Heterocalixarenes block copolymer and its production method

 

(57) Abstract:

Describes the new heterocalixarenes block copolymer that is represented by formula I, in which R1and R2connected together, means Ethylenedioxy (-O-CH(R')-CH2-Oh, in which R' means a hydrogen atom or a C1-6-alkyl), which can be substituted C1-6-alkyl, or in combination with each other means oxoprop (=O), L is a group (a), in which R3and R4independently mean a hydrogen atom, a C1-10is alkyl, aryl or aryl-C1-3is alkyl and r is an integer from 2 to 5, m means an integer from 2 to 10000, n means an integer from 2 to 10000, p is an integer from 1 to 5, q denotes an integer from 0 to 20, Z means that when q is zero, the hydrogen atom, alkaline metal, acetyl, acryloyl, methacryloyl, cynnamoyl, paratoluenesulfonyl, 2-mercaptopropionyl or 2-aminopropionic, or allyl, or vinylbenzyl, while, when q is an integer from 1 to 20, Z means WITH1-6-alkoxycarbonyl, carboxy-, mercapto - or amino group. The above-described oligomer or polymer to form a high-molecular micelle, which is stable in aqueous solvent. These oligomer or polymer may be useful as noiazei live circuits. 3 S. and 9 C. p. F.-ly, 1 tab., 8 Il. (a)

The present invention relates to heterodimerisation block-copolymer, which has a different functional groups at both ends of the molecule, to the method of its production and to its use for obtaining high-molecular micelle. More specifically, this invention describes a polymer, which has a different functional groups at both ends of the molecule and at the same time contain in the main chain of the polyethylene oxide as a hydrophilic segment and a polyester as a hydrophobic segment.

In this invention the term "polymer" includes oligomer.

Art

Currently, high-molecular micelle or nanospheres consisting of a block copolymer of hydrophilic/hydrophobic type, in which the hydrophilic polymer type polyethylene oxide is combined with a hydrophobic polymer at the molecular level, attract attention as a carrier when applying medication or similar Such macromolecular micelles and nanospheres were prepared from the block copolymer of hydrophilic/hydrophobic type, in which the hydrophilic polymer type polyethylene oxide is combined with a hydrophobic polymer at the molecular level.

However, the species introduced functional end groups, and were offered only block copolymers, in which functional groups were limited metaxylene and hydroxyl groups. If it were possible to carry out the introduction of the optional functional groups on the surface of the micelles in the selected ratio, it would be possible to develop functional macromolecular micelles, which could be useful for delivery of drugs to specific organs.

The closest analogue of the present invention is WO 95/03357, which describes particles that are not eliminated quickly from the blood stream by the macrophages reticuloendothelial system and can be modified to achieve different speeds of release or for admission to need certain cells or organs. Particles are biodegradable solid core containing a biologically active material and poly(acceleglove) groups on the surface.

In WO 95/03357 noted that protein, e.g. antibody, is connected through the terminal hydroxy group was alkylated poly(alkalophiles) that forms the surface of the particles. In WO 95/03357, however, not specified, not planned, such a block polymer as in the present invention, which has an aldehyde group at the end of the poly(ethylene glycol) (ospecialisto in this area, aldehyde group (-CHO) is easily converted into imine connection via a Schiff base, as shown in the following equation:

< / BR>
Thus, since the polymer of the present invention can easily form a polymer-protein conjugates by an amino group, which exists, for example, in the protein specified polymer of the present invention can be used much more convenient, for example, by modifications of the protein than the polymer specified in WO 95/03357.

Thus, the polymer of the present invention clearly differs from the prior art.

The aim of the present invention to provide a block copolymer, which has a different functional groups at both ends of the molecule, as a multifunctional polymer, capable of forming high-molecular micelle.

Description of the invention

The authors of the present invention found that it is possible to easily obtain a block copolymer having a protected or unprotected aldehyde group at one end of the molecule and various functional groups at the other end, when Allenova derivative having a specific type aldehyde group and a hydroxyl group is used Kli lactone.

They also confirmed that the thus obtained block copolymer forms a high-molecular micelle, which is quite stable in aqueous solvent.

This invention provides heterocalixarenes block copolymer, which has a different functional groups at both ends of the molecule and which is represented by the following formula:

< / BR>
in which R1and R2independently mean C1-10-alkoxy, aryloxy or aryl-C1-3-alkyloxy or R1and R2in combination with each other means Ethylenedioxy (-O-CH(R')-CH2-O-in which R' means a hydrogen atom or a C1-6-alkyl), which can be substituted C1-6-alkyl, or in combination with each other means oxoprop (=O), L stands for a group

< / BR>
in which R3and R4independently mean a hydrogen atom, a C1-10is alkyl, aryl or aryl-C1-3is alkyl and r is an integer from 2 to 5, m means an integer from 2 to 10000, n means an integer from 2 to 10000, p is an integer from 1 to 5, q denotes an integer from 0 to 20,

Z means that when q is zero, the hydrogen atom, alkaline metal, acetyl, acryloyl, methacryloyl, cynnamoyl, paratoluenesulfonyl, 2-mercaptopropionyl or 2-aminopropionic, Il, mercapto or amino group.

