EP1037672A1 - Conjugues polymeres dendritiques-saccharides, produits pharmaceutiques contenant ces conjugues, leur procede de production et leur utilisation - Google Patents

Conjugues polymeres dendritiques-saccharides, produits pharmaceutiques contenant ces conjugues, leur procede de production et leur utilisation

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Publication number
EP1037672A1
EP1037672A1 EP98966256A EP98966256A EP1037672A1 EP 1037672 A1 EP1037672 A1 EP 1037672A1 EP 98966256 A EP98966256 A EP 98966256A EP 98966256 A EP98966256 A EP 98966256A EP 1037672 A1 EP1037672 A1 EP 1037672A1
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EP
European Patent Office
Prior art keywords
mmol
title compound
group
conjugate
conjugates
Prior art date
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EP98966256A
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German (de)
English (en)
Inventor
Peter Mareski
Johannes Platzek
Bernd Radüchel
Hanns-Joachim Weinmann
Dietmar Berndorff
Bernd Misselwitz
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Bayer Pharma AG
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Schering AG
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G83/00—Macromolecular compounds not provided for in groups C08G2/00 - C08G81/00
    • C08G83/002—Dendritic macromolecules
    • C08G83/003—Dendrimers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/12—Macromolecular compounds
    • A61K49/124—Macromolecular compounds dendrimers, dendrons, hyperbranched compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5154—Antigen presenting cells [APCs], e.g. dendritic cells or macrophages

Definitions

  • Dendritic polymer-saccharide conjugates Dendritic polymer-saccharide conjugates, pharmaceutical compositions containing them, processes for their preparation and their
  • the invention relates to the subject matter characterized in the claims, that is to say conjugates consisting of an amino group-containing dendritic polymer, the branches of which are made from vinyl cyanide units, signaling group (s) containing metal ion (s) and mono- or oligosaccharides and optionally cations of inorganic and / or organic bases, amino acids or amino acid amides, pharmaceutical compositions containing these compounds, their use in diagnostics and methods for producing these compounds and compositions.
  • conjugates consisting of an amino group-containing dendritic polymer, the branches of which are made from vinyl cyanide units, signaling group (s) containing metal ion (s) and mono- or oligosaccharides and optionally cations of inorganic and / or organic bases, amino acids or amino acid amides, pharmaceutical compositions containing these compounds, their use in diagnostics and methods for producing these compounds and compositions.
  • Lymph node metastases become malignant in approximately 50-70% of patients
  • lymph nodes in a malignant disease has a significant influence on the therapeutic measures to be initiated. The earliest and most accurate diagnosis of lymph node involvement is therefore of the utmost importance for the patient.
  • Contrast-assisted lymphography has so far provided only unsatisfactory results in medical practice.
  • X-ray examinations with iodized oils e.g. with iodinated fatty acid esters of poppy oil, show good storage capacities in the lymph nodes and a useful contrast effect on the one hand, but on the other hand they are due to their known side effects (Keinert, K., Köhler, K., and Platzbecker, H. , Complications and contraindications In: M. Lüning, M. Wiljasalo, and H. Weissleder (eds.), Lymphography for malignant tumors, pp. 40-50. Stuttgart: Georg Thieme Verlag, 1976) neither general nor problem-free.
  • Water-soluble iodinated X-ray contrast media such as lotrolan (Isovist®) have only a limited area of application for the representation of the lymphatic system.
  • Isovist® Water-soluble iodinated X-ray contrast media
  • the highly water-soluble, low-molecular substances then diffuse from the lymphatic vessels into the interstitium. This disadvantage cannot be compensated for by the sensitive method of computed tomography.
  • radioactive ⁇ m Tc tracers are used for indirect lymph node imaging.
  • the disadvantages also apply here that only the lymph channels supplying the injection site are shown.
  • Superparamagnetic iron oxide particles are also suitable as lymphographics for nuclear magnetic resonance imaging, e.g. AMI-227, have been proposed (Guimaraes, R., Clement, O., Bittoun, J., Carnot, f., And Frija, G. MR lymphography with superparamagnetic iron nanoparticles in rats: pathologic basis for contrast enhancement. Am J. Roentgenol., 162, 201-207, 1994). However, the examination results obtained on the animal so far indicate unsatisfactory imaging despite the high dosage of the particles.
  • lymphographics (Hanka, L. et al., Radiology 1996, 198, 365-370) show such animal specificity (rat vs. guinea pig and rabbit) that their further development had to be stopped.
  • the conjugates according to the invention consist of a dendritic polymer containing amino groups, the branches of which are made from vinyl cyanide units, signaling group (s) containing metal ion (s) and mono- or oligosaccharides and optionally cations of inorganic and / or organic bases, amino acids or Amino acid amides are surprisingly particularly suitable for the production of NMR diagnostics, in particular for lymphography.
  • Lymph node tissue they show no deviating animal specificities.
  • K stands for a signaling group containing metal ion (s), L for a linker and Z for a mono- or oligosaccharide reduced by one hydroxyl group.
  • the polymer which stands for P and contains k amino groups, of which (n + m) are each reduced by one hydrogen atom, is a dendrimer prepared from vinyl group units, as described in the patent specifications WO 93/14147, WO 93/12073, WO 95/02008, WO 95/20619, WO 96/02588, EP 684044, EP 672703 and US Pat. No. 5,530,092 and which DSM polyamines are called, the repeating units being 3-amino-propylene or 3-amino-2-methyl-propylene groups [cf. see also pages 34 and 35 for the corresponding formulas].
  • the sum (n + m) of the signaling groups (K) and of the mono- or polysaccharides (Z) bound by L, each reduced by one hydroxyl group, is preferably equal to the number k of the amino groups contained in the polymer, ie. There is a complete occupation of the amino groups contained in P.
  • the polymers preferably contain 32 or 64 amino groups, of which, for example, 3, 4, 6, 7, 8, 11, 13, 14, 16, 18, 19, 21, 47 on signaling groups K and, for example, 9, 8, 18, 17 , 16, 13, 11, 10, 20, 6, 29, 27, 33 are bound to mono- or polysaccharides Z which are each bound via L and reduced by one hydroxyl group.
  • the sum (n + m) is preferably> k - 4.
  • the signaling group K is a chelate complex consisting of a radical of the general formef II, III, IV, V or VI.
  • R1 independently of one another is a hydrogen atom or a metal ion equivalent of the elements with a number of 20-32, 37-39, 42-44, 49 or 57-83,
  • R 2 is a hydrogen atom, a straight-chain or branched C 1 -C 7 -alkyl radical, a phenyl or benzyl radical,
  • U is a -CHR 3 -CONR 3 -M 1 or -CH2-CH (OH) -M 2 group with R 3 independently of one another in the meaning of R2 or the group -CH2- (CH2) 0 -
  • the metal ion of the signaling group must be paramagnetic.
