The polymer, a method of obtaining a polymer surface with a coating method of coating the surface

 

(57) Abstract:

Describes a polymer suitable for prolonged contact with living tissues and body fluids and proteinogram solutions. It is formed by radical polymerization of (i) zwitterionic monomer having the formula (I) where the values Y, B, X specified in paragraph 1 of the formula; (ii) the co monomer having svyazuyushaya surface group, which is co monomer having alkyl fluoride or siloxane group, of General formula (VII) or capable of blending the co monomer of General formula (VII A), where the values of R14AND1, Q, QQ specified in paragraph 1 of formula (XII) where the values Y2IN9, Q5also specified in paragraph 1 of the formula; and specified zwitterionic monomer and the specified comonomer introducing radical polymerization in a molar ratio in the range of from 5:95 to 95:5; and (iii) and optionally the monomer-diluent General formula (VI), where R14is hydrogen or methyl; and Q is C8-24-alkyl. Also describes the method of its production, surface coating and method of coating the surface. The technical result - the production of polymer with side groups with constant positive charge and the other side groups, can stably bind the polymer with erati group, linking the polymer with the surface by physical adsorption, covalent bonding or ionic interactions. In addition, the reactive group in the polymer can serve as a point for attaching ligands to the polymer in the coating on the surface. 4 C. and 26 C.p. f-crystals, 1 tab., 1 Il.

Y-B-X (I)

CH2= CR14-C(O)-A-QQ (VIIA),

< / BR>
Y2-B9-Q5(XII)

The invention relates to new polymers, methods for their preparation and methods for covering their surfaces. The invention also provides improved methods of obtaining some of the monomers and the number of new monomers used for polymers. Polymers suitable for coating on the surface of the devices and materials that are in contact with proteincalorie solutions and biological fluids, and the resulting surfaces are bio - and hemocompatible. Thus, the surface may be suitable for prolonged contact with living tissues and body fluids and proteinogram solutions.

The materials used in the manufacture of various devices in contact with blood, intraocular lenses, and other devices that% is jemimah physical and mechanical properties and taking into account their compatibility with proteincalorie or biological fluids. All these requirements is usually to combine simultaneously with any use of these materials, and often achieved a compromise, and then use the materials, even not quite optimal properties. But sometimes there are problems of a biological nature, even when using materials with optimal mechanical and physical properties. The problem often is that the detected unwanted deposits of biological components, particularly proteinaceous materials. While adsorption of this protein are formed as a result of blood clots on the materials in contact with blood. When the adsorption of the components tears on contact lenses on them are also formed deposits, the formation of deposits recorded and intraocular lenses, and for different separation media, the latter leads to blockage and damage to the separating device. These problems lead to significant performance deterioration and often completely fail and damage the device.

In the case of medical devices such as prostheses and parts installation hemodialysis, in conventional practice, in order to avoid adsorption of proteins, use of biocompatible polymers, at least for poluchaetsya problem for example, thrombosis, induced by the surface, is still a major difficulty, especially if a large amount of blood contact with foreign surfaces, such as artificial lungs and kidneys. The formation of clots in the artificial body is very severe or even catastrophic consequences, such as the blockage of the channels, which moves the blood in the system outside the body, or blockage of blood vessels, if the clot breaks off and gets into the blood vessels of man. This problem exists for devices such as heart valves, artificial blood, blood substitutes and artificial light.

It is known that materials for use as the biocompatible coating should ideally:

(a) be made in the form of pure materials;

(b) be applied to the surface without degradation or other adverse changes;

(c) to have the necessary mechanical properties and permeability required for the specific operation of the device in which it is used;

(d) to be sterilized without significant changes in properties such as mechanical and surface properties, and also without changing Prinzregent.

In cases of direct contact with blood, there are incremental restrictions. Materials must not:

(g) to induce significant adhesion;

(h) interfere with the normal clotting mechanism;

(i) to cause any significant damage to cellular elements or soluble components of blood.

There are a large number of attempts to obtain biocompatible and compatible with specific blood (i.e., gemosovmestimosti) surfaces, which are not activated by the coagulation process of the blood and does not stimulate the formation of blood clots. Such attempts include: obtaining negatively charged surfaces, such as the use of anionic polymers or oriented as desired, electret-polymers; receiving surfaces coated with an anticoagulant, such as natural heparin or its synthetic analogues; obtaining surfaces with low surface free energy, as for example when using siloxane rubber; obtaining surfaces with a coating of albumin; obtaining surfaces with a coating of such compounds, as some polymethine, adsorption of albumin from the blood. However, all these examples have certain limitations.

Polymers containing zwitterionic of the group represent the analogs of phospholipids zwitterionic patterns, such as phosphatidylcholine and sphingomyelin, which are important components of the outer membrane of all living cells. Thus, the present invention attempts to obtain a biocompatible surface of the substrate on which the deposition of proteins and cells would be minimized when the substrate with the coating comes in contact with proteincalorie solutions or biological fluids.

In addition, the polymers of the present invention can join various ligands or to the deposition of the polymer on the surface of the substrate, i.e., when the polymer still in solution, or Nivat methods of joining such ligands. The concept of ligand includes, but is not limited to, specific binding agents, for example, the immunoglobulin or the United extracts from it, such as those that provide specific properties and are suitable for diagnostic studies, photosensitive and heliocentrically fragments, which are suitable for detection and sensor applications. The ligand can include a therapeutic drug for the clinical treatment. Other ligands include peptide fragments, chemically bind to these polymers, the fragments that induce adherence of cells and therefore provides the binding of the cells to the polymer.

This invention provides a polymer of one or more radially polymerized, preferably ethylene unsaturated monomers which provide the polymer with side groups with centre positive DC charge, as well as other side groups, can stably bind the polymer to the surface. Such coatings contact surface with good adhesion, they are not in the environment in which these coatings are used, i.e., they can be used as coatings of surfaces in contact with blood.

Gruppering group similar to the structure of the head groups of the phospholipids in the cells. I suppose, but is not limited to this theory that the presence of such groups on the surface makes the surface more biocompatible.

The degree to which the polymer transforms the surface into a biocompatible, can be estimated by a combination of factors, such as caused by the surface reduction of the degree of activation of blood particles, adsorption of proteins (e.g judged by absorption of fibrinogen from human blood plasma) and reaction with C-reactive protein, which is caused by the presence on the surface of isolated zwitterionic, i.e., the ester groups of the ammonium phosphate. Mainly polymers of the invention when applying them to the substrate to reduce the activation of particles at least 70%, more preferably about 90%, as determined by the analysis described below, in comparison with the untreated substrate. It was also established that the polymers of the invention when applying them to the substrate are reduced absorption of fibrinogen at least 60%, as follows from the analysis presented below, and the index of the protein of less than 1,510-3in comparison with the untreated substrate. Index of protein evaluated relative absorption due to C-reactive protein and the change in the La-linking of the polymer with the surface, is selected depending on the nature of the surface coating is a polymer. If the surface is hydrophobic, the linking of the polymer surface can be used in groups, able to create on the surface of the physical solventnost. If the surface is hydrophilic and has a functional group for binding a polymer surface can be used group capable of reacting with the functional groups of the surface with the formation of covalent bonds. If the surface is charged, the binding polymer to the surface via ionic interactions can be used group having an ionic charge.

Depending on the nature of the surface of the polymers of the invention can be contacted with the surface by physical adsorption, covalent or ionic bonding. In some cases it is possible to use a combination of two mechanisms linking.

The group is able to stably bind the polymer to the surface, may be present in one and the same monomer as groups with constant positive charge or they can be in a variety of monomers, which when copolymerized give the desired polymer of the invention.

If the coating is applied on the hydrophobic surface, the groups capable of binding the polymer to the surface, can be used alkyl groups of 6 or more carbon atoms or alkyl fluoride group in which the carbon chain may contain one or more ether oxygen atoms, and possibly one or more double or triple bonds or siloxane groups containing predominantly from 1 to 50, more preferably from 5 to 30 silicon atoms. Such groups are capable of forming strong secondary interactions with the surface and possess the physical correntoso on the hydrophobic surface, i.e., to adsorb without covalent interaction.

In one embodiment of the present invention provides, therefore, a polymer obtained by using

(i) copolymerization radically polymerized, mainly ethylene-unsaturated, co monomer containing a group of permanent positive charge, which is preferably zwitterionic, and radically polymerized, mostly unsaturated, co monomer containing a radical curable portion and the alkyl group of 6 or more carbon atoms, and the alkyl group may contain the th group, which may contain one or more ether oxygen atoms and possibly one or more double or triple links, or a siloxane group; or

(ii) polymerization of radically polymerized, with the preferred ethylene-unsaturated, monomer containing a group of permanent positive charge, which preferably is zwitterionic, alkyl group of 6 or more carbon atoms, may contain one or more ether oxygen atoms, alkyl fluoride group may have one or more ether oxygen atoms, or a siloxane group.

Such a copolymer may be a copolymer comprising residues radically polymerized, mainly ethylene-unsaturated, co monomer containing a group of permanent positive charge, and radically polymerized, mainly ethylene-unsaturated co monomer containing, in addition, the radical curable portion, the alkyl group of 6 or more carbon atoms may have one or more etheric oxygen atoms and possibly one or more double or triple bonds, or alkyl fluoride group may have one or more ether oxygen atoms, or perhaps one ill or consist of residues radically polymerized, mainly ethylene-unsaturated monomer containing a group of permanent positive charge, and the alkyl group of 6 or more carbon atoms, may contain one or more ether oxygen atoms, or possibly one or more double or triple links, or alkyl fluoride group may have one or more atoms of the ether oxygen, or a siloxane group.

In this embodiment the polymer is preferably a copolymer containing residues of co monomer, having an adsorbing group, and co monomer including a group from the centre of permanent positive charge.

Assume that the adsorbing group is an alkyl or alkyl fluoride group may contain one or more double or triple bonds. Such a group may contain one or more ether oxygen atoms, but especially preferred option, not including the etheric oxygen atom.

In the first embodiment, if the adsorbing group is an alkyl or alkyl fluoride group, possibly with one or more ether oxygen atoms, this group does not include a double or triple bond.

If the coating is applied on the hydrophilic on the one covalently bind the polymer to the surface.

Thus, according to an alternative embodiment of the invention provides a polymer obtained by using

(i) copolymerization radically polymerized, mainly ethylene-unsaturated, co monomer containing a group of permanent positive charge, which is mainly zwitterions, and radically polymerized, mainly ethylene-unsaturated, co monomer with a reactive group capable of covalently bind the polymer to the surface; or

(ii) polymerization of radically polymerized, mainly ethylene-unsaturated, monomer containing a group of permanent positive charge, which is mainly zwitterionic, and a reactive group that covalently links the polymer to the surface.

Such a polymer may be a copolymer containing residues radically polymerized, mainly ethylene-unsaturated, co monomer containing a group of permanent positive charge, and radically polymerized, mainly ethylene-unsaturated, co monomer with a reactive group that can covalently contact surface.

Otherwise, such a war, monomer containing a group of permanent positive charge and a reactive group suitable for covalent bonding with the surface.

In this embodiment the polymer is a copolymer comprising residues of co monomer containing the group with a positively charged center, and co monomer containing a reactive group suitable for covalent bonding with the surface.

If the coating applied to the surface with the ion charge, the polymer of the invention as side groups can be ionic group capable of binding the polymer to a surface by ionic interaction.

According to a third embodiment of the invention provides a polymer obtained by using:

(i) copolymerization radically polymerized, mainly ethylene-unsaturated co monomer containing a group of permanent positive charge, which is mainly zwitterionic, and radically polymerized, mainly ethylene-unsaturated, co monomer having an ionic group capable of contact with the surface of ionic interaction, or

(ii) polymerization of radically polymerized, priority is predpochtitelno is zwitterionic, and an ionic group capable of contact with the surface of the ion interaction.

Such a polymer may be a copolymer containing residues radically polymerized, mainly ethylene-unsaturated, co monomer including a group from the centre of permanent positive charge, and the remains of the co monomer comprising an ionic group capable of contact with the surface via ionic interactions.

In other words, such a polymer may include or consist of residues radically polymerized, mainly ethylene-unsaturated, monomer containing a group of permanent positive charge and the ionic group capable of contact with the surface via ionic interactions.

In this embodiment the polymer is mainly a copolymer containing residues of co monomer including a group from the centre of permanent positive charge, and the remains of the co monomer comprising an ionic group capable of contact with the surface via ionic interactions.

It is possible, in any of the above embodiments, the polymers also include the remains of one or more diluents and/or cross-linking monomers.

The invention is of the rooms, and the method of application of these polymers on the surface. The proposed method, for example, includes the stages of (a) polymers by polymerization of the corresponding monomers, and (b) applying a polymeric coating to the surface. Moreover, the method includes the introduction of the ligand in the polymer or in the polymer solution before coating on a surface, or more preferably, in the coating process on the surface.

In addition, in the specific embodiment of the invention provides polymers containing residues of a crosslinking monomer, which are not stitched or when applied, or when not applied to the surface, and also polymers which are stitched together at their drawing to the surface. The invention provides further a method of crosslinking of these polymers when applying them to the surface.

Further, the invention provides for polymers of the invention some of the new monomers.

The monomers and comonomers that can be used to obtain polymers of the invention will be now described in more detail.

The terms used in the invention, (ALK) acrylate, (ALK) acrylic or (ALK) acrylamide mean acrylate or alkalimat, acrylic or alkalay, krylovii and altaceligit contain from 1 to 4 carbon atoms in the alkyl part, the most preferred group methacrylate, methacrylic or methacrylamide. Similarly, (meth) acrylate, (meth) acrylic and (meth) acrylamide will mean acrylate or methacrylate, acrylic or methacrylic, and acrylamide or methacrylamide respectively.

Monomers with a center of permanent positive charge

The monomer (or comonomer) with the center of permanent positive charge may be cationic or, more preferably, zwitterions. In the latter case, the monomer consists of not only a centre of permanent positive charge, but also the center of negative charge. Usually a centre of permanent positive charge is a Quaternary ammonium nitrogen atom.

Preferred comonomers, including the center with a positive charge, have the General formula (I)

Y-B-X (I)

where B is a straight or branched alkilinity, oxyalkylene or oligo-oxyalkylene chain containing one or more fluorine atoms, including perfluorinated chains, or B is a valence bond, if X contains a carbon-carbon chain between B and the center of positive charge or if Y contains a terminal carbon atom associated with B;

X is grutza polymerized unsaturated group, selected from

< / BR>
or

< / BR>
where R is hydrogen or C1-C4alkyl;

A - O - or-NR1where R1is hydrogen or C1-C4alkyl, or R1is - B-X where B and X above; and

K is a group - (CH2)pOC(O)-, -(CH2)pC(O)-, -(CH2)pOC(C)O-, -(CH2)pNR2-,

-(CH2)pNR2C(O)-, -(CH2)pC(O)NR2-,

-(CH2)pNR2C(O)(NR2)-;

(where the group R2the same or different) - (CH2)pO - (CH2)pSO3- or optimally in combination with the B - valence bond and p is from 1 to 12, R2is hydrogen or C1-C4alkyl.

If B is a valence bond, a centre of permanent positive charge in X connects with a heteroatom such as oxygen atom or nitrogen in Y.

Preferred monomers containing a group with a permanent positive charge, are compounds of General formula (II) or (III).

< / BR>
< / BR>
where R, A, B, K and X are the same as described above in reference to formula (I).

Preferably in compounds of formula (II) R is hydrogen, methyl or ethyl, mainly methyl, so that (II) is a derivative of the connection, B - group; K can be a group, B is a valence bond; and K, and B can be groups or and K, and B can be together a valence bond. Mostly B - group, when K is a valence bond.

If K - group, mainly p is 1 to 6, more preferably 1, 2 or 3 and is more likely to p = 1. If K is a group -(CH2)pNR2-, -(CH2)pNR2C(O)-,

-(CH2)pC(O)NR2, -(CH2)pNR2C(O)O-(CH2)pOC(O)NR2or (CH2)pNR2C(O)NR2-, R2- mostly hydrogen, methyl or ethyl, most likely hydrogen.

In the compounds of the formula (III), the vinyl group is predominantly in the para position relative to the group - K-B-X.

Mostly B is:

Allenova group of the formula-CR23)a- where the group -(CR23)- are the same or different and in each group -(CR23)- Deputy R3- same or different and each substituent R3is hydrogen, fluorine or C1-C4alkyl or foralkyl, mainly hydrogen, and a is from 1 to 12, most likely 1-6;

oxyalkylene group, such as alkoxyalkyl having from 1 to 6 carbon atoms in each ALK is R24)bO]c(CR24)bwhere group -(CR24)- - the same or different and in each group -(CR24- the substituents R4- same or different, and each of the substituents R4is hydrogen, fluorine, C1-C4alkyl or foralkyl, mainly hydrogen, and b is from 1 to 6, mostly 2 or 3, c is from 2 to 11, mostly 2-5 or

valence bond when X represents a carbon-carbon chain between B and the centre of permanent positive charge or if Y contains a terminal carbon atom.

Preferred groups B include alkylene, oxyalkylene and oligo-oxyalkylene groups of up to 12 carbon atoms and optionally one or more fluorine atoms. If the polymer is not intended to cover the hydrophobic surface and therefore do not need to bind it to the surface through physical adsorption, then B is mainly alkilinity, oxyalkylene or oligo-oxacillinases group that does not contain fluorine atoms.

In the compounds of the formula (III) is most preferable that K and B contain up to 12 carbon atoms.

Preferred groups X that contains the center of permanent positive charge is group, can be used in combination with additional monomers containing a group capable of contact with the surface, giving the copolymer of the invention. Most preferred are the groups of formula (IVB) - (IVF) and especially (IVC).

In addition, groups of formula (VA), (VB) and (VC) are predominantly monomers, and containing the center of permanent positive charge, and alkyl, alkyl fluoride or siloxane group, able to communicate with the surface through physical adsorption.

Group of the formula (IVA) are

-N(R5)3Z, (IVA)

where the group R5are the same or different and each is hydrogen or C1-C4the alkyl and Z- protivoiona.

Group R5are mainly the same. It is preferable that at least one of the groups R5was stands, and more preferably all of the groups R5were metelli.