In another aspect this invention provides a method of obtaining the block copolymer of the above formula (I), and this method includes the following stages:

Stage 1)

The polymerization initiator represented by the following formula (II)

< / BR>
in which R1-1and R2-1independently mean C1-10-alkoxygroup or in combination with each other means Ethylenedioxy, which may be substituted C1-6-alkyl, p is an integer from 1 to 5 and M means alkaline metal,

forced to interact with ethylene oxide so that it was possible to obtain the compound represented by the following formula (III):

< / BR>
in which R1-1, R2-1, p and M are such as defined in the formula (II), and m means an integer from 2 to 10000.

Stage 2)

The compound of formula (II) is allowed to react with lactide or lactone, which is represented by the following formula (III-a) or (III-b):

< / BR>
or

< / BR>
in which R3and R4independently mean a hydrogen atom, a C1-10is alkyl, aryl or aryl-C1-3is alkyl and r is an integer from 2 to 5,

thus, in order to obtain the compound represented by the following forms of the above.

The above stage provides obtaining of a live chain of the polymer of this invention (which is included in the polymer of formula (I)), which is used as intermediate compounds for the further expansion of a number of polymer segments, etc.

Stage 3)

i) an alkali metal Alkoxide of the formula (IV) selectively hydrolyzing, receiving the block copolymer of the following formula (V):

< / BR>
in which R1-1, R2-1, p, m, L and n are such as defined above; or

ii) a block copolymer of the formula (IV) fully hydrolized, receiving the block copolymer of the following formula (VI):

< / BR>
in which p, m, L and n are such as defined above.

The above stage provides obtaining the block copolymer of this invention, which has a protected aldehyde group or aldehyde group at the beginning of the polymer chain (terminal group) and a hydroxyl group at the end of the chain (terminal group).

Stage 4)

The block copolymer of the formula (V), which has a protected aldehyde group at the beginning of the polymer chain, allow to react with

i) acetic acid, acrylic acid, methacrylic acid, cinnamic acid or paratoluenesulfonyl acid, ili) halide, represented by the following formula (VII):

< / BR>
in which X represents a chlorine atom, bromine or iodine, q' is an integer from 1 to 20 and Z' is C1-6-alkoxycarbonyl or protected amino group;

with the formation of the block copolymers of this invention, each of which has a corresponding functional group different from the hydroxyl group at the end of the macromolecular chain.

Stage 5)

Obtained in stage 4)-(i) the ether paratoluenesulfonyl acid can be subjected to a further transformation, by means of transesterification, the block copolymer having other functional groups (for example, mercapto - or amino-) at the end of the polymer chain (). The block copolymer, which has eldegizids group or carboxylamide group and which was obtained by the above stages, can be converted by hydrolysis in the block copolymer of this invention in which one of the protecting groups or all protecting groups removed.

In accordance with another concept, this invention provides a high-molecular micelle based on the use of the block copolymer of the formula (I).

Part of the thus obtained heterocalixarenes polymers will be seen from their constituent components, it can be expected that these polymers will have a biological affinity and high biological suitability. Therefore, they can be used for the production of materials directly introduced into living organisms, such as media for delivering drugs. Moreover, in accordance with the third purpose of the invention it is high-molecular micelle, which is quite stable in aqueous solvent. Therefore, the polymer of this invention is also effective for delivering drugs to specific organs.

Brief description of drawings

In Fig. 1 shows the gel permeation chromatogram for preferenced/polylactide block copolymer with acetamino-terminal group and a hydroxyl terminal group (sample of Example 1).

Operating conditions: T - es - Kay - Gel G4000HXL, G3000HXL, G2500HXL)

Eluent: tetrahydrofuran containing 2% of triethylamine

Flow rate: 1 ml/min

In Fig. 2 shows the spectrum of proton nuclear magnetic resonance (PMR) polyethylene oxide/polylactide block copolymer with acetamino-terminal group and a hydroxyl terminal group (sample of Example 1).

In Fig. 3 presents a range of proton magnetic resoiling-terminal group (the sample of Example 3).

In Fig. 4 presents a range of proton magnetic resonance polyethyleneoxide/polylactide block copolymer with aldehyde-terminal group and a hydroxyl terminal group (the sample of Example 4).

In Fig. 5 presents a range of proton magnetic resonance polyethyleneoxide/polylactide block copolymer with acetamino-terminal group and methacryloyloxy-terminal group (the sample of Example 5).

