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WO2015081831A1 - 多臂聚乙二醇-叠氮衍生物 - Google Patents

多臂聚乙二醇-叠氮衍生物 Download PDF

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Publication number
WO2015081831A1
WO2015081831A1 PCT/CN2014/092737 CN2014092737W WO2015081831A1 WO 2015081831 A1 WO2015081831 A1 WO 2015081831A1 CN 2014092737 W CN2014092737 W CN 2014092737W WO 2015081831 A1 WO2015081831 A1 WO 2015081831A1
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Prior art keywords
group
polyethylene glycol
arm polyethylene
azide
derivative
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PCT/CN2014/092737
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English (en)
French (fr)
Inventor
陈晓萌
林美娜
赵宣
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天津键凯科技有限公司
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Priority to EP14866860.1A priority Critical patent/EP3078699B1/en
Publication of WO2015081831A1 publication Critical patent/WO2015081831A1/zh
Priority to US15/170,839 priority patent/US10039837B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • C—CHEMISTRY; METALLURGY
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    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/321—Polymers modified by chemical after-treatment with inorganic compounds
    • C08G65/325—Polymers modified by chemical after-treatment with inorganic compounds containing nitrogen
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    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
    • C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/3332—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing carboxamide group
    • C08G65/33327—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing carboxamide group cyclic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33331—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing imide group
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33331—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing imide group
    • C08G65/33337—Polymers modified by chemical after-treatment with organic compounds containing nitrogen containing imide group cyclic
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/333—Polymers modified by chemical after-treatment with organic compounds containing nitrogen
    • C08G65/33396—Polymers modified by chemical after-treatment with organic compounds containing nitrogen having oxygen in addition to nitrogen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/334—Polymers modified by chemical after-treatment with organic compounds containing sulfur
    • C08G65/3344—Polymers modified by chemical after-treatment with organic compounds containing sulfur containing oxygen in addition to sulfur
    • C08G65/3346—Polymers modified by chemical after-treatment with organic compounds containing sulfur containing oxygen in addition to sulfur having sulfur bound to carbon and oxygen
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/337—Polymers modified by chemical after-treatment with organic compounds containing other elements
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
    • C08G2650/30—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type branched

Definitions

  • the invention relates to a multi-arm polyethylene glycol active derivative, in particular to a multi-arm polyethylene glycol active derivative having an azide chain end and a preparation method thereof.
  • Polyethylene glycol is a widely used polyether polymer compound, which can be applied to many fields such as medicine, health, food, and chemical industry. PEG can be dissolved in water and many solvents, and the polymer has excellent biocompatibility, can be dissolved in the tissue fluid in the body, and can be quickly excreted by the body without any toxic side effects.
  • polyethylene glycol polymer segment is not limited to the terminal hydroxyl group, and the polyethylene glycol active derivative obtained by introducing other functionalized terminal groups such as an amino group, a carboxyl group or an aldehyde group can greatly broaden the polyethylene glycol.
  • the application range has broad application prospects in organic synthesis, peptide synthesis, polymer synthesis, sustained release and controlled release of drugs, and targeted application.
  • Azide not only has important physiological activities, such as azidonucleoside (AZT), it is currently the drug of choice for the treatment of AIDS, but also has a wide range of reactivity, such as reduction to amino groups, and alkyne can occur 1 , 3-dipolar cycloaddition reaction, Curtius reaction, etc.
  • the terminal nitrogen-based polymer obtained by the reduction of the terminal azide group plays an important role in the liquid phase synthesis of the polypeptide as a polymer carrier.
  • Patent WO2011075953A1 discloses a novel multi-arm polyethylene glycol having different types of active groups formed by polymerizing ethylene oxide from oligo-pentaerythritol as an initiator, and the terminal active group is selected from the group consisting of hydroxyl group, amino group, sulfhydryl group, The carboxyl group, the ester group, the aldehyde group, the acryl group and the maleimide group, and the undisclosed end group active group may be an azide group.
  • Non-patent literature "Synthesis and characterization of terminal azide-based polyethylene glycols” discloses the synthesis of a high molecular weight terminal azido polyethylene glycol The method, however, is a linear polyethylene glycol in the polymer prepared by the method, and is only loaded with an azide group, and cannot introduce other reactive groups.
  • the present invention provides a multi-arm polyethylene glycol-azide reactive derivative.
  • An object of the present invention is to provide a multi-arm polyethylene glycol-azide active derivative, which has multiple end groups and has multiple functions compared with a linear polyethylene glycol.
  • the introduction point of the group can load a plurality of different active end groups, and solve the problem that the polyethylene glycol azide derivative has poor flexibility and a small application range.
  • Another object of the present invention is to provide a multi-arm polyethylene glycol-azide reactive derivative which can react with other kinds of polymers, is used for gel preparation, and can reduce reaction formation conditions and shorten gel formation. time.
  • Still another object of the present invention is to provide a series of multi-arm polyethylene glycol-azide reactive derivatives having different structures, which can solve the problem that the release rate of the active ingredient cannot be obtained when the gel formed by the multi-arm polyethylene glycol-azid active derivative is formed. The issue of control.
  • the invention provides a multi-arm polyethylene glycol-azide derivative of the formula I:
  • R is a central molecule; is selected from a polyhydroxy structure, a polyamino structure or a polycarboxy structure;
  • n is the number of branches or the number of arms, n ⁇ 3;
  • PEG is the same or different -(CH 2 CH 2 O) m -, m has an average value of an integer of from 3 to 250;
  • X is a linking group of an azide end group selected from the group consisting of a C 1-12 alkyl group, an aralkyl group, an ester group, a carbonate group, an amide group, an amide ester group, an ether group, and a urethane group;
  • k is the number of branches having an azide end group, 2 ⁇ k ⁇ n;
  • F is a reactive end group other than azide, selected from the group consisting of an amino group, a carboxyl group, a thiol group, an ester group, a maleimido group, and an acrylic group;
  • Y is a terminal group
  • F is a linking group, selected from the group consisting of the group consisting of: (CH 2) i, ( CH 2) i NH, (CH 2) i OCOO -, (CH 2) i OCONH -, (CH 2 ) i NHCOO-, (CH 2 ) i NHCONH-, OC(CH 2 ) i COO-, (CH 2 ) i COO-, (CH 2 ) i CONH; i is an integer from 0 to 10.
  • R is a pentaerythritol or polypentaerythritol structure, methyl glucoside, sucrose glycerin or polyglycerol structure, and particularly, R is preferably
  • 1 is an integer of ⁇ 1 and ⁇ 10, preferably 1 is an integer of ⁇ 1 and ⁇ 6, and particularly preferably 1 is an integer of ⁇ 1 and ⁇ 4, and in a specific embodiment of the present invention, the 1 may preferably be 1, 2, 3, 4, 5 or 6.
  • n is the number of branches or the number of arms, n ⁇ 3, preferably 3 ⁇ n ⁇ 22, more preferably 3 ⁇ n ⁇ 14, most preferably 3 ⁇ n ⁇ 6.
  • k is the number of branches having an azide end group, 2 ⁇ k ⁇ n, preferably 2 ⁇ k ⁇ 16, more
  • 2 ⁇ k ⁇ 6, in the embodiment of the invention k may be 2, 4, 6, 8, 10, 12, 14, 16.