The counterion Zpresent in the compounds of formula (II) or (III) containing the group of formula (IVA) is such that these compounds generally are neutral salts. The counterion can be exchanged with ions in videoease the invention. However, the preferred physiologically acceptable counterions. As suitable such counterions as halogen anions such as chlorine or bromine ions, other inorganic ions such as sulfate, phosphate, postit, and organic anions, for example aliphatic mono-, di - or tricarboxylate anions containing from 2 to 25 carbon atoms and having one or more hydroxyl groups, i.e., acetate, citrate and lactate.

When X is a group of formula (IVA), B is primarily a group of the formula -(CR23)- or -(CR23)2-, such as -(CH2)- or -(CH2CH2)-.

Group of formula (IVB) are:

< / BR>
where the group R6- same or different and each is hydrogen or C1-C4the alkyl and d is from 2 to 4.

Group R6are mainly the same. It is preferable that at least one of the groups R6was stands, and more preferably all of the groups R6were metelli.

The preferred value of d is 2 or 3, especially 3.

When X is a group of formula (IVB), B is primarily a group of the formula -(CR23)- or -(CR23)2-, such as -(CH2)- Il is W hat or different, and each is hydrogen or C1-C4the alkyl and e is from 1 to 4.

Group R7are mainly the same. It is preferable that at least one of the groups R7was stands, and more preferably all groups 7were metelli.

The preferred value of e is 2 or 3, especially 2.

When X is a group of formula (IVC), B is primarily a group of the formula -(CR23)-, or -(CR23)2-, such as -(CH2)- or (CH2CH2)-.

The group of formula (IVD) are:

< / BR>
where the group R8- same or different and each is hydrogen or C1-C4the alkyl, R8ais hydrogen or more preferably the group-C(O)B1R8bwhere R8bis hydrogen or methyl, mainly methyl, B1is a valence bond, a straight or branched alkylen, oxyalkylene or oligo-oxyalkylene and f is from 1 to 4; and z = 1, if B is not a valence bond or if X is directly connected to the oxygen or nitrogen;

z = 0, if B is a valence bond

Group R8are mainly the same. It is preferable that at least one of the groups R8was stands, and more preferably, storeiostate B1is:

valence bond;

alkylenes group of the formula

-(CR23a)aa- where the groups -(CR23a)- are the same or different and in each group -(CR23a- the substituents R3A- same or different, and each of the substituents R3ais hydrogen or C1-C4the alkyl, particularly hydrogen, and aa - from 1 to 12, especially from 1 to 6,

oxyalkylene group, such as alkoxyalkyl containing from 1 to 6 carbon atoms in each alkyl part, especially preferred group-CH2O(CH2)4-;

oligo-oxyalkylene group of formula -[(CR24a)baO]ca- where the groups -(CR24a) - are the same or different and in each group -(CR24a- the substituents R4a- same or different and each of the substituents R4ais hydrogen or C1-C4the alkyl, particularly hydrogen, and ba from 1 to 6, especially 2 or 3, and ca - from 1 to 12, especially 1 to 6.

Mainly group B1is a valence bond and alkylenes, oxyalkylene and oligo-oxyalkylene group containing up to 12 carbon atoms.

Preferably the Oh group of the formula

-[(CR24CR24)cOb] CR24CR24-, such as -(CH2CH2)c(CH2CH2)-. Group of formula (IVE) are:

< / BR>
where the group R9- same or different and each is hydrogen or C1-C4the alkyl, R9ais hydrogen or, more likely, group-C(O)B2R9b, R9bis hydrogen or methyl, mainly methyl, B2is a valence bond or a straight or branched alkylen, oxyalkylene or oligo-oxyalkylene and g from 1 to 4; and z = 1, if B is not a valence bond; z = 0, if B is a valence bond; z is usually 1, if X is directly connected to the oxygen atom or nitrogen.

Group R9are mainly the same. It is preferable that at least one of the groups R9was stands, and more preferably all of the groups R9were metelli.

The preferred value of g is 1 or 2, especially 2.

Mostly B2are:

valence bond;

alkylenes group of the formula -(CR23b)ab- where the groups -(CR23b)- are the same or different and in each group -(CR23b- the substituents R3bthe same is gorodom, ab - from 1 to 12, especially 1 to 6;

oxyalkylene group, such as alkoxyalkyl containing from 1 to 6 carbon atoms in each alkyl part, especially preferred group-CH2O(CH2)4-; or

oligo-oxyalkylene group of formula -[(CR24b)bbO]c- where the groups -(CR24b)- are the same or different and in each group -(CR24b- the substituents R4b- same or different and each of the substituents R4bis hydrogen or C1-C4the alkyl, especially hydrogen, bb - 1 to 6, especially 2 or 3, and cb - 1 to 12, especially from 1 to 6.

Mainly group B2include valence bond, alkylenes, oxyalkylene and oligo-oxyalkylene group containing up to 12 carbon atoms.

Preferably, B and B2the same.

When X is a group of formula (IVE), B is primarily a group of formula -[(CR24CR24)bO]cCR24CR24- for example

-(CH2CH2O)cCH2CH2-.

Group of formula (IVF) are:

< / BR>
where the group R10- same or different and each is hydrogen or1-C is methyl, mainly methyl, B3is a valence bond or a straight or branched alkylen, oxyalkylene or oligo-oxyalkylene, h is from 1 to 4; and z = 1, if B is not a valence bond; z = 0, if B is a valence bond; z is usually 1, if X is directly connected to the oxygen atom or nitrogen.

Group R10are mainly the same. It is preferable that at least one of the groups R10was stands, and more preferably all of the groups R10were metelli.

Preferred values h - 1 or 2, especially 2.

Mostly B2is:

valence bond;

alkylenes group of the formula

-(CR23c)ac- where the groups -(CR23c)- are the same or different and in each group -(CR23c- the substituents R3c- same or different and each of the substituents R3cis hydrogen or C1-C4the alkyl, mainly hydrogen, ac - from 1 to 12, especially 1 to 6;

oxyalkylene group, such as alkoxyalkyl containing from 1 to 6 carbon atoms in each alkyl part, especially preferred group-CH2O(CH2)4-;

oligo-oxyalkylene group of formula -[(CR24c24c- the substituents R4c- same or different and each of the substituents R4cis hydrogen or C1-C4the alkyl, especially hydrogen, and bc - 1 to 6, mostly 2 or 3, and cc - 1 to 12, mainly 1-6.

Mainly group B3include valence bond, alkylenes, oxyalkylene and oligo-oxyalkylene group containing up to 12 carbon atoms.

Preferably, B and B3the same.

When X is a group of formula (IVF), mainly B is a group of formula -[(CR24CR24)bO]cCR24CR24- for example

-(CH2CH2O)cCH2CH2-.

Additional groups that have a constant positive charge, are of the formula (VA), (VB) and (VC). These groups also contain alkyl or foralkyl able to communicate with the surface through physical adsorption. Therefore, the monomers from this group are particularly suitable for use in obtaining polymers of the invention are possible without separation of the comonomers containing group capable of contact with a hydrophobic surface by physical adsorption.

aetsa hydrogen or C1-C4the alkyl, R11aor

(a) a group -[C(O)]vw(CR211b)ww(SiR211c)(OSiR211c)vvR11cin which the substituents R11b- same or different and each is hydrogen or C1-C4the alkyl, the substituents R11c- same or different, and each of them is C1-C4the alkyl or aralkyl, such as benzyl or venetiam, vw is 0 or 1, ww - 0 to 6 with the proviso that vw and ww - not both 0, and from 0 to 49; or

(b) a group of the formula-C(O)B4-R11din which R11dis hydrogen or methyl, B4is a valence bond, a straight or branched alkylen, oxyalkylene, or oligo-oxyalkylene, possibly containing one or more fluorine atoms, from 5 to 24, mostly 6-18 carbon atoms;

i from 1 to 4; and

z = 1 if B is not a valence bond;

z = 0, if B is a valence bond;

z usually 1, if X is directly connected to the oxygen atom or nitrogen.

Group R11are mainly the same. It is preferable that at least one of the groups R11was stands, and more preferably all of the groups R11were metelli.

The preferred value of i is 1 or 2, especially 2.

Esacove or different, mostly the same, and it is desirable that each of the groups R11bwas hydrogen. Preferred values ww - 2 to 4, especially 3, when vw is 0 or 2, when vw - 1. Group (SiR211c) is the same or different, mostly the same, and preferably each substituent R11cwas stands. Preferred values vv - from 4 to 29.

Mainly the group R11arepresents a group-C(O)B4R11das shown above. In this case, the most probable values of B4will be:

valence bond;

Allenova group of the formula -(CR23)adwhere group -(CR23d) is the same or different and in each group (CR23d) the substituents R3d- same or different, and each Deputy is hydrogen, fluorine or C1-C4the alkyl or perakyla, mostly hydrogen or fluorine, ad - 1 to 24, especially 6-18;

oxyalkylene group, such as alkoxyalkyl having from 1 to 6 carbon atoms and possibly one or more fluorine atoms in each alkyl part, or

oligo-oxyalkylene group of formula -[(CR24d)bdO]cd- where the groups -(CR24d) - are the same first Deputy R4dis hydrogen, fluorine or C1-C4the alkyl or perakyla, mostly hydrogen or fluorine and bd from 1 to 12, mainly from 1 to 6.

When B4is a group

-[(CR24d)bdO]cd- where all substituents R4dare hydrogen and in all the groups - [(CR24d)bdO]- bd - 2, residues of the monomer of formula (VA) is not able to form strong secondary valence interactions with hydrophobic surfaces. At the same time as the remains of such monomers may be incorporated in the polymer of the invention, it is usually necessary to include residues of monomers that can cause a strong secondary valence interactions, if these interactions link the polymer to the surface.

Monomers which have groups containing oligo (higher alkylene) oxide part, able to create strong secondary valence interactions, i.e., monomers containing oligoanilines part, in which at least 50, mainly 70 and more than likely 90 mol.% individual alkalinising elements include 3 or more carbon atoms. Thus, mixed oligo (ethylene oxide/propylene oxide) side chain has more elements p. the treatment is 2 to 50, mainly 70, more than likely 90 mol.% or less residues(CR24)O-.

If the group-B4-R11acapable of forming with the surface of a strong secondary valence interactions, the monomers containing the group (VA), is particularly suitable for use as monomers containing groups with constant positive charge and alkyl or alkyl fluoride group may containing one or more etheric oxygen atoms. Preferably in this case, B4-R11ais the alkyl group may contain one or more ether oxygen atoms, mostly 6 or more carbon atoms, the alkyl fluoride group may containing one or more etheric oxygen atoms and preferably 6 or more carbon atoms.

In one embodiment B and B4can be the same.

Group of the formula (VB) are:

< / BR>
where the group R12- same or different and each is hydrogen or C1-C4the alkyl, R12aor

(a) a group -[C(O)]tu(CR212b)uu(SiR212c)(OSiR212cR12cin which the substituents R12b- same or different, and SUB>-C4alkilani or aracelli, such as benzyl or venetiam, tu is 0 or 1, uu - from 0 to 6, provided that tu and uu are not both 0, and tt is from 0 to 49; and

(b) a group of the formula-C(O)B5-R12din which the substituent R12is hydrogen or methyl, B5is a valence bond or a straight or branched alkylen, oxyalkylene or oligo-oxyalkylene, possibly containing one or more fluorine atoms, from 6 to 24 carbon atoms, predominantly 6-18 carbon atoms;

j from 1 to 4; and

z = 1 if B is not a valence bond;

z = 0, if B is a valence bond;

z usually 1, if X is directly connected to the atoms of oxygen or nitrogen.

Group R12are mainly the same. It is preferable that at least one of R12was stands, and more preferably all of the groups R12were metelli.

The preferred value of j is 1 or 2, especially 2.

If R12a- siloxane group, as shown above in paragraph (a), group (CR212b) may be the same or different, mostly the same, and it is desirable that each of the groups R12bwas hydrogen. Preferred values uu - from 2 to 4, especially 3, when n is 0, or 2, when tu - 1. Group (SiR212c- etiam. Preferred values of tt - 4 to 29.

Mainly the group R12arepresents a group-C(O)B5R12as shown above. In this case, the most probable values of B5will be:

valence bond;

Allenova group of the formula -(CR23e)aewhere group -(CR23e) is the same or different and in each group (CR23e) the substituents R3e- same or different and each substituent R3eis hydrogen, fluorine or C1-C4the alkyl, perakyla, mostly hydrogen or fluorine, ae - 1 to 24, especially 6-18;

oxyalkylene group, such as alkoxyalkyl having from 1 to 6 carbon atoms and possibly one or more fluorine atoms in each alkyl part; and

oligo-oxyalkylene group of formula -[(CR24e)beO]ce- where the groups - (CR24e) - are the same or different and in each group (CR24e- the substituents R4e- same or different, each substituent R4eis hydrogen, fluorine or C1-C4the alkyl or perakyla, mostly hydrogen or fluorine and be from 2 to 6, mostly 3 or 4 and ce - 1 to 12, especially 1 to 6.

24e)beO] is 2, the residues of the monomer of formula (VB) is not able to form strong secondary valence interactions with hydrophobic

surface. While the remains of these monomers may be incorporated in the polymer of the invention, it is usually necessary to include residues of monomers that can cause a strong secondary valence interactions, if these interactions link the polymer to the surface. Monomers which have groups containing oligo (higher alkylene) oxide part, able to create strong secondary valence interactions, i.e., monomers containing oligoanilines part, in which at least 50, mainly 70, and more than likely 90 mol.% individual alkalinising elements include 3 or more carbon atoms. thus, mixed oligo (ethylene oxide/propylene oxide) side chain has more elements of propylene oxide than that of ethylene oxide.

When B5- group [(CR24e)beO]cepreferred values be - 2 to 50, mainly 70, more than likely 90 mol.% or less residues -[(CR24)beO] -. If the group-B5-R12acapable of forming with the surface of a strong secondary monomers, contains a group of permanent positive charge and alkyl alkyl fluoride group may containing one or more etheric oxygen atoms. Preferably in this case, B5-R12ais the alkyl group may contain one or more ether oxygen atoms, mostly 6 or more carbon atoms, the alkyl fluoride group may containing one or more atoms of the ether oxygen and preferably 6 or more carbon atoms.

In one embodiment B and B5can be the same.

Group of the formula (VC) are:

< / BR>
where the group R13- same or different and each is hydrogen or C1-C4the alkyl, R13aor

(a) a group -[C(O)]rs(CR213b)ss(SiR213c)(OSiR213c)rrR13cin which the substituents R13b- same or different and are hydrogen or C1-C4alkilani, the substituents R13c- same or different and are C1-C4alkilani or aracelli, such as benzyl, Venetian, rs is 0 or 1, ss - from 0 to 6, provided that rs and ss - not both 0, and rr is from 0 to 49; or

(b) a group of the formula-C(O)B6-R13in co, oxyalkylene or oligo-oxyalkylene, possibly containing one or more fluorine atoms, from 6 to 24 carbon atoms, predominantly 6-18 carbon atoms;

k is 1 to 4; and

z - 1 if B is not a valence bond;

z - 0, if B is a valence bond;

z usually 1, if X is directly connected to the atoms of oxygen or nitrogen.

Group R13are mainly the same. It is preferable that at least one of R13was stands, and more preferably all of the groups R13were metelli.

Preferred values k is 1 or 2, especially 2.

If R13a- siloxane group, as shown above in paragraph (a), group (CR213b) may be the same or different, mostly the same, and it is desirable that each of the substituents R13bwas hydrogen. Preferred values ss - 2 to 4, and most preferably 3, when rs = 0, or 2, when rs = 1. Group (SiR213c) is the same or different, mostly the same, and it is desirable that each of the substituents R13cwas stands. Preferred values rr - 4 to 29. Mainly the group R13arepresents a group - C(O)-B6R13das shown above. In this 23f)af- where the groups - (CR23f) - are the same or different and in each group (CR23f) the substituents R3f- same or different, each substituent R3fis hydrogen, fluorine or C1-C4the alkyl or perakyla, mostly hydrogen or fluorine and af - 1 to 24, especially from 6 to 18;

oxyalkylene group, such as alkoxyalkyl having from 1 to 6 carbon atoms and possibly one or more fluorine atoms in each alkyl part; and

oligo-oxyalkylene group of formula - [(CR24f)bfO]cf- where the groups - (CR24f) - are the same or different and in each group - (CR24f- the substituents R4f- same or different, each substituent R4fis hydrogen, fluorine or C1-C4the alkyl or perakyla, mostly hydrogen or fluorine and bf = 2 to 6, mostly 3 or 4, and cf from 1 to 12, mainly 1-6.

When B6is a group - [(CR24f)bfO]cf- where all substituents R4fare hydrogen and in all the groups [(CR24f)bfO] bf = 2, the residues of the monomer of formula (VC) is not able to form a strong WTO is to uchatsa in the polymer of the invention, usually you must enable and residues of monomers that can cause a strong secondary valence interactions, if these interactions link the polymer to the surface. Monomers which have groups containing oligo (higher alkylene) oxide part, able to create strong secondary valence interactions, i.e., monomers containing oligoanilines part, in which at least 50, mainly 70, and more than likely 90 mol.% individual alkalinising elements include 3 or more carbon atoms. Thus, mixed oligo (ethylene oxide/propylene oxide) side chain is used, provided that they have more elements of propylene oxide than that of ethylene oxide.

When B6group - [(CR24f)bfO]cf- preferred values of bf - 2 for only 50, mainly 70, more than likely 90 mol.% or less residues - [(CR24f)bfO]-.

If the group - B6-R13acapable of forming with the surface of a strong secondary valence interactions, the monomers containing the group (VC) is particularly suitable for use as monomers containing a group of permanent positive charge and the alkyl is in this case, that - B6-R13ais the alkyl group may contain one or more ether oxygen atoms, mostly 6 or more oxygen atoms, or alkyl fluoride group may containing one or more ether oxygen atoms, and preferably 6 or more carbon atoms.

In one embodiment B and B6can be the same.

Examples of preferred monomers, with the center of permanent positive charge are internal salt of 2-(methacryloyloxy)ethyl-2'-(ammonium)ethylphosphate, internal salt- 1-[4-(4'-vinylbenzyl)butane] -2'-(ammonium)ethylphosphate. Monomers with a center of permanent positive charge represented by the formulas (II) and (III) can be obtained by conventional methods, for example using the appropriate substituted alkyl (ALK) acrylate or the corresponding substituted styrene as the source. Examples of appropriate substituted alkyl (ALK) acrylate includes dimethylaminoethyl (meth) acrylate and 2-hydroxyethyl(meth)acrylate.

