MXPA98001148A - Block polymer that has functional groups in its two extreme - Google Patents

Abstract

The present invention provides a block polymer having functional groups at both its ends, and comprising hydrophilic and hydrophobic segments, as for the functional groups on both its ends, the block polymer has an amino group, a carboxyl group or an mercapto group on the alpha-terminal part and a hydroxyl group, a carboxyl group, an aldehyde group or a vinyl group on the omega-terminal part, the hydrophilic segment comprises polyethylene oxide, while the hydrophobic segment is derived from lactide, lactone or acid ester methacrylic, the block polymer of this invention forms a polymeric micelle that is usable as biocompatib material

Description

BLOCK POLYMER THAT HAS FUNCTIONAL GROUPS IN ITS TWO EXTREMES TECHNICAL FIELD The present invention relates to a block polymer having functional groups on its two ends, to a method for producing same and to its application for polymeric micelle. In more detail, this invention describes a polymer having functional groups at both ends while having, in its main chain, a polyethylene oxide chain as a hydrophilic segment and another chain derived from polyester or derived from methacrylic acid as a hydrophobic segment. In this invention the term "polymer" includes oligomers.

BACKGROUND OF THE INVENTION Currently, a micelle or polymer nanosphere composed of a hydrophilic / hydrophobic block polymer in which a hydrophilic polymer at a molecular level, such as polyethylene oxide, with a hydrophobic polymer, as a vehicle for the release of drugs or drugs, is attracting attention. Similar. Said micelle and polymeric nanosphere has been prepared from a hydrophilic / hydrophobic type block polymer, in which a hydrophilic polymer is combined with a hydrophobic polymer at the molecular level. However, in conventional processes for producing a hydrophilic / hydrophobic type block polymer, there is a limitation on the species of terminal functional groups to be introduced, and only block polymers whose functional groups are restricted to the methoxy or hydroxyl group have been proposed. If functional groups are successively introduced on the surface of the micelle in an optional proportion, it would be possible to provide a functional polymeric micelle that would be useful for the delivery of drugs to certain organs. In this way, the object of this invention is to provide a block polymer having functional groups on both ends of its main chain, such as a polyfunctional polymer capable of forming a polymeric micelle.

DESCRIPTION OF THE INVENTION The inventors of this invention have found that a block polymer having an amino group, a carboxyl group or a mercapto group, protected or unprotected, can easily be produced on one end of the molecule, and several functional groups on the other end, when an alkylene, phenylene or phenylalkylene derivative having a certain type of protected amino group, carboxyl group or mercapto group, and a hydroxyl group, is used as an active polymerization initiator and when ethylene oxide and lactide or lactone are polymerized or methacrylic acid ester as monomers, and further when an electrophilic agent is reacted if necessary. They have also confirmed that a block polymer obtained in this way forms a polymeric micelle which is very stable in an aqueous solvent. This invention, in this way, provides a block polymer having functional groups at both ends of the molecule and which is represented by the following formula (I): X-0- (CH2CH20) «~ (Y) n-Z (I) wherein X denotes an alkyl group having 1 to carbon atoms, having one or two substituents selected from the group consisting of amino group blocked with an amino protecting group, carboxyl group blocked with a carboxyl protecting group and mercapto group blocked with a mercapto protecting group, or phenyl group or phenylalkyl having the aforementioned substituents on the benzene ring; And denotes a group selected from the group consisting of the following recurring units: wherein R1 and R2 independently denote a hydrogen atom or alkyl group having from 1 to 5 carbon atoms; R3 denotes a hydrogen atom or a methyl group; R? denotes an alkyl group having from 1 to 5 carbon atoms, which is substituted with hydroxyl group under certain circumstances; q denotes an integer from 2 to 5; Z denotes a functional group selected from the group consisting of a hydrogen atom, an acryloyl group (CH2 = CH-C0-), a methacryloyl group (CH2 = C (CH3) -C0-), a vinylbenzyl group (CH = CH - g > - CH, -) an allyl group (CH2 = CH-CH2 -), a g-p-toluenesulfonyl group , a mercapto group, an alkyl group having an amino group which is mono or disubstituted under certain circumstances with an alkyl group having from 1 to 5 carbon atoms, an alkyl group having a carboxyl group or its ester group, a group alkyl having acetal group and a halogen atom; and m and n denote independently an integer from 2 to 10,000. The above block polymer can be easily produced from the active polymer represented by the following formula (II) according to the present invention. Therefore, this invention provides not only a process for producing the block polymer of formula (I) with the use of the active polymer represented by the following formula (II) as starting material, but also of the active polymer of formula (II) ) per se which is usable for the subsequent production of a block polymer having a hydrophilic or hydrophobic segment.

Xa-0 - (CH2CH2?) M - (Y) n-l-YaM + (II) wherein Xa denotes an alkyl group having from 1 to 10 carbon atoms, having one or two substituents selected from the group consisting of amino group blocked with an amino protecting group, carboxyl group blocked with a carboxyl protecting group and group mercapto blocked with a mercapto protecting group, or denotes phenyl or phenylalkyl group having the aforementioned substituents on the benzene ring; Y and Y denote a group selected from the group consisting of the groups represented by the following formulas o o O II II II II C CHOC CHOCH CHOCCHO? I I R 'R2 R R! OR | R3 CH2-C-. { I and -CH2-CT COOR * í COOR < R3 R3 -CH2-C- V -CH2-c? I / CN CN wherein R1 and R2 independently denote a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; R3 denotes a hydrogen atom or a methyl group; R ^ denotes an alkyl group having from 1 to 5 carbon atoms, which is substituted with hydroxyl group under certain circumstances; q denotes an integer from 2 to 5; M + denotes an alkali metal cation selected from the group consisting of lithium, sodium, potassium and cesium; and y n denote independently an integer of 2 10,000. The block polymer of the above formula (I) forms, when treated in a solvent, a stable polymeric micelle containing said block polymer as an active ingredient. In this way, this invention also provides this polymeric micelle. As will be seen from their substituent components, it is expected that the block polymers of formula (I) and the polymer micelles prepared therefrom have high bioaffinity or bioavailability. Therefore, these block polymers or polymeric micelles as they are, or polymers which are also prepared therefrom with the use of one or both of their terminal functional groups, can be used for the production of materials that are directly applicable to living organisms for example as a vehicle for drug delivery. In addition, since this invention provides a polymeric micelle that is very stable in an aqueous solvent, the polymer of this invention is also useful for delivery of drugs to a certain organ.

