WO2005075531A1

WO2005075531A1 - Amphiphilic block and graft copolymers containing heavy elements, method for the production thereof, and use of the same as x-ray contrast agents

Info

Publication number: WO2005075531A1
Application number: PCT/EP2005/000990
Authority: WO
Inventors: Andreas Thuenemann; Christoph Kozlowski; Joachim Storsberg; Werner Jaeger; André LASCHEWSKY; Stephan Kubowicz
Original assignee: Fraunhofer-Gesellschaft Zur Foerderung Der Angewandten Forschung E.V.
Priority date: 2004-02-03
Filing date: 2005-02-01
Publication date: 2005-08-18
Also published as: DE102004005304A1

Abstract

The invention relates to amphiphilic block or graft copolymers comprising radio-opaque hydrophobic blocks and having a high heavy metal content. Said copolymers consist of, or are formed by, the structural units (A) = [C(R1R2)-CHR3] and (B) = [C(R4R5)-CHR6], the proportion thereof being at least 70 wt. %. The blocks poly(A) and blocks poly(B) respectively contain a repeating unit consisting of two carbon atoms, at least one of said atoms carrying a substituent. Block A is a hydrophilic block carrying at least one hydrophilic substituent per C2 carbon unit, while block B is a hydrophobic block, the C2 carbon unit thereof carrying at least one hydrophobic radical. Block B also carries a high proportion of covalently bonded heavy metals. The inventive copolymers can be used to produce micelle suspensions that are suitable as x-ray contrast agents.

Description

Heavy element amphiphilic block and graft copolymers, process for their preparation and their use as X-ray contrast media

The invention relates to new amphiphilic block copolymers with radiopaque hydrophobic blocks and a high proportion of heavy elements. These polymers can form micelles and can therefore be used as X-ray contrast agents for computed tomography and are the subject of this invention.

It is known that block and graft copolymers consisting of a hydrophobic and a hydrophilic block form micelles in an aqueous medium. These are often of the core-shell type, the core being formed from the hydrophobic polymer blocks and the shell from the hydrophilic polymer blocks.

Computed tomography (CT) is an X-ray diagnostic procedure for generating body cross-sectional images that is becoming increasingly important for diagnostics in medicine. Often, intravenous administration of large amounts of contrast medium is necessary, which increases the image quality of the tissue around an organ of interest. Contrast agents for CT are substances that necessarily contain heavy elements, i.e. High atomic number elements, "heavy elements", are included to be radiopaque (x-ray contrast). The radiopaque iodinated contrast agents used today are small water-soluble organic molecules and are based on triiodobenzene derivatives (see W. Krause, Advanced Drug Delivery Reviews 1999, 37 , 159-173) For precise imaging of organs by means of CT, a high iodine concentration in the range of at least 1 g per liter of blood is necessary. At lower iodine concentrations there is no sufficient increase in the electron density which determines the image contrast of a total of up to 100-200 g of contrast agent formulation, which is very painful for the patient due to the high viscosity of the formulations, and immediately after administration of the contrast agent, the iodine-containing molecules are distributed in a short time - due to their small size - starting from the vascular Space evenly on vascular and interstitial space. The half-life for the distribution is only 6 to 10 minutes (see W. Krause, Invest. Radiol. 1996, 31, 91-100). This greatly limits the time for taking CT images. H. it must be completed before the contrast medium molecules diffuse into the interstitial space.

There has been no shortage of attempts to find suitable CT contrast media that have a longer residence time in the vascular space (so-called blood pool agents). At first, macromolecular compounds appeared suitable, as proposed in DE 692 28 999 T2 in the form of iodinated polyamine compounds. Typically, these are branched (polyethyleneimines) or dendritic polymers (polyethyleneimine dendrimers) which contain triiodobenzene groups. However, these contrast agents are difficult to excrete through the kidneys. The reasons for this presumably lie in excessively high molecular weights as well as the strongly positive charge of the polyamine compounds and the associated property of forming strong non-covalent bonds (complex formation of polyethyleneimine) (AF Thünemann, Prag. Polym. Sei. 2002, 27, 1473-1572) ,

An attractive alternative are micelle-forming block copolymers with a hydrophilic and a hydrophobic block. Such copolymers have been extensively investigated, e.g. B. in formulations with drugs against cancer. Above a characteristic critical micellization concentration (cmc), these block copolymers form micelles of the core-shell type. The core of the micelle consists of water-insoluble blocks and drug molecules, the shell of the water-soluble blocks. When diluted, these drug-laden block copolymer micelles below the cmc disintegrate into the individual molecules. This allows drug release and excretion of the block copolymers, e.g. B. over the kidney. Review articles on this topic can be found e.g. B. at Kataoka et. al., Advanced Drug Delivery Reviews 2001. 47. 113-131.

This principle of the reversibly micelle-forming block copolymers has been developed by Torchilin et. al. transferred to CT contrast media (see e.g. Trubetskoy, V.S. et al., J. Drug Targeting 1997, 4, 381-388 and Torchilin, V.P., Adv. Drug. Deliv. Rev. 2002, 54, 232-252). The reversible micelle-forming block copolymers described by them in US Patent No. 5,567,410 consist of a polyethylene oxide block and a hydrophobic block containing iodine. Reversibility here means that there are polymer micelles above a cmc, the core of which contains iodine. The micelle shell is made of polyethylene oxide. Below this cmc at a concentration of about 0.5-0.05 μmol / l (corresponds to 0.01-0.001 g / l), these micelles disintegrate, which should facilitate their elimination. The dissociation of the iodine-containing micelles into single molecules in vivo is described as crucial in US Pat. No. 5,567,410.