  • Suitable ions are, for example, chromium (III) -, iron (II) -, cobalt (II) -, nickel ( ll) -, copper (ll) -, Praseodymium (III), Neodymium (III), Samarium (III) and Ytterbium (III) ion. Because of their strong magnetic moment, gadolinium (III), terbium (III), dys ⁇ rosium (III), holmium (III), erbium (III), iron (III) and manganese (II) are particularly preferred. -ions.
  • the metal ion must be radioactive for the use of the compounds according to the invention in nuclear medicine.
  • radioisotopes of the elements copper, cobalt, gallium, germanium, yttrium, strontium, technetium, indium, ytterbium, gadolinium, samarium, iridium, rhenium and bismuth are suitable; technetium, gallium, indium and rhenium are preferred.
  • the metal ion is preferably derived from an element of a higher atomic number in order to achieve sufficient absorption of the X-rays. It has been found that diagnostic agents which contain a physiologically compatible complex salt with metal ions of elements of atomic numbers 25 and 26 and 57-83 are suitable for this purpose.
  • Manganese (II) -, iron (II) -, iron (III) -, praseodymium (III) -, neodymium (III) -, samarium (III) -, gadolinium (III) -, ytterbium (III) are preferred - or bismuth (III) ions, especially dysprosium (III) ions.
  • Acidic hydrogen atoms which may be present in R1 that is to say those which have not been substituted by the central ion, can, if appropriate, be replaced in whole or in part by cations of inorganic and / or organic bases or amino acids or amino acid amides.
  • Suitable inorganic cations are, for example, lithium ion, potassium ion, calcium ion and in particular sodium ion.
  • Suitable cations of organic bases include those of primary, secondary or tertiary amines, such as, for example, ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine and in particular N-methylglucamine.
  • Suitable cations of amino acids are, for example, those of lysine, arginine and ornithine and the amides of otherwise acidic or neutral amino acids.
  • the compounds according to the invention which have a molecular weight of 5,000-200,000 D, preferably 15,000-60,000 D, have the desired properties described at the outset. They contain the large number of metal ions required for their use which are stably bound in the complex.
  • saccharide-polymer complexes according to the invention are outstandingly suitable for the interstitial and especially for the i.v. Lymphography.
  • the contrast media according to the invention can be formulated as solutions isoosmolar to the blood and thereby reduce the osmotic load on the body, which is reflected in a reduced toxicity of the substance (higher toxic threshold). Lower doses and higher toxic thresholds lead to a significant increase in the safety of contrast medium applications in modern imaging processes.
  • R 2 are the hydrogen atom, the methyl, isopropyl, phenyl and benzyl group.
  • Examples of preferred groups standing for V are the CH2C6H4, CH2-O-C6H4, (CH2) 4, (CH 2 ) 6 and (CH2) ⁇ o groups, the C6H4 group being attached to T " ! is bound.
  • Preferred substituents for R 3 are the hydrogen atom, the methyl, CH 2 COOH and (CH 2 ) 2COOH group.
  • ⁇ indicates the link to the rest-CH (OH) - and ß the link to T 1 .
  • Groups Z for the monosaccharides are the hexoses, pentoses and N-acetyl-neuraminic acid, each reduced by one hydroxyl group, which are each in the pyranose or furanose form, and their derivatives.
  • Preferred are hexoses which are in the pyranose form, such as, for example, D-galactose, D-mannose, D-glucose, L-fucose, galactose-6-sulfate, mannose-6-sulfate, D-glucosamine. 6-sulfate, D-glucosamine-3,4,6-trisulfate and N-acetyl-glucosamine.
  • Examples of preferred monosaccharides are N-acetyl-2-amino-2-deoxy-D-glucose, -D-galactose and D-mannose, 6-deoxy-L-galactose and N-acetyl-neuraminic acid.
  • Z stands for oligosaccharides, these can be linear or branched from the monosaccharides mentioned above, and the linkage can be terminal or within the chain.
  • Examples of oligosaccharides are: sialyl-Lewis x (see, for example, H. Ohmoto et al, J. Med. Chem. 1996, 39, 1339); Deoxy-sialyl-Lewis x
  • the polymer is preferably bound (via the linker L) to the mono- or polysaccharides via the C-2 position, particularly preferably via the C-1 position of the sugars.
  • the groups M 3 are, for example
  • ⁇ indicates the junction at X and ⁇ the junction at T 2 .
  • M 3 preferably stands for a direct bond and for the groups
  • K ' is a radical of the general formula II ', III', IV, V or VI '
  • R 2 , V, o, p, T and U have the meaning given above, with n 'mono- or oligosaccharides of the general formula VIII
  • n ' 1-3 n
  • Z ' has the meaning given for Z, but the carboxy, amino and hydroxyl groups which may be present in Z are optionally protected,
  • R ⁇ meaning a straight-chain or branched C ⁇
  • M 3 has the meaning given for M 3 , but the carboxy groups which may be present in M 3 are optionally protected, and X represents NH, CO, O and S, or b) a polymer saccharide conjugate of the general formula IX
  • n ', L * and Z' have the meanings given above, with m 'complexes or complexing agents K * , where K * for compounds of the general formula
  • R1 ' represents an acid protecting group or if the caboxy groups contained in L', M 3 'and Z' are protected, lower alkyl, aryl and aralkyl groups, for example the methyl, ethyl, propyl, butyl, Phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis (p-nitrophenyl) methyl group, and trialkylsilyl groups in question.
  • the protective groups are split off by the processes known to the person skilled in the art (see, for example, E. Wünsch, Methods of Org. Chemistry, Houben-Weyl, Vol XV / 1st 4th Edition 1974, p. 315), for example by hydrolysis, hydrogenolysis, alkaline saponification of the esters with alkali in aqueous-alcoholic solution at temperatures from 0 ° C to 50 ° C, acid saponification with mineral acids or in the case of tert-butyl esters with the help of trifluoroacetic acid.
  • the hydroxyl protective groups are, for example, the benzyl, 4-methoxybenzyl, 4-nitrobenzyl, t ⁇ tyl, diphenylmethyl, t ⁇ methylsilyl, dimethyl-t-butylsilyl-diphenyl-t-butysilyl group as a protective group for the 1 -OH group of the mono- and / or oligosaccharides is also suitable for the methyl group
  • the hydroxyl groups can also, for example, as THP ether, alkyl ether, ⁇ -alkoxyethyl ether, MEM and MOM ether or as an ester with aromatic or aliphatic carboxylic acids, such as acetic acid and chloroacetic acid, benzoic acid, levulinic acid or 2 Chloroacetoxymethyl (or ethyl) benzoic acid (GIT horrz Lab 1996, 46) are present.