In Fig. 6 presents a range of proton magnetic resonance polyethyleneoxide/polylactide block copolymer with acetamino-terminal group and allyl-terminal group (the sample of Example 6).

In Fig. 7 presents a range of proton magnetic resonance polyethyleneoxide/polylactide block copolymer with acetamino-terminal group and paratoluenesulfonyl-terminal group (the sample of Example 7).

In Fig. 8 shows the size distribution of particles of high-molecular micelle found using dynamic laser scattering in aqueous solution of polyethylene oxide/polylactide block copolymer with aldehyde -terminal group and a hydroxyl terminal group (the sample of Example 4).

Paramgroup with a linear or branched chain. Therefore, the alkyl part is C1-10-alkoxygroup or C1-10the alkyl in the formula (II) and (III-a) include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, out-of pentyl, hexyl, 2-methylpentyl, 3-methylpentyl, octyl, 2-ethylhexyl, decyl and 4-propylpentyl. Of these alkyl part in alkoxygroup R1and R2preferably is alkyl (C1-6in particular alkyl (C1-3.

Therefore, particularly preferred examples of alkoxygroup R1and R2include methoxy, ethoxy-, propoxy -, isopropoxy-. Examples R1and R2include aryl, especially phenyl, and aryl (C1-3-alkyl, especially benzyl or phenethyl. These groups may be the same or different, but preferably they are the same. Although R1and R2in combination with each other can mean Ethylenedioxy (-O-CH(R')-CH2-O-, in which R' means a hydrogen atom or a C1-6-alkyl), which can be substituted C1-6-alkyl, preferably they are Ethylenedioxy, propylenediene - or 1,2-butylenediamine.

When the hydrolysis of the substituents R1and R2conveniently combined with the formation of the carbonyl group (= O), or in other words, with the formation of b is P> The symbol "p" in the formula (I) means an integer from 1 to 5. Due to the fact that the segment

< / BR>
produced from the polymerization initiator (see the formula (II)), in the process of this invention R1, R2and p is preferably chosen so that this segment amounted to block acetamino groups, such as dimethoxymethane-, 2,2-dimethoxyethoxy-, 3,3-dimethoxypropane-, 4,4-dimethoxyethoxy, diethoxymethane-, 2,2-diethoxyethane-, 3,3-diethoxypropane-, 4,4-diethoxybutane, disproportionate-, 2,2-disproportiate-, 3,3-dipropoxy - or 4,4-disproportionate-.

The radicals R3and R4can mean either a hydrogen atom or a C1-10-alkyl, or aryl, or aryl-C1-3-alkyl, since they are suitable for the purpose of this invention. However, from the point of view of biological suitability preferred is a hydrogen atom (made from glutaric acid) and methyl (produced from lactic acid).

In accordance with the method of obtaining, using living polymerization circuits of this invention, the character "m" in the formula (I) can theoretically take any value, if set, the quantitative ratio of Monomeric ethylene oxide and initiator of polymerization. However, on the segment could impart hydrophilicity of the block copolymer of this invention, preferably, m is an integer equal to at least 10. Order easily achieve a narrow molecular weight distribution this segment and provide excellent biological suitability of the block copolymer m is an integer equal to at least 500, preferably at least 200.

As for the sign "n", which means the molecular weight of the polyester segment of the formula (I), its optimum value varies depending on the properties of the groups R3and R4as can be understood from the fact that this segment mainly imparts hydrophobicity of the block copolymer of this invention. Following the polymerization method of this invention, n may take any value, in the same way as in the case of polietilenoksidnoy segment. Therefore, the value of n is not limited. However, it usually takes from 2 to 10000.

Moreover, to maintain a good balance of hydrophilicity and hydrophobicity relative to polietilenoksidnoy segment integer m preferably assumes values from 10 to 200, in particular from 10 to 100.

The segment of formula (I) mainly discusses functional group or reactive group)- terminal group of the block copolymer atzeni polyester segment), Z may be an alkaline metal. In this case, the polymer of this invention can be a "living" polymer. As such, the polymer of this invention can act as the initiator for further polymerization of the living chains, it is used as a precursor to polymers of various types. From this point of view, examples of the alkali metal include sodium, potassium and cesium.

Above the living polymer can easily provide a polymer in which Z signifies a hydrogen atom (or polymer that has a hydroxyl group in a-position), as alcoholate part of the living polymer is easily hydrolyzed. The specified hydroxyl group may be further transformed into other functional groups using a variety of reactions, such as esterification of the acid or alcohol. Thus, when q is zero, Z may be an acetyl (-COCH3), acryloyl (-COCH=CH2), methacryloyl (-COC(CH3)=CH2), cynnamoyl (-CHCH= CH-phenyl), and paratoluenesulfonyl (SO2-phenylene-CH3and, in addition, may be allyl (-CH2-CH=CH2and vinylbenzyl (-CH2-phenylene-CH=CH2). When these functional groups are ethylene unsaturated bond, using a given communication can be converted into another functional group by a known method using the transesterification. Therefore, Z can be 2-mercaptopropionyl or 2-aminopropionic.

