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    • 专利摘要:
    The present invention provides block polymers having functional groups at both ends of the molecule and consisting of hydrophilic / hydrophobic segments. The functional groups at both ends include an amino group, a carboxyl group, or a mercapto group at the α-terminus, and a hydroxyl group, a carboxyl group, an aldehyde group, a vinyl group, etc. at the? -Terminus, and the hydrophilic segment is made of polyoxyethylene, Is derived from lactide, lactone or (meth) acrylic acid esters. The block polymer of the present invention forms a polymer micelle and can be used for biocompatible materials and the like.
    公开号:KR19990014879A
    申请号:KR1019970708224
    申请日:1996-08-05
    公开日:1999-02-25
    发明作者:가타오카가즈노리；가토마사오；나가사키유키오；오카노데루오
    申请人:가타오카가즈노리；
    IPC主号:
    专利说明:

    Block polymers with functional groups at both ends
    Polymeric micelles or nanospheres made of hydrophilic / hydrophobic block polymers in which a hydrophilic polymer such as polyethylene oxide and other hydrophobic polymers are bonded at the molecular level are attracting attention as a carrier for drug support. The preparation of polymeric micelles and nanospheres is accomplished by hydrophilic / hydrophobic block polymers in which hydrophilic and hydrophobic polymers are bonded at the molecular level.
    However, in the method for producing a hydrophilic / hydrophobic block polymer according to the conventional method, there is a limit to introducing the terminal functional group, and only a block polymer having a limited functional group such as methoxy or hydroxyl group is proposed. In particular, if it succeeds in introducing arbitrary reactive functional groups in arbitrary ratios on the surface of micelles, it will be possible to provide functional polymer micelles which can be advantageously used for in vivo targeting of medicines and the like.
    Accordingly, an object of the present invention is to provide a block polymer having functional groups at both ends of a polymer backbone as a multifunctional polymer capable of forming a polymer micelle.
    Initiation of the invention
    The present inventors use alkylene, phenylene or phenylalkylene derivatives having any kind of protected amino group, carboxyl group or mercapto group and hydroxyl group as an initiator of the depolymerization, and as monomers ethylene oxide and lactide or lactone or When the (meth) acrylic acid ester is polymerized and an electrophilic agent is reacted, if necessary, at one terminal of the molecule, and optionally, a protected amino group, a carboxyl group or a mercapto group, and at the other terminal, various functional groups It has been found that a block polymer having a can be easily provided.
    Moreover, it was also confirmed that the block polymer thus obtained forms a polymer micelle that is extremely stable in an aqueous solvent.
    Thus, according to the present invention, block polymers each having functional groups at both ends of the molecule of formula (I) are provided.
    In Formula I,
    X optionally has 1 to 10 carbon atoms having a substituent selected from the group consisting of an amino group blocked by one or two amino protecting groups, a carboxyl group blocked by a carboxy protecting group and a mercapto group blocked by a mercapto protecting group An alkyl group or the phenyl group or phenylalkyl group which has the said substituent in a benzene ring,
    Y is a chemical formula

    Repeating units of (wherein R 1 and R 2 independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, R 3 represents a hydrogen atom or a methyl group, R 4 is optionally substituted with a hydroxyl group 1 An alkyl group of 5 to 5, q is an integer of 2 to 5), and a group selected from the group consisting of
    Z is a hydrogen atom, acryloyl group (CH 2 = CH-CO-), methacryloyl group (CH 2 = C (CH 3 ) -CO-), vinyl benzyl group ( ), Aryl group (CH 2 = CH-CH 2- ), paratoluenesulfonyl group ( ), A mercapto group, optionally a alkyl group having a mono- or di-substituted alkyl group having 1 to 5 carbon atoms, an alkyl group having a carboxyl group or an ester group thereof, an alkyl group having an acetal group, and a functional group selected from the group consisting of halogen atoms,
    m and n are independently integers from 2 to 10,000.
    The block polymer, according to the present invention, can be easily prepared from the leaving polymer of the formula (II). Thus, according to the present invention, in addition to the process for the preparation of the block polymer of the formula (I) using the leaving polymer of the formula (II) as a starting material and to the preparation thereof, for example, the preparation of the block polymer having another hydrophilic or hydrophobic segment There is also provided a leaving polymer of formula (II) itself which can also be used.
    In Chemical Formula II,
    Xa is an alkyl group having 1 to 10 carbon atoms having a substituent selected from the group consisting of an amino group blocked by one or two amino protecting groups, a carboxyl group blocked by a carboxy protecting group and a mercapto group blocked by a mercapto protecting group, or the substituent A phenyl group or a phenylalkyl group in the benzene ring;
    Y and Ya are each chemical formula
    Flag
    (Wherein R 1 and R 2 independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, R 3 represents a hydrogen atom or a methyl group, and R 4 is optionally 1 to 5 carbon atoms substituted by a hydroxyl group) And an alkyl group of q, q is an integer of 2 to 5).
    M + represents a cation of an alkali metal selected from the group consisting of lithium, sodium, potassium and cesium,
    n and m are independently integers from 2 to 10,000.
    In addition, the block polymer of the formula (I), by treatment in a solvent, forms a stable polymer micelle that contains it as an active ingredient. Therefore, according to this invention, such a polymer micelle is also provided.
    The block polymer of the formula (I) thus provided and the polymer micelles prepared therefrom can be expected to have high biocompatibility or high bioavailability as can be understood from their constituents. Therefore, as it is, or using one or both terminal functional groups, it can be used as another polymer, for example, the material applied directly to a living body, for example, a carrier material for supporting a medicine, etc., and especially this invention According to the third aspect of the present invention, since the polymer micelle that is extremely stable in an aqueous solvent can be provided, it is also useful as a target-oriented pharmaceutical carrier in vivo.
    FIELD OF THE INVENTION The present invention relates to block polymers having functional groups at both ends, methods for their preparation and their use in polymer micelles. More specifically, the present invention discloses block polymers having functional groups at both ends, polyoxyethylene chains as hydrophilic segments in the main chain, and chains derived from polyester or (meth) acrylic acid derivatives as hydrophobic segments. .
    In addition, the word polymer used in this invention is used by the concept containing an oligomer.
    Since the block polymers of the formula (I) have an amino, carboxyl or mercapto group in which the group X can be protected, as a substituent, they carry a free functional group at one end of the polymer, either protected or by leaving the protecting group. In the present specification, the terminal is referred to as the α-terminal for convenience.