  • the hydroxyl groups can also be protected in the form of ketals with, for example, acetone, acetaldehyde, cyclohexanone or benzaldehyde
  • hydroxyl protective groups can be released using the literature methods known to the person skilled in the art, for example by hydrogenolysis, reductive cleavage with lithium / ammonia, acid treatment of the ethers and ketals or alkali treatment of the esters (see, for example, “Protective Groups in Organic Synthesis”, TW Greene, John Wiley and Sons 1981)
  • the amine protecting groups are the benzyloxycarbonyl, tertiary-butoxycarbonyl, trifluoroacetyl, fluorenylmethoxycarbonyl, benzyl, formyl, 4-methoxybenzyl, 2,2,2-tr ⁇ chlorethoxycarbonyl, phthaloyl, 1,2- Oxazoline, tosyl, dithiasuccinoyl .AIIyloxycabonyl, sulfate, pent-4-encarbonyl, 2-chloroacetoxymethyl (or ethyl) benzoyl, tetrachlorophthaloyl, alkyloxycarbonyl groups [Th W Greene, PGM Wuts, Protective Groups in Organic Syntheses, 2nd ed, John Wiley and Sons (1991), S 309 - 385, E Meinjohanns et al, J Chem Soc Pekin Trans 1, 1995, 405, U Ellensik et al,
  • reaction indicated under a) is carried out according to the methods familiar to the person skilled in the art, such as, for example, in P Erbacher et al, Bioconjugate Chem 1995, 6, 401, G Molema et al, J Med Chem 1991, 34, 1137 JL Montero et al, Bull Soc. Chim. France, 1994, 1_31_, 854; P. Midoux et al, Nucleic Acids Research 1993, 21, 871; Andersson, M. et al., Bioconjugate Chem. 1993, 4, 246; R. Roy et al, Tetrahedron Letters 1995, 36 4377; UK Saha et al, J. Chem. Soc. Chem. Comm.
  • Examples include triethylamine, di-isopropyl-N-ethylamine (Hünig base), N-methylmorpholine, tributylamine, tetramethylethylenediamine, pyridine, lutedine, 2,4,6-trimethylpyridine, 4-dimethylaminopyridine, N-methylimidazole, tetramethylguanidine, DBU, Lithium, sodium, potassium, calcium, magnesium, barium hydroxide, carbonate, and hydrogen carbonate.
  • the reaction can also be carried out in the manner known to those skilled in the art
  • Buffer solutions preferably at pH 8 to 11, particularly preferably at pH 8.5 to 9.
  • the pH value is preferably maintained using a pH state. If T 2 'stands for a CHO group, coupling is carried out by reductive amination with the aid of a reducing agent according to methods known to the person skilled in the art (J.-P. Sabri et al, Tetrahedron Letters 1994, 35, 1181; MD Boma ⁇ n et al, J Org. Chem. 1995, 60, 5995; S. Bhattacharyya et al, J. Chem. Soz. Pekin Trans. I 1994, 1; OS Artyushin et al., Ser.
  • reducing agents are sodium borohydride, sodium cyanoborohydride, lithium borohydride, calcium borohydride, pyridine-BH3, lithium aluminum hydride and zinc borohydride.
  • Catalytic hydrogenation on, for example, palladium or nickel catalyst is also suitable.
  • Fg stands for an OH group
  • an in-situ activation with the coupling reagents known to the person skilled in the art such as e.g. DCCI, EEDQ,
  • reaction of the polymer saccharide conjugate of the general formula IX indicated under b) with the complexes or complexing agents K * of the general formula II "to VII" and II'a is also carried out in a manner known per se, as described, for example, in US Pat. No.
  • the pH is preferably maintained using a pH state of T. 2 'for a CHO group, a coupling is carried out by reductive amination with the aid of a reducing agent according to methods known to the person skilled in the art (J-P Sabri et al, Tetrahedron Letters 1994, 35, 1181, MD Bomann et al, 7 Org Chem 1995, 60, 5995, S Bhattacharyya et al, J Chem Soz Pekin Trans I 1994, 1, OS Artyushin et al, Ser Khim 1991, 9, 2154, RF Borch et al, JACS 1971, 93 2897)
  • the reducing agents used are, for example, sodium borohydride, sodium cyanoboron hydride, lithium borohydride, calcium borohydride, pyridine-BH3, lithium aluminum hydride and zinc borohydride. Catalytic hydrogenation is also suitable.
  • the reactions indicated under a) and b) are preferably carried out with an excess of the activated saccharide of the formula VIII or the activated complex or complexing agent K *, preferably with a 1.5 to 3-fold excess.
  • the occupancy ratio of the amino groups contained in the polymer is controlled by the ratio n ': m'.
  • the neutralization takes place with the aid of inorganic bases (for example hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium, lithium, magnesium or calcium and / or organic bases such as, inter alia, primary, secondary and tertiary amines, for example ethanolamine, morpholine, Glucamine, N-methyl- and N, N-dimethylglucamine, as well as basic amino acids, such as lysine, Arginine and ornithine or amides of originally neutral or acidic amino acids, such as, for example, hippuric acid, glycine acetamide.
  • inorganic bases for example hydroxides, carbonates or bicarbonates
  • inorganic bases for example hydroxides, carbonates or bicarbonates
  • organic bases such as, inter alia, primary, secondary and tertiary amines, for example ethanolamine, morpholine, Glucamine, N-methyl- and N, N-dimethylglucamine, as well as basic amino acids, such
  • the acidic complex salts in aqueous solution or suspension can be added with as much of the desired base that the neutral point is reached.
  • the solution obtained can then be evaporated to dryness in vacuo.
  • water-miscible solvents e.g. to precipitate lower alcohols (methanol, ethanol, isopropanol and others), lower ketones (acetone and others), polar ethers (tetrahydrofuran, dioxane, 1, 2-dimethoxyethane and others) and thus to obtain crystals that are easy to isolate and easy to clean. It has proven to be particularly advantageous to add the desired base already during the complex formation of the reaction mixture and thereby to save one process step.
  • acidic complex compounds contain several free acidic groups, it is often expedient to prepare neutral mixed salts which contain both inorganic and organic cations as counterions.
  • the order of base addition can also be reversed.
  • the polysaccharide conjugates obtained in this way are purified, if necessary after adjusting the pH, by adding an acid or base to pH 6 to 8, preferably about 7, preferably by ultrafiltration with membranes suitable pore size (e.g. Amicon-®XM30, Amicon®-YM10, Amicon®-YM3) or gel filtration on e.g. suitable Sephadex® gels.
  • suitable pore size e.g. Amicon-®XM30, Amicon®-YM10, Amicon®-YM3
  • suitable Sephadex® gels e.g. suitable Sephadex® gels.