Torchilin suggests using methyl poly (ethylene glycol) block poly (ε, N- (triiodobenzoyl) -L-lysine as a block copolymer to form the contrast-forming micelles, but block copolymers of this type have significant disadvantages. The first is in that that their synthesis is very complex and comprises a large number of stages first step, a monomethoxy PEG succinate is activated in the presence of dicylohexylcarbodiimide with N-hydroxysuccinimide to monomethoxy PEG succinimidyl succinate. This is followed by implementation with commercially available poly (CBZ) lysine protected in the ε position. The lysine amino groups are then deprotected with hydrogen bromide in acetic acid, and finally the triiodobenzene group is bound to the deblocked amino groups in the form of activated triiodobenzoic acid made from triiodobenzoic acid and N-hydroxysuccinimide.

In addition to the fact that six work steps are required for this synthesis, which precludes an economical industrial production of the block and graft copolymers mentioned, the process has a number of further disadvantages. Because of steric hindrance, only 80-90% of the amino groups bound to the polymer can be reacted with triiodobenzoyl groups (see US Pat. No. 5,567,410). Furthermore, the reactivity of the system used is limited because the triiodophenyl group is a very hydrophobic group and has a very low solubility. As a result, despite an incubation period of up to 2 days, Torchilin and his team received a product in which only 40% of the iodine-containing groups were covalently bound, while 60% were non-covalently attached and only loosely associated with the polymer, as in the purification revealed. In a specifically described example, the proportion of iodine is 44.7% by weight after synthesis (covalently plus non-covalently bound iodine groups) and 17.7% after purification to remove non-covalently bound triiodobenzoate. This high proportion of non-covalently bound iodine groups (in free triiodobenzoic acid), as mentioned by Torchiline itself, can be potentially toxic to the patient, which in turn severely limits the medical usability.

The object of the present invention is to provide an inexpensive to produce, in physiological environment hydrolytically stable contrast agent for X-ray examinations, the heavy element groups are completely covalently integrated into the molecular structure of the agent. The contrast medium should preferably be able to be prepared as a formulation of micelles with low viscosity, the application of which is less painful than the viscous formulations of low molecular weight substances which are customary today. If possible, the aim should be to produce copolymer micelles containing heavy elements that retain their structural integrity even when diluted heavily, i.e. do not disintegrate into their individual components. The object of the invention is achieved by the synthesis of a new type of amphiphilic block and graft copolymers containing heavy elements, in particular iodine. Surprisingly, it was found that such polymers can be produced in a cost-effective manner by a simple synthesis sequence. This can advantageously take place in a maximum of three synthesis stages, in which the hydrophilic and hydrophobic blocks are produced step by step and, if necessary, are coupled to one another and, if necessary, are reacted in a final step with a reagent containing heavy elements to form the target compound. The copolymers according to the invention can be converted in an aqueous medium, in particular in a physiological environment, into micelle formulations of the core-shell type which are suitable as X-ray contrast media.

The copolymers consist of blocks poly (A) and blocks poly (B) or contain them in large or substantial parts. In this context, the term “essential” is to be understood as meaning a proportion of at least approximately 70% by weight, preferably at least approximately 80 or 90% by weight. The blocks each contain a repeating unit of two carbon atoms, at least one of which carries a substituent, one of the blocks being a hydrophilic block (Block A) carrying at least one hydrophilic substituent per C ₂ carbon unit while the other is a hydrophobic block (block B) whose C ₂ carbon unit carries at least one hydrophobic residue.

The copolymer according to the invention is thus composed of or using the structural units (A):

and (B):

where R ¹ - (X) -COOR ', - (X) -OP (0) OR \ - (X) -NHC (O) R ", - (X) -NR" C (0) R ", - ( X) -C (O) NHR ", - (X) -C (0) N (R") ₂ , or - (X) -OH,

R ^{2 is} hydrogen, a methyl group or a radical -CH ₂ COOR ', -CH ₂ C (O) NHR ", -CH ₂ C (O) N (R") ₂ , -CH ₂ OC (0) R ", - Is CH ₂ NHR "C (O) R", or -CH ₂ C (0) N (R ") ₂ ,

R ^{3 is} hydrogen and, moreover, if R ^{2 is} hydrogen, it can be a radical -COOR *, C (O) NHR "or -C (O) N (R") ₂ ,

R 'is hydrogen, a monovalent metal cation, a corresponding proportion of a polyvalent metal cation, R "or a group (CH ₂ CH ₂ 0) _n R ⁷ , where several radicals R' can have the same or different meaning (s),

R "is a straight-chain, branched or cyclic alkyl group with preferably 1 to 8 carbon atoms, a benzyl group, an optionally alkyl-substituted aryl group with preferably 6 to 8 carbon atoms or a group (CH ₂ CH ₂ 0) _n R ⁷ , where several radicals R" can have the same or different meaning (s),

(X) a single bond, -OC (O) R ⁸ -, -OC (O) 0-R ⁸ -, -C (0) OR ⁸ -, -NR ⁷ C (0) R ⁸ -, -C (0 ) NR ⁷ R ⁸ -, -NR ⁷ C (0) OR ⁸ -, -N (R ⁸ -) C (O) OR ⁷ , -OC (0) NHR ⁸ -, -N (R ⁸ -) C ( O) R ⁷ or -R ⁹ -, where R ⁷ and / or R ⁸ and -R ⁹ - can carry substituents which are in particular selected from -COOR ', -S0 ₃ R \ -OSO ₃ R \ -N ⁺ R " ₄ , -OP (0) (OR ') ₂ , -P (0) (OR') ₂ , -NR ⁷ C (0) R ⁷ , -C (0) NR ⁷ R", -OH, - S (0) CH ₃ and -C (0) (0-CH ₂ .CH ₂ ) _r -OR ⁷ ,