  • the multi-arm polyethylene glycol-azido derivative has the structure of the following formula II:
  • 2 ⁇ k ⁇ 16 more preferably 2 ⁇ k ⁇ 6, and in the embodiment of the present invention, k may be 2, 4, 6, 8, 10, 12, 14, or 16.
  • the average value of m is an integer of from 3 to 250, preferably an integer of from 68 to 250, more preferably m is 68- An integer of 227.
  • X is a linking group of an azide terminal group selected from a C 1-12 alkyl group, an aralkyl group, and an ester group.
  • a group consisting of a carbonate group, an amide group, an amide group, an ether group, and a urethane group preferably (CH 2 ) i , (CH 2 ) i NH, (CH 2 ) i OCOO-, (CH 2 ) i OCONH -, (CH 2 ) i NHCOO -, (CH 2) i NHCONH-, OC (CH 2) i COO -, (CH 2) i COO -, (CH 2) i CONH, (CH 2) i More preferably, COO-; is (CH 2 ) i , (CH 2 ) i NH, (CH 2 ) i COO-, (CH 2 ) i CO-.
  • Y is a terminal group F linking group selected from the group consisting of: (CH 2 ) i , ( CH 2) i NH, (CH 2) i OCOO -, (CH 2) i OCONH -, (CH 2) i NHCOO -, (CH 2) i NHCONH-, OC (CH 2) i COO -, (CH 2 ) i COO -, (CH 2 ) i CONH; preferably (CH 2) i, (CH 2) i NH, (CH 2) i OCOO -, (CH 2) i OCONH -, (CH 2) i NHCOO- , (CH 2 ) i NHCONH-, OC(CH 2 ) i COO-, (CH 2 ) i COO-, (CH 2 ) i CONH, (CH 2 ) i COO-; more preferably (CH 2 ) i
  • i in X and Y is an integer of from 1 to 10, preferably an integer of from 1 to 5, more preferably from 1 to 3. In the specific embodiment of the present invention, the i is 1. 2, 3, 4 or 5.
  • F is a reactive terminal group different from the azide, and is selected from the group consisting of an amino group, a carboxyl group, a thiol group, and an ester group.
  • a base a maleimide group and an acrylic group; preferably -NH 2 , -COOH, -OCH 3 ,
  • the multi-arm polyethylene glycol-azide derivative of the formula I described in the present invention is:
  • the multi-arm polyethylene glycol-azide derivative of the formula I described in the present invention is:
  • the multi-arm polyethylene glycol has a molecular weight of 1000 to 80,000 Da. In a preferred embodiment of the present invention, the multi-arm polyethylene glycol has a molecular weight of 3,000 to 20,000 Da. In a more preferred embodiment of the present invention, the multi-arm polyethylene glycol has a molecular weight of 3000 to 10000 Da, and in a most preferred embodiment of the present invention, the molecular weight of the multi-arm polyethylene glycol can be It is 3000Da, 5000Da, 10000Da, 20000Da.
  • the multi-arm polyethylene glycol-azide derivative is a multi-arm polyethylene glycol azide-monoacetic acid having the structure of the following formula V:
  • the multi-arm polyethylene glycol-azide derivative has the structure of the following formula VI Multi-arm polyethylene glycol azide-polyacetic acid:
  • the multi-arm polyethylene glycol-azide derivative is a multi-arm polyethylene glycol azide-mono NHS ester having the structure of Formula VII below:
  • the multi-arm polyethylene glycol-azide derivative is a multi-arm polyethylene glycol azide-poly NHS ester having the structure of the following formula VIII:
  • the multi-arm polyethylene glycol-azide derivative is a multi-arm polyethylene glycol azide-monoamine group having the structure of the following formula IX:
  • the multi-arm polyethylene glycol-azide derivative is a multi-arm polyethylene glycol azide-polyamine group having the structure of the general formula X:
  • the multi-arm polyethylene glycol-azide derivative is a multi-arm polyethylene glycol azide-monomaleimide having the structure of the general formula XI:
  • the multi-arm polyethylene glycol-azide derivative is a multi-arm polyethylene glycol azide-polymaleimide having the structure of the general formula XII:
  • Another aspect of the present invention provides a process for preparing a multi-arm polyethylene glycol-azido derivative of the formula I, which comprises reacting a multi-arm polyethylene glycol with a methylsulfonyl chloride to obtain a multi-arm polyethylene An alcohol sulfonate, which reacts a multi-arm polyethylene glycol sulfonate with sodium azide to obtain a multi-arm polyethylene glycol-azido derivative.
  • Another aspect of the present invention provides a process for the preparation of a multi-arm polyethylene glycol-azido derivative of the formula I, which comprises: selecting a compound having two reactive groups to impart a multi-arm polyethylene glycol thereto After a reactive end group reaction is introduced into the linking group X, the azide end is introduced through another reactive end group.
  • Another aspect of the present invention provides a process for preparing a multi-arm polyethylene glycol-azido derivative of the formula I, which comprises: selecting an azide compound (PXN 3 ) having a reactive group P and multi-arm polyethylene The terminal hydroxyl group of the diol reacts to obtain an azide derivative.
  • the reactive group P is selected from the group consisting of an amino group, a carboxyl group, a thiol group, an ester group, a maleimido group, and an acrylic group; preferably -NH 2 , -COOH, -OCH 3 ,
  • the method for preparing the multi-arm polyethylene glycol-azido derivative of the formula I comprises:
  • the multi-arm polyethylene glycol-azido derivative of the formula I according to the invention can be used in combination with proteins, peptides and pharmaceutically active small molecules to improve targeting and drug efficacy and reduce toxicity.
  • the protein, peptide, and pharmaceutically active small molecule include, but are not limited to, analgesic and anti-inflammatory agents, antacids, anthelmintics, antiarrhythmic agents, antibacterial agents, anticoagulant (blood) agents, antidepressants , antidiabetic agents, antidiarrheal agents, antiepileptic drugs, antifungal agents, anti-gout drugs, antihypertensive drugs, antimalarials, anti-migraine drugs, antimuscarinic agents, antineoplastic agents and immunosuppressants, antigens Insecticides, antirheumatic drugs, antithyroid agents, antiviral agents, anti-anxiety agents, sedatives, eye drops and tranquilizers, beta-blockers, cardiac contractions, cortico
  • the multi-arm polyethylene glycol-azido derivative of the formula I according to the present invention can be combined with a protein, a peptide or a pharmaceutically active small molecule, as described in the patent CN102108119A, through the combination of the terminal group and the drug molecule. Things.
  • the multi-arm polyethylene glycol-azido derivative of the formula I according to the invention has a plurality of end groups, and thus has a plurality of functional groups, compared to a linear polyethylene glycol.
  • the introduction point can support multiple active end groups, which can not only increase the loading rate of azide active end groups, but also enhance the stability and safety of azide groups. Therefore, the multi-arm polyethylene glycol-azide derivative of the formula I provided by the present invention has greater flexibility and a wider range of applications, in organic synthesis, drug synthesis, and medical devices. Good application prospects.
  • the multi-armed polyethylene glycol azide derivative provided by the present invention is capable of reacting with other polymers, particularly polyethylene glycol alkynyl derivatives, to form a gel, and is derived by multi-arm polyethylene glycol azide.