  • the polymers of the general formula X can be used in the form of the free amines or in the form of their salts, for example as hydrochlorides, hydrobromides or hydrosulfates. They are known from the literature (e.g. WO 93/14147, WO 93/12073, WO 95/02008, WO 95/20619, WO 96/02588, EP 684044, EP 672703 and US-5,530,092).
  • EP 0430863 EP 255471, US-5,277,895, EP 0232751,
  • the mono- and oligosaccharides of the general formula VIII required as starting materials are likewise known from the literature or can be obtained analogously to methods known from the literature (see also experimental part): see, for example, EP 0 128097; AJ Jonas et al. Biochem. J. 1990, 268, 41; JP Patent 04211099; DH Buss et al, J. Chem. Soc. C. 1968, 1457; CM. Hilditch et al, J. Appl. Phycol. 1991, 3, 345; M. Monsigny et al, Biol.
  • compositions according to the invention are likewise prepared in a manner known per se by suspending or dissolving the complex compounds according to the invention - if appropriate with addition of the additives customary in galenicals - in an aqueous medium and then optionally sterilizing the suspension or solution.
  • suitable additives are, for example, physiologically harmless buffers (such as tromethamine), additions of complexing agents or weak complexes (such as diethylenetriaminepentaacetic acid or the corresponding Ca-polysaccharide-polymer complexes) or - if necessary - electrolytes such as sodium chloride or - if necessary required - antioxidants such as ascorbic acid.
  • suspensions or solutions of the agents according to the invention in water or physiological saline solution are desired for enteral administration or other purposes, they are mixed with one or more adjuvants common in galenics [e.g. Methyl cellulose, lactose, mannitol] and / the surfactant (s) [e.g. Lecithins, Tween®, Myrj®] and / or flavoring (s) for flavor correction [e.g. essential oils] mixed.
  • galenics e.g. Methyl cellulose, lactose, mannitol
  • surfactant e.g. Lecithins, Tween®, Myrj®
  • flavor correction e.g. essential oils
  • the invention therefore also relates to processes for the preparation of the complex compounds and their salts.
  • the final security is cleaning the isolated complex salt.
  • compositions according to the invention preferably contain 1 ⁇ mol - 1.3 mol / l of the complex salt and are generally dosed in amounts of 0.0001–5 mmol / kg. They are intended for enteral and parenteral administration.
  • the complex compounds according to the invention are used.
  • the agents according to the invention meet the diverse requirements for their suitability as contrast agents for magnetic resonance imaging. For example, after oral or parenteral application, they are excellently suited to improve the meaningfulness of the image obtained with the aid of an MRI scanner. They also show the high effectiveness that is necessary to burden the body with the smallest possible amount of foreign substances and the good tolerance that is necessary to maintain the non-invasive character of the examinations.
  • the agents according to the invention make it possible to produce highly concentrated solutions, so that the volume of the circulatory system can be kept within reasonable limits and to compensate for the dilution with the body fluid, i.e. NMR diagnostics must be 100 to 1000 times more water soluble than for them NMR spectroscopy.
  • the agents according to the invention not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that the release or exchange of the ions which are not covalently bound in the complexes - in themselves toxic - within the time who the new Contrast agents are completely excreted again, takes place only extremely slowly.
  • the agents according to the invention for use as NMR diagnostic agents are dosed in amounts of 0.0001-5 mmol / kg, preferably 0.005-0.5 mmol / kg. Details of the application are, for example, in H.-J. Weinmann et al., Am J. of Roentgenology 142, 619 (1984).
  • organ-specific NMR diagnostics can be used, for example, to detect tumors and heart attacks.
  • the agents according to the invention are also suitable as radio diagnostic agents. Details of their application and dosage are e.g. in "Radiotracers for Medical Applications", CRC-Press, Boca Raton, Florida.
  • positron emission tomography which is positron emitting isotopes such as 43 Sc, ⁇ 4 Sc,
  • the compounds according to the invention are surprisingly also suitable for differentiating malignant and benign tumors in areas without a blood-brain barrier. They are also characterized by the fact that they are completely eliminated from the body and are therefore well tolerated.
  • the substances according to the invention accumulate in malignant tumors (no diffusion into healthy tissues, but high permeability of tumor vessels), they can also support the radiation therapy of malignant tumors. This differs from the corresponding diagnostics only in the amount and type of isotope used.
  • the aim is to destroy tumor cells by high-energy short-wave radiation with the shortest possible range. Interactions of the metals contained in the complexes (such as iron or gadolinium) with ionizing radiation (eg X-rays) or with neutron beams are used for this purpose. By This effect significantly increases the local radiation dose at the location where the metal complex is located (e.g. in tumors).
  • the metal complex conjugates according to the invention are therefore also suitable as a radio-sensitive substance in radiation therapy of malignant tumors (Mössbauer effects or neutron capture therapy can also be used).
  • Suitable ⁇ -emitting ions are, for example, 46 Sc, 47 Sc, 48 Sc, ⁇ 2 Ga, 3 Ga unc j 90 ⁇ .
  • Suitable ⁇ -emitting ions with short half-lives are, for example, 211 Bi, 2 " ! 2 Bi, 2 1 3 Bi and 14ßi, with 2 1 2 Bi being preferred.
  • a suitable photon and electron emitting ion is 1 ⁇ 3 Gd, which can be obtained from 157 (3 (3 by neutron capture.
  • the therapeutic agents according to the invention When the therapeutic agents according to the invention are applied in vivo, they can be administered together with a suitable carrier such as serum or physiological saline and together with another protein such as human serum albumin.
  • a suitable carrier such as serum or physiological saline and together with another protein such as human serum albumin.
  • the dosage depends on the type of cellular disorder, the metal ion used and the type of imaging method.
  • the therapeutic agents according to the invention are administered parenterally, preferably IV.
  • radiotherapeutics are e.g. in R.W. Kozak et al. TIBTEC, October 1986, 262.
  • the agents according to the invention are outstandingly suitable as X-ray contrast agents, in particular for computed tomography (CT), it being particularly noteworthy that they do not show any signs of the anaphylaxis-like reactions known from the iodine-containing contrast agents in biochemical-pharmacological examinations. They are particularly valuable because of the favorable absorption properties in areas of higher tube voltages for digital subtraction techniques.
  • CT computed tomography
  • the agents according to the invention for use as X-ray contrast agents are dosed in amounts of 0.1-5 mmol / kg, preferably 0.25-1 mmol / kg, in analogy to meglumine diatrizoate.
  • Gd-DTPA Gadolinium complex of [bis- (2-aminoethyl) amine-N, N, N ', N ", N" - pentaacetic acid] monosodium salt
  • the ninhydrin reaction as well as the TNBS method, which are generally used for the quantitative determination of free amino functions, are negative, i. H. there are no free amino functions in the polymer.