R ⁴ , R ⁵ and R ⁶ independently of one another are hydrogen, R ", -OR", -OC (O) R ", -OC (0) OR", -C (O) OR ", -NR ⁷ C (0) R ", -C (O) NR ⁷ R", -NHC (O) OR ", -OC (O) NHR", -R ¹⁰ -R ¹⁰ ', -R ¹⁰ ' -R ¹⁰ , -R ⁰ -CH ₂ -R ¹⁰ \ -R ⁰ -CH ₂ -OR ¹⁰ ', -R ^10, -CH ₂ -R ¹⁰ , or -R ^10' -CH ₂ -OR ¹⁰ , with the proviso that at least one of the radicals R ⁴ , R ⁵ and R ⁶ are -R ¹⁰ -R ¹⁰ ', -R ¹⁰ ' -R ¹⁰ , -R ¹⁰ -CH ₂ -R ¹⁰ ', -R ¹⁰ -CH ₂ -OR ¹⁰ ', ~ R ¹⁰ '-CH ₂ -R ¹⁰ or -R ^10' -CH ₂ -OR ¹⁰ ,

R ^{7 is} hydrogen, an optionally substituted, straight-chain, branched or cyclic alkyl group with preferably 1 to 12 carbon atoms or an optionally substituted aryl, alkylaryl or arylalkyl group with preferably 6 to 24 carbon atoms,

R ^{8 is} an optionally substituted, straight-chain, branched or cyclic alkylene group with preferably 1 to 12 carbon atoms or an arylene, Is alkylarylene or arylalkylene group with preferably 6 to 24 carbon atoms, which may additionally be alkyl-substituted,

R ^{9 is} an optionally alkyl-substituted arylene group with preferably 6 to 10 carbon atoms,

R ^{10 is} an optionally alkyl-substituted aryl or arylene group with preferably 6 to 24 carbon atoms,

R ¹⁰ 'is an optionally alkyl-substituted arylene or aryl group, preferably having 6 to 24 carbon atoms, which is substituted one or more times with a heavy element, where R ¹⁰ and R ¹⁰ ' may optionally carry further substituents independently of one another, p and q are each independently an integer from 2 to 1000, and n and r are each an integer from 1 to 1000.

According to the invention, “heavy element” is understood to mean a chemical element with an atomic number higher than 31 and lower than 84 with the exception of the elements Kr and Xe, the elements I, Br, Sn, Sb, Te, Bi being preferred and the element l is particularly preferred.

R ¹ is preferably - (X) -COOR \, in particular where R 'is equal to the group (CH ₂ CH ₂ 0) _n R ⁷ , the length of the oxoalkylene group from ester group to ester group in the poly A block being able to vary statistically and preferably in the range from 5 to 20. (B) is very particularly preferably a single bond. R ⁷ is particularly preferably methyl or ethyl.

R ² is preferably hydrogen or methyl, very particularly preferably methyl.

R ³ is preferably hydrogen.

R ⁴ is preferably -R ¹⁰ -CH ² -OR ^{10 '} , where R ^{10 is} very particularly preferably a phenylene group and R ¹⁰ ' is particularly preferably a phenyl group which is whole is particularly preferably substituted with iodine or bromine, in particular with up to 3 iodine atoms.

(X) is preferably a single bond in a first embodiment, preferably -OC (0) R ⁸ -, -OC (0) OR ⁸ - or -C (0) OR ⁸ - in a second embodiment, preferred in a third embodiment - NR ⁷ C (O) R ⁸ -, -C (0) NR ⁷ R ⁸ -, -NR ⁷ C (O) OR ⁸ -, -N (R ⁸ -) C (0) OR ⁷ , -OC (0 ) NHR ⁸ -, or -N (R ⁸ -) C (O) R, and in a fourth embodiment preferably -R ⁹ -.

R ⁵ and R ⁶ are preferably hydrogen.

p is preferably 20 to 500, preferably 50 to 200. q is preferably 10 to 300, more preferably 30 to 80. n and r are preferably 2-100, more preferably 5-50. n is most preferably 6-12.

Monomers with which hydrophobic blocks (block B) can be produced by controlled radical or free radical polymerization are e.g. - but not limited to this selection - 4-vinylbenzyl chloride, 3-vinylbenzyl chloride, isomer mixtures of 4- and 3-vinylbenzyl chloride, glycidyl methacrylate, 2-bromoethyl methacrylate, glycidyl acrylate, 2-bromoethyl acrylate. 4-vinylbenzyl chloride is particularly preferred.

After their polymerization (homopolymerization or block copolymerization), these blocks can be reacted in a polymer-analogous reaction with a compound containing heavy elements, so that the group containing heavy elements is covalently bound to the polymer. For example, a poly (4-vinylbenzyl chloride) -containing polymer can be reacted with triiodophenol so that the triiodobenzene group is covalently bound to the polymer backbone to form an ether bond.

The heavy element-containing compound can, however, also be used directly as a free-radical (free or controlled) polymerizable monomeric compound for producing a hydrophobic polymer block already containing the heavy element. Monomeric compounds that already contain the heavy element can be - for example - but not limited to this representation or compounds - by reacting e.g. B. 4-vinylbenzyl chloride with e.g. Triiodophenol can be obtained.

Monomers with which hydrophilic blocks (Block A) can be produced by controlled radical or free radical polymerization are, for example - but not limited to this selection: Acrylic acid and its monovalent salts, itaconic acid and its monovalent salts,

Methacrylic acid and its monovalent salts,

2-Acrylamidoacetic acid and its monovalent salts, N-acryloylsarcosine and its monovalent salts, monovalent salts of 2-acrylamidopropionic acid, monovalent

Salts of 3-acrylamidopropionic acid, monovalent salts of

4-acrylamidobutyric acid, monovalent salts of 6-acrylamidocaproic acid, monovalent salts of acrylamidoundecanoic acid, monovalent salts of

Acrylamidododecanoic acid, N-acryloylproline and its monohydric salts,

N-acryloylhydroxyproline and its monovalent salts, 2-acrylamido-2-methyl-

1-propionic acid and its salts, monovalent salts of all isomers of acrylamido benzoic acid,

N-acryloyl taurine and its monovalent salts, N-acryloyl-N-methyl taurine and its monovalent salts, 2-acrylamido-2-methyl-1-propanesulfonic acid and its salts, all