  • the change in molecular weight and number of branches in the material enables control of the release rate of the active ingredient.
  • the above-mentioned four-arm polyglycol azide-monomethylacetate 5.0 g was dissolved in 50 ml of deaerated water, the pH was adjusted to 12.0 with a 0.5 N aqueous sodium hydroxide solution, and the reaction was carried out at room temperature for 2-2.5 hours, and the pH was adjusted with 1 N hydrochloric acid aqueous solution. To 2-3, 6.0 g of sodium chloride was added, and the mixture was extracted three times with 50 ml of dichloromethane. The organic phase was combined, dried over anhydrous sodium sulfate, filtered, and concentrated to viscous at 45 ° C. A four-arm polyethylene glycol-azido-monoacetic acid derivative was obtained.
  • the starting material was a four-arm polyethylene glycol-sulfonate-diacetic acid methyl ester (molecular weight: 5000), and the synthesis procedure was the same as in Example 3.
  • the starting material was four-arm polyethylene glycol-azido-diacetic acid (molecular weight: 5000), and the synthesis procedure was the same as in Example 4.
  • the starting material was a four-arm polyethylene glycol-hydroxy-diamine group (molecular weight: 5000), and the synthesis procedure was the same as in Example 7.
  • the starting material was a four-arm polyethylene glycol-azido-diamine group (molecular weight: 5000), and the synthesis procedure was the same as in Example 8.
  • Example 15 Four-arm polyethylene glycol-azide (molecular weight 5000) for the preparation of click gel and its in vitro release experiment
  • the above gel was placed in a dialysis bag (throttle molecular weight 5000), washed three times with 20 ml of water, until the aqueous solution was detected by high performance liquid chromatography without absorption of ultraviolet light, placed in a glass bottle, 20 ml of water was added, and the thermostat was stirred at 40 ° C. Shake in the middle. Samples were taken at 30 min, 2 h, and 4 h, and an aqueous solution of irinotecan-glycine hydrochloride of 0.0025 g/ml was used as a reference sample, and the release amount of the gel at each time point was measured by high performance liquid chromatography.
  • the release ratio of irinotecan-glycine was: 0.5% 21%, 2 hours 36%, 4 hours 42%.
  • Example 16 Four-arm polyethylene glycol-azide (molecular weight 10000) for the preparation of click gel and its in vitro release experiment
  • the above gel was placed in a dialysis bag (throttle molecular weight 5000), washed three times with 20 ml of water, until the aqueous solution was detected by high performance liquid chromatography without absorption of ultraviolet light, placed in a glass bottle, 20 ml of water was added, and the thermostat was stirred at 40 ° C. Shake in the middle. Samples were taken at 30 min, 2 h, and 4 h, and an aqueous solution of irinotecan-glycine hydrochloride of 0.0025 g/ml was used as a reference sample, and the release amount of the gel at each time point was measured by high performance liquid chromatography.
  • the release ratio of irinotecan-glycine was 0.55% 35%, 2 hours 54%, and 4 hours 69%.
  • Example 17 Preparation of an eight-arm polyethylene glycol-azide (molecular weight 10000) for click gel and its in vitro release experiment