DETAILED DESCRIPTION OF THE INVENTION The block polymer of formula (I) whose group X is substituted with an amino group, a carboxyl group or a mercapto group which may be protected, carries a free functional group in a terminal part of the polymer when it is protected as it is or when it is unprotected. In this specification, said terminal part is called alpha-terminal for convenience purposes. The protecting groups mentioned above include an amino protecting group, a carboxy protecting group and a mercapto protecting group that are commonly used in this field. Any of these groups can be employed as long as they can be removed by means of hydrolysis or catalytic hydrogenation and have no adverse effects on the active polymerization of this invention. Concrete examples of the amino protecting group include the benzylidene group which forms a Schiff base (imino group) together with the nitrogen atom of the amino group and whose benzene ring can be substituted with an alkyl group having from 1 to 3 carbon atoms. carbon, in particular methyl group or halogen atom, in particular fluorine or chlorine, preferably an unsubstituted benzylidene group; alkoxycarbonyl having from 1 to 5 carbon atoms, in particular the tert-butoxycarbonyl group; and the silyl group having three groups selected from the group consisting of alkyl group having from 1 to 3 carbon atoms and phenyl group, in particular trimethylsilyl, triethylsilyl and dimethylphenylsilyl. The amino group blocked with amino protecting group includes the cyano group which forms an amino group when reduced in a certain way. Concrete examples of carboxyl protecting groups include the alkoxy group having from 1 to 5 carbon atoms constituting an ester part with the carboxyl group, in particular methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy , phenyl-substituted methoxy, in particular benzyloxy, diphenylmethoxy and triphenylmethoxy. The carboxyl group blocked with the carboxyl protecting group includes the cyano group which forms the carboxyl group when it is hydrolyzed in a certain way. Concrete examples of the mercapto protecting group include phenyl, benzyl, trimethylsilyl, acetyl, o-, m-, p-methylbenzyl, triethylsilyl, o-, -, p-tolyl and tert-butylidimethyl lysyl. Examples of the alkyl group constituting the group X include alkyl groups such as those which are capable of forming a branched or straight-chain alkylene group, namely, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec. -butyl, n-pentyl, sec-pentyl, n-hexyl, heptyl and decyl, in particular, methyl, ethyl, n-propyl and n-butyl. The group X can be composed of phenyl or phenylalkyl, in particular benzyl or phenethyl. Such being the case, concrete examples of the group X (a part of Xa) having an amino protecting group include, without restriction, 1- or 2-benzalimino-ethyl, 1-, 2- or 3-benzalimino-propyl, 1-, 2-, 3- o -benzalimino-butyl, 1-, 2-, 3-, 4- or 5-benzalimino-phenyl, 2-, 3-, or 4-benzalimino-phenyl , 2-, 3-, or 4-benzalimino-benzyl, 2-, 3-, or 4-benzalimino-phenyl-phenethyl, N, N- (bistrimethylsilyl) aminomethyl, 1- or 2-N, N- (bistrimethylsilyl) aminomethyl, 1-, 2-, or 3-N, N- (bistrimethylsilyl) aminopropyl, 1-, 2-, 3- or 4-N, N- (bistrimethylsilyl) aminobutyl, 1-, 2-, 3-, 4 - or 5-N, N- (bistrimethylsilyl) aminophenyl, 2-, 3- or 4-N, N- (bistrimethylsilyl) aminophenyl, 2-, 3- or 4-N, N- (bistrimethylsilyl) aminobenzyl, 2- , 3- or 4-N, N- (bistrimethylsilyl) aminophenethyl, N-trimethylsilyl-N-methylaminomethyl, 1- or 2-N-trimethylsilyl-N-methylaminomethyl, 1-, 2- or 3-N-rimethylsilyl-N-methylaminopropyl , 1-, 2-, 3- or 4-N-trimethylsilyl-N-methylaminobutyl, 1-, 2-, 3-, 4- or 5-N-trimethylsilyl-N-methylaminophenyl, 2-, 3-, or 4 -N-trimethyl-silyl-N-methylaminophenyl, 2-, 3-, or 4-N-rimethylsilyl-N-ethylaminobenzyl, 2-, 3-, or 4-N-trimethylsilyl-N-methyl-aminophenethyl, N-trimethylsilyl -N -ethylaminomethyl, 1- or 2-N-trimethylsilyl-N-ethylaminoethyl, 1-, 2-, or 3-Nt-rimethylsilyl-N-ethylaminopropyl, 1-, 2-, 3- or 4-N-trimethylsilyl-N-ethyl -to -butyl, 1-, 2-, 3-, 4- or 5-N-trimethylsilyl-N-ethyl-a-phenyl, 2-, 3- or 4-N-trimethylsilyl-N-ethylaminophenyl, 2-, 3- or 4-N-trimethylsilyl-N-ethylaminobenzyl, 2-, 3- or 4-N-trimethylsilyl-N-ethylaminophenethyl, dimethylaminomethyl, 1- or 2-dimethylaminoethyl, 1-, 2- or 3-dimethylaminopropyl, 1-, 2 -, 3- or 4-dimethylaminobutyl, 1-, 2-, 3-, 4- or 5-dimethylaminopentyl, 2-, 3- or 4-dimethylaminophenyl, 2-, 3- or 4-dimethylaminobenzyl, 2-, 3- or 4-dimethylaminophenethyl, diethylaminomethyl, 1- or 2-diethylaminoethyl, 1-, 2- or 3-diethylaminopropyl, 1-, 2-, 3-, or 4-diethylaminobutyl, 1-, 2-, 3-, 4- or 5-diethylaminopentyl, 2-, 3- or 4-diethylaminopentyl, 2-, 3- or incidentally, when the protecting group is different from benzylidene, the protected amino group can be methyl amino, ethyl amino or propyl amino, or cyano group. The specific examples of the group X (a part of Xa) having a carboxyl protecting group include, without restriction, the methoxycarbonylmethyl group, 1-2-methoxycarbonyl-ethyl, 1-, 2- or 3-methoxycarbonylpropyl, 1- , 2-, 3- or 4-methoxycarbonyl-butyl, 1-, 2-, 3-, 4- or 5-methoxycarbonyl-pentyl, 2-, 3- or 4-methoxycarbonylphenyl, 2-, 3- or 4- ethoxycarbonylbenzyl , 2-, 3 or 4-methoxycarbonylphenethyl, ethoxycarbonylmethyl, 1- or 2-ethoxycarbonylethyl, 1-, 2- or 3-ethoxycarbomethylpropyl, 1-, 2-, 3- or 4-ethoxycarbonylbutyl, 1-, 2-, 3- , 4- or 5-ethoxycarbonylbenzyl, 2-, 3- or 4-ethoxycarbonylphenyl, 2-, 3- or 4-ethoxycarbonylbenzyl, 2-, 3- or 4-ethoxycarbonylphenethyl, tert-butoxycarbonylmethyl, 1- or 2-tert-butoxycarbonyl -ethyl, 1-, 2- or 3-tert-butoxycarbonyl-propyl, 1-, 2-, 3- or 4-tert-butoxycarbonyl butyl, 1-, 2-, 3-, 4- or 5-tert-butoxycarbonylpentyl, 2-, 3- or 4-tert-butoxycarbonylphenyl, 2-, 3- or 4-tert-butoxycarbonylbenzyl, 2-, 3- or 4-tert-butoxycarbonylphenethyl, nitrile, such as 3-cyanopropyl. Concrete examples of group X (a part of Xa) having a mercapto protecting group include, without restriction, the phenylmercaptomethyl group, 1- or 2-phenylmercaptoethyl, 1-, 2- or 3-phenylmercaptopropyl, 1-, 2- , 3-or 4-phenylmercapto-butyl, 1-, 2-, 3-, 4- or 5-phenylmercapto-pentyl, 2-, 3- or 4-phenylmercapto-phenyl, 2-, 3- or 4-phenylmercapto- benzyl, 2-, 3- or 4-phenylomercaptophenethyl, benzylmercaptomethyl, 1- or 2-benzylmercaptoethyl, 1-, 2- or 3-benzylmercapto-propyl, 1-, 2-, 3- or 4-benzylmercapto-butyl, 1- , 2-, 3-, 4- or 5-benzylmercapto-pentyl, 2-, 3- or 4-benzyl ercapto-phenyl, 2-, 3- or 4-benzylmercapto-benzyl, 2-, 3- or 4-benzylmercapto -phenethyl, tolyl mercapto-methyl, 1- or 2-tolyl ercapto-ethyl, 1-, 2- or 3-tolylmercapto-propyl, 1-, 2-, 3- or 4-tolyl-mercapto-butyl, 1- , 2-, 3-, 4- or 5-tolylmercapto-pentyl, 2-, 3- or 4-tolylmercapto-phenyl, 2-, 3- or 4-tolyl ercapto-benzyl, 2-, 3- or 4-tolylmercapto -phenethyl, and acetylthioethyl. Another segment Y, in addition to the oxyethylene segment in formula I, is a group derived from a cyclic diester formed by subjecting two molecules of α-hydroxy acid to dehydration and which is represented by the following formula: O 0 II II -C CHOC CHO- I I R1 R2 wherein R1 and R2 independently denote a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms. The aforementioned cyclic diester can be formed from -hydroxy acids, either similar or different, but is preferably derived from two similar α-hydroxy acid molecules. In the particularly preferred example of Y, both R1 as R2 denote either hydrogen atom or methyl group. Y can also be a group derived from a lactone such as that displayed by the following formula, namely lactone, beta-lactone, t-lactone, d-lactone or e-lactone: 0 in which q denotes an integer from 2 to 5. The mark q denotes preferably the integer 4 (Y is derived from t-lactone) or 5 (Y is derived from d-lactone). And it can also be a group derived from methacrylic acid ester or methacrylonitrile which is represented by the following formula: R3 R3 I I -CH2C- or ^ -CH2C-C00R4 CN in which R3 denotes a hydrogen atom or a methyl group, and R > denotes an alkyl group having from 1 to 5 carbon atoms which is substituted with a hydroxyl group which may be protected under certain circumstances. Concrete examples of R4 include methyl, ethyl, n-propyl, n-butyl, tert-butyl, 2-trimethylsiloxyethyl, 2- (tert-butildi etilsiloxietilo) and 2-hydroxyethyl. In this specification, the terms methacrylic acid and methacrylonitrile each comprise methacrylic acid and acrylic acid, and methacrylonitrile and aclonitrile. As for the number of oxyethylene segments in the formula, it can be any integer from 2 to 10,000. In accordance with the production method of this invention it can be obtained almost monodispersable segment (monomodal) having the desired number of m by adjusting the ratio of the amount of ethylene oxide to the initiator X-0 ~ M + for the polymerization of active anion. The block polymer of this invention is therefore conveniently used for the production of materials applicable to living organisms, and the above number m can be determined appropriately according to the particular use of the polymer. As for the segment Y, similarly, any desirable number of n of the integer can be selected from 2 to 10,000 so that the molecular weight distribution can be very narrow. The Z mark denotes a functional group on the other terminal part (hereinafter referred to as omega-terminal for convenience purposes, the terminal part on the right side in the structure of formula I) in addition to the a-terminal of the polymer of the previous block. Although filled with any functional group Z by reaction of electrophilic substitution on the anionic portion of the part omega-terminal polymer active block of formula II, the group is preferably used to improve biocompatibility, or to make it usable for subsequent reactions, in view of the objective of this invention. Being the case, examples of group Z in formula I include hydrogen atom (which forms hydroxyl group when Y is in particular derived from lactide or lactone), acryloyl group (CH2 = CH-C0), methacryloyl group > 9ruP ° rboxilo or ester group as etiloxicarbonilmetilo group (C2 Hs OCOCH2-), metiloxicarbonilmetilo group (CH3 OCOCH2-), carboxymethyl group (HOOC-CH- -), etiloxicarboniletilo group (C2 Hs OCOC2H-;-), carboxyethyl group ( HOOC-CH2CH2-); alkyl group having aldehyde or its acetal group such as formylethane (OCH-CH2CH2-). 3,3-dimethoxypropane ((CH 3 0) 2 CHCH 2 CH 2 -); p-toluenesulFonyl (CH3-) group, mercapto group; halogen atom such as chlorine, bromine and iodine; alkyl group which is mono- or di-substituted under certain circumstances with alkyl group having from 1 to 5 carbon atoms such as 2-aminoethyl, N-methyl-2-aminoethyl, N, N-dimethyl-2-aminoethyl. Incidentally, the mercapto group and the following can be used only when the Y segment is derived from lactide or lactone. When segment Y is derived from methacrylic acid ester or methacrylonitrile, for example, ethylene oxide is added to the omega-terminal part of the active block polymer of formula II, so that the 2-hydroxyethyl group can be formed and then, by its hydroxyl group, the above mentioned groups can be introduced. mercapto, halogen atom, and alkyl group which is mono- or di-substituted under certain circumstances with an alkyl group having from 1 to 5 carbon atoms. The table below shows examples of typical block polymers of this invention in which the above groups (or segments) combine to form it.