Isomers of acrylamidobenzenesulfonic acid and their salts,

2-methacrylamidoacetic acid and its monovalent salts, monovalent salts of

3-methacrylamidopropionic acid, monovalent salts of 4-methacrylamidobutyric acid, monovalent salts of 6-methacrylamidocaproic acid, monovalent salts of

Methacrylamidoundecanoic acid, monovalent salts of methacrylamidododecanoic acid,

2-methacrylamido-2-methyl-propionic acid and its salts, monovalent salts of all

Isomers of methacrylamidobenzoic acid,

N-methacryloyl taurine and its monovalent salts, 2-methacrylamido-2-methyl

1-propanesulfonic acid and its salts, all isomers of

Methacrylamidobenzenesulfonic acid and its salts,

Salts of 2- (acryloyloxy) ethyldimethylamine, salts of 3- (acryloyloxy) propyldimethylamine, salts of 2- (methacryloyloxy) ethyldimethylamine, salts of

3- (methacryloyloxy) propyldimethylamins,

Salts of 2- (acrylamido) ethyldimethylamine, salts of

3- (acrylamido) propylidimethylamine, salts of N-acryloyl-N'methyl-piperazine,

Salts of 2- (methacrylamido) ethyldimethylamine, salts of 3- (methacrylamido) propyldimethylamine,

2- (acrylamido) ethyltrimethylammonium sulfate, mesylate, tosylate, methosulfate or

halide,

2- (acrylamido) ethyl-benzyldimethylammonium sulfate, mesylate, tosylate,

methosulfate or halide, 3- (acrylamido) propyltrimethylammonium sulfate,

mesylate, tosylate, methosulfate or halide,

3- (acrylamido) propyl-benzyldimethylammonium sulfate, mesylate, tosylate,

methosulfate or halide, N-acryloyl-N'.N'-dimethylpiperazinium sulfate, mesylate, tosylate, methosulfate or halide,

2- (methacrylamido) ethyltrimethylammonium sulfate, mesylate, tosylate, methosulfate or halide, 2- (methacrylamido) ethyl benzyldimethylammonium sulfate, mesylate, tosylate, methosulfate or halide, 3- (methacrylamido) - propyltrimethylammonium sulfate, mesylate, tosylate, methosulfate or halide, 3- (methacrylamido) propylbenzyldimethylammonium sulfate, mesylate, tosylate, methosulfate or halide,

2- (acryloyloxy) ethyltrimethylammonium sulfate, mesylate, tosylate, methosulfate or halide, 2- (acryloyloxy) ethyl benzyldimethylammonium sulfate, mesylate, tosylate, methosulfate or halide, 3- (acryloyloxy) propyltrimethylammon sulfate, mesylate, tosylate, methosulfate or halide, 3- (acryloyloxy) propylbenzyldimethylammonium sulfate, mesylate, tosylate, methosulfate or halide, 2- (methacryloyloxy) ethyltrimethylammonium sulfate, mesylate, tosylate, methosulfate or halide, 2- (methacryloyloxy) ethyl-benzyldimethylammonium sulfate, mesylate, tosylate, methosulfate or halide, 3- (methacryloyloxy) propyltrimethylammonium sulfate, mesylate, tosylate or methosulfate -halide, 3- (methacryloyloxy) propyl-benzyldimethylammonium sulfate, mesylate, tosylate, methosulfate or halide, the monovalent salts of all isomers of vinylbenzoic acid, styrene sulfonic acid and their salts, 2-vinylpyridine, 3-vinylpyridine, 4-vinylpyridine , quaternized salts of 2-, 3- and 4-vinylp yridins with residues containing less than 8 carbon atoms, N-vinylimidazole, quaternized salts of N-vinylimidazole with residues containing less than 8 carbon atoms, all isomers of vinylbenzylamine, all isomers of quaternized salts of vinylbenzylamine with residues which together are less than Contain 13 carbon atoms,

Acrylamide, N-methyl acrylamide, N-ethyl acrylamide, N, N-dimethylacrylamide, N-acryloylmorpholine, N- (2-hydroxyethyl) acrylamide, N, N-bis (2-hydroxyethyl) acrylamide, N- (2-hydroxypropyl) acrylamide, N- (2-hydroxypropyl) methacrylamide, 2-acrylamidopropane-1,3-diol, 3-acrylamidopropane-1,2-diol, 2-methacrylamidopropane-1,3-diol, 3-methacrylic amidopropane-1,2-diol , N- (trismethyloimethyl) acrylamide, N-acryloyl-glucosamine, N-methacryloyl-glucosamine, N-acryloyl-N-methyl-glucosamine, glyceryl acrylate, glucosyl acrylate, sorbitol acrylate, sorbitan acrylate, poly (ethylene glycol) acrylate, poly (ethylene glycol monomethyl) 2-Methylsulfinylethylacrylat,

Glyceryl methacrylate, glucosyl methacrylate, sorbitol methacrylate, sorbitan methacrylate, poly (ethylene glycol) methacrylate, poly (ethylene glycol monomethyl ether) methacrylate, 2-methylsulfinyiethyl methacrylate, N-vinyl formamide, N-methyl-N-vinyl formamide, N-vinyl acetamide, N-methyl-N-vinyl lacetamide, N-vinyl pyrrolidone.

Particularly preferred monomeric hydrophilic starting compounds are

Poly (ethylene glycol) acrylate, poly (ethylene glycol monomethyl ether) acrylate,

Poly (ethylene glycol) methacrylate, poly (ethylene glycol monomethyl ether) methacrylate,

glyceryl acrylate,

G lyceryl methacrylate,

N, N-dimethyl acrylamide,

N-vinylpyrrolidone.

In an important embodiment of the invention, the radicals R ^{1 have} the meaning - (X) -COOR ', -C (0) NHR ", or - (X) -C (O) NR ^2π , where R' (CH ₂ CH ₂ 0) _{n is} R ^7. The presence of the polyethylene oxide units promotes micelle formation.