    The protecting group is an amino protecting group, a carboxy protecting group and a mercapto protecting group which are commonly used in the art, and may be released by hydrolysis or catalytic hydrogenation, and moreover, as long as it does not adversely affect the leaving polymerization according to the present invention, Any one is good.
    As a specific example of an amino protecting group, the benzene ring, which forms a nitrogen base and a shift base (imino group) of the amino group, may be substituted by an alkyl group having 1 to 3 carbon atoms, in particular a methyl group, or a halogen atom, in particular fluorine or chlorine, and benzyl A lidene group, preferably an unsubstituted benzylidene group; Alkoxycarbonyl having 1 to 5 carbon atoms, especially tert-butoxycarbonyl group; And silyl groups having three groups selected from alkyl groups having 1 to 3 carbon atoms and phenyl groups, in particular trimethylsilyl, triethylsilyl and dimethylphenylsilyl groups. The amino group blocked by an amino protecting group includes the cyano group which forms an amino group by constant reduction.
    Specific examples of the carboxy protecting group include alkoxy groups having 1 to 5 carbon atoms, in particular methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy and tert-parts, which form part of the ester with the carboxyl group. Oxy, phenyl substituted methoxy, in particular benzyloxy, diphenylmethoxy and triphenylmethoxy groups. Carboxyl groups blocked by carboxy protecting groups include cyano groups that form carboxyl groups by constant hydrolysis.
    Specific examples of the mercapto protecting group include phenyl, benzyl, trimethylsilyl, acetyl, o, m, p-methylbenzyl, triethylsilyl, o, m, p-tolyl and tert-butyldimethylsilyl groups.
    On the other hand, the alkyl group having 1 to 10 carbon atoms constituting the group X can form a linear or branched alkylene group, and specifically, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl , n-pentyl, sec-pentyl, n-hexyl, heptyl and densyl groups, and especially methyl, ethyl, n-propyl and n-butyl groups.
    The group X may also be composed of phenyl or phenylalkyl, in particular benzyl, phenethyl.
    Thus, specific examples of the group X having an amino protecting group (ie, part of Xa) include, but are not limited to, 1- or 2-benzyliminoethyl groups, 1-, 2- or 3-benzyliminopropyl groups, 1 -, 2-, 3- or 4-benzyl iminobutyl group, 1-, 2-, 3-, 4- or 5-benzyl iminopentyl group, 2-, 3- or 4-benzyl iminophenyl group, 2 -, 3- or 4-benzyl iminobenzyl group, 2-, 3- or 4- benzyliminophenethyl group, N, N- (bistrimethylsilyl) aminomethyl group, 1- or 2-N, N- (bis Trimethylsilyl) aminoethyl group, 1-, 2- or 3-N, N- (bistrimethylsilyl) aminopropyl group, 1-, 2-, 3- or 4-N, N- (bistrimethylsilyl) aminobutyl group , 1-, 2-, 3-, 4- or 5-N, N- (bistrimethylsilyl) aminopentyl group, 2-, 3- or 4-N, N- (bistrimethylsilyl) aminophenyl group, 2-, 3- or 4-N, N- (bistrimethylsilyl) aminobenzyl group, 2-, 3- or 4-N, N- (bistrimethylsilyl) aminophenethyl group, N-trimethylsilyl-N-methyla Minomethyl group, 1- or 2-N-trimethylsilyl-N-methylaminoethyl group, 1-, 2- or 3-N-trimethylsilyl-N-methylaminopropyl group, 1-, 2-, 3- or 4- N-trimethylsilyl-N-methylaminobutyl group, 1-, 2-, 3-, 4- or 5-N-trimethylsilyl-N-methylaminopentyl group, 2-, 3- or 4-N-trimethylsilyl- N-methylaminophenyl group, 2-, 3- or 4-N-trimethylsilyl-N-methylaminobenzyl group, 2-, 3- or 4-N-trimethylsilyl-N-methylaminophenethyl group, N-trimethylsilyl -N-ethylaminomethyl group, 1- or 2-N-trimethylsilyl-N-ethylaminoethyl group, 1-, 2- or 3-N-trimethylsilyl-N-ethylaminopropyl group, 1-, 2-, 3 Or 4-N-trimethylsilyl-N-ethylaminobutyl group, 1-, 2-, 3-, 4- or 5-N-trimethylsilyl-N-ethylaminopentyl group, 2-, 3- or 4-N -Trimethylsilyl-N-ethylaminophenyl group, 2-, 3- or 4-N-trimethylsilyl-N-ethylaminobenzyl group, 2-, 3- or 4-N-trimethylsilyl-N-ethylaminophenethyl , Dimethylaminomethyl group, 1- or 2-dimethylaminoethyl group, 1-, 2- or 3-dimethylaminopropyl group, 1-, 2-, 3- or 4-dimethylaminobutyl group, 1-, 2-, 3 -, 4- or 5-dimethylaminopentyl group, 2-, 3- or 4-dimethylaminophenyl group, 2-, 3- or 4-dimethylaminobenzyl group, 2-, 3- or 4-dimethylaminophenethyl group, di Ethylaminomethyl group, 1- or 2-diethylaminoethyl group, 1-, 2- or 3-diethylaminopropyl group, 1-, 2-, 3- or 4-diethylaminobutyl group, 1-, 2- , 3-, 4- or 5-diethylaminopentyl group, 2-, 3- or 4-diethylaminophenyl group, 2-, 3- or 4-diethylaminobenzyl group, 2-, 3- or 4-di Ethyl amino phenethyl group etc. are mentioned. In addition, when the protecting group is other than benzylidene, the protected amino group may be a protective amino group or cyano group of methylamino, ethylamino or propylamino.