TABLE X-0 - (CH2CH20) m- (Y) n - Z (I) In which m and n are each an optional integer of 2-10,000 Compound No, X Y 0 0 1 HO- H CH3 CH3 0 0 II II H2N-CH2CH2- CCHOCCHO - H I I CH3 CH3 0 0 0 3 CH2 0 0 0 II II II H2N-CH2CH2 CCHOCCHO- CC = CH2 CH3 CH3 CH3 0 0 II II NC- CH2JF CCHOCCHO- H CH3 CH3 0 0 0 II II II NC-ß-H2tir CCHOCCHO- CC = CH2 1 1 CH3 CH3 CH3 Compound No, X Y 0 0 0 II I! II NC-eCH2) t - CCHOCCHO - CCH = CH2 1 1 CH3 CH3 0 II NC- (CH2) t -C (CH2) 50- H 0 0 II II NC- ^ CHzT "-C (CH2) 50- CC = CH2 1 CH3 0 0 II II 10 N (MCH27T -C (CH2) 50- CCH = CH: 0 0 II II 11 H2N-6-H2 t - CCHOCCHO - H. 1 1 CH3 CH3 0 0 0 II II II 12 H2N-6CH2 ^ T - CCHOCCHO - CC = CH2 | | CH3 CH3 CH3 0 0 O II II ?? 13 H2N- CH2 t -CCHOCCHO- CCH = CH? I I CH3 CH3 14 H2N- CH2 t -C (CH2) sO- Compound No, X Y 0 0 11 II 15 H2f CH2 t -C (CH2) 50- CC = CH2 1 CH3 0 0 II II 16 H2N- CH2- ^ t -C (CH2) 50- CCH = CH2 0 0 II II 17 NC-. { CH27T- - CCHOCCHO-S02 < ^ CH3 1 1 CH3 CH3 0 0. 0 II II II 18 NC-tCH27T - CCHOCCHO - CH2CO-Bu (t) 1 1 CH3 CH3 0 0 II II 19 C-fCHz - CCHOCCHO - (CH2) 2CH (0CH2CH 1 1 CH3 CH3 0 0 II II 20 H2r CH27T - CCHOCCHO - S02 < 5 CH3 1 1 CH3 CH3 0 0 0 II II II 21 H2N- (CH2 t - CCHOCCHO - CH2C0 - Bu (t) 1 1 CH3 CH3 0 0 II II 22 - CCHOCCHO - CH i CH2 CHO CH3 CHs Compound No. XY I 23 NC- ^ CH2 > - -CH2C- H 1 COOCH 3 CH3 1 24 NC-CH2 > G -CH2C- CH2 CH20H 1 COOCH 3 CH3 0 1 II 25 NC-eCHüTT -CH2C- CHS, CH2OCC = CH2 I | C00CH3 CH3 CH3 1 26 H2N-tCH2-tt -CH2C-H | COOCH 3 CH3 1 27 H2N- CH2 ^ -CH2C- CH ZCH20H 1 C00CH3 CH3 0 1 II 28 H2N-fCH2-tt -CH2C- -CH 2CH2OCC = CH2 I | C00CH3 CH3 CH3 1 1 29 C-eCHz s -CH2C- H 1 COOCHzCH: 20Si (CH3) 2 Bu (t) Compound No. X Y Z CH3 H2N-6CH2 - -CH2 1 C00CH2CH20H 0 0 0 31 32 CH3 CH3 0 0 0 II II II 33 Bu (t) 0C- ^ CH2 ^ - CCHOCCHO - H | | CHs CH3 - 0 0 0 0 II II II II 34 Bu (t) 0C-CH2 - - CCHOCCHO - CC = CH2 1 1 | CH3 CH3 CH3 0 0 0 II II II 35 H0C- CH2 ^ - CCHOCCHO - H 1 1 CH3 CH3 36 Compound No. x Y 0 0 37 < ? cH2S-t.CH272- -CCHOCCHO- H CH3 CH3 0 0 II p 38 HS-H2) t -CCHOCCHO-. H I i CHs CH3 Bu (t) CH3"'I 40 H2N-CH2CH2- -CH2C- H COOCH2CH2OH In the previous table, Bu (t) denotes -C (CH3) 3. The above-mentioned block polymer that is provided by this invention can be efficiently produced in accordance with the following reaction schemes.