When q is an integer from 1 to 20, preferably from 1 to 4, particularly preferably 2, segment block means, for example, C1-6-alkoxy (e.g. methoxy, ethoxy - or propoxy-) carbonyl-methyl, -ethyl or-propyl, or 2-amino-ethyl, carboxy-methyl, -ethyl or-propyl.

In the example in the end of the description table lists examples of the block copolymers of this invention, which include the aforementioned substituents (or segments) in various mutual combinations.

The above-mentioned heterocalixarenes block copolymers, which can be represented by this invention effectively obtained by the method of this invention, which is illustrated by the reaction schemes (see below).

Obtain (B) from (A)

The acetal - protected alkoxide of an alkali metal (A) is forced to interact with the ethylene oxide with the formation of compound (B) to which is added polietilenoksidnoy segment. The compound (A) can be prepared by treating the acetal - protected alcohol gas metallizing reagent, such as an alkaline metal such as sodium or potassium; an ORGANOMETALLIC compound, such naphthas is potassium.

The above transformation (A) (B) shall take place without solvent or preferably in an anhydrous aprotic solvent and in a wide temperature range, for example from -50 to 300oC, preferably 10-60oC, conveniently at room temperature (20-30oC). This reaction can be carried out at elevated or at reduced pressure. Non-limiting examples of applicable solvents include benzene, toluene, xylene, tetrahydrofuran, dioxane and acetonitrile. Non-limiting examples of reactors include a round bottom flask, autoclave and sealed pressure tube. Preferably the reactor is hermetically sealed from air and more preferably filled with inert gas. The concentration of the reacting liquid is from 0.1 to 95 wt.%, preferably from 1 to 80 wt.%, most preferably from 3 to 10 wt.%.

Receiving (C) from (B)

The reaction mixture containing (B), allow to react with lactide or lactone with the formation of human chain block copolymer (C), in which the polyester segment is added at the terminal hydroxyl group of polyethylene oxide. Conditions for this reaction can be almost the same as for the previous transformation (A) (B). Used La 4 in group L of formula (I). Non-limiting examples of lactides include lactide of lactic acid and lactide and glycolic acid. On the other hand, examples of suitable lactones include beta-propiolactone, gamma-butyrolactone, Delta-valerolactone and Epsilon-caprolactone. Among them, preferred from the viewpoint of good reactivity, are γ-butyrolactone and δ-valerolactone.

In the above stages, the molar ratio of the polymerization initiator to ethylene oxide, lactide or lactone is from 1:1 to 1:10000, more preferably from 1:5 to 1:10000, most preferably from 1:10-200 to 1:50-200.

The method of this invention not only makes it possible to regulate the molecular weight of each segment in accordance with the ratio of the polymerization initiator used menomaru, but also provides monodisperse or modal block copolymer in which each of the received segments has a very narrow molecular weight distribution.

Received the above way of living polymer (C) is included in the scope of protection of the polymer of this invention. However, the alcoholate (C) may be converted (i) in the polymer D by partial hydrolysis in mild conditions is the situation and hydroxyl group in the terminal position, by processing C in the conditions in which acetaline group can be either hydrolyzed. This hydrolysis reaction can be carried out with or acids, such as triperoxonane acid, hydrochloric acid, sulfuric acid, nitric acid, formic acid and hydrofluoric acid, or alkalis such as sodium hydroxide and potassium hydroxide, and, if necessary, under heating.

Obtaining (E)-(G) from (D)

Initiate interaction D

i) acetic acid, acrylic acid, methacrylic acid or paratoluenesulfonyl acid with the formation of terminal acyl connection terminal group in a-position, or

ii) halide represented by the formula (V)

halogen-E,

where the halogen - and E in the formula (V) correspond to groups different from the acyl group in the unit of formula (I), with the formation of the essential connection terminal group in a-position.

The above reaction can be carried out using known processes of esterification of the acid or alcohol. As for the organic acid in the above stage i), it is convenient to use a reactive derivative of an organic acid, Taku is here, it is effective to initiate the interaction paratoluenesulfonyl connection F with an electrophilic reagent, such as thioacetic sodium, thioacetal potassium or potassium hydrosulfide, so that the thioester group you can enter in-terminal group, and then this thioester group treated with acid or alkali, and after that it is possible to obtain a polymer represented by the formula G.