In another important embodiment of the invention, R ¹ in copolymers according to the invention has the meaning - (X) -COOR ', where (X) is a single bond, where R' in turn is particularly preferably hydrogen or, likewise particularly preferably, (CH ₂ CH ₂ 0) nR ⁷ . Among the radicals R ⁷ , hydrogen or an alkyl group as defined above is again to be mentioned as preferred for this embodiment.

The copolymers according to the invention can be composed mainly or completely of a hydrophilic block poly (A) and a hydrophobic block poly (B). Alternatively, they can consist of three blocks (or contain substantial parts of them), and if the central block is hydrophobic, the two edge blocks are hydrophilic and vice versa. Alternatively, the copolymers according to the invention can be constructed from a block polymer which is grafted with the opposite block in each case. In a further embodiment of the invention, the hydrophilic block (A) itself can be a copolymer of randomly or alternately arranged, hydrophobic and hydrophilic units (A) and (B), provided that the block poly (A) still has such great hydrophilicity that it is water soluble. Suitable hydrophobic monomer units for the construction of such copolymers are, for example, styrene or methyl (meth) acrylate, maleic anhydride, (meth) acrylic acid, styrene sulfonic acid and its salts, vinylbenzoic acid and its salts as hydrophilic monomer units. The block and graft copolymers according to the invention can be produced by radical polymerization. An elegant synthesis consisting of only a few steps follows the following scheme:

1. Polymerization of a compound X (CH ₂ ) _m R ⁹ -CR ⁵ = CR ⁶ with m equal to 0 of the 1 and X being the same reactive radical, for example Cl or OH, to form a product with a reactive chain head (which is, for example - but not limited to the selection - can be a substituted nitroxyl or an ester of substituted or unsubstituted dithiobenzoic acid),

2. Polymerization of a compound R ¹ -CR ² = CR ³ , either in a preceding polymerization step with subsequent connection of the product to the product from step 1 or by direct polymerization of the individual molecules on the reactive chain head of the product from step 1, and

3. Reaction of a compound R ^10, (CH ₂ ) _o Y with the group X (CH ₂ ) _m R ¹⁰ - the product from step 2 to form the radical R ⁴ , where o + m together are 1 and Y is a suitable one Reaction partner is to bind R ¹⁰ 'via an ether bridge or directly to R ¹⁰ , for example OH or Cl.

It is favorable in the choice of this process that under the conditions of the first step a hydrophobic product is formed which is activated at the chain head and which can easily be used as a material for the polymerisation of the hydrophilic block, and that there are no protective groups for the subsequent attachment of the residue containing heavy elements requirement.

The invention thus provides copolymers and processes for their preparation,

1. which can be synthesized simply and therefore inexpensively via controlled radical polymerization and, if appropriate, polymer-analogous reaction,

2. in which the contrasting parts of the molecule are bound to the polymer backbone exclusively by covalent bonds,

3. which have a high stability to hydrolysis, in particular in a physiological environment,

4. form the micelles of the core-shell type with high structural integrity, which do not dissolve, especially when diluted, and

5. whose formulations in the form of core-shell micelles have a low viscosity even at high concentration. The synthesis is particularly simple using methods of so-called "controlled radical polymerization" (described, for example, in Matyjaszewski, K. (Editor), Controlled / Living Radical Polymerization, Progress in ATRP, NMP, and RAFT, ACS Symposium Series 768, American Chemical Society, Washington, DC, 2000, ISBN 0-8412-3707-7), as outlined on the following three-step synthesis scheme:

1. Production of an N-oxyl-terminated hydrophobic block by controlled radical polymerization (eg poly (vinylbenzyl chloride), see Example 1.1),

2. Production of an amphiphilic block copolymer by controlled radical polymerization of the hydrophobic, N-oxyl-terminated block (from synthesis step 1) with a suitable hydrophilic monomer (e.g. (meth)) acrylic acid, styrene sulfonic acid, and their salts, maleic anhydride, vinylbenzoic acid and their salts or poly (methoxypolyethylene glycol 350 methacrylate), see Example 1.2),

3. Polymer-analogous reaction of the hydrophobic block of the block copolymer (from synthesis step 2) with a benzene compound which contains heavy elements (e.g. triiodophenol, cf. Example 1.3). The hydrophobic block is reacted quantitatively with covalently bound triiodobenzene groups. The quantitative covalent binding of the iodine groups to the polymer backbone is demonstrated by means of ¹ H-NMR spectroscopy.

The order of synthesis of the hydrophobic and the hydrophilic block can also be easily interchanged in the synthesis scheme given. In addition, such heavy-element amphiphilic block or graft copolymers can alternatively also be prepared in only two synthesis steps if, for example, in the scheme described above in step 1 hydrophobic monomers are used which already contain heavy elements.

Furthermore, it was surprisingly found that the block and graft

Copolymers in aqueous solvents form micelles and aggregates that have a low viscosity even at high concentrations and a high X-ray

Show scatter contrast.

The invention will be explained in more detail below on the basis of exemplary embodiments. Example 1: Polymer synthesis

1.1 Synthesis of poly (vinylbenzyl chloride) with TBUNO (synthesis step 1)

The synthesis was carried out in a thermostattable 100 mL jacketed reactor. 3 mmol of N-fe f / ^' aer-butyl-1-diethylphosphono-2,2-dimethylpropylnitroxyl (TBUNO) and 50 g of 4-vinylbenzyl chloride (VBC) were dissolved in toluene. The solution was purged with argon for 1 h and then heated to 75 ° C. 2 mmol of 2,2-azobis (4-methoxy) -2,4-dimethylvaleronitrile (V70, WAKO) were then dissolved in 5 ml of toluene and added to the reaction mixture. The solution was stirred at 75 ° C for 1 hour to ensure complete disintegration of the V70. The temperature was then raised to 95 ° C. to start the polymerization. After a reaction time of 4 h, the mixture was stopped by allowing the mixture to cool. The polymer solution was poured into 1500 mL methanol and the polymer precipitated. The tube product was dissolved in 100 mL butanone and then precipitated again in 1500 mL methanol, filtered off and dried in vacuo. The yield was 50 g of PVBC.