Reaction Scheme C H 2 - * C H 2 Xa_0? Me _ ^ (A) X- O- ÍCH2CH20 > 5 rCH2CH2O? MF (B) (Y-inducible monomer) © X-a-O- (CH? CHAOTr YTü rYa M (JO Hydrolysis (and Xa deprotection under circumstances) Z-elect róf ilo introducible (I - 1) > , "Check out if necessary X-O-fCHsCHzO ÍY Z (1-2) (1-2): (when Z is CH3 nucleophile (I-3) (The Xa, X, M +, Y, Ya and Z tags in the above reaction are as defined above, and 1 'is a residue derived from nucleophile). Reaction from (A) to (II): The initiator (A) is diluted with an aprotic solvent and then ethylene oxide and hydrophobic monomer (monomer derivable from the Y segment) are added in this order to the reaction system so that it can proceed the polymerization reaction. Examples of aprotic solvent include benzene, toluene, hexane, tetrahydrofuran and dioxane. The initiator has a concentration of 0.1 to 95% by weight, preferably 1 to 70% by weight, most preferably 2 to 5% by weight. The ratio of initiator to ethylene oxide is, although polymerization is possible at any ratio in accordance with the desired number to be achieved, from 1: 1 to 1: 10,000, preferably 1: 1,000 and most preferably 1: 200. As for the ratio of initiator to hydrophobic monomer, although any proportion according to the desired number of n to be achieved is possible, it is from 1: 1 to 1: 10,000, preferably 1: 1,000, and most preferably 1: 200. The preferred reaction is carried out in a glass tube under pressure or in an autoclave. The reaction temperature is -50 ° C - 150 ° C, preferably 0 ° C - 100 ° C, and preferably 30 ° C to 50 ° C. The reaction pressure is 0.1 to 10 kgf / cm2 G, preferably 1 to 2 kgf / cm2G. As for reaction time, the ethylene oxide is allowed to react normally for 0.01 to 200 hours, preferably 1 to 100 hours, and most preferably for 20 to 50 hours and after adding the hydrophobic monomer to the reaction system, the system is it continues for 0.01 to 200 additional hours, preferably 1 to 100 hours, and most preferably 20 to 50 hours. The active block polymer obtained in this manner (II) has a functional group protected in the terminal part of initiator (α-terminal) quantitatively and an alkoxide of alkali metal in the other terminal part (omega-terminal). When the polymer of formula (II) is treated with acid for example, a block polymer having a functional group such as amino group, carboxyl group and mercapto group in o-terminal, and a hydroxyl group in omega-terminal ( the case in which Y is derived from lactide or lactone). This block polymer is included in the block polymer of formula (I). Other polymers represented by the formula (I) having various omega-terminal functional groups are produced by adding an electrophilic (reactive) to the active block polymer of the formula (II) in the above reaction system. Examples of electrophiles include compounds that are represented by the following formula R5 I A-C0C = CH2 N -SO: (OV CH D-CH2-Q in which A denotes a group that forms an active ester, for example, a portion that forms a halogen atom such as chlorine and bromine or an acid anhydride, D denotes chlorine, bromine or iodine, and Q denotes a group that contains a functional group such as: CH2CH2 (OCHj) 2.