The monomers of formula (II) and (III) containing a group of formula (IVA) can be obtained by known methods. The monomers containing the group of formula (IVB) or (IVC) can be obtained by methodyou formula (IVD), in which R8ais - C(O)B1R8bcan be obtained by selective acylation of primary hydroxyl group glycerophosphorylcholine or its analogues. As Alliluyeva agent use activated derivative of the acid such as the acid anhydrides O(C(O)B1R8b)2or the anhydrides of the acids R8bB1COHal where B1and R8babove, and Hal is halogen. Next acelerou secondary hydroxyl group with appropriate Alliluyeva agent, such as methacryloylamido. Purification, for example by chromatography on a column with a suitable carrier can be performed after each acylation or only after the second acylation. Suitable activated derivatives of the acid include acid anhydrides, acid anhydrides, reactive esters and imidazoline. The acylation is carried out in a suitable anhydrous aprotic solvent, for example N,N-dimethylformamide, possibly in the presence of dinucleophiles base, such as triethylamine.

Or primary alcohol group with glycerophosphorylcholine or its analogues can be protected with suitable protective group which is introduced by reaction with an appropriate reageer allermuir agent, such as metallorganic. Tert-butyldimethylsilyl protection may be removed by treatment with diluted organic or mineral acid, for example p-toluensulfonate acid, hydrochloric acid, or tetrabutylammonium. Free primary hydroxyl group may then be treated with activated acid derivative such as an acid anhydride O(C(O)B1R8b)2or the acid chloride of the acid R8bB1COHal where B1and R8babove, and Hal is halogen.

Analogues of glycerophosphorylcholine (the compounds of formula (II) or (III) containing the group (IVD), where R8a- hydrogen) is produced by reaction of phosphorus oxychloride with poslednym alcohol in an inert aprotic solvent such as dichloromethane, to form dichlorohydrin bromeliifolia acid. Thus obtained dichloropropane process then in the presence of a base, such as triethylamine, suitably protected derivative of glycerol, for example 2,2-dimethyl-1,3-dioxolane-4-methanol, followed by acid hydrolysis with the formation of bromeliifolia. This derivative is then treated with amine IIR38where R8above, for example triethylene R8and f are the same as those given for the groups of formula (IVD).

The monomers of formula (II) and (III) containing the group of formula (IVE) in which R9arepresents - C(O)B2R9breceive a selective acylation of glycerophosphorylcholine or its analogues on the primary hydroxyl group using as Alliluyeva agent, such as methacryloylamido. Next acelerou on the secondary hydroxyl group with an activated acid derivative such as an acid anhydride O(C(O)B2R9b)2or the acid chloride of the acid R9bB2COHal where B2and R9babove, Hal is halogen. Intermediate and final products are purified using chromatography on a column. You can use the introduction of protective groups, similar to those shown above upon receipt of the monomers containing the group of formula (IVD).

The monomers of formula (II) or (III) containing a group of formula (IVF), receive the same monomers containing groups of formula (IVD) or (IVE).

The monomers of formula (II) and (III) containing a group of formula (VA), (VB) or (VC), get methods, directly analogous to the methods described monomers containing groups of formula (IVD), (IVE) and (IVF), respectively.

As already mentioned, the nature of the group capable of contact with the surface, and therefore the nature of the comonomers containing such groups will depend on the nature of the surface, on which is applied to the polymer coating. Various types of such comonomers will be now described.

In some cases it is possible to use a combination of different comonomers containing group capable of contact with the surface. Mainly used comonomers of type (a), (b) and/or b) as shown below, or a combination of such comonomers, but it is more likely that only one of the co monomer of type a), b) and C).

Preferably the alkyl or alkyl fluoride groups contain up to 24 carbon atoms, for example up to 18 carbon atoms, a siloxane group contains up to 50 silicon atoms, mainly in the form of linear chains. Preferred comonomers containing an alkyl, alkyl fluoride or siloxane group expressed by General formula (VI)

Y1-Q, (VI)

where Y1- polymerised unsaturated group selected from

< / BR>
or

< / BR>
where R14is hydrogen or alkyl (C1-C4;

A' is - O - or-NR15- where R15is hydrogen or C1-C4alkyl, or R15= Q;

K1group -(CH2)e -(CH2)eC(O)NR16-, -(CH2)eNR16C(O)O-, -(CH2)eOC(O)NR16-,

-(CH2)eNR16C(O)NR16in which the substituents R16the same or different), -(CH2)eO-, -(CH2)eO3-, a valence bond and e is from 1 to 12, and R16is hydrogen or C1-C4alkyl; and

O (a) - straight or branched alkyl, alkoxyalkyl or (oligo-alkoxy)alkyl containing 6 or more, mostly 6-24, carbon atoms, unsubstituted or substituted by fluorine atoms and containing one or more double or triple bond, or

(b) a siloxane group - (CR216a)qq(SiR216b)(OSiR216)ppR16bin which the substituents R16a- same or different, and are hydrogen or alkyl (C1-C4or aralkyl, such as benzyl or venetiam, Deputy R16bis alkyl (C1-C4, qq is from 1 to 6 and pp is from 0 to 49.

Preferred comonomers of formula (VI) with group O, include compounds of formula (VII) and (VIII):

< / BR>
< / BR>
where R14, A1, K1and Q above in reference to formula (VI). Preferably in compounds of formula (VII) R14is hydrogen, stands akrilovoi, methacrylic or metacrilato acids.

In the compounds of the formula (VIII) K1can, for example, be a valence bond. If K1- the group, the prevailing values of l from 1 to 6, more likely 1, 2 or 3 and especially l = 1. If K1group -(CH2)lNR16-, -(CH2)lOC(O)NR16-, -(CH2)lNR16C(O)O-, -(CH2)lNR16C(O)-, -(CH2)lC(O)NR16- or -(CH2)NR16C(O)NR16-, R16- mostly hydrogen, methyl or ethyl, especially hydrogen.

In the compounds of the formula (VIII), the vinyl group is mainly in paraprotein to the group - K1-Q.

Preferably Q is an alkyl or perakyla, possibly containing one or more etheric oxygen atoms and possibly one or more double or triple bonds. The most probable values of Q:

the alkyl group of the formula -(CR217)mCR317where group - (CR217) is the same or different and in each group - (CR217- the substituents R17- same or different, each substituent R17is hydrogen, fluorine or C1-C4the alkyl or perakyla and

m = 5-23, if O does not contain fluorine atoms;< carbon atoms in each alkyl part, unsubstituted or substituted by one or more fluorine atoms; or

(oligo-alkoxy)alkyl group of formula -[(CR218)nO]o(CR218)nR18where group - (CR218) is the same or different, each substituent R18is hydrogen, fluorine, C1-C4the alkyl or perakyla, and n is from 2 to 6, mostly 3-4, and o is 1 to 12.

If Q is a group -[(CR218)nO]o(CR218)nR18where all groups R18are hydrogen and in all the groups -[(CR218)nO]- n equals 2, the group of formula Q is not able to form strong secondary interactions with the hydrophobic surface. While the remains of these monomers may be incorporated in the polymer of the invention, it is usually necessary to include the remains of comonomers that can cause a strong secondary valence interactions, if these interactions link the polymer to the surface. Monomers which have groups containing oligo (higher alkylene) oxide part, able to create strong secondary valence interactions, i.e., monomers containing oligoanilines part, in which at least 50 mol.% individualid/propylene oxide) side chain has more elements of propylene oxide, than of ethylene oxide.

When Q is an (oligo-alkoxy) alkyl group containing a residue -[(CR218)nO] -, where n = 2, then predominantly n = 2 for balance -[(CR218)nO]- with not more than 50 mol.%.

Moreover, Q can be a group, alkyl, CNS or (oligohaline) alkyl part of which alkyl or alkylene is replaced by the relevant alkenyl, quinil, albaniles or akinyan-substituents.

Preferred groups Q include alkyl, alkoxyalkyl and (oligohaline)alkyl groups may contain one or more carbon-carbon double or triple bond and consisting of 8 or more, mostly 10 or more, more likely 12 or more, for example 14 or more, as many as 16 or more carbon atoms. Such groups can contain one or more fluorine atoms and alkyl fluoride are therefore derived. More likely, however, that such groups do not contain fluorine atoms.

Particularly preferred groups which are straight alkyl or alkyl fluoride chain may contain one or more carbon-carbon double or triple bonds.

When Q is a siloxane group, the group -(CR2

most likely is hydrogen. Preferred values qq - 2 to 4, more likely 3. Group -(SiR216b) may be the same or different, mostly the same, and each of the substituents R16bmost likely methyl. Preferred values of pp from 4 to 29. The most preferred monomers with Q in the form of a siloxane group expressed by the formula (VII).

In one specific embodiment of the group Q contains no unsaturated part, i.e. a carbon-carbon double or triple bonds.

Particular examples of comonomers containing an alkyl, alkyl fluoride or siloxane group are n-dodecylmercaptan, octadecylammonium, hexadecimalscalar, 1H,1H,2H,2H-heptadecafluorooctyl, p-octillery, p-dodecylthio and siloxanes containing end monomethacrylate group.

Comonomers containing physically adsorbing alkyl or foralkyl substituents that do not contain carbon-carbon double or triple links, or siloxane Deputy of the formula (VII) and (VIII) are commercially available or can be obtained by conventional techniques using known reactions.

In the second specific vopl the e or triple bond. Such comonomers may, for example, contain vinyl, divinely, acetylene or diacetylene part. Comonomers containing acetylene part, in more preferred than those containing ethylene part, especially those comonomers which include single acetylene group.

Comonomers containing such unsaturated group capable of sew linear macromolecules of the polymer in applying it to the substrate, as well as link it to the substrate by physical adsorption. Such crosslinking improves the stability of the coating and is usually carried out using radiation, for example UV or irradiation. The stitching of such groups can be used, or one, or in combination when added to the co monomer containing the reactive group of the crosslinking of the co monomer described below.

Particularly preferred crosslinking comonomers which are capable of contacting the surface by physical adsorption, formula (VIIA) and (VIIIA):

CH2= CR14-C(O)-A-QQ (VIIA)

< / BR>
in which R14, A1and K1defined above, QQ is an alkyl group containing 6 or more carbon atoms or one or two, mostly one carbon-carbon triple snie gives as an additional feature of the comonomers of the formula (VIIA) and (VIIIA).

For such comonomers most preferred values QQ represent groups containing from 6 to 24 carbon atoms, mostly 8 or more, more likely 10 or more, better 12 or more, for example 14 or more, most likely 16 or more carbon atoms.

It is also desirable that the QQ group did not contain a limit Deputy acetylene part, i.e., group - CCH .

It is more likely that the QQ group is 7-dodecenyl and specific examples of the compounds of formula (VIIA), containing such a group is dodec-7-yl-1-ol.

The compounds of formula (VIIA) and (VIIIA) and other comonomers of the formula (VII) and (VIII) containing unsaturated adsorbing group, can be obtained by known methods. This technique is shown in example 5.

b) Comonomers containing reactive group

The comonomers that are most suitable for bonding with the hydrophilic surface, include a functional group that contain reactive substituents covalently bind to the surface, have the General formula (IX):

Y2-Q1(IX)

where Y2unsaturated curable group selected from:

< / BR>
or

< / BR>
where R19- hydrogen and/SUB>OC(O)O-,

-C(CH2)qNR20-, -(CH2)qNR20C(O)-, -(CH2)qC(O)NR20-, -(CH2)qNR20C(O)O-

-(CH2)qOC(O)NR20-, -(CH2)qNR20C(O)NR20in which groups R20- same or different), -(CH2)qO-, -(CH2)qSO3-, or a valence bond and q is from 1 to 12 and R20is hydrogen or C1-C4alkyl; and

Q1- reactive group capable of covalent binding to the surface.

Preferred comonomers of formula (IX) having a reactive group Q1include the compounds of formulas (X) and (XI) below.

The compounds of formula (X) are:

< / BR>
where R19is defined above in reference to formula (IX), Q2- reactive group.

Mainly in compounds of formula (X) R19is hydrogen, methyl or ethyl, more likely, methyl, so that the compounds of formula (X) are often derivatives of acrylic, methacrylic or metacrilato acids.

Q2mainly is hydrogen, especially - OH, or a group of the formula:

-T-B7-Q3,

where T Is-O-, -NR21- where R21-respectfully, straight or branched alkylen, oxyalkylene or oligo-oxyalkylene, and

Q3- reactive group capable of covalent binding to a surface, such as aldehyde or silane, or siloxane group containing one or more reactive substituents such as halogen, for example chlorine, alkoxy, typically containing from 1 to 4 carbon atoms, such as methoxy or ethoxyl, or most probable values of Q3is hydroxyl, amino, carboxyl, epoxy, -CHOHCH2Hal (in which Hal is a halogen atom such as chlorine, bromine or iodine), succinimido, toilet, such as 2-(N-methylpyridinium)toilet, treflan, imidazol-carbonyl-amino, or substituted triazine.

Mostly B7is:

alkylenes a group of the formula -(CR222)r- where the groups -(CR222) is the same or different and in each group -(CR222- the substituents R22- same or different, each substituent R22is hydrogen or C1-C4alkyl, preferably hydrogen, and r is 1 to 12, especially 1 to 6;

oxyalkylene group, such as alkoxyalkyl having from 1 to 6 carbon atoms in each alkyl part; or

oligo-UP>23
)- - the same or different and in each group -(CR223- the substituents R23- same or different, and each R23is hydrogen, C1-C4alkyl, preferably hydrogen, and s is from 1 to 6, especially 2 or 3, and t is from 1 to 11, mostly 1-5.

Preferred groups B7include alkylene, oxyalkylene oligo-oxyalkylene containing up to 12 carbon atoms.

If Q3- silane or siloxane group, then B7mainly is alkalinous group of from 1 to 6, especially 2 to 4, more likely 3 carbon atoms.

Examples of group B7are-CH2-, -CH2CH2- and -(CH2)6.

The compounds of formula (XI) are:

< / BR>
where K2defined above in reference to formula (IX);

B8- straight or branched Allenova, oxyalkylene or oligo-oxyalkylene chain;

Q4- reactive group capable of covalent binding to a surface such as an aldehyde group, or a silane or siloxane group containing one or more reactive substituents such as halogen, for example chlorine, or alkoxy, typically containing from 1 to 4 atoxyl, epoxy - CHOHCH2Hal (in which Hal is a halogen atom such as chlorine, bromine or iodine), succinimido, toilet, triplet, imidazolecarboxamide, substituted triazine group.

In the compounds of formula (XI) minimalna group is mainly in paraprotein to the group-K2-B8-Q4.

K2you can, for example, be a valence bond. If K2the group mainly has values from 1 to 6, more likely 1, 2 or 3 and especially 1. If K2group -(CH2)qNR20, -(CH2)qOC(O)NR20-, -(CH2)qNR20C(O)O-, -(CH2)qNR20C(O)-, -(CH2)qC(O)NR20- or -(CH2)qNR20C(O)NR20, R20is hydrogen,

methyl, ethyl, especially hydrogen.

Preferably B8is:

alkalinous group of the formula

-(CR224)u- where the groups -(CR224) is the same or different and in each group -(CR224- the substituents R24- same or different, each substituent R24is hydrogen or C1-C4mainly hydrogen, and u is from 1 to 12, especially 1 to 6;

oxyalkylene group, such as alkoxyalkyl containing from 1 to 6 atoms of the>]w(CR225)v- where the groups -(CR225)- - the same or different and in each group -(CR225- the substituents R25- same or different, each substituent R25is hydrogen, C1-C4alkyl, preferably hydrogen, and v is from 1 to 6, especially 2 or 3, and w is 1 to 12, especially 1 to 6.

Preferred groups B8include alkylene, oxyalkylene and oligo-oxyalkylene group containing up to 12 carbon atoms. In one embodiment of the B8and K2hold together up to 12 hydrogen atoms.

Examples of comonomers having a reactive group are chloromethylstyrene, methacrylic acid, 2-aminoethanethiol, 2,3-epoxypropanol, 3-chloro-2-hydroxypropylmethacrylate, 2-methacryloyloxy-ethyl-dihlotiazid, 3-chloro-2-hydroxypropylmethacrylamide and glycidylmethacrylate and reactive esters of methacrylic acid, containing the group HetC(O)O-, in which Het is a heterocyclic residue, e.g. benzotriazole or imidazole and reactive esters of methacrylic acid, containing the group R16OC(O) in which R16- succinimido or pentafluorophenyl group.

The most preferred comonomer the lat.

Comonomers with reactive groups capable of covalently contact surface having formula (X) or (XI) are commercially available or can be obtained by conventional methods.

The comonomers of the formula (X), which are dichlorotriazinyl monomers, can be obtained in a known manner, for example by reaction of substituted hydroxy-alkyl (ALK) acrylate or aminoalkyl (ALK) acrylate with trichlorotriazine in a suitable solvent in the presence of a base.

The comonomers of the formula (XI), which are esters of methacrylic acid, in which the ether group contains imidazole group can be obtained in a known manner by the reaction of substituted hydroxyalkyl (ALK) acrylate (i.e., 2-hydroxyethyl(meth)acrylate), polyethylene oxide(meth)acrylate or polypropyleneoxide(meth)acrylate with 1,1-carbonyl-diimidazole in a dry solvent. A similar method can be used when receiving operations and pentafluorophenyl esters of methacrylic acid of the formula (X), by reaction with reactive esters, anhydrides of the acids or anhydrides of acids.

If comonomers containing reactive group are used for covalent linking of the copolymer with powerha surface, moreover, these are not involved in the linking group can participate in other chemical processes. Such groups can in particular be the connection points, such as ligands to the polymer while applying it to the substrate.

Comonomers containing reactive group, such as compounds of formula (X) and (XI) can be used as comonomers containing crosslinking groups, which react with other crosslinking groups better than the monomer, which covalent is associated with the surface.