1.2 Synthesis of poly (vinylbenzyl chloride) block poly (ethylene oxide monomethyl ether methacrylate) PBVC block PMPEG350MA (synthesis step 2)

The synthesis was carried out in a thermostattable 100 mL jacketed reactor. 5 g (0.5 mmol) of PVBC (from synthesis step 1) and 40 g of MPEG350MA ("bisomer 350" methoxypolyethylene glycol 350 methacrylate, LAPORTE Performance Chemicals, average M _w = 350 g mol ^"1 ) were dissolved with 50 g of toluene. The solution is flushed with argon for 1 h. The mixture was then heated to 92 ° C. to start the polymerization. After 1 h, the mixture is stopped by allowing the batch to cool. The polymer solution was poured into 1500 ml of diethyl ether and the polymer precipitated. The crude product was dissolved in 50 ml of butanone and then precipitated again in 1500 ml of diethyl ether. After drying in a vacuum drying cabinet, about 12 g of PVBC-block-PMPEG350MA are obtained, corresponding to a molar mass ratio of the blocks of 1: 1.

¹ H-NMR (400 MHz, CDCI ₃ ): 1.3-1-9 ppm CH, CH> (main chain); 3.4 ppm O-CH ₃ ; 3.5-3.7 ppm O-CÜ; 4.0-4.2 ppm OCO-Chb (ester); 4.3-4.5 ppm Chb (benzyl); 6.3-7.2 ppm CH (aroma) 1.3 Synthesis of poly (vinylbenzyl triiodophenolate) block poly (ethylene oxide monomethyl ether methacrylate) PVBI-b-PMPEG350 A (synthesis step 3)

1.00 g of PVBC-b-PMPEG350MA (from synthesis step 2), 1.06 g of triiodophenol, 0.31 g of potassium carbonate and 0.02 g of potassium iodide were dissolved in 10 ml of anhydrous acetone. The mixture was then boiled under reflux for 3 h. The product was then transferred to a 9: 1 acetone / water solution and dialyzed in a 3.5 kD dialysis tube to a conductivity of 20 PS. The product was isolated by freeze drying.

¹ H NMR (400 MHz, CDCI ₃ ): 1.3-1-9 ppm CH, CH ₂ (main chain); 3.4 ppm O-CH ₃ ; 3.5-3.7 ppm 0-CH ₂ ; 4.0-4.2 ppm OCO-CH ₂ (ester) and CH ₂ -Ph (benzyl); 7.4-8.1 ppm CH (aroma)

The structural formula of the iodine-containing block copolymer after synthesis step 3 is shown below. The iodine content is 19.08 percent by weight.

Example 2: Synthesis of an iodine-containing, micelle-forming diblock copolymer:

Synthesis of Polv (vinylbenzyl chloride) (PVBC)

25 g (163.8 mmol) of 4-vinylbenzyl chloride were weighed into a Schlenk vessel with 0.2 g (0.68 mmol) of SG1 and 0.1 g (0.32 mmol) of V70 (Wako-Chemicals) and degassed. The reaction mixture was heated to 100 ° C. and stirred for 2 hours. The polymer solution was precipitated twice in methanol, the crude product obtained was dissolved in benzene and freeze-dried. Yield: 8.4 g

GPC (THF): Mn: 1850 g / mol; PD = 1.25

Synthesis of PVBC-b-PEG-methyl ether acrylate

5.62 g of inhibitor-free poly (ethylene glycol) methyl ether acrylate (Mw = 134.13 g / mol, Aldrich) and 0.71 g of PVBC were weighed into a Schlenk vessel and dissolved in 7 ml of toluene. The reaction mixture was degassed and stirred at 95 ° C for 2 h.

The polymer solution was precipitated in ice-cold diethyl ether and filtered off. That at

Room temperature oily product was in a tetrahydrofuran / water mixture

(1: 9) dissolved, dialyzed and freeze-dried.

(Yield: 1.18 g)

GPC (THF): Mn: 3300 g / mol; PD = 1.26

Synthesis of PVBC-TIP-b-PEG-methyl ether acrylate

1173 g of PVBC-b-PEG-methyl ether acrylate were weighed into a 100 ml three-necked flask under argon and dissolved in 40 ml of dry acetone. 23.3 mg of potassium iodide, 2.6444 g of triiodophenol and finally 0.7745 g of dried potassium carbonate were added. The reaction mixture was stirred under reflux and under an argon atmosphere for 2.5 h, then filtered and dialyzed against water for 2 days (Cellutrans dialysis tube, Mw cutoff 1000). Yield: 0.5 g

Example 3: Synthesis of a polymerizable. heavy element monomer:

Synthesis of p-vinylbenzyl (tribromophenyl) ether

3.25 g (21.2 mmol) of 4-vinylbenzyl chloride were weighed into a 100 ml three-necked flask and dissolved in 20 ml of dry acetone. 7.49 g (22.6 mmol) of 2,4,6-tribromophenol and a further 40 ml of acetone were added. After adding 2.94 g (21.2 mmol) of dried potassium carbonate (powder), the solution was stirred under reflux under a dry argon atmosphere for 23 h.