Specific examples of electrophiles include, without restriction, acrylic acid chloride, acrylic acid anhydride, acrylic acid, methacrylic acid chloride, methacrylic acid anhydride, methacrylic acid, vinylbenzyl chloride, vinylbenzylbromide, allyl chloride, bromide allyl, allyl iodide, p-toluenesulfonic acid chloride, ethyl chloroacetate, ethyl bromoacetate, 2-ethyl chloropropionate and 3,3-dimethoxypropyl bromide. When z is a p-toluenesulfonyl group and when Y is derived from glycolide or lactone, another functional group can be introduced by nucleophilic substitution by reacting a nucleophilic reagent in the omega-terrninal position which has been activated with p-toluenesulfonic acid. These reactions are each carried out by means of a normal method. Concrete examples of the above nucleophilic reagent include, without restriction, sodium hydrosulfide, potassium hydrosulfide, sodium 2-aminoethoxide, potassium 2-aethoxide and halogen. The protecting group (ester group, etc.) in the X portion and / or the Z portion of the block polymer obtained of the formula (I) can be removed, if necessary, by a hydrolysis reaction, reduction reaction or known catalytic hydrogenation . In this way, a block polymer of formula (I) can be provided in which the functional groups in the α-terminal part and / or the omega-terminal part are released. The block polymer of formula (I) includes its molecule a hydrophilic segment and a hydrophobic segment. Therefore, it is possible to adjust the balance between hydrophilicity and hydrophobicity by means of the selection of species or molecular weight of the segments appropriately. Therefore, the block polymer of formula (I) is capable of forming a polymeric micelle in a solvent. Treatments for preparing the polymeric micelle which is composed of the block polymer of formula (I) as a constituent component include heat treatment, ultrasonic treatment and organic solvent treatment which are performed separately or in combination. As for heat treatment, a mixture of one or more types of block polymer of formula (I) is dissolved in water, and the resulting solution is heated to 30 to 100 ° C. As for ultrasonic treatment, a mixture of one or more types of block polymer of formula (I) is dissolved in water, and the resulting solution is treated on the scale of 1 W to 20 W, preferably 2 to 4 W, during one second at 24 hours, preferably 30 minutes at 10 hours, most preferably 2 to 4 hours. For treatment with organic solvent, a mixture of one or more types of block polymer of formula (I) is dissolved in an organic solvent, and the resulting solution is dispersed in water, and then the organic solvent is evaporated. Examples of organic solvent include methanol, ethanol, tetrahydrofuran, dioxane, chloroform, benzene, toluene, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, and methylene chloride. The ratio of water to organic solvent may be optional. However, one to one thousand times, and preferably 5 to 20 times, is preferred. The treatment is carried out at a temperature ranging from 0 to 100 ° C, preferably 5 to 25 ° C. Dialysis can be used in these methods. In the following, this invention will be explained in more detail by means of examples, which however do not restrict the scope of this invention.

EXAMPLE 1 Preparation of a polymer represented by the following formula: 0 0 b c c c || d || d H2N-CH2CH20 (CH2CH20 r-eCCHOCCHO ^ rH CH3 CH3 a a ml of THF, 0.15 g of 2-benzaliminoethanol and 0.5 mole of potassium naphthalene / 2 ml of L-tetrahydrofuran solution were added to a reactor and stirred for 3 minutes under an argon atmosphere; a potassium compound of 2-benzaliminoethanol (potassium 2-benzaliminoethoxide) was produced. 8.8 g of ethylene oxide was added to this solution and stirred at room temperature under 1 atm. After reacting for two days, 7.2 g of lactide was added to this reaction solution, and stirred for another hour. After vacuum removal of the reacted solvent, 50 ml of 1 N hydrochloric acid was added and stirred for 2 hours at room temperature, and the protecting group was removed; then, this was poured into propanol, and the polymer produced was precipitated. The precipitate achieved with centrifuge separation was refined by freeze drying from benzene. The yield was 15.0 g (94%). The polymer obtained with gel permeation chromatography was monomodal, and the molecular weight of the polymer was about 15,000. According to the proton nuclear magnetic resonance spectrum with heavy chloroform of the polymer obtained, it was confirmed that this polymer is a heterotelelelic oligomer having both units, polyethylene oxide (PEO) and polylactide (PL), and quantitatively has an amino group on the a-terminal part and the hydroxyl group on the omega-terminal part. The chain length of the block polymer determined by the integral spectrum ratio was about 9000 for PEO and about 7000 for PL.

The results of the proton nuclear magnetic resonance spectrum are as follows: 1 H-NMR (DMSO), d (ppm) 1.6 (a: 294 H) 2.8 (b: 2 H) 3.6 (c: 820 H) 5.2 (d: 98 H) (The a - c marks correspond to the hydrogen atoms in the previous formula, the same applies to the following).

EXAMPLE 2 Preparation of a polymer represented by the following formula: O c d d d || b a a d H2N-CH2CH20 (CH2CH20) - - CCH2CH2CH2CH20! H ml of THF, 0.15 g of 2-benzaliminoethanol and 0.5 mole of potassium naphthalene / 2 ml of L-tetrahydrofuran solution were added to a reactor and stirred for 3 minutes under an argon atmosphere; a potassium compound of 2-benzaliminoethanol (potassium 2-benzaliminoethoxide) was produced. 8.8 g of ethylene oxide was added to this solution and stirred at room temperature under 1 atm. After reacting for two days, 5.0 g of d-valerolactone was added to this reaction solution, and stirred for another hour. After vacuum removal of the reacted solvent, 50 ml of 1 N hydrochloric acid was added and stirred for 2 hours at room temperature, and the protecting group was removed; then, this was poured into cold propanol, and the polymer produced was precipitated. The precipitate achieved with centrifuge separation was refined by freeze drying from benzene. The yield was 12.5 g (90%). The polymer obtained with gel penetration chromatography was monomodal, and the molecular weight of the polymer was about 14,000. According to the nuclear magnetic resonance spectrum with chloroform deuteride of the obtained polymer, it was confirmed that this polymer is a heterotelequic oligomer which it has both units, polyethylene oxide (PEO) and poly (d-valerolactone) (PVL), and quantitatively has an amino group on the a-terminal part and the hydroxyl group on the omega-terminal part. The chain length of the block polymer determined by the integral spectrum ratio was about 800 for PEO and about 5200 for PVL. The results of the proton nuclear magnetic resonance spectrum are as follows: i H-NMR (DMSO). d (ppm) 1.7 (a: 208 H) 2.4 (b: 104 H) 2.8 (c: 2 H) 3.6 (d: 904 H) EXAMPLE 3 Preparation of a polymer represented by the following formula: cdddba H2N-CH2CH2? (CH2CH2?) m - (CH2C (CH3) n - H COOCH2 CH2 OH ef 20 ml of THF, 0.15 g of 2-benzaliminoethanol and 0.5 mole of potassium naphthalene / 2 were added to a reactor. ml of L-tet rahi rofuran solution, and stirred for 3 minutes in an argon atmosphere, the potassium compound of 2-benzaliminoethanol (potassium 2-benzaliminoethoxide). 8.8 g of ethylene oxide was added to this solution and stirred at room temperature and at an atmosphere.