  • the percentage sulfur value of the elemental analysis of the titanium compound gives a degree of loading of the polymer with 40% ⁇ -D-galactose (corresponding to 26 galactose residues per molecule).
  • ERS ⁇ ZBL ⁇ T (RULE 26) Determination of sulfuric acid (Dubois et al., Anal. Chem. 1956, 28, 3, 350) to determine the average pyranose loading level of the polyamine gives a mean statistical loading level of 39.68% of D-galactose residues per molecule and is thus to be regarded as identical to the degree of loading, which was determined solely by the percentage element ratio (found here: 26 D-galactose residues per molecule).
  • the molar element ratio of gadolinium to sulfur thus results in an average degree of loading of the polymer of 60% Gd-DPTA and 40% D-galactose (corresponding to 38 Gd-DTPA units and 20-D-galactose residues per molecule). No free amino functions can be detected in the title compound by means of the quantitative ninhydrin reaction.
  • the quantitative ninhydrin reaction of the title compound is negative, i. H. the polymeric product contains no free amino functions.
  • the percentage sulfur of the elemental analysis of the title compound gives a degree of loading of the polymer with 40% -D-mannose (corresponding to 26 mannose residues per molecule).
  • the quantitative ninhydrin reaction of the title compound is negative, i. H. the polymeric product contains no free amino functions.
  • the percentage sulfur value of the elemental analysis of the title compound gives a degree of loading of the polymer with 40% D-glucose (corresponding to 26 glucose residues per molecule).
  • Example 3a 1.0 g (0.032 mmol; corresponding to 1.23 mmol of DTPA) of the title compound from Example 3a) are used in an analogous manner as described for Example 1 c) with 0.33 g (1.24 mmol) of gadolinium chloride, used in the form of an aqueous Gadolinium chloride solution, complexed. After working up and freeze-drying, 1.14 g (99.2% of theory) of the title compound is obtained as an amorphous powder. Water content: 5.47%
  • the quantitative ninhydrin reaction of the title compound is negative, i. H. the polymeric product contains no free amino functions.
  • the percentage sulfur value of the elemental analysis of the title compound gives a degree of loading of the polymer with 40% ⁇ -L-fucose (corresponding to 26 -L-fucose residues per molecule).
  • the quantitative ninhydrin reaction of the title compound is negative, ie the polymeric product does not contain any free amino functions.
  • the percentage sulfur value of the elemental analysis of the title compound gives a result Degree of loading of the polymer with 40% 2- [acetylamino-2-deoxy] -1-phenyl-ß-glucopyranose (corresponding to 26 2- [acetylamino-2-deoxy] -1-phenyl-ß-D-glucopyranose residues per molecule).
  • Example 5a 0.9 g (0.036 mmol; corresponding to 1.36 mmol of DTPA) of the title compound from Example 5a) are used in the same way as described for Example 1 c) with 0.38 g (1.45 mmol) of gadolinium chloride, used in the form of an aqueous Gadolinium chloride solution, complexed. After working up and freeze-drying, 1.26 g (92.3% of theory) of the title compound are obtained as an amorphous powder. Water content: 8.46%
  • the molar elemental ratios of gadolinium to sulfur thus result in an average degree of loading of the polymer of 60% Gd-DPTA and 40% N-acetyl-D-glucosamine (corresponding to 38 Gd-DTPA units and 26 N-acetyl-D-glucosamine residues per Molecule). No free amino functions can be detected in the title compound by means of the quantitative ninhydrin reaction.
  • 32-DSM polyamine is dissolved in 400 ml of distilled water and adjusted to a pH of 9.5 with 1 molar sodium hydroxide solution. Subsequently a total of 21.9 g (54.6 mmol) of DTPA monoanhydride monoethyl ester is added in portions, the pH of the reaction solution being kept constant at 9.5 by adding 1 molar sodium hydroxide solution. After the addition has ended, the mixture is stirred for a further 15 minutes at room temperature and then the pH of the reaction solution is adjusted to 11.5 by adding 32% sodium hydroxide solution. After a reaction time of 12 hours at room temperature, make up to a total volume of 800 ml with distilled water.
  • the aqueous product solution thus obtained was ultrafiltered three times using a YM3 ultrafiltration membrane (Amicon) against distilled water. The remaining residue is made up to a volume of 500 ml with deionized water and the aqueous product solution is freeze-dried.
  • the quantitative ninhydrin reaction of the title compound is negative, i. H. the polymeric product contains no free amino functions.
  • the percentage of sulfur in the elemental analysis of the title compound gives a degree of loading of the polymer with 44% ⁇ -D-galactose (corresponding to 14 ⁇ -galactose residues per molecule).
  • the colorimetric determination of phenol-sulfuric acid Dubois et al., Anal. Chem.
  • Example 6b 1.0 g (0.061 mmol; corresponding to 1.10 mmol of DTPA) of the title compound from Example 6b) are described in analogy to Example 1c) with 0.29 g (1.15 mmol) of gadolinium chloride used in the form of an aqueous gadolinium chloride solution , complexed. After working up and freeze-drying, 1.05 g (96.2% of theory) of the title compound is obtained as an amorphous powder. Water content: 4.93%
  • the molar element ratio of gadolinium to sulfur thus results in an average degree of loading of the polymer of 56% Gd-DPTA and 44% ß-D-galactose (corresponding to 18 Gd-DTPA units and 14 D-galactose residues per molecule). No free amino functions can be detected in the title compound by means of the quantitative ninhydrin reaction.
  • the quantitative ninhydrin reaction of the title compound is negative, i. H. the polymeric product contains no free amino functions.
  • the percentage sulfur value of the elemental analysis of the title compound gives a degree of loading of the polymer with 44% ⁇ D-mannose (corresponding to 14 ⁇ -D-ma ⁇ ose residues per molecule).
  • REPLACEMENT SHEET (RULE 21 1.1 g (0.067 mmol; corresponding to 1.21 mmol of DTPA) of the title compound from Example 7a) are used in the same way as described for Example 1 c) with 0.30 g (1.22 mmol) of gadolinium chloride, used in the form of an aqueous Gadolinium chloride solution, complexed. After working up and freeze-drying, 1.18 g (98.6% of theory) of the title compound are obtained as an amorphous powder. Water content: 3.98%
  • the molar elemental ratios of gadolinium to sulfur thus result in an average degree of loading of the polymer of 56% Gd-DPTA and 44% ⁇ -D-mannose (corresponding to 18 Gd-DTPA units and 14-D-mannose residues per molecule). No free amino functions can be detected in the title compound by means of the quantitative ninhydrin reaction.
  • the quantitative ninhydrin reaction of the title compound is negative, i. H. the polymeric product contains no free amino functions.