    Further, specific examples of the group X having a carboxy protecting group (ie, part of Xa) include, but are not limited to, a methoxycarbonylmethyl group, a 1- or 2-methoxycarbonylethyl group, 1-, 2- or 3- Methoxycarbonylpropyl group, 1-, 2-, 3- or 4-methoxycarbonylbutyl group, 1-, 2-, 3-, 4- or 5-methoxycarbonylpentyl group, 2-, 3- Or 4-methoxycarbonylphenyl group, 2-, 3- or 4-methoxycarbonylbenzyl group, 2-, 3- or 4-methoxycarbonylphenethyl group, ethoxycarbonylmethyl group, 1- or 2- Ethoxycarbonylethyl group, 1-, 2- or 3-ethoxycarbonylpropyl group, 1-, 2-, 3- or 4-ethoxycarbonyl nobutyl group, 1-, 2-, 3-, 4- Or 5-ethoxycarbonylbenzyl group, 2-, 3- or 4-ethoxycarbonylphenyl group, 2-, 3- or 4-ethoxycarbonylbenzyl group, 2-, 3- or 4-ethoxycarbono Nylphenethyl group, tert-butoxycarbonylmethyl group, 1- or 2-tert-butoxycarbonylethyl group, 1-, 2- or 3-tert-butoxycarbonylpropyl group, 1-, 2-, 3- Or 4-t ert-butoxycarbonyl nobutyl group, 1-, 2-, 3-, 4- or 5-tert-butoxycarbonylpentyl group, 2-, 3- or 4-tert-butoxycarbonylphenyl group, 2-, Nitrile groups such as 3- or 4-tert-butoxycarbonylbenzyl groups, 2-, 3- or 4-tert-butoxycarbonylphenethyl groups, and 3-cyanopropyl groups, and the like.
    Further, specific examples of the group X (ie, part of Xa) having a mercapto protecting group include, but are not limited to, a phenylmercaptomethyl group, 1- or 2-phenylmercaptoethyl group, 1-, 2- or 3-phenyl Mercaptopropyl group, 1-, 2-, 3- or 4-phenylmercaptobutyl group, 1-, 2-, 3-, 4- or 5-phenylmercaptopentyl group, 2-, 3- or 4-phenyl Mercaptopentyl group, 2-, 3- or 4-phenylmercaptobenzyl group, 2-, 3- or 4-phenylmercaptophenethyl group, benzyl mercaptomethyl group, 1- or 2-benzyl mercaptoethyl group, 1-, 2- or 3-benzyl mercaptopropyl group, 1-, 2-, 3- or 4-benzyl mercaptobutyl group, 1-, 2-, 3-, 4- or 5-benzyl mercaptopentyl group, 2-, 3- or 4-benzyl mercaptophenyl group, 2-, 3- or 4-benzyl mercapto benzyl group, 2-, 3- or 4-benzyl mercaptophenethyl group, trimercaptomethyl group, 1- or 2-trilmer Captoethyl group, 1-, 2- or 3-trimermercaptopropyl group, 1-, 2-, 3- or 4-trimermercaptobutyl group, 1-, 2-, 3-, 4- or 5-trimermercap Topentyl, 2-, 3-, or 4- trimer mercaptophenyl group, 2-, 3-, or 4- trimer mercapto benzyl group, 2-, 3-, or 4- trimer mercapto phenethyl group, an acetylthioethyl group, etc. are mentioned.
    In addition to the oxyethylene segment in formula (I), Y constituting another segment is represented by the formula

    Is a group derived from cyclic diesters produced by dehydration of two molecules of α-hydroxy acids (wherein R 1 and R 2 are independently a hydrogen atom or an alkyl group having 1 to 5 carbon atoms). The cyclic diester may be formed from the same or different α-hydroxy acids, but is preferably derived from the same two molecules of α-hydroxy acids. Especially preferably, R <1> and R <2> of Y represent a hydrogen atom simultaneously, or a methyl group simultaneously.
    In addition, Y is a chemical formula

    May be a lactone of, specifically, a group derived from α-lactone, β-lactone, γ-lactone, δ-lactone or ε-lactone, wherein q represents an integer from 2 to 5.
    Of these, q is preferably integer 4 (derived from γ-lactone) and integer 5 (derived from δ-lactone).
    And also Y is

    Groups derived from (meth) acrylic acid esters or (meth) acrylonitrile of wherein R 3 represents a hydrogen atom or a methyl group, and R 4 optionally has 1 to 5 carbon atoms substituted with a hydroxyl group which may be protected May represent an alkyl group).
    Specific examples of R 4 include methyl, ethyl, n-propyl, n-butyl, tert-butyl, 2-trimethylsiloxyethyl, 2- (tert-butyldimethylsiloxyethyl) and 2-hydroxyethyl. have. In addition, (meth) acrylic acid and (meth) acrylonitrile are used as showing methacrylic acid or acrylic acid, methacrylonitrile, or acrylonitrile.
    Segment oxyethylene of formula (I) can be any number of integers from 2 to 10,000 m, moreover, according to the process of the present invention, by adjusting the amount of ethylene oxide to the initiator (XO - M + ) of leaving anion polymerization It can be set as the segment which has the desired m value of almost monodispersity (or monolithic). Therefore, the block polymer of the present invention is suitable for providing to a biosynthetic material, and the m value can be appropriately selected depending on the specific application.
    Similarly, segment Y can also provide that n is extremely narrow in molecular weight distribution among the integers 2-10,000, and consists of desired n number.
    Z in the general formula (I) is a functional group of another terminal (hereinafter referred to as ω-terminal for convenience: corresponds to the right end of the structure of the general formula (I)) to the α-terminus of the block polymer.
    In theory, any functional group may be introduced as the Z moiety by the valence substitution reaction of the ω-terminal anion moiety of the living block polymer of Formula II, but for the purposes of the present invention, it is possible to improve biosynthesis. Groups that can be used for this reaction or for another reaction are preferred.
    Therefore, as the group Z of the formula (I), a hydrogen atom (particularly, when Y is derived from lactide or lactone, forms a hydroxyl group), an acryloyl group (CH 2 = CH-CO-), a methacryloyl group ( CH 2 = C (CH 3 ) -CO-), vinylbenzyl group ( ), An aryl group (CH 2 = CH-CH 2- ), an alkyl group having a carboxyl group or an ester group thereof, for example, ethyloxycarbonylmethyl group (C 2 H 5 OCOCH 2- ), methyloxycarbonylmethyl group (CH Aldehyde or an acetal group thereof, such as 3 OCOCH 2- ), carboxymethyl group (HOOC-CH 2- ), ethyloxycarbonylethyl group (C 2 H 5 O COCH 2- ), carboxyethyl group (HOOC-CH 2 CH 2- ) Alkyl groups having, for example, paratoluenesulfonyl groups such as formylethane (OCH-CH 2 CH 2- ), 3, 3-dimethoxypropane ((CH 3 O) 2 CHCH 2 CH 2- ) ), A mercapto group, a halogen atom, for example chlorine, bromine, iodine, optionally an alkyl group mono- or di-substituted with an alkyl group having 1 to 5 carbon atoms, for example 2-aminoethyl, N-methyl-2 -Aminoethyl, N, N-dimethyl-2-aminoethyl, etc. are mentioned. In addition, the group after said mercapto group is group which can be taken when the segment of Y is lactide or lactone origin. When the segment of Y is derived from (meth) acrylic acid ester or (meth) acrylonitrile, for example, ethylene oxide is added to the ω-terminus of the living block polymer of the formula (II) to form a 2-hydroxyethyl group After forming, through the hydroxyl group, the alkyl group mono- or di-substituted by the mercapto group, a halogen atom, optionally an alkyl group having 1 to 5 carbon atoms can be introduced.