After reaction for 2 days, 10.0 g of 2- (trimethylsiloxy) ethyl methacrylate was added to this reaction solution and stirred for another hour. After removal of the solvent of the reacted solvent, 50 ml of 1 N hydrochloric acid was added and stirred for 2 hours at room temperature, and the protective group was removed; then this was poured into cold propanol and the polymer produced was precipitated. The precipitate achieved with centrifugal separation was refined by freeze drying from benzene. The yield was 15.0 (96%). The polymer achieved with gel permeation chromatography was monomodal and the molecular weight of the polymer was about 14,000. According to the proton nuclear magnetic resonance spectrum with heavy methanol of the polymer achieved, it was confirmed that this polymer was a heterotelechlic oligomer which it had both units, polyethylene oxide (PEO) and poly-2-hydroxyethyl methacrylate (PHEMA), and had an amino group quantitatively on the a-terminal part. The chain length of the block polymer, determined by integral spectrum ratio was 8800 for PEO and approximately 7000 for PHEMA. The results of the proton nuclear magnetic resonance spectrum are as follows: 1 H-NMR (DMSO). d (ppm) 1.9-1.3 (a: 150 H) 2.0 (b: 100 H) 2.8 (c: 2 H) 3.6 (d: 800 H) 3.8 (e: 100 H) 4.1 (f: 100 H) EXAMPLE 4 Preparation of a polymer represented by the following formula: 0 0 ebcce J djd H0CCH2CH20 (CH2CH20) m - (CCH0CCH0) n - H 0 CH3 CH3 aa 20 ml of THF, 0.13 g of tert-butoxycarbonylethanol and 0.5 mole of potassium naphthalene / 2 ml of water were added to a reactor. solution of L-tetrahydrofuran, and stirred for 3 minutes in an argon atmosphere; The potassium compound of terbutoxycarbonyl ethanol (potassium tert-butoxycarbonylethoxide) was produced. 8.8 g of ethylene oxide was added to this solution and stirred at room temperature and at 1 atm. After reaction for 2 days, 7.2 g of lactide was added to this reaction solution, and stirred for another hour. After removal of the solvent of the reacted solvent, 50 ml of 1 N hydrochloric acid was added and stirred for 2 hours at room temperature, and the protective group was removed; then this was poured into cold propanol and the polymer produced was precipitated. The precipitate achieved with centrifugal separation was refined by freeze drying from benzene. The yield was 14.0 (88%). The polymer achieved with gel penetration chromatography was monomodal and the molecular weight of the polymer was about 14,000.

According to the proton nuclear magnetic resonance spectrum with heavy chloroform of the polymer achieved, it was confirmed that this polymer was a heterotelequélico olígómero that had both units, polyethylene oxide (PEO) and polylactide (PL), and had a group quantitatively carboxyl on α-terminal and hydroxyl group on the omega-ter inal part. The chain length of the block polymer, determined by integral spectrum ratio was about 8000 for PEO and about 6000 for PL. The results of the proton nuclear magnetic resonance spectrum are as follows: i H-NMR (DMSO). d (ppm) 1.6 (a: 252 H) 2.4 (b: 2 H) 3.6 (c: 730 H) 5.2 (d: 84 H) 9.8 (e: 1 H) EXAMPLE 5 Preparation of a polymer represented by the following formula: 0 0 a b b b I c | c HSCH2CH20 (CH2CH20) m - (CCH0CCH0) n - HC: HH33 CCfH3 aa 20 ml of THF, 0.13 g of benzylthiol and 0.5 mole of potassium naphthalene / 2 ml of L-tetrahydrofuran solution were added to a reactor, and stirred for 3 minutes in an argon atmosphere; the potassium benzylthiol compound (benzyolthiopotasium) was produced. 8.8 g of ethylene oxide was added to this solution and stirred at room temperature and at 1 atm. After reaction for 2 days, 7.2 g of lactide was added to this reaction solution, and stirred for another hour. After removal of the solvent from the reacted solvent, 50 ml of aqueous sodium borohydride solution was added and stirred for 2 hours at room temperature, and the protective group was removed; then this was poured into cold propanol and the polymer produced was precipitated. The precipitate achieved with centrifugal separation was refined by freeze drying from benzene. The yield was 14.5 (91%). The polymer achieved with gel penetration chromatography was monomodal and the molecular weight of the polymer was about 16,000. According to the proton nuclear magnetic resonance spectrum with heavy chloroform of the polymer achieved, it was confirmed that this polymer was a heterotelequic oligomer which it had both units, polyethylene oxide (PEO) and polylactide (PL), and had quantitatively a mercapto group on a-terminal and hydroxyl group on the omega-terminal part.

The results of the proton nuclear magnetic resonance spectrum are as follows: 1 H-NMR (DMSO). d (ppm) 1.6 (a: 300 H) 3.6 (b: 800 H) 5.2 (c: 100 H) EXAMPLE 6 Preparation of a polymer represented by the following formula: 0 0 ocddd S axis I f H2 N-CH2 CH20 (CH2 CH20) m - (CCH0CCH0) n --CC = CH2 CH3 CH3 CH3 aab 20 ml of THF, 0.15 g of 2-benzaliminoethanol and 0.5 were added to a reactor moles of potassium naphthalene / 2 ml of L-tetrahydrofuran solution, and stirred for 3 minutes in an argon atmosphere; the potassium compound of 2-benzaliminoethanol (potassium 2-benzaliminoethoxide) was produced. 8.8 g of ethylene oxide was added to this solution and stirred at room temperature and at 1 atm. After reaction for 2 days, 7.2 g of lactide was added to this reaction solution, and it was stirred for another hour. After removal of the solvent of the reacted solvent, 50 ml of 1 N hydrochloric acid was added and stirred for 2 hours at room temperature, and the protective group was removed; then this was poured into cold propanol and the polymer produced was precipitated. The precipitate achieved with centrifugal separation was refined by freeze drying from benzene. The yield was 14.0 g (88%). The polymer achieved with gel permeation chromatography was monomodal and the molecular weight of the polymer was about 15,000. According to the proton nuclear magnetic resonance spectrum with heavy chloroform of the polymer achieved, it was confirmed that this polymer was a heterotelequic oligomer which it had both units, polyethylene oxide (PEO) and polylactide (PL), and had quantitatively an amino group on a-terminal and methacryloyl group on the omega-terminal part. The chain length of the block polymer, determined by integral spectrum ratio was about 8000 for PEO and approximately 6800 for PL. The results of the proton nuclear magnetic resonance spectrum are as follows: i H-NMR (DMSO). d (ppm) 1.6 (a: 283 H) 1.9 (b: 3 H) 2.8 (c: 2 H) 3.6 (d: 800 H) 5.2 (e: 94 H) 5.7, 6.2 (f: 2 H) EXAMPLE 7 Preparation of a polymer represented by the following formula: 0 0 a e c c j d | d NC-CH2 CH2 CH2? - (CH2 CH2 0) m - (CCHOCCHO) n -H c H H33 CCH3 A reactor was charged with 20 ml of THF, 0.04 g of acetonitrile and 2 ml of dissolved potassium naphthalene solution tetrahydrofuran in a concentration of 0.5 mol / L-tetrahydrofuran, the resulting mixture was stirred for 3 minutes in an argon atmosphere and in this way, potassium cyanomethyl was formed. 4.4 g of ethylene oxide was added at the resulting resolution, which was then stirred at one atmosphere and at room temperature. The reaction was finished after 2 days of reaction, and 7.2 g of lactide was added to the reaction liquid, which was then allowed to react for an additional 1 hour. The solution produced in this way was poured into cold propanol, then the reaction solvent was distilled off, so that the polymer formed could be precipitated. The centrifuged precipitate was purified by freeze drying from benzene. The yield was 11.0 g (95%). Gel permeation chromatography taught that the obtained polymer was monomodal and had a number average molecular weight of about 11,000.