  • the above gel was placed in a dialysis bag (throttle molecular weight 5000), washed three times with 20 ml of water, until the aqueous solution was detected by high performance liquid chromatography without absorption of ultraviolet light, placed in a glass bottle, 20 ml of water was added, and the thermostat was stirred at 40 ° C. Shake in the middle. Samples were taken at 30 min, 2 h, and 4 h, and an aqueous solution of irinotecan-glycine hydrochloride of 0.0025 g/ml was used as a reference sample, and the release amount of the gel at each time point was measured by high performance liquid chromatography.
  • the release ratio of irinotecan-glycine was: 24 hours 24%, 2 hours 48%, 4 hours 60%.
  • the molecular weight and the number of polydiethanol branches can be used to influence or control the condensation.
  • the formation time of the gum, the smaller the molecular weight, the more the number of branches, the shorter the gel formation time, and the increased number of branches of polyethylene glycol can increase the gel formation rate more effectively.
  • the molecular weight and the number of branches have a significant effect on the release time in vitro. Therefore, the preparation of different multi-arm polyethylene glycol-azido derivatives can also be used to control the drug release process.
  • a four-arm polyethylene glycol-triazide-monoamine group (molecular weight 5000) 2.0 g was dissolved in 20 ml of dichloromethane, 0.12 ml of triethylamine was added, stirred for 10 minutes, and adamantane-1-carboxamide 0.23 was added. g, the reaction was carried out at room temperature overnight, concentrated at 45 ° C, dissolved in 40 ml of isopropanol, precipitated in an ice water bath, filtered, and the filter cake was washed twice with isopropyl alcohol, and dried under vacuum to obtain four-arm polyethylene glycol-triazide-adamantane.

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Abstract

本发明提供一种通式I的多臂聚乙二醇-叠氮衍生物，其中：R为中心分子；选自多羟基结构、多氨基结构或多羧基结构；n为分支数或臂数，n≥3；PEG为相同或不同的-(CH2CH2O)m-，m的平均值为3-250的整数；X为叠氮端基的连接基团；k为具有叠氮端基的分支数；F选自以下基团：氨基、羧基、巯基、酯基、马来亚酰胺基和丙烯酸基；Y为端基F的连接基团。

Description

多臂聚乙二醇-叠氮衍生物 技术领域
本发明涉及一种多臂聚乙二醇活性衍生物，尤其是涉及一种具有叠氮链末端的多臂聚乙二醇活性衍生物及其制备方法。
背景技术
聚乙二醇(PEG)是一种用途极为广泛的聚醚高分子化合物，它可应用于医药、卫生、食品、化工等众多领域。PEG能够溶解于水和许多溶剂中，且该聚合物具有优异的生物相容性，在体内能溶于组织液中，能被机体迅速排出体外而不产生任何毒副作用。
在聚乙二醇的应用中，端基起着决定性的作用，不同端基的聚乙二醇具有不同的用途。聚乙二醇高分子链段不仅局限于端羟基，通过引入其他功能化端基，如氨基、羧基、醛基等所得到的聚乙二醇活性衍生物，可以极大地拓宽聚乙二醇的应用范围，使它在有机合成、多肽合成、高分子合成及药物的缓释控释、靶向施药等多方面均具有广阔的应用前景。
聚乙二醇(PEG)活性衍生物在很多文献中均有报道。第5672662号美国专利描述了制备线形PEG的丙酸和丁酸以及它们的N-羟基丁二酰亚胺酯。第5643575号美国专利描述了一种U形结构的PEG衍生物。
叠氮化物不仅具有重要的生理活性，如叠氮核苷(AZT)，是目前治疗艾滋病(AIDS)的首选药物，而且也具有广泛的反应活性，如可还原成氨基，与炔烃可发生1，3-偶极环加成反应，发生Curtius反应等。通过端叠氮基还原所获得的端氮基聚合物作为高分子载体在多肽液相合成中起着重要的作用。
专利WO2011075953A1公开了一种由寡聚季戊四醇作为引发剂聚合环氧乙烷形成的新型的具有不同类型活性基团的多臂聚乙二醇，其端基活性集团选自：羟基、氨基、巯基、羧基、酯基、醛基、丙烯酸基和马来亚酰胺基，其未公开端基活性集团可以为叠氮集团。
非专利文献“端叠氮基聚乙二醇的合成和表征”(王晓红等，高分子学报，2000年6月，第3期)公开了一种高分子量端叠氮基聚乙二醇的合成方法，然而该方法制备得到的聚合物中为直链聚乙二醇，并且仅负载有叠氮基团，而无法引入其它活性基团。
为克服现有技术中的缺陷，本发明的提供的一种多臂聚乙二醇-叠氮活性衍生物。
发明内容
本发明一个目的是提供的一种多臂聚乙二醇-叠氮活性衍生物，与直链型聚乙二醇相比，多臂聚乙二醇具有多个端基，进而具有多个功能基团的引入点、可以负载多个不同的活性端基，解决聚乙二醇叠氮衍生物使用灵活性不佳、应用范围较小的问题。
本发明另一个目的是提供一种多臂聚乙二醇-叠氮活性衍生物，能够与其它种类的聚合物反应，用于凝胶的制备，并能够降低反应形成的条件、缩短凝胶形成的时间。
本发明还一个目的是提供一系列不同结构的多臂聚乙二醇-叠氮活性衍生物，解决了多臂聚乙二醇-叠氮活性衍生物形成的凝胶时无法对活性成分释放速度进行控制的问题。
本发明一方面提供一种通式为I的多臂聚乙二醇-叠氮衍生物：
Figure PCTCN2014092737-appb-000001
其中：