    As a typical example of the block polymer which concerns on this invention which each group (or segment) combines and comprises, the thing of the following table | surface is mentioned.
    Formula I

    (Where m and n each take any number within the range of an integer from 2 to 10,000)






    In the table above, Bu (t) is —C (CH 3 ) 3 .
    As mentioned above, the block copolymer provided by this invention can be manufactured efficiently according to Reaction Formula 1.
    In Scheme 1,
    Xa, X, M + , Y, Ya and Z are as defined above,
    Z 'is a residue derived from a nucleophilic reagent.
    Reaction from (A) to formula (II)
    In the polymerization reaction, the initiator (A) is diluted with an aprotic solvent and added to the reaction system in the order of ethylene oxide and a hydrophobic monomer (segment Y inducible monomer) to polymerize. Benzene, toluene, hexane, tetrahydrofuran, dioxane, etc. are used as an aprotic solvent. The initiator concentration is 0.1 to 95% by weight, preferably 1 to 70% by weight, most preferably 2 to 5% by weight. The ratio of the initiator to ethylene oxide can be polymerized in any ratio depending on the desired m value to be achieved, but is preferably 1: 1 to 1: 10,000, more preferably 1: 1,000, and 1: 200. Most preferably. The ratio of the hydrophobic monomer to the initiator may also be in any ratio depending on the desired n value to be achieved, but is preferably 1: 1 to 1: 10.000, more preferably 1: 1,000, and 1: 1. Most preferably, it is 200. It is preferable to perform a reaction container in a pressure-resistant glass tube or an autoclave. The reaction temperature is preferably -50 ° C to 150 ° C, most preferably 0 ° C to 100 ° C, and most preferably 30 ° C to 50 ° C. 0.1-10 kgf / cm <2> G is preferable and, as for reaction pressure, 1-2 kgf / cm <2> G is more preferable. As for the reaction time, 0.01-200 hours and 1-100 hours are more preferable with respect to ethylene oxide normally, Most preferably, after making it react 20 to 50 hours, adding a hydrophobic monomer to a reaction system and also 0.01-200 hours, More preferably, It is preferable to make it react for 1 to 100 hours, Most preferably, 20 to 50 hours.
    The living block polymer (II) thus obtained has a quantitatively protected functional group at the initiator terminal (α-terminus) and an alkali metal alkoxide at the other terminal (ω-terminus). Treatment of the polymer of the formula (II) with, for example, an acid yields a block polymer having functional groups such as amino groups, carboxyl groups, mercapto groups and the like, and hydroxyl groups at the ω-terminus (Y is derived from lactide or lactone). If). It is included in the block polymer of formula (I).
    The preparation of another polymer of the formula (I) having various functional groups at the ω-terminus is performed by reacting a living block polymer of the formula (II) with a reaction agent added to the reaction system.
    As the former agent, a chemical formula

    (Wherein A is a group forming an active ester, for example, a portion forming a halogen atom or acid anhydride such as chlorine, bromine, D is chlorine, bromine or iodine, and Q is a group containing a functional group) , For example, , -CH = CH 2 , -COOC 2 H 5 , -CH 2 CH 2 (OCH 3 ) 2, and the like. Although not limited, specific examples of the former are acrylic acid chloride, acrylic anhydride, acrylic acid, methacrylic acid chloride, methacrylic anhydride, methacrylic acid, vinylbenzyl chloride, vinylbenzyl bromide, aryl chloride, aryl bromide, aryl iodine , Paratoluic acid chloride, ethyl chloroacetate, ethyl bromoacetate, ethyl 2-chloropropionate, 3, 3-dimethoxypropyl bromide and the like.
    When Z is a paratoluenesulfonyl group and segment Y is derived from glycolide or lactone, a nucleophilic reagent is reacted at the ω-terminus activated by paratoluene sulfonic acid to perform nucleophilic substitution, thereby introducing another functional group. Can be. These reactions can be performed by a routine method, respectively. Specific examples of the nucleophilic reagents include, but are not limited to, sodium hydrosulfide, potassium hydrosulfide, sodium 2-aminoethoxide, potassium 2-aminoethoxide, halogen and the like.
    By the above, the obtained block polymer of the general formula (I) is capable of reacting the protecting group in the X moiety and / or the protecting group in the Z moiety (such as an ester group) with a hydrolysis reaction or reduction or contact, which is already known per se. It can leave by a hydrogenation reaction. In this way it is possible to provide block polymers of the formula (I) in which the α-terminal and / or ω-terminal functional groups are free.
    Since the block polymer of formula (I) contains a hydrophilic segment and a hydrophobic segment in a molecule | numerator, the balance of hydrophilicity and hydrophobicity can be suitably adjusted by selecting the kind or molecular weight of a segment suitably. Thus, block polymers of formula (I) can form polymeric micelles in a solvent.
    In order to manufacture the polymer micelle containing a block polymer (I) as a component, a heating process, an ultrasonic irradiation process, an organic solvent process, etc. are mentioned, These are used individually or in combination. In the warming treatment, one kind or a mixture of two or more kinds of the block polymers (I) are dissolved in water and prepared at a temperature of 30 ° C to 100 ° C. The ultrasonic irradiation treatment dissolves one kind or a mixture of two or more kinds of the block polymers (I) in water, and is 1 second to 24 hours in the range of 1W to 20W, preferably 2W to 4W, more preferably 30 minutes to 10 minutes. Most preferably, it is carried out for hours and for 2 to 4 hours. The organic solvent treatment dissolves one or two or more kinds of the block polymer (I) in an organic solvent, disperses the solution in water, and then evaporates the organic solvent. As the organic solvent, methanol, ethanol, tetrahydrofuran, dioxane, chloroform, benzene, toluene, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, methylene chloride and the like are used. Although water can be used in arbitrary ratio with respect to an organic solvent, the ratio of 1 to 1000 times, preferably 1 to 100 times, more preferably 5 to 20 times is preferable. As for manufacturing temperature, 0 degreeC-100 degreeC is good, Preferably 5 degreeC-25 degreeC is preferable. This method may use dialysis.
