-glutamic acid, glycine, Methionin, Gelucystine, aspartic acid, arginine, Tyrosine or Serine.
13, compound as claimed in claim 9, wherein, described R
1Be tetramethylolmethane, methylglucoside, sucrose, glycol ether, propylene glycol, glycerine or Polyglycerine structure.
14, compound as claimed in claim 9, wherein, described derivative is four fork branch polyoxyethylene glycol-glycine dipeptidase-N-hydroxy-succinamide esters of formula (7).
15, the many forks ramose polyoxyethylene glycol-amino acid oligopeptides of general formula I V and the binding substances of reactive derivative and drug molecule thereof:
Wherein:
P is many forks ramose polyoxyethylene glycol-amino acid oligopeptides or its reactive derivative as one of claim 1-13;
Ii is an integer among the 1-30;
TA is a drug molecule;
TA and P link by an ester bond, carbonic acid ester bond or carboxamide ester.
16, binding substances as claimed in claim 15, wherein, described drug molecule is selected from the group of being made up of amino acid, protein, enzyme, nucleosides, carbohydrate, organic acid, glucoside, flavonoid, quinones, terpene, the plain phenols of phenylpropyl alcohol, steroidal and glucoside thereof, alkaloid.
17, binding substances as claimed in claim 15, wherein, described drug molecule is selected from the group of being made up of Cinobufagin, glycyrrhetinic acid, Buxine, scutellarin and scopolactone.
18, binding substances as claimed in claim 15, wherein, described drug molecule is the antineoplastic agent that is selected from the group of being made up of taxol, camptothecine, Etoposide, cantharidimide, triptolide and their derivative.
19, binding substances as claimed in claim 18, wherein, described camptothecin derivative is selected from Rinotecan and topotecan.
20, binding substances as claimed in claim 18, wherein, the derivative of described taxol is selected from Docetaxel and takes off the acetyl taxol.
21, binding substances as claimed in claim 15, wherein, described binding substances is:
Four fork branch polyoxyethylene glycol-glycine dipeptidase-Japanese yew alcohol esters of formula (3)
TA=taxol wherein;
Four fork branch polyoxyethylene glycol-L-glutamic acid dipeptides-glycine-camptothecin esters of formula (4)
TA=camptothecine wherein;
Four fork branch polyoxyethylene glycol-L-glutamic acid dipeptides-Cinobufagin esters of formula (5)
TA=Cinobufagin wherein; Or
Four fork branch polyoxyethylene glycol-L-glutamic acid dipeptides-scopolactones of formula (6)
TA=scopolactone wherein.
22, comprise as each the described binding substances of claim 15-21 and the pharmaceutical composition of pharmacology acceptable carrier or vehicle.
23, composition as claimed in claim 22, described pharmaceutical composition are the formulation of tablet, suppository, pill, soft hard-gelatin capsules, powder, solution, suspensoid or aerosol.
24, a kind of by as the many forks ramose polyoxyethylene glycol-amino acid oligopeptides or derivatives thereof of one of claim 1-14 and the compound of general formula V
R
3-(Z
1)
l (V)
The gel that forms, wherein,
R
3Be selected from polyoxyethylene glycol, polypropylene glycol, polyvinyl alcohol, polypropylene morpholine, polyamino acid, their multipolymer and their derivative, Z
1Be R
3In can form group covalently bound or that non covalent bond is connected with group Y or Z reaction;
L is an integer among the 2-20.
25, gel as claimed in claim 24, wherein, described R
3Be selected from polylysine or polyglutamic acid.
26, gel as claimed in claim 24, wherein, described R
3Be selected from Methionin oligopeptides or Gelucystine oligopeptides.