R为中心分子；选自多羟基结构、多氨基结构或多羧基结构；
n为分支数或臂数，n≥3；
PEG为相同或不同的-(CH2CH2O)m-，m的平均值为3-250的整数；
X为叠氮端基的连接基团，选自C1-12烷基、芳烷基、酯基、碳酸酯基、酰胺基、酰胺酯基、醚基、氨基甲酸酯基组成的组；
k为具有叠氮端基的分支数，2≤k≤n；
F为不同于叠氮的活性端基基团，选自以下基团：氨基、羧基、巯基、酯基、马来亚酰胺基和丙烯酸基；
Y为端基F的连接基团，选自由以下基团组成的组：(CH2)i、(CH2)iNH、(CH2)iOCOO-、(CH2)iOCONH-、(CH2)iNHCOO-、(CH2)iNHCONH-、OC(CH2)iCOO-、(CH2)iCOO-、(CH2)iCONH；i为0-10的整数。
本发明中所述的通式为I的多臂聚乙二醇-叠氮衍生物中，R为季戊四醇或聚季戊四醇结构、甲基葡萄糖甙、蔗糖甘油或聚甘油结构，特别是，R优选为
Figure PCTCN2014092737-appb-000002
或者
Figure PCTCN2014092737-appb-000003
或者
Figure PCTCN2014092737-appb-000004
或者
Figure PCTCN2014092737-appb-000005
其中1为≥1且≤10的整数，优选1为≥1且≤6的整数，尤其优选1为≥1且≤4的整数，在本发明的具体实施方式中，所述的1可以优选为1、2、3、4、5或6。
本发明中所述的通式为I的多臂聚乙二醇-叠氮衍生物中，n为分支数或臂数，n≥3，优选的3≤n≤22，更为优选的3≤n≤14，最为优选的3≤n≤6。
本发明中所述的通式为I的多臂聚乙二醇-叠氮衍生物中，k为具有叠氮端基的分支数，2≤k≤n，优选的2≤k≤16，更为优选的2≤k≤6，在本发明的实施方式中k可以为2、4、6、8、10、12、14、16。
在本发明的一个实施方式中，k＝n，多臂聚乙二醇-叠氮衍生物具有以下通式II的结构：
Figure PCTCN2014092737-appb-000006
在本发明的一个实施方式中，n-k＝2，即多臂聚乙二醇-叠氮衍生物具有以下通式III的结构：
Figure PCTCN2014092737-appb-000007
其中优选的2≤k≤16，更为优选的2≤k≤6，在本发明的实施方式中k可以为2、4、6、8、10、12、14、16。
本发明中所述的通式为I的多臂聚乙二醇-叠氮衍生物中，m的平均值为3-250的整数，优选为68-250的整数，更优选为m为68-227的整数。
本发明中所述的通式为I的多臂聚乙二醇-叠氮衍生物中，X为叠氮端基的连接基团，选自C1-12烷基、芳烷基、酯基、碳酸酯基、酰胺基、酰胺酯基、醚基、氨基甲酸酯基组成的组；优选为(CH2)i、(CH2)iNH、(CH2)iOCOO-、(CH2)iOCONH-、(CH2)iNHCOO-、(CH2)iNHCONH-、OC(CH2)iCOO-、(CH2)iCOO-、(CH2)iCONH、(CH2)iCOO-；更优选为(CH2)i、(CH2)iNH、(CH2)iCOO-、(CH2)iCO-。
本发明中所述的通式为I的多臂聚乙二醇-叠氮衍生物中，Y为端基F的连接基团，选自由以下基团组成的组：(CH2)i、(CH2)iNH、(CH2)iOCOO-、(CH2)iOCONH-、(CH2)iNHCOO-、(CH2)iNHCONH-、OC(CH2)iCOO-、(CH2)iCOO-、(CH2)iCONH；优选为(CH2)i、(CH2)iNH、(CH2)iOCOO-、(CH2)iOCONH-、(CH2)iNHCOO-、(CH2)iNHCONH-、OC(CH2)iCOO-、(CH2)iCOO-、(CH2)iCONH、(CH2)iCOO-；更优选为(CH2)i、(CH2)iNH、(CH2)iCOO-、(CH2)iCO-。
本发明中所述的通式为I的多臂聚乙二醇-叠氮衍生物中，X、Y中i为1-10的整数，优选为1-5的整数，更优选为1-3的整数，在本发明的具体实施方式中，所述的i为1、 2、3、4或5。
本发明中所述的通式为I的多臂聚乙二醇-叠氮衍生物中，F为不同于叠氮的活性端基基团，选自以下基团：氨基、羧基、巯基、酯基、马来亚酰胺基和丙烯酸基；优选为-NH2、-COOH、-OCH3、
Figure PCTCN2014092737-appb-000008
在本发明的一个实施方式中，本发明中所述的通式为I的多臂聚乙二醇-叠氮衍生物中为：
Figure PCTCN2014092737-appb-000009
在本发明的一个实施方式中，本发明中所述的通式为I的多臂聚乙二醇-叠氮衍生物中为：
Figure PCTCN2014092737-appb-000010
在本发明具体的实施方案中，所述多臂聚乙二醇的分子量为1000-80000Da，在本发明优选的实施方案中，所述的多臂聚乙二醇的分子量为3000-20000Da，在本发明的更为优选的实施方案中，所述的多臂聚乙二醇的分子量为3000-10000Da，在本发明的最优选的实施方案中，所述的多臂聚乙二醇的分子量可以为3000Da、5000Da、10000Da、20000Da。
在一个具体的实施方案中，所述多臂聚乙二醇-叠氮衍生物，为具有以下通式V结构的多臂聚乙二醇叠氮-单乙酸：
Figure PCTCN2014092737-appb-000011
在一个具体的实施方案中，所述多臂聚乙二醇-叠氮衍生物，为具有以下通式Ⅵ结构 的多臂聚乙二醇叠氮-多乙酸：
Figure PCTCN2014092737-appb-000012
在一个具体的实施方案中，所述多臂聚乙二醇-叠氮衍生物，为具有以下通式VII结构的多臂聚乙二醇叠氮-单NHS酯：
Figure PCTCN2014092737-appb-000013
在一个具体的实施方案中，所述多臂聚乙二醇-叠氮衍生物，为具有以下通式VIII结构的多臂聚乙二醇叠氮-多NHS酯：
Figure PCTCN2014092737-appb-000014
在一个具体的实施方案中，所述多臂聚乙二醇-叠氮衍生物，为具有以下通式IX结构的多臂聚乙二醇叠氮-单胺基：
Figure PCTCN2014092737-appb-000015
在一个具体的实施方案中，所述多臂聚乙二醇-叠氮衍生物，为具有以下通式X结构的多臂聚乙二醇叠氮-多胺基：
Figure PCTCN2014092737-appb-000016
在一个具体的实施方案中，所述多臂聚乙二醇-叠氮衍生物，为具有以下通式XI结构的多臂聚乙二醇叠氮-单马来酰亚胺：
Figure PCTCN2014092737-appb-000017
在一个具体的实施方案中，所述多臂聚乙二醇-叠氮衍生物，为具有以下通式XII结构的多臂聚乙二醇叠氮-多马来酰亚胺：
Figure PCTCN2014092737-appb-000018
本发明的另一方面提供了一种通式I的多臂聚乙二醇-叠氮衍生物的制备方法，包括：将多臂聚乙二醇与甲基磺酰氯反应得到多臂聚乙二醇磺酸酯，将多臂聚乙二醇磺酸酯与叠氮钠反应得到多臂聚乙二醇-叠氮衍生物。
本发明的另一方面提供了一种通式I的多臂聚乙二醇-叠氮衍生物的制备方法，包括：选用具有两个活性基团的化合物，使多臂聚乙二醇与其中一个活性端基反应引入连接基团X后，再通过另一活性端基引入叠氮末端。
本发明的另一方面提供了一种通式I的多臂聚乙二醇-叠氮衍生物的制备方法，包括：选用具有活性基团P的叠氮化合物(P-X-N3)与多臂聚乙二醇的端羟基反应获得叠氮衍生物。其中活性基团P选自以下基团：氨基、羧基、巯基、酯基、马来亚酰胺基和丙烯酸基；优选为-NH2、-COOH、-OCH3、
Figure PCTCN2014092737-appb-000019
在本发明的一个具体实施方式中，所述通式I的多臂聚乙二醇-叠氮衍生物的制备方法，包括：