When it is necessary to introduce the amino-terminal part, it is effective to initiate hydrolysis of compound D using the electrophilic reagent, such as N-(2-bromacil)phthalimide, N-(3-bromopropyl)phthalimide, 1-bromo-2-(aminobenzoyl)ethane or N-(2-bromacil)benzylcarbamoyl, and then carry out the treatment with an acid or alkali in order to remove groups of R1and R2and to simultaneously hydrolyze-terminal kidney communication, and thus can be obtained a polymer which contains-terminal amino group.

Deleting groups R1and R2of polymers D, E, F and G, with the aim of obtaining aldehyde end-group in the-position, can be carried out in the above-mentioned transformations C and D'. With regard to the allocation of the polymer from the liquid reaction mixture, it is th, dialysis, ultrafiltration, or etc.

In the same way were obtained heterocalixarenes block copolymers of various types, represented by the formula (I) of this invention. The obtained polymers (with the exception of the living polymer) capable of forming high-molecular micelles, which are very stable in aqueous solvent.

This macromolecular micelle can be obtained, for example, as a result of exposure to the solution or suspension of the polymer in organic solvent, thermal and ultrasonic processing, separately or in combination. Heat treatment is carried out by dispersing or dissolving a mixture of one or more types of block copolymers of this invention in water at a temperature in the range from 30 to 100oC, more preferably from 30 to 50oC. the sonication carried out by dispersing or dissolving a mixture of one or more types of block copolymers of this invention in water when the power being in the range from 1 to 20 watts for 1 second to 24 hours, preferably in the range from 1 to 3 watts for 3 hours

Processing organic solvent is realized by means of the solution of the aqueous solution in water, followed by evaporation of the organic solvent. Examples of organic solvents include chloroform, benzene, toluene, methylene chloride, etc.

In addition, you can obtain high-molecular micelles of this invention by dissolving the aforementioned mixture in methanol, ethanol, tetrahydrofuran, dioxane, dimethylsulfoxide, dimethylformamide or similar solvent, and then the resulting solution is subjected to dialysis relative to the aqueous solvent. Fractional molecular weight of the membrane used for dialysis, is not limited, since its optimum value varies in accordance with the molecular weight of the block copolymer that is to be processed. However, it is usually a fractional molecular weight of the membrane is not more than 1,000,000, preferably from 5,000 to 20,000.

As the aqueous solvent can be used water and buffer solution. The ratio of the used aqueous solution to the above organic solvent by dialysis is usually from 1 to 1000 times, preferably from 10 to 100 times. Temperature is not specifically limited. Usually the treatment is carried out at 5 - 25oC.

Thus obtained high molecular micelles of this invention have a critical concentration of micelles is not above 4 - is a, which was examined in detail as a carrier for delivering drugs. This means that when introduced into the blood macromolecular micelles of this invention can be expected that it will have a much more typical life time in the blood, and thus, we can say that the polymer of this invention has excellent properties as a carrier for delivering drugs.

Below, this invention is explained in detail by working examples, however, these working examples in no way limit the scope of protection of this invention.

Example 1

In a reaction chamber is injected 20 ml of tetrahydrofuran, 0.15 g of 3,3-diethoxypropane and 2 ml of a 0.5 molar solution naphthalenide in tetrahydrofuran and stirred for 3 minutes in an argon atmosphere; receive 3,3-diethoxypropane potassium.

To this solution was added 8.8 g of ethylene oxide and stirred at room temperature and atmospheric pressure. After interaction within 2 days added to this reaction solution lactide in the amount of 7.2 g and then stirred for 1 hour. This solution was poured into a chilled propanol, precipitating the resulting polymer. This sediment allocate method centrifugation and purified by leofiles modal, its molecular weight is equal to 16000 (Fig. 1).

In accordance with the spectrum of proton nuclear magnetic resonance (PMR) of the polymer obtained in deuterium chloroform was determined that he is heterocalixarenes the oligomer having polietilenoksidnoy and polylactide blocks, and quantitatively contains acatalog group-end portion and a hydroxyl group-terminal part (Fig. 2). Srednetsenovoj molecular weight of each segment of the block polymer, was found in integral relation in the spectrum equal to 8800 for polyethylene oxide and 7000 for polylactide.

Example 2

In a reaction chamber is injected 20 ml of tetrahydrofuran, 0.15 g of 3,3-diethoxypropane and 2 ml of a 0.5 molar solution naphthalenide in tetrahydrofuran and stirred for 3 minutes in an argon atmosphere; receive 3,3-diethoxypropane potassium.

To this solution was added 5.7 g of ethylene oxide and stirred at room temperature and atmospheric pressure. After interaction within 2 days added to this reaction solution of 7.2 g of lactide and then stirred for 1 hour. This solution was poured into a chilled propanol, precipitating the resulting polymer. This sediment allocate by centrifuging and purify the medium is the her, is modal, with a molecular weight equal to 12,000.