If comonomers containing reactive group is used as the cross-linking groups, a crosslinking group and/or copolymerization conditions are selected so that when the copolymerization is not happening stitching, the product of the copolymerization will be a seamless linear copolymer, which can subsequently be crosslinked after application of the copolymer to the surface to enhance the stability of the coating. Cross-linking of linear polymer chains it may occur either between two cross-linking groups, or between cross-linking and inert groups of the remainder of the co monomer-diluent (presented later). Such stitching may be performed or a direct reaction SS="ptx2">

The remains of such comonomers may therefore be present in the polymers, which are intended for application on a hydrophobic surface and which contain residues of the monomer having a group with a constant positive charge, formula (VA), (VB) or (VC) or co monomer having alkyl, totoralillo or siloxane group of the formula (VII) or (VIII). Similarly, the remains of such comonomers may also be present in the polymers that are designed to bind to the surface via ionic interactions, which contain residues of compounds of formula (XIII) or (XIV) as shown below.

The most preferred reactive comonomers, which are used for stitching of co monomer and who better than the comonomers that provide covalent binding to the surface, are compounds of the formula (X) or (XI) in which Q2or Q4contain such cross-linking group, as stylepacks- -CHOCH2Hal (in which Hal is halogen), oximeter, silyl such unsaturated cross-linking group, as acetylene, diacetylene, vinyl, divinely, acetoacetate, chloralkali, mainly Kharatishvili.

Examples of comonomers containing by what acrylate, hydroxyethylmethacrylate, 3-(trimethoxysilyl)propylbetaine, 2-acetoacetotoluidide, 3-(vinylbenzyl)-2-chloramination.

When the polymers of the invention containing a crosslinking group, put on a surface, the polymer is essentially located in unstitched form. After coating the crosslinking groups, which increases the stability of the polymer coating.

Comonomers containing an ionic group

Preferred comonomers containing an ionic group capable of binding with the surface via ionic interactions, expressed by the formula (XII):

Y2-B9-Q5(XII),

where Y2- polymerized ethylene-unsaturated group selected from:

< / BR>
or

< / BR>
where R26is hydrogen, C1-C4alkyl;

A ' is - O - or-NR27- where R27is hydrogen or C1-C4alkyl, or R27group-B9-Q5;

B9is a valence bond, a straight or branched alkylen, oxyalkylene or oligo-oxyalkylene;

K3group -(CH2)xOC(O)-, -(CH2)xC(O)O-, (CH2)xOC(O)O-, -(CH2)xNR28-, -(CH2)xNR28C(O)-, -(CH2)xC(O)NR28-, -(CH2)xNR28C(O)O-, -(CH2)xO-, -(CH2)xSO3- valence bond (usually in combination with B9and x is from 1 to 12,

and R28is hydrogen or C1-C4alkyl;

Q5- ionic group capable of contact with the surface via ionic interactions.

Preferred compounds of formula (XII) are therefore compounds of the formula (XIII) and (XIV):

< / BR>
< / BR>
where R26, A", B9, K3and Q5presented above in reference to formula (XII).

In the compounds of formula (XIII), R26is predominantly hydrogen, stands or ethyl, more preferably the stands, so that the compounds of formula (XIII) are derivatives of acrylic, methacrylic or metacrilato acids.

In the compounds of formula (XIV) K3can, for example, be a valence bond. When K3- group, then x is mainly 1-6, more likely 1, 2 or 3, and especially 1. When K3group -(CH2)xNR26, -(CH2)xOC(O)NR26-, -(CH2)xNR26C(O)O-, -(CH2)xC(O)NR26- or -(CH2)xNR26C(O)NR26-, R26- mostly hydrogen, methyl or ethyl, especially hydrogen.

In the compounds of formula (XIV) minimumdistance B9is:

alkalinous group of the formula

-(CR229)y- where the groups -(CR229) is the same or different, in each group -(CR229- the substituents R29- same or different, each substituent R29is hydrogen or C1-C4alkyl, preferably hydrogen, and y is from 1 to 12, mainly 1-6;

oxyalkylene group, such as alkoxyalkyl having from 1 to 6 carbon atoms in each alkyl part, or

oligo-oxyalkylene group of formula -[(CR230)yyO]xx(CR230)yy- where the groups -(CR230)- - the same or different and in each group -(CR230- the substituents R30- same or different, each substituent R30is hydrogen or C1-C4alkyl, preferably hydrogen, and yy is from 1 to 6, especially 2 or 3, and xx is 1 to 12, especially 1 to 6.

Preferred groups B9include alkylene, oxyalkylene, oligo-oxyalkylene containing up to 12 carbon atoms.

Examples of groups B9are-CH2-, -CH2CH2- and -(CH2)6-.

Group Q5can be either anionic or cationic, depending on the nature of the cover p is p carboxylate, sulfonate, phosphate or phosphinate. Where the surface is anionic surface charge, the group Q5be cationic, for example, the group NR331in which the substituents R31- same or different, and represent hydrogen or C1-C6alkyl, two Deputy R31together can form a heterocyclic ring consisting of 5-7 atoms, most likely R31is hydrogen or methyl, a group of NHet, where Het is an unsaturated heterocyclic residue, such as pyridyl, substituted or unsubstituted, one or more C1-C4alkilani, a group of PR232in which the substituents R32may be the same or different, and represent hydrogen or C1-C6alkyl, two Deputy R32together can form a heterocyclic ring containing from 5 to 7 atoms, the most likely R32is methyl.

The most preferred comonomers having an ionic group are acrylic, methacrylic acid, 2-sulfoaildenafil, 2-methacryloyloxyethyl, and p-styrelseledamot acid, 2-(methacryloyloxyethyl)ammonium chloride, 3-aminopropionitrile, vinelott ion interaction, and expressed by the formula (XIII) and (XIV) are commercially available or can be synthesized by conventional methods.

The comonomers - thinners

In addition to (a) residues of monomers containing a group of permanent positive charge or (b) residues of comonomers containing group, a permanent positive charge and comonomers capable of contact with the surface, the polymers of the present invention may include the remains of the co monomer-diluent.

Such diluents are used in order to obtain a polymer with the desired mechanical and physical properties. It can be known radically polymerized, mainly ethylene-unsaturated, comonomers, compatible with other comonomers.

Examples of comonomers-thinners are alkyl(ALK)acrylates containing from 1 to 4 carbon atoms in the alkyl essential parts, such as methyl(ALK)acrylate, dialkylaminoalkyl(ALK)acrylate, mainly containing in each alkyl part of the amine from 1 to 4 carbon atoms and from 1 to 4 carbon atoms in alkalinous chain, such as 2-(dimethylamino)ethyl(ALK)acrylate; alkyl(ALK)acrylamide, mainly containing from 1 to 4 atoms peoplered hydroxyalkyl part, for example, 2-hydroxyethyl(ALK)acrylate, or a vinyl monomer such as N-vinylacetat, mainly containing from 5 to 7 atoms in the lactam ring, such as vinyl pyrrolidone; styrene or derivatives of styrene, having the substituents in the phenyl ring, such as one or more alkyl groups with 1-6, especially 1-4, carbon atoms and/or one or more halogen atoms such as fluorine, is-(pentafluorophenyl)styrene.

Other suitable comonomers-diluents are, for example, (ALK)acrylates and (Ala)acrylamide sugars, in which the alkyl group contains from 1 to 4 carbon atoms, such as the acrylates methacrylates, ethacrylate, acrylamide, methacrylamide and ethacrynic sugars. Suitable sugars are glucose and sorbitol. Examples of comonomers of diluents of this type are methacryloyloxy or Methacrylonitrile.

Additional diluents which may be offered include polymerized alkenes, especially with 2-4 carbon atoms, for example ethylene, diene, such as butadiene, alkylene anhydrides, for example maleic anhydride, and cyan-substituted alkylene, such as Acrylonitrile.

The comonomers diluent receive the usual known methods. From rassmussen and mechanical properties of comonomers, containing them. Others, such as hydroxyl(ALK)acrylates and polyhydroxy(ALK)acrylates, in addition what are the modifiers of the physical and mechanical properties have a specific reactivity. Such comonomers containing functional groups such as hydroxyl groups, which react with crosslinking groups or other reactive groups in other molecules to attach them to the copolymer.

Also it is shown that the alkyl(ALK)acrylates containing 6 or more carbon atoms in the alkyl part may be considered or as comonomers diluent, or as comonomers, are capable of binding the polymer to a surface by physical adsorption. In particular describes that a copolymer containing such comonomers as diluent and reactive comonomers capable of covalently contact surface, can be used for coating on a hydrophilic surface, while reactive comonomer enables linking of the polymer with the surface, and the solvent modifies the physical and chemical properties. However, such comonomer can be applied to a hydrophobic surface, in this case, comonomer-razbavitelyami covalently bind to the surface, will act as cross-linking of comonomer.

According to the features of this invention, the polymers can be obtained by using:

(a) copolymerization of co monomer containing a group of permanent positive charge, mainly zwitterion group, and co monomer containing a group capable of stably bind the polymer to the surface and, optionally, a diluent and/or cross-linking of the co monomer; or

b) polymerization of a monomer containing a group having a center of permanent positive charge, mainly zwitterion, and the group is able to stably bind the polymer to the surface, additional co monomer containing a group capable of stably bind the polymer to the surface and diluent and/or cross-linking of the co monomer.

For polymerization may be used any conventional methods, such as thermal or photochemical polymerization. If the polymer film contains comonomers capable of crosslinking, polymerization conditions are selected so that the polymerization did not occur stitching. So, for example, actinic radiation is not used to produce polymers containing comonomer that crature from 40 to 100oC, especially 50-80oC. For photochemical polymerization using actinic radiation such as UV, microwave, and visible radiation. Usually used UV irradiation with a wavelength of 200-400 nm.

The polymerization is usually performed in a reaction medium, which is, for example, a solution or dispersion, using as solvent acetonitrile, dimethylformamide, chloroform, dichloromethane, ethyl acetate, dimethyl sulfoxide, dioxane, benzene, toluene, tetrahydrofuran, or, if the polymer does not contain groups which react with proton solvents, water or alcohols containing from 1 to 4 carbon atoms, i.e. methanol, ethanol or propan-2-ol. Or a mixture of any of the aforementioned solvents.

The polymerization can be performed in the presence of one or more polymerization initiators such as benzoyl peroxide, 2,2-azo-Benz(2-methylpropionitrile) or benzoylmethylene ether. Other polymerization initiators that can be used are listed in "Polymer Handbook", 3rd edition, Ed.J. Brandrup and E. H. Immergut, Pub. Wiley. Interscience, New York, 1989.

As a rule, the polymerization is performed within 1-72 hours, mainly for 8-48, for example, for 6-24 hours, in an inert atmosphere, such as azon) or ultrafine filtration. The resulting polymer is dried, usually in a vacuum, 5-72 hours, and he has a molecular weight of from 10,000 to 10 million, mostly from 20,000 to 1 million.

Upon receipt of the copolymers according to the present invention, containing the remains of the co monomer including a group from the centre of permanent positive charge, and the remains of the co monomer comprising a group capable of stably bind the polymer to the surface, the exact value of such comonomers and their nature can be adjusted in order to obtain copolymers, the most suitable for their application, the coating on the surface. Thus can be chosen such proportion of the co monomer containing a group capable of stably bind the polymer to the surface, which would provide effective physical adsorption on a hydrophobic surface in accordance with the number of functional groups on the surface or would provide effective binding through ionic interactions with the surface.

Similarly, the ratio of co monomer containing a group of permanent positive charge, and diluent and / or cross-linking of the co monomer, can be adjusted to the desired biocompatibility, as well as physically is more of the same types of comonomers, contains a group of permanent positive charge, comonomers containing group, stably binding the polymer to a surface or cross-linking of the comonomers and/or comonomers-thinners.

Similarly, polymers containing residual monomer including a group from the centre of permanent positive charge and a group capable of stably bind the polymer to the surface, the nature of these groups allows you to adjust the desired biocompatibility, the efficiency of binding of the polymer to the surface, as well as physical and mechanical properties. If you're also using a diluent and/or a crosslinking monomer, the nature of the diluent and/or cross-linking of the co monomer and their ratio can also adjust the properties. In addition, note that to obtain the considered combination of properties use more than one type of monomer containing the group of permanent positive charge and a group of stably binding the polymer to the surface, and/or more than one type of diluent and/or cross-linking of the co monomer.

The composition of the monomer that undergoes polymerization to form the polymer of the invention, includes a minimum of 0.01%, mainly 1% better 5% weight is 9%, mostly 99%, most likely 95% of the weight of other monomer or monomers. Such another monomer

or the monomer may be a monomer or monomers containing a group of stably binding the polymer to the surface, the monomer or monomers, diluent and/or a crosslinking monomer or monomers.

The composition of the monomer, in addition, includes a minimum of 0.01%, mainly 1%, more likely 5% by weight of monomer or monomers containing a group capable of stably bind the polymer to the surface and a maximum of 99.9%, mainly 99%, most likely 95% of the weight of other monomer or monomers. Such other monomers may be monomers containing a group with a permanent positive charge, monomers, diluent and/or cross-linking monomers.

Note that if at least some of the monomers containing the group of permanent positive charge, also contain a group capable of stably bind the polymer to the surface, the ratio of the content of both these groups in the polymer is provided by the ratio of these groups in the monomer. In such cases, the polymer may be homopolymer monomer containing both these groups.

If the polymer is associated with over the military is not more than 90%, better not more than 80% of the weight of monomer or monomers containing alkyl, alkyl fluoride or siloxane Deputy, which are capable of binding the polymer to a surface by physical adsorption and which do not contain groups with constant positive charge, and balanced composition of the monomer or monomers containing a group of permanent positive charge, the monomer or monomers, diluent and/or a crosslinking monomer or monomers. Such a composition typically comprises up to 50% by weight of co monomer or comonomers-thinners. If there are comonomer is thinner, it is at least 1%, mainly 5% by weight of the total composition of the comonomers. If there is a crosslinking comonomers, they are, as a rule, from 0.1% to 20% by weight of the total composition of the comonomers.

If different comonomers provide a centre of permanent positive charge and physical adsorption, it is likely molar ratio in the copolymer residue of the co monomer with a center of permanent positive charge to the remains of the co monomer containing alkyl, alkyl fluoride or siloxane Deputy, capable of binding the polymer to a surface by physical adsorption, is from 50 to 25% molar, residues of monomer-diluent and/or from 0.1 to 20%, mainly from 1 to 10% molar, cross-linking residues of co monomer, and, if present in the residues and diluent, and a crosslinking monomer, they do not exceed the amount of 50%, mainly 35% molar.

If the polymer binds to the surface covalently, then the most likely composition of the monomers includes no more than 25%, mainly up to 20% and better up to 15% of the weight of monomer or monomers containing a group capable of covalently bind the polymer to the surface, and which does not include the group of permanent positive charge, and balanced composition of the monomer or monomers containing a group of permanent positive charge and possibly the monomer or monomers-thinners.

Such a composition typically comprises up to 95%, mainly 90% by weight of co monomer or comonomers-thinners. If there is comonomer-diluent, preferably it is at least 5%, mainly 10% by weight, of the total composition of the monomers.

Probable molar ratio in the copolymer residue of comonomers having a center of permanent positive charge, to the remains of comonomers containing reaktsionnosposobnykh is also the copolymer is likely to include from 5 to 50%, mostly from 10 to 25% molar, of the residues of the monomer-diluent and/or from 0.1 to 20%, mainly from 1 to 10% molar, cross-linking residues of co monomer, provided that if there are remnants and thinners, and cross-linking of the co monomer, they do not exceed the combination of 50%, mainly 35% molar.

If the polymer binds to the surface of the ion interaction, it is likely molar ratio in the copolymer residue of the co monomer with a center of permanent positive charge to the remains of the co monomer containing an ionic group, linking the polymer with the surface ion interaction is from 5:95 to 95:5, mostly from 50:50 to 90:10. Additionally, the copolymer mainly consist of from 5 to 50%, most likely from 10 to 25% molar, of the residues of the monomer-diluent and/or from 0.1 to 20%, most likely from 1 to 10% molar, cross-linking residues of co monomer, provided that if there are remnants and thinners, and cross-linking of the co monomer, they do not exceed the combination of 50%, mainly 35% molar.

In addition, the composition of monomers or comonomers may include additional components, such as initiators of polymerization, the regulator extent on the quantity of from 0.1 to 5%, usually from 0.2 to 3%, mainly about 0.5% by weight, each relative to the total weight of monomers.

As additional features of the present invention provides a method of obtaining a biocompatible surfaces, which comprises applying a polymer coating on a surface according to this invention. Depending on the nature of groups in the polymer capable of binding the polymer to a surface, the polymeric coating can be applied on various types of surfaces.

Especially suitable for coating hydrophobic surfaces, i.e. surfaces of polyethylene, polypropylene and polytetrafluoroethylene, polymers containing residues of monomers comprising alkyl, alkyl fluoride or siloxane groups, capable of binding the polymer to a surface by physical adsorption. Most successfully for surface coating of polytetrafluoroethylene use of fluorinated polymers.

The hydrophilic surface may become hydrophobic, and can be applied using a polymer coating known methods (see, for example, "Chemical Reactions of Polymers" Ed. E. M. Fettes, 1964, Interscience, London).

Processing this polymer is generally performed by coating the surface with a solution, dile or mixtures thereof, for example, methanol, ethanol, dichloromethane or freon. Treatment is usually performed at room or elevated temperatures, such as from 5 to 60oC.

In one specific embodiment of the invention the copolymer is applied to the surface in the form of microdisperse, such as microemulsions.

If the polymer comprises residues of a monomer containing a crosslinking group, it may be crosslinked after coating the surface with a known method of crosslinking crosslinking groups. The crosslinking can be carried out, for example, thermally, using actinic radiation, the change in pH with the use of reactive gases, such as ammonia, using difunctional additives or chemical activation, for example by known methods described in "Methods in Enzymology, volume 135, Immobilised Enzymes and Cells, part B, Ed K. Mosbach, Academic Press Inc., New York, 1987.

This activation can be performed at a dry coating, thermal method, or when the processing gas. Or for when you need a change in pH or cover the material in solution, which is not removed by the floor.

Especially suitable for processing the polymers of the invention containing a monomer comprising a group pic is Roxy, carboxyl or amino group. If necessary, the surface of the substrate before the processing can optionally be supplied with functional groups. Functional groups must be entered on a surface that does not have them, before processing the polymer. This process can be performed by known methods of etching or synthetic derivatives, such as plasma discharge, which enters the corresponding functionality of the surface (see, for example, "Chemical Reaction of Polymers" Ed. E. M. Fettes, 1964, Interscience, London).