    Hereinafter, although an Example demonstrates this invention still in detail, this Example does not limit the scope of this invention at all.
    Example 1 Formula
    Preparation of Polymers
    20 ml of tetrahydrofuran (THF), 0.15 g of 2-benzyliminoethanol and 2 ml of a 0.5 mol / L-THF solution of potassium naphthalene were added to the reaction vessel, which was stirred under an argon atmosphere for 3 minutes, followed by 2-benzyliminoethanol. Potassium chloride (potassium 2-benzyliminoethoxide) is produced.
    8.8g of ethylene oxide is added to this solution, and it stirred at 1 atmosphere and room temperature. After reacting for 2 days, 7.2 g of lactide was added to the reaction solution, and the mixture was further stirred for 1 hour. After distilling off the reaction solvent under reduced pressure, 50 ml of 1N hydrochloric acid was added, stirred at room temperature for 2 hours to remove the protecting group, and then poured into cold propanol to precipitate the resulting polymer. The precipitate obtained by centrifugation is purified by lyophilization from benzene. Yield is 15.0 g (94%). The polymer obtained by gel permeation chromatography is monolithic and the molecular weight of the polymer is about 15000.
    In the proton nuclear magnetic resonance spectrum of the obtained polymer in heavy chloroform, the polymer has both polyethylene oxide (PEO) and polylactide (PL) units, and an amino group at the α-terminus and a hydroxyl group at the ω-terminus. It is confirmed that it is a heterotelecyclic oligomer having. The chain length of the block polymer obtained from the integral ratio of this spectrum is about 9,000 for PEO and about 7,000 for PL.
    The proton nuclear magnetic resonance spectra are as follows.
    1 H-NMR (DMSO), δ (ppm): 1.6 (a; 294H), 2.8 (b; 2H), 3.6 (c; 820H), 5.2 (d; 98H), wherein a to c are Corresponds to the hydrogen atom indicated and is the same below)
    Example 2 Formula
    Preparation of Polymers
    20 ml of THF, 0.15 g of 2-benzylminoethanol and 2 ml of 0.5 mol / L-THF solution of potassium naphthalene were added to the reaction vessel, and stirred for 3 minutes under an argon atmosphere, to thereby prepare a potassium salt of 2-benzylaminoethanol (potassium 2). Benzyliminoethoxide).
    8.8g of ethylene oxide is added to this solution, and it stirred at 1 atmosphere and room temperature. After reacting for 2 days, 5.0 g of δ-valerolactone was added to the reaction solution, and the mixture was further stirred for 1 hour. After distilling off the reaction solvent under reduced pressure, 50 ml of 1N hydrochloric acid was added, stirred at room temperature for 2 hours to remove the protecting group, and then poured into cold propanol to precipitate the resulting polymer. The precipitate obtained by centrifugation is purified by lyophilization from benzene. Yield is 12.5 g (90%). The polymer obtained by gel permeation chromatography is monomodal and has a molecular weight of about 14000.
    In the proton nuclear magnetic resonance spectrum of the obtained polymer in deuterated chloroform, the polymer has both polyethylene oxide (PEO) and poly (δ-valerolactone) (PVL) units, an amino group at the α-terminus, an ω-terminus It is confirmed that it is a heterotelecyclic oligomer having a hydroxyl group quantitatively. The chain length of the block polymer obtained from the integral ratio of this spectrum is about 8,800 for PEO and about 5,200 for PVL.
    The proton nuclear magnetic resonance spectra are as follows.
    1 H-NMR (DMSO), δ (ppm): 1.7 (a; 208H), 2.4 (b; 104H), 2.8 (c; 2H), 3.6 (d; 904H)
    Example 3 Formula
    Preparation of Polymers
    20 ml of THF, 0.15 g of 2-benzylminoethanol and 2 ml of 0.5 mol / L-THF solution of potassium naphthalene were added to the reaction vessel, followed by stirring under an argon atmosphere for 3 minutes. Benzyliminoethoxide).
    8.8g of ethylene oxide is added to this solution, and it stirred at 1 atmosphere and room temperature. After reacting for 2 days, 10.0 g of 2- (trimethylsiloxy) ethyl methacrylic acid is added to the reaction solution and further stirred for 1 hour. After distilling off the reaction solvent under reduced pressure, 50 ml of 1N hydrochloric acid was added, stirred at room temperature for 2 hours to remove the protecting group, and then poured into cold propanol to precipitate the resulting polymer. The precipitate obtained by centrifugation is purified by lyophilization from benzene. Yield is 15.0 g (96%). The polymer obtained by gel permeation chromatography is monomodal and has a molecular weight of about 14000.
    In the proton nuclear magnetic resonance spectrum of the obtained polymer in biethanol, the polymer has both polyethylene oxide (PEO) and poly (methacrylate 2-hydroxyethyl) (PHEMA) units and an amino group at the α-terminus. It is confirmed that it is a heterotelecyclic oligomer having. The chain length of the block polymer obtained from the integral ratio of this spectrum is about 8.800 for PEO and about 7,000 for PHEMA.
    The proton nuclear magnetic resonance spectra are as follows.
    1 H-NMR (DMSO), δ (ppm): 0.9 to 1.3 (a; 150H), 2.0 (b; 100H), 2.8 (c; 2H), 3.6 (d; 800H), 3.8 (e; 100H), 4.1 (f; 100H)
    Example 4 Formula
    Preparation of Polymers
    20 ml of THF, 0.13 g of tert-butoxycarbonylethanol and 2 ml of 0.5 mol / L-THF solution of potassium naphthalene were added to the reaction vessel, stirred for 3 minutes under argon atmosphere, and potassium chloride of tert-butoxycarbonylethanol ( Potassium tert-butoxycarbonylethoxide).