  • the percentage of sulfur in the elemental analysis of the title compound gives a degree of loading of the polymer with 44% ⁇ -D-glucose (corresponding to 14 ⁇ -D-glucose residues per molecule).
  • the molar elemental ratios of gadolinium to sulfur thus result in an average degree of loading of the polymer of 56% Gd-DPTA and 44% ⁇ -D-glucose (corresponding to 18 Gd-DTPA units and 14 ⁇ -D-glucose residues per molecule). No free amino functions can be detected in the title compound by means of the quantitative ninhydrin reaction.
  • the quantitative ninhydrin reaction of the title compound is negative, i. H. the polymeric product contains no free amino functions.
  • the percentage sulfur value of the elemental analysis of the title compound gives a degree of loading of the polymer with 44% ⁇ -L-fucose (corresponding to 14 ⁇ -L-fucose residues per molecule).
  • Example 9a 1.1 g (0.068 mmol; corresponding to 1.22 mmol of DTPA) of the title compound from Example 9a) are used in the same way as described for Example 1c) with 0.31 g (1.24 mmol) of gadolinium chloride, used in the form of an aqueous gadolinium chloride solution , complexed. After working up and freeze-drying, 1.19 g (98.6% of theory) of the title compound is obtained as an amorphous powder. Water content: 7.23%
  • the quantitative ninhydrin reaction of the title compound is negative, i. H. the polymeric product contains no free amino functions. From the percentage sulfur value of the elemental analysis of the title compound, a degree of loading of the polymer with 44% N-acetyl-D-glucosamine (corresponding to 14 N-acetyl- ⁇ -D-glucosamine residues per molecule) results.
  • the molar elemental ratios of gadolinium to sulfur thus result in an average degree of loading of the polymer of 56% Gd-DPTA and 44% N-acetyl-ß-D-glucosamine (corresponding to 18 Gd-DTPA units and 14-N-acetyl-ß -D-glucosamine residues per molecule). No free amino functions can be detected in the title compound by means of the quantitative ninhydrin reaction.
  • the room temperature is made up to a total volume of 500 ml with dichloromethane.
  • the organic phase is washed successively twice with water and twice with saturated sodium bicarbonate solution and dried over sodium sulfate. After filtering, the solvent is removed to dryness in vacuo. 4.60 g (92.6% of theory) of the title compound are obtained as a colorless oil.
  • the quantitative ninhydrin reaction of the title compound is negative, i. H. free amino functions are no longer detectable in the polymer.
  • the aqueous product solution is extracted twice with 60 ml of diethyl ether each time.
  • the aqueous product solution is obtained by adding 10% aqu. Hydrochloric acid brought to pH 3.0, made up to a total volume of 800 ml with water and ultrafiltered three times using a YM3 ultrafiltration membrane (Amicon) against distilled water. The remaining residue is made up to a volume of 500 ml with deionized water and freeze-dried. Yield: 2.2 g (76.8% of theory) as an amorphous powder Water content: 7.37%
  • the molar element ratio of sulfur to gadolinium (1, 30) results in an average degree of loading of the polymer of 43.7% Gd-Gly-Me-DOTA and 56.3% ⁇ -D-mannose (corresponding to 28 Gd-Gly-Me -DOTA units and 36 ⁇ -D-mannose residues per molecule). No free amino functions can be detected in the title compound by means of a quantitative ninhydrin reaction.
  • SPARE BLADE (RULE 26) transferred. After a reaction time of 12 hours at room temperature, the mixture is made up to a total volume of 500 ml with dichloromethane. The organic phase is washed successively twice with water and twice with saturated sodium bicarbonate solution and dried over sodium sulfate. After filtering, the solvent is removed to dryness in vacuo. 3.32 g (85.1% of theory; based on the polyamine used) of the title compound are obtained as a colorless oil. The quantitative ninhydrin reaction of the title compound is negative, ie no free amino functions can be detected in the polymer.
  • the aqueous product solution is extracted twice with 60 ml of diethyl ether each time.
  • the aqueous product solution is mixed with 10% aqu.
  • Hydrochloric acid brought to pH 3.0 made up to a total volume of 800 ml with water and ultrafiltered three times using a YM3 ultrafiltration membrane (Amicon) against distilled water.
  • the remaining residue is made up to a volume of 500 ml with deionized water and freeze-dried. Yield: 2.37 g (76.2% of theory) of the above-mentioned title compound colorless and amorphous powder.
  • Water content 7.43%
  • the aqueous product solution is extracted twice with 60 ml of diethyl ether each time.
  • the aqueous product solution is mixed with 10% aqu.
  • Hydrochloric acid brought to pH 3.0 made up to a total volume of 800 ml with water and ultrafiltered three times using a YM3 ultrafiltration membrane (Amicon) against distilled water.
  • the remaining residue is made up to a volume of 500 ml with deionized water and freeze-dried. Yield: 1.97 g (78.8% of theory) as an amorphous powder
  • Water content 5.45%
  • the title compound from Example 13b) are dissolved in 40 ml of distilled water and the pH of the solution is adjusted to 2.0 by dropwise addition with 10% aqueous hydrochloric acid. Then 393 mg (1.50 mmol) of gadolinium chloride are added at room temperature and the reaction solution is stirred at 60 ° C. for 12 hours. At room temperature, the reaction solution is brought to pH 7.2 by adding 1 molar sodium hydroxide solution and made up to a total volume of 500 ml with distilled water. After three times ultrafiltration against distilled water over a YM3 ultrafiltration membrane (Amicon), the remaining residue is freeze-dried.
  • YM3 ultrafiltration membrane Amicon
  • the molar element ratio of sulfur to gadolinium (1, 32) results in an average degree of loading of the polymer of 43.4% Gd-Gly-Me-DOTA and 56.6% ß-D-glucose (corresponding to 28 Gd-Gly-Me -DOTA units and 36 ß-D-glucose residues per molecule). No free amino functions can be detected in the title compound by means of a quantitative ninhydrin reaction.
  • the room temperature is made up to a total volume of 500 ml with dichloromethane.
  • the organic phase is washed successively twice with water and twice with saturated sodium bicarbonate solution and dried over sodium sulfate. After filtering, the solvent is removed to dryness in vacuo. 4.44 g (89.4% of theory) of the title compound are obtained as a colorless oil.
  • the quantitative ninhydrin reaction of the The title compound is negative, ie no free amino functions can be detected in the polymer.
  • the title compound from Example 14b) is dissolved in 50 ml of distilled water and the pH of the solution is adjusted to 2.0 by dropwise addition with 10% aqueous hydrochloric acid. Then 520 mg (1.98 mmol) of gadolinium chloride are added at room temperature and the reaction solution is stirred at 60 ° C. for 12 hours. At room temperature, the reaction solution is brought to pH 7.2 by adding 1 molar sodium hydroxide solution and brought to a total volume of 800 ml with distilled water. After three times ultrafiltration against distilled water over a YM3 ultrafiltration membrane (Amicon), the remaining residue is freeze-dried. 2.20 g (95.3% of theory) of the title compound are obtained as an amorphous, colorless powder with a water content of 6.38%.