Figure PCTCN2014092737-appb-000020
本发明所述的通式I的多臂聚乙二醇-叠氮衍生物可以用于与蛋白质、肽、药物活性小分子相结合，提高靶向性和药物疗效，降低毒性。所述的蛋白质、肽、药物活性小分子包括但不限于：镇痛剂和消炎剂、抗酸剂、驱虫药、抗心律不齐药、抗菌剂、抗凝(血)剂、抗抑郁剂、抗糖尿病剂、止泻剂、抗癫痫药、防真菌剂、抗痛风药、抗高血压药、抗疟药、抗偏头痛药、抗毒蕈碱剂、抗瘤剂和免疫抑制剂、抗原虫药、抗风湿药、抗甲状腺剂、抗病毒剂、抗焦虑剂、镇静剂、安眼药和安定药、β-受体阻断剂、心脏收缩剂、皮质类甾醇、镇咳剂、细胞毒性剂、减充血剂、利尿剂、酶、抗帕金森氏症药、胃肠道药、组胺受体拮抗剂、油脂调节剂、局部麻醉剂、神经肌肉阻断剂、硝酸酯和抗心绞痛药、营养剂、麻醉性镇痛剂、口服疫苗、蛋白、肽和重组药物、性激素和避孕药、杀精子剂、和刺激剂。本发明所述的通式I的多臂聚乙二醇-叠氮衍生物与蛋白质、肽、药物活性小分子结合方式，可以如专利CN102108119A所描述，通过其端基与药物分子所形成的结合物。
本发明所述的通式I的多臂聚乙二醇-叠氮衍生物与直链型聚乙二醇相比，多臂聚乙二醇具有多个端基，进而具有多个功能基团的引入点、可以负载多个活性端基，不但能够提高叠氮活性端基的负载率，同时可以增强叠氮基团的稳定性与安全性。因此，本发明提供的所述的通式I的多臂聚乙二醇-叠氮衍生物具有更强的灵活性和更大的应用范围，在有机合成、药物合成及医疗器械等方面均有较好的应用前景。
另外，本发明提供的多臂聚乙二醇叠氮衍生物能够与其它聚合物，特别是聚乙二醇炔基衍生物发生反应形成凝胶，并且通过对多臂聚乙二醇叠氮衍生物中分子量、分支数的改变能够实现对活性成分的释放速率控制。
具体实施方式
实施例1：四臂聚乙二醇-叠氮衍生物的制备
Figure PCTCN2014092737-appb-000021
将四臂聚乙二醇(分子量为5000)10.0g溶于甲苯100ml中，氮气保护下，加热蒸出甲苯20ml，降至室温，加入二氯甲烷10ml、三乙胺1.45ml，搅拌10分钟，加入甲基磺酰氯742μl，密闭反应过夜，加入无水乙醇2ml，搅拌15分钟，过滤，60℃浓缩至黏稠，加入异丙醇150ml加热溶解，冰水浴沉淀，过滤，滤饼以异丙醇洗涤，产品真空干燥，得到四臂聚乙二醇磺酸酯。
将上述四臂聚乙二醇磺酸酯5.0g与叠氮钠(NaN3)0.52g溶于N，N-二甲基甲酰胺(DMF)25ml中，加热至90℃，反应2小时，降至室温，加入水25ml、氯化钠5g，二氯甲烷25ml萃取三次，合并有机相，无水硫酸钠干燥，过滤，50℃浓缩，加入乙醚100ml沉淀，过滤收集沉淀真空干燥，得到四臂聚乙二醇-叠氮衍生物。
IR：2110cm-1(-N-N＝N)
实施例2：八臂聚乙二醇-叠氮衍生物的制备
Figure PCTCN2014092737-appb-000022
将八臂聚乙二醇(分子量为10000)10.0g溶于甲苯100ml中，氮气保护下，加热蒸出甲苯20ml，降至室温，加入二氯甲烷10ml、三乙胺1.45ml，搅拌10分钟，加入甲基磺酰氯742μl，密闭反应过夜，加入无水乙醇2ml，搅拌15分钟，过滤，60℃浓缩至黏稠，加入异丙醇150ml加热溶解，冰水浴沉淀，过滤，滤饼以异丙醇洗涤，产品真空干燥，得到八臂聚乙二醇磺酸酯。
将上述八臂聚乙二醇磺酸酯5.0g与叠氮钠(NaN3)0.52g溶于N，N-二甲基甲酰胺(DMF)25ml中，加热至90℃，反应2小时，降至室温，加入水25ml、氯化钠5g，二氯甲烷25ml萃取三次，合并有机相，无水硫酸钠干燥，过滤，50℃浓缩，加入乙醚100ml沉淀，过滤收集沉淀真空干燥，得到八臂聚乙二醇-叠氮衍生物。
IR：2110cm-1(-N-N＝N)
实施例3：四臂聚乙二醇-叠氮-单乙酸衍生物的制备
Figure PCTCN2014092737-appb-000023
将四臂聚乙二醇磺酸酯-单乙酸甲酯(分子量为5000)6.0g与叠氮钠(NaN3)0.468g溶于N，N-二甲基甲酰胺(DMF)30ml中，加热至90℃，反应2小时，降至室温，加入水30ml、氯化钠7g，二氯甲烷30ml萃取三次，合并有机相，无水硫酸钠干燥，过滤，50℃浓缩，加入乙醚120ml沉淀，过滤收集沉淀真空干燥，得到四臂聚乙二醇-叠氮-单乙酸甲 酯。
将上述四臂聚乙二醇叠氮-单乙酸甲酯5.0g溶于50ml脱气水中，用0.5N氢氧化钠水溶液调节PH为12.0，室温下反应2-2.5小时，用1N盐酸水溶液调解PH为2-3，加入氯化钠6.0g，用二氯甲烷50ml萃取三次，合并有机相，无水硫酸钠干燥，过滤，45℃浓缩至黏稠，加入乙醚75ml沉淀，过滤收集沉淀真空干燥。得到四臂聚乙二醇-叠氮-单乙酸衍生物。
IR：2110cm-1(-N-N＝N)
1H-NMR(DMSO)δ：4.01(s，CH2COOH，2H)
实施例4：四臂聚乙二醇-叠氮-单NHS酯衍生物的制备
Figure PCTCN2014092737-appb-000024
称取四臂聚乙二醇-叠氮-单乙酸(分子量为5000)1.0g和N-羟基琥珀酰亚胺(NHS)0.0276g，用二氯甲烷10ml溶解，氮气保护下，加入N，N′-二环己基碳二亚胺(DCC)0.0536g，密闭反应过夜，过滤，40℃浓缩至干，用异丙醇20ml加热溶解后冰水浴沉淀，过滤，异丙醇洗涤滤饼2次，真空干燥得四臂聚乙二醇-叠氮-单NHS酯衍生物。
IR：2110cm-1(-N-N＝N)
1H-NMR(DMSO)δ：4.6(s，CH2CO，2H)，2.8(s，CH2ring，4H)
实施例5：四臂聚乙二醇-叠氮-二乙酸衍生物的制备
Figure PCTCN2014092737-appb-000025
起始物为四臂聚乙二醇-磺酸酯-二乙酸甲酯(分子量为5000)，合成步骤与实施例3相同。
IR：2110cm-1(-N-N＝N)
1H-NMR(DMSO)δ：4.01(s，CH2COOH，4H)
实施例6：四臂聚乙二醇-叠氮-二NHS酯衍生物的制备
Figure PCTCN2014092737-appb-000026
起始物为四臂聚乙二醇-叠氮-二乙酸(分子量为5000)，合成步骤与实施例4相同。
IR：2110cm-1(-N-N＝N)
1H-NMR(DMSO)δ：4.6(s，CH2CO，4H)，2.8(s，CH2ring，8H)
实施例7：四臂聚乙二醇-三叠氮-单胺基衍生物的制备
Figure PCTCN2014092737-appb-000027
将四臂聚乙二醇羟基-单胺基(分子量为5000)10.0g溶于二氯甲烷100ml中，加入三乙胺0.31ml，搅拌10分钟，加入二碳酸二叔丁酯(Boc2O)0.6ml，室温反应过夜，45℃浓缩，用100ml乙醚沉淀，过滤，真空干燥得四臂聚乙二醇羟基-单Boc酰胺。
将上述四臂聚乙二醇羟基-单Boc酰胺8.0g溶于甲苯80ml中，氮气保护下，加热蒸出甲苯15ml，降至室温，加入二氯甲烷8ml、三乙胺0.31ml，搅拌10分钟，加入甲基磺酰氯0.16ml，密闭反应过夜，加入无水乙醇0.5ml，搅拌15分钟，过滤，60℃浓缩至黏稠，加入异丙醇120ml加热溶解，冰水浴沉淀，过滤，滤饼以异丙醇洗涤，产品真空干燥，得到四臂聚乙二醇磺酸酯-单Boc酰胺。
将上述四臂聚乙二醇磺酸酯-单Boc酰胺5.0g与叠氮钠(NaN3)0.39g溶于N，N-二甲基甲酰胺(DMF)25ml中，加热至90℃，反应2小时，降至室温，加入水25ml、氯化钠5g，二氯甲烷25ml萃取三次，合并有机相，无水硫酸钠干燥，过滤，50℃浓缩，加入乙醚100ml沉淀，过滤收集沉淀真空干燥，得到四臂聚乙二醇-叠氮-单Boc酰胺。
将上述四臂聚乙二醇-叠氮-单Boc酰胺3.0g溶于二氯甲烷21ml中，加入三氟乙酸9ml， 反应3小时，45℃浓缩，60ml乙醚沉淀，过滤，真空干燥得四臂聚乙二醇-叠氮-单胺基衍生物。