In some cases you also need to activate the functional groups on the surface of the substrate and/or reactive groups of the polymer of the invention. This can be achieved by known methods using known activating agents such as carbodiimide, such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. Other suitable activating agents are presented in "Methods in Enzymology", mentioned above. It is shown that the appropriate methods of activating groups in the polymer can also be used for the connection of such parts as ligands to the polymer in the coating process on the substrate.

The processing of this polymer, as a rule, is obrabotka, as a rule, is performed at a temperature of from -5 to 50o, for from 0.1 to 24 hours and at a pH from 2 to 13.

For processing the polymers of the present invention containing residues of monomers having a group linking the polymer with the surface ion interaction, the most appropriate surface having ionic groups, such as carboxyl, sulphonate, phosphate, ammonium or postname.

If necessary, the surface of the substrate before the processing can be further provided with functional groups. On the surface, which have no ionic groups, should these groups be entered before processing them by the polymer. This process can be performed by known methods of etching or obtain derivatives, for example, using a plasma discharge, which enters the corresponding functionality of the surface (see, for example, "Chemical Reaction of Polymers" Ed. E. M. Fettes, 1964, Interscience, London).

The processing of this polymer, as a rule, is performed by processing the surface of the polymer solution, mostly alcoholic, aqueous-alcoholic or aqueous solution. Treatment most likely is carried out at a temperature of from -5 to 50oC, for from 0.1 to 24 hours and at a pH from 2 to 13.

The materials on the surface of which according to this invention is applied coating, can be used as construction material for implants or prostheses for humans or animals, especially if these implants or prostheses are in direct physical contact with blood and if you want to ensure biocompatibility and especially hemocompatibility, such as heart valves. The materials can also be used to create membranes and other devices in contact with blood or other body fluids, for example in the devices constituting the artificial heart, lungs, kidneys.

In addition, the polymers of the invention can be used to cover materials used in devices and appliances, laboratory equipment used when working with biological fluids, such as separation membranes and other. Especially the materials of the invention are suitable for use for modifying the surface properties of membranes for biofiltration in bioreactors and enzymatic systems, if these membranes are in direct contact with the integrated biologiczna particularly suitable for reducing the contamination of the membrane components used solution.

If the polymers of the present invention are used for coating the surface of a material, which is then used to create coatings of end devices, it is necessary to conduct special stage, which would protect the coating from damage and to preserve the effectiveness of the coating up to the final device.

In addition, the polymers of the present invention can be used for coating implants, dentures, contact lenses, intraocular lenses, and other devices that cause the polymer coating according to the present invention to enhance their biocompatibility.

Thus, the invention provides a device surface with a polymer coating.

Drawing compares Micrography scanning electron microscope Polimeni surfaces, treated and not treated with the copolymer of the invention and then come in contact with blood. Fig. 1 (a) shows Micrography scanning electron microscope (h) untreated poly(kidney) without subslot plate. Fig. 1 (b) shows Micrography scanning electron microscope (h) plate poly(acrylic acid) with subclaim of poly(imide), the less is the example 8.

Examples

The following methods of analysis were used to assess the polymeric coating of the present invention.

Adsorption of proteins using enzyme immunoassay.

This method determines the adsorption surface fibrinogen person. The method can be easily modified to determine the adsorption of other proteins.

Discs (7 mm in diameter) raw material (as a control) and treated with polymer material, as described below, were prepared, washed with phosphate saline buffer at least 10 minutes, in the recesses of the blade. Samples were incubated with human plasma (300 μl) for 10 minutes and then washed 3 times with phosphate saline buffer. Each of the test samples and each of the control samples were treated for 30 minutes with antibodies specific for fibrinogen person (300 ml) and then 3 times washed with phosphate saline buffer. As a control for nonspecific binding of antibodies with samples of each sample were incubated for 30 minutes with nonspecific antibody (300 μl). Conjugate of horseradish peroxidase secondary antibody specific for the first antibody (300 μl) was added to the test samples, IATA, was added a solution of 2,2-Azino-bis(3-ethyl-benzothiazoline-6-sulfonic acid (ABTS) in phosphate-citrate buffer (300 μl, 0.6 mg/l), the reaction was carried out for 10 minutes. Then aliquot of the mixture (200 μl) was removed and added to a solution of citric acid and of sodium azide in distilled water (20 μl, 0.21 g/ml and 2 mg/l, respectively). The optical density of the solutions was measured with an automated device Techgene at 650 nm using a standard solution ABTS.

Alternative methods each sample was placed in a deepening of the new blade, was treated with a solution of o-phenylenediamine (PDA) in phosphate-citrate buffer (300 μl, 0.4 mg/ml) instead of the solution ABTS and reaction was performed for 10 minutes. Then from each of deepening the selected aliquot of the mixture (200 μl), was measured by the instrument Techgene the optical density of the solution at 450 nm, as a standard solution was used to the FDA.

The study of the activation of particles

Blood samples were collected using the dual syringe in healthy adult volunteers, and the first 5 ml of blood was discarded. The blood was placed in a plastic tube into the solution trinacria citrate (32 g/l) in the ratio of 9 volumes of blood to 1 volume of citrate. The samples were passed before use at room the Ala in quality control and material the treated polymer, as described below, were prepared and placed in the recess of the blade. Samples were incubated for 30 minutes with a fresh blood with citrate (200 μl) on a rotary mixer, and then washed 4 times with phosphate saline buffer. Activation of the particles was measured by a proprietary method [Lindon. J. N. et al. , Blood, 68, 355 (1986) and British Patent Application N 91-25721.2].

Alternative methods half of the tested samples were incubated with blood with citrate (200 μl) and the remainder were incubated for 30 minutes with ethylendiaminetetraacetic acid (EDTU) treated with blood on phase vibrator, washed 4 times with phosphate saline buffer. Activation of the particles was measured by the method described above to detect proteinb enzyme immunoassay using antibodies against GMP140 to detect the presence of the activation marker particles on the surface of the biomaterial. In the presence of EDTU, which extracts calcium from internal particles, the activation is inhibited so that incubation with EDTU-treated blood acts as a control for nonspecific activation, eliminating the need for incubation with specific antibody.

Analysis of the binding of C-reactive protein (CRP)

C-reaktionerne group, for example phosphorylcholine that is attached to the surface.

Discs (7 mm in diameter) of the raw material and the material treated with a polymer, as described below, were prepared, washed with HEPES-buffered saline (NAS) solution for 10 minutes in the recesses of the blade. Samples were incubated for 45 minutes in an enzyme solution containing bovine serum albumin (ABS) (40 mg/ml) and PSA (0.012 mg/ml) in the NBS and calcium chloride (1 mm). In parallel, the same samples (coated and uncoated) were incubated or ABS/Ca2+the solution without the PSA, anti-lock brakes/PSA/Ca2+the solution in the presence of soluble phosphorylcholine (1.5 mg/ml), or anti-lock brakes/PSA solution containing EDTU (20 mm), better than calcium chloride.

After incubation, all samples were washed 3 times with phosphate saline buffer, incubated 1 h in G 300 ál conjugate commercially available antibodies anti-PSA with horseradish peroxidase; dilution 1:100, washed 3 times with phosphate saline buffer and put on a new blade and the solution was added to the FDA (0.4 mg/ml) in phosphate-citrate buffer. The reaction was carried out for 10 minutes. Then aliquot of the mixture (200 μl) of each recess was transferred into a new deepening, measured by the optical density of the solution in the device Techgen isolated groups of phosphorylcholine, get using agarose immobilized p-aminophenylacetylene. The specificity of the PSA-binding can be shown by the inhibition of phosphorylcholine and dependence on the presence of calcium.

Example 1

Obtain poly [internal salt of 2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and dodecylmercaptan] (1:2).

2-(Methacryloyloxyethyl)-2'-(ammonium)ethylphosphate (5.0 g, 0,0170 mol) and n-dodecylmercaptan (8,55 g, 0,0340 mol) was dissolved in methanol/THF (140 ml, 5:9). The solution was stirred (250 rpm/min.) at 23oC in nitrogen atmosphere (50 ml/min) for 30 minutes, was added 0.17 g, of 1.02 mmol 2,2'-azo-bis(2-methylpropionitrile) (0.17 g, of 1.02 mmol), reduced the flow of nitrogen to 10 ml/min, raised the temperature to 60oWith that kept in these conditions for 16 hours.

The mixture was cooled, filtered under vacuum. The filtrate was collected and the polymer was planted by adding dropwise acetone (1.2 l).

The polymer was isolated by filtration under vacuum in a nitrogen atmosphere, was dried under reduced pressure overnight at room temperature. The obtained polymer (9.5 g, 70%) of fine white powder.

Alternative method 2-(methacryloyloxyethyl)-2'-(ammonium)atilf Astor was stirred (250 rpm/min) at 23oC under a flow of nitrogen (50 ml/min) for 30 minutes, was added 2,2'-azo-bis-(2-methylpropionitrile) (0,0645 g 0,39 mmol), the flow of nitrogen was reduced to 10 ml/min, the temperature was raised to 60oC. These conditions are maintained for 40 hours.

The mixture was cooled, filtered under vacuum. The filtrate was evaporated on a rotary evaporator, dissolved in dichloromethane (120 ml) and methanol (10 ml). The polymer was isolated from this mixture by precipitation in acetone (2500 ml), filtered under vacuum and dried, the polymer was re-dissolved in dichloromethane (100 ml) and methanol (30 ml) and was isolated as described above.

The final polymer was obtained with 70-80% yield, he was a white powder.

NMR (200 MHz, d ppm CD3OD/CDCl3) of 4.2 and 4.4 (d), 3,8-4,2 (d), 3,6-3,8 (d), and 3.3 (C), 1,8-2,2 (d), 1,5-1,8 (l), 1,2-1,5(C) of 0.8-1.0 (C).

IR (cm-1, KBr, disk.) 3430, 2929, 2854, 1732, 1469, 1246, 1156, 1089, 968, 788.

Elemental analysis

Theoretical: C 64,5; H 9,9; N 1,8; P 3,9.

Received: C 59,0; H 10,0; N 1,8; P 3,9.

The polymer has a relative viscosity in ethanol:chloroform (50:50) at 25oC - 1,130,02 (when obtained using methanol:THF as the solvent) and 1,260,02 (when you get using propane-2-ol:ethyl acetate as solvent).

Example 2

Receiving the allocability] (1:2).

Polyethylene strip was rinsed with ethanol, dried in the air. Poly[2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and n-dodecylmercaptan] (1: 2) (50 kg) was dissolved in ethanol/chloroform (5 ml, 40:1) and the polyethylene in the first stage coating, dipping stretched slowly through the solution. Covered so the strip was dried in a dust free atmosphere at room temperature.

The treated polyethylene showed a 65% reduction in the absorption of protein in comparison with raw material and 83% reduction in the activation of particles (determined using analysis of Lindon and others) in comparison with the untreated material.

Analysis of the binding of C-reactive proteinb showed that the binding of PSA to the treated polyethylene surface no. In contrast, PSA binding was observed for the positive control. The specificity of this PSA binding shown by the fact that fixed the inhibition by phosphorylcholine and dependence on the presence of calcium.

Example 3

In a similar way as described in example 2, were coating of poly[2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and n-dodecylmercaptan] (1:2) to sample the if compared with untreated reduced adsorption proteinb 80% and processed samples of PVC showed a decrease in adsorption proteinb 70% compared to untreated.

The subsequent conduct of the enzyme immunoassay showed that the samples of stainless steel with polymeric coating in comparison with raw material reduced the adsorption of proteins by 84%, while conducting the above analysis of the activation of particles with the use of anti-GMP140 found that samples of stainless steel was reduced by 95% activation of the particles in comparison with the untreated material. Samples of PVC polymer coating showed a decrease in protein adsorption at 87% and a reduction in the activation of particles to 100% in comparison with the untreated material.

Example 4

Obtain poly[internal salt of 2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and n-dodecylamine] (1:4).

2-(Methacryloyloxyethyl)-2-(ammonium)ethylphosphate (10,77 g, 0,0339 mol) and n-dodecylmercaptan (35,56 g, 0,1400 mol) was dissolved in propan-2-OLE (200 ml) and ethyl acetate (200 ml). The solution was stirred (250 rpm/min.) at 23oC in a flow of nitrogen (50 ml/min) for 30 minutes, was added 2,2-azo-bis-(2-methyl-propionitrile) (0,0886 g, 0.54 mol), the flow of nitrogen was reduced to 10 ml/min, the reaction temperature was raised to 60oC. These conditions are maintained for 40 hours.

The mixture was cooled, filtered under vacuum. Fuegianum in acetone (500 ml) was filtered under vacuum and dried. The polymer was re-dissolved in dichloromethane (120 ml) and methanol (10 ml) and was isolated, as shown above.

The final polymer obtained with 70-80% yield, is a white solid.

NMR (200 MHz, d ppm CD3OD/CDCl3) of 4.2 and 4.4 (d), 3,8-4,2 (d), 3,6-3,8 (d), and 3.3 (C), 1,8-2,2 (d), 1,5-1,8 (l), 1,2-1,5 (C) of 0.8-1.0 (C).

IR (cm-1, KBr disk. ) 3430, 2929, 2854, 1732, 1469, 1246, 1156, 1089, 968, 788.

Elemental analysis

Theoretical: C 68,9; H 10,5; N 1,1; P 2,4.

Received: C 65,5; H 10,8; N 1,1; P 2,4.

The polymer had a relative viscosity in ethanol:chloroform (50:50) at 25oC 1,260,02.

For samples of polyethylene, steel and PVC was applied polymer coating using the methods described in examples 2 and 3. Enzyme immunoassay showed that to become watched by more than 80% reduction of protein adsorption to PVC - more than 70%.

Samples of stainless steel with polymeric coating showed a reduction in the adsorption of proteins at 80% (determined by enzymatic immunoassay as described above) and a 95 percent reduction of activated particles (determined by analysis of the activation of the particles described above using anti - MP140) compared with untreated material. Samples of PVC polymer poccia particles for 100%.

Example 5

Obtain poly[internal salt 20(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and 1H, 1H,2H,2H-heptadecafluorooctyl] (2:1)

2-(Methacryloyloxyethyl)-2'-(ammonium)phosphate (1.0 g, 0,0034 mol) and 1H,1H,2H,2H-heptadecafluorooctyl (0,90 g, 0,0017 mol) was dissolved in methanol (10 ml) t and tetrahydrofuran (10 ml). The solution was stirred (250 rpm/min.) at 23oC in a flow of nitrogen (50 ml/min) for 30 minutes, was added 2,2'-azo-bis-(2-methylpropionitrile) (0,0167 g, 0.10 mmol), the flow of nitrogen was reduced to 10 ml/min, the reaction temperature was raised to 60oC. These conditions are maintained for 16 hours.

The mixture was cooled, filtered under vacuum, the filtrate was evaporated to dryness on a rotary evaporator, the residue was dissolved in dichloromethane (10 ml) and methanol (10 ml). The polymer was isolated from the mixture by placing in acetone (500 ml), filtered under vacuum and dried. The polymer was re-dissolved in dichloromethane (10 ml) and methanol (10 ml) and was isolated, as shown above. The final polymer obtained with a yield of 70-80%, was a white powder.

NMR (200 MHz, d ppm CD3OD/CDCl3) 4,2-4,0 (e), 3,8-4,2 (d), 3,6-3,8 (d), and 3.3 (C), 2,4-2,7 (d), 2,2-1,7 (d), 1.2 to 1.5 (e), of 0.8-1.0 (e).

The polymer used for coating the membrane of the E. the change in velocity for bovine serum albumin and a very small contamination with proteins. The change in velocity in the case of the treated membranes ranged from 6000 to 5000 l/m2/h compared to untreated membranes, for which the decrease in current velocity ranged from 5000 to 500 l/m2/H. Both measurements were performed during the two-hour period.

Example 6

Obtain poly[internal salt of 2-(methacryloyloxyethyl)-2'-ammonium)ethylphosphate and n-hexadecyl methacrylate] (1:2)

2-(Methacryloyloxyethyl)-2-(ammonium)ethylphosphate (2.00 g, is 6.78 mmol) and n-hexadecimalscalar (4,21 g, 0,0136 mmol) was dissolved in propan-2-OLE (35,5 ml) and ethyl acetate (14,5 ml). The solution was stirred (250 rpm/min.) at 23oC in a flow of nitrogen (50 ml/min) for 30 minutes, was added 2,2'-azobis-(2-methylpropionitrile) (0,0168 g, 0.10 mmol), reduce the flow rate of nitrogen to 10 ml/min, increased the reaction temperature to 60oC. These conditions are maintained for 40 hours.

The mixture was cooled, filtered under vacuum. The filtrate was evaporated to dryness on a rotary evaporator, the residue of a solution in dichloromethane (10 ml) and methanol (10 ml). The polymer was isolated from the mixture by the planting of acetone (700 ml), filtered under vacuum, dried. The polymer was re-dissolved in dichloromethane (10 ml) and methanol (10 ml) and was isolated as described(200 MHz, D. ppm CD3OD/CDCl3) of 4.2 and 4.4 (d), 3,8-4,2 (d), 3,6-3,8 (d), and 3.3 (C), 1,8-2,2 (d), 1,5-1,8 (l), 1,2-1,5 (C) of 0.8-1.0 (C).

IR (cm-1) KBr disk) 3430, 2929, 2854, 1732, 1469, 1246, 1156, 1089, 968, 788.

Example 7

Obtain poly[internal salt of 2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and 2-aminoethylethanolamine] (9:1)

2-(Methacryloyloxyethyl)-2'-(ammonium)ethylphosphate (9,96 g, 0,0335 mol) was dissolved in methanol (10 ml), was added 2-aminoheterocycles (0,05571 g, 0,0034 mol) and added water (10 ml). The solution was stirred (250 rpm/min) at 22oC in a flow of nitrogen (70 ml/min) for 30 minutes, was added 2,2-azo-bis-(2-methylpropionitrile) (0.12 g, 0.73 mmol), reduced flow rate of nitrogen to 9 ml/min, the temperature was raised to 60oC. These conditions are maintained for 16 hours.

The mixture was cooled, placed in vials centrifuge. The samples were centrifuged for 30 minutes at 4000 revolutions/minute. The samples were combined, the polymer was planted by adding dropwise to acetone (800 ml). Acetone decantation from the polymer, the polymer was washed with acetone (200 ml). The polymer was isolated by filtration under vacuum in a nitrogen atmosphere, was dried overnight in vacuum at room temperature.