    8.8g of ethylene oxide is added to this solution, and it stirred at 1 atmosphere and room temperature. After reacting for 2 days, 7.2 g of lactide was added to the reaction solution, and the mixture was further stirred for 1 hour. After distilling off the reaction solvent under reduced pressure, 50 ml of 1N hydrochloric acid was added, stirred at room temperature for 2 hours to remove the protecting group, and then poured into cold propanol to precipitate the resulting polymer. The precipitate obtained by centrifugation is purified by lyophilization from benzene. Yield is 14.0 g (88%). The polymer obtained by gel permeation chromatography is monomodal and the molecular weight of the polymer is about 14000.
    In the proton nuclear magnetic resonance spectrum of the obtained polymer in heavy chloroform, the polymer has both polyethylene oxide (PEO) and polylactide (PL) units, and a carboxyl group at α-terminus and a hydroxyl group at ω-terminus. It is confirmed that it is a heterotelecyclic oligomer having. The chain length of the block polymer obtained from the integral ratio of this spectrum is about 8,000 PEO and about 6,000 PL.
    The proton nuclear magnetic resonance spectra are as follows.
    1 H-NMR (DMSO), δ (ppm): 1.6 (a; 252H), 2.4 (b; 2H), 3.6 (c; 730H), 5.2 (d; 84H), 9.8 (e; 1H)
    Example 5 Formula
    Preparation of Polymers
    20 ml of THF, 0.13 g of benzylthiol, and 2 ml of a 0.5 mol / L-THF solution of potassium naphthalene were added to the reaction vessel, followed by stirring for 3 minutes in an argon atmosphere to produce a potassium chloride (benzylthiopotassium) of benzylthiol.
    8.8g of ethylene oxide is added to this solution, and it stirred at 1 atmosphere and room temperature. After reacting for 2 days, 7.2 g of lactide was added to the reaction solution and further stirred for 1 hour. After distilling off the reaction solvent under reduced pressure, 50 ml of aqueous sodium borohydride solution was added, stirred at room temperature for 2 hours to remove the protecting group, and then poured into cold propanol to precipitate the resulting polymer. The precipitate obtained by centrifugation is purified by lyophilization from benzene. Yield is 14.5 g (91%). The polymer obtained by gel permeation chromatography is monomodal and has a molecular weight of about 16,000.
    From the proton nuclear magnetic resonance spectra of the obtained polymer in heavy chloroform, the polymer has both polyethylene oxide (PEO) and polylactide (PL) units, and quantitatively quantifies a mercapto group at the α-terminus and a hydroxyl group at the ω-terminus. It is confirmed that it is a hetero telecyclic oligomer which has.
    The proton nuclear magnetic resonance spectra are as follows.
    1 H-NMR (DMSO), δ (ppm): 1.6 (a; 300H), 3.6 (b; 800H), 5.2 (c; 100H)
    Example 6 Formula
    Preparation of Polymers
    20 ml of THF, 0.15 g of 2-benzylminoethanol and 2 ml of 0.5 mol / L-THF solution of potassium naphthalene were added to the reaction vessel, and stirred for 3 minutes under an argon atmosphere, to thereby prepare a potassium salt of 2-benzylaminoethanol (potassium 2). Benzyliminoethoxide).
    8.8g of ethylene oxide is added to this solution, and it stirred at 1 atmosphere and room temperature. After reacting for 2 days, 7.2 g of lactide was added to the reaction solution, the mixture was further stirred for 1 hour, 2 ml of methacrylic anhydride was added, and the reaction was further performed for 1 hour. After the reaction, the solvent was distilled off under reduced pressure, 50 ml of 0.1 N hydrochloric acid was added, and the protective group was removed by stirring at room temperature for 2 hours. The purified polymer is poured into cold propanol to precipitate the resulting polymer. The precipitate obtained by centrifugation is purified by lyophilization from benzene. Yield is 14.0 g (88%). The polymer obtained by gel permeation chromatography is monomodal and has a molecular weight of about 15,000.
    In the proton nuclear magnetic resonance spectrum of the obtained polymer in heavy chloroform, the polymer has both polyethylene oxide (PEO) and polylactide (PL) units, an amino group at the α-terminus and a methacryloyl group at the ω-terminus It is confirmed that it is a heterotelecyclic oligomer having quantitatively. From the integral ratio of this spectrum, the chain length of the block polymer is about 8,800 PEO and about 6,800 PL.
    The proton nuclear magnetic resonance spectra are as follows.
    1 H-NMR (DMSO), δ (ppm): 1.6 (a; 283H), 1.9 (b; 3H), 2.8 (c; 2H), 3.6 (d; 800H), 5.2 (e; 94H), 5.7, 6.2 (f; 2H)
    Example 7 Formula
    Preparation of Polymers
    20 ml of THF, 0.04 g of acetonitrile and 2 ml of a 0.5 mol / L-THF solution of potassium naphthalene were added to the reaction vessel, and stirred for 3 minutes in an argon atmosphere to produce cyanomethyl potassium.
    4.4g of ethylene oxide is added to this solution, and it stirred at 1 atmosphere and room temperature. After reacting for 2 days, 7.2 g of lactide was added to the reaction solution, followed by further reaction for 1 hour. The reaction solvent is distilled off under reduced pressure and then poured into cold propanol to precipitate the resulting polymer. The precipitate obtained by centrifugation is purified by lyophilization from benzene. Yield is 11.0 g (95%). The polymer obtained by gel permeation chromatography is monomodal and has a molecular weight of about 11,000.
    The proton nuclear magnetic resonance spectra are as follows.
    1 H-NMR (CDCl 3 ), δ (ppm): 2.4 (a; 2H), 1.8 (b; 2H), 3.6 (c; 400H), 5.2 (d; 50H), 1.6 (e; 150H)
    Example 8 Formula
    Preparation of Polymers
    20 ml of THF, 0.04 g of acetonitrile and 2 ml of a 0.5 mol / L-THF solution of potassium naphthalene were added to the reaction vessel, and stirred under an argon atmosphere for 3 minutes to produce cyanomethyl potassium. 4.4g of ethylene oxide is added to this solution, and it stirred at 1 atmosphere and room temperature. After reacting for 2 days, 7.2 g of lactide was added to the solution, followed by further reaction for 1 hour.
    10 g of methacrylic anhydride is added thereto and reacted for an additional 2 hours at room temperature. The reaction solvent is distilled off under reduced pressure and then poured into cold propanol to precipitate the resulting polymer. The precipitate obtained by centrifugation is purified by lyophilization from benzene. Yield is 10.5 g (91%). The polymer obtained by gel permeation chromatography is monomodal and has a molecular weight of about 11,000.