IR：2110cm-1(-N-N＝N)
1H-NMR(DMSO)δ：3.0(m，CH2NH2，2H)
实施例8：四臂聚乙二醇-叠氮-单马来酰亚胺衍生物的制备
Figure PCTCN2014092737-appb-000028
将四臂聚乙二醇-叠氮-单胺基(分子量为5000)1.0g溶于二氯甲烷10ml，在氮气保护下，加入三乙胺0.031ml，搅拌10分钟，加入MAL-NHS0.074g，避光反应过夜，40℃浓缩至干，用异丙醇20ml加热溶解，冰水浴沉淀，过滤，异丙醇洗涤滤饼2次，真空干燥得四臂聚乙二醇-叠氮-单马来酰亚胺衍生物。
IR：2110cm-1(-N-N＝N)
1H-NMR(DMSO)δ：2.32(t，
Figure PCTCN2014092737-appb-000029
2H)，7.0(s，CH ring，2H)
实施例9：四臂聚乙二醇-二叠氮-二胺基衍生物的制备
Figure PCTCN2014092737-appb-000030
起始物为四臂聚乙二醇-羟基-二胺基(分子量为5000)，合成步骤与实施例7相同。
IR：2110cm-1(-N-N＝N)
1H-NMR(DMSO)δ：3.0(m，CH2NH2，4H)
实施例10：四臂聚乙二醇-二叠氮-二马来酰亚胺衍生物的制备
Figure PCTCN2014092737-appb-000031
起始物为四臂聚乙二醇-叠氮-二胺基(分子量为5000)，合成步骤与实施例8相同。
IR：2110cm-1(-N-N＝N)
1H-NMR(DMSO)δ：2.32(t，
Figure PCTCN2014092737-appb-000032
4H)，7.0(s，CH ring，4H)
实施例11：八臂聚乙二醇-七叠氮-单乙酸衍生物的制备
Figure PCTCN2014092737-appb-000033
将八臂聚乙二醇磺酸酯-单乙酸甲酯(分子量为10000)10.0g与叠氮钠(NaN3)0.9lg溶于N，N-二甲基甲酰胺(DMF)50ml中，加热至90℃，反应2小时，降至室温，加入水50ml、氯化钠12g，二氯甲烷50ml萃取三次，合并有机相，无水硫酸钠干燥，过滤，50℃浓缩，加入乙醚200ml沉淀，过滤收集沉淀真空干燥，得到八臂聚乙二醇-叠氮-单乙酸甲酯。
将上述八臂聚乙二醇-叠氮-单乙酸甲酯5.0g溶于50ml脱气水中，用0.5N氢氧化钠水溶液调节PH为12.0，室温下反应2-2.5小时，用1N盐酸水溶液调解PH为2-3，加入氯化钠6.0g，用二氯甲烷50ml萃取三次，合并有机相，无水硫酸钠干燥，过滤，45℃浓缩至黏稠，加入乙醚75ml沉淀，过滤收集沉淀真空干燥，得到八臂聚乙二醇-叠氮-单乙酸衍生物。
IR：2110cm-1(-N-N＝N)
1H-NMR(DMSO)δ：4.01(s，CH2COOH，2H)
实施例12：八臂聚乙二醇-七叠氮-单NHS酯衍生物的制备
Figure PCTCN2014092737-appb-000034
称取八臂聚乙二醇-叠氮-单乙酸(分子量为10000)2.0g和N-羟基琥珀酰亚胺(NHS)0.03g，用二氯甲烷20ml溶解，氮气保护下，加入N，N′-二环己基碳二亚胺(DCC)0.058g，密闭反应过夜，过滤，40℃浓缩至干，用异丙醇40ml加热溶解后冰水浴沉淀，过滤，异丙醇洗涤滤饼2次，真空干燥得八臂聚乙二醇-七叠氮-单NHS酯衍生物。
IR：2110cm-1(-N-N＝N)
1H-NMR(DMSO)δ：4.6(s，CH2CO，2H)，2.8(s，CH2ring，4H)
实施例13：八臂聚乙二醇-七叠氮-单胺基衍生物的制备
Figure PCTCN2014092737-appb-000035
将八臂聚乙二醇羟基-单胺基(分子量为10000)10.0g溶于二氯甲烷100ml中，加入三乙胺0.16ml，搅拌10分钟，加入二碳酸二叔丁酯(Boc2O)0.3ml，室温反应过夜，45℃浓缩，用150ml乙醚沉淀，过滤，真空干燥得四臂聚乙二醇羟基-单Boc酰胺。
将上述八臂聚乙二醇羟基-单Boc酰胺8.0g溶于甲苯80ml中，氮气保护下，加热蒸出甲苯15ml，降至室温，加入二氯甲烷8ml、三乙胺0.16ml，搅拌10分钟，加入甲基磺酰氯0.08ml，密闭反应过夜，加入无水乙醇0.5ml，搅拌15分钟，过滤，60℃浓缩至黏稠，加入异丙醇120ml加热溶解，冰水浴沉淀，过滤，滤饼以异丙醇洗涤，产品真空干燥，得到八臂聚乙二醇磺酸酯-单Boc酰胺。
将上述八臂聚乙二醇磺酸酯-单Boc酰胺5.0g与叠氮钠(NaN3)0.455g溶于N，N-二甲基甲酰胺(DMF)25ml中，加热至90℃，反应2小时，降至室温，加入水25ml、氯化钠5g，二氯甲烷25ml萃取三次，合并有机相，无水硫酸钠干燥，过滤，50℃浓缩，加入乙醚100ml沉淀，过滤收集沉淀真空干燥。得到八臂聚乙二醇-叠氮-单Boc酰胺。
将上述八臂聚乙二醇-叠氮-单Boc酰胺3.0g溶于二氯甲烷21ml中，加入三氟乙酸9ml，反应3小时，45℃浓缩，60ml乙醚沉淀，过滤，真空干燥得八臂聚乙二醇-七叠氮-单胺基衍生物。
IR：2110cm-1(-N-N＝N)
1H-NMR(DMSO)δ：3.0(m，CH2NH2，2H)
实施例14：八臂聚乙二醇-七叠氮-单马来酰亚胺衍生物的制备
Figure PCTCN2014092737-appb-000036
将八臂聚乙二醇-叠氮-单胺基(分子量为10000)1.0g溶于二氯甲烷10ml，在氮气保护下，加入三乙胺0.016ml，搅拌10分钟，加入MAL-NHS0.037g，避光反应过夜，40℃浓缩至干，用异丙醇20ml加热溶解，冰水浴沉淀，过滤，异丙醇洗涤滤饼2次，真空干燥得八臂聚乙二醇-七叠氮-单马来酰亚胺衍生物。
IR：2110cm-1(-N-N＝N)
1H-NMR(DMSO)δ：2.32(t，
Figure PCTCN2014092737-appb-000037
2H)，7.0(s，CH ring，2H)
实施例15：四臂聚乙二醇-叠氮(分子量为5000)用于click凝胶的制备及其体外释药实验
将四臂聚乙二醇-叠氮(分子量为5000)0.25g、聚乙二醇炔基衍生物(分子量为5000)0.25g以及伊立替康-甘氨酸盐酸盐0.05g溶于水5ml，加入抗坏血酸钠0.008g、醋酸铜0.004g，室温下搅拌25分钟形成凝胶。
将以上凝胶放入透析袋(节流分子量5000)中，以水20ml洗涤三次，至水溶液用高效液相色谱检测紫外无吸收，放入玻璃瓶中，加入水20ml，于40℃恒温振荡器中振摇。在30min、2h、4h分别取样，以0.0025g/ml的伊立替康-甘氨酸盐酸盐的水溶液作为参比样品，高效液相色谱测定凝胶在各时间点的释放量。
伊立替康-甘氨酸的释放比例为：0.5小时21％，2小时36％，4小时42％。
实施例16：四臂聚乙二醇-叠氮(分子量为10000)用于click凝胶的制备及其体外释药实验
将四臂聚乙二醇-叠氮(分子量为10000)0.25g、聚乙二醇炔基衍生物(分子量为10000)0.25g以及伊立替康-甘氨酸盐酸盐0.05g溶于水5ml，加入抗坏血酸钠0.004g、醋酸铜0.002g，室温下搅拌1小时形成凝胶。
将以上凝胶放入透析袋(节流分子量5000)中，以水20ml洗涤三次，至水溶液用高效液相色谱检测紫外无吸收，放入玻璃瓶中，加入水20ml，于40℃恒温振荡器中振摇。在30min、2h、4h分别取样，以0.0025g/ml的伊立替康-甘氨酸盐酸盐的水溶液作为参比样品，高效液相色谱测定凝胶在各时间点的释放量。
伊立替康-甘氨酸的释放比例为：0.5小时35％，2小时54％，4小时69％。
实施例17：八臂聚乙二醇-叠氮(分子量为10000)用于click凝胶的制备及其体外释药实验