IR (cm-1: KBr disk) 3435, 2029, 2096, 1732, 1628, 1245, 1166, 1089, 970.

Example 8
Polyimide samples were placed in a plasma chamber of a plasma drum device for treating and was pumped by the pump to a pressure of 0.001 mbar, was introduced into the reactor oxygen. Plasma was launched with 90W energy forward and approximately 0W back. The pressure was approximately 0.7 mbar. The plasma was switched on for 5 minutes, then the high-frequency generator (13.56 MHz) was off for some time, as the oxygen flow was stopped. The pressure was decreased, the valve of the tank with acrylic acid was opened and let in the flow of monomer into the chamber (100% acrylic acid). The vacuum was reduced to 0.3 mbar. The high-frequency generator included with 30W energy forward, 0W-back energy and perform polymerization for 20 minutes. After turning off the high-frequency generator and close the valve on the tank with acrylic acid Luggage evaporated for 5 minutes to remove all traces of monomer.

The polyimide with a layer of poly(acrylic acid) cut 4 pieces of 1.5 cm2, washed with distilled water. These slices were then added to a 1.25% solution (6.3 ml)and poly[2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and 2-aminoheterocycles)] (9:1), made of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (20 g is vannoy water and dried.

Detecting activation of the particles on the surface

The blood of healthy adult volunteers were collected using a double syringe, and the first 5 ml of blood was discarded. The blood was placed in a plastic tube into the solution trinacria citrate (32 g/l) in the ratio of 9 volumes of blood to 1 volume of citrate. The samples were passed before use at room temperature, was stirred spiral agitator. Samples in 1 cm2from polyimide with pokrytie of poly[2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and 2-aminoethylethanolamine)] (9: 1), applied as shown above, and samples of polyimide uncoated for comparison were placed in 1 ml of fresh citrate blood, incubated for 30 minutes with a spiral stirrer at room temperature. The samples were then washed in phosphate saline buffer (FSB, pH 7,4) before fixation in the aliquot part of the next solution for 30 minutes.

2 ml of 25% wt./about. glutaraldehyde

83 ml of 0.15 M FSB (pH 7,4)

15 ml of saturated picric acid

Picric acid increases the storage of lipids, proteins. The samples were again washed in the FSB, dehydrational 70% and 100% methanol, treated with acetone, dried in the air. The samples were coated with platinum spray the E.

The activated particles were not observed for samples with polymer coating, while on the raw samples recorded strong adhesion and aggregation. (see drawing). The presence of polymer on the surface was confirmed by x-ray photoelectron spectroscopy. It is shown that the processing of polyimide, firstly, acrylic acid for application of the special layer above the surface in the reaction, and then the copolymer of the present invention for coating, greatly remove the hemostatic response to the polyimide.

Example 9

Obtain poly[2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and 3-chloro-2-hydroxypropylmethacrylate] (1:1)

2-(Methacryloyloxyethyl)-2'-(ammonium)ethylphosphate (7,46 g, 25,3 mol), 3-chloro-2-hydroxypropylmethacrylate (4,51 g, 25,3 mol) and monohydrate p-toluensulfonate acid (0,1048 g, 0.55 mmol) was dissolved in methanol (101 ml) was stirred (250 rpm/min.) at 23oC in a flow of nitrogen (50 ml/min) for 30 minutes, was added 2,2'-azo-bis-(2-methylpropionitrile) (0,0843 g, 0.51 mmol), the flow of nitrogen was reduced to 10 ml/min, the reaction temperature was raised to 60oC. These conditions are maintained for 16 hours.

The polymer was isolated by the Les (40 ml), and provided, as shown above, using acetone (1000 ml).

The final polymer obtained with a yield of 62% was a solid white color.

NMR (200 MHz, d ppm CD3OD/CDCl3) of 4.2 and 4.4 (d), a 4.3-4,0 (e), 3,6-3,8 (d), and 3.3 (C), 1,6-2,4 (l), 1.0 to 1.5 (e), 0,7-1,0 (e),

IR (cm-1, KBr disk) 3416, 2959, 1727, 1655, 1490, 1247, 1165, 1088, 968, 792, 748.

Example 10

Obtain poly[2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and 7-datetimecreated] (1:2)

The polymer was obtained in the same manner as in example 4, and 6, the method using 2-(methacryloyloxyethyl)-2-(ammonium)ethylphosphate (to 8.41 g, 0,0285 mol) and n-dodecylmercaptan (14,31 g, 0,0572 mol) dissolved in propan-2-OLE (160 ml) and ethyl acetate (60 ml).

The final polymer obtained with a yield of 35%, was a white powder.

NMR (100 MHz, d ppm CD3OD/CDCl3) of 4.2 and 4.4 (d), 3,8-4,2 (d), 3,6-3,8 (d), and 3.3 (C) of 2.25 (C), 1,8-2,2 (d), 1,5-1,8 (l), 1,2-1,5 (C) of 0.8-1.0 (C)

IR (cm-1, KBr disk) 3430, 2929, 2854, 1732, 1469, 1246, 1156, 1089, 968, 788.

Elemental analysis

Theoretical: C Of 65.1; H 9,0; N 1,8; P 3,9.

Received: C 54,9; H 8,5; N 1,9; P 4,4.

The relative viscosity (chloroform/ethanol 50:50, 30oC) 1,18.

The polymer may be crosslinked by gamma-irradiation, or exposure to the Tou, the treated polymer was shown to reduce adsorption of the protein of 68% was determined by enzymatic immunoassay described above) and reduced activation of particles 100% (determined by analysis of the activation of the particles described above, using anti-GMP-140) compared to untreated material. Samples of PVC polymer coating showed a reduction in the adsorption of protein 60% in comparison with the raw material in the definition of the same method of analysis.

Example 11

Obtain poly[2-(acryloyloxy)-2'-(ammonium)ethylphosphate and n-dodecylmercaptan] (1:2)

The polymer was obtained analogously to examples 4 and 6 using 2-(acryloyloxy)-2-(ammonium)ethylphosphate (3.0 g, 0,0107 mol) and n-dodecylmercaptan (5,42 g, 0,0214 mol) dissolved in propan-2-OLE (53 ml) and ethyl acetate (22 ml).

The final polymer obtained with a yield of 58% was a white solid.

NMR (100 MHz, d ppm CD3OD/CDCl3) of 4.2 and 4.4 (d), 3,8-4,2 (d), 3,6-3,8 (d), and 3.3 (C), 1,8-2,2 (d), 1,5-1,8 (l), 1,2-1,5 (C) of 0.8-1.0 (C).

IR (cm-1, KBr disk) 3430, 2929, 2854, 1732, 1469, 1246, 1156, 1089, 968, 788.

Elemental analysis

Theoretical: C 64,9; H 8,7; N 1,8; P 40,0.

Received: C Of 57.8; H 9,8; N 2.1, P 4,9.

Samples pravesam, described above) and decreased activation of particles 100% (determined by analysis of the activation of the particles described above, using anti-GMP140) compared to untreated material. Samples of PVC-treated polymer showed a reduction in the adsorption of proteins 68% and a decrease in the activation of particles 100% in comparison with the raw material when determining the same methods of analysis.

Example 12

Obtain poly[2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and n-exilicauda] (1:2)

The polymer was obtained analogously to examples 4 and 6 using 2-(methacryloyloxyethyl)-2'-(ammonium) ethylphosphate (2.0 g, 0,0068 mmol) n-exilicauda (2,31 g, 0,0136 mol) dissolved in propan-2-OLE (35,5 ml) and ethyl acetate (14,5 ml).

The final polymer obtained with a yield of 34%, was a white solid.

NMR (100 MHz, d, ppm CD3OD/CDCl3) of 4.2 and 4.4 (d), 3,8-4,2 (d), 3,6-3,8 (d), and 3.3 (C), 1,8-2,2 (d), 1,5-1,8 (l), 1,2-1,5 (C) of 0.8-1.0 (C).

IR (cm-1, KBr disk) 3430, 2929, 2854, 1732, 1469, 1246, 1156, 1089, 968, 788.

Elemental analysis

Theoretical: C Of 58.8; H 8,8; N 2,2; P 4,9.

Received: C 47,3; H 7,9; N 2,6; P 5,8.

Example 13

Obtain poly[2-(methacryloyloxyethyl)-2'-(ammonium)metilpolisiloxana-2'-(ammonium)ethylphosphate (3.0 g, 0,0102 mol) and n-octadecylsilane (6,90 g, 0,0204 mol) dissolved in methanol (30 ml) and THF (70 ml). The reaction mixture was stirred for 40 hours at 60oC. the Polymer was isolated from the mixture by placing in acetone (1200 ml), filtered under vacuum and dried. The final polymer obtained with a yield of 55%, rearranged a white solid.

NMR (100 MHz, d, ppm CD3OD/CDCl3) of 4.2 and 4.4 (d), 3,8-4,2 (d), 3,6-3,8 (d), and 3.3 (C), 1,8-2,2 (d), 1,5-1,8 (l), 1,2-1,5 (C) of 0.8-1.0 (C).

IR (cm-1, KBr disk) 3430, 2929, 2854, 1732, 1469, 1246, 1156, 1089, 968, 788.

Example 14

Obtain poly[2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and n-dodecylmercaptan and 2-hydroxyethylmethacrylate] (17:75:8)

The polymer was obtained analogously to examples 4 and 6 using 2-(methacryloyloxyethyl)-2-(ammonium)ethylphosphate (2.0 g, 0,0068 mol), n-dodecylmercaptan (of 7.65 g, 0,0301 mol) and 2-hydroxyethylmethacrylate (0,42 g, 0,0032 mol) dissolved in propan-2-OLE (70 ml) and ethyl acetate (30 ml).

The final polymer obtained with a yield of 53%, is a white solid.

NMR (100 MHz, d, ppm CD3OD/CDCl3) of 4.2 and 4.4 (d), 3,8-4,2 (d), 3,6-3,8 (d), and 3.3 (C), 1,8-2,2 (d), 1,5-1,8 (l), 1,2-1,5 (C) of 0.8-1.0 (C).

IR (cm-1, KBr disk) 3435, 2925, 2860, 1729, 1468, 1243, 1152, 1089, 969, 791.

Goth is ATA] and 2-hydroxyethylmethacrylate (0,5097 g) in propan-2-OLE (50 ml). A strip of aluminum was washed with propan-2-I, hexane and water, and dried. Pieces of aluminum strips (7.5 cm2) was treated with a solution for coating (0.5 ml) using a method with spin speed of 1200 revolutions per minute.

Example 15

Obtain poly[2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and methacrylic acid)] (7:3)

The polymer was obtained analogously to the methods of examples 4 and 6 using 2-(methacryloyloxyethyl)-2-(ammonium)ethylphosphate (4.44 g, 0,0149 mol) and methacrylic acid (0.54 g, 0,0063 mol) dissolved in propan-2-OLE (25 ml) and water (25 ml). The polymer was isolated by planting in acetone (500 ml), re-dissolved in methanol (50 ml) and were isolated by planting in diethyl ether (500 ml).

The final polymer obtained with 30% output, is a white solid.

NMR (100 MHz, d, ppm CD3OD/CDCl3) of 4.2 and 4.4 (d), 3,8-4,2 (d), 3,6-3,8 (d), and 3.3 (C), 1,8-2,2 (d), 1,5-1,8 (l), 1,2-1,5 (C) of 0.8-1.0 (C).

IR (cm-1, KBr disk) 3430, 2929, 2854, 1732, 1469, 1246, 1156, 1089, 968, 788.

This polymer is used for processing cellulose films, which were treated 2-by aminoethylethanolamine as follows.

Fragment cellulose membranes for dialysis (4x6 cm) were placed is freed from oxygen by passing N2within 10 minutes, and then the container was sealed and left for 2 hours at room temperature. Cellulose samples were then removed from the solution, washed in distilled water for 24 hours.

The presence hydrochloride.many part in the grafted sample was confirmed using different absorption of anionic and cationic dyes (Tryptan blue and methylene blue, respectively).

Strips of processed cellulose (0.5 cm x 2 cm) were placed in 10% V/in the solution of polymer in water. The samples were left for 1 hour at room temperature, then washed in distilled water (200 ml) for 2 hours.

Then the treated pulp was placed in a solution of acid molybdate, left for 1 hour, removed, washed with distilled water. The presence of phosphate groups on the samples was confirmed by the manifestation of blue.

Example 16

Obtain poly[2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and (2-methacryloyloxyethyl)ammonium chloride] (7:3)

2-(Methacryloyloxyethyl-2'-(ammonium)ethylphosphate (4,45 g, 0,0151 mol), 2-methacryloyloxyethyl (1,96 g of 75% aqueous solution, 0,0071 mol) was dissolved in ethanol (50 ml). The solution was stirred (250 rpm/minutoli), reduce the flow rate of nitrogen to 10 ml/min, the reaction temperature was raised to 60oC. These conditions are maintained for 40 hours. The mixture was cooled, filtered under vacuum. The polymer was isolated from the mixture by planting in diethyl ether (500 ml), filtered and dried.

The final polymer obtained with 68% yield, is a white solid.

NMR (100 MHz, d, ppm CD3OD/CDCl3) of 4.2 and 4.4 (d), 3,8-4,2 (d), 3,6-3,8 (d), and 3.3 (C), 1,8-2,2 (d), 1,5-1,8 (l), 1,2-1,5 (C) of 0.8-1.0 (C).

IR (cm-1, KBr disk) 3430, 2929, 2854, 1732, 1469, 1246, 1156, 1089, 968, 788.

The polymer used for processing cellulose film, which was treated with the potassium salt of 3-alphapapillomavirus using the method described in example 15, but using potassium salt 3-alphapapillomavirus (4,92 g) is better than using 2-aminopropionitrile.

The presence of sulfate part in the grafted sample was detected using various absorption of anionic and cationic dyes (Tryptone blue and methylene blue, respectively).

Strips of processed cellulose (0.5 cm x 2 cm) was treated with 10% V/in a solution of polymer in water in the manner similar to that described in example 15, and the presence of a phosphate group opredeliaete and n-dodecylmercaptan] (14:86)

The polymer was obtained similarly to the method shown in example 1, using a mixture of comonomers of 2-(methacryloyloxyethyl)-2-(ammonium)ethylphosphate and n-dodecylmercaptan in a molar ratio of 14:86, the solvent used propane-2-ol/ethyl acetate.

On PVC substrate was coated with a polymer using the method described in example 3.

Comparative example

The adsorption of fibrinogen binding of C-reactive protein on PVC substrate with a coating of polymers of the present invention obtained in examples 3 and 7, compared with similar characteristics to the copolymer of 2-(methacryloyloxyethyl)-2-(ammonium)ethylphosphate and butyl methacrylate in a molar ratio of 1:2 (comparison A), and in the ratio of 14:86 (comparison B).

Copolymers comparison was prepared similarly to the method of example 1, the coating on the PVC substrate was obtained using the method described in example 3. All copolymers were obtained by the method described in example 1, using as solvent propan-2-ol/ethyl acetate. The results are shown in the table at the end of the description.

The results were obtained using the methods described above, after inlatest in comparison with untreated grades. The value of C-reactive protein was expressed as spectral absorption capacity, characteristic of C-reactive protein; positive control showed the Binding of PSA. The index of the protein represents the ratio of binding of C-reactive protein for adsorption of fibrinogen.

These results showed that in order to get a good reduction of protein adsorption when using copolymers containing butylmethacrylate must have achieved a high binding of C-reactive protein.

In contrast, when using monomers with longer alkyl chains were in a good reduction in the adsorption of proteins and low binding of C-reactive protein, as well as good adhesion to the substrate and a low degree of crosslinking in aqueous media.

Copolymers containing comonomers with short alkyl chains up to 4 carbon atoms as a potential adsorbent groups, such as butylmethacrylate, smaller molar proportions, showed poor adhesion to hydrophobic surfaces and the high degree of crosslinking in aqueous media, which makes them unsuitable for application as a coating.

Example 18

The polymers and the example of the heart, using as a model the calf. Blood samples were pumped through the system at physiological temperature in the absence of anticoagulant with a rate of 3.5 l/min during the experiments was measured parameters of the circulating blood.

In fact, all of the tested parameters showed that the presence system remote handsets floor had less influence or no influence on blood parameters and physiological functions of animals (usually spent three identical experience consistently one per day, the results are reproducible when changing experimental animals).

In comparison with the above described experiment, the system extension tubes without coating was not able satisfactorily to work for 6 hours without the use of anticoagulant. In addition, an adverse effect on the blood parameters in a short period of time.

The test results of the adsorption of proteins and macroscopic observations of various fragments of the external piping system showed that both coatings worked at least as well as heparinised tubes, and that the parts of the system with high turbulence flow of blood had formed small blood clots.

Recognize The R> Receiving method shown in the reaction scheme As follows.

a) 2-Chloro-1,3-dioxaphospholane (1)

Into a flask equipped with addition funnel with pressure compensator, reflux condenser with safety tube with CaCl2and magnetic stirrer, was placed a solution of phosphorus trichloride (220 ml, 346,3 g, 2,52 mol) in dichloromethane (500 ml) was added dropwise ethylene glycol (139 ml, 154,7 g, 2.49 mol) with speed, providing not too intense emission of HCl. Then set the fridge for distillation and drove at atmospheric pressure dichloromethane. When the temperature of the distillate 60oC started vacuum distillation on a water-jet pump. When the distillation was obtained 2-chloro-1,3-dioxaphospholane (158 ml of 224.5 g, 71.3 per cent) as a colourless mobile liquid which fumes in the air), so Kip. 40oC/21 mm RT.article [for comparison of 45.5-47oC/20 mm RT. senior Lucas et al. J. Am. Chem. Soc. 72, 5491, (1950)].

IR (cm-1in a thin film) 2980, 2905, 1470, 1210, 1005, 930, 813, 770.

b) 2-Chloro-2-oxo-1,3,2-dioxaphospholane (2)

In a flask equipped with a magnetic stirrer, reflux with potassium chloride tube and bubbler for passing the gas, was placed a solution of 2-chloro-1,3,2-dioxaphospholane (100,8 g, 0,797 mol) in dry be the sky, the temperature was limited by the boiling point of the solvent. Oxygen was passed through the reaction mixture for 6 hours. The solvent was evaporated on a rotary evaporator and colorless movable residue was distilled to obtain 2-chloro-2-oxo-1,3,2-dioxaphospholane (2) (87,41 g, 77%) as a colourless mobile liquid, so Kip. 95-97oC/0.2 mbar [for comparison 102,5-105oC/1 mbar (Edmundson, Chem. Ind. (London) 1828 (1962); 79oC/0.4 mbar (Umeda et al., Macromol. Chem. Rapid. Commun. 3, 457, (1982)].