    The proton and carbon nuclear magnetic resonance spectra are as follows.
    1 H-NMR (CDCl 3 ), δ (ppm): 1.6 (f; 150H), 1.8 (b; 2H), 1.9 (h; 3H), 2.4 (a; 2H), 3.6 (c, d; 400H) , 5.2 (e; 50H), 5.6, 6.2 (g; 2H)
    13 C-NMR (CDCl 3 ), δ (ppm): 13.9 (2) *, 16.5 (10), 18.0 (8), 25.2 (3), 64.2 (7), 69.2 (9), 68.8 (4), 70.0 (5,6), 119.4 (1), 126.5 (13), 135.2 (12), 169.5 (8,11)
    In [* (), the chemical formula
    Corresponds to the carbon shown in
    Example 9 Formula
    Preparation of Polymers
    200 mg of the polymer obtained in Example 7 was dissolved in 40 ml of ammonia saturated methanol, and hydrogenated at 25 ° C. and 35 atm using 0.5 g of Raney Ni-W2. After 1 hour, the reaction solvent is distilled off under reduced pressure, and the polymer is recovered by cold propanol. The yield of polymer obtained by lyophilization from benzene is 180 mg (90%). The polymer obtained by gel permeation chromatography is monomodal and has a molecular weight of about 11,000.
    The proton and carbon nuclear magnetic resonance spectra are as follows.
    1 H-NMR (CDCl 3 ), δ (ppm): 1.6 (b, f; 150H), 1.8 (c; 2H), 2.7 (a; 2H), 3.6 (d; 400H), 5.2 (e; 50H)
    13 C-NMR (CDCl 3 ), δ (ppm): 16.5 (10) *, 25.1 (3), 26.4 (2), 40.9 (1), 64.2 (7), 68.8 (4), 69.2 (9), 70.0 (5, 6), 169.4 (8)
    In [* (), the chemical formula
    Corresponds to the carbon shown in
    Example 10 Preparation of Polymer Micelles
    50 mg of the block polymer sample obtained in Example 1 is dissolved in water or a suitable buffer solution to 0.01 to 0.1% (w / v). The micelle formation in the solution was confirmed by particle size distribution measurement by dynamic light scattering, and formation of a single polymer micelle having an average particle diameter of 30 nm was confirmed. The critical micelle concentration of the polymer micelles is 10 mg / L. The polymer micelle is a novel polymer micelle having a primary amino group on the surface of the micelle as a result of the structural analysis.
    Example 11 Preparation of Polymer Micelles
    50 mg of the block polymer sample obtained in Example 4 is dissolved in water or a suitable buffer solution to 0.01 to 0.1% (w / v). The micelle formation in the solution was confirmed by particle size distribution measurement by dynamic light scattering, and formation of a single polymer micelle having an average particle diameter of 28 nm was confirmed. The critical micelle concentration of the polymer micelles is 11 mg / L. The polymer micelle is a novel polymer micelle having a carboxyl group on the surface of the micelle as a result of the structural analysis.
    Example 12 Preparation of Polymer Micelles
    50 mg of the block polymer sample obtained in Example 6 is dissolved in water or a suitable buffer solution to 0.1% (w / v). The micelle formation in the solution was confirmed by particle size distribution measurement by dynamic light scattering, and formation of a single polymer micelle having an average particle diameter of 30 nm was confirmed. The critical micelle concentration of the polymer micelles is 10 mg / L. 0.01 g of benzoyl peroxide is solubilized in the micelle solution and reacted at 80 ° C. for 5 hours. After the reaction, the dialysis of water was carried out using a membrane filter having a fraction molecular weight of 12000 and confirmed by particle size distribution measurement by dynamic light scattering. The addition of dodecyl sulfuric acid does not change the micelle diameter, and it is confirmed that the micelles are efficiently crosslinked. The polymer micelle is a crosslinked novel polymer micelle having an amino group on the surface of the micelle as a result of the structural analysis.
    The block polymer which concerns on this invention has functional groups provided with proteins, such as an amino group, a carboxyl group, a hydroxyl group, and a mercapto group, at both ends, and may also have a vinyl group which can be used for further superposition | polymerization. In addition, it is possible to appropriately adjust the hydrophilicity and hydrophobicity balance in the molecule. Therefore, it can use advantageously in manufacture, processing industry, etc. of a biological synthetic material.
    In addition, the polymer micelle compound having functional groups such as amino groups, carboxyl groups, and mercapto groups on the surface that can be prepared from the polymer can be used for 1) chemical introduction into the nucleus in micelles, and 2) crosslinked micelles that are stable by ω-terminal functional groups. (Nanospheres) can be produced, and 3) surface functional groups are stable in water and can react with amines and thiols, so that biological molecules such as antibodies can be efficiently bound to micelles. On the other hand, it is known that all of the polyoxyethylene chain, polyglycolic acid and polylactone which are the constituent segments of the block polymer of the present invention are decomposed in vivo, and the charge on the surface of the polymer micelle can be freely changed. In view of this, the polymer micelle compound having a functional group on the surface provided by the present invention can be expected to be applied to pharmaceuticals, such as i) a drug delivery carrier having a target directivity, and ii) a diagnostic nanosphere.
    Thus, there is also applicability in the medical field.
    权利要求:
    Claims (10)
    [1" claim-type="Currently amended] Block polymers of formula (I).
    Formula 1

    In Formula I,
    X optionally has 1 to 10 carbon atoms having a substituent selected from the group consisting of an amino group blocked by one or two amino protecting groups, a carboxyl group blocked by a carboxy protecting group and a mercapto group blocked by a mercapto protecting group An alkyl group or the phenyl group or phenylalkyl group which has the said substituent in a benzene ring,
    Y is a chemical formula
    Repeat units of
    (Wherein R 1 and R 2 independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, R 3 represents a hydrogen atom or a methyl group, and R 4 optionally represents a carbon number substituted with a hydroxyl group which may be protected) An alkyl group of 1 to 5, q is an integer of 2 to 5), and a group selected from the group consisting of
    Z is a hydrogen atom, acryloyl group (CH 2 = CH-CO-), methacryloyl group (CH 2 = C (CH 3 ) -CO-), vinyl benzyl group ( ), Aryl group (CH 2 = CH-CH 2- ), paratoluenesulfonyl group ( ), A mercapto group, optionally a functional group selected from the group consisting of an alkyl group having an amino group mono-substituted or disubstituted with an alkyl group having 1 to 5 carbon atoms, an alkyl group having a carboxyl group or an ester group thereof, an alkyl group having an aldehyde or an acetal group thereof, and a halogen atom Indicates,
    m and n are independently integers from 2 to 10,000.