In accordance with the spectrum of proton nuclear magnetic resonance of the polymer obtained in deuterium chloroform was determined that he is heterocalixarenes the oligomer having polietilenoksidnoy and polylactide blocks, and quantitatively contains acatalog group-end portion and a hydroxyl group in the end. Srednetsenovoj molecular weight of each segment of the block polymer, was found in integral relation in the spectrum is equal to 5400 for polyethylene oxide (PEO) and 6600 for polylactide (PL).

Example 3

In a reaction chamber is injected 20 ml of tetrahydrofuran, 0.15 g of 3,3-diethoxypropane and 2 ml of a 0.5 molar solution naphthalenide in tetrahydrofuran and stirred for 3 minutes in an argon atmosphere; receive 3,3-diethoxypropane potassium.

To this solution was added 8.8 g of ethylene oxide and stirred at room temperature and atmospheric pressure. After interaction within 2 days added to this reaction solution of 5.0 g of Delta-valerolactone and stirred for 1 hour. This solution was poured into a chilled propanol, precipitating the resulting polymer. This sediment allocate method centrifugating permeation chromatography, is modal, its molecular weight is equal to 14000.

In accordance with the spectrum of proton nuclear magnetic resonance of the polymer obtained in deuterium chloroform was determined that he is heterocalixarenes the oligomer having polietilenoksidnoy and poly(Delta-valerolactone) blocks, and quantitatively contains acatalog group-end portion and a hydroxyl group-terminal part (Fig. 3). Srednetsenovoj molecular weight of each segment of the block polymer, was found in integral relation in the spectrum equal to 8800 for polyethylene oxide and 5200 for poly (Delta-valerolactone).

Example 4

Add 50 ml of 2-molar hydrochloric acid to 50 ml of methanol, in which is dissolved a sample of the block copolymer obtained in Example 2, the mixture is stirred for 1 hour at room temperature. After this, the solution is neutralized with an aqueous solution of sodium hydroxide and 4 hours to put his dialysis (fractional molecular weight of 1000) with respect to 20-fold amount of water and purified by means of freeze drying. The yield of 0.85 g (85%). It is established that the molecular weight of the polymer, isolated by gel-permeation chromatography, has not changed compared to the MoA of the polymer obtained in deuterium chloroform there is no acetaline group-end part and instead there peak, due to the aldehyde. It is established that the product is heterocalixarenes PEO/PL-oligomer containing aldehyde group-end portion and a hydroxyl group-terminal part (Fig. 4).

Example 5

Add 20 ml of pyridine and 1 g of methacrylic anhydride acid to 20 ml of chloroform, in which is dissolved 1 g of sample of the block copolymer obtained in Example 2 and the mixture is stirred for 24 hours at room temperature. After this, the solution is neutralized and washed with an aqueous solution of hydrochloric acid. Chloroformate phase was poured into a chilled propanol, precipitating the resulting polymer. The residue is allocated by the method of centrifugation, purified by freeze drying from benzene. Yield 0.8 g (80%). It is established that the molecular weight of the polymer, isolated by gel-permeation chromatography, has not changed in comparison with the molecular weight to the response.

In accordance with the spectrum of nuclear (carbon) magnetic resonance imaging of the polymer obtained in deuterium chloroform in there is a complete absence of hydroxyl group in the terminal part and instead there are peak due methacryloyloxy group. It is established that the product is heterocalixarenes PEO is Asti (Fig. 5).

Example 6

Add 2 ml of a 0.5 molar solution naphthalenide in tetrahydrofuran and 5 ml of allyl bromide to 20 ml of tetrahydrofuran, in which is dissolved 1 g of the block copolymer obtained in Example 2 and the mixture is stirred for 4 hours at room temperature. The resulting product was poured into a chilled propanol, precipitating the resulting polymer. The residue is allocated by the method of centrifugation, purified by freeze drying from benzene. The yield of 0.98 g (98%). It is established that the molecular weight of the polymer, isolated by gel-permeation chromatography, has not changed in comparison with the molecular weight to the response.

In accordance with the spectrum of nuclear (carbon) magnetic resonance imaging of the polymer obtained in deuterium chloroform in there is a complete absence of hydroxyl group-end part and instead there peak, due to the allyl group. It is established that the product is heterocalixarenes PEO/PL-oligomer containing acatalog group-end portion and allyl group-terminal part (Fig. 6).

Example 7

Add 2 ml of a 0.5 molar solution naphthalenide in tetrahydrofuran and 5 g of paratoluenesulfonyl to 20 ml tetrahedronal temperature. The resulting product was poured into a chilled propanol, precipitating the resulting polymer. The residue is allocated by the method of centrifugation, purified by freeze drying from benzene. The product yield 0.95 g (95%). It is established that the molecular weight of the polymer, isolated by gel-permeation chromatography, has not changed in comparison with the molecular weight to the response.