27, comprise operation resistance adhesion agent, surgical operation sealing material or pharmaceutical carrier as gel as described in one of claim 24-26.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100480166A CN100475837C (en) | 2004-06-11 | 2004-06-11 | Branched polyglycol-amino acid oligopeptide and active derivative and medicinal composition thereof |
| PCT/CN2005/000834 WO2005121181A1 (en) | 2004-06-11 | 2005-06-10 | Multi-drop tree branching polyethylene glycol-oligopeptides and active derivates and pharmaceutical compounds there of |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2004100480166A CN100475837C (en) | 2004-06-11 | 2004-06-11 | Branched polyglycol-amino acid oligopeptide and active derivative and medicinal composition thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1706865A CN1706865A (en) | 2005-12-14 |
| CN100475837C true CN100475837C (en) | 2009-04-08 |
Family
ID=35503014
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004100480166A Active CN100475837C (en) | 2004-06-11 | 2004-06-11 | Branched polyglycol-amino acid oligopeptide and active derivative and medicinal composition thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN100475837C (en) |
| WO (1) | WO2005121181A1 (en) |
Families Citing this family (36)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007001448A2 (en) | 2004-11-04 | 2007-01-04 | Massachusetts Institute Of Technology | Coated controlled release polymer particles as efficient oral delivery vehicles for biopharmaceuticals |
| ATE465205T1 (en) | 2005-12-05 | 2010-05-15 | Nitto Denko Corp | POLYGLUTAMAT-AMINO ACID CONJUGATES AND METHODS |
| WO2007067622A2 (en) * | 2005-12-06 | 2007-06-14 | Tyco Healthcare Group Lp | Carbodiimide crosslinking of functionalized polethylene glycols |
| US9267937B2 (en) | 2005-12-15 | 2016-02-23 | Massachusetts Institute Of Technology | System for screening particles |
| CN101573141B (en) | 2006-05-15 | 2016-05-04 | 麻省理工学院 | For the polymer of functional particles |
| WO2007150030A2 (en) | 2006-06-23 | 2007-12-27 | Massachusetts Institute Of Technology | Microfluidic synthesis of organic nanoparticles |
| CN101168594B (en) * | 2006-10-24 | 2011-07-27 | 北京键凯科技有限公司 | Polyglycol active derivative with oligopeptide as framework, preparation method thereof and conjugate of with pharmaceutical molecule |
| WO2008098165A2 (en) | 2007-02-09 | 2008-08-14 | Massachusetts Institute Of Technology | Oscillating cell culture bioreactor |
| EP2144600A4 (en) | 2007-04-04 | 2011-03-16 | Massachusetts Inst Technology | Poly (amino acid) targeting moieties |
| EP2620157A3 (en) | 2007-10-12 | 2013-10-16 | Massachusetts Institute of Technology | Vaccine nanotechnology |
| US8343497B2 (en) | 2008-10-12 | 2013-01-01 | The Brigham And Women's Hospital, Inc. | Targeting of antigen presenting cells with immunonanotherapeutics |
| US8343498B2 (en) | 2008-10-12 | 2013-01-01 | Massachusetts Institute Of Technology | Adjuvant incorporation in immunonanotherapeutics |
| US8277812B2 (en) | 2008-10-12 | 2012-10-02 | Massachusetts Institute Of Technology | Immunonanotherapeutics that provide IgG humoral response without T-cell antigen |
| US8591905B2 (en) | 2008-10-12 | 2013-11-26 | The Brigham And Women's Hospital, Inc. | Nicotine immunonanotherapeutics |
| ITRM20080551A1 (en) * | 2008-10-15 | 2010-04-16 | Univ Catania | AMPHIFYL DERIVATIVES OF POLYOSSIETHYLENE GLYCOL (PEG), PREPARATION PROCEDURE AND THEIR USE IN THE PREPARATION OF PHARMACEUTICAL SYSTEMS. |
| CN101724144A (en) | 2008-11-03 | 2010-06-09 | 北京键凯科技有限公司 | Novel multi-arm polyethylene glycol, preparation method and application thereof |
| CN103755949B (en) * | 2009-12-25 | 2016-04-13 | 天津键凯科技有限公司 | Multi-arm polyethylene glycol derivative and with the binding substances of medicine and gel |
| CN102266566B (en) * | 2010-06-03 | 2013-06-12 | 中国人民解放军军事医学科学院毒物药物研究所 | Magnetic compound, and preparation method and purpose thereof |