The results of the proton nuclear magnetic resonance spectrum are as follows: i H-NMR (DMSO). d (ppm) 2.4 (a: 2 H) 5 1.8 (b: 2 H) 3.6 (c: 400 H) 5.2 (d: 50 H) 1.6 (e: 150 H) 0 EXAMPLE 8 Preparation of a polymer represented by the following formula 0 0 or 5 J e NC-CH2CH2CH2? (CH2CH2! ??)) m, - (CCH u0CC 9 H0) "- CC = CH2 CH3 CH3 CH3 ffh" 0 A reactor was charged with 20 ml of THF, 0.04 g of acetonitrile and 2 ml of dissolved potassium naphthalene solution tetrahydrofuran at a concentration of 0.5 mol / L-tet rahidofofurano, and the resulting mixture was stirred for 3 minutes in an argon atmosphere and thus formed to form an aqueous solution. Potassium cyanomethyl, 4.4 g of ethylene oxide were added at the resulting resolution, which was then stirred at room temperature and the reaction was terminated after 2 days of reaction, and 7.2 g of lactide was added to the reaction liquid. Then, 10 hours of methacrylic acid anhydride were added to this system, which was then allowed to react for a further 2 hours at room temperature, the solution produced in this way was poured in cold propanol, then the solvent reacts The reaction was separated by distillation, so that the polymer formed could be precipitated. The centrifuged precipitate was purified by freeze drying from benzene. The yield was 10.5 g (91%). Gel permeation chromatography taught that the monomodal obtained polymer had a number average molecular weight of approximately 11,000. The results of the nuclear magnetic resonance spectrum of protons and carbon are as follows: i H-NMR (DMSO), d (ppm) 1.6 (f: 150 H) 1.8 (b: 2 H) 1.9 (h: 3 H) 2.4 (a: 2 H) 3.6 (c, d: 400 H) 5.2 (e: 50 H) 5.6 Hg: 2 H) 6.2 1 H-NMR (CDCl), d (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) * The figures in parentheses each correspond to the carbon atom in the following formula 9 0 0 12 1 2 3 4 5 5 6 7 i! 11 13 NC-CH 2 CH 2 CH 2? (CH 2 CH 2?) M -? - CH 2 CH 2 O - (CCHOCCHO) n- C C = CH 2 CH 3 CH 3 0 CH 3 10 14 EXAMPLE 9 Preparation of a polymer represented by the following formula 0 0 abcddd 1 e I e H2N-CH2CH2CH2CH2? - (CH2CH2?) M - (CCHOCCHO) n - H? CH3 CH3 ff 200 mg of the polymer obtained in Example 7 was dissolved in 40 ml of saturated ammonia-methanol, and The resulting solution was hydrogenated at 25 ° C and 35 atmospheres with the use of 0.5 g of Raney-Ni-W2. One hour later, the reaction solvent was distilled off and in this way the polymer was recovered with cold propanol. The yield of the polymer obtained by freeze drying from benzene was 180 mg (90%). Gel permeation chromatography taught that the obtained polymer was monomodal and had a number average molecular weight of about 11,000. The results of the proton and carbon nuclear magnetic resonance spectrum are as follows: i H-NMR (CDCls), d (ppm) 1.6 (b, f: 150 H) 1.8 (c: 2 H) 2.7 (a: 2 H ) 3.6 (d: 400 H) 5.2 (e: 50 H) 1 C-NMR (CDCl 3), d (ppm) 16.5 (10) 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) * The figures in parentheses each correspond to the carbon atom in the following formula 9 0 0 1 2 3 4 5 5 6 7 H2N-CH2CH2CH2CH2O- (CH2CH2?) M-l- - CH2CH2O- - (CCHOCCHO) n- • -H 8l CH3 l CH3 EXAMPLE 10 Preparation of the polymeric micelle A 50 mg sample of the block copolymer obtained in Example 1 was dissolved in water or in a regulated solution at its appropriate pH, so that the concentration could be 0.1 to 0.1% (w / v). With measurement of particle distribution by means of dynamic light screening, the formation of a single polymer micelle with an average grain diameter of 30 mm was confirmed in the solution. The critical micelle concentration of this polymer micelle was 10 mg / l. From the results of structure analysis, it was found that this polymer micelle is a new polymer micelle having an amino group on the surface of the micelle.

EXAMPLE 11 Preparation of the polymeric micelle A sample of 50 mg of block copolymer obtained in Example 4 was dissolved in water or in an appropriate solution regulated in its pH, so that the concentration could be 0. 01 to 0.1% (w / v). With measurement of particle distribution by dynamic light screening, the formation of a single polymer micelle with average grain diameter of 28 nm in the solution was confirmed. The critical micelle concentration of this polymer micelle was 11 mg / l. From the results of structural analysis, it was found that this polymer micelle was a new polymer micelle having a carboxyl group on the surface of the micelle.

EXAMPLE 12 Preparation of the polymeric micelle A sample of 50 mg of block copolymer obtained in Example 6 was dissolved in water, so that its concentration could be 0.01% (w / v). With measurement of particle distribution by dynamic light screening, the formation in the solution of a single polymer micelle with average grain diameter of 30 nm was confirmed. The critical micelle concentration of this polymer micelle was 10 mg / l. 0.01 g of benzoyl peroxide was dissolved in this micelle solution and reacted for 5 hours at 80 ° C. After the reaction, it was subjected to dialysis against water with a membrane filter of fractional molecular weight of 12,000, and from the results of structural analysis, it was found that this polymer micelle had an average grain diameter of 30 nm, without change from before the reaction. The diameter of the micelle was not changed yet by the addition of dodecyl sulfate, and it was confirmed that the micelles were effectively entangled. From the results of structural analysis, it was found that this polymer micelle was a new interlaced polymer micelle having an amino group on the surface of the micelle.

Industrial Applicability This invention provides a block polymer having at its two ends functional groups such as amino group, carboxyl group, hydroxyl group and mercapto group, which usually has a protein, and which under certain circumstances, has a vinyl group which can be polymerized subsequently. In addition, the balance between hydrophilicity and hydrophobicity in the molecule can be adjusted appropriately. Therefore, this block polymer can be used for sale in the field of the production and treatment of biocompatible materials. Furthermore, it is possible to efficiently bind molecules of living organisms, such as antibodies, to the polymeric micelle compounds which are produced from the above polymer and which have on their surface groups functions such as amino group, carboxyl group and mercapto group, since said micelle It has the following characteristics: 1) .- Drugs can be introduced into the core of the micelle; 2) .- Due to the omega-terminal functional group, a stable interlaced micelle can be prepared (nanosphere); and 3) .- The surface functional groups are stable in water and are capable of reacting with amine or thiol. On the other hand, it is known that the chain of polyethylene oxide, polyglycolic acid and polylactone, which are segments that make up the block polymer of this invention, are each decomposed in a living organism, and therefore, can be freely changing the electric charge on the surface of the polymeric micelle. Of these facts, the present inventors can expect that the polymeric micelle compounds provided by this invention and having on their surface functional groups, will be applicable as i) vehicle for drug delivery to a certain organ, and ii) medicine such as a diagnostic nanosphere. Therefore, there is a possibility that this invention will be applied in the field of medical treatment.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A block polymer that is represented by the following formula (I): XO- (CH2CH20) m- (Y) n -Z (I) wherein X denotes an alkyl group having from 1 to 10 carbon atoms, having one or two substituents selected from the group consisting of amino group blocked with an amino protecting group, carboxyl group blocked with a carboxyl protecting group and mercapto group blocked with a mercapto protecting group, or phenyl or phenylalkyl group having the substituents mentioned above on the benzene ring; And denotes a group selected from the group consisting of the following recurring units: o o o II 11 II -CCHOCCHO-. -C (CH.) Q-0- I I R1 R2