The reaction mixture was then filtered while hot. The filtrate was poured into 50 ml of distilled water (23 ° C). A white precipitate formed which was filtered off and dried under vacuum at room temperature. Yield: 2.0939g ¹ H-NMR (400 MHz; DMSO-D6; α in ppm): 7.98 (s, 2H), 7.52 (s, 4H), 6.80 - 6.73 (dd, 1 H), 5.90 - 5.85 (d, 1 H) , 5.31 - 5.28 (d, 1H), 4.97 (s, 2H)

Example 4: Preparation of a core-shell micelle formulation

A quantity of 20 mg of PVBI-b-PMPEG350MA (from example 1, synthesis step 3, compare section 1.3 of example 1) was dissolved in 15 ml of tetrahydrofuran in an ultrasound bath at 50 ° C., mixed dropwise with 20 ml of water at 50 ° C. and with stirring Let stand at constant temperature until the typical smell of tetrahydrofuran had disappeared. The amount of water evaporated was replaced and characterized using dynamic light scattering (A1-SP81 goniometer and ALV-5000 digital correlator from ALV Laser Vertriebsgesellschaft, Langen). The hydrodynamic radius of the micelles determined from the light scattering data using the Stokes-Einstein relationship was 62 nm. To determine the structural integrity of the micelles, the solutions were examined in the concentration interval from 10 ^"3 g / L to 10 g / L. With values between 60 and 65 nm showed no change in the hydrodynamic radius in the concentration range examined, characterized by viscometry

Viscometric measurements on the micellar solutions were carried out using a solution viscometer with automatic dilution (Viskoboy 2; Lauda) at 30 ° C. in 0.01 N sodium chloride solution. As can be seen in FIG. 1, it was found that the viscosity of the micelles produced according to Example 2 is low (eg 6 cm ³ g ^"1 at a concentration of 8 g L ^{" 1} ) and that their intrinsic viscosity also has a low value (approx. 5 cm ³ g ^"1 ). Furthermore, the viscosity increases linearly with the concentration (gradient approx. 0.16 cm ³ L g ^{" 2} ). The block copolymer micelles thus behave like ideally typical hard spheres with regard to their viscosity. No signs of the formation of higher degrees of association than the desired micelles (e.g. lamellar liquid crystals) were found in the concentration range investigated (2 to 8 g L ^"1 ).

Structure of the micelles

To determine the structure of the micelles of the block copolymers, the X-ray small-angle scattering intensity of a 1% by weight micellar solution of the micelles produced in Example 2 was determined (cf. FIG. 3). The structures were evaluated using the Percus-Yevick model (J. Percus, GH Yevick; Phys, Rev. 110 (1958), 1-13; MS Wertheim, Phys. Rev. Lett. 10 (1963), 321-323; NW Ashcroft et al., Phys. Rev. 145 (1966), 83-90; JA Barker et al., Rev. Mod. Phys. 48 (1976), 598-671) and gave 14 nm for the core radius of the micelles and an effective (hard sphere) radius of 16 nm. Since the X-ray contrast is largely determined by the iodine content of the polymers, it can be concluded from the X-ray small-angle data that the iodine-containing groups are located exclusively in a compact iodine-containing core of the micelles with a radius of 14 nm. In addition, the applicability of the Perkus-Yevik model shows that the micelles behave like ideally typical hard balls with regard to their scattering behavior.

Claims

Expectations:

1. Amphiphilic block or graft copolymer composed of or using the structural units (A):

and (B):

in a proportion of at least 70% by weight in which R ¹ - (X) -COOR ', - (X) -OP (0) OR', - (X) -NHC (0) R ", - (X) -NR "C (O) R", - (X) -C (0) NHR ", - (X) -C (0) N (R") ₂ , or - (X) -OH, R ^{2 is} hydrogen , a methyl group or a radical -CH ₂ COOR ', CH ₂ C (0) NHR ", CH ₂ C (O) N (R") ₂ , -CH ₂ OC (O) R ", CH ₂ NHR" C ( O) R ", or CH ₂ C (0) N (R") ₂ , R ^{3 is} hydrogen and also, when R ^{2 is} hydrogen, a radical -COOR ', C (0) NHR "or -C (O) N can be (R ") ₂ , R 'is hydrogen, a monovalent metal cation, a corresponding proportion of a polyvalent metal cation, R" or a group (CH2CH ₂ 0) _n R ⁷ , where several radicals R' are the same or different R (s) can have a straight-chain, branched or cyclic alkyl group with preferably 1 to 8 carbon atoms, a benzyl group, an optionally alkyl-substituted aryl group with preferably 6 to 8 carbon atoms or a group (CH ₂ CH ₂ O) _π R ⁷ , where several radicals R "have the same or different meaning (s) can, (X) a single bond, -OC (O) R ⁸ -, -OC (0) 0-R ⁸ -, -C (0) OR ⁸ -, -NR ⁷ C (0) R ⁸ -, -C (O) NR ⁷ R ⁸ -, -NR ⁷ C (O) OR ⁸ -, -N (R ⁸ -) C (0) OR ⁷ -OC (0) NHR ⁸ -, -N (R ⁸ -) C (0) R ⁷ or -R ⁹ -, where R ⁷ and / or R ⁸ and -R ⁹ - are substituents can wear, which are particularly selected from -COOR ', -S0 ₃ R',

-OSO ₃ R \ -N ⁺ R " ₄ , -OP (0) (OR ') ₂ , -P (O) (OR') ₂ , -NR ⁷ C (0) R ⁷ , -C (0) NR ⁷ R ",

-OH, -S (0) CH ₃ and -C (0) (0-CH ₂ .CH ₂ ) _r -OR ⁷ ,

R ⁴ , R ⁵ and R ⁶ independently of one another are hydrogen, R ", -OR", -OC (0) R ",

-OC (0) OR ", -C (0) OR", -NR ⁷ C (O) R ", -C (0) NR ⁷ R", -NHC (0) OR ",

-OC (O) NHR ", -R ¹⁰ -R ¹⁰ ', -R ^10, -R ¹⁰ , -R ¹⁰ -CH ₂ -R ¹⁰ ', -R ⁰ -CH ₂ -OR ¹⁰ ',

-R ¹⁰ '-CH ₂ -R ¹⁰ , or -R ^10' -CH ₂ -OR ¹⁰ , with the proviso that at least one of the radicals R ⁴ , R ⁵ and R ^{6 has} the meaning -R ¹⁰ -R ¹⁰ ' , -R ¹⁰ '-R ¹⁰ ,