IR (cm-1in a thin film) 2990, 2910, 1475, 1370, 1310, 1220, 1030, 930, 865, 830.

a) 2-(2-Oxo-1,3,2-dioxaphospholane-2-yloxy)ethyl methacrylate, (3)

Into the flask with magnetic stirrer, thermometer, addition funnel with pressure compensator and pressure relief tube with silica gel was placed a solution of 2-hydroxyethylmethacrylate (20,00 g, 0,154 mol) and triethylamine (15,60 g, 0,154 mol) in dry diethyl ether (300 ml). The solution was cooled to a temperature of -20 to -30oC and was mixed and added dropwise over 30 minutes a solution of fresh 2-chloro-2-oxo-1,3,2-dioxaphospholane (2) (21,9 g, 0,154 mol) in dry diethyl ether (20 ml), the reaction temperature during the addition was maintained -20oC.

At this temperature, the reaction mixture was stirred 1 hour, C is arid of triethylamine, washed well with dry ether. The combined filtrate and washings was evaporated on a rotary evaporator. Muddy oily residue was dissolved in 5 minutes with dry diethyl ether (50 ml) for additional weight of triethylamine hydrochloride which was filtered. The ether was removed on a rotary evaporator and received (3) (34,18 g, 94,3%) as a colorless viscous oil.

IR (cm-1in a thin film) 1720, 1640, 1450, 1360, 1310, 1290, 1170, 1030, 930, 850.

NMR (CDCl3, 60 MHz, ppm) of 1.95 (s, 3H), 4,25-4,70 (m, 8H), 5,70 (m, 1H), and 6.25 (m, 1H).

Rf0,9 (SiO2, elution with 10% methanol:90% dichloromethane; stain showed reagent molybdenum blue and iodine).

g) 2-(Methacryloyloxyethyl)-2'-(ammonium)ethylphosphate (4)

Phosfolan (3) (67,20 g, 0,285 mol) was dissolved in 100 ml of dry acetonitrile and placed in a thick-walled flask, and treated with a solution of anhydrous triethylamine (25,74 g, 0,436 mol) in dry acetonitrile (100 ml). The vessel was then closed, placed in a water bath and kept for 30 hours at 50oC. the Vessel was opened, the solution was heated to boiling, filtered hot and azide recrystallized. The product was filtered off, washed with anhydrous ether, dried under reduced pressure and got a white amorphous giglo further by crystallization at -20oC was isolated product (4). TLC plate of silica gel, was suirable with methanol/dichloromethane (1: 1, vol/about.)) found a spot with Rf0,1, which manifested itself reagent Dragendorff, reagent molybdenum blue and iodine.

IR (cm-1) 1720, 1640, 1320, 1300, 1230, 1170, 970, 750.

NMR (D2O; 60 MHz, ppm) of 2.0 (s, 3H), 3.27 to (s, 9H), 3,60-4,50 (m, 8H), 5,80 (m, 1H) and 6.25 (m, 1H).

CHII Found: C 42,88%; H 7,88% N 4,42% P 10,51%

CHII Theory: C 44,75%; H 7,46% 4,46% P 10,51%

Source for example 2

The synthesis of the internal salt of dimethyl(2-methacryloxyethyl)-1-(2-sulfopropyl)ammonium

(2-dimethylamino)ethyl methacrylate was distilled in a vacuum, was dissolved in 0.1 M dichloromethane, was added equimolar ratio sulfopropyl, then betaine was slowly thrown out of solution, was filtered off, washed with cold dichloromethane. The reaction is shown in reaction scheme B.

Source for example 3

Get the internal salt of 1-[4-(4'-vinylbenzyl)butane] -2"-(ammonium)ethylphosphate

The synthesis is shown in reaction scheme C

4-Hydroxy-1-(4'-vinylbenzyl)Bhutan (5)

Butanediol (40 ml, 40,68 g, 0,452 mol) was stirred in a 100 ml round bottom flask, was treated with portions of butoxide potassium (17,60 g, 0.144 mol). The start of the reaction was ekzotermicheskimi chloromethylstyrene (20,00 g, 0,131 mol). Pale green color layer of styrene was formed from the top (staining due to the presence of the inhibitor), the color of the layer is greatly darkened by adding 18-crown-6 (0,49 g, 1,8610-3mol). The flask was closed, protected from light, stirred for 28 hours at room temperature, poured into water (120 ml), was extracted with dichloromethane (4x50 ml). The combined organic extracts were dried (MgSO4) and was evaporated to a viscous yellow oil (932,7 g). This oil was distilled in the presence of small amounts of CuCl and received a product containing some impurities by TLC. The oil was then chromatographically on silica gel with elution with dichloromethane/petrol (1:1) to remove impurities.

The product was further purified on a column with ethyl acetate/petrol (1:1) as eluent. Evaporation of solvent gave a colorless oil, which was distilled, and required strabotomy alcohol as a colorless oil, so Kip. 150-152oC/0.4 mbar.

Output 18,70 g, 69.2 per cent.

NMR (60 MHz, CDCl3) of 1.55 (m, 4H, C-CH2-C); a 3.50 (m, 5H, 1H, O-CH2-, O-H) of 4.45 (s, 2H, Ar-CH2-), of 5.50 (DD, 2H, vinyl), to 6.75 (DD, vinyl), 7,40 (m, 4H, Ar-H).

IR 3402, 2938, 1888, 1631, 1602, 1582, 1511, 1480, 1445, 1382, 1320, 1116, 1063, 920, 907, 827, 801, 716 and 667 cm-1< / BR>
4-(2-Oxo-1 mmol) dry triethylamine (4,92 g, 48,69 mmol) was dissolved in dry ether (150 ml), the resulting ether was placed in a dry flask. The solution was cooled to -30oC, was introduced dropwise within 30 minutes of 2-chloro-2-oxo-1,3,2-dioxaphospholane (6,94 g, 48,69 mmol), keeping adding temperature -30oC. the Reaction mixture was stirred for 2 hours, the temperature was increased up to 10oC. the Mixture was filtered, the precipitate washed with dry ether, the filtrate was evaporated (20oC/21 mm) and received a turbid oil. The residue was dissolved in 50 ml dry ether and again filtered. The filtrate was evaporated and the obtained product in the form of a viscous yellow oil (13,73 g, 90.4 percent).

TLC (suirable with 10% methanol, 90% dichloromethane) showed one major spot, which showed acidic molybdenum reagent (Rf0,61), IR (thin film) 3458, 2945, 2917, 2860, 1630, 1602, 1581, 1475, 1419, 1363, 1283, 1103, 1032, 820, 842, 807, 800, 715, 610 and 421 cm-1.

1-[1-(4'-vinylbenzyl)butane]-2"-(ammonium)ethylphosphate (7)

The triethylamine (2.00 g, to 33.9 mmol) was distilled into the reaction flask, cooled with liquid nitrogen, was added 4-(2-oxo-1,3,2-dioxaphospholane-2-yloxy)-1-(4'-vinylbenzyl)Bhutan (6) (10,00 g, 32.1 mmol) in anhydrous acetonitrile (40 ml). The flask was sealed and placed in a thermostatted water bath (50oC, 50 hours). ZAT is a high volume (21 mm pressure). The concentrated solution was stirred at room temperature, was added dropwise anhydrous ether (200 ml) for planting the product as a viscous oil. The mixture was left for a few hours at -10oC. the Product was collected by decanting formed on top of the solid product. TLC (suirable methanol/dichloromethane 1:1) showed one major spot with Rf0,0-0,1, which was manifested reagent Dragendorff, and acid molybdate.

Source for example 4

Get the internal salt of 2-(acryloyloxy)-2'-(ammonium)ethylphosphate

Synthesis is carried out analogously to the method of example 1 and using the path represented by the reaction scheme A.

(a) 2-(2-Oxo-1,3,2-dioxaphospholane-1 yloxy)acrylate

2-hydroxyethylacrylate (11.5 ml, 0.1 M) and triethylamine (14.6 ml) in dry diethyl ether (250 ml) at -20oC in nitrogen atmosphere was added over 20 minutes a solution of 2-chloro-2-oxo-1,3,2-dioxaphospholane (14.3 g) in dry diethyl ether, stirred for 1 hour at this temperature, increased temperature up to 10oC and kept for 1 hour, filtered, washed with ethyl acetate (100 ml). The combined filtrate and wash solution was evaporated in vacuum and the obtained oil is a pale yellow color ) 2-(Acryloyloxy)-2'-(ammonium)ethylphosphate

A mixture of 2-(2-oxol, 3,2-dioxaborolan-2-yloxy)acrylate (21 g, 0,095 M) in acetonitrile (150 ml) and triethylamine (12.1 g) in acetonitrile (150 ml) was kept in the reactor at 50oC for 17 hours, cooled, and the excess triethylamine was evaporated in vacuum.

The solid product was filtered under nitrogen atmosphere, washed with acetonitrile (20 ml) and diethyl ether (50 ml), dried under vacuum and obtained colorless oil (12.1 g, 45%).

1H NMR (200 MHz) d (D2O) of 6.45 (1H, DD, J 1,2 and 17.1 Hz), and 6.25 (1H, DD, J 1.2 and of 10.25 Hz), of 6.02 (1H, DD, J 1,23 and of 10.25 Hz), 4,4 (2H, m), 4,3 (2H, m), 4.2V (2H, m), 3,6 (2H, m) and 3.2 (9H, s) ppm.

Source for example 5

Dodec-7-in-1-helmetcrest

To dodec-7-in-1-Olu (25 g) in dichloromethane (60 ml) was added to the distilled triethylamine (14.1 g), cooled in a bath with ice (0,5oC), with stirring for 10 minutes was added methacryloylamido (16.2 g) in dichloromethane (50 ml), the temperature of the reaction mixture was raised to room temperature and was stirred mixture of 2 hours, brought the water (150 ml). The organic layer was separated, was extracted with water (2 x 150 ml), saturated sodium bicarbonate solution (g ml), washed with brine (150 ml), dried over anhydrous sodium sulfate, the solvent was evaporated in vacuum and the received light yellow maslanistuyu, 17 g, 50% yield.

1H NMR (100 MHz, d, ppm, CDCl3: of 0.90 (t, 3H), of 1.45 (m, 10H), to 1.70(m, 2H), 1,95 (s, 3H), of 2.15 (m, 6H), is 4.15 (t, 2H), of 5.55 (s, 1H), 6,10 (s, 1H).

An example of A

Obtaining poly(internal salt of 2-(methacryloxyethyl)-2-(ammonium)ethylphosphate-CO-n - dodecylammonium-CO-3-methoxysilyl-propylbetaine)and subsequent crosslinking cast films.

This example illustrates the production of polymer containing 3-methoxydibenzoylmethane for subsequent stitching, in addition to phosphorylcholine for biocompatibility.

Internal salt of 2-(methacryloyloxyethyl)-2'-(ammonium)-ethylphosphate (9.6 g) was dissolved in 170 ml of isopropyl alcohol and stirred over molecular sieves for 0.5 hours. After that, the solution is filtered into the reaction flask and added 16.6 g of dodecylmercaptan and 4.6 g of 3-triethoxysilylpropyl together with 70 ml of ethyl acetate and 0,0618 g AIBN (2,2'-azo-bis(2-methylpropionitrile)). For 0.5 hours through a solution bubbled nitrogen and the temperature was raised to 60oC. the Reaction support at this temperature under stirring in nitrogen atmosphere for 23 hours, after which the solution is allowed to cool, and approximately half of the solvent is removed under reduced pressure the white solids. The coating polymer is obtained by irrigation of the polymer solution (about 10% V/V in methanol) containing 0.15 in/in dibutyltindilaurate tin based on weight of dry polymer on a glass plate and dried at 50oC for 12 hours.

Example B

Obtaining poly(internal salt of 2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate-CO-n - dodecylammonium-CO-3-chloro-2-hydroxy-propylbetaine)and biological testing of films applied to PE.

This example illustrates the production of polymer containing for biocompatibility 3-chloro-2-oxopropanenitrile as a crosslinking monomer, in addition to phosphorylcholine.

Internal salt of 2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate (69,41 g), n-dodecylmercaptan (120,85 g), AIBN (0,3939 g) and 3-chloro-2-oxopropanenitrile (6.3 g) was dissolved in isopropyl alcohol (1380 ml)/ethyl acetate (570 ml) and the solution obzharivayut for 0.3 hour. Then the reaction mixture was stirred at 60oC in nitrogen atmosphere for 40 hours, allowed to cool and then cooled in a large excess of acetone. The polymer is collected by filtration and dried.

Polymer films on sheets of polyethylene (pre-purified in denatured alcohol) sex is here introducing a hydroxide of butylamine in the solution for irrigation (30 mg/200 mg of dry polymer); about stitching judged by the fact that the film could not re-dissolve in the solvent. Analysis of the isolated antibody of fibrinogen shows a significant reduction in the binding of fibrinogen with unstitched and stitched film in comparison with HDPE substrate without coating.

Example C

Obtaining the copolymer of the inner salt of 2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and poly(dimethylsiloxane) with one end methacryloxypropyl group.

This example describes the production of polymer containing in addition phosphorylcholine group polysiloxan for physical adsorption on the surface.

Internal salt of 2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate (4,3094 g), poly(dimethylsiloxane) with one end methacryloxypropyl group having a molecular weight of 1000 D, (0,8791 g), AIBN (0,0103 g) dissolved in isopropyl alcohol (40 ml)/hexane (20 ml) and the solution obzharivayut for 0.3 hour. Then the reaction mixture was stirred at 60oC in nitrogen atmosphere for 46 hours, after which the solution is allowed to cool, and approximately half of the solvent is removed under reduced pressure. The polymer produce precipitation in acetone and collected by filtration, promyvochnye copolymer of the inner salt of 2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and poly(dimethylsiloxane) with one end methacryloxypropyl group.

This example describes the production of polymer containing in addition phosphorylcholine group polysiloxan for physical adsorption on the surface.

Internal salt of 2-(methacryloyloxyethyl-2'-(ammonium)ethylphosphate (3,6757 g), poly(dimethylsiloxane) with one end methacryloxypropyl group (used in example 21) (6,2619 g), AIBN (0,0062 g) dissolved in isopropyl alcohol (70 ml)/hexane (50 ml) and the solution obzharivayut for 0.3 hour. Then the reaction mixture was stirred at 60oC in nitrogen atmosphere for 46 hours, after which the solution is allowed to cool. The solvent is removed under reduced pressure and leave opalescent solution. After this, the solution is re-dissolved in a mixture of ethanol (15 ml)/hexane (10 ml). The polymer produce precipitation in diethyl ether, collected by filtration and dried in vacuum at 40oC for 16 hours. The obtained white solid with a yield 7,7178,

Example E.

Obtaining poly(internal salt of 2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate-CO-n - dodecylammonium-CO-1H,1H,2H,2H-heptadecafluorooctyl).

This example describes how to obtain ternary copolymer containing in addition to phosphorylcholine methacryloyloxyethyl)-2'-(ammonium)ethylphosphate, 2.35 g of n-dodecylmercaptan, to 4.92 g of 1H,1H,2H, 2H-heptadecafluorooctyl and 0,0162 g AIBN stirred at 60oC in a mixture of isopropanol (50 ml)/ethyl acetate (50 ml) in a nitrogen atmosphere for 40 hours. After removal of solvent, the polymer is removed by precipitation from dichloromethane in acetone. Output to 8.34,

Example F.

Obtaining poly(internal salt of 2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate-CO-n - dodecylammonium-CO-11-methacryloyloxyethyl-1-trimethylammonium)and (40:71:8)

Internal salt of 2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate (2,32 g, 0,0079 mol), n-dodecylmercaptan (3,61 g, 0,0142 mol) and 11-methacryloyloxyethyl-1-trimethylammonium (0,59 g, 0,0016 mol (synthesized according to example 1) are dissolved in 43 ml of propan-2-ol and 17 ml of ethyl acetate.

The solution of monomers carefully obzharivayut by ozonation through him dry gaseous nitrogen (dried over molecular sieves) for 30 minutes. After that, the solution was poured initiator of AIBN (0,01360 g, 0.02 weight. % solution) using 3 ml obezhirennogo ethanol. The solution in addition obzharivayut five minutes. Maintaining the solution at a slightly excess pressure of nitrogen (equivalent to several ml of mineral wt is following this the reaction mixture is allowed to cool to approximately 40oC before removing all of the solvent using a rotary evaporator under vacuum at approximately 40oC to obtain a solid foam.

This foam is then dissolved in 24 ml of dichloromethane and precipitated dropwise into an excess of 200 ml of acetone. The product is collected on a filter Buechner funnel and washed an additional three portions of 20 ml of acetone. White solid is dried in a vacuum oven for 16 hours at 40oC and weighed.

The final polymer obtained with a yield of 83%, is a white solid.

1H NMR (400 MHz, d, M. D., CD3OD/CDCl3) or 4.31 (W), 4,21 (W), 4,07 (W), 3,98 (W), and 3.72 (W), 3,37, 3,33, 3,29 (), 3,22, 3,17, 1,95, 1,84 (W), 1,67 (W), 1,33 (W), 1,06 (W), 0,93 ().

13C NMR (500 MHz, D., M. D., CD3OD/CDCl3) 176,37, 66,91, 65,90, 63,68, 60,05, 54,50, 53,37, 45,54, 32,69, 30,44, 30,13, 28,92, 26,93, 23,41, 17,31, 14,56.

Was prepared covering the polymer solution, 10 mg/ml in isopropyl alcohol and used to cover the surface of the 40-micron woven filter material of the type used in artificial blood circulation to eliminate blood clots. After applying the coating solution of the alcohol is evaporated, and remained floor associated with the surface of the/ml in phosphate buffered saline), then spolecnost in two stages, first a phosphate buffered saline solution and then with deionized water, and dried. After treated with heparin and not treated with heparin pass filters in parallel, the blood of the bull (3.5 l/min) for six hours. Blood contains 644 ED. heparin/kg

As treated with heparin, and not treated with heparin filters show a very good performance properties, manifested in significantly fewer blood clots than in the control uncoated filter materials, especially for extended periods of time.