R3 R3 | | -CH2C- o. -CH2C- I I

COOR4 CN wherein R1 and R2 independently denote a hydrogen atom or alkyl group having from 1 to 5 carbon atoms;

R3 denotes a hydrogen atom or a methyl group; R denotes an alkyl group having from 1 to 5 carbon atoms, which is substituted with hydroxyl group under certain circumstances; q denotes an integer from 2 to 5; Z denotes a functional group selected from the group consisting of a hydrogen atom, an acryloyl group (CH2 = CH-C0-), a methacryloyl group (CH2 = C (CH3) -C0-), a vinylbenzyl group ^ CH_CH -? VCH? ~) an allyl group (CH2 = CH-CH2 ~), a p-toluenesulfonyl group

(CH, .SO, -) , a mercapto group, an alkyl group having an amino group which is mono- or disubstituted under certain circumstances with an alkyl group having from 1 to 5 carbon atoms, an alkyl group having a carboxyl group or its ester group, an alkyl group having acetal group and a halogen atom; and m and n denote independently an integer from 2 to 10,000. 2. The block polymer according to claim 1, characterized in that X denotes an alkyl group having from 1 to 10 carbon atoms, which is substituted with amino group, a carboxyl group or a mercapto group which are not blocked with a protective group. 3. The block polymer according to claim 1, characterized in that X denotes an alkyl group having 1 to 10 carbon atoms, which is substituted with: an amino group blocked with amino protecting group selected from the group consisting of of alkoxycarbonyl groups of 1 to 5 carbon atoms; a benzylidene group whose benzene ring is substituted under certain circumstances with an alkyl group having from 1 to 3 carbon atoms or with a halogen atom; a silyl group having 3 groups selected from the group consisting of alkyl group having from 1 to 3 carbon atoms and phenyl group; and cyano group, or carboxyl group blocked with a carboxyl protecting group selected from the group consisting of alkoxy of 1 to 5 carbon atoms; benzyloxy group; diphenylmethoxy group; Triphenylmethoxy group; and cyano group, or a mercapto group blocked with a mercapto protecting group selected from the group consisting of phenyl and benzyl. 4. The block polymer according to claim 1, characterized in that X denotes an alkyl group having 1 to 10 carbon atoms, which is substituted with an amino group blocked with an amino protecting group which is the benzylidene group , the tri-ethylsilyl group or the cyano group, or is substituted with a carboxyl group blocked with a carboxyl-protecting group which is the tert-butoxy group. 5. The block polymer according to claim 1, characterized in that X denotes an alkyl group having 1 to 10 carbon atoms, which is substituted with an amino group or a carboxyl group, which are not blocked with a group protective.

6. - The block polymer according to claim 1, characterized in that Y denotes recurring units represented by the following formulas: 0 0 0 0 II II II II -CCH2OCH20-, -CCHOCCHO- I I CHs CHs or O II II -C- £ CH27s-0-, -C- ^ CHzJi-O- CH3 -CH2-CH- or ..- -CH8-C- I I C O O alk C O O alk in which alk denotes an alkyl group having from 1 to 3 carbon atoms, which is substituted, under certain circumstances, with a hydroxyl group.

7. The block polymer according to claim 1, characterized by Z denotes a hydrogen atom, an alcryloyl group or a methacryloyl group.

8. An active block polymer represented by the following formula (II): Xa -0- (CH2CH2?) M - (Y) n -? - YaM + (II) in which Xa denotes an alkyl group having 1 to 10 carbon atoms, having one or two substituents selected from the group consisting of amino group blocked with an amino protecting group, carboxyl group blocked with a carboxyl protecting group and mercapto group blocked with a mercapto protecting group, or denotes phenyl or phenylalkyl group having the substituents mentioned above on the benzene ring; And and already denote a group selected from the group consisting of the groups represented by the following formulas 0 II -C- O9 0 0 II II C CH2 hg-0O- and -CCCHz rO® R3 R3 I 1 CH2- -C- T -CH2-C iU T | | CN CN wherein R and R2 independently denote a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; R3 denotes a hydrogen atom or a methyl group; R denotes an alkyl group having from 1 to 5 carbon atoms, which is substituted with hydroxyl group under certain circumstances; q denotes an integer from 2 to 5; M + denotes an alkali metal cation selected from the group consisting of lithium, sodium, potassium and cesium; and m and n denote independently an integer from 2 to 10,000.

9. A method for producing the block polymer according to claim 1, comprising the following steps: (1) a step in which the active block polymer represented by the following formula (II): Xa-0- (CH2CH2?) M - (Y) n -? - YaM + (II), in which Xa denotes an alkyl group having from 1 to 10 carbon atoms, having one or two substituents selected from the group consisting of group amino blocked with an amino protecting group, carboxyl group blocked with a carboxyl protecting group and mercapto group blocked with a mercapto protecting group, or denotes phenyl or phenylalkyl group having the aforementioned substituents on the benzene ring; Y and Y denote a group selected from the group consisting of the groups represented by the following formulas 0 0 0 0 II II II II -C-CHOCCHO- and -C-CH0CCH00 I I I I R »R2 R1 R2 R3 R3 1 1 -CH2- -C- -CH2- | | CN CN wherein R1 and R2 independently denote a hydrogen atom or an alkyl group having from 1 to 5 carbon atoms; R3 denotes a hydrogen atom or a methyl group; R * denotes an alkyl group having 1 to 5 carbon atoms, which is substituted with hydroxyl group under certain circumstances; q denotes an integer from 2 to 5; M + denotes an alkali metal cation selected from the group consisting of lithium, sodium, potassium and cesium; and m and n denote independently an integer from 2 to 10,000; it is reacted in an inert solvent with an electrophile which is represented by the following formula: Rs I A-C0C = CH2 s -SW; (OV CH or D-CH2-Q, in which A denotes a group that forms an active ester, D denotes chlorine, bromine or iodine, and Q denotes -CH2 CH2 (OCH3) 2. (2) One step to convert, if necessary, linked to Ya in a mercapto group, an amino group which is mono- or di-substituted under certain circumstances with an alkyl group of 1 to 5 carbon atoms, a carboxyl group or a halogen atom, by the use of a nucleophilic reagent corresponding, and (3) a step to eliminate, if necessary, the protective group of Xa.

10. A polymeric micelle comprising the block polymer according to claim 1 as an effective ingredient.