  • the molar element ratio of sulfur to gadolinium gives an average degree of loading of the polymer of 42.2% Gd-Gly-Me-DOTA and 57.8% ß-D-galactose (corresponding to 27 Gd-Gly -Me-DOTA units and 36 ß-D-galactose residues per molecule). No free amino functions can be detected in the title compound by means of a quantitative ninhydrin reaction.
  • the watery Product solution is extracted twice with 60 ml of diethyl ether each, then by adding 10% aqueous solution. Hydrochloric acid brought to pH 3.0, made up to a total volume of 800 ml with water and ultrafiltered three times using a YM3 ultrafiltration membrane (Amicon) against distilled water. After renewed ultrafiltration, the remaining residue is made up to a volume of 500 ml with deionized water and freeze-dried. It is then taken up in 300 ml of water and the pH of the resulting product solution is adjusted to 7.2 by adding 1 molar sodium hydroxide solution. Yield: 3.16 g (87.0% of theory) as an amorphous and colorless powder. Water content: 5.89%
  • the ninhydrin reaction of the title compound is negative, i. H. free amino functions are no longer detectable in the polymer.
  • the molar elemental ratios of sulfur to gadolinium thus result in an average degree of loading of the polymer of 44% Gd-DTPA and 56% ⁇ -D-mannose (corresponding to 14 Gd-DTPA units and 18 ⁇ -D-mannose residues per molecule). No free amino functions can be detected in the title compound by ninhydrin reaction.
  • Hydrochloric acid brought to pH 3.0 made up to a total volume of 800 ml with water and ultrafiltered three times using a YM3 ultrafiltration membrane (Amicon) against distilled water. After renewed ultrafiltration, the remaining residue is made up to a volume of 500 ml with deionized water and freeze-dried. It is then taken up in 300 ml of water and the pH of the resulting product solution is adjusted to 7.2 by adding 1 molar sodium hydroxide solution. Yield: 3.16 g (87.0% of theory) as an amorphous and colorless powder.
  • the molar elemental ratios of sulfur to gadolinium thus result in an average degree of loading of the polymer of 44% Gd-DTPA and 56% ⁇ -D-glucose (corresponding to 14 Gd-DTPA units and 18 ⁇ -D-glucose residues per molecule). No free amino functions can be detected in the title compound by ninhydrin reaction.
  • ERS ⁇ TZBL ⁇ T (RULE 26) 25.0 g (40.46 mmol) 3,9-bis (t-butoxycarbonylmethyl) -3-carboxymethyl-3,6,9-triazaundecanedicarboxylic acid di-t-butyl ester (preparation as in the European patent applications: EP 0430863; EP 0331616 and EP 0271180) are dissolved in 100 ml of absolute dimethylformamide at room temperature and 5.58 g (48.50 mmol) of N-hydroxysuccinimide are added with stirring. The clear reaction mixture is then cooled to 0 ° C.
  • E - RSARZBLATT (RULE 21) Tetra-O-acetyl-1-thio- ⁇ -D-mannopyranosyl) propionic acid N-hydroxysuccinimide ester (Lee, YC et al., Biochemi., Vol. 15, No. 18, 1976, 3956-3963; Krohn , KA et al., J. Nucl. Med., Vol. 26, 10, 1985, 1157-1167) in 100 ml of dichloromethane. After a reaction time of 12 hours at room temperature, the mixture is made up to a total volume of 500 ml with dichloromethane.
  • Vacuum drawn to dryness The residue is dissolved in 100 ml of methanol and 50 ml of a 32% aqueous ammonia solution are added at room temperature. After a reaction time of 12 hours at room temperature, the solvent is removed in vacuo and the remaining residue is dissolved in 200 ml of distilled water. The aqueous product solution is extracted twice with 80 ml of diethyl ether each time. The aqueous product solution is then mixed with 10% aqu. hydrochloric acid
  • ⁇ - töATZBL ⁇ TT (RULE 26) brought to pH 3.0, made up to a total volume of 800 ml with water and ultrafiltered three times using a YM3 ultrafiltration membrane (Amicon) against distilled water. After renewed ultrafiltration, the remaining residue is made up to a volume of 500 ml with deionized water and freeze-dried. It is then taken up in 300 ml of water and the pH of the resulting product solution is adjusted to 7.2 by adding 1 molar sodium hydroxide solution. Yield: 2.78 g (84.7% of theory) as an amorphous and colorless powder. Water content: 8.94%
  • the ninhydrin reaction of the title compound is negative, i. H. free amino functions are no longer detectable in the polymer.
  • Example 17b In an analogous manner as described for Example 17b), the reaction of 5.0 g (0.44 mmol; corresponding to 8.4 mmol of free amine functions) of the title compound from Example 17a) with 4.88 g (9.23 mmol) 3- (2,3,4,6-Tetra-O-acetyl-1-thio- ⁇ -D-galactopyranosyl) propionic acid N-hydroxysuccinimide ester (representation according to: Lee.YC et al., Biochemi., Vol. 15 , No. 18, 1976, 3956-3963; Krohn, KA et al., J. Nucl. Med., Vol. 26, 10, 1985, 1157-1167) to form 7.48 g (88.3% of theory) . Th.) Of the above-mentioned title compound as a colorless oil.
  • the title compound shows a negative ninhydrin reaction.
  • the percentage sulfur value of the elemental analysis gives an average degree of contamination of the polymer with 19 ⁇ -D-galactose residues per molecule.
  • Example 17b In an analogous manner as described for Example 17b), the reaction of 6.0 g (0.53 mmol; corresponding to 10.03 mmol of free amine functions) of the title compound from Example 17a) with 5.83 g (11.03 mmol) 3- (2,3,4,6-Tetra-O-acetyl-1-thio- ⁇ -D-glucopyranosyl) propioic acid N-hydroxysuccinimide ester (representation according to: Lee.YC et al., Biochemi., Vol. 15 , No. 18, 1976, 3956-3963; Krohn, KA et al., J. Nucl. Med., Vol. 26, 10, 1985, 1157-1167) to form 8.70 g (85.6% of theory) . Th.) Of the above-mentioned title compound as a colorless oil.
  • the title association shows a negative ninhydrin reaction. From the percentage sulfur value of the elemental analysis, an average degree of exposure of the polymer with 19 ß-D-glucose residues per molecule results.