| US20140228279A1 (en) * | 2011-10-03 | 2014-08-14 | Nanyang Technological University | Cationic peptidopolysaccharides with excellent broad- spectrum antimicrobial activities and high selectivity |
| CN103083680B (en) * | 2011-11-07 | 2014-12-24 | 北京键凯科技有限公司 | Polyethylene glycol (PEG)-amino acid oligopeptide-irinotecan combo and its medicinal composition |
| 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 |
| CN104448295B (en) * | 2013-12-02 | 2018-01-23 | 北京键凯科技股份有限公司 | The rapamycin derivative of polyethylene glycol multijaw oligopeptides bonding |
| CN105017522A (en) * | 2015-07-20 | 2015-11-04 | 湖南华腾制药有限公司 | Polyethylene glycol-modified unnatural amino acid preparation method |
| CN106924753B (en) * | 2015-12-30 | 2021-11-09 | 北京大学 | Method for preparing protein-polyamino acid cyclic conjugate |
| 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 |
| CN108264538B (en) * | 2017-01-04 | 2023-08-29 | 辽宁药联制药有限公司 | Solid Phase Synthesis Method of Aspartic Acid Condensate |
| WO2018177055A1 (en) * | 2017-03-30 | 2018-10-04 | 北京键凯科技股份有限公司 | Method for preparing y-branched hydrophilic polymer carboxylic acid derivative |
| CN108659227B (en) * | 2017-03-30 | 2020-11-06 | 北京键凯科技股份有限公司 | Preparation method of Y-type branched hydrophilic polymer carboxylic acid derivative |
| CN108003342A (en) * | 2018-02-02 | 2018-05-08 | 中国科学院长春应用化学研究所 | Polyaminoacid, its preparation method and load medicinal gel |
| EP3778705A4 (en) * | 2018-03-29 | 2022-01-05 | NOF Corporation | Degradable polyethylene glycol derivative |
| CN109897179B (en) * | 2019-04-02 | 2021-08-17 | 中国科学院长春应用化学研究所 | Multi-arm polyethylene glycol-poly (L-glutamate) block copolymer, and preparation method and application thereof |
| EP4036149A4 (en) * | 2019-09-26 | 2023-10-25 | NOF Corporation | Heterobifunctional monodispersed polyethylene glycol having peptide linker |
| CN112251484B (en) * | 2020-10-26 | 2022-05-24 | 江南大学 | Method for preparing glycine oligopeptide-polyethylene glycol copolymer under catalysis of lipase |
| CN115975182A (en) * | 2023-01-10 | 2023-04-18 | 深圳市乐土生物医药有限公司 | Amino acid copolymer and application thereof |
| CN116178733B (en) * | 2023-03-03 | 2023-08-01 | 浙江博美生物技术有限公司 | Branched monodisperse PEG derivative based on trifunctional amino acid, preparation method and application |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1381512A (en) * | 2002-01-15 | 2002-11-27 | 泛亚生物技术有限公司 | Multi-arm fork type functional polyethylene glycol preparation method and its application in medicine |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP1251530A3 (en) * | 2001-04-16 | 2004-12-29 | Shipley Company LLC | Dielectric laminate for a capacitor |
| CN100475269C (en) * | 2002-03-05 | 2009-04-08 | 北京键凯科技有限公司 | Binding agent of hydrophilic polymer-glutamic acid oligopeptide and medicinal molecular, composition containing said binding agent and use thereof |
| CN1254496C (en) * | 2002-05-30 | 2006-05-03 | 中国科学院过程工程研究所 | Method of preparing branched polyethylene glycol |
-
2004
- 2004-06-11 CN CNB2004100480166A patent/CN100475837C/en active Active
-
2005
- 2005-06-10 WO PCT/CN2005/000834 patent/WO2005121181A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1381512A (en) * | 2002-01-15 | 2002-11-27 | 泛亚生物技术有限公司 | Multi-arm fork type functional polyethylene glycol preparation method and its application in medicine |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1706865A (en) | 2005-12-14 |
| WO2005121181A1 (en) | 2005-12-22 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN100475837C (en) | Branched polyglycol-amino acid oligopeptide and active derivative and medicinal composition thereof | |
| CN100475269C (en) | Binding agent of hydrophilic polymer-glutamic acid oligopeptide and medicinal molecular, composition containing said binding agent and use thereof | |
| CN103751795B (en) | Preparation and application of hyaluronic acid-antitumor drug conjugate and composite nanoparticle composition | |
| AU772074B2 (en) | Enzymatically activated polymeric drug conjugates | |