In accordance with the spectrum of nuclear (carbon) magnetic resonance imaging of the polymer obtained in deuterium chloroform in there is a complete absence of hydroxyl group-end part and instead there are peak due paratoluenesulfonyl group. It is established that the product is heterocalixarenes PEO/PL-oligomer containing acatalog group-end portion and paratoluenesulfonyl group-terminal part (Fig. 7).

Example 8

Dissolve 50 mg of block copolymer obtained in Example 2, in water or a suitable buffer solution to achieve a concentration of 0.01 - 0.1 weight. /vol.%. When the formation of micelles in the solution is confirmed by the distribution of particle sizes measured by dynamic light scattering, was established the formation of a single polymer micelles with the mg/l

Example 9

Charged to the reactor 30 ml of tetrahydrofuran, with 0.13 g of 3,3-diethoxypropane and 2 ml of a 0.5 molar solution naphthalenide in tetrahydrofuran and the resulting mixture stirred for 3 minutes in an argon atmosphere; thus receive 3,3-diethoxypropane potassium.

To this solution was added 7.0 g of ethylene oxide, which is then stirred at room temperature and atmospheric pressure. After interaction within 2 days added to this reaction solution of 7.2 g of lactide of lactic acid, and then stirred the mixture for another 1 hour. Thus obtained solution was poured into a chilled propanol, precipitating the resulting polymer. Sediment, isolated by centrifuging, purified by freeze drying from benzene. The yield of 11.5 g (79%). The polymer, isolated by gel-permeation chromatography, is modal, it srednetsenovoj molecular weight of 11000.

Range of proton nuclear magnetic resonance of the polymer obtained in deuterium chloroform shows that he is heterocalixarenes the oligomer having polietilenoksidnoy and polylactide blocks, and quantitatively contains acatalog group-end portion and hydroximino hidenaga by the integral ratio in the spectrum, it is equal to 5800 for polyethylene oxide and 5100 for polylactide.

Dissolve 200 mg of the obtained block copolymer in 40 ml of dimethylacetamide, and the resulting solution is subjected to dialysis against water using a membrane for dialysis, having a fractional molecular weight of 12000 - 14000, within 24 hours (water was changed after 2.5 and 8 h, each time for 2 litres). Measurement by dynamic light scattering showed that the obtained solution was formed macromolecular micelles with an average particle size of 40 nm. The critical concentration of micelles for this polymer micelles is 5 mg/L.

Example 10

Added dropwise to 0.1 normal hydrochloric acid to 10 ml of micellar solution obtained in Example 9, so that the pH value was set equal to 2, and then the solution is stirred for 2 h at room temperature. After this, the solution is neutralized with 0.1 normal aqueous sodium hydroxide solution and then the resulting solution is subjected to dialysis against water using a membrane for dialysis, having a fractional molecular weight of 12000 - 14000, within 24 hours (water was changed after 2.5 and 8 h, each time for 2 litres). Measurement by dynamic light scattering showed that the floor is the acidity of the micelles for this polymer micelles is 5 mg/L.

This micellar solution was subjected to freeze drying and then the residue was dissolved in deutero-sulfoxide and investigated by NMR. It was found that the signal due to the presence acetamino group at 1.2 and 4.6 M. D., completely disappeared and that the observed signal is due to the presence of hydrogen methylanthranilic group and the hydrogen of the aldehyde group 2,7 (triplet) and 9.8 M. D. (singlet), respectively. From the ratio of the area of these signals was found that 95% of acetal hydrolethalus in the aldehyde.

Example 11

Dissolve 200 mg of block copolymer PEO/VL (srednetsenovoj molecular weight of each segment is equal to 4500 for polyethylene oxide and 13000 for polylactide) obtained in the same manner as in Example 1, in 40 ml of dimethylacetamide. The resulting solution is subjected to dialysis against water using a membrane for dialysis, having a fractional molecular weight of 12000 - 14000, within 24 hours (water was changed after 2.5 and 8 h, each time for 2 litres). Measurement by dynamic light scattering showed that the obtained solution was formed macromolecular micelles with an average particle size of 30 nm. The critical concentration of micelles for this polymer micelles is 4 mg/L.