将八臂聚乙二醇-叠氮(分子量为10000)0.25g、聚乙二醇炔基衍生物(分子量为10000)0.25g以及伊立替康-甘氨酸盐酸盐0.05g溶于水5ml，加入抗坏血酸钠0.008g、醋酸铜0.004g，室温下搅拌10分钟形成凝胶。
将以上凝胶放入透析袋(节流分子量5000)中，以水20ml洗涤三次，至水溶液用高效液相色谱检测紫外无吸收，放入玻璃瓶中，加入水20ml，于40℃恒温振荡器中振摇。在30min、2h、4h分别取样，以0.0025g/ml的伊立替康-甘氨酸盐酸盐的水溶液作为参比样品，高效液相色谱测定凝胶在各时间点的释放量。
伊立替康-甘氨酸的释放比例为：0.5小时24％，2小时48％，4小时60％。
由实施例15-17可见，在多臂聚乙二醇-叠氮衍生物与其它聚乙二醇衍生物形成凝胶的制备中，分子量与聚二乙醇分支数均可以用来影响或控制凝胶的形成时间，分子量越小，分支数越多，凝胶的形成时间越短，而且增加聚乙二醇的分支数量可以更有效地提高凝胶的形成速度。同时，分子量与分支数对体外释药时间同样有显著地影响，因此，制备不同的多臂聚乙二醇-叠氮衍生物也可以用于控制药物缓释过程。
实施例18：四臂聚乙二醇-三叠氮-金刚烷及凝胶的制备
Figure PCTCN2014092737-appb-000038
将四臂聚乙二醇-三叠氮-单胺基(分子量为5000)2.0g溶于二氯甲烷20ml中，加入三乙胺0.12ml，搅拌10分钟，加入金刚烷-1-甲酰胺0.23g，室温反应过夜，45℃浓缩，用异丙醇40ml加热溶解，冰水浴沉淀，过滤，异丙醇洗涤滤饼2次，真空干燥得四臂聚乙二醇-三叠氮-金刚烷。
IR：2110cm-1(-N-N＝N)
1H-NMR(DMSO)δ：1.6(m，ring，6H)，1.7(m，ring，6H)，1.9(m，ring，3H)
将四臂聚乙二醇-三叠氮-金刚烷(分子量为5000)0.33g、聚乙二醇炔基衍生物(分子量为5000)0.25g溶于水6ml，加入抗坏血酸钠0.008g、醋酸铜0.004g，室温下搅拌30分钟形成凝胶。

Claims (17)

  1. 通式Ⅰ的多臂聚乙二醇-叠氮衍生物
    Figure PCTCN2014092737-appb-100001
    其中：
    R为中心分子；选自多羟基结构、多氨基结构或多羧基结构；
    n为分支数或臂数，n≥3；
    PEG为相同或不同的-(CH2CH2O)m-，m的平均值为3-250的整数；
    X为叠氮端基的连接基团，选自C1-12烷基、芳烷基、酯基、碳酸酯基、酰胺基、酰胺酯基、醚基、氨基甲酸酯基组成的组；
    k为具有叠氮端基的分支数，2≤k≤n；
    F选自以下基团：氨基、羧基、巯基、酯基、马来亚酰胺基和丙烯酸基；
    Y为端基F的连接基团，选自由以下基团组成的组：(CH2)i、(CH2)iNH、(CH2)iOCOO—、(CH2)iOCONH—、(CH2)iNHCOO—、(CH2)iNHCONH—、OC(CH2)iCOO—、(CH2)iCOO—、(CH2)iCONH；其中，i为0-10的整数。
  2. 如权利要求1所述的多臂聚乙二醇-叠氮衍生物，其中，所述的多臂聚乙二醇-叠氮衍生物具有以下通式Ⅱ的结构：
    Figure PCTCN2014092737-appb-100002
  3. 如权利要求1所述的多臂聚乙二醇-叠氮衍生物，其中，所述的多臂聚乙二醇-叠氮衍生物具有以下通式Ⅲ的结构：
    Figure PCTCN2014092737-appb-100003
  4. 如权利要求1所述的多臂聚乙二醇-叠氮衍生物，其中，R选自
    Figure PCTCN2014092737-appb-100004
    或者
    Figure PCTCN2014092737-appb-100005
    或者
    Figure PCTCN2014092737-appb-100006
    或者
    Figure PCTCN2014092737-appb-100007
    其中l为≥1且≤10的整数。
  5. 如权利要求1-4任一项所述的多臂聚乙二醇-叠氮衍生物，其中，3≤n≤22。
  6. 如权利要求1-4任一项所述的多臂聚乙二醇-叠氮衍生物，其中，3≤n≤6。
  7. 如权利要求1-4任一项所述的多臂聚乙二醇-叠氮衍生物，其中，2≤k≤16。
  8. 如权利要求1-3任一项所述的多臂聚乙二醇-叠氮衍生物，其中，k为2、4、6、8、10、12、14、16。
  9. 如权利要求4-8任一项所述的多臂聚乙二醇-叠氮衍生物，其中，所述l选自1、2、3、4、5或6。
  10. 如权利要求1-8任一项所述的多臂聚乙二醇-叠氮衍生物，其中，m的平均值为68-227的整数。
  11. 如权利要求1-8任一项所述的多臂聚乙二醇-叠氮衍生物，其中，X为选自(CH2)i、(CH2)iNH、(CH2)iOCOO—、(CH2)iOCONH—、(CH2)iNHCOO—、(CH2)iNHCONH—、OC(CH2)iCOO—、(CH2)iCOO—、(CH2)iCONH、(CH2)iCOO—。
  12. 如权利要求1-8任一项所述的多臂聚乙二醇-叠氮衍生物，其中，Y选自由以下基团组成的组：(CH2)i、(CH2)iNH、(CH2)iCOO—、(CH2)iCO—。
  13. 如权利要求11-12任一项所述的多臂聚乙二醇-叠氮衍生物，其中，所述的i为1、2、3、4或5。
  14. 如权利要求1-8任一项所述的多臂聚乙二醇-叠氮衍生物，其中，F为-NH2、-COOH、-OCH3、
    Figure PCTCN2014092737-appb-100008
  15. 如权利要求1所述的多臂聚乙二醇-叠氮衍生物，其中所述多臂聚乙二醇-叠氮衍生物为
    Figure PCTCN2014092737-appb-100009
    或者为
    Figure PCTCN2014092737-appb-100010
    或者为
    Figure PCTCN2014092737-appb-100011
    或者为
    Figure PCTCN2014092737-appb-100012
    或者为，
    Figure PCTCN2014092737-appb-100013
    或者为，
    Figure PCTCN2014092737-appb-100014
    或者为
    Figure PCTCN2014092737-appb-100015
    或者为
    Figure PCTCN2014092737-appb-100016
  16. 一种多臂聚乙二醇-叠氮衍生物，其中，多臂聚乙二醇-叠氮衍生物具有如下结构：
    Figure PCTCN2014092737-appb-100017
    其中，
    l选自1、2、3、4、5或6；
    X为叠氮端基的连接基团，选自C1-12烷基、芳烷基、酯基、碳酸酯基、酰胺基、酰胺酯基、醚基、氨基甲酸酯基组成的组。
  17. 一种多臂聚乙二醇-叠氮衍生物，其中，多臂聚乙二醇-叠氮衍生物具有如下结构：
    Figure PCTCN2014092737-appb-100018
    其中，
    l选自1、2、3、4、5或6；
    X为叠氮端基的连接基团，选自C1-12烷基、芳烷基、酯基、碳酸酯基、酰胺基、酰胺酯基、醚基、氨基甲酸酯基组成的组。
PCT/CN2014/092737 2013-12-02 2014-12-02 多臂聚乙二醇-叠氮衍生物 WO2015081831A1 (zh)

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