| CN101724144A (en) | Novel multi-arm polyethylene glycol, preparation method and application thereof | |
| KR100972264B1 (en) | Polyaminoacids functionalized by alpha tocopherol and uses thereof, particular for therapeutic applications | |
| US8323669B2 (en) | Polymer conjugate of taxane | |
| CN102108119A (en) | Multi-arm polyethylene glycol derivative, combination thereof with medicine, and gel | |
| US20020155992A1 (en) | Poly (dipeptide) as a drug carrier | |
| ES2659778T3 (en) | Polyethylene glycol-amino acid-irinotecan pharmaceutical conjugate and pharmaceutical composition thereof | |
| CN101448875A (en) | Polymer conjugate of podophyllotoxin | |
| CN1556828A (en) | Hydrophili polymer derirative having Y shaped branch, its preparation method, combined object with medicine molecule and medical compositon containing combined object | |
| CN101489592A (en) | Polymer conjugate of combretastatin | |
| CN100374443C (en) | Hydrophilic polymer-thunder good vine extract binding substance and its medicinal composition | |
| CN108026271A (en) | The macromolecule conjugate of 6 coordinate platinum complex | |
| CN101543632A (en) | Anti-tumor prodrug having accurate structure and taking novel amphipathic polymer as carrier and synthetic method thereof | |
| CN100531801C (en) | Polyethylene glycol prodrug of gambogicacid, its preparation method, formulation and use for preparing drug | |
| CN101168594B (en) | Polyglycol active derivative with oligopeptide as framework, preparation method thereof and conjugate of with pharmaceutical molecule | |
| CN100415801C (en) | Polyethylene glycol amino acid N-internal ring carbonyl anhydride active derivatives, and medicinal bonding compound and gel thereof | |
| CN1867578B (en) | The conjugates of a hydrophilic polymer-buxus's extracts and the pharmaceutical compositions of thereof | |
| CN1448420A (en) | Hydrophilic polymer and tanshinones medicine conjugation agent and medicine composition containing same | |
| CN1318426C (en) | Novel cantharidimide and norcantharidimide derivant and its application in medicine | |
| CN104548120A (en) | Polyethylene glycol-betulinic acid conjugate and preparation method thereof | |
| CN1446838A (en) | Hydrophilic polymer-combo of silybum mariamum extract product as well as medicinal combination containing the combo | |
| CN1556801A (en) | Hydrophilipolymer and flavone combined object and medicinal composition containing said combined object |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Effective date of registration: 20091202 Pledge (preservation): Pledge |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20110401 Granted publication date: 20090408 Pledgee: Bank of China, Limited by Share Ltd, Beijing subbranch Pledgor: Beijing Kai Kai Technology Co., Ltd.|Tianjin key Kay Technology Co., Ltd. Registration number: 2009110000662 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Branched polyglycol-amino acid oligopeptide and its active derivative and medicinal composition Effective date of registration: 20110629 Granted publication date: 20090408 Pledgee: Zhongguancun Beijing science and technology Company limited by guarantee Pledgor: Beijing Kai Kai Technology Co., Ltd.|Tianjin key Kay Technology Co., Ltd. Registration number: 2011990000250 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20120607 Granted publication date: 20090408 Pledgee: Zhongguancun Beijing science and technology Company limited by guarantee Pledgor: Beijing Kai Kai Technology Co., Ltd.|Tianjin key Kay Technology Co., Ltd. Registration number: 2011990000250 |
|
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20161223 Address after: 124000 Liaoning Province, Panjin city Shuangtaizi District Park Street, South and West No. 2111020090140248 Patentee after: Liaoning Kai Kai Technology Co., Ltd. Address before: 100085 Haidian District, Beijing on the road to information on the international science and Technology Park, building C, floor four, layer Patentee before: Beijing Jiankai Sci-Tech Co.,Ltd. |