1. Heterocalixarenes, block-copolymer, which is represented by the following formula:

< / BR>
in which R1and R2independently mean C1-10-alkoxy or aryl-C1-3-alkyloxy, or R1and R2connected together, means Ethylenedioxy (-O-CH(R')-CH2-O, in which R1means a hydrogen atom or a C1-6-alkyl), which may be substituted WITH1-6-alkyl, or in combination with each other, means oxoprop (=0);

L stands for a group

< / BR>
or

< / BR>
in which R3and R4independently mean a hydrogen atom, a C1 is 10000;

n means an integer from 2 to 10,000;

p is an integer from 1 to 5;

q denotes an integer from 0 to 20,

Z means that when q is zero, the hydrogen atom, alkaline metal, acetyl, acryloyl, methacryloyl, cynnamoyl, paratoluenesulfonyl, 2-mercaptopropionyl, or 2-aminopropionic, or allyl, or vinylbenzyl, while, when q is an integer from 1 to 20, Z means WITH1-6-alkoxycarbonyl, carboxy-, mercapto - or amino group.

2. Heterocalixarenes block copolymer under item 1, wherein R1and R2connected together, means oxoprop.

3. Heterocalixarenes block copolymer under item 1, wherein R1and R2independently mean C1-6-alkoxy - or benzyloxy, or, when connected together, means Ethylenedioxy, which may be substituted WITH1-3-alkyl.

4. Heterocalixarenes block copolymer under item 1, wherein R1and R2connected together, means oxoprop, and in group L as3and R4represent a hydrogen atom or methyl, or r is an integer equal to 4; and q denotes an integer from 0 to 3.

5. Heterocalixarenes block copolymer under item 1, characterized in that predstavlyaet a hydrogen atom or methyl, or r is an integer equal to 4; and q denotes an integer from 0 to 3.

6. Heterocalixarenes block copolymer under item 1, wherein m means an integer from 10 to 200, and n means an integer from 10 to 200.

7. Heterocalixarenes block copolymer under item 1, wherein R1and R2connected together, means oxoprop, and in group L as3and R4represent a hydrogen atom or methyl, or r is an integer equal to 4; q is zero, and Z means a hydrogen atom, acetyl, acryloyl, methacryloyl, cynnamoyl, paratoluenesulfonyl, allyl or vinylbenzyl.

8. Heterocalixarenes block copolymer under item 1, wherein R1and R2independently mean C1-6-alkoxygroup, and in group L as R3and R4are methyl, or r is an integer equal to 4; and q is zero; Z means a hydrogen atom or a sodium, potassium, or cesium.

9. Heterocalixarenes block copolymer under item 1, wherein R1and R2connected together, means oxoprop, and in group L as3and R4are methyl, or r is an integer equal to 4; q is an integer from 1 to, and Z means WITH1-6alkoxysilane formulas I through p. 1, comprising the following stages:

Stage 1)

the interaction initiator of polymerization, represented by the following formula II:

< / BR>
in which R1-1and R2-1independently mean C1-10-alkoxy, or together represent Ethylenedioxy, which may be substituted WITH1-6-alkyl, p is an integer from 1 to 5 and M means an alkali metal,

c with ethylene oxide so that it was possible to obtain the compound represented by the following formula III:

< / BR>
in which R1-1and R2-1, p and M are such as defined in formula II;

m means an integer from 2 to 10,000;

Stage 2)

the interaction of the compounds of formula III with lactide or lactone, which is represented by the following formula III-a or III-b:

< / BR>
or

< / BR>
in which R3and R4independently mean a hydrogen atom, a C1-10is alkyl, aryl or aryl-C1-3is alkyl and r is an integer from 2 to 5,

thus, in order to obtain a block copolymer represented by the following formula IV:

< / BR>
in which L stands for a group

< / BR>
or

< / BR>
R1-1, R2-1, p, m, n, M such as defined above;

and, in addition, in some cases,

Stage 3)

V:

< / BR>
in which R1-1, R2-1, p, m, L and n are such as defined above; or

ii) complete hydrolysis of the block copolymer of formula IV to obtain the block copolymer of the following formula VI:

< / BR>
in which p, m, L and n are such as defined above;

Stage 4)

the interaction of block copolymer of formula V with (i) acetic acid, acrylic acid, methacrylic acid, cinnamic acid or paratoluenesulfonyl acid or their reactive derivatives, or ii) allergologicum, or vinylbenzenesulfonic, or iii) halide represented by the following formula VII:

< / BR>
in which X represents a chlorine atom, bromine or iodine, q' is an integer from 1 to 20, and Z' is a C1-6- alkoxycarbonyl or protected amino group; and in some cases

Stage 5)

the transesterification obtained in stage 4)- (i) derived ether paratoluenesulfonyl acid or hydrolysis obtained at stages 4) - i), ii) or iii) derivatives.

11. Macromolecular micelle comprising as an active ingredient heterocalixarenes block copolymer of the formula I on p. 1, where Z means a group that is different from the alkali metal in water, buffer solution and/or organic restorer formula I on p. 1 Z means a group different from the alkali metal, while R1and R2connected together, means oxoprop.

 

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