  • Example 20a 0.5 g (0.03 mmol; corresponding to 0.54 mmol of DTPA) of the title compound from Example 20a) are analogous to that described for Example 1c) with 143 mg (0.55 mmol) of gadolinium oxide, dissolved in 7.5 ml distilled water, complexed. After working up and freeze-drying, 0.53 g (98.0% of theory) of the title compound is obtained as an amorphous powder. Water content: 7.23% Elemental analysis (calculated on anhydrous substance): calc .: C 39.59 H 6.26 N 8.87 Gd 15.45 Na 2.26 found: C 39.66 H 6.18 N 8.97 Gd 15.60 Na 2.30
  • Example 21 a 1.0 g (0.03 mmol; corresponding to 1.14 mmol of DTPA of the title compound from Example 21 a) are, in analogy to that described for Example 1 c), with 0.30 g (1.15 mmol) gadolinium oxide, dissolved in 10 ml of distilled water, complexed. After working up and freeze-drying, 1.06 g (96.3% of theory) of the title compound is obtained as an amorphous powder. Water content: 7.23%
  • a stirred suspension of 5.0 g (7.95 mmol) of the title compound from Example 22g) in 15 ml of absolute dimethyl sulfoxide is mixed at 70 ° C. with 0.68 g (15.9 mmol) of lithium chloride. After 30 minutes at 70 ° C., the now clear reaction solution is mixed in portions with a total of 1.83 g (15.9 mmol) of N-hydroxysuccinimide and the reaction mixture is kept at this temperature for 1 hour. After cooling to 13 ° C., 4.52 g (23.85 mmol) of dicyclohexylcarbodiimide are added and the reaction solution is stirred for a further hour at 13 ° C., followed by 12 hours at 22 ° C.
  • reaction solution of the N-hydroxysuccinimide ester of the title compound from Example 22g) thus obtained is now added dropwise at 22 ° C. with a solution of 1.43 g (0.20 mmol, corresponding to 13.23 mmol of free amine functions), 64-DSM polyamine , dissolved in 15 ml of absolute dimethyl sulfoxide. and stirred for a further 12 hours at room temperature.
  • the reaction solution is added dropwise in 1.5 l of acetone at 22 ° C., the title compound precipitating out as a colorless precipitate.
  • the precipitate is suctioned off, dissolved in 200 ml of distilled water and ultrafiltered three times over a YM3 ultrafiltration membrane (AMICON ®). The remaining residue is dissolved in 300 ml of distilled water, filtered and freeze-dried.
  • the degree of loading of the polymer is 59.3% Gd-Gly-Me-DOTA (corresponding to 38 Gd-Gly-Me-DOTA units per molecule).
  • the determination of the free amino functions remaining in the polymer by means of The mean value of ninhydrin and the TNBS method is 40.7% of free amino groups, ie there are 26 free amino functions in the polymer molecule.
  • the quantitative ninhydrin reaction as well as the TNBS method are negative, i. H. the polymeric product contains no free amino functions.
  • a degree of loading of the polymer with 26 ⁇ -D-galactose residues and 38 Gd-Gly-Me-DOTA complexes per molecule results from the molar sulfur value of the elemental analysis of the title compound.
  • the quantitative ninhydrin reaction as well as the TNBS method are negative, i. H. the polymeric product contains no free amino functions.
  • a degree of loading of the polymer with 26 ⁇ -L-fucose residues and 38 Gd-Gly-Me-DOTA complexes per molecule results from the molar sulfur value of the elemental analysis of the title compound.
  • the quantitative ninhydrin reaction as well as the TNBS method are negative, i. H. the polymeric product contains no free amino functions.
  • a degree of loading of the polymer with 26 ⁇ -D-mannose residues and 38 Gd-Gly-Me-DOTA complexes per molecule results from the molar sulfur value of the elemental analysis of the title compound.
  • the title compound from Example 2 [64-DSM-Polyami ⁇ - (Gd-DTPA) 38- [1- (4-thioureidophenyl) - ⁇ -D-mannopyranosyl] 26-conjugate] is in a dosage of 200 ⁇ mol Gd / kg body weight in Rats injected.
  • the Gd concentration in the tissues of the mononuclear phagocytic system is determined using ICP-AES.
  • the increase in Gd concentrations is most pronounced in the lymph nodes. From 1 h p.i. the absolute Gd concentration in the lymph nodes is also significantly higher than in the liver and spleen. The substance accumulates similarly well in all lymph node groups, because the Gd concentration is evenly distributed in the mesenteric and peripheral lymph nodes. Thus, the goal of substance accumulation in all lymph node groups is met by this, but also by the other substances according to the invention described here. Due to the extremely high Gd concentration in the lymph nodes 24h p.i.
  • these substances can also be used for intravenous MR lymphography with very low doses (> 10 ⁇ mol Gd / kg).
  • ERSA ⁇ ZBLA ⁇ T (RULE 26) T1-weighted ex vivo MR image (SE 400/15) of lymph node groups embedded in agar after intravenous application of 200 ⁇ mol of the title compound from Example 24 in rats ( Figures 1 and 2)

Abstract

L'invention concerne des conjugués constitués de polymères dendritiques contenant des groupes amino, dont les ramifications sont produites à partir d'unités vinylcyanide, d'un ou de plusieurs groupes émetteurs de signaux, contenant un ou plusieurs ions métal, des monosaccharides ou des oligosaccharides, et, éventuellement, des cations de bases inorganiques et/ou organiques, des aminoacides ou des amides d'aminoacide. Ces conjugués constituent des composés précieux pour le diagnostic et la thérapie.
EP98966256A 1997-12-18 1998-12-09 Conjugues polymeres dendritiques-saccharides, produits pharmaceutiques contenant ces conjugues, leur procede de production et leur utilisation Withdrawn EP1037672A1 (fr)

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DE19758105A DE19758105A1 (de) 1997-12-18 1997-12-18 Dendritische Polymer-Saccharid-Konjugate, diese enthaltende pharmazeutische Mittel, Verfahren zu ihrer Herstellung und ihre Verwendung
DE19758105 1997-12-18
PCT/EP1998/007927 WO1999032154A1 (fr) 1997-12-18 1998-12-09 Conjugues polymeres dendritiques-saccharides, produits pharmaceutiques contenant ces conjugues, leur procede de production et leur utilisation

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US6641797B2 (en) 2000-08-11 2003-11-04 Schering Aktiengesellschaft Perfluoroalkyl-containing complexes with sugar radicals, process for their production and their use
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US20060127899A1 (en) * 2002-05-08 2006-06-15 Ralf Krahmer Active carbohydrate containing protecting reagents for chemical modifications, their production and use
WO2009005353A1 (fr) * 2007-07-02 2009-01-08 Erasmus University Medical Center Rotterdam Composés d'oligosaccharide de liaison élevée, compositions et leurs utilisations
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