    [2" claim-type="Currently amended] The block polymer according to claim 1, wherein X has an amino group, a carboxyl group, or a mercapto group as a substituent which is not blocked by a protecting group.
    [3" claim-type="Currently amended] The alkyl group according to claim 1, wherein X is an alkoxycarbonyl group having 1 to 5 carbon atoms, a benzene ring is an alkyl group having 1 to 3 carbon atoms, or optionally a benzylidene group substituted by a halogen atom, and an alkyl group and phenyl group having 1 to 3 carbon atoms. An amino group blocked by an amino protecting group selected from the group consisting of a silyl group and a cyano group having three groups selected from; Or a carboxyl group blocked by a carboxy protecting group selected from the group consisting of alkoxy, benzyloxy, diphenylmethoxy, triphenylmethoxy and cyano groups having 1 to 5 carbon atoms, or a mercapto selected from the group consisting of phenyl and benzyl A block polymer having a mercapto group blocked by a protecting group as a substituent.
    [4" claim-type="Currently amended] The block polymer according to claim 1, wherein X is a group having a carboxyl group which is an amino group or a tert-butoxy group blocked by an amino protecting group which is a benzylidene group, a trimethylsilyl group or a cyano group.
    [5" claim-type="Currently amended] The block polymer according to claim 1, wherein X is an alkyl group having 1 to 10 carbon atoms having an amino group or a carboxyl group which is not blocked by a protecting group as a substituent.
    [6" claim-type="Currently amended] The compound of claim 1 wherein Y is

    The block polymer of which is a repeating unit of (where alk is a C1-C3 alkyl group substituted by a hydroxyl group as the case may be).
    [7" claim-type="Currently amended] The block polymer according to claim 1, wherein Z is a hydrogen atom, acryloyl group or methacryloyl group.
    [8" claim-type="Currently amended] Living Block Polymers of Formula (II).
    Formula II

    In Chemical Formula II,
    Xa is an alkyl group having 1 to 10 carbon atoms having a substituent selected from the group consisting of an amino group blocked by one or two amino protecting groups, a carboxyl group blocked by a carboxy protecting group and a mercapto group blocked by a mercapto protecting group, or the substituent A phenyl group or a phenylalkyl group in the benzene ring;
    Y and Ya are each chemical formula
    Flag
    (Wherein R 1 and R 2 independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, R 3 represents a hydrogen atom or a methyl group, and R 4 is optionally 1 to 5 carbon atoms substituted by a hydroxyl group) Is an alkyl group, q is an integer of 2 to 5), and is a group selected from the group consisting of
    M + represents a cation of an alkali metal selected from the group consisting of lithium, sodium, potassium and cesium,
    n and m are independently integers from 2 to 10,000.
    [9" claim-type="Currently amended] The living block polymer of formula (II) is formulated in an inert solvent An electrophilic agent, wherein A is a group forming an active ester, D is chlorine, bromine or iodine, and Q is , -CH = CH 2 , -COOC 2 H 5 or -CH 2 CH 2 (OCH 3 ) 2 ]. A step of converting a mercapto group, optionally a mono- or di-substituted amino group, a carboxyl group or a halogen atom into a mercapto group, optionally a C1-C5 alkyl group, using a corresponding nucleophilic reagent, and if necessary Thus, the process for producing a block polymer according to claim 1, comprising the step of leaving the protecting group of Xa.
    Formula II

    In Chemical Formula II,
    Xa is an alkyl group having 1 to 10 carbon atoms having a substituent selected from the group consisting of an amino group blocked by one or two amino protecting groups, a carboxyl group blocked by a carboxy protecting group and a mercapto group blocked by a mercapto protecting group, or the substituent A phenyl group or a phenyl alkyl group in the benzene ring;
    Y and Ya are each chemical formula


    (Wherein R 1 and R 2 independently represent a hydrogen atom, an alkyl group having 1 to 5 carbon atoms, R 3 represents a hydrogen atom or a methyl group, and R 4 is optionally 1 to 5 carbon atoms substituted by a hydroxyl group) An alkyl group of q, q is an integer of 2 to 5), and is a group selected from the group consisting of
    M + represents a cation of an alkali metal selected from the group consisting of lithium, sodium, potassium and cesium,
    n and m are independently integers from 2 to 10,000.
    [10" claim-type="Currently amended] A polymer micelle comprising the block polymer according to claim 1 as an active ingredient.
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    同族专利:
    公开号 | 公开日
    RU2174989C2|2001-10-20|
    US5929177A|1999-07-27|
    DE69624488T2|2003-06-26|
    SI9620107A|1998-10-31|
    DE69624488D1|2002-11-28|
    AT226604T|2002-11-15|
    JP3711288B2|2005-11-02|
    IL122021D0|1998-03-10|
    NO975584L|1997-12-03|
    HU9900662A2|1999-06-28|
    HU9900662A3|2006-04-28|
    BR9610053A|1999-07-06|
    NZ313769A|2000-02-28|
    EP0844269B1|2002-10-23|
    AU6631096A|1997-03-05|
    CA2229068A1|1997-02-20|
    NO975584D0|1997-12-03|
    WO1997006202A1|1997-02-20|
    CN1192759A|1998-09-09|
    EP0844269A4|1999-01-27|
    NO314589B1|2003-04-14|
    AU726749B2|2000-11-16|
    EP0844269A1|1998-05-27|
    CN1087317C|2002-07-10|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1995-08-10|Priority to JP20454795
    1995-08-10|Priority to JP95-204547
    1996-08-05|Application filed by 가타오카가즈노리
    1996-08-05|Priority to PCT/JP1996/002200
    1999-02-25|Publication of KR19990014879A
    优先权:
    申请号 | 申请日 | 专利标题
    JP20454795|1995-08-10|
    JP95-204547|1995-08-10|
    PCT/JP1996/002200|WO1997006202A1|1995-08-10|1996-08-05|Block polymer having functional groups at both ends|
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