Example G

Obtaining poly(internal salt of 2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate-CO-n - dodecylammonium-CO-polymethacrylate)

Carry out various polymerization reactions using a method similar to the method used in example F, but when using polymethacrylate instead of 11-methacryloyloxyethyl-1-trimethylammoniumchloride. Zwitterionic monomer, the monomer is lauryl(dodecyl)methacrylate and polymethacrylate mixed in a molar ratio shown in table 1, and as the initiator of the use of AIBN in the concentrations shown in the table. The table also Preout from example to example.

Polymers derive essentially the same method as in paragraph 1, although it was included additional stage of dissolution and precipitation to remove low molecular weight polymer.

In the polymer product was determined by chloride ions in order to establish the rate of introduction of cationic monomer in the product. In addition, there were a few rough definitions of molecular weight.

Example H

Internal salt of 2-(methacryloyloxyethyl)-6'-(trimethylammonium)phosphate and its polymers

H. 1. Synthesis of monomer

1. bromohexadecane

2. water/triethylamine

3. trimethylamine

------->

6-Bromohexyl-1-dichlorophosphate

6 Bromhexin-1-ol (5,90 g, a 32.6 mmol) in dry dichloromethane (30 ml) was added dropwise to phosphorus oxychloride (5.0 g, a 32.6 mmol) in dry dichloromethane (30 ml). Within four hours after the reaction mixture was bubbled nitrogen. The solvent is removed by rotary evaporation and receive 6-bromohexyl-1-dichlorophosphate, to 9.70 g, a 32.6 mmol, yield 100%.

Internal salt of 2-(methacryloyloxyethyl)-6'-(trimethylammonium)phosphate

6-Bromohexyl-1-dichlorophosphate (7,22 g, 24,23 mmol) in anhydrous ether (20 ml) are added to a solution of acetylsalicylate (3.0 g, 23,00 mmol) in anhydrous ether nitrogen for 3 hours. The reaction mixture was left to warm to room temperature and add triethylamine (2,45 g, 24,23 mmol), water (1 ml) and di-tertbutylphenol (about 10 mg). The reaction mixture was stirred at room temperature for 2 hours. The aqueous layer was extracted with ether (5 ml x 3), the combined ether layers are dried (sodium sulfate) and the solvent is removed by rotary evaporation to obtain the oil, which is dried in vacuum. The residue is dissolved in dry acetonitrile (20 ml) and added trimethylamine (3.0 g, 50.8 mmol) in dry acetonitrile (30 ml) with di-tertbutylphenol (about 10 mg). The reaction mixture is stirred at a temperature of 40oC in nitrogen atmosphere in a sealed vessel for 48 hours. After cooling, the solvents are removed by rotary evaporation and the residue purified column chromatography with elution using methanol: water (9:1). The fractions containing the product is evaporated to dryness obtaining 37% internal salt of 2-(methacryloyloxyethyl)-6'-(trimethylammonium)phosphate (2.9 g, 8,65 mmol). This compound indicated below as compound X.

1H NMR (200 MHz, CDCl3with tracks CD3OD), of 1.46 (4H, m), and 1.63 (2H, m), of 1.80 (2H, m), of 1.95 (3H, s), 3,17 (9H, s), 3,39 (2H, m), 3,86 (2H, HF), 4,07 (2H, HF), 4,34 (2H, t) 5,59 (1H, s), 6,13 (1H, s).

H. 2. Sprinklers shall PR methacrylate monomer (compound X) (4,92 g, 12.7 mmol) in dry isopropanol (60 ml) is treated with a solution of freshly lauriemittiet (6,47 g, and 25.4 mmol) in dry ethyl acetate (16 ml). Through the mixture for five minutes bubbled nitrogen, then add AIBN (20 mg) in ethyl acetate (2.5 ml), and stir the mixture heated to 62oC in nitrogen atmosphere for forty hours. The mixture is cooled to 40oC, filtered through filter paper and washed with isopropanol (8 ml). The solvents are removed by evaporation and painted the residue re-dissolved in dichloromethane (37 ml) and methanol (4 ml) and midline was added dropwise (approximately one hour) in a beaker containing vigorously stirred acetone (530 ml). On the surface of the vessel is formed of a resinous precipitate, which is dried in vacuum for 16 hours after decanting the solvent and washing the residue with additional acetone (150 ml). The residue is dissolved in dichloromethane (30 ml) and methanol (10 ml) and slowly added dropwise in a mixed solution of acetone (600 ml). Slowly precipitated resin, which leave at 4oC for 64 hours, then decanted into the acetone, the residue is washed with acetone (150 ml), dissolve it in methanol/dichloromethane and evaporated and dried in vacuum to obtain (C), 3,25-4,40 (12H, m).

13C NMR

H. 3. The application of the copolymer

A piece of polyethylene tubing (1.6 x 300 mm) was washed with ethanol (passed through a 2 μm filter, 400 µl at 60oC) for one minute. After decanting the ethanol into the tube at 60oC was placed a solution of the copolymer prepared in example H. 2 at 3 mg/ml and at 10 mg/ml, in ethanol (0,30 mm). After standing for one minute, the solution is removed and the tube is dried in a nitrogen atmosphere.

These samples show a decrease in the adsorption of fibrinogen on 74% and 85%, respectively.

Strips of plastic tape (102 x 25.5 mm) washed with ethanol at 20oC. These strips attach to a piece of tubing made of PVC (10 mm x 60 mm), which is mechanically lowered (25 mm-1in a bath containing solutions (3 mg/ml and 10 mg/ml) obtained in example H. 2 copolymer in ethanol (12.9 ml) at 65oC, leave for one minute and then remove with a speed of 4 mm/s Samples dried in the hood with laminar flow.

Coated samples have on the activation of thrombocytes in comparison with uncoated sample, using the analysis procedure described by E. J. Campbell, and others, M. R. S. symp. proc. vol. 255, pp. 229-236, (1992). These samples show a decrease in activation Travelocity)-2'-(ammonium)ethylphosphate : laurenmarie : 3-triethoxysilylpropyl : 3-oxopropanenitrile 23 : 47 : 5 : 25.

The polymer synthesized using the General method of example A, but using a four monomers in such quantities as to obtain a molar ratio indicated in the header. Coatings obtained by irrigation of the polymer solution in alcohol, the alcohol and the crosslinking of the polymer by heating to a temperature of about 180oC in the presence of moisture.

The polymer formed by radical polymerization of (i) zwitterionic monomer having the formula I

Y-B-X,

where In - alkylen with direct chain of formula - (CR23)a- where R3represent hydrogen, or a = 1 - 6;

X - zwitterion ammonium phosphate ester group of the formula IVC

< / BR>
where the group R7the same or different, and each represents hydrogen or C1-4-alkyl;

e = 1 to 4;

Y - is capable of polymerization ethylenediamino group of the formula

< / BR>
where R is hydrogen or (C1-C4)alkyl, and

(ii) the co monomer having a connecting surface group, which is co monomer having alkyl fluoride or siloxane group, of General formula VII

< / BR>
or capable of blending the co monomer of General formula VIIA

CH2= is of the alkyl fluoride groups of the formula (CR217)mCR317where groups (CR217same or different and in each group (CR217), R17the same, and each of the groups R17is hydrogen, fluorine or1-4-perakyla, and m has a value from 1 to 23, provided that at least one of the groups R17is other than hydrogen, and siloxane groups (CR216A)qq(SiR216b) (OSiR216b)ppR16bwhere each group R16ais hydrogen, each R16bis stands, qq has a value of from 1 to 6 and PP is from 0 to 49;

QQ - Alchemilla group containing 6 or more carbon atoms and one triple bond of carbon-carbon, provided that acetylene share is not directly related to A',

or ion co monomer of General formula XII

Y2-B9-Q5,

where Y2- capable of polymerization Ethylenediamine group of the formula

< / BR>
where R26is hydrogen or (C1-C4)alkyl;

IN9is a valence bond or Allenova group with a straight chain of the formula -(CR229)y- in which each of R29represents hydrogen, and y = 1 to 12;

Q5a cationic group fo the a and C1-4-alkyl, or reactive co monomer of General formula X

< / BR>
where R19is hydrogen or C1-4alkyl;

Q2- OH, or a group live TV7Q3where T denotes-O-,

B7- Allenova group of the formula - (CR222)rwhere each R22is hydrogen and r = 1 to 12;

Q3- reactive group selected from the group consisting of Milanovich and siloxane groups containing one or more substituents selected from halogen atoms and C1-4-alkoxygroup, hydroxyl group, amino group, carboxyl group, epoxypropyl, group - CHOHCH2Hal, where Hal is selected from chlorine atoms, bromine and iodine,

moreover, the specified zwitterionic monomer and the specified comonomer introducing radical polymerization in a molar ratio in the range of from 5 : 95 to 95 : 5, and

(iii) and optionally the monomer-diluent General formula VI

< / BR>
where R14hydrogen or methyl;

Q - C8-24-alkyl.

2. The polymer under item 1, characterized in that it e is equal to 2 and each R7represents methyl.

3. The polymer under item 1 or 2, wherein the group Q3selected from the group consisting of amino groups, group CHOHCH2Cl and trimet the Ute from the group consisting of 2-aminoethylethanolamine, 3-chloro-2-hydroxypropylmethacrylate and 3-triethoxysilylpropyl.

5. The polymer under item 1 or 2, characterized in that it specified comonomer is 7-dodecylmercaptan.

6. The polymer under item 1 or 2, characterized in that in it the group Q5is the ionic group -+NR331in which each group R31the same or different and is hydrogen or stands.

7. The polymer under item 1 or 2, wherein Q in the co monomer is an alkyl fluoride group containing at least 6 carbon atoms.

8. The polymer under item 7, characterized in that comonomer is 1H,1H,2H, 2H-heptadecafluorooctyl.

9. The polymer according to any one of paragraphs.1 to 8, characterized in that it is formed from monomers including the monomer-diluent and monomer-diluent is dodecylmercaptan.

10. Surface with a coating of polymer on p. 1 in contact with the protein, and side groups of the polymer can stably bind the polymer to the surface in the coating on the surface so that the surface thus becomes biocompatible.

11. The surface coating according to claim is the following cross-linking polymer.

12. A method of obtaining a polymer through radical polymerization of (i) zwitterionic monomer having the formula

Y-B-X,

where In - alkylen with direct chain of formula - (CR23)a- where each group R3represents hydrogen, and a is 2; X - zwitterion ammonium phosphate ester group of the formula IVC

< / BR>
where the group R7the same or different, and each represents hydrogen or C1-4-alkyl, and e has a value from 1 to 12; Y is capable of polymerization ethylenediamino group of the formula

< / BR>
where R is hydrogen or (C1- C4)alkyl, and

(ii) the co monomer having communicates with the surface group, which is co monomer having alkyl fluoride or siloxane group of the formula VII

< / BR>
or capable of blending the co monomer of General formula VIIA

CH2= CR14- C(O) - A' - QQ

where R14is hydrogen or C1- C4alkyl;

A' means OF;

Q - is chosen from alkyl fluoride groups of the formula (CR217)mCR317group (CR217same or different and in each group (CR217), R17the same, and each group R17the same, and cardamone, one of the groups R17is other than hydrogen, and siloxane groups (CR216A)qq(SiR216b) (OSiR216b)ppR16bwhere each group R16ais hydrogen, each R16bis stands, qq has a value of from 1 to 6 and PP is from 0 to 49;

QQ - Alchemilla group containing 6 or more carbon atoms and one triple bond of carbon-carbon, provided that acetylene share is not directly related to A',

or ion co monomer of General formula XII

Y2-B9-Q5,

where Y2- capable of polymerization Ethylenediamine group of the formula

< / BR>
where R26is hydrogen or (C1-C4)alkyl;

IN9is a valence bond or Allenova group with straight or branched chain of the formula -(CR229)y- in which each of R29represents hydrogen or C1-4is alkyl, and y has a value from 1 to 12;

Q5a cationic group of the formula+NR331where the group R31the same or different and each is selected from hydrogen and C1-4-alkyl,

or reactive co monomer of General formula X

< / BR>
where R19is hydrogen or C1-PPA formula -(CR222)r, where each R22is hydrogen and r means 1-12;

Q3- reactive group selected from the group consisting of Milanovich and siloxane groups containing one or more substituents selected from halogen atoms and C1-4-alkoxygroup, hydroxyl group, amino group, carboxyphenyl group, epoxypropyl, group-CHOHCH2Hal, where Hal is selected from chlorine atoms, bromine and iodine,

moreover, the specified zwitterionic monomer and the specified comonomer introducing radical polymerization in a molar ratio in the range of from 5 : 95 to 95 : 5, and (iii) and optionally the monomer-diluent General formula VI

< / BR>
where R14is hydrogen or methyl;

Q - C8-24-alkyl.

13. The method according to p. 12, wherein e is 2, and each of R7represents methyl.

14. The method according to p. 12 or 13, characterized in that the group Q3selected from the group consisting of amino groups, group CHOHCH2Cl and trimethoxysilyl group.

15. The method according to p. 14, characterized in that the specified comonomer selected from the group consisting of 2-aminoethylethanolamine, 3-chloro-2-hydroxypropylmethacrylate and 3-triethoxysilylpropyl.

16. The method according to p. 12 or 13, wherein the group Q5selected from the group consisting of carboxylate groups, and groups+NR331in which each group R31the same or different and is hydrogen or stands.

18. The method according to p. 12 or 13, characterized in that the co monomer Q is alkyl fluoride group containing at least 6 carbon atoms.

19. The method according to p. 18, wherein comonomer is 1H,1H,2H, 2H-heptadecafluorooctyl.

20. Method of surface coating, which consists in the fact that the surface of the substrate is covered with a polymer under item 1, and the polymer then sew.

21. The method according to p. 20, characterized in that the surface of the substrate contains side groups, and in which after coating group Q2interact with the formation of covalent bonds with the side groups of the substrate and also possibly with the formation of relationships by attaching ligands to the polymer.

22. The method according to p. 21, characterized in that the surface side groups are selected from the group comprising hydroxyl, carboxyl and amino group.

23. The method according to p. 20, wherein the group Q2and QQ on the polymer react with each other for the PE comonomer is 7-dodecylmercaptan, and acetylene group co monomer bound to each other by UV light or gamma-irradiation on the composition of the coating when it is applied to the surface.

25. The method according to p. 23, wherein comonomer represents a 3-chloro-2-hydroxypropylmethacrylate or 3-triethoxysilylpropyl.

26. The method according to p. 22, characterized in that the polymer is formed of an inner salt of 2-(methacryloyloxyethyl)-2'-(ammonium)ethylphosphate and 2-aminoethylethanolamine and covalent binding of the lateral amino groups with the surface containing the carboxylate side groups, is achieved through the formation of amide linkages.

27. The method according to p. 20, wherein the group Q5in the co monomer is an ionic group selected from carboxylate groups and group-NR331+in which each group R31the same or different and represents hydrogen or alkyl with 1-6 carbon atoms, and the surface contains groups with protivoyuznym charge.

28. The method according to p. 27, wherein the group Q5selected from the group consisting of carboxylate groups, and the groups-NR331+in which all groups of R31the same or different and is wakeley group of the formula (CR217)mCR317where groups (CR217same or different and in each group (CR217) group, R17the same or different, and each of the groups R17represents hydrogen, fluorine, or WITH1-4-alkyl, or foralkyl, provided that Q contains at least one fluorine atom and m has a value from 1 to 23.

30. The method according to p. 29, wherein comonomer is 1H,1H,2H,2H - heptadecafluorooctyl.

Priority points:

05.07.91, 08.08.91, 24.04.92 on PP.1,9,11,18;

05.07.91 on PP.2,12,20,24;

05.07.91, 24.04.92, 06.07.92 on PP.3,13,14;

05.07.91, 24.04.92, 06.07.92 on p. 4;

24.04.92 on PP.5,10,15,21,23,24,25,26;

08.08.91 on PP.6,7,16,17,27,28;

06.07.92 on PP.by 8.22;

05.07.91 on p. 19.

 

Same patents:

The invention relates to the field of application of non-stick, anti-adhesion, anti-corrosion coating by way of heterologously on a hard surface and can be used in the manufacture of chemical equipment, utensils, household appliances and so on

The invention relates to heat-resistant antifriction coatings and can be used as a primer, get on a flat metal substrate by the method of rolling, followed by molding, in particular - kitchen utensils

The invention relates to enamel for protective and decorative coatings wood and primed metal products and structures, used in the atmospheric conditions of temperate climate

Paint road marking // 2155200
The invention relates to coatings industry

The invention relates to a paint and varnish materials and can be used to protect metal, concrete and wood surfaces from atmospheric corrosion and destruction, protection of external surfaces of chemical equipment with high temperature of the walls of

Lacquer // 2045558
The invention relates to a quick-drying top coat lacquers and can be used for varnishing metals, glass, all kinds of wood

The invention relates to polymer composite materials used for protection against corrosion and fouling by marine biomass bottoms and other elements vessels, concrete structures, pipes, working in contact with sea water, as well as for corrosion protection galvanic baths, various chemicals
The invention relates to materials for protective equipment for the eyes, in particular materials for protective shields, guards, observation slits costumes welders, metallurgists, fire

The invention relates to the technology of surface treatment of vulcanized rubber

The invention relates to the rubber industry, in particular to compositions for protective coatings tire rubber

The invention relates to the rubber industry

The invention relates to the rubber industry

The invention relates to a powdered crosslinked polymers, absorbent fluid and blood /superabsorbents with improved properties in respect of swelling and retention with respect to aqueous liquids under load; the method of obtaining these polymers and their use in absorbent products sanitation, as in baby diapers, incontinence /incontinence/ adult hygiene items for women, and also for covering wounds

The invention relates to contact lenses, in particular colored contact lens and method of reception

The invention relates to a process for the manufacture of parts for optical instruments and may find application in instrumentation, in particular, for making petals and shutter-aperture cameras

The invention relates to the chemistry of the modified polymers, specifically to a new sodium salt of a copolymer of acentrella and maleic anhydride (SPAN-MA), and can be used in the chemical industry, including for the separation of mixtures of metal ions, as well as for deposition and codeposition of metals
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