-R ¹⁰ -CH ₂ -R ¹⁰ ', -R ¹⁰ -CH ₂ -OR ¹⁰ ', -R ^10, -CH ₂ -R ¹⁰ or -R ^{10 '} -CH ₂ -OR ¹⁰ ,

R ^{7 is} hydrogen, an optionally substituted, straight-chain, branched or cyclic alkyl group with preferably 1 to 12 carbon atoms or an optionally substituted aryl, alkylaryl or arylalkyl group with preferably

Is 6 to 24 carbon atoms,

R ^{8 is} an optionally substituted, straight-chain, branched or cyclic

Alkylene group preferably having 1 to 12 carbon atoms or one

Arylene, alkylarylene or arylalkylene group preferably having 6 to 24

Is carbon atoms, which may additionally be alkyl substituted,

R ^{9 is} an optionally alkyl-substituted arylene group with preferably 6 to 10

Carbon atoms is

R ^{10 is} an optionally alkyl-substituted aryl or arylene group with preferably

Is 6 to 24 carbon atoms,

R ¹⁰ 'preferably an alkyl-substituted arylene or aryl group

6 to 24 carbon atoms is one or more with a heavy one

Element is substituted, where R ¹⁰ and R ¹⁰ 'may optionally carry further substituents independently of one another, p and q are each independently an integer from 2 to 1000, and n and r are each an integer from 1 to 1000.

Amphiphilic block or graft copolymer according to claim 1, wherein R ¹ - (X) -COOR 'with R' is equal to the group (CH ₂ CH ₂ 0) _n R ⁷ , the length of the oxoalkylene group from ester group to ester group in the block Poly A varies statistically and is preferably in the range from 5 to 20.

Amphiphilic block or graft copolymer according to claim 2, wherein (X) is a single bond and / or R ^{7 is} methyl or ethyl.

4. Amphiphilic block or graft copolymer according to any one of the preceding claims, wherein R ^{2 is} hydrogen or methyl, preferably methyl.

5. Amphiphilic block or graft copolymer according to any one of the preceding claims, wherein R ^{3 is} hydrogen.

6. Amphiphilic block or graft copolymer according to any one of the preceding claims, wherein R ^{4 is} -R ¹⁰ -CH ₂ -OR ¹⁰ ', wherein R ^{10 is} preferably a phenylene group and R ^{10 is} preferably a phenyl group, which is very particularly preferably with Iodine or bromine, in particular with up to 3 iodine atoms, is substituted.

7. Amphiphilic block or graft copolymer according to any one of the preceding claims, wherein R ⁵ and R ^{6 are} both hydrogen.

8. Amphiphilic block or graft copolymer according to one of the preceding claims, wherein R ^{1 has} the meaning - (X) -COOR 'or - (X) -OP (O) OR', where R '(CH ₂ CH ₂ 0 ) _{n is} R ⁷ .

9. Amphiphilic block or graft copolymer according to one of the preceding claims, characterized in that the molar masses of the blocks poly (A) and poly (B) are each independently between 500 and 100,000, preferably between 1000 and 20,000.

10. Amphiphilic block or graft copolymer according to one of the preceding claims, in which the heavy element or elements are in the hydrophobic block.

11. Amphiphilic block or graft copolymer according to one of the preceding claims, characterized in that the content of heavy elements is 10 to 65% by weight, preferably between 15 and 50% by weight.

12. micelle suspension comprising micelles from an amphiphilic block or graft copolymer according to any one of claims 1 to 11 in an aqueous solvent.

13. micelle suspension according to claim 12, characterized in that the aqueous solvent is physiological saline or contains it as a base.

14. Micellar suspension according to one of claims 12 or 13 with a content of heavy elements of 10 to 100 g per liter, preferably between 15 and 60 g per liter.

15. Micelle suspension according to one of claims 12 to 14 with an intrinsic viscosity of ≤5 cm ³ per g.

16. Micelle suspension according to one of claims 12 to 15, characterized in that the micelles are core-shell micelles with a diameter of 5 to 500 nm, preferably between 10 and 100 nm and particularly preferably between 20 and 60 nm.

17. A method for producing an amphiphilic block or graft copolymer according to any one of claims 1 to 11, comprising the steps of: (a) polymerizing a monomer having the formula X (CH ₂ ) _m R ⁹ -CR ⁵ = CR ⁶ , wherein m is 0 of 1 and X is Cl or OH and the remaining radicals have the meaning given in claim 1, forming a product with a reactive chain head, (b) polymerizing a compound having the formula R ¹ -CR ² = CR ³ , in which the radicals have the meaning given in claim 1, either in a preceding polymerization step with subsequent attachment of the product to the product from step (a) or by direct polymerization of the individual molecules onto the reactive chain head of the product from step (a), and (c) Reacting a compound R ^10, (CH ₂ ) oY with the group X (CH ₂ ) _m R ⁹ - the product from step (b) to form the radical R ⁴ , where o + m together is 1 and Y is a suitable reaction partner is to R ¹⁰ 'to bind via an ether bridge or directly to R ¹⁰ , in particular OH or Cl, and the remaining radicals have the meaning given for claim 1.

18. A method for producing an amphiphilic block or graft copolymer according to claim 17, comprising the steps of: (i) producing an N-oxyl-terminated hydrophobic block by controlled radical polymerization of a hydrophobic vinyl compound, preferably vinylbenzyl chloride, (ii) producing an amphiphilic Block copolymer by controlled free-radical polymerization of the hydrophobic, N-oxyl-terminated block (from step (i)) with a suitable hydrophilic vinyl monomer, preferably (meth) acrylic acid, styrene sulfonic acid, and their salts, maleic anhydride, vinylbenzoic acid and their salts, glyceryl (meth ) acrylate, N, N-dimethylacrylamide or poly (methoxypolyethylene glycol 350 (meth) acrylate), (iii) polymer-analogous reaction of the hydrophobic block of the block copolymer (from step (ii)) with an aromatic compound which contains a heavy element, preferably with triiodophenol.

19. Use of a micelle suspension according to one of claims 12 to 16 as an X-ray contrast medium.